Drug levels and bleeding complications in atrial fibrillation patients treated with direct oral anticoagulants.

Essentials Currently, DOACs are given at fixed doses and do not require laboratory monitoring. Direct oral anticoagulant-specific measurements were performed at trough and peak. Patients who developed bleeding events showed higher DOAC plasma levels at peak. This study suggests the need of a more accurate DOAC dose assessment. Direct oral anticoagulants (DOACs) are administered at fixed dose. The aim of the study was to evaluate the relationship between DOAC C-trough or C-peak plasma levels and bleeding complications in patients with non-valvular atrial fibrillation (NVAF). Five hundred sixty five consecutive naive NVAF patients were enrolled. The DOAC measurements at C-trough and at C-peak (available in 411 patients) were performed at steady state, within the first month of treatment. Major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and minor bleeding (MinB), occurring during 1 year of follow-up after blood sampling, were recorded. For each DOAC, interval of C-trough and C-peak levels was subdivided into four equal classes and results were attributed to these classes; the median values of results were also calculated. Two hundred eight patients were on apixaban, 185 on dabigatran, and 172 on rivaroxaban. For 1-[qqqdeletezzz] year follow up for all patients, we observed: 19 MB (3.36%), 6 CRNMB (1.06%), and 47 MinB (8.31%). The prevalence of bleeding patients with anticoagulant levels in the upper classes of C-peak activity (II + III + IV) was higher than that in the lowest class. Normalized results of C-peak levels were higher in patients with bleeding than in those without bleeding. Bleeding complications during DOAC treatment were more frequent among atrial fibrillation (AF) patients with higher C-peak anticoagulant levels. In addition to a previous study that showed an increased risk of thrombotic complications in the patients with low C-trough levels, this study seems to indicate that patients with NVAF on DOACs would need a more accurate definition of their optimal therapeutic window.

Testa S ，Legnani C ，Antonucci E ，Paoletti O ，Dellanoce C ，Cosmi B ，Pengo V ，Poli D ，Morandini R ，Testa R ，Tripodi A ，Palareti G ，Coordinator of START2-Register ... -  《-》

Low drug levels and thrombotic complications in high-risk atrial fibrillation patients treated with direct oral anticoagulants.

Essentials Direct oral anticoagulants (DOACs) do not require laboratory monitoring currently. DOAC specific measurements were performed at trough in patients with atrial fibrillation. Patients who developed thromboembolic events showed lower DOAC plasma levels. This study supports the concept of measuring DOAC levels at steady state. Background Direct oral anticoagulants (DOACs) are administered at fixed doses without the need for dose adjustment according to laboratory testing. High interindividual variability in drug blood levels has been shown with all DOACs. To evaluate a possible relationship between DOAC C-trough anticoagulant levels and thromboembolic events, 565 consecutive naive patients with atrial fibrillation (AF) were enrolled in this study performed within the START Laboratory Registry. Methods DOAC-specific measurements (diluted thrombin time or anti-activated factor II calibrated for dabigatran; anti-activated FX calibrated for rivaroxaban or apixaban) at C-trough were performed locally at steady state within 15-25 days after the start of treatment. For each DOAC, the interval of C-trough levels, from the limit of quantification to the highest value, was subdivided into four equal classes, and results were attributed to these classes; the median values of results were also calculated. Thromboembolic complications occurring during 1 year of follow-up were recorded. Results Thromboembolic events (1.8%) occurred in 10 patients who had baseline C-trough levels in the lowest class of drug levels. The incidence of thromboembolic events among patients with DOAC C-trough levels in the lowest level class was 2.4%, and that in the remaining groups was 0%. The patients with thrombotic complications also had a higher mean CHA2 DS2 -VASc score than that of the total patient population: 5.3 (95% confidence interval [CI] 4.3-6.3 versus 3.0 (95% CI 2.9-3.1). Conclusion In this study cohort, thrombotic complications occurred only in DOAC-treated AF patients who had very low C-trough levels, with a relatively high CHA2 DS2 -VASc score. Larger studies are warranted to confirm these preliminary observations.

Testa S ，Paoletti O ，Legnani C ，Dellanoce C ，Antonucci E ，Cosmi B ，Pengo V ，Poli D ，Morandini R ，Testa R ，Tripodi A ，Palareti G ... -  《-》

Direct Oral Anticoagulants Plasma Levels in Patients with Atrial Fibrillation at the Time of Bleeding: A Pilot Prospective Study.

