Cost-Effectiveness and Budget Impact Analysis of Apixaban and Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Non-Valvular Atrial Fibrillation (NVAF) in Iran.

INTRODUCTION: This study evaluates the cost-effectiveness of Apixaban and Rivaroxaban, compared to Warfarin, for stroke prevention in patients with non-valvular atrial fibrillation in Iran. METHOD: A Markov model with a 30-year time horizon was employed to simulate and assess different treatment strategies' cost-effectiveness. The study population comprised Iranian adults with NVAF, identified through specialist consultations, hospital visits, and archival record reviews. Direct medical costs, direct nonmedical, and indirect costs were included. Quality-adjusted life years (QALY) were assessed using an EQ-5D questionnaire. This study utilized a cost-effectiveness threshold of $11 134 per QALY. RESULTS: Apixaban demonstrated superior cost-effectiveness compared to Rivaroxaban and Warfarin. Over 30 years, total costs were lower in the Apixaban and Rivaroxaban groups compared to the Warfarin group ($126.18 and $109.99 vs. $150.49). However, Apixaban showed higher total QALYs gained compared to others (0.134 vs. 0.133 and 0.116). The incremental cost-effectiveness ratio for comparing Apixaban to Warfarin was calculated at -1332.83 cost per QALY, below the threshold of $11 134, indicating Apixaban's cost-effectiveness. Sensitivity analyses confirmed the robustness of the findings, with ICER consistently remaining below the threshold. Over 5 years (2024-2028) of Apixaban usage, the incremental cost starts at USD 70 250 296 in the first year and gradually rises to USD 71 770 662 in the fifth year. DSA and PSA were assessed to prove the robustness of the results. CONCLUSION: This study shows that Apixaban is a cost-effective option for stroke prevention in non-valvular atrial fibrillation patients in Iran compared to Warfarin.

Population Dementia Incidence and Direct Oral Anticoagulant Use in a Representative Population With Atrial Fibrillation.

BACKGROUND AND OBJECTIVES: Incidence and prevalence of atrial fibrillation (AF), a risk factor of dementia, have been increasing over time. Oral anticoagulation reduces risk of stroke and other negative outcomes of AF and may reduce dementia health inequities. The objective of this study was to estimate dementia incidence in patients with newly-diagnosed AF and taking an anticoagulant as use of direct oral anticoagulants (DOACs) increased. METHODS: We used a retrospective cohort design with annual incident AF cohorts of community-dwelling Medicare Fee-for-Service beneficiaries, enrolled in Parts A, B, and D from 2007 to 2017. The sample was limited to beneficiaries aged 67 years and older with incident AF; no prior dementia; and use of anticoagulants warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban in year t. RESULTS: A total of 1,083,338 beneficiaries were included in the study, 58.5% female, with mean (SD) age 77.2 (6.75) years. Among anticoagulated, incident AF cohorts, use of DOACs increased from 10.6% in their first year of availability (2011) to 41.4% in 2017. Among incident AF cohorts taking any oral anticoagulant, 3-year dementia incidence did not change significantly over the cohorts after adjusting for confounders. For example, incidence was 9.1% (95% CI 8.9-9.4) among White persons diagnosed with AF in 2007 and 2008 and 8.9% (95% CI 8.7-9.1) in 2017. Across cohorts, dementia incidence was consistently highest for Black persons, followed by American Indian/Alaska Native and White persons, and lowest for Asian persons. In 2017, 10.9% (95% CI 10.4-11.3) of Black persons in the cohort developed dementia within 3 years, 9.4% (95% CI 8.0-10.9) of American Indian/Alaska Native, 8.9% (95% CI 8.7-9.1) of White, 8.7% (95% CI 8.2-9.1) of Hispanic, and 6.9% (95% CI 6.4-7.4) of Asian persons. Across race/ethnicity, 3-year stroke risk decreased consistently over time; however, the increasing availability of DOACs did not alter the trend. DISCUSSION: Increased use of DOACs among incident AF cohorts from 2007 to 2017 was not associated with significant declines in dementia or stroke risk. Consideration of similar stroke and dementia risk, as well as differences in cost, is warranted when weighing the risks and benefits of available oral anticoagulants.

Racial and Ethnic Disparities in Initiation of Direct Oral Anticoagulants Among Medicare Beneficiaries.

