The effectiveness of natalizumab vs fingolimod-A comparison of international registry studies
Johanna B Andersen 1, Sifat Sharmin 2, Mathilde Lefort 3, Nils Koch-Henriksen 4, Finn Sellebjerg 5, Per Soelberg Sørensen 6, Claudia C Hilt Christensen 7, Peter V Rasmussen 8, Michael B Jensen 9, Jette L Frederiksen 10, Stephan Bramow 5, Henrik K Mathiesen 6, Karen I Schreiber 5, Dana Horakova 11, Eva K Havrdova 11, Raed Alroughani 12, Guillermo Izquierdo 13, Sara Eichau 13, Serkan Ozakbas 14, Francesco Patti 15, Marco Onofrj 16, Alessandra Lugaresi 17, Murat Terzi 18, Pierre Grammond 19, Francois Grand Maison 20, Bassem Yamout 21, Alexandre Prat 22, Marc Girard 22, Pierre Duquette 22, Cavit Boz 23, Maria Trojano 24, Pamela McCombe 25, Mark Slee 26, Jeannette Lechner-Scott 27, Recai Turkoglu 28, Patrizia Sola 29, Diana Ferraro 29, Franco Granella 30, Vahid Shaygannejad 31, Julie Prevost 32, Olga Skibina 33, Claudio Solaro 34, Rana Karabudak 35, Bart V Wijmeersch 36, Tunde Csepany 37, Daniele Spitaleri 38, Steve Vucic 39, Romain Casey 40, Marc Debouverie 41, Gilles Edan 42, Jonathan Ciron 43, Aurélie Ruet 44, Jérôme D Sèze 45, Elisabeth Maillart 46, Hélène Zephir 47, Pierre Labauge 48, Gilles Defer 49, Christine Lebrun 50, Thibault Moreau 51, Eric Berger 52, Pierre Clavelou 53, Jean Pelletier 54, Bruno Stankoff 55, Olivier Gout 56, Eric Thouvenot 57, Olivier Heinzlef 58, Abdullatif Al-Khedr 59, Bertrand Bourre 60, Olivier Casez 61, Philippe Cabre 62, Alexis Montcuquet 63, Abir Wahab 64, Jean-Philippe Camdessanché 65, Aude Marousset 66, Ivania Patry 67, Karolina Hankiewicz 68, Corinne Pottier 69, Nicolas Maubeuge 70, Céline Labeyrie 71, Chantal Nifle 72, Emmanuelle Leray 3, David A Laplaud 73, Helmut Butzkueven 74, Tomas Kalincik 75, Sandra Vukusic 76, Melinda Magyari 77
Affiliations
Affiliations
- 1The Danish Multiple Sclerosis Registry, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. Electronic address: johanna.balslev.andersen@regionh.dk.
- 2CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.
- 3Rennes University, EHESP, REPERES - EA 7449, F-35000 Rennes, France; Univ Rennes, CHU Rennes, Inserm, CIC 1414 (Centre d'Investigation Clinique de Rennes), F-35000 Rennes, France.
- 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
- 5The Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet Glostrup, Denmark.
- 6The Danish Multiple Sclerosis Center, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
- 7Department of Neurology Aalborg University Hospital, Multiple Sclerosis Unit.
- 8Aarhus University Hospital, Neurology, PPJ Boulevard, DK-8200 Aarhus N.
- 9Department of Neurology, University Hospital of Northern Sealand.
- 10Danish Multiple Sclerosis Centre, Dept. of Neurology, Copenhagen University Hospital, Rigshospitalet in Glostrup, 2600 Glostrup, Denmark.
- 11Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic.
- 12Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait.
- 13Hospital Universitario Virgen Macarena, Sevilla, Spain.
- 14Dokuz Eylul University, Konak/Izmir, Turkey.
- 15GF Ingrassia Department, University of Catania, Catania, Policlinico G Rodolico, Italy.
- 16Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio, Chieti, Italy.
- 17Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
- 18Medical Faculty, 19 Mayis University, Samsun, Turkey.
- 19CISSS Chaudiere-Appalache, Levis, Canada.
- 20Neuro Rive-Sud, Quebec, Canada.
- 21Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon.
- 22Hopital Notre Dame, Montreal, Canada, CHUM and Universite de Montreal, Montreal, Canada.
- 23KTU Medical Faculty Farabi Hospital, Trabzon, Turkey.
- 24Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy.
- 25University of Queensland, Brisbane, Australia, Royal Brisbane and Women's Hospital.
- 26Flinders University, Adelaide, Australia.
- 27School of Medicine and Public Health, University Newcastle, Newcastle, Australia; Department of Neurology, John Hunter Hospital, Hunter New England Health, Newcastle, Australia.
- 28Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey.
- 29Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy.
- 30Department of Medicine and Surgery, University of Parma, Parma, Italy; Department of Emergency and General Medicine, Parma University Hospital, Parma, Italy.
- 31Isfahan University of Medical Sciences, Isfahan, Iran.
- 32CSSS Saint-Jerome, Saint-Jerome, Canada.
- 33Monash University, Melbourne, Australia.
- 34Department of Neurology, ASL3 Genovese, Genova, Italy; Department of Rehabilitaiton, ML Novarese Hospital Moncrivello.
- 35Hacettepe University, Ankara, Turkey.
- 36Rehabilitation and MS-Centre Overpelt and Hasselt University, Hasselt, Belgium.
- 37Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
- 38Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy.
- 39Westmead Hospital, Sydney, Australia.
