Advertisement

Informing Medication Discontinuation Decisions among Older Adults with Relapsing-Onset Multiple Sclerosis

Abstract

Background

For older adults with relapsing-onset multiple sclerosis (MS), limited information is available to inform if, or when, disease-modifying drugs (DMDs) may be safely discontinued.

Objective

The aim of this study was to project the outcomes of DMD discontinuation among older adults with relapsing-onset MS.

Methods

We projected the 10-year outcomes of discontinuation of a DMD (interferon-β, fingolimod, or natalizumab) among older adults (aged 55 or 70 years) who were relapse-free for 5 or more years and had not reached an Expanded Disability Status Scale (EDSS) score of 6. Outcomes included the percentage of people who had at least one relapse or reached EDSS 6, and quality-adjusted life-years (QALYs), which incorporated both relapses and disability. We used a simulation modeling approach. With increased age, relapses decreased and the effectiveness of DMDs for disability outcomes also decreased.

Results

We found lower projected benefits for DMD continuation at 70 years of age than at 55 years of age. Compared with discontinuation, the projected benefit of DMD continuation ranged from 0.007 to 0.017 QALYs at 55 years of age and dropped to 0.002–0.006 at 70 years of age. The annual projected benefits of DMD continuation (0.1–3.0 quality-adjusted life-days) were very low compared with typical patient preferences regarding treatment burden.

Conclusion

The benefits of DMDs may not be substantial among older adults with relapsing-onset MS. Direct clinical evidence remains limited and the decision of whether to discontinue a DMD should also take into account patient preferences. It is important to gain a better understanding of how age-related changes in the trajectory of relapsing-onset MS affect treatment effectiveness among older adults.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 49.95

Price includes VAT for USA

Fig. 1

References

  1. 1.

    Kingwell E, Zhu F, Marrie RA, et al. High incidence and increasing prevalence of multiple sclerosis in British Columbia, Canada: findings from over two decades (1991–2010). J Neurol. 2015;262:2352–63. https://doi.org/10.1007/s00415-015-7842-0.

  2. 2.

    Wallin MT, Culpepper WJ, Campbell JD, et al. The prevalence of MS in the United States: a population-based estimate using health claims data. Neurology. 2019;92(10):e1029–40. https://doi.org/10.1212/WNL.0000000000007035.

  3. 3.

    Biogen. Avonex (interferon beta-1a) prescribing information. Cambridge: Biogen; 2005.

  4. 4.

    Biogen. Tysabri (natalizumab) injection for intravenous use prescribing information. Cambridge: Biogen; 2018.

  5. 5.

    Novartis Pharmaceuticals Corporation. Gilenya (fingolimod) capsules prescribing information. East Hanover: Novartis; 2015.

  6. 6.

    Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis. Neurology. 2018;90:777–88. https://doi.org/10.1212/WNL.0000000000005347.

  7. 7.

    Hartung DM, Bourdette DN, Ahmed S, Whitham RH. The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: too big to fail? Neurology. 2015;84:2185–92. https://doi.org/10.1212/WNL.0000000000002095.

  8. 8.

    Signori A, Schiavetti I, Gallo F, Sormani MP. Subgroups of multiple sclerosis patients with larger treatment benefits: a meta-analysis of randomized trials. Eur J Neurol. 2015;22:960–6. https://doi.org/10.1111/ene.12690.

  9. 9.

    Palace J, Duddy M, Lawton M, et al. Assessing the long-term effectiveness of interferon-beta and glatiramer acetate in multiple sclerosis: final 10-year results from the UK multiple sclerosis risk-sharing scheme. J Neurol Neurosurg Psychiatry. 2019;90:251–60. https://doi.org/10.1136/jnnp-2018-318360.

  10. 10.

    Awad A, Sütve O. Multiple sclerosis in the elderly patient. Drugs Aging. 2010;27:283–94. https://doi.org/10.2165/11532120-000000000-00000.

  11. 11.

    Filippi M, Wolinsky JS, Sormani MP, Comi G. Enhancement frequency decreases with increasing age in relapsing-remitting multiple sclerosis. Neurology. 2001;56:422–3. https://doi.org/10.1212/WNL.56.3.422.

  12. 12.

    Tremlett H, Zhao Y, Joseph J, et al. Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry. 2008;79:1368–74. https://doi.org/10.1136/jnnp.2008.145805.

  13. 13.

    Soldán MMP, Novotna M, Zeid NA, et al. Relapses and disability accumulation in progressive multiple sclerosis. Neurology. 2015;84:81–8. https://doi.org/10.1212/WNL.0000000000001094.

  14. 14.

