Adherence, Persistence, and Switching Patterns of Dabigatran Etexilate | Page 1
Published Online: September 16, 2013
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
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.
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.
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.
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.
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