The Protocol Book for Intensive Care [5 ed.] 9789390020256, 9789352703050

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THE PROTOCOL BOOK for Intensive Care

THE PROTOCOL BOOK for Intensive Care FIFTH EDITION

Editor

Soumitra Kumar MD DM FCSI FACC FESC FSCAI FICC FIAE FICP Professor and Head Department of Cardiology Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

The Health Sciences Publisher New Delhi | London | Panama

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Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2018, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased WRPDNHWKHQHFHVVDU\DUUDQJHPHQWVDWWKH¿UVWRSSRUWXQLW\ Inquiries for bulk sales may be solicited at: [email protected] The Protocol Book for Intensive Care First Edition: 2003 (by Editor) Second Edition: 2008 Third Edition: 2010 Fourth Edition: 2014 Fifth Edition: 2018 ISBN: 978-93-5270-305-0

Dedicated to My family, Friends and Well-wishers

Swami Vivekananda

The secret of religion lies not in theories but in practice. To be good and to do good — that is the whole of religion.

Contributors Siddhartha Bandopadhyay

Debasis Datta

Consultant Cardiologist Fortis Hospital Kolkata, West Bengal, India

Consultant Gastroenterologist Fortis Hospital Kolkata, West Bengal, India

Sulagna Banerjee

Arup R Dutta

Medical Officer Division of Noninvasive Cardiology Ramakrishna Mission Seva Pratishthan Kolkata, West Bengal, India

Head Department of Nephrology Fortis Hospital Kolkata, West Bengal, India

Dilip Kumar Bera

Arunangshu Ganguly

Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Consultant Cardiologist Chairman Health World Hospitals Durgapur, West Bengal, India

Abhirup Chatterjee

Sougata Kumar Ghosh

Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Sudipto Chatterjee Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Nodee Chowdhury Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Manikanta Das

Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Sujoy Ghosh Associate Professor Department of Endocrinology Institute of Postgraduate Medical Education and Research Kolkata, West Bengal, India

Sumit Sen Gupta Consultant Pulmonologist AMRI Hospital Kolkata, West Bengal, India

Saubhik Kanjilal

Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Visiting Cardiologist Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Soumen Das

Debdatta Kar

Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

viii The Protocol Book for Intensive Care Niranjan Kumar

Sabyasachi Mitra

Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Registrar Department of Cardiology Fortis Hospital Kolkata, West Bengal, India

Soumitra Kumar Professor and Head Department of Cardiology Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Honey Maity Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Samar R Pal Associate Professor Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Yashesh Paliwal Consultant Intensivist In-Charge, ICU Fortis Hospital Kolkata, West Bengal, India

Sudip Kumar Paul Amitava Majumder Associate Professor Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Dipankar Pradhan Sudeshna Majumder Consultant Cardiologist Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Sujata Majumder Associate Professor Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Soma Mandal Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Vivek Ranjan Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Ankit Ray Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Shuvanan Ray Kayapanda M Mandana Consultant Cardiac Surgeon Fortis Hospital Kolkata, West Bengal, India

Director Cardiology Department Fortis Hospital Kolkata, West Bengal, India

Contributors ix

Debabrata Roy

Chanchal Samanta

Consultant Cardiologist Narayana Health-Rabindranath Tagore International Institute of Cardiac Sciences Kolkata, West Bengal, India

Senior Resident Department of Medicine Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Jayanta Roy Consultant Neurologist AMRI Hospital Kolkata, West Bengal, India

Achyut Sarkar Associate Professor Department of Cardiology Institute of Postgraduate Medical Education and Research Kolkata, West Bengal, India

ALL INDIA HEART FOUNDATION

NATIONAL HEART INSTITUTE

4874 (First Floor), Ansari Road 24, Daryaganj New Delhi-110 002

(WHO Collaborative Centre in Preventive Cardiology) 49, Community Centre East of Kailash New Delhi-110 065 E-mail : [email protected]

DR. S. PADMAVATI FRCP (Lond.) FRCPE, FACC, FAMS PRESIDENT-All India Heart Foundation DIRECTOR-National Heart Institute

Foreword to the First Edition The Protocol Book represents guidelines for the diagnosis and management of common medical emergencies seen in hospitals. It covers mostly cardiac problems but also includes respiratory, gastrointestinal, renal diseases and diabetes. It has the same objectives as the American Heart Association/ American College of Cardiology’s Pocket Guidelines Updates compiled by the Special Task Forces of these organizations which are proving extremely useful for practicing physicians. This book has been compiled by the postgraduate students of the Vivekananda Institute of Medical Sciences, Ramakrishna Mission Seva Pratishthan, Kolkata, West Bengal, India, under the guidance of senior consultants in these departments at the hospital and under the able Editorship of Dr Soumitra Kumar. The text is written in a typical ‘Senior Resident’ language that can be easily understood by their colleagues. The latest ‘state-of-the-art’ information and knowledge has been used in preparing the various sections. It is a very laudable effort on the part of the postgraduate staff. I am sure The Protocol Book will prove very useful for all categories of physicians dealing with acute emergencies in hospitals.

S Padmavati FRCP (London) FRCPE FACC FAMS

President, All India Heart Foundation Director, National Heart Institute

Preface The fifth edition has taken shape four years after the last, i.e. fourth edition which was published in 2014. Structurally, this edition is much alike its previous version; however, the content has been updated and revised in keeping with the recent developments in respective fields. Like the previous editions, the theme driving this one too is successful ‘complete management’ of the patient. Afterall, there is no reason for a cardiologist to feel triumphant about a procedure performed by him/her, if the patient does not ultimately leave the hospital safe and sound because of a non-cardiac problem. The same of course applies to all disciplines of medicine. I am personally grateful to all the contributing authors of this edition for their unstinting co-operation and support. My junior colleagues, mostly postgraduate students at Vivekananda Institute of Medical Sciences, Kolkata, West Bengal, India have toiled very hard to update the chapters to the best of their ability. More senior contributors, experts in their respective fields from the City of Joy, i.e. Kolkata, have supplemented this effort with their experienced and deft touches. I am particularly thankful to Mr B Mukherjee for his untiring support in primary composition of the chapters. I express my heartfelt acknowledgment of the sustained patronage of M/s. Zydus Pharmaceuticals for this title over nearly last one and half decade. Finally, words are not enough to express my gratitude to my family members (parents, wife and son) for their overbearing and ever-forgiving support.

Soumitra Kumar MD DM FCSI FACC FESC FSCAI FICC FIAE FICP

Professor and Head Department of Cardiology Vivekananda Institute of Medical Sciences Kolkata, West Bengal, India

Contents 1. Acute ST-Elevation Myocardial Infarction Chanchal Samanta, Debabrata Roy, Soumitra Kumar 2. Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction Nodee Chowdhury, Saubhik Kanjilal, Soumitra Kumar

1

34

3. Cardiogenic Shock Soumitra Kumar, Sudeshna Majumder, Ankit Ray

74

4. Acute Heart Failure Soma Mandal, Soumitra Kumar

89

5. Management of Chronic Heart Failure Sudip Kumar Paul, Nodee Chowdhury, Soumitra Kumar

130

6. Syncope Vivek Ranjan, Sulagna Banerjee, Soumitra Kumar

168

7. Atrial Fibrillation Debdatta Kar, Siddhartha Bandopadhyay, Soumitra Kumar

184

8. Tachycardias Soumen Das, Soumitra Kumar

224

9. Cardiopulmonary Resuscitation Honey Maity, Soumitra Kumar

266

10. Percutaneous Coronary Intervention in Acute Myocardial Infarction Sabyasachi Mitra, Shuvanan Ray

277

11. Vascular Emergencies Arunangshu Ganguly

296

12. Acute Cardiac Care in Pediatric Practice Achyut Sarkar

353

13. Hypertensive Crisis Abhirup Chatterjee, Soumitra Kumar

362

14. Acid-Base Disturbances Dilip Kumar Bera, Sujata Majumder, Amitava Majumder

377

xvi The Protocol Book for Intensive Care 15. Electrolyte Imbalance Dilip Kumar Bera, Sujata Majumder, Amitava Majumder

388

16. Management of Adult Severe Acute Asthma Sumit Sen Gupta, Sougata Kumar Ghosh

401

17. Management of Acute Exacerbation of Chronic Obstructive Pulmonary Disease Niranjan Kumar, Sumit Sen Gupta

410

18. Mechanical Ventilation Nodee Chowdhury, Sumit Sen Gupta

417

19. Acute Respiratory Distress Syndrome Sumit Sen Gupta, Dipankar Pradhan

436

20. Management of Upper Gastrointestinal Bleeding Manikanta Das, Debasis Datta

443

21. Stroke Niranjan Kumar, Jayanta Roy

454

22. Acute Kidney Injury Dipankar Pradhan, Arup R Dutta

479

23. Endocrine Emergencies Abhirup Chatterjee, Sudipto Chatterjee, Sujoy Ghosh

495

24. Rheumatological Emergencies Soumen Das, Samar R Pal

523

25. Antimicrobial Therapy Including Management of Septic Shock Ankit Ray, Yashesh Paliwal

534

26. Cardiac Surgery: Postoperative Care Kayapanda M Mandana

570

27. Drugs Used in Cardiovascular Emergency Vivek Ranjan, Abhirup Chatterjee, Soumitra Kumar

579

Index

607

C HAPTE R

1

Acute ST-Elevation Myocardial Infarction 1

Acute ST-Elevation Myocardial Infarction Chanchal Samanta, Debabrata Roy, Soumitra Kumar

ACUTE CORONARY SYNDROME The term ‘acute coronary syndrome’ (ACS) refers to a spectrum of conditions that occur due to acute myocardial ischemia and/or infarction as a result of an abrupt reduction in blood flow through the coronary artery circulation. ACS is divided into two main categories: (1) non-ST-elevation (NSTE)-ACS and (2) ST-elevation myocardial infarction (STEMI).

NSTE-ACS It is further divided into unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI). These two conditions resemble each other very closely. UA is distinguished from NSTEMI by the absence of an elevation of cardiac biomarker levels.

STEMI The major discriminating feature of STEMI is the presence of symptoms of myocardial ischemia/injury along with persistent echocardiogram (ECG) STsegment elevation in addition to the presence of cardiac biomarkers.

THIRD UNIVERSAL DEFINITION OF MI (JOINT ESC/ACCF/AHA/WHF TASK FORCE 2012) Criteria for Acute Myocardial Infarction The term acute myocardial infarction (AMI) should be used when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Under these conditions any one of the following criteria meets the diagnosis for MI: • Detection of rise and/or fall of cardiac biomarker values [preferably cardiac troponin (cTn)] with at least one value above the 99th percentile upper reference limit (URL) and with at least one of the following:

2 The Protocol Book for Intensive Care

•

•

•

•

ƒ Symptoms of ischemia ƒ New or presumed new significant ST-segment-T wave (ST-T) changes or new left bundle branch block (LBBB) ƒ Development of pathological Q-waves in the ECG ƒ Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality ƒ Identification of an intracoronary thrombus by angiography or autopsy. Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes, or new LBBB, but death occurred before cardiac biomarkers were obtained or before cardiac biomarker values would be increased. Percutaneous coronary intervention (PCI) related MI is arbitrarily defined by elevation of cTn values (! 5 u 99th percentile URL) in patients with normal baseline values (d 99th percentile URL) or a rise of cTn values more than 20% if the baseline values are elevated and are stable or falling. In addition either: ƒ Symptoms suggestive of myocardial ischemia, or ƒ New ischemic ECG changes, or ƒ Angiographic findings consistent with a procedural complication, or ƒ Imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality is required. Stent thrombosis associated with MI when detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker values with at least one value above the 99th percentile URL. Coronary artery bypass grafting (CABG) related MI is arbitrarily defined by elevation of cardiac biomarker values (! 10 u 99th percentile URL) in patients with normal baseline cTn values (d 99th percentile URL). In addition, either (i) new pathological Q-waves or new LBBB, or (ii) angiographically documented new graft or new native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

Criteria for Prior MI Any one of the following criteria meets the diagnosis for prior MI: • Pathological Q-waves with or without symptoms in the absence of nonischemic causes. • Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause. • Pathological findings of a prior MI.

Acute ST-Elevation Myocardial Infarction 3 Flowchart 1.1: &ODVVL¿FDWLRQRI$&6

LBBB: Left bundle branch block; NSTE-ACS: Non-ST-segment elevation acute coronary syndromes; QMI: Q-wave myocardial infarction; NQMI: Non-Q-wave myocardial infarction; MI: Myocardial infarction; STEMI: ST-segment elevation myocardial infarction; NSTEMI: Non-ST-segment elevation myocardial infarction

CLASSIFICATION Type I: Spontaneous MI Spontaneous MI related to atherosclerotic plaque rupture, ulceration, fissuring, erosion or dissection with resulting intraluminal thrombus in one or more of the coronary arteries leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. The patient may have underlying severe coronary artery disease (CAD) but on occasion nonobstructive or no CAD.

Type 2: MI Secondary to an Ischemic Imbalance In instances of myocardial injury with necrosis where a condition other than CAD contributes to an imbalance between myocardial oxygen supply and/ or demand, e.g. coronary endothelial dysfunction, coronary artery spasm, coronary embolism, achyarrhythmia/bradyarrhythmia, anemia, respiratory failure, hypotension and hypertension with or without left ventricular hypertrophy (LVH).

4 The Protocol Book for Intensive Care Flowchart 1.2:,QLWLDOKRVSLWDOPDQDJHPHQWDQGVHOHFWLRQRIUHSHUIXVLRQWKHUDS\

LBBB: Left bundle branch block; NSTEMI: Non-ST-segment elevation myocardial infarction; PCI: Percutaneous coronary intervention; PPCI: Primary percutaneous coronary intervention; AVM: Arteriovenous malformations; DBP: Diastolic blood pressure; CPR: Cardiopulmonary resuscitation; NTG: Nitroglycerine; APTT: Activated partial thromboplastin time

Acute ST-Elevation Myocardial Infarction 5

Type 3: MI Resulting in Death When Biomarker Values are Unavailable Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes or new LBBB, but death occurring before blood samples could be obtained, before cardiac biomarker could rise, or in rare cases, cardiac biomarkers were not collected.

Type 4a: MI Related to PCI MI associated with PCI is arbitrarily defined by elevation of cTn values more than 5 u 99th percentile URL in patients with normal baseline values (d 99th percentile URL) or a rise of cTn values more than 20%, if the baseline values are elevated and are stable or falling. In addition, either: • Symptoms suggestive of myocardial ischemia, or • New ischemic ECG changes or new LBBB, or • Angiographic loss of patency of a major coronary artery or a side branch or persistent slow- or no-flow or embolization, or • Imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality is required.

Type 4b: MI Related to Stent Thrombosis MI associated with stent thrombosis is detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarkers values with at least one value above the 99th percentile URL.

Type 5: MI Related to CABG MI associated with CABG is arbitrarily defined by elevation of cardiac biomarker values more than 10 u 99th percentile URL. In addition, either: • New pathological Q-waves or new LBBB, or • Angiographic documented new graft or new native coronary artery occlusion, or • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality is required.

PREHOSPITAL ISSUES Time from symptom onset to reperfusion with primary PCI or fibrinolytic drug, is called total ischemic time and is particularly important for patients with STEMI. Longer total ischemic times are associated with more myocardial damage and adverse clinical consequences. Incidentally, prehospital delay comprises about 60–70% of the total ischemic time. Figure depicts a hypothetical construct of the relationship among duration of symptoms of

6 The Protocol Book for Intensive Care

Fig. 1.1: Relationship of outcome and myocardial salvage as a function of total ischemic WLPH

AMI before reperfusion therapy, mortality reduction and extent of myocardial salvage. Reperfusion therapy results in the highest mortality benefit in the first 2–3 hours after onset of symptoms of AMI, most likely a consequence of myocardial salvage. The exact duration of this critical early period may be modified by several factors, including presence of functioning collateral coronary arteries, ischemic preconditioning, myocardial oxygen demands and duration of sustained ischemia. After this early period, the magnitude of the mortality benefit is much reduced and as the mortality reduction curve flattens, time to reperfusion therapy is less critical. Between 6 and 12 hours after onset of symptoms, opening the infarct-related artery (IRA) is the primary goal of reperfusion therapy and myocardial salvage in this period is the secondary and uncertain goal. The over-reaching goal is to keep total ischemic time with 120 minutes (ideally within 60 minutes) from symptom onset to initiation of reperfusion treatment. The following modus operandi should be followed by medical system based on the mode of patient transportation and capabilities of the hospital which receives the patient. Transportation by emergency medical services (EMS) is recommended and self-transportation should be discouraged. If the EMS has fibrinolytic capability and patient qualifies for therapy, prehospital fibrinolysis should be done within 30 minutes of arrival of EMS on the scene. If EMS is not capable of administering prehospital fibrinolysis and patient is transported to a non-PCI-capable hospital, door to needle time should be within 30 minutes, if fibrinolysis is indicated. However, if EMS is not capable of administering

Acute ST-Elevation Myocardial Infarction 7

prehospital fibrinolysis and patient is transported to a PCI-capable hospital, EMS arrival-to-balloon time should be within 90 minutes. Following presentation to a non-PCI-capable hospital, it may be considered appropriate to consider emergency inter-hospital transfer of the patient to a PCI-capable hospital for mechanical revascularization in following three situations: 1. Fibrinolysis is contraindicated. 2. PCI can be initiated promptly within 90 minutes from EMS arrival-toballoon time at the PCI-capable hospital or within 60 minutes compared with when fibrinolysis with a fibrin-specific agent could be initiated at the initial receiving hospital. 3. Fibrinolysis is administered and unsuccessful, i.e. ‘rescue PCI’ is indicated.

INITIAL HOSPITAL MANAGEMENT •

•

•

•

• •

STEMI patients should be admitted to the quiet and comfortable environment of coronary care unit (CCU) that provides for continuous monitoring of the ECG and pulse oximetry and has ready access to facilities for hemodynamic monitoring and defibrillation. Bedside chair or commode is allowed when patient becomes stable. Oxygen by nasal cannula at 2 L/minute is administered for initial 6 hours and continued thereafter only if oxygen saturation is less than 90%. Patients initially admitted to CCU who demonstrate 12–24 hours of clinical stability may be transferred to the step down unit. Low-risk STEMI patients who have undergone successful PCI may be admitted directly to step down unit for post-PCI care rather than to the CCU. An intravenous (IV) access is mandatory with a running infusion (NS/ D5W) to keep the vein open. A second IV access to be started if IV medication is being given. This may be a saline lock. Continuous ECG monitoring for arrhythmias and ST segment deviation is mandatory. Vital signs need to be monitored every 1.5 hours until stable, then every 4 hours and as needed. Continuous oximetry monitoring is also recommended. Nasal cannula at 2 L/minute when stable for 6 hours; thereafter reassess for oxygen need (i.e. oxygen saturation  90%) and consider discontinuing oxygen. Patient should not be administered oral feeds except sips of water until stable. Thereafter, a therapeutic lifestyle change (TLC) diet comprising 2 g sodium/day, low saturated fat ( 7% of total calories/day), low cholesterol ( 200 mg/day) diet is advised. Bed rest is recommended during the acute, unstable phase; however, bedside commode and light activity are permitted when stable. Blood sample for laboratory tests are to be sent immediately on admission but one should not wait for results before implementing reperfusion

8 The Protocol Book for Intensive Care

•

strategy. These include serum biomarkers for cardiac damage, CBC with platelet count, prothrombin time with International Normalized Ratio (INR), activated partial thromboplastin time (aPTT), electrolytes, magnesium, BUN, creatinine, glucose and serum lipids. Antiplatelet and antithrombotic cotherapies (as per ESC guidelines for the management of STEMI 2012 and ACCF/AHA guidelines for management of STEMI 2013).

Antiplatelet Drugs •

•

•

ASPIRIN: Primary PCI (Class IB recommendation): Loading dose of 150–300 mg orally or 80–150 mg IV, if oral ingestion is not possible, followed by a maintenance dose of 75–100 mg/day to be continued indefinitely. [ACC/AHA 2013 Guidelines 81 mg is the preferred dose]. ƒ With fibrinolytic therapy: Starting dose 150–500 mg orally or IV dose of 250 mg if oral ingestion is not possible followed by maintenance dose of 75–100 mg/day indefinitely. ƒ Without reperfusion therapy: Starting dose 150–500 mg orally. ƒ Chronic kidney disease: No dose adjustment. CLOPIDOGREL: Primary PCI (Class IC recommendation): Loading dose of 600 mg orally, followed by maintenance dose of 75 mg/day for 1 year. ƒ With fibrinolytic therapy: Loading dose of 300 mg orally if aged less than or equal to 75 years, followed by a maintenance dose of 75 mg/ day for 1 year. ƒ If aged more than 75 years: no loading dose, give 75 mg (1A) followed by 75 mg daily for at least 14 days (1A) and up to 1 year in absence of bleeding (1C) (ACCF/AHA 2013). ƒ If patient has not received a loading dose of Clopidogrel. ƒ If PCI performed less than or equal to 24 hours after fibrinolysis: Clopidogrel 300 mg before or at time of PCI. ƒ If PCI performed more than 24 hours after fibrinolysis: Clopidogrel 600 mg loading before or at time of PCI. ƒ Without reperfusion therapy: 75 mg/day orally for 1 year. ƒ Chronic kidney disease: No dose adjustment. PRASUGREL: Primary PCI (Class IB recommendation): Loading dose of 60 mg orally, followed by a maintenance dose of 10 mg/day for 1 year. In patients with body weight less than 60 kg, if used, a maintenance dose of 5 mg is recommended. ƒ In patients more than 75 years, prasugrel is generally not recommended, but a dose of 5 mg should be used, if treatment is deemed necessary. If loading dose of prasugrel not given. ƒ If PCI is performed more than 24 hours after treatment with a fibrin-specific agent or more than 48 hours after a nonfibrin specific agent: Prasugrel 60 mg at time of PCI.

Acute ST-Elevation Myocardial Infarction 9

•

•

ƒ Chronic kidney disease: No dose adjustment. No experience with end-stage renal disease/dialysis. TICAGRELOR: Primary PCI (Class IB recommendation): Loading dose of 180 mg orally, followed by 90 mg bid for 1 year. ƒ Chronic kidney disease: No dose adjustment. No experience with end-stage renal disease/dialysis. ƒ Congrelor may be considered in patients who have not received P2Y12 receptor inhibitors. GLYCOPROTEIN IIB/IIIA (GP IIB/IIIA) INHIBITORS: Primary PCI: ƒ GP IIb/IIIa inhibitors should be considered for bailout therapy if there is angiographic evidence of massive thrombus, slow or no reflow or a thrombotic complication (Class IIa recommendation). ƒ Routine use of a GP IIb/IIIa inhibitor as an adjunct to primary PCI performed with unfractionated heparin may be considered in patients without contraindications (Class IIb recommendation). ƒ Upstream use of GP IIb/IIIa inhibitor (vs in-lab use) may be considered in high-risk patients undergoing transfer for primary PCI (Class IIb recommendation).

Dosage • • •

ABCIXIMAB: Bolus of 0.25 mg/kg IV or 0.125 Pg/kg/minute infusion (maximum 10 Pg/minute) for 12 hours. EPTIFIBATIDE: Double bolus of 180 Pg/kg IV (given at 10 minute interval) followed by an infusion of 2.0 Pg/kg/minute for 18 hours. TIROFIBAN: 25 Pg/kg over 3 minutes IV, followed by a maintenance infusion of 0.15 Pg/kg/minute for 18 hours. All the three agents have Class IIa recommendation as per recent ACCF/ AHA 2013 Guidelines with abciximab having level A of evidence again B for other two.

Antithrombotic Drugs •

•

UNFRACTIONATED HEPARIN: Primary PCI: (1) 70–100 u/kg IV bolus when no GP IIb/IIIa inhibitor is planned (Class IC recommendation), (2)  50–70 u/kg IV bolus with GP IIb/IIIa inhibitors (Class IC recommendation). ƒ With fibrinolytic therapy: 60 u/kg IV bolus with a maximum of 4,000 u followed by an IV infusion of 12 u/kg with a maximum of 1,000 u/h for 24–48 hours (Class IC recommendation). ƒ Target aPTT: 50–70 seconds or 1.5–2.0 times that of control to be monitored at 3, 6, 12 and 24 hours. ƒ Without reperfusion therapy: Same dose as with fibrinolytic therapy. ƒ Chronic kidney disease: No adjustment of bolus dose. ENOXAPARIN ƒ With primacy PCI: 0.5 mg/kg IV bolus (ESC Class IIb recommendation; ACCF/AHA-no recommendation).

10 The Protocol Book for Intensive Care

•

•

•

ƒ With fibrinolytic therapy: In patients less than 75 years of age, 30 mg IV bolus followed 15 minutes later by 1 mg/kg SC every 12 hours until hospital discharge for a maximum of 8 days. The first two doses should not exceed 100 mg. ƒ In patients more than 75 years of age, no IV bolus; start with subcutaneous dose of 0.75 mg/kg with a maximum of 75 mg for the first two subcutaneous doses (Class IA recommendation). ƒ In patients with creatinine clearance of less than 30 mL/minute, regardless of age, the SC doses are given once every 24 hours. ƒ Without reperfusion therapy: Same dose as with fibrinolytic therapy. ƒ Chronic kidney disease: No adjustment of bolus dose. Following thrombolysis, in patients with creatinine clearance less than 30 mL/ minute, the SC doses are given once every 24 hours. BIVALIRUDIN ƒ With primary PCI: 0.75 mg/kg IV bolus followed by IV infusion of 1.75 mg/kg/hour for up to 4 hours after the procedure as clinically warranted (Class IB recommendation). After the cessation of the 1.75 mg/ kg/hour infusion, a reduced infusion dose of 0.25 mg/hour may be continued for 4–12 hours as clinically necessary. Preferred over UFH with GP IIb/IIIa receptor antagonists in patients with high risk of bleeding (Class IIa recommendation). Chronic kidney disease ƒ In patients with moderate renal insufficiency (GFR 30–59 mL/minute) a lower initial infusion rate of 1.4 mg/kg/hour should be given. The bolus dose should not be changed. ƒ In patients with severe renal insufficiency (GFR < 30 mL/minute) and in dialysis-dependent patients bivalirudin is contraindicated (ESC 2012); as per ACCF/AH 2013 guidelines, reduce infusion to 1 mg/kg/ hour if GFR less than 30 mL/minute. FONDAPARINUX ƒ With primary PCI: Not recommended as sole anticoagulant. ƒ With fibrinolytic therapy (with Streptokinase only - ESC 2017 STEMI guidelines): 2.5 mg IV bolus followed by a SC dose of 2.5 mg once daily up to 8 days or hospital discharge. ƒ Without reperfusion therapy ƒ Same dose as with fibrinolytic therapy.

Contraindicated if CrCl < 30 mL/minute (ACCF/AHA 2013) No experience in patients with end-stage renal disease or dialysis patients. Duration of thienopyridine therapy for patients receiving a stent (BMS or drug-eluting stent [DES]) during PCI for ACS, clopidogrel 75 mg daily [IB] or prasugrel 10 mg daily [IB] should be given for at least 12 months. If the risks

Acute ST-Elevation Myocardial Infarction 11

of morbidity because of bleeding outweigh the anticipated benefit afforded by thienopyridine therapy, earlier discontinuation should be considered [IC]. If CABG is planned and can be delayed, as mentioned earlier, clopidogrel should be withdrawn for at least 5 days and prasugrel for at least 7 days prior to CABG, unless the need for CABG and/or the net benefit of the thienopyridine outweighs the potential risks of excess bleeding [IC]. Continuation of clopidogrel or prasugrel beyond 15 months may be considered in patients undergoing DES placement (IIb-c). In STEMI with a prior history of stroke and transient ischemic at least for whom primary PCI is planned, prasugrel is not recommended as part of a dual antiplatelet therapy regimen. Nitroglycerin (NTG): Patients with ongoing ischemic discomfort should receive sublingual nitroglycerin (0.4 mg) every 5 minutes for a total of three doses, after which as assessment should be made about the need for IV nitroglycerin [IC]. Analgesia: Morphine sulfate (2–4 mg IV with increment of 2–8 mg IV repeated at 5–15 minutes intervals) is the analgesic of choice for management of pain associated with STEMI [IC]. Patients routinely taking NSAIDs (except for aspirin) both nonselective as well as COX-2 selective agents before STEMI should have those agents discontinued at the time of presentation with STEMI because of the increased risk of mortality, reinfarction, hypertension, heart failure and myocardial rupture associated with their use [IC]. Beta-Blockers: Oral beta-blockers therapy should be initiated in the first 24 hours for patients who do not have any of the following: • Signs of heart failure. • Evidence of a low cardiac output state. • Increased risk for cardiogenic shock (age !70 years, SBP  120 mm Hg, heart rate ! 110 bpm or 60 bpm and increased time since onset of symptoms of STEMI). • Other relative contraindications to beta-blockade (PR interval !0.24 second or third degree heart block, active asthma or reactive airway disease) [IC]. It is reasonable to administer an IV beta-blocker at the time of presentation to STEMI patients who are hypertensive and who do not have the contraindications as mentioned for oral formulations of beta-blockers [IIA-B]. Patients with early contraindications within first 24 hours of STEMI should be reevaluated for candidacy for beta-blocker therapy as secondary prevention [IC]. Inhibitors of renin-angiotensin-aldosterone system: An angiotensinconverting enzyme (ACE) inhibitor should be administered orally within the first 24 hours of STEMI to patients with anterior infarction, pulmonary congestion or left ventricular ejection fraction (LVEF) less than 0.40, in the absence of hypotension (systolic blood pressure 100 mm Hg or  30 mm Hg

12 The Protocol Book for Intensive Care below baseline) or known contraindications to that class of medications [IA]. For patients presenting within 24 hours of non-anterior wall STEMI but with the pulmonary congestion or LVEF less than 0.40, ACEIs have Class IIa recommendation (Level of evidence: B) in absence of contraindications mentioned above. An angiotensin receptor blocker (ARB) should be administered to STEMI patients who are intolerant of ACEIs and who have either clinical or radiological signs of heart failure or LVEF  0.40 (IC). Valsartan and candesartan have established efficacy for this recommendation. An IV ACEI should not be given to patients within the first 24 hours of STEMI because of risk of hypotension. Refractory hypertension may be one possible exception. Aldosterone blockade is recommended [IA] for postSTEMI patients without significant renal dysfunction (creatinine should be d2.5 mg/dL in men and d2.0 mg/dL in women) or hyperkalemia (potassium should be d5.0 mEq/L) who are already receiving therapeutic doses of an ACE inhibitor, have an LVEF less than or equal to 40% and have either symptomatic congestive heart failure (CHF) or diabetes. In the (ACC 2013) REMINDER trial, 1,012 subjects with acute STEMI without diagnosis of heart failure, and with LVEF more than 40% were randomized to receive either eplerenone 25 mg or placebo within 24 hours of onset of symptoms on top of standard therapy. The primary composite endpoint (which comprised of CV mortality, rehospitalization or hospitalization extended due to HF, sustained VT or VF, EF d40% after 1 month, natriuretic peptide elevation more than 1 month) was significantly altered in favor of eplerenone (P  0.0001). However, despite numerical trends (nonsignificant) in favor of VT/VF and HF rehospitalization, biomarker component of the endpoint accounted for most of the overall benefit. Hyperkalemia was not significantly increased. An exploratory analysis of the acute STEMI subgroup in ALBATROSS trial, composite outcomes were significantly reduced in the active treatment group (simple i.v. bolus of potassium can renoate 200 mg/day). Future studies will clarify the role of MRA treatment in this setting. Metabolic modulation of glucose-insulin axis: An insulin infusion to normalize blood glucose is recommended for patients with STEMI and complicated course [IB]. During the acute phase (first 24-hour after STEMI), it is reasonable to administer an insulin infusion to maintain blood glucose in patients less than 180 mg/dL with an uncomplicated or complicated course while avoiding hypoglycemia [IIB]. Recently reported NICE-SUGAR trial has reported excess deaths, predominantly cardiovascular, in the intensive glycemic control arm of critically ill medical and surgical patients. Whether these results can be extrapolated to management of patients with STEMI is unclear but above-mentioned note of caution about hypoglycemia in 2009 update of ACC/AHA guidelines on STEMI has been made in the light of these findings.

Acute ST-Elevation Myocardial Infarction 13

After the acute phase of STEMI, it is reasonable to individualize treatment of diabetics, selecting from a combination of insulin, insulin analogs and oral hypoglycemic agents that achieve moderate glycemic control acutely and are well tolerated. Lipid management: Statins are recommended in all patients with AMI (irrespective of cholesterol concentration) at present. They should be initiated as early as possible since there are early and sustained benefits to be accrued. High-intensity statins are to preferred unless there is history of intolerance to high intensity statins or there are other safety issues (eg. elderly, hepatic or renal impairment or interaction with concomitant therapy). The treatment goal is an LDL-C of 1.8 mmol/L (70 mg/dL) or at least 50% reduction in LDL-C if baseline LDL-C level is 1.8–3.5 mmol/L. A lipid profile should be obtained as early as possible after admission with STEMI and can be nonfasting. Lipids should be reevaluated 4-6 weeks after the ACS to determine if target levels have been reached or not and for safety issues. Based on some recent trial evidence (eg. IMPROVE-IT with Simvastatin  Ezetimibe and FOURIER with PCSK9 inhibitor), clinicians should consider adding a nonstatin treatment to patients at high risk who do not reach treatment targets after STEMI despite the maximum tolerated dose of statin. Some recent guidelines (eg. AACE) have stressed on a stringent LDL-C goal of  55 mg/dL for diabetic patients suffering from ACS. Magnesium: It is reasonable that documented magnesium deficits be corrected, especially in patients receiving diuretics before onset of STEMI [IIA-C]. It is also reasonable that episode of torsade de pointes-type ventricular tachycardia (VT) associated with a prolonged QT interval be treated with 1–2 g of magnesium administered as an IV bolus over 5 minutes [IIA-C]. However, in absence of documented deficit or torsade de pointes-type VT, routine IV magnesium should not be administered to STEMI patients at any level of risk. Calcium channel blockers: There is no Class I recommendation to use of calcium channel blockers (CCBs) after STEMI; however, effect of administration of nondihydropyridine CCBs verapamil and diltiazem initiated later after AMI were studied in the DAVIT-II and MDPIT trials respectively. Based on results of these trials, Class IIa recommendation has been accorded to administration of verapamil or diltiazem for relief of ischemia or control of atrial tachyarrhythmias after STEMI to patients in whom beta-blockers are ineffective or contraindicated and in whom there are no signs of CHF, LV dysfunction or AV block (Level of evidence: C). Short-acting dihydropyridine CCB nifedipine is contraindicated in the treatment of STEMI. Glucose insulin potassium: Despite report of mortality benefit from metaanalysis of early trials with IV infusion of glucose-insulin-potassium (GIK), more recent large-scale studies (including CREATE-ECLA trial with over 20,000

14 The Protocol Book for Intensive Care Table 1.1: Routine medical therapies in AMI (ESC Guidelines 2012). Class of recommendation

Level of evidence

Oral treatment with beta-blockers is indicated in patients with heart failure or LV dysfunction

I

A

Intravenous beta-blockers to be considered at presentation only in patients with high blood pressure, tachycardia and no signs of heart failure

IIA

B

High dose statins to be initiated early after admission in all STEMI patients without contraindication regardless of initial cholesterol values

I

A

Verapamil may be considered for secondary prevention with absolute contraindication to beta-blockers and no heart failure

IIB

B

ACE-inhibitors to be started within first 24-hour of STEMI in patients with evidence of heart failure, LV systolic dysfunction, diabetes or an anterior infarct

I

A

An ARB, preferably valsartan, is an alternative to ACE-inhibitors in patients with heart failure or LV systolic dysfunction, particularly those who are intolerant to ACE-inhibitors

I

B

Aldosterone antagonists, e.g. eplerenone, are indicated in patients with an ejection fraction ≤ 40% and heart failure or diabetes, provided no renal failure or hyperkalemia

I

B

Oral treatment with beta-blockers should be considered during hospital stay and continued thereafter in all STEMI patients without contraindications

IIA

B

ACE-inhibitors should be considered in all patients in the absence of contraindications

IIA

A

Agent and indication

LV: Left ventricular; AMI: Acute myocardial infarction ESC: European Society of Cardiology; STEMI: STelevation myocardial infarction; ACE: angiotensin-converting enzyme

patients) have not supported those conclusions. The more recent IMMEDIATE trial evaluated efficacy of IV GIK in patients with CS (including STEMI). There was no significant difference in rate of progression to MI or 30-day-mortality. However, there was a statistically 52% reduction in composite endpoint of cardiac arrest or in-hospital mortality and in a select group undergoing imaging, infarct size was seem to be reduced. This has rekindled interest in this therapy but there is no clear-cut recommendation till date. Above-mentioned recommendations for initial management of acute STEMI are based on most recent ACCF/AHA Guidelines 2013 for Management of Patients with STEMI. Recommendations by the Task Force on the management of ST-segment elevation AMI of the European Society of Cardiology 2012 for initial management of acute STEMI are similar and are enlisted in table.

