Real-World Analysis of More Than 44,000 Patients Reinforces Safety and Effectiveness of Pradaxa® (dabigatran etexilate mesylate) in Routine Clinical Care

RIDGEFIELD, Conn., Nov. 9, 2015 /PRNewswire/ -- Brigham and Women's Hospital in Boston and Boehringer Ingelheim today announced the results of a new interim analysis from a long-term study evaluating the safety and effectiveness of Pradaxa® (dabigatran etexilate mesylate) relative to warfarin in routine clinical practice. These data, from a pooled analysis of two large U.S. commercial health insurance databases, showed that patients with non-valvular atrial fibrillation (NVAF) treated with PRADAXA – a novel oral anticoagulant (NOAC) – had fewer strokes and fewer major bleeding events compared to NVAF patients treated with warfarin. The findings were presented at the American Heart Association (AHA) Scientific Sessions 2015 in Orlando.

"Beyond clinical trials, there is a wealth of available health insurance data that provides an excellent opportunity to grow our knowledge of oral anticoagulant use and outcomes for patients," said lead investigator John Seeger, PharmD, DrPH, Department of Medicine, Brigham and Women's Hospital, a teaching-affiliate of Harvard Medical School. "These real-world data further define the safety and effectiveness of dabigatran for patients and its use in routine care, and are consistent with the results of the pivotal RE-LY clinical trial."

The primary study outcomes were stroke and major bleeding rates during PRADAXA and warfarin treatment, based on data collected over 32 months from 44,672 NVAF patients (22,336 propensity score matched PRADAXA and warfarin treatment initiators) in two insurance databases — Truven MarketScan (18,276 patients per group) and Optum Clinformatics (4,060 patients per group). Researchers identified 65 strokes for PRADAXA-treated patients (0.73 incidence rate per 100 patient years) and 78 strokes for warfarin-treated patients (1.08 incidence rate per 100 patient years), representing a 28 percent reduction in stroke risk for PRADAXA compared to warfarin (HR 0.72; 95% CI 0.52 – 1.00). In addition, researchers reported 395 major bleeding events for PRADAXA-treated patients (4.47 incidence rate per 100 patient years), compared to 459 events for warfarin-treated patients (6.42 incidence rate per 100 patient years), representing a 26 percent reduction in the risk of major bleeding events with PRADAXA compared to warfarin (HR 0.74; 95% CI 0.64 – 0.84). There were 238 major gastrointestinal bleeding events for PRADAXA-treated patients (2.69 incidence rate per 100 patient years) and 213 for warfarin treated patients ((2.97 incidence rate per 100 patient years); HR 0.95; 95% CI 0.79 – 1.14).

"With this long-term study program, in collaboration with Brigham and Women's Hospital, we are seeking to expand awareness and understanding of real-world experiences with NOACs and the impact on reducing stroke risk, which remains a major public health concern," said Sabine Luik, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim. "These data add to the robust research program supporting the real-world value of PRADAXA, the only NOAC with both proven superiority to warfarin in reducing stroke risk in NVAF patients and a specific reversal agent."

Additional Study Details 
The analysis is part of an ongoing research program to evaluate prescribing patterns and real-world safety and effectiveness of oral anticoagulants, including PRADAXA, for reducing stroke risk. Data were collected from the two databases between October 2010 and June 2013.

New users of PRADAXA or warfarin were matched on various demographic and clinical criteria ("propensity-score-matched"). There were 22,336 propensity-score-matched NVAF patients in the PRADAXA and warfarin groups when numbers were pooled across the two data sources. Patients were followed up until they switched or discontinued anticoagulant treatment, experienced an outcome event or discontinued enrollment. The average follow-up period was five months for PRADAXA-treated patients and four months for warfarin-treated patients. Effectiveness assessments beyond the first six months of therapy were limited by the short average follow-up time. Future analyses from this sequential long term study program will yield more stable estimates including a larger number of patients.

With this collaboration, Boehringer Ingelheim and Brigham and Women's Hospital aim to gather data representing more than 100,000 NVAF patients in the U.S.

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

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.  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), 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.

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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