Allison Keshishian

Background Studies have shown that patients with non-valvular atrial fibrillation (NVAF) who discontinue oral anticoagulants (OACs) are at higher risk of complications such as stroke. Objective This analysis compared the risk of non-persistence with OACs among patients with NVAF. Methods Adult patients with NVAF who initiated apixaban, dabigatran, rivaroxaban, or warfarin were identified using 01JAN2013–30JUN2019 data from Centers for Medicare and Medicaid Services and four US commercial claims databases. Non-persistence was defined as discontinuation (no evidence of index OAC use for ≥ 60 days from the last days’ supply) or switch to another OAC. Kaplan–Meier curves were generated to illustrate time to non-persistence along with cumulative incidences of non-persistence. Baseline and time-varying covariates were evaluated, and adjusted Cox proportional hazards models were used to evaluate non-persistence risk. Results In total, 363,823 patients receiving apixaban, 57,121 receiving dabigatran, 282,831 receiving rivaroxaban, and 317,337 receiving warfarin were included. Of these, 47–72% discontinued/switched OAC therapy within an average 9-month follow-up. Apixaban was associated with a lower risk of non-persistence than were dabigatran (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.61–0.62), rivaroxaban (HR 0.76; 95% CI 0.75–0.76), and warfarin (HR 0.74; 95% CI 0.74–0.75). Dabigatran was associated with a higher risk of non-persistence than were warfarin (HR 1.21; 95% CI 1.19–1.22) and rivaroxaban (HR 1.23; 95% CI 1.22–1.25), and rivaroxaban was associated with a lower risk of non-persistence than was warfarin (HR 0.98; 95% CI 0.97–0.98). Clinical events (stroke/systemic embolism and major bleeding [MB]) during follow-up were predictors of non-persistence (stroke HR 1.57; 95% CI 1.53–1.61; MB HR 2.96; 95% CI 2.92–3.00). Conclusion In over one million patients with NVAF, our results suggest differences in anticoagulation treatment persistence across OAC agents, even after accounting for clinical events after OAC initiation. It is important for clinicians and patients to take these differences into consideration, especially as non-persistence to OAC therapy is associated with thromboembolic complications.

Background: Among non-valvular atrial fibrillation (NVAF) patients with a history of bleeding, there is a reluctance to use oral anticoagulants (OACs) due to concerns about the risk of bleeding associated with OACs. However, lack of OAC treatments for NVAF patients is associated with a higher risk of stroke and mortality. Non-vitamin K antagonist OAC (NOACs) have been approved for the prevention of stroke in NVAF patients. There are limited data comparing the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between patients prescribed NOACs and with a history of bleeding. Purpose: This study used multiple United States data sources to evaluate the risk of S/SE and MB among NVAF patients with prior bleeding events who were prescribed NOACs. Methods: This retrospective observational study used data from CMS Medicare and four commercial databases–covering >180 million beneficiaries. The study selected adult NVAF patients who were prescribed apixaban, dabigatran, or rivaroxaban (01JAN2013–30JUN2019) and had a prior bleeding event which was defined as a hospitalization with a bleeding diagnosis (intracranial hemorrhage [ICH], gastrointestinal [GI] bleeding, or other bleeding sites) prior to or during the index treatment episode. After 1:1 propensity-score-matched (PSM) in each database between NOACs (apixaban-dabigatran, apixaban-rivaroxaban, and dabigatran-rivaroxaban), the resulting patient records were pooled. S/SE and MB (identified by inpatient claims) were captured during the follow-up period, which was defined as the time between the day after the index treatment date and treatment discontinuation or switch, death, end of study period, or end of medical and pharmacy enrollment. Hazard ratios of S/SE and MB were calculated using Cox proportional hazards models. Results: Of the overall NVAF population treated with NOACs, 6.2% had a prior bleeding event (ICH: 13.5%; GI: 61.8%; Other: 24.6%). After PSM, a total of 11,106 apixaban-dabigatran, 30,665 apixaban-rivaroxaban, and 11,148 dabigatran-rivaroxaban pairs were matched. Apixaban was associated with a lower risk of S/SE compared to dabigatran and rivaroxaban, and dabigatran was associated with a similar risk of S/SE compared to rivaroxaban. Apixaban was associated with a lower risk of MB compared to dabigatran and rivaroxaban, and dabigatran was associated with a lower risk of MB compared to rivaroxaban (Figure). Conclusions: In this subgroup of NVAF patients with a history of bleeding, apixaban was associated with a lower risk of S/SE and MB compared to dabigatran and rivaroxaban. Dabigatran was associated with a lower risk of MB compared to rivaroxaban. These results are informative for understanding the impact of NOAC treatment in NVAF patients with prior bleeding events. Funding Acknowledgement: Type of funding sources: Private company. Main funding source(s): Bristol-Myers Squibb Company and Pfizer, Inc.

