Cardiovascular Pharmacotherapy : A Point-of-Care Guide [1 ed.] 9781585283200, 9781585282159

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Cardiovascular Pharmacotherapy A Point-of-Care Guide

Michael A. Crouch, Pharm.D., FASHP, BCPS (AQ Cardiology) Professor and Chair Department of Pharmacy Practice South University School of Pharmacy Savannah, Georgia

American Society of Health-System Pharmacists® Bethesda, Maryland

Any correspondence regarding this publication should be sent to the publisher, American Society of Health-System Pharmacists, 7272 Wisconsin Avenue, Bethesda, MD 20814, attention: Special Publishing. The information presented herein reflects the opinions of the contributors and advisors. It should not be interpreted as an official policy of ASHP or as an endorsement of any product. Because of ongoing research and improvements in technology, the information and its applications contained in this text are constantly evolving and are subject to the professional judgment and interpretation of the practitioner due to the uniqueness of a clinical situation. The editors, contributors, and ASHP have made reasonable efforts to ensure the accuracy and appropriateness of the information presented in this document. However, any user of this information is advised that the editors, contributors, advisors, and ASHP are not responsible for the continued currency of the information, for any errors or omissions, and/or for any consequences arising from the use of the information in the document in any and all practice settings. Any reader of this document is cautioned that ASHP makes no representation, guarantee, or warranty, express or implied, as to the accuracy and appropriateness of the information contained in this document and specifically disclaims any liability to any party for the accuracy and/or completeness of the material or for any damages arising out of the use or non-use of any of the information contained in this document. Director, Special Publishing: Jack Bruggeman Acquisitions Editor: Rebecca Olson Senior Editorial Project Manager: Dana Battaglia Production Editor: Johnna Hershey Design and Composition: David Wade Library of Congress Cataloging-in-Publication Data Cardiovascular pharmacotherapy : a point-of-care guide / [edited by] Michael A. Crouch. p. ; cm. Includes bibliographical references and index. ISBN 978-1-58528-215-9 1. Heart--Diseases--Chemotherapy--Handbooks, manuals, etc. 2. Cardiovascular agents--Handbooks, manuals, etc. I. Crouch, Michael A. (Michael Andrew), 1969- II. American Society of Health-System Pharmacists. [DNLM: 1. Cardiovascular Diseases--drug therapy--Handbooks. 2. Cardiovascular Agents--Handbooks. WG 39 C2677 2010] RC684.C48C393 2010 616.1'2061--dc22 2009050210 ©2010, American Society of Health-System Pharmacists, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without written permission from the American Society of Health-System Pharmacists. ASHP is a service mark of the American Society of Health-System Pharmacists, Inc.; registered in the U.S. Patent and Trademark Office. ISBN: 978-1-58528-215-9

DEDICATION

To my amazing wife, Candace, and three wonderful children, Jack, Julia, and Anna, for their love, patience, and unconditional support of my professional endeavors

ACKNOWLEDGMENTS

Throughout the development of this first edition, I have been fortunate to work with a distinguished group of individuals. Anyone who has labored on a project of this magnitude realizes its success hinges on collaboration. I am indebted to the exceptional contributing authors and reviewers that worked to ensure each chapter represents the most up-to-date information. Moreover, I am grateful for the extensive guidance provided by the ASHP Publications staff, including Rebecca Olson (Acquisitions Editor), Dana Battaglia (Senior Editorial Project Manager), Johnna Hershey (Director, Production Center), and Rachel Alberts (Marketing Manager). Without the hard work of these talented individuals, this reference would not have come to fruition. Likewise, I wish to acknowledge the numerous mentors that have guided me throughout my career. These individuals—too many to list—along with colleagues, trainees, and patients have inspired me to improve the care of those with cardiovascular disease. This book would not be possible without their encouragement and counsel. Finally, I want to thank two people who have inspired me the most in my life, my parents Phillip and Sandra. These phenomenal role models have supported all my professional aspirations, while demonstrating how to be a servant leader. This acknowledgment honors their example of faith, family, and friends. Michael A. Cr ouch Crouch ouch, Pharm.D., FASHP, BCPS (AQ Cardiology)

CONTENTS*

Acknowledgments -------------------------------------------------------------------- iii Foreword -------------------------------------------------------------------------------- vi Preface ---------------------------------------------------------------------------------- vii Online Content and Updates ------------------------------------------------------ viii Contributors --------------------------------------------------------------------------- ix Reviewers ------------------------------------------------------------------------------- xi Chapter 1. Cardiovascular Testing ------------------------------------------------- 1 by Michael A. Crouch Chapter 2. Drug-Induced Cardiac Disease -------------------------------------- 29 by Kelly M. Summers and Kristin Watson Chapter 3. Hypertension ----------------------------------------------------------- 63 by Joseph J. Saseen Chapter 4. Hypertensive Crisis ---------------------------------------------------- 79 by Kimberly L. Tackett and Michael A. Crouch Chapter 5. Dyslipidemia ------------------------------------------------------------ 95 by Barbara S. Wiggins Chapter 6. Chronic Stable Angina ---------------------------------------------- 121 by Robert J. DiDomenico and Larisa H. Cavallari Chapter 7. Acute Coronary Syndrome ----------------------------------------- 143 by Paul P. Dobesh Chapter 8. Chronic Heart Failure ----------------------------------------------- 169 by Michael A. Crouch Chapter 9. Acute Decompensated Heart Failure ----------------------------- 187 by Jo E. Rodgers *ALL CHAPTER REFERENCES ARE INCLUDED ONLINE AT WWW.ASHP.ORG/CARDIOVASCULAR. SEE PAGE VIII FOR MORE INFORMATION.

iv Cardiovascular Pharmacotherapy

CONTENTS* (continued)

Chapter 10. Cardiac Transplantation ------------------------------------------- 207 by Robert Lee Page II Chapter 11. Atrial Arrhythmias ------------------------------------------------- 235 by Amy L. Seybert and James C. Coons Chapter 12. Ventricular Arrhythmias and Related Emergency Cardiovascular Care ----------------------------------------------- 259 by Cynthia A. Sanoski Chapter 13. Ischemic Stroke ----------------------------------------------------- 283 by Stacy A. Voils Chapter 14. Peripheral Arterial Disease ---------------------------------------- 303 by Zachary A. Stacy Chapter 15. Venous Thromboembolism --------------------------------------- 319 by Toby C. Trujillo Chapter 16. Valvular Heart Disease --------------------------------------------- 345 by Angie Veverka Chapter 17. Pericarditis ----------------------------------------------------------- 371 by Tien M.H. Ng Chapter 18. Pulmonary Arterial Hypertension ------------------------------- 391 by William D. Cahoon, Jr. APPENDICES Appendix A ---------------------------------------------------------------------- 409 Appendix B ---------------------------------------------------------------------- 412 Appendix C ---------------------------------------------------------------------- 415 Index --------------------------------------------------------------------------------- 471 *ALL CHAPTER REFERENCES ARE INCLUDED ONLINE AT WWW.ASHP.ORG/CARDIOVASCULAR. SEE PAGE VIII FOR MORE INFORMATION.

v Cardiovascular Pharmacotherapy

FOREWORD

As an educator who teaches pharmacy students both in the classroom and at the bedside, I often struggle with making sure students have the proper resources to answer cardiology pharmacotherapy questions accurately and with supporting details and rationale. In addition, “non-cardiology” colleagues or those starting off their career in cardiology pharmacy practice often ask me for up-to-date resources to assist them in understanding the rationale behind some cardiovascular drug therapy selections and patient management dilemmas. This new text, ASHP’s pocket-sized reference entitled Cardiovascular Pharmacotherapy: A Point-of-Care Guide, easily serves both roles. Each of the 18 book chapters uniquely summarizes a cardiovascular disease in a size that can be transported in a lab coat pocket. There are brief pathophysiology, clinical presentation, diagnosis, and risk stratification sections that give an appropriate background for the reader to understand the rationale for pharmacotherapy. Helpful disease-based tables are included; for example, the CHADS2 score for the discussion on stroke risk in atrial fibrillation. Next, tables listing specific recommendations from current practice guidelines for each cardiovascular disease are included in chapters and both non-drug and drug therapy summarized. What makes this book stand out amongst others, however, is that the chapters are not written as in-depth reviews of clinical trials but rather as a practical approach applying those trials and guidelines. In addition to the “usual fare” of cardiovascular topics like hypertension, chronic heart failure, and arrhythmias, there are concise chapters written for a pharmacist audience that you simply cannot find elsewhere like pericarditis, valvular heart disease, pulmonary hypertension, and cardiac transplantation. What does this book offer that a guideline or an on-line disease-based information resource cannot? It is the attention to details regarding drug therapy. Dr. Crouch and the chapter authors have put a tremendous effort into creating what I feel are the best cardiology drug tables currently available. There is specific information on drug doses, pharmacokinetics, and monitoring parameters for important agents for each cardiovascular disease. What does this book offer to the seasoned cardiology pharmacist practitioner? Each chapter has a valuable treatment algorithm that places the data into the context of practice. Each chapter has one or more clinical controversies that are explained and referenced at the depth needed for an experienced clinician but that can be easily understood by a pharmacy student. In short, the book’s title says it all. It is an affordable resource to students and clinicians alike that can be used at the Point-of-Care.

