Effectiveness and safety in non-valvular atrial fibrillation patients switching from warfarin to direct oral anticoagulants in US healthcare claims.

INTRODUCTION: There is a paucity of real-world studies examining the risks of stroke/systemic embolism (SE) and major bleeding (MB) among non-valvular atrial fibrillation (NVAF) patients switching from warfarin to a direct oral anticoagulant (DOAC). This retrospective study was conducted to compare the stroke/SE and MB risks between patients switched from warfarin to apixaban, dabigatran, or rivaroxaban in real-world clinical practice. MATERIALS AND METHODS: This study used data from four United States commercial claims databases from January 1, 2012 to June 30, 2019. The study population included NVAF patients initially treated with warfarin and switched to apixaban, dabigatran, or rivaroxaban within 90 days of their warfarin prescription ending. Patients were matched 1:1 between the DOACs in each database using propensity scores and then pooled for the final analysis. Cox proportional hazards models were used to calculate the risk of stroke/SE and MB. RESULTS AND CONCLUSIONS: The final population consisted of 2,611 apixaban-dabigatran, 12,165 apixaban-rivaroxaban, and 2,672 dabigatran-rivaroxaban pairs. Apixaban vs. dabigatran was associated with a lower risk of stroke/SE (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.39-0.96) and MB (HR: 0.67; 95% CI: 0.50-0.91). Apixaban vs. rivaroxaban was associated with a similar risk of stroke/SE (HR: 0.88; 95% CI: 0.73-1.07) and a lower risk of MB (HR: 0.60; 95% CI: 0.52-0.68). There was no significant difference in either risk between dabigatran and rivaroxaban. These results provide important insights into how the risks of stroke/SE and MB for NVAF patients vary when switching from warfarin to different DOACs.

Clinical Impact of Switching or Continuation of Apixaban or Rivaroxaban among Patients with Non-Valvular Atrial Fibrillation.

BACKGROUND: Real-world evidence on direct oral anticoagulant outcomes among Non-Valvular Atrial Fibrillation (NVAF) patients is limited. We aimed to evaluate stroke/systemic embolism (SE) and major bleeding (MB) risks among NVAF patients continuing or switching to different oral anticoagulants. METHODS: Using Optum's de-identified Clinformatics® Data Mart Database, we identified NVAF patients initiating apixaban or rivaroxaban between 1 January 2013 and 31 December 2021. Patients switching therapies within 30 days before or 90 days after discontinuing their initial DOAC and those who continued initial therapy were included. The index date was the switch date for switchers, while continuers were assigned a hypothetic index date. Switchers and continuers were propensity score matched based on pre-index characteristics. RESULTS: Among 167,868 apixaban and 65,888 rivaroxaban initiators, 2900 apixaban-to-rivaroxaban switchers were matched with 14,500 apixaban continuers, and 2873 rivaroxaban-to-apixaban switchers were matched with 14,365 rivaroxaban continuers. Apixaban-to-rivaroxaban switching was associated with higher stroke/SE risk (HR: 1.99, 95% CI: 1.38-2.88) and MB risk (HR:1.80, 95% CI: 1.46-2.23) than continuing apixaban. Rivaroxaban-to-apixaban switching had similar stroke/SE risk (HR: 0.74, 95% CI: 0.45-1.22) but lower MB risk (HR: 0.49, 95% CI: 0.38-0.65) than continuing rivaroxaban. CONCLUSIONS: These findings may aid physicians and patients in making informed decisions when considering a switch between apixaban and rivaroxaban.

Journey to anticoagulant access following payer rejection of apixaban.