Background: Clinical trials and real-world database studies have shown the benefits of non-vitamin K antagonist oral anticoagulants (NOACs) compared to warfarin; however, measures of functional outcomes are critical in evaluating a patient's quality of life. Previous measures of time spent out of hospital in a home setting and time spent receiving disease-related care among non-valvular atrial fibrillation (NVAF) patients are lacking in the current literature. Purpose: This analysis was based on the previously published ARISTOPHANES study, and used multiple data sources to evaluate the amount of time spent at a patient's home among NVAF patients who were prescribed NOACs versus warfarin. Methods: This retrospective observational study used US data from CMS Medicare and four commercial databases to select adult NVAF patients who initiated apixaban, dabigatran, rivaroxaban, or warfarin (01JAN2013–30SEP2015). Time at home and time at home without external AF-related care were measured during the 180 days after the index date (OAC prescription). Time at home was defined as days from index date without any of the following: an inpatient, skilled nursing facility or nursing facility, hospice, or inpatient rehabilitation facility admission. Time at home and without external AF-related care was defined as days away from home and days with a claim for bleeding, stroke/systemic embolism, AF, or an INR test. Each day a claim was observed was counted as one day. In each database, three 1:1 NOAC-warfarin propensity-score-matched (PSM) cohorts were created before pooling the results. After PSM, a subgroup of patients who were alive and had ≥180 days of follow-up was created. Poisson regression was conducted in each NOAC-warfarin matched cohort to compare time at home and time at home without external AF-related care. Results: After matching, a total of 100,977 apixaban-warfarin, 36,990 dabigatran-warfarin, and 125,068 rivaroxaban-warfarin patient pairs were selected. Of those patients, 38–46% had 180 days of follow-up available. Across treatment cohorts, approximately 75% of patients were at home for the 180-day follow-up. Apixaban, dabigatran, and rivaroxaban patients had 1.3, 0.9, and 0.8 more days at home, respectively, compared to warfarin patients. Patients treated with apixaban had 13.4 more days at home without AF-related care compared to warfarin, while dabigatran and rivaroxaban had 11.6 and 11.7 more days at home without AF-related care compared to warfarin. A greater proportion of warfarin patients than NOAC patients had an INR test (81–82% vs 14–21%), and days with INR testing were the main driver for external AF-related care for warfarin patients. Conclusion: Among NVAF patients treated with OACs, NOACs were associated with a longer time at home and time at home without external AF-related care compared to warfarin. These results can help inform healthcare providers and patients regarding the impact of NOAC treatment in NVAF patients. Funding Acknowledgement: Type of funding sources: Private company. Main funding source(s): Bristol-Myers Squibb Company and Pfizer Inc.

