New Oral Anticoagulants Markets

  • March 2013
  • -
  • TriMark Publications
  • -
  • 246 pages

Anticoagulants decrease the ability of the blood to create harmful blood clots that can ultimately leading to a heart attack or stroke. Although sometimes referred to as blood thinners, they do not actually thin the blood and only help prevent the formation of new blood clots. For more than 50 years and until recently, the only oral anticoagulants were vitamin K antagonists such as warfarin. Pradaxa (dabigatran), Xarelto (rivaroxaban), Eliquis (apixaban) and other new oral anticoagulants have several advantages over warfarin, including no periodical laboratory monitoring and more predictable effects with fixed doses. This TriMark Publications report provides a thorough overview of these and other new oral anticoagulants, their approved indications, drug profiles, pharmacokinetic parameters and the respective areas of market growth. The study also analyzes almost all of the companies known to be marketing, manufacturing or developing oral anticoagulant products in the U.S. and worldwide. Detailed tables and charts with sales forecasts and marketshare data are also included.

Table Of Contents

TABLE OF CONTENTS

1. Introduction 11
1.1 Scope of this Report 11
1.2 Methodology 11
1.3 Executive Summary 12

2. An Overview of Anticoagulants 16
2.1 Scope of this Chapter 16
2.1.1 Unmet Medical Needs with Existing Anticoagulants 17
2.1.2 Pharmacology of Injectable Anticoagulants 18
2.1.3 Marketed and Registered Drugs for Anticoagulation and Related Disorders 19
2.2 Oral Anticoagulants 21
2.2.1 Potential Limitations of New Oral Anticoagulants 23
2.2.2 Desired Attributes of Anticoagulants 24
2.2.3 Comparison of New Anticoagulants 24
2.2.4 Bleed Rates of New Anticoagulants 27

3. Selected Oral Anticoagulants 30
3.1 Warfarin 30
3.1.1 Warfarin’s Place in Clinical Therapy 31
3.1.2 Drug Interaction with Warfarin 31
3.1.3 Warfarin’s Interactions with Food 32
3.1.4 Interactions of Warfarin with Dietary Vitamin K 34
3.2 Dabigatran (Pradaxa) 36
3.2.1 Use of Dabigatran in Particular Situations 38
3.2.2 Measuring the Anticoagulant Effect of Dabigatran 38
3.2.3 Activated Partial Thromboplastin Time (aPTT) 38
3.2.4 Thrombin Time (TT) and Hemoclot 39
3.2.5 Ecarin Clotting Time (ECT) 39
3.2.6 Prothrombin Time (PT) and INR 39
3.2.7 Measures for Overdose 40
3.2.8 Management of Bleeding Complications 40
3.2.9 For Patients Undergoing Surgical Intervention 40
3.2.10 For Dental Interventions 40
3.2.11 For Spinal Anesthesia/Epidural Anesthesia/Lumbar Puncture 41
3.2.12 For Patients with Acute Coronary Syndrome (ACS) 41
3.2.13 Cardioversion in Dabigatran Treated Patients 41
3.2.14 For Patients with Stroke 41
3.2.15 Dabigatran after Ischemic Stroke 41
3.2.16 Strengths and Weaknesses of Dabigatran 42
3.2.16.1 Strengths of Dabigatran in Metabolism, Pharmacokinetics and
Pharmacodynamics 42
3.2.16.2 Weaknesses of Dabigatran in Metabolism, Pharmacokinetics and
Pharmacodynamics 43
3.2.16.3 Strengths of Dabigatran in Laboratory Monitoring 43
3.2.16.4 Weaknesses of Dabigatran in Laboratory Monitoring 43
3.2.16.5 Strengths of Dabigatran in Clinical Efficacy 44
3.2.16.6 Weaknesses of Dabigatran in Clinical Efficacy 44
3.2.16.7 Strengths of Dabigatran in Controlling Bleeding 44
3.2.17 Comparison of Dabigatran and Rivaroxaban in Sites of Action 45
3.3 Rivaroxaban (Xarelto) 45
3.3.1 Dosage and Administration 46
3.3.2 Risk of Stroke after Discontinuation in Non-Valvular Atrial Fibrillation
47
3.3.3 Risk of Bleeding 47
3.3.4 Bleeding Events in ROCKET AF Trial 48
3.3.5 Bleeding Events in RECORD Trial 48
3.3.6 Overdosage 49
3.3.7 Mechanism of Action 50
3.3.8 Comparable Efficacy of Rivaroxaban 50
3.3.9 Prophylaxis of Deep Vein Thrombosis 52
3.4 Eliquis (Apixaban) 53
3.4.1 AVERROES Results 56
3.5 Edoxaban 58
3.6 Betrixaban 59
3.7 Pipeline Agents 63
3.8 Comparison of Oral Anticoagulants 66
3.9 Heparins 68
3.10 Dalteparin (Fragmin) 70
3.11 Enoxaparin (Lovenox) 70
3.11.1 Indications and Usage 70
3.11.2 Percutaneous Coronary Revascularization Procedures 71
3.11.3 Use of Lovenox with Concomitant Medical Conditions 71
3.11.3.1 Thrombocytopenia 71
3.11.3.2 Interchangeability with Other Heparins 72
3.11.3.3 Pregnant Women with Mechanical Prosthetic Heart Valves 72
3.11.3.4 Laboratory Tests 72
3.11.3.5 Pharmacodynamics 72
3.11.3.6 Pharmacokinetics 72
3.12 Fondaparinux (Arixtra) 73
3.13 Tinzaparin (Innohep) 74
3.14 Semuloparin Sodium (AVE5026) 75
3.15 Idrabiotaparinux 75
3.16 Otamixaban 75
3.17 RB006 75
3.18 Reversal Agents and Antidotes 76
3.18.1 Vitamin K 78
3.18.2 Recombinant Factor VIIa 78
3.18.3 Prothrombin Complex Concentrates 80

