New Pooled Analysis Reports Pradaxa^® (dabigatran etexilate mesylate) May Be Associated With Better Patient Outcomes After a Major Bleeding Event Compared to Warfarin

Ridgefield, CT, October 2, 2013 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced results from a retrospective analysis comparing clinical management and patient outcomes following a major bleeding event during treatment with dabigatran or warfarin. The findings show that outcomes after a major bleed on dabigatran were not worse than after a warfarin-associated bleed, and may be better despite the lack of a specific reversal agent for dabigatran. These data were published in the journal Circulation.

This pooled analysis is comprised of data gathered from five phase III trials, including the pivotal RE-LY^® trial which enrolled more than 18,000 patients with non-valvular atrial fibrillation (NVAF). The analysis showed that patients treated with dabigatran 150 mg twice daily experienced fewer intracranial hemorrhages, but more gastrointestinal hemorrhages. Major bleeding in patients treated with dabigatran 150 mg twice daily was associated with more frequent treatment with blood transfusions, but fewer plasma transfusions, compared to patients treated with warfarin. Overall, patients treated with dabigatran 150 mg twice daily had shorter stays in an intensive care unit and reduced odds for mortality than patients treated with warfarin.

“It is well-known that all blood thinners carry an increased risk of bleeding, which must be balanced against the risk of a potentially debilitating or even fatal stroke,” said Sam Schulman, M.D., Ph.D., FRCPC(C), professor, Department of Medicine, McMaster University, Ontario, Canada. “This analysis suggests that major bleeding with dabigatran 150 mg twice daily was primarily managed with routine measures and supportive care, and that the prognosis was not worse compared to a warfarin-associated bleed.”  

In this study, sponsored by Boehringer Ingelheim, investigators assessed 1,121 reports of major bleeds from 1,034 patients (627 of 16,755 dabigatran patients, and 407 of 10,002 warfarin patients).  The reports were gathered from data from the RE-LY trial and four Phase III trials assessing dabigatran in the acute treatment and reduction in the risk of recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE), specifically RE-COVERTM I and II, RE-MEDYSM and RE-SONATE^®. Two independent investigators reviewed major bleeding reports on study treatment, or within three days of treatment discontinuation from all five studies.1 Data reviewed included patient characteristics, treatments given for the bleeding, length of stay in the hospital and death after the bleeding. Major bleeding was defined according to the International Society of Thrombosis and Hemostasis (ISTH) criteria in all five trials.

“Patient safety and education is, and always will be, our top priority at Boehringer Ingelheim,” said Sabine Luik, senior vice president, Medicine & Regulatory Affairs, U.S. Regional Medical Director, Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). “We are pleased with the findings from this pooled analysis, which reinforce the positive benefit-risk profile of PRADAXA 150 mg twice daily when used as directed to reduce the risk of stroke and systemic embolism in patients with NVAF.”

This analysis showed the outcomes of major bleeding events in patients given dabigatran 150 mg twice daily was similar to or better than outcomes seen in patients given warfarin

• Dabigatran 150 mg twice daily, compared to warfarin, was associated with fewer intracranial hemorrhages (29 vs. 90 events, p<0.001) and intramuscular hemorrhages (6 vs. 20 events, p=0.007), and more gastrointestinal hemorrhages (218 vs. 151 events, p<0.001). The numbers of bleeding events at other sites were not significantly different.
• In the RE-LY study, major bleeding in patients treated with dabigatran 150 mg twice daily was more frequently managed with red blood cell transfusions than in warfarin-treated patients (61.4 percent vs. 49.9 percent, P<0.001), but plasma was given less often (21.6 percent for dabigatran vs. 30.2 percent with warfarin, P=0.005).
  • Dialysis to eliminate dabigatran was only employed in a single case and the response was recorded in the narrative as good.
• In the RE-LY study, the length of stay in the intensive care unit after major bleeding events was shorter with dabigatran 150 mg twice daily: 1.9 nights vs. 2.7 nights (p=0.10). The percent of patients hospitalized for a major bleeding event tended to be greater with dabigatran 150 mg twice daily than with warfarin (61.8 percent vs. 56.5 percent, p = 0.10), but the length of hospital stay was similar for both groups: 8.5 days vs. 8.9 days (p=0.68). 
• The pooled odds ratio for death within 30 days following the first bleeding event, after adjusting for sex, age, weight, kidney function and additional antithrombotic therapy, was reduced for dabigatran 150 mg twice daily relative to warfarin: 0.68 (95% CI: 0.42-1.08). In only the RE-LY population, the adjusted odds ratio for 30-day mortality for dabigatran 150 mg was 0.52 (95% CI: 0.31-0.88).