Background: Patients with non-valvular atrial fibrillation (NVAF) use oral anticoagulants such as warfarin or non-vitamin K antagonist oral anticoagulants (NOACs) for the prevention of stroke. However, the effectiveness and safety of warfarin and NOACs can be influenced by pre-existing patient comorbidities, such as a history of bleeding, and limited evidence are available to inform the choice of the most appropriate anticoagulant treatment for NVAF patients with bleeding history. Purpose: This study used five United States insurance claims databases to evaluate the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) among NVAF patients with prior bleeding events who were prescribed NOACs versus warfarin. Methods: This retrospective observational study used data from 5 databases (CMS Medicare and four commercial databases, covering >180 million beneficiaries) to select adult NVAF patients who were treated with apixaban, dabigatran, rivaroxaban, or warfarin (01JAN2013–30JUN2019). Patients were required to have a prior bleeding event, defined as a hospitalization with a diagnosis for intracranial hemorrhage (ICH), gastrointestinal (GI) bleeding or bleeding at other key sites prior to or during the index treatment episode. In each database, three 1:1 NOAC-warfarin propensity-score-matched (PSM) cohorts were created before pooling the results. Outcome measures were time to first stroke/SE, (ischemic stroke, hemorrhagic stroke, and SE), and time to first MB (gastrointestinal bleeding, intracranial hemorrhage, and MB at other key sites), and were measured from the index treatment episode to treatment discontinuation or switch, death, health plan disenrollment, or end of study period. Hazard ratios of S/SE and MB were calculated using Cox proportional hazards models. Results: Among the eligible NVAF population, 8.2% of patients had a prior bleeding event (ICH: 12.3%; GI: 60.7%; Other: 27.0%). After PSM, a total of 43,092 apixaban-warfarin, 11,295 dabigatran-warfarin, and 32,723 rivaroxaban-warfarin patient pairs with prior bleeding were selected with a mean follow-up of 8–9 months. Apixaban and rivaroxaban were associated with a lower risk of S/SE, and dabigatran was associated with a similar risk of S/SE when compared to warfarin. Apixaban and dabigatran were associated with a lower risk of MB, and rivaroxaban was associated with a similar risk of MB, compared to warfarin (Figure). Conclusion: Among NVAF patients with prior bleeding events, NOACs were associated with varying risks of S/SE and MB compared to warfarin. These results can help inform healthcare providers concerning the impact of OAC treatment in NVAF patients with history of bleeding. Funding Acknowledgement: Type of funding sources: Private company. Main funding source(s): Bristol-Myers Squibb Company and Pfizer, Inc.

This study integrated 5 United States healthcare claims databases to evaluate the risk of recurrent venous thromboembolism (VTE) and major bleeding (MB) among VTE patients who initiated apixaban vs. warfarin, stratified by obesity. Obese and morbidly obese patients were identified based on diagnosis codes. Stabilized inverse probability treatment weighting (IPTW) was conducted to balance observed patient characteristics between treatment cohorts. An interaction analysis was conducted to evaluate treatment effects of apixaban vs. warfarin according to obesity status. Cox proportional hazard models were used to evaluate the risk of recurrent VTE and MB among IPTW weighted obese and morbidly obese patients. A total of 112,024 non-obese patients and 43,095 obese patients were identified, of whom 19,751 were morbidly obese. When stratified by obesity status post-IPTW, no significant interactions were observed for effects of apixaban vs. warfarin on recurrent VTE or MB (interaction p > 0.10). Among IPTW obese and morbidly obese patients, apixaban was associated with a significantly lower risk of recurrent VTE (obese: 0.73 [0.64–0.84]; morbidly obese: 0.65 [0.53–0.80]) and MB (obese: 0.73 [0.62–0.85]; morbidly obese: 0.68 [0.54–0.86]) as compared with warfarin. In this large sample of obese and morbidly obese VTE patients, apixaban had a significantly lower risk of recurrent VTE and MB vs. warfarin.

Gastrointestinal (GI) bleeding is the most common type of major bleeding associated with oral anticoagulant (OAC) treatment. Patients with major bleeding are at an increased risk of a stroke if an OAC is not reinitiated. Non-valvular atrial fibrillation (NVAF) patients initiating OACs were identified from the Centers for Medicare and Medicaid Services (CMS) Medicare data and four US commercial claims databases. Patients who had a major GI bleeding event (hospitalization with primary diagnosis of GI bleeding) while on an OAC were selected. A control cohort of patients without a major GI bleed during OAC treatment was matched to major GI bleeding patients using propensity scores. Stroke/systemic embolism (SE), major bleeding, and mortality (in the CMS population) were examined using Cox proportional hazards models with robust sandwich estimates. A total of 15,888 patients with major GI bleeding and 833,052 patients without major GI bleeding were included in the study. Within 90 days of the major GI bleed, 58% of patients discontinued the initial OAC treatment. Patients with a major GI bleed had a higher risk of stroke/SE [hazard ratio (HR): 1.57, 95% confidence interval (CI): 1.42–1.74], major bleeding (HR: 2.79, 95% CI: 2.64–2.95), and all-cause mortality (HR: 1.29, 95% CI: 1.23–1.36) than patients without a major GI bleed. Patients with a major GI bleed on OAC had a high rate of OAC discontinuation and significantly higher risk of stroke/SE, major bleeding, and mortality after hospital discharge than those without. Effective management strategies are needed for patients with risk factors for major GI bleeding.