Acute ST-Elevation Myocardial Infarction 15 Table 1.2: Recommendations for Reperfusion Therapy (2017 ESC Guidelines for STEMI).

•

Reperfusion therapy is indicated in all patients with symptoms of ischemia of d 12 h duration and persistent ST-segment elevation

IA (Boersma et al.)

•

A primary PCI strategy is recommended over fibrinolysis within indicated timeframes

IA (Keeley et al., Andersen et al., Cucherat et al., Dalby et al)

•

If timely primary PCI cannot be performed after STEMI diagnosis, fibrinolytic therapy is recommended within 12 h of symptom onset in patients without contraindications

IA (Pinto et al.)

•

In patients with time from symptom onset !12 h, a primary PCI strategy is indicated in the presence of ongoing symptoms suggestive of ischemia, hemodynamic instability, or lifethreatening arrhythmias

IC (PL-ACS Study)

•

A routine primary PCI strategy should be considered in patients presenting late (12–48 h) after symptom onset**

IIaB (Schomee et al., Ndrepepa et al., Busk et al.)

•

In asymptomatic patients, routine PCI of an occluded IRA !48 h after onset of STEMI is not indicated

IIIA OAT trial (Ioannidis et al.)

**In asymptomatic patients without persistent symptoms 12–48 h after symptom onset, a small (n = 347) randomized study showed improved myocardial salvage and 4 year survival in patients treated with primary PCI compared with conservative treatment alone.

SELECTION OF REPERFUSION STRATEGY Hospitals with PCI Capability A total of 23 published randomized controlled trials have compared primary PCI with fibrinolytic therapy in patients with STEMI. A meta-analysis reported the short- and long-term outcomes of the 7,730 patients (3,872 randomized to primary PCI and 3,867 randomized to fibrinolytic therapy) enrolled in these trials. In this analysis, primary PCI was superior to fibrinolytic therapy in reducing overall short-term death (7% vs 9%, P 0.0002), nonfatal reinfarction (3% vs 7%, P  0.0007), stroke (1.0% vs 2.0%, P 0.0004), and the combined endpoint of death, nonfatal reinfarction and stroke (8% vs 14%, P  0.0001). Advantages of primary PCI include achieving complete reperfusion in 90–95% of patients, having lower risk for reinfarction and stroke, and allowing definitive characterization of coronary anatomy and LV function. On the basis of these data, patients with STEMI who present to hospitals with PCI capability should have primary PCI as the preferred and routine reperfusion strategy. Summary of current recommendations based on ACCF/AHA 2013 Guidelines is as following; most of the recommendations match with ESC 2012 Guidelines except where indicated.

16 The Protocol Book for Intensive Care Table 1.3: Indications for coronary angiography ± PCI of infarct-related artery in SDWLHQWVZKRZHUHPDQDJHGZLWK¿EULQRO\WLFRUZKRGLGQRWUHFHLYHUHSHUIXVLRQ therapy. Subset

Class of recommendation

Level of evidence

•

Cardiogenic shock or acute severe HF that develops after initial presentation

I

B

Wu et al. Hochman et al. Steg et al.

•

Intermediate or high-risk findings on predischarge noninvasive ischemic testing

I

B

SWISS II DANAMI

•

Spontaneous or easily provoked myocardial ischemia

I

C

—

•

Failed reperfusion or reocclusion after fibrinolytic therapy

IIa

B

Gershlick et al. Sutton et al. Gibson et al.

•

Stable patients after successful fibrinolysis, before discharge and ideally between 3 and 24 hours

IIa [ESC 2012 Task Force recommendation: IA]

B

GRACIA SIAM WEST CAPITAL-AMI CARESS-in-AMI TRANSFER-AMI STREAM

•

PCI for stable patients  > 24 hours after successful fibrinolysis

IIb

•

Delayed PCI of a totally occluded infarct artery > 24 hours after STEMI in stable patients

III, No benefit

Evidence base

Hochman et al. DANAMI DECOPI D’Souza et al. Gibson et al. B

Hochman et al. Ioannidis et al.

HF: Heart failure; PCI: Percutaneous coronary intervention; STEMI: ST-elevation myocardial infarction.

FIBRINOLYTIC THERAPY More than two decades of clinical trial experience have elapsed involving more than 100,000 patients enrolled in clinical trials. Initial trials of streptokinase (SK) performed in 1980s showed a pronounced mortality benefit, with an 18% mortality reduction in the GISSI-1 trial and a 25% reduction in the ISIS-2 trial. The benefit extended to 42% reduction when aspirin and SK were combined. The GUSTO-1 trial showed a slight mortality benefit (14%) in patients receiving tPA and IV heparin and compared with SK (with either IV or subcutaneous heparin). Risk of hemorrhagic stroke was statistically lower in patients receiving SK compared with those receiving tPA group (6.9% vs 7.8%, P = 0.006).

Acute ST-Elevation Myocardial Infarction 17

Trials of rPA (GUSTO-3) and tenecteplase (TNK) (ASSENT-2) showed similar rates of mortality and ICH as tPA, with an overall rate of death or nonfatal stroke of approximately 7%. TNK was, however, associated with fewer noncerebral bleeding complications and lower rates of transfusion in ASSENT-2 trial. Thus, newer bolus agents have not surpassed the mortality benefits seen with tPA. However, combined benefits of the ease of administration, diminished potential for dosing errors and lower rates of noncerebral bleeding have led to increasing use of these agents in most centers.

Status of Different Thrombolytic Agents Streptokinase: Approved for general use Alteplase: Established standard Reteplase: Approved for general use Tenecteplase (TNK-tPA): Approved for general use and likely to replace alteplase because: • Bolus injection simplifies administration even in prehospital setting and reduces potential for medication errors. • Increased fibrin specificity provided by TNK-tPA does confer a significant decrease in major systemic bleeding. A comparison of different thrombolytic agents along with their dosage has been shown in the table.

ECG Features Justifying Fibrinolytic Therapy • •

• •

New ST-elevation at the J-point greater than 0.1 mV in two contiguous leads other than leads V2-V3, where the following cut points apply More than or equal to 0.2 mV in man more than 40 years and more than or equal to 0.25 mV in men less than 40 years or more than or equal to 0.15 mV in women New or presumable new LBBB (IA) 12 lead ECG findings consistent with true posterior MI (IIaC)

Contraindications to Fibrinolysis Absolute Contraindications • • • • • • • •

Any prior ICH Known structural cerebral vascular lesion (e.g. arteriovenous malformation) Known malignant intracranial neoplasm (primary or metastatic) Ischemic stroke within 3 months EXCEPT acute ischemic stroke within 4.5 hours Suspected aortic dissection Active bleeding or bleeding diathesis (excluding menses) Significant closed-head or facial trauma within 3 months Intracranial or intraspinal surgery within 2 months

18 The Protocol Book for Intensive Care Table 1.4: Comparison of thrombolytic agents. Property

SK

tPA

rPA

Fibrin specificity

–

++

+

TNK-tPA +++

Antigenic

+

–

–

––

Hypotension

+

–

–

––

Patency at 90 minutes

+

+++

++++

+++

Hemorrhagic stroke

+

++

++

++

Mortality reduction

+

+++

+++

+++

Cost

+

+++

+++

+++

Concomitant heparin

+(LMWH)

+

+

+

Bleeding (noncerebral)

+++

++

++

+

SK: Streptokinase; tPA: tissue-type plasminogen-activator (alteplase); rPA: Reteplase plasminogenactivator; tPA: tissue-type plasminogen-activator

7DEOH'RVHVRI¿EULQRO\WLFDJHQWVDQGDQWLWKURPERWLFFRWKHUDSLHV(6& Guidelines for STEMI) Doses of fibrinolytic therapy Streptokinase

1.5 millions units over 30–60 min IV

Alteplase (tPA)

15 mg IV bolus 0.75 mg/kg over 30 min (upto 50 mg) then 0.5/kg iv over 60 min (upto 35 mg)

Reteplase (rPA)

10 units + 10 units IV bolus given 30 mins apart

Tenecteplase (TNK tpA)

Single IV bolus 30 mg if 75 years of age, loading dose of 75 mg followed by a maintenance dose of 75 mg/day

Doses of anticoagulant co-therapies Enoxaparin

In patients 75 years of age no IV bolus; start with first s.c. dose of 0.75 mg/kg with a maximum of 75 mg per injection for the first two s.c. doses (Contd.)

Acute ST-Elevation Myocardial Infarction 19 (Contd.) In patients with eGFR 48 hours after randomization and cardiogenic shock) was found between the three strategies at 90 days. Rather, bleeding was significantly increased in patients who were randomized to facilitated PCI, especially in those receiving half-dose reteplase

Acute ST-Elevation Myocardial Infarction 25

and abciximab. FINESSE trial thus seems to have finally drawn the curtains down for the concept of facilitated PCI.

EARLY PCI Initial trials of PCI within 24 hours of successful fibrinolysis reported increased rates of bleeding, recurrent ischemia, emergency CABG and death. With the advent of stents and GP IIb/IIIa inhibitors, the scenario has been changed considerably, and recent trials with early PCI after fibrinolytic therapy report more favorable results. The important trials in this regard are CARESS-in-AMI, CAPITALAMI, GRACIA, SIAM-III, WEST and the more recent TRANSFER-AMI and STREAM. Both CAPITAL-AMI and CARESS-in-AMI included patients less than 75 years of age with high-risk features and they underwent PCI within 3 hours of fibrinolytic therapy. Whereas CAPITAL-AMI compared full dose TNK immediate PCI versus TNK alone and standard care, CARESS-in-AMI compared a strategy of half dose reteplase and abciximab with or without immediate PCI. CAPITAL-AMI reported a significant decrease in the composite endpoint of death, reinfarction recurrent ischemia and stroke at 6 months and CARESS-in-AMI reported a significant decrease in primary endpoints of death, reinfarction and recurrent ischemia at 30 days. Notably, there was no increase in bleeding rates in either of the trials. Twelve-month follow-up CARESS-in-AMI showed persistent significant benefit in the PCI arm for refractory ischemia and recurrent MI but no difference in terms of death and admission for heart failure. In comparison to early routine invasive approach in aforesaid two trials, GRACIA-1 and WEST trials performed PCI following successful fibrinolysis relatively late (12–24 hours): GRACIA-1 reported a significant decrease in primary endpoint of death, reinfarction or revascularization at 1 year compared with standard care (9% vs 21%, P = 0.0008). In contrast, the smaller WEST trial showed just nonsignificant trends toward differences in primary endpoints of death, reinfarction, refractory ischemia, cardiogenic shock and major ventricular arrhythmias at 30 days between the PCI and the conservative arms. Other studies (SIAM III, GRACIA-2) have assessed outcomes of PCI performed in the intermediate period (3–12 hours) after successful fibrinolysis. In these trials, routine PCI was performed after full dose reteplase or TNK and benefit was demonstrated both in terms of epicardial and myocardial reperfusion and composite clinical endpoints at 6 months. More recent in these series of trials has been TRANSFER-AMI. More than 1,000 high-risk patients with STEMI in this study were randomly assigned to inter-hospital transfer for intended routine early PCI (within 6 hours after fibrinolysis) or an ischemia-guided strategy, in which patients

26 The Protocol Book for Intensive Care were transferred for angiography only in the case of failed fibrinolysis or recurrent ischemia. The actual median interval from lysis to balloon inflation was 3.9 hours. As in the early trials, rate of recurrent ischemia was significantly reduced with early routine PCI as compared with a selective invasive approach, without any significant increase in rates of bleeding. The latest of the reports has been AMICO Registry. In this Registry, FAST-PCI strategy (reduced-dose fibrinolytic therapy followed by urgent PCI) was shown to reduce the mortality and combined endpoint of death, reinfarction and stroke among STEMI patients, without increasing the risk of stroke or bleeding, compared with PCI. Fibrinolysis before hospital admission also increased the initial IRA patency and decreased the likelihood of shock at presentation. The latest in this list of trials is STREAM which included 1,832 patients with STEMI who presented within 3 hours after symptom onset and who were unable to undergo primary PCI within 1 hour. Patients were randomly assigned to undergo either primary PCI or fibrinolytic therapy with bolus TNK (amended to half-dose in patients > 75 years of age), clopidogrel and enoxaparin before transport to a PCI-capable hospital. Emergency coronary angiography was performed if fibrinolysis failed; otherwise angiography was performed 6–24 hours after randomization. Primary endpoint was a composite of death, shock, CHF or reinfarction up to 30 days. There was no statistically significant difference (P = 0.21) between the fibrinolysis and primary PCI group. Thus, this study showed a strategic alignment of prehospital or early fibrinolysis and contemporary antithrombotic cotherapy coupled with timely coronary angiography resulting in effective reperfusion in a specific onset of patients with STEMI (as described earlier). However, early fibrinolysis was associated with a slightly increased risk of intracranial bleeding. The average time of interval from fibrinolysis to PCI in the trials mentioned earlier has been 2–17 hours implying that transfer for PCI need not be undertaken on an emergency basis. Such a strategy (often referred to as pharmacoinvasive strategy) emphasizes on very early fibrinolysis (< 2 hours) for achieving greater rates of successful reperfusion and at the same time allows a transition of care that causes less stress both to the patient and to ambulance crews. The ESC 2012 has accorded Class I (Level of evidence: A) status to PCI after successful lysis within 24 hours of fibrinolysis therapy independent from angina and/or ischemia. In the latest ACCF/AHA 2013 STEMI guidelines, coronary angiography + PCI in stable patients after successful fibrinolysis before discharge and ideally between 3 and 24 hours has been accorded Class IIa of recommendation (Level of evidence: B). Considerations should be given in both groups to initiating a preparatory antithrombotic (anticoagulant plus antiplatelet) regimen before and during patient transfer to the catheterization laboratory.

Acute ST-Elevation Myocardial Infarction 27 Flowchart 1.4:$SSURDFKWRUHSHUIXVLRQLQ67(0,

STEMI: ST-segment elevation myocardial infarction; PCI: Percutaneous coronary intervention; PPCI: Primary percutaneous coronary intervention; CABG: Coronary artery bypass grafting

DELAYED PCI This hypothesis postulates that benefit in terms of improved ventricular function, increased electrical stability and provision of collaterals can be gained by late (12 hours to 3 months) patency of occluded infarct arteries. However, occluded artery trial (OAT) failed to show benefit of angioplasty for late total occlusion within 3–28 days after MI. Despite achieving a high rate of initial procedural success with good 1-year patency (among a subset), the expected decline in death, MI and heart failure did not occur. In fact, there was a statistically greater incidence of fatal and nonfatal MI in the intervention versus medical group as ascertained by investigators. Criticism of this trial includes exclusion of high-risk patients with New York Heart Association (NYHA) Class III or IV heart failure, rest angina, clinical instability, multivessel disease (left main or three vessel disease) or severe individual ischemia on stress testing. Regardless of these concerns, this study has led to a new Class III recommendation against PCI of a totally occluded artery more than 48 hours after STEMI in asymptomatic patients without the previously noted high-risk criteria (ESC 2017 STEMI Guidelines).

28 The Protocol Book for Intensive Care However, OAT trial has not closed the chapter of open artery hypothesis. Two years after publication of the OAT trial, a meta-analysis of 10 studies enrolling 3,560 patients that were randomized to either late PCI of the IRA (range 1–26 days after the MI) or optimal medical treatment was published. The primary endpoint of this meta-analysis was all cause mortality. In addition, left cardiac remodeling was also assessed in those studies with echocardiographic analysis. Late PCI was shown to improve survival as compared with medical treatment [or 0.49 (95% CI 0.26–0.94), P = 0.030] during a followup period of 2.8 years (42 days to 10 years). This beneficial effect in all-cause Flowchart 1.5:0DQDJHPHQWRIDUUK\WKPLDVIROORZLQJ67(0,

RCA: Right coronary artery; NTG: Nitroglycerine

Acute ST-Elevation Myocardial Infarction 29 Flowchart 1.6:,QGLFDWLRQVIRUSDFLQJIROORZLQJ67(0,

VT: Ventricular tachycardia; MI: Myocardial infarction; STEMI: ST-elevation myocardial infarction; CHF: Congestive heart failure

30 The Protocol Book for Intensive Care mortality reduction was associated with favorable effects on cardiac function and remodeling. Late PCI demonstrated significantly greater improvement in LV ejection fraction and LV end-diastolic and end-systolic volume indices. This meta-analysis by virtue of an adequate final sample size and long clinical follow-up fully addressed the open artery hypothesis. This hypothesis postulates that survival after MI depends on the effect of mechanical recanalization of the IRA which serves to improve LV remodeling and healing and enhances electrical stability. Most of the patients included in the analysis (84%) showed total IRA occlusion. Degree of angiographic success was variable (range 72–100%) as were both the rates of stent implantation (range 0–100%) and the glycoprotein IIb/IIIa inhibitor usage. Thus, the setting in this meta-analysis was poorly representative of the current PCI technology and outcomes, and yet late PCI was still able to significantly reduce the all-cause mortality rate. Patients with subtotal occlusion derived greater benefit than patients with total occlusion. Patients symptomatic for angina or heart failure and those with residual ischemia or documented viability are more likely to benefit from late PCI at a long-term follow-up. Patients with uncomplicated AMI, especially with reduced life expectancy, however, may not benefit from routine PCI. Benefit in terms of remodeling was seen to be more obvious with a median follow-up of 4 years and this lends support to the hypothesis that restoration of antegrade blood flow to the peri-infarct area interrupts progressive apoptosis of the hibernating myocardium and prevents development of cardiomyopathy. A routine primary PCI in patients presenting late (12-48 hours) after symptom onset has been given Class IIaB status by ESC 2017 STEMI guidelines. At the extreme end of the spectrum are patients with a chronic total occlusion (CTO), defined as a complete occlusion at least 3 months old. Benefit from recanalization in this setting is independent of time and is based on relieving symptomatic ischemia and angina, enhancing LV function, reducing predisposition to ventricular arrhythmias and improving tolerance of contralateral coronary occlusion. From a clinical standpoint, CTO recanalization is usually rewarding in symptomatic patients, or in patients with evidence of silent ischemia in a large territory at risk and/or with presence of viable myocardium.

INDICATIONS OF CABG IN PATIENTS •

•

Urgent CABG is indicated in patients with STEMI and coronary anatomy not amenable to PCI who have ongoing or recurrent ischemia, cardiogenic shock, severe HF or other high-risk features: Class of recommendation I (Level of evidence: B). CABG is recommended in patients with STEMI at the time of operative repair of mechanical defects: Class of recommendation I (Level of evidence: B).

Acute ST-Elevation Myocardial Infarction 31

•

• • •

Emergency CABG within 6 hours of symptom onset may be considered in patients with STEMI who do not have cardiogenic shock and are not candidates for PCI or fibrinolytic therapy (IIb-C). Aspirin should not be withheld before urgent CABG. Clopidogrel or ticagrelor should be discontinued at least 24 hours before urgent on-pump CABG, if possible. Eptifibatide and tirofiban should be discontinued at least 2–4 hours before urgent CABG; abciximab should be discontinued at least 12 hours before urgent CABG.

OTHER COMPLICATIONS OF AMI i. Ventricular septal rupture (VSR) Incidence: 1–2% in prethrombolytic era, now dramatically reduced. Time of occurrence: Usually 2–5 days after MI. Therapy: Surgery, percutaneous closure ii. Mitral regurgitation (MR) Incidence: Mild to moderate MR, 13–45%. Severe MR leading to cardiogenic shock: 1% Time of occurrence: 2–7 days after MI. Therapy: Surgical repair or less commonly replacement of mitral valve PCI has no role. iii. Cardiac rupture Incidence: 3% of post-MI patients. Time of occurrence: 50% occur in first 5 days; 90% occur within 2 weeks. Therapy: Immediate pericardiocentesis in case of subacute rupture; Acute rupture is often immediately fatal. iv. Pseudoaneurysm (contained rupture) Communicate with body of left ventricle through a narrow neck. May be clinically silent; diagnosed by Echo/CT/MRI. Therapy: Surgical resection because spontaneous rupture may occur. v. Ventricular aneurysm Acute aneurysm: Occur with transmural anteroapical infarcts and expand during systole. May result in severe heart failure or even cardiogenic shock. Chronic aneurysm: Are those which persist more than 6 weeks. They are less compliant and rarely expand during systole. Therapy: Anticoagulation if a mural thrombus is demonstrated surgical therapy (Aneurysmorrhaphy) in patients with refractory heart failure and ventricular arrhythmias. PCI after 12 hours of MI, but before 24 hours of MI in patients not reperfused earlier may be beneficial in those with acute aneurysm. vi. Dynamic left ventricular outflow tract (LVOT) obstruction: Uncommon complication after acute anterior MI resulting from hyperkinesis

32 The Protocol Book for Intensive Care of basal and mid segments of LV. Resultant venturi effect cause LVOT obstruction and MR. Free-wall rupture can occur. Therapy: Slow addition of beta-blockers, small boluses of IV normal saline may reduce LVOT gradient. vii. Pericarditis a. Early pericarditis Incidence: 10% (approx) Time of occurrence: 24–96 hours after MI. Therapy: Aspirin 650 mg every 4–6 hours. Avoid NSAIDs and corticosteroids colchicine for recurrent pericarditis. b. Late pericarditis or Dressler’s syndrome Incidence: 1–3% Time of occurrence: 1–8 weeks. Therapy: Aspirin if more than 4 weeks have elapsed after MI, NSAIDs and even steroids may be started for severe symptoms.

Secondary Prevention after STEMI • • • • • •

•

•

•

•

Smoking: Complete cessation and also avoid second hand smoke. Physical activity: Minimum goal—30 minutes 3–4 days per week; optimal daily. Weight management: Goal—BMI 18.5–24.9 kg/m2. Blood pressure: Goal—less than 140/90 mm Hg or less than 130/80 mm Hg if chronic kidney disease or diabetes. Diabetes management: Goal—HbA1C less than 7%. Lipid management: High dose statins for all unless contraindicated; primary goal LDL less than 70 mg/dL. Non-HDL-C less than 100 mg/dL. Antiplatelet drugs: Aspirin 75–162 mg/day if not contraindicated to continue indefinitely clopidogrel 75 mg/day for 1 year. Prasugrel (10 mg/day) or ticagrelor (90 mg twice daily) following PCI up to 1 year. ACE-inhibitors in patients post-STEMI with history of heart failure, LV systolic dysfunction, diabetes or anterior infarction (Class IA); for all patients post-STEMI unless contraindicated (Class IIaA); ARBs preferably valsartan to be prescribed in case of ACEI intolerance. Beta-blockers for post-STEMI patients with history of heart failure or LV systolic dysfunction (IA) beta-blockers for all STEMI patients in absence of contraindications (IIaB). Aldosterone antagonists, for example, eplerenone, for post-STEMI patients with LVEF less than or equal to 40% and heart failure or diabetes, provided no renal failure or hyperkalemia.

Acute ST-Elevation Myocardial Infarction 33

SUGGESTED READING 1.

2. 3.

4.

5. 6.

Guha S, Sethi R, Ray S, et al. Cardiological Society of India: position statement for management of ST elevation myocardial infarction in India. Indian Heart J. 2017;69(Suppl 1):S63-S97. Kumar S, Cannon CP. Acute coronary syndrome. M Cmillan’s Reference Series. ST-elevation Myocardial Infarction. 2012:33-70. O’Gara PT, Kushner FG, Ascheim DD, et al. ACCF/AHA Guidelines for the management of ST-elevation myocardial infarction: executive summary. Circulation. 2013;127(4):529-55. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33(20):2569-619. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J. 2012;33(20):2551-67. 2017 ESC Guidelines for the management of acute myocardial infarction in patients with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). European Heart Journal, ehx 393, https://doi.org/10.1093/eurheartj/ ehx393.

C HAPTER

2

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction Nodee Chowdhury, Saubhik Kanjilal, Soumitra Kumar

Flowchart 2.1: Approach to a patient presenting with acute onset chest pain.

ACS: Acute coronary syndrome; ECG: Electrocardiogram; CK-MB: Creatinine kinase MB; OPD: Out patient department.

Non-ST-Elevation-acute coronary syndrom (NSTE-ACS) is diagnosed when chest pain, typically severe, has one of the following three features: (i) Occurs at rest, for more than 20 minutes (prolonged angina), (ii) it is of relatively recent onset, within prior 2 weeks (de novo angina) and (iii) occurs with a crescendo pattern. Postmyocardial infarction (P-MI) angina may also present as NSTE-ACS.

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 35

Unstable angina (UA) is different from non-ST-elevation myocardial infarction (NSTEMI) by not having any markers of myocyte necrosis, that is, cardiac biomarkers are not elevated in UA. Acute coronary syndrome (ACS) UA

NQMI

QMI ECG ST ↑ ←⎯⎯⎯ → ( STEM )

ECG ST ↓ ←⎯⎯⎯ → ( NSTEMI ) CKMB ←⎯⎯⎯ → Trop T/ I ←⎯⎯⎯⎯⎯ → CRP ←⎯⎯⎯⎯⎯ →

Fig. 2.1:&ODVVL¿FDWLRQRI$&6RQWKHEDVLVRI(&*DQGELRPDUNHUV

INITIAL EVALUATION Electrocardiogram (ECG) in NSTEMI/UA An ECG should be obtained within 10 minutes of first medical contact. In onethird patients, it may be normal, and needs to be repeated within 15–30 minutes if symptoms persist. Additionally, V7–V9 and V3R and V4R may need to be taken to rule out left circumflex (LCX) infarct and right ventricular MI respectively (Class IC AHA/ACC 2014). Findings may be persistent ST depression, transient ST-elevation or depression. T-wave changes are less specific unless new and deep T inversions greater than or equal to 0.3 mV are found.

CARDIAC BIOMARKERS IN ACS At present cardiac troponins (cTn) (preferably high sensitivity), creatinine kinase (CK)-MB, and copeptin have been found to be clinically relevant.

Cardiac Troponins cTn is at present the preferred biomarker for diagnosis of acute myocardial infarction (AMI). Since it has a higher sensitivity for detecting myocardial injury than CK-MB and also provides useful information about prognosis. The degree of elevation of cTn has been shown to correspond with a gradient or mortality risk. According to the European Society of Cardiology (ESC) 2015 guidelines, dynamic elevation of cTn above the 99th percentile of healthy individuals is diagnostic of MI. Advancements in technology have led to the development of high sensitivity cardiac troponin (hscTn) assays that can detect a rise within 1 hour of onset of chest pain and remain elevated for 7–14 days. These assays, as compared with standard

36 The Protocol Book for Intensive Care troponin assays, have (i) 20% relative increase in detection of type 1 and two-fold increase in type 2 MI, (ii) reduce the troponin blind interval for AMI and (iii) have higher negative predictive value for MI. The higher the absolute level or dynamic change the greater the likelihood of MI. Blood samples for measurement of troponin should be drawn on first assessment and if negative, 3 hours later (Class IA). If the change in value is more than upper limit of normal, then invasive management is required. A rule-in, rule-out algorithm may be applied for NSTEMI with very low hs-cTn at 0 hour (first value) or insignificant change at 1 hour or 3 hours. Troponin elevations result from myocardial necrosis and it is not synonymous with ischemia. Clinical situations in which cTn can be raised in the absence of overt ischemic heart disease are large in number. They include: • Congestive heart failure—acute and chronic • Cardiac contusion or trauma including surgery, ablation, pacing and more • Pulmonary embolism, severe pulmonary hypertension • Aortic dissection • Renal failure • Apical ballooning syndrome or takotsubo cardiomyopathy (TCM) • Hypertrophic cardiomyopathy • Tachyarrhythmias or bradyarrhythmias or heart block • Rhabdomyolysis with cardiac injury • Stroke and subarachnoid hemorrhage • Infiltrative disease, for example, amyloidosis, hemochromatosis, sarcoidosis or scleroderma • Myopericarditis or myocardial extension of endocarditis • Drug toxicity or toxins • Burns, especially with affection of more than 30% of body surface area • Critically ill patients especially with respiratory failure or sepsis • Extreme exertion

Creatinine Kinase-MB It is a systolic carrier protein for high-energy phosphates and for a long time it has been the gold standard for AMI diagnosis. Its elevation occurs 4–8 hours after MI and peaking occurs at 18–24 hours. Hence, sensitivity of CK-MB for AMI is only 50% when measured early at the time of presentation. Its sensitivity and specificity can be increased by serial testing. Cardiac muscle damage is likely if the CK-MB is more than 3–5% of total CK activity. False positive results can be obtained in skeletal muscle injury, postsurgery, renal failure and peripartum period. After the introduction of cTn assays in clinical practice, CK-MB has had a progressive diminution in its role in diagnosis and prognostication of ACS.

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 37

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Copeptin Copeptin is the C-terminal part of the vasopressin prohormone, and has shown promise in the quantification of endogenous cardiac stress in MI when used in addition to standard cTn assays. Thus the ESC 2015 consensus recommends its use whenever hs-cTn is not available, and it may even be superior for ruling out of MI earlier as compared with hs-cTn.

Myoglobin By virtue of its some molecular mass, myoglobin leaks from necrotic myocardium far more rapidly than aspartate aminotransferase (AST), CK or lactate dehydrogenase (LDH). Early rise and high sensitivity is reported, but its low specificity makes it inferior to hs-cTn in the diagnosis of AMI.

Emerging Biomarkers Brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-ProBNP): Like atrial natriuretic peptide, BNP is secreted from the heart in response to stimulation of stretch receptors within heart wall following cardiac volume overload states. Hence, BNP and NT-ProBNP have become well-established biomarkers for left ventricular dysfunction. However, they are also now being investigated for acute myocardial ischemia and infarction and they have emerged as prognostic indicators of long-term mortality early after an acute coronary event. This association was observed across the spectrum of ACS, including patients with STEMI,

38 The Protocol Book for Intensive Care NSTEMI and UA, those with or without elevated cTn and those with or without clinical evidence of heart failure. The therapeutic benefits that can be derived from BNP and NT-ProBNP assays in ACS are not fully clear at till date. However, in a substudy of FRISC II trial, a trend toward better outcomes was observed following an early invasive strategy in patients with NT-ProBNP in the highest tertile.

C-reactive Protein C-reactive protein (CRP) is a biomarker widely in use as a marker of general inflammatory process. It is an acute phase reactant, synthesized in liver after stimulation by cytokines mainly IL-6. CRP can provide supportive diagnostic and prognostic information in this setting. The cut-point for hs-CRP in ACS setting is much higher than in stable Coronary artery disease (CAD). Measurement of hs-CRP in patients with ACS had been recommended as reasonable (Class IIa) for risk stratification when additional prognostic information is desired by the clinician.

Multimarker Approach In an analysis made by Sabatine et al. in 450 patients of OPUS-TIMI-16 and in 1,635 patients of TACTICS-TIMI-18, an approach with multiple markers in ACS without ST-elevation were investigated and BNP, CRP and cTn were all found to be independent predictors of adverse outcome. The incidence of adverse events correlated not only with positivity of each marker but also with number of positive markers.

Emerging Biomarkers Presently available biomarkers have facilitated diagnosis and prognostication of ACS to a great extent but the areas where they have been found to be deficient are: • Low sensitivity in the first 4–6 hours after onset of chest pain (potentially being addressed now by ultrasensitive troponins). • Poor markers of ischemia in absence of myocardial necrosis. • Affected by inflammation or injury to other body systems. The arrival of hs-cTn has mostly alleviated these problems. A number of novel biomarkers are in developmental stage in recent years and some have shown promise in terms of earlier diagnosis and risk-stratification over and above existing biomarkers. None are yet ready for regular use. A brief account of most promising of these biomarkers is presented in the following table.

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 39 Table 2.1: Biomarkers in ACS. Biomarker

Clinical application

Special characters

hs-CRP

Plaque destabilization

Acute phase reactant, elevated several times more in necrosis than stable CAD

Myeloperoxidase

Plaque destabilization

Degranulation product of WBC, responsible for development of lipid-laden soft plaque, marker of inflammation

MMP-9

Plaque destabilization

Localized in the plaque shoulder, the thinner area prone to rupture. Proximal biomarker for cardiac remodeling

sCD40L

Plaque destabilization

Signaling protein that reflects both inflammatory and platelet interactions with the plaque

PAPP-A

Plaque destabilization

A member of IGF family, marker of incipient plaque rupture

PIGF

Plaque destabilization

Upregulated in atherosclerosis

IL-6

Plaque destabilization

Cytokine involved in pathogenesis of ACS

Ischemia modified albumin

Ischemia

Strong negative predictive value for ischemia even prior to necrosis

Glycogen phosphorylase BB

Ischemia

Ischemia makes it soluble, rises 1–4 hour after onset of chest pain, elevated up to 1–2 days

Fatty acid binding proteins

Ischemia, acute heart failure

Heart type FABP (H-FABP) appears in the blood soon after onset of infarction (within 2–3 hours after MI) and returns to the normal range within 12–24 hours

Unbound free fatty acids

Ischemia

Determined by total serum FFAs/ total serum albumin, increased due to catecholamine stimulated lipolysis

Phospholipase enzymes A-D, Lp-associated PLA2

Ischemia

Correlates to level of LDL

hs-cTn

Early necrosis

As above

Myoglobin

Early necrosis

As above

CK-MB2

Early necrosis

As above

CK-MB

Late necrosis

As above

Heart failure

Established marker for HF, class IIbB for diagnosis and IB for prognosis in NSTEMI

nT-ProBNP

Heart failure

0030DWUL[PHWDOORSURWHLQDVHV&'/6ROXEOHOLJDQGIRU&'3$33$3UHJQDQF\DVVRFLDWHGSODVPDSURWHLQ$3,*)3ODFHQWDOJURZWKIDFWRU,/,QWHUOHXNLQ-KV&53+LJKVHQVLWLYLW\ &UHDFWLYHSURWHLQ&$'&RURQDU\DUWHU\GLVHDVH$&6$FXWHFRURQDU\V\QGURP/'//RZGHQsity lipoprotein. Mid-regional pro-adrenomedullin, growth differentiation factor 15, is also being considered as possible new biomarker.