4. A Brief Overview of Antiplatelets 83
4.1 Overview of this Chapter 83
4.1.1 Differences between Antiplatelets and Anticoagulants 84
4.1.2 Need for Antiplatelets 84
4.1.3 Side Effects of Antiplatelets 85
4.1.4 Choosing an Antiplatelet 86
4.1.5 Role of Platelets in Thrombosis 87
4.1.6 Inhibitors of Platelet Adhesion 88
4.1.7 Inhibitors of Platelet Activation 88
4.1.7.1 Inhibitors of TXA2 Pathway 88
4.1.7.2 Inhibitors of P2Y12 88
4.1.7.3 PAR-1 Inhibitors 89
4.1.7.4 Phosphodiesterase Inhibitors 89
4.2 Antiplatelet Drugs 89
4.2.1 Aspirin 89
4.2.2 Aggrenox 90
4.2.3 Ticagrelor (Brilinta) 91
4.2.4 Clopidogrel (Plavix) 92
4.2.4.1 Indications and Usage 92
4.2.4.2 General Risk of Bleeding 93
4.2.5 Effient (Prasugrel) 96

5. Coagulation Assays 97
5.1 Clotting Assays 97
5.1.1 Chromogenic Methods 97
5.1.2 Prothrombin Time 97
5.1.3 Activated Partial Thromboplastin Time 97
5.1.4 Thrombin Time 97
5.1.5 Fibrinogen (Clauss Method) 97
5.1.6 Derived Fibrinogen 97
5.1.7 Antithrombin 97
5.1.8 Protein C 97
5.1.9 Protein S 98
5.1.10 Lupus Anticoagulants 98
5.1.11 ProC Global Assay and APC Resistance (APCR) 98
5.2 Influence of New Anticoagulants on Coagulation Assays 98

