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
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 pharma-cokinetics, 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-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

1 Beta-Blockers: The Cornerstone of Cardiac Drug Therapy 1

This chapter tells you 1

Beta-Blockers and Cardioprotection 2

Beta-Receptors 6

Mechanism of Action 9

      Other Important Clinically Beneficial Mechanisms 10

      Beta-Blocker Effect on Calcium Availability 10

Dosage Considerations 11

Pharmacologic Properties and Clinical Implications 14

      Cardioselectivity 14

      Intrinsic Sympathomimetic Activity 18

      Membrane-Stabilizing Activity 19

      Effects on Renin 19

      Lipid Solubility 20

      Plasma Volume 20

      Hepatic Metabolism 21

      Effects on Blood and Arteries 21

      Effect on Serum Potassium 22

Salutary Effects of Beta-Adrenergic Blockade 23

Beta-Blockers Versus Calcium Antagonists and Oral Nitrates 24

Indications for Beta-Blockers 26

      Angina 26

      Arrhythmias 26

      Acute Myocardial Infarction 29

      Elective Percutaneous Coronary Intervention (PCI) 29

      Heart Failure 31

      Prolonged QT Interval Syndromes 33

      Dissecting Aneurysm 33

      Mitral Valve Prolapse 34

      Mitral Regurgitation and Mitral Stenosis 34

      Tetralogy of Fallot 34

      Hypertrophic Cardiomyopathy 34

      Marfan's Syndrome 35

      Subarachnoid Hemorrhage 36

      Perioperative Mortality 36

      Neurocardiogenic Syncope (Vasovagal/Vasodepressor Syncope) 38

      Diabetic Patients 39

      Chronic Obstructive Pulmonary Disease 39

      Noncardiac Indications 41

Advice and Adverse Effects 41

      Warnings 41

      Side Effects 43

Individual Beta-Blockers 44

      Dosage (Further Advice) 47

      Action 48

      Indications 48

      Dosage (Further Advice) 49

      Action 50

      Indications 50

      Dosage (Further Advice) 52

      Indications 56

      Indications 57

      Contraindications 58

Which Beta-Blocker Is Best for Your Patients? 58

References 61

2 Beta-Blocker Controversies 69

Beta-Blockers Are not a Good Initial Choice for Hypertension: True or False? 69

Beta-Blockers Are not Recommended for Treatment of Elderly Hypertensives: True or False? 73

Beta-Blockers Cause Genuine Diabetes Mellitus:True or False? 74

Do all Beta-Blockers Cause Benign Glucose Intolerance? 78

Beta-Blockers Should not Be Given to Patients During the Early Hours of Acute Mi: True or False? 79