RISK STRATIFICATION IN UA/NSTEMI The initial medical history, physical examination, ECG, assessment of renal function and cardiac biomarker measurement in patients with symptoms suggestive of ACS can be integrated into an estimation of risk. It is useful in selection of the site of care and selection of initial medical and interventional

40 The Protocol Book for Intensive Care therapies. The TIMI, GRACE and PURSUIT risk scores have been developed for short- and long-term risk assessment. TIMI Risk Score tool, composed of 7 (1 point) risk indicators rated on presentation, has been developed and validated for UA/NSTEMI patients. It is useful to predict both 30 days and 1 year mortality. History • Age ≥ 65 years • More than or equal to 3 CAD risk factors • Known CAD (stenosis ≥ 50%) • ASA in past 7 days

Presentation • Recent severe angina (at least 2 episodes over last 24 hours) • ↑Cardiac markers • ST deviation more than or equal to 0.5 mm

TIMI Risk Score 0–2 points: Low risk TIMI Risk Score 3–4 points: Intermediate risk TIMI Risk Score 5–7 points: High risk GRACE Risk Score is based on a large unselected population of an international registry with a full spectrum of ACS patients. Table 2.2: GRACE prediction score card. Medical history 1.

2.

3.

Age in years

Points

Findings at initial hospital presentation

Findings during hospitalization

4.

7.

Resting heart rate points beats/min

Initial serum creatinine mg/dL

Points

≤ 29

0

30–39

0

< 49.9

0

0–0.39

1

40–49

18

50 69.9

3

0.4–0.79

3

50–59

36

70–89.9

9

0.8–1.19

5

60–69

55

90–109.9

11

1.2–1.59

7

70–79

73

110–149.9

23

1.6–1.99

9

80–89

91

150–199.9

35

2–3.99

15

≥ 90

100

> 200

43

>4

20

History of congestive heart failure

24

History of myocardial infarction

12

5.

6.

Systolic blood pressure < 79.9

24

80–99.9

22

100–119.9

18

120–139.9

14

140–159.9

10

160–199.9

4

> 200

0

ST-segment depression

11

8.

Elevated cardiac enzymes 15

9.

No. in-hospital precutaneous coronary intervention

14

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 41 Table 2.3: Total risk score = Sum of points. GRACE risk score

in-hospital riskstratification

GRACE risk-score

Postdischarge to 6 months risk stratification

< 108

Low

< 108

Low

109–140

Intermediate

89–118

Intermediate

> 140

High

> 118

High

A GRACE 2.0 medical app is available online to calculate this score easily without serum creatinine or Killip class using the ‘mini-GRACE’ algorithm. GRACE 2.0 risk score makes it possible to assess risk of in-hospital and 1 and 3 years’ risk of death. It is applicable to both ST-elevation and non-STelevation ACS. The PURSUIT risk model was developed on the basis of the PURSUIT trial and it is another useful tool to predict the 30-day incidence of death and composite of death and MI. The markers included in the risk model (in order of strength) are: (1) Age, (2) heart rate, (3) systolic blood pressure, (4) ST-segment depression, (5) signs of heart failure and (6) cardiac biomarkers. Cardiac Rhythm monitoring is indicated for less than 24 hours or till revascularization for low-risk patients, and more than 24 hours in an intensive care setup for patients at high risk for arrhythmias.

INITIAL MANAGEMENT OF NSTE-ACS General Measures A randomized comparison of oxygen versus air administration in 441 normoxemic patients with STEMI in the AVOID trial showed no benefit and possibly harm associated with oxygen administration. Oxygen should be administered only when blood oxygen saturation is less than 90% or if the patient is in respiratory distress. Opiates should be added if pain is not relieved by nitrates alone.

Nitrates Intravenous (IV) nitrates are more useful than sublingual ones in an acute presentation (ESC Class IC). IV Glyceryl trinitrate should be started and carefully up-titrated keeping a check on the blood pressure and till any side effects appear. They are only indicated for symptom control and may be stopped once pain recedes. The last dose of any phosphodiesterase 5 inhibitor, if taken, should be 24 hours apart, as it poses the risk of severe hypotension.

Other Anti-Ischemic Therapies •

Ranolazine: It exerts antianginal effect by inhibiting late sodium current. MERLIN-TIMI-36 trial showed ranolazine was safe and reduced recurrent

42 The Protocol Book for Intensive Care Flowchart 2.2:,QLWLDOKRVSLWDOPDQDJHPHQWRI167($&6

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•

ischemic events but did not reduce composite of death or MI. It is indicated alone or in combination with nitrates, beta blockers or amlodipine for the treatment of chronic refractory angina. Nicorandil: It is a K-ATP channel opener. A pilot double blind, placebocontrolled study of 245 patients with UA/NSTEMI showed that when nicorandil was added to conventional treatment the number of episodes of transient myocardial ischemic and different tachyarrhythymias was significantly reduced. Further trials are underway; for patients with refractory angina nicorandil can be added as IV infusion at the rate of 2–6 mg/ hour. Unlike classical nitrates, hemodynamic tolerance does not develop with prolonged use of nicorandil.

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 43

•

•

Ivabradine: Ivabradine selectively inhibits the primary pacemaker current in the sinus node and may be used in patients with beta blocker contraindication. Trimetazidine and perhexiline: Trimetazidine and perhexiline exert metabolic effects without hemodynamic changes.

Beta Blockers Beta blockers are recommended in absence of contraindications particularly in patients with hypertension or tachycardia. Two separate meta-analyses for use of beta blockers in ACS showed a reduction in risk of 13% and 8%. However, there was increased mortality due to cardiogenic shock when used in age more than 70 years, heart rate more than 110 beats/minutes, systolic blood pressure less than 120 mm Hg within the first 24 hours, so early use of beta blockers are best avoided in such patients. Patients on chronic beta blocker therapy admitted with ACS should be continued on beta blocker therapy if not in Killip Class !III (ESC Class IB). Oral beta blocker treatment is indicated in all patients with LV dysfunction without contraindication (ESC Class IB). IV beta blockers may be considered in stable hemodynamic state with hypertension and tachycardia (ESC Class IIaC). IV beta blockers: • Esmolol (50–300 mg/kg/minutes) • Metoprolol (5 mg every 5 minutes) • Atenolol (5 mg IV) (monitor H/R, BP, ECG, rales, rhonchi). Oral beta blockers: • Metoprolol (50–200 mg BD) • Propranolol (80–320 mg 2–4 dose) • Atenolol (25–100 mg OD) • Bisoprolol (5–20 mg OD). Target heart rate: 50–60/minutes

Calcium Channel Blockers (Verapamil and Diltiazem) •

For symptom-relief in patients already on nitrates and beta blockers (ESC Class IB) and in patients with contraindications to beta blockers (ESC Class IIaB) • Vasospastic angina Nifedipine or other dihydropyridines should not be used unless combined with beta blockers.

ANTIPLATELET TREATMENT IN NSTE-ACS Antiplatelets are the mainstay of ACS management but pose a bleeding risk, which must be minimized.

44 The Protocol Book for Intensive Care The Can Rapid Risk Stratification of UA Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) bleeding risk score was developed from a cohort of 71,277 patients for assessing the likelihood of an in-hospital bleed. The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) also looked at 30-day nonCoronary Artery Bypass Graft (CABG) related major bleeds and subsequent 1-year mortality. Overall, they gave reasonable predictive value for major bleeds in ACS patients undergoing coronary angiography, with CRUSADE being more discriminatory.

Aspirin It remains the gold standard of antiplatelet therapy. Aspirin irreversibly inhibits TXA2 production by inhibiting cyclo-oxygenase-1 (Cox-1) enzyme thereby diminishing platelet aggregation. Four clinical trials in the pre-Percutaneous coronary intervention (PCI) era with differing designs and aspirin doses (75– 1,300 mg daily) have shown 46% reduction in odds ratio of death or MI in patients presenting with UA (NSTEMI) treated with aspirin up to 2 years. The Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS-7) trial showed no improvement of high dose (300–325 mg) aspirin over 75–100 mg. The Antiplatelet Trialists’ meta-analysis also found the risk reduction did not significantly differ among aspirin doses ranges from 75 to 1,500 mg/day. The risk of bleeding was seen to rise when daily dose exceeded 200 mg. Thus, a dose of 75–162 mg daily could be the optimal dose for long-term therapy and should be taken indefinitely. However, a loading dose of 150–300 mg (non-enteric coated and chewed) is recommended (Class IA). Absolute contraindications of aspirin therapy are aspirin allergy, active bleeding or a known platelet disorder. Clopidogrel is an alternative to aspirin in case of aspirin intolerance. Aspirin resistance: Although it is often used to describe failure of aspirin to prevent vascular events in some patients, yet it actually means that there is failure of aspirin to inhibit TXA2 production. It might result from non-compliance, inadequate dose, poor absorption or rapid metabolism and systemic interference with aspirin access to the active site of COX-1 enzyme.

Clopidogrel •

•

Based on CURE trial results, 300 mg of Clopidogrel as loading dose followed by 75 mg/day as maintenance dose is indicated in all NSTE-ACS patients with aspirin (Class IB). Patients undergoing PCI (PCI-CURE trial) also benefited from clopidogrel; although bleeding risk was increased, reduction of

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 45

ischemic complications overweighed the bleeding risk. Aspirin dose reduction to 75–100 mg/day in combination with clopidogrel reduces bleeding risk. • In ARMYDA-2 study, use of a 600 mg loading dose of clopidogrel 4–8 hours prior to planned PCI was associated with a reduction of the composite endpoint (death/MI/target vessel revascularization) within 30 days as compared with the standard loading dose of 300 mg. • In ALBION study too, higher loading doses of 600 and 900 mg of clopidogrel in NSTE-ACS induced higher levels of inhibition on platelet aggregation with a faster onset of action; however, no reduction of ischemic complications or increase in bleeding risk was noted. Currently, 900 mg loading dose is not recommended for routine clinical use. • CURE study showed a trend toward increased bleeding rates in patients undergoing bypass grafting in whom clopidogrel was not discontinued 5 days prior to the procedure. In the more recent CURRENT OASIS-7 trial, 25,086 patients with an ACS who were referred for an invasive strategy were randomized to either doubledose clopidogrel (a 600 mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300 mg loading dose and 75 mg thereafter) and either higher dose aspirin (300–325 mg daily) or lower dose aspirin (75–100 mg daily). The primary outcome was cardiovascular death, MI or stroke at 30 days. No significant difference was noted between a 7-day, double-dose clopidogrel regimen and standard regimen, or between higher dose aspirin and lower dose aspirin in terms of the primary outcome. However, in distinction to aspirin, there was a key sub-group of interest; among patients who underwent PCI those who received higher-dose clopidogrel (600 mg loading dose, 150 mg once daily) seemed to benefit. In this population, there was a 15% overall reduction in the primary endpoint of cardiovascular death, MI or stroke again with a small penalty to be paid with an increased rate of bleeding, but no major excess in the more severe bleeding categories. Dual antiplatelet therapy (DAPT) is thus better than aspirin alone, but up to 10% of patients treated with the combination of aspirin and clopidogrel will have a recurrent ischemic event in the first year after an ACS, with a rate of stent thrombosis of up to 2%, possibly due to insufficient platelet inhibition. Monitoring antiplatelet therapy with platelet function tests may identify poor responders who would benefit from a change in therapy, such as a dosage increase. Gold standard to monitor clopidogrel is the vasodilatorstimulated phosphoprotein (VASP) assay due to its P2Y12 selectivity and the fact that it does not require pretreatment measurement. In contrast to the VASP assay, light transmission aggregometry (LTA) requires pretreatment measurement. ‘Verify now’ was developed as a point of care, whole blood, semiautomated, cartridge-based platelet function test to determine the

46 The Protocol Book for Intensive Care response to antiplatelet agents (both aspirin and clopidogrel). The platelet function analyzer PFA-100 can be used to identify patients with severe platelet defects or von Willebrand disease. Despite availability of several tests, it is however still unclear whether results of platelet function tests can be used in clinical decision-making. Clopidogrel involves several cytochrome P (CYP450) isoenzymes, especially CYP 2C19 for conversion to active metabolic R130964. This major genetic polymorphism is associated with loss of function: CYP2C19*1, CYP2C19*2 and CYP2C19*3. The CYP2619*3 accounts for 99% of Asians. Selective and limited approach to platelet genotype assessment and platelet function testing is needed until better clinical evidence exist (Class IIb recommendation).

NEWER THIENOPYRIDINE DERIVATIVES: NEWER ANTIPLATELET DRUGS Prasugrel: It provides more profound and faster antiplatelet effect than clopidogrel. TRITON-TIMI38 demonstrated reduction in ischemic events with prasugrel, but an increase in major bleeding episodes compared with clopidogrel (0.4% vs 0.1%; P = 0.0002). There was overall 13% better outcome with prasugrel and 52% lesser incidence of stent thrombosis (both early and late). Excess bleeding with prasugrel was not seen in diabetes which can probably be explained by the fact that platelets are known to be more hyperactive in diabetics. In PRINCIPLE-TIMI 44 and ACAPULCO studies, prasugrel achieved higher levels of platelet inhibition. Prasugrel should be considered in patients who present with stent thrombosis despite compliance with clopidogrel therapy. It is contraindicated in prior stroke/TIA, and has no added benefits for more than 70 years of age and at body weight less than 60 kg. Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial showed similar risks and benefit as clopidogrel. Ticagrelor: It is reversible inhibitor of P2Y12 receptor with a half-life of approximately 12 hours. A large clinical trial, PLATO (platelet inhibition and patient outcomes), compared ticagrelor with clopidogrel in approximately 18,000 ACS patients, with primary endpoint of cardiovascular death, MI and stroke at 12 months. Results of PLATO trial reported that ticagrelor reduced the primary composite of vascular death, nonfatal MI, or nonfatal stroke compared with clopidogrel, while achieving a similar safety profile. Of note, the use of this agent was shown to be associated with an increase in two adverse events, dyspnea and ventricular pauses. These side effects were of mild-to-moderate intensity and also occurred in patients with clopidogrel. Both Prasugrel and Ticagrelor have a Class IB indication of use in ACS.

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 47

Cangrelor: A potent, short-acting IV ATP-analogue P2Y12 receptor inhibitor has rapid onset of action and also has reversibility. Three large randomized clinical trials have tested Cangrelor in PCI (CHAMPION PCI, CHAMPIONPHOENIX and CHAMPION-PLATFORM) with a composite primary endpoint of death, MI and urgent target vessel revascularization at 48  hours. In CHAMPION PCI, Cangrelor administered intravenously 30 minutes before PCI and continued for 2 hours after PCI, was not superior to 600 mg of oral loading of clopidogrel in reducing composite endpoint of death from any cause, MI or ischemia-driven revascularization at 48 hours. In the most recent CHAMPION PHOENIX trial, Cangrelor significantly reduced rate of ischemic events, including stent thrombosis during PCI (both urgent and elective) compared with clopidogrel (600 mg or 300 mg). Primary endpoints of composite of death, MI, ischemia driven revascularization or stent thrombosis were significantly lowered in cangrelor arm by 22% and this was mainly contributed by significant risk reduction in periprocedural MI (20%) and stent-thrombosis (38%). Cangrelor was not associated with an increase in bleeding complications and has been granted marketing authorization since March 2015.

Thrombin-Receptor Antagonist (TRAS) Vorapaxar (Formerly SCH 530348) is a TRA that blocks platelet protease activated receptor-1. A recent trial (TRA 2P–TIM150) by Morrow et al. found no change in all cause mortality while decreasing the risk for cardiovascular death and ischemic events and increasing risk for major bleeding.

GLYCOPROTEIN IIB/IIIA INHIBITORS There are three IV platelet glycoprotein (GP) IIb/IIIa receptor antagonists that have been approved for use in ACS. 1. Abciximab: It is the Fab fragment of the chimeric human-murine monoclonal antibody c7E3. 2. Eptifibatide: It is a nonimmunogenic cycle heptapeptide with an active pharmacophore that is derived from the structure of barbourin, a platelet GP II/b/IIIa inhibitor from the venom of the southeastern pygmy rattlesnake. 3. Tirofiban: It is a tyrosine derivative with a molecular weight of 495 kd and is a nonpeptide inhibitor (peptidomimetic) of the platelet GP IIb/IIIa receptor.

GP IIb/IIIa inhibitors in a consecutive strategy All three GP IIb/IIIa inhibitors were tested in trials where an invasive strategy was not encouraged. • A meta-analysis including 31,402 NSTE-ACS patients treated in clinical trials using GP IIb/IIIa inhibitors showed a 9% significant risk reduction for death and MI at 30 days with GP IIb/IIIa inhibitors (11.8% vs 10.8%).

48 The Protocol Book for Intensive Care Table 2.4: 5LVN6WUDWL¿FDWLRQRISDWLHQWVZLWK8$ Feature:

High risk: (At least 1 of the following features must be present)

Intemediate risk: (No high-risk feature but must have 1 of the following)

History

Accelerating tempo of ischemic symptoms in preceeding 48 hours

Prior MI, peripheral or cerebrovascular disease, or CABG prior aspirin use

Character of pain

Prolonged ongoing (!20 minutes) rest pain

Prolonged (!20 min) rest angina, now resolved, with moderate or high likelihood of CAD, Rest angina (20 min) or relieved with rest or sublingual nitroglycerin

Clinical findings

Pulmonary edema, most likely due to ischemia; New or worsening MR murmur; S3 or new/worsening rales Hypotension, bradycardia, tachycardia

Age > 70 years

Electrocardiogram

Angina at rest with T-wave inversions > transient; 0.2mV, pathological ST-segment changes Q waves ! 0.05 mV; Bundle-branch block, new or presumed new; Sustained ventricular tachycardia

Cardiac markers

Elevated (e.g., TnT or Tnl > ng/mL)

Low risk (No high- or intermediaterisk feature but may have any of the following features)

New-onset or progressive Canadian Classification System (CCS) Class III or IV angina in previous 2 weeks without prolonged (! 20 min) rest pain, but with moderate or high likelihood of CAD

Normal or unchanged ECG during an episode of chest discomfort

Slightly elevated (e.g., Normal TnT > 0.01 but < 0.1 ng/mL)

7DEOHUHSURGXFHGZLWKSHUPLVVLRQIURP/HSRU1(5HY&DUGLRYDVF0HG6XSSO 6±6 (VWLPDWLRQRIWKHVKRUWWHUPULVNVRIGHDWKDQGQRQIDWDOFDUGLDFLVFKHPLFHYHQWVLQXQVWDEOHDQJLQD LVDFRPSOH[PXOWLYDULDEOHSUREOHPWKDWFDQQRWEHIXOO\VSHFL¿HGLQDWDEOHVXFKDVWKLVWKHUHIRUH WKLVWDEOHLVPHDQWWRRIIHUJHQHUDOJXLGDQFHDQGLOOXVWUDWLRQUDWKHUWKDQULJLGDOJRULWKPV 0,P\RFDUGLDOLQIDUFWLRQ&$%*FRURQDU\DUWHU\E\SDVVJUDIW&$'FRURQDU\DUWHU\GLVHDVH17*: QLWURJO\FHULQ05: mitral regurgitation; ECG: electrocardiogram; TnT: Troponin T; TnI: Troponin I. Source:-,QYDVLYH&DUGLoO‹+HDOWK0DQDJHPHQW3XEOLFDWLRQV,QF

•

In GUSTO-4-ACS trial, 7,000 patients on aspirin and UFH were randomized to one of the three drug regimens: (1) placebo, (2) abciximab bolus plus 24 hours infusion and (3) abciximab bolus plus v48 hours infusion. No significant benefit was demonstrated for the two groups treated with abciximab and an increased bleeding risk was observed.

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 49

•

In PURSUIT trial comparison involved high-dose eptifibatide regimen versus placebo, although significant benefit was observed in eptifibatide arm, chance of bleeding risk was more. Tirofiban has been tested in two separate trials: 1. In PRISM trial, tirofiban showed significant reduction in the composite endpoint of death. MI or refractory ischemia than UFH up to 30 days but not beyond that. 2. In PRISM-Plus trial which considered higher risk patient than PRISM trial were randomized to three different arms: (1) Tirofiban alone, (2) tirofiban plus UFH or (3) UFH alone. The tirofiban alone arm was stopped soon after the start of trial because of an excess adverse event but tirofiban + UFH group showed significant reduction of the risk of death, MI and refractory ischemia compared with UFH alone.

GP IIB/IIIA inhibitors in an Invasive Strategy Consistent results have been obtained in three different meta-analysis exploring the impact of the use of GP IIb/IIIa inhibitors in the setting of PCI. • The meta-analyses showed that a significant risk reduction for death and MI at 30 days could be achieved when GP IIb/IIIa inhibitors were administered before taking patients to the catheterization laboratory and maintained during PCI. • In CAPTURE, in patients with UA/NSTEMI and planned PCI were pretreated with abciximab for 24 hours and maintained for 12 hours. Trial results showed without routine use of stents and clopidogrel, abciximab significantly reduced rate of death, MI and need for urgent intervention for recurrent ischemia when compared with placebo at 30 days (11.3% vs 15.9%, P = 0.012). The benefit was restricted to patients with elevated TnT levels. • In ISAR-REACT-2 high-risk NSTE-ACS patients were randomized following pretreatment with aspirin and 600 mg clopidogrel to either abciximab or placecbo. Abciximab-treated patients showed significantly lower target vessel revascularization, death or MI compared with placebo (8.9% vs 11.9%, P = 0.03) and the effect was more pronounced in troponin-positive patients. • ESPRIT trial showed that when eptifibatide was used as a bolus of 180 μg/kg followed by an infusion of 2.0 μg/kg/minutes for 18–24 hours, it caused significant reduction of death, MI, urgent TVR than placebo in patients undergoing PCI. • In RESTORE trial, patients presenting with ACS who underwent PCI within 72 hours of presentation were treated with heparin and aspirin with the addition of tirofiban or placebo. Treatment with tirofiban showed reduction in the short-term rate of death, MI or revascularization for failed PTCA or recurrent ischemia without an increase in major bleeding.

50 The Protocol Book for Intensive Care •

The ACCOAST trial disproved need of pretreatment with prasugrel in patients planned for PCI.

GP IIB/IIIA Inhibitors and CABG Inhibition of platelet aggregation may result in bleeding complications, either spontaneously or at the time of cardiac surgery. GP IIb/IIIa inhibitors should be discontinued at the time of cardiac surgery. Eptifibatide and tirofiban have a short half-life and hence platelet function should be expected to recover by the end of CABG. Abciximab has a longer effective half-life and earlier discontinuation may be needed.

Adjunctive Therapy Several trials in the field of NSTE-ACS, as well as observational studies in PCI, have shown that low molecular weight heparin (LMWH), predominantly enoxaparin, can be safely used with GP IIb/IIIa inhibitors without compromising efficacy. In OASIS-5, GP IIb/IIIa inhibitors were used with aspirin, clopidogrel and fondaparinux in 1,308 patients or enoxaparin in 1,273 patients. Overall bleeding complications were lower with fonxaparinux than with enoxaparin. The ISAR-REACT-2 STUDY showed that better outcome can be obtained with abciximab added to pretreatment with aspirin and a 600 mg loading dose of clopidogrel when compared with only aspirin plus clopidogrel in the students of high-risk PCI patients with UA/NSTEMI. ACUITY trial showed bivalirudin with combination of GP IIb/IIIa inhibitor has higher bleeding risk than bivalirudin alone.

What is the best time to initiate therapy? (Upstream or in the catheterization laboratory) Two randomized trials have explored alternative dosing regimens with eptifibatide. 1. In the BRIEF-PCI trial, a short infusion of less than 2 hours was compared with the longer standard infusion of 18 hours. No differences were found between the two groups in terms of periprocedural myonecrosis or ischemic events at the end of 30 days; however, bleeding rates were higher in the standard infusion group (4.2% vs 1.0%, P = 0.02). 2. In the ACUITY timing trial, 9,207 patients in the 2GPI (GP IIb/IIIa inhibitors) arms (heparin with GPI and bivalirudin with GPI) underwent a second randomization to either early (at randomization) GPI or deferred selective GPI (at time of PCI). At 30 days, deferred GPI was associated with a non-significant greater rate of composite ischemia and major bleeding events were significantly reduced in this group.

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 51

In the EARLY-ACS trial, in 9,492 patients with high-risk NSTE-ACS undergoing angiography at 12–96 hours, the strategy of early, routine double-bolus eptifibatide followed by an infusion was compared with a strategy of initial placebo followed by provisional eptifibatide (at the operator’s discretion). Routine early eptifibatide was not superior to delayed provisional used and increased the risk of major bleeding and red-cell transfusions by 42% (P = 0.015) and 31% (P < 0.001), respectively. Thus, these trials do not support routine upstream use of GP IIb/IIIa inhibitors.

Is Addition of GP IIb/IIIa Inhibitors Necessary during PCI in Patients Pretreated with High-Dose Clopidogrel? This question cropped up when the results of ISAR-REACT study became available showing that low- and moderate-risk patients undergoing planned PCI pretreated with a 600 mg loading dose of clopidogrel at least 2 hours prior to the procedure may not benefit from administration of a GP IIb/IIIa inhibitor (death, MI, urgent TVR; placebo vs abciximab 4.0 vs 4.2%, P = NS). The ISAR-REACT-2 study had a design similar to ISAR-REACT but involved patients with ACS. Addition of abciximab to aspirin 500 mg and clopidogrel (600 mg at least 2 hours prior to PCI) was associated with a significant reduction in the primary endpoint (abciximab vs placebo, 8.9% vs 11.9%, RR = 0.75, P = 0.03), with the most pronounced difference in patients with a positive troponin test at baseline [for troponin (+), abciximab vs placebo, 13.1% vs 18.3%, RR = 0.71, P = 0.98]. There were no differences in the rate of major and minor bleeding events or urgent blood transfusions.

Can Direct Thrombin Inhibitors (DTI) Be Used as an Alternative to GP IIb/IIIa Inhibitors? This concept will be discussed in details in the section on DTI. In low-risk patients with NSTE-ACS, DTI offer an alternative to combination of UFH and GP IIb/IIIa inhibitors. The value of combined therapy with aspirin, clopidogrel and bivalirudin as an alternative to aspirin, clopidogrel, UFH and GP IIb/IIIa inhibitor in high-risk patients (NSTEMI) requires further randomized studies.

Duration of DAPT Current ESC recommendation is to continue DAPT for 1 year after ACS. Clopidogrel for the Reduction of Events During Observation (CREDO) trial and the PEGASUS TIMI 54 compared 1 month versus 1 yearlong DAPT with clopidogrel and ticagrelor respectively and found no interaction between ACS and therapy, thus recommending yearlong dual antiplatelet use. The DAPT study published in 2016 shows lower rates of stent thrombosis and recurrent MIs

52 The Protocol Book for Intensive Care in those treated with 30 months of DAPT following index event rather than 12 months. Trials like PRODIGY, RESET and OPTIMIZE have recommended 3–6 months while DES-LATE and EXCELLENT recommend longer than 12 months’ use of DAPT.

Oral Anticoagulation along with Antiplatelets (Duration and Safety) Around 6–8% of patients undergoing PCI may require OACs due to concomitant causes such as atrial fibrillation. Supported by the ZEUS trial, the 2015 ESC recommendations are to first calculate HAS-BLED score, and administer DAPT along with oral anticoagulants (VKA or NOAC) for 4 weeks in those with HAS-BLED more than or equal to 3 and 6 months for less than or equal to 2. After 1 year only OAC is to continue. Those with HAS-BLED less than or equal to 2 are recommended drug eluting stents, while individualization between BMS and DES may be made for that more than or equal to 3.

Antithrombin Treatment in Patients with NSTE-ACS Better anticoagulation regimens have been developed given the limitations of unfractionated heparin (UFH), which include its sometimes difficult to manage effects on coagulation, the need for repeated monitoring of coagulation, narrow therapeutic window, potential induction of platelet activation and risk of thrombocytopenia. The three new anticoagulants: (1) Enoxaparin, (2) fondaparinux and (3) bivalirudin have demonstrated improvements against UFH and represent new alternative therapies.

UNFRACTIONATED HEPARIN (UFH) UFH has long been the only thrombin inhibitor used in UA patients, despite the lack of definitive proven benefit over placebo in ACS patients treated with aspirin. One of the many recognized challenges of UFH therapy is achieving and maintaining a target level of anticoagulation. For this, frequent monitoring of the activated partial thromboplastin time (aPTT) is recommended. Duration of treatment of UFH: It is determined by the patient’s overall clinical status; however, in most instances a period of 48–72 hours is adequate. Weaning is recommended to minimize ‘rebound’ thrombin generation. Heparin-induced thrombocytopenia (HIT): It is a devastating complication that occurs in up to 5% of patients who receive IV UFH with a lower incidence when LMWH is utilized, ranging from 0.5 to 1.0%. HIT is due to formation of antibodies against a complex of heparin and platelet factor 4 and it results in disseminated thrombotic vascular occlusion (DVT, PE, MI, stroke, etc.).

(Contd.)

Dosage

Use for PCI

Use for medical treatment for ACS

Extended (2 h)

++ UA/NSTEMI 0.4 μg/kg /min IV for 30 min followed by 0.1 μg/kg/min IV infusion x at least 48 hrs. Maximum duration: 108 hrs. If PCI performed, continue infusion through angiography and continued x 12–24 hrs postangioplasty/ atherectomy. PCI w/o prior treatment for UA/ UNSTEMI 10 μg/kg/kg IV administered over 3 min immediately prior to procedure followed by 0.15 μg/kg/min IV infusion x 26 hrs.

+++ UA/NSTEMI 180 μg/kg/IV bolus over 1–2 min Followed by 2 μg/kg/min continuous IV x 72–96 hrs. If PCI is performed during therapy, continue for 18–24 hrs post PCI. PCI without prior Rx for UA/NSTEMI 180 μg/kg IV bolus x 2 doses 10 min apart then, 2 μg/kg/min IV x 18–4 hrs.

0,25 meg/kg as IV bolus (over 1 min) 0.125 μg/kg/min as continuous infusion Maximum dose: 10 μg/min For stabilization of UA Start the bolus dose, followed by IV infusion up to 24 hrs prior to possible intervention and then stop 12 hrs after intervention For the prevention of ischemic cardiac complication related to PCI Start the bolus dose 10-60 min prior to the intervention followed by the infusion for 12 hrs.

+++

+++

–4 hrs

Short (S)> 250

+++

–4 hrs

Short (5) 250–2500

~500

Nonpeptide

Tirofiban

++*

12 hrs

Extended (2 h)

Short (min) Long (h) 1.5–2.0

Plasma half-life

Platelet bound half-life

Drug to GF IIb/III a receptor ratio 50% return of platelet function (without transfusion)

~800

~50,000

Molecular weight

Eptifibatide Peptide

Abciximab Antibody

Characteristic

Type

Table 2.5: Comparison of GP IIb/IIIa receptor inhibitor

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 53

8$ 8QVWDEOH DQJLQD 167(0, QRQ67HOHYDWLRQ P\RFDUGLDO LQIDUFWLRQ 3&, 3HUFXWDQHRXV FRURQDU\ LQWHUYHQWLRQ

+++ Marked benefit; ++ Moderate benefit; *Refractory angina if PCI performed within 12 hrs **Monitor platelet counts prior to therapy, 2–4 hrs after bolus and at 24 hrs ***Monitor platelet count, Hb, Hct prior to therapy, 6 hrs after bolus and then daily.

Hypersensitivity

Peripheral edema

Fever and chills

Rash

Nausea

Pain in extremities

Hypotension

Headache

Hypersensitivity (Anaphylaxis, rash, urticaria)

Nausea, vomiting

Thrombocytopenia**

Bleeding

Dosage adaptation is required in renal failure. Fifty percent of the dose only If CrCI  30 mL/min.

Bradycadia

Bleeding Hypotenslon

Bleeding

Adverse reactions

Since 50% cleared through kidney, infusion dose should be reduced to 1 μg/kg/min in such patients. Dose of bolus remains unchanged at 180 μg/kg. Eptifibatide is contraindicated in patients with a.cr.a 30 mL/min.

Thrombocytopenia**

No specific recommendations for use or for dose adjunstment in case of renal failure.

Dosage in chronic kidney disease

(Contd.)

54 The Protocol Book for Intensive Care

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 55 7DEOH3DWLHQWVSHFL¿FKHSDULQGRVLQJQRPRJUDP aPTT

Repeat aPTT

Repeat bolus**

Rate change

35 second

60 u/kg

↑ 4 u/kg/hour

4 hour

35–49 second

30 u/kg

↑ 3 u/kg/hour

6 hour

50–70 second***

0

No change

6 hour

71–90 second

0

↓ 2 u/kg/hour

6 hour

!90 second

0

↓ 3 u/kg/hour

4 hour

a

PTT: Activated partial thromboplastin time. “Initial dose: 60 u/kg bolus (not to exceed 5,000 u); maintenance infusion: 15–18 u/kg/hour. Begin infusion at < 1,200 u/hour ** Patients > 65 years of age and those receiving fibrinolytics and/or GP IIb/llla antagonists have reduced heparin requirements (bolus and infusion) *** Target range (for acute coronary syndrome).

Treatment: • Stop heparin including LMWH • Lepirudin: IV bolus of 0.4 mg/kg; continuous infusion 0.15 mg/kg/hour • Argatroban: Continuous IV infusion 2 μg/kg/minutes.

LOW MOLECULAR WEIGHT HEPARIN (LMWH) Necessity of close monitoring of anticoagulant activity, as well as a high incidence of HIT encouraged the development of alternative antithrombin strategies, namely LMWH. Several randomized clinical trials have compared the efficacy and safety of LMWH (Enoxaparin, Dalteparin, Fraxiparine) and UFH among initially medically managed patients presenting with ACS. Among those, enoxaparin was the only LMWH to demonstrate a significant and sustained benefit over UFH; in the meta-analysis of TIMI 11B and ESSENCE trials, enoxaparin was associated with a significant reduction of death and MI at 8, 14 and 43 days. Dosage in NSTE-ACS: Enoxaparin: 1 mg/kg SCq12 hours (Class IB) Dalteparin: 120 IU/kg SCq12 hours Chronic kidney disease: GFR 10–50 mL/minutes—usual dosage GFR less than 10 mL/minutes—50% of usual dosage or avoid Monitoring: No routine laboratory monitoring is required except platelet count at baseline and periodically thereafter. However, in certain clinical settings (e.g. renal insufficiency, severe obesity), an anti-Xa level can be measured. Commonly accepted therapeutic range is 0.5–1.0 anti-Xa units/mL.

