Researchers Publish Largest Observational Study To-Date Comparing Novel Oral Anticoagulants (NOACs) Pradaxa^® (dabigatran etexilate mesylate) and Rivaroxaban

Ridgefield, Conn., October 6, 2016 –In a study of elderly Medicare patients with nonvalvular atrial fibrillation (NVAF), U.S. Food and Drug Administration (FDA) researchers found that, compared to Pradaxa^® (dabigatran etexilate mesylate), treatment with rivaroxaban was associated with statistically significant increases in intracranial hemorrhage (ICH) and major extracranial bleeding, including major gastrointestinal bleeding. The study also found that, compared to PRADAXA, rivaroxaban was associated with a statistically nonsignificant reduction in stroke and a statistically nonsignificant increase in mortality in patients being treated for NVAF. The results were published in JAMA Internal Medicine.

“A lot of research exists comparing warfarin and novel oral anticoagulants (NOACs), but this study provides important new information about the real-world use of NOACs, including PRADAXA,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “These findings add to the body of research demonstrating the positive risk-benefit profile of PRADAXA as a treatment option to reduce the risk of stroke in patients with NVAF.”

The data is based on an analysis of 118,891 patients older than 65 years enrolled in Medicare who started treatment with PRADAXA 150mg twice daily or rivaroxaban 20mg once daily from November 4, 2011, through June 30, 2014. A total of 52,240 PRADAXA patients and 66,651 rivaroxaban patients were included in the retrospective new-user cohort analysis. Differences in baseline characteristics were adjusted using stabilized inverse probability of treatment weights based on propensity scores. The data analysis was performed from May 7, 2015, through June 30, 2016. Primary outcomes in the study were thromboembolic stroke, ICH, major extracranial bleeding events, including major gastrointestinal bleeding, and mortality.

After adjustment, the incidence rate differences per 1,000 person years for rivaroxaban-treated patients compared to PRADAXA patients were:

• 2.3 excess cases of ICH (HR, 1.65; 95% CI, 1.20-2.26; P = .002)
• 13.0 excess cases of major extracranial bleeding (HR, 1.48; 95% CI, 1.32-1.67; P < .001), including major gastrointestinal bleeding (HR, 1.40; 95% CI, 1.23-1.59; P < .001)
• 1.8 fewer cases of thromboembolic stroke (HR, 0.81; 95% CI, 0.65-1.01; P = .07)
• 3.1 excess deaths (HR, 1.15; 95% CI, 1.00-1.32; P = .051)

In the study, the limitations included mean follow-up time of four months, which led to a smaller sample size at longer durations of use. The study was also restricted to patients aged 65 years and older. While this age group accounts for 80 percent of patients with NVAF, the comparative effects of treatment with PRADAXA and rivaroxaban could be different in younger populations. Because the study was observational, it may also be subject to residual confounding by unmeasured factors. The study examined first-time users of PRADAXA and rivaroxaban. Results could differ in patients switching from warfarin to a NOAC.

Approved in 2010, PRADAXA was the first oral anticoagulant approved by the U.S. Food and Drug Administration in more than 50 years to reduce the risk of stroke and systemic embolism in patients with NVAF. It is currently the only NOAC with a specific reversal agent available.

About Pradaxa^® (dabigatran etexilate mesylate)

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 and restart PRADAXA as soon as medically appropriate.
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 (idarucizumab) for dabigatran is available when reversal of the anticoagulant effect of dabigatran is needed:
  • For emergency surgery/urgent procedures
  • In life-threatening or uncontrolled bleeding
    Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited. Prothrombin complex concentrates or recombinant Factor VIIa 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), reduce 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)

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 full Prescribing Information, including boxed WARNING and Medication Guide.

About Boehringer Ingelheim
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation.

Boehringer Ingelheim is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, the company operates globally with 145 affiliates and more than 47,000 employees. Since its founding in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel treatments for human and veterinary medicine.

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Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the trademark Pradaxa^® under license.

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