Value through InnovationOctober 26 2016
May 14, 2014

As the Benefits and Safety of Pradaxa® (dabigatran etexilate mesylate) are Once Again Confirmed, Boehringer Ingelheim Continues to Look for New Ways for Pradaxa to Help More Patients

  • Most patients with non-valvular atrial fibrillation (NVAF) at risk of stroke need to take an anti-coagulant. NVAF patients face a five-fold increased risk of having a stroke.

  • PRADAXA 150 mg is the only novel oral anticoagulant which in its pivotal study vs. warfarin (RE-LY®) showed a superior reduction of ischemic strokes (the most common stroke for NVAF patients). The most serious adverse reactions reported with PRADAXA were related to bleeding.

  • Time and again, the benefits and safety of PRADAXA have been confirmed. A recent targeted review of data from the RE-LY trial has re-confirmed the study’s findings on stroke, major bleeds, life-threatening bleeds, and fatal bleeds.

  • Boehringer Ingelheim continues to invest in research to learn how PRADAXA can help more patients.

The Benefits and Safety of Pradaxa® Have Been Confirmed

  • More than 100 regulatory agencies around the world approved PRADAXA for reducing the risk of stroke and systemic embolism in NVAF based on the RE-LY “mega-trial” – a clinical study involving more than 18,000 patients in over 40 countries.

  • Boehringer Ingelheim scientists, external researchers, and regulators have analyzed RE-LY® and patients’ experience with PRADAXA.  RE-LY’s conclusions remain unchanged.

  • The FDA has publicly stated that PRADAXA 150 mg twice daily offers a positive benefit-risk profile and provides an important health benefit when used as directed to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF).

  • On May 13, 2014 the FDA once again reaffirmed the positive benefit-risk profile of PRADAXA when used as directed when it issued a Drug Safety Communication that included results from a Medicare study of more than 134,000 patients 65 years of age or older comparing PRADAXA to warfarin. The new study found that, among new users of blood-thinning drugs, Pradaxa was associated with a lower risk of clot-related strokes, bleeding in the brain, and death.  The study also found an increased risk of major gastrointestinal bleeding with Pradaxa and a similar risk of MI compared to warfarin.  
  • In November 2013, at the American Heart Association Scientific Sessions, Boehringer Ingelheim announced the then recent results from a long-term, combined analysis of the pivotal RE-LY trial and its extension safety study RELY-ABLE®.  There were no new safety findings identified in a long-term extension trial over 2 additional years. Rates of total bleeding, life threatening bleeding and major bleeding were similar to those seen during the RE-LY trial. There was no adjudication of outcome events occurring in RELY-ABLE.

  • In April 2014, the U.S. FDA approved PRADAXA for additional indications: 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.  

Boehringer Ingelheim Recently Confirmed RE-LY’s Conclusions Again

  • During the US litigation involving Pradaxa®, BI learned that there might be previously uncategorized major bleeding events in the RE-LY trial. There was one case of a patient who suffered a ruptured spleen due to a car accident, resulting in trauma, bleeding and ultimately death.  The death was properly reported and included in the RE-LY findings, but was not counted as a major bleed.  Boehringer Ingelheim conducted its own, targeted review of RE-LY. We sought to determine whether there might have been other similar situations and how any such cases were distributed across treatment groups, including warfarin, during the RE-LY trial. 

  • The cases identified in the new review frequently reflected complicated medical circumstances where the patient had multiple health issues and experienced multiple clinical events. Most of the cases involved a patient who died, and, importantly, all of those deaths were already properly reported in the RE-LY study. What resulted from the targeted review is that additional events (namely bleeding and stroke) have now been captured. What makes a study such as RE-LY sufficiently robust is that the study was properly designed to minimize bias and systematic error, and had a sufficient number of participants such that any instances of human error would not affect the study’s outcome.  That is exactly how RE-LY was conducted. 

  • Indeed, one of the strengths of RE-LY being such a sizeable trial, with multiple treatment arms, is that since the participant numbers are so large, the overall study results regarding bleeding would have changed only if there were a large number of additional unidentified major bleeds in the groups of patients that took PRADAXA and not in the group that took warfarin.  

  • Boehringer Ingelheim conducted the targeted review and then provided documentation to the Population Health Research Institute (PHRI), a research institution in Hamilton, Ontario that served as the central coordinating center for RE-LY.  PHRI then had two external experts review the documents. The external experts independently evaluated and categorized case events and determined whether the cases presented events in RE-LY that had not yet been counted as bleeds or strokes.

