The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of dabigatran etexilate (Boehringer Ingelheim’s Pradaxa) in the member states of the European Union for the prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation with one or more risk factors.
Dabigatran etexilate 150mg bid is the only novel oral anticoagulant proven superior to well-controlled warfarin treatment (Median TTR 67%)2 in reducing stroke and systemic embolism in an intention-to-treat analysis. This analysis represents the highest standard for analysing superiority in non-inferiority trials. These groundbreaking results were shown in RE-LY, a PROBE (prospective, randomised, open-label with blinded endpoint evaluation) trial designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran etexilate (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin.
Dabigatran etexilate 110 mg bid was shown to be as effective as warfarin. Both doses of dabigatran etexilate showed significantly lower intracranial bleeding compared to well-controlled warfarin. Dabigatran etexilate does not require routine coagulation monitoring or dose adjustments, is not affected by food and has a low potential for drug-drug interactions.
Professor Klaus Dugi, corporate senior vice president Medicine, Boehringer Ingelheim, commented, “After 50 years, a more effective alternative to warfarin is finally being made available to patients. The positive opinion from the CHMP for dabigatran etexilate represents another significant milestone in the history of stroke prevention in AF. When approved in the EU, dabigatran etexilate (150mg bid) will improve the lives of many patients by significantly reducing the risk of strokes compared to warfarin and avoid immense suffering for a vast proportion of them.”
Outside the EU dabigatran etexilate has been approved for stroke risk reduction in patients with AF in the USA, Canada, Japan, South Korea, New Zealand, Israel, Malaysia, Philippines, Singapore, Namibia, Colombia, Netherlands Antilles, Suriname and Indonesia; details of these approvals may however differ from the label recommended by CHMP.
The CHMP positive opinion is based on the results from the RE-LY trial, the largest AF trial completed to date. The data showed that dabigatran etexilate 150mg bid significantly reduced the risk of stroke and systemic embolism by 35% in addition to significantly lowering the risk of life-threatening and intracranial bleeding compared to well controlled warfarin.
RE-LY(Randomised evaluation of long term anticoagulant therapy) was a global, phase III, PROBE (prospective, randomised, open-label with blinded endpoint evaluation) trial of 18,113 patients enrolled in over 900 centres in 44 countries designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110mg and 150mg bid) each administered in a blinded manner, with well controlled (INR 2.0-3.0, median TTR 67%) open label warfarin. Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.
The primary endpoint of the trial was incidence of stroke (including haemorrhagic) or systemic embolism. Secondary outcome measures included all-cause death, incidence of stroke (including haemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular death (including death from bleeding).
Compared to well controlled warfarin, dabigatran etexilate showed in the trial:
– Significant reduction in the risk of stroke and systemic embolism – including haemorrhagic strokes with dabigatran etexilate 150mg bid
– Similar rates of stroke/systemic embolism with dabigatran etexilate 110mg bid
– Significantly lower major bleeding events with dabigatran etexilate 110mg bid
– Significantly lower life threatening and intracranial bleeding with both doses
– Significant reduction in vascular mortality with dabigatran etexilate 150mg bid.
About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs) targeting a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.
Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin (both free and clot-bound), the central enzyme in the process responsible for clot (thrombus) formation. In contrast to vitamin-K antagonists, which variably act via different coagulation factors, dabigatran etexilate provides effective, predictable and consistent anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or dose adjustment.
Dabigatran etexilate has already been approved for stroke risk reduction in patients with AF in 14 countries under the trademark Pradaxa (In Canada: Pradax and in Japan: Prazaxa). Details of these approvals may however differ from the label recommended by CHMP.
It has also been approved for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery in 83 countries under the trademark Pradaxa (in Canada: Pradax).
About the dabigatran etexilate clinical trial programme
Boehringer Ingelheim’s clinical trial programme to evaluate the efficacy and safety of dabigatran etexilate encompasses studies in:
– Primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee replacement surgeries
– Treatment of acute VTE
– Secondary prevention of VTE
– Stroke prevention in AF.