    Hua LH, Fan TH, Conway D, et al. Discontinuation of disease-modifying therapy in patients with multiple sclerosis over age 60. Mult Scler J. 2019;25(5):699–708. https://doi.org/10.1177/1352458518765656.

  15. 15.

    Shirani A, Zhao Y, Karim ME, et al. Investigation of heterogeneity in the association between interferon beta and disability progression in multiple sclerosis: an observational study. Eur J Neurol. 2014;21:835–844. https://doi.org/10.1111/ene.12324.

  16. 16.

    Birnbaum G. Stopping disease-modifying therapy in nonrelapsing multiple sclerosis: experience from a clinical practice. Int J MS Care. 2017;19:11–4. https://doi.org/10.7224/1537-2073.2015-032.

  17. 17.

    Bsteh G, Feige J, Ehling R, et al. Discontinuation of disease-modifying therapies in multiple sclerosis—Clinical outcome and prognostic factors. Mult Scler J. 2017;23(9):1241–8. https://doi.org/10.1177/1352458516675751.

  18. 18.

    Kister I, Spelman T, Alroughani R, et al. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016;87:1133–7. https://doi.org/10.1136/jnnp-2016-313760.

  19. 19.

    US National Library of Medicine. Discontinuation of Disease Modifying Therapies (DMTs) in Multiple Sclerosis (MS) (DISCOMS). ClinicalTrials.gov Identifier: NCT03073603. 2017. https://clinicaltrials.gov/ct2/show/NCT03073603. Accessed 26 Oct 2018.

  20. 20.

    Tramacere I, Del Giovane C, Salanti G, et al. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2015. https://doi.org/10.1002/14651858.CD011381.pub2.

  21. 21.

    Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444. https://doi.org/10.1212/WNL.33.11.1444.

  22. 22.

    Ebers GC, Heigenhauser L, Daumer M, et al. Disability as an outcome in MS clinical trials. Neurology. 2008;71:624–31. https://doi.org/10.1212/01.wnl.0000313034.46883.16.

  23. 23.

    Frischer JM, Bramow S, Dal-Bianco A, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132:1175–89. https://doi.org/10.1093/brain/awp070.

  24. 24.

    Statistics Canada. Life tables, Canada Provinces and Territories: 2000 to 2002 (updated July 2006). 2006. https://www150.statcan.gc.ca/n1/en/pub/84-537-x/2006001/4227757-eng.pdf?st=rJtWeNUj.

  25. 25.

    Ragonese P, Aridon P, Salemi G, et al. Mortality in multiple sclerosis: a review. Eur J Neurol. 2008;15:123–7. https://doi.org/10.1111/j.1468-1331.2007.02019.x.

  26. 26.

    Scalfari A, Knappertz V, Cutter G, et al. Mortality in patients with multiple sclerosis. Neurology. 2013;81:184–92. https://doi.org/10.1212/WNL.0b013e31829a3388.

  27. 27.

    Kingwell E, Leray E, Zhu F, et al. Multiple sclerosis: effect of beta interferon treatment on survival. Brain. 2019;142:1324–33. https://doi.org/10.1093/brain/awz055.

  28. 28.

    Tremlett H, Zhao Y, Rieckmann P, Hutchinson M. New perspectives in the natural history of multiple sclerosis. Neurology. 2010;74:2004–15. https://doi.org/10.1212/WNL.0b013e3181e3973f.

  29. 29.

    Scalfari A, Neuhaus A, Degenhardt A, et al. The natural history of multiple sclerosis, a geographically based study 10: relapses and long-term disability. Brain. 2010;133:1914–29. https://doi.org/10.1093/brain/awq118.

  30. 30.

    Tremlett H, Paty D, Devonshire V. Disability progression in multiple sclerosis is slower than previously reported. Neurology. 2006;66:172–7. https://doi.org/10.1212/01.wnl.0000194259.90286.fe.

  31. 31.

    Shirani A, Zhao Y, Karim ME, et al. Association between use of beta-interferon and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308:247–56.

  32. 32.

    Schwehr N, Kuntz K, Butler M, et al. Age-related decreases in relapses among adults with relapsing-onset multiple sclerosis. Mult Scler J. 2019. https://doi.org/10.1177/1352458519866613(epub 29 Jul 2019).

  33. 33.

    Prosser L, Kuntz K. Cost effectiveness of interferon beta-1a, interferon beta-1b, and glatiramer acetate in newly diagnosed non-primary progressive multiple sclerosis. Value Health. 2004;7:554–68.

  34. 34.

    Bell C, Graham J, Earnshaw S, et al. Cost-effectiveness of four immunomodulatory therapies for relapsing-remitting multiple sclerosis: a Markov model based on long-term clinical data. J Manag Care Pharm. 2007;13:245–61. https://doi.org/10.18553/jmcp.2007.13.3.245.

