Risk of major bleeding in elderly patients with atrial fibrillation on direct oral anticoagulants: real world experience.

Background The efficacy and safety of direct oral anticoagulants is well established in patients with atrial fibrillation. However, data on their use in the oldest old patients (≥ 85 years), who have the highest risk of bleeding, is scarce. Objective The aim of this study was to evaluate the safety of direct oral anticoagulants in the oldest old patients with atrial fibrillation and assess the impact of age on major bleeding events. Setting Anticoagulation Clinic of the Department of Vascular Diseases, University Medical Centre Ljubljana, Slovenia. Methods From our single-centre prospective registry we enrolled 2260 consecutive atrial fibrillation patients aged ≥ 65 years that were started on dabigatran, rivaroxaban or apixaban. The mean duration of treatment exposure was 735 days. The primary outcome was the incidence of major bleeding. The incidence of thromboembolic events and death were also assessed. Potential risk factors for major bleeding were evaluated using Cox regression analysis. Main outcome measure Rate of major bleeding. Results During the follow-up 106 patients experienced major bleeding (2.3%/year). The oldest old patients (≥ 85 years) had the highest risk of any major bleeding (HR 2.50, 95% CI 1.44-4.32, p = 0.001), intracranial bleeding (HR 4.74, 95% CI 1.48-15.14, p < 0.01) and major gastrointestinal bleeding (HR 2.32, 95% CI 1.10-4.89, p < 0.03) compared to the group of patients aged 65-74 years, even though the majority of them were treated with reduced doses of direct oral anticoagulants. Significant predictors for major bleeding were age group ≥ 85 years (HR 2.52, 95% CI 1.43-4.47, p = 0.001) and history of bleeding (HR 3.32, 95% CI 1.87-5.90, p < 0.001). The incidence of a composite of stroke, transient ischemic attack and systemic embolism was 1.3%/year. Conclusion In this prospective real-world clinical study we have shown that the oldest old patients have the highest risk of major bleeding, which is further increased with a patient's history of bleeding.

Diluted thrombin time reliably measures low to intermediate plasma dabigatran concentrations.

BACKGROUND: Direct oral anticoagulant dabigatran was first introduced as a fixed-dose drug without routine coagulation monitoring, but current recommendations suggest that diluted thrombin time can be used to estimate plasma drug level. The aim of this study was to assess a diluted thrombin time assay based on the same thrombin reagent already used for traditional thrombin time measurements that reliably measure low to intermediate plasma dabigatran levels. METHODS: We included 44 patients with atrial fibrillation who started treatment with dabigatran 150 mg (23 patients) or 110 mg (21 patients) twice a day. Blood samples were collected at baseline (no dabigatran) and 2-4 weeks after the beginning of dabigatran therapy at trough and at peak. Plasma dabigatran levels were measured with diluted thrombin time and compared to liquid chromatography with tandem mass spectrometry as the reference method. The performance of the diluted thrombin time was compared to Hemoclot® Thrombin Inhibitor and Ecarin Chromogenic Assay. RESULTS: In ex vivo plasma samples, diluted thrombin time highly correlated with the liquid chromatography with tandem mass spectrometry (Pearson's R = 0.9799). In the low to intermediate range (dabigatran concentration ≤ 100 µg/L) diluted thrombin time correlated significantly more closely to the liquid chromatography with tandem mass spectrometry (R = 0.964) than Hemoclot® Thrombin Inhibitor (R = 0.935, p = 0.05) or Ecarin Chromogenic Assay (R = 0.915, p < 0.01). It was also the only functional assay without any significant bias in the low to intermediate range. Both trough and peak diluted thrombin time values were similar to liquid chromatography with tandem mass spectrometry. CONCLUSION: We conclude that the diluted thrombin time assay presented in this study reliably detects dabigatran and that it is superior to the Hemoclot® Thrombin Inhibitor assay in the low to intermediate range.

Dabigatran Concentration: Variability and Potential Bleeding Prediction In "Real-Life" Patients With Atrial Fibrillation.

Routine laboratory monitoring is currently not recommended in patients receiving dabigatran despite its considerable variation in plasma concentration. However, in certain clinical situations, measurements of the dabigatran effect may be desirable. We aimed to assess the variability of dabigatran trough and peak concentration and explore the potential relationship between dabigatran concentration and adverse events. We included 44 patients with atrial fibrillation who started treatment with dabigatran 150 mg (D150) or 110 mg (D110) twice daily. They contributed 170 trough and peak blood samples that were collected 2-4 and 6-8 weeks after dabigatran initiation. Plasma dabigatran concentration was measured by LC-MS/MS and indirectly, by selected coagulation tests. D110 patients were older (74 ± 7 versus 68 ± 6 years), had lower creatinine clearance (68 ± 21 versus 92 ± 24 mL/min) and higher CHA2 DS2 -VASc score (3.1 ± 1.3 versus 2.3 ± 0.9) compared to D150 patients (all p < 0.05), but both had similar dabigatran concentrations in both trough and peak samples. Dabigatran concentrations varied less in trough than in peak samples (17.0 ± 13.6 versus 26.6 ± 19.2%, p = 0.02). During the 12-month follow-up, 4 patients on D150 and 6 on D110 suffered minor bleeding. There was no major bleeding or thromboembolic event. Patients with bleeding had significantly higher average trough dabigatran concentrations (93 ± 36 versus 72 ± 62 µg/L, p = 0.02) than patients without bleeding, while peak dabigatran values had no predictive value. Dabigatran dose selection according to the guidelines resulted in appropriate trough concentrations with acceptable repeatability. High trough concentrations may predispose patients to the risk of minor bleeding.