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Cause of death in MS: long-term follow-up of a randomised cohort, 21 years after the start of the pivotal IFNβ-1b study
  1. Douglas S Goodin1,
  2. George C Ebers2,
  3. Gary Cutter3,
  4. Stuart D Cook4,
  5. Timothy O'Donnell5,
  6. Anthony T Reder6,
  7. Marcelo Kremenchutzky7,
  8. Joel Oger8,
  9. Mark Rametta9,10,11,
  10. Karola Beckmann9,10,11,
  11. Volker Knappertz9,10,11,12
  1. 1Department of Neurology, University of California, San Francisco, California, USA
  2. 2University Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK
  3. 3Department of Biostatistics, UAB School of Public Health, Birmingham, Alabama, USA
  4. 4Department of Neurosciences, UMD New Jersey Medical School, Newark, New Jersey, USA
  5. 5Pompton Lakes Pulmonary P.C., Lincoln Park, New Jersey, USA
  6. 6Department of Neurology, University of Chicago, Chicago, Illinois, USA
  7. 7Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada
  8. 8Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada
  9. 9Bayer HealthCare Pharmaceuticals, Wayne, New Jersey, USA
  10. 10Bayer HealthCare Pharmaceuticals, Berlin, Germany
  11. 11Bayer HealthCare Pharmaceuticals, Montville, New Jersey, USA
  12. 12Heinrich-Heine-Universität, Düsseldorf, Germany
  1. Correspondence to Douglas S Goodin; douglas.goodin{at}ucsf.edu

Abstract

Objectives Compared with controls, multiple sclerosis (MS) patients die, on average, 7–14 years prematurely. Previously, we reported that, 21 years after their participation in the pivotal randomised, controlled trial (RCT) of interferon β-1b, mortality was reduced by 46–47% in the two groups who received active therapy during the RCT. To determine whether the excessive deaths observed in placebo-treated patients was due to MS-related causes, we analysed the causes-of-death (CODs) in these three, randomised, patient cohorts.

Design Long-term follow-up (LTF) of the pivotal RCT of interferon β-1b.

Setting Eleven North American MS-centres participated.

Participants In the original RCT, 372 patients participated, of whom 366 (98.4%) were identified after a median of 21.1 years from RCT enrolment.

Interventions Using multiple information sources, we attempted to establish COD and its relationship to MS in deceased patients.

Primary outcome An independent adjudication committee, masked to treatment assignment and using prespecified criteria, determined the likely CODs and their MS relationships.

Results Among the 366 MS patients included in this LTF study, 81 deaths were recorded. Mean age-at-death was 51.7 (±8.7) years. COD, MS relationship, or both were determined for 88% of deaths (71/81). Patients were assigned to one of nine COD categories: cardiovascular disease/stroke; cancer; pulmonary infections; sepsis; accidents; suicide; death due to MS; other known CODs; and unknown COD. Of the 69 patients for whom information on the relationship of death to MS was available, 78.3% (54/69) were adjudicated to be MS related. Patients randomised to receive placebo during the RCT (compared with patients receiving active treatment) experienced an excessive number of MS-related deaths.

Conclusions In this long-term, randomised, cohort study, MS patients receiving placebo during the RCT experienced greater all-cause mortality compared to those on active treatment. The excessive mortality in the original placebo group was largely from MS-related causes, especially, MS-related pulmonary infections.

  • Epidemiology
  • Health Economics

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