6. Disease Conditions Targeted by Anticoagulants 100
6.1 Cardiovascular Diseases 100
6.1.1 Stroke 100
6.1.2 Ischemic Stroke 101
6.1.3 Hemorragic Stroke 101
6.1.4 Subarachnoid Hemorrage 102
6.1.5 Global Incidence and Prevalence of Stroke 102
6.1.6 Incidence of Stroke in the U.S. 103
6.1.7 Mortality from Heart Disease and Stroke in Selected OECD Countries 106
6.1.8 Anticoagulants Used in the Treatment for Stroke 106
6.1.8.1 Heparin 106
6.1.8.2 Warfarin 107
6.1.9 Antiplatelets 107
6.1.9.1 Aspirin 107
6.1.9.2 Dipyridamole 107
6.1.9.3 Clopidogrel 107
6.1.10 Transient Ischemic Attack (Mini Stroke) 107
6.1.10.1 Drug Therapy for Mini Stroke 108
6.1.11 Market for Stroke Medication 108
6.2 Cardiac Arrhythmia 109
6.2.1 Tachycardias 109
6.2.2 Bradycardias 111
6.2.3 Medications for Arrhythmias 111
6.2.4 Anticoagulants Used to Treat Arrhythmias 111
6.2.5 Global Market for Atrial Fibrillation Drugs 111
6.2.6 Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation 112
6.2.7 Clinical Data on Direct Thrombin Inhibitors 113
6.2.7.1 Dabigatran 113
6.2.7.2 Clinical Data on Oral Factor Xa Inhibitors 116
6.2.8 Rivaroxaban 116
6.2.9 Apixaban 117
6.2.10 Betrixaban 117
6.2.11 Edoxaban 117
6.3 Coronary Artery Disease 117
6.3.1 Global CAD Therapeutics Market 118
6.3.2 Anticoagulation in Acute Coronary Syndrome 118
6.3.3 Antiplatelet Therapy 119
6.3.4 Antricoagulants Therapy 119
6.4 Heart Attack (Myocardial Infarction) 123
6.4.1 Global Market for CHF Pharmaceuticals 124
6.4.2 Declining Trend in the U.S. Heart Attack Rates 124
6.4.3 Cost of Cardiovascular Diseases 125
6.5 Heart Valve Replacement 125
6.5.1 Market Trends in Prosthetic Heart Valves 126
6.5.2 Market for Mechanical Heart Valves 127
6.5.3 Market for Tissue Heart Valves 127
6.5.4 Heart Valve Replacement and Anticoagulants 128
6.5.4.1 Anticoagulation Therapy in Patients with Prosthetic Heart Valves 129
6.6 Deep Vein Thrombosis (DVT) 130
6.6.1 Commonly Recognized Signs and Symptoms of DVT 131
6.6.2 Complications of VTE 131
6.6.3 Use of Risk Assessment Tools in the Diagnosis of DVT 131
6.6.4 Current Anticoagulants Treatment Modalities for DVT 132
6.6.5 Use of Xarelto 133
6.6.6 Use of Enoxaparin: Inpatient and Outpatient 133
6.6.7 Use of Fondaparinux: Inpatient 133
6.6.8 Prophylactic Interventions 134
6.7 Joint Replacement Surgery and Risk of Blood Clot Formation 135
6.7.1 Joint Replacement Surgeries in the U.S. 136
6.7.2 Hip and Knee Replacement Surgeries in OECD Countries 138
6.7.3 Global Orthopedic Industry 139
6.7.4 Hip Replacement 140
6.7.4.1 U.S. Market for Hip Replacement 140
6.7.5 Knee Replacement 141
6.7.5.1 U.S. Knee Replacement Market 141
6.7.6 Shoulder Replacement 142
6.7.6.1 Global Shoulder Replacement Market 142
6.7.7 Oral Thrombophylaxis Following Total Hip and Knee Replacement 142
6.7.7.1 Thrombophylactic Agents 143
6.7.7.2 Reasons for Increased Clot Risk after Surgery 143
6.8 Prophylactic Anticoagulation after a Hip Fracture 143
6.8.1 Pharmacologic Prevention of Blood Clots after a Hip Fracture 144
6.8.1.1 Aspirin 144
6.8.1.2 Warfarin 144
6.8.1.3 Heparins 144
6.8.1.4 Fondaparinux 145
6.8.2 Duration of Prophylaxis after Hip Fracture 145
6.9 Pulmonary Embolism (Blood Clot in the Lung) 145
6.9.1 Signs and Symptoms of Pulmonary Embolism 146
6.9.2 Anticoagulation Therapy for Pulmonary Embolism 146
6.10 Oral Surgery and Anticoagulation Therapy 147
6.10.1 Required Laboratory Investigations for Dental Patients on Anticoagulation
147
6.11 Hemodialysis 147
6.11.1 Global Market for Hemodialysis 148
6.11.2 Global Operators of Dialysis Clinics 148
6.11.3 Global Leaders in Hemodialysis Products 149
6.11.4 Global Leaders in Peritoneal Dialysis Products 150
6.11.5 Anticoagulation in Hemodialysis 151
6.12 Cancer 151
6.12.1 Global Market for Cancer Therapeutics 152
6.12.2 The Cancer-Thrombosis Connection 152

