Treatments for relapsing remitting multiple sclerosis: summarising current information by network meta-analysis

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1 DOI /s SHORT COMMUNICATION Treatments for relapsing remitting multiple sclerosis: summarising current information by network meta-analysis Fabiola Del Santo & Dario Maratea & Valeria Fadda & Sabrina Trippoli & Andrea Messori Received: 1 August 2011 / Accepted: 5 October 2011 # Springer-Verlag 2011 Abstract Objectives Oral drugs for relapsing remitting multiple sclerosis (RRMS) have been recently investigated and, one of these, fingolimod, is already available in several countries. In this framework, an analysis of the data in terms of the comparative effectiveness for all treatments thus far approved for RRMS can be useful to reappraise their place in therapy. Methods After a MEDLINE search, we selected all randomised trials studying the effectiveness of drugs for RRMS and included in our analysis those randomised trials in which interferon, glatiramer, natalizumab or fingolimod were studied. The end-point was the relapse-free rate at 12 months, which was compared between the various treatments. Direct comparisons, based on actual randomised trials, were handled by calculating the trial-specific hazard ratio (HR) or the meta-analytic value of HR (when at least 2 trials were available). Indirect comparisons for which data from actual trials were missing were instead managed through a network meta-analysis. Results Ten randomised trials met the criteria set for our analysis. All active treatments were found to be significantly more effective than placebo (direct comparisons) in terms of freedom from relapse at the 12-month follow-up assessments; the values of HR ranged from 1.28 for glatiramer to 1.53 for interferon beta. The comparisons between active agents revealed that fingolimod was superior to interferon (HR=1.18; direct comparison) and F. Del Santo : D. Maratea : V. Fadda : S. Trippoli : A. Messori (*) Laboratorio SIFO di Farmacoeconomia, c/o Area Vasta Centro Toscana, Regional Health System, Via Guimaraes 9-11, Prato, Italy andreamessori@interfree.it glatiramer (HR=1.23; indirect comparison), while the other four head-to-head comparisons of treatments revealed no significant difference. Conclusions On the basis of the effectiveness data presently available, fingolimod seems to offer the advantage of oral administration together with the most favorable profile in terms of relapse-free rate at the 1-year follow-up assessment. Keywords Relapsing remitting multiple sclerosis. Network meta-analysis. Interferon. Glatiramer. Natalizumab. Fingolimod Introduction Interferon beta was the first widely used pharmacological treatment for multiple sclerosis [1]. Following the introduction of this drug in clinical practice around 1993, a great deal of clinical research effort has been made to devise further pharmacological advancements, particularly in terms of developing effective therapeutic treatments for the relapsing remitting form of this disease (RRMS). To date, however only a few agents (namely, glatiramer and natalizumab) have shown positive results in clinical trials and entered into routine clinical use [2]. This scenario is going to change shortly because a new oral drug (fingolimod) has completed all phases of clinical development for use in treating RRMS and has received approval by both the Federal Drug Administration (FDA) and the European Medicines Agency (EMA) [2]. The drug has already been approved in over 50 countries, including the USA and EU member-states. Network meta-analysis [3] is a useful tool for summarising clinical evidence, particularly when three or more different treatments are available for the same clinical

