New Alternatives Match Efficacy to Warfarin in High-Risk Subgroups

AMSTERDAM, The Netherlands—Patients with atrial fibrillation (A-fib) and either peripheral artery disease (PAD) or valvular heart disease receive similar stroke protection from novel anticoagulants and warfarin. The findings, from the ROCKET-AF and ARISTOTLE trials, were presented in oral abstracts on September 3, 2013, at the European Society of Cardiology Congress.

PAD Patients Still Stand to Benefit from Rivaroxaban

ROCKET AF, published in 2011 in the New England Journal of Medicine, randomized 14,264 patients with nonvalvular A-fib to fixed dose rivaroxaban (20 mg or 15 mg daily) or dose-adjusted warfarin (target INR 2.0-3.0). The main efficacy analysis of the per-protocol population showed rivaroxaban to be noninferior to warfarin for the primary endpoint of stroke or systemic embolism. Risks of major or non-major clinically relevant bleeding also were equivalent between groups.

For the subanalysis, W. Schuyler Jones, MD, of Duke University Medical Center (Durham, NC), and colleagues focused on the 839 patients (5.9%) who had PAD in addition to A-fib. PAD patients were a higher-risk cohort compared with the rest of the study population; for example, they were on more concomitant medications and had higher CHADS2 scores (3.7% vs. 3.5%; P < 0.001). However, rates of stroke or systemic embolism were equivalent regardless of PAD status (P = 0.84), as were the risks of major or non-major clinically relevant bleeding (P = 0.17).

Rivaroxaban had similar efficacy in terms of stroke or systemic embolism compared with warfarin in both the PAD and no PAD groups (P for interaction = 0.34), though major or non-major clinically relevant bleeding was elevated in combination with PAD (P for interaction = 0.037; table 1).

Table 1. ROCKET-AF

Per 100 Patient-Years

Rivaroxaban

Warfarin

HR (95% CI)

Stroke or Systemic Embolism
PAD
No PAD

 
2.61
1.93

 
2.23
2.25

 
1.19 (0.63-2.22)
0.86 (0.73-1.02)

Major or Non-Major Clinically Relevant Bleeding
PAD
No PAD

 

 21.02
14.59

 

 15.12
14.48

 

 1.40 (1.06-1.86)
1.03 (0.95-1.11)

 
There also were no interactions between PAD and treatment for stroke, all-cause death, or major bleeding.

While the study identified an increased risk of major or non-major clinically relevant bleeding with rivaroxaban vs. warfarin in PAD patients, Dr. Jones noted, “the risk of fatal and/or intracranial bleeding was extremely low.”

Regarding antiplatelet therapy, Dr. Jones reported that at baseline 39% of PAD patients and 36% of non-PAD patients were on aspirin. “Throughout the trial, it varied. We looked at 6-month intervals . . . and there did not appear to be a significant interaction,” he said. “However, it was difficult to tell when bleeding occurred and when antiplatelet therapy was modified.”

Valve Disease Does Not Impede Apixaban

Investigators led by Alvaro Avezum, MD, of Dante Pazzanese Institute of Cardiology (Sao Paulo, Brazil), concentrated on the 2,894 (26.4%) of 18,197 patients in the ARISTOTLE trial who had valvular heart disease (defined as moderate/severe valve disease or prior valve surgery).

ARISTOTLE, published in the NEJM in 2011, randomized patients with A-fib and at least 1 additional stroke risk factor to apixaban (5 mg twice daily, or 2.5 mg twice daily in patients at high bleeding risk) or warfarin (target INR 2.0-3.0). Apixaban proved superior at reducing the risk of stroke or systemic embolism and also reduced bleeding and all-cause mortality.

Patients with clinically significant mitral stenosis or mechanical prosthetic cardiac valves were excluded from the original trial. Among the population with valvular heart disease, 74.4% had some form of mitral valve disease (largely regurgitation), while 23.9% had aortic valve disease, 44.2% had tricuspid regurgitation, and 5.2% had previously undergone valve surgery.

Numerous baseline characteristics differed by valve disease status. For example, patients with valvular disease were older and had more prior MI and bleeding, higher mean CHADS2 score, and less hypertension and diabetes. They also were less likely to be receiving a calcium blocker at the time of randomization but more likely to be taking an ACE inhibitor or ARB, beta-blocker, digoxin, statin, or gastric antacid drug.

Overall, valvular disease conferred higher rates of stroke or systemic embolism and of bleeding. Even so, the benefits of apixaban over warfarin were consistent (table 2).

Table 2. ARISTOTLE: Apixaban vs. Warfarin

HR (95% CI)

Valve Disease

No Valve Disease

P for Interaction

Stroke or Systemic Embolism

0.70 (0.51-0.97)

0.84 (0.67-1.04)

0.378

Death from Any Cause

1.01 (0.84-1.22)

0.84 (0.732-0.96)

0.101

Major Bleeding

0.79 (0.61-1.04)

0.65 (0.55-0.77)

0.228

Net Benefit

0.94 (0.81-1.09)

0.81 (0.73-0.90)

0.109


Dr. Avezum cautioned that the subanalysis was not prespecified and likely underpowered, and he noted that the literature offers no clear definitions of valvular heart disease and non-valvular A-fib. “Lastly, there was no available information on the etiology of valvular disease in our analysis,” he added.

In addition, the current results do not apply to patients with clinically significant mitral stenosis or mechanical prosthetic valves, Dr. Avezum emphasized, concluding. “Thus, for such patients . . . apixaban should not be used.”

 


Sources:
1. Avezum A. Apixaban versus warfarin in patients with atrial fibrillation and valvular heart disease: Findings from the ARISTOTLE study. Presented at: European Society of Cardiology Congress; September 3, 2013; Amsterdam, The Netherlands.

2. Jones WS. Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and nonvalvular atrial fibrillation: Insights from the ROCKET-AF trial. Presented at: European Society of Cardiology Congress; September 3, 2013; Amsterdam, The Netherlands.

 

 

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Disclosures
  • The ARISTOTLE analysis was sponsored by Bristol-Myers Squibb and Pfizer.
  • Dr. Avezum reports receiving research contracts from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer.
  • Dr. Jones reports receiving speaker’s fees/honoraria from the American Physician Institute and research support from the Agency for Healthcare Research &amp; Quality, AstraZeneca, and Bristol-Myers Squibb.

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