7. Market Analysis: Anticoagulants 154
7.1 Overview of this Chapter 154
7.2 Oral Anticoagulants 156
7.2.1 Vitamin K Antagonists 157
7.2.1.1 Global Market for Warfarin 158
7.2.1.2 The Threatened Position of Warfarin in the Anticoagulants Market 159
7.2.1.3 Newer Oral Anticoagulants to Replace Warfarin 160
7.2.1.4 Potential Alternatives to Warfarin 160
7.2.2 Factor Xa Inhibitors 160
7.2.2.1 Global Market for Factor Xa Inhibitors 160
7.2.3 Global Market for Xarelto (Rivaroxaban) 161
7.2.3.1 Xarelto: A Great Promise 162
7.2.3.2 U.S. Market for Xarelto 162
7.2.3.3 U.S. Market Share for Eliquis, Xarelto and Pradaxa 163
7.2.4 Direct Thrombin Inhibitors (DTI) 164
7.2.4.1 Global Market for Direct Thrombin Inhibitors 165
7.2.5 Global Market for Pradaxa (Dabigatran) 166
7.2.5.1 Dawning of the Age of Dabigatran 167
7.2.5.2 Pradaxa: Bringing Potential Sea Change in AF 167
7.2.5.3 Dabigatran’s First Year in the Market 168
7.3 Parenteral Anticoagulants 168
7.3.1 Pharmacology of Parenteral Anticoagulants 169
7.3.2 Adverse Effects of Parenteral Anticoagulants 169
7.3.3 Parenteral Thrombin Inhibitors 170
7.3.3.1 Parenteral Indirect Thrombin Inhibitors 170
7.3.3.2 Market for Unfractionated Heparin (UFH) 171
7.3.3.3 Market for Low Molecular Weight Heparin (LMWH) 172
7.3.3.4 Distribution of LMWH Sales per Indication 173
7.3.4 Global Market for Lovenox 173
7.3.4.1 Lovenox: The Broadest Label 174
7.3.5 Pentasaccharide Anticogulants 174
7.3.5.1 Fondaparinux (Arixtra) 175
7.3.5.2 Arixtra: A Missed Opportunity 176
7.3.6 Parenteral Direct Thrombin Inhibitors 176
7.3.6.1 Bivalirudin (Angiomax) 176
7.4 Market for Venous Thromboembolic Drugs 177
7.5 Market for Direct Thrombin Inhibitors 178
7.6 Comparisons of Market Opportunities for Anti-Thrombotic Agents 179
7.7 Global Market for Anticoagulants 180
7.7.1 Market Share of Anticoagulants by Type 181
7.8 U.S. Market for Anticoagulants 182
7.9 More Anticoagulants in Pipeline 183

8. Market for Antiplatelets 184
8.1 Overview of this Chapter 184
8.2 The Threatened Market of Plavix 185
8.2.1 Patent Loss of Plavix 186
8.2.2 Patent Loss of Plavix and Competitive Advantages for New Entrants 187
8.3 Market for Effient (Prasugrel) 187
8.3.1 Slow Uptake of Effient 188
8.4 Market for Pletal (Cilostazol) 189
8.5 Market for Activase (Alteplase) 190
8.6 Market for Aggrenox 191
8.7 Market for CardioAspirin 192
8.8 Market for Opalmon 192
8.9 Market for Integrilin (Eptifibatide) 193
8.10 Market for ReoPro (Abciximab) 194
8.11 Market for Brilinta 195
8.12 Market for Diagnostic Assays of Platelet Function 196
8.13 The Anti-Platelet Pipeline 196

9. Deals in Anti-Thrombotic Therapeutics Sector 198
9.1 Sanofi’s Extensive Anti-Thrombotic Partnering Landscape 198
9.2 Daiichi Sankyo’s Licensing Portfolio 199
9.3 Merck andamp; Co. Agreements for Arterial Thrombotic Therapeutics 199
9.4 Deals between Bristol-Myer’s Squibb and Pfizer 200
9.5 Partnership between Ortho-McNeil and Bayer for Xarelto 200

10. Utilization of Anticoagulants and Antiplatelets in the U.S. 201
10.1 Anti-Thrombotic Drugs Used in Asia-Pacific Countries 201
10.2 Antiplatelets Used in Asia-Pacific for Stroke Prevention 201
10.3 Antithrombotic Strategy According to CHADS2 202
10.4 Antithrombotic Strategy for Patients with No Risk Factors (CHADS2=0) 203
10.5 Antithrombotic Strategy for Patients with 1 Risk Factor (CHADS2=1) 204
10.6 Antithrombotic Strategy for Patients with (CHADS2=2) Score 2 205
10.7 Adjustment of INR According to Age 206
10.8 Antithrombotic Treatment for Paroxysmal vs. Persistent AF 207
10.9 Oral Anticoagulation during Tooth Extraction 208
10.10 Oral Anticoagulation during Endoscopy or General Surgery 209
10.11 Oral Anticoagulation during Cardioversion for Persistent AF and Paroxysmal
AF 210
10.12 Awareness Levels about New Anticoagulants 211
10.13 Reasons for Prescribing Dabigatran 212