Sarah A. Spinler Spinler, Pharm.D., FAHA, FCCP, BCPS (AQ Cardiology) Professor of Clinical Pharmacy Residency and Fellowship Program Coordinator Philadelphia College of Pharmacy University of the Sciences in Philadelphia Philadelphia, Pennsylvania September 2009 vi Cardiovascular Pharmacotherapy

PREFACE

Colleagues, residents, and students have frequently asked me to recommend a handy yet comprehensive book related to cardiovascular pharmacotherapy. Although numerous quality textbooks are available for health care professions that, in one fashion or another, address cardiovascular disease, none sufficiently reviews the topic in a convenient manner designed for direct patient care. In 2007, ASHP Publications presented me with an opportunity to develop a unique reference to fulfill this unmet need. Cardiovascular Pharmacotherapy: A Point-of-Care Guide aims to serve as a contemporary and easy-to-use reference for clinical pharmacists, other health care practitioners, residents, and students. Given the high incidence of heart disease within our society, the book’s clinical applicability translates to both the inpatient and outpatient settings. The guide is designed to integrate basic disease and drug information in a way that is useful to didactic and experiential students, but it also provides sufficient detail to educate and challenge residents. Moreover, it incorporates guideline statements, recent literature, and clinical controversies in a way that informs even the most seasoned clinician. The guide consists of 18 chapters authored by a variety of cardiovascular pharmacotherapy experts throughout the country. It begins with chapters on cardiovascular testing and drug-induced cardiac disease since this information is relevant throughout the book. Ensuing disease-focused chapters review cardiovascular risk factors and ailments commonly encountered by all clinicians, including hypertension, dyslipidemia, stable angina, and heart failure. Intermixed within these topics are chapters that tackle urgent conditions such as hypertensive crisis, acute coronary syndrome, acute heart failure, and ischemic stroke. Clinicians with a specialty practice such as those in the cardiology, emergency, and intensive care settings will find these sections of particular interest. Disease-focused chapters follow a standard format allowing for quick retrieval of information. Each chapter begins with a review of the disease pathophysiology, clinical presentation, and diagnosis. Subsequent sections examine treatment principles, with a candid assessment of non-pharmacological and pharmacological considerations. Liberal use of tables and figures support each topic and offer unique treatment algorithms as well as selected guideline statements from the American Heart Association, the American College of Cardiology, and other authoritative sources. The final section of disease-focused chapters reviews monitoring considerations, clinical controversies, and potential future treatments. The book concludes with the point-of-care drug information appendix, which allows readers to retrieve essential drug facts quickly for common cardiovascular agents. Distinctive features of this table include clear identification of high-risk drugs (e.g., black boxed warnings); a listing of generic, brand, and combination products; and emphasis on drug details necessary at the patient’s bedside or in the clinic setting. Moreover, the table presents brief monitoring parameters that clinicians should consider in concert with specified warnings and precautions, common adverse drug events, and known interactions. vii Cardiovascular Pharmacotherapy

PREFACE (continued) Inevitably, new research and guidelines will render certain aspects of this book less useful. For instance, revised hypertension and dyslipidemia guidelines will be available in the summer of 2010, according to the National Heart Lung and Blood Institute. Therefore, a website located at www.ashp.org/cardiovascular supports the book and provides endless opportunities for the reader to access the most current cardiovascular disease and drug information. Please see the “Online Content and Updates” section that follows for further details on the website. My hope is that you find this guide useful, irrespective of your discipline or current level of training. It is designed to be a straightforward reference suitable for students at any level, but it also addresses higher level issues relevant to advanced trainees and experienced clinicians. My ultimate goal is that this reference provides health care practitioners a tool that improves the care of patients with cardiovascular disease.

Michael A. Cr ouch Crouch ouch, Pharm.D., FASHP, BCPS (AQ Cardiology)

ONLINE CONTENT AND UPDATES .ashp.or g/car diovascular supports the book and proA website located at www www.ashp.or .ashp.org/car g/cardiovascular vides regular updates regarding current research, guidelines, and drug information. Using a password, readers will have access to the following features: • References for each chapter, including hyperlinks • An exclusive newsletter, Cardiovascular Pharmacotherapy Quarterly Report, covering the most recent research and advances in the field • Links to the latest guidelines—check in summer of 2010 for revised hypertension and dyslipidemia guidelines from the National Heart Lung and Blood Institute • Shockwave presentations that review important cardiovascular drug classes • Cardiovascular pharmacotherapy teaching resources • Printable drug monographs for new cardiovascular drug approvals

To access exclusive content, when pr ompted at the site, please enter prompted either your ASHP number egister as a new user to obtain your number,, or rregister passwor d. password. viii Cardiovascular Pharmacotherapy

CONTRIBUTORS WILLIAM D. CAHOON, JR., PHARM.D., BCPS Clinical Specialist, Cardiology Clinical Assistant Professor Virginia Commonwealth University Health System and School of Pharmacy Richmond, Virginia

PAUL P. DOBESH, PHARM.D., FCCP, BCPS (AQ CARDIOLOGY) Associate Professor Department of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center Omaha, Nebraska

LARISA H. CAVALLARI, PHARM.D. Associate Professor Department of Pharmacy Practice University of Illinois at Chicago College of Pharmacy Chicago, Illinois

TIEN M.H. NG, PHARM.D., BCPS (AQ CARDIOLOGY) Associate Professor of Clinical Pharmacy Director, PGY2 Residency in Cardiology University of Southern California School of Pharmacy Los Angeles, California

JAMES C. COONS, PHARM.D., BCPS Clinical Specialist, Cardiology Adjunct Instructor Duquesne University and University of Pittsburgh Schools of Pharmacy Allegheny General Hospital Pittsburgh, Pennsylvania MICHAEL A. CROUCH, PHARM.D., FASHP, BCPS (AQ CARDIOLOGY) Professor and Chair Department of Pharmacy Practice South University School of Pharmacy Savannah, Georgia ROBERT J. DIDOMENICO, PHARM.D. Clinical Associate Professor Department of Pharmacy Practice University of Illinois at Chicago College of Pharmacy Chicago, Illinois

ROBERT LEE PAGE II, PHARM.D., MSPH, FCCP, FAHA, FASHP, BCPS, CGP Associate Professor Departments of Clinical Pharmacy and Physical Medicine/Rehabilitation University of Colorado Denver, Schools of Pharmacy and Medicine Aurora, Colorado JO E. RODGERS, PHARM.D., FCCP, BCPS (AQ CARDIOLOGY) Clinical Associate Professor Division of Pharmacotherapy and Experimental Therapeutics Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill, North Carolina CYNTHIA A. SANOSKI, B.S., PHARM.D., BCPS, FCCP Chair and Associate Professor Department of Pharmacy Practice Jefferson School of Pharmacy Thomas Jefferson University Philadelphia, Pennsylvania

ix Cardiovascular Pharmacotherapy

CONTRIBUTORS (continued) JOSEPH J. SASEEN, PHARM.D., FCCP, FNLA, BCPS, CLS Professor Departments of Clinical Pharmacy and Family Medicine University of Colorado Denver, Schools of Pharmacy and Medicine Aurora, Colorado

TOBY C. TRUJILLO, PHARM.D., BCPS (AQ CARDIOLOGY) Clinical Specialist—Anticoagulation/Cardiology University of Colorado Hospital Associate Professor University of Colorado Denver—School of Pharmacy Aurora, Colorado

AMY L. SEYBERT, PHARM.D. Associate Professor Department of Pharmacy and Therapeutics University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania

ANGIE VEVERKA, PHARM.D. Associate Professor Wingate University School of Pharmacy Wingate, North Carolina

ZACHARY A. STACY, PHARM.D., BCPS Associate Professor Department of Pharmacy Practice St. Louis College of Pharmacy St. Louis, Missouri

STACY A. VOILS, PHARM.D., BCPS Critical Care Specialist, Neurosurgery/ Cardiac Surgery Clinical Assistant Professor Virginia Commonwealth University Health System and School of Pharmacy Richmond, Virginia

KELLY M. SUMMERS, PHARM.D., BCPS Assistant Professor Department of Pharmacy Practice and Sciences University of Maryland School of Pharmacy Baltimore, Maryland

KRISTIN WATSON, PHARM.D., BCPS Assistant Professor Department of Pharmacy Practice and Sciences University of Maryland, School of Pharmacy Baltimore, Maryland

KIMBERLY L. TACKETT, PHARM.D, CDE, BCPS (AQ INFECTIOUS DISEASE) Assistant Professor Department of Pharmacy Practice South University School of Pharmacy Savannah, Georgia

