CARDIAC DRUGS CARDIAC DRUGS Editors Kanu Chatterjee MBBS FRCP (London) FRCP (Edin) FCCP FACC MACP Clinical Professor of Medicine Division of Cardiology The Carver College of Medicine University of Iowa Iowa City, Iowa, USA Emeritus Professor of Medicine University of California San Francisco, California, USA Eric J Topol MD FACC Director, Scripps Translational Science Institute Chief Academic Officer, Scripps Health Vice Chairman, West Wireless Health Institute The Gary and Mary West Chair of Innovative Medicine Professor of Translational Genomics The Scripps Research Institute La Jolla, California, USA JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi ● Panama City ● London ● Dhaka ● Kathmandu Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: jaypee@jaypeebrothers.com Overseas Offices J.P Medical Ltd 83 Victoria Street London Jaypee-Highlights Medical Publishers Inc SW1H 0HW (UK) City of Knowledge, Bld 237, Clayton Phone: +44-2031708910 Panama City, Panama Fax: +02-03-0086180 Phone: +507-317-0160 Email: info@jpmedpub.com Fax: +507-301-0499 Email: cservice@jphmedical.com Jaypee Brothers Medical Publishers (P) Ltd 17/1-B Babar Road, Block-B, Shaymali Jaypee Brothers Medical Publishers (P) Ltd Mohammadpur, Dhaka-1207 Shorakhute, Kathmandu Bangladesh Nepal Mobile: +08801912003485 Phone: +00977-9841528578 Email: jaypeedhaka@gmail.com Email: jaypee.nepal@gmail.com Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2013, Jaypee Brothers Medical Publishers All rights reserved No part of this book may be reproduced in any form or by any means without the prior permission of the publisher Inquiries for bulk sales may be solicited at: jaypee@jaypeebrothers.com This book has been published in good faith that the contents provided by the contributors contained herein are original, and is intended for educational purposes only While every effort is made to ensure the accuracy of information, the publisher and the editors specifically disclaim any damage, liability, or loss incurred, directly or indirectly, from the use or application of any of the contents of this work If not specifically stated, all figures and tables are courtesy of the contributors Where appropriate, the readers should consult with a specialist or contact the manufacturer of the drug or device Cardiac Drugs/Editors Kanu Chatterjee, Eric J Topol First Edition: 2013 ISBN 978-93-5025-879-8 Printed at: Dedicated to Our wives Docey Chatterjee and Susan Topol CONTENTS Contributors ix Preface xi Acknowledgments xiii CHAPTER Angiotensin, Aldosterone, and Renin Inhibition in Cardiovascular Disease Abdallah Kamouh, Gary S Francis, Kanu Chatterjee CHAPTER Positive Inotropic Drugs: A Limited but Important Role 34 Carl V Leier, Garrie J Haas, Philip F Binkley CHAPTER Antihypertensive Drugs 72 William J Lawton, Kanu Chatterjee CHAPTER Diuretics 158 Michael E Ernst CHAPTER Drugs for Dyslipidemias 184 Byron Vandenberg CHAPTER Drugs for Diabetes and Cardiodysmetabolic Syndrome 242 Prakash Deedwania, Sundararajan Srikanth CHAPTER Drugs for Acute Coronary Syndromes 267 Stephen W Waldo, Yerem Yeghiazarians, Kanu Chatterjee CHAPTER Drugs for Dysrhythmia 326 Rakesh Gopinathannair, Brian Olshansky vii CARDIAC DRUGS CHAPTER Drugs for Heart Failure 389 Kanu Chatterjee CHAPTER 10 Drugs for Stable Angina 424 Kanu Chatterjee, Wassef Karrowni CHAPTER 11 Drugs for Pulmonary Hypertension 454 Ravinder Kumar, Sif Hansdottir CHAPTER 12 Cardiac Drugs in Pregnancy and Lactation 485 Wassef Karrowni, Kanu Chatterjee CHAPTER 13 Future Directions: Role of Genetics in Drug Therapy 506 Eric J Topol Index 509 viii CONTRIBUTORS EDITORS Kanu Chatterjee MBBS FRCP (London) FRCP (Edin) FCCP FACC MACP Clinical Professor of Medicine Division of Cardiology The Carver College of Medicine University of Iowa Iowa City, Iowa, USA Emeritus Professor of Medicine University of California, San Francisco, California, USA Eric J Topol MD FACC Director, Scripps Translational Science Institute Chief Academic