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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Prof. Martina Brueckmann
Prof. Stuart J Connolly,
Dr. John W Eikelboom
In valvular disease, valve replacement does not translate into a definite cure of the patient (1). Thrombogenicity of the prosthesis has major impact on the outcome of the patient, and bleeding complications, embolism and thrombosis remain an ongoing concern. (2). Despite modern anticoagulation strategies, the incidence of thromboembolic events with mechanical valves ranges between 0.6-2.3 % per patient-year and is influenced by patient risk factors, anticoagulation intensity, aortic or mitral position and prosthesis related factors (3). So far, oral anticoagulation with vitamin K antagonists has been the cornerstone of long term management in mechanical valve prostheses. Hopes for a simplified and safer treatment were raised by the event of novel oral anticoagulants such as dabigatran, an oral direct thrombin inhibitor with excellent results in stroke prevention in atrial fibrillation patients (4,5-7). Preclinical studies pointed towards favourable applicability of dabigatran in mechanical valve prosthesis anticoagulation (8).
In the current RE-ALIGN study (9), a new dosing regimen of dabigatran was evaluated in mechanical heart valve patients, but was terminated prematurely due to an excess of thromboembolic and bleeding events in the dabigatran group as compared to warfarin (8). Questions occur to the reasons for these detrimental findings. The trial was undertaken in 39 centers in 10 countries in patients undergoing mechanical bileaflet valve implantation in the aortic (68%) or mitral (28%) position, or in both (4%), and was designed as a 12 week study with a planned extension arm up to 84 months. The mean duration of treatment was finally 136-143 days in dabigatran and 143-152 days in the warfarin group due to termination of the study. The baseline age in the dabigatran group was 56.0±9.4 and 55.7±10.4 years with warfarin, and the logistic EuroScore was low (mean 2.3). Two populations were analyzed: an early- and late postoperative group. Population A consisted of 199 “early” patients (79%) included within 3-7 days after valve surgery, and population B included 53 patients (21%) >3 months after implantation, randomized to dabigatran or warfarin in a ratio 2:1. Depending on presurgical creatinine clearance, the dabigatran starting dose was 150, 220 or 300mg bid. Further adjustment was determined by target trough plasma level of dabigatran ≥50ng/ml. Dose adjustment of dabigatran or discontinuation due to was required overall in 32% of patients. In 8% of patients, dabigatran had to be discontinued due to a trough level <50 ng/ml despite treatment with the highest dose of 300 mg twice daily, these patients were switched to warfarin. In warfarin patients, the targeted INR (international normalized ratio) for warfarin was 2-3 in low thromboembolic risk and 2.5-3.5 in intermediate or high risk (mechanical aortic valve with additional risk factors or a mechanical mitral valve). Surprisingly, there was no association of dabigatran plasma levels and the occurrence of bleeding or thromboembolic events. In the early postoperative population A, the average time was 84% above the targeted dabigatran level, whereas plasma levels were significantly higher in the late postoperative population B (average time 96%). However, in the warfarin groups the time in the therapeutic range was even lower with 49% in population A and 51% in population B. Nevertheless, the Kaplan Meier analysis of event-free survival shows a clear superiority of warfarin over dabigatran for thromboembolic or bleeding events, respectively (Figure 1). Thromboembolic complications occurred significantly more often in the dabigatran group of population A within the first 90 days after surgery. Bleeding was more frequent in dabigatran patients, similarly in the early and the late postoperative population. Major bleeding was pericardial in all patients, and occurred within 2 weeks of surgery more frequently in the dabigatran group. There are several contributing factors that might explain these negative results, e.g. age, the dosing regimen, coagulation factors, but also shear stress, flow factors across the mechanical valve and postoperative surgical factors, especially thrombogenicity of the artificial valve leaflet surface and lack of endothelialisation of the sewing ring in the early phase. The study cohort was significantly younger than the elderly patients studied with atrial fibrillation and creatinine clearance was generally higher. Consequently, the dabigatran dosages used were significantly higher in the present study, with adjustments according to renal function and measured trough plasma levels. Furthermore, the coagulation model of blood stasis in atrial fibrillation apparently may not be transferrable to the mechanical valve situation. An important factor to consider is that the majority of patients (population A) were randomized during their hospital stay of valve implantation, so they were in the very early postoperative phase of surgery, in which a very high state of pro-coagulation activity is known to be present with increased inflammation and circulating tissue factors. Conversely, in the first 4 weeks plasma levels of dabigatran were even lower than projected, and drug bioavailability may have been additionally influenced by postsurgical factors such as gut absorption.
