Comparison of rivaroxaban and low molecular weight heparin in the treatment of cancer-associated venous thromboembolism: a Swedish national population-based register study.

BACKGROUND: Treating cancer-associated venous thromboembolism (CAT) with anticoagulation prevents recurrent venous thromboembolism (rVTE), but increases bleeding risk. OBJECTIVES: To compare incidence of rVTE, major bleeding, and all-cause mortality for rivaroxaban versus low molecular weight heparin (LMWH) in patients with CAT. METHODS: We developed a cohort study using Swedish national registers 2013-2019. Patients with CAT (venous thromboembolism within 6 months of cancer diagnosis) were included. Those with other indications or with high bleeding risk cancers were excluded (according to guidelines). Follow-up was from index-CAT until outcome, death, emigration, or end of study. Incidence rates (IR) per 1000 person-years with 95% confidence interval (CI) and propensity score overlap-weighted hazard ratios (HRs) for rivaroxaban versus LMWH were estimated. RESULTS: We included 283 patients on rivaroxaban and 5181 on LMWH. The IR for rVTE was 68.7 (95% CI 40.0-109.9) for rivaroxaban, compared with 91.6 (95% CI 81.9-102.0) for LMWH, with adjusted HR 0.77 (95% CI 0.43-1.35). The IR for major bleeding was 23.5 (95% CI 8.6-51.1) for rivaroxaban versus 49.2 (95% CI 42.3-56.9) for LMWH, with adjusted HR 0.62 (95% CI 0.26-1.49). The IR for all-cause mortality was 146.8 (95% CI 103.9-201.5) for rivaroxaban and 565.6 (95% CI 541.8-590.2) for LMWH with adjusted HR 0.48 (95% CI 0.34-0.67). CONCLUSIONS: Rivaroxaban performed similarly to LMWH for patients with CAT for rVTE and major bleeding. An all-cause mortality benefit was observed for rivaroxaban which potentially may be attributed to residual confounding. TRIAL REGISTRATION NUMBER: NCT05150938 (Registered 9 December 2021).

Andexanet alfa versus PCC products for factor Xa inhibitor bleeding: A systematic review with meta-analysis.

Previous meta-analyses assessed andexanet alfa (AA) or prothrombin complex concentrate (PCC) products for the treatment of Factor Xa inhibitor (FXaI)-associated major bleeding. However, they did not include recent studies or assess the impact of the risk of bias. We conducted a systematic review with meta-analysis on the effectiveness of AA versus PCC products for FXaI-associated major bleeding, inclusive of the studies' risk of bias. PubMed and Embase were searched for comparative studies assessing major bleeding in patients using FXaI who received AA or PCC. We used the Methodological Index for NOn-Randomized Studies (MINORS) checklist and one question from the Joanna Briggs Institute (JBI) Critical Appraisal of Case Series tool to assess the risk of bias. Random-effects meta-analyses were performed to provide a pooled estimate for the effect of AA versus PCC products on hemostatic efficacy, in-hospital mortality, 30-day mortality, and thrombotic events. Low-moderate risk of bias studies were meta-analyzed separately, as well as combined with high risk of bias studies. Eighteen comparative evaluations of AA versus PCC were identified. Twenty-eight percent of the studies (n = 5) had low-moderate risk and 72% (n = 13) had a high risk of bias. Studies with low-moderate risk of bias suggested improvements in hemostatic efficacy [Odds Ratio (OR) 2.72 (95% Confidence Interval (CI): 1.15-6.44); one study], lower in-hospital mortality [OR 0.48 (95% CI: 0.38-0.61); three studies], and reduced 30-day mortality [OR 0.49 (95% CI: 0.30-0.80); two studies] when AA was used versus PCC products. When studies were included regardless of the risk of bias, pooled effects showed improvements in hemostatic efficacy [OR 1.36 (95% CI: 1.01-1.84); 12 studies] and reductions in 30-day mortality [OR 0.53 (95% CI: 0.37-0.76); six studies] for AA versus PCC. The difference in thrombotic events with AA versus PCC was not statistically significant in the low-moderate, high, or combined risk of bias groups. The evidence from low-moderate quality real-world studies suggests that AA is superior to PCC in enhancing hemostatic efficacy and reducing in-hospital and 30-day mortality. When studies are assessed regardless of the risk of bias, the pooled hemostatic efficacy and 30-day mortality risk remain significantly better with AA versus PCC.

Agreement between 30-day and 90-day modified Rankin Scale score and utility-weighted modified Rankin Scale score in acute intracerebral hemorrhage: An analysis of ATACH-2 trial data.