References 80

3 Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers 85

Mechanism of Action 86

ACE Inhibitors Versus Other Vasodilators 93

Clinical Indications 94

      Hypertension 94

      Heart Failure 97

      Acute Myocardial Infarction 100

      Renoprotection 101

      Coarctation of the Aorta 104

      Pulmonary Hypertension 105

      Scleroderma Renal Crisis 105

      Bartter's Syndrome 105

      ACE Inhibitors/ARBs and Diabetes 105

Contraindications 106

Advice, Adverse Effects, and Interactions 107

      Hypotension 107

      Renal Failure 107

      Hyperkalemia 107

      Cough 107

      Loss of Taste Sensation 108

      Angioedema 108

      Rash 109

      Proteinuria 109

      Neutropenia and Agranulocytosis 109

      Mild Dyspnea and/or Wheeze 109

      Anaphylactoid Reactions 109

      Uncommon Adverse Effects 110

      Interactions 110

Individual ACE Inhibitors 110

      Pharmacologic Profile and Individual Differences 110

      Subtle Differences 110

      Hypotension 111

      Dosage (Further Advice) 112

      Pharmacokinetics 112

      Dosage (Further Advice) 113

      Pharmacokinetics 114

      Dosage (Further Advice) 115

      Pharmacokinetics 115

      Dosage (Further Advice) 116

Angiotensin II Receptor Blockers 119

      Clinical Trials 120

References 124

4 ACE Inhibitor ARB Controversies 129

ACE Inhibitors Versus ARBs: Does the Choice Matter? 129

ACE Inhibitors/ARBs Cause Renoprotection: True or False? 132

ACE Inhibitors Decrease the Incidence of Diabetes: True or False? 134

Combination of ACE Inhibitor and ARB Proven Effective: True or False? 135

References 136

5 Calcium Antagonists (Calcium Channel Blockers) 139

Mechanism of Action 140

      Action 143

      Adverse Effects and Interactions for DHPs 144

      Action 147

      Adverse Effects and Interactions 147

      Action 149

      Advice, Adverse Effects, and Interactions 150

      Dosage (Further Advice) 153

Indications for Calcium Antagonists 153

      Hypertension 153

      Stable Angina 154

References 158

6 Calcium Antagonist Controversies 161

Calcium Antagonists Cause an Increased Incidence of HF and MI: True or False? 161

Newer Calcium Antagonists Are Better Than Older Agents: True or False? 162

Are Calcium Antagonists Safe for Hypertensives with CAD? 163

      INVEST 163

      CONVINCE 164

References 166

7 Diuretics 167

Indications 170

      Hypertension 170

      Heart Failure 171

Thiazides 172

Loop Diuretics 174

      Mechanism of Action 174

      Dosage (Further Advice) 175

      Action and Pharmacokinetics 175

Potassium-Sparing Diuretics 179

Advantages 182

Disadvantages 183

Combination of a Thiazide or Furosemide and Potassium-Sparing Diuretic 185

Other Diuretics 186

Potassium Chloride Supplements 187

      Potassium Chloride 190

      Salt Substitutes 190

Further Advice 192

      Torsemide 192

      Aldosterone Antagonists 192

References 195

8 Hypertension 199

Relevant Key Issues 199

Controversies 205

Definitions 206

      Isolated Systolic Hypertension in Older Patients 206

      Pseudohypertension 207

      Home Measurements 208

Nondrug Therapy 208

Which Drugs to Choose 209

      Recommendations for Patients Without Coexisting Disease 210

      Therapy for Patients with Coexisting Diseases 220

Beta-Blockers 223

      Dosage 223

      Action of Beta-Blockers 224

Diuretics 227

      Action 227

      Use Proven in Elderly 229

      Chlorthalidone 231

ACE Inhibitors and Angiotensin II Receptor Blockers 234

      Adverse Effects and Interactions 236

      Contraindications 237

      Dosage (Further Advice) 238

      ACE Inhibitor-Diuretic Combination 239

Calcium Antagonists 240

Alphal-Blockers 243

Centrally Acting Drugs 244

Resistant Hypertension 244

Cathetehr-Based Radiofrequency Renal Denervation 246

Hypertensive Crisis 247

      Action and Metabolism 250

      Advice, Adverse Effects, and Interactions 250

References 253

9 Hypertension Controversies 261

Beta-Blockers Should Not Remain First Choice in the Treatment of Primary Hypertension: True or False? 261

