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Multiplehttp://msj.sagepub.com/ Sclerosis Journal Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence G Giovannoni, E Southam and E Waubant Mult Scler 2012 18: 932 originally published online 16 January 2012 DOI: 10.1177/1352458511433302 The online version of this article can be found at: http://msj.sagepub.com/content/18/7/932 Published by: http://www.sagepublications.com Additional services and information for Multiple Sclerosis Journal can be found at: Email Alerts: http://msj.sagepub.com/cgi/alerts Subscriptions: http://msj.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav >> Version of Record - Jun 27, 2012 OnlineFirst Version of Record - Jan 16, 2012 What is This? Downloaded from msj.sagepub.com by guest on December 6, 2012 33302 MSJ18710.1177/1352458511433302Giovannoni et al.Multiple Sclerosis Journal MULTIPLE SCLEROSIS MSJ JOURNAL Review Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence Multiple Sclerosis Journal 18(7) 932–946 © The Author(s) 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458511433302 msj.sagepub.com G Giovannoni1, E Southam2 and E Waubant3 Abstract Reviews of therapeutic drugs usually focus on the highly selected and closely monitored patient populations from randomized controlled trials. The objective of this study was to review systematically the tolerability and adherence of multiple sclerosis disease-modifying therapies, using data from both randomized controlled trials and observational settings. Relevant literature was identified using predefined search terms, and adverse event and study discontinuation data were extracted and categorized according to study type (randomized controlled trial or observational) and study duration. A total of 151 papers were selected for analysis; 33% were classified as randomized controlled trials and 62% as observational studies. Most of the papers concerned interferon preparations and glatiramer acetate; the limited available information on mitoxantrone and natalizumab precluded extensive examination of these. The most common adverse events were flu-like symptoms (interferon therapies only) and injection-site reactions. Mean discontinuation rates ranged from 16% to 27%. There were no marked differences in tolerability or adherence data from randomized controlled trials and observational studies, but the incidence of adverse events remained high in lengthy studies and discontinuations accumulated with time. The present systematic review of randomized clinical trial and observational data highlights the tolerability and adherence issues associated with commonly used first-line multiple sclerosis treatments. Keywords adherence, glatiramer acetate, interferon, multiple sclerosis, review, tolerability Date received: 30th March 2011; revised: 5th November 2011; accepted: 7th November 2011 Introduction Subcutaneous interferon β-1b (IFNβ-1b SC; Betaferon®), the first approved disease-modifying therapy (DMT) for multiple sclerosis (MS), was launched in 1993. Since then, other IFNβ formulations for intramuscular (IFNβ-1a IM, Avonex®) or subcutaneous (IFNβ-1a SC, Rebif®) administration, together with DMTs with different mechanisms of action, including glatiramer acetate (GA SC, Copaxone®), natalizumab (Tysabri®) and mitoxantrone (Novantrone®), have been licensed for use in relapsing–remitting MS (RRMS). Previous reviews of primary clinical data suggest that the clinical impact of IFNβ therapy is modest and that the benefits of long-term treatment are unclear.1–3 Comparisons of GA SC and IFNβ-1a SC suggest similar levels of efficacy.4–6 Comparisons of natalizumab and mitoxantrone with interferon and GA therapies are limited.7–9 All current first-line DMTs require regular, long-term, parenteral administration. As with other chronic conditions, long-term adherence to treatment regimens involving self-injection may affect adherence and hence reduce the likelihood of achieving maximum treatment efficacy. Systematic reviews tend to have narrow inclusion criteria and focus on placebo-controlled, randomized clinical trials (RCTs) because these studies are considered to produce the highest quality of evidence supporting treatment 1Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 2Oxford PharmaGenesis Ltd TM, Oxford, UK. 3University of California San Francisco, Regional Pediatric Multiple Sclerosis Center, 350 Parnassus Ave, Ste 908, San Francisco, CA, USA. Corresponding author: Gavin Giovannoni, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Email: [email protected] Downloaded from msj.sagepub.com by guest on December 6, 2012 933 Giovannoni et al. benefits.1,2 However, such studies usually include highly selected, closely monitored patient populations; in clinical practice, patient populations receiving DMTs will be more heterogeneous and may lack regular contact with healthcare professionals. Although RCTs are necessary to gain regulatory