Background: In randomized clinical trials direct oral anticoagulants (DOAC) were shown to be safe and effective in atrial fibrillation (AF) patients and were rapidly taken up in clinical use. First quality analyses from daily-care are emerging, but there is only scarce data on DOAC safety in elderly patients and the necessity of laboratory monitoring in case of an adverse event.
Methods: In our prospective non-interventional study we included AF patients who were treated at the Anticoagulation clinic of the Department of vascular diseases, University Medical Centre Ljubljana, from year 2012 until march 2017. Patients treated with dabigatran (N = 1308), rivaroxaban (N = 1102) or apixaban (N = 850) were enrolled and their data has been managed with computer software Trombo. We evaluated rates of major bleeding and thromboembolic events. In the second part of the study we included 44 AF patients who started treatment with dabigatran 150 and 110 mg twice daily. Each patient contributed 2 trough and 2 peak blood samples that were collected during dabigatran treatment in steady-state approximately one month apart. Plasma concentration was measured by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and indirectly estimated by selected coagulation tests. Patients were followed for 12 months and relationship between plasma dabigatran concentrations and adverse events was assessed.
Results: Patients were followed for a mean of 621 ± 464 days. Rates of major bleeding were 1,5, 2,6 and 2,5 %/year and rates of combined endpoint of stroke and systemic embolism were 0,9, 1,3 and 1,0 %/year on treatment with dabigatran, rivaroxaban and apixaban, respectively. Patients who were prescribed DOAC in a low dose were older, had worse renal function and higher CHADS2 score than patients who were prescribed DOAC in a high dose. Differences in the rates of major bleeding and thromboembolism were not significantly different between patients on high and low dose of DOAC. Despite dose adjustment, patients aged ≥ 85 years had significantly higher rates of major bleeding (4,6 vs. 1,8 %/year, p = 0,003), intracranial bleeding (1,3 vs. 0,4 %/year, p = 0,032) and major gastrointestinal bleeding (2,6 vs. 1,0 %/year, p = 0,035) than patients aged < 85 years. Rates of thromboembolic events did not significantly differ between the two groups (2,9 vs. 1,8 %/year, p = 0,463). The best correlations between LC-MS/MS and coagulation tests for determining dabigatran concentration were expressed by in-house diluted thrombin time (in-house dTT) and ecarin chromogenic assay. Patients receiving dabigatran in high (N = 23) and low dose (N = 21) had similar dabigatran concentrations in both trough and peak samples. Dabigatran concentration varied less in trough than in peak samples (17,0 ± 13,6 vs. 26,6 ± 19,2 %, p = 0,02). During the 12-month follow-up, 10 patients suffered minor bleeding. There was no major bleeding or thromboembolic event. Patients with bleeding had significantly higher average trough dabigatran concentrations than patients without bleeding (93 ± 36 vs. 72 ± 62 μg/L, p = 0,02).
Conclusions: Results from our clinical practice have shown sufficient efficacy and safety of DOAC in AF patients. AF patients aged ≥ 85 years were at highest risk of major bleeding, therefore the risks and benefits of anticoagulation treatment should be carefully assessed before prescribing them DOAC. In-house dTT, which is available in clinical practice, reliably estimates dabigatran plasma concentration and is an appropriate method to use in case of adverse events. For laboratory monitoring of dabigatran treatment one measurement of dabigatran trough concentration is more reliable than measurement of dabigatran peak concentration due to its lower intraindividual variability. High trough concentrations may predispose patients to higher risk of bleeding.