Elsevier

Clinical Therapeutics

Volume 35, Issue 8, August 2013, Pages 1201-1210
Clinical Therapeutics

Warfarin Use and Stroke Risk Among Patients With Nonvalvular Atrial Fibrillation in a Large Managed Care Population

https://doi.org/10.1016/j.clinthera.2013.06.005Get rights and content

ABSTRACT

Background

Stroke prevention is a goal of atrial fibrillation (AF) management, but discontinuation of warfarin anticoagulation therapy is common.

Objective

To investigate the association between warfarin discontinuation and hospitalization for stroke among nonvalvular AF (NVAF) patients enrolled in managed care.

Methods

Patients with NVAF who initiated warfarin therapy from January 2005 through June 2009 were included. Warfarin discontinuation was defined as a supply gap >60 days without evidence of International Normalized Ratio measurements. Follow-up, which was a variable time period from warfarin initiation until the earlier of death, disenrollment from the health plan, or June 30, 2010, was divided into periods of warfarin treatment and discontinuation. Stroke events were identified based on claims for inpatient stays with a primary diagnosis of stroke or transient ischemic attack. Cox proportional hazards models were constructed to assess the relationship between warfarin discontinuation and incident stroke while adjusting for baseline demographics, stroke and bleeding risk, and comorbidities, as well as time-dependent antiplatelet use, stroke, and bleeding events in the previous warfarin treatment period.

Results

Among warfarin initiators with NVAF (N = 16,253), 51.4% discontinued warfarin therapy at least once during a mean follow-up of 668 days. Stroke risk was significantly greater during warfarin discontinuation periods compared with therapy periods (hazard ratio = 1.60; 95% CI, 1.35–1.90; P < 0.001).

Conclusions

More than half of patients on warfarin had treatment gaps or discontinued therapy. Therapy gaps were associated with increased stroke risk.

Introduction

Atrial fibrillation (AF) is a common cardiac rhythm disorder1 with prevalence estimates for the United States ranging from 2.7 million to 6.1 million adults in 2010.2, 3, 4 Nonvalvular AF (NVAF), the most common type,5 occurs in the absence of rheumatic mitral valve disease, mitral valve repair, or a prosthetic heart valve.1

AF is a risk factor for stroke, and preventing thromboembolism is a primary management objective.1, 6, 7, 8, 9, 10 Anticoagulation, often with warfarin,11, 12 is recommended for patients at moderate or high risk for stroke.1 Although warfarin therapy effectively decreases stroke risk and reduces mortality in AF patients, it also increases the risk of bleeding, and concern about bleeding is a reason for its under utilization.13, 14, 15 Warfarin suppresses vitamin K–dependent clotting factor synthesis, and the anticoagulant effect occurs as factor concentrations diminish over a span of hours to days.16 A few days of therapy are typically necessary to reach a therapeutic level,16 but warfarin’s multiple drug-drug and drug-diet interactions impede establishment and maintenance of therapeutic effects.17, 18, 19 Even when warfarin therapy is initiated appropriately, monitoring and dose adjustments are required.20

Many patients do not demonstrate persistence with long-term therapy for chronic conditions,21 which may put them at risk for adverse consequences of disease. Warfarin discontinuation among real-world NVAF patients is common,22 and, given the narrow therapeutic window of warfarin therapy, benefit diminishes within days among patients who stop therapy. Our objective was to investigate the association between warfarin discontinuation and the risk of hospitalization for stroke among NVAF patients enrolled in managed care. We hypothesized that warfarin discontinuation would increase the risk of stroke among patients in this real-world population.

Section snippets

Study Design and Data Sources

Data for this retrospective, longitudinal cohort study, including deidentified enrollment information and administrative health care claims for commercially insured and Medicare Advantage enrollees, were obtained from the Optum Research Database. Commercial claims data in the database originate primarily from patients enrolled in discounted fee-for-service independent practice association model plans, and membership in the plans is geographically diverse across the United States. Dates of death

Patient Characteristics

A total of 16,253 patients met all eligibility criteria for the study (Figure 1). Characteristics of the study sample are described in Table I. The mean (SD) age of the study sample was 67 (12) years, and 65% of the patients were male. Mean (SD) baseline CHADS2 score was 1.84 (1.30) and mean (SD) HAS-BLED score was 2.00 (1.18). The mean (SD) duration of the follow-up period was 668 (474) days (median, 574 days). Patients who discontinued warfarin at least once were younger, had lower CHADS2 and

Discussion

A large number of patients observed in this study had gaps in warfarin therapy, and the incidence of hospitalization for stroke increased during those gaps. Nonpersistence with therapy was also found to be common in a community-based cohort of NVAF patients studied by Fang et al.22 Approximately one fourth of patients in their study had a prolonged discontinuation (≥180 days) within 1 year of initiating therapy. Although comparable to our study, their study population was older (77% vs 58% were

Conclusions

More than half of patients on anticoagulation therapy had treatment gaps or permanently discontinued therapy in this real-world study. Gaps in warfarin therapy, as well as previous bleeding, were associated with increased stroke risk after adjusting for patient demographics and baseline risk.

Conflicts of Interest

Drs. Jing and Graham are employees of Bristol-Myers Squibb and own stock in the company. Dr. Wiederkehr is an employee of Pfizer and owns stock in the company. Ms. Buysman, Mr. Pinsky, and Mr. Lacey are employees of Optum, which received financial support from Bristol-Myers Squibb and Pfizer to conduct this study and prepare this manuscript. Dr. Deitelzweig is a paid consultant for Optum in connection with conducting this study. This research was supported by Bristol-Myers Squibb and Pfizer.

Acknowledgments

The authors thank Dinara Makenbaeva, MD, MBA, of Bristol-Myers Squibb for thoughtful input on the research design, Ying Fan, MS, Jane Sullivan, MPH, and Felix Cao, PhD, from Optum for programming the dataset, and Elizabeth J. Davis, PhD, from Optum for medical writing support in developing this manuscript. Manuscript preparation was funded by Bristol-Myers Squibb and Pfizer. Ms. Buysman conducted the data interpretation and data analysis of this manuscript. Mr. Pinsky contributed to the data

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