FONDAPARINUX Fondaparinux is a synthetic pentasaccharide and is a specific inhibitor of factor Xa activity. Its pharmacokinetic properties allow for a simple, fixed

56 The Protocol Book for Intensive Care Flowchart 2.3 $OJRULWKPIRUXVHRI/0:+IURP&&8WRFDWKODE

/0:+ /RZ PROHFXODU ZHLJKW KHSDULQ 8$ 8QVWDEOH DQJLQD 167(0, QRQ67HOHYDWLRQ P\RFDUGLDO LQIDUFWLRQ *3 *O\FRSURWHLQ 8)+ 8QIUDFWLRQDWHG KHSDULQ 3&, 3HUFXWDQHRXV FRURQDU\ LQWHUYHQWLRQ

dose, once daily regimen of subcutaneous injections, without the need for monitoring. In OASIS-5 trial, a total of 20,078 patients with NSTE-ACS received either fondaparinux (2.5 mg given SC once daily) or enoxaparin (1 mg/kg given SC twice daily) for a mean of 6 days. The number of patients experiencing death, MI or refractory ischemia at 9 days was similar between groups; however, the rate of major bleeding was reduced by 50% with fondaparinux and a composite of the primary outcome and major bleeding favored fondaparinux at 9 days. Fondaparinux was associated with a significantly reduced number of deaths at 30 days and 180 days. A subgroup analysis for both primary efficacy endpoint and major bleeding suggests that fondaparinux may be particularly beneficial among patients with impaired renal performance. In 6,207 patients of OASIS-5 undergoing PCI, a significant increase in rate of catheter thrombus was reported in fondaparinux treated patients compared with enoxaparin treated patients, although acute coronary complications remained similar. This serious drawback for PCI was also found in ASPIRE and OASIS-6 studies. The adjunct of a full dose of UFH has been recommended on top of the fondaparinux treatment to perform PCI to avoid this excess of risk in catheter thrombosis. OASIS-8 trial has supported the use of a standard dose of UFH prior to PCI in the patients pretreated with fondaparinux in preference to low-dose UFH.

Dosage of Fondaparinux in ACS: 2.5 mg Once Daily (Class IB) Dosage in patients with chronic kidney disease: Contraindicated in severe renal failure (CrCl  30 mL/minutes). However, as much lower risk of bleeding

No

Protamine

Antidote

None

1 mg/kg q12 h subcut

ACS

No

None

2.5 mg/day subcut

ACS

No

1,020 min

Renal

No

+/-

+/-

No

No

Synthetic peptide

Fondaparinux

8)+ 8QIUDFWLRQDWHG KHSDULQ$&6$FXWH FRURQDU\ V\QGURPH 3&, 3HUFXWDQHRXV FRURQDU\ LQWHUYHQWLRQ

PCI, ACS 70 u/kg IV bolus (max 5,000 u), then 12–15uAg/ hr (max 1,000 u/hr)

Yes

Dosage

270 min

60-90 min

Elimination t1/2

Anticoagulation monitoring

Indication

Renal

Endothelial and renal

Clearance

4/Reduced

No Yes

PF4 complexlng and risk of heparin induced thrombocytopenia

+/-

Inhibition of thrombin mediated platelet activation

No No

Inhibition of fibrin-bound thrombin

Yes

Action independent of antithrombin

Animal origin

Animal origin

Chemistry

Thrombin binding

Yes

Enoxaparin

UFH

Table 2.7: Major characteristics of the different anticoagulats.

None

0.75 mg/kg IV bolus followed by 1.75 mg/kg/hr IV infusion (REPLACE 2) or 1 mg/kg IV bolus followed by 2.5 mg/kg/hr IV infusion (ACUITY)

PCI

No

25 min

Proteolytic 20% renal

No

Yes

Yes

Yes

Bivalent reversible

Synthetic peptide

Bivalirudin

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 57

58 The Protocol Book for Intensive Care complications was observed in OASIS-5 with fondaparinux as compared with enoxaparin, even in patients with severe renal failure, this drug might be the anticoagulant of choice in this situation.

DIRECT THROMBIN INHIBITORS (DTIS) These include bivalent agents, such as hirudin, bivalirudin, lepirudin; and univalent ones such as argatroban, dabigatran, ximelagatran. The DTI hirudin has shown some promise in preventing early ischemic/ thrombotic events in patients with ACS in GUSTO-IIb and OASIS-2 studies. However, these efficacy results were balanced by an excess of major bleeding requiring transfusion with hirudin. The safety concerns were then raised against the use of hirudin and probably caused the interruption of further development of this agent. Bivalirudin (or hirulog) has been investigated more than 10 years ago as an adjunctive therapy for high-risk PCI and is now the only DTI labelled for PCI. After the dose-ranging studies, the REPLACE-1 and REPLACE-2 trials have shown that bivalirudin provided similar protection from ischemic events as UFH/enoxaparin plus GP IIb/IIIa inhibitors, with markedly reduced bleeding. On the basis of these preliminary studies, it appeared that bivalirudin has the safety and efficacy potential to replace UFH in treatment of ACS. Additional information in the contemporary setting of ACS was brought by the results of ACUITY trial. The study was designed to test the hypotheses that in moderate-to-high risk patients with ACS undergoing an invasive strategy, compared with UFH or LMWH + GP IIb/IIIa inhibitors, (i) bivalirudin + GP IIb/IIIa inhibitors will result in less adverse ischemic events and less bleeding (Class IA) and (ii) bivalirudin alone will result in similar rates of ischemic events and markedly reduced bleeding. Triple ischemic endpoint (death/MI/ urgent revascularization) occurred similarly among three treatment arms, satisfying the criteria of noninferiority of bivalirudin alone or with GPI compared with UFH/enoxaparin + GPI. Bivalirudin alone was found superior to heparin + GPI in reducing the incidence of major bleedings and in terms of net clinical outcome; bivalirudin was superior to heparin + GPI. In the ISAR REACT 3 Study, a head to head comparison of UFH and bivalirudin showed it to be non-inferior with comparable rates of death, MI and urgent revascularization at 30 days but reduction in bleeding with bivalirudin. In the HEAT PPCI trial, bivalirudin was compared with UFH in prepercutaneous coronary intervention (P-PCI) patients presenting with ACS. Compared with bivalirudin, heparin had reduced major adverse ischemic events, with no increase in bleeding manifestations and substantial reduction of cost. Dosage of bivalirudin: IV bolus of 0.1 mg/kg and infusion of 0.25 mg/kg/ hour. Additional IV bolus 0.5 mg/kg and infusion increased to 1.75 mg/kg/ hour before PCI.

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 59

Dosage in NSTE-ACS patients with chronic kidney disease: If the CrCl less than 30 mL/minutes, reduction of the infusion rate to 1.0 mg/kg/hour should be considered. If a patient is on hemodialysis, the infusion should be reduced to 0.25 mg/kg/hour. No reduction in the bolus dose is needed. The future may bring expanded use of DTIs. Despite many favorable features, ximelagatran was withdrawn because of evidence of hepatotoxicity. Currently, at least 7 DTIs are being evaluated in clinical trials involving deep venous thrombosis, ischemic heart disease and atrial fibrillation. The oral DTI dabigatran is clearly the leader in the path of development with major trials in all three arenas.

Newer Antithrombotics Factor Xa inhibitors: Currently, a number of IV and oral direct factor Xa inhibitors are in the process of clinical development. Some information on initial clinical results are already available with one parenteral (otamixaban) and several oral inhibitors of factor Xa: edoxaban apixaban, rivaroxaban, waroxaban and YM150. Results of a phase-2 study with otamixaban in the context of PCI have been published recently. In the recent ATLAS-ACS 2 trial, rivaroxaban reduced the risk of composite endpoint of death from CV causes, MI or stroke. It increased the risk of major bleeding and intracranial hemorrhage but not risk of fatal bleeding. In contrast in APRAISE-2 trial apixaban at a dose of 5 mg twice daily when added to high-risk patients after an ACS increased the number of major bleeding events without a significant reduction in recurrent ischemic events. The NICE draft has approved the use of rivaroxaban in ACS including both STEMI and NSTEMI as adjunctive therapy.

Newer Anticoagulants Apart from DTIs, other oral and parenteral anticoagulants are also under development. These agents can be divided into two groups based on their primary target in the coagulation cascade: (i) inhibitors of initiation of coagulation that target tissue factor, tissue factor VIIa complex and active site-blocked FVIIa. A parenteral recombinant protein (g NAAAP c2) has been successfully tested in phase-2 trial of patients of NSTE-ACS, (ii) inhibitors of the propagation of coagulation which target factor IXa, Xa or their respective cofactors (factor VIIIa, Va). These drugs are based on aptamer technology, single-stranded nuclei acids that can be tailored for specific targets with a high affinity.

Other Therapies Inhibitors of the Renin-angiotensin-aldosterone System In AMI patients GISS-3, ISIS-4, and trial found a 0.5% reduction in absolute mortality with ACE inhibitors initiated within 24 hours. The angiotensin

60 The Protocol Book for Intensive Care receptor blocker, valsartan has been found to be as effective as captopril in patients at high risk of CV events after MI. However, a combination of the two was found to be harmful. In patients with UA/NSTEMI it is recommended that in the absence of hypotension or other known contraindications, an ACE inhibitor (or angiotensin-receptor blocker in patients intolerant of ACE inhibitors) should be administered orally within the first 24 hours in to patients with pulmonary congestion or LVEF less than or equal to 0.04 (Class IA) and state that these can also be useful in patients without these features (Class IIaB for ARB; IIbB for ACEI). The selective aldosterone receptor blocker eplerenone, used in patients with MI complicated by LV dysfunction and either heart failure or diabetes, reduced morbidity and mortality in the EPHESUS trial and is indicated long term for patients without significant renal dysfunction or hyperkalemia.

Lipid-lowering Therapy A fasting lipid profile should be obtained within first 24 hours of admission for ACS. In the absence of contraindications, regardless of baseline lowdensity lipoprotein (LDL)-C levels, statins should be given to post-UA/ NSTEMI patients, including postrevascularization patients. The benefit was first observed in LIPID trial in which pravastatin led to 26% reduction immortality (P 0.004). In the PROVE-IT TIMI-22 trial, a 16% reduction in the hazard ratio for primary composite endpoint of all causes death, MI and stroke was seen with high dose atorvastatin 80 mg compared with standard dose pravastatin 40 mg in patients within 10 days of an ACS. In the IMPROVE-IT trial, ezetimibe when added to statin therapy in stable patients who had an acute coronary syndrome and who had LDL cholesterol within guideline recommendations further lowered the risk of cardiovascular events without any adverse events. Thus, lowering LDL-cholesterol to levels below previous targets (≤ 53.7 mg/dl in ezetimibe group) provided additional benefit).

Recommendations for Oral Antiplatelet Agents (ESC 2015 Guidelines) Aspirin should be given to all patients without contraindications at an initial loading dose of 150–300 mg, and at a maintenance dose of 75–100 mg daily long-term regardless of treatment strategy A P2Y12-inhibitor should be added to aspirin as soon as possible and maintained over 12 months, unless there are contraindications such as exercise risk of bleeding

Classa I

Levelb A

I

A

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 61

A proton pump inhibitor (preferably not omeprazole) in combination with DAPT is recommended in patients with a history of gastrointestinal hemorrhage or peptic ulcer, and appropriate for patients with multiple other risk factors (Helicobacter pylori infection, age t65 years, concurrent use of anticoagulants or steroids) Prolonged or permanent withdrawal of P2Y12 inhibitors within 12 months after the index event is discouraged unless clinically indicated Ticagrelor (180 mg loading dose, 90 mg twice daily) is recommended for all patients at moderate-to-high risk of ischemic events (e.g., elevated troponins), regardless of initial treatment strategy and including those pretreated with clopidogrel (which should be discontinued when ticagrelor is commenced) Prasugrel (60 mg loading dose, 10 mg daily dose) is recommended for P2Y12-inhibitor-naïve patients (especially diabetics) in whom coronary anatomy is known and who are proceeding to PCI unless there is a high risk of lifethreatening bleeding or other contraindications Clopidogrel (300 mg loading dose, 75 mg daily dose) is recommended for patients who cannot receive ticagrelor or prasugrel A 600 mg loading dose of clopidogrel (or a supplementary 300 mg dose at PCI following an initial 300 mg loading dose) is recommended for patients scheduled for an invasive strategy when ticagrelor or prasugrel is not an option A higher maintenance dose of clopidogrel 150 mg daily should be considered for the first 7 days in patients managed with PCI and without increased risk of bleeding Increasing the maintenance dose of clopidogrel based on platelet function testing is not advised as routine, but may be considered in selected cases Genotyping and/or platelet function testing may be considered in selected cases when clopidogrel is used In patients pretreated with P2Y12 inhibitors who need to undergo nonemergent major surgery (including CABG), postponing surgery at least for 5 days after cessation of ticagrelor or clopidogrel, and 7 days for prasugrel, if clinically feasible and unless the patient is at high risk of ischemic events should be considered

Classa I

Levelb A

I

C

I

B

I

B

I

B*

I

B

IIa

B

IIb

B

IIb

B

IIa

C

62 The Protocol Book for Intensive Care Ticagrelor or clopidogrel should be considered to be (re-) started after CABG surgery as soon as considered safe The combination of aspirin with an NSAID (selective COX-2 inhibitors and nonselective NSAID) is not recommended P2Y12 inhibition administration for a shorter duration of 3–6 months after DES Implantation may be considered in patients Demand at high bleeding risk P2Y12 inhibition administration in addition to aspirin beyond 1 year may be considered in patients deemed at high bleeding risk

Classa IIa

Levelb B

III

C IIb A

a

Class of recommendation Level of evidence COX: Cyclo-oxygenase; CABG: Coronary artery bypass graft; DAPT: Dual (oral) antiplatelet therapy; NSAID: Nonsteroidal anti-inflammatory drug; PCI: Percutaneous coronary intervention.

b

Recommendations for GP IIB/IIIa Receptor Inhibitors (ESC 2015 Guidelines) Classa

Levelb

In patients with NSTE-ACS and high-risk features, I not adequately treated with ticagrelor or clopidogrel, it is useful to administer a GP IIb/IIIa inhibitor at the time of PCI

A

Among patients who are already treated with DAPT, I the addition of a GP IIb/IIIa receptor inhibitor for high-risk PCI (elevated troponin, visible thrombus) is recommended if the risk of bleeding is low

B

Eptifibatide or tirofiban added to aspirin should be IIa considered prior to angiography in high-risk patients not preloaded with P2Y12 inhibitors

C

In high-risk patients eptifibatide or tirofiban may be IIb considered prior to early angiography in addition to DAPT, if there is ongoing ischemia and the risk of bleeding is low

C

GP IIb/IIIa receptor inhibitors are not recommended III routinely before angiography in an invasive treatment strategy

A

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 63

Classa GP IIb/IIIa receptor inhibitors are not recommended III for patients on DAPT who are treated conservatively a b

Levelb A

Class of recommendation Level of evidence

GP: Glycoprotein; DAPT: Dual (oral) antiplatelet therapy; LMWH: Lowmolecular-weight heparin; PCI: Percutaneous coronary intervention; UFH: Unfractionated heparin. Recommendations for Anticoagulants (ESC 2015 Guidelines) Classa

Levelb

Anticoagulation is recommended for all patients in I addition to antiplatelet therapy

A

The anticoagulation should be selected according to I both ischemic and bleeding risk, and accordingly to the efficacy-safety profile of the chosen agent

C

Fondaparinux (2.5 mg SC daily) is recommended as I having the most favorable efficacy–safety profile with respect to anticoagulation

A

If the initial anticoagulant is fondaparinux, a single I bolus of UFH (85 IU/kg adapted to Activated clotting time (ACT), or 60 IU in the case of concomitant use of GP IIb/IIIa receptor inhibitors) should be added at the time of PCI

B

Enoxaparin (1 mg/kg twice daily) is Recommended I when fondaparinux is not available

B

If fondaparinux or enoxaparin are not available, UFH I with a target aPTT of 50–70s or other LMWHs at the specific recommended doses are indicated

C

Bivalirudin plus provisional GP IIb/IIIa receptor I inhibitors are recommended as an alternative to UFH plus GP IIb/IIIa receptor inhibitors in patients with an intended urgent or early invasive strategy, particularly with a high risk of bleeding

B

In a purely conservative strategy, anticoagulation IIa should be maintained up to hospital discharge. Discontinuation of anticoagulation should be considered after an invasive procedure unless otherwise indicated

C

64 The Protocol Book for Intensive Care Classa Crossover of heparins (UFH and LMWH) is not rec- III ommended

Levelb B

a

Class of recommendations Level of evidence GP: Glycoprotein; DAPT: Dual A (oral) antiplatelet therapy; ACT: Activated clotting time; aPTT: Activated partial thromboplastin time; GP: Glycoprotein; LMWH: Low-molecular-weight heparin; PCI: Percutaneous coronary intervention; UFH: Unfractionated heparin. b

INVASIVE STRATEGIES AND REVASCULARIZATION Coronary Revascularization Procedures A number of randomized trials have been conducted in the content of increasing procedural experience, technological improvements in revascularization procedures and the development of new antiplatelet and anticoagulant regimen. Two general approaches have emerged from reviews of these studies: • Early invasive management: It involves routine cardiac catheterization and revascularization with PCI or CABG, depending on the coronary anatomy. It may be (a) immediate (< 2 hours or as quickly as possible after hospital presentation) in patients with NSTE-ACS with refractory angina or electrical instability, Class IA or (b) early (within 24 hours preferably, maximally up to 72 hours). • Early conservative management: It is the initial medical management with catheterization and revascularization carried out only if the patient demonstrates recurrent ischemia either at rest or on a noninvasive stress test. It is also termed as ‘ischemia guided’ or ‘selective invasive strategy.’

Comparison of Early Invasive and Conservative Strategies Nine randomized trials have assessed two general strategies, with first three trials demonstrating no significant difference, whereas the remaining six trials have shown a significant benefit of an early invasive strategy. A few selected trials are discussed here. TIMI-3B: A total of 1,473 patients were randomized to early invasive versus early conservative therapy. There was no difference in the rate of primary endpoint, death, MI or strongly positive exercise test at 6 weeks (16.2% in early invasive group vs 18.1% in conservative group, P = NS). Similarly, there was no difference in the incidence of death or MI at 6 weeks or 1 year (10.8% vs 12.2%, P = NS). VANQUISH: A total of 920 patients were randomized on the basis of CK-MB elevation within 72 hours of admission. More patients in the early invasive

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 65

group experience in-hospital death (21% vs 6%, P = 0.007) or a composite death or MI (36% vs 15%, P = 0.004); statistically differences persistent as 1 year and a trend toward higher mortality was still observed at 2 years. FRISC-II study: A total of 2,457 patients were enrolled with chest pain within the previous 48 hours plus either: (a) ST- or T-wave changes, (b) elevated troponin T or CK-MB. They received subcutaneous dalteparin in-hospital and then were randomized to an invasive versus conservative strategy. There was also a second randomization to prolonged (3 months) versus only in-hospital LMWH. The primary endpoint, death or MI at 6 months was significantly lower in the invasive versus conservative group (9.4% vs 12.1%, P = 0.031). Additional analysis showed greater benefit of the invasive strategy in higher risk group (ST-depression, Troponin-T positive). Five-year follow-up data are now available, and overall death or MI was lower with an invasive strategy (PR = 0.81, P = 0.009) but there was no significant difference in 5-year mortality. TACTICS-TIMI-18: This study used GP IIb/IIIa inhibitor tirofiban in all patients. Here, 2,220 patients were randomized to invasive therapy or conservative therapy. The primary outcome of death, nonfatal MI or rehospitalization for ACS at 6 months was 15.9% in invasive group and 19.4% in conservative group (P = 0.025). Using the TIMI risk score, there was significant benefit of the early invasive strategy in intermediate (score 3–4) and high-risk (5–7) patients, where low-risk (0–2) patients had similar outcomes when managed with either strategy. RITA-3: Enrolled 1,810 patients and randomized to early intervention and medical management group. At 4 months, the primary endpoint of death, MI, or refractory angina was significantly lower in earlier intervention group (9.6% vs 14.5%, P = 0.001). At 5-year follow-up, there was still significantly reduced death and MI in early invasive arm (P = 0.044). A meta-analysis of these five and two smaller trials found that the incidence of death or nonfatal MI in the invasive group was 1.2% versus 14.4% in the conservative group (P ≤ 0.001). VINO: This small study comprising 131 patients who showed significant reduction in death and MI in early intervention group compared with ischemia-guided strategy (6.2% vs 22.3%, P < 0.001). ISAR-COOL: This study was designed to determine whether prolonged antithrombotic pretreatment might improve the outcomes of patients undergoing routine invasive management. Total 410 patients were enrolled. All patients received UFH, aspirin, clopidogrel and tirofiban and were randomized to early (< 6 hours) or delayed (3–5 days) angiography or revascularization. The primary outcome of nonfatal MI or death occurred in 5.19% of the early invasive group compared with 11.6% of the delayed invasive group by 30 days (PR = 0.51, P = 0.04).

66 The Protocol Book for Intensive Care ICTUS: A total of 1,200 ACS patients with elevated troponin T level were enrolled. All patients were treated with optimal medical therapy that included aspirin, clopidogrel, LMWH and lipid-lowering therapy; abciximab was given to those undergoing revascularization. At 1 year, there was no significant difference in the rate of primary endpoint, death MI, or rehospitalization for angina in the invasive versus conservative strategy (22.7% vs 21.2%, P = 0.33). Three-year follow-up results of the ICTUS trial showed that an early invasive strategy was no better than a selective invasive strategy in reducing the rate of the primary endpoint (P = 0.09). TIMACS: This trial randomly assigned 3,031 non–ST-elevation ACS patients to routine early intervention (coronary angiography within 24 hours) or to delayed intervention (coronary angiography at 36 hours or more). Overall difference between two groups in terms of the primary endpoint (composite of death, MI or stroke) was not statistically different. However, early intervention reduced the composite of death, MI or refractory ischemia (secondary endpoint) and in high-risk patients, was superior to a delayed invasive strategy. On analysis of the clinical settings in which the trials were performed, it is conspicuous that the first three trials, TIMI IIIB, VANQUISH, and MATE, had no or negligible stent use, no clopidogrel before or after PCI and no GP IIb/ IIIa receptor antagonists. In this respect, they differ from the modern trials with substantial stent use and modern antiplatelet therapy. If only the trials of modern era are analyzed, the fixed effects model demonstrated a significant benefit with respect to death and MI at 6–12 months with the invasive strategy when compared with the conservative strategy. Nevertheless, there is still substantial heterogeneity, which can be largely attributed to ICTUS. In the random effects model, the point estimate for the odds ratio for death and MI at 6–12 months is more in favor of the invasive strategy. Among the markers of risk in NSTE-ACS, troponin-T is considered the most robust; however, ICTUS trial tells us that apparently not all patients with elevated troponins gain from revascularization. There appear to be some groups in which the initial hazard is not rewarded by a long-term benefit. There are two potential consequences from this conclusion. First, any effort should be made to reduce the early hazard of the intervention, for example, pretreatment with clopidogrel 600 mg. The second consequence would be to lay down criteria that identify patients who may not benefit from revascularization in ACS. Until there criteria are validated in appropriately sized clinical studies, it appears prudent to pursue the invasive strategy in most patients with high-risk NSTE-ACS, given the evidence from all previous trials. In addition, the results of the ISAR-COOL trial suggest that when pursuing the invasive strategy, intervention should be performed as early as possible because most cardiac complications occur within the first day after hospital

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 67

admission. TIMACS suggests that early invasive strategy within 12–24 hours (medium 14 hours) is preferred in high-risk patients, whereas a more delayed approach may be beneficial in low-to-intermediate risk patients. Michelangelo: OASIS-5 women’s substudy presented in 2007, worse outcome was reported with invasive strategy among women with NSTE-ACS. Women did not benefit from a routine invasive strategy (within 7 days). Similar trends have been reported by subgroup analysis of FRISC-II and RITA-3 in the past. This issue too needs to be addressed specifically in a separate large trial.

Indications of Immediate (< 2 Hours) Invasive Strategy Urgent coronary angiography and revascularization should be undertaken within 2 hours in the following patients (very high risk criteria): • Hemodynamic instability or cardiogenic shock • Recurrent or ongoing chest pain refractory to medical treatment • Life-threatening arrhythmias or cardiac arrest • Mechanical complications of MI • Acute heart failure • Recurrent dynamic ST- or T-wave changes, particularly with intermittent ST-elevation

Early Invasive Strategy (< 24 Hours) is Indicated for High-Risk Criteria • • •

Rise of fall in cTn compatible with MI Dynamic ST- or T-wave changes (symptomatic or silent) GRACE score more than 140

Invasive Strategy (< 72 Hours) is Indicated for Intermediate Risk Group Criteria • • • • • • •

Diabetes mellitus Reduced renal function (GFR < 60 mL/minutes/1.73 m2) Depressed LVEF less than 40% GRACE risk score more than 109 and less than 140 Early post-MI angina Prior PCI Prior CABG. An updated meta-analysis by Bonello et al. (2016) regarding timing of coronary invasive strategy in NSTE-ACS and clinical outcomes suggested that an early invasive strategy does not reduce the risk for death or MI compared with a delayed strategy. Recurrent ischemia and length of stay were however significant reduced with an early invasive strategy.

68 The Protocol Book for Intensive Care 7DEOH5LVNVWUDWL¿FDWLRQRISDWLHQWVZLWK86167(0,E\QRQLQYDVLYHWHVWLQJ High-risk (Annual mortality > 3%)

Intermediate risk (Annual mortality 1–3%)

Low-risk (Annual mortality < 1%)

Severe resting LV dysfunction (LVEF< 35%) High-risk treadmill score (score -11 or less) Severe-exercise LV dysfunction (Exercise LVEF 35%) Stress induced large perfusion defect (particularly If anterior) Stress induced multiple perfusion defects of moderate size Large, fixed perfusion defect with LV dilation or Increased lung uptake (Thallium 201) Stress-Induced moderate perfusion defect with LV dilation or increased lung uptake (Thallium 201) Echocardiography wall-motion abnormality (> 2 segments) developing at lowdosedobutamine(10 μg/kg/min or less or at low heart rate (< 120/min) Stress echocardiography evidence of extensive ischemia

Mild/moderate resting LV dysfunction (LVEF 35–49%) Intermediate risk treadmill score (–11 to 5) Stress induced moderate perfusion defect without LV dilation or increased lung intake (Thallium 201) Limited stress echocardiography ischemia with a wall-motion abnormality only at higher doses of dobutamine involving < 2 segments

Low-risk treadmill score (5 or greater) Normal or small myocardial perfusion defect at rest or with stress Normal stress echocardiography wall motion or no change of limited resting wall motion abnormalities during stress

Flowchart 2.4:5HYDVFXODUL]DWLRQVWUDWHJ\LQPXOWLYHVVHOGLVHDVHLQ8$167(0,

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Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 69

Indications of Conservative (No PCI/Elective PCI) Strategy This is recommended in patients, who have following features: • No recurrence of chest pain • No signs of heart failure • No abnormalities in the initial ECG or a second ECG (6–12 hours) • No elevation of troponins (on arrival and at 6–12 hours) The further management in these patients is similar to the evaluation of stable CAD. Before discharge, a stress test for inducible ischemia is useful for further decision-making.

Emerging Role of CCTA Recently published ROMICAT II trial on 1,370 subjects with possible ACS, a coronary computer tomographic angiography (CCTA)-based strategy for low-to-intermediate risk patients appeared to allow safe, expedited discharge from the emergency department of many patients, who would otherwise be admitted. A higher rate of detection of coronary disease was also observed.

Percutaneous Coronary Intervention or CABG Patients with NSTE-ACS are not a homogenous population. Left ventricular function is prognostically very important. Coronary pathology varies from single-vessel disease involving small territory to severe multivessel disease. Several trials have compared PTCA and CABG in patients with ischemic heart disease, many of whom had UA, with both revascularization strategies resulting in similar rates of death or MI, but a greater need for additional procedures in those initially treated with PTCA (RITA trial, ERACI trial). But in the BARI trial, diabetics with triple-vessel disease had a significantly lower mortality with CABG compared with PTCA at 5 years (80.6% vs 65.5%), P = 0.003). SYNTAX trial compared PCI using drug-eluting stents to CABG in triple vessel or left main CAD. Rates of primary endpoint were significantly higher in the PCI group versus CABG (17.8% vs 12.4%, P = 0.002) in large part because of an increased rate of repeat revascularization (13.5% vs 5.9%, P < 0.001). Patients with left ventricular dysfunction in particular often have severe multivessel disease which may not be amenable to PCI and these patients may have to be referred for CABG. The 2015 ACC/AHA UA/NSTEMI guidelines recommend CABG as the preferred revascularization strategy for patients with significant left main disease (> 50% stenosis) (Class I), patients with three- or two-vessel disease, who have significant proximal LAD stenosis and either treated diabetes mellitus (Class IIa) or LV dysfunction (Class I). Angiography should be preferable via the radial route (Class IC). The ESC 2015 guidelines recommend addition of aspirin 6–24 hours post CABG with addition of a P2Y12 inhibitor and continuation for 12 months unless there are contraindications such as bleeding risk.

70 The Protocol Book for Intensive Care With regard to treating the non-infarct related artery in the PRAMI study, opposed to only the culprit vessel in a multivessel scenario, reduced MACE and all-cause mortality was noted. A recent review and meta-analysis by Gaffar et al. (2017) suggested that single-stage complete revascularization is safe and is associated with a trend toward lower long-term risks of mortality and MACE. It will be further discussed in subsequent chapters.

COMORBID CONDITIONS Recommendations for Patients with CKD (ESC 2011 NSTE-ACS Guidelines) Classa

Levelb

It is recommended to assess kidney function by eGFR I in all patients.

C

Patients with NSTE-ACS and CKD should receive the I same first-line antithrombotic treatment as patients devoid of CKD, with appropriate dose adjustments according to the severity of renal dysfunction.

B

Depending on the degree of renal dysfunction, dose I adjustment or switch to UFH with fondaparinux, enoxaparin, bivalirudin, as well as dose adjustment with small molecule GP IIb/IIIa receptor inhibitors are indicated

B

UFH infusion adjusted to aPTT is recommended I when CrCl is < 30 mL/minutes or eGFR is < 30 mL/ minutes/1.73 m2 with most anticoagulants (fondaparinux < 20 mL/minutes).

C

In patients with NSTE-ACS and CKDI considered for I invasive strategy, hydration and low- or iso-osmolar contrast medium at low volume (< 4 mL/kg) are recommended

A*

Coronary angiography and, if needed, revasculariza- I tion are recommended after careful assessment of the risk–benefit ratio, in particular with respect to the severity of renal dysfunction.

B*

In patients undergoing PCI, new-generation DESs I are recommended over BMSs.

B*

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Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 71

DISCHARGE AND LONG-TERM THERAPY Medical Regimen on Discharge •

•

• •

•

•

•

• •

For UA/NSTEMI patients treated medically without stenting, aspirin should be prescribed indefinitely; clopidogrel (75 mg/day) or ticagrelor (90 mg twice daily) should be prescribed for up to 12 months. Recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily. For aspirin allergic patients, use either clopidogrel or ticagrelor alone (indefinitely) or try aspirin desensitization. There are no data for therapy with two concurrent P2Y12 receptor inhibitors and this is not recommended in case of aspirin allergy. For UA/NSTEMI patients treated with a stent (BMS or DES), aspirin should be continued indefinitely. Clopidogrel 75 mg daily, prasugrel 10 mg daily or ticagrelor 90 mg twice daily should be given for at least 12 months to patients receiving DES and up to 12 months for patients receiving BMS continuation of a P2Y12 receptor inhibitor beyond 12 months may be considered following DES placement (Class IIaB recommendation). Beta blockers especially in patients with reduced LV function on long term (IA). ACE inhibitors indicated long term in all patients with LVEF less than 40% and in patients with diabetes, hypertension or chronic kidney unless contraindicated (IA). Angiotensin-receptor blockers should be considered in patients who are intolerant to ACE inhibitors and/or who have heart failure or MI with LVEF less than 40% (IA). Aldosterone receptor antagonists (blockade) should be considered in patients after MI who are already treated with ACE inhibitors and beta blockers and who have an LVEF less than 40% and either diabetes or heart failure (IA). High intensity statins are recommended in all NSTE-ACS patients (in absence of contraindications) irrespective of cholesterol levels initiated early (within 1–4 days) after admission. Intensive lipid lowering therapy (e.g., simvastatin 40 mg as in IMPROVE-IT trial) with target LDL-C less than 70 mg% is advised, if required with addition of ezetimibe 10 mg (Class IIaB). Calcium channel blockers are indicated especially in hypertensive patients, either alone or in combination with beta blockers. Long-term nitrates are indicated in patients with angina.

Risk Factor Modification • •

Stop smoking Weight reduction

72 The Protocol Book for Intensive Care • • • •

Control of diabetes HbA1C less than 7% Control of hypertension BP less than 140/90 (Class IA according to ESC 2015) LDL less than 100 mg% or preferably less than 70 mg% HDL more than 40 mg% (men) or more than 50 mg% (women).

SUGGESTED READING 1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association TaskForce on Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139-228. 2. Fox K, Garcia MA, Ardissino D, et al. Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J. 2006;27(11):1341-81. 3. Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent STsegment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32(23):2999-3054, doi 10.1093/euheartj/ehr236. 4. Hamm CW, Mollmann H, Bassand JP, et al. The ESC Textbook of Cardiovascular Medicine, 2nd edition. Oxford University Press, 2009. 5. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology, Bassand JP, Hamm CW, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J. 2007;28(13):1598-660. 6. Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS); European Association for Percutaneous Cardiovascular Interventions (EAPCI), Wijns W, Kolh P, et al. Guidelines on Myocardial Revascularization. The Task Force on Myocardial Revascularization Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2010;31(20):2501-55. 7. Thygesen K, Mair J, Katus H, et al. Recommendations for the use of cardiac troponin measurement in acute cardiac care. Eur Heart J. 2010,31(18):2197-204. 8. Van de Werf F, Bax J, Betrju A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute

Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction 73

Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2008;29(23):2909-45. 9. Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA focussed update of the Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines developed in collaboration with the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011,57(19):1920-59. 10. 2015 ESC guidelines for the management of ACS in patients presenting without persistent ST segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(3):267-315.

C HAPTER

3

Cardiogenic Shock Soumitra Kumar, Sudeshna Majumder, Ankit Ray

DEFINITION Clinical evidence of systemic hypoperfusion with: • Systolic blood pressure (SBP) less than 90 mm Hg for at least 30 minutes or vasopressors required to maintain SBP more than 90 mm Hg. • Pulmonary congestion or elevated left-ventricular filling pressures. • Signs of impaired organ perfusion with at least one of the following criteria: (a) altered mental status, (b) cold, clammy skin, (c) oliguria and (d) increased serum-lactate more than 2 mmol/L.

