State-of-the-Art Paper
New Oral Anticoagulants in Atrial Fibrillation and Acute Coronary Syndromes: ESC Working Group on Thrombosis—Task Force on Anticoagulants in Heart Disease Position Paper

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Until recently, vitamin K antagonists were the only available oral anticoagulants, but with numerous limitations that prompted the introduction of new oral anticoagulants targeting the single coagulation enzymes thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, and edoxaban) and given in fixed doses without coagulation monitoring. Here we review the pharmacology and the results of clinical trials with these new agents in stroke prevention in atrial fibrillation and secondary prevention after acute coronary syndromes, providing perspectives on their future incorporation into clinical practice. In phase III trials in atrial fibrillation, compared with warfarin, dabigatran etexilate 150 mg B.I.D. reduced the rates of stroke/systemic embolism without any difference in major bleeding; dabigatran etexilate 110 mg B.I.D. had similar efficacy with decreased bleeding; apixaban 5 mg B.I.D. reduced stroke, systemic embolism, and mortality as well as major bleeding; and rivaroxaban 20 mg Q.D. was noninferior to warfarin for stroke and systemic embolism without a difference in major bleeding. All these agents reduced intracranial hemorrhage. Edoxaban is currently being evaluated in a further large phase III trial. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischemia in patients with acute coronary syndromes who were mostly receiving dual antiplatelet therapy, with conflicting results on efficacy but consistent results for increased major bleeding. Overall, the new oral anticoagulants are poised to replace vitamin K antagonists for many patients with atrial fibrillation and may have a role after acute coronary syndromes. Although convenient to administer and manage, they present challenges that need to be addressed.

Key Words

acute coronary syndromes
anticoagulants
apixaban
atrial fibrillation
dabigatran etexilate
edoxaban
rivaroxaban
vitamin K antagonists

Abbreviations and Acronyms

B.I.D.
twice daily
CI
confidence interval
CrCl
creatinine clearance
CYP
cytochrome P450
DTI
direct thrombin inhibitor
F
factor
HR
hazard ratio
INR
international normalized ratio
NSTE
non–ST-segment elevation
P-gp
P-glycoprotein
Q.D.
once daily
TIMI
Thrombolysis In Myocardial Infarction
TTR
time in therapeutic range
VKA
vitamin K antagonist

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Dr. De Caterina receives consultant and speaker fees from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, and Lilly; and research grants from AstraZeneca and Boehringer-Ingelheim. Dr. Husted receives advisory board or speaker fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis; and research grants from AstraZeneca, Bayer, Pfizer, Boehringer Ingelheim, and Bristol-Myers Squibb. Dr. Wallentin receives consultant fees from Athera, Behring, Evolva, Portola, and Roche Diagnostics; and institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Pfizer, and Schering-Plough. Dr. Andreotti receives consultant or speaker fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo, and Lilly. Dr. Huber receives lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, and The Medicines Company. Dr. Kristensen receives lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Pfizer, and The Medicines Company. Dr. Lip receives lecture fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Sanofi-Aventis; and consultant fees from Astellas, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Merck, Sanofi-Aventis, Portola, and Pfizer. Dr. Morais receives consultant fees from AstraZeneca, Bayer, Jaba Recordati, MSD, Lilly Portugal, and Merck. Dr. Siegbahn receives institutional grants from AstraZeneca and Boehringer Ingelheim. Dr. Verheugt receives consultant fees from Bayer, Daiichi Sankyo, Pfizer, Eli Lilly, Merck, and The Medicines Company; and educational and research grants from Bayer, Boehringer Ingelheim, Eli Lilly, and Roche. Dr. Weitz receives consultant fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Janssen Pharmaceuticals, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.