Benefit-Risk Assessment of Rivaroxaban for Extended Thromboprophylaxis After Hospitalization for Medical Illness.

Background Venous thromboembolism (VTE) often occurs after hospitalization in medically ill patients, but the population benefit-risk of extended thromboprophylaxis remains uncertain. Methods and Results The MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) study (NCT02111564) was a randomized double-blind trial that compared thromboprophylaxis with rivaroxaban 10 mg daily versus placebo for 45 days after hospital discharge in medically ill patients with a creatinine clearance ≥50 mL/min. The benefit-risk balance in this population was quantified by calculating the between-treatment rate differences in efficacy and safety end points per 10 000 patients treated. Clinical characteristics of the study population were consistent with a hospitalized medical population at risk for VTE. Treating 10 000 patients with rivaroxaban resulted in 32.5 fewer symptomatic VTE and VTE-related deaths but was associated with 8 additional major bleeding events. The treatment benefit was driven by the prevention of nonfatal symptomatic VTE (26 fewer events). There was no between-treatment difference in the composite of critical site or fatal bleeding. Conclusions Extending thromboprophylaxis with rivaroxaban for 45 days after hospitalization provides a positive benefit-risk balance in medically ill patients at risk for VTE who are not at high risk for bleeding. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT02111564.

Extended Thromboprophylaxis in Hospitalized Patients with Heart Failure: A Post Hoc Analysis of the MAGELLAN Study.

This post hoc subgroup analysis examined efficacy and safety outcomes with extended thromboprophylaxis rivaroxaban compared with in-hospital enoxaparin in 2,078 patients from the MAGELLAN study who had a hospitalization for heart failure or a history of heart failure and a lower risk of bleeding. A significant 36% reduction in the composite endpoint of asymptomatic proximal deep vein thrombosis (DVT) in the lower extremity, symptomatic DVT in the lower extremity (proximal or distal), symptomatic nonfatal pulmonary embolism, and venous thromboembolism-related death was observed with rivaroxaban. Major bleeding was low in both groups and not significantly increased with rivaroxaban.

Rivaroxaban Plus Aspirin for Extended Thromboprophylaxis in Acutely Ill Medical Patients: Insights from the MARINER Trial.

Background The MARINER trial evaluated whether postdischarge thromboprophylaxis with rivaroxaban could reduce the primary outcome of symptomatic venous thromboembolism (VTE) or VTE-related death in acutely ill medical patients at risk for VTE. Although aspirin use was not randomized, approximately half of the enrolled patients were receiving aspirin at baseline. We hypothesized that thromboprophylaxis with once-daily rivaroxaban (10 mg or, if creatinine clearance was 30-49 mL/min, 7.5 mg) plus aspirin (R/A) would be superior to placebo without aspirin (no thromboprophylaxis [no TP]). Methods We compared the primary and major secondary outcomes in the intention-to-treat population in four subgroups defined at baseline: (1) R/A ( N = 3,159); (2) rivaroxaban alone ( N = 2,848); (3) aspirin alone ( N = 3,046); and (4) no TP ( N = 2,966). Major bleeding (MB) and nonmajor clinically relevant (NMCR) bleeding were assessed in the safety population on treatment plus 2 days. Results Patients on R/A had reduced symptomatic VTE and VTE-related death compared with no TP (0.76 vs 1.28%, p = 0.042), and experienced less symptomatic VTE and all-cause mortality ( p = 0.005) and all-cause mortality alone ( p = 0.01) compared with no TP. Event incidences for rivaroxaban alone (0.91%) or aspirin alone (0.92%) were similar. MB was low in all groups but lowest in the no TP group. NMCR bleeding was increased with R/A compared with no TP ( p = 0.009). Limitations Aspirin use was not randomized. Conclusion Extended postdischarge thromboprophylaxis with R/A was associated with less symptomatic VTE and VTE-related death compared with no TP in previously hospitalized medical patients at risk for VTE. NMCR bleeding was increased with R/A compared with no TP. These post hoc findings need confirmation in a prospective trial.

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. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: MAGELLAN, NCT00571649. URL: https://www. CLINICALTRIALS: gov; Unique identifier: MARINER, NCT02111564.

Cost-Effectiveness of Combination of Baricitinib and Remdesivir in Hospitalized Patients with COVID-19 in the United States: A Modelling Study.

