In AVERROES, ELIQUIS was associated with an increase in major bleeding compared to aspirin that was not statistically significant (1.41%/year versus 0.92%/year, HR 1.54, (95% CI, 0.96 to 2.45); P = 0.07).
ELIQUIS was superior to warfarin in the key secondary endpoint of all-cause mortality, with an 11% relative risk reduction (3.5%/year versus 3.9%/year, HR=0.89, p= 0.046), primarily because of a reduction in cardiovascular death, particularly stroke deaths. Non-vascular death rates were similar in the treatment arms.
The most common and most serious adverse reactions observed in the ARISTOTLE and AVERROES clinical trials with ELIQUIS were related to bleeding. The most common reason for treatment discontinuation was for bleeding-related adverse reactions; in ARISTOTLE, this occurred in 1.7% and 2.5% of patients treated with ELIQUIS and warfarin, respectively. Patients taking ELIQUIS should be carefully observed and counseled on the symptoms and signs of bleeding.
The FDA has determined that a Risk Evaluation and Mitigation Strategy (REMS) is necessary to ensure that the benefits of ELIQUIS outweigh the potential risks in patients with nonvalvular atrial fibrillation. The ELIQUIS REMS consists of a communication plan to inform healthcare professionals about the increased risk of thrombotic events, including stroke when discontinuing ELIQUIS without an adequate alternative anticoagulant and the importance of following the recommendations in the U.S. Prescribing Information on how to convert patients with nonvalvular atrial fibrillation from ELIQUIS to warfarin or other anticoagulants.ELIQUIS Dosage and Administration The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily. In patients with any two of the following characteristics (age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5mg/dL), the recommended dose of ELIQUIS is 2.5 mg twice daily. The dose of ELIQUIS should be decreased to 2.5 mg twice daily when coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp, (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin). In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with strong dual inhibitors of CYP3A4 and P-gp. ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled. For more detailed information on the dosing of ELIQUIS, please refer to Section 2 of the Full Prescribing Information.