Therapeutic Drug Monitoring of Direct Oral Anticoagulants May Increase Their Benefit-Risk Ratio.

The attractiveness of direct oral anticoagulants (DOACs) over vitamin K antagonists, in addition to a better benefit-risk ratio, stems from the fact that no therapeutic drug monitoring is deemed necessary. This has been recently mitigated by the fact that increased dabigatran (D) plasma levels have been associated with hemorrhages, and is currently under scrutiny of the European Medicines Agency. We aimed to evaluate, in real conditions of use, whether patients with out-of-range DOAC blood concentrations (too high or too low) were associated with bleeding or thrombosis. Patients treated with D or rivaroxaban (R) were prospectively included in a hospital cohort. D and R plasma levels were measured by high-pressure liquid chromatography-tandem mass spectrometry-at the physician's demand. We defined concentration range as "expected" within the 95% confidence interval of the mean concentration obtained from pivotal trials, and "out of range" when concentrations were outside of that interval. A blind assessment of concentrations versus occurrence of bleeding or thrombosis was performed by means of univariate and multivariate analysis. Three hundred and twenty-two patients (mean age 78.5 years ± 13.1), treated with D or R were included consecutively. They had a mean CHA2DS2-VASc at 4.4 ± 1.7 and a mean HAS-BLED score at 1.7 ± 0.9. Irrespective of the DOAC prescribed, patients presenting with out-of-range concentrations had significantly more bleeding or thrombosis than patients with expected concentrations (P < 0.001). Patients with bleeding were more prone to have concentrations beyond the 95 percentile (N = 62, P < 0.001), whereas patients with thrombosis were more likely to have concentrations below the fifth percentile (N = 26, P < 0.05). The main risks associated with hemorrhages were abnormal concentrations, a high HAS-BLED score, the patient's age, and the creatinine blood level. For thrombosis, a concentration below the fifth percentile was the only risk factor that was significant in our cohort. While D and R under current recommendation have a better benefit-risk ratio than warfarin, their safe usage could be further optimized by some degree of therapeutic monitoring.

Major bleeding events in octagenarians associated with drug interactions between dabigatran and P-gp inhibitors.

BACKGROUND: The direct oral anticoagulant dabigatran does not require any routine therapeutic drug monitoring. Yet, concerns about possible drug interactions susceptible to increase its inherent bleeding risk, especially in very elderly patients, have been raised recently. The aim of our study was to evaluate to what extent the co-prescription of P-gp inhibitors with dabigatran may increase its plasma levels and lead to bleeding complications, in usual conditions of care of the very elderly. METHODS: Fifty-eight patients over 85 years old with non valvular atrial fibrillation receiving dabigatran were included in a prospective cohort. Prescriptions were screened for the presence of P-gp inhibitors (Group A) or not (Group B). RESULTS: Patients from Group A had increased dabigatran mean plasma concentrations as compared with patients from Group B (A vs. B: 182.2 ± 147.3 vs. 93.7 ± 64.9 ng/mL). One third of the patients from Group A had dabigatran concentrations that were deemed "out of range" versus none in Group B (P = 0.05). This was associated with more frequent bleeding complications in Group A (A: 30.4%, B: 8.6%, P = 0.04). CONCLUSION: In our cohort of very elderly patients, at least, the co-prescription of dabigatran with P-gp inhibitors in usual conditions of care resulted in higher dabigatran plasma concentrations and more frequent bleeding occurrences.