Subanalysis of Phase III ARISTOTLE trial of Eliquis® (apixaban) demonstrated consistent results versus warfarin in patients with NVAF with or without valvular heart disease

Bristol-Myers Squibb Company (NYSE: BMY) and Pfizer Inc. (NYSE: PFE) today announced at the ESC Congress 2013, organized by the European Society of Cardiology, results of a post-hoc subanalysis from the Phase III ARISTOTLE trial, which was designed to demonstrate the efficacy and safety of Eliquiscompared to warfarin for the prevention of stroke or systemic embolism in nonvalvular atrial fibrillation (NVAF) patients. The ARISTOTLE trial excluded patients with clinically significant mitral stenosis, or a mechanical prosthetic heart valve. This subanalysis evaluated Eliquis compared to warfarin in patients with or without other types of valvular heart disease (VHD) who were eligible for enrollment in the ARISTOTLE trial, including mitral regurgitation, mitral stenosis, aortic regurgitation, aortic stenosis, tricuspid regurgitation, or valve surgery. Those 4,808 patients were the focus of this subanalysis.

The results of this subanalysis were consistent with the results of the overall ARISTOTLE trial and demonstrated that Eliquis compared with warfarin reduced stroke or systemic embolism, caused fewer major bleeding events, and reduced all-cause mortality in NVAF patients with or without VHD. These results were presented in an oral session today at the ESC Congress 2013 in Amsterdam, The Netherlands.

“This subanalysis provides better insight into the efficacy and safety of apixaban in nonvalvular atrial fibrillation patients with certain types of valvular heart disease, which are common in an elderly population,” said study lead author Dr. Alvaro Avezum of the Dante Pazzanese Institute of Cardiology in San Paulo, Brazil. ”These patients are generally older and considered to be at greater risk for clinical events than NVAF patients without VHD.”

This subanalysis evaluated data from 4,808 NVAF patients (26.4 percent of the ARISTOTLE trial population) who had both VHD and NVAF. For the purpose of this analysis, subjects with VHD were identified by any history of at least moderate mitral regurgitation (N=3,526), mitral stenosis (N=131), aortic regurgitation (N=384), aortic stenosis (N=887), tricuspid regurgitation (N=2,124), or valve surgery (N=251). Note that some of these patients had more than one valvular abnormality.

In this subanalysis, overall patients with these types of VHD had higher rates of stroke or systemic embolism and of major bleeding than patients without VHD, regardless of treatment. Moreover, patients randomized to Eliquis had lower rates of stroke or systemic embolism and of major bleeding compared with patients randomized to warfarin, both among patients with and without VHD. All p-values for interaction (due to presence or absence of VHD) were non-significant for the major outcomes of stroke and systemic embolism, major bleeding, and death. This means that patients in the ARISTOTLE trial had similar outcomes with Eliquis regardless of whether they had VHD, and that the results of this subanalysis were consistent with the overall results of the trial.

About ARISTOTLE

The ARISTOTLE study was designed to evaluate the efficacy and safety of Eliquisversus warfarin for the prevention of stroke or systemic embolism. In ARISTOTLE, 18,201 patients were randomized (9,120 patients to Eliquis 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 Eliquis5 mg orally twice daily (or 2.5 mg twice daily in selected patients, representing 4.7 percent of all patients) or warfarin (target INR range 2.0-3.0), and followed for a median of 1.8 years.

About Atrial Fibrillation

Atrial fibrillation is the most common cardiac arrhythmia (irregular heart beat). It is estimated that approximately 5.8 million Americans and six million individuals in Europe have atrial fibrillation. The lifetime risk of developing atrial fibrillation is estimated to be approximately 25 percent for individuals 40 years of age or older. One of the most serious medical concerns for individuals with atrial fibrillation is the increased risk of stroke, which is five times higher in people with atrial fibrillation than those without atrial fibrillation. In fact, 15 percent of all strokes are attributable to atrial fibrillation in the U.S. Additionally, strokes due to atrial fibrillation are more burdensome than strokes due to other causes. Atrial fibrillation-related strokes are more severe than other strokes, with an associated 30-day mortality of 24 percent and a 50 percent likelihood of death within one year in patients who are not treated with an antithrombotic.

About Eliquis®

Eliquis® (apixaban) is an oral direct Factor Xa inhibitor. By inhibiting Factor Xa, a key blood clotting protein, Eliquis prevents thrombin generation and blood clot formation. Eliquis is approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation in the United States, European Union (which includes 28 member states plus Iceland and Norway), Japan and a number of other countries around the world. Eliquis is approved for prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery in the European Union (which includes 28 member states plus Iceland and Norway) and a number of other countries around the world. Eliquisis not approved for this indication in the U.S. or Japan.

IMPORTANT SAFETY INFORMATION FOR ELIQUIS

BOXED WARNING: DISCONTINUING ELIQUIS IN PATIENTS WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE.

Discontinuing ELIQUIS places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following discontinuation of ELIQUIS in clinical trials in patients with nonvalvular atrial fibrillation. If anticoagulation with ELIQUIS must be discontinued for a reason other than pathological bleeding, coverage with another anticoagulant should be strongly considered.

CONTRAINDICATIONS

– Active pathological bleeding

– Severe hypersensitivity reaction to ELIQUIS (apixaban) (i.e., anaphylactic reactions)

WARNINGS AND PRECAUTIONS

Increased Risk of Stroke with Discontinuation of ELIQUIS: Discontinuing ELIQUIS in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from ELIQUIS to warfarin in clinical trials in patients with nonvalvular atrial fibrillation. If ELIQUIS must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.

Bleeding Risk: ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal bleeding. Concomitant use of drugs affecting hemostasis increases the risk of bleeding including aspirin and other anti-platelet agents, other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs, and NSAIDs. Patients should be made aware of signs or symptoms of blood loss and instructed to immediately report to an emergency room. Discontinue ELIQUIS in patients with active pathological hemorrhage. There is no established way to reverse the anticoagulant effect of apixaban, which can be expected to persist for about 24 hours after the last dose (i.e., about two half-lives). A specific antidote for ELIQUIS is not available. Because of high plasma protein binding, apixaban is not expected to be dialyzable. Protamine sulfate and vitamin K would not be expected to affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is neither scientific rationale for reversal nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving apixaban. Use of procoagulant reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa may be considered but has not been evaluated in clinical studies. Activated charcoal reduces absorption of apixaban thereby lowering apixaban plasma concentrations.

Prosthetic Heart Valves: The safety and efficacy of ELIQUIS has not been studied in patients with prosthetic heart valves and is not recommended in these patients.

ADVERSE REACTIONS

The most common and most serious adverse reactions reported with ELIQUIS (apixaban) were related to bleeding.

DISCONTINUATIONS FOR SURGERY AND OTHER INTERVENTIONS

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 noncritical in location and easily controlled.

DRUG INTERACTIONS

Strong Dual Inhibitors of CYP3A4 and P-gp: Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. Decrease the dose of ELIQUIS 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 ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp.

Strong Dual Inducers of CYP3A4 and P-gp: Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke. Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban.

Anticoagulants and Antiplatelet Agents: Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo.

PREGNANCY CATEGORY B

There are no adequate and well-controlled studies of ELIQUIS in pregnant women. Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. ELIQUIS should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus.

Please see full Prescribing Information including BOXED WARNING and Medication Guide available at www.bms.com