OBJECTIVES: To investigate the journey to oral anticoagulant (OAC) access following formulary-related rejection of apixaban (Eliquis) and evaluate characteristics associated with failure to achieve OAC access among patients with atrial fibrillation (AF). STUDY DESIGN: Retrospective study using the Optum Market Clarity Data from January 2016 through February 2020. METHODS: Patients had at least 1 claim rejection for apixaban due to prior authorization (PA), formulary exclusion (FE), or quantity limit (QL) and at least 1 AF diagnosis on or before the rejected claim. Descriptive statistics summarized transaction journeys by type of formulary restriction. Multivariable regression assessed patient characteristics associated with not receiving an OAC within 60 days after initial rejection. RESULTS: Among 18,434 patients in the analytic sample, QL was the most common reason for rejection (68.7%), followed by PA (21.2%) and FE (10.2%). Most patients received a paid OAC claim within 60 days after rejection (82.2%-85.5% across restriction types). Mean time from rejection to paid claim ranged from 5.2 to 10.7 days among patients with a paid OAC claim and 12.4 to 17.6 days among those with multiple attempts before OAC receipt. Characteristics associated with higher odds of not receiving OAC treatment included being male, beingAfrican American, having Medicaid coverage, possessing a high stroke risk score, exhibiting no evidence of prior apixaban treatment, and being prescribed a low dose of apixaban on the initial rejected claim. CONCLUSIONS: Most patients with a claim rejection for apixaban received approval for apixaban within 60 days, suggesting that initial rejection merely created a delay in treatment. Vulnerable populations were at greater risk of not receiving a paid OAC claim.

Payer formulary tier increases of apixaban: how patients respond and potential implications.

OBJECTIVE: To assess potential impacts of formulary tier increases of apixaban-an efficacious oral anticoagulant (OAC) for preventing stroke in patients with atrial fibrillation (AF)-on patients' prescription drug plan (PDP) switching and OAC treatment patterns. METHODS: Nationwide claims data for Medicare beneficiaries with Parts A, B, and D (100% sample) were used to assess apixaban-treated AF patients who faced a formulary tier increase for apixaban in 2017 by their Part D PDP. Patients' out-of-pocket (OOP) costs for apixaban were described, along with PDP switching and OAC treatment patterns. RESULTS: Among 1845 included patients, 97.7% had apixaban on tier 3 of their plan's formulary in 2016 and faced its increase to tier 4 for 2017. Approximately 4% (N = 81) of patients pre-emptively switched to a different PDP for 2017 with almost all switching to plans with apixaban on a lower formulary tier and 85.2% continuing apixaban treatment. Among the 96% (N = 1764) of patients who remained on the same PDP for 2017, over half (57.5%) continued apixaban treatment, despite increased OOP costs ($54 vs. $135 for a 30-day supply in 2016 vs. 2017). Only 12.4% of those who remained on the same plan for 2017 switched to another OAC, while as much as 30.1% discontinued OACs. These discontinuers exhibited higher comorbidity burdens than patients continuing on any OAC. CONCLUSION: The majority of patients continued on apixaban despite higher OOP cost, suggesting patients' reluctance to change treatment for non-medical reasons; however, 30% of patients discontinued OAC treatment after higher apixaban tier placement.

Delaying clinical events among patients with non-valvular atrial fibrillation treated with oral anticoagulants: Insights from the ARISTOPHANES study.

BACKGROUND: Oral anticoagulants (OACs) mitigate stroke and systemic embolism (SE) risk in non-valvular atrial fibrillation (AF) patients but can increase the risk of major bleeding (MB). This study analyzed the gains in event-free time for these outcomes among OAC treatment options represented in the ARISTOPHANES study. METHODS: This sub-analysis consisted of NVAF patients who initiated warfarin, apixaban, dabigatran, or rivaroxaban from 01JAN2013-30SEP2015, with data pooled from Medicare and 4 US commercial claims databases. Propensity score matching was conducted between non-vitamin K antagonist OAC (NOAC) and warfarin cohorts in each database and results were pooled. Laplace regression was used to evaluate the delay in time to stroke/SE and MB events between NOACs and warfarin and between NOACs after the first 12-months of follow-up. RESULTS: The population included 466,991 patients (167,413 warfarin; 108,852 apixaban; 37,724 dabigatran; and 153,002 rivaroxaban). Event-free time gain (95% confidence interval) for apixaban versus warfarin was 101 days (78- 124) for stroke/SE and 116 (103- 130) days for MB. The gain in event-free time for dabigatran versus warfarin was 45 days (3- 87) for stroke/SE and 92 (68- 116) days for MB. The gain in event-free time for rivaroxaban versus warfarin was 63 days (42- 84) for stroke/SE but event-free time decreased by 18 (-31-6) days for MB. CONCLUSIONS: Over 12 months after initiation, apixaban and dabigatran conferred progressive increases in event free time for stroke/SE and MB vs warfarin, whereas rivaroxaban conferred an increase in stroke/SE-free time but a loss in MB-free time vs warfarin.