Officer, Scripps Health Vice-Chairman, West Wireless Health Institute The Gary and Mary West Chair of Innovative Medicine Professor of Translational Genomics The Scripps Research Institute La Jolla, California, USA CONTRIBUTING AUTHORS Philip F Binkley MD MPH Wilson Professor of Medicine College of Medicine, The Ohio State University Professor of Epidemiology College of Public Health, The Ohio State University Vice Chairman for Academic Affairs Department of Internal Medicine, The Ohio State University Director, Center for FAME Associate Dean for Faculty Affairs College of Medicine, The Ohio State University Columbus, Ohio, USA Michael E Ernst Pharm D Professor (Clinical) Department of Pharmacy Practice and Science College of Pharmacy Department of Family Medicine Carver College of Medicine The University of Iowa Iowa City, Iowa, USA Prakash Deedwania MD FACC Rakesh Gopinathannair MD MA Director Cardiac Electrophysiology University of Louisville Hospital Assistant Professor of Medicine Division of Cardiology University of Louisville Louisville, Kentucky, USA FACP FAHA Chief of Cardiology Division VACCHCS/UMC, UCSF Program at Fresno, Fresno, California, USA Professor of Medicine UCSF School of Medicine San Francisco, California, USA Gary S Francis MD Professor of Medicine Cardiovascular Division University of Minnesota Minneapolis, Minnesota, USA ix 500 II IV III Ia Ic Ic III Metoprolol Verapamil Sotalol Procainamide Flecainide Propafenone Amiodarone D C C C B C C USFDA category *Vaughan Williams classification of antiarrhythmic drugs Drug class* Drug Yes Yes Yes Yes Yes Yes Yes Placental permeability Avoid Unknown Fetal hypothyroidism, hyperthyroidism, goiter, bradycardia, growth retardation, premature birth Limited experience Safe in structurally normal hearts Lupus-like syndrome with long-term use, Torsade de Pointes Compatible but longterm therapy should be avoided Compatible Bradycardia and hypoglycaemia in fetus; Torsade de Pointes Maternal hypotension, fetal bradycardia, and heart block Bradycardia and hypoglycemia in fetus Reported adverse effects Compatible Compatible Compatible Breastfeeding considerations Drugs Commonly Used for Treatment of Ventricular Tachyarrythmias During Pregnancy and Lactation TABLE CARDIAC DRUGS Cardiac Drugs in Pregnancy and Lactation fashion.2 This can be achieved via electrical cardioversion, antitachycardia pacing, or antiarrhythmic drugs.2 Intravenous sotalol (in the absence of prolonged QT interval) or procainamide should be considered in monomorphic VT (IIa; conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure and the weight of evidence favors usefulness/efficacy) The use of intravenous amiodarone should be reserved for patients with sustained monomorphic VT that is hemodynamically unstable, refractory to conversion, or recurrent despite other agents (IIa).2 Oral metoprolol, propranolol, or verapamil is recommended for long-term management of idiopathic sustained VT (class I) If these drugs fail, oral sotalol, flecainide, or propafenone should be considered (IIa) For long-term management of the congenital long QT syndrome, β-blocking agents are recommended during pregnancy and also postpartum (class I).2 VENOUS THROMBOEMBOLISM AND THROMBOPROPHYLAXIS IN PREGNANCY AND LACTATION In addition to venous thromboembolism (VTE) that occurs in increased frequency during pregnancy and postpartum period and represents a significant cause of morbidity and mortality, there are multiple other conditions, which need antithrombotic therapy during pregnancy and lactation The increased thromboembolic risk in atrial fibrillation is assessed with the CHADS2 (C: congestive heart failure (or LV systolic dysfunction); H: hypertension: blood pressure consistently above 140/90 mmHg (or treated hypertension on medication); A: age ≥75 years; D: diabetes; S: prior stroke or transient ischemic attack) score or the CHA2DS2VASC (C: congestive heart failure (or LV systolic dysfunction); H: hypertension: blood pressure consistently above 140/90 mmHg (or treated hypertension on medication); A: age ≥75 years; D: diabetes; S: prior stroke or transient ischemic attack, or thromboembolism; V: vascular disease; A: age 65–74 years; Sc: sex category) score, and thromboprophylaxis is recommended in high-risk pregnant patients.2 Thromboprophylaxis is also advisable in PPCM patients from the time of the diagnosis until LV function recovers (LV ejection fraction (LVEF) >35%), because of the high incidence of thromboembolism (particularly during pregnancy and the first 6–8 weeks postpartum).22 Patients with mechanical valves carry the risk of valve thrombosis, which is increased during pregnancy Thus, anticoagulation therapy (Table 9) in these women is recommended to prevent the 501 502 B B D UFH LMWH Warfarin Yes No No Placental permeability Osteoporosis (long-term use); markedly less thrombocytopenia than UFH 4–6 hour peak anti-Xa values of 0.6–1.2 IU/mL* INR 2–3** No Yes (well tolerated) Embryopathy (mainly first trimester), bleeding Osteoporosis (long-term use) and thrombocytopenia aPTT ratio 1.5–2.5 times the control value* No Reported adverse effects Therapeutic level Transfer to milk UFH, unfractionated heparin; LMWH, low-molecular weight heparin; aPTT, activated partial thromboplastin time ratio; INR, international normalized ratio *Dose-adjusted UFH (a PTT ≥2 times control) or adjusted-dose LMWH (target anti-Xa level 4–6 hours post-dose 0.8–1.2 U/mL) in mechanical valve patients **In atrial fibrillarion, INR can be kept between 2.0 and 2.5 to minimize the risk USFDA category Drug Commonly Used Anticoagulation Drugs in Pregnancy and Lactation TABLE CARDIAC DRUGS Cardiac Drugs in Pregnancy and Lactation occurrence of valve thrombosis and its lethal consequences for both mother and fetus.2 The choice of the anticoagulant is made according to the condition being treated and the stage of pregnancy Low molecular weight heparin (LMWH) has become the drug of choice for the treatment of VTE (pulmonary embolism or deep vein thrombosis) in pregnancy Because of more risk of thrombocytopenia, osteoporosis, and less convenient dosing when compared with LMWH, unfractionated heparin is favored only in special situations like in patients with renal failure and in the acute treatment of massive pulmonary embolism.2 On the other hand, multiple studies have shown that heparin therapy is associated with a higher incidence of thrombotic complications when given instead of oral anticoagulants in pregnant patients with mechanical valves.32 Thus, in this patient population, low-dose warfarin use throughout pregnancy under strict international normalized ratio (INR) control is the safest approach from the maternal perspective The use of warfarin during first trimester has been associated with a risk for embryopathy However, the absolute incidence is unknown and the risk is dose-related and appears to be very low in patients taking mg/day or less.33 Thus, continuation of oral anticoagulants should be considered during first trimester if the warfarin dose required for therapeutic anticoagulation is 5 mg/day, discontinuation of oral anticoagulation between weeks and 12 and replacement by adjusted-dose heparin should be considered.2 To minimize the risk of fetal intracranial hemorrhage during delivery, heparin should be restarted at 36th week of gestation.32 Cesarean delivery is indicated if delivery starts while on oral anticoagulants.2 There is scarcity of evidence regarding the safety of LMWH during pregnancy in women with mechanical prostheses, and, thus, its use is still controversial The regimen for anticoagulation in pregnant patients with atrial fibrillation and high-risk of thromboembolism follow the same rationale like the mechanical valve patients The only exception is that LMWH is effective and is the drug of choice during first trimester and last month of pregnancy.34 There is evidence of fetotoxicity with high doses of the new oral