Importance: The influence of race and ethnicity on initiation of direct oral anticoagulants (DOACs) is relatively understudied in Medicare data. Objective: To investigate disparities in the initiation of DOACs compared with warfarin by race, ethnicity, and social vulnerability. Design, Setting, and Participants: This retrospective cohort study used a 50% sample of Medicare fee-for-service data from January 1, 2010, to December 31, 2019 (mean patient enrollment duration, 7.7 years). Analysis took place between January 2023 and February 2024. A cohort of older adults (aged ≥65 years) with atrial fibrillation who newly initiated warfarin or DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) was identified. Exposure: Patients were classified as non-Hispanic White, non-Hispanic Black, and Hispanic. Main Outcomes and Measures: The likelihood of starting use of DOACs compared with warfarin was modeled, adjusting for race, ethnicity, age, sex, county-level social vulnerability, and other clinical factors. Results: Among 950 698 anticoagulation initiations, consisting of 680 974 DOAC users and 269 724 warfarin users (mean [SD] age, 78.5 [7.6] years; 52.6% female), 5.2% were Black, 4.3% were Hispanic, and 86.7% were White. During the 10-year study period, DOAC use increased for all demographic groups. After adjustment, compared with White patients, Black patients were 23% less likely (adjusted odds ratio [AOR, 0.77; 95% CI, 0.75-0.79) and Hispanic patients were 13% less likely (AOR, 0.87; 95% CI, 0.85-0.89) to initiate DOAC use. Disparities in DOAC initiation were greatest among Black patients in the earlier years but attenuated during the study period. For instance, in 2010, the OR of Black patients initiating DOACs was 0.54 (95% CI, 0.50-0.57), attenuating linearly over time to 0.69 by 2013 (95% CI, 0.65-0.74) and 0.83 (95% CI, 0.78-0.89) by 2017. By 2019, these differences became nonsignificant (OR, 1.08; 95% CI, 0.99-1.18). Conclusions and Relevance: In this cohort study of Medicare patients with atrial fibrillation, Black and Hispanic patients were less likely to initiate DOACs for atrial fibrillation, although these differences diminished over time. Identifying the factors behind these early disparities is crucial for ensuring equitable access to novel therapies as they emerge for Black and Hispanic populations.

Assessment of Days Alive Out of Hospital as a Possible End Point in Trials of Stroke Prevention for Atrial Fibrillation: A ROCKET AF Analysis.

BACKGROUND: Days alive out of hospital (DAOH) is an objective and patient-centered net benefit end point. There are no assessments of DAOH in clinical trials of interventions for atrial fibrillation (AF), and it is not known whether this end point is of clinical utility in these populations. METHODS AND RESULTS: ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was an international double-blind, double-dummy randomized clinical trial that compared rivaroxaban with warfarin in patients with atrial fibrillation at increased risk for stroke. We assessed DAOH using investigator-reported event data for up to 12 months after randomization in ROCKET AF. We assessed DAOH overall, by treatment group, and by subgroup, including age, sex, and comorbidities, using Poisson regression. The mean±SD number of days dead was 7.3±41.2, days hospitalized was 1.2±7.2, and mean DAOH was 350.7±56.2, with notable left skew. Patients with comorbidities had fewer DAOH overall. There were no differences in DAOH by treatment arm, with mean DAOH of 350.6±56.5 for those randomized to rivaroxaban and 350.7±55.8 for those randomized to warfarin (P=0.86). A sensitivity analysis found no difference in DAOH not disabled with rivaroxaban versus warfarin (DAOH not disabled, 349.2±59.5 days and 349.1 days±59.3 days, respectively, P=0.88). CONCLUSIONS: DAOH did not identify a treatment difference between patients randomized to rivaroxaban versus warfarin. This may be driven in part by the low overall event rates in atrial fibrillation anticoagulation trials, which leads to substantial left skew in measures of DAOH.

Predictors of adherence to direct oral anticoagulants after cardiovascular or bleeding events in Medicare Advantage Plan enrollees with atrial fibrillation.

