Interim Data Reinforce Safety and Effectiveness of Pradaxa^® (dabigatran etexilate mesylate) versus Warfarin in Routine Care of Patients with Non-valvular Atrial Fibrillation

Ridgefield, CT, November 18, 2014 – Brigham and Women’s Hospital and Boehringer Ingelheim Pharmaceuticals, Inc. today announced interim findings from an analysis of two health insurance databases showing that in routine care, non-valvular atrial fibrillation (NVAF) patients treated with Pradaxa^® (dabigatran etexilate mesylate) had fewer strokes and fewer major bleeding events compared to patients treated with warfarin. The data were described in a poster presentation at the American Heart Association’s Scientific Sessions 2014.

The primary outcomes measured in the analysis were stroke and major hemorrhage. Data from 38,378 NVAF patients in two health insurance databases, MarketScan (31,058 patients) and UnitedHealth (7,320 patients), showed a 25 percent reduction in the rate of major hemorrhage with PRADAXA compared to warfarin (hazard ratio [HR] 0.75, 95 percent confidence interval [CI] 0.65-0.87, 354 vs. 395 events). The data also showed a 23 percent reduction in strokes in patients taking PRADAXA compared to warfarin in this pooled analysis of both databases (HR 0.77, CI 0.54-1.09, 62 vs. 69 events). The researchers concluded that, while the interim results are limited by small event numbers (e.g. stroke and systemic embolism), future analyses from this long-term study program will yield more stable estimates.

“Our interim data are encouraging with respect to the safety and effectiveness of PRADAXA in this real-world analysis since they are consistent with what was seen in the pivotal clinical trial, RE-LY^®,” said lead investigator John Seeger, PharmD, DrPH, Department of Medicine, Brigham and Women’s Hospital, a teaching-affiliate of Harvard Medical School. “We will continue to gather data through this long-term study program and look forward to sharing future follow-up analyses.”

In individual analyses of the two databases, major hemorrhages were reduced with PRADAXA in each database (MarketScan: HR 0.78, CI 0.67- 0.91; UnitedHealth: HR 0.56, CI 0.36-0.86). In the larger MarketScan database, the stroke rate reduction was 36 percent (HR 0.64, CI 0.44-0.95). In the smaller UnitedHealth database, stroke rates were not different with the two anticoagulants, as there were a low number of events which led to a wide confidence interval.

“These interim results in a large number of patients add to the growing body of evidence supporting the safety and effectiveness of PRADAXA as a treatment option to reduce stroke risk in NVAF patients,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “We are honored to partner with Brigham and Women's Hospital on this innovative long-term study program, which will continue to evaluate the safety and effectiveness of PRADAXA in routine clinical practice over time, with the study's patient population increasing.”

For secondary outcomes, the investigators determined the event rates per 100 patient-years* for PRADAXA compared to warfarin (see Table below).

Table: Event rates per 100 patient-years* for secondary outcomes 

Secondary Outcome	PRADAXA	Warfarin	HR, 95% CI
Stroke or systemic embolism	1.03	1.27	0.87, 0.64-1.19
Systemic embolism	0.27	0.2	1.51, 0.76-3.00
Ischemic stroke	0.69	0.81	0.92, 0.62-1.35
Hemorrhagic stroke	0.07	0.26	0.31, 0.12-0.82
Stroke uncertain classification	0	0	N/A
TIA	0.24	0.43	0.57, 0.32-1.03
MI	0.55	0.62	0.89, 0.57-1.38
VTE	0.84	1.3	0.73, 0.53-1.01
DVT	0.58	0.95	0.70, 0.48-1.03
Pulmonary embolism	0.36	0.48	0.84, 0.50-1.40
Major intracranial bleeding	0.21	0.74	0.31, 0.17-0.54
Major extracranial bleeding	4.21	5.5	0.81, 0.69-0.94
Major GI bleeding	2.65	2.85	0.97, 0.79-1.18
Major upper GI bleed	0.46	0.93	0.51, 0.34-0.77
Major lower GI bleed	2.54	2.64	1.00, 0.82-1.23
Major urogenital bleeding	0.01	0.02	0.91, 0.06-14.60
Other major bleed	2.42	3.71	0.69, 0.57-0.84

* Patient-years are calculated as the number of patients who experience an event divided by the total time of exposure across all patients in a study. They are used to determine event rates in a population when the length of time of treatment or exposure varies among patients in a study. An event rate of one per 100 patient-years means it would be expected to occur in one of 100 patients during one year, or one of 10 patients during 10 years. 

The analysis is part of an ongoing research program initiated, and announced, in 2013 to assess prescribing patterns and real-world safety and effectiveness of oral anticoagulants, including PRADAXA, for the reduction of stroke risk. The study program is expected to run through the end of 2016. Boehringer Ingelheim and Brigham and Women’s Hospital are aiming to gather data from more than 100,000 U.S. NVAF patients.

