Editor's Note: Based on Eikelboom JW, Connolly SJ, Brueckmann M. et al. Dabigatran versus Warfarin in Patients with Mechanical Heart Valves. N Engl J Med 2013;369:1206-14.

Background

Patients with mechanical heart valves are at a high risk of thromboembolic events.^1,2 According to the current ACC/AHA guidelines, standard of care involves anticoagulation with vitamin K antagonists (VKAs) along with low dose aspirin.³ However, given the challenges innate to tight INR monitoring, a search for newer antithrombotic agents has been underway. Thus, a study was undertaken to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN).¹

Methods

This was a prospective, randomized, phase 2 validation study. Patients were divided into two populations: those who had aortic or mitral mechanical valve replacement within the past seven days and those who had such replacement at least three months prior to randomization. Patients were randomly assigned to receive dabigatran or warfarin in a 2:1 ratio with dabigatran renally dosed at 150, 220, or 300 mg twice daily to achieve plasma trough of at least 50ng per milliliter, which had been determined to be adequate to prevent valve thrombosis. Warfarin was dosed to achieve INR 2.0-3.0 or 2.5-3.5, depending on patients' thromboembolic risk. The primary end point of the trial was the trough level of dabigatran.¹

Results

The study was discontinued early due to excessive thromboembolic and bleeding events among patients treated with dabigatran. In the dabigatran group, stroke occurred in 5% of patients and myocardial infarction (MI) occurred in 2% of patients versus no stroke or MI events in the warfarin group. Bleeding of any type occurred in 27% of patients in the dabigatran group versus 12% in warfarin group (hazard ratio, 2.45; 95% confidence interval, 1.23 to 4.86; P=0.01).¹

Conclusion

Dabigatran is associated with increased risk of thromboembolic and bleeding events in patients with mechanical heart valves compared with warfarin.¹

Commentary/Perspective

This study by Eikelboom et al.¹ argues against the use of dabigatran at the doses tested in patients with mechanical heart valves. There are two broad classes of explanations for the negative results of this study related to: 1) dabigatran, and 2) the trial design.

Firstly, the increased bleeding rates observed with dabigatran may have been due to insufficient inhibition of the coagulation cascade. The pathophysiology of thrombus formation in atrial fibrillation is different from that in patients with mechanical heart valves. In atrial fibrillation, thrombus forms secondary to endothelial dysfunction in low flow, low shear conditions, whereas in mechanical valves, thrombi are induced by release of tissue factor from damaged tissue and exposure of foreign material to blood. Since warfarin acts on factors XII, IX, and X and thus inhibits tissue factor-dependent, contact-dependent, and common pathway-induced coagulations, it may be superior to dabigatran which only targets thrombin.

Furthermore, the dose and/or frequency of dabigatran might not have been optimal. While an increase in thromboembolic events could be explained by sub-therapeutic dabigatran levels, it would be difficult to test higher doses of dabigatran given the already increased bleeding risk observed with the doses studied. However, it is interesting to speculate whether TID administration of the same total daily dose (which should then result in higher trough and lower peak levels of dabigatran) might result in less bleeding and thrombosis. One take-away message from this study is that the dose, regimen, and drug level of a novel factor-specific anticoagulant that is safe and effective for a given indication (e.g., atrial fibrillation) may not translate well for another disease state (e.g., mechanical heart valves).

In addition, several features of the study design itself may have contributed to the negative results. Since the majority of the patients in the trial had recent surgery, a period characterized with high inflammatory and pro-thrombotic state, it is standard therapy to bridge patients with heparin and closely monitor the activated partial thromboplastin time until a therapeutic INR is reached. Given that in these post-operative patients careful individualized titration of INR is necessary, testing a fixed-dose drug regimen may have been suboptimal.⁴

It is also important to consider the baseline characteristics of the study population, whose mean age was 55 years. Older patients (>70 years) treated with an anticoagulant have increased risk of thromboembolic and bleeding events.⁵ Younger patients who generally have fewer comorbidities tolerate warfarin better than older patients and typically are easier to maintain in a therapeutic range. Thus, the younger average age in the RE-ALIGN study may have contributed to the excellent results in the warfarin group (no thromboembolic events, only 2% major bleeds), results that may not be representative of a typical clinical practice.

With this study, Eikelboom et al.¹ provide an important contribution warning against the use of dabigatran in patients with mechanical heart valves in the early post-operative period at the doses tested. However, before we completely abandon the use of factor-specific oral anticoagulants in patients with mechanical heart valves, we should take note of the trial design and possible confounders. Caution is recommended when attempting to translate dosing of anticoagulants across different indications.

References

1. Eikelboom JW, Connolly SJ, Brueckmann M. et al. Dabigatran versus Warfarin in Patients with Mechanical Heart Valves.N Engl J Med2013;369:1206-14.
2. Cannegieter SC, Rosendaal FR, Briët E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses.Circulation1994;89:635-41.
3. Bonow RO, Carabello BA, Chatterjee K, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force onPractice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.J Am Coll Cardiol2008;52:e1-142.
4. Hylek E. Dabigatran and mechanical heart valves -- not as easy as we hoped. N Engl J Med2013;369:1264-6.
5. Cannegieter S.C., Rosendaal F.R., Wintzen A.R., et al. Optimal Oral Anticoagulant Therapy in Patients with Mechanical Heart Valves. N Engl J Med 1995; 333:11-17.

Keywords: Anticoagulants, Aspirin, Atrial Fibrillation, Heparin, Myocardial Infarction, Partial Thromboplastin Time, Stroke, Thromboplastin, Thrombosis, Warfarin

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