The relationship between 30- and 90-day modified Rankin Scale (mRS) scores in intracerebral hemorrhage (ICH) patients was evaluated. This post hoc cohort analysis of the ATACH-2 trial included patients with acute ICH who were alive at 30 days and who had mRS scores reported at 30 and 90 days. The mRS score was then converted to a utility (EuroQol-5 Dimension-3 Level [EQ-5D-3L])-weighted mRS score. After adjustment of 30-day mRS score for key covariates using multivariable ordinal regression, the relationship between 30-day and observed 90-day functional outcome was assessed via absolute difference in the utility-weighted version. Of the 1000 trial subjects, 898 met inclusion criteria. This low-moderate severity ICH cohort had a median baseline GCS score of 15 and median hematoma volume of 9.7 mL. Observed 30-day mRS had the largest association with observed 90-day values (χ2 = 302.9, p < 0.0001). Patients generally either maintained the same mRS scores between 30 and 90 days (48 %) or experienced a 1-point (32 %) or 2-point (10 %) improvement by 90 days. The mean ± standard deviation (SD) EQ-5D-3L at 90 days was 0.67 ± 0.26. Following adjustment, the mean absolute difference between predicted and observed utility-weighted 90-day mRS scores was 0.006 ± 0.13 points and less than the estimated minimal clinically important difference of 0.13 points. The difference in average utility-weighted mRS scores at 30 and 90 days was not clinically relevant, suggesting 30-day score may be a reasonable proxy for 90-day values in patients with ICH when 90-day values are not available.

Comparison of Clinical Outcomes in Patients with Active Cancer Receiving Rivaroxaban or Low-Molecular-Weight Heparin: The OSCAR-UK Study.

BACKGROUND: In most patients with cancer-associated venous thromboembolism (CT), essentially those not at high risk of bleeding, guidelines recommend treatment with direct oral anticoagulants as an alternative to low-molecular-weight heparins (LMWHs). Population-based studies comparing these therapies are scarce. OBJECTIVES: To compare the risk of venous thromboembolism (VTE) recurrences, significant bleeding, and all-cause mortality in patients with CT receiving rivaroxaban or LMWHs. PATIENTS/METHODS: Using UK Clinical Practice Research Datalink data from 2013 to 2020, we generated a cohort of patients with first CT treated initially with either rivaroxaban or LMWH. Patients were observed 12 months for VTE recurrences, significant bleeds (major bleeds or clinically relevant nonmajor bleeding requiring hospitalization), and all-cause mortality. Overlap weighted sub-distribution hazard ratios (SHRs) compared rivaroxaban with LMWH in an intention-to-treat analysis. RESULTS: The cohort consisted of 2,259 patients with first CT, 314 receiving rivaroxaban, and 1,945 LMWH, mean age 72.4 and 66.9 years, respectively. In the 12-month observational period, 184 person-years following rivaroxaban and 1,057 following LMWH, 10 and 66 incident recurrent VTE events, 20 and 102 significant bleeds, and 10 and 133 deaths were observed in rivaroxaban and LMWH users, respectively. The weighted SHR at 12 months for VTE recurrences in rivaroxaban compared with LMWH were 0.80 (0.37-1.73); for significant bleeds 1.01 (0.57-1.81); and for all-cause mortality 0.49 (0.23-1.06). CONCLUSION: Patients with CT, not at high risk of bleeding, treated with either rivaroxaban or LMWH have comparable effectiveness and safety outcomes. This supports the recommendation that rivaroxaban is a reasonable alternative to LMWH for the treatment of CT.

Lower mortality with andexanet alfa vs 4-factor prothrombin complex concentrate for factor Xa inhibitor-related major bleeding in a U.S. hospital-based observational study.

Background: Well-designed studies with sufficient sample size comparing andexanet alfa vs 4-factor prothrombin complex concentrate (4F-PCC) in routine clinical practice to evaluate clinical outcomes are limited. Objectives: To compare in-hospital mortality in patients hospitalized with rivaroxaban- or apixaban-related major bleeding who were treated with andexanet alfa or 4F-PCC. Methods: An observational cohort study (ClinicalTrials.gov identifier: NCT05548777) was conducted using electronic health records between May 2018 and September 2022 from 354 U.S. hospitals. Inclusion criteria were age ≥18 years, inpatient admission with diagnosis code D68.32 (bleeding due to extrinsic anticoagulation), a record of use of the factor Xa inhibitors rivaroxaban or apixaban, andexanet alfa or 4F-PCC treatment during index hospitalization, and a documented discharge disposition. Multivariable logistic regression on in-hospital mortality with andexanet alfa vs 4F-PCC was performed. The robustness of the results was assessed via a supportive propensity score-weighted logistic regression. Results: The analysis included 4395 patients (andexanet alfa, n = 2122; 4F-PCC, n = 2273). There were 1328 patients with intracranial hemorrhage (ICH), 2567 with gastrointestinal (GI) bleeds, and 500 with critical compartment or other bleed types. In the multivariable analysis, odds of in-hospital mortality were 50% lower for andexanet alfa vs 4F-PCC (odds ratio [OR], 0.50; 95% CI, 0.39-0.65; P < .01) and were consistent for both ICH (OR, 0.55; [0.39-0.76]; P < .01) and GI bleeds (OR, 0.49 [0.29-0.81]; P = .01). Similar results were obtained from the supporting propensity score-weighted logistic regression analyses. Conclusion: In this large observational study, treatment with andexanet alfa in patients hospitalized with rivaroxaban- or apixaban-related major bleeds was associated with 50% lower odds of in-hospital mortality than 4F-PCC. The magnitude of the risk reduction was similar in ICH and GI bleeds.