- 40Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 69677 Lyon/Bron, France; Centre des Neurosciences de Lyon, Observatoire Français de la Sclérose en Plaques, INSERM 1028 et CNRS UMR5292, 69003 Lyon, France ; Université Claude Bernard Lyon 1, Faculté de médecine Lyon Est, F-69000 Lyon, France, Eugene Devic EDMUS Foundation, 69677 Lyon/Bron, France.
- 41Centre hospitalier régional universitaire de Nancy, Hôpital central, Service de neurologie, Nancy, France.
- 42Centre hospitalier universitaire de Rennes, Hôpital Pontchaillou, Service de neurologie, Rennes, France.
- 43Centre hospitalier universitaire de Toulouse, Hôpital Purpan, Service de neurologie inflammatoire et neuro-oncologie, Toulouse, France.
- 44Centre hospitalier universitaire de Bordeaux, Hôpital Pellegrin, Service de neurologie, Bordeaux, France.
- 45Hôpitaux universitaire de Strasbourg, Hôpital de Hautepierre, Service des maladies inflammatoires du système nerveux - neurologie, Strasbourg, France.
- 46Assistance publique des hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Service de neurologie, Paris, France.
- 47Centre hospitalier universitaire de Lille, Hôpital Salengro, Service de neurologie D, Lille, France.
- 48Centre hospitalier universitaire de Montpellier, Hôpital Gui de Chauliac, Service de neurologie, Montpellier, France.
- 49Centre hospitalier universitaire de Caen Normandie, Service de neurologie, Hôpital Côte de Nacre, Caen, France.
- 50Centre hospitalier universitaire de Nice, Université Nice Côte d'Azur, Hôpital Pasteur, Service de neurologie, Nice, France.
- 51Centre hospitalier universitaire Dijon Bourgogne, Hôpital François Mitterrand, Service de neurologie, maladies inflammatoires du système nerveux et neurologie générale, Dijon, France.
- 52Centre hospitalier régional universitaire de Besançon, Hôpital Jean Minjoz, Service de neurologie, Besançon, France.
- 53Centre hospitalier universitaire de Clermont-Ferrand, Hôpital Gabriel-Montpied, Service de neurologie, Clermont-Ferrand, France.
- 54Assistance publique des hôpitaux de Marseille, Centre hospitalier de la Timone, Service de neurologie et unité neuro-vasculaire, Marseille, France.
- 55Assistance publique des hôpitaux de Paris, Hôpital Saint-Antoine, Service de neurologie, Paris, France.
- 56Fondation Adolphe de Rothschild de l'œil et du cerveau, Service de neurologie, Paris, France.
- 57Centre hospitalier universitaire de Nîmes, Hôpital Carémeau, Service de neurologie, Nîmes, France.
- 58Centre hospitalier intercommunal de Poissy Saint-Germain-en-Laye, Service de neurologie, Poissy, France.
- 59Centre hospitalier universitaire d'Amiens Picardie, Site sud, Service de neurologie, Amiens, France.
- 60Centre hospitalier universitaire Rouen Normandie, Hôpital Charles-Nicolle, Service de neurologie, Rouen, France.
- 61Centre hospitalier universitaire Grenoble-Alpes, Site nord, Service de neurologie, Grenoble/La Tronche, France.
- 62Centre hospitalier universitaire de Martinique, Hôpital Pierre Zobda-Quitman, Service de Neurologie, Fort-de-France, France.
- 63Centre hospitalier universitaire Limoges, Hôpital Dupuytren, Service de neurologie, Limoges, France.
- 64Hôpital Henri Mondor, Department of Neurology, F-94000 Créteil, France.
- 65Centre hospitalier universitaire de Saint-Étienne, Hôpital Nord, Service de neurologie, Saint-Étienne, France.
- 66Centre hospitalier régional universitaire de Tours, Hôpital Bretonneau, Service de neurologie, Tours, France.
- 67Centre hospitalier sud francilien, Service de neurologie, Corbeil-Essonnes, France.
- 68Centre hospitalier de Saint-Denis, Hôpital Casanova, Service de neurologie, Saint-Denis, France.
- 69Centre hospitalier de Pontoise, Service de neurologie, Pontoise, France.
- 70Centre hospitalier universitaire de Poitiers, Site de la Milétrie, Service de neurologie, Poitiers, France.
- 71Assistance publique des hôpitaux de Paris, Hôpital Bicêtre, Service de neurologie, Le Kremlin-Bicêtre, France.
- 72Centre hospitalier de Versailles, Hôpital André-Mignot, Service de neurologie, Le Chesnay, France.
- 73CHU de Nantes, Service de Neurologie & CIC015 INSERM, F-44093 Nantes, France; INSERM CR1064, F-44000 Nantes, France.
- 74Central Clinical School, Monash University, Melbourne, Australia; Department of Neurology, The Alfred Hospital, Melbourne, Australia; Department of Neurology, Box Hill Hospital, Monash University, Melbourne, Australia.
- 75CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.
- 76The Danish Multiple Sclerosis Registry, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark; The Danish Multiple Sclerosis Center, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
- 77The Danish Multiple Sclerosis Registry, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark; The Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet Glostrup, Denmark.
Abstract
Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening.
Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting.
Results: The pooled analyses comprised 968 natalizumab- and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod.
Conclusion: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.
Keywords: Fingolimod; Head-to-head comparison; Multiple sclerosis; Natalizumab; Treatment effectiveness.
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