Payer formulary exclusions of apixaban: how patients respond and potential implications.

In recent years, US payers have increased usage of formulary exclusions as a means to help manage costs. Earlier this year, one of the largest pharmacy benefit managers in the country added Eliquis (apixaban), the most widely used anticoagulant, to its list of excluded medicines from its formulary, raising concerns by physicians and patients. In this commentary, we examine the potential impacts of formulary exclusion of a drug like apixaban-a treatment for patients with atrial fibrillation and venous thromboembolism to help prevent stroke and clotting events and which has been demonstrated to have a strong efficacy and safety profile. We discuss the effect of formulary exclusions on patients' ability to access the most clinically appropriate treatment for their health needs, along with possible effects on their health and well-being. We also report descriptive results on apixaban-treated patients with traditional Medicare coverage who faced a formulary exclusion of apixaban in 2017, and these patients' observed behaviors. We found that the majority of these patients remained on apixaban either through pre-emptively switching to a different Part D drug plan with apixaban coverage or applying for formulary exception. Our findings suggest that formulary exclusion did not help to achieve the goal of switching patients to less costly medications but created additional hurdles for patients to access their preferred treatment and increased patient burden. Alternative ways to manage payer costs may be needed to help avoid poor outcomes and reduce the burden placed on patients in their efforts to access life-saving medications.

Effectiveness and safety of oral anticoagulants in non-valvular atrial fibrillation patients with prior bleeding events: a retrospective analysis of administrative claims databases.

INTRODUCTION: There are a paucity of real-world data examining effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in nonvalvular atrial fibrillation (NVAF) patients with prior bleeding. METHODS: This retrospective analysis included data from 5 insurance claims databases and included NVAF patients prescribed OACs with prior bleeding. One-to-one propensity score matching was conducted between NOACs and warfarin and between NOACs in each database. Cox proportional hazards models were used to evaluate the risk of stroke/systemic embolism (SE) and MB. RESULTS: A total of 244,563 patients (mean age 77; 50% female) with prior bleeding included 55,094 (22.5%) treated with apixaban, 12,500 (5.1%) with dabigatran, 38,246 (15.6%) with rivaroxaban, and 138,723 (56.7%) with warfarin. Apixaban (hazard ratio [HR]: 0.76 [95% CI: 0.70, 0.83]) and rivaroxaban (HR: 0.79 [95% CI: 0.71, 0.87]) had a lower risk of stroke/SE vs. warfarin. Apixaban (HR: 0.67 [95% CI: 0.64, 0.70]) and dabigatran (HR: 0.88 [95% CI: 0.81, 0.96]) had a lower risk of MB vs. warfarin. Apixaban patients had a lower risk of stroke/SE vs. dabigatran (HR: 0.70 [95% CI: 0.57, 0.86]) and rivaroxaban (HR: 0.85 [95% CI: 0.76, 0.96]) and a lower risk of MB than dabigatran (HR: 0.73 [95% CI: 0.67, 0.81]) and rivaroxaban (HR: 0.64 [95% CI: 0.61, 0.68]). CONCLUSIONS: In this real-world analysis of a large sample of NVAF patients with prior bleeding, NOACs were associated with similar or lower risk of stroke/SE and MB vs. warfarin and variable risk of stroke/SE and MB against each other.

Real-world evidence comparing oral anticoagulants in non-valvular atrial fibrillation: a systematic review and network meta-analysis.

Aim: To compare real-world effectiveness/safety of non-vitamin K antagonist oral anticoagulants and vitamin K antagonists among patients with non-valvular atrial fibrillation. Materials & methods: A systematic review of electronic databases yielded 7661 citations published from January 2013 to January 2020. Fifty-five studies were included in Bayesian network meta-analyses of hazard ratios. Results & conclusion: In comparison with vitamin K antagonists, apixaban, dabigatran and rivaroxaban were associated with a reduced risk of stroke or systemic embolism, ischemic stroke, intracranial hemorrhage and all-cause mortality. Apixaban, dabigatran and edoxaban, but not rivaroxaban, were associated with a reduced risk of major bleeding. This study confirmed the effectiveness and safety of non-vitamin K antagonist oral anticoagulants for the treatment of non-valvular atrial fibrillation in real-world settings, consistent with clinical trial evidence.

