Dabigatran Use in Mechanical Heart Valve Patients
Dabigatran Use in Mechanical Heart Valve Patients
The RE-ALIGN study by Eikelboom et al. is the first randomized prospective study to validate a dabigatran dosing regimen for the prevention of thrombosis in mechanical heart valve patients. The trial was prematurely terminated due to excess bleeding events among patients receiving dabigatran. A possible explanation for dabigatran failure could be attributed to lack of data on adequate plasma concentrations for patients with a mechanical heart valve. The target plasma level of 50 ng/ml was extrapolated from pharmacokinetic studies from the RE-LY trial in patients with atrial fibrillation, which was not validated in patients with mechanical valves. Dabigatran levels are dependent on patients' renal function, age and weight. It can be speculated that the difference in median age of patients and renal function in the RE-LY versus the RE-ALIGN studies could have affected the dabigatran levels (younger patients with better renal function in the RE-ALIGN trial resulted in lower plasma levels). Lower than expected dabigatran levels in the first 4 weeks, and consequently more incidents of thromboembolic complications in population A in the RE-ALIGN study, may suggest that higher plasma levels are needed for anticoagulation in mechanical valve patients. The median time to reach target plasma levels was 8 days in the dabigatran group, which could have contributed to the increased rate of thromboembolic complications. Subtherapeutic anticoagulation during this period might have resulted in subclinical, nonobstructive prosthetic valve thrombosis, which might have worsened during follow-up.
The propensity of thrombus formation in atrial fibrillation is explained by Virchow's triad. By contrast, thrombosis in patients with a mechanical valve is strongly associated with activated platelets and circulating procoagulant tissue factors from damaged tissues during surgery.
An immediate postoperative period is tumultuous for multiple reasons and may not be a good time to investigate a new anticoagulant in high-risk patients, such as those with mechanical valves. Perhaps, the investigators would have fared better if they had enrolled patients at least 6 months after mechanical valve implants and avoided the immediate postoperative period. Cardiopulmonary bypass results not only in platelet activation, but platelet dysfunction as well. Contact with foreign surfaces results in activation of the coagulation cascade and depletion of coagulation factors. Intense inflammatory response occurs with activation of neutrophils, as well as release of inflammatory cytokines, which in turn affects the coagulation cascade. Patients may not be able to take whole dabigatran capsules or it may not be absorbed well because of the ileus or use of narcotics. In addition, raw surgical surfaces such as the pericardium are prone to bleeding. Nonendothelialized valve sewing rings will have a tendency to clot and this may propagate under inadequate anticoagulation. Low flow states may promote valve thrombosis. It is also possible that use of low-dose aspirin may potentially lower thrombotic risk in medium- to high-risk patients. Whether other novel anticoagulants such as rivaroxaban and apixaban (factor Xa inhibitors) would result in better outcomes compared with dabigatran (direct thrombin inhibitor) is subject to speculation.
Significance
The RE-ALIGN study by Eikelboom et al. is the first randomized prospective study to validate a dabigatran dosing regimen for the prevention of thrombosis in mechanical heart valve patients. The trial was prematurely terminated due to excess bleeding events among patients receiving dabigatran. A possible explanation for dabigatran failure could be attributed to lack of data on adequate plasma concentrations for patients with a mechanical heart valve. The target plasma level of 50 ng/ml was extrapolated from pharmacokinetic studies from the RE-LY trial in patients with atrial fibrillation, which was not validated in patients with mechanical valves. Dabigatran levels are dependent on patients' renal function, age and weight. It can be speculated that the difference in median age of patients and renal function in the RE-LY versus the RE-ALIGN studies could have affected the dabigatran levels (younger patients with better renal function in the RE-ALIGN trial resulted in lower plasma levels). Lower than expected dabigatran levels in the first 4 weeks, and consequently more incidents of thromboembolic complications in population A in the RE-ALIGN study, may suggest that higher plasma levels are needed for anticoagulation in mechanical valve patients. The median time to reach target plasma levels was 8 days in the dabigatran group, which could have contributed to the increased rate of thromboembolic complications. Subtherapeutic anticoagulation during this period might have resulted in subclinical, nonobstructive prosthetic valve thrombosis, which might have worsened during follow-up.
The propensity of thrombus formation in atrial fibrillation is explained by Virchow's triad. By contrast, thrombosis in patients with a mechanical valve is strongly associated with activated platelets and circulating procoagulant tissue factors from damaged tissues during surgery.
An immediate postoperative period is tumultuous for multiple reasons and may not be a good time to investigate a new anticoagulant in high-risk patients, such as those with mechanical valves. Perhaps, the investigators would have fared better if they had enrolled patients at least 6 months after mechanical valve implants and avoided the immediate postoperative period. Cardiopulmonary bypass results not only in platelet activation, but platelet dysfunction as well. Contact with foreign surfaces results in activation of the coagulation cascade and depletion of coagulation factors. Intense inflammatory response occurs with activation of neutrophils, as well as release of inflammatory cytokines, which in turn affects the coagulation cascade. Patients may not be able to take whole dabigatran capsules or it may not be absorbed well because of the ileus or use of narcotics. In addition, raw surgical surfaces such as the pericardium are prone to bleeding. Nonendothelialized valve sewing rings will have a tendency to clot and this may propagate under inadequate anticoagulation. Low flow states may promote valve thrombosis. It is also possible that use of low-dose aspirin may potentially lower thrombotic risk in medium- to high-risk patients. Whether other novel anticoagulants such as rivaroxaban and apixaban (factor Xa inhibitors) would result in better outcomes compared with dabigatran (direct thrombin inhibitor) is subject to speculation.