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.

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.

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.

Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

Trends in Oral Anticoagulant Use and Individual Expenditures Across the United States from 2014 to 2020.

BACKGROUND: Landmark clinical trials have expended the indications for the direct oral anticoagulants (DOACs), but contemporary data on usage and expenditure patterns are lacking. OBJECTIVE: This study aimed to assess annual trends in oral anticoagulant (OAC) utilization and expenditure across the United States (US) from 2014 to 2020. METHODS: We utilized the Medical Expenditure Panel Survey (MEPS) to study the trends of use and expenditures of warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban between 2014 and 2020 in the US. Survey respondents reported OAC use within the past year, which was verified against pharmacy records. Payment information was obtained from the respondent's pharmacy and was categorized as third-party or self/out-of-pocket. Potential indications and medical conditions of interest for OAC therapy were identified from respondent-reported medical conditions. We estimated the national number of OAC users and total expenditures across age, sex, race, ethnicity, insurance, and medical condition subgroups. Trends of OAC users' characteristics, expenditure, and number of prescriptions were evaluated using the Mann-Kendall test for trends. RESULTS: Between 2014 and 2020, the number of warfarin users decreased from 3.8 million (70% of all OAC users) to 2.2 million (p = 0.007) [29% of all OAC users], while the number of DOAC users increased from 1.6 million (30% of all OAC users) to 5.4 million (p = 0.003) [70% of all OAC users]. The total expenditure of OACs in the US increased from $3.4 billion in 2014 to $17.8 billion in 2020 (p = 0.003), which was driven by the increase in DOAC expenditures (p = 0.003). CONCLUSIONS: DOACs have replaced warfarin as the preferred OAC in the US. The increased costs associated with DOAC use may decline when generic formulations are approved.

Genetic-Guided Pharmacotherapy for Coronary Artery Disease: A Systematic and Critical Review of Economic Evaluations.

BACKGROUND: Genetic-guided pharmacotherapy (PGx) is not recommended in clinical guidelines for coronary artery disease (CAD). We aimed to examine the extent and quality of evidence from economic evaluations of PGx in CAD and to identify variables influential in changing conclusions on cost-effectiveness. METHODS AND RESULTS: From systematic searches across 6 databases, 2 independent reviewers screened, included, and rated the methodological quality of economic evaluations of PGx testing to guide pharmacotherapy for patients with CAD. Of 35 economic evaluations included, most were model-based cost-utility analyses alone, or alongside cost-effectiveness analyses of PGx testing to stratify patients into antiplatelets (25/35), statins (2/35), pain killers (1/35), or angiotensin-converting enzyme inhibitors (1/35) to predict CAD risk (8/35) or to determine the coumadin doses (1/35). To stratify patients into antiplatelets (96/151 comparisons with complete findings of PGx versus non-PGx), PGx was more effective and more costly than non-PGx clopidogrel (28/43) but less costly than non-PGx prasugrel (10/15) and less costly and less effective than non-PGx ticagrelor (22/25). To predict CAD risk (51/151 comparisons), PGx using genetic risk scores was more effective and less costly than clinical risk score (13/17) but more costly than no risk score (16/19) or no treatment (9/9). The remaining comparisons were too few to observe any trend. Mortality risk was the most common variable (47/294) changing conclusions. CONCLUSIONS: Economic evaluations to date found PGx to stratify patients with CAD into antiplatelets or to predict CAD risk to be cost-effective, but findings varied based on the non-PGx comparators, underscoring the importance of considering local practice in deciding whether to adopt PGx.

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.

Trends in Drug Spending of Oral Anticoagulants for Atrial Fibrillation, 2014-2021.