2 condition and need to be compared with one another. In its simplest implementation, network meta-analysis generates a summary graph wherein all binary comparisons are denoted with labels indicating superiority, inferiority or no difference [4 8]. In this report, we applied our simplified implementation of network meta-analysis [4] to carry out an evidence-based comparison of the main treatments currently available for RRMS, including fingolimod. Methods Design The first phase of our study was a literature search aimed at identifying all randomised studies conducted in patients with RRMS to assess the efficacy of each of the following treatments: interferon beta, glatiramer, natalizumab and fingolimod. Thereafter, these studies were examined to determine whether they presented suitable information to extract the crude rates of our pre-specified clinical end-point for each treatment group. Finally, these rates, when available, were converted into values of hazard ratio (HR) by using standard techniques of traditional metaanalysis based on the results of randomised controlled trials (direct comparisons). On the other hand, when data from an actual clinical trial were unavailable, the head-to-head comparisons (in this case, indirect comparisons) were handled through network meta-analysis and consequently assigned a statistical result in terms of superiority/inferiority or no difference along with its level of statistical significance. In line with our study design, all treatments based on interferon beta were pooled together irrespective of whether the preparation was beta-1a or beta-1b and the route of administration was subcutaneous or intramuscular. This methodological choice was based on the aim of our study, which was to produce a synthesised body of evidence rather than analytical evidence. In addition, although three different preparations are available in most countries, neurologists generally handle interferon-based approaches as a single therapeutic modality in which differences in effectiveness tend to be irrelevant, whereas the side-effect profiles guide the selection of a specific preparation in each individual patient. Literature search Our literature search was based exclusively on the PubMed version of MEDLINE. Eligible studies were extracted using the following keywords: multiple sclerosis AND relapsing remitting AND interferon OR glatiramer OR natalizumab OR fingolimod, combined with the limitation: randomised controlled trial. Study selection and data extraction The first step was to select those randomised studies based on a follow-up of at least 12 months and then to identify all trials in which at least one of the treatments under study involved interferon beta-1b (at 250 mcg by subcutaneous route every other day), interferon beta-1a (at least 44 mcg by subcutaneous route 3 times per week or 30 mcg by intramuscular route weekly), glatiramer (20 mg daily by subcutaneous route), natalizumab (300 mg intravenously every 4 weeks) or fingolimod (0.5 mg orally once daily). We extracted from these trials the crude relapse-free rates at 12 months of follow-up for each treatment group. Finally, the trials that met all of these criteria were included in our meta-analytic assessment. Traditional meta-analysis: statistical calculations Binary comparisons were evaluated by determining the risk ratio (or HR) for freedom from relapse at 12 months of follow-up with its 95% confidence interval (CI). The statistical calculations were carried out using the fixedeffect model of the Cochrane software program (REV- MAN Software, Cochrane Collaboration, Copenhagen, Denmark). Heterogeneity was determined according to the I 2 statistics along with the related levels of statistical significance. When a single randomised trial was available for a given binary comparison, the meta-analytic section of the REV- MAN software was not used. and we restricted the use of this software to the trial-specific section (i.e. analysis of a 2 2 contingency table with determination of the trialspecific HR with its 95% CI). Network meta-analysis: statistical calculations and graph generation The HR (with 95% CI) for each indirect comparison was estimated according to the ITC software (Canadian Agency for Drugs and Technologies in Health, Indirect Treatment Comparison software, Ottawa, Ontario, Canada). This approach allows an indirect HR (with 95% CI) to be estimated upon the condition that both treatments included in the indirect comparison have been compared in actual trials against a common comparator. Graphs were plotted (according to our simplified implementation [4]) using GRNETMA.EXE software (Società Italiana di Farmacia Ospedaliera, Milan, Italy). Results The randomised trials that met the criteria for our analysis are described in Table 1. After application of the appropriate meta-analysis technique, the results of our analysis were determined for all direct and indirect comparisons. The overall results (presented in terms of either superiority/ inferiority or no difference) are shown in Fig. 1.

