SÃO PAULO, BRAZIL — An analysis of a subset of patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial who had valvular heart disease revealed that apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) is as safe and effective as warfarin, even though it is approved only for "nonvalvular" heart disease, researchers report, in an article published July 6, 2015 in Circulation[1].
Classifying the patients in the ARISTOTLE safety and efficacy trial as having "nonvalvular" heart disease is inaccurate, since a quarter of them had valvular heart disease, although they did not have clinically significant mitral stenosis or mechanical prosthetic heart valves, which were exclusion criteria, Dr Alvaro Avezum (Dante Pazzanese Institute of Cardiology, São Paulo, Brazil) and colleagues point out.
"Many physicians and patients believe that . . . the new oral anticoagulants that are indicated in patients with 'nonvalvular' AF are not known to be safe and effective in patients with valvular heart disease other than mitral stenosis and mechanical prosthetic heart valves," Avezum told heartwire from Medscape.
Moreover, "the current labeling and description of these new oral anticoagulants as being indicated for 'nonvalvular' atrial fibrillation may be leading to undertreatment of one of the groups of patients that could benefit most from the advantages of these new anticoagulants," the researchers write.
Avezum could not comment on whether Bristol-Myer Squibb or Pfizer will contact the US Food and Drug Administration (FDA) about these new findings, but "some of my coauthors have discussed communicating with the FDA about the need to clarify what 'nonvalvular' atrial fibrillation means," he said.
Patients in ARISTOTLE With vs Without Valvular Disease
The direct oral factor Xa inhibitor apixaban reduced stroke or systemic embolism, caused less bleeding, and reduced mortality compared with warfarin in ARISTOTLE, which led to its approval to reduce the risk of stroke and systemic embolism in patients with "nonvalvular" atrial fibrillation, Avezum and colleagues explain. However, it included a "substantial number" of patients with other valvular diseases such as aortic stenosis, aortic regurgitation, mild mitral stenosis, mitral regurgitation, tricuspid stenosis, tricuspid regurgitation, valve repair, or bioprosthetic valve replacement.
The researchers aimed to investigate the prevalence and characteristics of patients with valvular heart disease in ARISTOTLE and compare efficacy and safety outcomes in patients with AF with and without valvular heart disease.
Of 18,201 patients with AF and at least one risk factor for stroke who were randomized in ARISTOTLE, 18,197 patients had data on valvular heart disease status, and of these, 4808 patients (26.4%) had moderate or severe valvular heart disease or prior valve surgery.
Most of the 4808 patients had moderate or severe valvular heart disease (most often mitral-valve or tricuspid-valve regurgitation and less often aortic-valve regurgitation or mitral- or aortic-valve stenosis), and 5.2% had prior valve surgery.
Compared with patients without valvular heart disease, those with valvular heart disease were older (mean age 71 vs 69) and more often female (40.3% vs 33.5%). They also were more likely to have prior MI, prior bleeding, persistent or permanent AF, and a higher mean CHADS2 score with less hypertension and diabetes.
Compared with the other patients in ARISTOTLE, those with valvular heart disease had significantly higher rates of stroke or systemic embolism (3.2% vs 2.4%), death (9.1% vs 6.2%), and major bleeding (4.6% vs 4.3%).
However, outcomes during follow-up were similar with apixaban vs warfarin, in patients with and without the included types of valvular heart disease.
Risk of Outcomes During Follow-up, Apixaban vs Warfarin, in Patients With and Without Valvular Heart Disease
| Outcome | With valvular heart disease, HR (95% CI) | Without valvular heart disease, HR (95% CI) | Interaction P |
| Reduced stroke or systemic embolism | 0.70 (0.51–0.97) | 0.84 (1.67–1.04) | 0.38 |
| Reduced mortality | 1.01 (0.84–1.22) | 0.84 (0.73–0.96) | 0.10 |
| Less bleeding | 0.79 (0.61–1.04) | 0.65 (0.55–0.77) | 0.23 |
ARISTOTLE was designed to be a noninferiority trial of apixaban vs warfarin, and earlier warfarin-vs-placebo trials had excluded patients with mitral stenosis, since warfarin was known to be effective in preventing stroke in these high-risk patients; therefore, assignment to control was considered unethical.
Now, "there is no reason to think that apixaban wouldn't be effective for stroke prevention in patients with clinically important mitral stenosis; however, before its use can be recommended, additional randomized data in patients" are needed, according to Avezum and colleagues. Similarly, more data are needed to determine whether apixaban is safe and effective for patients with AF who have a bioprosthetic valve.
In the meantime, "with the exception of those with clinically significant mitral stenosis or mechanical prosthetic heart valves, apixaban is an attractive alternative to warfarin in patients with atrial fibrillation and valvular heart disease," Avezum and colleagues conclude.
The ARISTOTLE trial was supported by Bristol-Myers Squibb and Pfizer. Avezum reports consulting and advisory board fees from Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer. Disclosures for the coauthors are listed in the article.
Heartwire from Medscape © 2015 Medscape, LLC
Cite this: Apixaban in Some Kinds of "Valvular" AF: Support From ARISTOTLE - Medscape - Jul 09, 2015.
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