11. Selected Company Profiles 215
11.1 Akers Biosciences, Inc. 215
11.1.1 PIFA Heparin/Platelet Factor 4 Rapid Assay 215
11.2 Anthera Pharmaceuticals, Inc. 215
11.2.1 Varespladib/A-002 216
11.3 ARYx Therapeutics, Inc. 216
11.3.1 Tecarfarin 216
11.3.2 Tecarfarin Development Status 217
11.4 AstraZeneca, PLC 217
11.4.1 Brilinta (Ticagrelor) 218
11.5 Boehringer Ingelheim GmbH 218
11.5.1 Boehringer’s Dedication to Innovation 218
11.5.2 Boehringer’s Therapeutic Breakthrough 219
11.5.3 Registration Study RE-LY 219
11.6 Cipla Limited 220
11.7 Daiichi Sankyo Company Ltd. 221
11.7.1 LIXIANA 221
11.8 Eisai Co., Ltd. 221
11.8.1 Fragmin 221
11.9 Eli Lilly andamp; Co 222
11.9.1 Effient (Daiichi Sankyo) 222
11.9.2 General Risk of Bleeding 223
11.9.3 Coronary Artery By-Pass Graft Surgery-Related Bleeding 224
11.9.4 Discontinuation of Effient 224
11.9.5 Thrombotic Thrombocytopenic Purpura 224
11.9.6 Hypersensitivity Including Angiodema 225
11.9.7 Clinical Studies 225
11.10 Genentech, Inc. 227
11.10.1 Activase (Altepase) 227
11.11 GlaxoSmithKline PLC 227
11.11.1 Fondaparinux 228
11.12 Medicure, Inc. 228
11.12.1 Aggrastat 228
11.13 Merck andamp; Co., Inc. 229
11.13.1 SCH 5303348 229
11.14 Novartis AG 229
11.14.1 Elinogrel 229
11.15 Ortho-McNeil Pharmaceutical, Inc. 229
11.15.1 Rivaroxaban (Xarelto) 230
11.16 Pfizer, Inc. 230
11.16.1 Eliquis (Apixaban) 230
11.17 Pharmion, LLC 230
11.17.1 Tinzaparin (Innohep) 231
11.18 Portola Pharmaceuticals, Inc. 231
11.19 Sanofi 232
11.19.1 Lovenox (Enoxaparin) 232
11.19.2 Idrabiotaparinux 233
11.20 The Medicines Company 233
11.20.1 Argatroban 233
11.20.2 Angiomax (Bivalirudin) 234

Appendix 1: Innovations in Cardiac Rhythm Management with New Anticoagulants 235
Appendix 1.1: Dual Antiplatelet Therapy 236
Appendix 1.2: Direct Thrombin Inhibitors 236
Appendix 1.3: Factor Xa Inhibitors 238
Appendix 1.4: Comparing the Trials 240
Appendix 1.5: Interventions Targeting the Left Atrial Appendage 241
Appendix 2: Oral Contraceptives and the Risk of Venous Thromboembolism 244
Appendix 2.1: Hormonal Effects on Venus Thromboembolism 244
Appendix 2.2: Assessing Venous Thromboembolism Risks of Oral Contraceptives 245
Appendix 2.3: Recent Research 245