This study aimed to compare real-world effectiveness/safety of non-vitamin K antagonist oral anticoagulants and vitamin K antagonists among patients with non-valvular atrial fibrillation. A systematic review was conducted from January 2013 to January 2020, and a total of 7661 references were assessed for relevance. Fifty-five studies were combined in the analysis; in comparison with vitamin K antagonists, apixaban, dabigatran and rivaroxaban were associated with a reduced risk of stroke or systemic embolism, ischemic stroke, intracranial hemorrhage and all-cause mortality. Apixaban, dabigatran and edoxaban, but not rivaroxaban, were associated with a reduced risk of major bleeding. This study confirmed the effectiveness and safety of non-vitamin K antagonist oral anticoagulants for the treatment of non-valvular atrial fibrillation in real-world settings, consistent with clinical trial evidence.

Effectiveness and Safety of Apixaban Versus Warfarin in Obese Patients with Nonvalvular Atrial Fibrillation Enrolled in Medicare and Veteran Affairs.

Real-world studies have evaluated the use of anticoagulants in obese patients with nonvalvular atrial fibrillation (NVAF), but they have been limited by sample size or the use of diagnosis codes on claims to define obesity. This retrospective study used body weight data of ≥100 kg or a body mass index of ≥30 kg/m2 to identify elderly (aged ≥65 years) NVAF patients with obesity in dually enrolled Veterans Affairs and fee-for-service Medicare patients. It evaluated the risk of stroke/systemic embolism (SE) and major bleeding (MB) in patients that initiated apixaban versus warfarin. Stabilized inverse probability treatment weighting was used to balance the baseline characteristics between patients prescribed apixaban and warfarin in obese patients. Cox models were used to evaluate the relative risk of stroke/SE and MB. Overall, 35.9% (n = 26,522) of the NVAF population were obese, of which 13,604 apixaban and 12,918 warfarin patients were included. After inverse probability treatment weighting, patient characteristics were balanced. The mean age was 75 years, the mean CHA2DS2-VASc score (Congestive Heart Failure, Hypertension, Age ≥75 [Doubled], Diabetes Mellitus, Prior Stroke or Transient Ischemic Attack [Doubled], Vascular Disease, Age 65-74, Female) was 3.8, the mean HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) Score was ∼2.6, and >98% of patients were males. Obese apixaban patients were associated with a similar risk of stroke/SE (hazard ratio: 0.82; 95% confidence interval: 0.66 to 1.03) and a significantly lower risk of MB (hazard ratio: 0.62; 95% confidence interval: 0.54 to 0.70) versus warfarin. No significant interaction was observed between treatment and obesity status (nonobese, obese/nonmorbid, obese/morbid) for stroke/SE (interaction p = 0.602) or MB (interaction p = 0.385). In obese patients with NVAF, apixaban was associated with a similar risk of stroke/SE and a significantly lower risk of MB versus warfarin.

Cost-effectiveness analysis of apixaban versus vitamin K antagonists for antithrombotic therapy in patients with atrial fibrillation after acute coronary syndrome or percutaneous coronary intervention in Spain.

BACKGROUND/OBJECTIVE: AUGUSTUS trial demonstrated that, for patients with atrial fibrillation (AF) having acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI), an antithrombotic regimen with apixaban and P2Y12 resulted in less bleeding, fewer hospitalizations, and similar ischemic events than regimens including a vitamin K antagonist (VKA), aspirin, or both. This study objective was to evaluate long-term health and economic outcomes and the cost-effectiveness of apixaban over VKA, as a treatment option for patients with AF having ACS/PCI. METHODS: A lifetime Markov cohort model was developed comparing apixaban versus VKA across multiple treatment strategies (triple [with P2Y12 + aspirin] or dual [with P2Y12] therapy followed by monotherapy [apixaban or VKA]; triple followed by dual and then monotherapy; dual followed by monotherapy). The model adopted the Spanish healthcare perspective, with a 3-month cycle length and costs and health outcomes discounted at 3%. RESULTS: Treatment with apixaban resulted in total cost savings of €883 and higher life years (LYs) and quality-adjusted LYs (QALYs) per patient than VKA (net difference, LYs: 0.13; QALYs: 0.11). Bleeding and ischemic events (per 100 patients) were lower with apixaban than VKA (net difference, -13.9 and -1.8, respectively). Incremental net monetary benefit for apixaban was €3,041, using a willingness-to-pay threshold of €20,000 per QALY. In probabilistic sensitivity analysis, apixaban was dominant in the majority of simulations (92.6%), providing additional QALYs at lower costs than VKA. CONCLUSIONS: Apixaban was a dominant treatment strategy than VKA from both the Spanish payer's and societal perspectives, regardless of treatment strategy considered.

Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients With Active Cancer.

BACKGROUND: Patients with cancer are more likely to develop nonvalvular atrial fibrillation (NVAF). Currently there are no definitive clinical trials or treatment guidelines for NVAF patients with concurrent cancer. OBJECTIVES: This subgroup analysis of the ARISTOPHANES study compared the risk of stroke/systemic embolism (stroke/SE) and major bleeding (MB) among NVAF patients with active cancer who were prescribed non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin. METHODS: A retrospective observational study was conducted in NVAF patients with active cancer who newly initiated apixaban, dabigatran, rivaroxaban, or warfarin from January 1, 2013, through September 30, 2015, with the use of Medicare and 4 U.S. commercial claims databases. Cox models were used to estimate the risk of stroke/SE and MB in the pooled propensity score-matched cohorts. RESULTS: A total of 40,271 patients were included, with main cancer types of prostate (29%), female breast (17%), genitourinary (14%), and lung (13%). Compared with warfarin, apixaban was associated with a lower risk of stroke/SE (hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.45-0.78) and MB (HR: 0.58; 95% CI: 0.50-0.68); dabigatran and rivaroxaban had similar risks of stroke/SE (dabigatran: HR: 0.88 [95% CI: 0.54-1.41]; rivaroxaban: HR: 0.82 [95% CI: 0.62-1.08]) and MB (dabigatran: HR: 0.76 [95% CI: 0.57-1.01]; rivaroxaban: HR: 0.95 [95% CI: 0.85-1.06]). Risks of stroke/SE and MB varied among NOAC-NOAC comparisons, while consistent treatment effects were seen for all treatment comparisons across key cancer types. CONCLUSIONS: Among this cohort of NVAF patients with active cancer, the risk of stroke/SE and MB varied among oral anticoagulants and were consistent across cancer types.

Oral Anticoagulants for Nonvalvular Atrial Fibrillation in Patients With High Risk of Gastrointestinal Bleeding.

Importance: Many patients with nonvalvular atrial fibrillation (NVAF) are at a high risk of gastrointestinal (GI) bleeding due to conditions including older age; stage III to V chronic kidney disease (CKD); HAS-BLED (hypertension, kidney or liver disease, stroke history, prior bleeding, unstable international normalized ratio, age >65, drug or alcohol use) score of 3 or greater; corticosteroid, antiplatelet or nonsteroidal anti-inflammatory drug (NSAID) use; or GI conditions. Objective: To compare the risk of stroke and/or systemic embolism (SE) and major bleeding (MB) among patients with NVAF and high risk of GI bleeding who received non-vitamin K antagonist oral anticoagulants (NOACs) vs those who received warfarin. Design, Setting, and Participants: This retrospective cohort study included patients with NVAF who were 75 years and older; had stage III to V CKD; had an HAS-BLED score of 3 or greater; used corticosteroids, antiplatelets, or NSAIDs; or had GI conditions. Data were collected from the Centers for Medicare & Medicaid Services and 4 commercial insurance databases between January 1, 2012, and September 30, 2015. Data analysis was conducted from January 2012 to September 2015. Exposures: New prescription for apixaban, dabigatran, rivaroxaban, or warfarin between January 1, 2013, and September 30, 2015 (identification period). Main Outcomes and Measures: Six propensity score-matched cohorts were created to compare between study drugs. For the primary objective, Cox models were used to estimate stroke and/or SE and MB hazard ratios (HRs). Results: A total of 381 054 patients (187 489 [49.2%] women) with NVAF and at least 1 high-risk GI bleeding factor were identified (HAS-BLED score ≥3: 284 527 [74.7%]; aged ≥75 years: 252 835 [66.4%]; corticosteroid, antiplatelet, or NSAID therapy: 107 675 [28.3%]; prior GI bleeding conditions: 74 818 [19.6%]; and stage III-V CKD: 56 892 [14.9%]). All NOACs were associated with a lower risk of stroke and/or SE vs warfarin (apixaban: HR, 0.60; 95% CI, 0.52-0.68; dabigatran: HR, 0.75; 95% CI, 0.64-0.88; rivaroxaban: HR, 0.79; 95% CI, 0.73-0.86). Compared with warfarin, apixaban and dabigatran were associated with a lower risk of MB (apixaban: HR, 0.59; 95% CI, 0.56-0.63; dabigatran: HR, 0.78; 95% CI, 0.70-0.86), while rivaroxaban was associated with a higher risk (HR, 1.11; 95% CI, 1.05-1.16). Conclusions and Relevance: In this study of patients with NVAF and high risk of GI bleed, NOACs were associated with lower rates of stroke and/or SE, but NOACs had varying risks of MB compared with warfarin. These results may help inform treatment options in this patient population.

