Thrombotic and bleeding events, mortality, and anticoagulant use among 546,656 hospitalized patients with COVID-19 in the United States: a retrospective cohort study.

This study describes demographics, thrombotic and bleeding events, mortality, and anticoagulant use among hospitalized patients with COVID-19 in the United States. Premier Healthcare Database data were analyzed to identify inpatients with a discharge diagnosis for COVID-19 (ICD-10-CM code: U07.1) from April 1, 2020 to March 31, 2021, and matched historical controls without COVID-19 (inpatients discharged between April 1, 2018 and March 31, 2019). Thrombotic [including venous thromboembolism (VTE)] and bleeding events were based on ICD-10-CM discharge diagnosis codes. Of the 546,656 patients hospitalized with COVID-19, 20.1% were admitted to the ICU, 62.8% were aged ≥ 60 years, 51.5% were male, and 31.0% were non-white. Any thrombotic event was diagnosed in 10.0% of hospitalized and 20.8% of ICU patients with COVID-19 versus (vs) 11.5% and 24.4% for historical controls, respectively. More VTE events were observed in hospitalized and ICU patients with COVID-19 than historical controls (hospitalized: 4.4% vs 2.7%, respectively; ICU: 8.3% vs 5.2%, respectively; both P < 0.0001). Bleeding events were diagnosed in 10.2% of hospitalized and 21.8% of ICU patients with COVID-19 vs 16.0% and 33.2% for historical controls, respectively. Mortality among hospitalized (12.4%) and ICU (38.5%) patients with COVID-19 was higher vs historical controls (2.4%, P < 0.0001 and 9.4%, P < 0.0001, respectively) and higher in hospitalized patients with COVID-19 who had thrombotic events (29.4%) vs those without thrombotic events (10.8%, P < 0.0001). VTE and mortality were higher in hospitalized and ICU patients with COVID-19 vs historical controls. The presence of thrombotic events was associated with worse outcomes.

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.

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.

All-Cause, Stroke/Systemic Embolism-, and Major Bleeding-Related Health-Care Costs Among Elderly Patients With Nonvalvular Atrial Fibrillation Treated With Oral Anticoagulants.

In this study, all-cause, stroke/systemic embolism (SE)-related, and major bleeding (MB)-related health-care costs among elderly patients with nonvalvular atrial fibrillation (NVAF) initiating treatment with different oral anticoagulants (OACs) were compared. Patients ≥65 years of age initiating OACs, including apixaban, rivaroxaban, dabigatran, and warfarin, were identified from the Humana Research Database between January 1, 2013, and September 30, 2015. Propensity score matching was used to separately match the different OAC cohorts with the apixaban cohort. All-cause health-care costs and stroke/SE-related and MB-related medical costs per patient per month (PPPM) were compared using generalized linear or 2-part regression models. Compared to apixaban, rivaroxaban was associated with significantly higher all-cause health-care costs (US$2234 vs US$1846 PPPM, P < .001) and MB-related medical costs (US$106 vs US$47 PPPM, P < .001), dabigatran was associated with significantly higher all-cause health-care costs (US$1980 vs US$1801 PPPM, P = .007), and warfarin was associated with significantly higher all-cause health-care costs (US$2386 vs US$1929 PPPM, P < .001), stroke/SE-related medical costs (US$42 vs US$18 PPPM, P < .001), and MB-related medical costs (US$132 vs US$51 PPPM, P < .001). Among elderly patients with NVAF, other OACs were associated with higher all-cause health-care costs than apixaban.

Apixaban 5 and 2.5 mg twice-daily versus warfarin for stroke prevention in nonvalvular atrial fibrillation patients: Comparative effectiveness and safety evaluated using a propensity-score-matched approach.

