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Oral Anticoagulant Discontinuation in Patients With Nonvalvular Atrial Fibrillation
Sumesh Kachroo, PhD; Melissa Hamilton, MPH; Xianchen Liu, MD, PhD; Xianying Pan, MS; Diana Brixner, PhD; Nassir Marrouche, MD; and Joseph Biskupiak, PhD, MBA

Oral Anticoagulant Discontinuation in Patients With Nonvalvular Atrial Fibrillation

Sumesh Kachroo, PhD; Melissa Hamilton, MPH; Xianchen Liu, MD, PhD; Xianying Pan, MS; Diana Brixner, PhD; Nassir Marrouche, MD; and Joseph Biskupiak, PhD, MBA
The risk of discontinuation of oral anticoagulant therapy (both warfarin and direct oral anticoagulant therapies [DOACs]) among nonvalvular atrial fibrillation patients was high. Although the hazard ratio for discontinuation favors DOACs, it is unlikely that the small difference in discontinuation relative to warfarin is clinically meaningful.
Table 2 presents the overall discontinuation rate and the days to discontinuation for both warfarin users and DOAC users. Figure 3 depicts the Kaplan-Meier (K-M) curves that show risk of discontinuation for warfarin and DOAC therapy with time, and Table 3 shows the factors associated with the risk of discontinuation. Patients taking DOAC therapy were significantly less likely to discontinue compared with patients taking warfarin (reference = warfarin) (HR, 0.91; 95% CI, 0.86-0.97; P = .002). As age increased (reference group = aged 18-34 years), the magnitude of risk of discontinuation decreased, with significant results for patients in the age groups 45 to 54 years (HR, 0.56; 95% CI, 0.44-0.71; P = .000), 55 to 64 years (HR, 0.42; 95% CI, 0.33-0.53; P = .000), and 65 years or older (HR, 0.32; 95% CI, 0.24-0.43; P = .000). The patients from the western region of the United States were significantly more likely to discontinue (reference = northeast region) (HR, 1.14; 95% CI, 1.04-1.24; P = .003). Patients with prior bleeding events were also more likely to discontinue (HR, 1.20; 95% CI, 1.08-1.34; P = .001). The baseline comorbidities that significantly decreased the risk of discontinuation include prior stroke/transient ischemic attack (TIA) (HR, 0.65; 95% CI, 0.56-0.75; P = .000), prior PE (HR, 0.71; 95% CI,  0.58-0.88; P = .001), a diagnosis of diabetes (HR, 0.84; 95% CI,  0.77-0.90; P = .000), and a diagnosis of CHF (HR, 0.80; 95% CI,  0.74-0.87; P = .000).

 

DISCUSSION
This study highlights the high frequency of all-cause discontinuation of OAC therapy among NVAF patients. Close to half (47%) discontinued during follow-up with a mean time to discontinuation of 120 days. This is consistent with the current literature. Patel et al reported that about 37% of warfarin initiators had discontinued warfarin within 90 days after the initiation of therapy, with 65% discontinuing warfarin therapy within 1 year.30 Deitelzweig et al reported that 51.4% of warfarin initiators with NVAF discontinued warfarin therapy at least once during follow-up.31 Several other studies suggest that approximately 25% of patients on warfarin discontinue therapy within the first year of use.32-37 Casciano et al have also reported that the underutilization of warfarin is prevalent in NVAF patients and, in addition, nonadherence to warfarin therapy presents additional economic burden on the healthcare system.38 Adherence to therapy is absolutely essential for NVAF patients, as stroke risk is significantly higher during the warfarin discontinuation periods in comparison with periods when the patients are on therapy.31 Ewen et al have also reported that patients who experience 2 or more interruptions in warfarin use have more than twice the risk for stroke (mean follow-up period = 3.4 years) compared with patients with no interruptions.39

In addition, a key highlight of the present study is that patients taking DOAC therapy were less likely than patients taking warfarin to discontinue. This result, however, needs to be interpreted with caution. Although the overall risk of discontinuation via the Cox Hazard Model demonstrates the lower risk for DOAC patients compared with warfarin patients (Table 3), it is unclear whether this translates into a meaningful clinical benefit. The K-M curves for discontinuation (Figure 3) show little difference for those patients continuing OAC therapy between the warfarin and DOAC cohorts. Further, the mean time to discontinuation (Table 2) indicates that among patients who discontinue, warfarin patients remain on therapy slightly longer than DOAC patients.

The existing literature has well documented the challenges that plague warfarin therapy, including variable dose requirements and numerous dietary and medication interactions, as well as a lifelong, regular, frequent monitoring of INR to ensure it is within the recommended range.4,17-19,40,41 On the other hand, DOACs offer patients flexibility, with the absence of required frequent anticoagulation monitoring. Further, DOACs have a more favorable dietary and medication interaction profile compared with warfarin.42-44

A major reason for discontinuing warfarin therapy is its associated bleeding complications and the resulting costs. In their study assessing warfarin-associated bleeding in AF patients, Ghate et al reported the mean adjusted all-cause annual costs as $42,574, $36,571, $22,824, and $22,507 for subjects with intracranial hemorrhage, major gastrointestinal (GI) bleeding, minor GI bleeding, and no bleeding, respectively.45 Kim et al reported a mean cost of $10,819 (SD = $11,536) for hospitalizations due to warfarin-associated bleeding.46 On the other hand, clinical trials and published meta-analyses of the DOACs have shown lower bleeding rates compared with warfarin.22-24,47,48

