PARIS, France—Two important categories of patients with atrial fibrillation (A-fib) can also realize the benefits of novel anticoagulants that have proven superior to warfarin: those with moderate renal dysfunction and those in need of concomitant antiplatelet therapy due to stenting or acute coronary syndromes (ACS).

These conclusions stem from substudies of the ROCKET-AF and RE-LY trials, both presented August 28, 2011, at the European Society of Cardiology (ESC) Congress. The ROCKET-AF substudy also was published simultaneously online ahead of print in the European Heart Journal.

Benefit of Rivaroxaban Unaffected by Renal Function

Rivaroxaban (Xarelto, Bayer Healthcare, Leverkusen, Germany) is an oral direct factor Xa inhibitor; it was recently approved by the US Food and Drug Administration for prevention of deep vein thrombosis in patients undergoing knee or hip replacement.

In the main ROCKET-AF trial, more than 14,000 patients with nonvalvular A-fib and moderate to high stroke risk were randomized to fixed-dose rivaroxaban (20 mg once daily or 15 mg once daily for those with creatinine clearance 30-49 mL/min) or warfarin titrated to an international normalized ratio (INR) of 2.5 (range 2.0-3.0). In a per-protocol analysis, rivaroxaban was found to be noninferior to warfarin for the primary efficacy endpoint of stroke or systemic embolism.

In a subanalysis, investigators led by Keith A.A. Fox, MB, ChB, of the University of Edinburgh (Edinburgh, Scotland) looked at outcomes in the cohort of 2,950 (20.7%) patients with moderate renal impairment (creatine clearance 30-49 mL/min) who received the 15-mg dose of rivoraxaban. These patients were older and had a higher CHADS2 score as well as more heart failure, peripheral vascular disease, and prior MI. Rates of stroke and systemic embolism were higher in these patients than those with normal kidney function regardless of treatment.

However, overall rates for the primary efficacy outcome were consistent between patients with moderate renal dysfunction and those with normal renal function (table 1).

Table 1. Primary Efficacy Outcome^a

^a Per-protocol analysis

The same pattern was seen for the composite of major and clinically relevant nonmajor bleeding, the primary safety endpoint (table 2).

Table 2. Primary Safety Outcome^a

^a Per-protocol analysis

In particular, fatal bleeding was reduced by rivaroxaban in patients with moderate renal dysfunction (0.28% vs. 0.74% per 100 patient years; P = 0.047). Except for more frequent gastrointestinal bleeding in the rivaroxaban group (2.88% vs. 1.77%; P = 0.02), there were no other differences in bleeding between the 2 therapies.

Dr. Fox concluded that although the study was underpowered to prove the noninferiority or superiority of rivaroxaban over warfarin in the moderate renal dysfunction group, no heterogeneity in the impact of rivaroxaban vs. warfarin emerged for the different levels of renal function. In short, rivoraxaban preserved the protection of warfarin without an increase in adverse events, and produced less fatal bleeding, he said.

Among the strengths of the study are its large size, inclusion of high-risk patients, and the choice of dose based on careful pharmacokinetic considerations, said discussant Stefan H. Hohnloser, MD, of J.W. Goethe University (Frankfurt, Germany). One unresolved issue, however, is whether kidney function needs to be monitored over time for possible dose adjustments, he noted. In addition, there remains almost no data on appropriate therapy for severe renal dysfunction.

Antiplatelet Theray Does Not Diminish Dabigatran’s Advantage

A post hoc analysis from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, presented by Antonio M. Dans, MD, of the University of the Philippines School of Medicine (Manila, the Philippines), investigated the relative safety and efficacy of concomitant use of aspirin or clopidogrel in A-fib patients who had been randomized to the direct thrombin inhibitor dabigatran or warfarin.

In the original trial, a 110 mg dose of dabigatran produced similar rates of stroke and systemic embolism, the primary outcome, but lower rates of major hemorrhage compared with warfarin in patients with A-fib. Patients who received a 150 mg dose of dabigatran, meanwhile, had lower rates of the primary endpoint and similar rates of major bleeding.

A total of 6,952 patients (38.4%) received concomitant aspirin or clopidogrel during the study. As with the main results, dabigatran at 110 mg twice daily was noninferior to warfarin in terms of the primary endpoint. This was true whether patients were receiving concomitant antiplatelet therapy (HR = 0.93; 95% CI 0.70-1.25) or not (HR = 0.87; 95% CI 0.66-1.15; P for interaction = 0.7377). In terms of the main safety outcome of major bleeding, the lower dose of dabigatran was again superior to warfarin. This was also unaffected by concomitant antiplatelet use (HR = 0.82; 95% CI 0.67-1.00 for patients on antiplatelet therapy; HR = 0.79; 95% CI 0.64-0.96 for patients not on antiplatelet therapy; P for interaction = 0.7945).

The higher dose of dabigatran was superior to warfarin in terms of the primary efficacy outcome, particularly among patients who were not on antiplatelet therapy (HR = 0.52; 95% CI 0.38-0.72). This effect seemed to diminish when concomitant antiplatelet agents were given (HR = 0.80; 95% CI 0.59-1.08), with the difference just missing statistical significance (P for interaction = 0.0578), and even moreso after adjustment for variables. With respect to major bleeding, 150-mg dabigatran was similar to warfarin regardless of concomitant antiplatelet use (HR = 0.93; 95% CI 0.76-1.12 for patients on antiplatelets; HR = 0.94; 95% CI 0.78-1.15 for patients not on antiplatelets; P for interaction = 0.8746).

Overall, the rates of major bleeding increased when antiplatelet agents were given together with anticoagulants (adjusted HR = 1.60; 95% CI 1.41-1.81). The relative increase was consistent whether patients were on either dose of dabigatran or warfarin, but the absolute risks were lowest with 110-mg dabigatran.

The results were unaffected by the duration of antiplatelet use (< 50% or > 50% of the trial period) or number of antiplatelet agents used (aspirin alone, clopidogrel alone, or dual therapy).

Low-Dose Dabigatran May Be Best

According to discussant Freek W.A.Verheugt, MD, PhD, of University Medical Center Nijmegen (Nijmegen, The Netherlands), the potential need for concomitant antiplatelet and anticoagulant  therapy is an important problem—one that is even bigger in the real world than in clinical trials like RE-LY—so the current results are reassuring.

Among the study’s weaknesses, however, are its retrospective nature and relatively small size. In addition, the antiplatelet therapy was not randomized, and no data were provided on single vs. dual therapy.

The ischemic and bleeding advantages of dabigatran over warfarin were maintained, Dr. Verheugt observed, and interestingly, the lowest rate of intracranial hemorrhage was provided by the lower dose of dabigatran. Thus, it seems a good candidate for patients with A-fib who need antiplatelet therapy due to stenting or ACS, he said. Current ESC guidelines recommend that strategy should be tailored according to patients’ bleeding risk, clinical setting (elective vs. ACS), and stent type (DES vs. BMS), he noted.

 

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Sources:
1. Fox KAA. ROCKET AF: Prevention of stroke and non-CNS embolism withrivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation and moderate renal impairment. Presented at: ESC Congress; August 28, 2011; Paris, France.

2. Fox KAA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxabancompared with warfarin in patients with nonvalvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;Epub ahead of print.

3. Dans AM. RE-LY: Concomitant use of antiplatelet therapy with dabigatran or warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Presented at: ESC Congress; August 28, 2011; Paris, France.

 

 

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