INDEX OF FIGURES

Figure 2.1: Almost 100 Years of Anticoagulation Therapy 17
Figure 2.2: Site of Action of New Anticoagulants 22
Figure 3.1: Pathway of Dabigatran Action 36
Figure 3.2: Sites of Action of Dabigatran and Rivaroxaban 45
Figure 3.3: Time to First Occurrence of Stroke by Treatment Group 52
Figure 3.4: Apixaban in Patients with Atrial Fibrillation 57
Figure 3.5: Management of Bleeding Complications (For all Oral Anticoagulants)
67
Figure 3.6: Blood Coagulation System Context for Heparin Anticoagulant Action 69
Figure 4.1: Role of Platelets in Thrombosis 87
Figure 4.2: Sites of Actions of Antiplatelets 87
Figure 6.1: Global Incidence and Prevalence of Stroke 102
Figure 6.2: U.S. Hospitalization Rates for Stroke for those Aged 65 and Over,
1989-2009 103
Figure 6.3: Mortality Rates for Ischemic Heart Disease in Selected OECD
Countries, 2009 105
Figure 6.4: Global Market for Stroke Medications, 2012-2019 108
Figure 6.5: Global Market for Atrial Fibrillation Drugs, 2012-2019 112
Figure 6.6: Coagulation Cascade 113
Figure 6.7: Cumulative Hazard Rates for the Primary Endpoint in the RE-LY Trial
114
Figure 6.8: Percentage of Cumulative Hazard Rates for the Primary Endpoint in
the RE-LY Trial 115
Figure 6.9: All-Cause Mortality in the RE-LY Trial 116
Figure 6.10: Global CAD Therapeutics Market, 2012-2019 118
Figure 6.11: Management of UA/NSTEMI 119
Figure 6.12: Global Market for CHF Pharmaceuticals, 2012-2019 124
Figure 6.13: Global Market for Prosthetic Heart Valves, 2012-2019 126
Figure 6.14: Global Market for Mechanical Heart Valves, 2012-2019 127
Figure 6.15: Global Market for Tissue Heart Valves, 2012-2019 128
Figure 6.16: Recommendations from the Seventh ACCP Consensus Conference 129
Figure 6.17: Algorithm for Antithrombotic Therapy for Prosthetic Heart Valves
130
Figure 6.18: Phases of VT and Conventional Treatments with Anticoagulants 135
Figure 6.19: Estimated Increase of THR and TKR in the U.S., 2005-2030 136
Figure 6.20: Hip Replacement Surgery in OECD Countries, 2009 137
Figure 6.21: Knee Replacement Surgeries in OECD Countries, 2009 138
Figure 6.22: U.S. Hip Replacement Market, 2012-2019 140
Figure 6.23: U.S. Knee Replacement Market, 2012-2019 141
Figure 6.24: Global Shoulder Replacement Market, 2012-2019 142
Figure 6.25: Global Market for Hemodialysis, 2012-2019 148
Figure 6.26: Percent Global Operators of Dialysis Clinics by Country, 2011 149
Figure 6.27: Global Leaders in Dialysis Products 149
Figure 6.28: Global Hemodialysis Products Market by Vendor, 2011 150
Figure 6.29: Global Leaders in Peritoneal Dialysis Products Market, 2011 150
Figure 6.30: Global Market for Cancer Therapeutics, 2012-2019 152
Figure 7.1: Estimated Global Market for Coagulation Testing, 2012-2019 155
Figure 7.2: Anticoagulant Market Segments 156
Figure 7.3: Mechanism of Action of Warfarin 158
Figure 7.4: Global Market for Warfarin, 2011-2016 159
Figure 7.5: Global Market for Factor Xa Inhibitors, 2012-2019 161
Figure 7.6: Global Market for Rivaroxaban, 2012-2019 162
Figure 7.7: U.S. Market for Xarelto, 2012-2019 163
