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Persistence with Dimethyl Fumarate in Relapsing-Remitting Multiple Sclerosis: a Population-Based Cohort Study

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Persistence with Dimethyl Fumarate in Relapsing-Remitting Multiple Sclerosis: a Population-Based Cohort Study Eur J Clin Pharmacol https://doi.org/10.1007/s00228-017-2366-4 PHARMACOEPIDEMIOLOGY AND PRESCRIPTION Persistence with dimethyl fumarate in relapsing-remitting multiple sclerosis: a population-based cohort study Irene Eriksson1,2 & Thomas Cars3 & Fredrik Piehl4 & Rickard E. Malmström1,5 & Björn Wettermark1,2 & Mia von Euler1,5,6 Received: 21 June 2017 /Accepted: 30 October 2017 # The Author(s) 2017. This article is an open access publication Abstract DMF discontinuation (treatment gap ≥ 60 days) or switching Purpose To describe patients initiating dimethyl fumarate to another DMT. (DMF) and measure persistence with DMF, discontinuation, Results The study included 400 patients (median follow- and switching in treatment-naïve DMF patients and patients up = 2.5 years). The majority had previously been treated with switching to DMF from other multiple sclerosis disease- other DMTs (61%). Throughout the follow-up period, 124 modifying treatments (DMTs). patients (31%) discontinued DMF and 114 patients (29%) Methods A population-based cohort study of all Stockholm switched treatment. Overall, 34% of patients initiating DMF County residents initiating DMF from 9 May 2014 until 31 stopped treatment within 1 year and only 43% of patients May 2017. All data were derived from a regional database that remained on DMF at 2 years from treatment initiation. collects individual-level data on healthcare and drug utiliza- Conclusions DMF had a rapid market uptake likely due to tion of all residents. The study outcomes were persistence with high expectations held by both patients and clinicians. DMF and DMF discontinuation and switching to other DMTs. However, persistence with DMF in routine clinical practice Persistence was measured as the number of days until either was found to be low. Keywords Multiple sclerosis, relapsing-remitting . Dimethyl fumarate . Drug utilization . Persistence Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-017-2366-4) contains supplementary material, which is available to authorized users. Introduction * Irene Eriksson [email protected] The introduction of interferon therapy improved the prognosis of relapsing-remitting multiple sclerosis (RRMS) [1]. 1 Department of Medicine Solna, Karolinska Institutet, However, a significant unmet medical need has remained for Stockholm, Sweden patients with treatment intolerance and for those who experi- 2 Department of Healthcare Development, Stockholm County ence disease progression while on therapy. Consequently, an- Council, Stockholm, Sweden ticipation and expectations for the next generation disease- 3 Department of Medical Sciences, Uppsala University, modifying treatments (DMTs), particularly oral formulations, Uppsala, Sweden have been high [2]. The first oral DMT for RRMS patients, 4 Department of Clinical Neuroscience, Karolinska Institutet, fingolimod, was introduced in 2011 in Europe [3]followedby Stockholm, Sweden teriflunomide and dimethyl fumarate (DMF) in 2013 [4, 5]. 5 Clinical Pharmacology, Karolinska University Hospital, There have also been new hospital-administered DMTs devel- Stockholm, Sweden oped, including alemtuzumab and daclizumab [6]. In addition, 6 Department of Clinical Science and Education, Södersjukhuset, in recent years, the B-lymphocyte-depleting drug rituximab Karolinska Institutet, Stockholm, Sweden has increasingly been used off-label for treatment of both Eur J Clin Pharmacol RRMS and, to some extent, progressive MS, especially in Information on patient age, sex as well as migration and Sweden [7, 8]. death records were also obtained from VAL. The rapidly changing MS treatment landscape poses a chal- lenge for clinicians to select the most optimal DMT for their Study population patients. Even though risk-benefit profiles of the new DMTs have been assessed in clinical trials, there are uncertainties We selected all Stockholm County residents initiating DMF about their effectiveness and safety as well as long-term out- from 9 May 2014 until 31 May 2017. The index date was comes when used in routine clinical practice [9, 10]. defined as the date of the first DMF dispensation. In this pop- When DMF was introduced, the expectations were high ulation, we then identified MS treatment-naïve DMF patients both from patients and clinicians [2]. On the other hand, there and patients switching to DMF from other DMTs. Treatment- were concerns about increasing costs as DMF is more expen- naïve DMF patients were defined as patients who had no sive than existing injectable DMTs [11, 12] and about dropout history of dispensation or inpatient administration of DMTs rates that were relatively high in the pivotal DMF trials [13, for at least 1 year prior to the index date. To allow for assess- 14]. However, so far, real-world data on DMF are scarce. In ment of baseline characteristics and prior DMT use, patients this study, we analyzed DMF utilization patterns in routine with less than 1 year of continuous residence in the