Rivaroxaban Versus Low-Molecular-Weight Heparins in a Broad Cohort of Patients With Cancer-Associated Venous Thromboembolism: An Analysis of the OSCAR-US Program.

Cancer-associated venous thromboembolism (CAT) guidelines recommend direct oral anticoagulants as alternatives to low-molecular-weight heparin (LMWH) in most patients. This study compared the effectiveness and safety of rivaroxaban versus LMWH for a broad CAT cohort. The cohort study used electronic health data from January 2012 to December 2020 to evaluate patients with active cancer experiencing acute venous thromboembolism (VTE) and treated with rivaroxaban or LMWH. Propensity score-overlap weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for VTE, bleeding-related hospitalization, and all-cause mortality were calculated. In total, 4935 patients were identified (27.9% on rivaroxaban and 72.1% on LMWH). The cancer types included gastrointestinal (29.4%), genitourinary (26.2%), lung (24.0%), breast (19.7%), and hematologic (14.4%). Rivaroxaban was associated with a reduction in recurrent VTE versus LMWH among all patients with cancer (HR = 0.78; 95%CI = 0.61-0.99) at 3 months. No differences in bleeding-related hospitalization or all-cause mortality were observed. Directionally similar results to those at 3 months were observed at 6 months for all outcomes. In conclusion, we observed fewer recurrent VTE cases and no increase in bleeding-related hospitalizations with rivaroxaban versus LMWH at 3 months in this patient cohort with various cancer types.

Comparative outcomes associated with rivaroxaban versus warfarin use in elderly patients with atrial fibrillation or acute venous thromboembolism managed in the United States: a systematic review of observational studies.

BACKGROUND: Advancing age is a risk factor for developing non-valvular atrial fibrillation (NVAF) or acute venous thromboembolism (VTE). We assessed the comparative effectiveness, safety, costs, and healthcare utilization associated with rivaroxaban versus warfarin in patients of advanced age managed in the United States (US). METHODS: We conducted a systematic review of Medline and Embase through April 2023 to identify real-world evidence (RWE) studies of older adults (at least 65+ years of age) with either NVAF or VTE who received either rivaroxaban or warfarin in the US and reported an outcome of stroke or systemic embolism (SSE), ischemic stroke (IS), recurrent VTE, major bleeding, intracranial hemorrhage, costs, or healthcare resource utilization. We classified each outcome of interest per study as "positive" (lower risk), "negative" (higher risk), or "neutral" based upon the summary effect size of rivaroxaban versus warfarin. RESULTS: Twenty-nine RWE studies met inclusion criteria, mostly (83%) in NVAF populations. For SSE with rivaroxaban versus warfarin, 68.8% of studies showed positive effects and 31.2% showed neutral outcome. For major bleeding, 57.7% showed neutral effects, 38.5% showed negative effects, and 3.8% of studies showed positive effects with rivaroxaban versus warfarin. Of the two studies reporting cost data, both were positive, showing lower costs for SSE for rivaroxaban versus warfarin and neutral cost for major bleeding costs. CONCLUSIONS: This systematic review supports findings from subgroup analyses of randomized controlled trials that, compared with warfarin, rivaroxaban is associated with generally neutral or positive effects on thrombosis and a mixed picture on bleeding outcomes in older adults with either NVAF or VTE treated in the United States.

Rivaroxaban versus Apixaban for Treatment of Cancer-Associated Venous Thromboembolism in Patients at Lower Risk of Bleeding.