BARBARA S. WIGGINS, PHARM.D., BCPS (AQ CARDIOLOGY), CLS, FAHA, FNLA, FCCP Pharmacy Clinical Specialist–Cardiology Clinical Assistant Professor in Internal Medicine University of Virginia Health System and School of Medicine Charlottesville, Virginia

x Cardiovascular Pharmacotherapy

REVIEWERS

The editor and ASHP gratefully acknowledge the following individuals who donated their expertise in reviewing the chapters for this book: JAMES S. KALUS, PHARM.D., BCPS (AQ CARDIOLOGY) Senior Manager, Patient Care Services Department of Pharmacy Services Henry Ford Hospital Detroit, Michigan MICHAEL P. DORSCH, PHARM.D., M.S., BCPS (AQ CARDIOLOGY) Clinical Pharmacist, Cardiology Adjunct Clinical Assistant Professor University of Michigan Health System and College of Pharmacy Ann Arbor, Michigan WENDY CANTRELL, PHARM.D., BCNSP, CACP Cardiology Specialist University Medical Center of Southern Nevada Assistant Professor University of Southern Nevada College of Pharmacy Las Vegas, Nevada SARAH A. SPINLER, PHARM.D., FAHA, FCCP, BCPS (AQ CARDIOLOGY) Professor of Clinical Pharmacy Residency and Fellowship Program Coordinator Philadelphia College of Pharmacy University of the Sciences in Philadelphia Philadelphia, Pennsylvania HEATHER M. GROESCHEN-WIND, PHARM.D. Bethesda, Maryland

xi Cardiovascular Pharmacotherapy

1

Cardiovascular Testing Michael A. Crouch INTRODUCTION

Despite recent data suggesting a decline in mortality associated with cardiovascular disease (CVD), the burden associated with CVD remains high. Table 1-1 provides general epidemiologic data.1 Nearly 2,400 Americans die daily from CVD, corresponding to one death every 37 seconds. CVD deaths exceed 860,000 annually, and 17% of patients are less than 65 years of age. About every 25 seconds, an American will have a coronary event, accounting for 785,000 new coronary events and 470,000 recurrent attacks.1 According to the National Center for Health Statistics (NCHS), mortality from CVD surpasses the other leading causes of death in the United States, including cancer, chronic lower respiratory diseases, accidents, and diabetes.2

Table 1-1: Epidemiologic data for cardiovascular disease Prevalence (age > 20 yr)

Mortality (2005) Hospital Discharges (2006)

Cost (2009)

80,000,000

864,480

$475.3 billion

7,095,000

Adapted from reference 1. Given the prevalence of CVD and the fact that many events occur in individuals without a previous diagnosis, aggressive evaluation is required for those at risk of disease. Evaluation is also critically important to characterize disease burden in individuals with an established diagnosis. Subsequent chapters in this point-of-care guide will describe the various types of cardiovascular disease that practitioners encounter on a daily basis. Globally, cardiovascular disease 1

ONE

Chapter

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can be categorized into altered perfusion (ischemia in the coronary, cerebral, and/or peripheral arteries), altered cardiac output (e.g., heart failure), abnormal anatomy (congenital or acquired), and abnormalities of electrical conduction. Table 1-2 lists common tests used to evaluate each of these areas.

Table 1-2: Common cardiovascular tests* Perfusion

Cardiac Output

Anatomy

Electrical Conduction

Angiography Nuclear imaging

Angiography

Angiography

Electrocardiogram

Nuclear imaging

Echocardiogram

Exercise stress testing

Echocardiogram

Computed tomography scan

* Other tests that may be used in selected situations include intravascular ultrasound (IVUS), magnetic resonance imaging (MRI), positron emission tomography (PET), and electrophysiologic (EP) study.

BASIC TESTING Before providing a review of advanced cardiovascular assessment, this chapter will offer a brief synopsis of general testing. This chapter does not address aspects of the history and physical exam (e.g., heart sounds and murmurs), although they are critical to the workup of a patient and should be completed before advanced cardiovascular testing. Subsequent chapters in this point-ofcare guide will highlight important findings (e.g., history and physical exam) related to cardiovascular diseases encountered in clinical practice. General tests that are obtained in concert with a physical examination include blood pressure, pulse, and chest radiograph. Blood pressure should be checked during any encounter within the health care system. Specific recommendations from the U.S. Preventive Services Task Force (USPSTF) strongly recommend clinicians screen for high blood pressure in adults aged 18 years and older (grade “A” recommendation).3 The previous Joint National Committee (JNC) VI guidelines recommended routine blood pressure measurement at least once every 2 years for adults with a blood pressure below 130/85 mmHg.4 Measurement occurs more often in people with a diagnosis of hypertension. When obtaining blood pressure, clinicians must use the proper cuff size (cuff bladder encircling at least 80% of the arm). Before blood pressure mea-

Cardiovascular Testing

3

surement, a person should be seated in a chair for 5 minutes (feet on the ground, arms supported) and abstain from caffeine, exercise, and smoking for at least 30 minutes. Classification of blood pressure, in adults greater than 18 years of age, is based on the average of two or more properly measured blood pressures on each of two or more office visits.5 Clinicians should categorize blood pressure as normal (160/100 mmHg). See Chapter 3 (Hypertension) for a detailed description regarding evaluation, treatment, and monitoring of high blood pressure. In addition to measuring blood pressure in the office, ambulatory blood pressure monitoring (ABPM) provides insight regarding blood pressure control. Blood pressure readings with ABPM are typically lower than office measurements. Indications to use this approach include suspected “white-coat” hypertension, drug resistance, hypotensive episodes with treatment, episodic hypertension, and autonomic dysfunction.5 The heart rate should be obtained whenever measuring blood pressure and should include a description of both the rate and rhythm. Although the pulse may be taken at various locations, the arterial pulse is used most often. This is a measurement of the ventricular rate, and it should be obtained in a way that calculates an average rate for 60 seconds. For instance, the common method is determining the rate over 15 seconds and multiplying by 4. This evaluation period is insufficient if an irregular rhythm is identified (e.g., atrial fibrillation); a longer period of evaluation (e.g., 1–2 minutes) should be used to better characterize the rhythm variability and the average heart rate. In patients with atrial fibrillation, clinicians can use a stethoscope or electrocardiogram (ECG) to obtain a more accurate determination of the average pulse rate. The chest radiograph is the typical first diagnostic test, and it supplements the history and physical examination. The standard radiograph is obtained at maximal inspiration in the standing posterioanterior and lateral views. Portable radiographs may be necessary based on the patient’s condition, but the results can be suboptimal due to poor positioning of the patient, inadequate inspiratory effort, and/or limited penetration of the radiograph. Radiographs should be compared to previous films, when available. Overall, the radiograph provides a general observation of gross structures, including the cardiac silhouette (e.g., size and placement, cardiac border, chambers size, and pericardial space), aorta, and lungs (e.g., vasculature, presence of fluid, and plural effusions). It does not provide the detail obtained with advanced testing (e.g., computed tomography).

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Echocardiogram and ultrasonography The echocardiogram (oftentimes referred to as ECHO) and ultrasound both use sound waves to visualize structures within the body. The echocardiogram visualizes the heart, and it can be used to estimate the left ventricular ejection fraction as well as examine chamber wall thickness, the heart valves, and the pericardium. This non-invasive, low-cost procedure can be performed in various situations, including at the bedside and in a physician’s office. (An example of echocardiogram is provided in Figur Figuree 1-1 1-1.) The echocardiogram is the preferred non-invasive technique to determine a patient’s ejection fraction. See Chapter 8 (Chronic Heart Failure) for detailed a description regarding evaluation, treatment, and monitoring of patients with a reduced ejection fraction. The echocardiogram is also the common initial test if auscultation suggests a valvular abnormality. See Chapter 16 (Valvular Heart Disease) for a detailed description regarding evaluation, treatment, and monitoring of valvular abnormalities. In children, echocardiograms are used to evaluate potential congenital defects, where indicated. Indirectly, echocardiographic wall motion abnormalities observed during a cardiac stress test suggest ongoing ischemia.6

Figure 1-1: Example echocardiogram showing the four chambers of the heart and heart valves

Cardiovascular Testing

5

The echocardiogram is either a transthoracic echocardiogram (TTE) or transesophageal echocardiogram (TEE). Irrespective of the chosen position, the results of both types are operator dependent. In TTE, the transducer is placed on the chest wall and in M-mode or 2D mode. In the M-mode, the transducer is placed at a single position on the chest and provides static pictures (as a window). In the 2D mode (two-dimensional), multiple windows are provided, which gives better visualization and accuracy. Doppler technology can be used during an echocardiogram, which evaluates sound reflecting from moving objects (e.g., blood). In this approach, blood flow can be visualized so that the clinician can observe the effects of structural heart disease. TEE is chosen when better visualization is necessary, specifically for the left side of the heart. TEE is usually reserved as a second-line echocardiogram since it requires the transducer to be placed in the esophagus. Example situations where it may be chosen include the evaluation of patients with suspected infective endocarditis and those with atrial fibrillation when a left atrial thrombus is a concern. Selected recommendation from ACC/AHA guidelines regarding echocardiography are provided in Table 1-3 1-3.6

Table 1-3: Selected recommendations for echocardiography ACC/AHA/ASE Class I • Dyspnea with clinical signs of heart disease (regional left ventricular function). • Use of echocardiography (especially TEE) in guiding the performance of interventional techniques and surgery (e.g., balloon valvotomy and valve repair) for valvular disease (prosthetic valves). • If TTE is equivocal, TEE evaluation of staphylococcus bacteremia without a known source (infective endocarditis: native valves). • Assessment of the effects of medical therapy on the severity of regurgitation and ventricular compensation and function when it might change medical management (native valve regurgitation). • Assessment of myocardial viability when required to define potential efficacy of revascularization; dobutamine stress echocardiography (acute ischemic syndromes). Class IIa • Evaluation of persistent nonstaphylococcus bacteremia without a known source; TEE may frequently provide incremental value in addition to information obtained by TTE. The role of TEE in first-line examination awaits further study (infective endocarditis: native valves). • Detection of myocardial ischemia in women with a low or intermediate pretest likelihood of CAD; dobutamine stress echocardiogram (chronic ischemic heart disease).