3 Table 1 Characteristics of the ten randomised trials a included in our analyses First author Design b End-point Relapse-free rate Hazard ratio (95% CI) Treatment Control group group [n, (%)] [n, (%)] Data source for the relapse-free rates Jacobs et al. (1996) Interferon β-1a (i.m.) vs. placebo No relapse PRISMS Study Group (1998) Interferon β-1a (s.c.) vs. placebo No relapse The IFNB Multiple Interferon β-1b vs. No relapse Sclerosis Study placebo Group (1993) Bornstein et al. (1987) Glatiramer vs. placebo No relapse Comi et al. (2001) Glatiramer vs. placebo No relapse Cadavid et al. (2009) Interferon β-1b vs. No relapse glatiramer Mikol et al. (2000) Interferon β-1a No relapse (s.c.) vs. glatiramer Polman et al. (2006) Natalizumab vs. No relapse placebo Cohen et al. (2010) Fingolimod vs. No relapse interferon β-1a (i.m.) Kappos et al. (2010) Fingolimod vs. No relapse placebo 70/158 (44%) 51/143 (36%) 1.24 ( ) c These results are reported by Freedman et al. (2008), page 5, Fig. 1, panel b ( see Appendix 1} 83/184 (45%) 41/187 (22%) 2.06 Table 2, page 1501 ( ) c 87/207 (42%) 61/209 (29%) 1.44 Fig. 2, page 658 ( ) c Fig. 5, page 17 Fig. 5, page 17 Table 3, page 1981 Fig. 3, page /25 (72%) 6/23 (26%) 2.76 ( ) d 66/119 (55%) 59/120 (49%) 1.13 ( ) d 26/36 (72%) 28/39 (72%) 1.01 ( ) e 289/386 (75%) 272/378 (72%) 1.04 ( ) e 483/627 (77%) 176/315 (56%) 1.38 Page 903 ( ) 354/429 (82%) 302/431 (70%) 1.18 Table 2, page 408 ( ) 344/425 (81%) 263/418 (63%) 1.29 Fig. 2A, page 396 ( ) s.c., Subcutaneous route; i.m., intramuscular route; CI confidence interval a The complete bibliographic details of the ten studies included in our analysis are presented in Appendix 1 b The effectiveness data refer to the following dosing schemes: interferon beta-1a s.c., 44 μg 3 times per week; interferon beta-1a i.m., 30 μg/weekly; interferon beta-1b s.c., 250 μg every other day; glatiramer, 20 mg/daily s.c; natalizumab, 300 mg every 4 weeks i.v; fingolimod, 0.5 mg/day orally c Meta-analysis of these two studies gave a hazard ration (HR) of1.53 (95% CI ); method = fixed effect model according to the REVMAN software e Meta-analysis of these two studies gave HR=1.04 (95% CI ); method = fixed effect model according to the REVMAN software d Meta-analyses of these two studies gave a HR=1.28 (95% CI ) as reported by La Mantia et al. (2010); see Appendix 1 All active treatments were found to be significantly more effective than placebo in terms of freedom from relapse at 12 months (4 direct comparisons). The values of HR as follows: 1.53 (95% CI ) for interferon, 1.28 (95% CI ) for glatiramer, 1.38 (95%CI ) for natalizumab and 1.29 (95% CI ) for fingolimod. In line with our study design, the three placebo-controlled trials available for the two types of interferon (2 trials for interferon beta-1a, 1 for interferon beta-1b) were pooled into a single therapeutic modality; the indexes of heterogeneity in this meta-analysis were as follows: χ 2 =5.74 (df=2, p=0.06) and I 2 =65%. In terms of indirect comparisons, the HR value for natalizumab versus interferon beta was 0.90 (95% CI ), which was not a statistically significant difference. The HR values for the other indirect comparisons were 0.93 (95% CI ) for fingolimod versus natalizumab, 1.23 (95% CI ) for fingolimod versus glatiramer, and 1.08 (95% CI ) for natalizumab versus glatiramer. No significant difference was found, with the exception of the superiority of fingolimod versus glatiramer. Our study is described in detail in Appendix 1, which contains the bibliographic details of the clinical studies included in our analysis, information on the studies that met some but not all of our inclusion criteria, details on the traditional meta-analysis and information on the sources of the trial-specific raw data on the event rates included in our analysis. Discussion The main advantage of network meta-analysis is that, in the assessment of a given therapeutic problem, an original synthesis is constructed of all information available in terms of comparative effectiveness. According to this analytical approach, our results indicate that the profile of fingolimod is favourable. In fact, regardless of whether the comparisons were direct or