Stockholm clinical practice using a database that contains individual- County prior to the index date were excluded. level data on healthcare and drug utilization of all residents Patients were followed from the index date until the earliest of the largest administrative region in Sweden. of the following: the end of continuous residence in the Stockholm County or the end of study period (31 May 2017). Furthermore, because women are advised to dis- continue DMTs during pregnancy, women with a delivery Methods diagnosis code (ICD-10 codes: O80-O84) were censored 280 days prior to the delivery date. Study design Study variables This is a population-based cohort study of all Stockholm County residents initiating DMF (Tecfidera) from 9 Exposure May 2014 (the date when reimbursement of DMF was ap- proved in Sweden) until 31 May 2017. The study was ap- The following DMTs were available in the Stockholm County proved by the regional ethics committee in Stockholm, during the study period: interferon-beta-1a, peginterferon-be- Sweden (Ref. no. 2015-2329-31-4). ta-1a, interferon-beta-1b, glatiramer acetate, fingolimod, di- methyl fumarate, teriflunomide, natalizumab, alemtuzumab, Data sources daclizumab, and rituximab though not formally approved as an MS DMT. ATC codes were used to identify the study drugs All data used in our analyses were derived from VAL, an in- in the database (see Online Resource 1). house regional repository that collects reimbursement claims and other health-related data of all Stockholm County resi- Outcomes dents (2.3 million; approximately 23% of the population of Sweden) [15–17]. The primary study outcome was persistence with DMF. We We used hospital discharge (inpatient) data and data on also assessed DMF discontinuation and switching to other outpatient specialist and primary care visits to obtain informa- DMTs. To operationalize the outcome definitions, we first tion on diagnoses [International Classification of Diseases identified treatment gaps. Treatment gap was measured as (ICD)-10], procedures [Swedish Classification of Health time between the end of DMF supply dispensed (dispensation Interventions and the Nordic Medico-Statistical Committee date plus days of supply) until the date of the next dispensa- (NOMESCO) codes] [18] as well as overall utilization of tion. Days of DMF supply were estimated using the informa- healthcare services from 1 January 2010 until 31 May 2017. tion on type and number of dispensed packages and typical Information on outpatient drug utilization was derived DMF administration regimen (twice daily). The estimated from outpatient pharmacy dispensation data [19]. DMTs ad- days of supply were then used in the calculation of the vari- ministered in hospitals were identified using procedure codes ables related to treatment gaps. and drug codes [Anatomical Therapeutic Chemical (ATC) We assumed that patient discontinued DMF if they had a classification] recorded in the inpatient and outpatient special- treatment gap of at least 60 days. Time to discontinuation (in ist visit data. Data on drug utilization were derived from 1 days) was measured as time between the index date and the July 2010 until 31 May 2017. end of supply of the DMF prescriptions dispensed. If after this Eur J Clin Pharmacol gap the patient was dispensed DMF, we classified this as a Persistence was plotted using Kaplan-Meier survival restart of DMF treatment. Information on the number of pa- curves. In our sensitivity analyses, we changed the permissible tients restarting DMF was provided for descriptive purposes. treatment gap period to 30 and 180 days. Patients with a dispensation or in-hospital administration of Data management and analyses were conducted using SAS another DMT within the gap period were classified as 9.4 (Cary, NC). switching. Time to switching (in days) was measured as time between the index date and the dispensation or in-hospital administration date of the subsequent DMT. We calculated Results time to switching only for the first switching. In addition, we described which other DMTs DMF patients switched to re- During the study period, 425 patients initiated DMF in the gardless of the length of the gap period. Stockholm County; of these, 400 met our study’s selection Persistence was measured as the number of days from the criteria (see Fig. 1). index date until either discontinuation or switching to another One hundred and fifty-six patients (39%) were treatment- DMT (if switching occurred after the end of DMF supply, we naïve and 244 (61%) were previously treated with other used the number of days from the index date until the end of DMTs. From May to December 2014, 221 patients initiated DMF supply). DMF with the majority (71%) switching to DMF from other We also described prior DMT utilization patterns in pa- DMTs. There were fewer patients starting each subsequent tients switching to DMF from other DMTs (with data avail- year: 112 in 2015 and 47 in 2016. The initiation patterns are able as far back as 1 July 2010). illustrated in Fig. 2 and baseline characteristics of the study patients are presented in Table 1 (for information on comorbidities, comedications, and healthcare resource Covariates utilization see Online Resource 3).
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