MORE EARLY BLEEDS ASSOCIATED WITH HIGH BASELINE DIRECT ORAL ANTICOAGULANT LEVELS IN ATRIAL FIBRILLATION: THE MAS STUDY.

Treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) patients is effective and safe. However, bleeding complications still occur. Whether the measurement of DOAC levels may further improve treatment efficacy and safety is still an open issue. In the "Measure and See" (MAS) Study (#NCT03803579) venous blood was collected 15-30 days after DOAC initiation in AF patients who were then followed for one year to record the occurrence of major and clinically relevant non-major bleeding. DOAC plasma levels were measured in one laboratory, and results were kept blind to patients and treating doctors. Trough DOAC levels were assessed in 1657 patients [957 (57.7%) and 700 treated with standard and low-dose, respectively]. Fifty bleeding events were recorded during 1606 years of follow-up (3.11% pt/yrs). Fifteen bleeding events (4.97% pt/yrs) occurred in patients with C-trough standardized values in the highest activity class (> 0.50); whereas 35 events (2.69% pt/yrs) occurred in those with values in the two lower classes ( 0.50, p= 0.0401). Increasing DOAC levels and low-dose DOAC use were associated with increased bleeding risk in the first three months of treatment. 19% of patients receiving low doses had standardized activity values in the highest class. More bleeding occurred in patients treated with low (4.3% pt/yrs) than standard (2.2% pt/yrs; p= 0.0160) dose DOAC. Early measurement of DOAC levels in AF patients identified many subjects with high activity levels despite the low doses use and had more bleeding risk during the first 3 months of treatment.

Thrombotic events associated with low baseline direct oral anticoagulant levels in atrial fibrillation: the MAS study.

ABSTRACT: Although effective and safe, treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) is still associated with thrombotic complications. Whether the measurement of DOAC levels may improve treatment efficacy is an open issue. We carried out the observational, prospective, multicenter Measure and See (MAS) study. Blood was collected 15 to 30 days after starting DOAC treatment in patients with AF who were followed-up for 1 year. Plasma samples were centralized for DOAC level measurement. Patients' DOAC levels were converted into drug/dosage standardized values to allow a pooled analysis in a time-dependent, competitive-risk model. The measured values were transformed into standardized values (representing the distance of each value from the overall mean) by subtracting the DOAC-specific mean value from the original values and dividing by the standard deviation. Trough and peak DOAC levels were assessed in 1657 and 1303 patients, respectively. In total, 21 thrombotic complications were recorded during 1606 years of follow-up (incidence of 1.31% of patients per year). Of 21 thrombotic events, 17 occurred in patients whose standardized activity levels were below the mean of each DOAC (0); the incidence was the highest (4.82% of patients per year) in patients whose standardized values were in the lowest class (-1.00 or less). Early measurement of DOAC levels in patients with AF allowed us to identify most of the patients who, having low baseline DOAC levels, subsequently developed thrombotic complications. Further studies are warranted to assess whether thrombotic complications may be reduced by measuring baseline DOAC levels and modifying treatment when indicated. This trial was registered at www.ClinicalTrials.gov as #NCT03803579.

Prevalence of asymptomatic deep vein thrombosis in patients hospitalized with SARS-CoV-2 pneumonia: a cross-sectional study.

The association between coronavirus disease 2019 (COVID-19) pneumonia and venous thrombotic disorders is still unclear. We assessed the association between COVID-19 infection-related pneumonia and proximal deep-vein thrombosis (DVT) in a cohort of patients admitted to our hospital during the European outbreak in the front line of Cremona, Lombardy. In a single-center cross-sectional study, all patients hospitalized for more than 5 days in Internal Medicine Department with confirmed COVID-19 pneumonia received 2-point compressive ultrasound assessment (CUS) of the leg vein system during a single day. Ninety-four percent of patients received enoxaparin as standard pharmacological prophylaxis for venous thromboembolism. The presence of DVT was defined as incompressibility of popliteal or common femoral vein. Out of 121 patients with COVID-19 pneumonia (mean age 71.8, 66.3% males) hospitalized on March 31st, 70 stayed in hospital for over 5 days and 66 of them underwent CUS of deep venous system of the legs. The presence of asymptomatic DVT was found in 9 patients (13.6%). No symptomatic DVT was found. Patients with DVT showed mean age = 75.7 years, mean D-dimer levels = 4.02 ng/ml and all of them received enoxaparin for thromboprophylaxis, except one. Computed tomography pulmonary angiogram confirmed pulmonary embolism in five patients. One every seven patients with COVID-19-related pneumonia, hospitalized for more than 5 days, had asymptomatic proximal DVT and half of them had confirmed PE despite standard pharmacological thromboprophylaxis. This observational study suggests the need of an active surveillance through CUS in patients hospitalized with acute SARS-COV-2 and underline the need of a more intense thromboprophylaxis.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The effect of management models on thromboembolic and bleeding rates in anticoagulated patients: an ecological study.