INTRODUCTION: Baricitinib-remdesivir (BARI-REM) combination is superior to remdesivir (REM) in reducing recovery time and accelerating clinical improvement among hospitalized patients with coronavirus disease 2019 (COVID-19), specifically those receiving high-flow oxygen/noninvasive ventilation. Here we assessed the cost-effectiveness of BARI-REM versus REM in hospitalized patients with COVID-19 in the USA. METHODS: A three-state model was developed addressing costs and patient utility associated with COVID-19 hospitalization, immediate post hospital care, and subsequent lifetime medical care. Analysis was performed from the perspective of a payer and a hospital. Both perspectives evaluated two subgroups: all patients and patients who required oxygen. The primary measures of benefit in the model were patient quality-adjusted life years (QALYs) accrued during and after hospitalization, cost per life years gained, cost per death avoided, and cost per use of mechanical ventilation avoided. RESULTS: In the base-case payer perspective with a lifetime horizon, treatment with BARI-REM versus REM resulted in an incremental total cost of $7962, a gain of 0.446 life years and gain of 0.3565 QALYs over REM. The incremental cost-effectiveness ratios of using BARI-REM were estimated as $22,334 per QALY and $17,858 per life year. The base-case and sensitivity analyses showed that the total incremental cost per QALY falls within the reduced willingness-to-pay threshold of $50,000/QALY applied under health emergencies. In all hospitalized patients, treatment with BARI-REM versus REM reduced total hospital expenditures per patient by $1778 and total reimbursement payments by $1526, resulting in a $252 reduction in net costs per patient; it also resulted in a net gain of 0.0018 QALYs and increased survival of COVID-19 hospitalizations by 2.7%. CONCLUSION: Our study showed that BARI-REM is cost-effective compared to using REM for hospitalized patients with COVID-19. The base-case results of this cost-effectiveness model were most sensitive to average annual medical costs for recovered patients.

Risk of Severe Bleeding With Extended Rivaroxaban to Prevent Venous Thromboembolism in Acute Medically Ill Patients With Bronchiectasis.

Background: Bronchiectasis is a chronic inflammation of the bronchi with recurrent infections and hemoptysis. The MAGELLAN study compared oral rivaroxaban, 10 mg once daily (QD), for 35 ± 4 days with subcutaneous enoxaparin 40 mg QD for 10 ± 4 days followed by placebo for 25 ± 4 days to prevent venous thromboembolism in patients hospitalized with an acute medical illness. MAGELLAN included a subset of patients with bronchiectasis. In a post hoc analysis, we evaluated the incidence and severity of pulmonary bleeding in patients with bronchiectasis who were hospitalized for an acute medical illness. This analysis included MAGELLAN patients diagnosed with bronchiectasis at baseline. Patients were evaluated by treatment group for International Society on Thrombosis and Haemostasis major bleeding, non-major clinically relevant (NMCR) bleeding, and the composite of the 2 (ie, clinically relevant bleeding). Results: Medically ill patients with bronchiectasis were randomized to rivaroxaban (n = 60) or enoxaparin/placebo (n = 61). There were 2 fatal pulmonary bleeds and 1 fatal gastrointestinal bleed in the rivaroxaban arm and no fatal or major bleeding in the enoxaparin/placebo arm. The incidence of major bleeding was 5% in the rivaroxaban arm. One NMCR bleed occurred in the rivaroxaban arm and 2 NMCR bleeds occurred in the enoxaparin/placebo arm. The incidence of clinically relevant bleeding was 6.7% versus 3.3% in the rivaroxaban and enoxaparin/placebo groups, respectively (relative risk = 2.06 [95% confidence interval: 0.351-12.046]). Conclusion: In-patients hospitalized with bronchiectasis and an acute medical illness, clinically relevant bleeding, including fatal pulmonary hemorrhage, occurs more frequently with extended rivaroxaban thromboprophylaxis than with enoxaparin followed by placebo.

Benefit-Risk of Rivaroxaban for Extended Thromboprophylaxis After Hospitalization for Medical Illness: Pooled Analysis From MAGELLAN and MARINER.

