Thomas J. Bunz

Effectiveness and Safety of Apixaban, Dabigatran, and Rivaroxaban Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation and Previous Stroke or Transient Ischemic Attack

Background and Purpose— Limited real-world data exist comparing each non–vitamin K antagonist oral anticoagulant (NOAC) to warfarin in patients with nonvalvular atrial fibrillation who have had a previous ischemic stroke or transient ischemic attack. Methods— Using MarketScan claims from January 2012 to June 2015, we identified adults newly initiated on oral anticoagulation, with ≥2 diagnosis codes for nonvalvular atrial fibrillation, a history of previous ischemic stroke/transient ischemic attack, and ≥180 days of continuous medical and prescription benefits before anticoagulation initiation. Three analyses were performed comparing 1:1 propensity score–matched cohorts of apixaban versus warfarin (n=2514), dabigatran versus warfarin (n=1962), and rivaroxaban versus warfarin (n=5208). Patients were followed until occurrence of a combined end point of ischemic stroke and intracranial hemorrhage (ICH) or major bleed, switch/discontinuation of index oral anticoagulation, insurance disenrollment, or end of follow-up. Mean follow-up was 0.5 to 0.6 years for all matched cohorts. Results— Using Cox regression, neither apixaban nor dabigatran reduced the combined primary end point of ischemic stroke or ICH (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.33–1.48 and HR, 0.53; 95% CI, 0.26–1.07) and had nonsignificant effect on hazards of major bleeding (HR, 0.79; 95% CI, 0.38–1.64 and HR, 0.58; 95% CI, 0.26–1.27) versus warfarin. Rivaroxaban reduced the combined end point of ischemic stroke or ICH (HR, 0.45; 95% CI, 0.29–0.72) without an effect on major bleeding (HR, 1.07; 95% CI, 0.71–1.61). ICH occurred at rates of 0.16 to 0.61 events per 100 person-years in the 3 NOAC analyses, with no significant difference for any NOAC versus warfarin. Conclusions— Results from our study of the 3 NOACs versus warfarin in nonvalvular atrial fibrillation patients with a previous history of stroke/transient ischemic attack are relatively consistent with their respective phase III trials and previous stroke/transient ischemic attack subgroup analyses. All NOACs seemed no worse than warfarin in respect to ischemic stroke, ICH, or major bleeding risk.

Derivation and validation of the In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) prediction rule

Abstract Introduction: Existing prediction rules for prospectively prognosticating early mortality following pulmonary embolism (PE) require clinical and/or laboratory data, and are rarely suitable for claims database analyses. We sought to develop a claims-based prediction rule that retrospectively classifies PE patients into low- or higher-risk in-hospital mortality categories. Materials and methods: We randomly assigned MarketScan database patient admitted for PE between April 2010 and September 2013 into derivation (80%) and validation (20%) cohorts. A prediction rule (In-hospital Mortality for PulmonAry embolism using Claims daTa or IMPACT) was derived using multivariable logistic regression, with in-hospital mortality as the dependent variable and demographic/comorbidity data available in claims databases as independent variables. In-hospital mortality rates for low- and higher-risk patients were compared across the derivation and validation cohorts, and prediction rule performance was assessed by evaluating sensitivity and specificity estimates. Results: A total of 27,833 patients admitted for PE were included. The IMPACT rule consisted of 12 risk factors, and categorized 46% of patients as low-risk in both cohorts. Patients classified as low-risk by IMPACT (defined as an estimated in-hospital mortality risk ≤1.5%) had average in-hospital mortality rates of 0.81% (95% confidence interval [CI], 0.65–1.00) in the derivation and 0.77% (95% CI, 0.50–1.18) in the validation cohort. Higher-risk patients had average in-hospital mortality rates of 4.61% (95% CI, 4.25–5.01) and 5.02% (95% CI, 4.30–5.85), respectively. The IMPACT rule had high sensitivity for classifying in-hospital mortality risk (0.87 in both cohorts), but moderate specificity (0.47 for both cohorts). Limitations: We were unable to assess 30 day mortality as an endpoint. IMPACT was only validated in an internal sample. Conclusions: The IMPACT prediction rule may be able to retrospectively classify PE patients’ in-hospital mortality risk with high sensitivity and moderate specificity.

