Cardiac drug therapy humana press (2015)

Contemporary Cardiology

Series Editor: Christopher P. Cannon

M. Gabriel Khan

Cardiac
Drug Therapy
8th Edition


CONTEMPORARY CARDIOLOGY
CHRISTOPHER P. CANNON, MD
SERIES EDITOR

More information about this series at

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M. Gabriel Khan

Cardiac Drug
Therapy
8th Edition


M. Gabriel Khan, MD, FRCPC, FRCP (London), FACC
University of Ottawa
The Ottawa Hospital
Ottawa, ON, Canada

ISSN 2196-8969
ISSN 2196-8977 (electronic)
ISBN 978-1-61779-961-7
ISBN 978-1-61779-962-4 (eBook)
DOI 10.1007/978-1-61779-962-4
Springer Totowa Heidelberg New York Dordrecht London
Library of Congress Control Number: 2014952818
© Springer Science+Business Media New York 2015
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Springer is part of Springer Science+Business Media (www.springer.com)


To My wife Brigid
and to our
Children
Susan, Christine, Yasmin,
Jacqueline, Stephen,
and Natasha
And to our
Grandchildren
Sarah, Patrick, Emma,
Kathleen, Michael, Roxanna,
Fiona, Jaxson, James, Fraea,
Esmé, Jordan, and Joshua



Preface

Several foreign translations and favorable reviews of earlier editions provided the impetus to produce an eighth edition of Cardiac Drug Therapy. Here is a review of the fifth
edition in Clinical Cardiology: “this is an excellent book. It
succeeds in being practical while presenting the major evidence in relation to its recommendations. Of value to absolutely anyone who prescribes for cardiac patients on the
day-to-day basis. From the trainee to the experienced consultant, all will find it useful. The author stamps his authority very clearly throughout the text by very clear assertions
of his own recommendations even when these recommendations are at odds with those of official bodies. In such situations the ‘official’ recommendations are also stated but
clearly are not preferred.”
And for the fourth edition a cardiologist reviewer states
that it is “by far the best handbook on cardiovascular therapeutics I have ever had the pleasure of reading. The information given in each chapter is up-to-date, accurate, clearly

written, eminently readable and well referenced.”
The entire text has been revised and, most importantly, continues to give practical clinical advice. New chapters include:
• Endocrine Heart Diseases
• Management of Cardiomyopathies
• Newer Agents

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viii

Preface

A new feature involves diagnosis.
• Because appropriate therapy requires sound diagnosis the

short sections on diagnosis given in previous editions have
been expanded.

Other highlights include:
• Chapter 11: “Acute Myocardial Infarction” contains more
than 24 relevant ECG tracings; an echocardiogram depicting
Takotsubo syndrome is shown to remind readers that this
syndrome mimics acute MI.
• Chapter 14: “Management of Cardiac Arrhythmias” provides more than 24 ECG samples.
• Chapter 22: “Hallmark Clinical Trials” has been expanded
to accommodate the wealth of practical information derived
from recent randomized clinical trials.

As in all previous editions, therapeutic strategies and

advice are based on a thorough review of the scientific literature, applied logically:
• Scientific documentation regarding which drugs are
superior.
• Information on which cardiovascular drugs to choose and
which agents to avoid in various clinical situations.
• Information that assists with the rapid writing of prescriptions. To write a prescription accurately, a practitioner needs
to know how a drug is supplied and its dosage. Thus, supply
and dosage are given first, followed by action and pharmacokinetics, and then advice as to efficacy and comparison
with other drugs, indications, adverse effects, and
interactions.

The text contains practical advice, such as the following:
The life-saving potential of 160–240 mg chewable aspirin is
denied to many individuals who succumb to an acute coronary syndrome because of poor dissemination of clinically
proven, documented facts. The text advises: three ~80 mg
chewable aspirins should be placed in the cap of a nitrolin-


Preface

ix

gual spray container to be used before proceeding to an
emergency room. Clinicians should inform patients that
rapidly acting chewable aspirin may prevent a heart attack
or death but that nitroglycerin does not. The world faces an
epidemic of heart failure [HF].
Although medical therapy for acute HF has improved
dramatically from 1990, unfortunately more than 50 % of
patients require readmission within 6 months of discharge.

