RE-COVER at ASH: Dabigatran equals warfarin for VTE treatment Reply

Dabigatran (Pradaxa) is as effective as warfarin for the treatment of VTE, according to results of the RE-COVER study presented today at the American Society of Hematology meeting today and published online in the New England Journal of Medicine.

Sam Schulman and colleagues randomized 2539 patients with acute VTE to warfarin or dabigatran (150 mg twice daily) for 6 months. Patients were initially treated with heparin for 5 to 11 days. At 6 months the incidence of recurrent VTE was 2.2% (27 patients) in the warfarin group versus 2.4% (30 patients) in the dabigatran group, a difference which fell within the prespecified margin for noninferiority (p<0.0001). Major bleeding occurred in 20 dabigatran-treated patients and 24 warfarin-treated patients. There were no significant differences in mortality, ACS, or liver function test abnormalities.

Interest in dabigatran grew intense last August at the ESC with the presentation of the RE-LY trial, which studied more than 18,000 atrial fibrillation patients and also turned up promising results for dabigatran. (Click here for our earlier story on RE-LY.)

RE-LY randomized 18,113 AF patients to either one of two fixed doses of dabigatran (110 mg or 150 mg twice daily) or warfarin. The results of RE-LY were presented this morning at the ESC and published simultaneously in the New England Journal of Medicine. The RE-LY investigators concluded that “compared with warfarin, the 110-mg dose of dabigatran was associated with similar rates of stroke and systemic embolism and lower rates of major hemorrhage; the 150-mg dose of dabigatran was associated with lower rates of stroke and systemic embolism but with a similar rate of major hemorrhage.”

In their NEJM paper the authors, led by Samuel Z Goldhaber, concluded:

“Our trial provides data to support dabigatran as a fixed-dose oral treatment for acute deep-vein thrombosis and pulmonary embolism. For patients and health care providers, dabigatran is a far more convenient drug than warfarin because it has no known interactions with foods and minimal interactions with other drugs and therefore does not require routine blood-coagulation testing.”

The investigators noted that a previous direct thrombin inhibitor, ximelagatran, had also been able to demonstrate noninferiority to warfarin for this indication, but liver toxicity had ultimately prevented further development of the drug. No such toxicity has been observed with dabigatran in either RE-LY or RE-COVER. The only adverse effect attributed to the study drug in RE-COVER was dyspepsia, which occurred in 3% of patients in the dabigatran group.

Clinically relevant nonmajor bleeding was significantly reduced from 8.8% in the warfarin group to 5.6% in the dabigatran group (p=0.002). The authors commented that “clinically relevant nonmajor bleeding is an important factor to consider, since its management is time-consuming and costly and since bleeding is the most important reason for the perception of decreased health and quality of life among patients treated with warfarin.”

Chris Cannon– who told CardioBrief that “this is great news!”– echoed the growing ebullience of cardiologists over the prospect of an oral direct thrombin inhibitor that doesn’t require dose adjustments or anticoagulation monitoring. Dan Hackam, of the Division of Clinical Pharmacology at the University of Western Ontario, had a similarly positive but somewhat more measured response:

Overall, RE-COVER appears to be another important advance for dabigatran. While the trial did not demonstrate superiority over warfarin, the non-inferiority criterion was met and total rates of bleeding were lower. One small concern I have is the somewhat higher rates of withdrawal in the dabigatran group – and again we see a signal of higher rates of dyspepsia. In the real world, we would already have an option for treating such patients; and that option would be warfarin. I am very pleased that we are not seeing the transaminitis issue which sunk ximelagatran (Exanta). There were too few acute coronary syndromes in this study to say anything about the safety of this drug with respect to ACS.

Here is the Boehringer Ingelheim press release:

RE-COVER Study Evaluating Dabigatran Etexilate Met Primary Outcome for the Six-Month Treatment of Patients with Acute Venous Thromboembolism (VTE)

  • Dabigatran etexilate was non-inferior to warfarin (target INR 2.0 to 3.0) in preventing recurrent symptomatic VTE or VTE-related death1
  • Thirty-seven percent fewer patients treated with dabigatran etexilate (71) experienced major or clinically relevant non-major bleeds versus patients treated with warfarin (111)1

Ridgefield, CT, December 6, 2009 – Boehringer Ingelheim today announced results from the RE-COVER™ study investigating dabigatran etexilate (150 mg BID), a direct thrombin inhibitor (DTI),2 compared to dose-adjusted warfarin in patients with acute VTE. Results of the trial were presented at the 51st American Society of Hematology Annual Meeting and simultaneously published online in the New England Journal of Medicine.1

