Boehringer Ingelheim Initiates
RE-CIRCUIT™ Trial, Evaluating Pradaxa® (dabigatran etexilate mesylate) in NVAF Patients Undergoing Ablation

Ridgefield, CT, June 20,2014 – Boehringer Ingelheim announced today the initiation of a new international study of Pradaxa® (dabigatran etexilate mesylate). The RE-CIRCUIT™ trial (Randomized Evaluation of dabigatran etexilate Compared to warfarIn in pulmonaRy vein ablation: assessment of different peri-proCedUral antIcoagulation sTrategies) will evaluate uninterrupted treatment with PRADAXA, compared to warfarin, in patients with paroxysmal or persistent non-valvular atrial fibrillation (NVAF) who are scheduled to undergo a first ablation procedure.

The primary endpoint is the frequency of major bleeding, as defined by the International Society of Haematology (ISTH), at 90 days after the ablation procedure. Secondary endpoints include:

  • The frequency of stroke or systemic embolism in the first 30 days and then at 90 days after the procedure
  • ISTH major bleeding 30 days after the procedure
  • The net clinical benefit (combined frequency of ISTH major bleeding events and thromboembolic events) at day 30 and day 90 after the procedure
  • Vascular access complications
  • Hemorrhagic pericardial effusion (bleeding between the membrane which surrounds the heart and the heart itself)
  • Pericardial tamponade (fluid accumulation resulting from pericardial effusion which compresses the heart and impairs its ability to function)
  • All cause mortality

Ablation is a procedure which is performed to help correct heart rhythm problems. An estimated 50,000 AFib ablations were performed in the U.S. in 2013. For most AFib patients, taking an anticoagulant is essential because their irregular heart beat increases their risk of an ischemic, or clot-based, stroke by up to five times. Reducing the risk of blood clots during ablation is extremely important, because the procedure itself can temporarily increase the risk of blood clots in patients.

“Currently there are no international guidelines regarding the specific use of novel oral anticoagulants (NOACs) during ablation procedures, despite their wide use in patients with NVAF,” said Dr. 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, Maryland. “This study will provide valuable insights regarding the practical management of NVAF patients requiring anticoagulation during these procedures.”

In RE-CIRCUIT, treatment will be equally and randomly split between 610 NVAF patients from 80 international sites who will receive either PRADAXA 150 mg twice daily or warfarin at an International Normalized Ratio (INR) of 2.0 to 3.0. Patients will be followed for 90 days following their procedure. Results of the study are expected in 2016.

RE-CIRCUIT is part of Boehringer Ingelheim’s extensive clinical trial program, RE-VOLUTION™. With the recently announced RE-DUAL PCI™ and RE-SPECT ESUS™ studies, the entire program will include 15 clinical trials involving over 55,000 patients in more than 44 countries globally once these new trials are completed.

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. Eight million prescriptions for PRADAXA 150 mg and 75 mg have been filled for more than 850,000 NVAF patients in the U.S. 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 healthcare 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

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 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

ADVERSE REACTIONS
The most serious adverse reactions reported with PRADAXA were related to bleeding.

NVAF

  • 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).

DVT/PE

  • 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.

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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 142 affiliates and more than 47,400 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.

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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 trademark of Boehringer Ingelheim International GmbH and used under license.

RE-CIRCUIT™, RE-DUAL PCI™, RE-SPECT ESUS™ AND RE-VOLUTION™ are trademarks of Boehringer Ingelheim International GmbH and used under license.

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