Uninterrupted Pradaxa^® (dabigatran etexilate mesylate) Showed Less Major Bleeding than Warfarin in Atrial Fibrillation Patients Undergoing Catheter Ablation

Ridgefield, CT, March 19, 2017 – Important new data from the RE-CIRCUIT^® study show a better safety profile for Pradaxa^® (dabigatran etexilate mesylate) compared to warfarin in atrial fibrillation (AFib) patients undergoing catheter ablation. AFib patients who underwent catheter ablation while being treated with uninterrupted PRADAXA experienced less major bleeding and fewer serious adverse events compared to those treated with uninterrupted warfarin. The results were presented in a late-breaking session at the American College of Cardiology 66^th Annual Scientific Session in Washington, D.C. and simultaneously published in the New England Journal of Medicine.

In the RE-CIRCUIT trial, uninterrupted PRADAXA significantly reduced the risk of major bleeding complications compared with uninterrupted warfarin. The trial showed a 5.3% absolute risk reduction in its primary endpoint, with major bleeds occurring in 5/317 of patients receiving PRADAXA versus 22/318 of patients receiving warfarin (77.2% relative risk reduction). PRADAXA showed a similar incidence of minor bleeding complications compared to warfarin (59/317 versus 54/318). There were no thromboembolic events in patients taking PRADAXA and one in patients taking warfarin. Six hundred and thirty-five patients with paroxysmal or persistent AFib undergoing catheter ablation were included in the RE-CIRCUIT trial. These patients were reflective of the types of patients undergoing the procedure in routine clinical practice, providing relevant new data to treating physicians.

“These results are exciting news for the medical community,” said Professor Hugh Calkins, Chairman of the RE-CIRCUIT Study Steering Committee and Professor of Cardiology and Director of the Electrophysiology Laboratory and Arrhythmia Service, Johns Hopkins Hospital, Baltimore, USA. “During an ablation procedure, patients are at risk of potential major complications, including stroke and bleeding. Therefore anticoagulation management at the time of AFib ablation is critically important. In RE-CIRCUIT, we have seen that uninterrupted anticoagulation with dabigatran showed significantly lower major bleeding complications than warfarin in atrial fibrillation patients undergoing cardiac ablation.”

Every year more than 200,000 ablation procedures are conducted globally in patients with AFib, the most common heart rhythm irregularity. Ablation is a common treatment for the irregular heart beat experienced by AFib patients. The procedure involves passing a catheter through a vein or artery in the groin or arm into the heart and then using radiofrequency energy, extreme heat or extreme cold energy to destroy or isolate the area that is generating the abnormal heart rhythm. Catheter ablation is associated with a risk of both thromboembolism and bleeding. Anticoagulation before, during, and after ablation needs to be carefully managed to minimize these risks. RE-CIRCUIT has now provided specific data on this clinical situation for PRADAXA, a non-vitamin K antagonist oral anticoagulant (NOAC).

“The RE-CIRCUIT trial is evidence of Boehringer Ingelheim’s commitment to conducting research that can improve our understanding of treatment for atrial fibrillation patients,” said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “We are excited to present these results, which we believe will provide valuable insights for physicians treating atrial fibrillation patients undergoing catheter ablation.”

About the RE-CIRCUIT^® study

The RE-CIRCUIT study (Randomised Evaluation of dabigatran etexilate Compared to warfarIn in pulmonaRy vein ablation: assessment of different peri-proCedUral antIcoagulation sTrategies) is an exploratory prospective, randomized, open-label, blinded endpoint, multicenter, active controlled trial. Patients with paroxysmal or persistent NVAF scheduled for catheter ablation and eligible for dabigatran 150 mg twice daily were included in the trial. Patients were randomly assigned to dabigatran etexilate mesylate 150 mg twice daily or warfarin (target INR 2.0–3.0) in a 1:1 ratio and remained on this treatment for the duration of the trial.

The study enrolled 704 patients across 104 sites, with 635 patients undergoing ablation with uninterrupted anticoagulation treatment. All patients were screened with a transesophageal echocardiogram before their ablation procedure to determine whether any blood clots were present in the upper left heart chamber (left atrium). The safety and efficacy of the therapies were assessed during the three to four month treatment period and follow-up visit one week after treatment end.

The primary endpoint of the RE-CIRCUIT study was the incidence of major bleeding events, as defined by the International Society on Thrombosis and Hemostasis (ISTH), during the ablation procedure and up to two months post-ablation. Secondary endpoints included thromboembolic events (stroke/systemic embolism/transient ischemic attack), minor bleeding events or a composite of both the efficacy and safety endpoints during ablation and up to two months after the procedure.

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 146 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 trademarks Pradaxa^® and RE-CIRCUIT^® under license.

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