Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)


Pharmaceutical Sciences

First Advisor

Cynthia Willey


Introduction: Atrial fibrillation (AF) is a very common condition that causes cardiac rhythm disturbance and affects 2.7 to 6.1 million individuals in the United States (US). Warfarin, which is considered as a gold standard anticoagulant for the last 50 years to treat AF has limitations pertaining to the risk of bleeding, interaction with drugs and requires frequent monitoring. Novel Oral Anti-Coagulants (NOAC including dabigatran and rivaroxaban) are new promising drugs which have shown better or similar efficacy to lower stroke risk and fewer side effects compared to warfarin in the clinical trials. To compete with warfarin, NOACs may need to demonstrate substantial real-world evidence in regards to improving clinical outcomes and cost savings.

Objective: The study was designed to evaluate the extent of undertreatment (adherence), and its predictors along with the impact of adherence on clinical outcomes, including ischemic stroke, bleeding, and Deep Vein Thrombosis and Pulmonary Embolism (DVTPE). Furthermore, the analysis helped to estimate the economic burden of NOACs vs. warfarin and identify specific subgroups with high-cost drivers and Healthcare Resource Utilization (HCRU) to achieve optimal benefits and devise strategies for cost-savings. The objective was achieved by conducting the following studies:

Study 1 - To examine patterns of medication adherence (measured by Proportion of Days Covered [PDC]) in patients with atrial fibrillation taking NOACs vs. warfarin for 6 or 12 months (post index). Furthermore, the study examined the short and long-term factors predicting adherence to the NOAC therapy after controlling potential confounders.

Study 2 - To examine the impact of adherence on the short and long-term risk of ischemic stroke, bleeding DVTPE and recurrent DVTPE in patients with AF taking NOACs during a one-year period (post index). The impact of adherence on outcomes was investigated by comparison of risk among propensity-matched adherence (adherent vs. non-adherent) cohorts.

Study 3 – To describe and compare the economic burden (cost and HCRU) in patients using NOACs vs. warfarin therapy. Furthermore, the study aimed to identify specific subgroups and key drivers of high-costs and HCRU. The final aim of the study was to explore if there are any differences in cost/HCRU between adherent and non-adherent NOAC patients.

Methods: The research utilized a retrospective cohort study design. Atrial fibrillation patients (ICD-9-CM codes 427.31/32), with ≥2 prescription fills for NOAC or warfarin, CHA2DS2VASC score ≥1, and 6-months pre-index continuous enrollment from the Optum® Clinformatics™ Data Mart (Optum Insight, Eden Prairie, MN) (Jan 1, 2010 and Dec 31, 2012) were included. The index date was the first prescription claim for NOAC or warfarin. Adherence was calculated using Proportion of Days Covered (PDC) over a 1-year period. Predictors of adherence (PDC ≥ 80%) were examined using a logistic regression model controlling for the covariates including age, gender, stroke risk, co-morbidities, insurance type, region, pre-index cardiac drug use (beta-blocker, Angiotensin II receptor blockers [ARB] or Angiotensin-converting enzyme [ACE] inhibitor, statin), etc. For the second study, adherent (PDC ≥ 80%) and non-adherent patients were matched on the above covariates using propensity score (Inverse Probability Treatment Weighting). The adjusted risk estimates were obtained at 6 and 12 months using a Cox proportional hazards model or generalized linear models (Poisson, negative Binomial) and compared across adherence based matched cohorts. In the final study, the economic value in terms of adjusted healthcare costs (inpatient, outpatient, and drug costs) and HCRU was estimated using a GLM model with gamma distribution and compared between patients taking NOACs vs. warfarin. Unadjusted costs were presented using descriptive analysis by subgroups based on demographic and clinical characteristics (age, gender, Charlson’s comorbidity index (CCI), insurance type, CHA2DS2VASC score, region, pre-index cardiac drug use, including beta-blocker, ARB-ACE inhibitor, statin use). Cost specific to bleeding events were calculated as an exploratory analysis. Similarly, the costs and HCRU were descriptively compared between the adherent and non-adherent patients taking NOACs.

Results: A total of 5057 (N=1770 NOAC vs. N=3287 warfarin) patients with mean age of 66 years were included in the cohort based on the inclusion and exclusion criteria. For a 12-month follow-up, the proportion of adherent (PDC ≥80%) patients were higher among NOACs users (78.42%) compared to warfarin users (61.88%). Using multivariate logistic model controlling for the confounders; Age, CCI and statin use were major predictors of both short (6-month) and long-term (12-month) adherence to NOACs. The CHA2DS2VASC score was significantly associated with the short-term adherence while but not associated with the long-term adherence.

For 12-month of adherence assessment, the three cohorts for bleeding, ischemic stroke, and DVTPE included 1617, 1651, 1739 patients (N=3440 for recurrent DVTPE at 6-month assessment). For 12-month drug use, the incidence of bleeding, ischemic stroke, and DVTPE was 4.21%, 3.11%, and 1.11% respectively. Based on the multivariate analysis at 6 and 12 months of adherence assessment, the non-adherence was significantly associated with 1.72 and 1.94 times increase in the stroke risk respectively. Similarly, non-adherence was found to be significantly associated with elevated risk of recurrent DVTPE 3 and 6 months and DVTPE risk at 3, 6, 9 months. The risk of bleeding in non-adherent patients was slightly lower (HR= 0.84 – 6 months, HR= 0.94 – 12 months) but not significant compared to the risk of bleeding in adherent patients. High annual drug cost for NOAC users ($4988 vs. $331) was offset by higher medical (inpatient and outpatient) costs for warfarin users (Total annual cost for warfarin $31,400 vs. $22,134). The mean of annual ER visits (14 vs. 13) and office visits (76 vs. 49) was also higher for warfarin users compared to the patients taking NOACs.

Overall, among warfarin users, female patients had higher HCRU, patients from the South had higher medical costs and office visits. Highest cost drivers for drug cost for warfarin users was patients from Northeast. Conversely, highest cost drivers for medical cost were patients less than <65 years and patients with CCI +3.

For NOACs, the highest cost driver for the drugs was user who were 65 and above, from Northeast, CHA2DS2VASC >2 (mod-high risk), and independent insurance. Additionally, medical cost was driven by EPO insurance and CCI+3.

Although medical costs and HCRU were lower for adherent vs. non-adherent patients taking NOACs, the differences were non-significant.

Conclusion: Use of NOACs due to its better adherence compared to warfarin may help prevent inadequate anticoagulation and complications. Determining the factors influencing the adherence such as age, CCI, and stroke risk can help plan targeted approaches and interventions to improve adherence. Our results can help healthcare providers and managed care organizations to recognize the importance of adherence to NOAC medications among patients to prevent clinical risks including stroke, DVTPE and bleeding events. The study provides a valuable estimate of the economic burden in AF patients using NOACs and warfarin. These cost estimates can be further used as inputs in the studies involving cost-effectiveness analysis and indirect treatment comparisons. We found the higher drug costs for NOACs were offset by lower inpatient costs, outpatient costs, and HCRU; which can lead to overall monetary savings to the patient taking NOACs and to the healthcare system. Overall, the conducted research provides comprehensive evidence to help support NOACs as an optimal treatment choice for the AF patients.

Available for download on Wednesday, December 13, 2017