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Table 1-3: Selected recommendations for echocardiography (cont’d) • Pulmonary emboli and suspected clots in the right atrium or ventricle or main pulmonary artery branches; TEE is indicated when TTE studies are not diagnostic (pulmonary disease). • TEE or intracardiac ultrasound guidance of radiofrequency ablative procedures (arrhythmias and palpitations). Class IIb • Dobutamine echocardiography for the evaluation of patients with low-gradient aortic stenosis and ventricular dysfunction (native valve stenosis). • Patients with mitral valve disease or hypertrophic cardiomyopathy who have been on longterm anticoagulation at therapeutic levels before cardioversion unless there are other reasons for anticoagulation; e.g., prior embolus or known thrombus on previous TEE (arrhythmias and palpitations). Class III • Evaluation of transient fever without evidence of bacteremia or new murmur (infective endocarditis: native valves). • Patients who have been on long-term anticoagulation at therapeutic levels and who do not have mitral valve disease or hypertrophic cardiomyopathy before cardioversion unless there are other reasons for anticoagulation; e.g., prior embolus or known thrombus on previous TEE (arrhythmias and palpitations). ACC = American College of Cardiology; AHA = American Heart Association; ASE = American Society of Echocardiography; CAD = coronary artery disease; TEE = transesophageal echocardiogram; TTE = transthoracic echocardiogram

Adapted from reference 6. Ultrasonography uses sound wave technology to visualize the vasculature (vein or artery). The most common use is in a patient being evaluated for deep vein thrombosis, with or without established pulmonary embolism. It can be used to visualize thrombi and assess the risk of embolism. Additionally, it can be used to visualize arteries. For instance, after sheath removal from the femoral artery (cardiac catheterization), ultrasonography can be used to visualize the vessel and assess if damage has occurred (e.g., aneurysm).

Electrocardiogram The electrocardiogram (ECG) is a simple, low-cost, non-invasive test to evaluate various aspects of cardiovascular disease. Although evaluation of the cardiac rate and rhythm are typical reasons to perform the test, it also provides the cardiac axis, the existence of myocardial hypertrophy, and the presence of ischemia. An ECG should be obtained at baseline and during follow-up visits in all patients with known cardiovascular disease.7,8

Cardiovascular Testing

7

When an ECG is performed, sensors are placed on the chest wall and on the Figur limbs, in addition to a ground lead (Figur Figuree 1-2 1-2). The six limb sensors look at the heart as a single frontal plane, which provide leads I, II, III, aVR, aVL, and aVF. The chest sensors move from the patient’s right-hand side to the left across the chest wall and represent leads V1 through V6. Each lead detects electrical movement within the chest cavity; as an impulse progresses through the cardiac tissue, an upward movement on the ECG represents the wave of depolarization moving towards a positive electrode. V1 and aVR are considered right-sided leads and because of the movement of electric impulses, the resulting waveforms are inverted. From these leads, the stanFigur dard 12-lead ECG is obtained (Figur Figuree 1-3 1-3).

Chest leads

Chest leads

Limb lead Limb lead

Ground lead

Ground lead

Limb lead Limb lead

Limb lead

Limb lead

Figure 1-2: Sensor placement to obtain a 12-lead electrocardiogram; placement of three limb sensors, six chest sensors, and a ground lead

When reviewing an ECG, one should consider some basic features. The paper is divided into squares of 1 mm. Each square, given the normal paper speed of 25 mm/s, equates to 0.04 seconds. Therefore, each large box on the tracing, which is five small boxes, corresponds to 0.2 seconds. Based on a cycle of depolarization and repolarization, typical ECG waveforms are Figur generated (Figur Figuree 14 ).12 These waveforms include the P wave (atrial depolarization), the QRS complex (ventricular depolarization), and the T wave (ventricular repolarization). From these waveforms, ECG

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Cardiovascular Pharmacotherapy

Figure 1-3: Standard 12-lead electrocardiogram; the standard 12-lead ECG consist of limb leads (I, II, III, aVR, aVL, and aVF) and chest leads (V1–V6) intervals can also be determined such as the PR interval (normal 140 mm Hg or diastolic blood pressure >90 mm Hg), smoking, diabetes, and family history of heart attack or sudden cardiac death in a first-degree relative younger than 60 years. An alternative approach might be to select patients with a Framingham risk score consistent with at least a moderate risk of serious cardiac events within 5 years. ACC = American College of Cardiology; AHA = American Heart Association; CAD = coronary artery disease; ECG = electrocardiogram

Adapted from reference 12. Patients can be challenged pharmacologically if they cannot exercise based on age or physical infirmity (e.g., amputation) or choose not to perform exercise testing. Testing modalities include dobutamine, adenosine, and dipyridamole. Dobutamine (70% will likely lead to ischemic symptoms with exertion. See Chapter 6 (Chronic Stable Angina) for a detailed description regarding evaluation, treatment, and monitoring of exertion angina. If an occlusion is found during coronary angiography, various interventions can be used to expand the lumen, including angioplasty, atherectomy, or intracoronary stent placement. Angioplasty was the initial technique, which includes expanding a balloon catheter at the site of coronary occlusion. This procedure is effective, but it has the risk of abrupt closure and long-term restenosis. Intracoronary stent placement, performed with angioplasty, has improved the technique. In this approach, the balloon is surrounded by the stent (metal fabric that can be expanded); when the balloon expands, so does the stent. The stent, however, remains expanded and serves as scaffolding to maintain the diameter of the vessel lumen. Tissue may abnormally grow at the location of the stent, and drug-eluting stents have been developed. These devices

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Cardiovascular Pharmacotherapy

Left main artery (hidden)

Circumflex artery

Right coronary artery

Left anterior descending artery

Figure 1-6: Major coronary arteries observed during angiography/cardiac catheterization exude small amounts of antiproliferative drugs (e.g., sirolimus, tacrolimus, or everolimus), which inhibit this tissue growth.15,16 For all stents, thrombus may form on the foreign material until endothelial cells cover the metal device. For bare-metal stents, endothelialization takes approximately 3 weeks. Conversely, it takes months for it to occur with drugeluting stents. Although these periods represent the general time for endothelialization to occur, variance may arise based on a number of factors (e.g., location of stent). Before endothelialization occurs, the risk of thrombus formation on intracoronary stents can lead to disastrous outcomes such as acute coronary syndrome. Patients take aspirin and clopidogrel after stent placement, with aspirin continued long term in all patients. Clopidogrel duration depends on the type of stent deployed, and is given a minimum of 1 month for bare metal stents and ideally up to 12 months. For drug-eluting stents, clopidogrel is given for at least 12 months if the patient is not at high risk of bleeding.16 If patients cannot comply with dual antiplatelet therapy (aspirin plus clopidogrel) for 12 months, a drug-eluting stent should be avoided. See Table 1-8 for a specific recommendation for percutaneous coronary intervention.

Cardiovascular Testing

21

Table 1-8: Selected recommendations for percutaneous coronary intervention ACC/AHA/SCAI Class I • If immediately available, primary PCI should be performed in patients with STEMI (including true posterior MI) or MI with new or presumably new LBBB who can undergo PCI of the infarct artery within 12 hours of symptom onset, if performed in a timely fashion (balloon inflation goal within 90 minutes of presentation) by persons skilled in the procedure. (Individuals should have performed >75 PCI procedures per year, ideally at least 11 PCIs per year for STEMI.) The procedure should be supported by experienced personnel in an appropriate laboratory environment. (The test environment should have performed >200 PCI procedures per year, of which at least 36 should be primary PCI for STEMI and have cardiac surgery capability.) (Level of Evidence: A). Primary PCI should be performed as quickly as possible, with a goal of a medical contact-to-balloon or door-to-balloon time within 90 minutes (Level of Evidence: B). • Primary PCI should be performed in fibrinolytic-ineligible patients who present with STEMI within 12 hours of symptom onset (Level of Evidence: C). • An early invasive PCI strategy is indicated for patients with UA/NSTEMI who have no serious comorbidity (severe hepatic, pulmonary, or renal failure, or active/inoperable cancer; clinical judgment is required in such case) and who have coronary lesions amenable to PCI and who have characteristics for invasive therapy (Level of Evidence: A). • Percutaneous coronary intervention (or CABG) is recommended for UA/NSTEMI patients with 1- or 2-vessel CAD, with or without significant proximal left anterior descending CAD, but with a large area of viable myocardium and high-risk criteria on noninvasive testing (Level of Evidence: B). • Percutaneous coronary intervention (or CABG) is recommended for UA/NSTEMI patients with multivessel coronary disease with suitable coronary anatomy, with normal LV function, and without diabetes mellitus (Level of Evidence: A). • An early invasive strategy (i.e., diagnostic angiography with intent-to-perform revascularization) is indicated in UA/NSTEMI patients who have refractory angina or hemodynamic or electrical instability (without serious comorbidities or contraindications to such procedures) (Level of Evidence: B). Class IIa • PCI is reasonable in patients with asymptomatic ischemia or CCS class I or II angina and with one or more significant lesions in one or two coronary arteries suitable for PCI with a high likelihood of success and a low risk of morbidity and mortality. The vessels to be dilated must subtend a moderate to large area of viable myocardium or be associated with a moderate to severe degree of ischemia on noninvasive testing (Level of Evidence: B). • Use of PCI is reasonable in patients with asymptomatic ischemia or CCS class I or II angina with significant left main CAD (>50% diameter stenosis) who are candidates for revascularization but are not eligible for CABG (Level of Evidence: B). • It is reasonable that PCI be performed in patients with CCS class III angina and single-vessel or multivessel CAD who are undergoing medical therapy and who have one or more