This ARISTOPHANES analysis examined stroke/systemic embolism (SE) and major bleeding (MB) among a subgroup of nonvalvular atrial fibrillation (NVAF) patients with obesity prescribed warfarin or non-vitamin K antagonist oral anticoagulants (NOACs) in order to inform clinical decision making. A retrospective observational study was conducted among NVAF patients who were obese and initiated apixaban, dabigatran, rivaroxaban, or warfarin from 1 January 2013–30 September 2015, with data pooled from CMS Medicare and four US commercial claims databases. Propensity score matching was completed between NOACs and against warfarin in each database, and the results were pooled. Cox models were used to evaluate the risks of stroke/SE and MB. A total of 88,461 patients with obesity were included in the study. Apixaban and rivaroxaban were associated with a lower risk of stroke/SE vs. warfarin (HR: 0.63, 95% CI: 0.49–0.82 and HR: 0.84, 95% CI: 0.72–0.98). Dabigatran was associated with a similar risk of stroke/SE compared to warfarin. Compared with warfarin, apixaban and dabigatran had a lower risk of MB (HR: 0.54, 95% CI: 0.49–0.61 and HR: 0.75, 95% CI: 0.63–0.91). Rivaroxaban was associated with a similar risk of MB compared to warfarin. In this high-risk population with obesity, NOACs had a varying risk of stroke/SE and MB vs. warfarin.

BACKGROUND: Venous thromboembolism (VTE) is the second leading cause of death in cancer patients. The treatment of cancer-associated VTE carries a significantly greater risk of major bleeding (MB) and recurrent VTE compared to that in non-cancer patients. CHEST Guidelines suggest the use of low molecular weight heparin (LMWH) over a vitamin K antagonist (VKA) in patients diagnosed with VTE and cancer. The last decade has seen an emergence of non-VKA anticoagulants (NOACs) for the treatment of VTE. Despite completed and ongoing clinical trials, there is a lack of real-world evidence comparing the effectiveness and safety of LWMH with VKAs and NOACs among VTE patients with active cancer. Therefore, this study evaluates the risk of MB, clinically relevant non-MB (CRNMB), and recurrent VTE (fatal or non-fatal) among VTE patients with active cancer prescribed apixaban, LMWH, or warfarin in routine clinical practice. METHODS: Four US commercial insurance claims databases were used to identify VTE patients with active cancer (defined as cancer diagnosis or cancer treatment [chemotherapy, radiation and cancer-related surgery] within 6 months before or 30 days after VTE diagnosis) who initiated apixaban, LMWH, or warfarin within 30-days following the first VTE event (01SEP2014-31MAR2018). Patients who used LMWH as bridging therapy for warfarin (≤14 days before or after warfarin initiation) were classified as warfarin users. Patients were followed to the earliest of: health plan disenrollment, death, index therapy discontinuation, switch to another anticoagulant, study end, or a maximum of 6 months. Additional analysis using all available follow-up was also conducted. Stabilized inverse probability treatment weighting (IPTW) was used to balance treatment cohorts. Cox proportional hazard models were used to evaluate the risk of MB, CRNMB, and recurrent VTE. RESULTS: After applying all eligibility criteria, 3,393 apixaban, 6,108 LMWH, and 4,585 warfarin patients were identified with mean ages of 65, 64, and 64 years, respectively. After IPTW, all patient characteristics were balanced. The mean follow-up was 105, 88, and 113 days for apixaban, LMWH, and warfarin, respectively. Among the weighted VTE cancer population, 51% of the patients had metastatic cancer and 77% of patients received cancer treatment. Further, 15% of patients had very high-risk cancer (brain, stomach, or pancreas), and 40% patients had high-risk cancer (lung, lymphoma, gynecologic, bladder, testicular, renal cell carcinoma). Apixaban patients had a lower risk of MB, CRNM bleeding, and recurrent VTE compared to LMWH. Apixaban patients also had a lower risk of recurrent VTE and a similar risk of MB and CRNM bleeding compared to warfarin. Warfarin patients had a similar risk of MB, CRNM bleeding, and recurrent VTE compared to LMWH (Figure). When the entire available follow-up period (mean follow-up was 137, 106, and 166 days for apixaban, LMWH, and warfarin, respectively) was used, the trends were similar to the 6-month analysis for apixaban vs. LMWH and warfarin vs. LMWH. However, apixaban patients were associated with a lower risk of both MB and recurrent VTE compared to warfarin patients. CONCLUSION: VTE patients with active cancer initiating apixaban had significantly lower risk of MB, CRNM bleeding, and recurrent VTE compared to LMWH patients. Apixaban patients also had a lower risk of recurrent VTE compared to warfarin patients. These results may be helpful for clinicians in evaluating different anticoagulation treatments for VTE patients with active cancer. Further studies are needed to evaluate these outcomes between different anticoagulation treatment options. Figure Disclosures: Cohen: Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Temasek Capital: Consultancy; ACI Clinical: Consultancy; Navigant: Consultancy; McKinsey: Consultancy; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy; Aspen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boston Scientific: Consultancy; Boehringer-Ingelheim: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; GLG: Consultancy; Guidepoint Global: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy; Medscape: Consultancy, Speakers Bureau. Keshishian:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Bristol-Myers Squibb Company and Pfizer Inc.. Lee:Pfizer Inc.: Employment, Equity Ownership. Wygant:Bristol-Myers Squibb Company: Employment. Rosenblatt:Bristol-Myers Squibb: Other: Stock Owner ; Bristol-Myers Squibb Company: Employment. Hlavacek:Pfizer Inc.: Employment. Mardekian:Pfizer Inc.: Employment. Wiederkehr:Pfizer Inc.: Employment. Sah:STATinMED Research: Other: I am a paid employee of...