      Conclusion 268

Diabetic Risk with Beta-Blockers and Diuretics 269

      An Increased Risk: True or False? 269

Hypertensive Agents Increase Heart Failure Risk: True or False? 271

Age and Ethnicity Hold the Key for Drug Choice 272

References 278

10 Angina 283

Salient Clinical Features 283

      Pathophysiologic Implications 284

Treatment of Stable Angina 285

      Beta-Adrenoceptor Blocking Agents 286

      Cardioprotection and Dosage of Beta-Blocker 290

      Contraindications to Beta-Blockers 290

      Combination of Beta-Blockers and Calcium Antagonists 292

      Nitrates 292

      Cutaneous Nitroglycerins 293

      Cutaneous Nitrates 295

      Indications 298

      Aspirin 299

      Ranolazine 301

Consider Interventional Therapy 303

Management of Unstable Angina 303

      Investigations 303

      Medications 304

Statins 306

Variant Angina (Prinzmetal's) 306

References 307

11 Myocardial Infarction 311

Overview 311

      TRIGGERS for ACS 313

DIAGNOSIS 314

Electrocardiographs Features 317

      Inferior MI Diagnosis 317

      Anterior MI Diagnosis 317

      ECG Mimics of Acute Myocardial Infarction 320

Therapy 330

      Pain Relief 332

Percutaneous Coronary Intervention 334

      Clopidogrel 335

      Prasugrel 335

      Ticagrelor (BRILJNTA; Brilique in UK) 336

Thrombolytic Therapy 339

      The incidence of ICH in RCTs was reported as follows 341

      Contraindications 341

      Streptokinase [Kabikinase, Streptase] 342

      Tenecteplase 343

Enoxaparin 343

Fondaparinux 344

Beta-Blockers 345

ACE Inhibitors 348

NITRATES 349

STATINS 350

Management of Complications of Infarction 350

      Arrhythmias 350

      Heart Failure 353

      Right Ventricular Infarction 354

      Cardiogenic Shock 354

      Management 355

      Early Reperfusion 356

Management of Non-ST-Elevation Myocardial Infarction 357

      Conservative Generally Preferred [angiogram 24-36 h] 360

Medications on Discharge 360

References 361

12 Heart Failure 369

The Size of the Problem 369

Causes of Heart Failure 372

      Basic Cause 372

Diagnosis 376

Pathophysiology 379

      Management Guide 381

Vasodilators 382

      ACE Inhibitors/Angiotensin II Receptor Blockers 382

      Angiotensin-Receptor Blockers 387

Transcend (2008) 388

Hydralazine 389

Calcium Antagonists 389

      Amlodipine 389

Diuretics 389

      Indications and Guidelines 389

Aldosterone Antagonists 390

Beta-Blockers 393

Inotropic Agents 399

      Digoxin Studies 399

      Dosage Considerations 405

      Symptoms of Toxicity 409

      Beta-Stimulants 412

New Developments 413

      Spironolactone 413

      Istaroxime 413

      Omecamtiv mecarbil 414

      SERCA2a 413

      Serelaxin 414

      Rosuvastatin 415

      LCZ696 415

Management of Pulmonary Edema 415

References 417

13 Heart Failure Controversies 423

Are ARBs as Effective as ACE Inhibitor Therapy for Heart Failure? 423

Management of Heart Failure Preserved Ejection Fraction 424

Treatment 426

Digoxin Is Not Useful for HFPEF: True or False? 427

      Is CHARM-Preserved a Clear Study of HFPEF? 427

Does an ACE Inhibitor Combined with an ARB Improve Outcomes? 428

Heart Failure in Blacks: Do Differences Exist? 429

Are Statins Recommended for Patients with Heart Failure? 429

References 430

14 Arrhythmias 433

Classification 434

Diagnosis of Arrhythmias 435

      Arrhythmias with Narrow QRS Complex 437

      Arrhythmias with Wide QRS Complex 437

Management of Supraventricular Arrhythmias 454

      AV Nodal Reentrant Tachycardia 454

      Multifocal Atrial Tachycardia (Chaotic Atrial Tachycardia) 459

      Paroxysmal Atrial Tachycardia with Block 459

      Atrial Premature Contractions 460

      Atrial Flutter 460

      Atrial Fibrillation 462

Chronic Atrial Fibrillation 465

      Atrial Fibrillation Post Surgery 466

      Synchronized DC Cardioversion 466

      Rate Control Versus Rhythm Control 467

Anticoagulants for AF 469

Newer Anticoagulants 470

Genetically Mediated Arrhythmic Disorders 472

      Wolff-Parkinson-White Syndrome 472

Ventricular Arrhythmias 477

      Premature Ventricular Contractions: Benign Arrhythmias 477

Ventricular Tachycardia 478

      Fatal Ventricular Arrhythmias 478

Antiarrhythmic Agents 481

      Class IA 481

Advice, Adverse Effects, and Interactions 483

      Class IB 486

      Class IC 488

      Class II 490

      Class III 492

      Adverse Effects 494

References 496

15 Cardiac Arrest 503

"Time Is of the Essence" 503

Two Cardiac Rhythms 505

Basic Life Support 507

      Defibrillation 510

Drug Therapy 512

      Asystole and Pulseless Idioventricular Rhythms 514

      Isoproterenol Is Contraindicated in the Treatment of Cardiac Arrest 514

      Beta-Blockers 514

References 514

16 Infective Endocarditis 517

Classification and Diagnosis 518

      Diagnostic Guidelines 518

Therapy 522

      S. aureus Endocarditis 523

      Prosthetic Valve Endocarditis 525

      Native Valve Endocarditis Caused by Staphylococci 525

      Native Valve Endocarditis 525

      Prosthetic Valve Endocarditis Caused by Susceptible S. viridans or S. bovis Infections 526