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Table 1-8: Selected recommendations for percutaneous coronary intervention (cont’d) significant lesions in one or more coronary arteries suitable for PCI with a high likelihood of success and low risk of morbidity or mortality (Level of Evidence: B). Class IIb • PCI may be considered in patients with CCS class III angina with single-vessel or multivessel CAD who are undergoing medical therapy and who have one or more lesions to be dilated with a reduced likelihood of success (Level of Evidence: B). Class III • PCI is not recommended in patients with asymptomatic ischemia or CCS class I, II, III angina who do not meet the criteria as listed under the class II recommendations or who have one or more of the following (all Level of Evidence: C): - Only a small area of viable myocardium at risk - No objective evidence of ischemia - Lesions that have a low likelihood of successful dilatation - Mild symptoms that are unlikely to be due to myocardial ischemia - Factors associated with increased risk of morbidity or mortality - Left main disease and eligibility for CABG - Insignificant disease (9 (definite); 5–8 (probable); 1–4 (possible); 0 (doubtful)

Adapted from reference 10. Another recently developed ADR evaluation algorithm, published by Koh and Li, exhibited a 98% congruency rate with the Kramer method compared to a 94% rate achieved by the Naranjo scale.9 The Koh method is described in Table 2-3 2-3. Clinicians should begin evaluating a potential ADE by using the Naranjo scale, and use other validated algorithms as needed to support their clinical judgment.

Table 2-3: Koh and Li algorithm for identification of ADEs Question

Yes / Score

No / Score

Not Sure or Not Applicable / Score

Is there a reasonable time interval (24–48 hours) between administration of the suspected drug and the adverse reaction?

+2

-4

0

Has the adverse reaction been associated with the suspected drug before?

+2

-2

0

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33

Table 2-3: Koh and Li algorithm for identification of ADEs (cont’d) No / Score

Not Sure or Not Applicable / Score

0

+4

0

Is there any overdose of the suspected drug?

+2

0

0

If the drug was discontinued, did the adverse reaction improve? (If irreversible changes occurred, classify as “not sure.”)

+1

-2

0

If the drug was NOT discontinued, did the reaction resolve on its own?

-2

0

0

Did the reaction improve when a specific antagonist/ antidote was administered?

+4

0

+1

Did the adverse reaction recur when the suspected drug was discontinued and later re-administered?

+4

-2

0

Question Could this adverse reaction be due to an existing clinical condition?

Yes / Score

TO TOTTAL SCORE

Total Score >12 (definite); 8–11 (probable); 0–7 (possible); 30 kg/m2), physical inactivity, dyslipidemia, diabetes mellitus, age >55 for men and >65 for female, family history of premature cardiovascular disease, advanced age

Oral contraceptives

• Family history of HTN • History of HTN during pregnancy

Anthracyclines

• Cumulative dose (>550 mg/m2 for doxorubicin), single bolus doses • Advanced age, female gender, mediastinal radiation therapy, history of cardiac disorder

Bevacizumab

• Anthracycline exposure and/or left wall chest radiation

Cyclophosphamide

• Dose given prior to anthracycline use, mediastinal radiation therapy

Ifosfamide

• Cumulative dose of >12.5 g/m2

Trastuzumab

• Anthracycline exposure, age >50, NYHA class II–IV prior to therapy

Antimigraine drugs (ergot alkaloids and sumatriptan)

• Existing cardiac disease

Atypical antipsychotics

• Use of clozapine and olanzapine

Cocaine

• Within first hour of acute ingestion • Young, non-Caucasian, male, other substance abuse

Estrogen/progestin replacement therapy

• Presence of underlying cardiovascular risk factors • Age >60, >10 years post-menopause

Heart failure

Myocardial ischemia

Risk FFactors actors

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Table 2-4: Risk factors for specific cardiac ADEs (cont’d) ADE

Bradycardia/ block

Drug

Risk FFactors actors

Fluorouracil

• Existing cardiac disease, higher doses (>800 mg/m2) • Earlier doses in cycle, higher rates of administration

NSAIDs

• Existing cardiac disease, higher COX-2 selectivity, longer durations of use, higher doses of COX-2

Oral contraceptives

• >35 years, smokers, HTN • Potential use of second-generation agents

Vinca alkaloids

• Existing cardiac disease

Any drug causally associated with bradycardia or AV block

• Pre-treatment HR 0.20 seconds • Underlying SA or AV nodal disease • Renal dysfunction if drug is primarily renally cleared (atenolol, sotalol, nadolol, digoxin, disopyramide, flecainide) • Concomitant use of other agents associated with this adverse effect

Digoxin

• Renal dysfunction, drug interactionsa • Hypomagnesemia, hypokalemia, hypercalcemia • Drug concentrations >2 ng/mL

Lidocaine

• Drug concentrations >2–4 mcg/mL

Atrial fibrillation Alcohol

• Increased total dose (e.g., >30 g /day) • Chronic heavy use in men • Alcohol withdrawal syndromes

Multifocal atrial tachycardia

Theophylline

• Drug interactionsb • Drug concentrations >20 mcg/mL

Ventricular tachycardia

Class Ia, Ic antiarrhythmics

• Structural heart disease • History of ventricular tachycardia

Digoxin

• Renal dysfunction, drug interactionsa • Hypomagnesemia, hypokalemia, hypercalcemia • Drug concentrations >2 ng/mL

Drug-Induced Cardiac Disease

37

Table 2-4: Risk factors for specific cardiac ADEs (cont’d) ADE

Torsades de pointes

Drug

Risk FFactors actors

Tricyclic antidepressants

• Increased total body concentrations (in intentional or unintentional overdose, liver dysfunction, drug interactionsc)

Any drug causally associated with Tdp

• Structural heart disease, female sex, elderly, bradycardia, history of Tdp, hypokalemia or hypomagnesemia, presence of hERG channel polymorphism or genetic long QT syndrome, drug interactionsd • QTc >500 msec or increase >60 msec following drug administration

ADE = adverse drug event; AV = atrioventricular; BMI = body mass index; BP = blood pressure; COX = cyclooxygenase; hERG = human ether-a-go-go; HR = heart rate; HTN = hypertension; NYHA = New York Heart Association; NSAIDs = non-steroidal anti-inflammatory drugs; SA = sinoatrial; Tdp = torsades de pointes Amiodarone, azole antifungals, beta-blockers, non-dihydropyridine calcium channel blockers, cyclosporine, diuretics, macrolide antibiotics, protease inhibitors, quinidine, quinine. b Competitive substrates or inhibitors of cytochrome P450 1A2, 3A4, and 2E1 inhibitors. c Drugs that may decrease TCA metabolism, including buproprion, duloxetine, SSRIs, cimetidine, and methylphenidate, amiodarone, haloperidol, thioridazine, and ritonavir. d Commonly, inhibitors of CYP P450 1A2, 2C, 2D6, and 3A4 isoenzymes. However, clinicians are advised to use drug interaction software for comprehensive assessment of potential drug interactions. a

Adapted from references 12–18. If a drug is deemed the culprit for a patient’s presentation, the drug should be discontinued immediately, if possible, or changed to an alternative agent. The frequency of clinical monitoring should be increased until signs and symptoms have abated. Following this time period, monitoring for the ADE recurrence may be required if the drug cannot be discontinued or if the patient is switched to a drug in the same mechanistic class. Treatments specific to individual drug-induced conditions are found in their respective sections of this chapter and in Table 2-5 2-5.18–27

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Table 2-5: Specific management strategies for cardiac ADEs Drug

ADE

Managementa

Erythropoietin-alfa and darbepoetin-alfa

HTN

• Use lowest dose possible • Follow prescribing guidelines based on hemoglobin level

