New Subanalyses of the RE-LY Trial Showed Pradaxa Reduced Stroke Risk in Patients with Varying CHA₂DS₂-VASc Scores and Types of Non-Valvular Atrial Fibrillation

Ridgefield, CT, April 4, 2011 – Two new retrospective subanalyses of the RE-LY^® trial, involving Pradaxa^® (dabigatran etexilate mesylate) capsules, suggested that the reduction in stroke risk achieved with PRADAXA 150mg over warfarin¹ occurred irrespective of CHA₂DS₂-VASc risk score² and the type of non-valvular atrial fibrillation (NVAF) (permanent, persistent and paroxysmal).³ The results were presented at the American College of Cardiology’s 60th Annual Scientific Session.^2,3 

The first subanalysis assessed the impact of the novel CHA₂DS₂-VASc risk score,² which determines stroke risk based on age, sex and the presence of comorbidities,⁴ on outcomes in the RE-LY trial. Patients were grouped into quartiles based on CHA₂DS₂-VASc score (0-2, 3, 4, 5-9)² and results showed that PRADAXA 150mg was associated with reductions in stroke risk compared to warfarin for all four quartiles (0-2, RR = 0.63; 3, RR = 0.61; 4, RR = 0.53; 5-9, RR = 0.77; interaction p-value = 0.60).² Results of the analysis showed there was a significant interaction between CHA₂DS₂-VASc score and rates of major bleeding, with lower rates for PRADAXA 150mg compared to warfarin for patients in the first three quartiles, but an increased rate of major bleeding for the quartile at greatest risk (0-2, RR = 0.75; 3, RR = 0.74; 4, RR = 0.83; 5-9, RR = 1.33; interaction p-value = 0.003).²

"This analysis suggests that PRADAXA 150mg taken twice daily may reduce the risk of stroke compared to warfarin across the levels of NVAF-associated stroke risk, as determined by the CHA₂DS₂-VASc score," said Paul Reilly, PhD, clinical program director, Boehringer Ingelheim Pharmaceuticals, Inc. "These findings are important because the risk of stroke in patients with NVAF increases significantly with the presence of comorbidities, such as diabetes or hypertension."

PRADAXA was also evaluated in a second RE-LY subanalysis, which assessed efficacy and safety among the 18,107 patients for whom information was available about the type of NVAF³ they had - permanent (long-standing),⁵ paroxysmal (arrhythmia terminating spontaneously)⁵ or persistent (lasting beyond seven days).⁵ Findings showed that PRADAXA 150mg reduced the risk of stroke and systemic embolism compared to warfarin across all three subgroups (permanent, HR = 0.7; paroxysmal, HR = 0.61; persistent, HR = 0.64; interaction p-value = 0.88).^3,6 The analysis also showed the following rates of major bleeding: permanent: PRADAXA 150mg: 3.07%/yr, warfarin: 2.96%/yr; paroxysmal: PRADAXA 150mg: 3.74%/yr, warfarin: 3.91%/yr; persistent: PRADAXA 150mg: 3.14%/yr, warfarin: 3.88%/yr (interaction p-value = 0.34).^3,6

"Stroke risk is similar regardless of the type of non-valvular atrial fibrillation," said Greg Flaker, M.D., chair of cardiovascular research, University of Missouri. "These data showed PRADAXA 150mg twice daily was associated with lower rates of stroke than warfarin in patients with all three types of non-valvular atrial fibrillation."

PRADAXA was approved by the U.S. Food and Drug Administration in October 2010 to reduce the risk of stroke and systemic embolism in patients with NVAF.¹ PRADAXA 150mg is the only approved oral anticoagulant that has been shown to significantly reduce the risk of stroke compared to warfarin.¹ Effects of Pradaxa were more apparent in patients with lower levels of INR control.¹ 

Dabigatran was recently recommended in an update to AFib treatment guidelines.