4 Fig. 1 Results of our network meta-analysis. Each direct comparison is represented by a solid line and each indirect comparison by a dotted line. The end-point is the proportion of patients relapse-free. Plus sign (+) indicates which treatment is favoured at levels of statistical significance, minus sign ( ) indicates which treatment is not statistically significant, equal sign (=) denotes comparisons showing no significant difference, and t indicates which treatment is favoured by a trend in cases of no significant difference indirect, this oral agent showed its superiority over the other comparators (with the only exception of no difference between fingolimod and natalizumab). Although the characteristics of the trials that we examined were not perfectly identical and the definition of relapse was not exactly the same across all studies, the overall message conveyed by our analysis is quite clear and supports the view that fingolimod has not only the advantage of the oral route, but it also represents a potential improvement in outcome as measured by the relapse-free rate. On the other hand, one should keep in mind that network meta-analyses are known to be associated with important limitations [3]; therefore, while our results can contribute to the understanding of this therapeutic problem, they are not intended to be conclusive. One potential bias favouring fingolimod in our analysis is related to the inclusion criteria of the randomised trial (TRANFORMS trial) that compared interferon beta and fingolimod: this trial has in fact been criticised because some of the patients randomised to interferon were not treatment naive at the inclusion [9, 10]. As this limitation was inherent to the trial s design, it could not be corrected in our meta-analysis. Our analysis was restricted to the end-point of freedom from relapse at 12 months, although the trials included in our meta-analysis also determined a number of other outcome measures (e.g. proportion of relapsefree patients at 24 months, development of sustained disability at different time points, annualised relative relapse rate, etc). However, as with the vast majority of meta-analyses, our study was only able to examine those outcome measures that were expressed as a dichotomous index and determined in all of the clinical trials evaluating the four agents. This criterion was met by the end-point of freedom of relapse at 12 months; in contrast, freedom from relapse at 24 months was missing in some of the clinical studies and therefore could not be assessed in our analysis. The annualised relapse rate could potentially satisfy the above criteria, but the need to limit our analysis at 12 months prompted us to only present freedom from relapse at 12 months and not the annualised parameter. While extending our meta-analysis

5 to other outcome measures beyond the relapse-free rate at 12 months would have improved the scientific value of our study, the pooled results based only on this end-point at 12 months offer a sufficiently clear picture of the comparative effectiveness of the various treatments. The transferability of the results of clinical trials into the real world is always a matter of uncertainty; therefore, while robust data are available on the outcome of interferon treatment in real practice [11, 12], it should be stressed that this information is not presently available for the new oral agent. Finally, although our choice to pool all data on interferon beta into a single therapeutic strategy is a potential limitation of our study, little or no evidence supports the view that different beta interferons can have different levels of effectiveness [13]. This is in keeping with our finding (data not shown in detail) that the heterogeneity across the different interferon-based treatments was not statistically significant. Appendix 1 This Appendix contains four sections: Section 1, which presents the bibliographic details for the clinical studies included in our analysis; Section 2, which presents details on the studies that met some but not all of our inclusion criteria and were therefore excluded from our analysis; Section 3, which presents details on the traditional metaanalysis carried out in our study as well as those resulting from the analysis of a single trial; Section 4, which presents detailed information on the sources of the trial-specific raw data on event rate. Section 1: Bibliographic details for the studies included in the analysis Bornstein MB, Miller A, Slagle S, Weitzman M, Crystal H, Drexler E et al (1987) A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Eng J Med 317(7): Cadavid D, Wolansky LJ, Skurnick J, Lincoln J, Cheriyan J, Szczepanowski K, Kamin SS, Pachner AR, Halper J, Cook SD (2009) Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology 72 (23): Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L, TRANSFORMS Study Group (2010) Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362(5): Comi G, Filippi M, Wolinsky JS, the European/ Canadian Glatiramer Acetate Study Group (2001) European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of Glatiramer acetate on magnetic resonance imagingmeasured disease activity and burden in patients with