Several of these patients are not administered appropriate
medications to prevent a recurrence. The chapter on heart
failure gives practical advice as do other chapters on what
drugs are best for a given situation.
Notable physicians have stated that the beta-blockers
should not be prescribed for primary hypertension because of
their ineffectiveness. Many investigators have reported in
peer-reviewed journals that diuretics and beta-blockers cause
diabetes and their use should be restricted for the management of hypertension. Chapter 2 discusses these controversies and gives clear answers to clinicians worldwide.
The information provided in the eighth edition should
serve as a refresher for cardiologists and internists. The
information should improve the therapeutic skills of interns,
medical residents, generalists, and all who care for patients
with cardiac problems.
Ottawa, ON

M. Gabriel Khan



Acknowledgment

I have quoted the published works of several investigators. These persevering women and men of medicine
deserve my respect and my thanks.
A special, thank you, to my wife Brigid, who has allowed
me to be a student of the science of Medicine to this day.
Ottawa, ON

M. Gabriel Khan

xi



Contents

1

Beta-Blockers: The Cornerstone
of Cardiac Drug Therapy.................................
This chapter tells you ........................................
Beta-Blockers and Cardioprotection ..............
Beta-Receptors ..................................................
Mechanism of Action ........................................
Other Important Clinically Beneficial
Mechanisms ....................................................
Beta-Blocker Effect on Calcium
Availability ......................................................
Dosage Considerations .....................................
Pharmacologic Properties and Clinical
Implications ........................................................
Cardioselectivity.............................................
Intrinsic Sympathomimetic Activity ............
Membrane-Stabilizing Activity ....................
Effects on Renin ............................................
Lipid Solubility ...............................................
Plasma Volume ...............................................
Hepatic Metabolism ......................................
Effects on Blood and Arteries .....................
Effect on Serum Potassium...........................

Salutary Effects of Beta-Adrenergic
Blockade .............................................................

xiii

1
1
2
6
9
10
10
11
14
14
18
19
19
20
20
21
21
22
23


xiv

Contents

Beta-Blockers Versus Calcium Antagonists
and Oral Nitrates ...............................................
Indications for Beta-Blockers ..........................
Angina .............................................................
Arrhythmias ....................................................
Acute Myocardial Infarction ........................
Elective Percutaneous Coronary
Intervention (PCI) .........................................
Heart Failure ..................................................
Prolonged QT Interval Syndromes .............
Dissecting Aneurysm .....................................
Mitral Valve Prolapse ....................................
Mitral Regurgitation and Mitral Stenosis ...
Tetralogy of Fallot ..........................................
Hypertrophic Cardiomyopathy ....................
Marfan’s Syndrome .......................................
Subarachnoid Hemorrhage...........................
Perioperative Mortality .................................
Neurocardiogenic Syncope (Vasovagal/
Vasodepressor Syncope) ...............................
Diabetic Patients ............................................
Chronic Obstructive Pulmonary Disease ...
Noncardiac Indications .................................
Advice and Adverse Effects.............................
Warnings..........................................................
Side Effects .....................................................
Individual Beta-Blockers ..................................
Dosage (Further Advice) ..............................
Action ..............................................................
Indications.......................................................

Dosage (Further Advice) ..............................
Action ..............................................................
Indications.......................................................
Dosage (Further Advice) ..............................
Indications.......................................................
Indications.......................................................
Contraindications ...........................................

24
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26
26
29
29
31
33
33
34
34
34
34
35
36
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38
39
39
41
41
41

43
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50
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52
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57
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Contents

Which Beta-Blocker Is Best
for Your Patients? ..............................................
References ..........................................................
2

3

Beta-Blocker Controversies .............................
Beta-Blockers Are not a Good Initial
Choice for Hypertension: True or False? ........
Beta-Blockers Are not Recommended
for Treatment of Elderly Hypertensives:
True or False? .....................................................
Beta-Blockers Cause Genuine Diabetes

Mellitus: True or False?. ....................................
Do all Beta-Blockers Cause Benign
Glucose Intolerance? ........................................
Beta-Blockers Should not Be Given
to Patients During the Early Hours
of Acute Mi: True or False? ..............................
References ..........................................................
Angiotensin-Converting Enzyme
Inhibitors and Angiotensin II Receptor
Blockers ..............................................................
Mechanism of Action ........................................
ACE Inhibitors Versus Other Vasodilators ....
Clinical Indications ............................................
Hypertension ..................................................
Heart Failure ..................................................
Acute Myocardial Infarction ........................
Renoprotection ..............................................
Coarctation of the Aorta...............................
Pulmonary Hypertension ..............................
Scleroderma Renal Crisis .............................
Bartter’s Syndrome ........................................
ACE Inhibitors/ARBs and Diabetes...........
Contraindications ..............................................
Advice, Adverse Effects, and Interactions .....
Hypotension ...................................................
Renal Failure ..................................................

