TY - JOUR
T1 - Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis
T2 - Causal inference to emulate a multiarm randomised trial
AU - Diouf, Ibrahima
AU - Malpas, Charles B.
AU - Sharmin, Sifat
AU - Roos, Izanne
AU - Horakova, Dana
AU - Kubala Havrdova, Eva
AU - Patti, Francesco
AU - Shaygannejad, Vahid
AU - Ozakbas, Serkan
AU - Eichau, Sara
AU - Onofrj, Marco
AU - Lugaresi, Alessandra
AU - Alroughani, Raed
AU - Prat, Alexandre
AU - Duquette, Pierre
AU - Terzi, Murat
AU - Boz, Cavit
AU - Grand'maison, Francois
AU - Sola, Patrizia
AU - Ferraro, Diana
AU - Grammond, Pierre
AU - Yamout, Bassem
AU - Altintas, Ayse
AU - Gerlach, Oliver
AU - Lechner-Scott, Jeannette
AU - Bergamaschi, Roberto
AU - Karabudak, Rana
AU - Iuliano, Gerardo
AU - McGuigan, Christopher
AU - Cartechini, Elisabetta
AU - Hughes, Stella
AU - Sa, Maria Jose
AU - Solaro, Claudio
AU - Kappos, Ludwig
AU - Hodgkinson, Suzanne
AU - Slee, Mark
AU - Granella, Franco
AU - De Gans, Koen
AU - McCombe, Pamela A.
AU - Ampapa, Radek
AU - Van Der Walt, Anneke
AU - Butzkueven, Helmut
AU - Sánchez-Menoyo, José Luis
AU - Vucic, Steve
AU - Laureys, Guy
AU - Sidhom, Youssef
AU - Gouider, Riadh
AU - Castillo-Trivino, Tamara
AU - Gray, Orla
AU - Aguera-Morales, Eduardo
AU - Al-Asmi, Abdullah
AU - Shaw, Cameron
AU - Al-Harbi, Talal M.
AU - Csepany, Tunde
AU - Sempere, Angel P.
AU - Treviño Frenk, Irene
AU - Stuart, Elizabeth A.
AU - Kalincik, Tomas
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Background Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. Methods Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. Results 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. Conclusions The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.
AB - Background Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. Methods Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. Results 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. Conclusions The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.
KW - Multiple Sclerosis
KW - Statistics
UR - http://www.scopus.com/inward/record.url?scp=85177103067&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1129189
UR - http://purl.org/au-research/grants/NHMRC/1140766
UR - http://purl.org/au-research/grants/NHMRC/1080518
U2 - 10.1136/jnnp-2023-331499
DO - 10.1136/jnnp-2023-331499
M3 - Article
C2 - 37414534
AN - SCOPUS:85177103067
SN - 0022-3050
VL - 94
SP - 1004
EP - 1011
JO - Journal of Neurology, Neurosurgery and Psychiatry
JF - Journal of Neurology, Neurosurgery and Psychiatry
IS - 12
ER -