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The American Journal of Managed Care September 2013
Referring Patients for Telephone Counseling to Promote Colorectal Cancer Screening
Roger Luckmann, MD, MPH; Mary E. Costanza, MD; Milagros Rosal, PhD; Mary Jo White, MS, MPH; and Caroline Cranos, MPH
Improving BP Control Through Electronic Communications: An Economic Evaluation
Paul A. Fishman, PhD; Andrea J. Cook, PhD; Melissa L. Anderson, MS; James D. Ralston, PhD, MPH; Sheryl L. Catz, PhD; David Carrell, PhD; James Carlson, PharmD; and Beverly B. Green, MD, MPH
Risk-Stratification Methods for Identifying Patients for Care Coordination
Lindsey R. Haas, MPH; Paul Y. Takahashi, MD; Nilay D. Shah, PhD; Robert J. Stroebel, MD; Matthew E. Bernard, MD; Dawn M. Finnie, MPA; and James M. Naessens, ScD
Out-of-Pocket Costs and Prescription Reversals With Oral Linezolid
Margaret K. Pasquale, PhD; Anthony M. Louder, PhD, RPh; Michael C. Deminski, MS, RPh; Richard B. Chambers, MSPH; and Seema Haider, MSc
FDA Warning and Removal of Rosiglitazone From VA National Formulary
Sherrie L. Aspinall, PharmD, MSc; Xinhua Zhao, PhD; Chester B. Good, MD, MPH; Roslyn A. Stone, PhD; Kenneth J. Smith, MD, MS; and Francesca E. Cunningham, PharmD
Emerging and Encouraging Trends in E-Prescribing Adoption Among Providers and Pharmacies
Meghan H. Gabriel, PhD; Michael F. Furukawa, PhD; and Varun Vaidya, PhD
Improving Pneumococcal and Herpes Zoster Vaccination Uptake: Expanding Pharmacist Privileges
Michael S. Taitel, PhD; Leonard E. Fensterheim, MPH; Adam E. Cannon, MPH; and Edward S. Cohen, PharmD
Testimonials Do Not Convert Patients From Brand to Generic Medication
John Beshears, PhD; James J. Choi, PhD; David Laibson, PhD; Brigitte C. Madrian, PhD; and Gwendolyn Reynolds, MTS
Outpatient Parenteral Antimicrobial Therapy at Large Veterans Administration Medical Center
Andrew Lai, MD; Thuong Tran, PharmD; Hien M. Nguyen, MD; Jacob Fleischmann, MD; David O. Beenhouwer, MD; and Christopher J. Graber, MD, MPH
Currently Reading
Adherence, Persistence, and Switching Patterns of Dabigatran Etexilate
Kimberly Tsai, PharmD; Sara C. Erickson, PharmD; Jianing Yang, MS; Ann S. M. Harada, PhD, MPH; Brian K. Solow, MD; and Heidi C. Lew, PharmD

Adherence, Persistence, and Switching Patterns of Dabigatran Etexilate

Kimberly Tsai, PharmD; Sara C. Erickson, PharmD; Jianing Yang, MS; Ann S. M. Harada, PhD, MPH; Brian K. Solow, MD; and Heidi C. Lew, PharmD
We present a descriptive analysis utilizing pharmacy claims from a managed care population to quantify adherence, persistence, and switching patterns for patients initiating dabigatran.
Objective: To investigate adherence, persistence, and switching in patients initiating dabigatran.

Study Design: Descriptive analysis using pharmacy claims databases.

Methods: Patients with a claim for dabigatran and who were continuously enrolled in pharmacy benefits for 180 days prior to and 180 days following the initiation of dabigatran were identified and stratified by whether there was a history of warfarin treatment prior to dabigatran initiation. Medication adherence was calculated as the proportion of days covered (PDC). Persistence to treatment at 180 days was measured. Among patients who discontinued dabigatran, time to initiating warfarin was determined.

Results: In the overall population, 39.9% of 17,691 patients were nonpersistent to dabigatran. The PDC for the warfarin-naïve cohort was 0.674 (standard deviation [SD] 0.364), and 0.712 (SD 0.354) for the warfarin-experienced cohort. For patients persistent to dabigatran, the PDCs for warfarin-naïve and warfarin-experienced cohorts were 0.935 (SD 0.075) and 0.937 (SD 0.074), respectively. In patients discontinuing dabigatran, 16.1% of warfarin-naïve and 41.1% of warfarinexperienced patients initiated warfarin. Among patients discontinuing dabigatran, the mean time to discontinuation in warfarin-naïve and warfarinexperienced cohorts, respectively, was 59.8 (SD 36.2) and 59.6 (SD 36.2) days. The mean time to initiating warfarin in  warfarin-naïve and warfarin experienced cohorts, respectively, was 62.5 (SD 47.2) and 60.5 (SD 43.0) days.

