Results from the subanalysis of the ARISTOTLE trial, published in Circulation, have shown that the reductions in stroke or systemic embolism, number of major bleeding events and mortality demonstrated with Apixaban ( Eliquis ) compared to Warfarin ( Coumadin ) were consistent across subgroups defined based on levels of International Normalized Ratio ( INR ) control in patients with non-valvular atrial fibrillation.

Concerning the quality of Warfarin treatment, there is a large variation in time in therapeutic range among different countries and centers, which affects outcomes. This subanalysis was conducted to determine whether the treatment effects of Apixaban were similar in centers and patients with high quality Warfarin care.

Variations in time in therapeutic range ( TTR ) can affect outcomes for atrial fibrillation patients being treated with Vitamin K antagonists such as Warfarin for stroke prevention, leading to an increased risk of stroke when INR levels are below, or bleeding when INR levels are above, the therapeutic range.
For patients in the ARISTOTLE trial, the quality of Warfarin management was defined by TTR, with a target INR of 2-3. In the ARISTOTLE trial, patients in the Warfarin group had an INR in the therapeutic range ( 2 to 3 ) for a median of 66.0% of the time.
For context, the median time for INR in the therapeutic range varies across the globe. In clinical practice settings in the United States, it is approximately 57-59%.

The ARISTOTLE trial randomized 18,201 patients from 1,034 clinical centers in 39 countries. In the subanalysis, for each patient, a center average TTR ( cTTR ) was estimated using a linear mixed model based on the real TTRs in Warfarin treated patients with a fixed effect for country and random effect for center.
Study centers were placed into one of four similarly sized quartile groups based on cTTR ( <60.5%; 60.6%-66.3%; 66.4%-71.1%; and >71.2% ).
The rates of stroke or systemic embolism, major bleeding and mortality were consistently lower with Apixaban than Warfarin across the cTTR quartiles. Similar results were seen when an individual TTR ( iTTR ), predicted using a model including patient characteristics, was examined in a post-hoc analysis.

While demonstrating consistency across a broad range of Warfarin control, results of this subanalysis suggest a trend toward reduction of the treatment effects at centers and in patients with predicted excellent INR control. In these centers, interaction tests are less reliable because of low numbers of events, and thereby lack statistical power.

Based on the results of the subanalysis, the benefits of Apixaban compared with Warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers’ and patients’ quality of INR control.

The ARISTOTLE study was designed to demonstrate the efficacy and safety of Apixaban versus Warfarin for the prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation. In ARISTOTLE, 18,201 patients were randomized ( 9,120 patients to Apixaban and 9,081 to Warfarin ).
ARISTOTLE was an active-controlled, randomized, double-blind, multi-national trial in patients with nonvalvular atrial fibrillation or atrial flutter, and at least one additional risk factor for stroke.
Patients were randomized to treatment with Apixaban 5 mg orally twice daily ( or 2.5 mg twice daily in selected patients, representing 4.7% of all patients ) or Warfarin ( target INR range 2.0-3.0 ), and followed for a median of 1.8 years.

Aapixaban is an oral direct factor Xa inhibitor. By inhibiting factor Xa, a key blood clotting protein, Apixaban prevents thrombin generation and blood clot formation.

Source: BMS and Pfizer, 2013

XagenaMedicine2013