Oral contraceptive pills

HTN

• Change to low estrogen (550 mg/ m2 for doxorubicin).45 Rates of HF reported with other chemotherapeutic agents include mitoxantrone (1.5 to >5%), cyclophosphamide (7–25% in adults and 5% in children), bevacizumab (1.7%), and sunitinib (8%).16,32,40,42,43 The rates of HF in patients receiving paclitaxel (18%) and mitomycin (15.3%) in combination with doxorubicin have been shown to be higher than rates in those treated with doxorubicin by itself. Therefore, paclitaxel and mitomycin alone may increase the risk of cardiomyopathy.16,45 The rate of HF reported with trastuzumab ranges from 2.8 to 28%; this is typically seen when used concomitantly with an anthracycline.4 Risk factors for chemotherapy-induced HF are found in Table 27. Non-chemotherapeutic agents have also been linked to HF. Non-steroidal anti-inflammatory agent use has been shown to increase the risk of first hospitalization for HF in a cohort of elderly patients [RR 1.8 (95% CI, 1.4–2.4)].46 In a case-control study of patients admitted to the emergency department, the use of NSAIDs was associated with an increased risk of hospitalization for HF [RR 2.1 (95% CI, 1.2–3.3)].47 In a retrospective cohort using a health claim database, the hazard ratio for HF with TZD use was 1.76 (95% CI, 1.43–2.18, p < 0.001).48 Based on preliminary data that suggested tumor necrosis factor (TNF) inhibitors may benefit patients with HF, infliximab was studied in patients with New York Heart Association class III/IV symptoms and a left ventricular ejection fraction (LVEF) typical for hyperprolactinemia, weight gain, and new-onset diabetes. b Protease inhibitors and stavudine. a

Adapted from references 14–19, 35, and 57–59. Cardiovascular events were shown to occur in the range of 0.65–3.6% of patients taking COX-2 inhibitors in phase III trials, while the non-selective COX inhibitors naproxen and diclofenac have exhibited rates of 0.5 and 1–2.2%, respectively.60 In one meta-analysis of 121 randomized trials of COX-2 inhibitors, the reported relative risk versus placebo for myocardial infarction (MI) was 1.36 (95% CI, 1.33–2.59) for COX-2 inhibitors. In the same meta-analysis, for 91 randomized trials of nonselective NSAIDs, the following relative risks versus placebo for vascular death were reported: 0.92 (95% CI, 0.67–1.26) for naproxen, 1.51 (95% CI, 0.96–2.37) for ibuprofen, and 1.63 (95% CI, 1.12– 2.37) for diclofenac. When considering these occurrence rates and relative risks,

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one should remember that they occurred under clinical trial conditions and included counts of cerebrovascular ischemia in some cases.61 Clinical trials of first-, second-, and third-generation OCPs have demonstrated rates of MI of 9.5–28% with associated relative risks of 0.6–5.14 Comparatively, the use of HT (estrogen + progestin) in postmenopausal women was reported to result in coronary artery disease (CAD) in 0.37% of subjects annually in the originally published Women’s Health Initiative (WHI) trial and at 36.2 events per 1,000 person-years in another randomized trial.62,63 Cocaine-related chest pain has been associated with a 0.6–6% incidence of resultant MI;18 a lifetime risk of ischemia in chronic cocaine abusers has been reported as 6–7 times that of the normal population.17 Thiazide diuretics have been shown to lead to increases in both triglycerides and LDL of approximately 8–25% each, though these changes often occur only in the short term and become comparatively null with respect to other antihypertensives over time.64 Protease inhibitors cause dyslipidemia (primarily hypercholesterolemia and hypertriglyceridemia) in up to 75% of patients and insulin resistance in up to 50%.15 Odds ratios for dyslipidemia for protease inhibitors compared to other highly active antiretroviral therapy (HAART) range from 1.7–6.2 in various cohort studies.15 Atypical antipsychotic agents are well known to cause metabolic syndrome; comparative rates of significant weight gain among various secondgeneration drugs have been reported in one large clinical study as 30% for olanzapine, 16% for quetiapine, 14% for risperidone, and 7% for ziprasidone over 6 months.13 The odds ratio for new-onset diabetes was 4.7 (95% CI, 1.5– 4.9).58 Specific pathophysiological mechanisms associated with cardiac-related ADEs are listed in Table 2-8. Acute drug-induced myocardial ischemia is most often due to the offending drug’s ability to alter the heart’s myocardial oxygen supply and demand relationship such that the metabolic needs of the myocardium are subsequently not met. Commonly, these mechanisms include alterations in heart rate, myocardial contractility, BP, or coronary vasoconstriction. A few drug classes can cause myocardial ischemia with abrupt discontinuation; among them are calcium channel- and beta-blockers and nitroglycerin. It should be noted that a drug-induced supply-demand mismatch is most likely to be of clinical significance when a patient has underlying heart disease. Acute MIs also can be elicited by drugs such as cocaine, erythropoietin, and estrogen that cause coronary thrombosis or vasospasm even in the absence of established atherosclerosis. In chronic drug-induced myocardial ischemia, the long-term use of certain drugs essentially acts as a cardiovascular risk factor by accelerating the body’s natural

Drug-Induced Cardiac Disease

51

timeline of atherosclerosis, causing HTN, promoting weight gain, or causing insulin resistance. Examples of drugs leading to accelerated atherosclerosis include cocaine and protease inhibitors, while atypical antipsychotics are associated with new-onset diabetes.15,17,18,58 Predicting who will ultimately experience this ADE (myocardial ischemia) can be difficult, but specific risk factors exist (see Table 2-4) for some drugs. Patients with underlying heart disease are particularly susceptible to ischemia incited by aggressive antihypertensive use, abrupt withdrawal of antihypertensives, and the use of nitrates with phosphodiesterase-5-inhibitors. These patients may also be more likely to exhibit symptoms of coronary vasoconstriction induced by ergot alkaloids or sumatriptan.17 In regards to NSAID use, increased COX-2 selectivity, higher doses of COX-2 inhibitors, increased duration of use, and heart disease history have all been associated with increased MI risk.60 Several observational studies indicate significantly increased risk of MI with second-generation OCPs as compared to third-generation OCPs; however, other analyses have not yielded the same conclusions. More widely accepted is the increased risk of thrombosis occurring in OCP users over the age of 35 who also smoke.14 Among the protease inhibitors, ritonavir appears to have the highest risk of dyslipidemia, while atazanavir, saquinavir, and indinavir have the lowest risk.15 When drug-induced myocardial ischemia does occur, the presenting signs and symptoms as well as diagnosis are no different than those associated with CAD. In patients with no established CAD or cardiovascular risk factors, diagnosis of an ADE can be made with much greater certainty. The diagnosis remains based on symptoms and monitoring of ECG and cardiac markers.17 Patients with a suspected ADE should be treated per guidelines like other patients experiencing chronic or acute myocardial ischemia (see Chapter 6, Chronic Stable Angina, and Chapter 7, Acute Coronary Syndrome). In the case of cocaine abuse, the majority of users experiencing acute chest pain will present with symptoms within several hours of ingestion, although reports of symptom presentation out to several days are documented. While the clinical management of cocaine-induced MI is very similar to that recommended for traditional MI, a few notable exceptions exist. Benzodiazepines are recommended early after presentation in lieu of morphine to aid in chest pain relief and to improve hemodynamics. Nitroglycerin is the preferred agent for associated HTN, though IV phentolamine and nitroprusside are recommended as alternative agents. Because of the concern for unopposed alpha stimulation with a nonselective beta-blocker that would contribute to the already over-stimulated adrenergic tone of cocaine abusers, beta-blockers are not recommended acutely and are recommended at discharge only in those patients in whom the

52

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benefit may outweigh the risk (e.g., with documented MI, LVEF 20 mcg/ L.82 Thus, clinicians should note that this arrhythmia can occur even at concentrations within therapeutic range. Symptoms of this drug-induced arrhythmia mirror other atrial tachycardias; specific management is described in Table 25.81

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Cardiovascular Pharmacotherapy

Ventricular tachycardias Monomorphic VT presents on ECG as abnormally but similarly shaped wide QRS complexes, while polymorphic VT is characterized by the presence of >1 abnormal QRS morphologies. In both arrhythmias, the abnormal QRS complexes must occur consecutively and must last for at least 30 seconds to be classified as “sustained” VT. Associated heart rates must exceed 100 beats per minute. The most commonly implicated cause of drug-induced VT is use of Class Ic antiarrhythmics. Their predilection for causing VT has to do with their slower rates of dissociation from the sodium channels they block mechanistically. Flecainide, propafenone, and moricizine have demonstrated reported rates of VT of 2.3–19%, 10–19%, and 3–23%, respectively. 67,83 The class Ia antiarrhythmics have been associated with VT as well due to their intermediate rates of dissociation from sodium channels. Quinidine, procainamide, and disopyramide have been reported as causing rates of VT of 2%, 5–7%, and 5%, respectively.83 Lidocaine, with its fast dissociation from sodium channels, is not commonly associated with VT.21 Drug-induced VT is also associated with the following agents (incidence noted in parentheses if known): amiodarone (1– 2%),83 sotalol,67 digoxin,21,23 Lily-of-the-Valley (a glycoside-like herbal product),19 ibutilide (0.2–4.9%),67, 84 and tricyclic antidepressants (TCAs) (4%, generally in overdose situations).22 The mechanism behind drug-induced VT is not known beyond alterations of sodium-channel functioning that lead to significant slowing of impulse conduction velocity in ventricular tissue. Class Ia agents also have properties of potassium channel blockade, which causes prolongation of repolarization and subsequent increased potential for reentry occurrence. Sotalol, amiodarone, and ibutilide all are potassium channel blockers; amiodarone specifically has fast dissociation sodium channel-blocking properties too. The tricyclic antidepressants are known to exhibit Class Ia-like properties on the sodium channel. Imipramine also has been shown to exhibit potassium channel-blocking activity in animal models.75 Patients with structural heart disease (CAD, HF, valvular disease, and HTN with left ventricular hypertrophy) or a history of sustained VT are far more likely to experience drug-induced VT.67 Increased mortality has been associated, especially with Class Ia and Ic antiarrhythmics, in patients with CAD.85,86 Thus, such patients should be closely monitored upon the initiation of a potential culprit drug. Presenting symptoms are similar to non-drug-induced VT, and treatment follows that of other types of VT (see Chapter 12, Ventricular Arrhythmias). Specific management of VT caused by TCA overdose is found in Table 2-5.