ETIOLOGY Acute myocardial infarction:

Pump failure (65–80%) • Large infarct size • Small infarct with preexisting severe LV dysfunction

Mechanical (12%) • Acute mitral regurgitation (MR) • Ventricular septal rupture • Free wall rupture • Pericardial tamponade • Right ventricular myocardial infarction (RVMI)

Other conditions: • Fulminant myocarditis or end-stage cardiomyopathy • Severe myocardial contusion • Prolonged hypotension with pre-existing severe coronary artery disease (CAD) and severe left ventricle (LV) dysfunction • Prolonged cardiopulmonary bypass Aortic stenosis •

LV outflow tract obstruction Hypertrophic cardiomyopathy (HCM)

Cardiogenic Shock 75

Mitral stenosis •

LV filling obstruction

• • • •

Left atrial myxoma Septic shock with severe myocardial depression Acute MR Acute aortic regurgitation Iatrogenic

EPIDEMIOLOGY OF CARDIOGENIC SHOCK Cardiogenic shock (CS) complicates 5–8% of cases of ST-elevation myocardial infarction (STEMI) and 2.5% of cases of non-ST-elevation myocardial infarction (NSTEMI) patients. In these individuals with CS, a vicious cycle is set into motion as profound depression of myocardial contractility leads to low cardiac output (CO) and low blood pressure, thereby leading to further coronary insufficiency, and further reduction in contractility and CO (Fig. 3.1). Cotter, et al. demonstrated the importance of cardiac power in shock patients for risk stratification and selection of therapy. Cardiac power output (CPO) is the product of CO and mean arterial pressure (CPO CO u MAP/451) and is a useful indicator of prognosis. A CPO less than 1 is an indication for administration of inotropes. A value of CPO less than 0.6 indicates hemodynamic compromise and requires institution of LV assist devices. A CPO less than 0.53 signifies an irreversible stage in cardiac decompensation and is incompatible with life. Hence, there is an extremely small ‘window of opportunity’ once hemodynamic compromise develops and quick and effective intervention is required to save the patient.

Fig. 3.1: Vicious cycle in cardiogenic shock.

76 The Protocol Book for Intensive Care In the SHOCK trial, CPO was the hemodynamic variable most strongly associated with inhospital mortality. A subset of patients in the SHOCK registry were diagnosed with CS without hypotension based on systemic hypoperfusion, low CO and elevated ventricular filling pressures. The patient’s inhospital mortality rate (43%) was lower than the mortality rate of those with hypotensive shock (66%), despite similar baseline left ventricular ejection fraction (LVEF) (34%), cardiac index (1.9 L/minute/m2) and pulmonary capillary wedge pressure (25 mm Hg) between the two groups. CPO is also prognostically important because it reflects myocardial reserve adequate to generate flow, albeit reduced, in the face of high resistance. Myocardial infarction (MI) patients with CS have a higher mortality rate (71.7%) than those without CS (12%, P < 0.001). Mortality with CS from NSTEMI is higher than that with STEMI (7.25% vs 6.3%, P = 0.05). With more aggressive triaging and increasing use of primary percutaneous coronary intervention (PCI) for STEMI and early invasive strategy for NSTEMI, incidence of CS with acute myocardial infarction (AMI) is declining. Patients who develop CS, it occurs within 24–48 hours in 59–74% of patients, within 3–4 days in 11% of patients and later than 4 days after the infarction in 30% of patients. CS occurs earlier when it is due to left main CAD or right CAD rather than left anterior descending CAD. A slight majority of pump failure cases have threevessel CAD (56%) or left main stem disease (16%). Left anterior descending coronary artery disease is responsible for 42% of CS cases, right coronary artery (RCA) disease for 30%, and left circumflex disease for only 14%. There are differences in the populations of patients with STEMI and NSTEMI that develop CS. NSTEMI patients are older and more commonly diabetic, and generally have underlying multivessel disease and develop shock progressively while in the hospital rather than at admission.

RISK FACTORS Patients with Ischemic cause of Cardiogenic Shock Identification of high-risk patients is important as CS has a poor prognosis (70–90% mortality); therefore, prevention by treating this high-risk group promptly before onset of CS definitely decreases the mortality. Risk factors are: • Age • SBP at presentation • Killip class at entry • Heart rate • Anterior infarction • Height • Weight • Time to treatment

Cardiogenic Shock 77

• • • • • • • • • • • •

Diabetes mellitus History of cigarette smoking Current smoking Previous coronary artery bypass grafting Hypertension Stroke Recurrent infarctions. Of these, the following have a 90% sensitivity to predict outcome: Age SBP at entry Killip class at entry Heart rate Location of infarction

DIAGNOSIS • •

History of acute MI/cardiac disease with accompanying symptoms Physical findings: ƒ Hemodynamic instability—hypotension, tachycardia, tachypnea ƒ Peripheral vasoconstriction—cool extremities with cyanosis ƒ Pulmonary congestion—diffuse rales in the chest ƒ Systemic congestion—prominent neck veins, edema, gallop rhythm, murmur of VSD or MR, electromechanical dissociation in free wall rupture ƒ Findings specific to the underlying cause

MANAGEMENT Once clinical diagnosis of shock is established. American College of Cardiology/American Heart Association (ACC/ AHA) indications for pulmonary artery catheterization in acute infarction classes is as follows.

Class I • • •

Severe or progressive congestive heart failure (CHF) or pulmonary edema CS or progressive hypotension Suspected mechanical complications of acute infarction

Class II Hypotension which does not respond promptly to fluid administration in a patient without pulmonary congestion.

78 The Protocol Book for Intensive Care Flowchart 3.1: Plan of management in cardiogenic shock.

MI: Myocardial infarction; ECG: Electrocardiogram; LV: Left ventricle; CXR: Chest X-ray; BUN: Blood urea nitrogen; VSR: Ventricular septal rupture; MR: Mitral regurgitation.

Mechanical Support Devices • • • •

Intra-aortic balloon pump (IABP) Percutaneous cardiopulmonary support Left ventricular assist devices Extracorporeal life support.

IABP • • • •

•

Intra-aortic balloon pump has long been the most widely used device for mechanical therapy for CS Inserted through common femoral artery with proximal end placed just distal to distal left subclavian artery The 30–50 cc helium-filled balloon is inflated in diastole (improved coronary and peripheral perfusion) and deflates in systole (decreased afterload) Hemodynamic effects: ƒ ↓ peak systolic arterial pressure ƒ ↓ heart rate ƒ CO and ↑↑ end-diastolic aortic pressure ƒ ↔ LVEDP/PCWP ƒ ↑↑↑↑ diastolic aortic pressure ƒ ↑↑↑↑ mean aortic pressure Indications: ƒ AMI ± CS ƒ Refractory unstable angina ƒ Stabilization of left main disease

Cardiogenic Shock 79

ƒ ƒ ƒ ƒ ƒ ƒ ƒ ƒ

Complications of AMI Weaning from cardiopulmonary bypass High-risk cardiac percutaneous revascularization Bridge to cardiac transplantation High-risk noncardiac surgery in coronary patients Refractory arrhythmias Myocardial contusion Right ventricular failure.

Contraindications • • •

Severe peripheral vascular disease Severe aortic incompetence Active bleeding

Flowchart 3.2: Hemodynamic stabilization in cardiogenic shock.

80 The Protocol Book for Intensive Care

ABG: Artery bypass grafting; PCWP: Pulmonary capillary wedge pressure; SBP: Systolic blood pressure; MR: Mitral regurgitation; IABP: Intra-aortic balloon pump; SVR: Systemic vascular resistance.

• • •

Patients with contraindications to anticoagulation Thrombocytopenia (50,000) Acute stroke.

Complications • • •

Limb ischemia Cholesterol embolization Infection.

Does IABP Extend Life in CS? Previous studies have been inconclusive; however, the recently published IABP-SHOCK II trial in which IABP was compared to optimal medical therapy (OMT) on top of PCI in STEMI patients with CS, IABP was not shown to have any edge over OMT in terms of the primary endpoint of 30-day mortality. Lack of benefit in terms of primary endpoint benefit is supported by lack of benefit in terms of secondary endpoints of serum lactate, hemodynamic parameters, SAPS-2 score, serial creatinine, CRP, etc.

Cardiogenic Shock 81

Percutaneous Cardiopulmonary Support • •

• •

Provides complete circulatory support during PCI independent of the underlying cardiac rhythm and cardiac function. It can be used in: – High-risk PCI – Myocardial jeopardy score more than 3 – Vessel in question is the last remaining vessel. Standby CPS is preferred than prophylactic CPS except in patients with extremely depressed LV function (EF 20%). It involves insertion of large bore cannula in femoral artery and vein. Blood is drawn via cannula placed at right atrium level and circulated through a membrane oxygenator and heat exchanger and reintroduced through femoral artery.

Flowchart 3.3: Revascularization in cardiogenic shock.

82 The Protocol Book for Intensive Care Flowchart 3.4: Approach to revascularization in cardiogenic shock.

*PCI in noninfarcted artery is indicated in hemodynamically compromised patients if the stenotic DUWHU\SHUIXVHVDODUJHDUHDRIP\RFDUGLXPDQGWKHSURFHGXUHFDQEHSHUIRUPHGHI¿FLHQWO\ LBBB: Left bundle branch block; LMCA: Left main coronary artery; PCI: Percutaneous coronary intervention; IABP: Intra-aortic balloon pump; CAD: Coronary artery disease; CABG: Coronary artery bypass grafting.

Percutaneous Left Ventricular Assist Devices (LVADs) Currently, available devices include: • TandemHeartTM (Cardiac Assist Inc, Pittsburgh, USA) • Microaxial Impella“ 2.5, 3.5, 5.0 and CP systems (Abiomed Europe, Aachen, Germany) • Newly available paracorporeal pulsatile device iVAC 2L“ (PulseCath BV, the Netherlands). TandemHeart pVAD: It is a left atrial to femoral arterial pVAD driver by a lowspeed centrifugal continuous flow pump. It removes blood from the left atrium by using cannula that is inserted through the femoral vein and into the left atrium via transseptal puncture. Blood is then returned to a systemic artery usually femoral with retrograde perfusion of abdominal and thoracic aorta. Microaxial Impella system: It is a miniature 12F rotatory pump placed across the aortic valve that directly aspirates blood from LV cavity and expels into

Cardiogenic Shock 83

ascending aorta. It is distally connected to a portable mobile console that displays actual revolution/minute. At its maximum speed of 51,000 rpm, it provides output of 2.5 L/minute. Impella 5 system is also available. PROTEFT I trial has demonstrated that Impella 2.5 system provides excellent hemodynamic support during high-risk PCI. iVAC 2L: It is introduced percutaneously through the femoral artery and can provide a pulsatile support of ~2 L/minute using an extracorporeal membrane pump via a 17F cannula. When the heart is in the systolic phase, blood is aspirated from the left ventricle through the catheter lumen into the membrane pump. During the diastolic phase, the pump ejects the blood back through the catheter, subsequently opening the catheter valve and delivering the blood to the ascending aorta through the side outflow port, thereby creating an ‘extra heart beat’ The device directly unloads the ventricle by active aspiration and simultaneously creates a counter pulsating flow in the ascending aorta.

Table 3.1: Therapeutic recommendations for cardiogenic shock (ESC STEMI Guidelines 2012) Class of recommendation

Level of evidence

I

C

Urgent echocardiography/Doppler must be performed to detect mechanical complications, assess systolic function and loading conditions

I

C

High-risk patients must be transferred early to tertiary centers

I

C

Emergency revascularization with either PCI or CABG in suitable patients must be considered

I

B

Fibrinolysis should be considered if revascularization is unavailable

IIa

C

Intra-aortic balloon pumping may be considered

IIb

B

LV assist device may be considered for circulatory support in patients with refractory shock

IIb

C

Hemodynamic assessment with balloon floating catheter may be considered

IIb

B

Dopamine

IIa

C

Dobutamine

IIa

C

Norepinephrine (preferred over dopamine when blood pressure is low)

IIb

B

Recommendation Oxygen/mechanical respiratory support is indicated according to blood gases

Inotropic/Vasopressor agents should be considered

PCI: Percutaneous coronary intervention; CABG: Coronary artery bypass grafting.

84 The Protocol Book for Intensive Care

Fig. 3.2: Schematic drawings of current percutaneous mechanical support devices for cardiogenic shock.

Advantages over IABP IABP requires certain residual level of left ventricular function whereas LVADs provide active circulatory support and better hemodynamic profile even in high-risk cases or cases with poor LVEF. Patients treated with active LVADs demonstrated higher cardiac index, higher mean arterial pressure and lower pulmonary capillary wedge pressure. No trials for iVAC are available, however.

Disadvantages over IABP LVAD are not currently recommended as first line treatment in CS because, although they have better hemodynamic profile, bleeding complications and inflammation were more frequent with LVAD therapy, with no difference in 30-day mortality.

Extracorporeal Life-support Systems •

• •

•

It involves extracorporeal circulation of blood through an extracorporeal membrane oxygenator (ECMO) which relieves both the right and left heart and the lungs of the part of their workload. Anticoagulation is required. It might be considered as destination therapy or bridge to transplant, however, there is a limited experience with these devices, and observational studies have had conflicting results with no systematic direct comparison. Main drawbacks of these devices are large cannula sizes potentially causing lower limb ischemia and bleeding complications, frequent requirement of perfusionists, lack of direct left ventricular unloading, rise in afterload and a limited support time. Furthermore, complications are substantial with lower extremity ischemia, compartment syndrome, amputation, stroke, major bleeding and significant infection.

Cardiogenic Shock 85

SHOCK TRIAL REGISTRY The randomized SHOCK trial registry compared a direct invasive strategy of emergency early revascularization to initial medical stabilization including thrombolysis and IABP, followed by delayed revascularization as clinically determined. At 6 and 12 months, 13 lives were saved for every 100 patients treated with early revascularization compared with the second group. The improved survival was seen for patients with early and late shock and regardless of infarct location or the presence of comorbidities (e.g. diabetes, prior hypertension or MI). Although the small subgroup of those older than 75 years did not appear to benefit, there were imbalances between the groups and larger registries demonstrate a markedly lower inhospital mortality for early patients, who were clinically selected for early revascularization, even after adjustment for their lower risk profile. More than 80% of trial survivors were NYHA CHF Class I and Class II at 1-year post infarct. Use of stents and GP IIb/IIIa antagonists are independently associated with improved survival. PCI should be performed with IABP support and low-osmolality ionic Flowchart 3.5: Management of mechanical complications of MI.

VSD: Ventricular septal defect; CABG: Coronary artery bypass grafting; MI: Myocardial infarction; LV: Left ventricle; MR: Mitral regurgitation; IABP: Intra-aortic balloon pump.

86 The Protocol Book for Intensive Care contrast dye should be used. Outcome of patients who underwent rescue PCI after thrombolysis was similar to those who underwent direct PCI in the SHOCK trial. Low PCI success rates and no reflow remain challenges. Approximately, one-third of patients improve rapidly and dramatically after PCI, whereas most show no immediate hemodynamic improvement. Patients may deteriorate hemodynamically after reperfusion is established, particularly if they are reperfused late. Patients with CS and non-ST-segment Flowchart 3.6: Management of right ventricular infarction.

Cardiogenic Shock 87

elevation MI have a higher risk profile than shock patients with ST-segment elevation but similar inhospital mortality.

DOSAGE Inotropes •

• •

•

Inj dopamine—infusion rate of 2–5 Pg/kg/minute and increased every 2–5 minutes to a maximum of 50 Pg/kg/minute. Route of administration—central/peripheral. Inj dobutamine—infusion rate of 2.5–10 Pg/kg/minute. Route of administration—central/peripheral. Inj norepinephrine—infusion rate of 2–4 Pg/minute till a maximum of 15 Pg/minute. To be combined with Inj dopamine (2–5 Pg/minute) for renal protection. Route of administration—central. Inj amrinone—bolus of 0.75 mg/kg over 2–3 minute. If effective then 5–10 Pg/kg/minute. If required, doses may be increased to 15 Pg/kg/minute for short periods.

Vasodilators • •

Inj sodium nitroprusside—infusion at 20 Pg/minute with increments till a maximum of 200–300 Pg/minute. Inj nitroglycerin—infusion at 5–10 μg/minute to a maximum of 100–150 μg/minute.

Newer Agents Levosimendan is a relatively new calcium sensitization and K-ATP channel opener, which improves myocardial contractility without increasing oxygen requirements. It also induces peripheral and coronary vasodilation. Although levosimendan is well-studied in acute heart failure, yet in view of its vasodilatory effects with subsequent blood pressure lowering, it is unlikely to become the drug of first choice in CS. However, it can improve hemodynamics in CS when combined with catecholamines to maintain adequate perfusion pressures. Its current role in CS needs to be defined in further studies. Nitric oxide (NO) synthase inhibitors are another group of agents that are being tried in CS in view of hyperactivity of eNOS and iNOS. Following the dose-ranging SHOCK-2 study, the TRIUMPH trial (tilarginine acetate injection in a randomized international study on unstable MI patients with CS), the largest study in CS, investigated if the use of tilarginine improved survival in CS. Despite showing an immediate increase in blood pressure, NO synthase inhibition failed to demonstrate a survival benefit, which led to discontinuation of the trial after inclusion of 398 patients based on a prespecified interim analysis.

88 The Protocol Book for Intensive Care

Some Formulae 1. Systemic vascular resistance 2. Cardiac index =

CO Body surface area

= 80 (MAP – CVP) 10 = 1,000–1,500 dynes/sec/cm– 5 = 2.5–4.5 L/minute/m2

3. CO (echocardiography) of any valve = πr2 × velocity time integral × heart rate (where ‘r’ is the radius at the level of the valve).

SUGGESTED READING 1. Cotter G, Moshkovitz Y, Kaluski E, et al. The role of cardiac power and systemic vascular resistance in the pathophysiology and diagnosis of patients with acute congestive heart failure. Eur J Heart Fail. 2003;5(4):443-51. 2. Hochman JS, Buller CE, Sleeper LA, et al. Cardiogenic shock complicating acute myocardial infarction—etiologies management and outcome: a report from the SHOCK Trial Registry. Should we emergently revascularize occluded coronaries for cardiogenic shock? J Am Coll Cardiol. 2000;36(suppl A):1063-70. 3. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization and longterm survival in cardiogenic shock complicating acute myocardial infarction. JAMA. 2006;295(21):2511-5. 4. Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation. 2008;117(5):686-97. 5. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, Atar D, et al. ESC guidelines on the management of acute myocardial infarction in patients of acute persistent ST-segment elevation. Eur Heart J. 2012;33(20):2569-619. 6. The TRIUMPH Investigators, Alexander JH, Reynolds HR, et al. Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock the TRIUMPH randomized controlled trial. JAMA. 2007;297(15):1657-66. 7. Thiele H, Allam B, Chateller G, et al. Shock in acute myocardial infarction: the Cape Horn for trials. Eur Heart J. 2010;31(15):1828-35. 8. Webb JG, Lowe AM, Sanboen TA, et al. Percutaneous coronary intervention for cardiogenic shock in the SHOCK trial. J Am Coll Cardiol. 2003;42(8):1380-6.

C HAPTE R

4

Acute Heart Failure Soma Mandal, Soumitra Kumar

DEFINITION Heart failure (HF) is a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that is accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral edema) caused by structural and/or functional cardiac abnormality, resulting in a decreased cardiac output and/or elevated intracardiac pressure at rest or during stress. Acute heart failure (AHF) refers to rapid onset or worsening of symptoms and/or signs of HF.

TYPES OF HEART FAILURE 1. Heart failure with reduced ejection fraction (HFrEF) a. Symptoms + signs b. Left ventricular ejection fraction (LVEF) less than 40% Table 4.1: &ODVVL¿FDWLRQ RI +HDUW )DLOXUH.

CRITERIA

Type of HF

HFrEF

HFmrEF

HFpEF

1

Symptoms ± Signsa

Symptoms ± Signsa

Symptoms ± Signsa

2

LVEF  40%

LVEF 40–49%

LVEF > 50%

3

–

1. Elevated levels of natriuretic peptidesb 2. At least one additional criterion: a. Relevant structural heart disease (LVH aod/or LAE) b. Diastolic dysfunction (for details see Section 4.3.2).

1. Elevated levels of natriuretic peptidesb 2. At least one additional criterion: a. Relevant structural heart disease (LVH aod/or LAE) b. Diastolic dysfunction (for details see Section 4.3.2).

BNP: ¾ B-type natriuretic peptide; HF: ¼ heart failure; HFmrEF: ¼ heart failure with mid-range ejection fraction; HFpEF: ¼ heart failure with preserved ejection fraction; HFrEF: ¼ heart failure with reduced ejection fraction; LAE: ¼ left atrial ventricular ejection fraction; LVH: ¼ left atrial ventricular hypertrophy; NT-proBNP: ¼ N-terminal pro-B type natriuretic peptide. a Signs may not be present in the early stages of HF (especially in HFpEF) and in patients treated with diuretics. b BNP 35 pg/mL and/or NT-proBNP 125 pg/mL.

90 The Protocol Book for Intensive Care 2. Heart failure with mid-range ejection fraction (HFmrEF) a. Symptoms + signs b. LVEF 40%–49% c. Elevated levels of natriuretic peptides (BNP 35 pg/mL and/or NTproBNP 125 pg/mL) d. At least one additional criteria – Relevant structural heart disease (LVH and/or LAE) – Diastolic dysfunction 3. Heart failure with preserved ejection fraction (HFpEF) a. Symptoms  signs b. LVEF more than 50% c. Elevated levels of natriuretic peptides (BNP 35 pg/mL and/or NTproBNP 125 pg/mL) d. At least one additional criteria – Relevant structural heart disease (LVH and/or LAE) – Diastolic dysfunction

TRIGGERING FACTORS OF ACUTE HEART FAILURE 1. Acute coronary syndrome (ACS) 2. Tachyarrythmia (AF, VT) 3. Excessive rise in BP 4. Bradyarrythmia 5. Infection (pneumonia, sepsis, infective endocarditis) 6. Nonadherence with salt or fluid intake or medications 7. Alcohol or recreational drugs 8. Pulmonary embolism 9. Exacerbation of chronic obstructive pulmonary disease (COPD) 10. Stress-related cardiomyopathy 11. Surgery and perioperative complications 12. Drugs [nonsteroidal anti-inflammatory drugs (NSAIDs), cardiotoxic chemotherapeutics] 13. Metabolic causes (thyroid dysfunction, diabetic ketosis, adrenal dysfunction, pregnancy and peripartum-related abnormalities) 14. Acute mechanical causes [myocardial rupture complicating ACS—free wall rupture, ventricular septal defect (VSD), acute mitral regurgitation (MR)], chest trauma or cardiac intervention, aortic dissection.

Mechanisms Underlying Decompensation of Chronic Heart Failure a. Noncompliance with treatment (42%) b. Inadequate preadmission treatment (12%) c. Ischemia (14%)

Acute Heart Failure 91 7DEOH&ODVVL¿FDWLRQRIDFXWHKHDUWIDLOXUHEDVHGRQ&OLQLFDODQG+HPRG\QDPLF 6WXG\E\)RUUHVWHU  Mortality (%) Class I (warm and dry)

Cardiac index 2.2–3.5 L/m/m2 PCWP 18 mm Hg Normal tissue perfusion

2.2

Class II (warm and wet)

Cardiac index 2.2–3.5 L/m/m2 PCWP !18 mm Hg Normal tissue perfusion

10.1

Class III (cold and dry)

Cardiac index 2.2 L/m/m2 PCWP 18 mm Hg Severe tissue hypoperfusion

22.4

Class IV (cold and wet) cardiogenic shock

Cardiac index 2.2 L/m/m2 PCWP !18 mm Hg Severe tissue hypoperfusion

55.5

PCWP: Pulmonary capillary wedge pressure.

7DEOH&OLQLFDOSUR¿OHVRISDWLHQWVZLWKDFXWHKHDUWIDLOXUHEDVHGRQSUHVHQFH DEVHQFHRIFRQJHVWLRQDQGRUK\SRSHUIXVLRQ Congestion

Hypoperfusion

WARM–DRY

–

–

1.

+

–

2. Cold–Dry

Warm–Wet

–

+

3.

+

+

Cold–Wet

d. Arrhythmias (6%) e. Poor BP control (6%) f. No precipitating cause (20%)

Features of Congestion a. Pulmonary congestion b. Orthopnea/PND c. Peripheral B/L edema d. Increased JVP e. Congested hepatomegaly f. Gut congestion, ascites g. Hepatojugular reflux

Features of Hypoperfusion a. Cold sweated extremities b. Oliguria

92 The Protocol Book for Intensive Care )ORZFKDUW Initial approach to a patient with acute heart failure.

AHF: Acute heart failure.

c. Mental confusion d. Dizziness e. Narrow pulse pressure

INVESTIGATIONS ACC/AHA and ESC guidelines for initial evaluation of patients with heart failure (2009 focused update of ACC/AHA 2005 guideline and ESC 2016 guideline).

Class-I Indications 1. Thorough history and physical examination to identify cardiac and noncardiac disorders/behaviors that might cause HF/accelerate its development/progress (level of evidence: C). 2. Obtain careful history of current and past use of alcohol, drugs, current or past standard or alternative medicines (level of evidence: C). 3. Initial assessment of the patients ability to perform routine and desired activities of daily life (level of evidence: C).

Acute Heart Failure 93 )ORZFKDUW0DQDJHPHQWRI$+)EDVHGRQFOLQLFDOSUR¿OHRIWKHSDWLHQW

AHF: Acute heart failure.

4. Assess volume status; orthostatic blood pressure changes, measure height, weight, body mass index (level of evidence: C). 5. Initial lab: Complete blood count, urine routine examination, serum electrolytes (including calcium and magnesium), blood urea nitrogen, creatinine, fasting blood sugar, HbA1C, lipid profile, liver function test and thyroid-stimulating hormone (level of evidence: C). 6. 12-lead ECG and chest radiography (posteroanterior) (level of evidence: C). 7. Two-dimensional echocardiography with Doppler is recommended immediately in hemodynamically unstable AHF patients and within

94 The Protocol Book for Intensive Care 48 hours when cardiac structure and function are either not known (level of evidence: C). 8. Coronary arteriography in patients with angina, significant ischemia except those who are not eligible for revascularization (level of evidence: C). 9. At presentation measurement of plasma natriuretic peptide level (BNP, NT-proBNP, MR-proANP) is recommended in all patients with acute dyspnea and suspected AHF for differentiation of AHF from noncardiac causes of acute dyspnea. In 20% of patients, CXR is normal, helps to identify noncardiac causes simulating AHF (pneumonia).

ECG A normal electrocardiogram (ECG) is uncommon in heart failure. It helps to identify: (a) rhythm, (b) etiology in AHF and (c) loading conditions of the heart.

Biomarkers 1. Inflammation (elucidating the pathogenesis of HF; provide prognostic information and risk stratification; identify subjects at risk for HF): a. CRP b. TNF c. Fas (APO-1) d. IL-1,6,18 2. Oxidative stress (elucidating pathogens B; provide prognostic information and risk stratification and potential targets of therapy): a. Oxidized low density lipoproteins b. Myeloperoxidase c. Urinary biopyrrins d. Urinary and plasma isoprostane e. Plasma malondialdehyde 3. Extracellular matrix remodeling (pathogenesis and targets of therapy): a. Matrix metalloproteinases (MMP) b. Tissue inhibitors of metalloproteinase c. Collagen propeptides d. Propeptide; procollagen type I e. Plasma procollagen type III 4. Neurohormones (pathogenesis, risk stratification and target of therapy): a. Norepinephrine b. Renin c. Angiotensin-II d. Aldosterone e. Arginine vasopressin

f. Endothelin

5. Myocyte injury (pathogenesis, risk stratification and target therapy): a. Cardiac specific troponin I and T b. Myosin light chain kinase-I c. Heart type fatty acid protein d. CKMB

Acute Heart Failure 95

6. Myocyte stress (risk stratification, subjects at risk, target of therapy and diagnosis and monitoring of therapy): a. BNP b. Amino-terminal pro-B type natriuretic peptide (NT-proBNP) c. Mid-regional fragment of proadrenomedullin d. ST2 7. New biomarkers (prognostic information and risk stratification): a. Chromogranin b. Galectin 3 c. Osteoprotegerin d. Adiponectin e. Growth differentiation factor 15

Brain Natriuretic Peptide 1. Levels increase progressively with worsening NYHA class 2. Levels are higher in HF with low EF than HF with preserved EF 3. Levels ↑ with age and worsening renal function 4. Levels are more in female than in male 5. Inverse relationship with BMI 6. Level does not necessarily indicate that decompensation is present/even imminent because stable HF patients have high value. 7. Increased in some conditions Cardiac condition: a. ACS b. Heart failure c. Myocarditis a. LVH b. Hypertrophic or restrictive cardiomyopathy c. Valvular and congenital heart disease d. Atrial and ventricular tachyarrthymia h. Cardioversion, ICD shock i. RV dysfunction as a result of pulmonary embolism j. Pulmonary hypertension or severe lung disease Non-cardiac conditions: a. Sepsis b. Hyperthyroidism c. Cirrhosis d. Ischemic stroke e. Subarachnoid stroke f. Renal dysfunction g. COPD h. Paraneoplastic syndrome i. Diabetic ketosis

96 The Protocol Book for Intensive Care 8. Patient with flash pulmonary edema may not have elevated levels because they are often evaluated before natriuretic peptide (NP) is released from LV 9. Patient with pericardial restriction do not have ↑ BNP as LV wall stress is only minimally elevated. Patients with normal NP concentrations are unlikely to have heart failure. The upper limit of normal in non-acute setting for BNP is 35 pg/mL, NT-proBNP 125 pg/mL and in acute setting BNP less than 100 pg/mL. NTproBNP less than 300 pg/mL, MR-proANP less than 120 pg/mL makes the diagnosis of AHF unlikely.

Bedside Echocardiography Presence of updated portable machines has made bedside assessment convenient and extremely useful in emergency cardiac management. Decrease in size (hand carried devices) and technical upgradation (e.g. CW Doppler, color flow imaging, tissue harmonic imaging, tissue Doppler imaging, etc.) have made this tool almost mandatory in routine management of cardiac emergencies. Such devices are also useful in outpatient department as an adjunct to physical examination and for medical student teaching.

Hemodynamic Assessment by Echocardiography Assessment of Ventricular Function Load dependent variable: i. Stroke volume (diameterLVOT)2 u 0.785 u VTILVOT (VTI velocity time integral) ii. Cardiac output (heart rate u stroke volume)/body surface area iii. Ejection fraction (LVEF) from volume data obtained by Simpson’s method EF (LVEDV – LVESV)/LVEDV u 100% iv. dp/dt: Rate of pressure increase during isovolumic contraction and can be estimated from continuous wave Doppler MR jet. dp pressure change between 1 m/s and 3 m/s = time difference between 1 m/s and 3 m/s dt v. Myocardial performance index (Tei index) ICT  IRT/ET. (ICT isovolumic contraction time; IRT isovolumic relaxation time; ET relaxation time). Normal value is 0.39 r 0.05. This index is altered in both systolic and diastolic myocardial dysfunctions and may also play an important role in assessing RV function. Load independent variables: i. Velocity of circumferential fiber shortening

Acute Heart Failure 97 7DEOH  6XJJHVWHG FXWRII YDOXHV IRU %13 DQG 17SUR%13 XVH LQ VSHFL¿F VLWXDWLRQV Cut-off value Pg/mL To rule-out BNP NT-proBNP MR-proANP To diagnose ADHF Single test screening strategy BNP NT-proBNP Multiple test screening strategy BNP NT-proBNP, age-stratified Approach Special situations Renal dysfunction (GFR  60 mL-Min – 1.73 m–2) BNP NT-proBNP

Obesity BNP NT-proBNP

Sensitivity (%)

Specificity (%)

30–40 300

97 99

62 68

100 900

90 90

76 85

100 to exclude 100–400 gray zone !400 include in  450 for age 50 years 900 for age 50–75 years 1,800 for age !75 years  200 (1)  1,200 all ages Or (2) age-stratified approach Above

– 63 90

– 91 84

88 89

63 72

170 for BMI 25 kg/m2 110 for BMI 25–35 kg/m2 54 for BMI t35 kg/m2 900, no adjustment for BMI Age-stratified out points, No adjustment for BMI

90 90 91 87

77 77 70 76 90

86

PPV: Positive predictive value; NPV: Negative predictive value; ADHF: Acutely decompensated heart failure; BNP: Brain natriuretic peptide; NT-proBNP: amino-terminal pro-B type natriuretic SHSWLGH*)5*ORPHUXODU¿OWUDWLRQUDWH%0,%RG\PDVVLQGH[ *Indicates not applicable.

i. Maximal elastance Emax iii. Preload recruitable stroke work (dp/dt max/EDV) iv. Preload-adjusted maximal power and preload adjusted peak power

ECHO BASED ETIOLOGICAL DIAGNOSIS OF AHF IN AMI Estimation of LV Filling Pressure LV filling pressure is the most important hemodynamic data to obtain in the ICU. a. Features in echocardiographic assessment which suggest elevated LV filling pressure (in absence of mitral stenosis): 1. Enlarged LA size (LAVI—Left atrial volume index ! 34 mL/mm) 2. LVMI (Left ventricular mass index) more than 115 g/mm for males and more than 95 g/mm for females 3. Transmitral E/A ratio more than 2

98 The Protocol Book for Intensive Care 4. Deceleration time (DT) less than 150 ms 5. Pulmonary venous flow: S/D less than 40% • E/Ea more than 13 • Color M-mode flow propagation velocity PV less than 45 cm/sec • E/Vp more than 2.0 b. Estimation of LV filling pressure: 1. Sinus rhythm: 1.24 (E/Ea)  1.9 2. Sinus tachycardia: 1.47 (E/Ea)  1.55 3. Atrial fibrillation: 0.82 (E/Ea)  6.49 E Mitral E wave velocity; Ea Mitral annular tissue Dopper velocity; Vp Propagation velocity of LV inflow on color M mode; SF Systolic fraction of pulmonary venous flow.

Pulmonary Artery Systolic Pressure This can be estimated from tricuspid regurgitation (TR) peak velocity: RVSP = PASP = 4 × (peak TR velocity)2 + estimated RA pressure RVSP = Right ventricular systolic pressure Estimation of right atrial (RA) pressure is done from size of inferior vena cava and its response to changes in respiration or a sniff.

Pulmonary Vascular Resistance PVR (Wood units) = 10 × TRV/TVIRVOT. (TRV Tricuspid regurgitant velocity; TVIRVOT  Right ventricular outflow tract time velocity integral). In patients with increase PASP on Doppler echocardiography, an elevated PVR is suggested by TRV/TVIRVOT ratio of more than 0.2.

RV Function Assessment Tricuspid annular plane systolic excursion (TAPSE) is a simple echocardiographic measure of RV ejection fraction but may be affected by coexisting COPD. A cut-off of 14 mm of TAPSE is independently associated with mortality in an unselected population of patients admitted for HF, even after adjusting for other known risk factors including LV ejection fraction or presence of valvular disease. Maximum velocity of systolic displacement wave of tricuspid annular plane can also be studied using Doppler tissue imaging to assess systolic dysfunction of RV (normal value 14 cm/sec).

HEMODYNAMIC MONITORING IN AHF i. Central venous pressure (CVP): Useful for delivery of fluids and drugs and can also be used to monitor CVP and venous oxygen saturation (SVO2). In patients with AHF, CVP rarely correlates with left atrial pressures and

Acute Heart Failure 99 )ORZFKDUW Echocardiography in etiologic assessment of acute heart failure.

ABP: Intra-aortic balloon pump; PAC: Pulmonary artery catheter; MR: Mitral regurgitation; TEE: Transesophageal echocardiography; IVS: Interventricular septum; SAM: Systolic anterior motion RIWKHPLWUDOYDOYH/927/HIWYHQWULFXODURXWÀRZWUDFW&$%*&RURQDU\DUWHU\E\SDVVJUDIWLQJ VAD: Ventricular assist device.