Patients who experienced major bleeding with dabigatran were older than patients in the warfarin group (mean age of 75.3 and 71.8, respectively) and had lower median creatinine clearance (53 mL/min and 62 mL/min, respectively). Further, more patients treated with dabigatran who experienced bleeding were also simultaneously taking aspirin (30.9 percent and 24.6 percent, respectively) or non-steroidal anti-inflammatory drugs (NSAIDs) (12.9 percent and 8.4 percent, respectively).

PRADAXA is currently approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), and was the first oral anticoagulant approved by the FDA in more than 50 years for this indication. PRADAXA 150mg twice daily is the only medication among the new generation of OACs to demonstrate superior reduction of ischemic stroke compared to warfarin in patients with NVAF. Nearly nine out of 10 strokes caused by atrial fibrillation (AFib) are ischemic strokes. PRADAXA demonstrated a similar rate of major bleeding events compared to warfarin in patients with NVAF.

Prescribing experience with Pradaxa continues to grow with more than 6 million prescriptions for PRADAXA 150mg and 75mg filled for more than 800,000 NVAF patients in the U.S. since its approval in October of 2010. PRADAXA is included on formularies that insure about 95 percent of covered lives in the U.S., through commercial and Medicare Part D plans. PRADAXA is also included in recommendations from three leading U.S. cardiology guidelines for stroke prevention in AFib.

About Pradaxa^®  (dabigatran etexilate mesylate) Capsules

Indications and Usage
Pradaxa^® (dabigatran etexilate mesylate) capsules is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

IMPORTANT SAFETY INFORMATION ABOUT PRADAXA

WARNING: DISCONTINUING PRADAXA IN PATIENTS WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE. Discontinuing PRADAXA places patients at an increased risk of thrombotic events. If anticoagulation with PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.

CONTRAINDICATIONS
PRADAXA is contraindicated in patients with:
-     active pathological bleeding;
-     known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to
      PRADAXA;
-     mechanical prosthetic heart valve

WARNINGS & PRECAUTIONS

Increased Risk of Stroke with Discontinuation of PRADAXA
Discontinuing PRADAXA in absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.

Risk of Bleeding

• PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.
• Risk factors for bleeding include concomitant use of medications that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA’s anticoagulant activity and half-life are increased in patients with renal impairment.
• A specific reversal agent for dabigatran is not available. Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited. Activated prothrombin complex concentrates, recombinant Factor VIIa, or concentrates of factors II, IX or X may be considered but their use has not been evaluated. Protamine sulfate and vitamin K are not expected to affect dabigatran anticoagulant activity. Consider administration of platelet concentrates where thrombocytopenia is present or long-acting antiplatelet drugs have been used.

Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
The safety and efficacy of PRADAXA in patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than 3 months prior to enrollment) was evaluated in the phase 2 RE-ALIGN trial. RE-ALIGN was terminated early because of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) for PRADAXA vs warfarin. Therefore, the use of PRADAXA is contraindicated in patients with mechanical prosthetic valves.

Use of PRADAXA for the prophylaxis of thromboembolic events in patients with AFib in the setting of other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.

Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are major independent factors in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone.

• For patients with moderate renal impairment (CrCl 30-50 mL/min), consider reducing the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA.
• For patients with severe renal impairment (CrCl 15-30 mL/min), avoid concomitant use of PRADAXA and P-gp inhibitors.

ADVERSE REACTIONS
In the pivotal trial comparing PRADAXA to warfarin, the most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal (GI) events. PRADAXA 150 mg resulted in higher rates of major GI bleeds and any GI bleeds compared to warfarin. In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin. Patients on PRADAXA 150 mg had an increased incidence of GI adverse reactions. These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer). Drug hypersensitivity reactions were reported in <0.1% of patients receiving PRADAXA.

Other Measures Evaluated
In the pivotal trial, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

Click here for full Prescribing Information, including Boxed WARNING, and Medication Guide.

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About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim has a demonstrated commitment to corporate social responsibility. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.

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