      Other Bacteria Causing IE 528

      Right-Sided Endocarditis 528

      Fungal Endocarditis 530

      Heart Failure Complicating Endocarditis 532

Prophylaxis of Bacterial Endocarditis 533

      Older Regimen Acceptable to Many 535

References 538

17 Dyslipidemias 541

Diagnosis 541

Fasting or Non-fasting LDL-C? 541

      Conversion Formula for mg to mmol 543

      Secondary Causes of Dyslipidemias 543

Dietary Therapy 545

Drug Therapy 547

Statins 549

      Statins Possess Subtle Differences 550

      Advice and Adverse Effects 550

Nicotinic Acid 561

      Adverse Effects and Interactions 562

Fibrates 563

HDL Lowering 565

      Evacetrapib 565

References 566

18 Endocrine Heart Diseases 571

Acromegaly 571

      Management 571

Carcinoid Syndrome 572

Cushing's Syndrome 573

Diabetes and the Heart 573

      Which Cardiovascular Drugs Are Best ACE Inhibitors/ARBS? 574

      Beta-Blockers Underused in Diabetics 574

      Aspirin 575

      Dyslipidemia in Diabetics 575

      Blood Pressure Control 576

Oral Diabetic Agents 577

      Metformin 577

      Sulfonylurea 578

      Thiazolidinediones 579

      Acarbose (Glucobay) 579

      Dipeptidyl Peptidase-4 (DPP-4) Inhibitors (Gliptins) 580

Hyperaldosteronism 581

Pheochromocytoma 581

Hyperthyroidism 586

      Cardiac Disturbances 586

Hypothyroidism 588

      Cardiac Involvement 588

References 588

19 Antiplatelet Agents, Anticoagulants, Factor Xa Inhibitors, and Thrombin Inhibitors 593

Antiplatelet Agents 593

      Historical Review 597

Actions 599

      Aspirin Resistance 601

      Indications 602

      Platelet Glycoprotein IIb/IIIa Receptor Blockers 608

Anticoagulants 610

      Low-Molecular-Weight Heparin 612

      Specific Thrombin Inhibitors 613

      Factor Xa Inhibitors 615

References 618

20 Cardiac Drugs During Pregnancy and Lactation 623

Antihypertensive Agents in Pregnancy 623

      Methyldopa 625

      Calcium Antagonists 631

      ACE Inhibitors 632

      Magnesium Sulfate 632

      Aspirin 633

Drug Therapy for Heart Failure 634

      Diuretics 636

Antiarrhythmics in Pregnancy 636

      Adenosine 636

      Beta-Adrenergic Blockers 637

      Disopyramide 637

      Lidocaine 637

Cardiac Drugs During Lactation 638

References 642

21 Drug Interactions 645

Interactions of Cardiovascular Drugs 646

      ACE Inhibitors/ARBs 646

Antiarrhythmic Agents 649

      Adenosine 649

      Amiodarone 649

      Disopyramide 651

      Flecainide 651

      Lidocaine or Lignocaine 651

      Mexiletine 652

      Phenytoin 652

      Propafenone 652

      Procainamide 652

      Quinidine 653

Antiplatelet Agents/Anticoagulants 653

Beta-Blockers 654

Calcium Antagonists 655

Digoxin 658

Diuretics 658

Nitrates 659

Lipid-Lowering Agents 660

      Statins 660

Interactions of Cardiac and Noncardiac Drugs 660

      Antibiotics 660

      Antimalarials 663

      Anticonvulsants 663

      Cyclosporine 663

      Lithium 664

      Nonsteroidal Anti-inflammatory Drugs 664