Background Thromboprophylaxis extended after hospital discharge in medically ill patients currently is not recommended by practice guidelines because of uncertainty about the benefit for preventing major or fatal thromboembolic events, and the risk of bleeding. Methods and Results We assessed the benefit and risk of thromboprophylaxis with rivaroxaban 10 mg once daily extended for 25 to 45 days after hospitalization for preventing major thromboembolism in medically ill patients using the pooled data in 16 496 patients from 2 randomized trials, MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) and MAGELLAN (Multicenter, randomized, parallel-group efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically ill patients comparing rivaroxaban with enoxaparin). The data from the MARINER trial were pooled with the data from the MAGELLAN trial in patients who were free of thrombotic or bleeding events up to the last dose of enoxaparin/placebo and who continued in the outpatient phase of thromboprophylaxis. The composite outcome of major thromboembolic events (symptomatic deep vein thrombosis, nonfatal pulmonary embolism, myocardial infarction, and nonhemorrhagic stroke) and all-cause mortality was used to assess benefit and was compared with the risk of the composite of fatal and critical site bleeding. The incidence of the composite efficacy outcome was 1.80% (148 of 8222 patients) in the rivaroxaban group, compared with 2.31% (191 of 8274 patients in the placebo group) (HR, 0.78 [95% CI, 0.63-0.97], P=0.024). Fatal or critical site bleeding events were infrequent and occurred in <0.1% of patients in both groups (rivaroxaban 0.09%; placebo 0.04%; HR, 2.36; P=0.214). Conclusions The results suggest a benefit for reducing major thromboembolic outcomes (number needed to treat: 197), with a favorable trade-off to fatal or critical site bleeding (number needed to harm: 2045). Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00571649 and NCT02111564.

Cost-Effectiveness of Baricitinib Compared With Standard of Care: A Modeling Study in Hospitalized Patients With COVID-19 in the United States.

PURPOSE: In the Phase III COV-BARRIER (Efficacy and Safety of Baricitinib for the Treatment of Hospitalised Adults With COVID-19) trial, treatment with baricitinib, an oral selective Janus kinase 1/2 inhibitor, in addition to standard of care (SOC), was associated with significantly reduced mortality over 28 days in hospitalized patients with coronavirus disease-2019 (COVID-19), with a safety profile similar to that of SOC alone. This study assessed the cost-effectiveness of baricitinib + SOC versus SOC alone (which included systemic corticosteroids and remdesivir) in hospitalized patients with COVID-19 in the United States. METHODS: An economic model was developed to simulate inpatients' stay, discharge to postacute care, and recovery. Costs modeled included payor costs, hospital costs, and indirect costs. Benefits modeled included life-years (LYs) gained, quality-adjusted life-years (QALYs) gained, deaths avoided, and use of mechanical ventilation avoided. The primary analysis was performed from a payor perspective over a lifetime horizon; a secondary analysis was performed from a hospital perspective. The base-case analysis modeled the numeric differences in treatment effectiveness observed in the COV-BARRIER trial. Scenario analyses were also performed in which the clinical benefit of baricitinib was limited to the statistically significant reduction in mortality demonstrated in the trial. FINDINGS: In the base-case payor perspective model, an incremental total cost of 17,276 US dollars (USD), total QALYs gained of 0.6703, and total LYs gained of 0.837 were found with baricitinib + SOC compared with SOC alone. With the addition of baricitinib, survival was increased by 5.1% and the use of mechanical ventilation was reduced by 1.6%. The base-case incremental cost-effectiveness ratios were 25,774 USD/QALY gained and 20,638 USD/LY gained; a "mortality-only" scenario analysis yielded similar results of 26,862 USD/QALY gained and 21,433 USD/LY gained. From the hospital perspective, combination treatment with baricitinib + SOC was more effective and less costly than was SOC alone in the base case, with an incremental cost of 38,964 USD per death avoided in the mortality-only scenario. IMPLICATIONS: In hospitalized patients with COVID-19 in the United States, the addition of baricitinib to SOC was cost-effective. Cost-effectiveness was demonstrated from both the payor and the hospital perspectives. These findings were robust to sensitivity analysis and to conservative assumptions limiting the clinical benefits of baricitinib to the statistically significant reduction in mortality demonstrated in the COV-BARRIER trial.

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, 1.52-3.51; P<0.0001) and symptomatic VTE (mortality, 29.2%; HR, 9.42; 95% CI, 4.18-21.20; P<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.clinicaltrials.gov; Unique identifier: NCT00571649.

Post-Discharge Prophylaxis With Rivaroxaban Reduces Fatal and Major Thromboembolic Events in Medically Ill Patients.

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).

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the prevention of venous thromboembolism.

Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. The study objective was to assess the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism (VTE) prophylaxis (VTE-P) after hip/knee replacement surgery. Post hoc exposure-response analyses were conducted using data from the phase 3 RECORD1-4 studies, in which 12,729 patients were randomized to rivaroxaban 10 mg once daily or enoxaparin for ≤ 39 days. Multivariate regression approaches were used to correlate model-predicted individual rivaroxaban exposures and patient characteristics with outcomes. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and by making use of the known correlation between rivaroxaban plasma concentration and dynamics of PT. No significant associations between rivaroxaban exposure and total VTE or major bleeding were identified. A significant association between exposure and a composite of major or non-major clinically relevant (NMCR) bleeding from day 4 after surgery was observed. The relationship was shallow, with an approximate predicted absolute increase in a composite of major or NMCR bleeding from 1.08 [95% confidence interval (CI) 0.76-1.54] to 2.18% (95% CI 1.51-3.17) at the 5th and 95th percentiles of trough plasma concentration, respectively. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Hence, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-P.

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the treatment of venous thromboembolism.

Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN-DVT and EINSTEIN-PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure-response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure-efficacy relationships were shallow. Exposure-safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.

Modified IMPROVE VTE Risk Score and Elevated D-Dimer Identify a High Venous Thromboembolism Risk in Acutely Ill Medical Population for Extended Thromboprophylaxis.

An individualized approach to identify acutely ill medical patients at increased risk of venous thromboembolism (VTE) and a low risk of bleeding to optimize the benefit and risk of extended thromboprophylaxis (ET) is needed. The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE risk score has undergone extensive external validation in medically ill patients for in-hospital use and a modified model was used in the MARINER trial of ET also incorporating an elevated D-dimer. The MAGELLAN study demonstrated efficacy with rivaroxaban but had excess bleeding. This retrospective analysis investigated whether the modified IMPROVE VTE model with an elevated D-dimer could identify a high VTE risk subgroup of patients for ET from a subpopulation of the MAGELLAN study, which was previously identified as having a lower risk of bleeding. We incorporated the modified IMPROVE VTE score using a cutoff score of 4 or more or 2 and 3 with an elevated D-dimer (>2 times the upper limit of normal) to the MAGELLAN subpopulation. In total, 56% of the patients met the high-risk criteria. In the placebo group, the total VTE event rate at Day 35 was 7.94% in the high-risk group and 2.83% for patients in the lower-risk group. A reduction in VTE was observed with rivaroxaban in the high-risk group (relative risk [RR]: 0.68, 95% confidence interval [CI]: 0.51-0.91, p = 0.008) and in the lower-risk group (RR: 0.69, 95% CI: 0.40 -1.20, p = 0.187). The modified IMPROVE VTE score with an elevated D-dimer identified a nearly threefold higher VTE risk subpopulation of patients where a significant benefit exists for ET using rivaroxaban.

Natriuretic Peptide-Based Inclusion Criteria in a Heart Failure Clinical Trial: Insights From COMMANDER HF.

OBJECTIVES: This study investigated the effects of a mid-trial protocol amendment requiring elevated natriuretic peptides for inclusion in the COMMANDER-HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) trial. BACKGROUND: Heart failure (HF) trials that select patients based on history of HF hospitalization alone are susceptible to regional variations in event rates. Elevated plasma concentrations of natriuretic peptides (NPs) as selection criteria may help HF ascertainment and risk enrichment. In the COMMANDER-HF trial, B-type natriuretic peptide ≥200 ng/l or N-terminal pro-B-type natriuretic peptide ≥800 ng/l were added to inclusion criteria as a mid-trial protocol amendment, providing a unique case-study of NP-based inclusion criteria. METHODS: We compared the baseline characteristics, event rates, and treatment effects for patients enrolled before and after the NP protocol amendment. The primary endpoint was all-cause death, myocardial infarction, or stroke. Secondary endpoints included HF rehospitalization and cardiovascular death. RESULTS: A total of 5,022 patients with left ventricular ejection fraction ≤40% and coronary artery disease were included. Compared to patients enrolled before the NP protocol amendment, those enrolled post-amendment (n = 3,867, 77%) were older, more often had diabetes, and had lower values for body mass index, left ventricular ejection fraction, and estimated glomerular filtration rate, higher heart rate, and higher event rates: primary endpoint (hazard ratio [HR]: 1.32; 95% confidence interval [CI]: 1.16 to 1.50), cardiovascular death (HR: 1.29; 95% CI: 1.11 to 1.50), HF rehospitalization (HR: 1.31; 95% CI: 1.15 to 1.49), and major bleeding (HR: 1.71; 95% CI: 1.11 to 2.65). Differences between pre- and post-amendment rates were confined to and driven by Eastern Europe. This protocol amendment did not modify the neutral effect of rivaroxaban on the primary endpoint (p interaction = 0.36) or secondary endpoints. CONCLUSIONS: In a global event-driven trial of rivaroxaban in HF, requiring elevated NPs for inclusion increased event rates allowing earlier completion of the trial but did not modify treatment effect. These data inform future HF trials regarding the expected impact of NP-based inclusion criteria on patient characteristics and event rates. (COMMANDER HF [A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure] NCT01877915).