Is Rivaroxaban Associated With Shorter Hospital Stays and Reduced Costs Versus Parenteral Bridging to Warfarin Among Patients With Pulmonary Embolism

Objective: We sought to compare the length of stay (LOS) and total costs for patients with pulmonary embolism (PE) treated with either rivaroxaban or parenterally bridged warfarin. Methods: This retrospective claims analysis was performed in the Premier Database from November 2012 to March 2015. Adult patients were included if they had a hospital encounter for PE (an International Classification of Diseases, Ninth Revision code = 415.1×) in the primary position, a claim for ≥1 diagnostic test for PE on day 0 to 2, and initiated rivaroxaban or parenteral anticoagulation/warfarin. Rivaroxaban users (allowing ≤2 days of prior parenteral therapy) were 1:1 propensity score matched to patients receiving parenterally bridged warfarin. Length of stay, total costs, and readmission for venous thromboembolism (VTE) or major bleeding during the same or subsequent 2 months following the index event were compared between cohorts. Analysis restricted to patients with low-risk PE was also performed. Results: Characteristics of the matched PE cohorts (n = 3466 per treatment) were well balanced. Rivaroxaban use was associated with a 1.36-day shorter LOS and

Effectiveness and Safety of Apixaban, Dabigatran, and Rivaroxaban Versus Warfarin in Frail Patients With Nonvalvular Atrial Fibrillation

2304 reduction in total costs compared to parenterally bridged warfarin (P < .001 for both). Rates of readmission for VTE were similar between cohorts (1.7% vs 1.6%; P = .64). No difference was observed between treatments for readmission for major bleeding (0.2% vs 0.2%; P > .99). In analyses restricted to low-risk patients (n = 1551 per treatment), rivaroxaban was associated with a 1.01-day and a

Effectiveness and safety of rivaroxaban versus warfarin in patients with provoked venous thromboembolism.

1855 reduction in LOS and costs, respectively (P < .001 for both). Rates of readmission were again similar between treatments (P > .56 for all). Conclusion: Rivaroxaban significantly reduced hospital LOS and costs compared to parenterally bridged warfarin, without increasing the risk of readmission.

Effectiveness and safety of rivaroxaban versus warfarin in patients with unprovoked venous thromboembolism: A propensity-score weighted administrative claims cohort study

Background Frailty predicts poorer outcomes and decreased anticoagulation use in patients with nonvalvular atrial fibrillation. We sought to assess the effectiveness and safety of apixaban, dabigatran and rivaroxaban versus warfarin in frail nonvalvular atrial fibrillation patients. Methods and Results Using US MarketScan claims data from November 2011 to December 2016, we identified frail oral anticoagulant‐naïve nonvalvular atrial fibrillation patients with ≥12 months of continuous insurance coverage before oral anticoagulant initiation. Frailty status was determined using the Johns Hopkins Claims‐based Frailty Indicator score (≥0.20 indicating frailty). Users of apixaban, dabigatran, or rivaroxaban were separately 1:1 matched to warfarin users via propensity‐scores, with residual absolute standardized differences <0.1 being achieved for all covariates after matching. Patients were followed for up to 2 years or until an event, insurance disenrollment or end of follow‐up. Rates of stroke or systemic embolism and major bleeding were compared using Cox regression and reported as hazard ratios (HRs) and 95% confidence intervals (CIs). In total, 2700, 2784, and 5270 patients were included in the apixaban, dabigatran, and rivaroxaban 1:1 matched analyses to warfarin. At 2 years, neither apixaban nor dabigatran were associated with differences in the hazard of stroke or systemic embolism (HR=0.78; 95% CI=0.46–1.35 and HR=0.94; 0.60–1.45) or major bleeding (HR=0.72; 95% CI=0.49–1.06 and HR=0.87; 95% CI=0.63–1.19) versus warfarin. Rivaroxaban was associated with reduced stroke or systemic embolism at 2 years (HR=0.68; 95% CI=0.49–0.95) without significantly altering major bleeding risk (HR=1.07; 95% CI=0.81–1.32). Conclusions Our study found rivaroxaban but not apixaban or dabigatran to be associated with reduced SSE versus warfarin in frail nonvalvular atrial fibrillation patients. No direct‐acting oral anticoagulants demonstrated a significant difference in major bleeding versus warfarin.