INTRODUCTION: This study documents cost trends in oral anticoagulants (OAC) in patients with newly diagnosed atrial fibrillation. METHODS: Using MarketScan databases, the mean annual patients' out-of-pocket costs, insurance payments, and the proportion of patients initiating OAC within 90 days from atrial fibrillation diagnosis were calculated from July 2014 to June 2021. Costs of OACs (apixaban, dabigatran, edoxaban, rivaroxaban, and warfarin) and the payments by three insurance types (commercial payers, Medicare, and Medicaid) were calculated. Patients' out-of-pocket costs and insurance payments were adjusted to 2021 prices. Joinpoint regression models were used to test trends of outcomes and average annual percent changes (AAPC) were reported. Data analyses were performed in 2022-2023. RESULTS: From July 2014 to June 2021, the mean annual out-of-pocket costs of any OAC increased for commercial insurance (AAPC 3.0%) and Medicare (AAPC 5.1%) but decreased for Medicaid (AAPC -3.3%). The mean annual insurance payments for any OAC significantly increased for all insurance groups (AAPC 13.1% [95% CI 11.3-15.0] for Medicare; AAPC 11.8% [95% CI 8.0-15.6] for commercial insurance; and AAPC 16.3% [95% CI 11.3-21.4] for Medicaid). The initiation of any OAC increased (AAPC 7.3% for commercial insurance; AAPC 10.2% for Medicare; AAPC 5.3% for Medicaid). CONCLUSIONS: There was a substantial increase in the overall cost burden of OACs and OAC initiation rates in patients with newly diagnosed atrial fibrillation in 2014-2021; these findings provide insights into the current and anticipated impact of rising drug prices on patients' and payers' financial burden.

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.

Outcomes of Warfarin Home INR Monitoring vs Office-Based Monitoring: a Retrospective Claims-Based Analysis.

BACKGROUND: Home INR testing (patient self-testing) is feasible and effective for warfarin patients but little is known about real-world differences in outcomes for patients using PST versus laboratory-based INR monitoring. OBJECTIVE: To compare the safety/efficacy of patient self-testing of real-world warfarin therapy versus office/lab-based monitoring of therapy. DESIGN/SETTING/PARTICIPANTS/EXPOSURE: A retrospective claims-based analysis of warfarin patients enrolled in the MarketScan® Commercial Claims and Encounters and Medicare databases between January 1, 2013, and March 30, 2020. Stratification was based on INR testing method: patient self-testing versus testing at physicians' offices/local laboratory. The probability of adverse events in each cohort was determined after adjusting for demographic and baseline clinical characteristics using a repeated measures analysis. MAIN MEASURES: Rates of all adverse events: deep venous thrombosis, pulmonary embolism, bleeding, and stroke. A secondary outcome of interest was emergency department visits. KEY RESULTS: A total of 37,837 patients were included in the analysis: 1592 patients in the patient self-testing group and 36,245 in the office-based therapy group. After adjusting for demographic and baseline clinical characteristics, patients in the office-based group had statistically significantly higher rates of all adverse events (incidence rate ratio [IRR]=2.07, 95% CI [1.82, 2.36]), and specific adverse events including thromboembolism (IRR=4.38, 95% CI [3.29, 5.84]), major bleed (IRR=1.45, 95% CI [1.28, 1.64]), and stroke (IRR=1.30, 95% CI [1.05, 1.61]) than patients in the patient self-testing group. Office-based patients also had a statistically significant higher rate of emergency department visits than patient self-testing patients (IRR = 1.65, 95% CI [1.47, 1.84]). CONCLUSIONS/RELEVANCE: This analysis of real-world claims data shows lower rates of stroke, thromboembolism, and major bleeding, as well as fewer emergency department visits, with patient self-testing compared to office-based/lab INR monitoring. Our finding that PST is safe and effective among current users suggests that more patients may benefit from its use.

Analysis of one-year follow-up results and treatment costs of patients with PTE in a tertiary care center.