Thromboprophylaxis with Rivaroxaban in Acutely Ill Medical Patients with Renal Impairment: Insights from the MAGELLAN and MARINER Trials.

Patients with renal impairment are at higher risk of thrombosis and bleeding than those with normal renal function. The optimal rivaroxaban dose for thromboprophylaxis in acutely ill medical patients with renal impairment is unknown. MARINER and MAGELLAN were multicenter, randomized clinical trials of rivaroxaban in acutely ill medical patients. Efficacy and safety outcomes in patients with renal impairment in MARINER (7.5 mg once daily) were compared with those in patients with normal renal function in MARINER (10 mg once daily) and in a subpopulation of MAGELLAN that excluded patients at high risk for bleeding at baseline (10 mg once daily). Compared with enoxaparin/placebo in the MAGELLAN subpopulation, the relative risk (RR) of symptomatic venous thromboembolism (VTE) and VTE-related death with rivaroxaban 10 mg in patients with renal impairment (RR = 0.62; 95% confidence interval [CI] 0.27-1.44) was similar to that in those with normal renal function (RR = 0.78; 95% CI 0.44-1.40), while in MARINER, the 7.5 mg dose did not reduce the risk in patients with renal impairment (hazard ratio = 1.00; 95% CI 0.52-1.92). Major bleeding with rivaroxaban 10 mg once daily was higher in patients with renal impairment than in those with normal renal function in MAGELLAN (1.54% vs. 0.98%) and in the MAGELLAN subpopulation (0.94% vs. 0.61%). At a dose of 10 mg once daily, rivaroxaban is effective for thromboprophylaxis in acutely ill medical patients with impaired or normal renal function. The safety of this regimen is enhanced without loss of efficacy by excluding patients at high risk for bleeding, but not by using a reduced-dose strategy. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00571649 for the MAGELLAN trial, NCT02111564 for the MARINER trial.

Improved Benefit Risk Profile of Rivaroxaban in a Subpopulation of the MAGELLAN Study.

Acutely ill medical patients are at risk of venous thromboembolism (VTE) and VTE-related mortality during hospitalization and posthospital discharge, but widespread adoption of extended thromboprophylaxis has not occurred. We analyzed a subpopulation within the MAGELLAN study of extended thromboprophylaxis with rivaroxaban to reevaluate the benefit risk profile. We identified 5 risk factors for major and fatal bleeding after a clinical analysis of the MAGELLAN study and analyzed efficacy and safety with these patients excluded (n = 1551). Risk factors included: active cancer, dual antiplatelet therapy at baseline, bronchiectasis/pulmonary cavitation, gastroduodenal ulcer, or bleeding within 3 months before randomization. We evaluated efficacy, safety, and benefit risk using clinically comparable endpoints in the subpopulation. At day 10, rivaroxaban was noninferior to enoxaparin (relative risk [RR] = 0.82, 95% confidence interval [CI] = 0.58-1.15) and at day 35 rivaroxaban was significantly better than enoxaparin/placebo (RR = 0.68, 95% CI = 0.53-0.88) in reducing VTE and VTE-related death. Major bleeding was reduced at day 10 (RR = 2.18, 95% CI = 1.07-4.44 vs 1.19, 95% CI = 0.54-2.65) and at day 35 (2.87, 95% CI = 1.60-5.15 vs 1.48, 95% CI = 0.77-2.84) for MAGELLAN versus this subpopulation, respectively. The benefit risk profile was favorable in this subpopulation treated for 35 days, with the number needed to treat ranging from 55 to 481 and number needed to harm from 455 to 1067 for all pairwise evaluations. Five exclusionary criteria defined a subpopulation of acutely ill medical patients with a positive benefit risk profile for in-hospital and extended thromboprophylaxis with rivaroxaban.