xv

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61
69
69

73
74
78

79
80

85
86
93
94
94
97
100
101
104
105
105
105
105
106
107
107
107

xvi

4

Contents

Hyperkalemia .................................................
Cough ..............................................................
Loss of Taste Sensation .................................
Angioedema ...................................................
Rash .................................................................
Proteinuria ......................................................
Neutropenia and Agranulocytosis ...............
Mild Dyspnea and/or Wheeze ......................
Anaphylactoid Reactions ..............................
Uncommon Adverse Effects ........................
Interactions .....................................................
Individual ACE Inhibitors ................................
Pharmacologic Profile and Individual
Differences ......................................................
Subtle Differences .........................................
Hypotension ...................................................
Dosage (Further Advice) ..............................
Pharmacokinetics ...........................................
Dosage (Further Advice) ..............................
Pharmacokinetics ...........................................
Dosage (Further Advice) ..............................
Pharmacokinetics ...........................................
Dosage (Further Advice) ..............................
Angiotensin II Receptor Blockers ..................

Clinical Trials ..................................................
References ..........................................................

107
107
108
108
109
109
109
109
109
110
110
110

ACE Inhibitor ARB Controversies.................
ACE Inhibitors Versus ARBs:
Does the Choice Matter? .................................
ACE Inhibitors/ARBs Cause
Renoprotection: True or False?........................
ACE Inhibitors Decrease the Incidence
of Diabetes: True or False? ...............................
Combination of ACE Inhibitor and ARB
Proven Effective: True or False? ......................
References ..........................................................

129

110

110
111
112
112
113
114
115
115
116
119
120
124

129
132
134
135
136


Contents

5

6

7

Calcium Antagonists
(Calcium Channel Blockers) ............................

Mechanism of Action ........................................
Action ..............................................................
Adverse Effects and Interactions
for DHPs .........................................................
Action ..............................................................
Adverse Effects and Interactions ................
Action ..............................................................
Advice, Adverse Effects, and Interactions ....
Dosage (Further Advice) ..............................
Indications for Calcium Antagonists...............
Hypertension ..................................................
Stable Angina .................................................
References ..........................................................

xvii

139
140
143
144
147
147
149
150
153
153
153
154
158

Calcium Antagonist Controversies..................
Calcium Antagonists Cause an Increased
Incidence of HF and MI: True or False? .........
Newer Calcium Antagonists Are Better
Than Older Agents: True or False? .................
Are Calcium Antagonists Safe
for Hypertensives with CAD? .........................
INVEST ..........................................................
CONVINCE ...................................................
References ..........................................................

161

Diuretics..............................................................
Indications ..........................................................
Hypertension ..................................................
Heart Failure ..................................................
Thiazides .............................................................
Loop Diuretics ...................................................
Mechanism of Action ....................................
Dosage (Further Advice) ..............................
Action and Pharmacokinetics ......................
Potassium-Sparing Diuretics ............................

167
170
170
171
172
174

174
175
175
179

161
162
163
163
164
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xviii

8

Contents

Advantages .....................................................
Disadvantages.................................................
Combination of a Thiazide
or Furosemide and Potassium-Sparing
Diuretic ...........................................................
Other Diuretics ..................................................
Potassium Chloride Supplements ....................
Potassium Chloride ........................................
Salt Substitutes ...............................................
Further Advice ...................................................
Torsemide........................................................

Aldosterone Antagonists ..............................
References ..........................................................

182
183

Hypertension ......................................................
Relevant Key Issues ..........................................
Controversies .....................................................
Definitions ..........................................................
Isolated Systolic Hypertension
in Older Patients ............................................
Pseudohypertension.......................................
Home Measurements ....................................
Nondrug Therapy...............................................
Which Drugs to Choose....................................
Recommendations for Patients
Without Coexisting Disease .........................
Therapy for Patients with Coexisting
Diseases ...........................................................
Beta-Blockers.....................................................
Dosage .............................................................
Action of Beta-Blockers ...............................
Diuretics..............................................................
Action ..............................................................
Use Proven in Elderly ...................................
Chlorthalidone ...............................................
ACE Inhibitors and Angiotensin II
Receptor Blockers .............................................

