Ann S. M. Harada, PhD, MPH

 To investigate adherence, persistence, and switching in patients initiating dabigatran.

 Descriptive analysis using pharmacy claims databases.

 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.

 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.

 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.

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.

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.

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.

 Another study demonstrated a correlation between warfarin nonadherence and the risk for ischemic stroke.

 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;

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.

 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.

 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.

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],

 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 

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.

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

 test. All comparisons were 2-sided and performed at a 0.05 level of significance.

There were 7322 patients identified for the warfarin-naïve cohort, and 10,369 patients identified for the warfarin-experienced cohort (

). 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, 

 <.001). Chronic concomitant conditions included hypertension (88.9% and 92.6% of the warfarin-naïve and warfarin-experienced cohorts, respectively,  

 <.001), CHD (69.8% and 71.9% of the warfarin-naïve and warfarin-experienced cohorts, respectively, 

 = .002), and dyslipidemia (58.2% and 63.0% of the warfarin-naïve and warfarin-experienced cohorts, respectively, 

 <.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 (

<.001). The mean Chronic Disease Scores were 4.2 and 6.4 (

 <.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 (

). 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 (

 = .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 (

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 (

= .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 (

). 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 (

 <.001). The Kaplan-Meier curves for the time to discontinuation and time to switch to warfarin are shown in Figures 1 and 2.

Patients with a history of warfarin use prior to initiating dabigatran therapy had a greater burden of comorbidity than those without prior warfarin use, as demonstrated by a greater prevalence of CHF, DM, HTN, CHD, dyslipidemia, a higher CDS score, and a greater total number of medications compared with warfarin-naïve patients. Other statistically significant differences between the cohorts were likely driven by the large size of the study population. Examples of variables with small, but statistically significant, differences include mean age (76.0 years in warfarin-naïve versus 76.7 years in warfarin-experienced patients, P <.001), patients with concomitant diabetes mellitus (21.2% in warfarin-naïve vs 22.5% in warfarin-experienced  patients, P = .03), and the percentage of patients with PDP coverage (77.2% in warfarin-naïve vs 80.6% in warfarin-experienced patients, P <.001). Among patients persistent to dabigatran therapy, both cohorts demonstrated good adherence with mean PDC values of 0.935 (warfarin-naïve) and 0.937 (warfarin-experienced). The suboptimal adherence of the overall cohort (including both patients persistent and nonpersistent to dabigatran therapy) appears to be attributed to nonpersistence. In the overall study cohort, 40% of patients were nonpersistent to dabigatran therapy (ie, discontinued dabigatran therapy). In patients nonpersistent to dabigatran therapy, the mean trial of dabigatran (ie, time to discontinuation) was a length of 60 days.

Among patients who were nonpersistent to dabigatran therapy, approximately 50% of patients discontinued by 30 days and approximately 80% had discontinued by 90 days. The observed decline in persistence at these points likely reflects discontinuation after only the first fill (either a 30- or 90-day supply). Of patients switching to warfarin, the mean time to switch was also approximately 60 days. In patients nonpersistent to dabigatran therapy, the majority did not switch to warfarin in either cohort. This suggests that most patients may discontinue dabigatran without being switched to warfarin, despite the need for patients with atrial fibrillation to be persistent to chronic anticoagulation therapy. It is possible that patients may have discontinued dabigatran therapy at their own discretion without informing their healthcare providers. If this is the case, then patients taking dabigatran still may require closer monitoring, in spite of the lack of need for laboratory monitoring with  dabigatran therapy. It may be necessary for healthcare professionals and managed care organizations to provide additional support and counseling for patients on dabigatran therapy.

The results of this study should be interpreted with caution, as it was not possible to verify reasons for dabigatran  discontinuation. Potential reasons may include adverse event occurrence (eg, a bleeding episode or dyspepsia as was observed in the RE-LY trial

), a switch to aspirin or rivaroxaban, or use of dabigatran for an off-label indication with a shorter duration of treatment. In terms of adverse events, in the RE-LY trial,8 reasons for discontinuation that were reported included gastrointestinal bleeding, gastrointestinal symptoms, a serious adverse event, an outcome event, and patient’s decision. (For reference, in the RE-LY trial,

gastrointestinal bleeding was cited as the reason for discontinuation in 1.3% of patients taking dabigatran 150 mg vs 0.9% of patients who were taking warfarin [P value not reported]. Gastrointestinal side effects led to discontinuation in 2.1% of patients taking 150 mg dabigatran vs 0.6% of patients who were taking warfarin [

value not reported].) Rivaroxaban was initially approved in the United States on July 1, 2011, for the prevention of deep vein thrombosis (DVT) in patients undergoing knee or hip replacement surgery. According to the time frame of this study (with the latest possible day of the post-index period as December 31, 2011), some patients could have switched from dabigatran to rivaroxaban, accounting for some of the nonpersistence. However, this is less likely, as a very low incidence of switching from dabigatran to rivaroxaban was observed in a prescription claims study examining switch rates among oral anticoagulants (warfarin, dabigatran, and rivaroxaban).