100 The Protocol Book for Intensive Care

$3HDNODWHGLDVWROLFWUDQVPLWUDOÀRZYHORFLW\$GXU'XUDWLRQRIDZDYH$5GXU3HDNSXOPRQDU\ YHQRXVDWULDOUHYHUVDOÀRZYHORFLW\GXUDWLRQ'3HDNGLDVWROLF'7'HFHOHUDWLRQWLPH(3HDNHDUO\ GLDVWROLFWUDQVPLWUDOÀRZYHORFLW\(D3HDNHDUO\GLDVWROLFP\RFDUGLDOYHORFLW\/9/HIWYHQWULFXODU S: Peak systolic PV: Flow velocity; Vp: Flow propagation velocity.

)LJ Role of echo in diastolic function evaluation. Table 4.5: Estimation of RA pressure from echo-evaluation of IVC. IVC

Change with respiration/ sniff

Estimated RA pressure

Normal ( 2 cm)

Decrease  50%

10 mm Hg

Dilated (> 2 cm)

Decrease  50%

15 mm Hg

Dilated with dilated hepatic veins

No change

20 mm Hg

IVC: Inferior vena cava; RA: Right atrial.

therefore, left ventricular (LV) filling pressures. CVP: measurements are also influenced by presence of significant tricuspid regurgitation (TR) and positive end-expiratory pressure (PEEP) ventilation.

Acute Heart Failure 101

ii. Pulmonary artery catheter (PAC): PAC is a balloon floatation catheter that measures pressures in the superior vena cava (SVC), right atrium (RA), right ventricle (RV) and pulmonary artery (PA) as well as cardiac output by thermodilution (Fig. 4.2). Modern catheters can measure the cardiac output semicontinuously as well as mixed venous oxygen saturation and RV end-diastolic pressure and ejection fraction: • Insertion of a PAC for diagnosis of AHF is usually unnecessary except in complex patients with concurrent cardiac and pulmonary disease. • PCWP is not an accurate reflection of LVEDP in patients with mitral stenosis, aortic regurgitation, ventricular interdependence, high airway pressure or stiff LV. • Several retrospective studies assessing the use of PAC in acute myocardial infarction demonstrated increased mortality with the PAC mostly because of inappropriate use of information derived from the catheter. • Use of a PAC is recommended in hemodynamically unstable patients, who are not responding in a predictable fashion to traditional treatments and in patients with a combination of congestion and hypoperfusion. • In cardiogenic shock and prolonged severe low output syndrome, it is recommended that the mixed venous oxygen saturation (SVO2) from the pulmonary artery be measured as an estimation of oxygen extraction. The aim should be to maintain SVO2 above 65% in patients with AHF. iii. Additional methods of hemodynamic assessment: a. Bedside echocardiography: Already discussed in this chapter. b. Noninvasive methods that are used to determine cardiac output include Doppler probes positioned in the suprasternal notch, the esophagus or the aorta. Currently, this technology does not compare reliably with thermodilution techniques and is not routinely used.

)LJ Pressure tracing seen during advancement of a pulmonary artery catheter.

102 The Protocol Book for Intensive Care 7DEOH1RUPDOUDQJHRIULJKWKHDUWSUHVVXUHV Site

Pressure/mm Hg 0–5

Right atrium (RA) Right ventricle (RV) Systolic

15–30

Diastolic

0–6

Pulmonary artery (PA) Systolic

15–30

Diastolic

5–13 2–12

Pulmonary wedge (PCWP)

c. Bioimpedance: Methodology quantitates flow through the thoracic aorta by assessing changes in impedance when current is applied across the thorax. Topical electrodes are placed on the chest and neck. The technique has been shown to correlate favorably with thermodilution methods in a wide spectrum of critically ill patients but is less reliable in conditions which significantly change the fluid content of the thorax, for exapmle, severe pulmonary edema, pleural effusions, hemothorax, etc.

Some Calculations 80 (MAP – CVP) CO = 1000 – 1500 dynes/s/cm–5 80 (MPAP – PCWP) Pulmonary vascular resistance (PVR) = CO = 120 – 250 dynes/s/cm–5 CO = 2.5 – 4.5 L/min/m2 Cardiac index = Body surface area Systemic vascular resistance (SVR) =

7DEOH+HPRG\QDPLFSDUDPHWHUVLQGLIIHUHQWFRQGLWLRQV Conditions

RA

PA

PCWP

CI

PVR

SVR

LV infarction

↔ or ↑

↔

↑↑

↓

↓

↑

RV infarction

↑

↓

↓

↓

↓

↑

VSD

↔ or ↑

↑

↑

↑

↑

↑

Papillary muscle rupture

↔ or ↑

↑

↑↑

↓

↑

↑

↑

↑

↓

↓

↑↑

↑

↑↑

↓

– to RA

↓

↔

↑

Early septicemia

↓

↓

↓

↑

↓

↓

Late septicemia

↔ or ↑

↔ or ↑

↑

↑

↑

↓

↓

↓

↓

↔

↑

Massive pulmonary embolism Tamponade

Hypovolemia

RA: Right atrium; PA: Pulmonary artery; PCWP: Pulmonary capillary wedge pressure; SVR: Systemic vascular resistance; VSD: Ventricular septal defect; LV: Left ventricle.

Acute Heart Failure 103 )ORZFKDUW Approach to the patient with acute heart failure.

ALS: Advanced life support; BLS: Basic life support; CPAP: Continuous positive airway pressure therapy; NIPPV: Noninvasive positive pressure ventilation; PAC: Pulmonary artery catheter.

FURTHER MANAGEMENT OF HYPOTENSION DEPENDING ON HEMODYNAMIC SUBSETS SVO2 !60%, CI !2.2 L/min/m2, SVR 1,300 dynes/s/cm5 • Reassure frequently • Management of hypotension, hypoxia, oliguria, metabolic acidosis SVO2 !60%, CI !2.2 L/min/m2, SVR !1,300 dynes/s/cm5 • IV nitrates (nitroglycerin or isosorbide dinitrates) ± fluids • Consider inodilators (amrinone, milrinone) SVO2 60%, CI !2.2 L/min/m2, PMP mm Hg • Fluid challenge → MAP !60 mm Hg → IV nitrates r consider inodilators CI !2.2 L/min/m2, SVO2 60%, MAP !60 mm Hg • ↑ Dobutamine • Consider inodilators (milrinone/amrinone) CI !2.2 L/min/m2, SVO2 !60%, MAP 60 mm Hg • Noradrenaline 0.05 μg/kg/min, increase by 0.05 μg/kg/min increments • Consider sepsis syndrome and manage accordingly. SVO2  60%, CI  2.2 l/min/m2, PCWP  18-20 mm Hg.

104 The Protocol Book for Intensive Care )ORZFKDUW Approach to AHF with systolic dysfunction.

SBP: Systolic blood pressure.

)ORZFKDUW Approach to AHF with hypotension.

ABG: Arterial blood gas; CVP: Central venous pressure; PA: Pulmonary artery.

Acute Heart Failure 105 )ORZFKDUW Approach to AHF with hypotension (contd.).

PCWP: Pulmonary capillary wedge pressure; IABP: Intra-aortic balloon pump.

Treatment Goals for Patients Admitted for ADHF Immediate (ED/ICU/CCU) a. Improve hemodynamics and organ perfusion b. Improve oxygenation c. Alleviate symptoms d. Limit cardiac and renal damage e. Prevention of thromboembolism f. Minimize ICU stay

Intermediate (in-hospital) a. Identify cause and relevant comorbidities b. Titration of therapy for control symptoms and congestion and optimize BP c. Initiate and up titrate disease modifying pharmacological therapy d. Device therapy in suitable patients

Predischarge and Long-term Management a. Develop a care plan that provides a schedule for up titration of drugs Need and timing for review for device therapy Who will see the patient for follow-up and when

106 The Protocol Book for Intensive Care b. Enroll in disease management program, educate and initiate lifestyle adjustments c. Prevent early readmission d. Improve symptoms, survival

RECOMMENDATION FOR HOSPITALIZATION PATIENTS WITH ACUTE DECOMPENSATED HEART FAILURE (ADHF) Hospitalization Recommended For high risk patients, initial care must be provided in high dependency setting: • Persistent and significant dyspnea • Hemodynamically unstable • Recurrent arrhythmia • Associated ACS

Criteria for ICU/CCU Admission (any of Following) • • • • • •

Intubation required Symptoms/signs of hypoperfusion SpO2 90% (with oxygen) Respiratory rate !25/min, accessory muscles working HR 40 or !130/min SBP 90 mm Hg 7DEOH0RQLWRULQJUHFRPPHQGDWLRQVIRUSDWLHQWVKRVSLWDOL]HGZLWK$'+) Frequency

Value

Specifics

At least daily

Weight

Determine after voiding in the morning Account for possible increased food intake due to improved appetite

At least daily

Fluid intake and output

More than daily

Vital signs

Heart rate, respiratory rate, blood pressure and oxygen saturation

At least daily

Signs

Edema, ascites, pulmonary rales, hepatomegaly, increased JVP, hepatojugular reflux, liver tenderness

At least daily

Symptoms

Orthopnea, PND or cough, nocturnal cough, dyspnea, fatigue lightheadednsss

At least daily

Electrolytes

Potassium, sodium

At least daily

Renal function

BUN, serum creatinine

$'+)$FXWHO\GHFRPSHQVDWHGKHDUWIDLOXUH31'3DUR[\VPDOQRFWXUQDOG\VSQHD%81%ORRG urea nitro; JVP: Jugular venous pressure.

Acute Heart Failure 107

• •

The remaining patients with AHF need hospitalization in ordinary ward Step down care from the ICU/CCU is determined by clinical improvement and resolution of morbid conditions

PHASE OF MANAGEMENT Phase I Management in ED Dyspnea is the most common complaint in ADHF patients the initial management of uncomplicated ADHF is management of respiratory issue. Recommendations for the management of AHF with oxygen therapy and ventilator support: 1. Transcutaneous SpO2 monitoring needed (Class 1C) 2. Oxygen therapy is recommended in SpO2 less than90% or PaO2 less than 60 mm Hg to correct hypoxemia (Class 1C) ESC 2016 3. Noninvasive positive pressure ventilation (NIV)—CPAP, BiPAP should be considered in patients having respiratory distress (RR !25/min, SpO2 90%) (Class 11aB) but NIPPV may cause decreased BP so requiring careful monitoring of BP. 4. Intubation is recommended, if respiratory failure leads to hypoxemia (PaO2 60 mm Hg ), hypercapnia (PaCO2 !50 mm Hg) and acidosis (Ph 7.35), cannot be managed noninvasively (Class 1C) 5. Addition of thiazide type diuretic or spironololactone in patients with resistant edema or insufficient symptomatic response. 7DEOH'LXUHWLFWKHUDS\LQ$+) Indication

Diuretics

Doses

Comments

Moderate volume overload

Furosemide or Bumetanide or Torsemide

20–40 mg 0.5–1 mg 10–20 mg

Titrate dose accordingly monitor Na+ , K+, Mg2, Cr. and BP

Severe volume overload

Furosemide (oral) Furosemide (IV infusion) Bumetanide Torsemide

40–100 mg 5–40 mg/hr 1–4 mg (oral/IV) 20–100 mg (oral/IV)

Refractory to diuresis

Add: Hydrochlorthiazide or metolazone or spironolactone

50–100 mg

With Alkalosis

Acetazolamide

0.5 mg

Refractory to loop and thiazide diuretics

Add: Dopamine (renal vasodilatation) or dobutamine

2.5–10 mg 25–50 mg

Combination better than very high dose F More potent of Cr.Ct.  30 mL/min Best if no renal failure Normal/low K+ I/V Consider UF/HD if underlying CRF

108 The Protocol Book for Intensive Care

Diuretics 1. Most important drug in a patient with ADHF. 2. ESC Guideline 2016 recommends that intravenous loop diuretics for all patients with AHF presented with symptoms and signs of volume overload with regular monitoring of symptoms, urine output, renal function and electrolytes (Class 1C). 3. Initial dose should be 20–40 mg IV furosemide, for those on chronic diuretic therapy, initial IV dose must be equivalent to oral dose (Class 1B ESC 2016). REALITY-AHF study as conclusively shown that early treatment [defined as door-to-furosemide (D2F) time 60 minutes] with intravenous loop diuretics was associated with lower in-hospital mortality in patients presenting at the ED for AHF. 4. Diuretics will be given as intermittent bolus doses or as a continuous infusion (Class 1B). 5. Addition of thiazide type diuretic or spironololactone in patients with resistant edema or insufficient symptomatic response. DOSE trial: Optimal dose and means of administration. Initial result from DOSE study have demonstrated bolus every 12 hours and continuous infusion appear to be equivalent in terms of symptom relief, changes of renal function and measure of congestion. Although high dose therapy (2.4 u oral dose given IV) was not superior to low dose (1 u oral dose) on the basis of the primary efficacy end-point of global symptom relief during 72 hours; high dose was associated with improvement in dyspnea, resolution of signs, symptoms of congestion, net fluid loss and greater decrease in NT-proBNP.

VASODILATORS Glyceryl Trinitrate (GTN) Indication: AHF with adequate BP Vasodilator to be avoided in SBP < 90 mm Hg and be cautiously used in mitral or aortic stenosis

Nesiritide Recombinant form of human BNP available as IV drug; currently approved by FDA. It is a balanced vasodilator with ↑ CO independent of changes in cardiac contractility and heart rate and less consistently natriuresis and diuresis. The effect of nesitride was prospectively studied in ASCEND-HF study. Inotropes with vasodialatory properties: Significantly ↓ PCWP and ↑ CO. Retrospective data shows IV use of inotropes in AHF (except digoxin) ↑ longterm mortality rate. Despite having side effects in North American (ADHERE

Acute Heart Failure 109 Table 4.10: 9DVRGLODWRUV LQ $+). Indication

Vasodilator

Dosing

Comments

Pulmonary congestion or edema and SBP should be t90 mm Hg

Nitroglycerin

Start 10–20 Pg/min ↑ up to 200 Pg/min Start 1 mg/hr ↑ up to 10 mg/hr Start 0.3 Pg/kg/min and ↑ up to 5 Pg/kg/min Bolus 2 Pg/kg + Infusion 0.01 Pg/kg/min

Hypotension headache, tolerance Hypotension headache, tolerance Hypotension, light sensitive Isocyanate toxicity Hypotension

Isosorbide Nitroprusside (Hypertensive HF) Nesiritide

SBP: Systolic blood pressure; HF: Heart failure.

and OPTIMIZE-HF) and European registries approximately 15% and 25% of patients were treated with inotropes. The use of these drugs should be limited to patients with hypotension (SBP 90 mm Hg) and or symptoms or signs of hypoperfusion despite adequate filling status, to increase cardiac output and BP, improve peripheral perfusion (Class 11aB-ESC 2016) Milrinone: PDE3 inhibitor approved for short-term circulatory support for advanced HF. In a prospective study OPTIME-HF it did not improve hospital mortality rate; 60-days mortality rate or composite incidence of death/ readmission; however, more patients developed severe hypotension and atrial/ventricular arrythmias especially those who have coronary artery disease. Levosimendan: Calcium sensitization and ATP dependent K+ channel opener that has positive inotrope and vasodilatory effect. IV infusion of levosimendan or a PDE3 inhibitor may be considered to reverse the effect of beta-blockade, if it contributes to hypotension and hypoperfusion (Class 11bC). In REVIVE-II study an improvement in patient self-assessment, a decreased level of BNP and a shorter hospital stay was noted in response to levosimendan when added to standard therapy. However, compared to placebo, it was associated with more hypotension (50% vs 30%) ventricular tachycardia (25% vs 17%) and atrial fibrillation 9% vs 2%). In SURVIVE study, 6 months of follow-up mortality was 26% in levosimendan group and 28% in dobutamine group. Levosimendan should be considered for patients with low cardiac output states despite the use of oral therapies. A meta-analysis updated 2008 including 3,650 patients (collected on 19 randomized controlled trials) with acute severe heart failure concluded that levosimendan improved hemodynamic parameters when compared with placebo and levosimendan improved both hemodynamic and survival when compared with dobutamine. Levosimendan has also been reported to improve right ventricular contractility and reduce RV afterload. However, in

110 The Protocol Book for Intensive Care Table 4.11: ,QRWURSHV LQ $+) Inotropic agent

Bolus

Infusion rate

Dobutamine

No

(p+) 2–20 Pg/kg/min

Dopamine

No

(G)  3 Pg/kg/min Renal inflow (E) 3-5 P/kg/min Inotropic (E)(D) !5 Pg/kg/min Vasopressor

Milrinone

25–75 Pg/kg over 10–20 min (Optimal)

0.375 – 0.75 Pg/kg/min

Enoximone

0.5–1 mg/kg over 5–10 min

5–20 Pg/kg/min

Levosimendan

12 Pg/kg during 10 min (optional)

0.1 Pg/kg/min whom can be ↓ to 0.05/↑ to 0.2 μg/kg

Norepinephrine

No

0.2–1 Pg/kg/min

Epinephrine

Bolus 1 mg can be given IV during resuscitation Repeat every 3–5 min

0.05–0.5 Pg/kg/min

patients with cardiac insufficiency, it has been shown to increase the incidence of arrhythmias like atrial fibrillation and ventricular tachycardia. Ongoing studies are looking at combinations of levosimendan with thrombocytic therapy and beta-blockers. Vasopressor agents: • Phenylephrine • Norepinephrine • Digoxin • Arginine vasopressin agents known as the antidiuretic hormone A vasopressor preferably norepinephrine may be considered in case of cardiogenic shock, despite treatment with other inotrope, to raise BP and vital organ perfusion (Class 11B) and ECG and BP to be closely monitored while using inotrops and vasopressor agents (ESC 2016). The main regulator of plasma osmolarity. It acts by binding to three receptors: i. V1a: Most wide spread; present in smooth muscle, mediates vasoconstriction. ii. V1b: Anterior pituitary and brain, regulates neural pathway. iii. V2: Renal collecting duct; main regulator of antidiuretic action. Currently, available antagonists are tolvaptan (oral; selective V2 receptor antagonist); conivaptan (IV; V1 and V2). In EVEREST trial with tolvaptan, the composite end-point of CV death/hospitalization for heart failure was not significantly different than placebo. However, in the short-term studies, when added to standard therapy modestly improves signs and symptoms during hospitalization and decrease bodyweight without affecting heart failure status. In patients with AHF addition of Conivaptan to standard therapy increases urine output without improvement of symptoms or decreasing bodyweight.

Acute Heart Failure 111

Currently, conivaptan (intravenous) and Tolvaptan (oral) are approved for treatment of euvolemic hyponatremia in hospital patients with heart failure. Side-effects include infusion site phlebitis (for conivaptan), hypokalemia, headache and neurologic deficits (from over-rapid correction of hyponatremia). Recently, FDA has announced a warning in view of the risk of potentially fatal liver injury with tolvaptan. These agents are also known as 'Aquaretics.' IV beta-blockers: As general rule de novo therapy with beta-blocker should not be started during initial phase of AHFS as it acutely decrease cardiac contractility. However, short-acting IV blocker such as esmolol may be considered when AHF is precipitated by AF and atrial flutter with rapid ventricular rate. These agents should be continued during hospitalization in patients already receiving beta-blocker unless shock or severe hypotension or bradycardia is present. On the basis of results of B-CONVINCED trial. OTHER DRUGS: DIGOXIN (bolus of 0.25–0.5 mg IV) may be used for acute control of ventricular rate in atrial fibrillation, amiodarone may be used (Class 11) • Thromboembolic prophylaxis with LMWH is recommended in patients not already anticoagulated or having no contraindication to anticoagulation, to reduce incidence of DVT and PE (Class 1B indication ESC 2016) • Opiates may be used to relieve anxiety but severe dyspnea can occur • Cautious use of diazepam or lorazepam may be used as sedative

Phase II Management This is the continuation phase of management after emergency department management. This includes optimization of medical therapy and diagnostic work-up. i. Treatment of clinical and hemodynamic congestion: In patients with congestion, diuretics usually continued and switched from IV to an oral form. Oral diuretics (loop diuretics) should be given twice daily to achieve maximum euvolemia without worsening renal function, for those who not respond to loop diuretics, drugs like thiazide and metolazone (more potent if CrCl 30) should be considered. Also spironolactone/ eplerenone may be added in patient with hypokalemia. Daily laboratory investigation include Na+, K+, Mg2+, BUN, creatinine and intake output. Body-weight should be measured to monitor optimal diuretic therapy without undue complication. ii. Implementation of evidence based interventions known to improve outcome in HF: Both ACC/AHA and ESC guidelines support continuation of ACEIs/ARBs, beta-blockers, aldosterone antagonist during hospitalization for ADHF unless hemodynamic instability or other contraindication present. Aldosterone blocking agents are contraindicated for patients with K + !5 mEq/L or Cr !2.2 mg/dL.

112 The Protocol Book for Intensive Care •

•

•

The DIG trial showed addition of digoxin to angiotensin converting enzyme (ACE) inhibitors and diuretics reduces rehospitalization and in retrospect mortality in patients with serum concentration of drug less than 1 ng/mL. These benefits were observed particularly in patients with very low EF. CRT: Approximately 40% of ADFS patients with reduced EF have wide QRS, CRT should be considered for symptomatic patients with heart failure in sinus rhythm with QRS duration more than 150 msec and LBBB QRS morphology and LVEF less than 35% despite optimal medical therapy to improve symptoms and reduce mortality (Class 1A). ICD: ICD is recommended to reduce the risk of sudden cardiac death in patients with symptomatic HF with LVEF less than 35% despite more than 3 months of optimal medical treatment, provided they are expected to survive more than 1 year with good functional status (ESC 2016).

Revascularization Patient with obstructive CAD may benefit from revascularization procedures particularly when there is significant documented ischemia or hibernating myocardium.

Recommendation Prior to Discharge a. Check exercise capacity b. Educate patient and family member regarding disease process and outcomes c. Life style modification d. Address potential for micro- and macronutrient

Phase III Management (after Discharge and during Vulnerable Phase) a. Schedule the follow-up according to disease severity (1 week to 1 month) b. Ensure early follow-up with monitoring of BP, bodyweight, renal function, electrolytes and possibly BNP

Potential New Therapies 1. Soluble guanylate cyclase activators (SGC): Cinaciguat is a novel nitric oxide (NO) independent activator of SGC and activates soluble form of guanylate cyclase in smooth muscle cell. Thus, leading to the synthesis of cGMP and subsequent vasodilation. During periods of increased oxidative stress as ADHF, a significant proportion of heme bound may become Fe oxidized, potentially blunting the effect of NO donors but it is heme

Acute Heart Failure 113

independent guanyl cyclase activator that is now under investigation in COMPOSE trial. 2. Chimeric natriuretic peptides (CD-NP): Combines the beneficial aspects of C type NP with 15-amino acid C-terminal tail of dendroaspis NP (DNP)/N(DNP). CNP lacks the natriuretic effect of ANP/BNP but has benefit of less hypotension because of primary venodilatation as opposed to BNP which is both arteriovenous dilator. DNP has got significant natriuretic effects but also cause hypotension. CD-NP ideally combines the lack of unwanted atrial vasodilation of CNP with positive natriuretic effect. 3. Direct renin inhibitors: Inhibition of the 1st enzymatic step in the RAAS cascade, leading to profound suppression of this neurohormonal system. Aliskiren is an example. It has been tested in the ASTRONAUT trial which was presented in ACC 2013 (discussed in chapter ‘Chronic Heart Failure’). 4. Adenosine antagonist rolofylline: Which is a highly selective adenosine A1-receptor has been studied in PROTECT pilot study. The phase III PROTECT II trial showed only mild benefit of symptom but no effect on the renal protection and had CNS side-effects. 5. Ularitide: Synthetic analog of urodilatin, a natriuretic and diuretic hormone of the family of A type NP produced by renal tubular cells. It has been investigated in SIRUS trial which showed improved clinical status, hemodynamics and neurohormonal profile; however, it was associated with significant hypotension. 6. Endothelin antagonist: Endothelin is most potent endogenous vasoconstrictor and is produced by vascular smooth muscle cell. Tazosentan a nonselective ET A-B antagonist has been shown to improve hemodynamics in HF. In VERITAS study addition of IV tazosentan to standard therapy did not improve symptoms or survival at 7 days. 7. Cardiac myosin activators: COSMIC-HF trial shows Omecamtiv mecarbil significantly improved cardiac function in patients with chronic heart failure marked dose dependent ↑ of EF with reflex bradycardia. 8. Istaroxime: New class of drug has dual action on myocyte. By inhibition of membrane bound Na+K+ATPase and by enhancing the activity of the sarcoendoplasmic reticulum Ca2+ ATPase type 2a (SERCA2a). HORIZONHF Study shows this drugs improve LEF, reduce heart rate and ventricular stiffness. 9. Stresscopin: The peptide human urocortin 2 (h-UCN2) is now in phase II trial. 10. Serelaxin: Recombinant human relax in – 2 tesyed in RELAX – AHF trial. Future prospect: At present outer management consist of treating manufacturers rather than pathophysiology process. Thus a better understanding of cardiac metabolism of dysfunctional but viable myocardium

↑

↑↑

↑↑↑

0

0, ↑ ↑↑↑

0

↑

↑↑↑

0

↑

↑↑↑

2.0

0.01-–0.1

Isoproterenol (β1 ! β2)

↑

0

↓

0

0

↑↑

↑

150

Bolus: 50–75 (10 min) Drip: 0.375–0.75

Milrinone (PDE inhibitor)

0

↓

↑↑↑

0

↑↑↑

↓

0

20

0.2–0.3

Phenylephrine (a-agonist)

n: Increase; 0: No change;p: Decrease; Elim t1/2: Elimination half-life; HD: High dose; PDE: Phosphodiesterase; SVR: Systemic vascular resistance.

↑

↑↑ HD ↑

0 ↑↑

Diuretic effect (direct)

Arrhythmia risk

↑ ↑

0, ↑ HD ↑

↑ ↑

HD ↑

↑↑

Chronotropic effect

HD ↑↑

HD ↑

Vasoconstriction

↑

↑↑

2.0

0.01–0.03 max. 0.1-0.3

Epinephrine (β1 = β2 !a)

0

↑

3.0

0.01–0.03 max. 0.1

Norepinephrine (β1 !a !β2)

Blood pressure effect

↑↑ ↑↑

↑↑ ↑

Inotropic effect

Anteriolar vasodilation

2.0

2.4

Elim t1/2 (min)

2–5 renal effect 5–10 inotropic 10–20 SVR ↑

Dopamine (Dopaminergic !β; High-dose a)

2–15

Dobutamine (β1 ! β2 !a)

Dose infusion (μg/kg/ min)

Drugs and mediating receptors

7DEOH6\PSDWKRPLPHWLFLQRWURSHVIRUDFXWHFDUGLDFIDLOXUHWKHUDS\

114 The Protocol Book for Intensive Care

Acute Heart Failure 115

will allow development of specific therapy and because we deal with heterogeneous population of patients, it is unlikely that a ‘One Therapy will fit All’.

DISCHARGE CRITERIA FOR PATIENTS WITH AHF Recommended for All AHF Patients i. Exacerbating factor addressed ii. Near optimal volume status observed iii. Transition from IV to oral diuretic successfully completed; salt and fluid intake regime laid down iv. Patients and family education completed including clear discharge instructions v. LVEF documented vi. Smoking cessation counseling initiated vii. Near optimal pharmacotherapy achieved including ACE I, beta-blockers for patients with ↓ LVEF or intolerance documented viii. Follow-up clinic visit scheduled usually 7–10 days

Should be Considered for Patients with Advanced HF/ Recurrent Admission for HF • • • • •

Oral indication regimen stable for 24 hours No IV vasodilator/inotropes for 24 hours Ambulation before discharge to assess the functional capacity after therapy Plan for postdischarge management Referral for disease management if available

CARDIAC DISEASE AND AHF REQUIRING SURGICAL TREATMENT • • • • • • •

Cardiogenic shock after AMI in patients with mutlivessel ischemic heart disease Postinfarction ventricular septal defect Free wall rupture Acute decompensation of pre-existing heart valve disease Prosthetic valve failure or thrombosis Aortic aneurysm or aortic dissection rupture into the pericardial sac Acute MR from: ƒ Ischemic papillary muscle rupture ƒ Ischemic papillary muscle dysfunction ƒ Myxomatous chordal rupture ƒ Endocarditis ƒ Trauma

116 The Protocol Book for Intensive Care •

• •

Acute aortic regurgitation from: ƒ Endocarditis ƒ Aortic dissection ƒ Closed chest trauma Ruptured aneurysm of the sinus of valsalva Acute decompensation of chronic cardiomyopathy requiring support by mechanical assist devices

SCOPE OF LV ASSIST DEVICES IN AHF Patients potentially eligible for implantation of left ventricular assist device (LVAD). Patients with more than 2 months of severe symptoms despite optimal medical and device therapy and more than 1 of following: 1. LVEF less than 25% and peak VO2 less than 12 mL/kg/min 2. More than three hospitalization due to HF in previous 12 months without an obvious precipitating cause 3. Dependence on IV inotropic therapy )ORZFKDUW Sequential management of AHF.

IV: Intravenous; CNS: Central nervous system.

Acute Heart Failure 117

4. Progressive end organ dysfunction (deteriorating renal or hepatic function) due to reduced perfusion

Characteristic of Mechanical Circulatory Support Devices 1. Extracorporeal: ƒ Pump located outside body ƒ LV support (LVAD) ƒ Mechanism—pulsatile, volume displacement, pneumatic actuation ƒ Used for short-term purpose for days to weeks (BTR indication) 2. Intracorporeal: ƒ Pump implanted within body RV support (RVAD) ƒ Mechanism: continuous flow rotary pump, axial flow design used for long-term months to years (BTT OR DT indication) 3. Paracorporeal: ƒ Biventricular support (BVAD), continuous flow rotary pump, pump located outside but adjacent to body 4. Orthotopic position: Biventricular replacement—total artificial heart (TAH)

HEART FAILURE WITH PRESERVED EJECTION FRACTION It has been projected that underlying HFpEF may account for up to 65% of patients hospitalized for HF. Although diagnostic accuracy is limited in patients with more than one contributor for their dyspnea, the overall prevalence of HFpEF has been estimated as being between 1.1% and 3% of the whole population, with much higher percentage of patients having subclinical diastolic dysfunction. In patients over the age of 65 years, the prevalence ranges from 3.1 to 5.5%. The increase in HFpEF prevalence reflects the changing demographic of the general population, including increasing longevity, obesity and diabetes and the persistent presence of poorly controlled hypertension. Each of these factors is known to affect myocardial and vascular stiffness, pulmonary systolic pressure and left ventricular diastolic dysfunction. Community studies of healthy volunteers demonstrate that derangements in diastolic function are more common than in systolic function, and progress at a greater rate. Noncardiac comorbidities such as chronic kidney disease, anemia, malignancy and thyroid dysfunction quite frequent common in HFpEF; chronic kidney disease in particular may play a dual role in that it contributes to extracardiac volume overload and the development of the cardiorenal syndrome. Obesity is a predictor for HFpEF but not for HFrEF, and the adverse cardiac remodeling and biochemical abnormalities linked with the metabolic syndrome predispose to the development of increased myocardial stiffness and diastolic dysfunction. The total influence of comorbidities

118 The Protocol Book for Intensive Care on myocardial dysfunction and functional capacity is higher in patients with HFpEF than in those with HFrEF. Large scale studies are in progress to target this mechanism.

Preamble to Understanding of Hemodynamic Abnormalities in Heart Failure Architectural arrangement of LV myocardial fibers comprises of endo- and epicardial fibers and mid-myocardial circumferential fibers. Shortening of longitudinal fibers in systole causes displacement of the LV basal plane toward or stationery apex and contraction of circumferential fibers causes inward deformation of the LV cavity. LV ejection fraction (LVEF) refers to contribution by both longitudinal and circumferential fibers without distinguishing between relative contributions of the two. However, in many cardiac pathologies, longitudinal muscles fiber shortening is impaired prior to any impairment of circumferential muscle fiber shortening and in fact, in this initial period, circumferential function can even to a certain extent compensate for the impaired longitudinal function. This accounts for situations where despite a normal or even increased LVEF, subclinical LV dysfunction caused by deranged longitudinal function sets the break drop of “HFpEF.” Assessment of myocardial deformation in different planes can now be studied by Table 4.13: *UDGLQJRIFRQJHVWLRQ Variables

1

0

1

2

3

A. Bedside assessment 1. Orthopnea* 2. JVP (cm) 3. Hepatomegaly

—  8 and no hepatojugular reflex (HJR) Absent in the setting of normal JVP

None — Absent

Mild 8–10/hepatojugular reflex Liver edge

Moderate 11–15 Moderate pulsatile enlargement

Severe/worst ! 16 Massive tender enlargement is extending to midline 3+/4+

—

None

1+

2+

B. Laboratory Natriuretic peptides (One) BNP NT-proBNP

4. Edema

— —

 100  400

100–299 400–1,500

300–500 1,500–3,000

> 500 > 3,000

C. Dynamic Maneuvers 1. Orthostatic testing 2. 6 min walk test 3. 6 min walk test/ (distance in meters) 4. Valsalva maneuver

Significant ↓ in SBP/↑ HR — > 400 Normal response

No change in SBP/HR No difficulty 300–400 —

— Mild 200–300 Absent/ overshoot pattern

— Moderate 100–200 Square wave pattern

— Severe/worst  100 —

Congestion grade: < 1: None; 1–7: Mild; 8–14: Moderate; 5–20: Severe. *Orthopnea absent; 1: Mild (use of one pillow); 2: Moderate (! 1 pillow); 3: Severe (sleeps in DUPFKDLURQDVHWWLQJSRVLWLRQ 0RGL¿HGIURP*KHRUJKLDGH0)ROODWK)3RQLNRZVNL3HWDO(XU J Heart Fail. 2010;12(5):423-33.

Acute Heart Failure 119

several echocardiographic methods, for example, tissue Doppler imaging and more recent two and three dimensional speckle-tracking echocardiography which can provide data on myocardial deformation by measuring strain an strain rate. Strain and strain rate are less load-dependent than LVEF and provide earlier insight into myocardial dysfunction than LVEF. When there is an ultimate impairment of circumferential deformation with disease progression, an impairment of LVEF occurs, inducing the transition from HFpEF to HFrEF.

Cardiac Factors in HFpEF Hemodynamics Significantly, it has been shown that HFpEF patients—despite the measured LVEF in the normal or near-normal range—have subtle systolic dysfunction at rest as demonstrated by reduced LV strain at echocardiographic imaging, and this dysfunction has prognostic relevance. Moreover, it has been suggested that contractile dysfunction may contribute to inadequate myocardial response to exertion, leading to the appearance and exacerbation of HF symptoms. Indeed, a recent study in HFpEF subjects examined cardiac systolic reserve during exercise and found that positive contractility response was depressed. Hence, the exercise test may unravel mild deficits in systolic function in HFpEF. There is a high prevalence of pulmonary hypertension (PH) in HFpEF. A study has shown that pulmonary artery systolic pressure (PASP) rises along with pulmonary artery capillary wedge pressure (PAWP) in patients with both hypertension and HFpEF. However, PASP remains higher in HFpEF, even when adjusting for PAWP, suggesting a precapillary component to PH on top of pulmonary venous hypertension. An invasive hemodynamic study has recently shown that RV dysfunction is common in HFpEF and is contributed by both RV contractile impairment and afterload mismatch from PH. It has also been demonstrated that patients with HFpEF exhibit impaired RV reserve during exercise that is associated with high filling pressures and inadequate cardiac output responses. These findings emphasize the coexistence of biventricular dysfunction in HFpEF hemodynamics. Chronotropic incompetence represents another important facet of HFpEF, which has been described in approximately 30% of patients. Chronotropic incompetence may help to partially explain why most patients with HFpEF complain of symptoms predominantly during physical exertion. Since the rise in plasma catecholamine with exercise is similar in HFpEF and healthy controls, it has been proposed that chronotropic incompetence may be linked to deficits in beta-adrenergic stimulation. In addition, autonomic dysfunction may be a contributing factor, as heart rate recovery is abnormal and baroreflex sensitivity is attenuated in HFpEF.