BACKGROUND: Direct oral anticoagulants (DOACs) are recommended for patients with atrial fibrillation (AF) given their improved safety profile. Suboptimal adherence to DOACs remains a significant concern among individuals with AF. However, the extent of adherence to DOACs following a cardiovascular or bleeding event has not been fully evaluated. OBJECTIVE: To evaluate the pattern of adherence trajectories of DOACs after a cardiovascular or bleeding event and to investigate the sociodemographic and clinical predictors associated with each adherence trajectory by using claims-based data. METHODS: This retrospective study was conducted among patients with AF prescribed with DOACs (dabigatran/apixaban/rivaroxaban) between July 2016 and December 2017 and who were continuously enrolled in the Texas-based Medicare Advantage Plan. Patients who experienced a cardiovascular or bleeding event while using the DOACs were further included in the analysis. The sample was limited to patients who experienced a clinical event such as a cardiovascular or bleeding event while using the DOACs. The clinical events considered in this study were cardiovascular (stroke, congestive heart failure, myocardial infarction, systemic embolism) and bleeding events. To assess adherence patterns, each patient with a DOAC prescription was followed up for a year after experiencing a clinical event. The monthly adherence to DOACs after these events was evaluated using the proportion of days covered (PDC). A group-based trajectory model incorporated the monthly PDC to classify groups of patients based on their distinct patterns of adherence. Predictors associated with each trajectory were assessed using a multinomial logistic regression model, with the adherent trajectory serving as the reference group in the outcome variable. RESULTS: Among the 694 patients with AF who experienced clinical events after the initiation of DOACs, 3 distinct adherence trajectories were identified: intermediate nonadherent (30.50%), adherent (37.7%), and low adherent (31.8%); the mean PDC was 0.47 for the intermediate nonadherent trajectory, 0.93 for the adherent trajectory, and 0.01 for low adherent trajectory. The low-income subsidy was significantly associated with lower adherence trajectories (odds ratio [OR] = 4.81; 95% CI = 3.07-7.51) and with intermediate nonadherent trajectories (OR = 1.57; 95% CI = 1.06-2.34). Also, nonsteroidal anti-inflammatory drug use was significantly associated with lower adherence trajectories (OR = 5.10; 95% CI = 1.95-13.36) and intermediate nonadherent trajectories (OR = 3.17; 95% CI = 1.26-7.93). Other predictors significantly associated with both nonadherent trajectories are type of DOACs (OR = 0.53; 95% CI = 0.35-0.79), presence of coronary artery disease (OR = 1.89; 95% CI = 1.01-3.55), and having 2 or more clinical events (OR = 1.65; 95% CI = 1.09-2.50). CONCLUSIONS: Predictors identified provide valuable insights into the suboptimal adherence of DOACs among Medicare Advantage Plan enrollees with AF, which can guide the development of targeted interventions to enhance adherence in this high-risk patient population.

Serious Bleeding in Patients With Atrial Fibrillation Using Diltiazem With Apixaban or Rivaroxaban.

Importance: Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation. Objective: To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol. Design, Setting, and Participants: This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024. Exposures: Diltiazem and metoprolol. Main Outcomes and Measures: The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting. Results: The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26). Conclusions and Relevance: In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.

Dispensing pharmacy chains and direct anticoagulants: Potential associations with patient outcomes.

PURPOSE: Pharmacy chains can differ with respect to the characteristics of their patient populations as well as their nonprescription products, services, and practices, and thus may serve as a surrogate for potential unmeasured confounding in observational studies of prescription drugs. This study evaluates whether a single-source drug can have different patient outcomes based on the dispensing pharmacy chain. METHODS: Separate analyses for two anticoagulant drugs, rivaroxaban and apixaban, were conducted using Medicare Fee-for-Service claims evaluating the association between dispensing pharmacy chain and outcomes of acute myocardial infarction, ischemic stroke, intracranial hemorrhage, gastrointestinal (GI) bleeding, all-cause mortality, and major GI bleeding. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates across pharmacy chain cohorts, and outcome association was assessed with a Cox Proportional Hazards model. RESULTS: We observed no differences in outcomes across pharmacy chains for apixaban recipients. Rivaroxaban recipients from pharmacy chain C, however, had lower rates of GI bleeding (adjusted HR 0.83; 95% CI 0.69-1.00) and ischemic stroke (adjusted HR 0.57; 95% CI 0.38-0.87) as compared to chain A in primary analyses with a 3-day grace period. The results moved closer to the null when 14- and 30-day grace periods were implemented. CONCLUSIONS: These results suggest that dispensing pharmacy chains may have the potential to act as a confounder of associations between drug exposure and outcome in some observational studies. Additional studies of potential confounding by pharmacy chain are needed. Further evaluation of potential pharmacy chain effects on safe use would be of value.

Cost-Effectiveness Analysis of Pharmacogenomics (PGx)-Based Warfarin, Apixaban, and Rivaroxaban Versus Standard Warfarin for the Management of Atrial Fibrillation in Ontario, Canada.

OBJECTIVE: To assess the cost-effectiveness of pharmacogenomics (PGx)-based warfarin (i.e., warfarin dosing following genetic testing), apixaban, and rivaroxaban oral anticoagulation versus standard warfarin for the treatment of newly diagnosed patients with nonvalvular atrial fibrillation (AF) aged ≥ 65 years. METHODS: We developed a Markov decision-analytic model to compare costs [2017 Canadian dollars (C$)] and quality-adjusted life years (QALYs) from the Ontario health care payer perspective over a life-time horizon. The parameters used in the model were derived from the published literature, the Ontario health care administrative database, and expert opinion. To account for the uncertainty of model parameters, we conducted extensive deterministic and probabilistic sensitivity analyses. The results were summarized using incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves. RESULTS: We found that PGx-based warfarin had an ICER of C$17,584/QALY compared with standard warfarin, and apixaban had an ICER of C$64,590/QALY compared with PGx-based warfarin in our base-case analysis. Rivaroxaban was extendedly dominated by PGx-based warfarin and apixaban. The probabilistic sensitivity analysis showed that apixaban, rivaroxaban, PGx-based warfarin, and standard warfarin were cost-effective at some willingness-to-pay (WTP) thresholds. PGx-based warfarin had a higher probability of being cost-effective than apixaban (51.3% versus 14.3%) at a WTP threshold of C$50,000/QALY. At a WTP threshold of C$100,000/QALY, apixaban had a higher probability of being cost-effective than PGx-based warfarin (54.6% versus 22.6%). CONCLUSION: We found that PGx-based warfarin for patients with AF is cost-effective at a WTP threshold of C$50,000/QALY. Apixaban had a higher probability of being cost-effective (> 50%) at a WTP threshold of C$93,000/QALY.