thrombin antagonists, such as dabigatran and thus should not be used.2 503 CARDIAC DRUGS CONCLUSION In several instances, drug therapy for patients with CVD during pregnancy and lactation is necessary The risk to mother, fetus, and neonate must be considered and weighed against the benefit There are general principles that apply to the medical therapy of patient with CVD during pregnancy and lactation Given the highest risk during first trimester of pregnancy, drug therapy should be avoided during this period, if possible If needed, drugs with the longest record of safety should be used as first-line therapy and combination drug therapy should be avoided The lowest effective dose of a medication should be used and short-acting drugs are preferred Finally, patients should always be informed about the risks and benefits of each medical therapy and should be involved in the decisionmaking process REFERENCES Weiss BM, von Segesser LK, Alon E, Seifert B, Turina MI Outcome of cardiovascular surgery and pregnancy: a systematic review of the period 19841996 Am J Obstet Gynecol 1998;179(6 Pt 1):1643-53 European Society of Gynecology; Association for European Paediatric Cardiology; German Society for Gender Medicine; Authors/Task Force Members; RegitzZagrosek V, Blomstrom Lundqvist C, Borghi C, Cifkova R, Ferreira R, Foidart JM, et al ESC guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC) Eur Heart J 2011;32(24):3147-97 Koren G, Pastuszak A, Ito S Drugs in pregnancy N Engl J Med 1998;338(16): 1128-37 Buhimschi CS, Weiner CP Medications in pregnancy and lactation: part Teratology Obstet Gynecol 2009;113(1):166-88 James PR, Nelson-Piercy C Management of hypertension before, during, and after pregnancy Heart 2004;90(12):1499-504 Helewa ME, Burrows RF, Smith J, Williams K, Brain P, Rabkin SW Report of the Canadian Hypertension Society Consensus Conference: Definitions, evaluation and classification of hypertensive disorders in pregnancy CMAJ 1997;157(6): 715-25 Abalos E, Duley L, Steyn DW, Henderson-Smart DJ Antihypertensive drug therapy for mild to moderate hypertension during pregnancy Cochrane Database Syst Rev 2007;(1):CD002252 Ghanem FA, Movahed A Use of antihypertensive drugs during pregnancy and lactation Cardiovasc Ther 2008;26(1):38-49 Cockburn J, Moar VA, Ounsted M, Redman CW Final report of study on hypertension during pregnancy: the effects of specific treatment on the growth and development of the children Lancet 1982;1(8273):647-9 10 Roth A, Elkayam U Acute myocardial infarction associated with pregnancy J Am Coll Cardiol 2008;52(3):171-80 11 Leonhardt G, Gaul C, Nietsch HH, Buerke M, Schleussner E Thrombolytic therapy in pregnancy J Thromb Thrombolysis 2006;21(3):271-6 12 Arnoni RT, Arnoni AS, Bonini RC, de Almeida AF, Neto CA, Dinkhuysen JJ, et al Risk factors associated with cardiac surgery during pregnancy Ann Thorac Surg 2003;76(5):1605-8 13 CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women CLASP (Collaborative Lowdose Aspirin Study in Pregnancy) Collaborative Group Lancet 1994;343(8898): 619-29 14 Roberts JM, Catov JM Aspirin for pre-eclampsia: compelling data on benefit and risk Lancet 2007;369(9575):1765-6 504 Cardiac Drugs in Pregnancy and Lactation 15 Turrentine MA, Braems G, Ramirez MM Use of thrombolytics for the treatment of thromboembolic disease during pregnancy Obstet Gynecol Surv 1995;50(7):534-41 16 Ahearn GS, Hadjiliadis D, Govert JA, Tapson VF Massive pulmonary embolism during pregnancy successfully treated with recombinant tissue plasminogen activator: a case report and review of treatment options Arch Intern Med 2002;162(11):1221-7 17 Pollack PS, Shields KE, Burnett DM, Osborne MJ, Cunningham ML, Stepanavage ME Pregnancy outcomes after maternal exposure to simvastatin and lovastatin Birth Defects Res A Clin Mol Teratol 2005;73(11):888-96 18 Tan HL, Lie KI Treatment of tachyarrhythmias during pregnancy and lactation Eur Heart J 2001;22(6):458-64 19 Pearson GD, Veille JC, Rahimtoola