Rationale and design for the study of rivaroxaban to reduce thrombotic events, hospitalization and death in outpatients with COVID-19: The PREVENT-HD study

© 2021 Elsevier Inc. Background: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. Study Design: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. Conclusions: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19

Cluster randomized trial assessing the effects of rapid ethical assessment on informed consent comprehension in a low-resource setting

Background Maximizing comprehension is a major challenge for informed consent processes in low-literacy and resource-limited settings. Application of rapid qualitative assessments to improve the informed consent process is increasingly considered useful. This study assessed the effects of Rapid Ethical Assessment (REA) on comprehension, retention and quality of the informed consent process. Methods A cluster randomized trial was conducted among participants of HPV sero-prevalence study in two districts of Northern Ethiopia, in 2013. A total of 300 study participants, 150 in the intervention and 150 in the control group, were included in the study. For the intervention group, the informed consent process was designed with further revisions based on REA findings. Informed consent comprehension levels and quality of the consent process were measured using the Modular Informed Consent Comprehension Assessment (MICCA) and Quality of Informed Consent (QuIC) process assessment tools, respectively. Result Study recruitment rates were 88.7 % and 80.7 % (p = 0.05), while study retention rates were 85.7 % and 70.3 % (p < 0.005) for the intervention and control groups respectively. Overall, the mean informed consent comprehension scores for the intervention and control groups were 73.1 % and 45.2 %, respectively, with a mean difference in comprehension score of 27.9 % (95 % CI 24.0 % - 33.4 %; p < 0.001,). Mean scores for quality of informed consent for the intervention and control groups were 89.1 % and 78.5 %, respectively, with a mean difference of 10.5 % (95 % CI 6.8 -14.2 %; p < 0.001). Conclusion Levels of informed consent comprehension, quality of the consent process, study recruitment and retention rates were significantly improved in the intervention group. We recommend REA as a potential modality to improve informed consent comprehension and quality of informed consent process in low resource settings

Association between asymptomatic proximal deep vein thrombosis and mortality in acutely ill medical patients

BACKGROUND: Asymptomatic proximal deep vein thrombosis (DVT) is an end point frequently used to evaluate the efficacy of anticoagulant thromboprophylaxis in medical patients. Recently, the clinical relevance of asymptomatic DVT has been challenged. METHODS AND RESULTS: The objective of this study was to evaluate the relationship between asymptomatic proximal DVT and all-cause mortality (ACM) using a cohort analysis of a randomized trial for the prevention of venous thromboembolism (VTE) in acutely ill medical patients. Patients who received at least 1 dose of study drug and had an adequate compression ultrasound examination of the legs on either day 10 or day 35 were categorized into 1 of 3 cohorts: no VTE, asymptomatic proximal DVT, or symptomatic DVT. Cox proportional hazards model, with adjustment for significant independent predictors of mortality, were used to compare the incidences of ACM. Of the 7036 patients, 6776 had no VTE, 236 had asymptomatic DVT, and 24 had symptomatic VTE. The incidence of ACM was 4.8% in patients without VTE. Both asymptomatic proximal DVT (mortality, 11.4%; hazard ratio [HR], 2.31; 95% CI, 1.52\u20133.51; P&lt;0.0001) and symptomatic VTE (mortality, 29.2%; HR, 9.42; 95% CI, 4.18\u201321.20; P&lt;0.0001) were independently associated with significant increases in ACM. The analysis was post hoc, and ultrasound results were not available for all patients. Adjustment for baseline variables significantly associated with ACM may not fully compensate for differences. CONCLUSIONS: Asymptomatic proximal DVT is associated with higher ACM than no VTE and remains a relevant end point to evaluate the efficacy of anticoagulant thromboprophylaxis in medical patients. REGISTRATION: URL: https://www.clini\u200bcaltr\u200bials.gov; Unique identifier: NCT00571649

Association of Bleeding Severity With Mortality in Extended Thromboprophylaxis of Medically Ill Patients in the MAGELLAN and MARINER Trials

Background: Extended thromboprophylaxis has not been widely implemented in acutely ill medical patients because of bleeding concerns. The MAGELLAN (Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Medically Ill Patients Comparing Rivaroxaban With Enoxaparin) and MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) trials evaluated whether rivaroxaban compared with enoxaparin or placebo could prevent venous thromboembolism without increased bleeding. We hypothesized that patients with major bleeding but not those with nonmajor clinically relevant bleeding would be at an increased risk of all-cause mortality (ACM). Methods: We evaluated all bleeding events in patients taking at least 1 dose of study drug and their association with ACM in 4 mutually exclusive groups: (1) no bleeding, or first event was (2) nonmajor clinically relevant bleeding, (3) major bleeding, or (4) trivial bleeding. Using a Cox proportional hazards model adjusted for differences in baseline characteristics associated with ACM, we assessed the risk of ACM after such events. Results: Compared with patients with no bleeding, the risk of ACM for patients with nonmajor clinically relevant bleeding was not increased in MARINER (hazard ratio, 0.43; P=0.235) but was increased in MAGELLAN (hazard ratio, 1.74; P=0.021). Major bleeding was associated with a higher incidence of ACM in both studies, whereas trivial bleeding was not associated with ACM in either study. Conclusions: Patients with major bleeding had an increased risk of ACM, whereas nonmajor clinically relevant bleeding was not consistently associated with an increased risk of death. These results inform the risk-benefit calculus of extended thromboprophylaxis in medically ill patients