Does prescribing apixaban or rivaroxaban versus warfarin for patients diagnosed with atrial fibrillation save health system costs? A multivalued treatment effects analysis.

BACKGROUND: Non-valvular atrial fibrillation (AF) is a common heart arrhythmia in the elderly population. AF patients are at high-risk of ischemic strokes, but oral anticoagulant (OAC) therapy reduces such risks. Warfarin had been the standard OAC for AF patients, however its effectiveness is highly variable and dependent on close monitoring of the anticoagulant response. Newer OACs such as rivaroxaban and apixaban address these drawbacks but are more costly. It is uncertain which OAC therapy for AF is cost-saving from the healthcare system perspective. METHODS: We followed a cohort of patients in Ontario, Canada, aged ≥ 66 who were newly diagnosed with AF and prescribed OACs between 2012 and 2017. We used a two-stage estimation procedure. First, we account for the patient selection into OACs using a multinomial logit regression model and estimated propensity scores. Second, we used an inverse probability weighted regression adjustment approach to determine cost-saving OAC options. We also examined component-specific costs (i.e., drug, hospitalization, emergency department and physician) to understand the drivers of cost-saving OACs. RESULTS: We found that compared to warfarin, rivaroxaban and apixaban treatments were cost-saving options, with per-patient 1-year healthcare cost savings at $2436 and $1764, respectively. These savings were driven by cost-savings in hospitalization, emergency department visits, and physician visits, outweighing higher drug costs. These results were robust to alternative model specifications and estimation procedures. CONCLUSIONS: Treating AF patients with rivaroxaban and apixaban than warfarin reduces healthcare costs. OAC reimbursement policies for AF patients should consider rivaroxaban or apixaban over warfarin as the first-line treatment.

Medications mostly associated with hematuria: assessment of the EudraVigilance and Food and Drug Administration pharmacovigilance databases entries.

BACKGROUND: Drugs may have a direct causative role in triggering hematuria. The range of medications which may be responsible for hematuria is wide, but little is known on those which are most frequently involved. The aim of our study was to identify and compare drugs mostly related with hematuria. METHODS: The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and the EudraVigilance (EV) database were queried to identify the drugs which were associated the most with hematuria individual reports till 30 September 2021. Rivaroxaban, aspirin, warfarin sodium, clopidogrel bisulfate, dabigatran etexilate mesylate, apixaban, warfarin, cyclophosphamide, lansoprazole, enoxaparin sodium, and ibuprofen were analyzed. Analysis per gender, age and severity was performed. Disproportional analysis was performed to compare drugs. RESULTS: Overall, 15,687 reports of hematuria were recorded in the FDA database and 15 007 in the EV database. Rivaroxaban and Warfarin appear to be the most dangerous medications in terms of hematuria when compared to the other medications (PRR>1, P<0.05) while apixaban is the safest one (PRR<1, P<0.05) when compared to the other medications. In terms of severity only 162/15 007 (1.08%) were fatal. Between the drugs analyzed cyclophosphamide 7.2%, enoxaparin (3%) and dabigatran (2.5%) presented a higher number of fatal hematuria episodes when compared to the other drugs (<1%). CONCLUSIONS: Anticoagulants and antiplatelets are more frequently related to hematuria episodes however some differences exist between them. Particularly warfarin and rivaroxaban should be prescribed with caution in patients at increased risk of hematuria. Prescribers should inform those treated with these medications about the risk of hematuria and its sequelae.

Comparative Safety and Effectiveness of Warfarin or Rivaroxaban Versus Apixaban in Patients With Advanced CKD and Atrial Fibrillation: Nationwide US Cohort Study.