120 The Protocol Book for Intensive Care Cardiac function is determined by the net balance between afterload and preload. Central aortic stiffness, increasing systolic load and negatively directed ventricular-vascular coupling, may accelerate HF development in at-risk patients. Aortic stiffness increases with age, ventricular systolic stiffening also increases, and this coupled ventricular-vascular stiffening is a hallmark of HFpEF. This restricts LV systolic reserve, augments the cardiac energy demands required to enhance cardiac output, and plays a key role in arterial pressure liability accompanying small changes in LV preload. HFpEF has remained a diagnostic challenge with variable definitions over the past decade, culminating in the development of a stricter definition in the recently published European Society of Cardiology guidelines. The diagnosis of HFpEF can be somewhat difficult to make, and often occurs after significant much delay and consideration of alternative diagnoses for dyspnea. For most patients, recognition of the typical features of HFpEF on resting echocardiography with the clinical syndrome of HF aids the diagnosis, and where the diagnosis remains unclear stress testing should be considered. An approach to diagnosing HFpEF is given in flowchart below.

Treatment The heterogeneity of the patient population, the wide range of clinical phenotype and short comings with a clear definition around HFpEF have led to largely negative clinical trials and a paucity of effective treatment options. Despite these limitations, a careful application of the trial outcomes together with a mechanistic understanding have led to basic principles for the treatment of the patient with HFpEF.

Non-pharmacological Therapy Approaches in HFpEF Exercise: In the Ex-DHF pilot trial, 64 patients with HFpEF were treated either according to the current recommendations or were exposed to an additional 7DEOH'LIIHUHQFHVEHWZHHQFDUGLRJHQLFDQGQRQFDUGLRJHQLFSXOPRQDU\HGHPD Cardiogenic

Noncardiogenic

History

Cardiac event, e.g. orthopnea

Severe noncardiac illness

Examination

Cool peripheries, S3, JVP↑, ‘Moist’ crackles

Usually warm peripheries, JVP↓, no S3, ‘dry‘ and more extensive crackles

ECG

Usually abnormal

Usually normal

CXR

Peripheral distribution

Peripheral distribution

PCWP

> 20 mm Hg

 20 mm Hg

Echo

Almost always abnormal

Usually normal

JVP: Jugular venous pressure; ECG: Echocardiogram; CXR: Chest X-ray; PCWP: Pulmonary capillary wedge pressure.

Acute Heart Failure 121 )ORZFKDUW Schematic representation of HFpEF hemodynamics.

HFpEF: Heart failure with preserved ejection fraction; LVEDP: Left ventricular end diastolic pressure; HF: Heart failure.

7DEOH'LDJQRVWLF&ULWHULDIRU+)3()

•

•

•

•

Presence of symptoms and signs typical of heart failure: ƒ

Note that signs are not always evident in patients with HFpEF, as filling pressures may only increase with exercise, the JVP may not be elevated at rest

ƒ

Typical signs and symptoms include breathlessness, reduced exercise tolerance, fatigue and ankle swelling; features such as a displaced apex beat and third heart sound are absent

A preserved ejection fraction (LVEF t50%): ƒ

Previous studies have included patients with LVEF ≥40%

ƒ

New guidelines suggest a gray zone between LVEF 40% and 50%

Elevated levels of natriuretic peptides#: ƒ

BNP level t35 pg/mL

ƒ

NT-proBNP level t125 pg/mL

Objective evidence of other cardiac structural or functional alteration: ƒ

Either left ventricular hypertrophy (increased left ventricular mass index) or left atrial enlargement

ƒ

Diastolic dysfunction on echo (increased E/e’ or decreased e’) or cardiac catheterization (increased LVEFP or PCWP, particularly with exercise).

BNP: Brain natriuretic peptide; HFpEF: Heart failure with preserved ejection fraction; JVP: Jugular venous pressure; LVEFP: Left ventricular end diastolic pressure; LVEF: Left ventricular ejection fraction; NT-proBNP: Amino-terminal pro-B type natriuretic peptide; PCWP: Pulmonary capillary wedge pressure. Adapted from the 2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart failure.

122 The Protocol Book for Intensive Care 7DEOH$QDSSURDFKWRGLDJQRVLVKHDUWIDLOXUHZLWKSUHVHUYHGHMHFWLRQIUDFWLRQ Patient presents with exertional dyspnea

• • • •

Take history and perform physical examination Measure natriuretic peptides Exclude other causes (pulmonary disease, ischemic heart diseases, anemia, physical deconditioning) Assess risk factor profile (advanced age, hypertension, raised BMl)

Clinical diagnosis of heart failure made when following diagnostic criteria met: • Presence of typical symptoms and signs of heart failure (including breathlessness, reduced exercise tolerance, fatigue and ankle swelling)—features such as a displaced apex beat and third heart sound may be absent In heart failure • Elevated natriuretic peptides (BNP t35 pg/mL or NT-proBNP t125 pg/mL) • Other causes excluded (pulmonary disease, ischemic heart diseases, anemia, physical deconditioning) Perform transthoracic echocardiography (resting) The following features on resting echocardiography are consistent with a diagnosis of HFpEF (not all need be present) • Raised pulmonary pressures (TR Jet velocity !2.8 m/s) • Left atrial enlargement (left atrial volume index !34 mL/m2) • Raised E/é ratio (t13)* • Increased wall thickness (LV mass index !115 g/m2 for men; !95 g/m2 for women) Consider exercise study in consultation with cardiologist to confirm impaired diastolic performance and elevated filling pressures • Exercise right heart catheterization—the gold standard measurement of hemodynamics, but not available In all centers • Stress echocardiography—noninvasive, but relies on good image quality and the presence of tricuspid regurgitation. BMl: Body PDVV LQGH[ %13 %UDLQ QDWULXUHWLF SHSWLGH +)S() +HDUW IDLOXUH ZLWK SUHVHUYHG ejection fraction: LV: Left ventricle: NT-proBNP: Amino-terminal pro-B type natriuretic peptide; TR: Tricuspid regurgitant. * E/é measured on tissue Doppler echocardiography.

dedicated training program. After 3 months, patients in the intervention group exhibited an improved peak VO2 and improved physical fitness. This was associated with an improvement of both diastolic and atrial function. These finding were corroborated by a recent meta-analysis by Pandey et al. Diet: In a very small study, 3 weeks of treatment with a salt-restricted DASH diet improved diastolic function, arterial stiffness, and ventricular-arterial coupling in 13 subjects with HFpEF. Further, a 20-week caloric restriction diet was feasible in obese HFpEF patients, and improved symptom burden, peak oxygen consumption and quality of life. Quantitatively, the improvement in quality of life was greater with diet than exercise. The combination of diet

Acute Heart Failure 123 7DEOH'LIIHUHQFHVEHWZHHQV\VWROLFDQGGLDVWROLFIDLOXUH Systolic failure

Diastolic failure

History

Coronary disease

Hypertension

Examination

S3

S4

Chest X-ray

Cardiomegaly present

Generally absent

ECG

Q-waves, low R-wave voltage, ST elevation

Electrical LVH

ECG: Echocardiogram; LVH: Left ventricular hypertrophy.

with endurance exercise training appeared supplementary. However, much larger studies are required before making firm clinical recommendations.

Principles of Management in Patients with HFpEF A. Avoid tachycardia: • Use digoxin or beta-blockers in patients with atrial fibrillation B. Control blood pressure: • ACE inhibitors, angiotensin receptor blockers and mineralocorticoid receptor antagonists may be of greatest benefit due to the physiological benefits seen in HFrEF; further studies are required C. Treat co-morbid conditions: • Optimize cardiac and noncardiac conditions (commonly atrial fibrillation, pulmonary disease, anemia and obesity) D. Relieve congestion with diuretics: • Judicious use of loop diuretic with careful monitoring of renal function E. Encourage exercise training: • Improves exercise capacity and physical function

Management of Comorbid Conditions It has been suggested that the root cause of myocardial, vascular and peripheral dysfunction in patients with HFpEF may be precipitated by the proinflammatory milieu created by the presence of multiple comorbid conditions. Increasing numbers of comorbidities correlate with higher frequency of hospital admissions, and patients with HFpEF have higher rates of noncardiac comorbidities compared with those with HFrEF. Patients with HFpEF who have diabetes have greater left ventricular wall thickness and reduced physical function compared with those with HFpEF without diabetes. Patients with COPD have a worse prognosis in HFpEF than see with HFrEF.

Fluid Retention In HFrEF, fluid retention can be treated with diuretics. Mechanistically, patients with HFrEF and HFpEF differ regarding changes in total blood

124 The Protocol Book for Intensive Care volume (TBV). TBV expansion in HFpEF is mainly characterized by a red cell mass deficit, indicating that true anemia (i.e. hemoglobin concentration 12 mg/dL) and a compensatory plasma volume expansion reflects the qualitative changes of TBV in most of the decompensated HFpEF patients. Loop diuretics, thiazide and thiazide-like drugs are necessary to overcome TBV expansion and congestion in both forms of HF. Differences among loop diuretics for the treatment of HFpEF could be of great potential interest, since smaller studies have suggested that torasemide, in contrast to furosemide, may have additional positive effects on collagen metabolism by inhibition of procollagen type I (PIP). The Hong Kong Diastolic Heart Failure Study showed that the quality of life can be improved by a monotherapy with diuretics, and this effect was amplified when ACEi was added. Thus, diuretics appear indispensable for the improvement of symptom relief. According to the report of a small study, adding the vasopressin antagonist tolvaptan can be effective in severe cases accompanied by hyponatremia. However, an excessive preload reduction by diuretics can lead to an under-filling of the left ventricle, therefore, to a reduction of stroke volume and cardiac output. This can be a specific problem in HFpEF patients with pronounced left ventricular hypertrophy and small ventricles.

ATRIAL CONTRACTION Patients with HFpEF tolerate atrial fibrillation poorly, especially when ventricular heart rate is high. Cessation of the atrial contraction diminishes the left ventricular filling and along with that, decreases cardiac output. Hence, restoration of sinus rhythm including ablation strategies and pharmacologic interventions including class I, II or III antiarrhythmic drugs may improve clinical symptoms. If this is not possible, ventricular heart rate should be lowered using beta-blockers or heart rate lowering calcium antagonists. Theoretically, late sodium current-inhibitors like ranolazine or eleclazine may exhibit ancillary antiarrythmic effects and may be considered in HFpEF patients with angina symptoms to maintain sinus rhythm.

ACE Inhibitors and Angiotensin Receptor Blockers ACE inhibition has become a pharmacological mainstay in the treatment of patients with low ejection fraction HF (i.e. HFrEF), significantly reducing morbidity and mortality and also favorably altering ventricular remodeling. Neurohormonal activation is evident across the spectrum of HF, irrespective of ejection fraction; however, one study of perindopril in HFpEF has shown benefits on HF hospitalization with ACE inhibitor therapy within the first year, but did not achieve its primary endpoint. Two large trials have examined the role of angiotensin receptor blockade in patients with HFpEF. I-PRESERVE

Acute Heart Failure 125

(Irbesartan in Heart Failure with Preserved Ejection Fraction Study), a large trial of more than 4,000 patients with HFpEF, with clinical characteristics typical of HFpEF, showed no impact of irbesartan on death, hospitalization or quality of life. CHARM-Preserved (Candesartan in Heart Failure—Assessment of Mortality and Morbidity; in patients with LVEF higher than 40%) demonstrated a modest impact of candesartan on hospitalization in an HFpEF, although it is important to note the less stringent entry criteria in this trial, including inclusion of patients with an ejection fraction down to 40%.

Aldosterone Blockade Aldosterone has a major role in myocardial collagen formation, suggesting a role for spironolactone in the treatment of patients with HFpEF. Early trials demonstrated a reduction in left ventricular filling pressures, culminating in the international TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial), which enrolled 3,445 patients. Although the study was neutral regarding mortality and hospitalization, post hoc analysis demonstrated significant regional variation in outcomes between patients enrolled in Russia/Georgia and those from the Americas, with the latter group demonstrating a significant reduction in cardiovascular death and hospitalization for HF. In support of these findings, a smaller randomized study of 131 patients with HFpEF demonstrated improvements in exercise capacity and echocardiographic parameters of diastolic function after taking spironolactone for 6 months. These findings support future trials with aldosterone antagonists. However, it is important to remember that impaired renal function and hyperkalemia were more common in patients taking spironolactone, particularly in the patients who gained most benefit, and that renal function and biochemistry must be carefully monitored for patients on these agents.

Heart Rate Modification Diastole is shortened during tachycardia, and a reduction in heart rate would be presumed to improve symptoms in patients with HFpEF. Trials of betablockers have been negative in this regard, probably due to the presence of chronotropic incompetence in certain patients with HFpEF. Trials of heart rate modification with ivabradine, an If-channel blocker with effects on heart rate but not blood pressure, have shown early positive results, but not consistently across all studies.

Other Pharmacotherapy Pulmonary hypertension secondary to elevated left ventricular pressures is a key component in the pathophysiology of HFpEF; however, trials of

126 The Protocol Book for Intensive Care sildenafil, soluble guanylate cyclase inhibitors and isosorbide mononitrate have been neutral. Neprilysin inhibition, recently demonstrated to reduce mortality with startling success in patients with HFrEF, is under investigation in patients with HFpEF in the ongoing PARAGON trial.

Device Therapy The management of patients with HFrEF has become noteworthy for the beneficial combined effects of pharmacotherapy and device therapy, including implantable cardiac defibrillators and cardiac resynchronization therapy demonstrating remarkable impacts on morbidity and mortality. In patients with HFpEF, the fundamental physiological target is the elevated left atrial pressure. To offset left atrial pressure, an interatrial shunt can be inserted percutaneously, with recent trial results suggesting significant improvements in quality of life and functional capacity. Beyond this approach, early trials targeted to offset chronotropic incompetence and improve dyssynchrony with atrial pacing, with larger trials yet to be completed.

Emerging Therapies in HFpEF 1. Device therapy for HFpEF a. Online monitoring Increased pressures in the left atrium and the small circulation result in the symptoms of HFpEF. Importantly, the rise in atrial and right-sided pressures can be detected prior to symptom deterioration or overt decompensation. Online hemodynamic monitoring could detect such early markers of incipient decompensation. The CardioMEMS device is a small pressure sensor and monitor, which is implanted into the pulmonary artery and calibrated in the course of a right-heart catheter procedure. Following discharge, the patients record their pulmonary artery pressure via a cushion-based wireless radiofrequency transmitter. These values are online-monitored by dedicated staff and may be used to adjust medication. In the CHAMPION trial use of CardioMEMS transmitted information lowered hospitalization rates of NYHA III patients with either HFrEF or HFpEF. The CardioMEMS system was approved recently for Europe and the US. The LAPTOP device is a second system that measures left atrial pressure directly but its safety has been questioned due to complications during the implantation procedure which led to a premature termination of the trial. b. Atrial shunt device The reduction of increased left atrial pressure belongs to the hemodynamic objectives of treating HFpEF. The hypothesis that a small,

Acute Heart Failure 127

artificially induced left-right shunt might function as an overflow valve is based on historical observations showing that patients with an untreated mitral stenosis and concomitant atrial defect had better survival (Lutembacher syndrome). In a small study of 11 HFpEF patients (EF !45%, PCP !15 mm Hg at rest, or PCP !25 mm Hg during exercise) an interatrial septal device (IASD) was implanted in the septum using a catheter-based technique enabling a small shunt. After 30 days the filling pressure had fallen by 5 mm Hg and mean NYHA classification had improved. No patient developed pulmonary hypertension over this time. More recently, the REDUCE LAP-HF study analyzed. HFpEF patients (EF !40%, PCP !15 mm Hg at rest or PCP !25 mm Hg during exercise) who underwent IASD implantation. After 6 months 52% of patients showed a reduction in PCP at rest, 58% had a lower PCP during exertion, and 39% fulfilled both criteria. These encouraging results need to be repeated in long-term trials. c. Cardiac resynchronization therapy (CRT) Approximately 20% of HFpEF patients exhibit left ventricular asynchrony, which is associated with about 15% myocardical energy and contractility loss. Unpublished results of an Asian study investigating about 130 HFpEF patients with mechanical asynchrony (regional level mechanical delay !65 ms) suggest that temporary stimulation with a CRT system may improve diastolic parameters. Currently, a safety study in HFpEF patients with mechanical delay is being planned investigating the effect of so-called “fusion pacing,” a novel CRT pacing method. d. Cardiac contractility modulation (CCM) This device delivers a strong electrical current in the refractory period into the septum thus triggering molecular remodeling, which is thought to improve EF and optimize symptoms of symptomatic HFrEF patients. The effect seems to be more pronounced in patients with a better EF (i.e. !35%). A recent case series found that early after initiating CCM treatment patients improved in NYHA classification, 6 minute walking distance, quality of life, and showed a significant reduction of the diastolic filling index (E/é) and in improvement in EF reserve. A clinical phase-II trial investigating the effect of CCM in non-HFrEF patients, including a 2:1 HFpEF: HFmrEF randomization, has been initiated. 2. New developments among causal therapeutic strategies for HFpEF Novel strategies for the treatment of HFrEF include the regulation of energy and calcium homoeostasis, matrix regulation, inflammation, angiogenesis and oxidative stress. The myocyte decline of cGMP appears to be a specific mechanism during HFpEF and differs from HFrEF. A disorder in this signal cascade contributes to the development of concen-

128 The Protocol Book for Intensive Care tric remodeling, increased cardiomyocyte stiffness by disturbances of regulation of titin and to an increase of fibrosis. This new concept has consequences for the development of new therapeutic options, because it may be possible to mechanistically intervene with NO-donators, phosphodiesterase-5 inhibitors, by dipeptidyl peptidase 4 inhibitors (DPPIV), orally available soluble guanylate cyclase stimulators like vericiguat or by neprilysin inhibition. a. Organic nitrates and endothelial NO-synthase (eNOS) activators As of now, only short-acting nitrates are recommend to overcome angina symptoms in HFpEF. By contrast, eNOS activators like the eNOS transcription amplifier AVE3085 have been promisingly investigated in animal experiments and await clinical testing. b. Angiotensin receptor and neprilysin inhibition (ARNI) Natriuretic peptides exert antifibrotic, vasodilatory and natriuretic effects. Besides blood pressure reduction, the induction of diuresis by BNP can reduce volume overload and pulmonary pressure. This concept was investigated in the phase II PARAMOUNT trial. A decline in NT-proBNP levels after 12 weeks, the primary endpoint, was observed in the LCZ696 group, and atrial volumes were reduced and NYHA functional class improved after 36 weeks. Currently, the PARAGON-HF trial further explores these encouraging findings investigating the effect of LCZ696 on mortality risk among patients with HFpEF. c. Phosphodiesterase-5 inhibitors Patients suffering from primary pulmonary hypertension often also have concomitant diastolic dysfunction. In 44 patients with pulmonary hypertension and HFpEF (EF !50%) treatment with the phosphodiesterase-5 inhibitor sildenafil attenuated pulmonary pressure and improved diastolic function. However, these results were not confirmed in the placebo-controlled RELAX study investigating elderly HFpEF patients without pulmonary hypertension. Application of sildenafil among HFpEF patients without pulmonary hypertension can therefore not be recommended. The DILATE-1 trial examined the use of riociguat in patients with HFpEF and pulmonary hypertension. Thirty-six HF patients with EF more than 50%, mean PAP more than or equal to 25 mm Hg, and PAWP more than 15 mm Hg were randomized to riociguat. While there was no effect on peak decrease in mean PAP, riociguat (2 mg dose) increased stroke volume and cardiac index, and decreased systolic blood pressure and right ventricular end-diastolic area. Further studies are ongoing to investigate the effects of this drug class in HFpEF. d. Endothelin receptor (ET) antagonism Inhibition of ET receptors is used for the treatment of pulmonary hypertension. Experimental studies suggest that the dual ETA/ETB antagonist macitentan improved diastolic function in a murine model of HFpEF. Further studies on ET antagonism in HFpEF are ongoing.

Acute Heart Failure 129

e. Inflammation and cytokine inhibition Patients with HFpEF exhibit signs of chronic myocardial inflammation. Similarly, new adhesion molecule antagonists targeting integrins (ICAM or VCAM) are under investigation as is the role of colchicine to prevent myocardial invasion of inflammatory cells. f. Matrix regulation by 'cross-link breakers' Lysyl oxidase-like 2 (Loxl2) is an enzyme that crosslinks collagen and which has been shown to be essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. Antibodymediated inhibition of Loxl2 in mice has been shown to greatly reduce stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Further studies are ongoing to prove this antibody under clinical conditions. g. Micro-RNA regulation Currently, the importance of miRNAs and/or certain inhibitors (antagomirs) are investigated as inducers of angioneogenesis or modifiers of fibrosis, for example, inhibition of miRNA. For this molecule, antiapoptotic and antifibrotic effects were shown in an animal experiment related to diastolic heart failure. Further miRNAs are presently being discussed as possible therapeutic targets for the treatment of HFpEF.

SUGGESTED READING 1. Nanayakkara S, Kaye DM. Management of heart failure with preserved ejection fraction: a review. Clin Ther. 2015;37(10):2186-98. 2. Nanayakkara S, Mariani JA, Kaye DM. Heart failure with preserved ejection fraction: improving diagnosis and management. Med Today. 2017;18(1):37-42. 3. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129-200. 4. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, et al. 2013 ACCF/AHA guidelines for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-e327. 5. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guidelines for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-61.

C HAPTER

5

Management of Chronic Heart Failure Sudip Kumar Paul, Nodee Chowdhury, Soumitra Kumar

CHRONIC HEART FAILURE Definition A syndrome characterized by either or both pulmonary and systemic venous congestion and/or inadequate peripheral oxygen delivery at rest or during stress, caused by cardiac dysfunction. In congestive heart failure (CHF), right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP) ratio is important. RAP is often but not always correlated with PCWP. There are situations where RAP matches or exceeds PCWP; but there are also situations where right ventricular function is relatively preserved and RAP is less than PCWP. For practical purposes, the task force for the diagnosis and treatment of CHF, European Society of Cardiology considers the essential components of heart failure to be a syndrome in which patients should have the following features: (i) Symptoms of heart failure (typically breathlessness or fatigue) either at rest or during exertion, (ii) objective evidence (preferably by echocardiography) of cardiac dysfunction (systolic and/or diastolic) at rest and 7DEOH'H¿QLWLRQRI+)S()+)PU()DQG+)U() Types of HF

HFrEF

HFmrEF

HFpEF

1

Symptoms r Signs

Symptoms r Signs

Symptoms r Signs

2

LVEF 40%

LVEF 40–49%

LVEF !50%

3

—

1. Elevated levels of natriuretic peptides 2. At least one additional criterion: (a) relevant structural heart disease (LVH and/or LAE), (b) diastolic dysfunction

1. Elevated levels of natriuretic peptides 2. At least one additional criterion: (a) relevant structural heart disease (LVH and/or LAE), (b) diastolic dysfunction

HFpEF: Heart failure with preserved ejection fraction: HFmrEF: Heart failure with mild-range ejection fraction; HFrEF: Heart failure with reduced ejection fraction; LVEF: Left ventricular ejection fraction; LVH: Left ventricular hypertrophy; LAE: Left atrial enlargement

Management of Chronic Heart Failure 131

(iii) a response to treatment directed toward heart failure (e.g. diuretic administration). Criteria I and II should be fulfilled in all cases.

PRINCIPLES OF TREATMENT Based on: • History • Clinical examination • Investigation

1. Identification of primary cause 2. Evolution of stages of heart failure 3. Removal of precipitating cause.

HISTORY • • • •

Dyspnea, orthopnea, paroxysmal nocturnal dyspnea (PND) Fatigue and weakness Abdominal symptoms, for example, anorexia, nausea, pain, fullness of abdomen Cerebral symptoms, for example (in severe heart failure (HF)), headache, insomnia, anxiety, confusion, impairment of memory.

CLINICAL EXAMINATION Look for: Cyanosis, icterus, malar flush, cachexia, edema, coldness of extremities, raised jugular venous pressure (JVP), tachycardia, pulsus alternans • Hypotension • Bilateral pulmonary rales • Wheeze • Pleural effusion • Hepatomegaly, ascites • Cardiomegaly, gallop sound • S3, S4.

INVESTIGATION • •

•

complete blood count (CBC), Hb%, electrolytes, renal function, LFT, T3, T4, TSH B-type natriuretic peptide—Bedside assay can be useful in establishing or excluding the diagnosis of CHF in patients with acute dyspnea. In a recent study, diagnostic accuracy of B-type natriuretic peptide at a cutoff of 100 pg/mL was 83.4%. The negative predictive value of B-type natriuretic peptide at levels of less than 50 pg/mL was 96% Chest X-ray, electrocardiograph (ECG), arterial blood gas (ABG) test

132 The Protocol Book for Intensive Care )ORZFKDUW Diagnostic algorithm for a diagnosis of hart failure of non-acute onset.

BNP: B-type natriuretic peptide; CAD: Coronary artery disease; HF: Heart failure; MI: Myocardial infarction; HT: profit-jp, N-terminal pro-B type natriuretic peptide. *Patient Reporting symptoms typical of HF. Normal ventricular and atrial weakness and function. Consider other causes of elevated natriuretic peptides.

• • • • • • •

Echocardiography (Bedside) Stress test Radionuclide ventriculography Coronary angiography Cardiac magnetic resonance (CMR) imaging. Identification of primary cause of heart failure and treatment accordingly Removal and correction of precipitating cause: for example ƒ Anemia, infection, thyrotoxicosis, hypertension ƒ Arrhythmia, thromboembolism, obesity, pulmonary embolism ƒ Volume overload (e.g. pregnancy), dietary excess ƒ Physical and mental stress ƒ Drugs: Salt and water retaining drugs, cardiac depressant.

Management of Chronic Heart Failure 133

BIOMARKERS IN HEART FAILURE Established Biomarkers An ideal biomarker in chronic heart failure should have the following characteristics: • Highly sensitive or specific • Provide clinically relevant meaningful information • Should have the ability to guide therapy. • Cost effective • Can be easily monitored during therapy B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP): Diagnostic value of these biomarkers in CHF has been discussed in the chapter on ‘Acute Heart Failure’. Is there a role of BNP guided therapy in heart failure? STARS-BNP trial showed that CHF-related death or hospital stay for CHF was significantly lower in BNP guided group (24% vs 52%, p  0.001) suggesting that therapy directed by BNP level is superior to clinical based therapy.

7DEOH3DWKRSK\VLRORJLFDOFODVVHVRIELRPDUNHUV A. Myocardial stretch ANP, BNP, NT-proBNP, MR-proBNP, neuregulin, GDF-15 and sST2 B. Matrix remodeling MMP, TIMP1, IL-6, collagenase propeptides, N-terminal collagen type III peptide, syndecan-4, myostatin, galectin-3, sST2 and osteopontin C. Myocyte injury TnT, TnI, hsTrop, CK-MB, heart-type fatty acid-binding protein, heart shock protein 60, sFAS, sTRAIL and pentraxin 3 D. Oxidative stress MPO, oxidized LDL, urinary and plasma isoprostanes, urinary biopyrrins, urinary 8-hydroxy-2deoxyguanosine and plasma malondialdehyde E. Inflammation CRP, TNF-α, LP-PLA2, TWEAK, IL-6, FAS (APO-1), prolactinoma and cytokines F. Neurohormonal activation Norepinephrine, renin, angiotensin II, aldosterone, arginine vasopressin (AVP), endothelin-1, copeptin, urocortin, chromogranin A and B, MR-proADM and adrenomedullin G. Renal dysfunction Neutral gelatinase-associated lipocalin, kidney injury molecule, NAG, quiescin Q6, B-trace protein, cystatin C and FGF-23

ANP: Atrial natriuretic peptide; BNP: B-type natriuretic peptide; CK-MB: Creatinine kinase MB: fraction; CRP: C-reactive protein; FAS: Tumor necrosis superfamily; FGF: Fibroblast growth factor; GDF-15: Growth differentiating factor 15; hsTrop: Highsensitivity troponin; LDL: Low-density lipoprotein; LP-PLA2: Lipoprotein-associated phospholipase 2; MPO: Myeloperoxidase; MR-proADM: Mid-regional-pro adrenomedullin; NAG: N-acetyl-E-d-glucosaminidase; NT-proBNP: N-terminal proBNP; TNF-D: Tumor necrosis factor-D; TnI: Troponin I; TnT: Troponin T; TWEAK: TNF-like weak inducer of apoptos.

134 The Protocol Book for Intensive Care 7DEOH3URPLVLQJELRPDUNHUVLQFKURQLFKHDUWIDLOXUH

Potential role in patients with Biomarker

Proposed pathophysiology

chronic HF

Natriuretic peptides: ANP, BNP and C-type

Upon myocardial pressure or volume loading, precursor BNP released by the ventricles is cleaved into active BNP and inactive NT-proBNP which can thus be measured

Gold standard for biomarkers in chronic HF AHA recommendation class IA for diagnosis and prognosis of HF In PARADIGM-HF trial, they have become inclusion criteria: a BNP of !150 pg/mL or an NT-proBNP of t600 pg/mL, or if hospitalized for HF within the previous year then a BNP of !100 pg/mL or an NT-proBNP t400 pg/mL

sST2 (soluble toll-like receptor 2)

Member of the IL-1 receptor family that is secreted from myocytes induced by biomechanical strain. With myocardial stretch, IL-33 is released and when bound to the transmembrane ST2 legend (ST2L), it is involved in cardioprotective signaling, which prevents fibrosis and hypertrophy

Many HF trials found that elevated sST2 levels were associated with an increased risk of HF severity, mortality, cardiac transplantation, cardiovascular events and hospitalization

Galectin 3

β-galactoside-binding lectin produced by several tissues promotes cardiac fibroblast proliferation and collagen synthesis (maladaptive remodeling)

In the COACH trial, increased galectin-3 levels were predictive of poor outcomes independent of age, sex, BNP, renal function and diabetes

Copeptin

Stable plasma surrogate for vasopressin, which is released from the hypothalamus in response to changes in plasma osmolarity and reduced cardiac output

Independent role as a prognostic marker in patients with chronic HF. Probable role as molecular marker for tailored therapies with vasopressin antagonism

GDF-15

Member of the TGF-β cytokine family expressed in most tissues including myocytes

Predictive of mortality in patients with chronic HF beyond established biomarkers Serial changes are prognostically important Could lead to the development of specific treatments for patients with chronic HF

Mid-regional Pro-adrenoMedullin (MRpro-ADM)

Produced by various tissues within the cardiovascular system in response to hemodynamic stress Promotes positive inotropy and vasodilation

Likely to add prognostic value to predictive models for patients with chronic HF beyond that provided by natriuretic peptides and conventional clinical risk factors

Neuregulin 1

Represents a family of growth factors with an important role in cardiac development and the pathogenesis of chronic HF Has a significant role in promoting cardiomyocyte growth and function, and regulation of the stress response

Trials with recombinant neuregulin are ongoing, with a phase II trial showing improvement in cardiac structure and function

ANP: Atrial natriuretic peptide; BNP: B-type natriuretic peptide; HF: Heart failure; NT-proBNP: N-terminal proBNP

Management of Chronic Heart Failure 135

Predischarge BNP level is an independent prognostic marker of outcome after discharge in patients admitted for heart failure. A study by Logeart et al. reported that patients with heart failure whose BNP level does not decline to below 600 pg/mL should receive intensified treatment before discharge.

Which One is Better to Evaluate Heart Failure: BNP or NT-proBNP? Longer half-life of NT-proBNP makes it a better reflector of ventricular stress and hence also a better prognostic marker.

STAGES OF HEART FAILURE Stage A Patients at high-risk for developing heart failure with no structural heart disease, for example, patients with hypertension, atherosclerotic disease, diabetes, obesity, metabolic syndrome or patients using cardiotoxins or with family history of cardiomyopathy.

Stage B Patients with structural heart disease who have not yet developed symptoms of heart failure, for example, patients with previous myocardial infarction (MI), LV remodeling including Left ventricle (LV) hypertrophy and low ejection fraction, asymptomatic valvular disease.

Stage C Patients with past or current symptoms of heart failure associated with underlying structural heart disease.

Stage D Patients with refractory (end-stage) heart failure who require specialized intervention, for example, patients who have marked symptoms at rest despite maximal medical therapy.

OUTLINE OF TREATMENT OF CHF Stage A •

• •

Life-style modification: ƒ Regular exercise ƒ Smoking cessation ƒ Discourage alcohol intake and illicit drug use Treat hypertension, lipid disorders, metabolic syndrome Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) in appropriate patients, for example, for vascular disease or diabetes.

136 The Protocol Book for Intensive Care

Stage B • • • •

All measures under stage A ACEI or ARB in appropriate patients (vide latter sections) Beta-blockers in appropriate patients (vide latter sections) Implantable defibrillators in selected patients.

)ORZFKDUW ESC 2012 treatment algorithm.

ESC 2012 treatment algorithm. ACE: Angiotensin-converting enzyme inhibitors; LVEF: Left ventricular ejection fraction, HR: &KURQLF KHDUW ,&' ,PSODQWDEOH &DUGLRYHUWHU 'H¿EULOODWRU /9$' /HIW YHQWULFXODU DVVLVW GHYLFHV NYHA: New York Heart Association; CRT-P: Cardiac resynchronization therapy pacemaker; CRT-D: Cardiac resynchronization therapy device; H-ISDN: Hydralazine–isosorbide dinitrate

Management of Chronic Heart Failure 137

Stage C • • • •

•

All measures under stages A and B Dietary salt restriction Routine use of diuretics for fluid retention, ACEI, beta-blockers, Mineralocorticoid-receptor (MR) antagonist, ARNI Use in selected patients of: ƒ Ivabradine ƒ ARBs ƒ Digitalis ƒ Hydralazine/nitrates Devices in selected patients ƒ Biventricular pacing ƒ Implantable defibrillators.

Stage D • •

Appropriate measures under stages A, B and C Decision re: appropriate level of care. Options: a. Compassionate end-of-life care/hospice b. Extraordinary measures: ƒ Heart transplant ƒ Chronic inotropes ƒ Permanent mechanical support ƒ Experimental surgery or drugs.

PHARMACOTHERAPY OF CHF DIURETICS Proven Indication of Diuretics (Always Acceptable) •

Symptomatic improvement in case of congestion (New York Heart Association (NYHA) II-IV).