S, Hsia J, Oakley CM, Hosenpud JD, et al Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review JAMA 2000;283(9):1183-8 20 Sliwa K, Hilfiker-Kleiner D, Petrie MC, Mebazaa A, Pieske B, Buchmann E, et al Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy Eur J Heart Fail 2010;12(8):767-78 21 Elkayam U, Akhter MW, Singh H, Khan S, Bitar F, Hameed A, et al Pregnancyassociated cardiomyopathy: clinical characteristics and a comparison between early and late presentation Circulation 2005;111(16):2050-5 22 Elkayam U Clinical characteristics of peripartum cardiomyopathy in the United States: diagnosis, prognosis, and management J Am Coll Cardiol 2011;58(7): 659-70 23 Alwan S, Polifka JE, Friedman JM Angiotensin II receptor antagonist treatment during pregnancy Birth Defects Res A Clin Mol Teratol 2005;73(2):123-30 24 Siu SC, Sermer M, Colman JM, Alvarez AN, Mercier LA, Morton BC, et al Prospective multicenter study of pregnancy outcomes in women with heart disease Circulation 2001;104(5):515-21 25 American Academy of Pediatrics Committee on Drugs Transfer of drugs and other chemicals into human milk Pediatrics 2001;108(3):776-89 26 Mirshahi M, Ayani E, Nicolas C, Golestaneh N, Ferrari P, Valamanesh F, et al The blockade of mineralocorticoid hormone signaling provokes dramatic teratogenesis in cultured rat embryos Int J Toxicol 2002;21(3):191-9 27 Safirstein JG, Ro AS, Grandhi S, Wang L, Fett JD, Staniloae C Predictors of left ventricular recovery in a cohort of peripartum cardiomyopathy patients recruited via the internet Int J Cardiol 2012;154(1):27-31 28 Widerhorn J, Widerhorn AL, Rahimtoola SH, Elkayam U WPW syndrome during pregnancy: increased incidence of supraventricular arrhythmias Am Heart J 1992;123(3):796-8 29 Perloff JK Pregnancy and congenital heart disease J Am Coll Cardiol 1991; 18(2):340-2 30 Shotan A, Ostrzega E, Mehra A, Johnson JV, Elkayam U Incidence of arrhythmias in normal pregnancy and relation to palpitations, dizziness, and syncope Am J Cardiol 1997;79(8):1061-4 31 Joglar JA, Page RL Antiarrhythmic drugs in pregnancy Curr Opin Cardiol 2001;16(1):40-5 32 Salazar E, Izaguirre R, Verdejo J, Mutchinick O Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses J Am Coll Cardiol 1996; 27(7): 1698-703 33 Vitale N, De Feo M, De Santo LS, Pollice A, Tedesco N, Cotrufo M Dosedependent fetal complications of warfarin in pregnant women with mechanical heart valves J Am Coll Cardiol 1999;33(6):1637-41 34 European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery; Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) Europace 2010;12(10):1360-420 505 13 C H A P T E R Future Directions: Role of Genetics in Drug Therapy Eric J Topol Our contemporary approach of exploring the human genome offers new and exiciting opportunities for improving therapeutic precision in cardiovascular medicine There are essentially three different genomic methodologies that have been applied to identify specific DNA sequence variations, which are associated with either significant side effects or responsiveness to a drug All of them are free from hypothesis, representing a major departure from an older era of genomic science when candidate gene variants were typically published and eventually lacked independent replication But the methodologies of genomewide association studies (GWAS), exome sequencing, and whole genome sequencing are being successfully applied to many cardiovascular drugs and conditions GWAS refers to the scanning of genome with approximately 500,000 to million single nucleotide variants that tag the hundreds of thousands of bins (also known as haplotype blocks or what can be conceived as “zip codes” of linkage disequilibrium) Essentially, this technique identifies the bin(s) of the genome that unequivocally tracks down the clinical condition we are interested in For example, it has been remarkably useful for determining the principal gene associated with statin-induced myopathy (SCLOB1) Although it has