RATIONALE & OBJECTIVE: Head-to-head data comparing the effectiveness and safety of oral anticoagulants in patients with atrial fibrillation (AF) and advanced chronic kidney disease (CKD) are lacking. We compared the safety and effectiveness of warfarin or rivaroxaban versus apixaban in patients with AF and non-dialysis-dependent CKD stage 4/5. STUDY DESIGN: Propensity score-matched cohort study. SETTING & PARTICIPANTS: 2 nationwide US claims databases, Medicare and Optum's deidentified Clinformatics Data Mart Database, were searched for the interval from January 1, 2013, through March 31, 2022, for patients with nonvalvular AF and CKD stage 4/5 who initiated warfarin versus apixaban (matched cohort, n=12,488) and rivaroxaban versus apixaban (matched cohort, n = 5,720). EXPOSURES: Warfarin, rivaroxaban, or apixaban. OUTCOMES: Primary outcomes included major bleeding and ischemic stroke. Secondary outcomes included all-cause mortality, major gastrointestinal bleeding, and intracranial bleeding. ANALYTICAL APPROACH: Cox regression was used to estimate HRs, and 1:1 propensity-score matching was used to adjust for 80 potential confounders. RESULTS: Compared with apixaban, warfarin initiation was associated with a higher rate of major bleeding (HR, 1.85; 95% CI, 1.59-2.15), including major gastrointestinal bleeding (1.86; 1.53-2.25) and intracranial bleeding (2.15; 1.42-3.25). Compared with apixaban, rivaroxaban was also associated with a higher rate of major bleeding (1.69; 1.33-2.15). All-cause mortality was similar for warfarin (1.08; 0.98-1.18) and rivaroxaban (0.94; 0.81-1.10) versus apixaban. Furthermore, no statistically significant differences for ischemic stroke were observed for warfarin (1.14; 0.83-1.57) or rivaroxaban (0.71; 0.40-1.24) versus apixaban, but the CIs were wide. Similar results were observed for warfarin versus apixaban in the positive control cohort of patients with CKD stage 3, consistent with randomized trial findings. LIMITATIONS: Few ischemic stroke events, potential residual confounding. CONCLUSIONS: In patients with AF and advanced CKD, rivaroxaban and warfarin were associated with higher rates of major bleeding compared with apixaban, suggesting a superior safety profile for apixaban in this high-risk population. PLAIN-LANGUAGE SUMMARY: Different anticoagulants have been shown to reduce the risk of stroke in patients with atrial fibrillation, such as warfarin and direct oral anticoagulants like apixaban and rivaroxaban. Unfortunately, the large-scale randomized trials that compared direct anticoagulants versus warfarin excluded patients with advanced chronic kidney disease. Therefore, the comparative safety and effectiveness of warfarin, apixaban, and rivaroxaban are uncertain in this population. In this study, we used administrative claims data from the United States to answer this question. We found that warfarin and rivaroxaban were associated with increased risks of major bleeding compared with apixaban. There were few stroke events, with no major differences among the 3 drugs in the risk of stroke. In conclusion, this study suggests that apixaban has a better safety profile than warfarin and rivaroxaban.

Assessing the impact of a financial incentive and refill reminder program on medication adherence and costs.

BACKGROUND: Improving medication adherence remains an important goal to improve therapeutic outcomes and lower health care costs. Point-of-sale prescription costs and forgetfulness remain top reasons why patients do not adhere to medications. Programs using both text message-based reminders and financial incentives may encourage patients to refill their prescriptions on time by reducing copays through discounts at the point of sale. Sempre Health, the subject of our analysis, provides both text message refill reminders and a dynamic discount incentive program to improve medication adherence. OBJECTIVE: To evaluate the impact of a financial incentive/refill reminder program on medication adherence and total cost of care for patients taking the antithrombotic agents ticagrelor, apixaban, or rivaroxaban in a large regional health plan. METHODS: After propensity-score matching on demographics, socioeconomic status, baseline copay, prior pharmacy/medical spend, and morbidity, we compared-using a difference-in-differences analytic approach-adherence (measured by proportion of days covered), unplanned health care utilization, and costs (total cost of care, medical, and pharmacy cost) of health plan members who did and did not enroll in the financial incentive/refill reminder program between February 1, 2019, and October 31, 2021, over 1 and 2 years. Because of differences in patient characteristics, we analyzed patients on ticagrelor (the antiplatelet group), apixaban, and rivaroxaban (the anticoagulant group) separately. RESULTS: There were a total of 1,292 one-to-one program and control propensity-matched patients: 166 each for the antiplatelet group and 480 each for the anticoagulant group. The average age of the anticoagulant group was 62 years; more than 60% were male, and approximately 45% had no prior unplanned care events. In contrast, the average age of the antiplatelet group was 57 years; more than 70% were male, and approximately 21% had no prior unplanned care events. In the antiplatelet group, the proportions adherent (proportion of days covered ≥80%) were 63.3% vs 42.8% (P = 0.0002) for program vs controls. Similarly, in the anticoagulant group, the proportion adherent was 77.9% vs 60.2% (P < 0.0001) for program vs controls. Reflecting improved adherence, costs of apixaban and rivaroxaban increased by $79 per member per month (PMPM) (P < 0.0001), with no statistically significant differences in other costs. Similarly, the cost of ticagrelor increased by $77 PMPM (P = 0.0102) with no statistically significant differences in other costs. Finally, there was a 16% (P = 0.032) reduction in emergency department use for those in the program. CONCLUSIONS: The financial incentive and refill reminder program was associated with improved adherence to antithrombotic medications, reduced emergency department use, and increased medication costs, but not in total pharmacy, medical, or total cost of care in both subgroups.

