First study to evaluate alternative to warfarin for mechanical heart valve patients launched with Pradaxa® (dabigatran etexilate)

The American Heart Journal has published the design of the RE-ALIGN study, the first study to evaluate a novel oral anticoagulant as alternative to warfarin for use in patients with mechanical heart valves requiring anticoagulation therapy. 1 The Randomized, phase II study to Evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacemeNt (RE-ALIGN), addresses current limitations experienced with warfarin and is designed to identify safe and effective dosing regimen of Pradaxa® for the prevention of valve thrombosis, stroke and systemic embolism in this patient population, prior to further investigation in a larger phase III study. 1 The current approval of Pradaxa® does not cover the use in patients with mechanical heart valves.

Every year, approximately 300,000 patients undergo heart valve surgery worldwide, with numbers expected to rise in the future. 2 Mechanical valves are associated with a superior durability but also with a much higher and persistent risk of thromboembolism, requiring lifelong anticoagulation therapy. Vitamin K antagonists, such as warfarin, are the current long-term standard for anticoagulation of patients with a cardiac valve replacement. However, there is only limited information available on the long-term risk of thrombotic and haemorrhagic complications associated with this therapy in patients with modern mechanical bileaflet valves. Additionally, in spite of frequent INR monitoring, patients treated with warfarin spend less that 65% of the time within the targeted therapeutic range (TTR) 3, with TTR in the first three months following valve replacement surgery reported to be as low as 48.5%. 4

Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim, commented, “It is vital that patients with mechanical heart valves are provided with anticoagulant therapies that are safe and effective over the long-term. The current treatment with vitamin K antagonists is associated with significant limitations, creating a need for novel options which have fewer interactions and do not require regular monitoring. We are proud to be the first company looking for an alternative option for these patients by investigating Pradaxa® in the RE-ALIGN trial.”

The RE-ALIGN study, a prospective, randomized, phase II study, evaluates Pradaxa® in patients with mechanical bileaflet heart valve during a follow-up period of 12 weeks. 1 Based on the results, a sufficiently powered phase III study is planned to investigate efficacy outcomes for Pradaxa® in this patient population.

“Pradaxa® has already been proven to be a safe and efficacious anticoagulant treatment for stroke prevention in patients with atrial fibrillation,” stated Professor Frans Van de Werf, Department of Cardiovascular Medicine, University Hospitals Leuven, Belgium. “However, the presence of a mechanical heart valve is a distinct clinical situation requiring different dosing. The aim of the RE-ALIGN study is to identify dosing regimens of Pradaxa® that are expected to be safe and effective for the prevention of thromboembolic complications in patients with mechanical heart valves.”

The different dosing regimens that are under investigation for Pradaxa® in RE-ALIGN are 150 mg bid, 220 mg bid, and 300 mg bid, with the starting dose determined by the individual patient’s creatinine clearance. The study includes patients with recent surgery for implantation of mechanical bileaflet heart valve who have not yet started oral anticoagulation, and patients who had surgery at least three months before randomization and are currently taking an oral vitamin K antagonist. Patients are randomized to receive either Pradaxa® or the vitamin K antagonist warfarin. After the 12 week study period, patients are given the opportunity to opt-in to continue treatment with Pradaxa® within the REALIGN-extension trial, allowing investigators to collect long-term safety data. 1

To date, no investigation has been undertaken to determine the efficacy and safety of any novel oral anticoagulant including Pradaxa® in patients with mechanical heart valves. Until such data are available, the use of Pradaxa® for the prevention of thromboembolic complications in patients with mechanical heart valves is not recommended nor approved for clinical practice and is restricted to the setting of a randomized clinical trial only.

About RE-ALIGN

RE-ALIGN is the first study to test an alternative to warfarin in patients with mechanical heart valves. RE-ALIGN is a prospective, Randomized, phase II study, to Evaluate the s Afety and pharmacokinetics of oraL Pradaxa® (dab IGatran etexilate) in patients after heart valve replaceme Nt. Patients aged >18 years and <75 years, either undergoing implantation of a mechanical bileaflet valve (aortic or mitral or both) during the current hospital stay or having undergone implantation of a bileaflet valve 3 months before randomization, will be randomized between dabigatran etexilate (150, 200 or 300mg bid respectively) or warfarin. 1 Approximately 270 patients will be treated with dabigatran etexilate from a total study population of approximately 405 patients. 1

About dabigatran etexilate

Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs) 5 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.

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 surgery
• Treatment of acute VTE
• Secondary prevention of VTE
• Stroke prevention in AF
• Prevention of thromboembolism after heart valve replacement.

References

1. Van de Werf F, Brueckmann M, et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: The Randomized, phase II study to Evaluate the sAfety and pharmacokinetics of oraL dabIGatran etexilate in patients after heart valve replacemeNt (RE-ALIGN). Am Heart J 2012; http://dx.doi.org/10.1016/j.ahj.2012.03.011
2. Sun JC, et al. Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends. Lancet 2009;374:565-76.
3. Eitz T, et al. International normalized ratio self-management lowers the risk of thromboembolic events after prosthetic heart valve replacement. Ann Thorac Surg 2008;85:949-55.
4. Meijer K, et al. Decreasing warfarin sensitivity during the first three months after heart valve surgery: implications for dosing. Thrombosis Research 2010;125:224-9.
5. Di Nisio M, et al. Direct Thrombin Inhibitors. N Eng J Med 2005; 353:1028-40.