Use of Non-Vitamin K Antagonist Oral Anticoagulants Among Patients with Nonvalvular Atrial Fibrillation and Multimorbidity.

INTRODUCTION: Non-valvular atrial fibrillation (NVAF) is often accompanied by multiple comorbid conditions, which increase the associated risks and complexity of patient management. This study evaluated the risk of stroke/systemic embolism (SE) and major bleeding (MB) among multimorbid patients with NVAF who were prescribed non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin. METHODS: A retrospective study of patients with NVAF and high multimorbidity who initiated apixaban, dabigatran, rivaroxaban, or warfarin from 1 January 2013 to 30 September 2015 was conducted using five insurance claims databases. Multimorbidity was defined as six or more comorbid conditions, and 1:1 propensity score matching (PSM) was conducted between the NOAC-warfarin and NOAC-NOAC cohorts. Cox proportional hazard models were used to evaluate the hazard ratios of stroke/SE and MB. RESULTS: Of the NVAF population (n = 466,991), 33.4% (n = 155,959) had multimorbidity, including 36,921 apixaban, 10,248 dabigatran, 45,509 rivaroxaban, and 63,281 warfarin patients. Compared to warfarin, apixaban and rivaroxaban were associated with a lower risk of stroke/SE (hazard ratio [HR] 0.63, 95% CI 0.54-0.74; HR 0.70, 95% CI 0.64-0.77, respectively). Apixaban and dabigatran were associated with a lower risk of MB (HR 0.61, 95% CI 0.56-0.67; HR 0.75, 95% CI 0.66-0.86, respectively) and rivaroxaban was associated with a higher risk of MB (HR 1.06, 95% CI 1.01-1.12) compared to warfarin. CONCLUSIONS: Among patients with NVAF and six or more comorbid conditions, NOACs were associated with varying risk of stroke/SE and MB compared to warfarin and to each other. Rather than a "one drug fits all" approach, our results may be useful for appropriate OAC treatment for multimorbid patients.

Burden of major gastrointestinal bleeding among oral anticoagulant-treated non-valvular atrial fibrillation patients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Real-world persistence to direct oral anticoagulants in patients with atrial fibrillation: a systematic review and network meta-analysis.

OBJECTIVE: To conduct a systematic review and network meta-analysis of real-world evidence comparing adherence, persistence, cost, and utilization between oral anticoagulant (OAC) in non-valvular atrial fibrillation (NVAF) patients. METHODS: A systematic search of MEDLINE and Embase (inception-July 2019) was conducted for published observational cohort studies comparing outcomes between ≥2 OACs. A network meta-analysis was performed to estimate odds ratios for non-persistence using a random-effects model. RESULTS: There were 80 studies evaluating the outcomes of interest. However, due to a paucity in adherence studies and heterogeneity in adherence, cost, and utilization definitions, persistence was the focus of this network meta-analysis. There were 36 studies evaluating non-persistence in 395,593 participants, 24 of which used 3 gap definitions (30-, 60-, and 90-days); 18 unique studies evaluating non-persistence at 12 months were included in the network meta-analysis. Using 30- and 90-day gaps, all NOACs, when compared with VKAs, had lower odds of non-persistence (30-day OR (95%CI): apixaban: 0.63 (0.58, 0.69); rivaroxaban: 0.69 (0.62, 0.76); dabigatran: 0.89 (0.82, 0.97); 90-day OR (95%CI): apixaban: 0.33 (0.22, 0.47); rivaroxaban: 0.47 (0.36, 0.61); dabigatran 0.61 (0.44, 0.85)). When using a 60-day gap, dabigatran had higher odds of non-persistence vs VKAs (OR: 1.35; 95%CI: 1.12, 1.61), but there were no significant differences for apixaban and rivaroxaban. Apixaban had the lowest probability of non-persistence across the 3-gap definitions (95.7% with 30-day gap, 76.9% with 60-day gap, 98.4% with 90-day gap). CONCLUSIONS: The current findings, despite multiple limitations, can raise awareness and understanding of real-world persistence associated with OAC therapy in NVAF patients.

