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.

Cancer-Associated ThrOmboSIs - Patient-Reported OutcoMes With RivarOxaban (COSIMO) - Baseline characteristics and clinical outcomes.

BACKGROUND: Patients with cancer-associated thrombosis (CAT) have a high risk of recurrent venous thromboembolic events, which contribute to significant morbidity and mortality. Direct oral anticoagulants may provide a convenient treatment option for these patients. OBJECTIVES: To assess clinical characteristics and outcomes of patients with active cancer changing to rivaroxaban after ≥4 weeks of standard therapy for the treatment of venous thromboembolism (VTE) in clinical practice. This analysis focused on secondary outcomes of Cancer-associated thrOmboSIs - Patient-reported outcoMes with rivarOxaban (COSIMO). PATIENTS: COSIMO was a multinational, prospective, noninterventional, single-arm cohort study. Overall, 505 patients received at least one dose of rivaroxaban; 96.6% changing from low-molecular-weight heparin, 1.6% from a vitamin K antagonist, and 1.8% from fondaparinux. RESULTS: Most patients had solid tumors (n = 449; 88.9%) and approximately half of these patients had metastases. The qualifying venous thromboembolic event was deep vein thrombosis (DVT) in 45.3% of patients, pulmonary embolism (PE) in 37.2% of patients, DVT with PE in 9.7% of patients, and catheter-associated DVT in 7.5% of patients. Approximately 75.1% of patients received rivaroxaban for at least 3 months; 150 (29.7%) patients received concomitant chemotherapy during the study. VTE recurrence, major bleeding, nonmajor bleeding, and major adverse cardiovascular events occurred in 18 (3.6%), 18 (3.6%), 81 (16.0%), and 12 (2.4%) patients, respectively. CONCLUSIONS: In patients with CAT who changed to rivaroxaban treatment after ≥4 weeks of standard therapy, the observed incidence proportions of recurrent VTE and bleeding events were in keeping with the recognized effectiveness and safety profile of rivaroxaban for the treatment of CAT.

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.

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.

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.

Body Composition in Patients with Radioactive Iodine-Refractory, Advanced Differentiated Thyroid Cancer Treated with Sorafenib or Placebo: A Retrospective Analysis of the Phase III DECISION Trial.

Background: Rates of adverse events with sorafenib were higher in the DECISION trial in radioactive iodine-refractory, advanced differentiated thyroid cancer (DTC) than in trials of sorafenib for other tumor types. One possible explanation is that sarcopenia, a known predictive factor of toxicity in patients with cancer, is more common in patients with DTC due to hormone suppressive therapy. Methods: This retrospective exploratory analysis was performed to assess whether the risk of early toxicity leading to dose modification (DMT) with sorafenib was higher in patients with sarcopenia compared with those without sarcopenia. The data set comprised patients from the phase III DECISION trial with a computed tomography scan available to determine muscle mass. The skeletal muscle (SM) cross-sectional area was used to determine the SM index and define sarcopenia. The end points were changes in body composition, DMT, early DMT (within 1 month), severe toxic events (STEs), and early STEs. Results: Overall, 365 patients were eligible for this analysis; baseline characteristics were well balanced between patients receiving sorafenib (n = 180) versus placebo (n = 185). Using a sarcopenia definition of an SM index less than the median sex-specific SM index, approximately half of the patients receiving sorafenib were at risk of sarcopenia (89/180; 49.4%), with wide geographical variation. At 6 months, the mean weight, body mass index, and lean body mass of patients receiving sorafenib were lower than at baseline and significantly lower than for patients receiving placebo (all p < 0.0001). Most DMTs and STEs occurred in the first month of treatment. There was a nonsignificant trend for more early DMTs in patients with sarcopenia compared with those without sarcopenia (55.3% vs. 44.7%, respectively; p = 0.2273). Conclusions: These results show a significant effect of sorafenib on muscle mass. However, there was no association between sarcopenia and DMT or early DMT, in contrast to observations in hepatocellular and renal cell carcinoma.

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.

Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies.

