Apixaban in patients with atrial fibrillation and prior coronary artery disease: Insights from the ARISTOTLE trial,☆☆

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Abstract

Background

A substantial portion of patients with atrial fibrillation (AF) also have coronary artery disease (CAD) and are at risk for coronary events. Warfarin is known to reduce these events, but increase the risk of bleeding. We assessed the effects of apixaban compared with warfarin in AF patients with and without prior CAD.

Methods and results

In ARISTOTLE, 18,201 patients with AF were randomized to apixaban or warfarin. History of CAD was defined as documented CAD, prior myocardial infarction, and/or history of coronary revascularization. We analyzed baseline characteristics and clinical outcomes of patients with and without prior CAD and compared outcomes by randomized treatment using Cox models. A total of 6639 (36.5%) patients had prior CAD. These patients were more often male, more likely to have prior stroke, diabetes, and hypertension, and more often received aspirin at baseline (42.2% vs. 24.5%). The effects of apixaban were similar among patients with and without prior CAD on reducing stroke or systemic embolism and death from any cause (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.71–1.27, P for interaction = 0.12; HR 0.96, 95% CI 0.81–1.13, P for interaction = 0.28). Rates of myocardial infarction were numerically lower with apixaban than warfarin among patients with and without prior CAD. The effect of apixaban on reducing major bleeding and intracranial hemorrhage was consistent in patients with and without CAD.

Conclusions

In patients with AF, apixaban more often prevented stroke or systemic embolism and death and caused less bleeding than warfarin, regardless of the presence of prior CAD. Given the common occurrence of AF and CAD and the higher rates of cardiovascular events and death, our results indicate that apixaban may be a better treatment option than warfarin for these high-risk patients.

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice and is associated with significant morbidity and mortality [1], [2], [3], [4], [5]. Patients with AF have reduced quality of life, a higher risk of developing heart failure, cognitive impairment, and approximately one-third have a history of coronary artery disease (CAD) [6]. The estimated prevalence of AF in a large international cohort is 12.5% in patients with CAD [7]. In addition, patients with both AF and CAD are at an increased risk for ischemic events and cardiovascular death [7].

Oral anticoagulation with warfarin, a vitamin K antagonist, is known to reduce stroke in patients with AF [8] and also to reduce stroke and mortality in patients with AF following myocardial infarction (MI) [9], [10]. Recently, 3 pivotal trials have demonstrated benefits of the new oral anticoagulants dabigatran [11], [12], rivaroxaban [13], [14], and apixaban [15], [16] compared with warfarin in patients with AF and an increased risk of stroke. A recent subgroup analysis of the RE-LY study showed that the beneficial effects of dabigatran over warfarin were similar in AF patients with and without prior CAD [17], although there was a higher rate of MI with dabigatran compared with warfarin in the trial [12]. In contrast, there was no difference in the rate of MI when comparing apixaban with warfarin in the ARISTOTLE trial or with aspirin in the AVERROES trial [18]. When comparing the 5 mg twice daily dose of apixaban with placebo in patients on antiplatelet agents after an acute coronary syndrome in the prematurely terminated APPRAISE-2 trial, there was no significant reduction in ischemic events [19]. This finding is in contrast to the reduction with low doses of rivaroxaban in the ATLAS-2 trial [20]. However, in both trials there was a 2–3 times increase in major bleeding when adding the factor Xa inhibitors to antiplatelet treatment in patients with CAD. Thus, the usefulness of novel oral anticoagulants in patients with AF and CAD needs further definition.

In the ARISTOTLE [16] trial, 18,201 patients with AF and at least 1 additional risk factor for stroke were randomized to apixaban or dose-adjusted warfarin. In the apixaban group there was a 21% relative reduction in the rate of the primary outcome (stroke or systemic embolism), 31% in major bleeding, and 11% in death from any cause. In this pre-specified subgroup analysis, we evaluated the treatment effects of apixaban compared with warfarin in patients with and without prior CAD.

Section snippets

Study population

The design and results of the ARISTOTLE trial have been reported [15], [16]. Briefly, 18,201 patients with AF or atrial flutter were randomly assigned to receive apixaban or dose-adjusted warfarin. The dose of apixaban (or matching placebo) was 5 mg twice daily or 2.5 mg twice daily for patients with 2 or more of the following factors: age ≥ 80 years, body weight ≤ 60 kg, and serum creatinine ≥ 1.5 mg/dL (133 μmol/L). Patients were enrolled in 39 countries between 2006 and 2010. The median duration of

Baseline characteristics

Of the 18,201 patients included in the ARISTOTLE study, excluding the 17 with missing data on CAD, 6639 (36.5%) had prior CAD. Of those, 2585 (38.9%) had prior MI, 1206 (18.2%) had prior CABG, and 1651 (24.9%) had prior PCI. Of patients with a history of PCI, 694 had a bare-metal stent and 388 received a drug-eluting stent. Baseline characteristics are shown in Table 1. Patients with prior CAD were more often male, and more commonly had prior peripheral arterial disease (PAD) and paroxysmal AF.

Discussion

In this analysis of the ARISTOTLE study, patients with prior CAD had an increased risk of death and MI and higher aspirin use at baseline than those without prior CAD. The treatment effects of apixaban on stroke or systemic embolism, major bleeding, and death were consistent regardless of the presence of prior CAD. These results remained consistent after adjusting for baseline use of aspirin. Rates of MI were numerically lower in patients assigned to receive apixaban as compared with warfarin,

Conclusion

In conclusion, in patients with AF, apixaban as compared with warfarin reduces stroke or systemic embolism and death and causes less bleeding regardless of the presence of prior CAD. Given the common occurrence of both AF and CAD and the higher rates of cardiovascular events and death, the current results from ARISTOTLE indicate that apixaban may be a better treatment option than warfarin for these high-risk patients.

Disclosures

Bahit: Consulting fees/honoraria and research support from Bristol-Myers Squibb.

Lopes: Grants from Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, and Daiichi Sankyo; consulting fees from Bristol-Myers Squibb.

Wojdyla: None.

Hohnloser: Consulting fees from Sanofi-Aventis, St. Jude Medical, Boehringer Ingelheim, Cardiome, and Medtronic Vascular; lecture fees from Sanofi-Aventis, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and St. Jude Medical.

Alexander: Grants from

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    Funding sources: ARISTOTLE was supported by Bristol-Myers Squibb and Pfizer.

    ☆☆

    Potential conflicts of interest: Please see Disclosures section.

    1

    These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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