The findings of this study suggest that certain clinical, demographic, and/or healthcare-related characteristics were significantly associated with discontinuation of OACs. We observed that patients with prior bleeding events were more likely to discontinue. Suh et al reported that patients with recent bleeding were more likely to discontinue warfarin compared with patients without recent bleeding (relative risk, 1.35; 95% CI, 1.16-1.58).49 The baseline comorbidities that significantly decreased the risk of discontinuation included increasing age, prior stroke/TIA, prior PE, a diagnosis of diabetes, and a diagnosis of CHF. Fang et al reported that the risk of discontinuation was higher in patients 65 years or older compared with patients 85 years or older (HR, 1.33; 95% CI, 1.03-1.72).33 On the contrary, Suh et al reported older age as a risk factor for discontinuation.49 It would be difficult to draw definitive conclusions on the impact of clinical, demographic, and/or healthcare-related characteristics on the discontinuation of OACs. Additional research is needed to build a more detailed understanding, as well as to conduct a comprehensive evaluation on treatment patterns with DOACs using real-world data.

Understanding the real-world usage of warfarin and DOACs is needed to improve existing treatment algorithms. The consequences of discontinuation are immense, often leading to negative health outcomes and increased healthcare costs.38,45,46 Given that existing research indicates that the bleeding complications associated with warfarin are a major reason for the drug’s discontinuation,20,49 it is necessary to thoroughly evaluate how DOACs—which reduce bleeding and/or have a comparatively better bleeding profile50,51—may encourage improved compliance and thereby provide continuous, uninterrupted stroke protection.

Strengths and Limitations

One key strength of our study is its analysis of real-world data on DOACs. The MarketScan claims database, which provides data on patients across the United States, incorporates all medical and pharmacy claims of patients and allows for longitudinal analysis. However, our analysis also has several limitations. The database does not uniformly capture the use of over-the-counter medications, such as aspirin, which are used to help prevent stroke in AF patients and could have an impact on the treatment patterns of the anticoagulants being studied. Also, while the discontinuation of therapy was based on a 60-day gap in pharmacy claims, a lack of INR monitoring means we can’t assess whether the gap was clinically meaningful. In this study, too, we haven’t separately accounted for AF patients who are on short courses of anticoagulation for specific reasons (ie, scheduled for imminent cardioversion or AF ablation procedures). Also, we were not able to identify patients with AF postoperatively, who may have had a short course of anticoagulation therapy. In addition, our analysis was based on early utilization of DOAC, which may change over time. Also, generalizability may be limited because the portion of the study population insured by Medicare only includes that subset of Medicare recipients who are Medicare-eligible retirees with employer-sponsored Medicare Supplemental plans. This patient population may not be representative of all AF patients 65 years or older. In addition, the data do not include uninsured patients.

CONCLUSIONS
This study highlights the high risk of discontinuation of OAC therapy among NVAF patients. Despite the Cox Hazard Model indicating a statistically significant reduction in risk of discontinuation for DOAC versus warfarin, the K-M curves are very similar and it is unlikely the small difference seen in discontinuation is clinically relevant. More research utilizing real-world data needs to be conducted to foster detailed understanding of DOAC treatment patterns.

Acknowledgments

The authors would like to thank Sameer R. Ghate, PhD, for his work in the initial stages of the study. The results of this manuscript were presented at the American Heart Association Scientific Sessions, Dallas, Texas, November 16-20, 2013.

Author Affiliations: Bristol-Myers Squibb Global Health Economics and Outcomes Research (SK, MH, XP), Princeton, NJ; Pfizer Global Health Economics and Outcomes Research (XL), New York City, NY; University of Utah Program in Personalized Health Care (DB), Salt Lake City, UT; University of Utah College of Pharmacy (DB, JB), Salt Lake City, UT; University of Utah Comprehensive Arrhythmia Research & Management Center (NM), Salt Lake City, UT.

Source of Funding: This study was sponsored by Bristol-Myers Squibb and Pfizer.     
      
Author Disclosures: Dr Kachroo, Ms Hamilton, and Ms. Pan are employees and stockholders of Bristol-Myers Squibb (BMS). Dr Liu is a Pfizer employee and stockholder. Drs Brixner and Biskupiak received financial support from BMS and Pfizer to conduct this research. Dr Marrouche reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (JB, DB, XL, MH, XP); acquisition of data (JB); analysis and interpretation of data (JB, DB, SK, XL, MH, XP); drafting of the manuscript (JB, SK, XL, MH, XP); critical revision of the manuscript for important intellectual content (JB, SK, XL, MH, XP); statistical analysis (JB, SK, DB); obtaining funding (JB, DB); administrative, technical, or logistic support (JB); and supervision (JB).

Address correspondence to: Joseph Biskupiak, PhD, MBA, Department of Pharmacotherapy, University of Utah College of Pharmacy, L.S. Skaggs Pharmacy Institute, 30 South 2000 East, Rm 4962, Salt Lake City, UT 84112. E-mail: joe.biskupiak@utah.edu.
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