146

Comparative Efficacy and Safety of the Non–Vitamin K Antagonist Oral Anticoagulants for Patients with Nonvalvular Atrial Fibrillation Gregory Y. H. Lip, MD1,2

1 Centre for Cardiovascular Sciences, City Hospital, University of

Birmingham, Birmingham, United Kingdom 2 Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

Address for correspondence Gregory Y. H. Lip, MD, University of Birmingham Centre for Cardiovascular Sciences, City Hospital Dudley Road Birmingham, B18 7QH United Kingdom (e-mail: [email protected]).

Semin Thromb Hemost 2015;41:146–153.

Abstract

Keywords

► non-VKA oral anticoagulants ► vitamin K antagonist ► atrial fibrillation ► stroke prevention ► clinical trial

The non–vitamin K antagonist oral anticoagulants (NOACs), such as the thrombin inhibitor (dabigatran) and the direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), have been shown to be at least as efficacious and safe as conventional oral anticoagulants, such as the vitamin K antagonists (VKAs) (e.g., warfarin), for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). Each NOAC has various advantages and specific features, and therefore decisions regarding appropriate stroke prevention require individual assessment of stroke and bleeding risk on anticoagulation with VKA therapy and NOACs when starting on any of these drugs. This review briefly describes the results of the four NOACs clinical randomized trials and discusses how they might impact clinical practice and choice of anticoagulants in atrial fibrillation patients. Moreover, this review discusses the differences of the proposed management of antithrombotic therapy in several international guidelines and pragmatic issues of NOACs for stroke prophylaxis.

Nonvalvular atrial fibrillation (NVAF) is the most common cardiac arrhythmia, potentially resulting in serious consequences from increased mortality and morbidity from cerebral and noncerebral embolism and heart failure. Stroke prevention is central to the management of patients with NVAF and depends on additional risk factors for stroke.1 Stroke risk in NVAF is not homogeneous and patients can be risk stratified by using the CHADS2 score (Congestive heart failure, Hypertension, Age
75 years, Diabetes mellitus, and previous Stroke/transient ischemic attack [double]) or more recently, by the CHA2DS2-VASc score (Congestive heart failure, Hypertension, Age
75 years [double], Diabetes mellitus, previous Stroke/transient ischemic attack/thromboembolism [double], Vascular disease, Age 65–74 years, and female gender) (see ►Table 1). Anticoagulation with VKAs has been for many decades the standard treatment for stroke prevention in NVAF patients.2,3 Although the VKAs are effective in stroke

prevention, treatment with the VKAs requires monitoring of the anticoagulant effect with dose adjustments, because of the wide spectrum of food and drug interactions and the influence of genetic variants of metabolism of VKAs. 4 This has led to suboptimal anticoagulation use, although some regional variations may be evident.5,6 Considering the additional disadvantages of these drugs in relation to efficacy and safety, several new oral anticoagulants have been developed that act via direct inhibition of thrombin (dabigatran) or activated factor X (rivaroxaban, apixaban, and edoxaban).7 These non–vitamin K antagonist oral anticoagulants (NOACs, previously referred to as new or novel oral anticoagulants8) are already available for clinical use in stroke prevention, and offer potential advantages over VKA. Unlike the VKAs, multiple food and drug interactions are not observed in these NOACs and, thus routine monitoring of a coagulation assay is not required.4

published online February 15, 2015

Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

Issue Theme Anticoagulant Therapy: Present and Future; Guest Editor: Job Harenberg, MD.

DOI http://dx.doi.org/ 10.1055/s-0035-1544156. ISSN 0094-6176.

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Keitaro Senoo, MD1

Table 1 The CHADS2 and the CHA2DS2-VASc scores as a stroke risk stratification Risk factor

CHADS2 score

CHA2DS2-VASc score

Risk score

Risk score

CHF or LVEF 40%

1

1

hypertension

1

1

Age
75

1

2

Diabetes mellitus

1

1

Stroke/TIA/TE

2

2

Vascular disease

1

Age 65–74

1

Sex category (female) Max score

1 6

9

Abbreviations: CHADS2 score, Congestive heart failure, Hypertension, Age
75 years, Diabetes mellitus, and previous Stroke/transient ischemic attack (double); CHA2DS2-VASc score, Congestive heart failure, Hypertension, Age
75 years (double), Diabetes mellitus, previous Stroke/transient ischemic attack/thromboembolism (double), Vascular disease, Age 65–74 years, and female gender; CHF, congestive heart failure; LVEF, left ventricular ejection fraction; TE, thromboembolism; TIA, transient ischemic attack.

A Brief Overview of the Phase III Randomized Trials with the NOACs for Stroke Prevention in NVAF Baseline characteristics of the four randomized trials9–12 are shown in ►Table 2. The average age of patients was similar between these trials. However, the ROCKET-AF (Rivaroxaban

Senoo, Lip

Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial10 enrolled patients with a higher mean CHADS2 score (3.5) than the other studies. The ENGAGE-AF (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial12 and the ROCKET-AF trials had more patients with heart failure and with hypertension compared with the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial9 and the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.11 The median time in therapeutic range (TTR) in patients in the warfarin group showed 64% in the RE-LY, 55% in the ROCKET-AF, 62% in the ARISTOTLE, and 68% in the ENGAGE-AF trial, respectively. ►Tables 3 and 4 summarize the results of efficacy and safety outcomes from the four randomized trials, respectively.

Primary Efficacy Outcomes Both the RE-LY and the ARISTOTLE trials reported that the dose regimen of dabigatran 150 mg twice a day (bid) and apixaban 5 mg bid (2.5 mg bid in patients who met at least two of the following criteria: age >80 years, weight 1.5 mg/dL) were statistically superior to warfarin in the primary efficacy outcomes of stroke and systemic embolism 9,11 (relative risk [RR] ¼ 0.66; 95% confidential interval [CI]: 0.53–0.82, and hazard ratio [HR] ¼ 0.79; 95% CI: 0.66–0.95), respectively. Dabigatran 110 mg bid was noninferior to warfarin (RR ¼ 0.91; 95% CI: 0.74–1.11); similar findings were observed with edoxaban 30 mg daily (HR ¼ 1.13; 95% CI: 0.96–1.34) and 60 mg daily (HR ¼ 0.87; 95% CI: 0.73–1.04) in the ENGAGE AF trial (half-dose at any time during the study in patients who met

Table 2 Patients characteristics in the four phase III randomized trials4–7 RE-LY4

ROCKET AF5

ARISTOTLE6

ENGAGE AF-TIMI 487

Drug

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Number of patients

18,113

14,264

18,201

21,105

Study design

Open (PROBE)

Double-blind

Double-blind

Double-blind

CHF or LVEF

32%a

62.6%b

35.5%c

58%

Hypertension

79%

91%

87%

94%

Age (years)

Mean 72

Median 73

Median 70

Median 72

Diabetes mellitus

23%

40%

25%

36%

Prior stroke, TIA

20%

55%

19%

28%

CHADS2 score:

0/1: 31.9% 2: 35.6%
3: 32.4%

0/1: