Real-world adherence to, and persistence with, once- and twice-daily oral disease-modifying drugs in patients with multiple sclerosis: a systematic review and meta-analysis

Jacqueline A Nicholas, Natalie C Edwards, Roger A Edwards, Anna Dellarole, Megan Grosso, Amy L Phillips, Jacqueline A Nicholas, Natalie C Edwards, Roger A Edwards, Anna Dellarole, Megan Grosso, Amy L Phillips

Abstract

Background: Nonadherence to disease-modifying drugs (DMDs) for multiple sclerosis (MS) is associated with poorer clinical outcomes, including higher rates of relapse and disease progression, and higher medical resource use. A systematic review and quantification of adherence and persistence with oral DMDs would help clarify the extent of nonadherence and nonpersistence in patients with MS to help prescribers make informed treatment plans and optimize patient care. The objectives were to: 1) conduct a systematic literature review to assess the availability and variability of oral DMD adherence and/or persistence rates across 'real-world' data sources; and 2) conduct meta-analyses of the rates of adherence and persistence for once- and twice-daily oral DMDs in patients with MS using real-world data.

Methods: A systematic review of studies published between January 2010 and April 2018 in the PubMed database was performed. Only studies assessing once- and twice-daily oral DMDs were available for inclusion in the analysis. Study quality was evaluated using a modified version of the Newcastle-Ottawa Scale, a tool for assessing quality of observational studies. The random effects model evaluated pooled summary estimates of nonadherence.

Results: From 510 abstracts, 31 studies comprising 16,398 patients with MS treated with daily oral DMDs were included. Overall 1-year mean medication possession ratio (MPR; n = 4 studies) was 83.3% (95% confidence interval [CI] 74.5-92.1%) and proportion of days covered (PDC; n = 4 studies) was 76.5% (95% CI 72.0-81.1%). Pooled 1-year MPR ≥80% adherence (n = 6) was 78.5% (95% CI 63.5-88.5%) and PDC ≥80% (n = 5 studies) was 71.8% (95% CI 59.1-81.9%). Pooled 1-year discontinuation (n = 20) was 25.4% (95% CI 21.6-29.7%).

Conclusions: Approximately one in five patients with MS do not adhere to, and one in four discontinue, daily oral DMDs before 1 year. Opportunities to improve adherence and ultimately patient outcomes, such as patient education, medication support/reminders, simplified dosing regimens, and reducing administration or monitoring requirements, remain. Implementation of efforts to improve adherence are essential to improving care of patients with MS.

Keywords: Adherence; Dimethyl fumarate; Discontinuation; Fingolimod; Meta-analysis; Persistence; Real-world; Teriflunomide.

Conflict of interest statement

JN has received consulting fees for speaking, advising, and consulting from: Biogen Idec, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, Genzyme, Genentech, MSAA, MS World, and Novartis. She has received research grants from Genzyme, Biogen, and Novartis. NCE and RAE are employees of Health Services Consulting Corporation. AD is an employee of Fair Dynamics Consulting and worked on behalf of Health Services Consulting Corporation. Health Services Consulting Corporation received funding from EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, to run the analysis. MG and ALP are employees of EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany.

Figures

Fig. 1
Fig. 1
Study selection flowchart. Abbreviations:DMD disease-modifying drug
Fig. 2
Fig. 2
Meta-analysis of mean adherence rate as determined by a) MPR or b) PDC. Note: For studies for which results for treatment-naive and treatment-experienced patients were reported separately (combined data were not available), data were combined; for studies reporting data for more than 1 oral DMD (combined data were not reported), data were combined; for studies reporting data for subgroups (combined data were not reported), data were combined. The area of each grey square is proportional to the study’s weight in the meta-analysis. Weight values are rounded. Abbreviations: CI, confidence interval; DMD, disease-modifying drug; MPR, medication possession ratio; MRAW, raw mean; PDC, proportion of days covered
Fig. 3
Fig. 3
Meta-analysis of proportion of patients adherent to a DMD as determined by MPR or PDC. Note: For studies for which results for treatment-naive and treatment-experienced patients were reported separately (combined data were not available), data were combined; for studies reporting data for more than 1 oral DMD (combined data were not reported), data were combined; for studies reporting data for subgroups (combined data were not reported), data were combined. The area of each grey square is proportional to the study’s weight in the meta-analysis. Weight values are rounded. Abbreviations: CI: confidence interval; DMD: disease-modifying drug; MPR: medication possession ratio; PDC: proportion of days covered
Fig. 4
Fig. 4
Meta-analysis of proportion of patients discontinuing a DMD. Note: For studies for which results for treatment-naive and treatment-experienced patients were reported separately (combined data were not available), data were combined; for studies reporting data for more than 1 oral DMD (combined data were not reported), data were combined; for studies reporting data for subgroups (combined data were not reported), data were combined; for Lattanzi et al., number of patients discontinuing at 12 months included patients for whom data were not available at 12 months because they stopped taking medications (n = 34); 34 + 46 = 80 of 307 or 26.05%; for Vollmer et al. and He et al., for which data were reported in Kaplan–Meier curves only, 1-year persistence rates were extracted from the curves using a digitizer (Guyot P et al. 2012); for Zhovtis et al. 2016, number of patients discontinuing at 12 months was derived from the reported 14-month rate (n = 76.4). The area of each grey square is proportional to the study’s weight in the meta-analysis. Weight values are rounded. Abbreviations: CI, confidence interval; DMD, disease-modifying drug
Fig. 5
Fig. 5
Subgroup meta-analyses of proportion of patients discontinuing a DMD. Note: For studies for which results for treatment naive and treatment-experienced patients were reported separately (combined data were not available), data were combined; for studies reporting data for more than 1 oral DMD (combined data were not reported), data were combined; for studies reporting data for subgroups (combined data were not reported), data were combined. The area of each grey square is proportional to the study’s weight in the meta-analysis. Weight values are rounded. Abbreviations: ACD, administrative claims database; CI, confidence interval; MCR, medical chart review; PC, prospective cohort

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