External Validation of the Multivariable ‘In-Hospital Mortality for Pulmonary Embolism Using Claims Data’ Prediction Rule in the Premier Hospital Database

A paucity of real-world data evaluating rivaroxaban in provoked venous thromboembolism (VTE) exists. We assessed the effectiveness and safety of rivaroxaban versus warfarin in provoked VTE patients treated in routine practice. Using MarketScan claims data from 1/2012 to 12/2016, we identified adults who had ≥ 1 primary hospitalization/emergency department discharge diagnosis code for VTE (index event) and a provoking factor, received rivaroxaban or warfarin as their first outpatient oral anticoagulant within 30-days of the index event and had ≥ 12-month of insurance coverage prior the index VTE. Provoking factors included cancer, hospital admission for ≥ 3-consecutive days over the prior 3-months, major surgery, trauma or fracture within 90-days or pregnancy within 42-weeks of the index VTE. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weights based on propensity-scores (residual standardized differences < 0.1 achieved for all covariates after adjustment). The incidence of the composite endpoint of recurrent VTE or major bleeding at 3- and 6-months was compared using Cox regression and reported as hazard ratios (HRs) and 95% confidence intervals (CIs). We included 4454 rivaroxaban and 13,164 warfarin users with provoked VTE. At 3- and 6-months, rivaroxaban was associated with a reduced hazard of the composite endpoint (HR 0.72, 95% CI 0.61–0.84 and HR 0.69, 95% CI 0.60–0.80) and recurrent VTE (HR 0.70, 95% CI 0.59–0.84 and HR 0.71, 95% CI 0.60–0.84) versus warfarin. Major bleeding was non-significantly reduced at 3-months (HR 0.77, 95% CI 0.57–1.06) and significantly reduced at 6-months (HR 0.68, 95% CI 0.53–0.88) with rivaroxaban. Rivaroxaban reduces recurrent VTE and major bleeding risk versus warfarin in provoked VTE patients treated in routine practice.

Effectiveness and safety of outpatient rivaroxaban versus warfarin for treatment of venous thromboembolism in patients with a known primary hypercoagulable state

BACKGROUND In phase III trials, rivaroxaban demonstrated non-inferiority over enoxaparin/warfarin to prevent recurrent venous thromboembolism (VTE), with a reduction of major bleeding. However, compared to provoked VTE, the risk-benefit ratio of rivaroxaban may be different for patients with unprovoked VTE. METHODS In a retrospective claims data analysis using US MarketScan claims from 1/2012 to 12/2016, we included adults with a primary diagnosis of VTE newly-initiated on rivaroxaban or warfarin within 30-days of the incident VTE and with ≥12-months of continuous insurance benefits prior to the VTE (baseline). Patients with provoked VTE, a claim for anticoagulation during baseline or who redeemed prescriptions for ≥1 oral anticoagulant were excluded. Our primary outcomes were recurrent VTE and major bleeding at 6-months using an intention-to-treat (ITT) analysis. Three-month ITT and 12-month on-treatment (30-day permissible gap) analyses were also performed. Inverse probability-of-treatment weights based on propensity-scores and Cox regression were used to compare outcomes. FINDINGS We identified 10,489 rivaroxaban users and 26,364 warfarin users with incident unprovoked VTE. At 6-months, rivaroxaban was associated with a hazard ratio (HR) of 0.60 (95% confidence interval [CI] = 0.54-0.67) for recurrent VTE (number-needed-to-treat: 59; 95%CI 49-76) and a HR = 0.80 (95% CI = 0.66-0.98) for major bleeding versus warfarin. Our findings remained consistent in the 3- and 12-month analyses. INTERPRETATION Consistent with the results from the EINSTEIN phase-III trials, findings of our routine practice study suggest that, in patients with unprovoked VTE, rivaroxaban has the potential to reduce both the risk of major bleeding and recurrent VTE compared to warfarin.

