First U.S. Patients Enroll in Boehringer Ingelheim’s Global RE-DUAL PCI™ and RE-CIRCUIT™ Trials Evaluating Pradaxa® (dabigatran etexilate mesylate)

• RE-DUAL PCI to evaluate PRADAXA in patients with NVAF undergoing angioplasty with stenting

• RE-CIRCUIT to investigate PRADAXA in patients with NVAF undergoing ablation

Ridgefield, CT, July 29, 2015 – Boehringer Ingelheim announced today that the first U.S. patients have been enrolled in two of the company’s international clinical trials, RE-DUAL PCI™ (NCT02164864) and RE-CIRCUIT™ (NCT02348723). RE-DUAL PCI will evaluate the efficacy and safety of Pradaxa® (dabigatran etexilate mesylate) in patients with non-valvular atrial fibrillation (NVAF) who have undergone percutaneous coronary intervention (PCI), also known as angioplasty, with stent placement. RE-CIRCUIT will evaluate the safety of PRADAXA in NVAF patients undergoing a first ablation procedure, which is conducted to help prevent heart rhythm problems.

“Despite current strategies for reducing vascular risk factors in NVAF, there is still a need to decrease the risk of stroke in patients requiring anticoagulation during interventions such as PCI and ablation,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “The initiation of these two studies reinforces Boehringer Ingelheim’s commitment to examining appropriate anticoagulation with PRADAXA to improve outcomes in patients undergoing these procedures.”

Both trials are part of Boehringer Ingelheim’s extensive RE-VOLUTION® clinical trial program for PRADAXA. The program includes 14 studies and is expected to involve more than 50,000 patients in more than 44 countries globally. PRADAXA was initially approved by the FDA in 2010 to reduce the risk of stroke and systemic embolism in patients with NVAF. In 2014, the FDA approved two additional indications for PRADAXA for the treatment of DVT and 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.

About RE-DUAL PCI™
Randomized Evaluation of DUAL Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with NVAF That Have Undergone PCI with Stenting

RE-DUAL PCI is an event-driven, open label trial and will evaluate dual therapy of PRADAXA (150 mg or 110 mg twice daily) plus single antiplatelet therapy (clopidogrel or ticagrelor) compared to the current standard of care of triple therapy, which includes warfarin plus two antiplatelet agents (clopidogrel or ticagrelor, and aspirin in the trial). The trial will enroll an estimated 8,520 NVAF patients at 401 study locations around the globe.

“Currently there are limited data about appropriate anticoagulation treatment for patients with NVAF undergoing PCI, but with the plan to enroll more than 8,500 patients, we expect RE-DUAL PCI to provide robust data to help us better understand and care for this patient population,” said Christopher Cannon, M.D., RE-DUAL PCI lead investigator, cardiologist, Brigham and Women’s Hospital in Boston and Professor of Medicine, Harvard Medical School.  

The primary efficacy endpoint of the trial is the time to death or first thrombotic event (all death, myocardial infarction, stroke or systemic embolism). The primary safety endpoint is the time to first major bleeding event, as defined by the International Society of Haematology (ISTH). Secondary endpoints include time to the individual events included in the primary efficacy endpoint, as well as time to:

  • Undetermined cause of death
  • Non-cardiovascular death
  • Cardiovascular death
  • All death 
  • Myocardial infarction
  • Stroke
  • Systematic embolism
  • Stent thrombosis
  • Composite endpoint of death, myocardial infarction and stroke
  • Repeated revascularization by PCI or coronary artery bypass graft

All endpoints will be assessed at time points up to 30 months following randomization to the three treatment groups. Results of the study are expected in 2017.

About RE-CIRCUIT™
Randomized Evaluation of Dabigatran Etexilate Compared to WarfarIn in Pulmonary Vein Ablation: Assessment of Different Peri-procedUral Anticoagulation Strategy

The open label RE-CIRCUIT study will evaluate the safety of uninterrupted treatment with PRADAXA 150 mg twice daily compared to uninterrupted warfarin (International Normalized Ratio [INR] of 2.0 to 3.0) in NVAF patients undergoing a first ablation procedure. The trial will enroll an estimated 724 patients at 85 international study locations.

“The RE-CIRCUIT trial provides an important opportunity to expand knowledge and the potential to help inform guidelines for appropriate use of novel oral anticoagulants in NVAF patients undergoing ablation procedures,”  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.

The primary endpoint is the incidence of major bleeding events, as defined by the International Society of Haematology (ISTH). Secondary efficacy and safety endpoints include:

  • Stroke, systemic embolism or transient ischemic attack events
  • Minor bleeding events
  • Composite of major bleeding events and thromboembolic events (stroke, systematic embolism or transient ischemic attack)

All endpoints will be assessed at time points during ablation and up 2 months post ablation.

About PCI
PCI is a general term to describe non-surgical revascularization procedures of the coronary arteries to improve blood flow in the heart. A small, flexible tube (catheter) with an attached deflated balloon is threaded through a coronary artery and inflated to widen areas where blood flow has been reduced or blocked. PCI often also involves placement of a stent to help prop the artery open and decrease the chance of another blockage.

Approximately 600,000 PCI procedures are performed in the United States each year; an estimated 5 to 7 percent involve patients with atrial fibrillation (AFib) or another condition requiring anticoagulant therapy. Research currently shows that about one in every 20 patients undergoing PCI also show a need for anticoagulant therapy to reduce their risk of stroke due to either AFib or another condition.

About Ablation
Ablation, also called radiofrequency ablation, uses catheters threaded through blood vessels in the legs and into the inner heart, where the catheters transmit energy to correct structural problems that cause an abnormal heart rhythm (arrhythmias). An irregular heartbeat increases the risk of an ischemic, or clot-based, stroke by up to five times. Ablation is effective at restoring a patient’s normal heart rhythm, but the procedure itself may temporarily increase the risk of blood clots. An estimated 50,000 AFib ablations were performed in the United States in 2013.

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 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

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.

Social responsibility is a central element of Boehringer Ingelheim's culture. 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 2013, Boehringer Ingelheim achieved net sales of about $18.7 billion (14.1 billion euro). R&D expenditure in the Prescription Medicines business corresponds to 19.5% of its net sales.

For more information please visit www.us.boehringer-ingelheim.com/

Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the trademarks Pradaxa®, PRADAXA with associated design®, RE-DUAL PCI™ and RE-CIRCUIT™ under license.

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