key: cord-288626-7bp92xyo
authors: Spyropoulos, Alex C.; Ageno, Walter; Albers, Gregory W.; Elliott, C. Gregory; Halperin, Jonathan L.; Hiatt, William R.; Maynard, Gregory A.; Steg, P. Gabriel; Weitz, Jeffrey I.; Lu, Wentao; Spiro, Theodore E.; Barnathan, Elliot S.; Raskob, Gary. E.
title: Post-Discharge Prophylaxis With Rivaroxaban Reduces Fatal and Major Thromboembolic Events in Medically Ill Patients
date: 2020-06-30
journal: J Am Coll Cardiol
DOI: 10.1016/j.jacc.2020.04.071
sha: 
doc_id: 288626
cord_uid: 7bp92xyo

BACKGROUND: Hospitalized acutely ill medical patients are at risk for fatal and major thromboembolic events. Whether use of extended-duration primary thromboprophylaxis can prevent such events is unknown. OBJECTIVES: The purpose of this study was to evaluate whether extended-duration rivaroxaban reduces the risk of venous and arterial fatal and major thromboembolic events without significantly increasing major bleeding in acutely ill medical patients after discharge. METHODS: MARINER (A Study of Rivaroxaban [JNJ-39039039] on the Venous Thromboembolic Risk in Post-Hospital Discharge Patients) studied acutely ill medical patients with additional risk factors for venous thromboembolism (VTE). Medically ill patients with a baseline creatinine clearance ≥50 ml/min were randomized in a double-blind fashion to rivaroxaban 10 mg or placebo daily at hospital discharge for 45 days. Exploratory efficacy analyses were performed with the intent-to-treat population including all data through day 45. Time-to-event curves were calculated using the Kaplan-Meier method. A blinded independent committee adjudicated all clinical events. RESULTS: In total, 4,909 patients were assigned to rivaroxaban and 4,913 patients to placebo. The mean age was 67.8 years, 55.5% were men, mean baseline creatinine clearance was 87.8 ml/min, and mean duration of hospitalization was 6.7 days. The pre-specified composite efficacy endpoint (symptomatic VTE, myocardial infarction, nonhemorrhagic stroke, and cardiovascular death) occurred in 1.28% and 1.77% of patients in the rivaroxaban and placebo groups, respectively (hazard ratio: 0.72; 95% confidence interval: 0.52 to 1.00; p = 0.049), whereas major bleeding occurred in 0.27% and 0.18% of patients in the rivaroxaban and placebo groups, respectively (hazard ratio: 1.44; 95% confidence interval: 0.62 to 3.37; p = 0.398). CONCLUSIONS: Extended-duration rivaroxaban in hospitalized medically ill patients resulted in a 28% reduction in fatal and major thromboembolic events without a significant increase in major bleeding. (A Study of Rivaroxaban [JNJ-39039039] on the Venous Thromboembolic Risk in Post-Hospital Discharge Patients [MARINER]; NCT02111564)

A large proportion of the approximately 8 million acute medically ill patients each year in the United States are at risk for venous thromboembolism (VTE) (1) . Hospitalization is considered the single most important risk factor for developing these events (2) , and the risk of VTE continues beyond hospitalization, especially within the first 6 weeks after discharge (3) . Although the relationship between VTE and atherothrombosis/ arterial thromboembolism has been known for some time due to the shared mechanisms of inflammation, hypercoagulability, and endothelial injury inherent to both disease processes and due to common patient-level risk factors, such as obesity, dyslipidemia, and tobacco use (4, 5) , it has only recently been appreciated that medically ill patients are also at increased risk of arterial thromboembolic events in the post-hospital discharge period (6, 7) . Retrospective data also reveal that extended duration of a prophylactic dose of a direct oral anticoagulant in medically ill patients may reduce the risk of fatal and major arterial thromboembolism by 30% to 50% (6, 7) . Although the trial did not demonstrate a reduction in the primary endpoint of symptomatic VTE and VTE-related death, key secondary efficacy endpoints revealed a 56% reduction in symptomatic VTE and a 27% reduction in symptomatic VTE and all-cause mortality. The lower 7.5 mg dose of rivaroxaban used in patients with moderate renal insufficiency was found to be ineffective (8) A meta-analysis of arterial thrombosis (including MI and ischemic stroke) of older studies involving w11,000 medically ill inpatients receiving heparinbased prophylaxis did not find a reduction of these events compared with control subjects (odds ratio: On-treatment includes all data from randomization to 2 days after the last dose of the study drug (inclusive). Subjects who do not have events are censored on the minimum of last visit before or on death, or last dose þ2 days. CI ¼ confidence interval; HR ¼ hazard ratio.

Spyropoulos et al. (19) . In the large population of at-risk medically ill patients each year, this strategy would have the potential to prevent 12,000 fatal and major thromboembolic events annually at the cost of one-fourth to one-half that number of major or fatal bleeds (19) .

STUDY LIMITATIONS. Limitations of this study include its exploratory nature, because the MARINER study failed to meet its primary efficacy endpoint. We cannot exclude potential under-reporting of arterial thromboembolic events as the trial was powered to assess the risk of VTE, although this is unlikely because a standardized case report form was used with careful study oversight of outcomes and central adjudication of all of these events. In addition, the composite endpoint was driven primarily by a reduction in symptomatic VTE and ischemic stroke.

Although event rates may be considered low (<2.0%), the time-to-event curves suggest that events continued to accumulate after the study period of that rivaroxaban continues to reduce these events over a longer period of time. Our study also excluded subjects with moderate renal insufficiency because the reduced dose chosen (7.5 mg) was deemed inadequate. However, a recent study has demonstrated efficacy in this population with 10 mg daily of rivaroxaban with a favorable benefit risk profile (9) . As approximately 50% of our study population had baseline aspirin use, an important antithrombotic synergy between prophylactic dose rivaroxaban and antiplatelet therapy cannot be excluded, and there are mechanistic implications of such a synergistic antithrombotic strategy that may lead to reductions in CV outcomes (15, 16) .

Our analysis suggests that in at-risk medically ill patients who are discharged from the hospital, extended-duration rivaroxaban at the 10 mg daily dose leads to a significant risk reduction in a composite of fatal and major thromboembolic eventsincluding symptomatic VTE, MI, nonhemorrhagic stroke, and CV death-without a significant increase in major bleeding, compared with placebo. These data suggest that in properly selected patients at risk for VTE and at low risk for bleeding, that extendedduration rivaroxaban at 10 mg has a favorable benefit risk profile.

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