Effectiveness and Safety of Rivaroxaban in Patients With Cancer-Associated Venous Thrombosis

A tool that allows researchers, payers, and hospital administrators to retrospectively estimate the early mortality risk in patients diagnosed with pulmonary embolism (PE) may enable epidemiologic research and influence hospital resource utilization. The multivariable I n-hospital M ortality for P ulmon A ry embolism using C laims da T a (IMPACT) prediction rule was recently derived for this purpose.1 While clinical data-based rules for the risk stratification of patients with PE are available, their implementation requires access to vital sign and laboratory data not commonly found or easily accessible in claims databases. Here we sought to externally validate IMPACT using administrative claims data at the time of PE patient admission from the Premier Hospital Database. This analysis was performed in the United States (US) Premier Hospital Database. Since data were de-identified, our study was exempt from institutional review board oversight. To be included, patients had to be ≥18 years-of-age, have an International Classification of Disease, ninth-edition, Clinical Modification (ICD-9-CM) diagnosis code for PE (415.1x) in the primary position, ≥1 claim for a diagnostic test for PE (i.e., computed tomography, pulmonary angiography, and ventilation/perfusion lung scan) on Days 0–2 and claims evidence of pharmacologic (anticoagulation, thrombolysis) and/or non-pharmacologic (pulmonary embolectomy or inferior vena cava placement) treatment. We used the IMPACT prediction rule [1/(1 + exp(− x )); where x = −5.833 + (0.026 × age) + (0.402 × myocardial infarction) + (0.368 × chronic lung disease) + (0.464 × stroke) + (0.638 × prior major bleeding) + (0.298 × atrial fibrillation) + (1.061 × cognitive impairment) + (0.554 × heart failure) + (0.364 × renal failure) …

Comparative Risk of Major Bleeding with Rivaroxaban and Warfarin: Population Based Cohort Study of Unprovoked Venous Thromboembolism

INTRODUCTION Screening for primary hypercoagulable states (PHSs) in venous thromboembolism (VTE) patients was not mandated in the EINSTEIN trials; and therefore, few patients with a known PHS were available for analysis. We sought to assess the effectiveness and safety of rivaroxaban versus warfarin for treatment of VTE in patients with a known PHS. METHODS Using MarketScan claims data from 1/2012-9/2015, we identified adults with a primary diagnosis of VTE during a hospitalization/emergency department visit (the index event), with ≥180-days of continuous insurance coverage prior to the index event, a documented diagnosis for a PHS and newly-initiated as an outpatient on rivaroxaban or warfarin within 30-days of the index VTE. Rivaroxaban and warfarin users were 1:1 propensity-score matched. Balance between cohorts was evaluated by inspecting standardized differences for baseline covariates (<0.1 considered well-balanced). Patients were followed up to 12-months from the index event or until occurrence of an endpoint, switch/discontinuation of index oral anticoagulation or insurance disenrollment. Rates of recurrent VTE and major bleeding were compared using Cox regression and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS We matched 403 rivaroxaban and 403 warfarin patients with VTE and a known PHS. All baseline covariates had a standardized difference < 0.1. Rivaroxaban use was associated with a non-significant reduction in recurrent VTE (HR = 0.70, 95%CI = 0.33-1.49) and major bleeding (HR = 0.55, 95%CI = 0.16-1.86) versus warfarin. CONCLUSIONS In routine practice, the effectiveness and safety of rivaroxaban versus warfarin in VTE patients with a known PHS appears to be similar to that observed in the EINSTEIN trial program.