• Cardiology Clinical Trials
• Cerebrovascular Disease
• Arrhythmias

Results from the ARISTOTLE (Apixaban for Reduction In STrOke and other ThromboemboLic Events in atrial fibrillation [NCT00412984]) trial showed that treatment with apixaban results in a lower rate of stroke or systemic embolism (SSE), less bleeding, and lower mortality compared with warfarin therapy [Granger CB et al. N Engl J Med 2011]. Lars Wallentin, MD, Uppsala University, Uppsala, Sweden, discussed the results of a subanalysis of data from ARISTOTLE, which demonstrated that the benefit of apixaban over warfarin was not related to the quality of INR control at the individual ARISTOTLE study centers.

A total of 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke from 1034 centers in 39 countries were randomized to double-blind, double-dummy treatment with apixaban 5 mg BID versus warfarin (target INR 2.0 to 3.0). In the main trial results, both the primary efficacy outcome of SSE (HR, 0.79; 95% CI, 0.66 to 0.95; p=0.01) and the primary safety outcome of ISTH major bleeding (HR, 0.69; 95% CI, 0.60 to 0.80; p<0.001) were reduced with apixaban compared with warfarin. The purpose of the current analysis was to assess whether the benefits of apixaban were consistent among centers that achieved similar time-in-therapeutic range (TTR). Each center's TTR was calculated as the median of all individuals' TTRs in warfarin-treated patients and then assigned as a measure of quality of INR control for all patients. Analyses were adjusted for differences in baseline variables with the potential to influence TTR and/or outcome (eg, age, sex, body weight, CHADS₂ score, prior stroke, diabetes mellitus, hypertension, heart failure, and baseline medications).

Consistent with the main trial results, when stratified by the centers' TTRs, there was a directionally consistent reduction in the primary endpoint with apixaban compared with warfarin in each stratum (Table 1). There was no significant interaction between efficacy and the quartile of center-based TTR (p interaction=0.29). Similarly, the primary safety endpoint of ISTH major bleeding was reduced in each center-based TTR stratum with apixaban compared with warfarin, with a trend toward greater reduction at centers with lower TTRs but with no statistically significant interaction (p interaction=0.10; Table 2). The secondary safety endpoint of major or clinically relevant minor bleeding was also reduced with apixaban, with a more robust reduction at centers with lower TTRs and significant interaction (p interaction=0.005; Table 2).

There were consistent reductions in mortality and the composite efficacy endpoint of SSE and myocardial infarction with apixaban in each stratum, with no interaction, based on TTR (p interaction=0.39 and 0.27, respectively). There was also a reduction in the incidence of hemorrhagic stroke and an improved net clinical benefit with apixaban, neither of which was related to the quartile of center-based TTR.

Prof. Wallentin concluded, “In patients with atrial fibrillation, treatment with apixaban is more effective and safer than treatment with warfarin across a wide range of warfarin management.” It should be noted that the comparisons of results by center-based TTR in trials that have compared novel anticoagulants that do not use INR with warfarin that is being titrated to the INR are challenging and have several limitations. A patient's TTR may be modified by many factors, including region, center, logistical issues, and individual patient characteristics. The current analysis grouped patients across a group of centers into one of four quartiles, according to the center's average TTR for all patients who were treated with warfarin at that center, and does not represent an adjustment at the patient level. These results should be applied with caution by clinicians, especially when faced with individual patients who have been able to achieve excellent therapeutic control with warfarin.

• © 2011 MD Conference Express