Prior real-world studies have shown that apixaban is associated with a reduced risk of stroke/systemic embolism (stroke/SE) and major bleeding versus warfarin. However, few studies evaluated the effectiveness and safety of apixaban according to its dosage, and most studies contained limited numbers of patients prescribed 2.5 mg twice-daily (BID) apixaban. Using pooled data from 4 American claims database sources, baseline characteristics and outcomes for patients prescribed 5 mg BID and 2.5 mg BID apixaban versus warfarin were compared. After 1:1 propensity-score matching, 31,827 5 mg BID apixaban-matched warfarin patients and 6600 2.5 mg BID apixaban-matched warfarin patients were identified. Patients prescribed 2.5 mg BID apixaban were older, had clinically more severe comorbidities, and were more likely to have a history of stroke and bleeding compared with 5 mg BID apixaban patients. Compared with warfarin, 5 mg BID apixaban was associated with a lower risk of stroke/SE (hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.60-0.81) and major bleeding (HR: 0.59, 95% CI: 0.53-0.66). Compared with warfarin, 2.5 mg BID apixaban was also associated with a lower risk of stroke/SE (HR: 0.63, 95% CI: 0.49-0.81) and major bleeding (HR: 0.59, 95% CI: 0.49-0.71). In this real-world study, both apixaban doses were assessed in 2 patient groups differing in age and clinical characteristics. Each apixaban dose was associated with a lower risk of stroke/SE and major bleeding compared with warfarin in the distinct population for which it is being prescribed in United States clinical practice. TRIAL REGISTRATION: Clinicaltrials.Gov Identifier: NCT03087487.

Effectiveness and safety of apixaban versus warfarin in non-valvular atrial fibrillation patients in "real-world" clinical practice. A propensity-matched analysis of 76,940 patients.

The ARISTOTLE trial showed a risk reduction of stroke/systemic embolism (SE) and major bleeding in non-valvular atrial fibrillation (NVAF) patients treated with apixaban compared to warfarin. This retrospective study used four large US claims databases (MarketScan, PharMetrics, Optum, and Humana) of NVAF patients newly initiating apixaban or warfarin from January 1, 2013 to September 30, 2015. After 1:1 warfarin-apixaban propensity score matching (PSM) within each database, the resulting patient records were pooled. Kaplan-Meier curves and Cox proportional hazards models were used to estimate the cumulative incidence and hazard ratios (HRs) of stroke/SE and major bleeding (identified using the first listed diagnosis of inpatient claims) within one year of therapy initiation. The study included a total of 76,940 (38,470 warfarin and 38,470 apixaban) patients. Among the 38,470 matched pairs, 14,563 were from MarketScan, 7,683 were from PharMetrics, 7,894 were from Optum, and 8,330 were from Humana. Baseline characteristics were balanced between the two cohorts with a mean (standard deviation [SD]) age of 71 (12) years and a mean (SD) CHA2DS2-VASc score of 3.2 (1.7). Apixaban initiators had a significantly lower risk of stroke/SE (HR: 0.67, 95 % CI: 0.59-0.76) and major bleeding (HR: 0.60, 95 % CI: 0.54-0.65) than warfarin initiators. Different types of stroke/SE and major bleeding - including ischaemic stroke, haemorrhagic stroke, SE, intracranial haemorrhage, gastrointestinal bleeding, and other major bleeding - were all significantly lower for apixaban compared to warfarin treatment. Subgroup analyses (apixaban dosage, age strata, CHA2DS2-VASc or HAS-BLED score strata, or dataset source) all show consistently lower risks of stroke/SE and major bleeding associated with apixaban as compared to warfarin treatment. This is the largest "real-world" study on apixaban effectiveness and safety to date, showing that apixaban initiation was associated with significant risk reductions in stroke/SE and major bleeding compared to warfarin initiation after PSM. These benefits were consistent across various high-risk subgroups and both the standard- and low-dose apixaban dose regimens.

Warfarin time in therapeutic range and its impact on healthcare resource utilization and costs among patients with nonvalvular atrial fibrillation.

BACKGROUND: Warfarin is efficacious for reducing stroke risk among patients with nonvalvular atrial fibrillation (NVAF). However, the efficacy and safety of warfarin are influenced by its time in therapeutic range (TTR). OBJECTIVE: To assess differences in healthcare resource utilization and costs among NVAF patients with low (<60%) and high (≥60%) warfarin TTRs in an integrated delivery network (IDN) setting. METHODS: Patients with NVAF were identified from an electronic medical record database. Patients were required to have ≥6 international normalized prothrombin time ratio (INR) tests. NVAF patients were grouped into two cohorts: those with warfarin TTR <60% (low TTR) and those with warfarin TTR ≥60% (high TTR). Healthcare resource utilization and costs were evaluated during a 12 month follow-up period. Multivariable regressions were used to assess the impact of different warfarin TTRs on healthcare costs. RESULTS: Among the study population, greater than half (54%, n = 1595) had a low TTR, and 46% (n = 1356) had a high TTR. Total all-cause healthcare resource utilization was higher among patients in the low TTR cohort vs. the high TTR cohort (number of encounters: 70.2 vs. 56.1, p < 0.001). After adjusting for patient characteristics, total all-cause healthcare costs and stroke-related healthcare costs were $2398 (p < 0.001) and $687 (p = 0.02) higher, respectively, for patients in the low TTR cohort vs. the high TTR cohort. LIMITATIONS: In this retrospective study, we were only able to evaluate the association and not the causality between healthcare resource utilization and costs with the different warfarin TTRs. CONCLUSION: Many warfarin-treated NVAF patients have a low warfarin TTR. NVAF patients with low vs. patients with high warfarin TTR used healthcare resources to a greater extent, which was reflected in higher healthcare costs.

