RE-LY Sub-Analysis Suggests Pradaxa® (dabigatran etexilate mesylate) Associated with Similar Bleeding Rates and Thromboembolic Complications in Surgery Versus Warfarin

Ridgefield, CT, June 18, 2012– A new retrospective sub-analysis of the RE-LY® trial suggested similar rates of peri-procedural bleeding and thromboembolic complications, such as a stroke or systemic embolism, in non-valvular atrial fibrillation (NVAF) patients undergoing a surgical or invasive procedure treated with Pradaxa® (dabigatran etexilate mesylate) capsules 150mg taken twice daily compared to warfarin. The peri-procedural period was defined in this sub-analysis as seven days prior to a procedure until 30 days afterwards. Results were published online first in Circulation: Journal of the American Heart Association.

For patients with atrial fibrillation (AFib) being treated with an oral anticoagulant (OAC), it is often necessary to stop treatment before a surgical or invasive procedure to reduce the risk of bleeding. However, stopping treatment for even a short period of time can increase a patient’s risk of thromboembolic complications. Therefore, physicians prescribing OACs are faced with a challenge as they must limit a patient's time off treatment while managing the risk of bleeding during surgery.

In the sub-analysis, there were similar rates of bleeding between treatment groups in those undergoing urgent surgery, despite the fact that a specific reversal agent for PRADAXA is not available. Warfarin-treated patients could have received reversal therapy, such as vitamin K or fresh-frozen plasma.

“Interrupting anticoagulation for any reason increases the risk of stroke and embolism in patients with non-valvular atrial fibrillation, and a patient’s length of time off treatment should be minimized,” said John Smith, M.D., Ph.D., senior vice president for clinical development and medical affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “In this sub-analysis, nearly half of patients receiving PRADAXA 150mg underwent surgery within two days of interrupting treatment, compared to 11 percent of patients on warfarin.”

Over a two-year period, a total of 4,591 out of 18,113 patients in the RE-LY trial had OAC therapy interrupted at least once to have surgery or an invasive procedure with similar distribution across treatment arms. The sub-analysis suggests similar rates of peri-procedural major bleeding (the primary bleeding outcome) between patients receiving PRADAXA 150mg versus warfarin (5.1% vs. 4.6%, respectively; RR=1.09, 95% CI: 0.80-1.49). Additionally, patients treated with PRADAXA 150mg who discontinued treatment within 24 to 48 hours prior to surgery showed nearly three times lower rates of major bleeding compared to warfarin (3.3% vs. 9.0%; RR=0.36, 95% CI: 0.16-0.82).

“Since physicians are accustomed to having a reversal agent for warfarin and the RE-LY trial was conducted without one for PRADAXA, we felt it was important to review and evaluate the data in patients requiring surgery, particularly urgent surgeries,” said Paul A. Reilly, Ph.D., clinical program director, Boehringer Ingelheim Pharmaceuticals, Inc. and an author of the sub-analysis. “These findings suggest that in patients requiring invasive procedures, including urgent surgery, the risk of bleeding and thromboembolic complications are similar between PRADAXA and warfarin.”

Additional findings of the sub-analysis include:

  • Rates of thromboembolic events were low and similar between PRADAXA 150mg and warfarin; these included stroke (0.5% vs. 0.6%, respectively; RR=0.71, 95% CI: 0.27-1.85), cardiovascular death (0.5% vs. 0.5%; RR=1.01, 95% CI: 0.35-2.96), systemic embolism (0.1% vs. 0.1%; RR=1.01, 95% CI: 0.06-16.1), myocardial infarction (0.5% vs. 0.3%; RR=1.61, 95% CI: 0.53-4.92) or pulmonary embolism (0.1% vs. 0.2%; RR=0.67, 95% CI: 0.11-4.02). The composite rate of thromboembolic events for PRADAXA 150mg vs. warfarin was 1.5 percent and 1.2 percent, respectively; RR=1.29, 95% CI: 0.70-2.38.
  • The results for other bleeding outcomes in patients who interrupted anticoagulation due to surgery for PRADAXA 150mg vs. warfarin included: minor (9.0% vs. 7.8%, respectively; RR=1.15, 95% CI: 0.91-1.45), fatal (0.1% vs. 0.1%; RR=1.01, 95% CI: 0.14-7.15), bleeding requiring re-operation (1.4% vs. 1.0%, RR=1.39, 95% CI: 0.73-2.63) and bleeding requiring transfusion of red blood cells (3.5% vs. 4.0%, RR=0.86, 95% CI: 0.60-1.23).
  • The rates of major bleeding in other patient subgroups also were consistent with the primary outcome of major bleeding for PRADAXA 150mg vs. warfarin, including urgent surgery (17.7% vs. 21.6%; RR=0.82, 95% CI: 0.50-1.35); elective surgery (3.8% vs. 3.3%; RR=1.14, 95% CI: 0.77-1.67); major surgery (6.5% vs. 7.8%; RR=0.82, 95% CI: 0.53-1.29) and minor surgery (3.2% vs. 1.8%; RR=1.75, 95% CI: 0.74-4.14).
  • The rates of major bleeding by timing of treatment discontinuation prior to surgery for PRADAXA 150mg vs. warfarin included: less than 24 hours (6.8% vs. 15.4%; RR=0.44, 95% CI: 0.21-0.92), 24 to 48 hours (3.3% vs. 9.0%; RR=0.36, 95% CI: 0.16-0.82), 48 to 72 hours (4.5% vs. 5.7%; RR=0.79, 95% CI: 0.33-1.91), more than 72 hours (6.2% vs. 3.6%; RR=1.70, 95% CI: 1.08-2.68).
  • The most common surgeries and procedures were: pacemaker or defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy (8.6%) and joint replacement (6.2%).

In the pivotal RE-LY® trial, PRADAXA 150mg twice daily was superior in reducing ischemic and hemorrhagic stroke compared to warfarin in patients with NVAF. The risk of major bleeds was similar with PRADAXA 150mg and warfarin across major subgroups with the exception of age, where there was a trend towards a higher incidence of major bleeding with PRADAXA for patients ≥75 years of age. There were higher rates of major gastrointestinal (GI) bleeding and total GI bleeding with PRADAXA 150mg than warfarin. The incidence of intracranial bleeding, or bleeding inside the skull, was 59 percent lower with PRADAXA 150mg than warfarin in this patient population.

The U.S. Prescribing Information recommends, if possible, to discontinue PRADAXA one to two days (CrCl ≥50 mL/min) or three to five days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleeding. Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required.

About RE-LY®
RE-LY was a global, Phase III, randomized trial of 18,113 patients enrolled in 951 centers in 44 countries, investigating whether dabigatran etexilate (two blinded doses) was as effective as well-controlled warfarin – INR 2.0 - 3.0 – (open label) for stroke prevention. Patients with non-valvular AFib and at least one other risk factor for stroke (i.e., previous ischemic 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) were enrolled in the study for two years with a minimum follow-up period of one year.

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

The primary endpoint of the trial was incidence of stroke (including ischemic and hemorrhagic) and systemic embolism. The primary safety endpoint was major bleeding, defined as a reduction in the hemoglobin level of at least 2.0 g/dL, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. Other 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.

In the RE-LY trial, all clinical outcomes were adjudicated in a blinded manner to assess outcomes for each treatment.

Although studied in the RE-LY trial, dabigatran 110mg is not approved by the U.S. FDA. PRADAXA® is a registered trademark of Boehringer Ingelheim Pharma GmbH and Co. KG and used under license.

About Pradaxa® (dabigatran etexilate mesylate) 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 & PRECAUTIONS
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, such as a drop in hemoglobin and/or hematocrit or hypotension. Discontinue PRADAXA in patients with active pathological bleeding.
  • Risk factors for bleeding include 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.
  • A specific reversal agent for dabigatran is not available. Dabigatran can be dialyzed (removal of about 60% of drug over 2-3 hours) but data supporting this 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.

Temporary Discontinuation of PRADAXA
Discontinuing PRADAXA for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Minimize lapses in therapy.

Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure
The 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.

  • 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
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
In the pivotal trial, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

RE-LY is a registered service mark of Boehringer Ingelheim International GmbH and used under license.

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

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