Acceptable Indication but of Uncertain Efficacy May Be Controversial •

Long-term treatment in conjunction with other drugs for heart failure such as ACEIs, vasodilator, beta-blockers. Withdrawal of diuretics in stable compensated patients with CHF has been shown in several studies to result in symptoms of congestion. A history of hypertension, baseline frusemide dose more than 40 mg/day, and a low-LV ejection fraction (27%) were independent predictors of diuretic reinitiation.

Not Proven: Potentially Harmful or Contraindicated • •

Heart failure without congestion or edema Severe decompensated hypokalemia or hyperuricemia.

138 The Protocol Book for Intensive Care )ORZFKDUW Pharmacotherapy of CHF. 2016 Update for therapeutic algorithm by ESC/AHA.

HFrEF: Reduced ejection fraction (HFeEF); ACEI: Angiotensin-converting enzyme inhibitors; /9() /HIW YHQWULFXODU HMHFWLRQ IUDFWLRQ  ,&' ,PSODQWDEOH &DUGLRYHUWHU 'H¿EULOODWRU $51, Angiotensin-recepter-neprilysin inhibitors; MR: Mineralocorticoid-receptor; OMT: Osteopathic PDQLSXODWLYH WUHDWPHQW 97 9HQWULFXODU 7DFK\FDUGLD 9) 9HQWULFXODU ¿EULOODWLRQ +5 +HDUW rate; CRT: Cardiac resynchronization therapy; H-ISDN: Hydralazine–isosorbide dinitrate; ARB: Angiotensin II receptor blockers; ARNI: Angiotensin-recepter-neprilysin inhibitors

ESC 2016 CLASS IB recommendation: Diuretics are recommended in order to improve symptoms and exercise capacity in patients with features of congestion.

GUIDELINES FOR USE OF DIURETICS Initial Diuretic Treatment •

Loop diuretics or thiazides always combined with an ACEI if tolerated (on the assumption that ACEI would suppress the adverse neurohormonal effect of diuretics, although this effect is not uniform)

Management of Chronic Heart Failure 139

•

If glomerular filtration rate (GFR) less than 30 mL/minute, do not use thiazides, except as therapy prescribed synergistically with loop diuretics.

Insufficient Response • • • •

Increase dose of diuretic Administer loop diuretics twice daily Combine loop diuretics twice daily In severe CHF, add metolazone with frequent measurements of serum creatinine and electrolytes.

Potassium Sparing Diuretics (Other than Spironolactone or Eplerenone) •

•

•

Use only if hypokalemia persists despite ACE-I or in severe heart failure, despite the combination of ACE-I and low doses of an aldosterone antagonist. Start with a 1-week low dose administration, check serum potassium and creatinine after 5–7 days and titrate accordingly. Recheck after 5–7 days until potassium values are stable. Potassium supplements are generally ineffective in cases of persistent hypokalemia. ESC 2016 CLASS IB recommendation: same as diuretics.

Aldosterone Antagonist Recommendations for Use in Systolic Heart Failure Proven Indications Class I: Administration of aldosterone antagonist is recommended for patients with NYHA classes II–IV from reduced Left ventricular ejection fraction (LVEF) of less than 35% while receiving standard therapy, including ACEI (or ARB) and beta-blocker (Level of evidence: A). Class IIa: Administration of an aldosterone antagonist would be considered in patients following an acute MI with clinical heart failure or history of diabetes mellitus and LVEF of less than 40%. Patients should be on standard therapy, including ACEI (or ARB) and a beta-blocker (Level of evidence: A).

Potentially Harmful or Contraindicated Class III: Aldosterone antagonists are not recommended when creatinine is 2.5 mg/dL or creatinine clearance is less than 30 mL/minute or serum creatinine is 5 mmol/L or in conjunction with other potassium-sparing diuretics (Level of evidence: A).

140 The Protocol Book for Intensive Care

Administration and Dosing Consideration with Aldosterone Antagonists (Spironolactone, Eplerenone) • • • • • •

Consider whether a patient is in severe heart failure (NYHA II-IV) despite ACE-inhibition/diuretics. Check serum potassium (5.0 mmol/L) and creatinine (2.5 mg/dL). Add a low dose (spironolactone 12.5–25 mg, eplerenone 25 mg) daily. Check serum potassium and creatinine after 4–6 days. If at any time serum potassium 5–5.5 mmol/L, reduce dose by 50%. Stop if serum potassium more than 5.50 mmol/L. If after 1 month, symptoms persist and normokalemia exists, increase to 50 mg daily. Check serum potassium, creatinine after 1 week.

Evidence Base of Aldosterone Antagonists • •

RALES (Spironolactone), EPHESUS (Eplerenone), EMPHASIS-HF (Eplerenone) AREA-IN-CHF (Canrenone—an active metabolite of spironolactone).

Are All Loop Diuretics Equal in Terms of Prognosis? The answer is yet unclear but in TORIC study, oral torasemide group showed significantly less total and cardiac mortality compared to oral frusemide group. Whether benefits were due to greater bioavailability of torsemide and its antialdosteronergic effects remain to be explained.

ACE-Inhibitors Proven Indications of ACEIs in Heart Failure: Always Acceptable •

•

•

Symptomatic CHF and documented systolic myocardial dysfunction: improved survival, reduced morbidity, symptomatic improvement and enhanced exercise capacity have all been demonstrated. Following acute MI with clinical signs of heart failure or significant systolic dysfunction (ejection fraction 40%). Improved survival and reduced morbidity demonstrated. Prevention of cardiovascular events, including heart failure in patients with atherosclerotic disease or in patients with diabetes mellitus and additional risk factors.

Acceptable Indication but Uncertain Efficacy and may Be Controversial •

Heart failure from diastolic dysfunction.

Management of Chronic Heart Failure 141

Not Proven: Potentially Harmful or Contraindicated • • •

Treatment of patients with significant aortic or mitral stenosis Treatment of patients with hypotension (SBP 80 mm Hg) Treatment of patients with pronounced renal failure (Serum creatinine !3.0 mg/dL and/or potassium !5.5 mg/dL). CLASS IA recommendation: According to the ESC 2016 update and ACC/AHA/HFSA update 2016: ACEIs/ARBs should be used in all patients with a reduced EF to prevent symptomatic heart failure, even if they do not have a history of MI. In all patients with a recent or remote history of MI or ACS and reduced EF, ACEIs should be used to prevent symptomatic heart failure and reduce mortality. In patients intolerant of ACEIs, ARBs are appropriate unless contraindicated.

Evidence Base of ACEIs •

Consensus, V-HeFT II, SAVE, SOLVD, AIRE, ATLAS, TRACE trials.

ANGIOTENSIN-RECEPTOR BLOCKERS Proven Indications of ARBs in Heart Failure: Always Acceptable •

Symptomatic treatment of patients with heart failure who do not tolerate ACEIs.

Acceptable Indications but of Uncertain Efficacy and may be Controversial •

Symptomatic treatment in patients who do not tolerate beta-blockers (in patients on ACEIs, diuretics) • Treatment of patients with a background therapy of both an ACEI and a beta-blocker. CLASS IA Recommendation: According to the ESC 2016 update and ACC/AHA/HFSA update 2016: The use of ARBs are recommended to reduce mortality and morbidity in patients with prior or current symptoms of chronic HFrEF in those who are intolerant to ACEIs due to cough or angioedema.

Evidence Base of ARBs •

RESOLVD, ELITE I and II, Val HeFT, CHARM, VALIANT, OPTIMAAL trials.

GUIDELINES FOR USE OF ACEIs AND ARBs • •

Review the need and dose of diuretics and other vasodilators. Avoid excessive diuresis before initiation of treatment. Consider reducing or withholding diuretics, if being used for 24 hours.

142 The Protocol Book for Intensive Care • • •

• • •

It may be advisable to start treatment in the evening, when the patient is supine, to minimize the potential negative effects on blood pressure. Start with a low dose and build-up to maintenance doses shown to be effective in large trials. If renal function deteriorates substantially (!25% increase in serum creatinine from baseline), or hyperkalemia ensues (K !5.5 mEq/L), stop treatment. Avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and Coxibs. Check blood pressure, renal function and electrolytes 1–2 weeks after each dose increment, at 3 months and subsequently at 6 months intervals. Addition of ARB with combination of ACEI and aldosterone antagonist, that is, triple drug combination increases risk of hypotension, renal dysfunction and hyperkalemia. Until trial results prove favorable, such combinations are not recommended.

BETA-BLOCKERS Proven Indications of Beta-blockers in Heart Failure • •

• •

To improve long-term survival in patients with mild to severe heart failure. To improve cardiac function and symptoms in patients with symptomatic chronic heart failure, already on conventional treatment with ACEIs (or an ARB), diuretics or digitalis. To improve outcome in patients with acute MI and left ventricular dysfunction with or without symptomatic heart failure. Symptomatic treatment of patients who do not tolerate ACEIs.

Acceptable Indication but of Uncertain Efficacy and may Be Controversial •

Symptomatic heart failure from diastolic dysfunction.

Not Proven: Potentially Harmful or Contraindicated • •

Acute decompensated heart failure CHF with pronounced hypotension and/or bradycardia. ESC 2016 CLASS IA recommendation: According to the ESC 2016 update: Beta-blockers should be used in all patients with a reduced EF to prevent symptomatic heart failure, even if they do not have a history of MI. ESC Class IB recommendation: In all patients with a recent or remote history of MI or ACS and reduced EF, evidence-based beta-blockers should be used to reduce mortality.

GUIDELINES FOR USE OF BETA-BLOCKER •

The patient should be on a background therapy with ACE-inhibition, if not contraindicated. (However, CIBIS III trial has recently demonstrated

Management of Chronic Heart Failure 143

•

• • • • •

•

in 1,010 patients with mild to moderate CHF and LVEF less than or equal to 35% that it may be as safe and efficacious to initiate treatment for CHF with bisoprolol as with enalapril.) The patient should be in a relatively stable condition, without the need of intravenous inotropic therapy and without signs of marked fluid retention. Start with low dose, double dose every 1–2 weeks till the dosage evidenced in large trials is reached. Most patients can be managed as outpatients. If worsening of heart failure occurs, first increase dose of diuretics or ACEIs, then temporarily reduce dose of beta-blocker, if necessary. If hypotension, first reduce dose of vasodilators and then reduce the dose of beta-blocker, if necessary. If bradycardia, reduce or discontinue drugs that may lower heart rate; reduce dose of beta-blocker, if necessary; but discontinue only if clearly necessary. Always consider reintroduction and/or uptitration of the beta-blocker when the patient becomes stable. If a patient develops decompensation of heart failure while on betablocker, reduce dose of beta-blockers by 25–50%, rather than withdraw beta-blockers unless heart failure is severe and refractory. If inotropic support is needed to treat a decompensated patient on beta-blocker, phosphodiesterase inhibitors or levosimendan should be preferred because their hemodynamic effects are not antagonized by beta-blocker agents.

Evidence Base of Beta-blockers in CHF ANZ, BEST, CIBIS I-III, COMET, COPERNICUS, MERIT HF, SENIORS, US CARVEDILOL, PRECISE, MOCHA, CAPRICORN trials. Trial data favor use of carvedilol, metoprolol, bisoprolol and, more recently, nebivolol (on the basis of SENIORS trial).

ANGIOTENSIN-RECEPTOR-NEPRILYSIN INHIBITOR (ARNI) Neprilysin is a neutral endopeptidase. Inhibition of the enzyme increases the bioavailability of natriuretic peptidase, Bradykinin and substance P causing natriuresis, vasodilation, antiproliferative activity. These produce ventricular unloading with antihypertensive response. LCZ696 (valsartan/sacubitril) which is first in class ARNI. The ARNI LCZ696 reduces CV deaths and all cause mortality compared to Enalapril in patient with CHF in PARADIGM-HF trial of 8,399 patients with CHF. NYHA classes II–IV symptoms. LVEF less than or equal to 40 receiving guideline recommended medical therapy followed for a median of 27 months. CV mortality was reduced by LCZ [HR 0.8, 95% confidence interval 0.72–0.89 p  0.001]. Both sudden cardiac death (HR 0.8, 95% CI 0.68–0.94 and p  0.008) and death due to worsening heart failure (HR 0.79, 95% CI 0.64–0.98, p  0.034) were reduced by treatment with LCZ 696 compared with

144 The Protocol Book for Intensive Care Enalapril. There was also 21% reduction in hospitalization for heart failure and 16% reduction in all-cause mortality. PARAMOUNT, PARAMETER and PARAGON are important studies in this respect. Due to this very impressive effect on mortality in heart failure patients, LCZ received fast track approval by U S Food and Drug Administration Home (USFDA). CLASS IB recommendation: According to the ESC 2016 update: Sacubitril/valsartan is recommended as a substitute for ACEI to reduce risk of heart failure hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite ACEI, beta-blockers and MRA. CLASS IB-R recommendation: According to the ACC/AHA/HFSA 2016 update: In patients with chronic symptomatic HFrEF who tolerate ACEI/ARB well, switch to ARNI should be made to reduce mortality and morbidity. Class IIIB-R: (Harm) ARNI should not be administered concomitantly with ACEI or within 36 hours of last ACEI administration. Class IIIC-EO: (Harm) ARNI should not be administered to patients with a history of angioedema. Dosage: 50–200 mg twice daily Side Effects: Similar to ACEI/ARB • Significant hyperkalemia, angioedema, renal impairment comparable to ACEI/ARB.

DIGITALIS Proven Indications of Digitalis in Heart Failure Atrial fibrillation and any degree of symptomatic heart failure whether or not left ventricular dysfunction is the cause.

Acceptable Indications but Somewhat Controversial • •

Combination of digoxin and beta-blockade appears superior to either agent alone in patients with AF. Digoxin has no effect on mortality but may reduce hospitalizations for worsening of CHF in patients with CHF caused by LV systolic dysfunction in sinus rhythm and treated already with ACEIs, beta-blockers and diuretics. Studies have shown that withdrawal of digoxin is often associated with worsening clinical status.

Evidence Base of Digitalis in CHF: PROVED, RADIANCE, DIG Trials Dosage of Digoxin: It is recommended that dose of digoxin based on lean body mass, renal function and concomitant medications, should be 0.125 mg daily in the majority of patients and serum digoxin level should be less than

Management of Chronic Heart Failure 145

1.0 mg/mL. High dose of digoxin (maintenance dose !0.25 mg daily) for the purpose of rate control in atrial fibrillation is not recommended. ESC 2016 CLASS IIbB recommendation: To be considered in symptomatic patients on ACEI, beta-blockers and MRA to reduce risk of hospitalization.

VASODILATORS •

Hydralazine-isosorbide dinitrate: It may be used as adjunctive therapy in the management of CHF. In case of intolerance of ACEIs and ARBs, the combination of hydralazine/nitrates can be tried. In the African-American Heart Failure Trial (A-HeFT) Investigators, addition of a fixed dose of isosorbide dinitrate (20 mg) and hydralazine (37.5 mg) (1–2 tablets TID) in blacks including neurohormonal blockers (ACEIs, ARBs, betablockers, digoxin, diuretics) was shown to be efficacious and increased survival among black patients with advanced heart failure. This combination is recommended in African Americans who have been symptomatic despite optimal therapy. In others, if patients are intolerant of ACEIs, the combination may be considered an option despite lack of symptomatic data. However, the combination has poor compliance because of high incidence of side effects. • Nitrates alone: No evidence to support use in CHF. • Alpha-adrenergic blocking drugs: No evidence to support use in CHF. • Calcium Channel Blockers (CCBs): Diltiazem and verapamil are not recommended in CHF secondary to systolic dysfunction. Newer CCBs (Felodipine and amlodipine) may be considered as additional therapy for concomitant arterial hypertension or angina not controlled by ACEIs, beta-blockers and nitrates but they do not provide a better effect on survival when compared with placebo. ESC 2016 CLASS IIaB recommendation: To be considered in self identified black patients with LVEF less than 35% or less than 45% with dilated LV cavity, while on ACEI, beta-blockers and MRA to reduce risk of hospitalization and death.

Other Options in Medical Management •

Ivabradine: It is inhibitor of I(f ) channel in sinus node. It slows down the heart rate in sinus rhythm but ineffective in slowing down ventricular rate in atrial fibrillation. SHIFT as well as BEAUTIFUL trials, showed reduction in hospitalization from heart failure (relative risk reduction 26%) but not in cardiovascular death or all-cause mortality. Administration and dosing consideration: Usual starting dose is 2.5–5.0 mg BID in heart failure associated with tachycardia (not controlled with beta-blockers) and increase to 7.5 mg BID. It is usually well-tolerated

146 The Protocol Book for Intensive Care

•

•

•

•

except for rare side effects like symptomatic bradycardia and visual effects secondary to phosphenes. ESC 2016 Class IIaB recommendation and ACC/AHA/HFSA 2016 Class IIaB-R recommendation: Ivabradine may be added in chronic stable HFrEF to reduce heart failure hospitalization and death with LVEF less than 35% in those already on beta-blockers at maximally tolerated dose, with sinus rhythm and HR more than 70 bpm, along with ACEI/ARB and MRA/ARB. ESC 2016 Class IIaC recommendation: May be added in chronic stable HFrEF to reduce heart failure hospitalization and death with LVEF less than 35% in those with contraindication to beta-blockers, with sinus rhythm and HR more than 70 bpm, along with ACEI/ARB and MRA/ARB. Direct Renin Inhibitors: Loss of negative feedback inhibition of renin release during chronic treatment with an ACE inhibitor leads to a compensatory rise in renin secretion and downstream components of RAAS cascade. This may overcome ACE-inhibition but should be blocked by a direct renin inhibitor. In the ALOFT trial, addition of aliskiren to an ACE inhibitor (or angiotensin receptor blocker) and beta-blocker had favorable neurohormonal effects in heart failure and appeared to be well-tolerated. However, in the recently presented ASTRONAUT trial, Aliskiren had no benefit over placebo in terms of CV-related death or heart failure –related hospitalization. What was troubling was that despite the fact that these patients were very well-treated with background medications, these patients had high mortality in both the groups i.e. Aliskiren and placebo. Statins: The CORONA and GISSI-HF trials with rosuvastatin versus placebo did not show any favorable effect in terms of the primary end point. However, meta-analysis has reported that effects of statins on heart failure are not a class effect and a significant benefit was noted using lipophilic atorvastatin but not hydrophilic rosuvastatin. Therefore, there is a possibility that lipophilic statins are more useful than hydrophilic statins for the treatment of CHF. Recently, PEARL study involving Pitavastatin, a lipophilic statin has been reported. In the overall Japanese study population, Pitavastatin did not reduce cardiac death or hospitalization for worsening heart failure. However, in patients with LVEF more than or equal to 30% a significant reduction in the primary outcome of composite of cardiac death or hospitalization for worsening heart failure was observed. Interestingly, only 27.4% of patients had ischemic heart failure in PEARL study compared to 40% in GISSI-HF and 100% in CORONA study. Further, randomized clinical trials are indicated. Vasopressin Receptor Antagonists: These have been discussed in the chapter on “Acute Heart Failure.” Their place in chronic heart failure remains uncertain at this point. Sildenafil: In rat models, sildenafil has been demonstrated to have beneficial, afterload independent effects on pressure-loaded right ventricle,

Management of Chronic Heart Failure 147

but not on the volume-overloaded right ventricle. Since left heart failure may be associated with pulmonary hypertension “out of proportion” of left heart disease, sildenafil may have beneficial effect in such patients. However, in the recently presented RELAX trial with sildenafil in diastolic heart failure, no improvement was noted compared to placebo in terms of exercise capacity.

POSITIVE INOTROPIC THERAPY •

•

Repeated or prolonged treatment with oral inotropic agents (Enoximone, vesanarinone, etc.) increases mortality (generally secondary to arrhythmias) and is not recommended in CHF. Intravenous administration of inotropic agents is commonly used in patients with severe episodes of worsening heart failure with signs of both pulmonary congestion and peripheral hypoperfusion. However, treatment-related complications may occur and their effect on prognosis is uncertain.

ANTITHROMBOTICS •

Anticoagulants (Warfarin) is indicated in: ƒ CHF with atrial fibrillation, previous thromboembolic event or a mobile left ventricular thrombus (Class of recommendation I; Level of evidence: A). ƒ Warfarin anticoagulation may be considered in patients with dilated cardiomyopathy and LVEF less than 35%. • Antiplatelets agents are indicated in: ƒ CHF who has underlying coronary artery disease for prevention of MI and death (Class of recommendation IIa; Level of evidence: B). Aspirin should be avoided in patients with recurrent hospitalization with worsening heart failure. There is little evidence to support concomitant treatment with an ACE-inhibitor and aspirin in heart failure.

ANTIARRHYTHMICS • •

•

Beta-blockers reduce sudden death in heart failure (Class of recommendation I; Level of evidence: A). Beta-blockers may also be indicated alone or in combination with amiodarone or nonpharmacological therapy in the management of sustained or nonsustained ventricular tachyarrhythmias (Class of recommendation IIa; Level of evidence: C). Amiodarone is effective agent for most supraventricular and ventricular arrhythmias (Class of recommendation I; Level of evidence: A). It is the preferred treatment in atrial fibrillation and CHF.

148 The Protocol Book for Intensive Care •

•

•

Amiodarone is not recommended for primary prevention of sudden death in patients with heart failure (Class of recommendation III; Level of evidence: A). Large trials have shown that prophylactic use of amiodarone in patients with nonsustained asymptomatic ventricular arrhythmias and heart failure does not affect total mortality. Class I antiarrhythmics reduce survival in heart failure and should be avoided.

Worsening Heart Failure Generally the most frequent causes of worsening heart failure are: A. CARDIAC 1. Dysrhythmias a. Bradycardia: (i) Sinus, (ii) Atrioventricular blocks (iii) Bundle branch blocks b. Tachycardias: (i) Atrial fibrillation, (ii) Other supraventricular tachycardias (iii) Ventricular tachyarrhythmias

7DEOH5HFRPPHQGDWLRQVWRSUHYHQWRUGHOD\WKHGHYHORSPHQWRIRYHUWKHDUW IDLOXUHRUSUHYHQWGHDWKEHIRUHWKHRQVHWRIV\PSWRPV Recommendations

Class*

Levelb

Treatment of hypertension is recommended to prevent or delay the onset of HF and prolong life.

I

A

Treatment with statins is recommended in patients with or at high-risk of CAD whether or not they have LV systolic dysfunction, in order to prevent or delay the onset of HF and prolong life.

I

A

Counseling and treatment for smoking cessation and alcohol intake reduction is recommended for people who smoke or who consume excess alcohol in order to prevent or delay the onset of HF.

I

C

Treating other risk factors of HF (e.g., obesity, dysglycemia) should be considered in order to prevent or delay the onset of HF.

IIa

C

Empagliflozin should be considered in patients with type 2 diabetes in order to prevent or delay the onset of HF and prolong life.

IIa

B

ACE-I is recommended in patients with asymptomatic LV systolic dysfunction and a history of MI in order to prevent or delay the onset of HF and prolong life.

I

A

ACE-I is recommended in patients with asymptomatic LV systolic dysfunction without a history of MI, in order to prevent or delay the onset of HF.

I

B

ACE-I should be considered in patients with stable CAD even if they do not have LV systolic dysfunction in order to prevent or delay the onset of HF.

IIa

A

Beta-blocker is recommended in patients with asymptomatic LV systolic dysfunction and a history of MI, in order to prevent or delay the onset of HF or prolong life.

I

B

HF: Heart failure; CAD: Coronary artery disease; LV: Left ventricle; ACE-I: Angiotensin-converting enzyme inhibitors; MI: Myocardial infarction.

Management of Chronic Heart Failure 149

2. Decompensation of valvular heart disease: a. Mitral regurgitation b. Tricuspid regurgitation 3. Coronary artery disease (Symptomatic) a. Ischemia b. Infarction 4. Over-reduction of preload (diuretics + ACEIs) B. EXTRA-CARDIAC 1. Non-compliance with prescribed regimen 2. Recently added adjunct drugs (beta-blockers, NSAIDs, verapamil diltiazem, etc.) 3. Ethanol abuse 4. Renal derangement (overuse of diuretics) 5. Infection 6. Pulmonary embolism 7. Thyroid dysfunction (e.g. Amiodarone induced) 8. Anemia (e.g. Internal bleeding).

Management of End-Stage Heart Failure (NYHA CLASS IV) Heart transplant remains the gold standard for the treatment of stage D heart failure. Recently, durable mechanical assist devices have become an appealing option in light of the limited availability of heart donors. The first step is to look for any potentially treatable precipitating cause mentioned above, which, if taken care of, results in marked improvement. Options of maximizing medical management including meticulous identification of fluid retention. Surgical options especially revascularization in ischemic cardiomyopathy and cardiac resynchronization therapy (CRT) (± implantable cardioverter defibrillator) should be considered before accepting the heart failure as refractory. If indeed heart failure is refractory, following guidelines are to be followed: • Refer potentially eligible patient for cardiac transplantation ACC/AHA Guidelines Class I recommendation (Level of evidence: B). • Refer patient to a heart failure program with expertise in the management of refractory heart failure ACCF/AHA Guideline Class I recommendation (Level of evidence: A). • Discuss option for end-of-life care with patient and family when severe symptoms persist despite application of all recommended therapies ACCF/AHA Guidelines Class I recommendation (Level of evidence: C). • Offer patients with implantable cardioverter defibrillators and end-stage disease, the option to inactivate defibrillation. ACCF/AHA Guideline Class I recommendation (Level of evidence: C). • Consider an LV assist device as permanent or destination therapy in highly selected patients with refractory end-stage heart failure, and an estimated

150 The Protocol Book for Intensive Care 1-year mortality more than 50% than with medical therapy. ACCF/AHA Class IIa recommendation (Level of evidence: B).

EMERGING PHARMACOLOGIC TREATMENT A. Empagliflozin It is a sodium-glucose cotransporter-2 (SGLT2) inhibitor that has positive effects on the markers of arterial stiffness and vascular resistance, visceral adiposity, albuminuria, plasma urate. The EMPA-REG trial has proven greater benefit of empagliflozin as compared to placebo with regards to death from cardiovascular causes (3.7% vs 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause. As per ESC 2016 recommendations, Metformin is the drug of choice in patients with heart failure and adrenomedullin (DM); in conjunction with empagliflozin it reduces heart failure hospitalization and mortality in patients with DM & high CV risk. B. Iron therapy A meta-analysis of 907 patients from five clinical trials show that IV iron therapy significantly reduced the rate of hospitalizations for heart failure. Most data in the meta-analysis came from two larger trials; CONFIRM-HF and FAIR-HF. Effectiveness of Intravenous iron treatment versus standard care in patients with heart failure and iron deficiency: a randomized, open-label multicentre trial (IRON-MAN), Confirm-AHF and AffirmAHF are going on to determine efficacy of iron replenishment in patients with current or recent (within 6 months) heart failure hospitalization and patients with NT-proBNP more than 250 ng/L in sinus rhythm or more than 1,000, ng/L in AF. Oral iron replenishment is also being assessed by the IRON-OUT study. At present ESC 2016 gives it as a IIa B recommendation: Intravenous FCM should be considered in symptomatic patients with HFrEF and iron deficiency (serum ferritin 100 μg/L, or ferritin between 100–299 μg/L and transferrin saturation 20%) in order to alleviate heart failure symptoms, and improve exercise capacity and quality-of-life. C. Omecamtiv mecarbil—a cardiac-specific myosin activator Omecamtiv mecarbil (OM) increases the rate of myosin binding with actin thus improving stroke volume and duration of systole without consuming more oxygen or increasing intracellular calcium. ATOMIC-AHF for intravenous and COSMIC-HF for oral OM studies are in the pipeline, preliminary studies show improved cardiac function as compared to placebo. D. Ularitide (Urodilatin) Urodilatin, a compound secreted by renal distal tubular cells, binds downstream in the inner medullary collecting duct to NPR-A and acts via cGMP

Management of Chronic Heart Failure 151

to inhibit Na resorption. The vasodilatory, neurohumoral and natriuretic effects of urodilatin were also an exciting prospect. Though both TRUE AHF and SIRIUS 1 and 2 have been conducted to assess its efficacy in decompensated heart failure versus placebo, great strides in heart failure management with ularitide are yet to be documented. E. Influenza vaccination People with chronic heart failure are at a higher risk of developing serious complications from influenza. RCT-IVVE (Influenza Vaccine to prevent adverse Vascular Events) and INVESTED (INfluenza Vaccine to Effectively Stop cardio Thoracic Events and Decompensated heart failure) trials are in progress to demonstrate benefit of Influenza vaccine in heart failure. F. Serelaxin Relaxin is a polypeptide molecule released primarily from the female endometrium. Serelaxin is recombinant human relaxin 2. It increases cardiac output, arterial compliance and renal blood flow during pregnancy. Despite the initial promise show by results of RELAX-AHF trial where serelaxin met its primary end point of improving dyspnea through day five in patients admitted for AHF, RELAX-AHF2 did not meet its primary end points of 180day cardiovascular death and worsening heart failure through day five. G. Rivaroxaban Rivaroxaban is a well-known anticoagulant already used in cardiologic practice. The COMMANDER-HF (Cardiovascular Outcome Modification, Measurement AND Evaluation of Rivaroxaban in patients with Heart Failure) trial is being undertaken to assess the effects of rivaroxaban of heart failure. It hypothesizes that rivaroxaban will reduce morbidity and mortality in patients with heart failure due to CHD. H. Vericiguat SOCRATES-REDUCED (Soluble guanylate Cyclase stimulatoR in heArT failure Studies) trial is looking at the effects of soluble GMP on heart failure using an SGC stimulator, Vericiguat. It proposes to study the effect of SGC stimulator molecule on natriuretic peptide levels in patients of worsening heart failure. I. Patiromer calcium and Sodium Zirconium cyclosilicate (ZS-9) The real world risk of hyperkalemia, unlike shown in many clinical trials, in HFrEF patients on therapy with MRAs and ACEIs is 3–6-fold higher, resulting in an increase in hospitalizations. To alleviate this problem, two novel drugs are being developed to improve the side effect of hyperkalemia as caused by various heart failure drugs, by increased potassium loss via the GI tract. Patiromer is an oral suspension allowing calcium potassium exchange in the large bowel while sodium zirconium silicate is a crystalline lattice structure that specifically traps potassium in the small bowel. In contrast to sodium polystyrene sulfonate (SPS), these show

152 The Protocol Book for Intensive Care greater selectivity for potassium. HARMONIZE trial tested ZS-9 while PEARL-HF, AMETHYST-DN and OPAL-HK tested Patiromer; Like SPS, both agents have been associated with GI disturbances and hypokalemia. J. Istaroxime It is a positive inotropic agent that by inhibitory action on Na/K ATPase reverses the Na/Ca exchanger and facilitates calcium entry, thereby promoting cell contraction. Studies such as HORIZON-HF show that it enhances SERCA2a activity and improves calcium cycling, thus possibly improving heart failure by relieving phospholamban inhibition. It might turn out to be the rising star in new modalities of heart failure management. 7DEOH5HFRPPHQGDWLRQVIRUFDUGLDFUHV\QFKURQL]DWLRQWKHUDS\LPSODQWDWLRQ LQSDWLHQWVZLWKKHDUWIDLOXUH Recommendations

Class*

Levelb

CRT is recommended for symptomatic patient with HF in sinus rhythm with a QRS duration ≥150 msec and LBBB QRS morphology and with LVEF d35% despite OMT in order to improve symptoms and reduce morbidity and mortality.

I

A

CRT should be considered for symptomatic patients with HF in sinus rhythm with a QRS duration ≥150 msec and non-LBBB QRS morphology and with LVEF d35% despite OMT in order to improve symptoms and reduce morbidity and mortality.

IIa

B

CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration of 130–149 msec and LBBB QRS morphology and with LVEF d35% despite OMT in order to improve symptoms and reduce morbidity and mortality.

I

B

CRT may be considered for symptomatic patients with HF in sinus rhythm with a QRS duration of 130–149 msec and non-LBBB QRS morphology and with LVEF d35% despite OMT in order to improve symptoms and reduce morbidity and mortality.

IIb

B

CRT rather than RV pacing is recommended for patients with HFrEF regardless of NYHA class who have an indication for ventricular pacing and high degree AV block in order to reduce morbidity. This includes patients with AF.c

I

A

CRT should be considered for patients with LVEF d35% in NYHA Classes III– IVd despite OMT in order to improve symptoms and reduce morbidity and mortality, if they are in AF and have a QRS duration t130 msec provided a strategy to ensure biventricular capture is in place or the patient is expected to return to sinus rhythm.

IIa

B

Patients with HFrEF who have received a conventional pacemaker or an ICD and subsequently develop worsening HF despite OMT and who have a high proportion of RV pacing may be considered for upgrade to CRT. This does not apply to patients with sable HF.

IIb

B

CRT is contraindicated in patients with a QRS duration < 130 msec.

III

A



CRT: Cardiac resynchronization therapy; LVEF: Left ventricular ejection fraction; HF: Heart failure; LBBB: Left bundle branch block; OMT: Osteopathic manipulative treatment; HFrEF: Reduced ejection fraction; NYHA: New York Heart Association; AV: Atrioventricular; AF: Atrial ¿EULOODWLRQ ,&' ,PSODQWDEOH FDUGLRYHUWHU GH¿EULOODWRU

Management of Chronic Heart Failure 153

Cardiac Resynchronization Therapy The clinical effects of long-term CRT have been evaluated in a large number of randomized multicenter trials with crossover or parallel treatment assignment. In NYHA Class III/IV patients, MUSTIC-SR, MUSTIC, MIRACLE, PATH-CHF, MIRACE ICD, PATH-CHF II, COMPANION, CARE-HF trials have confirmed a significant alleviation of symptoms and increase in exercise capacity conferred by CRT. Functional benefits and quality-of-life improvement including reduction in unplanned hospitalization has been sustained. CARE-HF and COMPANION were trials powered to examine the effects of CRT on combined primary end points of mortality. In COMPANION, CRT-D was associated with a significant decrease in all-cause mortality (relative reduction: 36%, p = 0.003). In CARE-HF, where only CRT-P was assessed, a 36% relative reduction in risk of death (p  0.002) was observed after a mean RCTs, ESC recommendation in patients with heart failure in NYHA Class III/IV are: Heart failure in NYHA Class III/IV are: CRT-P/CRT-D is recommended to reduce morbidity and mortality in following population: • NYHA function was Class III/IV • LVEF less than or equal to 35% • QRS more than or equal to 130 ms • Sinus rhythm • Optimal medical therapy • Class IV patients should be ambulatory. [Class I recommendation, Level of evidence: A] LV dilatation is no longer required in the recommendation and patients should have reasonable expectation of survival with good functional status for more than 1 year for CRT-D. Evidence is strongest for patients with typical LBBB. Two recent, randomized, prospective, multicenter trials, MADIT-CRT and REVERSE demonstrated reduced morbidity in NYHA Classes I and II patients on optimal medical therapy. Only 18% of patients in REVERSE and

7DEOH5HFRPPHQGDWLRQVIRU&57DQG,&' Recommendations

Patient population

Level of evidence

CRT-P/CRT-D should be considered to reduce morbidity

NYHA function Class III/IV LVEF d35%, QRS ≥130 ms Pacemaker dependency induced by AV nodal ablation

IIa (B)

CRT-P/CRT-D should be considered to reduce morbidity

NYHA function Class III/IVLVEF d35%, QRS ≥130 ms slow ventricular rate and frequent pacing

IIa (C)

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