199
199
205
206

185
186
187
190
190
192
192
192
195

206
207
208
208
209
210
220
223
223
224
227
227
229
231
234

Contents

Adverse Effects and Interactions ................
Contraindications ...........................................
Dosage (Further Advice) ..............................
ACE Inhibitor-Diuretic Combination .........
Calcium Antagonists .........................................
Alpha1-Blockers ................................................
Centrally Acting Drugs .....................................
Resistant Hypertension ....................................
Cathetehr-Based Radiofrequency Renal
Denervation........................................................
Hypertensive Crisis ...........................................
Action and Metabolism.................................
Advice, Adverse Effects, and Interactions ....
References ..........................................................
9

10

xix

236
237
238
239
240
243

244
244
246
247
250
250
253

Hypertension Controversies.............................
Beta-Blockers Should Not Remain First
Choice in the Treatment of Primary
Hypertension: True or False? ...........................
Conclusion ......................................................
Diabetic Risk with Beta-Blockers
and Diuretics ......................................................
An Increased Risk: True or False? ...............
Hypertensive Agents Increase Heart
Failure Risk: True or False? ..............................
Age and Ethnicity Hold the Key
for Drug Choice .................................................
References ..........................................................

261

Angina.................................................................
Salient Clinical Features ...................................
Pathophysiologic Implications .....................
Treatment of Stable Angina .............................
Beta-Adrenoceptor Blocking Agents..........
Cardioprotection and Dosage

of Beta-Blocker ..............................................
Contraindications to Beta-Blockers ............

283
283
284
285
286

261
268
269
269
271
272
278

290
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xx

Contents

Combination of Beta-Blockers
and Calcium Antagonists ..............................
Nitrates ............................................................
Cutaneous Nitroglycerins .............................
Cutaneous Nitrates ........................................

Indications.......................................................
Aspirin .............................................................
Ranolazine ......................................................
Consider Interventional Therapy ....................
Management of Unstable Angina ...................
Investigations ..................................................
Medications.....................................................
Statins ..................................................................
Variant Angina (Prinzmetal’s) .........................
References ..........................................................
11

Myocardial Infarction .......................................
Overview.............................................................
TRIGGERS for ACS ....................................
DIAGNOSIS ......................................................
Electrocardiographic Features .........................
Inferior MI Diagnosis ....................................
Anterior MI Diagnosis ..................................
ECG Mimics of Acute Myocardial
Infarction.........................................................
Therapy ...............................................................
Pain Relief ......................................................
Percutaneous Coronary Intervention .............
Clopidogrel .....................................................
Prasugrel .........................................................
Ticagrelor (BRILINTA; Brilique in UK) .....
Thrombolytic Therapy.......................................
The incidence of ICH in RCTs
was reported as follows .................................

Contraindications ...........................................

292
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298
299
301
303
303
303
304
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306
307
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313
314
317
317
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336

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Contents

Streptokinase [Kabikinase, Streptase].........
Tenecteplase ...................................................
Enoxaparin .........................................................
Fondaparinux .....................................................
Beta-Blockers.....................................................
ACE Inhibitors ..................................................
NITRATES ........................................................
STATINS ............................................................
Management of Complications
of Infarction........................................................
Arrhythmias ....................................................
Heart Failure ..................................................
Right Ventricular Infarction .........................
Cardiogenic Shock .........................................
Management ...................................................
Early Reperfusion ..........................................
Management of Non-ST-Elevation
Myocardial Infarction .......................................
Conservative Generally Preferred
[angiogram 24–36 h] ......................................
Medications on Discharge ................................
References ..........................................................
12

Heart Failure ......................................................
The Size of the Problem ...................................
Causes of Heart Failure ....................................
Basic Cause .....................................................
Diagnosis ............................................................
Pathophysiology.................................................
Management Guide .......................................
Vasodilators ........................................................
ACE Inhibitors/Angiotensin II
Receptor Blockers .........................................
Angiotensin-Receptor Blockers...................
Transcend (2008)................................................

xxi

342
343
343
344
345
348
349
350
350
350
353
354
354
355

356
357
360
360
361
369
369
372
372
376
379
381
382
382
387
388


xxii

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Contents

Hydralazine ........................................................
Calcium Antagonists .........................................
Amlodipine .....................................................
Diuretics..............................................................
Indications and Guidelines ...........................
Aldosterone Antagonists ..................................