relapsing-remitting multiple sclerosis. Ann Neurol 149(3): Filippi M, Rocca MA, Camesasca F, Cook S, O'Connor P, Arnason BG, Kappos L, Goodin D, Jeffery D, Hartung HP, Comi G, Wolinsky JS, Bogumil T, Pohl C, Beckmann K, Sandbrink R, Croze E, Brown C, Desimone TM, Arnold DL, Cutter G, Knappertz V (2011) Interferon β-1b and glatiramer acetate effects on permanent black hole evolution. Neurology 76 (14): Freedman MS, Hughes B, Mikol DD, Bennett R, Cuffel B, Divan V, LaVallee N, Al-Sabbagh A (2008) Efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis: a systematic comparison. Eur Neurol 60(1):1 11 IFNB Multiple Sclerosis Study Group (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43(4): Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Granger CV, Simon JH, Alam JJ, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE 3rd, Priore RL, Pullicino PM, Scherokman BJ, Whitham RH et al (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 39(3): Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P, FREEDOMS Study Group (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362: La Mantia L, Munari LM, Lovati R (2010) Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev May 12;(5):CD Messori A, Trippoli G, Vaiani M, Cattel F (2000) Survival meta-analysis of individual patient data and survival meta-analysis of published (aggregate) data. Clin Drug Invest 20: Mikol DD, Barkhof F, Chang P, Coyle PK, Jeffery DR, Schwid SR, Stubinski B, Uitdehaag BM, REGARD Study Group (2008) Comparison of subcutaneous

6 interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol 7(10): O'Connor P, Filippi M, Arnason B, Comi G, Cook S, Goodin D, Hartung HP, Jeffery D, Kappos L, Boateng F, Filippov V, Groth M, Knappertz V, Kraus C, Sandbrink R, Pohl C, Bogumil T, BEYOND Study Group, O'Connor P, Filippi M, Arnason B, Cook S, Goodin D, Harung HP, Kappos L, Jeffery D, Comi G (2009) 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol 8(10): Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW, AFFIRM Investigators (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354(9): PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group (1998) Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 352 (9139): Section 2: Medline search Using the keywords multiple sclerosis AND relapsing remitting AND interferon OR glatiramer OR natalizumab Fig. 2 Forest plots for the direct comparisons including two or more clinical trials. Three separate traditional meta-analyses were carried out. In each case, the REVMAN software was used to determine the pooled value of the risk ratio (with 95% CI) between the intervention group and the control group; the end-point was freedom from relapse. The three graphs generated by this software are shown along with the study-specific event rates extracted from each trial. Superiority in the intervention arm was found in the first two analyses (interferon vs. placebo and glatiramer vs. placebo, respectively), while the third (interferon vs. glatiramer) showed no significant difference. Depending on the direction of the comparison being considered, the values of risk ratio were incorporated into our network meta-analysis either without any change or after conversion into their reciprocal

7 OR fingolimod combined with the limitation randomised controlled trial, a MEDLINE search was run on 25 July 2011, which retrieved a total of 197 studies. Ten studies met our inclusion criteria (see Table 1). For the comparison between interferon and glatiramer, the BEYOND trial, which has been described in two separate papers (Filippi et al. 2011; O Connor et al see Section 1 of Appendix), could not be included in our analysis for the following reasons: (1) the paper by O Connor et al. (2009) presented the relapse-free rate at 2 years (520/897, i.e. 58% in the interferon group vs. 262/448, i.e. 59% in the glatiramer group), but not, while the paper by Filippi et al. (2011) was based exclusively on the assessment of new lesions evolving into permanent black holes and did not report any information on the relapse-free rates. However, even if the BEYOND trial was excluded from our analysis, the two trials studying interferon versus glatiramer that were included instead (Cadavid et al. 2009; Mikol et al see Section 1 of Appendix) gave nearly identical results to those found in the BEYOND trial. Section 3: Traditional meta-analysis of the direct comparisons based on two or more clinical trials and analysis of data sets based on a single trial Traditional meta-analysis According to our study design, the three placebo-controlled trials available for the two types of interferon were pooled into a single therapeutic modality, and a meta-analysis was carried out accordingly. Other