Results from the CHA₂DS₂-VASc Subanalysis 
In the subanalysis, patients were grouped into quartiles based on CHA₂DS₂-VASc score (0-2, n = 4,042; 3, n = 5,365; 4, n = 4,374; 5-9, n = 4,327).² The results of the subanalysis showed that PRADAXA 150mg was associated with reductions in stroke risk compared to warfarin for all four quartiles (0-2: PRADAXA 150 mg: 0.5%/yr, warfarin: 0.8%/yr; 3: PRADAXA 150mg: 0.8%/yr, warfarin: 1.4%/yr; 4: PRADAXA 150mg: 1.0%/yr, warfarin: 2.0%/yr; 5-9: PRADAXA 150mg: 2.1%/yr, warfarin: 2.8%/yr; interaction p-value = 0.60).²

Results of the analysis showed there was a significant interaction between CHA₂DS₂-VASc score and rates of major bleeding, with lower rates for PRADAXA 150mg compared to warfarin for patients in the first three quartiles, but an increased rate of major bleeding for the quartile at greatest risk (0-2: PRADAXA 150mg: 1.8%/yr, warfarin: 2.4%/yr; 3: PRADAXA 150mg: 2.6%/yr, warfarin: 3.5%/yr; 4: PRADAXA 150mg: 3.2%/yr, warfarin: 3.9%/yr; 5-9: PRADAXA 150mg: 5.8%/yr, warfarin: 4.4%/yr; interaction p-value =0.003).²

Results from the Different Types of NVAF Subanalysis
In the subanalysis, patients were classified by type of NVAF - 6,375 had permanent NVAF,³ 5,943 had paroxysmal NVAF³ and 5,789 had persistent NVAF.³ Results showed that PRADAXA 150mg reduced the risk of stroke and systemic embolism compared to warfarin across all three subgroups (permanent: PRADAXA 150mg: 1.11%/yr, warfarin: 1.58%/yr; paroxysmal: PRADAXA 150mg: 1.09%/yr, warfarin: 1.77%/yr; persistent: PRADAXA 150mg: 1.14%/yr, warfarin: 1.80%/yr; interaction p-value = 0.88).^3,6 

About CHA₂DS₂-VASc
The CHA₂DS₂-VASc risk stratification scheme was developed by investigators at the University of Birmingham Centre for Cardiovascular Sciences in 2009,⁴ and was included in the 2010 European Society of Cardiology Guidelines for the Management of Atrial Fibrillation.⁷ The risk stratification scheme assigns one point for congestive heart failure/left ventrical dysfunction, hypertension, diabetes, vascular disease, age 65-74 and female sex, and assigns two points for age > 75 and previous stroke/TIA.⁴ Patients with a CHA₂DS₂-VASc score of zero are considered to be at low risk of stroke, patients with a score of one are considered to be at moderate risk of stroke and patients with a score of two or higher are considered to be at high risk of stroke.⁴

About RE-LY^®
RE-LY^® was a prospective, multicenter, randomized, parallel-group trial of 18,113 patients¹ enrolled in 951 centers in 44 countries.⁸ RE-LY^® investigated whether PRADAXA (two blinded doses) was non-inferior in reducing the occurrence of the composite endpoint of stroke (ischemic and hemorrhagic) and systemic embolism, compared to open-label warfarin adjusted locally to an international normalized ratio (INR) of 2.0 to 3.0,¹ with the INR measured at least monthly.⁹ Patients with NVAF and at least one other risk factor for stroke (i.e., previous stroke, transient ischemic attack, or systemic embolism, left ventricular dysfunction, age > 75 years, age > 65 years with either diabetes mellitus, history of coronary artery disease, or hypertension)¹ were enrolled in the study with a median follow-up period of two years.⁸ RE-LY^® enrolled a comparable number of patients in each stroke risk group,¹⁰ providing a broad representation of patients with NVAF.