Figure 7.8: Estimated U.S. Market Share of New Anticoagulants in 2019 164
Figure 7.9: Binding Sites of Univalent and Bivalent DTIs 164
Figure 7.10: Global Market for Direct Thrombin Inhibitors, 2012-2019 166
Figure 7.11: Global Market for Pradaxa (Dabigatran), 2012-2019 167
Figure 7.12: Mechanism of Thrombin Inhibition 170
Figure 7.13: Mechanism of Action of Indirect Thrombin Inhibitors 171
Figure 7.14: Global Market for Unfractionated Heparin (UFH), 2012-2019 171
Figure 7.15: Global Market for LMWHs, 2012-2019 172
Figure 7.16: Distribution of LMWH Sales per Indication 173
Figure 7.17: Global Market for Lovenox (Enoxaparin), 2012-2019 174
Figure 7.18: Sales of Arixtra, 2005-2009 175
Figure 7.19: U.S. Sales of Angiomax, 2001-2010 177
Figure 7.20: Global Market for Venous Thromboembolic Drugs, 2012-2019 178
Figure 7.21: Global Market for Direct Thrombin Inhibitors, 2012-2019 179
Figure 7.22: Overall Global Market for Anticoagulants, 2012-2019 181
Figure 7.23: Global Market Share of Anticoagulants by Type, 2011 182
Figure 7.24: U.S. Market for Anticoagulants, 2012-2019 182
Figure 8.1: Global Market for Antiplatelets, 2012-2019 185
Figure 8.2: The Declining Market for Plavix, 2012-2015 186
Figure 8.3: Market for Effient (Prasugrel), 2012-2019 188
Figure 8.4: Market for Pletal, 2012-2019 190
Figure 8.5: Market for Activase (Alteplase), 2012-2019 191
Figure 8.6: Market for Aggrenox, 2012-2019 191
Figure 8.7: Market for CardioAspirin, 2012-2019 192
Figure 8.8: Market for Opalmon (Limaprost), 2012-2019 193
Figure 8.9: Market for Integrilin, 2012-2019 194
Figure 8.10: Market for ReoPro, 2012-2019 195
Figure 8.11: Estimated Market for Diagnostic Assays of Platelet Function,
2013-2018 196
Figure 10.1: Anti-Thrombotics Prescribed for Stroke Prevention in Asia-Pacific,
2012 201
Figure 10.2: Antiplatelets Prescribed for Stroke Prevention in Asia-Pacific,
2012 202
Figure 10.3: Antithrombotic Strategy According to CHADS2 Score, 2012 203
Figure 10.4: Antithrombotic Strategy for Patients with No Risk Factors
(CHADS2=0), 2012 204
Figure 10.5: Antithrombotic Strategy for Patients with 1 Risk Factor (CHADS2=1),
2012 205
Figure 10.6: Antithrombotic Strategy for Patients with (CADS2=2) Score 2, 2012
206
Figure 10.7: Adjustment of INR According to Age 207
Figure 10.8: Antithrombotic Treatment for Paroxysmal vs. Persistent AF 208
Figure 10.9: Oral Anticoagulation during Tooth Extraction 209
Figure 10.10: Oral Anticoagulation during Endoscopy or General Surgery 210
Figure 10.11: Oral Anticoagulation during Cardioversion for Persistent AF 211
Figure 10.12: Awareness Levels about New Anticoagulants 212
Figure 10.13: Awareness about Dabigatran 213
Figure 10.14: Top Three Reasons for Prescribing Dabigatran in Place of Warfarin
214
Figure 11.1: Boehringer’s Pipeline (84 Products in Development) 218
Figure 11.2: The 3D Structure of Dabigatran in Complex with Thrombin 219
Figure 11.3: Non-CABC-Related TIMI Major or Minor Bleeding Events 223
Figure 11.4: Time to First Event of CV Death, MI or Stroke (TRITON-TIMI 38) 226
Figure A1.1: Transesophageal Echocardiogram Showing Thrombus in the Left Atrial
Appendage 235