Clinical trials have demonstrated that direct oral anticoagulants (DOACs) are at least non-inferior to warfarin in reducing the risk of stroke/systemic embolism (SE) among patients with non-valvular atrial fibrillation (NVAF), but the comparative risk of major bleeding varies between DOACs and warfarin. Using US Department of Defense (DOD) data, this study compared the risk of stroke/SE and major bleeding for DOACs relative to warfarin. Adult patients with ≥1 pharmacy claim for apixaban, dabigatran, rivaroxaban, or warfarin from 01 Jan 2013–30 Sep 2015 were selected. Patients were required to have ≥1 medical claim for atrial fibrillation during the 12-month baseline period. Patients with a warfarin or DOAC claim during the 12-month baseline period were excluded. Each DOAC cohort was matched to the warfarin cohort using propensity score matching (PSM). Cox proportional hazards models were conducted to evaluate the risk of stroke/SE and major bleeding of each DOAC vs warfarin. Of 41,001 identified patients, there were 3691 dabigatran-warfarin, 8226 rivaroxaban-warfarin, and 7607 apixaban-warfarin matched patient pairs. Apixaban was the only DOAC found to be associated with a significantly lower risk of stroke/SE (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.39, 0.77; p < 0.001) and major bleeding (HR: 0.65; 95% CI: 0.53, 0.80; p < 0.001) compared to warfarin. Dabigatran and rivaroxaban initiation were associated with similar risk of stroke/SE (dabigatran: HR: 0.68; 95% CI: 0.43, 1.07; p = 0.096; rivaroxaban: HR: 0.83; 95% CI: 0.64, 1.09; p = 0.187) and major bleeding (dabigatran: HR: 1.05; 95% CI: 0.79, 1.40; p = 0.730; rivaroxaban: HR: 1.07; 95% CI: 0.91, 1.27; p = 0.423) compared to warfarin. Among NVAF patients in the US DOD population, apixaban was associated with significantly lower risk of stroke/SE and major bleeding compared to warfarin. Dabigatran and rivaroxaban were associated with similar risk of stroke/SE and major bleeding compared to warfarin.

BACKGROUND: The ARISTOTLE trial demonstrated that apixaban had significantly lower rates of stroke/systemic embolism (SE) and major bleeding than warfarin; however, no direct clinical trials between apixaban and other direct oral anticoagulants (DOACs) are available. Few real-world studies comparing the effectiveness and safety between DOACs have been conducted. OBJECTIVE: To compare effectiveness, safety, and health care costs among oral anticoagulants (OACs) for nonvalvular atrial fibrillation (NVAF) patients in the U.S. Department of Defense (DoD) population. METHODS: Adult NVAF patients initiating warfarin or DOACs (apixaban, rivaroxaban, and dabigatran) were selected from U.S. DoD data from January 1, 2013, to September 30, 2015. The first OAC claim date was designated as the index date. Patients initiating another OAC were matched 1:1 to apixaban patients using propensity score matching to balance demographics and clinical characteristics. Cox proportional hazards models were used to estimate the ri...