Beta-Blockers.....................................................
Inotropic Agents ................................................
Digoxin Studies ..............................................
Dosage Considerations .................................
Symptoms of Toxicity ....................................
Beta-Stimulants ..............................................
New Developments ...........................................
Spironolactone ...............................................
Istaroxime .......................................................
Omecamtiv mecarbil .....................................
SERCA2a........................................................
Serelaxin ..........................................................
Rosuvastatin ...................................................
LCZ696 ...........................................................
Management of Pulmonary Edema ................
References ..........................................................

389
389
389
389
389
390
393
399
399
405
409
412
413

413
413
414
413
414
415
415
415
417

Heart Failure Controversies .............................
Are ARBs as Effective as ACE Inhibitor
Therapy for Heart Failure? ..............................
Management of Heart Failure Preserved
Ejection Fraction ...............................................
Treatment............................................................
Digoxin Is Not Useful for HFPEF:
True or False? .....................................................
Is CHARM-Preserved a Clear Study
of HFPEF? ......................................................
Does an ACE Inhibitor Combined
with an ARB Improve Outcomes?..................
Heart Failure in Blacks:
Do Differences Exist? .......................................

423
423
424
426
427

427
428
429


Contents

xxiii

Are Statins Recommended
for Patients with Heart Failure? ...................... 429
References .......................................................... 430
14

Arrhythmias .......................................................
Classification ......................................................
Diagnosis of Arrhythmias.................................
Arrhythmias with Narrow QRS
Complex ..........................................................
Arrhythmias with Wide QRS
Complex ..........................................................
Management of Supraventricular
Arrhythmias .......................................................
AV Nodal Reentrant Tachycardia ...............
Multifocal Atrial Tachycardia
(Chaotic Atrial Tachycardia) ........................
Paroxysmal Atrial Tachycardia
with Block .......................................................
Atrial Premature Contractions ....................
Atrial Flutter ..................................................

Atrial Fibrillation ...........................................
Chronic Atrial Fibrillation ................................
Atrial Fibrillation Post Surgery ....................
Synchronized DC Cardioversion .................
Rate Control Versus Rhythm Control ........
Anticoagulants for AF ......................................
Newer Anticoagulants.......................................
Genetically Mediated Arrhythmic
Disorders ............................................................
Wolff–Parkinson–White Syndrome .............
Ventricular Arrhythmias ...................................
Premature Ventricular Contractions:
Benign Arrhythmias ......................................
Ventricular Tachycardia ....................................
Fatal Ventricular Arrhythmias ......................
Antiarrhythmic Agents .....................................

433
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435
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454
459
459
460
460
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465

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469
470
472
472
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477
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16

Contents

Class IA ...........................................................
Advice, Adverse Effects, and Interactions .....
Class IB ...........................................................
Class IC ...........................................................
Class II.............................................................
Class III ...........................................................
Adverse Effects ..............................................
References ..........................................................

481
483
486
488
490
492
494
496

Cardiac Arrest ....................................................
“Time Is of the Essence” ..................................
Two Cardiac Rhythms .......................................
Basic Life Support .............................................
Defibrillation ..................................................
Drug Therapy .....................................................
Asystole and Pulseless Idioventricular
Rhythms ..........................................................
Isoproterenol Is Contraindicated
in the Treatment of Cardiac Arrest .............
Beta-Blockers .................................................
References ..........................................................

503
503
505
507
510
512

Infective Endocarditis .......................................
Classification and Diagnosis ............................
Diagnostic Guidelines ...................................
Therapy ...............................................................
S. aureus Endocarditis ...................................
Prosthetic Valve Endocarditis ......................
Native Valve Endocarditis Caused by
Staphylococci ..................................................
Native Valve Endocarditis ............................
Prosthetic Valve Endocarditis Caused
by Susceptible S. viridans or S. bovis
Infections.........................................................
Other Bacteria Causing IE ...........................
Right-Sided Endocarditis ..............................
Fungal Endocarditis.......................................

517
518
518
522
523
525

514
514
514
514

525
525

526
528
528
530