This retrospective study, utilizing U.S. electronic health record (EHR) data from January 2013 to December 2020, sought to assess whether rivaroxaban and apixaban had similar effectiveness and safety in the treatment of cancer-associated venous thromboembolism (VTE) in patients with a cancer type not associated with a high risk of bleeding. We included adults diagnosed with active cancer, excluding esophageal, gastric, unresected colorectal, bladder, noncerebral central nervous system cancers and leukemia, who experienced VTE and received a therapeutic VTE dose of rivaroxaban or apixaban on day 7 post-VTE, and were active in the EHR ≥12 months prior to the VTE. Primary outcome was the composite of recurrent VTE or any bleed resulting in hospitalization at 3 months. Secondary outcomes included recurrent VTE, any bleed resulting in hospitalization, any critical organ bleed, and composites of these outcomes at 3 and 6 months. Inverse probability of treatment-weighted Cox regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). We included 1,344 apixaban and 1,093 rivaroxaban patients. At 3 months, rivaroxaban was found to have similar hazard to apixaban for developing recurrent VTE or any bleed resulting in hospitalization (HR: 0.87; 95% CI: 0.60-1.27). No differences were observed between cohorts for this outcome at 6 months (HR: 1.00; 95% CI: 0.71-1.40) or for any other outcome at 3 or 6 months. In conclusion, patients receiving rivaroxaban or apixaban showed similar risks of the composite of recurrent VTE or any bleed resulting in hospitalization in patients with cancer-associated VTE. This study was registered at www.clinicaltrials.gov as #NCT05461807. Key Points Rivaroxaban and apixaban have similar effectiveness and safety for treatment of cancer-associated VTE through 6 months.Clinicians should therefore consider patient preference and adherence when choosing the optimal anticoagulant.

Effectiveness and Safety of Rivaroxaban and Low Molecular Weight Heparin in Cancer-Associated Venous Thromboembolism.

Background: Direct-acting oral anticoagulants (DOACs) are alternatives to low molecular weight heparin (LMWH) in most cancer-associated thrombosis (CAT) patients. Objectives: This study sought to compare the effectiveness and safety of rivaroxaban and LMWH for venous thromboembolism (VTE) treatment in patients with an active cancer type not associated with a high risk of DOAC bleeding. Methods: An analysis of electronic health records from January 2012 to December 2020 was performed. Patients were adults, had active cancer, experienced an index CAT event, and were treated with rivaroxaban or LMWH. Patients with cancers with an established high risk of bleeding on DOACs were excluded. Baseline covariates were balanced using propensity score-overlap weighting. HRs with 95% CIs were calculated. Results: We identified 3,708 CAT patients treated with rivaroxaban (29.5%) or LMWH (70.5%). The median (25th-75th percentiles) time on anticoagulation was 180 (69-365) and 96 (40-336) days for rivaroxaban and LMWH patients. At 3 months, rivaroxaban was associated with a 31% reduced risk of recurrent VTE vs LMWH (4.2% vs 6.1%; HR: 0.69; 95% CI: 0.51-0.92). No difference in bleeding-related hospitalizations or all-cause mortality was observed (HR: 0.79; 95% CI: 0.55-1.13 and HR: 1.07; 95% CI: 0.85-1.35, respectively). Rivaroxaban reduced the recurrent VTE risk (HR: 0.74; 95% CI: 0.57-0.97) but not bleeding-related hospitalizations or all-cause mortality at 6 months. At 12 months, no difference was observed between cohorts for any of the previously mentioned outcomes. Conclusions: Among active cancer patients experiencing VTE and not at high risk of bleeding on DOACs, rivaroxaban was associated with a reduced risk of recurrent VTE versus LMWHs at 3 and 6 months but not 12 months. (Observational Study in Cancer-Associated Thrombosis for Rivaroxaban-United States Cohort [OSCAR-US]; NCT04979780).

Clinical and health care resource use burden of hospitalizations for oral factor Xa inhibitor-associated major bleeding: A real-world analysis of Medicare beneficiaries.

Objective: To characterize the burden of illness associated with oral factor Xa (FXa) inhibitor-related bleeding in the US Medicare population. Methods: This retrospective cohort study used the full 20% Medicare random sample claims database to identify patients who experienced their first hospitalization for an FXa inhibitor-related major bleed between October 2013 and September 2017. Bleeding types were classified as intracranial hemorrhage (ICH), gastrointestinal (GI), and other. Associations between risk factors and outcomes (in-hospital and 30-day mortality, 30-day readmission, and discharge to a location other than home) adjusted for patient demographic characteristics, baseline clinical conditions, index event characteristics, treatment with hemostatic/factor replacement agents or transfusion (ie, usual care prereversal agent availability), multicompartment ICH and neurosurgical procedures (ICH cohort), and endoscopy (GI cohort) were assessed using multivariable regression and reported as crude incidences and adjusted odds ratios (ORs) stratified by bleed type. Results: Of the 11,593 patients identified, 2737 (23.6%) had ICH, 8169 (70.5%) had GI bleeds, and 687 (5.9%) had other bleeds. The incidences of in-hospital mortality, 30-day mortality, need for postdischarge out-of-home care, and 30-day readmission were 15.7%, 29.1%, 78.3%, and 20.3% in the single-compartment ICH cohort, respectively; and 1.7%, 6.8%, 41.3%, and 18.8% in the GI bleeds cohort, respectively. Increased odds of both in-hospital mortality and 30-day mortality were significantly associated with: multicompartment ICH (reference, single compartment ICH; OR = 3.35 [95% confidence interval (CI): 2.41-4.66]; 2.18 [95% CI: 1.63-2.91]), loss of consciousness during index hospitalization (yes vs no; OR = 2.03 [95% CI: 1.38-2.97]; 1.49 [95% CI: 1.11-2.02]), receiving usual care (yes vs no; OR = 1.55 [95% CI: 1.22-1.98]; 1.33 [95% CI: 1.09-1.63]) during index hospitalization, and increasing number of Elixhauser comorbidities at baseline (OR = 1.07 [95% CI: 1.03-1.10]; 1.09 [95% CI: 1.06-1.12]) in the ICH cohort; intensive care unit admission (yes vs no; OR = 1.88 [95% CI: 1.32-2.67]; 1.51 [95% CI: 1.26-1.81]), increasing number of Elixhauser comorbidities at baseline (OR = 1.12 [95% CI: 1.07-1.18]; 1.15 [1.12-1.18]), and increasing age on index date (OR = 1.04 [95% CI: 1.02-1.07]; 1.05 [95% CI: 1.04-1.07]) in the GI bleeds cohort. Conclusions: In this large sample of Medicare patients, FXa inhibitor-related major bleeding was associated with substantial burden in terms of adverse clinical outcomes and health care resource use. Incidence of ICH was lower than GI bleeds; however, burden of illness was notably higher with ICH.

Effectiveness and Safety of Rivaroxaban Versus Warfarin among Nonvalvular Atrial Fibrillation Patients with Concomitant Obstructive Sleep Apnea.

Background Obstructive sleep apnea (OSA) is associated with an increased incidence of atrial fibrillation (AF), hypertension, diabetes, heart failure, coronary heart disease, stroke, and death. We sought to evaluate the effectiveness and safety of rivaroxaban versus warfarin in nonvalvular AF (NVAF) patients with concomitant OSA. Methods This was an analysis of electronic health record (EHR) data from November 2010 to December 2021. We included adults with NVAF and OSA at baseline, newly initiated on rivaroxaban or warfarin, and with ≥12 months of prior EHR activity. Patients with valvular disease, alternative indications for oral anticoagulation, or who were pregnant were excluded. The incidence rates of developing stroke or systemic embolism (SSE) and bleeding-related hospitalization were evaluated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using propensity score-overlap weighted proportional hazards regression. Multiple sensitivity and subgroup analyses were performed. Results We included 21,940 rivaroxaban (20.1% at the 15 mg dose) and 38,213 warfarin (time-in-therapeutic range = 47.3 ± 28.3%) patients. Rivaroxaban was found to have similar hazard of SSE compared to warfarin (HR = 0.92, 95% CI = 0.82-1.03). Rivaroxaban was associated with a reduced rate of bleeding-related hospitalizations (HR = 0.85, 95% CI = 0.78-0.92) versus warfarin, as well as reductions in intracranial (HR = 0.76, 95% CI = 0.62-0.94) and extracranial (HR = 0.89, 95%CI = 0.81-0.97) bleeding. Upon sensitivity analysis restricting the population to men with a CHA 2 DS 2 VASc score ≥2 or women with a score ≥3, rivaroxaban was associated with a significant 33% risk reduction in SSE and 43% reduction in the risk of bleeding-related hospitalization. No significant interaction for the SSE or bleeding-related hospitalization outcomes was observed upon subgroup analyses. Conclusion Among patients with NVAF and OSA, rivaroxaban had similar SSE risk versus warfarin but was associated with reductions in any intracranial and extracranial bleeding-related hospitalizations. Rivaroxaban was associated with significant reductions in SSE and bleeding-related hospitalizations when the study population was restricted to patients with a moderate-to-high risk of SSE. These data should provide prescribers with additional confidence in selecting rivaroxaban in NVAF patients who have OSA at the time of anticoagulation initiation.

Derivation and validation of a composite scoring system (SAVED2) for prediction of unfavorable modified Rankin scale score following intracerebral hemorrhage.