The study found that only 0.02% of switchers changed from dabigatran to rivaroxaban, while 87.3% of switchers changed from warfarin to dabigatran. Lastly, it is possible that some discontinuation occurred appropriately and may be accounted for by patients who were treated with dabigatran, off label, for a fi nite duration (eg, DVT prophylaxis in patient undergoing knee or hip replacement surgery). However, it is less  likely that this accounts for the majority of discontinuations observed in this study, for several reasons. First, dabigatran required Prior Authorization (PA) approval for benefit coverage in this population. A review of PA cases among Part D patients during a 4-month period found that less than 1% had off-label indications for finite duration of dabigatran therapy, and the majority of indications were for atrial fi brillation,requiring chronic dabigatran therapy. Secondly, the findings of an observational study reported that during the identification period of our study (October 29, 2010, through June 30, 2011), the majority of patients in the United States were using dabigatran for the atrial fi brillation indication.

 The research utilized the IMS Health National Disease and Therapeutic Index, a nationally representative audit of office-based providers, to quantify patterns of oral anticoagulant use for the prevention of thromboembolism. The authors found that dabigatran has been rapidly adopted into ambulatory practice in the United States, primarily for the treatment of atrial fi brillation, but increasingly is being used for off-label indications. They found that the proportion of US patients who used dabigatran for the indication of atrial fi brillation was 92% in the last quarter of 2010 and 63% in the last quarter of 2011. Thus, we believe that the majority of discontinuations observed in our study are due to true nonpersistence, rather than appropriate discontinuations for off-label indications. A follow-up study, with pharmacy and medical claims, could offer explanations for nonpersistence (eg, capturing a medical claim with the 

diagnosis code for hemorrhage of gastrointestinal tract may indicate that a patient discontinued because of a gastrointestinal bleed).

Limitations of this prescription claims database study include lack of information regarding diagnoses and medical claims. Comorbidities were inferred from pharmacy claims, by assuming that taking certain medications indicates the presence of a particular disease state. (Validation of the proxy measures was done by reviewing published studies and referencing an internal process performing similar identifications of disease states through pharmacy claims.) Secondly, measures of adherence and persistence were based on claims data, which assumes that the patient is taking the medication rather than stockpiling it. It is not possible in a claims analysis to determine whether patients discontinued at their own discretion or upon the direction of their healthcare provider, nor is it possible to determine reasons behind discontinuations of therapy. Having this information could aid in the design of potential specific interventions to increase adherence and persistence to therapy. Lastly, claims data do not capture plan exclusion OTC utilization or other patient out-of-pocket purchases, which could contribute to a more comprehensive understanding of patient practices.

Two in 5 patients discontinued dabigatran therapy within 6 months in this observational, retrospective analysis using administrative pharmacy claims from a large PBM. The majority of patients discontinuing dabigatran therapy were not anticoagulated with warfarin during the post-index period. These findings highlight potential gaps in the care of patients treated with dabigatran therapy in routine practice. Patients should be educated to report intolerance, adverse events, or cost burden to their healthcare provider, instead of discontinuing therapy on their own. Due to the dependence on good adherence and persistence to dabigatran therapy for prevention of stroke and thromboembolic events, there may be a need for healthcare professionals and managed care organizations to provide additional patient support and counseling on this medication. Further research is needed to explain the reasons for nonpersistence to dabigatran therapy.

From OptumRx (KT, SCE, JY, ASMH, BKS, HCL), Irvine, CA.

 The authors (KT, SCE, JY, ASMH, BKS, HCL) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Concept and design (KT, SCE, BKS, HCL); acquisition of data (KT, JY); analysis and interpretation of data (KT, SCE, JY, ASMH, BKS); drafting of the manuscript (KT, SCE, ASMH); critical revision of the manuscript for important intellectual content (KT, SCE, ASMH); statistical analysis (KT, JY); provision of study materials or patients (KT); administrative, technical, or logistic support (ASMH, BKS, HCL); and supervision (SCE, BKS, HCL).

 Kimberly Tsai, PharmD, 2300 Main St, CA 134-0404, Irvine, CA 92614. E-mail: kimberly.tsai@optum.com.

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3. Platt AB, Localio AR, Brensinger CM, et al. Risk factors for nonadherence to warfarin: results from the IN-RANGE study. Pharmacoepidemiol Drug Saf. 2008;17(9):853-860.

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5. Stanek E, Agatep BC, Herrera V, et al. Assessment of initial U.S. dabigatran utilization and short-term persistence [abstract].  Circulation.2011;124:A16675.

6. Michel J, Mundell D, Boga T, Sasse A. Dabigatran for anticoagulation in atrial fibrillation — early clinical experience in a hospital population and comparison to trial data. Heart Lung Circ. 2013;22(1):50-55.

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Articles

We present a descriptive analysis utilizing pharmacy claims from a managed care population to quantify adherence, persistence, and switching patterns for patients initiating dabigatran.

Adherence, Persistence, and Switching Patterns of Dabigatran Etexilate

: To examine the effect of a multiple sclerosis (MS) disease therapy management (DTM) program that incorporates a disease self-management component and a medication therapy management component within a structured 7-month program.

: Pharmacy claims were evaluated over an 8-month follow-up period to calculate injectable MS medication adherence and persistence among 156 continuously eligible patients who completed the DTM program compared with 156 patients in each of 2 propensity score—matched control groups (retail pharmacy patients and specialty pharmacy patients). For 283 patients completing the DTM program, the Short Form 12, Work Productivity Activity Impairment questionnaire, and MS relapses were assessed at month 0 and at month 6.

: Injectable MS medication adherence was significantly higher for DTM patients compared with retail pharmacy patients (0.92 vs 0.86,

 <.001) and was similar for DTM patients and specialty pharmacy patients (0.92 vs 0.90, 

 = .23). The DTM patients demonstrated significantly greater persistence on therapy (220 days) compared with the specialty pharmacy patients (188 days) (

 = .002) and the retail pharmacy patients (177 days) (

 <.01). The Short Form 12 and Work Productivity Activity Impairment results did not significantly change from month 0 to month 6. Multiple sclerosis relapses were reported by 14.0% of patients at month 0 and by 9.3% of patients at month 6 (

 = .03). Ninety-seven percent of patients at month 6 reported that the DTM

program was very helpful or somewhat helpful in enabling them to better manage their health. 

: An MS DTM program incorporating medication management resulted in increased adherence and persistence to injectable MS medications and decreased MS relapses. Quality of life and work productivity were not significantly changed. Patients reported improved ability to manage their health.

This study is the first to date to examine the effect of a multiple sclerosis (MS) disease therapy management (DTM) program that incorporates a disease self-management component and a medication therapy management component.

The MS DTM program increased adherence and persistence to injectable MS medications and decreased MS relapses.

No improvement to health-related quality of life or work productivity was demonstrated by the program.

Patients indicated that the program was helpful in enabling them to better manage their health.

Multiple sclerosis (MS) is a chronic inflammatory neurologic disease requiring lifelong adjustments and coping skills. Because of the chronic, disabling, and potentially progressive nature of MS, programs that promote symptom management, medication adherence, and health-promoting lifestyle are crucial in the management of MS. Self-management programs among patients with MS have been largely directed at improving physical activity, fatigue, or health-related quality of life (HRQOL).

In 2007, a national pharmacy benefit management (PBM) company implemented an MS disease therapy management (DTM) program that combines a disease self-management component and a medication therapy management component. The program is designed to improve patients’ knowledge of MS and treatment options, maximize therapeutic outcomes, promote self-management, and enhance HRQOL.

Eligible patients were identified on a weekly basis and were sent a DTM welcome packet. An outbound call was made to patients who returned a patient availability form indicating their preferred day and time for the telephone consultation. During the initial consultation (month 0), clinicians (registered nurse or pharmacist) used the INTERMED, a validated observer-rated instrument for assessing case complexity and healthcare needs using a biopsychosocial model,

 to stratify patients into the regular-intensity program (score, 0-20) or the high-intensity program (score, ≥21).

The DTM patients received telephone consultations, care plan mailings, and educational material mailings based on the predefined schedule for their level of intensity. For the regular-intensity program, consultations were conducted intermittently at enrollment (month 0), month 1, month 4, and month 6. For the high-intensity program, consultations were conducted monthly throughout the 7-month program. The initial consultation typically lasted 40 to 60 minutes, and follow-up consultations lasted 20 to 30 minutes. During each consultation, the clinician assessed patient knowledge and health concerns and provided education on core topics (

). Each clinician developed a personalized care plan that summarized the telephone consultation and sent it to the patient and to the prescriber of the injectable MS medication. Patients also received monthly educational mailings specific to MS for 6 months.

To evaluate the MS DTM program, data were obtained from the DTM program database and from electronic pharmacy claims for patients participating in Medicare Advantage Prescription Drug Plan, prescription drug plan, or commercial health plans that use the PBM’s specialty pharmacy. Exemption certification was obtained from an external institutional review board. 

There were 2 analysis populations, a claims data population and a  patient-reported population (patients enrolled in the DTM program who completed the month 0 and month 6 consultations). Patients were eligible for the claims data population if they were enrolled in the DTM program and completed the month 0 and month 6 consultations, filled a prescription for an injectable MS medication at the PBM’s specialty pharmacy during the identification period (March through November 2007), and were continuously enrolled in the health plan for 4 months before (preperiod) and 8 months after (postperiod) the identification date.

Two control groups (retail pharmacy patients and specialty pharmacy patients) were compared with the claims data population. Retail pharmacy patients were those who filled a prescription for an injectable MS medication at a retail pharmacy but who did not have any prescriptions for injectable MS medications filled through the PBM’s specialty pharmacy. Specialty pharmacy patients were those who filled a prescription for an injectable MS medication at the PBM’s specialty pharmacy but who did not participate in the DTM program. Patients in both control groups had to be continuously enrolled during the preperiod and the postperiod.

To be included in the control groups, a patient also had to be matched 1:1 with a patient in the DTM group. Matching was performed using the propensity score method.

 Logistic regression analysis was used to calculate a propensity score, which represents each patient’s likelihood of participating in the DTM program. Variables included in the propensity score were age, sex, health plan type, Chronic Disease Score

 during the preperiod, and index injectable MS medication. Variables that were unavailable in claims data such as type or duration of MS and duration of injectable MS medication use (unable to determine history before plan enrollment) were not included in the propensity score model. Patients in the retail pharmacy group were first matched to a patient in the DTM group, and then patients meeting the criteria for the specialty pharmacy group were matched to each patient in this DTM and retail pharmacy—matched population.

The primary outcome was adherence to injectable MS medications for DTM patients versus retail pharmacy patients. Adherence to injectable MS medications was measured using the medication possession ratio (MPR), which was defined as the sum of days’ supply for all fills during the postperiod, divided by the number of days of therapy between the first fill and the last fill during the postperiod plus the days’ supply for the last fill. 

Additional medication utilization outcomes evaluated during the postperiod among the claims data population included the following: duration of therapy (number of days of therapy between the first fill and the last fill plus the days’ supply for the last fill), medication persistence (number of days on therapy until a gap of ≥30 days), medication discontinuation (gap of ≥30 days past the end of supply date for the last filled prescription and the end of the postperiod), medication switching (prescription fill of an injectable MS medication other than the index medication), and pharmacy ingredient costs.

Secondary outcome measures of changes in HRQOL, work productivity, and MS relapse rates from month 0 to month 6 were determined for the patient-reported population. The HRQOL was measured using the Short Form 12 (SF-12) (version 2; Quality Metric, Lincoln, RI), as the performance of this instrument has been previously evaluated in patients with MS.

 Work productivity was measured using the Work Productivity and Activity Impairment (WPAI) questionnaire (general health version 2.0; Reilly Associates, New York, NY).

 Multiple sclerosis relapses were evaluated by asking the patient, “During the last month, have you had exacerbation(s) or relapse(s) of your MS that interfered with your daily life?”

Data extraction and statistical analysis were performed using SAS (version 9.1; SAS Institute, Cary, NC). Comparisons were performed using 

 test for percentages. Multiple sclerosis relapse rates were evaluated using McNemar test (patients who were unsure if they had a relapse were categorized as having had a relapse) and conditional logistic regression analysis (assigning a score of 0, 1, and 2 for no relapse, unsure if had relapse, and had relapse, respectively). All comparisons were 2-sided and were performed at a .05 level of significance.

Baseline characteristics were similar for the DTM, specialty pharmacy, and retail pharmacy groups (n = 156 each) except for the geographic state distribution for the DTM and retail pharmacy groups (

 <.001). These results are summarized in 

During the postperiod, the DTM group had the highest medication adherence (MPR, 0.92), followed by the specialty pharmacy group (MPR, 0.90) and the retail pharmacy group (MPR, 0.86) (

). Adherence to injectable MS medications was statistically significantly better in DTM patients versus retail pharmacy patients (

 <.001). Compared with the specialty pharmacy group or the retail pharmacy group, the DTM group demonstrated a significantly longer duration of therapy, greater medication persistence, and a lower medication discontinuation rate. The improved medication utilization patterns demonstrated by the DTM group resulted in significantly higher pharmacy ingredient costs.