direct comparisons based on two or more trials and requiring a traditional meta-analysis were glatiramer versus placebo and interferon versus glatiramer, respectively. Figure 2 shows the results generated by the REVMAN software (including the information on heterogeneity). Analysis of data sets based on a single-trial There were three such data sets (namely, natalizumab vs, placebo, fingolimod vs. placebo, and fingolimod vs, interferon). Despite the fact that these analyses were not a metaanalysis, the REVMAN software was used to determine the Fig. 3 Event-rate analysis for the direct comparisons based on a single clinical trial. Three separate analyses were carried out. For each of these three direct comparisons, the REVMAN software was used to determine the trial-specific value of the risk ratio (with 95% CI) between the intervention group and the control group. The graphs generated through these analyses are shown below along with the study-specific event rates extracted from each trial. All of these three comparisons showed superiority for the intervention group in comparison with the control group (namely, superiority of natalizumab vs. placebo, of fingolimod vs. placebo, and of fingolimod vs. interferon, respectively). Depending on the direction of the comparison being considered, the values of risk ratio resulting from these analyses were incorporated into our network meta-analysis either without any change or after conversion into their reciprocal

8 trial-specific statistical indexes. Figure 3 shows the results generated by the REVMAN software (including the information on heterogeneity). Section 4: Detailed information on the sources of the trialspecific raw data of event rate a First author (a) Jacobs et al. (1996) PRISMS Study Group (1998) The IFNB Multiple Sclerosis Study Group (1993) Bornstein et al. (1987) Comi et al. (2001) Data source for the relapse-free rates These results are reported by Freedman et al. (2008), page 5, Fig. 1, panel b Table 2, page 1501 Fig. 2, page 658 b Fig. 5, page 17 of the paper by La Mantia et al. (2010) Fig. 5, page 17 of the paper by La Mantia et al. (2010) Cadavid et al. (2009) Table 3, page 1981 Mikol et al. (2000) Fig. 3, page 907 b Polman et al. (2006) Page 903 Cohen et al. (2010) Table 2, page 408 Kappos et al. (2010) Fig. 2A, page 396 b a See Section 1 of the Appendix for a full description of the references b While the relapse-free rates at 2 years were reported by these authors in numerical form, this information was available only in graphical form; the event rate expressed in numerical form was therefore estimated from the Kaplan Meier curve published in the referenced figure according to the procedure described by Messori et al. (2000) References 1. Plosker GL (2011) Interferon-β-1b: a review of its use in multiple sclerosis. CNS Drugs 25(1): Cohen JA (2009) Emerging therapies for relapsing multiple sclerosis. Arch Neurol 66(7): Caldwell DM, Ades AE, Higgins JPT (2005) Simultaneous comparison of multiple treatments: combining direct and indirect evidence. Br Med J 331: Fadda V, Maratea D, Trippoli S, Messori A (2011) Network metaanalysis. Results can be summarised in a simple figure. Br Med J 342:d1555. doi: /bmj.d Messori A, Del Santo F, Maratea D (2011) First-line treatments for hepatitis C. Aliment Pharmacol Ther 33: Fadda V, Maratea D, Trippoli S, Messori A (2011) Treatments for macular degeneration: summarising evidence using network metaanalysis. Br J Ophthalmol. doi: /bjophthalmol Passaro D, Fadda V, Maratea D, Messori A (2011) Anti-platelet treatments in acute coronary syndrome: simplified network metaanalysis. Int J Cardiol 150(3): Maratea D, Fadda V, Trippoli S, Messori A (2011) Prevention of venous thromboembolism after major orthopedic surgery: indirect comparison of three new oral anticoagulants. J Thromb Haemost 9 (9): Cohen D (2011) NICE rules out NHS prescription of fingolimod for multiple sclerosis. Br Med J 343:d NICE. Fingolimod: appraisal consultation evaluation report. Available at: Latest. Accessed 1 Oct Freedman MS (2011) Long-term follow-up of clinical trials of multiple sclerosis therapies. Neurology 76(1 Suppl 1):S26 S Boggild M, Palace J, Barton P, Ben-Shlomo Y, Bregenzer T, Dobson C, Gray R (2009) Multiple sclerosis risk sharing scheme: two year results of clinical cohort study with historical comparator. Br Med J 339:b4677. doi: /bmj.b Guo S, Bozkaya D, Ward A, O'Brien JA, Ishak K, Bennett R, Al- Sabbagh A, Meletiche DM (2009) Treating relapsing multiple sclerosis with subcutaneous versus intramuscular interferon-beta- 1a: modelling the clinical and economic implications. PharmacoEconomics 27(1):39 53

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