approval and can inform clinical practice, realworld observations may reflect the experience of the majority of patients more accurately. In other therapeutic areas, such as heart failure and digestive surgery,10,11 reviews of observational studies have provided additional information from clinical practice that complements information from RCTs. This systematic review of the literature was intended to be comprehensive, and therefore includes RCTs and observational studies of patients receiving current MS DMTs: IFNβ-1a IM, IFNβ-1a SC, IFNβ-1b SC, GA SC, natalizumab and mitoxantrone. The report examines DMTs from the perspective of the patient and focuses on measures of tolerability and adherence. Methods Literature search criteria Literature to evaluate clinical impact and tolerability of licensed DMTs for MS was identified by searching PubMed using the following string: (multiple AND sclerosis) AND (interferon OR Betaferon OR Avonex OR Rebif) OR (Tysabri OR Antegren OR natalizumab) OR (glatiramer acetate OR Copaxone OR copolymer 1) OR (mitoxantrone OR Novantrone). The search was limited to: English language, clinical trials (to avoid inclusion of reviews), humans, adults and papers published from January 1993 to October 2008. The results were refined by manually examining the titles of all of the papers identified in the search and discarding any that did not obviously fit the criteria. Literature to evaluate the impact of therapies on adherence to treatment was identified by searching PubMed using the following strings: (multiple AND sclerosis) AND (interferon OR Betaferon OR Avonex OR Rebif OR glatiramer acetate OR Copaxone OR Tysabri OR Antegren OR natalizumab OR mitoxantrone OR Novantrone) AND (adherence OR compliance OR concordance OR withdrawal OR dropout OR satisfaction); (multiple AND sclerosis) AND (disease AND modifying AND therapy) AND (adherence OR compliance OR concordance OR withdrawal OR dropout OR satisfaction). The quality of life and adherence searches were limited by the following criteria: publication from January 1993 to October 2008, English language and human studies in adults. Because information on quality of life, adherence and patient satisfaction was limited, these searches were not restricted to clinical studies, ensuring that potentially relevant papers were not missed. The titles of the references identified were examined manually to exclude those that were clearly irrelevant to the review. Identifying papers for inclusion The results from the searches were combined, duplicate citations were removed, and the abstracts examined to exclude those papers that were clearly irrelevant to the review. Papers with no abstract were rejected. Studies involving 40 or more patients with RRMS given active treatment with IFNβ, GA, natalizumab or mitoxantrone were retained if the abstract reported either clinical outcomes (relapse rates, disability) and/or safety outcomes. Owing to the limited available information, no patientnumber restrictions were applied if adherence or patient satisfaction were reported, providing patients with RRMS treated with a DMT were included. Papers with abstracts reporting only MRI outcome measures, small clinical studies (< 40 patients) with abstracts that did not report adherence or quality of life outcomes, or studies that did not include treatment of RRMS with a DMT were rejected. Papers reporting treatment with natural (i.e. non-recombinant) or oral IFNβ, oral GA or studies in forms of MS that did not include RRMS were excluded. The full text of references selected on the basis of their abstracts was examined to ensure that the above criteria were all fulfilled. Papers that reviewed other information without presenting new analyses were excluded. Although adherence outcomes reported from studies involving fewer than 40 patients treated with DMT were included, clinical and tolerability outcomes from these studies were excluded to ensure consistency in approach with the exclusion of small studies (< 40 patients treated with DMT) reporting only clinical and tolerability outcomes. Analysis of the incidence of adverse events and rates of discontinuation A minimum of five or more published studies (each involving > 40 patients) was required for a DMT to be analysed in depth. In considering tolerability issues from the perspective of the patient, this review excluded laboratory outcomes. To keep data to manageable levels, an initial adverse event incidence rate threshold of 10% was set for each individual study for inclusion in ranking adverse events according to their incidence as a proportion of the overall patient population in all studies. Ranking was based on the number of patients reporting particular adverse events across all included studies as a proportion of numbers of participants in the studies. Based on the results of the ranking, further analyses focused on the incidence of flu-like symptoms (FLSs) and injection-site reactions (ISRs). The occurrence of these adverse events was analysed by study type (RCT or observational) and duration based on the incidence rates in all those studies in which the adverse event was reported (including those in which incidence rates of FLSs and ISRs were below 10%). In longitudinal studies, when tolerability Downloaded from msj.sagepub.com by guest on December 6, 2012 934 Multiple Sclerosis Journal 18(7) data from the same patient population were reported more than once, data from each time point were included when analyses fell in different study duration categories. Reasons for discontinuation were characterized as: lack of efficacy (including disease progression, disease activity, signs and symptoms, treatment failure, disability progression, need for > 3 courses of steroids, exacerbation, aggravation of MS, relapse), adverse events, patient decision (including voluntary withdrawal, consent withdrawal, rejected treatment, psychopathological reasons, doctor recommendation, cost, hassle, patient preference), lost to follow-up (including moved away from area, no longer a patient of investigator, patient failed to return), pregnancy (including the desire to become pregnant) and death. Reasons for discontinuation of therapy were presented as the percentage of total discontinuations for each DMT for which reasons were reported. Discontinuation rates were stratified by study duration (≤ 12 months, 13–24 months, or > 24 months). Mean (SD) values were calculated when data from five or more studies were available (IFNβ-1a IM, IFNβ-1a SC, IFNβ-1b SC and GA SC). If the same patient population featured in multiple published papers (e.g. longitudinal studies), only the latest dataset was used for the analysis of overall discontinuation rates. Results Overview of studies included in the review A total of 1152 papers that reported the clinical impact and tolerability of current DMTs for MS were identified. Searches for literature on adherence in MS identified 70 references. Combining the searches, removing duplicate references and checking the titles and abstracts resulted in 183 papers of potential interest. After checking the full papers, 151 references fulfilled the criteria for inclusion in the review. The number of relevant publications increased with each 5-year period (1993–1997: 10 papers; 1998–2002: 45 papers; 2003–2007: 84 papers; see the Online Supplementary Appendix, Supplementary Figure 1). Table 1 shows the numbers of papers included in the review according to treatment and study type. A third of papers (33%; 50/151) were classified as RCTs. The majority of papers in the review (62%; 93/151) reported openlabel treatment (including open-label follow-up to RCTs) and were classified as observational studies. The remaining papers, including those reporting results of surveys, models or studies using historical comparator groups were classified as ‘other studies’. A total of 91 papers (60% of those included in the review) reported studies involving a single DMT. Almost half of these (43/91, 47%) described RCTs of which 22 (51%) were placebo-controlled, and 8 (19%) investigated the impact of analgesic, cognitive or other interventions on injection tolerability. Papers reporting studies with licensed IFNβ preparations made up 70% of the papers describing Figure 1. Incidence of flu-like symptoms by (A) study type and (B) duration of treatment. Data are presented as the proportions of patients with FLSs in each study (horizontal lines represent man values) for the disease-modifying therapies IFNβ-1a 30 µg IM q.w.; IFNβ-1a 44 µg SC t.i.w.; IFNβ-1b 250 µg SC e.o.d. Where publications reported different aspects of FLSs, the most frequently reported symptom is presented; likewise. e.o.d., every other day; FLSs, flu-like symptoms; IFN, interferon; IM, intramuscular; q.w., once per week; SC subcutaneous; t.i.w., three times per week. Sources of data panel A: IFNβ-1a IM q.w.;12,14,15,19–30 IFNβ-1a SC t.i.w.;13,25,26,29,31–34 IFNβ-1b SC e.o.d.14,21,28,29,34–44 Sources of data panel B: IFNβ-1a 30 µg IM q.w.;12,14,15,19,20,22–30,45,46 IFNβ-1a 44 µg SC t.i.w.;13,16,25–27,29,31–34,47–49 IFNβ-1b 250 µg SC e.o.d.14,28,29,34,35,37–43,50 RCTs of a single DMT, with studies on GA contributing a further 14% to the total. Details of the papers included in the review that describe studies of MS DMTs are summarized in the Online Supplementary Appendix (Supplementary Tables 1–5). A total of 60 papers (40% of included papers) were identified that reported studies of more than one DMT. Observational studies comprise the majority of these papers (48, 80%), with seven RCTs and five other studies (predominantly surveys) also included (Online Supplementary Appendix, Supplementary Table 6). Studies involving various IFNβ preparations are reported by 60% of the papers on multiple DMTs, with publications of IFNβ/GA studies Downloaded from msj.sagepub.com by guest on December 6, 2012 935 Giovannoni et al. Table 1. Numbers of papers (patient numbers) analysed in the review by therapy and study type. DMT RCT Observational Other Total One DMT only IFNβ-1a IM IFNβ-1a SC IFNβ-1b SC GA Natalizumab Mitoxantrone Multiple DMTs IFNβ-1a IM/IFNβ-1a SC IFNβ-1a IM/IFNβ-1b SC IFNβ-1a SC/IFNβ-1b SC Any/all/unspecified IFNβ IFNβ/GA Other combinations Total 43 (8261) 12 (2222) 9 (3566) 9 (1374) 6 (770) 5 (233) 2 (96) 7 (7739) 3 (4173) 1 (188) 0 (0) 1 (94) 0 (0) 2 (3284) 50 (16,000) 45 (9937) 13 (1630) 5 (2841) 12 (2360) 12 (2818) 0 (0) 3 (288) 48 (23,044) 2 (231) 5 (776) 4 (1010) 20 (16,185) 11 (4074) 6 (768) 93 (32981) 3 (133) 0 (0) 1 (1) 2 (132) 0 (0) 0 (0) 0 (0) 5 (3080) 0 (0) 0 (0) 0 (0) 0 (0) 2 (770) 3 (2310) 8 (3213) 91 (18,331) 25 (3852) 15 (6408) 23 (3866) 18 (3588) 5 (233) 5 (384) 60 (33,863) 5 (4404) 6 (964) 4 (1010) 21 (16,279) 13 (4844) 11 (6362) 151 (52,194) DMT, disease-modifying therapy; GA, glatiramer acetate; IFN, interferon; IM, intramuscular; RCT, randomized controlled trial; SC, subcutaneous. comprising a further 22% of these papers. Several studies reported switching between different DMTs (Online Supplementary Appendix, Supplementary Table 7). Tolerability of treatments All eligible papers were examined for information on tolerability. The incidence of all adverse events that occurred in > 10% of patients in each individual study was extracted from each paper and the overall incidence of adverse events in the combined patient populations for IFNβ and GA treatments are ranked according to their designation in the source papers in Table 2. Excluding laboratory outcomes, the most commonly reported adverse events in patients receiving IFNβ-1a IM, IFNβ-1a SC, IFNβ-1b SC and GA SC were FLSs (interferon treatments only) and ISRs. The occurrence of these adverse events is examined in more detail below. The small number of studies did not permit an extensive analysis of the tolerability profiles of mitoxantrone and natalizumab in RCTs and observational studies. Table 3 reports the results of the analysis of all reports of FLSs and ISRs (including incidence rates of < 10%). FLSs were reported in all interferon treatment groups with an incidence of 57% of 3861 patients receiving IFNβ-1a IM, 40% of 1833 patients receiving IFNβ-1a SC and 32% of 3811 patients receiving IFNβ-1b SC. The proportion of patients receiving interferon treatments reporting FLSs by study type is summarized in Figure 1A.12–16,19–50 With the caveat that inter-study variability in the reporting of FLSs was high, there was no clear evidence of a consistent difference in incidence rates of FLSs between the two study types for all three interferon treatments. In RCT and observational studies, respectively, the mean ± SD incidences of FLSs in patients receiving interferon treatments were: IFNβ-1a IM, 57 ± 23% versus 57 ± 26%; IFNβ-1a SC, 52 ± 17% versus 25 ± 27; IFNβ-1b SC, 44 ± 29% versus 34 ± 23%. The proportion of patients reporting FLSs over different durations of interferon treatment is shown in Figure 1B. Although the number of studies in each study duration category is too small to permit firm conclusions, there appears to be no evidence of the incidence of FLSs changing as a result of the extended administration of IFNβ. In studies exceeding 24 months duration, the mean incidence of FLSs ranged from 22% (IFNβ-1a SC, 3 studies) to 55% (IFNβ-1a IM, 4 studies). ISRs were more commonly reported in patients receiving IFNβ-1a SC (65% of 2676 patients) and GA SC (61% of 1997 patients) than in patients receiving IFNβ-1b SC (33% of 3466 patients) or IFNβ-1a IM (22% of 2885 patients). A breakdown of patients who experienced ISRs by study type is summarized in Figure 2A.14–22,24–27,29,31–42, 47–49,51–61 Again, with the caveat that inter-study variability in the reporting of ISRs was high, there was no consistent difference in the reporting rates of ISRs between the two study types for all of the MS DMTs. In RCT and observational studies, respectively, the mean ± SD incidences of ISRs in patients receiving interferon treatments were: IFNβ-1a IM, 21 ± 12% versus 20 ± 11%; IFNβ-1a SC, 70 ± 8% versus 41 ± 30%; IFNβ-1b SC, 56 ± 31% versus 37 ± 21%; GA SC, 78 ± 12% versus 56 ± 29%. Figure 2B presents the occurrence of ISRs according to study duration. Although the numbers of studies in each study duration category is too small to permit firm conclusions, there appears to be no amelioration of the incidence of ISRs as a result of the extended administration of these parenteral DMTs. In studies exceeding 24 months duration, the mean incidence of ISRs ranged from 22% (IFNβ-1a IM, 2 studies) to 60% (IFNβ-1b SC, 2 studies). Downloaded from msj.sagepub.com by guest on December 6, 2012 Downloaded from msj.sagepub.com by guest on December 6, 2012 55.3 24.4 14.4 14.3 11.8 10.9 7.3 6.9 5.4 5.4 5.1 5.1 4.9 4.8 3.6 3.4 3.3 3.1 3.1 2.9 2.7 2.6 2.2 2.2 2.1 2.0 1.9 1.8 Flu-like symptoms Headache Myalgia/muscle ache Depression Injection-site reactions Fatigue Accidental injury Fever Nausea Insomnia Nasopharyngitis Cold symptoms Asthenia Ill/distressed after injection Chills Sinusitis Diarrhoea Pain (unspecified) Limb pain Arthralgia Injection-site pain Paraesthesia Loss of strength Hypesthesia/numbness Muscle weakness Dizziness Indigestion and dyspepsia Loss of control of limbs/ hypertonia injection-site redness Malaise Pharyngitis Injection-site ecchymosis Back pain Injection-site reactions Flu-like symptoms Injection-site inflammation Headache Fatigue Rhinitis Myalgia/muscle ache Injection-site pain Fever Depression Other injection-site reactions Rigors Hepatic disorders Injection-site erythema Arthralgia Menstrual disorders Nasopharyngitis IFNβ-1a SC (n = 2682) 56.4 27.6 19.2 18.2 10.6 8.7 7.0 5.7 5.3 4.8 4.4 2.0 1.3 0.7 0.6 0.4 0.4 % Flu-like symptoms Injection-site reactions Cutaneous lesions Systemic symptoms Fever Arthralgia Asthenia Fatigue Injection-site inflammation Depression Headache Myalgia/muscle ache Feels ill/distressed Injection-site erythema Paraesthesia Weakness Rhinitis Unspecified pain Lymphadenopathy IFNβ-1b SC (n = 3960) 30.0 18.3 14.3 7.6 5.7 4.4 3.6 2.3 2.3 1.9 1.7 1.7 1.1 1.0 1.0 0.9 0.6 0.4 0.2 % Injection-site reactions Systemic injection reaction Immediate injection-site reaction Local symptoms Injection-site pain Injection-site erythema Injection-site pruritus Injection-site mass Chest tightening Injection-site inflammation Depression Injection-site ecchymosis Injection-site induration Flushing Injection-site burning Paraesthesia Muscle spasm GA SC (n = 1997) 54.6 9.2 7.8 6.6 4.5 3.6 2.4 2.1 1.8 1.7 1.6 1.4 1.2 0.5 0.3 0.3 0.1 % Adverse events were ranked in order of their incidence in the overall patient population. An adverse event incidence rate threshold of 10% was set for each individual study for inclusion in this analysis. Laboratory outcomes were not included in this analysis. GA, glatiramer acetate; IFN, interferon; IM, intramuscular; SC, subcutaneous. 1.3 0.8 0.8 0.5 0.5 % IFNβ-1a IM (n = 3921) Table 2. Incidence (%) of reported adverse events in overall patient populations ranked in decreasing order. 936 Multiple Sclerosis Journal 18(7) 937 Giovannoni et al. Table 3. Incidence of flu-like symptoms and injection-site reactions associated with MS disease-modifying therapies. FLSs IFNβ-1a 30 µg IM q.w. IFNβ-1a 44 µg SC t.i.w. IFNβ-1b 250 µg SC e.o.d. ISRs IFNβ-1a 30 µg IM q.w. IFNβ-1a 44 µg SC t.i.w. IFNβ-1b 250 µg SC e.o.d. GA 20 mg SC o.d. Total number of patients Number (%) reported FLSs or ISRs Maximum incidence in single dataset Mean (SD) incidence across all datasets 3861 1833 3811 2198 (57%) 741 (40%) 1222 (32%) 92% [12] 71%[13] 77%[14] 54 (27) 38 (25) 39 (26) 2855 2676 3466 1997 626 (22%) 1744 (65%) 1153 (33%) 1226 (61%) 39%[15] 85%[16] 98%[17] 90%[18] 20 (11) 54 (26) 46 (27) 64 (26) When individual publications report different flu-like or injection-related adverse events, the highest values were analysed. e.o.d., every other day; FLSs, flu-like symptoms; GA, glatiramer acetate; IFN, interferon; IM, intramuscular; ISRs, injection-site reactions; q.w., once weekly; o.d., once daily; SC, subcutaneous; t.i.w., three times per week. Headache, fatigue and muscle aches/myalgia were commonly reported by patients receiving both IM and SC IFNβ-1a preparations. Across the 19 analysed studies on IFNβ-1a IM, the overall incidence of headache was 25% (maximum 67%),19 fatigue was 13% (maximum 64%)15 and myalgia/muscle ache was 14% (maximum 85%).15 Across the 10 analysed studies on IFNβ-1a SC, the overall incidence of headache was 27% (maximum 73%),47 fatigue was 15% (maximum 44%)47 and muscle ache/myalgia was 10% (maximum 30%).47 In contrast, the mean reported incidence of these symptoms was ≤5% in patients receiving IFNβ-1b SC and GA SC although considerably higher rates were reported in individual studies (e.g. headache in 51% of patients receiving IFNβ-1b SC).35 Although possibly confounded by its co-morbidity with MS, depression was experienced by 11% of patients receiving IFNβ-1a IM (maximum 40%)20 and 7% of patients receiving IFNβ-1a SC (maximum 33%),47 but by < 2% of patients receiving IFNβ-1b SC and GA SC. Adverse event data was limited for mitoxantrone and natalizumab, but commonly reported adverse events associated with the former were nausea (reported in ≤ 27% of patients), alopecia/hair loss (≤ 33%) and amenorrhoea (≤ 37%)62–64 and with the latter were headache (≤ 47%) and infections (including nasopharyngitis and urinary tract infections, ≤ 79%).65–67 Adherence to treatments Overall (mean ± SD) discontinuation rates were: IFNβ-1a IM, 20% of 5898 patients (20 ± 14%, 32 studies); IFNβ-1a SC, 17% of 3446 patients (16% ± 11%, 17 studies); IFNβ-1b SC, 23% of 3942 patients (22% ± 15%, 25 studies) and GA SC, 36% of 2855 patients (27% ± 18%, 15 studies). Figure 3A summarizes the discontinuation rates for the IFNβ and GA treatments according to study type (RCT and observational studies). The figure demonstrates that there was considerable variation between the studies in discontinuation rates for each DMT and that there is no clear pattern emerging for data from RCTs compared with that from obser vational studies.13–17,19–25,27–32,34,35,37–40,42,44,45,48,49,54–61,68–94 Figure 3B presents discontinuation rates for the IFNβ therapies and GA according to duration of treatment. Mean ± SD percentage discontinuation rates in long-term studies (> 24 months) were: IFNβ-1a IM, 30 ± 16%; IFNβ-1a SC, 22 ± 10%; IFNβ-1b SC, 34 ± 14%; and GA SC, 43 ± 14%. A total of 12% of 343 patients (4 studies) discontinued mitoxantrone before the end of the planned regimen, and 11% of 755 patients (3 studies) discontinued natalizumab. Owing to the limited data, discontinuation rates for mitoxantrone and natalizumab were not analysed further. The reasons for discontinuation were grouped according to the following categories: lack of efficacy, adverse events, patient decision, change in dose/therapy, lost to follow-up, pregnancy, death and other. Figure 4 presents each of the reported reasons for discontinuation as a proportion of the total reasons for discontinuation for each therapy.13–17,19–25, 27–32,34,35,38–40,42,44,45,47,49,54–56,59–61,68–73,75–85,88–94 The occurrence of adverse events was the most common explanation for the discontinuation of IFNβ-1a SC (64% of 256 reasons for discontinuation of the licensed dose, 14 studies) and IFNβ-1b SC (44% of 730 reasons, 23 studies), and also accounted for 23% (of 851 reasons, 30 studies) and 19% (of 870 reasons, 12 studies) of the discontinuations of IFNβ-1a IM and GA SC treatment, respectively. Perceived lack of efficacy was the most frequently provided explanation for discontinuing IFNβ-1a IM treatment (28%), and accounted for 26% of the reasons provided for ceasing IFNβ-1b SC treatment, but was a minor cause of discontinuing IFNβ-1a SC (11%) and GA SC (6%). Patient decision was recorded as the reason for discontinuing treatment in 11–19% of cases across therapy groups. Over a third (37%) of discontinuations of GA SC therapy were reported as lost to follow-up (compared with < 5% for IFNβ-1a IM, IFNβ-1a SC and IFNβ-1b SC). Downloaded from msj.sagepub.com by guest on December 6, 2012 938 Multiple Sclerosis Journal 18(7) Figure 2. Incidence of injection-site reactions by (A) study type and (B) duration of treatment. Data are presented as the proportions of patients with ISRs in each study (horizontal lines represent mean values) for the disease-modifying therapies IFNβ-1a 30 µg IM q.w.; IFNβ-1a 44 µg SC t.i.w.; IFNβ-1b 250 µg SC e.o.d.; GA 20 mg SC o.d. Where papers reported different aspects of ISRs, the most frequently reported symptom is presented. e.o.d., every other day; GA, glatiramer acetate; IFN, interferon; IM, intramuscular; ISRs, injection-site reactions; o.d., once daily; q.w., once per week; SC subcutaneous; t.i.w., three times per week. Sources of data panel A: IFNβ-1a IM q.w.;14,15,19–22,24–27,29,51 IFNβ-1a SC t.i.w.;13,16,25–27,29,31–34,47–49,52,53 IFNβ-1b SC e.o.d.;14,21,29,34–42,51 GA SC o.d.18,21,54–61 Source of data panel B: IFNβ-1a 30 µg IM q.w.;14,15,19,20,22,24–27,29,51 IFNβ-1a 44 µg SC t.i.w.;13,16,25–27,29,31–34,47–49 IFNβ-1b 250 µg SC e.o.d.;14,17,29,34,35,37–42,51 GA 20 mg SC o.d.18,54–61 Discussion and conclusions The data generated in this review highlight the tolerability and adherence issues associated with current commonly used MS DMTs. The majority of studies included in this analysis concern treatment with IFNβ preparations and GA. The limited number of studies reporting mitoxantrone and natalizumab use precluded a detailed analysis of their tolerability issues. IFNβ therapies were associated with high levels of FLSs and high levels of ISRs were observed in Figure 3. Treatment discontinuation by (A) study type and (B) duration of treatment. Data are presented as the proportions of patients (horizontal lines represent mean values) discontinuing from the the disease-modifying therapies IFNβ-1a 30 µg IM q.w.; IFNβ-1a 44 µg SC t.i.w.; IFNβ-1b 250 µg SC e.o.d.; GA 20 mg SC o.d. e.o.d., every other day; GA, glatiramer acetate; IFN, interferon; IM, intramuscular; o.d., once per day; q.w., once per week; SC subcutaneous; t.i.w., three times per week. Sources of data panel A: IFNβ-1a IM q.w.;14,15,19–25,28,29,45,68–86 IFNβ-1a SC t.i.w.;13,16,25,27,29,31,32,34,48,49,73,81–84,87 IFNβ-1b SC e.o.d.;14,17,21,28,29,34,35,37–40,42,44,73,80–85,88–90 GA SC o.d.18,21,54–58,60,61,85,91–93 Sources of data panel B: IFNβ-1a 30 µg IM q.w.;14,15,19,20,22–25,28–30,45,68–72,74– 85 IFNβ-1a 44 µg SC t.i.w.;13,16,25,27,29,31,32,34,49,81–84,87 IFNβ-1b 250 µg SC e.o.d.;14,17,28,29,34,35,38–40,42,44,80–85,88–90,94 GA 20 mg SC o.d.18,54–57,59–61,85,91–93 patients receiving parenteral DMTs. The incidence of adverse events was highly variable between studies, but there was no consistent evidence of differences between RCTs and observational studies for all DMTs, or of attenuation in longer-term studies. Discontinuation of treatment ranged from 17% (IFNβ-1a SC) to 36% (GA SC) with the most common reasons for discontinuation reported to be the occurrence of adverse events and lack of treatment efficacy. This survey identified FLSs and ISRs as the most common tolerability issues associated with these widely used MS DMTs. FLSs frequently occur in patients treated with Downloaded from msj.sagepub.com by guest on December 6, 2012 939 Giovannoni et al. Figure 4. Reasons for discontinuation of therapy. The proportions of discontinuations in each column include only those discontinuations for which the reasons were reported. Total numbers of reported reasons for discontinuation for each disease-modifying therapies were: IFNβ-1a IM, 831; IFNβ-1a SC, 198; IFNβ-1b SC, 578; GA SC, 870. Lack of efficacy includes: disease progression, disease activity, signs and symptoms, treatment failure, disability progression, need for > 3 courses of steroids, exacerbation, aggravation of MS, relapse. Adverse events include: allergic reaction, needle phobia, polyneuritis, injections, positive needle prick test. Patient decision includes: voluntary withdrawal, consent withdrawal, rejected treatment, psychopathological reasons, doctor recommendations, cost, hassle, patient preference. Lost to follow-up includes: moved away from area, no longer a patient of investigator, patient failed to return. Pregnancy includes the desire to become pregnant. AE, adverse events; e.o.d., every other day; GA, glatiramer acetate; IFN, interferon; IM, intramuscular; o.d., once per day; q.w., once per week; SC subcutaneous; t.i.w., three times per week. Data sources: IFNβ-1a 30 µg IM q.w.;14,15,19–25,28–30,45,68–73,75–85 IFNβ-1a 44 µg SC t.i.w.;13,16,25,27,29,31,32,34,47,49,73,81,83,84 IFNβ-1b 250 µg SC e.o.d.;14,17,21,28,29,34,35,38–40,42,44,73,80–85,88–90,94 GA 20 mg SC o.d.21,54–56,59–61,85,91–93 interferon preparations, although patients receiving IFNβ-1a IM reported more FLSs (over half) than patients receiving IFNβ-1a SC or IFNβ-1b SC. FLSs with interferon preparations were observed despite the inclusion of studies that used symptomatic treatments and dosage regimens aimed at reducing their incidence.12,36,45,46,68 FLSs were not reported in any GA SC or mitoxantrone studies, and were reported only in a single study of natalizumab. The finding of ISRs as a significant tolerability issue for all parenterally administered MS DMTs was anticipated. SC administration was associated with more frequent ISRs than IM administration, with only 22% of surveyed patients receiving IFNβ-1a IM reporting ISRs compared with 65% and 61% of patients, respectively, receiving IFNβ-1a SC and GA SC. This review revealed rates of discontinuation from MS DMTs ranging from 17% (IFNβ-1a SC) to 36% (GA SC). The occurrence of adverse events was the most common reason for the discontinuation of IFNβ-1a SC and IFNβ-1b SC. ISRs lead directly to discontinuation and several studies also reported psychological factors associated with regular injections, including anxiety and injection phobia, that may adversely impact adherence to current MS DMTs.21,45,69,70,95–98 Patients receiving software-facilitated telephone counselling or telephone-administered cognitive behavioural therapy to support IFNβ administration were more likely to adhere to therapy.71,72 The large proportion of patients who discontinued GA SC therapy and were lost to follow-up (37%) may have been influenced by the large number of patients (159 of 247 reasons for discontinuation) who were lost to follow-up in a single study.54 Perceived lack of efficacy was identified as a key factor in poor patient adherence,73 particularly to IFNβ-1a IM and IFNβ-1b SC, although it was only a minor cause of discontinuing GA. Adverse events may reduce patient perceptions of the benefits of treatment, such that some patients may prefer not to be treated.100 Although efficacy outcomes have not been reported here, other reviews indicate that the improvement in relapse rates with commonly used DMTs is modest.1–5,99 It is, therefore, possible that a proportion of the patients whose withdrawal from IFNβ and GA therapies was due to ‘patient decision’ and/or a ‘change in dose/therapy’ was because of unidentified tolerability issues or the desire for more effective treatment. Patients who do not discontinue entirely from a DMT may fail to take the medication according to the indicated dosing schedule. In a study to assess MS DMT adherence, 14% of patients taking IFNβ or GA took fewer than 80% of prescribed doses during the previous month.101 A survey of 681 patients found that 117 (17%) stopped taking their DMT but restarted again within 4 months on at least one occasion.102 Other factors associated with poor adherence to DMTs were investigated in studies included in the review. A study of IFNβ-1a IM found that women were more likely to discontinue than men, but discontinuations were not correlated with walking ability, time on medication or education.71 More years since MS diagnosis and low belief in efficacy of treatment were associated with lower adherence101. In another study of patients prescribed GA, four significant predictors of adherence were identified: high levels of self-efficacy (measured using the MS Self-Efficacy scale), hope (measured using the Herth Hope Index), belief that physicians were supportive, and no previous use of immunomodulators.103 In a prospective study, score on the MS Self-Efficacy scale predicted adherence to GA.91 Study duration was not clearly shown to clearly affect the reporting of tolerability issues, despite examples of the incidence of FLSs declining within a single study.15,22 In studies exceeding 24 months’ duration, the incidences of FLSs and ISRs were not markedly different than with shorter-term therapy. However, there was a trend for each Downloaded from msj.sagepub.com by guest on December 6, 2012 940 Multiple Sclerosis Journal 18(7) of the DMTs for discontinuations to accumulate with time. These data suggest that tolerability issues persist during extended treatment with DMTs. Taken together, the observations on tolerability and adherence suggest that there is patient dissatisfaction with current DMTs. The high level of use of complementary and alternative medicines (by an estimated 57–70% of patients with MS) supports the view that conventional therapies are not adequately meeting patient needs.104,105 There is, therefore, an impetus to enhance adherence to MS DMTs in the future. The occurrence of FLSs is related to the mechanism of action of IFNβ treatments and ISRs are inherent to parenterally administered drugs. Ongoing strategies to improve adherence include amelioration of FLSs and ISRs through dose titration, a reduction in the gauge of syringe needles, cognitive therapy and the prophylactic use of anti-inflammatory drugs, and the development of oral therapies with modes of action that differ from current approved medications.106 Systematic reviews tend to concentrate on RCTs rather than observational studies. This review is unique as it encompasses 151 MS studies including both RCTs and observational clinical surveys. A central objective of these analyses was to investigate how well outcomes from RCTs are reflected in observational studies that are conducted in less rigorously controlled but more realistic clinical settings. Although the extent of inter-study variability may have obscured subtle differences, no consistent differences in the incidence of FLSs and ISRs were detected in RCTs and observational studies of MS DMTs. Similarly, although it has been previously reported that adherence rates of firstline MS DMTs are higher in clinical trials than in clinical practice,107 the present review found no discernable differences between rates of discontinuation of MS DMTs in RCT and observational studies. Based on this survey of first-line MS DMTs therefore, it appears that it is appropriate to include observational studies in a systematic review of MS DMTs, at least with regard to tolerability and adherence data. Moreover, this review indicates that tolerability and adherence issues are associated with the use of firstline DMTs in uncontrolled, real-life environments as well as RCT settings. It is also important to recognize the limitations of the present analyses. The synthesis of outcome measures with different dosage regimens, assessed at a wide range of time points, inevitably led to broad categorization of data (e.g. use of time periods, rather than specific time points) and precludes extensive statistical analysis. Some of the variability apparent in the figures presented here may be due to these methodological considerations. The lack of standardization of adverse events and reasons for discontinuation may have contributed to some of the inter-study variation observed. By setting an initial incidence rate threshold of 10% for each study for adverse event data to be included in the analysis, it is likely that the present review has underestimated the overall incidence of adverse events, particularly those that occur relatively infrequently. Although such methodological considerations may have obscured some subtle effects and resulted in infrequent events being overlooked, the all-encompassing nature of the present analyses suggest that the central conclusions regarding the incidence of adverse events, particularly FLSs and ISRs, and adherence rates are robust. In conclusion, this review of 151 published studies assessed both RCT and observational studies and found that patients treated with commonly used MS DMTs experience high rates of adverse events, particularly FLSs and ISRs. Furthermore, adherence to currents treatments is poor. 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