A comprehensive analysis of the effects of rivaroxaban on stroke or transient ischaemic attack in patients with heart failure, coronary artery disease, and sinus rhythm: the COMMANDER HF trial.

AIMS: Stroke is often a devastating event among patients with heart failure with reduced ejection (HFrEF). In COMMANDER HF, rivaroxaban 2.5 mg b.i.d. did not reduce the composite of first occurrence of death, stroke, or myocardial infarction compared with placebo in patients with HFrEF, coronary artery disease (CAD), and sinus rhythm. We now examine the incidence, timing, type, severity, and predictors of stroke or a transient ischaemic attack (TIA), and seek to establish the net clinical benefit of treatment with low-dose rivaroxaban. METHODS AND RESULTS: In this double-blind, randomized trial, 5022 patients who had HFrEF(≤40%), elevated natriuretic peptides, CAD, and who were in sinus rhythm were treated with rivaroxaban 2.5 mg b.i.d. or placebo in addition to antiplatelet therapy, after an episode of worsening HF. The primary neurological outcome for this post hoc analysis was time to first event of any stroke or TIA. Over a median follow-up of 20.5 (25th-75th percentiles 20.0-20.9) months, 150 all-cause stroke (127) or TIA (23) events occurred (ischaemic stroke in 82% and haemorrhagic stroke in 11% of stroke events). Overall, 47.5% of first-time strokes were either disabling (16.5%) or fatal (31%). Prior stroke, low body mass index, geographic region, and the CHA2DS2-VASc score were predictors of stroke/TIA. Rivaroxaban significantly reduced the primary neurological endpoint of all-cause stroke or TIA compared with placebo by 32% (1.29 events vs. 1.90 events per 100 patient-years), adjusted for the time from index HF event to randomization and stratified by geographic region (adjusted hazard ratio 0.68, 95% confidence interval 0.49-0.94), with a number needed to treat of 164 patients per year to prevent one stroke/TIA event. The principal safety endpoint of fatal bleeding or bleeding into a critical space, occurred at a similar rate on rivaroxaban and placebo (0.44 events vs. 0.55 events per 100 patient-years). CONCLUSIONS: Patients with HFrEF and CAD are at risk for stroke or TIA in the period following an episode of worsening heart failure in the absence of atrial fibrillation. Most strokes are of ischaemic origin and nearly half are either disabling or fatal. Rivaroxaban at a dose of 2.5 mg b.i.d. reduced rates of stroke or TIA compared with placebo in this population. TRIAL REGISTRATION: COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure); ClinicalTrials.gov NCT01877915.

Enhancing the Quality of Rivaroxaban Exposure Estimates Using Prothrombin Time in the Absence of Pharmacokinetic Sampling.

Prothrombin time (PT) is a measure of coagulation status and was assessed in the majority of patients in the rivaroxaban phase II and III clinical trials as a pharmacodynamic marker. In the absence of sufficient phase III pharmacokinetic (PK) data to provide individual exposure measures for input into rivaroxaban exposure-response analyses, the aim of the present study was to investigate the use of PT-adjustment approaches (i.e., the use of observed individual PT measurements) to enhance the prediction of individual rivaroxaban exposure metrics (derived using a previously developed integrated population PK model) based on the observed linear relationship between PT and rivaroxaban plasma concentrations. The PT-adjustment approaches were established using time-matched PK and PT measurements, which were available from 1,779 patients across four phase II trials and one phase III trial of rivaroxaban. PT-adjusted exposure estimates improved the identification of statistically significant effects when compared with covariate-only exposure estimates.

Association of Rivaroxaban With Thromboembolic Events in Patients With Heart Failure, Coronary Disease, and Sinus Rhythm: A Post Hoc Analysis of the COMMANDER HF Trial.