An early evaluation of bleeding-related hospital readmissions among hospitalized patients with nonvalvular atrial fibrillation treated with direct oral anticoagulants.

OBJECTIVE: Clinical trials have demonstrated that direct oral anticoagulants (DOACs) are efficacious in reducing stroke risk among patients with nonvalvular atrial fibrillation (NVAF) with differences in the reduction of bleeding risks vs. warfarin. The objective of this study was to assess bleeding-related hospital readmissions among hospitalized NVAF patients treated with dabigatran, rivaroxaban, and apixaban in the US. RESEARCH DESIGN AND METHODS: Patients (≥18 years) with a discharge diagnosis of NVAF who received apixaban, dabigatran, or rivaroxaban during hospitalization were identified from the Premier Hospital database (1 January 2012-31 March 2014) and the Cerner Health Facts hospital database (1 January 2012-31 August 2014). Patients identified from each database were analyzed separately and grouped into three cohorts depending on which DOAC was received. Patient characteristics, hospital resource use and costs, and frequency of readmissions within 1 month were evaluated. RESULTS: Among study populations identified from the Premier database (N = 74,730) and the Cerner database (N = 14,201), patients who received apixaban were older, had greater comorbidity, and had higher stroke and bleeding risks. After controlling for patient characteristics, including comorbidity and stroke and bleeding risks, compared with patients who received apixaban during their index hospitalizations, the odds of bleeding-related hospital readmissions were significantly greater by 1.4-fold (p < 0.01) for patients who received rivaroxaban and 1.2-fold (p = 0.16) numerically greater for patients who received dabigatran among patients identified from the Premier Hospital database. Among patients in the Cerner Health Facts hospital database, bleeding-related hospital readmissions were significantly greater by 1.6-fold (p = 0.04) for patients who received rivaroxaban and 1.3-fold (p = 0.30) numerically greater for patients who received dabigatran compared to patients who received apixaban. LIMITATIONS: No causal relationship between treatment and outcomes can be concluded. CONCLUSIONS: NVAF patients using different DOACs had different characteristics, including stroke and bleeding risks. Use of rivaroxaban, compared to apixaban was associated with significantly greater risk of bleeding-related readmissions across two database claims analyses.

Comparison of Medical Costs of Patients With Atrial Fibrillation Unsuitable for Warfarin Treatment With Apixaban or Aspirin Based on AVERROES Trial.

BACKGROUND: The AVERROES trial name is the following: The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial demonstrated that apixaban reduced the risk of stroke relative to aspirin, without significantly increasing major bleeding risk in patients with atrial fibrillation (AF) considered unsuitable for warfarin therapy. Based on AVERROES trial results, this study compared the medical costs for clinical end points among patients with AF treated with either apixaban or aspirin. METHODS: Medical costs per patient-year for clinical events were determined. Based on clinical event rates for patients in the AVERROES trial, medical costs excluding drug costs were estimated for apixaban- and aspirin-treated patient groups. RESULTS AND CONCLUSIONS: Based on AVERROES trial results, among patients with AF unsuitable for warfarin therapy, apixaban use was estimated to be associated with a mean medical cost avoidance of US$735 in a patient-year relative to aspirin. The primary driver was the significant reduction in ischemic stroke rate. The medical cost reduction associated with apixaban use was consistent in sensitivity analyses.

Estimation of the impact of warfarin's time-in-therapeutic range on stroke and major bleeding rates and its influence on the medical cost avoidance associated with novel oral anticoagulant use-learnings from ARISTOTLE, ROCKET-AF, and RE-LY trials.