Additional Study Details
Patients who were new users of PRADAXA or warfarin were matched on various demographic and clinical criteria (“propensity score matched”). There were 19,189 propensity-score-matched NVAF patients each in the PRADAXA and warfarin groups when numbers are pooled across the two data sources. Patients were followed up until a switch or discontinuation of the anticoagulant, an outcome event, or disenrollment. The average follow-up was five months for patients in the PRADAXA group and four months for those taking warfarin. Assessments of effectiveness beyond the first six months of therapy are limited by the short average follow-up.

Current Experience with PRADAXA
PRADAXA is approved to reduce the risk of stroke and systemic embolism in patients with NVAF, for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for five to 10 days and to reduce the risk of recurrent DVT and PE in patients who have been previously treated. Nine million prescriptions for PRADAXA 150 mg and 75 mg have been filled for more than 935,000 NVAF patients in the United States since its approval in October of 2010.

PRADAXA 150 mg twice daily is the only oral anticoagulant to demonstrate superior reduction of ischemic stroke compared to warfarin in patients with NVAF. PRADAXA also demonstrated a similar rate of major bleeding events. Ischemic strokes are the most common type of stroke that NVAF patients experience.  

The efficacy and safety of PRADAXA in NVAF were established in the RE-LY^® trial, one of the largest stroke prevention clinical studies ever conducted with NVAF patients. The 18,113-patient RE-LY trial showed that, compared to well-controlled warfarin (N=6,022), PRADAXA 150 mg (N=6,076) significantly reduced the risk of stroke and systemic embolism by 35 percent (primary efficacy endpoint: 134 [2.2%] vs. 202 [3.4%] events, HR: 0.65, 95% CI [0.52, 0.81], P=0.0001), ischemic stroke by 25 percent (103 [1.7%] vs. 134 [2.2%] events, HR: 0.75, 95% CI [0.58, 0.97], P=0.0296) and hemorrhagic stroke by 74 percent (12 [0.2%] vs. 45 [0.8%] events, HR: 0.26, 95% CI [0.14, 0.49], P<0.0001). The rate of all-cause mortality was lower with PRADAXA 150 mg than with warfarin (3.6 percent per year versus 4.1 percent per year). PRADAXA had a higher rate of total gastrointestinal bleeds (6.1% vs. 4.0%) and major GI bleeds (1.6% vs. 1.1%; 50 percent increased risk with the 150 mg dose compared to warfarin). Treatment with PRADAXA 150 mg led to a 59 percent reduction in intracranial hemorrhage, compared to warfarin (38 vs. 90), and showed numerically lower rates of fatal and life-threatening bleeds (28 vs. 39 and 179 vs. 218, respectively).

Through the PradaxaLink^™ program, patients, caregivers and health care providers can access a variety of valuable resources and 24-hour support regarding PRADAXA medication.

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: (A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

(A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including PRADAXA, increases the risk of thrombotic events. If anticoagulation with PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant  
(B) SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas may occur in patients treated with PRADAXA who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

• use of indwelling epidural catheters
• concomitant use of other drugs that affect hemostasis, such as non-steroidal anti‑inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
• a history of traumatic or repeated epidural or spinal punctures
• a history of spinal deformity or spinal surgery
• optimal timing between the administration of PRADAXA and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.  Consider the benefits and risks before neuraxial intervention in patients who are or will be anticoagulated.

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 Thrombotic Events after Premature Discontinuation
Premature discontinuation of any oral anticoagulant, including PRADAXA, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events.  If PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, 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.
• Reversal of Anticoagulant Effect: 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 use of PRADAXA is contraindicated in patients with mechanical prosthetic valves due to a higher risk for thromboembolic events, especially in the post-operative period, and an excess of major bleeding for PRADAXA vs. warfarin. 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
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.
Reduction of Risk of Stroke/Systemic Embolism in NVAF

• 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
The most serious adverse reactions reported with PRADAXA were related to bleeding.

• Most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding & gastrointestinal (GI) events.
• PRADAXA 150 mg resulted in higher rates of major and any GI bleeds compared to warfarin.
• In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA vs 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 NVAF patients, a higher rate of clinical MI was reported in patients who received PRADAXA (0.7/100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

Please see accompanying full Prescribing Information, including boxed WARNING and Medication Guide.

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PRADAXA^® is a registered trademark of Boehringer Ingelheim Pharma GmbH and Co. KG and used under license.

RE-LY^® is a registered trademark of Boehringer Ingelheim International GmbH and used under license.

PradaxaLink^™ is a trademark of Boehringer Ingelheim Pharmaceuticals, Inc.

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