Objective: To develop a composite score for predicting functional outcome post-intracerebral hemorrhage (ICeH) using proxy measures that can be assessed retrospectively. Methods: Data from the observational ERICH study were used to derive a composite score (SAVED2) to predict an unfavorable 90-day modified Rankin scale (mRS) score. Independent predictors of unfavorable mRS were identified via multivariable logistic regression and assigned score weights based on effect size. Area under the curve (AUC) was used to measure the score's discriminative ability. External validation was performed in the randomized ATACH-2 trial. Results: There were 2,449 patients from ERICH with valid mRS data who survived to hospital discharge. Predictors associated with unfavorable 90-day mRS score and their corresponding point values were: age ≥70 years (odds ratio [OR], 3.8; 1-point); prior stroke (OR, 2.8; 1-point); need for ventilation (OR, 2.7; 1-point); extended hospital stay (OR, 2.7; 1-point); and non-home discharge location (OR, 5.3; 2-points). Incidence of unfavorable 90-day mRS increased with higher SAVED2 scores (P < 0.001); AUC in ERICH was 0.82 (95% CI, 0.80-0.84). External validation in ATACH-2 (n = 904) found an AUC of 0.74 (95% CI, 0.70-0.77). Conclusions: Using data collected at hospital discharge, the SAVED2 score predicted unfavorable mRS in patients with ICeH.

A RIVA-DM Subanalysis Investigating Patients With Nonvalvular Atrial Fibrillation and Type 2 Diabetes Aged Under Versus Over 80 Years.

BACKGROUND: Advanced age and type 2 diabetes (T2D) are common in patients with nonvalvular atrial fibrillation (NVAF). We evaluated the impact of age on the effectiveness and safety of rivaroxaban versus warfarin in this population. METHODS: We analyzed electronic health record data from November 2010, to December 2019 including adults with NVAF and T2D, newly started on rivaroxaban or warfarin. Propensity score-overlap weighted hazard ratios (HRs) for stroke/systemic embolism (SSE), hospitalization for major or clinically relevant nonmajor bleeding (CRNMB), vascular death, major adverse limb events (MALE), major bleeding, and intracranial hemorrhage (ICH) were calculated for older (≥80 years) and younger (<80 years) cohorts. RESULTS: We included 32 078 rivaroxaban and 83 971 warfarin users (6606 rivaroxaban and 25,335 warfarin patients were aged ≥80 years). No significant interaction for rivaroxaban versus warfarin by age was observed for any outcome, including SSE (HR = 1.05 vs 0.95), hospitalization for major or CRNMB (HR = 1.06 vs 0.90), vascular death (HR = 0.92 vs 0.90), MALE (HR = 0.80 vs 0.76), major bleeding or ICH. CONCLUSIONS: The effectiveness and safety of rivaroxaban versus warfarin remained consistent across patient age subgroups.

Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage: a propensity score-overlap weighted analysis.

BACKGROUND: Andexanet alfa is approved (FDA "accelerated approval"; EMA "conditional approval") as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH). METHODS: This two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included. Patients with a Glasgow Coma Scale (GCS) score < 7, hematoma volume > 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression. RESULTS: The study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16-6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13-0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC. CONCLUSIONS: In this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC. Trial registration NCT02329327; registration date: December 31, 2014.

Worsening of kidney function in patients with atrial fibrillation and chronic kidney disease: evidence from the real-world CALLIPER study.

OBJECTIVE: Evidence is needed on the impact of anticoagulation therapy on kidney function in patients with atrial fibrillation (AF). The objective of this analysis, which is part of the CALLIPER study, was to investigate the risk of worsening kidney function with rivaroxaban 15 mg once daily compared with warfarin in patients with AF and moderate-to-severe chronic kidney disease (CKD) in routine clinical practice in the United States. METHODS: CALLIPER was an observational, retrospective, new-user cohort study. Adult patients with AF in the US IBM Watson MarketScan databases who newly initiated anticoagulation with rivaroxaban 15 mg once daily or warfarin between January 2013 and December 2017 were included. Comparative analysis was performed using Cox proportional hazards regression after adjustment for potential confounding by the stabilized inverse probability of treatment weighting approach and propensity score matching. One of the main study outcomes was worsening kidney function (composite of progression to CKD stage 5, kidney failure, or need for dialysis), besides traditional AF-related outcomes. RESULTS: The cohort included 7368 patients: 5903 (80.1%) initiating warfarin and 1465 (19.9%) initiating rivaroxaban 15 mg once daily. Rivaroxaban 15 mg was associated with a significant 47% reduction in the risk of worsening kidney function versus warfarin (hazard ratio 0.53; 95% confidence interval 0.35-0.78). Similar results were observed in the subgroup of patients with type 2 diabetes. CONCLUSIONS: Rivaroxaban 15 mg may be associated with a lower risk of worsening kidney function as compared with warfarin in the atrial fibrillation population with moderate-to-severe CKD. TRIAL REGISTRATION NUMBER: NCT03359876.

Combination anticoagulant or P2Y12 inhibitor with low-dose aspirin versus low-dose aspirin alone in patients at risk or with documented coronary and/or peripheral artery disease.

