Eliquis for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, approved in European Union
The European Commission ( EU ) has approved Eliquis ( Apixaban ) for prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation ( NVAF ) with one or more risk factors.
Apixaban is an oral direct Factor Xa inhibitor, part of a novel therapeutic class. Apixaban prevents thrombin generation and blood clot formation.
The marketing authorization for Eliquis is supported by the pivotal Phase 3 trials ARISTOTLE and AVERROES, which evaluated approximately 24,000 patients with non-valvular atrial fibrillation.
Eliquis 5 mg is indicated as a twice-daily oral medication for prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as prior stroke or transient ischaemic attack ( TIA ); age greater than or equal to 75 years; hypertension; diabetes mellitus; symptomatic heart failure ( NYHA Class greater than and equal to II ).
Apixaban does not require International Normalized Ratio ( INR ) monitoring and there are no known dietary restrictions.
In the ARISTOTLE ( Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation ) trial, Apixaban achieved statistically significant superiority in the primary endpoint of prevention of stroke ( haemorrhagic or ischaemic ) and systemic embolism compared with Warfarin ( Coumadin ).
Apixaban was superior to Warfarin in the primary efficacy endpoint of stroke or systemic embolism, with a 21% relative risk reduction beyond Warfarin ( 1.27% vs 1.60%, hazarad ratio, HR=0.79; P=0.0114 ).
Apixaban was superior to Warfarin for the primary safety endpoint of major bleeding, with a 31% relative risk reduction ( 2.13% vs 3.09%, HR=0.69, P less than 0.0001 ).
Intracranial hemorrhage, a subset of major bleeding, occurred with lower incidence with Apixaban compared to Warfarin ( 0.33% vs 0.80%, HR=0.42, P less than 0.0001 ).
Apixaban was superior to Warfarin in the key secondary endpoint of all-cause death, with an 11% relative risk reduction ( 3.52% vs 3.94%, HR=0.89; P= 0.0465 ).
The use of Apixaban did not result in an increase in myocardial infarction in the ARISTOTLE trial.
The overall discontinuation rate due to adverse reactions was 1.8% for Apixaban and 2.6% for Warfarin in the ARISTOTLE study.
The AVERROES ( Apixaban Versus Acetylsalicylic Acid to Prevent Strokes ) trial was designed to demonstrate the efficacy and safety of Apixaban versus Acetylsalicylic Acid ( Aspirin ) for the prevention of stroke or systemic embolism in patients who were unsuitable for vitamin K antagonist ( VKA ) therapy.
AVERROES was stopped early based on the recommendation of the trials independent Data Monitoring Committee due to clear evidence of reduction of stroke and systemic embolism with an acceptable safety profile.
In AVERROES, Apixaban was statistically superior to Acetylsalicylic Acid in the primary endpoint of prevention of stroke ( hemorrhagic or ischemic ) and systemic embolism compared to Acetylsalicylic Acid ( 1.62% vs. 3.63%, HR=0.45; P less than 0.0001 ), as well as in the key secondary composite endpoint of stroke, systemic embolism, myocardial infarction or vascular death ( 4.21% vs 6.35%, HR=0.66; P=0.003 ).
While not significant, there was an increase in the incidence of major bleeding with Apixaban compared to Aspirin ( 1.41%/year vs 0.92%/year ).
The incidence of fatal bleeding ( 0.16%/year vs. 0.16%/year ) and intracranial bleeding ( 0.34%/year vs. 0.35%/year ) were similar in the Apixaban and Acetylsalicylic Acid treatment groups.
The safety of Apixaban has been investigated in 11,886 patients in NVAF studies treated for an average total exposure of 1.7 years. In ARISTOTLE and AVERROES, 24.4% ( Apixaban vs Warfarin ) and 9.6% ( Apixaban vs Acetylsalicylic Acid ) of the patients treated with Apixaban ( 5 mg or 2.5 mg ) twice daily experienced adverse reactions.
Common adverse reactions were epistaxis, contusion, haematuria, haematoma, eye haemorrhage, and gastrointestinal haemorrhage.
The overall incidence of adverse reactions related to bleeding with Apixaban was 24.3% in the Apixaban vs Warfarin study and was 9.6% in the Apixaban vs Acetylsalicylic Acid study.
In ARISTOTLE study, the incidence of ISTH major gastrointestinal bleeds ( including upper GI, lower GI, and rectal bleeding ) with Apixaban was .76%/year. The incidence of ISTH major intraocular bleeding with Apixaban was 0.18%/year.
Source: BMS and Pfizer, 2012