Robert P. Giugliano

Clinical Validation of a Point-of-Care Whole Blood Coagulometer in Patients on Factor Xa Inhibitors

Abstract Background Currently, no sensitive, widely available, rapid turnaround assays to measure the effect on coagulation of direct oral anticoagulants exist. Methods The point-of-care ClotChek (Perosphere Technologies Inc.) coagulometer was developed to address this unmet need with high sensitivity and precision. This proof-of-concept study aimed to determine normal clotting time in healthy, non-anticoagulated subjects; summarize clotting times at trough and peak drug concentrations in patients taking apixaban and rivaroxaban; and identify cut-points that maximize both sensitivity and specificity for predicting whether an individual is meaningfully anticoagulated. Results In 141 normal subjects, the mean clotting time was 244.2 ± 25.8 seconds (median 244.0 seconds; range 183–296 seconds). In 39 patients on apixaban, mean clotting times were 293.9 ± 32.5 seconds at trough and 323.1 ± 27.9 seconds at peak. In 42 patients on rivaroxaban, mean clotting times were 287.8 ± 44.9 seconds at trough and 380.4 ± 41.2 seconds at peak. Strong positive correlations are seen between the anticoagulant drug response determined by the assay and anticoagulant drug levels for apixaban (Spearman's rho = 0.74, p  < 0.0001) and for rivaroxaban (Spearman's rho = 0.82, p  < 0.0001). ClotChek clotting times showed good sensitivity and specificity to identify meaningful anticoagulation (>75 ng/mL) among patients taking apixaban (AUC = 0.91, 83% sensitivity, 86% specificity) or rivaroxaban (AUC = 0.96, 91% sensitivity, 90% specificity). Similar results were seen using the lower threshold of >30 ng/mL. Conclusion These results require clinical validation in further studies but suggest that the ClotChek assay could aid physicians at the point of care in making therapeutic decisions in patients with adverse events associated with oral factor Xa inhibitors.

Incidence and Predictors of Extracranial Bleeding on Oral Anticoagulants for Stroke Prevention in Patients With Atrial Fibrillation: A COMBINE-AF Analysis.

BACKGROUND Extracranial bleeding is the most common complication of oral anticoagulant (OAC) therapy for atrial fibrillation (AF), but its clinical importance for patients may be underrecognized. We sought to characterize extracranial bleeding events according to standardized severity definitions, identify baseline risk factors for bleeding, and quantify their population attributable fraction in patients with AF receiving OACs. METHODS We analyzed patients receiving OACs from 5 pivotal randomized trials testing a direct OAC or warfarin in patients with AF (COMBINE-AF [A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation]). The primary outcome was extracranial clinically relevant bleeding, defined as a first episode of extracranial major or clinically relevant nonmajor bleeding according to International Society on Thrombosis and Haemostasis criteria. The Kaplan-Meier method was used to calculate the cumulative incidence of bleeding by category. Multivariable Cox regression models were used to estimate adjusted hazard ratios (HRs) with 95% CI. Logistic regression models were used to calculate average population attributable fraction with 95% CI. RESULTS Of 73 737 patients treated with OACs, 10 634 experienced clinically relevant extracranial bleeding over a mean follow-up of 705 days (cumulative incidence, 26% [95% CI, 18%-35%]; 7.6 per 100 person-years). This included 3188 major bleeds (cumulative incidence, 7% [95% CI, 6%-7%]; 2.1 per 100 person-years) and 7446 clinically relevant nonmajor bleeds (cumulative incidence, 19% [95% CI, 12%-28%]; 5.2 per 100 person-years). The distribution of bleeding sites differed by severity, with gastrointestinal bleeds comprising 26% of clinically relevant bleeds, 49% of major bleeds, and 15% of clinically relevant nonmajor bleeds. Risk factors for extracranial bleeding were consistent across severity bleeding categories, and baseline covariates in our multivariable models accounted for 66% to 69% of the population attributable bleeding risk. CONCLUSIONS Extracranial clinically relevant bleeding is common among patients with AF treated with OACs and may more accurately reflect the overall burden of bleeding than major bleeding alone. Our models explained about two-thirds of the average population attributable risk, suggesting that additional unmeasured or unknown factors contribute to bleeding risk.

Thrombosis and Haemostasis Clinical Validation of a Point-of-Care Whole Blood Coagulometer in Patients on Factor Xa Inhibitors

Contemporary patients with atrial fibrillation are not anticoagulated despite risks of stroke - Insights from GARDENIA

Perceived risk of bleeding was the leading cause for non-treatment with OACs in high-risk AF patients, and risk prediction modelling indicated that the benefits of anticoagulation in stroke and mortality reduction outweigh the risk of bleeding.