OBJECTIVE: To perform a systematic literature review and indirect treatment comparison (ITC) to identify, summarize and quantify randomized controlled trial (RCT) evidence evaluating combination anticoagulant or P2Y12 inhibitor with low-dose aspirin versus low-dose aspirin alone for the prevention of atherothrombotic events in patients with stable coronary artery disease (CAD) and/or peripheral artery disease (PAD). METHODS: We performed an updated search of CENTRAL, MEDLINE and EMBASE through 23 August 2021 to identify RCTs of adult patients with chronic CAD and/or PAD that compared combination anticoagulant or P2Y12 inhibitor with low-dose aspirin to low-dose aspirin alone. Outcomes of interest included major adverse cardiovascular events (MACEs) including cardiovascular death, stroke, or myocardial infarction (MI) and bleeding. When needed, outcomes were pooled using random-effects models to generate hazard or risk ratios (HRs or RRs) and accompanying 95% confidence intervals (CIs). Adjusted ITCs using subsequent pooled HRs/RRs were then performed. RESULTS: Six publications reporting the results of two unique RCTs (one evaluating clopidogrel + aspirin vs. aspirin alone and the other rivaroxaban 2.5 mg twice daily + aspirin vs. aspirin alone) were analyzed. The ITC suggested that rivaroxaban + aspirin was associated with a lower risk of MACEs compared with clopidogrel + aspirin (HR = 0.82, 95% CI = 0.68-0.98). When looking at the individual components of MACE, rivaroxaban + aspirin was associated with lower risk of cardiovascular death (HR = 0.75, 95% CI = 0.57-0.98) and stroke (RR = 0.67, 95 CI = 0.49-0.93) and similar risk of MI (RR = 0.93, 95% CI = 0.70-1.23) versus clopidogrel + aspirin. No evidence of a difference in moderate-to-severe bleeding, fatal bleeding or intracranial hemorrhage (ICH) was seen between the two treatment strategies. CONCLUSIONS: Compared to clopidogrel + low-dose aspirin, the use of rivaroxaban 2.5 mg twice daily + low-dose aspirin reduced the risk of MACE, CV death and stroke including ischemic stroke in patients with or at high risk for chronic CAD and/or PAD. These benefits of rivaroxaban 2.5 mg twice daily + low-dose aspirin compared to clopidogrel + low-dose aspirin appear to be achieved without significantly increasing patients' risk of moderate-to-severe bleeding, including ICH or fatal bleeding.

Adherence and persistence to rivaroxaban in non-valvular atrial fibrillation patients receiving 30- or 90-day supply prescription fills.

BACKGROUND: It is unclear whether 90-day supply fills with rivaroxaban result in better adherence and persistence compared to 30-day supply fills. We assessed patients' adherence and persistence to rivaroxaban at 12- and 24-months in nonvalvular atrial fibrillation (NVAF) patients whose rivaroxaban prescriptions were filled every 30- vs. 90-days. METHODS: Using the IBM MarketScan Commercial and Medicare Supplemental data sets, we identified adult NVAF patients with ≥12-months of continuous insurance coverage who filled a prescription in May 2018 and their immediate subsequent prescription for rivaroxaban for the same days' supply. We propensity score-matched 30- and 90-day rivaroxaban interval fill patients and compared the percentage with a proportion of days covered (PDC) ≥80%, mean PDC, and percentage persistent to rivaroxaban therapy over 12- and 24-months of follow-up. RESULTS: Following propensity score matching, 2237 patients were included in the rivaroxaban 30- and 90-day supply fill cohorts. The proportion of patients with a PDC ≥80% was greater in the 90-day vs. 30-day cohort at both 12-months (odds ratio [OR] = 1.75, 95% confidence interval [CI] = 1.54-1.97) and 24-months (OR = 1.78, 95%CI = 1.58-2.00), as were mean PDC values (absolute difference in mean PDC = 9.4%, 95%CI = 8.2-10.7% at 12-months and 11.2%, 95%CI = 9.5-12.9% higher at 24-months, respectively). Persistence to rivaroxaban was not found to significantly differ between the 30- and 90-day supply cohorts at 12- or 24-months (assuming a 30-day permissible gap); however, greater persistence was observed with 90-day fills at both time points when a 14-day gap was utilized (HR = 1.22, 95%CI = 1.10-1.36 at 12-months and HR = 1.12, 95%CI = 1.02-1.22 at 24-months). CONCLUSIONS: Dispensing 90-day supply fills with rivaroxaban appears to increase the proportion of patients achieving acceptable (PDC ≥80%) adherence as well as mean adherence compared to 30-day supply fills. Ninety-day rivaroxaban fills may also result in improved persistence vs. 30-day fills.

Kidney, limb and ophthalmic complications, and death in patients with nonvalvular atrial fibrillation and type 2 diabetes prescribed rivaroxaban or warfarin: an electronic health record analysis.