Introduction: Pulmonary thromboembolism (PTE) is a life-threatening disease, with substantial treatment-related complications, difficult follow-up, treatment compliance, and high costs. This study aimed to assess treatment costs with various maintenance therapy regimens, complications, and patient adherence to treatment over a one-year follow-up period. Materials and Methods: This observational, prospective study included 142 patients with PTE who received maintenance anticoagulation therapy between November 2020 and March 2023. The patients were observed at three-month intervals for a year. Possible treatment-related complications, recurrence, mortality, and treatment costs were recorded. Result: Our results showed that there was no significant difference in bleeding risk based on the drugs used for initial or maintenance treatment. In maintenance therapy, low-molecular-weight heparin (LMWH), warfarin, and direct oral anticoagulant (DOAC) treatment regimens had similar treatment adherence and comparable efficacy and safety in terms of recurrence and bleeding (p> 0.05). Four patients (2.8%) were diagnosed with chronic thromboembolic disease. The one-year mortality rate was 24.6% (n= 35), of which 82.9% (n= 29) occurred within the first three months. Hospital mortality rates with the different maintenance therapies were 8.8% in the LMWH group, 5.7% in the warfarin group, and 3.2% in the DOAC group. The annual cost of using LMWH was higher than that of rivaroxaban, apixaban, and warfarin (p< 0.001) while there was no significant cost difference between DOACs and warfarin (p> 0.05). Conclusions: In our study, the LMWH, warfarin, and DOAC treatment regimens had similar efficacy, safety, and patient compliance. In terms of cost, LMWH was the costliest while DOAC and warfarin were similar.

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.

Cost-effectiveness of left atrial appendage closure with Watchman for non-valvular atrial fibrillation patients in Japan.

AIMS: Left atrial appendage closure (LAAC) has been demonstrated to be cost-saving relative to oral anticoagulants for stroke prophylaxis in patients with non-valvular atrial fibrillation (NVAF) in the United States and Europe. This study assessed the cost-effectiveness of LAAC with the Watchman device relative to warfarin and direct oral anticoagulants (DOACs) for stroke risk reduction in NVAF from a Japanese public healthcare payer perspective. METHODS: A Markov model was developed with 70-year-old patients using a lifetime time horizon. LAAC clinical inputs were from pooled, 5-year PROTECT AF and PREVAIL trials; warfarin and DOAC inputs were from published meta-analyses. Baseline stroke and bleeding risks were from the SALUTE trial on LAAC. Cost inputs were from the Japanese Medical Data Vision database. Probabilistic and one-way sensitivity analyses were performed. RESULTS: Over the lifetime time horizon, LAAC was less costly than warfarin (savings of JPY 1,878,335, equivalent to US $17,600) and DOACs (savings of JPY 1,198,096, equivalent to US $11,226). LAAC also provided 1.500 more incremental quality-adjusted life years (QALYs) than warfarin and 0.996 more than DOACs. In probabilistic sensitivity analysis, LAAC was cost-effective relative to warfarin and DOACs in 99.98% and 99.73% of simulations, respectively. LAAC dominated (had higher cumulative QALYs and was less costly than) warfarin and DOACs in 89.94% and 83.35% of simulations, respectively. CONCLUSIONS: Over a lifetime time horizon, LAAC is cost-saving relative to warfarin and DOACs for stroke risk reduction in NVAF patients in Japan and is associated with improved quality-of-life.

This study examined the cost-effectiveness of left atrial appendage closure (LAAC) compared to oral anticoagulants for stroke risk reduction among individuals with a specific type of irregular heart rhythm called non-valvular atrial fibrillation (NVAF). This study evaluated the cost-effectiveness of LAAC using the Watchman device in comparison to warfarin and direct oral anticoagulants (DOACs) from the perspective of Japan's public healthcare system. To investigate this, a computer-based model was developed involving 70-year-old patients over their lifetime. Data from notable studies such as the PROTECT AF and PREVAIL trials (covering 5 years) for LAAC and published meta-analyses for warfarin and DOACs were incorporated into the model. Baseline stroke and bleeding risks were derived from the SALUTE trial on LAAC. Cost inputs were based on data from the Japanese Medical Data Vision database. Additionally, we performed thorough cost-effectiveness analyses, including probabilistic and one-way sensitivity assessments. Our findings revealed that, over a lifetime, LAAC was more cost-effective than both warfarin and DOACs. Further, LAAC contributed an additional 1.500 quality-adjusted life years (QALYs) compared to warfarin and 0.996 QALYs compared to DOACs. In the long-term, adopting LAAC as an alternative to warfarin and DOACs is a cost-effective strategy for reducing stroke risk in NVAF patients in Japan. Moreover, it is associated with enhanced quality-of-life. These findings hold significant implications for informing decision-making in healthcare policies and clinical practices for NVAF patients.

Functional Characterization of 29 Cytochrome P450 4F2 Variants Identified in a Population of 8380 Japanese Subjects and Assessment of Arachidonic Acid ω-Hydroxylation.

