DOD Study Supports Benefit-Risk Profile of Pradaxa for AFib

Boehringer Ingelheim's Pradaxa receives support from US Department of Defense study

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Ridgefield, CT, November 17, 2014 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced results from a U.S. Department of Defense cohort analysis of the Military Health System database showing that non-valvular atrial fibrillation (NVAF) patients treated with Pradaxa® (dabigatran etexilate mesylate) in routine clinical care experienced reduced rates of stroke, major bleeding, death and other types of bleeding, along with increased lower gastrointestinal (GI) bleeding, compared to patients treated with warfarin.

The data were presented in a poster at the American Heart Association’s Scientific Sessions 2014.

In this retrospective analysis, which evaluated the safety and effectiveness of PRADAXA versus warfarin in 25,586 NVAF patients, PRADAXA was associated with a 27 percent reduced risk of stroke, a primary outcome (hazard ratio [HR] 0.73, 95 percent confidence interval [CI] 0.55-0.97, event rate per 100 patient-years [ER] 0.92 vs. 1.32, respectively). The risk of major bleeding, the second primary outcome, was 13 percent less with PRADAXA (HR 0.87, CI 0.74-1.02, ER 3.08 vs. 3.70, respectively).

“Data like these are important because they demonstrate the favorable benefit-risk profile of PRADAXA in real-world settings,” said Lieutenant Colonel Todd C. Villines, MD, Walter Reed National Military Medical Center, Bethesda, Maryland, and lead investigator of the Department of Defense study. “These efficacy and safety results are consistent with what we’ve seen in the pivotal RE-LY® study, and support its findings in a very large, diverse and older patient population that is typical of the NVAF patients clinicians see every day.”

For secondary outcomes, the investigators determined the event rates per 100 patient-years for secondary outcomes with PRADAXA compared to warfarin (see Table below).1 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.

“Boehringer Ingelheim is committed to evaluating how PRADAXA performs in real-world settings, outside of controlled clinical trials,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “We are pleased that these latest findings reinforce the favorable risk-benefit profile of PRADAXA compared to warfarin in NVAF, and are consistent with results from the pivotal clinical trial RE-LY® and the increasing volume of long-term, real-world data, which includes recent analyses by FDA. It’s important for physicians to weigh efficacy in stroke risk reduction against the risk of major bleeding to determine the appropriate course of NVAF treatment for patients.”

Additional Study Details
In this retrospective cohort study, patients 18 to 89 years of age were included if their first prescription claim for either PRADAXA or warfarin was between October 1, 2010 and July 31, 2013, and if they were diagnosed with NVAF within the 12-month baseline period before their first treatment with one of the two oral anticoagulants (OACs). Patients were excluded if they had heart valve disorders or prosthetic heart valves, transient causes of NVAF, or any OAC use during the baseline period. 

From a total of 167,364 patients prescribed dabigatran or warfarin in the Military Health System database, investigators identified 12,793 patients each in the PRADAXA and warfarin groups who met the study criteria and were matched based on demographic and baseline clinical characteristics:

  • Average age 73.8 and 74 years
  • 58.8 percent and 58.9 percent male
  • At high risk for stroke, based on a score of (high risk, based on a common measure called CHA2DS2-VASc, which ranges from 0 [low risk] to 9 [highest risk])
  • Baseline mean HAS-BLED bleeding risk 3.4 and 3.6 (intermediate risk, scale 0 to 9)
  • Various conditions such as hypertension, coronary heart disease and heart failure
  • Use of other medications

The average follow-up was 297.2 vs. 215.5 days for the PRADAXA and warfarin groups, respectively.

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;
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



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
  • 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.

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 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.

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