The RE-LY^® trial utilized the established PROBE (prospective, randomized, open-label, blinded endpoint evaluation) clinical trial protocol,⁹ which has been used in the previous trials of anticoagulation for stroke prevention in patients with atrial fibrillation.⁹ A PROBE design may reflect the differences in the management of warfarin and PRADAXA in clinical practice.⁹

The primary efficacy outcome of the trial was stroke (ischemic and hemorrhagic) or systemic embolism.⁹  Safety endpoints included bleeding events (major and minor), intracerebral hemorrhage, other intracranial hemorrhage, elevations in liver transaminases, bilirubin and hepatic dysfunction and other adverse events.⁹

In the RE-LY^® trial, all clinical outcomes were adjudicated in a blinded manner to minimize bias in assessment of outcomes for each treatment.⁹

About Atrial Fibrillation and Stroke 
Atrial fibrillation, characterized by an irregular heartbeat,¹¹ can cause blood clots to form in the heart that can travel to the brain and cause a stroke.¹¹ An estimated 2.3 million Americans are living with atrial fibrillation,¹² and the prevalence is expected to increase to 5.6 million by 2050.¹²  Non-valvular atrial fibrillation, which accounts for 95 percent of diagnosed cases of atrial fibrillation,¹² refers to cases of atrial fibrillation without rheumatic mitral valve disease, prosthetic heart valve or valve repair, according to the 2006 ACC/AHA/ESC guidelines.⁵ Atrial fibrillation increases the risk of stroke nearly five times⁵ and is associated with up to 15 percent of all strokes in the U.S.5 Atrial fibrillation imposes a substantial economic burden to the healthcare system,¹³ specifically the high costs associated with stroke.¹⁴

About the Storage and Handling of PRADAXA
PRADAXA must be stored in its original packaging¹ and patients should not transfer the capsules to pill boxes or pill organizers.¹⁵ Once the bottle is opened, the product must be used within 30 days.¹ Patients must close the bottle tightly immediately after removing one capsule¹ and must not alter the child-proof cap.¹⁵ It is recommended that patients date the bottle to expire 30 days after first opening. When more than one bottle is dispensed, patients should only open one bottle at a time.¹⁵ When packaged in a blister package, each capsule should only be removed at time of use.¹

About Pradaxa^® (dabigatran etexilate) Capsules

Indications and Usage
PRADAXA is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

IMPORTANT SAFETY INFORMATION ABOUT PRADAXA

CONTRAINDICATIONS
PRADAXA is contraindicated in patients with active pathological bleeding and patients with a known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA.

WARNINGS AND PRECAUTIONS
Risk of Bleeding
PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding.

Risk factors for bleeding include:

• Medications that increase the risk of bleeding in general (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs).
• Labor and delivery

Promptly evaluate any signs or symptoms of blood loss, such as a drop in hemoglobin and/or hematocrit or hypotension. Discontinue PRADAXA in patients with active pathological bleeding.

Temporary Discontinuation of PRADAXA
Discontinuing PRADAXA for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke.  Lapses in therapy should be avoided, and if PRADAXA must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.

Effect of P-gp Inducers and Inhibitors on PRADAXA Exposure
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces dabigatran exposure and should generally be avoided. P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin, do not require dose adjustments. These results should not be extrapolated to other 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 a higher rate 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

The risk of myocardial infarction was numerically greater in patients who received PRADAXA 150 mg than in those who received warfarin.  

For full PRADAXA prescribing information and medication guide, please visit www.pradaxa.com or contact Boehringer Ingelheim's Drug Information Unit at 1-800-542-6257.

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 142 affiliates in 50 countries and more than 41,500 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2009, Boehringer Ingelheim posted net sales of U.S. $17.7 billion (12.7 billion euro) while spending 21% of net sales in its largest business segment, Prescription Medicines, on research and development.

For more information, please visit http://us.boehringer-ingelheim.com and follow us on Twitter at http://twitter.com/boehringerus.