Warfarin's time-in-therapeutic range (TTR) is highly variable among patients with nonvalvular atrial fibrillation (NVAF). The objective of this study was to estimate the impact of variations in wafarin's TTR on rates of stroke/systemic embolism (SSE) and major bleedings among NVAF patients in the ARISTOTLE, ROCKET-AF, and RE-LY trials. Additionally, differences in medical costs for clinical endpoints when novel oral anticoagulants (NOACs) were used instead of warfarin at different TTR values were estimated. Quartile ranges of TTR values and corresponding event rates (%/patient - year = %/py) of SSE and major bleedings among NVAF patients treated with warfarin were estimated from published literature and FDA documents. The associations of SSE and major bleeding rates with TTR values were evaluated by regression analysis and then the calculated regression coefficients were used in analysis of medical cost differences associated with use of each NOAC versus warfarin (2010 costs; US payer perspective) at different TTRs. Each 10 % increase in warfarin's TTR correlated with a -0.32%/py decrease in SSE rate (R(2) = 0.61; p < 0.001). Although, the rate of major bleedings decreased as TTR increased, it was not significant (-0.035%/py, p = 0.63). As warfarin's TTR increased from 30 to 90% the estimated medical cost decreased from -$902 to -$83 for apixaban, from -$506 to +$314 for rivaroxaban, and from -$596 to +$223 for dabigatran. Among NVAF patients there is a significant negative correlation between warfarin's TTR and SSE rate, but not major bleedings. The variations in warfarin's TTR impacted the economic comparison of use of individual NOACs versus warfarin.

Medical costs in the US of clinical events associated with oral anticoagulant (OAC) use compared to warfarin among non-valvular atrial fibrillation patients ≥75 and <75 years of age, based on the ARISTOTLE, RE-LY, and ROCKET-AF trials.

OBJECTIVES: Based on clinical trials the oral anticoagulants (OACs) apixaban, dabigatran, and rivaroxaban are efficacious for reducing stroke risk for non-valvular atrial fibrillation (NVAF) patients. Based on the clinical trials, this study evaluated the medical costs for clinical events among NVAF patients ≥75 and <75 years of age treated with individual OACs vs warfarin. METHODS: Rates for primary and secondary efficacy and safety outcomes (i.e., clinical events) among NVAF patients receiving warfarin or each of the OACs were determined for NVAF populations aged ≥75 years and <75 years of age from the OAC vs warfarin trials. One-year incremental costs among patients with clinical events were obtained from published literature and inflation adjusted to 2010 costs. Medical costs, excluding medication costs, for clinical events associated with each OAC and warfarin were then estimated and compared. RESULTS: Among NVAF patients aged ≥75, compared to warfarin, use of either apixaban or rivaroxaban was associated with a reduction in medical costs per patient year (apixaban = -$825, rivaroxaban =-$23), while dabigatran use was associated with increased medical costs of $180 per patient year. Among NVAF patients <75 years of age medical costs per patient year were estimated to be reduced -$254, -$367, and -$88, for apixaban, dabigatran, and rivaroxaban, respectively, in comparison to warfarin. LIMITATIONS: This economic analysis was based on clinical trial data and, therefore, the direct application of the results to routine clinical practice will require further assessment. CONCLUSIONS: Difference in medical costs between OAC and warfarin treated NVAF patients vary by age group and individual OACs. Although reductions in medical costs for NVAF patients aged ≥75 and <75 were observed for those using either apixaban or rivaroxaban vs warfarin, the reductions were greater per patient year for both the older and younger NVAF populations using apixaban.

Medical Costs of Oral Anticoagulants vs Warfarin for Atrial Fibrillation Patients with Different Stroke Risks.

INTRODUCTION: The Apixaban for the Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE), Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY), and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trials demonstrated that the oral anticoagulants (OACs), apixaban, dabigatran, and rivaroxaban, respectively, are efficacious for stroke prevention among nonvalvular atrial fibrillation (NVAF) patients. Based on clinical trial results this study evaluated medical costs of clinical events associated with use of individual OACs relative to those of warfarin in NVAF patients with moderate and high stroke risk. METHODS: Rates for primary and secondary efficacy and safety outcomes (i.e., clinical events) among NVAF patients with CHADS2 = 2 and ≥3 were determined from the three OAC trials. One-year incremental costs among patients with clinical events from a US payer perspective were obtained from the literature and inflation adjusted to 2010 costs. Medical costs for clinical events associated with each OAC vs. warfarin were estimated and compared. RESULTS: For NVAF patients with moderate stroke risk (CHADS2 = 2) differences in clinical event medical costs vs. warfarin were -$298, -$143, and +$117 per patient year for apixaban, dabigatran (150 mg), and rivaroxaban, respectively (negative numbers indicate cost reduction). For NVAF patients with high stroke risk (CHADS2 ≥ 3) differences in clinical event medical costs vs. warfarin were -$697, +$2, and -$100 for apixaban, dabigatran (150 mg), and rivaroxaban, respectively. CONCLUSIONS: Medical cost differences associated with OACs vs. warfarin vary according to stroke risk. Of the three OACs, apixaban demonstrated consistent medical cost reductions vs. warfarin for NVAF patients with moderate and high stroke risks.