Conclusions: Two in 5 patients discontinued dabigatran therapy within 6 months, and the majority of these patients were not anticoagulated with warfarin upon discontinuation. These findings highlight potential gaps in the care of patients treated with dabigatran in routine practice.

Am J Manag Care. 2013;19(9):e325--e332
Dabigatran has been shown in trials to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. However, patterns of dabigatran use inroutine practice remain unknown. The objective of the study is to investigate adherence, persistence, and switching to warfarin upon dabigatran discontinuation, in patients initiating dabigatran therapy.
  • Findings may highlight gaps in the care of patients treated with dabigatran.

  • Due to the dependence on adherence and persistence to dabigatran for prevention of stroke and thromboembolic events, there may be a need for healthcare professionals to provide additional patient support with this medication.
Dabigatran, an oral direct thrombin inhibitor, was approved by the US Food and Drug Administration (FDA) in October 2010 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. It was the first oral anticoagulant to be introduced in the over 50 years since warfarin was approved. Dabigatran does not share warfarin’s potential limitations of having a variable response, extensive food and drug interactions, lab monitoring requirements, and narrow therapeutic index  concerns. However, dabigatran is dosed twice daily rather than once daily for warfarin, and is likely to have an increased  prescription cost burden to patients and payers.

Adherence is defined as the extent to which a patient follows directions for a prescribed medication, whereas persistence is defined as the act of continuing the treatment for the prescribed duration.1 In the setting of prescription claims analyses, drug adherence and persistence could be markers of drug efficacy and tolerability, and therapy switches may indicate unsatisfactory treatment response and/or unacceptable adverse effects.2 Understanding patient adherence and persistence to anticoagulation therapy in routine practice is important, since nonadherence and nonpersistence to anticoagulation therapy could potentially result in subtherapeutic responses and increased riskof thromboembolic events. Although warfarin has a long  istory as a standard of care in anticoagulation, warfarin nonadherence continues to be a substantial problem that has been linked to risk of ischemic stroke. In a prospective cohort study of adults initiating warfarin in anticoagulation clinics, patients exhibited nonadherence on 21% of the measured patient-days.3 Another study demonstrated a correlation between warfarin nonadherence and the risk for ischemic stroke.4 In a recent retrospective medical claims analysis of 14,149 Medicare patients with a diagnosis of non-valvular atrial fibrillation, adherence to warfarinwas measured using proportion of days covered (PDC).  the risk for ischemic stroke was significantly lower in those with better adherence to warfarin, with a PDC >80%, compared with those with a lower adherence to warfarin, with a PDC <0% (adjusted odds ratio, 0.59; 95% confidence interval, 0.48-0.72; P <.001).

There have been few findings regarding the use of dabigatran outside clinical trials. One study, which used medical and pharmacy claims, assessed demographic and clinical characteristics, prescriber specialty, and persistence to dabigatran therapy over a 4-month period.5 Results showed that 17% of all patients (n = 1143) were nonpersistent over a 4-month follow-up period, and 71% of these patients had a history of warfarin use in the 6 months prior. However, these results may be limited because of the short identification period of 2 months immediately following FDA approval. In a New Zealand study of inpatients starting dabigatran, the authors found that over a follow-up period of 1 to 7 months, 24% of all patients discontinued, with a median treatment duration of 140.5 days.6 Approximately 10% of the overall population discontinued due to the side effects of dabigatran (eg, gastrointestinal side effects, bleeding, major adverse cardiovascular events). An additional 8% of patients stopped dabigatran due to planned discontinuation of therapy after electrical cardioversion, adverse media coverage, or medication adherence issues. Results of this study may be limited by a smaller study size of 70 patients. Therefore, there is a need to study dabigatran in a larger population over a longer time period to further explore the real-world use of dabigatran. The objective of our study is to investigate adherence and persistence to dabigatran therapy, and switching to warfarin upon dabigatran discontinuation, in patients initiating dabigatran therapy.

METHODS

Study Design and Identification Periods


This was a descriptive, retrospective, observational analysis using administrative pharmacy claims from a large pharmacy benefits manager (PBM). The study was conducted using prescription claims from Medicare Part D Prescription Drug Plan (PDP), Medicare Advantage Prescription Drug (MAPD), commercial, and Medicaid plan patients. Patients were identified by a first fill (index fill) of dabigatran during the identification period of October 29, 2010, through June 30, 2011. The pre-index period was defined as 180 days prior to the index date, and the post-index period was defined as 180 days after the index date. The inclusion criteria were that patients had at least 1 fill of dabigatran during the identification period, and that they were continuously eligible for pharmacy benefits during the pre-index and postindex periods.