Patients with atrial fibrillation (AF) on long-term direct oral anticoagulants (DOACs) may be at higher risk of bleeding because of higher anti-Xa or anti-IIa levels. However, there is no postmarketing study investigating these DOAC plasma levels at the time of bleeding. The aim of this study was to evaluate DOAC levels at the time of a bleeding emergency. We analyzed 5440 patients examined at our Emergency Department in from April 1, 2019, to September 30, 2019. During this period, we prospective identified 105 consecutive patients with bleeding while on long-term antithrombotic therapy; 49 patients had AF on DOACs. We compared DOAC levels in patients who bled against a control sample of 55 patients who tolerated long-term high dose DOAC therapy without any emergency. Samples of these patients were tested with drug-specific anti-Xa chromogenic analysis (rivaroxaban and apixaban) and with Hemoclot Thrombin Inhibitor assay (dabigatran). Dabigatran-treated patients who bled had significantly higher anti-IIa levels when compared with trough (261.4 ± 163.7 vs. 85.4 ± 57.2 ng/mL, P < 0.001) and peak samples of controls (261.4 ± 163.7 vs. 138.8 ± 78.7 ng/mL, P < 0.05). Similarly, there were significantly higher anti-Xa levels in rivaroxaban-treated and apixaban-treated patients with bleeding compared with trough control samples (rivaroxaban: 245.9 ± 150.2 vs. 52.5 ± 36.4 ng/mL, P <0.001 and apixaban: 311.8 ± 142.5 vs. 119.9 ± 81.7 ng/mL, P < 0.001), as well as in apixaban-treated patients when compared with peak control samples (311.8 ± 142.5 vs. 210.9 ± 88.7 ng/mL, P < 0.05). Finally, rivaroxaban anti-Xa levels in patients who bled tended to be higher compared with peak control samples (245.9 ± 150.2 vs. 177.6 ± 38.6 ng/mL, P = 0.13). This observational study showed a significant difference in anti-IIa and anti-Xa plasma levels in patients with AF with bleeding complications compared with those who tolerated long-term high-dose DOAC therapy without bleeding complications.

Škorňová I ，Samoš M ，Bolek T ，Kamenišťáková A ，Stančiaková L ，Galajda P ，Staško J ，Kubisz P ，Mokáň M ... -  《-》

Direct oral anticoagulant plasma levels' striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents: The Cremona experience.

Antiviral drugs are administered in patients with severe COVID-19 respiratory syndrome, including those treated with direct oral anticoagulants (DOACs). Concomitant administration of antiviral agents has the potential to increase their plasma concentration. A series of patients managed in the Cremona Thrombosis Center were admitted at Cremona Hospital for SARS-CoV-2 and started antiviral drugs without stopping DOAC therapy. DOAC plasma levels were measured in hospital and results compared with those recorded before hospitalization. All consecutive patients on DOACs were candidates for administration of antiviral agents (lopinavir, ritonavir, or darunavir). Plasma samples for DOAC measurement were collected 2to 4 days after starting antiviral treatment, at 12 hours from the last dose intake in patients on dabigatran and apixaban, and at 24 hours in those on rivaroxaban and edoxaban. For each patient, C-trough DOAC level, expressed as ng/mL, was compared with the one measured before hospitalization. Of the 1039 patients hospitalized between February 22 and March 15, 2020 with COVID-19 pneumonia and candidates for antiviral therapy, 32 were on treatment with a DOAC. DOAC was stopped in 20 and continued in the remaining 12. On average, C-trough levels were 6.14 times higher during hospitalization than in the pre-hospitalization period. DOAC patients treated with antiviral drugs show an alarming increase in DOAC plasma levels. In order to prevent bleeding complications, we believe that physicians should consider withholding DOACs from patients with SARS-CoV-2 and replacing them with alternative parenteral antithrombotic strategies for as long as antiviral agents are deemed necessary and until discharge.

Testa S ，Prandoni P ，Paoletti O ，Morandini R ，Tala M ，Dellanoce C ，Giorgi-Pierfranceschi M ，Betti M ，Danzi GB ，Pan A ，Palareti G ... -  《-》

Bleeding Risk of Add-On Anti-Platelet Agents to Direct Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation (From 2216 Patients in the DIRECT Registry).

Clinical outcomes of the real-world Asian nonvalvular atrial fibrillation (NVAF) patients treated with DOAC and the incremental bleeding risk of add-on antiplatelet therapy to direct oral anticoagulants (DOACs) are still to be investigated. We conducted a single-center prospective observational registry of NVAF patients treated with DOACs: the DIRECT registry (UMIN000033283). All patients with NVAF (N = 2216) who were users of dabigatran (N = 648), rivaroxaban (N = 538), apixaban (N = 599), or edoxaban (N = 431) from June 2011 to November 2017 were enrolled (71.6 ± 10.8 years, 36.4% female, follow-up duration: 407.2 ± 388.3 days). No add-on antiplatelet agent was prescribed to 1,739 patients, while single and dual antiplatelet therapy (SAPT and DAPT) in combination with DOAC were prescribed to 411 and 66 patients, respectively. The primary safety endpoint was any bleeding which was defined as a composite of major bleeding according to the International Society on Thrombosis and Hemostasis criteria and clinically relevant non-major bleeding. Patients treated with add-on antiplatelet agents irrespective of SAPT or DAPT had a higher any-bleeding risk than those without (hazard ratio: 1.42; 95% confidence interval 1.16-1.74, p = 0.001). Multivariate adjusted hazard of add-on antiplatelet therapy was not statistically significant (hazard ratio: 1.20; 95% confidence interval 0.94-1.53, p = 0.147). In conclusion, NVAF patients treated with antiplatelet agents and DOAC had a significantly higher bleeding risk than those using DOAC only. However, after adjustment of patients' background, add-on antiplatelet therapy to DOAC itself did not influence to a bleeding risk.

Sotomi Y ，Hirata A ，Amiya R ，Kobayashi T ，Hirayama A ，Sakata Y ，Higuchi Y ... -  《-》