not been applied clinically yet, an individual having two copies of the variant identified in this gene is at a 20-fold increased risk of developing significant myositis, which is the most common side effect for statin therapy With statins being the most widely prescribed group of medicines, one can make a strong case to screen individuals who are being considered for a new prescription in order to preempt side effects Another example in favor of efficacy of GWAS is the analysis of responsiveness of patients receiving clopidogrel, one of the other most widely prescribed drugs in cardiovascular medicine Clopidogrel is an inert drug that needs to be metabolized in order to affect its target platelet receptor, P2Y12 The main route 506 Future Directions: Role of Genetics in Drug Therapy of metabolism is via a P450 cytochrome known as CYP2C19 A GWAS study has shown that the principal signal for clopidogrel responsiveness is localized to variations in the CYP2C19 gene There are multiple loss-of-function alleles in this gene that are commonly present in 30% of individuals of European ancestry and 40–50% of people of African or Asian ancestry Amongst the patients who undergo coronary stenting, and are only carriers of one of the loss-of-function variants, the risk for stent thrombosis is increased by 300% , manifested either as myocardial infarction or sudden cardiac death To assure platelet responsiveness of carriers or homozygotes of loss-offunction alleles, rapid point-of-care platelet function studies can be organized which can be helpful in assessing the usage of much higher doses of clopidogrel in such cases or alternative P2Y12 blockers (prasugrel and ticagrelor) This constitutes the prototypic case of pharmacogenomics, since the clinical stakes are high and the genotype information is highly actionable GWAS also determined the principal gene variants for warfarin responsiveness, but the data has unfortunately not yet influenced clinical practice because of the cost and the time consumed in performing genotyping GWAS studies are now giving way to two more informative approaches involving sequencing of the genome rather than just scanning The diploid human genome is comprised of copies of billion base pairs (A, T, C, G) By only scanning million single nucleotide variants, GWAS has a limited access to only 0.03% of the genome Now we can readily sequence the exome, the entire set of protein-coding elements of the genome, but still this only accounts for 1.5% of the genome The fact that the coding elements of the genome (“exome”) account for such a small portion of entire genome, is frequently not appreciated Furthermore, the importance of non-coding elements of the genome has been greatly emphasized by many seminal studies in the past couple of years Exome sequencing is now being applied to many commonly used drugs in cardiovascular medicine We have already identified some additional sequence variants that predict clopidogrel responsiveness beyond CYP2C19 Whole genome sequencing, in which all billion base pairs are determined, is the current method that is receiving considerable attention, for it moves us closer to “full disclosure” of DNA description In 2012, it has been predicted that whole genome sequencing will be performed within hours at a cost of approximately $1000 The tremendous advances in the technology of sequencing are epitomized by the fact that in 507 CARDIAC DRUGS 1991 its cost was $10 per base pair; in 2001, it decreased to 10 cents, and in 2011, it dropped down to 0.001 cents! With the cost of sequencing decreasing so dramatically, and our increasing ability to determine genomic variations that are undeniably linked to efficacy or side effects of the cardiac drugs, the field of cardiovascular pharmacogenomics is set to take off Once specific genomic variations are identified and replicated, they can be quickly assayed by point-of-care genotyping systems A handheld device that can perform genotyping in