Among the patient-reported population (n = 283), 68.9% of patients reported having the relapsing-remitting form of MS. The mean (SD) duration of MS was 11.7 (8.8) years, and 80.6% patients were not working outside of the home.

At month 0, the mean (SD) SF-12 physical and mental component scores were 37.7 (10.1) and 48.4 (10.4), respectively; at month 6, the scores were 37.9 (10.0) and 49.9 (11.1), respectively, which were not significantly changed. The mean (SD) work productivity loss on the WPAI for patients working outside of the home was 17.3% (26.4%) at month 0 and was similar at 20.4% (25.5%) at month 6. Multiple sclerosis relapses were reported by 14.0% of patients at month 0 and by 9.3% of patients at month 6 (

Ninety-seven percent of patients at month 6 reported that the program was very helpful or somewhat helpful when they were asked, “Overall, how helpful was the program in better managing your health?” The program was rated as very good or excellent by 91.5% of patients.

An MS DTM program focusing on medication management was successful in improving adherence and persistence to injectable MS medications. The percentage of DTM patients reporting an MS relapse decreased by 33.6% from month 0 to month 6. The SF-12 and WPAI results did not change significantly from month 0 to month 6. Most DTM patients indicated that the program was helpful in enabling them to better manage their health.

Previous studies have shown that approximately 80% of patients with MS adhere 80% of the time to injectable MS therapy for 6 months

 and that 60% to 76% of patients with MS adhere to therapy for 2 to 5 years.

 However, 43% of patients initiating therapy become nonpersistent within 14 months.

 Problems with injections, perceived lack of efficacy, and adverse events are considered major barriers to sustained adherence among patients with MS.

 The higher medication adherence and persistence rates observed with our MS DTM program may indicate a positive influence of the program on patients’ behavior.

Considering that previous research evaluating the effect of injectable MS medications on HRQOL has had varying results,

 it is not surprising that patients described herein who participated in the program did not experience improvements on the SF-12. In the present study, patients were not necessarily new to therapy, which may have reduced the ability to demonstrate a change in HRQOL among patients participating in the program. Because of a lack of published information on the WPAI in patients with MS, it is possible that the WPAI is not sensitive enough to detect changes in work productivity that may have occurred as the result of increased adherence to injectable MS medication therapy. Because only 19.4% of study patients worked outside of the home, the WPAI results are further complicated by the small sample size.

With previously published findings indicating that insured patients with MS incur 2 to 3 times more expense than average insured patients,

 managed care organizations may be interested in clinical programs that reduce additional medical expenditures incurred by patients with MS. Based on a 33.6% reduction in patients experiencing an MS relapse, a DTM intervention targeting 283 patients would be estimated to result in 13.3 fewer patients with an MS relapse. Using the mean cost of an MS relapse of $13,026 from a previous study,

the MS DTM intervention can be estimated to avoid $173,246 in relapse costs (about $612 per participating patient).

Although variables available in pharmacy claims were included in the propensity score—matching process to control for potential differences between groups, we were unable to match on additional clinical variables such as type and duration of MS that are unobservable in the pharmacy claims database. The consequence of this potential bias is unknown.

Because the DTM group consisted of patients who participated in and completed the DTM program, there was a potential selection bias favoring the more compliant patients to be included in this group. Because this potential limitation is inherent to all clinical programs that require patient participation, managed care organizations have a role in promoting and encouraging patient participation in their clinical programs by increasing patient understanding of the value that such programs can provide.

Furthermore, because patient-reported data were unavailable for patients in the specialty pharmacy and retail pharmacy groups, patient-reported data for the DTM group had to be evaluated with a preperiod versus postperiod design, which is not ideal in a progressively disabling condition such as MS. In addition, more accurate measures of MS relapse rates and health plan costs would have been yielded if medical claims data had been available.

In conclusion, an MS DTM program focusing on medication management resulted in increased adherence and persistence to injectable MS medications and decreased MS relapses, but there were no significant changes in HRQOL or work productivity. Patients indicated that the program was helpful in enabling them to better manage their health.

We thank Jenni Stroup for managing the program operations and Gary Oakes for building the DTM database.

 From Prescription Solutions (KMS, JSS, SG, ASMH, BKS, HCL), Irvine, CA.

No outside funding was obtained for this study.

 Dr Stockl reports owning stock in United Healthcare, the parent company of Prescription Solutions. The other authors (JSS, SG, ASMH, BKS, HCL) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

This study evaluated the effect of a multiple sclerosis disease therapy management program on medication adherence, therapy persistence, relapses, work productivity, and quality of life.

Ann S. M. Harada, PhD, MPH

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