Cytochrome P450 4F2 (CYP4F2) is an enzyme that is involved in the metabolism of arachidonic acid (AA), vitamin E and K, and xenobiotics including drugs. CYP4F2*3 polymorphism (rs2108622; c.1297G>A; p.Val433Met) has been associated with hypertension, ischemic stroke, and variation in the effectiveness of the anticoagulant drug warfarin. In this study, we characterized wild-type CYP4F2 and 28 CYP4F2 variants, including a Val433Met substitution, detected in 8380 Japanese subjects. The CYP4F2 variants were heterologously expressed in 293FT cells to measure the concentrations of CYP4F2 variant holoenzymes using carbon monoxide-reduced difference spectroscopy, where the wild type and 18 holoenzyme variants showed a peak at 450 nm. Kinetic parameters [Vmax , substrate concentration producing half of Vmax (S50 ), and intrinsic clearance (CL int ) as Vmax /S50 ] of AA ω-hydroxylation were determined for the wild type and 21 variants with enzyme activity. Compared with the wild type, two variants showed significantly decreased CL int values for AA ω-hydroxylation. The values for seven variants could not be determined because no enzymatic activity was detected at the highest substrate concentration used. Three-dimensional structural modeling was performed to determine the reason for reduced enzymatic activity of the CYP4F2 variants. Our findings contribute to a better understanding of CYP4F2 variant-associated diseases and possible future therapeutic strategies. SIGNIFICANCE STATEMENT: CYP4F2 is involved in the metabolism of arachidonic acid and vitamin K, and CYP4F2*3 polymorphisms have been associated with hypertension and variation in the effectiveness of the anticoagulant drug warfarin. This study presents a functional analysis of 28 CYP4F2 variants identified in Japanese subjects, demonstrating that seven gene polymorphisms cause loss of CYP4F2 function, and proposes structural changes that lead to altered function.

Assessment of the relationship between the level of patient knowledge on warfarin therapy and the quality of oral anticoagulation: A systematic review and meta-analysis.

The present study aimed to investigate the relationship between the level of patient knowledge on warfarin therapy and the quality of oral anticoagulation. This is a systematic review and meta-analysis written on the basis of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Searches at MEDLINE, EMBASE, Scopus and LILACS electronic databases were carried out on February 13, 2023, using the descriptors "Patient Medication Knowledge", "Patient Education as Topic", "Health Education", "Patient Education" and Warfarin. The steps of selection, data extraction and quality analysis of articles were performed independently by two reviewers. The analysis was performed considering patient knowledge as a possible modifier of time in therapeutic range (TTR). The meta-analysis included studies that reported the correlation coefficient (Pearson or Spearman) between patient knowledge and TTR. A subgroup analysis was performed according to questionnaires employed to measure patient knowledge. Twelve studies were selected with an overall sample size of 7634 participants and mean age 58.2 (standard deviation (SD)±12,8) years. Eleven (92.0%) cross-sectional studies. The mean TTR was 57.8% (SD±11,3%) and the average level of knowledge was 60.4%. The meta-analysis indicated that patient level of knowledge on warfarin therapy was moderately associated with TTR (rs = 0.435; 95% confidence interval (CI) = 0.163-0.645; I2 = 96%). Subgroup analysis indicated association between knowledge level and TTR in studies employing the OAK test (rs = 0.617; 95% CI = 0.192-0.847; I2 = 97%) and the AKA (rs = 0.269; 95% CI = 0.002 to 0.501; I2 = 94%). However, the subgroup analysis presented no significant difference between them (p = 0.14). The meta-regression showed a non-significant negative effect of age on the correlation (estimate = -0.028, 95% CI = -0.073 to 0.016, p = 0.207). No publication bias was noted (p = 0.881). To our knowledge, this is the first systematic review and meta-analysis gathering evidence about the relationship between the level of patient knowledge on oral anticoagulation with warfarin and TTR. The implementation of structured and patient-centered educational interventions is essential to effectively increase the level of patient knowledge and, thus, to improve the quality and safety of warfarin therapy. Systematic review registration number: PROSPERO CRD42023398030.