Why is warfarin underused for stroke prevention in atrial fibrillation? A detailed review of electronic medical records.

OBJECTIVE: Automated electronic queries of structured data fields in electronic medical records (EMR) found no barriers to warfarin in 42% of patients with atrial fibrillation or atrial flutter (AF) with moderate or high risk of stroke and no warfarin. A thorough manual review of records (including text reports) from the same EMR may better identify physicians' reasons for not using warfarin. METHODS: This was a cross-sectional, retrospective, manual EMR review. Patients identified in a previous automated EMR study with a CHADS2 (Chronic heart failure, Hypertension, Age >75 years, Diabetes mellitus, Stroke) score≥2, no record of warfarin, no barrier to warfarin use, and (in the present study) confirmation of AF diagnosis were included in the manual EMR review. A structured chart abstraction form was used to extract data visible in the clinicians' EMR user interface. Reasons why warfarin had not been prescribed were reported using descriptive statistics. RESULTS: Among 408 patients with 'no barriers' to warfarin in the automated EMR review, AF diagnosis was confirmed in 319 patients (mean age 74.8; 65% female). Forty-one percent (n=132) did not have chart records explaining why they were not on warfarin. Among the 59% (187) with a rationale against warfarin found in the records, the most common category (52%) was indicative of the risk of bleeding, either risk of fall or history of recent bleeding. The second most common category (16%) reflected that the patient was back in sinus rhythm. These findings are subject to inherent limitations of retrospective chart reviews. CONCLUSIONS: Many patients with AF and moderate-to-high risk of stroke are not treated with warfarin, and reasons for not using warfarin could not always be identified in patient records. Among patients with documented reasons, risk of bleeding (risk of fall or recent bleeding) was the most common category.

Medical cost reductions associated with the usage of novel oral anticoagulants vs warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF, and ARISTOTLE trials.

OBJECTIVE: The randomized clinical trials, RE-LY, ROCKET-AF, and ARISTOTLE, demonstrate that the novel oral anticoagulants (NOACs) are effective options for stroke prevention among non-valvular atrial fibrillation (AF) patients. This study aimed to evaluate the medical cost reductions associated with the use of individual NOACs instead of warfarin from the US payer perspective. METHODS: Rates for efficacy and safety clinical events for warfarin were estimated as the weighted averages from the RE-LY, ROCKET-AF and ARISTOTLE trials, and event rates for NOACs were determined by applying trial hazard ratios or relative risk ratios to such weighted averages. Incremental medical costs to a US health payer of an AF patient experiencing a clinical event during 1 year following the event were obtained from published literature and inflation adjusted to 2010 cost levels. Medical costs, excluding drug costs, were evaluated and compared for each NOAC vs warfarin. Sensitivity analyses were conducted to determine the influence of variations in clinical event rates and incremental costs on the medical cost reduction. RESULTS: In a patient year, the medical cost reduction associated with NOAC usage instead of warfarin was estimated to be -$179, -$89, and -$485 for dabigatran, rivaroxaban, and apixaban, respectively. When clinical event rates and costs were allowed to vary simultaneously, through a Monte Carlo simulation, the 95% confidence interval of annual medical costs differences ranged between -$424 and +$71 for dabigatran, -$301 and +$135 for rivaroxaban, and -$741 and -$252 for apixaban, with a negative number indicating a cost reduction. Of the 10,000 Monte-Carlo iterations 92.6%, 79.8%, and 100.0% were associated with a medical cost reduction >$0 for dabigatran, rivaroxaban, and apixaban, respectively. CONCLUSIONS: Usage of the NOACs, dabigatran, rivaroxaban, and apixaban may be associated with lower medical (excluding drug costs) costs relative to warfarin, with apixaban having the most substantial medical cost reduction.