INDEX OF TABLES

Table 2.1: Limitations and Consequences of Vitamin K Antagonists 18
Table 2.2: Pharmacokinetics of Injectable Anticoagulants 18
Table 2.3: Marketed and Registered Drugs for Anticoagulation and Related
Disorders 19
Table 2.4: Desired Attributes of Newly Developed Anticoagulants 24
Table 2.5: Comparison of New Anticoagulants 25
Table 3.1: Examples of Drugs that Interact with Warfarin 32
Table 3.2: Vitamin K Content of Selected Vegetables 33
Table 3.3: Weekly Requirements of Vegetables Based on Age and Gender 34
Table 3.4: Vitamin K Content of Commonly Used Oils 34
Table 3.5: Vitamin K Content in the Oil of Fast and Processed Foods 35
Table 3.6: Vitamin K Content in Nutritional Supplements per 8 OZ 35
Table 3.7: Mean Dabigatran Plasma Concentration and the 25th-75th Percentiles 38
Table 3.8: Discontinuation Rules before Surgical Procedures 40
Table 3.9: Strengths and Weaknesses of Dabigatran Compared with Others 43
Table 3.10: Bleeding Events in ROCKET AF Trial 48
Table 3.11: Bleeding Events in Patients Undergoing Hip or Knee Replacement
Surgeries (RECORD) 49
Table 3.12: Other Adverse Reactions Reported in RECORD 1-3 Studies 50
Table 3.13: Clinical Outcomes of EINSTEIN PE 51
Table 3.14: Primary Composite Endpoint Results in ROCKET AF Study 51
Table 3.15: Key Efficacy Analysis Results from RECORD Trial 53
Table 3.16: Phase III AF Trials 58
Table 3.17: Drugs in Development for Anticoagulation and Related Disorders 63
Table 3.18: Comparison of Oral Anticoagulants 66
Table 3.19: Pharmacokinetic Parameters after Five Days of 1.5 mg/kg SC Once
Daily Doses of Enoxaparin Sodium Using 100 mg/mL or 200 mg/mL Concentrations 73
Table 3.20: Pharmacokinetic Parameters of Fondaparinux and Other Anticoagulants
74
Table 3.21: Composition of 20,000 Anti-Xa IU/mL Innohep 74
Table 3.22: Comparison of Characteristics of AVE5026, Idrabiotaparinux,
Otamixaban and RB006 76
Table 4.1: Comparison of Top Five Antiplatelets 83
Table 4.2: Estimated Yearly Incidence of Bleeding with Antiplatelets 85
Table 4.3: Summary of Evidence for Antiplatelets 86
Table 4.4: Cost of Antiplatelets 86
Table 4.5: Information on Ticagrelor 91
Table 4.6: Product Information on Clopidogrel 93
Table 4.7: CURE Incidence of Bleeding Complications (% Patients) 94
Table 4.8: Incidence of Bleeding Event in COMMIT (% Patients) 95
Table 5.1: Influence of Anticoagulants on Routine Coagulation Assays 99
Table 5.2: Influence of Anticoagulants on Thrombophilia Assays 99
Table 6.1: ACC/AHS Recommendations for Antiplatelet Therapy in Patients with
NSTEMI or UA 119
Table 6.2: Dosing of LMWH, Fondaparinux and Bivalirudin in Patients with NSTEMI
or UA 120
Table 6.3: ACC/AHA Recommendations for Anticoagulants Therapy in Patients with
NSTEMI or UA 120
Table 6.4: Antiplatelet Therapy in Patients with STEMI 121
Table 6.5: Anticoagulants Therapy in Patients with STEMI Who Receive
Fibrinolytic Therapy 121
Table 6.6: Anticoagulants Therapy in Patients with STEMI Who Undergo Primary PCI
122
Table 6.7: ACCP Recommendations for Thromboprophylactic Strategy Based on Risk
for VTE 122
Table 6.8: Anticoagulants Treatments for VTE 123
Table 6.9: Projections of Crude Cardiovascular Disease Prevalence, 2010-2030 125
Table 6.10: Projected Direct Medical Costs for Cardiovascular Diseases,
2010-2030 125
Table 6.11: Hamilton Score 131
Table 6.12: Modified Wells Score 132
Table 6.13: Low Molecular Weight Heparin or Pentasaccharide Indications for VTE
Treatment 133
Table 6.14: Drugs to Prevent Thromboembolism after Hip Fracture 145
Table 6.15: Complete Blood Count Components 147
Table 7.1: Oral Anticoagulants Utilization and Cost per Claim 156
Table 7.2: Oral Anticoagulation Utilization by Age Band, 2011 157
Table 7.3: Users New to Anticoagulation Therapy and Switch Rate, 2011 157
Table 7.4: Alternatives to Warfarin 160
Table 7.5: FDA-Approved Direct Thrombin Inhibitors 165
Table 7.6: FDA-Approved Parenteral Anticoagulants 169
Table 7.7: Pharmacokinetics of Parenteral Anticoagulants 169
Table 7.8: Adverse Effects of Parenteral Anticoagulants 170
Table 7.9: Available Forms of Parenteral Anticoagulants 170
Table 7.10: Characteristics of Available LMWH 173
Table 7.11: Risk Factors for Venous Thromboembolism 177
Table 7.12: Anti-Thrombotic Agents Market, 2012 and 2019 180
Table 7.13: Partial List of Anticoagulants in Development 183
Table 8.1: Comparison of Antiplatelets 184
Table 8.2: History of Prasugrel 189
Table 9.1: Selected Sanofi’s Agreements for Antithrombotics 199
Table 9.2: Selected Daiichi Sankyo’s Agreements for Anti-Thrombotics 199
Table 9.3: Agreements for Integrilin 200
Table 9.4: Agreements for Aggrastat 200
Table 9.5: Notable High-Value Deals for Anti-Thrombotics 200
Table 11.1: Cipla’s Anticoagulant and Antithrombotic Products 220
Table 11.2: Dosage and Administration of Fragmin 222
Table 11.3: Patients with Outcome Events in TRITON-TIMI 38 227
Table 11.4: Medication Information for Tinzaparin 231
Table 11.5: Product Pipeline from Portola 232
Table 11.6: Dosage and Administration of Lovenox 233
Table A1.1: Risk Factors for Thromboembolism and Latest Guideline Management
Recommendations 235
Table A1.2: Comparison of the Three Studies of New Anticoagulants for Atrial
Fibrillation 240

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