BACKGROUND & AIMS: Sorafenib, an oral multikinase inhibitor, significantly prolonged overall survival (OS) vs. placebo in patients with unresectable hepatocellular carcinoma (HCC) in two phase III studies, SHARP (Sorafenib HCC Assessment Randomized Protocol) and Asia Pacific (AP). To assess prognostic factors for HCC and predictive factors of sorafenib benefit, we conducted a pooled exploratory analysis from these placebo-controlled phase III studies. METHODS: To identify potential prognostic factors for OS, univariate and multivariate (MV) analyses were performed for baseline variables by Cox proportional hazards model. Hazard ratios (HRs) and median OS were evaluated across pooled subgroups. To assess factors predictive of sorafenib benefit, the interaction term between treatment for each subgroup was evaluated by Cox proportional hazard model. RESULTS: In 827 patients (448 sorafenib; 379 placebo) analyzed, strong prognostic factors for poorer OS identified from MV analysis in both treatment arms were presence of macroscopic vascular invasion (MVI), high alpha-fetoprotein (AFP), and high neutrophil-to-lymphocyte ratio (NLR; ⩽ vs. >median [3.1]). Sorafenib OS benefit was consistently observed across all subgroups. Significantly greater OS sorafenib benefit vs. placebo was observed in patients without extrahepatic spread (EHS; HR, 0.55 vs. 0.84), with hepatitis C virus (HCV) (HR, 0.47 vs. 0.81), and a low NLR (HR, 0.59 vs. 0.84). CONCLUSIONS: In this exploratory analysis, presence of MVI, high AFP, and high NLR were prognostic factors of poorer OS. Sorafenib benefit was consistently observed irrespective of prognostic factors. Lack of EHS, HCV, and lower NLR were predictive of a greater OS benefit with sorafenib. LAY SUMMARY: This exploratory pooled analysis showed that treatment with sorafenib provides a survival benefit in all subgroups of patients with HCC; however, the magnitude of benefit is greater in patients with disease confined to the liver (without extrahepatic spread), or in those with hepatitis C virus, or a lower neutrophil-to-lymphocyte ratio, an indicator of inflammation status. These results help inform the prognosis of patients receiving sorafenib therapy and provide further refinements for the design of trials testing new agents vs. sorafenib. Clinical Trial Numbers: NCT00105443 and NCT00492752.

Predicting the risk of venous thromboembolism in patients hospitalized with heart failure.

BACKGROUND: Whether heart failure (HF) increases the risk of venous thromboembolism (VTE) is not well established. In the phase III MAGELLAN (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically iLL patients comparing rivaroxabAN with enoxaparin) trial, extended-duration rivaroxaban was compared with standard-duration enoxaparin followed by placebo for VTE prevention in 8101 hospitalized acutely ill patients with or without HF. The aim of this analysis was to evaluate the relationship between HF severity and the risk of VTE in MAGELLAN patients. METHODS AND RESULTS: Hospitalized patients diagnosed with HF were included according to New York Heart Association class III or IV at admission (n=2593). HF severity was determined by N-terminal probrain natriuretic peptide (NT-proBNP) plasma concentrations (median 1904 pg/mL). Baseline plasma D-dimer concentrations ranged from 0.6 to 1.7 µg/L for the less and more severe HF subgroups. Patients with more severe HF had a greater incidence of VTE versus patients with less severe HF, with a significant trend up to Day 10 (4.3% versus 2.2%; P=0.0108) and Day 35 (7.2% versus 4.1%; P=0.0150). Multivariable analysis confirmed that NT-proBNP concentration was associated with VTE risk up to Day 10 (P=0.017) and D-dimer concentration with VTE risk up to Day 35 (P=0.005). The association between VTE risk and HF severity that was observed in the enoxaparin/placebo group was not seen in the extended-duration rivaroxaban group. CONCLUSIONS: Patients with more severe HF, as defined by high NT-proBNP plasma concentration, were at increased risk of VTE. NT-proBNP may be useful to identify high short-term risk, whereas elevated D-dimer may be suggestive of high midterm risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00571649.