Study Cohorts

Patients were stratified by presence of a warfarin claim (“warfarin-experienced”) or absence of a warfarin claim (“warfarin-naïve”) in the pre-index period to analyze the cohorts separately. It was hypothesized that there could potentially be differences in behavior between the 2 cohorts, based on previous use of anticoagulants.

Study Measures

The study measures included a description of various demographic characteristics (ie, age, gender, plan type, and geographical region) and clinical characteristics (ie, frequency of chronic heart failure [CHF], diabetes mellitus [DM], hypertension [HTN], coronary heart disease [CHD], and dyslipidemia, Chronic Disease Score [CDS],7 and number of concomitant medications, measured by the number of prescriptions with days supply on the index date). The presence of concomitant diseases was detected by proxy of specific medication classes in the pre-index period (details can be found in the Appendix; www.ajmc.com).

The primary outcomes measures included persistence, as defined by continuous use of dabigatran with no days supply gap of 30 days or more during the post-index period, and adherence, as described by the PDC calculated as the number of calendar days that patients had a supply of dabigatran during the post-index period divided by 180 days. In patients nonpersistent to dabigatran therapy, time to discontinuation (number of days from the index date to the last day of supply prior to a gap in therapy of 30 days or greater), incidence of switching to warfarin (number of patients who had a claim for warfarin in the post-index period), and time to switch to warfarin (number of days from the index date to the first fill of warfarin in the post-index period) were measured.

Statistical Methods

All statistical tests were performed using SAS version 9.2. Means were tested for variance and compared by independent t tests, and proportions were compared using the χ2 test. All comparisons were 2-sided and performed at a 0.05 level of significance.

RESULTS

There were 7322 patients identified for the warfarin-naïve cohort, and 10,369 patients identified for the warfarin-experienced cohort (Table 1). The average age of the study population was 76 years, and the majority of patients were enrolled in a PDP plan (77.2% for the warfarin-naïve cohort and 80.6% for the warfarin-experienced cohort, P <.001). Chronic concomitant conditions included hypertension (88.9% and 92.6% of the warfarin-naïve and warfarin-experienced cohorts, respectively,  P <.001), CHD (69.8% and 71.9% of the warfarin-naïve and warfarin-experienced cohorts, respectively, P = .002), and dyslipidemia (58.2% and 63.0% of the warfarin-naïve and warfarin-experienced cohorts, respectively, P <.001). Warfarin-naïve patients had a mean of 6.4 total prescriptions (including dabigatran), and warfarin-experienced patients had a mean of 7.5 total prescriptions (including dabigatran) with days supply on the index date (P <.001). The mean Chronic Disease Scores were 4.2 and 6.4 (P <.001) for tively. While other statistically significant differences were observed for characteristics between the cohorts, a number of the statistically significant differences may be driven by the large population size and may not be of clinical significance.

The number of patients persistent to dabigatran therapy was 4137 (56.5%) in the warfarin-naïve cohort and 6492 (62.6%) in the warfarin-experienced cohort (P <.001) (Table 2). Of all 17,691 patients, 7062 (39.9%) were nonpersistent to dabigatran therapy over the 6-month period. Adherence was determined using PDC for the overall population and also for patients persistent to dabigatran therapy. The mean PDC for patients persistent to dabigatran therapy was 0.935 (standard deviation [SD] 0.075) for the warfarin-naïve cohort and 0.937 (SD 0.074) for the warfarin-experienced cohort (P = .28). In the overall population, the mean PDC was 0.674 (SD 0.364) for the warfarin-naïve cohort and 0.712 (SD 0.354) for the warfarin-experienced cohort (P <.001).

Among patients discontinuing dabigatran therapy, the mean time to discontinuation in warfarin-naïve and warfarinexperienced cohorts, respectively, was 59.8 (SD 36.2) days the warfarin-naïve and warfarin-experienced cohorts, respectively, was 59.8 (SD 36.2) days and 59.6 (SD 36.2) days (P = .83), with approximately 50% of patients discontinuing after the first 30-day fill of dabigatran. The mean time to initiating warfarin in warfarin-naïve and warfarin-experienced cohorts, respectively, was 62.5 (SD 47.2) and 60.5 (SD 43.0) days (P = .35) (Table 3, Figure 1, Figure 2). The number of patients nonpersistent to dabigatran therapy who switched to warfarin was 513 (16.1%) in the warfarin-naïve cohort and 1595 (41.1%) in the warfarinexperienced cohort (P <.001). The Kaplan-Meier curves for the time to discontinuation and time to switch to warfarin are shown in Figures 1 and 2.

DISCUSSION

 
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