Drug-Induced Cardiac Disease

55

QT prolongation and torsades de pointes Torsades de pointes is a specific type of polymorphic VT characterized by prolongation of the QT interval on ECG prior to the development of classic “twisting” of wide polymorphic QRS complexes around an isoelectric axis. The relationship of QT prolongation and the development of Tdp is peculiar, being both non-linear and unpredictable. Neither the extent nor frequency of QT prolongation predicts the likelihood of Tdp occurrence.87 While many drugs have the ability to induce QT prolongation, clinicians should foremost be aware not all drugs that prolong QT intervals ever clinically cause88 Tdp. Some drugs (e.g., amiodarone) routinely and extensively prolong QT intervals but have demonstrated little incidence of Tdp. On the other hand, other drugs cause only slight increases in QT intervals yet have been associated with a high risk of Tdp (especially in patients with risk factors).89 Historically, a significant percentage of those drugs removed from the market by the FDA have been as a consequence of their resulting in QT prolongation and Tdp. Notable examples include terfenadine, cisapride, astemizole, grepafloxacin, sertindole, levomethadyl, and droperidol.87 Several extensive reviews of the literature have been published on drugs most likely to prolong QT intervals and cause Tdp.87–89 In addition, the Arizona Center for Education and Research on Therapeutics (Arizona CERT), an independently funded research center, maintains a comprehensive list of QTprolonging drugs at www.torsades.org. This list is divided into three categories of risk for causing Tdp: drugs “generally accepted” to have risk, drugs with possible risk, and drugs with “conditional” (i.e., in the presence of certain risk factors) risk.90 Table 2-975,88,90,91 summarizes those drugs considered to have probable and possible association with Tdp. Lengthening of the QT interval is the manifestation of prolonged ventricular repolarization and correspondingly prolonged action potential duration. QT interval on the surface ECG is an aggregated representation of the repolarization activity in all ventricular cells. On an individual cell level, certain areas of the myocardium may actually be more repolarized than others at any given time during the action potential. The ability of the myocardium to be in different stages of repolarization is termed “myocardial heterogeneity.” This heterogeneity is also expressed by the varying degrees of responsiveness that different cell types’ action potentials will have to pharmacologic agents.92 Inappropriate extension of the action potential in vulnerable cell populations creates the opportunity for reentry circuits and triggered automaticity [e.g., early after-depolarizations (EADs) in phase 3 and delayed after-depolarizations (DADs) in phase 4 of the cardiac cycle]. Typically the mechanistic sequence occurs as follows: a

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Cardiovascular Pharmacotherapy

Table 2-9: Drugs that may induce torsades de pointesa Probable Risk

Possible Risk

Arsenic Antimalarialsb Antipsychotics (first generation)c Class Ia antiarrhythmics Class III antiarrhythmicsd Pentamidine Macrolides (clarithromycin and erythromycin) Methadone Tricyclic antidepressantse

Alfuzosin Amantadine Antipsychotics (second generation)f Atazanavir Chloral hydrate Felbamate Flecainide Fluoroquinolones Foscarnet Fosphenytoin Lithium Macrolides (azithromycin and telithromycin) Oxytocin Ranolazine Selective 5HT3 receptor antagonistsg Tacrolimus Tizanidine Tyrosine kinase inhibitorsh Venlafaxine Voriconazole Vardenafil Tamoxifen Cesium Cocaine Hawthorn (Crataegus) Licorice

List is not exhaustive. Refer to www.torsades.org or references.87–89 Quinine derivatives, halofantrine. c Risk considered low with amiodarone. d Chlorpromazine, haloperidol (IV>PO and larger doses have highest risk), droperidol, thioridazine, mesoridazine, pimozide. e Usually only in overdose situations. f Greater risk with quetiapine and ziprasidone than aripiprazole, clozapine, olanzapine, and risperdal due to their higher comparative affinities for hERG channels. g Ondansetron, granisetron, dolasetron. h Lapatinib, nilotinib, sunitinib. a

b

Adapted from references 75, 88, 90, and 91.

Drug-Induced Cardiac Disease

57

premature ventricular beat, a subsequent compensatory pause, a sinus beat with prolonged QT interval, and finally, another premature beat that precipitates Tdp. This cycle can then continue to repeat itself.87,88 The vast majority of drugs that prolong the QT interval do so by blocking the rapid (Ikr) or slow (Iks) components of the delayed rectifier potassium current that allow potassium efflux during the rapid repolarization phase of the action potential. Imipramine, amitriptyline, haloperidol, and amiodarone may also prolong the QT interval by blockade of L-type calcium channels that permit calcium influx during the plateau phase.75,89,91 Both mechanisms alter the cell membrane voltage, allowing EADs to reach threshold and Tdp to occur. Notably, while amiodarone commonly prolongs the QT interval, it is unlikely to cause Tdp. Unlike other antiarrhythmics, it blocks the slow component potassium channels (Iks), thereby lessening the chance of EAD and DAD development. In addition, amiodarone prolongs the action potential in a uniform (rather than heterogenous) manner across all ventricular myocardium cell types, lowering the likelihood of creating reentry circuits.88,92 Several risk factors for drug-induced Tdp have been identified and are summarized in Table 2-4. Identified risk factors with the strongest degree of association with Tdp include female sex, advanced age, structural heart disease (history of myocardial infarction, heart failure, and valvular disease), hypokalemia, hypomagnesemia, bradycardia (60 msec from baseline occurs or if the QTc interval exceeds 500 msec.87,89,95,96 After correcting potential risk factors for the QT prolongation, the drug may be restarted; if risk factors cannot be altered, the drug should be permanently discontinued. These management guidelines do not apply to amiodarone because it usually causes innocuous rises in QT interval.88 Clinicians should ensure ECGs are monitored once the drug has reached steady-state concentrations. In the acute setting, ECGs should be obtained when patients experience clinical conditions that would predispose them to QT interval prolongation such as increased diuretic use, new dialysis initiation, acute myocardial ischemia, addition of a drug with a potential interaction, and worsening kidney or hepatic function. With chronic treatment, ECGs should be obtained every 3–6 months.87,95 Diagnosis of Tdp is made by 12-lead ECG. While Tdp can spontaneously remit without intervention, it is potentially life threatening due to its ability to degenerate into ventricular fibrillation. Tdp symptoms include those typically present with other ventricular tachycardias such as palpitations, shortness of breath, fatigue, dizziness, lightheadedness, and syncope. Sudden cardiac death (SCD) is also known to occur with drugs that are likely to cause Tdp. For example, amitriptyline users (>100 mg) have demonstrated a RR for SCD of 1.80 (95% CI, 1.16–2.79) compared to nonusers.97 Patients with HF and CAD are particularly prone to experiencing signs and symptoms of diminished cardiac output and chest pain, respectfully.67 If Tdp occurs, the first-line treatment includes immediate cessation of suspected offending drugs and correction of any existing hypomagnesemia and hypokalemia. Acute and long-term overdrive pacing is a first-line therapy for patients with heart block and symptomatic bradycardia and those with recurrent-pause dependent Tdp. Magnesium is the drug of choice for Tdp with long QT interval. Use of either isoproterenol or beta-blockers with pacing is an alternative strategy for acutely treating Tdp that is pause-dependent or associated with sinus bradycardia, respectively (see Chapter 12, Ventricular Arrhythmias).21

CLINICAL CONTROVERSIES Should dexrazoxane be used to minimize car diotoxicity in patients rreceiving eceiving cardiotoxicity anthracycline therapy? Dexrazoxane (Zinecard®) inhibits the conversion of superoxide anions and hydrogen peroxide to super hydroxide free radicals; use has been shown to decrease the rate of HF and minimize the change in LVEF in