The Cost-Effectiveness of Rivaroxaban Plus Aspirin Compared with Aspirin Alone in the COMPASS Trial: A US Perspective.

BACKGROUND: Rivaroxaban 2.5 mg twice daily with aspirin 100 mg daily was shown to be better than aspirin 100 mg daily for preventing cardiovascular (CV) death, stroke or myocardial infarction in patients with either stable coronary artery disease (CAD) or peripheral artery disease (PAD). The cost-effectiveness of this regimen in this population is essential for decision-makers to know. METHODS: US direct healthcare system costs (in USD) were applied to hospitalized events, procedures and study drugs utilized by all patients. We determined the mean cost per participant for the full duration of the trial (mean follow-up of 23 months) plus quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) over a lifetime using a two-state Markov model with 1-year cycle length. Sensitivity analyses were performed on the price of rivaroxaban and the annual discontinuation rate. RESULTS: The costs of events and procedures were reduced for Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) patients who received rivaroxaban 2.5 mg orally (BID) plus acetylsalicylic acid (ASA) compared with ASA alone. Total costs were higher for the combination group ($7426 versus $4173) after considering acquisition costs of the study drug. Over a lifetime, patients receiving rivaroxaban plus ASA incurred $27,255 more and gained 1.17 QALYs compared with those receiving ASA alone resulting in an ICER of $23,295/QALY. ICERs for PAD only and polyvascular disease subgroups were lower. CONCLUSION: Rivaroxaban 2.5 mg BID plus ASA compared with ASA alone was cost-effective (high value) in the USA. COMPASS ClinicalTrials.gov identifier: NCT01776424.

Assessment of clinical and economic impact of rivaroxaban plus aspirin vs. aspirin alone as a secondary prophylaxis in patients with chronic and symptomatic peripheral arterial disease in the United States.

AIM: The objective in this study was to assess the clinical and economic implications of the inclusion of rivaroxaban as a secondary prophylaxis in patients with chronic or symptomatic peripheral artery disease (PAD) in the United States (US). METHODS: A cost-consequence model was adapted to evaluate the economic impact of rivaroxaban plus aspirin in a hypothetical 1-million-member health plan. The model inputs were taken from multiple sources: efficacy and safety of rivaroxaban + aspirin vs. aspirin alone were abstracted from COMPASS and VOYAGER randomized clinical trials; the prevalence of chronic and symptomatic PAD and incidence rates of clinical events (major adverse cardiac events [MACE], major adverse limb events [MALE], and major bleeding), were abstracted from the analysis of claims data; healthcare costs of clinical events and wholesale acquisition costs for rivaroxaban were abstracted from the literature and Red Book, respectively (2022 USD). One-way sensitivity analyses and subgroup analyses were also conducted. RESULTS: Over one year, with a 5% uptake of rivaroxaban, the model estimated rivaroxaban + aspirin to reduce 21 MACE/MALE events in the PAD patient population. The reduction in these clinical events offsets the increased risk of major bleeding (16 additional events), demonstrating a positive health benefit of the rivaroxaban addition. These benefits led to a $0.27 incremental cost per member per month (PMPM) to a US plan. The major driver of the incremental cost was the cost of rivaroxaban. In a subgroup of patients with the presence of any high-risk factor (heart failure, diabetes, renal insufficiency, or history of vascular disease affecting two or more vascular beds), the incremental PMPM cost was $0.13. CONCLUSIONS: Rivaroxaban + aspirin was found to provide positive net clinical benefit on the annual number of MACE/MALE avoided, with a modest increase in the PMPM cost.

Benefits and Harms of Standard Versus Reduced-Dose Direct Oral Anticoagulant Therapy for Older Adults With Multiple Morbidities and Atrial Fibrillation.

Background Dose reduction of direct oral anticoagulant (DOAC) medications is inconsistently applied to older adults with multiple morbidities, potentially due to perceived harms and unknown benefits of standard dosing. Methods and Results Using 2013 to 2017 US Medicare claims linked to Minimum Data Set records, we conducted a retrospective cohort study. We identified DOAC initiators (apixaban, dabigatran, rivaroxaban) aged ≥65 years with nonvalvular atrial fibrillation residing in a nursing home. We estimated inverse-probability of treatment weights for DOAC dose using propensity scores. We examined safety (hospitalization for major bleeding) and effectiveness outcomes (all-cause mortality, thrombosis [myocardial infarction, stroke, systemic embolism, venous thromboembolism]). We estimated hazard ratios (HRs) and 95% CIs using cause-specific hazard-regression models. Of 21 878 DOAC initiators, 48% received reduced dosing. The mean age of residents was 82.0 years, 66% were female, and 31% had moderate/severe cognitive impairment. After estimating inverse-probability of treatment weights, standard dosing was associated with a higher rate of bleeding (HR, 1.18 [95% CI, 1.03-1.37]; 9.4 versus 8.0 events per 100 person-years). Standard-dose therapy was associated with the highest rates of bleeding among those aged >80 years (9.1 versus 6.7 events per 100 person-years) and with a body mass index <30 kg/m2 (9.4 versus 7.4 events per 100 person-years). There was no association of dosing with mortality (HR, 0.99 [95% CI, 0.96-1.06]) or thrombotic events (HR, 1.16 [95% CI, 0.96-1.41]). Conclusions In this nationwide study of nursing home residents with nonvalvular atrial fibrillation, we found a higher rate of bleeding and little difference in effectiveness of standard versus reduced-dose DOAC treatment. Our results support the use of reduced-dose DOACs for many older adults with multiple morbidities.