BACKGROUND: Patients with nonvalvular atrial fibrillation (NVAF) and type 2 diabetes are at risk of kidney, limb, and ophthalmic complications. We evaluated the rate of these complications and death in patients with NVAF and type 2 diabetes prescribed rivaroxaban or warfarin. METHODS: We analyzed Optum de-Identified electronic health record (EHR) data from 11/2010-12/2019. We included adults with NVAF and T2D newly initiated on rivaroxaban or warfarin with ≥12 months of prior EHR activity. Patients with another indication for anticoagulation, valve disease, history of end-stage renal disease, major adverse limb events (MALE), diabetic retinopathy or pregnancy were excluded. We evaluated the incidence rate of developing a composite outcome of >40% decrease in estimated glomerular filtration incidence rate (eGFR) from baseline, eGFR < 15 mL/minute/1.73 m2, need for dialysis or kidney transplant, MALE, diabetic retinopathy or death. Overlap weighting was used to balance baseline characteristics between cohorts while preserving sample size. Hazard ratios with 95% confidence intervals were calculated using propensity score-overlap weighted Cox regression. RESULTS: We included 24,912 rivaroxaban and 58,270 warfarin users. The mean ± standard deviation (SD) CHA2DS2VASc score was 4.3 ± 1.5 and modified HASBLED score was 1.5 ± 0.8. Thirty percent of rivaroxaban patients were started on 15 mg once daily, with the rest prescribed 20 mg once daily. Warfarin patients had a mean time in therapeutic range of 47 ± 28%. Patients were followed for a mean of 2.89 ± 1.95 years. Rivaroxaban was associated with a reduced hazard of the composite outcome (HR = 0.93, 95%CI = 0.91-0.95; absolute risk reduction = 1.97 events per 1000 patient-years; number needed-to-treat = 51) versus warfarin. Rivaroxaban was also associated with significant reductions in the relative hazard of > 40% decrease in eGFR from baseline (HR = 0.96), need for dialysis or renal transplant (HR = 0.81), and limb revascularization or major amputation (HR = 0.85). Death occurred at a lower incidence rate with rivaroxaban (HR = 0.92, 95%CI = 0.89-0.95). CONCLUSIONS: Rivaroxaban was associated with reduced incidence rates of kidney and limb complications, and death in NVAF patients with type 2 diabetes compared to warfarin. ClinicalTrials.gov Identifier: NCT04509193.

Thromboembolism, bleeding and vascular death in nonvalvular atrial fibrillation patients with type 2 diabetes receiving rivaroxaban or warfarin.

BACKGROUND: Diabetes increases a patient's risk of developing atrial fibrillation by 49%. Patients with nonvalvular atrial fibrillation are at a fivefold increased risk of stroke and die more frequently from vascular causes. We sought to evaluate the effectiveness and safety of rivaroxaban versus warfarin in nonvalvular atrial fibrillation patients with type 2 diabetes. METHODS: This was an analysis of Optum® De-Identified electronic health record data from 11/2010 to 12/2019. We included adults with nonvalvular atrial fibrillation and type 2 diabetes, newly started on rivaroxaban or warfarin and with ≥ 12-months of prior electronic health record activity. Patients who were pregnant, had alternative indications for oral anticoagulation or valvular heart disease were excluded. We evaluated the incidence rate (%/year) of developing the composite outcome of stroke/systemic embolism or vascular death and major or clinically relevant nonmajor bleeding as well as each endpoint individually. Hazard ratios with 95% confidence intervals were calculated using propensity score-overlap weighted proportional hazards regression. RESULTS: We included 32,078 rivaroxaban (31% initiated on 15 mg dose) and 83,971warfarin users (time-in-therapeutic range = 47 ± 28%). Rivaroxaban was associated with a reduced risk of stroke/systemic embolism or vascular death (3.79 vs. 4.19; hazard ratio = 0.91, 95% confdience interval = 0.88-0.95), driven mostly by reductions in vascular death (2.81 vs 3.18, hazard ratio = 0.90, 95% confidence interval = 0.86-0.95) and systemic embolism (0.13 vs. 0.16; hazard ratio = 0.82, 95% confidence interval = 0.66-1.02). Major/clinically relevant nonmajor bleeding was less frequent with rivaroxaban versus warfarin (2.17 vs. 2.31; hazard ratio = 0.94, 95% confidence interval = 0.89-0.99) due to decreased critical organ bleeding (including intracranial hemorrhage) (0.35 vs. 0.54; hazard ratio = 0.63, 95% confidence interval = 0.55-0.72). CONCLUSIONS: In nonvalvular atrial fibrillation patients with type 2 diabetes, rivaroxaban was associated with an ~ 10% relative reduction in vascular mortality and fewer bleeding-related hospitalizations versus warfarin.