Importance: Whether anticoagulation benefits patients with heart failure (HF) in sinus rhythm is uncertain. The COMMANDER HF randomized clinical trial evaluated the effects of adding low-dose rivaroxaban to antiplatelet therapy in patients with recent worsening of chronic HF with reduced ejection fraction, coronary artery disease (CAD), and sinus rhythm. Although the primary end point of all-cause mortality, myocardial infarction, or stroke did not differ between rivaroxaban and placebo, there were numerical advantages favoring rivaroxaban for myocardial infarction and stroke. Objective: To examine whether low-dose rivaroxaban was associated with reduced thromboembolic events in patients enrolled in the COMMANDER HF trial. Design, Setting, and Participants: Post hoc analysis of the COMMANDER HF multicenter, randomized, double-blind, placebo-controlled trial in patients with CAD and worsening HF. The trial randomized 5022 patients postdischarge from a hospital or outpatient clinic after treatment for worsening HF between September 2013 and October 2017. Patients were required to be receiving standard care for HF and CAD and were excluded for a medical condition requiring anticoagulation or a bleeding history. Patients were randomized in a 1:1 ratio. Analysis was conducted from June 2018 and January 2019. Intervention: Patients were randomly assigned to receive 2.5 mg of rivaroxaban given orally twice daily or placebo in addition to their standard therapy. Main Outcomes and Measures: For this post hoc analysis, a thromboembolic composite was defined as either (1) myocardial infarction, ischemic stroke, sudden/unwitnessed death, symptomatic pulmonary embolism, or symptomatic deep venous thrombosis or (2) all of the previous components except sudden/unwitnessed deaths because not all of these are caused by thromboembolic events. Results: Of 5022 patients, 3872 (77.1%) were men, and the overall mean (SD) age was 66.4 (10.2) years. Over a median (interquartile range) follow-up of 19.6 (11.7-30.8) months, fewer patients assigned to rivaroxaban compared with placebo had a thromboembolic event including sudden/unwitnessed deaths: 328 (13.1%) vs 390 (15.5%) (hazard ratio, 0.83; 95% CI, 0.72-0.96; P = .01). When sudden/unwitnessed deaths were excluded, the results analyzing thromboembolic events were similar: 153 (6.1%) vs 190 patients (7.6%) with an event (hazard ratio, 0.80; 95% CI, 0.64-0.98; P = .04). Conclusions and Relevance: In this study, thromboembolic events occurred frequently in patients with HF, CAD, and sinus rhythm. Rivaroxaban may reduce the risk of thromboembolic events in this population, but these events are not the major cause of morbidity and mortality in patients with recent worsening of HF for which rivaroxaban had no effect. While consistent with other studies, these results require confirmation in prospective randomized clinical trials. Trial Registration: ClinicalTrials.gov identifier: NCT01877915.

Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness.

BACKGROUND: Patients who are hospitalized for medical illness remain at risk for venous thromboembolism after discharge, but the role of extended thromboprophylaxis in the treatment of such patients is a subject of controversy. METHODS: In this randomized, double-blind trial, medically ill patients who were at increased risk for venous thromboembolism on the basis of a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (scores range from 0 to 10, with higher scores indicating a higher risk of venous thromboembolism) or a score of 2 or 3 plus a plasma d-dimer level of more than twice the upper limit of the normal range (defined according to local laboratory criteria) were assigned at hospital discharge to either once-daily rivaroxaban at a dose of 10 mg (with the dose adjusted for renal insufficiency) or placebo for 45 days. The primary efficacy outcome was a composite of symptomatic venous thromboembolism or death due to venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: Of the 12,024 patients who underwent randomization, 12,019 were included in the intention-to-treat analysis. The primary efficacy outcome occurred in 50 of 6007 patients (0.83%) who were given rivaroxaban and in 66 of 6012 patients (1.10%) who were given placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.52 to 1.09; P=0.14). The prespecified secondary outcome of symptomatic nonfatal venous thromboembolism occurred in 0.18% of patients in the rivaroxaban group and 0.42% of patients in the placebo group (hazard ratio, 0.44; 95% CI, 0.22 to 0.89). Major bleeding occurred in 17 of 5982 patients (0.28%) in the rivaroxaban group and in 9 of 5980 patients (0.15%) in the placebo group (hazard ratio, 1.88; 95% CI, 0.84 to 4.23). CONCLUSIONS: Rivaroxaban, given to medical patients for 45 days after hospital discharge, was not associated with a significantly lower risk of symptomatic venous thromboembolism and death due to venous thromboembolism than placebo. The incidence of major bleeding was low. (Funded by Janssen Research and Development; MARINER ClinicalTrials.gov number, NCT02111564 .).