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Dabigatran for patients with a mechanical valve
LETTERS TO THE EDITOR
Letters to the Editor Keywords. Dabigatran; Valvular hear disease
Dabigatran for patients with a mechanical valve Dear Editor,
1 On
behalf of the Operations Committee of REALIGN: Stuart Connolly MD, Pieter Kappetein MD, Chris Granger MD, Martina Brueckmann MD, Michael Mack MD.
W
e read with great interest the case report by Stewart et al. [1], describing a 62 year-old Caucasian patient who suffered thrombosis of a mechanical aortic valve and an embolic stroke whilst being treated for more than eight months with dabigatran (150 mg b.i.d.) and 100 mg aspirin. Dabigatran etexilate is a new oral direct thrombin inhibitor currently approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In the RELY study [2], a dose of 150 mg b.i.d. was shown to be associated with a significantly lower risk of stroke and systemic embolism with a similar risk of major bleeding when compared with warfarin. The exposure to dabigatran and thus its anticoagulant effect is affected by renal function [3]. The authors do not report the creatinine clearance of this patient around the time of stroke but simulations [4], based on pharmacokinetic data from the RELY trial suggest that higher dosages of dabigatran may be required to achieve a sufficient level of anticoagulation in patients with a mechanical heart valve who have preserved renal function. The recently launched phase II study in patients with a mechanical heart valve (REALIGN-Randomised, phase II study to Evaluate the sAfety and pharmacokinetics of oraL dabIGatran etexilate in patients after heart valve replacement) will evaluate the appropriate dosing of dabigatran in this population. In REALIGN, patients below the age of 75 years will be studied and dabigatran will be given in doses ranging from 150 mg b.i.d. to 300 mg b.i.d. Since there are no high quality data on the use of dabigatran in patients with mechanical heart valves and a highly effective alternative is available (i.e., oral vitamin K antagonists such as warfarin) we recommend not using dabigatran outside well controlled, randomised trials until the results of these trials are known and the agent is approved for this indication. Frans Van de Werf, MD, PhD ∗,1 Department of Cardiovascular Medicine, University of Leuven, Belgium John Eikelboom, MD 1 McMaster University, Hamilton, Canada Corresponding author. E-mail address: [email protected] (F. Van de Werf)
Available online 1 December 2011
References [1] Stewart RAH, Astell H, Young, White HD. Thrombosis on a mechanical aortic valve whilst anti-coagulated with Dabigatran. Heart Lung Circ 2011:1–3. [2] Connolly SJ, Ezekowitz MB, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. [3] Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate—an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010;49(4):250–68. [4] Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification—using pharmacokinetic modeling and simulation. J Clin Pharmacol 2011, doi:10.1177/0091270011417716 [published online 28 September]. doi:10.1016/j.hlc.2011.10.011
Re: Letter responding to “Dabigatran for patients with a mechanical valve – by F. Van de Werf and J. Eikelboom” Dear Sir, We thank Drs Van De Werf and Eikelboom for drawing attention to the potential for differences in renal function to influence the efficacy as well as safety of dabigatran. Our patient suffered thrombosis on a St Jude aortic valve whilst taking dabigatran 150 mg bd and aspirin 100 mg daily. His calculated serum creatinine clearance was 66 ml/min/1.73 m2 , which is similar to the average creatinine clearance of patients who participated in the RELY trial [1]. It is therefore unlikely plasma levels of dabigatran were lower than expected because of good renal function. We agree that in general dabigatran and other novel anticoagulants should not be used in patients with mechanical heart valves outside the well organised randomised clinical trials needed to establish their efficacy. First experience of a novel treatment indication will always involve risk, and this was accepted by our patient who had significant and intolerable side effects on several oral vitamin K antagonists. We wish the REALIGN investigators success with this important study [2], but are aware of several challenges. More consistent anticoagulation may be needed to prevent thrombosis on a prosthetic valve compared to prevent-
© 2011 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
1443-9506/04/$36.00
Letters to the Editor Keywords. Dabigatran; Valvular hear disease
Dabigatran for patients with a mechanical valve Dear Editor,
1 On
behalf of the Operations Committee of REALIGN: Stuart Connolly MD, Pieter Kappetein MD, Chris Granger MD, Martina Brueckmann MD, Michael Mack MD.