Effectiveness and safety of oral anticoagulants among non-valvular atrial fibrillation patients with polypharmacy.

AIMS: Polypharmacy is prevalent among non-valvular atrial fibrillation (NVAF) patients and presents a potential issue for the effective management of NVAF. This study compared the risk of stroke/systemic embolism (SE) and major bleeding (MB) among NVAF patients with polypharmacy newly prescribed oral anticoagulants (OACs). METHODS AND RESULTS: A retrospective study of NVAF patients with polypharmacy who initiated OACs from 01 January 2013 to 30 September 2015 was conducted using US CMS Medicare and four commercial databases. Polypharmacy was defined as ≥6 concomitant medications on the index date. Propensity score matching was conducted to compare non-vitamin K antagonists OACs (NOACs) to warfarin as well as between NOACs. Cox proportional hazard models were used to evaluate the risk of stroke/SE and MB. A total of 188 893 patients with polypharmacy were included, with an average of 8 concomitant medications (interquartile range 6-9). Compared to warfarin, apixaban [hazard ratio (HR): 0.59, 95% confidence interval (CI): 0.52-0.68], and rivaroxaban (HR: 0.75, 95% CI: 0.69-0.83) were associated with a lower risk of stroke/SE. Apixaban (HR: 0.57, 95% CI: 0.54-0.61) and dabigatran (HR: 0.76, 95% CI: 0.66-0.88) were associated with a decreased risk of MB compared with warfarin. Compared with dabigatran and rivaroxaban, apixaban was associated with a lower risk of stroke/SE and MB. Dabigatran was associated with lower risk of MB compared with rivaroxaban. CONCLUSIONS: In this observational study of anticoagulated NVAF patients with polypharmacy, effectiveness and safety profiles are more favourable for NOACs vs. warfarin. Our observations are hypothesis generating and may help inform future clinical trials regarding appropriate OAC treatment selection in polypharmacy patients.

A review of global health technology assessments of non-VKA oral anticoagulants in non-valvular atrial fibrillation.

BACKGROUND: This review assessed global health technology assessment (HTA) reports and recommendations of non-vitamin K oral anticoagulants (NOACs) in non-valvular atrial fibrillation (NVAF). METHODS: NHTA agency websites were searched for HTA reports evaluating NOACs versus NOACs or vitamin K antagonists. HTA methods and information on patient involvement/access were collected and empirically analyzed. RESULTS: The review identified 38 unique HTA reports published between 2012 and 2017 in 16 countries including 11 in Europe. NOACs that were cost-effective per local willingness-to-pay (WTP) thresholds were positively recommended for the treatment of NVAF. WTP thresholds ranged from €20,000 to 69,000. Apixaban was recommended in 10/12 (83%) countries, dabigatran in 9/13 (69%) countries, and rivaroxaban in 10/13 (76%) over warfarin. Edoxaban was recommended in 5/7 (71%) countries. Economic evaluations and recommendations comparing NOACs were sparse (two or three countries per NOAC) and generally favored apixaban and edoxaban, followed by dabigatran. Eleven HTA reports from four countries considered the patient voice (Canada [n = 3], Scotland [n = 3], England [n = 4], Brazil [n = 1]); however, only 2/11 (18%) developed recommendations based on this. Among the reports with a positive recommendation, 26/30 (87%) featured a decision that aligned with the approved regulatory label. CONCLUSIONS: Most agencies recommended NOACs over warfarin for patients with NVAF. Few countries made statements recommending one NOAC over another. Given different WTP thresholds, a drug that is cost-effective in one market may not be in another. Therefore, the various NOAC recommendations from HTA agencies cannot be generalized across different countries.

Effectiveness and Safety of Oral Anticoagulants among NVAF Patients with Obesity: Insights from the ARISTOPHANES Study.

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.