A 54-year-old male with a history of a bi-leaflet mechanical mitral valve implantation secondary to rheumatic heart disease is admitted for an episode of epistaxis requiring nasal packing in the setting of an INR of 4.6. On review of the medical records, you notice that since the mechanical mitral valve implantation five years ago, he has been admitted twice for suspected TIAs and once for a small ischemic stroke with INRs <2.0. Since then, he has been managed with warfarin and aspirin. On review of laboratory data, it appears that his time in therapeutic range is limited with supratherapeutic INR values observed quite frequently.
During the history, he reports being concerned about continuing on warfarin, stating "I cannot keep my blood thinner levels steady – no matter what I do! And between my job and small children, I cannot keep coming back to get my blood checked and ending up in the hospital." His medical history is otherwise unremarkable and laboratory studies are noteworthy for normal liver and renal function, with a reduced hemoglobin of 9.9 gm/dL (previously 13.5 gm/dL). A 12-lead ECG reveals atrial fibrillation with a regular rate.
His wife asks "Can my husband try one of the new blood thinners?"
What is the most appropriate anticoagulation strategy for this patient upon discharge?
Show Answer
The correct answer is: 2. Continue warfarin (target INR 2.5 to 3.5) and aspirin therapy. Evaluate new strategies to maintain better compliance.
Despite difficulty in maintaining the INR within range on some patients, warfarin is the only FDA-approved anticoagulant for patients with a mechanical heart valve.1 Home INR testing and management has been shown to lower the risk of thromboembolic events, and should be considered; especially for younger patients and those with mechanical heart valves.2 For patients with a mechanical heart valve who are in atrial fibrillation, the INR target is 2.5 to 3.5. The target range may be increased to 3.5 to 4.5 if a thromboembolic event is documented during adequate anticoagulation. For the patient above, medical records indicate the INR was subtherapeutic when he experienced his prior embolic events. In addition, guidelines recommend concomitant therapy with aspirin 75 to 100mg daily for all patients with prosthetic heart valves.
For patients that are difficult to maintain within the therapeutic range despite compliance, novel agents are an attractive alternative to warfarin. In the above case, the patient had experienced both complications of under- and over-treatment with vitamin K antagonism. Unfortunately, there are no data on the efficacy and safety of the factor Xa antagonists (e.g., rivaroxaban, apixaban, or edoxaban) in patients with mechanical heart valves. The benefits of their use obtained in ARISTOTLE (apixaban) and ROCKET-AF (rivaroxaban) confirm their efficacy and safety in patients with non-valvular atrial fibrillation, but these data cannot be extrapolated to other populations.
The RE-ALIGN trial studied the use of dabigatran, an oral direct thrombin inhibitor in patients with mechanical aortic and/or mitral valves.3 The study was a randomized, open-label, phase II, dose-validation study comparing dabigatran (dose-adjusted by creatinine clearance with subsequent uptitration in patients with plasma levels <50 ng/mL) versus warfarin. The trial was stopped early due to safety from a recommendation by the Data Safety Monitoring Board.
RE-ALIGN studied two patient populations. Population A was randomized within one week of valve implantation while Population B was randomized at least three months after having undergone valve implantation. Noticeable is that both thromboembolic and bleeding events were increased in the dabigatran arm (TABLE).
It is not well understood why both thromboembolic and bleeding events were increased in this population. In the RE-LY trial, dabigatran versus warfarin for nonvalvular atrial fibrillation, dabigatran 110mg BID demonstrated similar thromboembolic protection but less major bleeding than warfarin. The other dose tested, 150mg BID, was found to reduce thromboembolic events with similar rates of major bleeding to warfarin. In RE-ALIGN, while inadequate trough levels of dabigatran may have been a partial explanation for the increased thromboembolic events, the concomitant increase in bleeding with dabigatran 300mg BID would likely have prohibited using a larger dose. Much of the underlying reason may have involved different mechanisms of clot formation in patients with valvular disease. Major bleeding was confined to pericardial bleeds in the group with recent surgery.
Thrombus formation in atrial fibrillation typically is triggered by blood stasis and endothelial dysfunction.4 In contrast, in the setting of a mechanical valve, tissue damage from surgery as well as exposure to prosthetic materials may activate both the intrinsic and extrinsic pathways. Dabigatran only inhibits thrombin. Warfarin, on the other hand, depletes multiple vitamin K dependent clotting factors (i.e., VII, IX, and X) in addition to thrombin, and may thus be a more effective anticoagulant. The FDA has issued a safety announcement warning against the use of dabigatran in patients with mechanical prosthetic heart valves.5
References
American College of Cardiology et al. 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 on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006; 48:e1-148.
Heneghan, C. et al. Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data. Lancet 2012; 379:322-334.
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.
Hylek EM. Dabigatran and mechanical heart valves--not as easy as we hoped. N Engl J Med 2013;369:1264-6.
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