  • The external experts reported back to Boehringer Ingelheim and, while there are additional events that RE-LY needs to account for, RE-LY’s conclusions remain unchanged.  The additional events were nearly evenly distributed across treatment groups, including warfarin, and confirmed the study’s findings on major bleeds, life-threatening bleeds, fatal bleeds, or stroke.

Boehringer Ingelheim Continues to Invest in Researching Pradaxa

  • On August 15, 2013, Boehringer Ingelheim announced a multi-year agreement with Brigham and Women’s Hospital, an internationally recognized teaching affiliate of Harvard Medical School to conduct a long-term study program to assess comparative effectiveness and safety, as well as prescribing patterns, of oral anticoagulants, including PRADAXA for the reduction of stroke risk in U.S. patients with non-valvular atrial fibrillation.

  • On September 3, 2013, Boehringer Ingelheim announced plans for two future studies of PRADAXA in new cardiovascular patient populations, as well as further plans to gather real-world evidence in NVAF patients. These plans are the cornerstone of an initiative to expand the scientific knowledge of stroke prevention and interventional cardiology with PRADAXA.

  • In November 2013 Boehringer Ingelheim presented results from a Phase I trial for an antidote for PRADAXA.  The results showed that a compound the company developed specifically for PRADAXA immediately, completely and sustainably reversed the anticoagulation effect of PRADAXA in healthy male volunteers. Boehringer Ingelheim has initiated the next phase of studies in patients.

  • On March 11, 2014, Boehringer Ingelheim announced the enrollment of the 10,000th patient in to its AF registry program GLORIA™-AF, the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation, one of the largest AF registry programs currently running worldwide. The GLORIA-AF Registry Program is expected to be one of the largest worldwide registries and is actively recruiting patients with the aim of including up to 56,000 patients across 2,200 sites in 35 countries.

  • Boehringer Ingelheim also has a research agreement with the health insurer Humana to conduct real-world clinical analyses. Further, we are working with several other entities to conduct health economic research, including HealthCore, the health outcomes subsidiary of Wellpoint, and the healthcare research consultancy Trinity Partners to assess data from the Department of Defense.

About Pradaxa

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;
  • for the treatment of deep venous thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days;
  • to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in patients who have been previously treated

Important Safety Information ABOUT PRADAXA


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 
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
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. 

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

Increased Risk of Stroke with Discontinuation of PRADAXA
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.

Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulants are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. To reduce potential risk of bleeding with concurrent use of dabigatran and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dabigatran. Placement/removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low but exact timing to reach a sufficiently low anticoagulant effect in each patient is unknown. If anticoagulation is administered with epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently for signs/symptoms of neurological impairment, i.e., midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs/symptoms. If spinal hematoma is suspected, initiate urgent diagnosis and treatment; consider spinal cord decompression even though it may not prevent or reverse neurological sequelae.

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
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.

Treatment and Reduction in the Risk of Recurrence of DVT/PE

  • For patients with CrCl <50 mL/min, avoid use of PRADAXA and concomitant P-gp inhibitors

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).


  • Rates of any GI bleeds were higher in patients receiving PRADAXA 150 mg vs warfarin and placebo
  • In the active-controlled studies, there was a higher rate of clinical myocardial infarction (MI) in PRADAXA patients [20 (0.66/100) patient-years)] vs warfarin [5 (0.17/100 patient-years)].  In the placebo-controlled study, there was similar rate of non-fatal and fatal clinical MI in PRADAXA patients [1 (0.32/100 patient-years)] vs placebo [1 (0.34/100 patient-years)].
  • GI adverse reactions were similar in patients receiving PRADAXA 150 mg vs warfarin.  They were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis and gastric hemorrhage).

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 full Prescribing Information including Boxed WARNING, and Medication Guide.

About the Boehringer Ingelheim Cares Foundation Patient Assistance Programs
For more than 125 years, Boehringer Ingelheim has been focused on improving the lives of patients. In keeping with the company commitment to do the most good for the most people, Boehringer Ingelheim works hard to ensure its medicines are accessible to everyone who needs them, including senior citizens and families on limited incomes. The Boehringer Ingelheim Cares Foundation Patient Assistance Programs (BI-PAP) make Boehringer Ingelheim medicines available free of charge to patients who are without pharmaceutical insurance coverage, and who meet certain household income levels.

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.

In 2012, Boehringer Ingelheim achieved net sales of about $19.1 billion (14.7 billion euro). R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.

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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 service mark of Boehringer Ingelheim International GmbH and used under license.


Media Contact

  • Mary Lewis

    Public Relations
    Boehringer Ingelheim
    Pharmaceuticals, Inc.