W
e read with great interest the case report by Stewart et al. [1], describing a 62 year-old Caucasian patient who suffered thrombosis of a mechanical aortic valve and an embolic stroke whilst being treated for more than eight months with dabigatran (150 mg b.i.d.) and 100 mg aspirin. Dabigatran etexilate is a new oral direct thrombin inhibitor currently approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In the RELY study [2], a dose of 150 mg b.i.d. was shown to be associated with a significantly lower risk of stroke and systemic embolism with a similar risk of major bleeding when compared with warfarin. The exposure to dabigatran and thus its anticoagulant effect is affected by renal function [3]. The authors do not report the creatinine clearance of this patient around the time of stroke but simulations [4], based on pharmacokinetic data from the RELY trial suggest that higher dosages of dabigatran may be required to achieve a sufficient level of anticoagulation in patients with a mechanical heart valve who have preserved renal function. The recently launched phase II study in patients with a mechanical heart valve (REALIGN-Randomised, phase II study to Evaluate the sAfety and pharmacokinetics of oraL dabIGatran etexilate in patients after heart valve replacement) will evaluate the appropriate dosing of dabigatran in this population. In REALIGN, patients below the age of 75 years will be studied and dabigatran will be given in doses ranging from 150 mg b.i.d. to 300 mg b.i.d. Since there are no high quality data on the use of dabigatran in patients with mechanical heart valves and a highly effective alternative is available (i.e., oral vitamin K antagonists such as warfarin) we recommend not using dabigatran outside well controlled, randomised trials until the results of these trials are known and the agent is approved for this indication. Frans Van de Werf, MD, PhD ∗,1 Department of Cardiovascular Medicine, University of Leuven, Belgium John Eikelboom, MD 1 McMaster University, Hamilton, Canada Corresponding author. E-mail address: [email protected] (F. Van de Werf)
Available online 1 December 2011
References [1] Stewart RAH, Astell H, Young, White HD. Thrombosis on a mechanical aortic valve whilst anti-coagulated with Dabigatran. Heart Lung Circ 2011:1–3. [2] Connolly SJ, Ezekowitz MB, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. [3] Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate—an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010;49(4):250–68. [4] Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification—using pharmacokinetic modeling and simulation. J Clin Pharmacol 2011, doi:10.1177/0091270011417716 [published online 28 September]. doi:10.1016/j.hlc.2011.10.011
Re: Letter responding to “Dabigatran for patients with a mechanical valve – by F. Van de Werf and J. Eikelboom” Dear Sir, We thank Drs Van De Werf and Eikelboom for drawing attention to the potential for differences in renal function to influence the efficacy as well as safety of dabigatran. Our patient suffered thrombosis on a St Jude aortic valve whilst taking dabigatran 150 mg bd and aspirin 100 mg daily. His calculated serum creatinine clearance was 66 ml/min/1.73 m2 , which is similar to the average creatinine clearance of patients who participated in the RELY trial [1]. It is therefore unlikely plasma levels of dabigatran were lower than expected because of good renal function. We agree that in general dabigatran and other novel anticoagulants should not be used in patients with mechanical heart valves outside the well organised randomised clinical trials needed to establish their efficacy. First experience of a novel treatment indication will always involve risk, and this was accepted by our patient who had significant and intolerable side effects on several oral vitamin K antagonists. We wish the REALIGN investigators success with this important study [2], but are aware of several challenges. More consistent anticoagulation may be needed to prevent thrombosis on a prosthetic valve compared to prevent-
© 2011 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
1443-9506/04/$36.00