The primary study objective is to compare the outcomes of patients taking oral anticoagulant medications in two distinct populations treated according to different management models (comprehensive vs. usual care). (Design: regional prospective cohort study; setting: hospital admission data from two regions). Eligible partecipants were patients taking oral anticoagulant drugs (vitamin K antagonist or direct oral anticoagulants), residents in the Vicenza and Cremona districts from February 1st, 2016 to June 30th, 2017. Patients were identified by accessing the administrative databases of patient drug prescriptions. The primary study outcome was admission to the Emergency Department for stroke, systemic arterial embolism, recurrence of venous thromboembolism or major bleeding. The study evaluated outcomes in 14,226 patients taking oral anticoagulants, of whom 6725 being followed in Cremona with a comprehensive management model. There were 19 and 45 thromboembolic events over 6205 and 6530 patient-years in the Cremona and Vicenza cohort, respectively (IRR 0.44, 95% CI 0.24-0.77). The reduction of events in the Cremona cohort was almost entirely explained by a decrease of events in patients taking VKA (IRR 0.41, 95% CI 0.20-0.78) but not DOACs (IRR 1.08, 95% CI 0.25-5.24). The rate of major bleeding was non-significantly higher in Cremona than in Vicenza (IRI 1.32; 95% CI 0.74-2.40). Across the two cohorts, the risk of bleeding was lower in patients being treated with DOACs rather than warfarin (10/4574 vs. 42/8161 event/person-years, respectively, IRR 0.42 95% CI 0.19-0.86). We conclude that a comprehensive management model providing centralized dose prescription and follow-up may significantly reduce the rate of thromboembolic complications, without substantially increasing the number of bleeding complications. Patients treated with direct oral anticoagulants appear to have a rate of thromboembolic complications comparable to VKA patients under the best management model, with a reduction of major bleeding.

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. BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Edoxaban plasma levels in patients with non-valvular atrial fibrillation: Inter and intra-individual variability, correlation with coagulation screening test and renal function.

BACKGROUND: High inter-individual variability of the anticoagulant plasma levels of the first three direct oral anticoagulants was previously reported. Aims of the present study were to evaluate edoxaban inter and intra-individual variability in patients with non valvular atrial fibrillation and to assess correlation between edoxaban plasma levels and coagulation screening test and renal function. METHODS: From January 31st 2017 to June 30th 2018, a total of 101 NVAF patients were enrolled: 48 patients were on edoxaban 60 mg and 53 on edoxaban 30 mg, once daily. Blood samples were taken at C-trough and at C-peak within the first month (15-25 days) of treatment and then at C-trough each three months. Prothrombin time (PT), activated partial thromboplastin time (aPTT), specific anti-FXa chromogenic test were performed. Creatinine clearance (CrCl) was calculated using the Cockcroft-Gault formula. RESULTS: Mean inter-individual variability expressed as overall coefficient of variation (CV%) values was lower at C-peak (CV% = 49) than at C-trough (CV% = 68). Mean CV% intra-individual variability was 26.5. No significant correlation was found between edoxaban plasma levels and CrCl (C-trough r/r2 = -0.007/0.000; C-peak r/r2 = 0.129/0.017). Correlations (r/r2), at C-trough and C-peak, between edoxaban levels and PT and aPTT, were 0.386/0.149-0.922/0.851 and 0.283/0.080-0.567/0.321, respectively. Significant discrepancies between PT or aPTT and edoxaban levels were found. CONCLUSIONS: This study confirms also for edoxaban a high inter-individual variability in NVAF patients. PT and aPTT are not useful to measure this drug. As for the other two anti-FXa drugs, the absence of a significant correlation between CrCl and edoxaban plasma levels was observed.

Management of major bleeding and outcomes in patients treated with direct oral anticoagulants: results from the START-Event registry.

The management of major bleeding in patients treated with direct oral anticoagulants (DOACs) is still not well established. START-Events, a branch of the START registry (Survey on anTicoagulated pAtients RegisTer) (NCT02219984), aims to describe the actual management of bleeding or recurrent thrombotic events in routine clinical practice. We here present the results of the management of bleeding patients. The START-Event registry is a prospective, observational, multicenter, international study. Baseline characteristics (demographic, clinical, risk factors) of patients, laboratory data at admission and during follow-up, site of bleeding, therapeutic strategies, and outcomes at the time of hospital discharge and after 6 months were recorded on a web-based case report form. Between January 2015 and December 2016, 117 patients with major bleeding events were enrolled. Non-valvular atrial fibrillation (NVAF) was the indication for treatment in 84% (62% males); 53 patients had intracranial bleeding (13 fatal), 42 had gastrointestinal bleeding (1 fatal), and 22 had bleeding in other sites. Therapeutic interventions for the management of bleeding were performed in 71% of patients. Therapeutic strategies with/without surgery or invasive procedures included: fluid replacement or red blood cells transfusion, prothrombin complex concentrates (3 or 4 factors), antifibrinolytic drugs, and the administration of idarucizumab. Creatinine, blood cell count, and PT/aPTT were the most frequent tests requested, while specific DOAC measurements were performed in 23% of patients. Mortality during hospitalization was 11.9%, at 6-month follow-up 15.5%. Our data confirm a high heterogeneity in the management of bleeding complications in patients treated with DOACs.

Dabigatran Plasma Measurement to Guide the Management of Acute Bleeding and Thrombotic Complications.

Oral anticoagulant therapy is recommended for the prevention and treatment of venous thromboembolism and to prevent stroke in non-valvular atrial fibrillation. Until a few years ago, vitamin K antagonists were the only drugs available, but direct oral anticoagulants have recently been introduced into clinical practice for the same clinical indications. Unlike the situation with VKAs, fixed-dose administration was proposed for DOACs, without the necessity for routine laboratory monitoring. However, in clinical practice a high inter-variability in DOAC plasma levels, independently of the type of drug and patient characteristics, was observed and the importance of measuring DOAC anticoagulant activity to support treatment decisions has therefore been recognized. We describe two clinical cases in order to highlight the role and importance of dabigatran-specific measurements to guide patient management in case of major complications. LEARNING POINT: Direct oral anticoagulants (DOACs) have been used in clinical practice at fixed doses without laboratory monitoring.However, the importance of measuring DOAC anticoagulant activity to support treatment decisions, particularly in emergency conditions, has been recognized.The clinical value of DOAC measurement is highlighted in the two described cases where the anticoagulation level was taken into consideration when deciding on treatment.