Finally, a very likely explanation is the mechanism of action of the different anticoagulants itself. The Vitamin K antagonist warfarin antagonizes both the activation of tissue factor- induced coagulation by synthesis inhibition of Factor VII and the contact pathway- induced coagulation by synthesis inhibition of Factor IX, and also inhibits the synthesis of Factor X and thrombin in the common pathway. In contrast, dabigatran only and directly inhibits thrombin (Figure 2). It might be postulated that in the highly increased pro-coagulation activation after valve surgery, sole thrombin- inhibition may not be sufficient by dabigatran and lead to thrombus formation at the artificial valve. It is unknown whether other novel anticoagulants e.g. direct Factor Xa inhibitors are similar in this limitation, but their use also cannot be recommended at this time.
In conclusion, the study reported a worse outcome with the use of dabigatran compared to anticoagulation with warfarin in mechanical valve prosthesis patients. At present, dabigatran remains contraindicated in patients with valve prosthesis.
1. Pibarot P, Dumesnil JG. Prosthetic heart valves: selection of the optimal prosthesis and long-term management. Circulation. 2009;119(7):1034-482. Butchart EG, Payne N, Li HH, Buchan K, Mandana K, Grunkemeier GL. Better anticoagulation control improves survival after valve replacement. J Thorac Cardiovasc Surg 2002; 123:715-233. Roudaut R, Serri K, Lafitte S. Thrombosis of prosthetic heart valves: diagnosis and therapeutic considerations. Heart 2007;93(1):137-42.4. Hylek EM. Dabigatran and mechanical heart valves--not as easy as we hoped. N Engl J Med. 2013 Sep 26;369(13):1264-65. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-516. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ; RE-LY investigators. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010;376(9745):975-837. Connolly SJ, Wallentin L, Ezekowitz MD, Eikelboom J, Oldgren J, Reilly PA, Brueckmann M, Pogue J, Alings M, Amerena JV, Avezum A, Baumgartner I, Budaj AJ, Chen JH, Dans AL, Darius H, Di Pasquale G, Ferreira J, Flaker GC, Flather MD, Franzosi MG, Golitsyn SP, Halon DA, Heidbuchel H, Hohnloser SH, Huber K, Jansky P, Kamensky G, Keltai M, Kim SS, Lau CP, Le Heuzey JY, Lewis BS, Liu L, Nanas J, Omar R, Pais P, Pedersen KE, Piegas LS, Raev D, Smith PJ, Talajic M, Tan RS, Tanomsup S, Toivonen L, Vinereanu D, Xavier D, Zhu J, Wang SQ, Duffy CO, Themeles E, Yusuf S. The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study. Circulation. 2013 Jul 16;128(3):237-438. Schomburg JL, Medina EM, Lahti MT, Bianco RW. Dabigatran versus warfarin after mechanical mitral valve replacement in the swine model. J Invest Surg 2012;25:150-5.9. Dabigatran versus warfarin in patients with mechanical heart valves. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, Harper R, Khder Y, Lobmeyer MT, Maas H, Voigt JU, Simoons ML, Van de Werf F; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013 Sep 26;369(13):1206-14
Figure 1. Kaplan Meier analysis of event free survival. (from Eikelboom JW et al, NEJM 2013; 369(13):1206-14)
Figure 2. Coagulation and mechanism of dabigatran or warfarin (from: Van de Werf F, presentation at ESC 2013. http://www.escardio.org/about/press/esc-congress-2013/press-conferences/Documents/slides/van-de-werf.pdf )
Presented by Jutta Bergler-Klein, MD, Prof. , Dept. of Cardiology, Med. Univ. of Vienna, Vienna, Austria Dabigatran versus warfarin in patients with mechanical heart valves. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, Harper R, Khder Y, Lobmeyer MT, Maas H, Voigt JU, Simoons ML, Van de Werf F; RE-ALIGN Investigators. N Engl J Med 2013 Sep 26;369(13):1206-14
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