      Psychotropic Agents 664

      Theophylline 665

      Thyroxine 665

Cardiac Effects of Noncardiac Drugs 667

      Antibiotics 667

      Antimalarials 667

      Histamine H_1 Antagonists 667

      Antidepressants 669

      Cancer Chemotherapeutic Agents 670

      Other Agents 670

References 673

22 Hallmark Clinical Trials 675

Acute Coronary Syndrome RCTs 676

      ATLAS ACS 2-TIMI51: Rivaroxaban for ACS 676

      Bivalirudin for ACS 677

      LMWH and Major Bleeding Advice 681

IV Metoprolol Studies 689

      COMMIT/CCS-2: Second Chinese Cardiac Study (CCS-2) (31) 690

      The METOCARD-CNIC 691

Aspirin for Cardiovascular Disease Prevention 692

      Aspirin Pseudoresistance 692

Angina RCTs 692

      PCI Versus Optimal Medical Therapy 692

      Carvedilol in Postinfarct Patients 694

Atrial Fibrillation RCTs 694

      Lenient Rate Control 694

      Rate Versus Rhythm Control in Atrial Fibrillation 695

      Newer Anticoagulants for Reduction in Stroke 696

      RE-LY 2010: Dabigatran Versus Warfarin in Patients with Atrial Fibrillation 696

Colchicine for Cardiovascualr Disease 698

      Colchicine for Stable Coronary Artery Disease 698

      Colchicine for pericarditis 699

      Colchicine for Post-op Atrial Fibrillation 699

Heart Failure RCTs 701

      COPERNICUS 2001: Carvedilol in Severe Chronic HF 701

Heart Failure Trials 702

      MERIT-HF 2000: Metoprolol CR/XL in Chronic Heart Failure 702

The Seniors Study: Nebivolol for Heart Failure 702

      Aldosterone Antagonist Trials 703

ACE Inhibitors and ARB RCTs 704

      PRoFESS 2008: Telmisartan to Prevent Recurrent Stroke 707

Hypertension Trials 709

      ALLHAT 2002 709

      Nebivolol Combined with Valsartan Study 710

Dyslipidemia RCTs 712

      Early and Late Benefits of High-Dose Atorvastatin 712

Arrhythmia RCTs 718

      AFFIRM (2002): Rate Versus Rhythm Control in Atrial Fibrillation 718

Beta-Blockers And Diabetes 718

      GEMINI (2004): Beta-Blockers for Hypertensive Diabetics 718

Clopidogrel 719

      PCI-Clarity: Clopidogrel Before PCI 719

Folic Acid/B6,B12 720

      HOPE-2: Homocysteine Lowering 720

References 721

23 Management of Cardiomyopathies 729

Hypertrophic Cardiomyopathy 729

      Pathophysiology 730

      Clinical Diagnosis 731

      Therapy 735

      Implantable Cardioverter-Defibrillators 738

      Risk Factors for Sudden Death and Guide for ICD Include 738

Dilated Cardiomyopathy 739

      Diagnosis 739

      Physical Signs 740

      Echocardiogram 741

      Therapy 741

Restrictive Cardiomyopathy 744

      Clinical Features 745

      Therapy 748

Peripartum Cardiomyopathy 748

      Treatment 749

References 750

24 Newer Agents 755

Apixaban 755

Rivaroxaban 757

Dabigatran 758

      Edoxaban 760

Conclusion 760

Omecamtiv Mecarbila 761

Celivarone 761

Dronedarone 762

Nebivolol 763

Prasugrel [Efient IN UK] 763

Ticagrelor [Brilrnta; Brilique in UK] 764

Cangrelor 765

Evacetrapib 765

References 766

Index 769

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