Frailty, Home Time, and Health Care Costs in Older Adults With Atrial Fibrillation Receiving Oral Anticoagulants.

Importance: There are no data on patient-centered outcomes and health care costs by frailty in patients with atrial fibrillation (AF) taking oral anticoagulants (OACs). Objective: To compare home time, clinical events, and health care costs associated with OACs by frailty levels in older adults with AF. Design, Setting, and Participants: This community-based cohort study assessed Medicare fee-for-service beneficiaries 65 years or older with AF from January 1, 2013, to December 31, 2019. Data analysis was performed from January to December 2022. Exposures: Apixaban, rivaroxaban, and warfarin use were measured from prescription claims. Frailty was measured using a validated claims-based frailty index. Main outcomes and measures: Outcome measures were (1) home time (days alive out of the hospital and skilled nursing facility) loss greater than 14 days; (2) a composite end point of ischemic stroke, systemic embolism, major bleeding, or death; and (3) total cost per member per year after propensity score overlap weighting. Results: The weighted population comprised 136 551 beneficiaries, including 45 950 taking apixaban (mean [SD] age, 77.6 [7.3] years; 51.3% female), 45 320 taking rivaroxaban (mean [SD] age, 77.6 [7.3] years; 51.9% female), and 45 281 taking warfarin (mean [SD] age, 77.6 [7.3] years; 52.0% female). Compared with apixaban, rivaroxaban was associated with increased risk of home time lost greater than 14 days (risk difference per 100 persons, 1.8 [95% CI, 1.5-2.1]), composite end point (rate difference per 1000 person-years, 21.3 [95% CI, 16.4-26.2]), and total cost (mean difference, $890 [95% CI, $652-$1127]), with greater differences among the beneficiaries with frailty. Use of warfarin relative to apixaban was associated with increased home time lost (risk difference per 100 persons, 3.2 [95% CI, 2.9-3.5]) and composite end point (rate difference per 1000 person-years, 29.4 [95% CI, 24.5-34.3]), with greater differences among the beneficiaries with frailty. Compared with apixaban, warfarin was associated with lower total cost (mean difference, -$1166 [95% CI, -$1396 to -$937]) but higher cost when excluding OAC cost (mean difference, $1409 [95% CI, $1177 to $1642]) regardless of frailty levels. Conclusions and Relevance: In older adults with AF, apixaban was associated with increased home time and lower rates of clinical events than rivaroxaban and warfarin, especially for those with frailty. Apixaban was associated with lower total cost compared with rivaroxaban but higher cost compared with warfarin due to higher OAC cost. These findings suggest that apixaban may be preferred for older adults with AF, particularly those with frailty.

Availability of comparative real-world evidence research in Medicare patients: implications for Centers for Medicare and Medicaid Services drug price negotiations.

Aim: To evaluate the availability of published comparative real-world evidence (RWE) studies in Medicare patients for the ten drugs set to undergo Centers for Medicare and Medicaid Services (CMS) price negotiations in 2026. Materials & methods: A scoping review was completed in MEDLINE/PubMed to evaluate the availability of comparative RWE investigations conducted among Medicare-eligible patient populations in the US for the following drugs: apixaban, rivaroxaban, sitagliptin, ibrutinib, empagliflozin, etanercept, dapagliflozin, sacubitril/valsartan, ustekinumab and insulin aspart. Results: Of the 170 real-world comparative studies identified, 55 (32.4%) used Medicare real-world data (RWD) while 34 (20.0%) used commercial claims data in conjunction with either Medicare Advantage or Medicare Supplementary databases. The number of studies varied considerably by drug with apixaban and rivaroxaban studies accounting for the majority (i.e., 67.1%) of comparative RWE studies. Approximately a third or less of the comparative RWE studies were conducted in CMS RWD per drug. Conclusion: Our results demonstrate there is a considerable amount of comparative RWE for apixaban, rivaroxaban, and etanercept but limited comparative RWE for the other drugs set to undergo CMS price negotiations in 2026; additionally, our findings set up a number of next steps (e.g., risk of bias assessments) for further exploration of the available evidence base. Overall, CMS and manufacturers should consider proactively generating high-quality comparative RWE studies in the Medicare population to ensure that future price negotiations are based on robust evidence.