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patients with metastatic breast cancer treated with doxorubicin. Despite the cardioprotective benefits of dexrazoxane, therapy may interfere with the antitumor efficacy of chemotherapy. Additionally, dexrazoxane has not been shown to improve mortality.98,99 Recommendations for use are available from the American Society of Clinical Oncology in the 2008 Chemotherapy and Radiation Therapy Protectants Guideline Update.98 Ar diovascular events than selecAree nonselective NSAIDs associated with fewer car cardiovascular tive NSAIDs? While the majority of attention originally focused on the safety of COX-2 selective NSAIDs, the relative safety of nonselective NSAIDs are also of concern. To answer this question, clinicians should remember the comparative COX-2:COX-1 selectivity of different agents is important because selectivity plays a role in drug-induced cardiac disease. The most clinically used NSAIDs, in increasing order of COX-2 selectivity, are ketorolac, indomethacin, aspirin, naproxen, ibuprofen, fenoprofen, diflunisal, piroxicam, diclofenac, celecoxib, meloxicam, etodolac, valdecoxib, etoricoxib, rofecoxib, and lumiracoxib.100 The exact mechanisms behind NSAID-induced MI are briefly reviewed in Table 2-8; clinicians are referred elsewhere for more detailed discussions.101 One recent meta-analysis of 121 randomized controlled trials of rofecoxib, celecoxib, etoricoxib, lumiracoxib, and valdecoxib described a rate ratio versus placebo for MI of 1.86 (95% CI, 1.33–2.59). Although MI was not directly reported in this meta-analysis of nonselective agents versus placebo, reported rate ratios of vascular events was 0.92 (95% CI, 0.67–1.26) for naproxen, 1.51 (95% CI, 0.96–2.37) for ibuprofen, and 1.63 (95% CI, 1.12–2.37) for diclofenac.61 The data, therefore, give some evidence of increasing cardiovascular risk with increasing selectivity of the traditional NSAID. When the metaanalysis directly compared data for COX-2 inhibitors and traditional NSAIDs from 91 trials, COX-2 inhibitors were associated with a rate ratio of MI of 2.04 (95% CI, 1.41–2.96) when compared to naproxen, 1.20 (95% CI, 0.85–1.68) versus any “non-naproxen” drug, and 1.53 (95% CI, 1.19–1.97) versus any nonselective NSAID.61 It would appear from these results that naproxen is the safest nonselective NSAID. However, when interpreting these comparative rate ratios, it is impossible to tell if any risks specific to a nonselective NSAID are vastly outweighed by a high risk associated with the COX-2 selective agent. Another meta-analysis of 17 case-control studies combined with six cohort studies found a summary relative risk for cardiovascular events of 1.06 (95% CI, 0.91–1.23) with celecoxib, of 2.19 (95% CI, 1.64–2.91) with rofecoxib (>25 mg per day), and of 1.25 (95% CI, 1.00–1.55) with meloxicam. Comparatively, summary relative risks were 0.94 (95% CI, 0.87–1.07) for naproxen, 1.40 (95% CI, 1.16–1.70) for diclofenac, 1.07 (95% CI, 0.97–1.18) for ibuprofen,

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1.30 (95% CI, 1.07–1.60) for indomethacin, and 1.03 (95% CI, 0.70–1.59) for piroxicam. In this meta-analysis, the relative risk of MI in patients using naproxen was 0.75 (95% CI, 0.63–0.88) compared to patients using diclofenac or indomethacin.61 Considering these results, evidence supports the conclusions that naproxen and ibuprofen have less risk for MI compared to other NSAIDs and diclofenac has the highest risk. If use of a NSAID is deemed necessary for control of pain or inflammation, the American Heart Association recommends nonselective NSAIDs as first-line therapy, with preferential consideration given to naproxen. NSAIDs with some COX-2 activity are considered second line before resorting to COX-2 inhibitors. Emphasis is placed on limiting the duration and total doses used in all cases, as even nonselective agents have demonstrated some degree of risk. Finally, if ibuprofen and aspirin are used concomitantly, ibuprofen must be given at least 30 minutes following aspirin administration to prevent potential inhibition of aspirin’s antithrombotic effects by means of a pharmacodynamic interaction.60 Does hor mone therapy incr ease car diac risk in all populations of post-menohormone increase cardiac pausal women? Considerable debate and controversy continues to exist regarding the risk-to-benefit ratio of prescribing HT (estrogen-progestin combinations or estrogen alone) in post-menopausal women. While HT undoubtedly is effective in decreasing postmenopausal vasomotor symptoms, questions rage on as to the veracity that HT is cardioprotective. Numerous observational studies, notably the large Nurses Health Study,102 have demonstrated a 35–50% reduction in coronary event rates in HT users.103 Large, randomized trials such as the Heart and Estrogen/Progestin Replacement Study (HERS)63 and the WHI trials62,104 were subsequently conducted to verify these findings. The HERS trial did not show a statistically significant difference in coronary events of women with a history of coronary disease who used conjugated estrogen plus medroxyprogesterone compared to placebo users. The WHI trial, which included women with no history of coronary events, likewise did not show a statistical difference between conjugated estrogen plus medroxyprogesterone and placebo or between estrogen and placebo in preventing coronary events. However, in both HERS and WHI, use of estrogen plus progestin was associated with a statistically significant increase in cardiac risk in year 1 only. After year 1, risk was non-statistically higher with HT in years 2–5.62 This evidence was surprising and seemed to indicate a potential increase in cardiovascular risk with HT use. In the WHI trial, the absolute risk associated with HT use was a relatively small 8 events per 10,000 women treated for 1 year. Additionally, when the confidence interval for the primary outcome HR was adjusted for multiple statistical comparisons, the risk was no longer statistically significant.62,103

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The most likely explanation for these data discrepancies is that cardiac risk is highest only when HT is initiated in older patients and those >10 years postmenopause. It has been suggested that estrogen, through its beneficial effects on LDL, HDL, and vascular reactivity, exhibits less cardiac risk in younger, healthier patients because it interrupts early rather than late-stage atherosclerosis.105 A meta-analysis of 23 randomized trials (N = 39,049) of HT demonstrated a risk of 0.68 (95% CI, 0.48–0.96) for women 60 years.106 A post-hoc analysis of combined WHI trial data showed similar findings for younger (50–59 years) and older (60–69 years) women. This analysis also demonstrated the following risks according to initiation of use post-menopause: within 20 years, HR 1.28 (95% CI, 1.03–1.58).107 Primarily based on these data, the North American Menopause Society,108 the American Association of Clinical Endocrinologists,105 and the American College of Obstetricians and Gynecologists109 have all concluded in position statements that younger patients and those with early menopause likely have lower cardiac risk with use of HT. These patients should be counseled that they may experience a higher benefit-to-risk ratio when comparing the benefits of vasomotor symptom treatment to their lower cardiac risk. However, each patient should be considered carefully for cardiac risk factors and use of HT should be evaluated on an individual basis. As duration of use or age of the patient increases, or if new cardiac risk factors emerge, HT should be re-evaluated. At all times, the lowest effective dose should be utilized.105,108,109

FUTURE DIRECTIONS To improve patient safety and to better identify risks of adverse cardiac events secondary to medications, pharmacogenomic testing should be incorporated into all phases of clinical trials. For example, determining the likelihood of any newly developed drug to affect hERG channels has been advocated. To further reduce the risk of the ADEs, prescribers need to make it a standard of practice to screen patients for predisposing risk factors and drug interactions.

3

Hypertension Joseph J. Saseen INTRODUCTION

Hypertension is one of the most common chronic medical conditions.1 It affects Table 3-1 approximately one in three adult Americans (T 3-1). Historically hypertension has been nicknamed the “silent killer,” owing to an absence of symptoms despite the ongoing vascular damage that increases risk of cardiovascular (CV) events. Years ago, it was thought that patients with hypertension required chronically elevated blood pressure (BP) for adequate perfusion of essential organs, thus explaining the origin of the term “essential hypertension.” However, landmark evidence established that treating hypertension significantly reduces the risk of hypertension-associated complications. These complications, referred to as target organ damage or CV events, are responsible for the morbidity, mortality, and most of the costs related to hypertension. Clinicians should remember that the purpose of treating hypertension is to decrease the risk of developing these associated complications (i.e., CV events). The treatment of hypertension follows an evidence-based medicine philosophy. Multiple clinical trials evaluating antihypertensive pharmacotherapy have been completed and provide the evidence needed for the development of consensus guidelines. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) is the most identifiable, evidence-based guidelines for hypertension.2 However, newer data have been published since the release of these guidelines in 2003, and the next update (JNC8) will not be available until 2010. The 2007 Treatment of Hypertension Scientific Statement from the American Heart Association (AHA) Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention is the most up-to-date, evidence-based guideline for treating hypertension. 3 Many core recommendations are similar between these two guidelines. However, the 2007 AHA guideline identifies lower goal BP for patients at high 63

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risk for CV events, and it does not recommend beta-blocker therapy as a first-line treatment option for primary prevention patients.

Table 3-1: Epidemiologic data for hypertension Prevalence (2006) 73,600,000

Prevalence among Older PPersons ersons (2005–2006)

Ambulatory Medical Care Utilization Estimated Mortality (2005) Estimates (2006) Costs (2009)

Age 65–74 yrs: 54,356 •64.7% men (~319,000 for •69.6% women total mention mortality) Age >75 yrs: •64.1% men •76.4% women

44,879,000

$73.4 billion

Adapted from reference 1. The overall clinical management of hypertension is suboptimal. The most recent estimates from the National Health and Nutrition Examination Surveys (NHANES) from 2003 to 2004 indicate that prevalence, awareness, and treatment rates of hypertension have not significantly improved when compared to previous estimates from 1999 to 2000.4 However, control of BP (