Dabigatran etexilate met the primary outcome of the trial, six month incidence of recurrent symptomatic VTE and related deaths, and was non-inferior to dose-adjusted warfarin in patients with acute VTE (2.4 percent versus 2.1 percent).1 There were 37 percent fewer patients treated with dabigatran etexilate (71) who experienced major or clinically relevant non-major bleeds versus patients treated with warfarin (111).1 The percentage of patients experiencing major bleeds was 1.6 in the dabigatran etexilate group and 1.9 in the warfarin group.1 The number of patients with any bleeding was 29 percent lower in the group treated with dabigatran etexilate.1

Among adverse events with an incidence of at least three percent, dyspepsia was the only one that was more common between treatment arms (2.9 percent in the dabigatran etexilate group versus 0.6 percent in the warfarin group).1 There were 115 patients in the dabigatran etexilate group (9.0 percent) and 86 patients in the warfarin group (6.8 percent) who had an adverse event that led to discontinuation of the study drug (HR, 1.33; 95 percent CI, 1.01 to 1.76; P=0.05).1

“The standard of care for patients with VTE is anticoagulation,” said Dr. Janet Schnee, clinical program director, Boehringer Ingelheim Pharmaceuticals,

Inc. “It is encouraging to see that the results of this study suggest that dabigatran etexilate has the potential to be an alternative treatment for VTE.”

Venous thromboembolism is a condition which includes deep vein thrombosis (DVT) and its potentially fatal acute complication pulmonary embolism (PE). The condition results from the formation of blood clots that block the flow of blood in the veins, most frequently occurring in the legs (DVT). Clots that become dislodged from affected veins can migrate to and obstruct the blood vessels that supply the lungs (PE). Venous thromboembolism is the third most common cause of cardiovascular death after myocardial infarction and stroke.1

Current guidelines recommend treating acute, clinically documented VTE with a parenteral heparin preparation for at least five days followed by oral anticoagulation with a vitamin K antagonist, such as warfarin.3

“We are committed to improving the treatment options for patients with thromboembolic diseases,” said Wa’el Hashad, vice president, Cardiovascular and Metabolics Marketing, Boehringer Ingelheim Pharmaceuticals, Inc. “The RE-COVER study results suggest dabigatran etexilate could potentially provide a convenient treatment option for patients with VTE.”

In total, four trials involving 8,900 patients are exploring dabigatran etexilate in VTE: RE-COVER™ and RE-COVER™II in acute VTE and RE-MEDY™ and RE-SONATE™ in prevention of secondary VTE.1, 4, 5, 6

About RE-COVER™1

RE-COVER™ is a global, phase III, randomized, double-blind, double-dummy, parallel-group study comparing the efficacy and safety of oral dabigatran etexilate (150 mg BID) to warfarin (target INR 2.0-3.0) for six months of treatment of acute symptomatic VTE, following initial treatment with a parenteral anticoagulant approved for this indication. The study involved 2,539 patients. The primary efficacy endpoint was a composite of recurrent symptomatic VTE and deaths related to VTE.

About VTE

Venous thromboembolism refers to blood clots (thrombi) which originate in the veins, and includes DVT and its potentially fatal acute complication PE. Pulmonary embolism is a leading cause of in-hospital death, accounting for approximately 10 percent of all hospital deaths.7

About dabigatran etexilate

Dabigatran etexilate is an investigational oral DTI,2 being studied in the prevention and treatment of acute and chronic thromboembolic diseases.4, 5, 6, 8, 9, 10, 11, 12, 13, 14 Dabigatran etexilate is not approved by the FDA. Dabigatranetexilate is approved and marketed as Pradaxa® in 40 countries outside the

U.S. for the primary prevention of venous thromboembolic events (blood clots) in patients who have undergone elective total hip or elective total knee replacement surgery.

About the dabigatran etexilate clinical trial program

RE-COVER™ is part of Boehringer Ingelheim’s clinical trial program evaluating the efficacy and safety of dabigatran etexilate.4, 5, 6, 8, 9, 10, 11, 12, 13, 14 In addition to RE-COVER, the development program encompasses studies in:

• Primary prevention of VTE in patients undergoing elective total hip and knee replacement surgeries10, 11, 14

• Treatment of acute VTE4

• Secondary prevention of VTE5, 6

• Prevention of atherothrombotic events in patients with acute coronary

syndrome9

• Stroke prevention in atrial fibrillation13

About Boehringer Ingelheim 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 138 affiliates in 47 countries and approximately 41,300 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2008, Boehringer Ingelheim posted net sales of US $17 billion (11.6 billion euro) while spending approximately one-fifth of net sales in its largest business segment, Prescription Medicines, on research and development.

For more information, please visit http://us.boehringer-ingelheim.com.

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