Cost-effectiveness of apixaban and rivaroxaban in thromboprophylaxis of cancer patients treated with chemotherapy in Spain.

BACKGROUND: Apixaban and rivaroxaban are two direct-acting oral anticoagulants (DOACs) recommended for thromboprophylaxis in cancer patients treated with chemotherapy in an ambulatory setting. We aimed to assess the cost-utility of thromboprophylaxis with apixaban and rivaroxaban vs no thromboprophylaxis in ambulatory cancer patients starting chemotherapy with an intermediate-to-high risk of venous thromboembolism (VTE), Khorana score ≥ 2 points. METHODS: A cost-effectiveness analysis was performed from the perspective of Spain's National Health System (NHS) using an analytical decision model in the short-term (180 days) and a Markov model in the long-term (5 years). Transition probabilities were obtained from randomized, double-blind, placebo-controlled clinical trials of apixaban and rivaroxaban in adult ambulatory patients with cancer at risk for VTE, treated with chemotherapy (AVERT and CASSINI trials). The costs (€2,021) were taken from Spanish sources. The utilities of the model were obtained through the EQ-5D questionnaire. Deterministic (base case) and probabilistic (second-order Monte Carlo simulation) analyses were conducted. RESULTS: In the probabilistic sensitivity analysis, apixaban generated a cost per patient of €1,082 ± 187, with a 95% confidence interval (CI) of €713-1,442, while no prophylaxis produced a cost per patient of €1,146 ± 218, with a 95% CI of €700-1,491, with a saving of €64 per patient and a gain of 0.008 QALYs. Likewise, rivaroxaban provided a cost per patient of €993 ± 133, with a 95% CI of €748-1,310, while no prophylaxis produced a cost per patient of €872 ± 152, with a 95% CI of €602-1,250, with an additional expense of €121 per patient and a gain of 0.008 QALYs. CONCLUSIONS: In thromboprophylaxis of cancer patients, the use of apixaban and rivaroxaban generated similar costs compared to non-prophylaxis, without the difference found being statistically significant, with a clinically insignificant QALY gain.

Utilization outcomes of direct oral anticoagulants in Medicare patients.

OBJECTIVE: To compare the adherence, persistence, discontinuation and switching rates of direct oral anticoagulants (DOACs) for Medicare patients with non-valvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). METHODS: This was retrospective observational cohort study design. Medicare Part D claims files were used for the study duration (2015-2018). Inclusion-exclusion criteria were applied to identify the NVAF and VTE sample using dabigatran, rivaroxaban, apixaban, edoxaban and warfarin during the identification period (2016-2017). Outcomes of adherence, persistence, time to non-persistence and time to discontinuation were assessed in those who did not switch the index drug in the follow-up period (365 days from the index date). Switching rates were assessed in those who switched the index drug at least once in the aforementioned follow-up period. Descriptive statistics were conducted for all the outcomes, and comparisons were made using t-tests, chi-square, and ANOVA. Logistic regression was conducted to compare the odds of being adherent and the odds of switching in NVAF and VTE patient cohorts. RESULTS: Of all the DOACs, patients with NVAF or VTE were most adherent to apixaban (PDC = 76.88). Among all the DOACs, non-persistence and discontinuation rates were highest for warfarin. Majority of the switches were reported from dabigatran to other DOAC and to apixaban from other DOAC. Despite the better utilization outcomes reported for apixaban users, Medicare plans covered rivaroxaban favorably. It was associated with the lowest mean amount paid by the patient (NVAF: $76; VTE: $59), and the highest mean amount paid by the plans (NVAF: $359; VTE: $326). CONCLUSION: Medicare plans need to consider adherence, persistence, discontinuation and switching rates of DOACs to make the coverage decisions.

Healthcare resources and costs associated with nonvalvular atrial fibrillation in Spain: apixaban versus acenocoumarol.

Aim: Healthcare resources usage and costs associated to nonvalvular atrial fibrillation (NVAF) were analyzed in Spain. Methods: This is an observational and retrospective study on patients with NVAF who started their treatment with apixaban or acenocoumarol between 1 January 2015 and 31 December 2017. Results: 2160 patients treated with apixaban were paired (1:1) with patients treated with acenocoumarol (propensity score matching). Apixaban reduced the incidence of strokes and systemic embolisms, minor and major bleedings and deaths, versus acenocoumarol. Apixaban led to reductions of 80, 55 and 43% in costs related to nursing visits, hospitalizations, and emergency visits, respectively, leading to annual cost savings of €274/patient, from the perspective of society. Conclusion: Our results suggested that apixaban is a cost-effective alternative for patients with NVAF.