  35. 35.

    Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003;61:1528–32. https://doi.org/10.1212/01.WNL.0000096175.39831.21.

  36. 36.

    Hirst C, Ingram G, Pearson O, et al. Contribution of relapses to disability in multiple sclerosis. J Neurol. 2008;255:280–7. https://doi.org/10.1007/s00415-008-0743-8.

  37. 37.

    Vercellino M, Romagnolo A, Mattioda A, et al. Multiple sclerosis relapses: a multivariable analysis of residual disability determinants. Acta Neurol Scand. 2009;119:126–30.

  38. 38.

    Kapoor R, Ho PR, Campbell N, et al. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol. 2018;17:405–15. https://doi.org/10.1016/S1474-4422(18)30069-3.

  39. 39.

    Hutchinson M, Kappos L, Calabresi PA, et al. The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL. J Neurol. 2009;256:405–15. https://doi.org/10.1007/s00415-009-0093-1.

  40. 40.

    Kobelt G, Berg J, Atherly D, Hadjimichael O. Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States. Neurology. 2006;66:1696–702. https://doi.org/10.1212/01.wnl.0000218309.01322.5c.

  41. 41.

    Prosser LA, Kuntz KM, Bar-Or A, Weinstein MC. Patient and community preferences for treatments and health states in multiple sclerosis. Mult Scler. 2003;9:311–9. https://doi.org/10.1191/1352458503ms903oa.

  42. 42.

    Matza LS, Deger KA, Vo P, et al. Health state utilities associated with attributes of migraine preventive treatments based on patient and general population preferences. Qual Life Res. 2019;28(9):2359–72. https://doi.org/10.1007/s11136-019-02163-3.

  43. 43.

    Brennan VK, Dixon S. Incorporating process utility into quality adjusted life years: a systematic review of empirical studies. Pharmacoeconomics. 2013;31:677–91. https://doi.org/10.1007/s40273-013-0066-1.

  44. 44.

    Kremer IEH, Evers SMAA, Jongen PJ, Hiligsmann M. Comparison of preferences of healthcare professionals and MS patients for attributes of disease-modifying drugs: a best-worst scaling. Health Expect. 2018;21(1):171–80. https://doi.org/10.1111/hex.12599.

  45. 45.

    Weideman AM, Tapia-Maltos MA, Johnson K, et al. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. 2017;8:577. https://doi.org/10.3389/fneur.2017.00577.

  46. 46.

    Chilcott J, McCabe C, Tappenden P, et al. Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis. Br Med J. 2003;326:522–5. https://doi.org/10.1136/bmj.326.7388.522.

  47. 47.

    Sanchez-De La Rosa R, Sabater E, Casado M, Arroyo R. Cost-effectiveness analysis of disease modifiying drugs (interferons and glatiramer acetate) as first line treatments in remitting-relapsing multiple sclerosis patients. J Med Econ. 2012;15:424–433. https://doi.org/10.3111/13696998.2012.654868.

  48. 48.

    Bin Sawad A, Seoane-Vazquez E, Rodriguez-Monguio R, Turkistani F. Cost-effectiveness of different strategies for treatment relapsing-remitting multiple sclerosis. J Comp Eff Res. 2017;6:97–108.

  49. 49.

    Bonenfant J, Bajeux E, Deburghgraeve V, et al. Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis? Eur J Neurol. 2017;24(2):237–44. https://doi.org/10.1111/ene.13181.

  50. 50.

    Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015;14:183–93. https://doi.org/10.1016/S1474-4422(14)70256-X.

  51. 51.

    Cree BAC, Hollenbach JA, Bove R, et al. Silent progression in disease activity–free relapsing multiple sclerosis. Ann Neurol. 2019;85:653–66. https://doi.org/10.1002/ana.25463.

  52. 52.

    Claflin SB, Broadley S, Taylor BV. The effect of disease modifying therapies on disability progression in multiple sclerosis: a systematic overview of meta-analyses. Front Neurol. 2019;9:1150. https://doi.org/10.3389/fneur.2018.01150.

  53. 53.

    Fogarty E, Schmitz S, Tubridy N, et al. Comparative efficacy of disease-modifying therapies for patients with relapsing remitting multiple sclerosis: systematic review and network meta-analysis. Mult Scler Relat Disord. 2016;9:23–30. https://doi.org/10.1016/j.msard.2016.06.001.

  54. 54.

    Butler M, Forte ML, Schwehr N, et al Decisional dilemmas in discontinuing prolonged disease-modifying treatment for multiple sclerosis. Report no.: 15-EHC012-EF. Rockville: Agency for Healthcare Research and Quality; 2015.

  55. 55.

    Tan I, McArthur J, Clifford D, et al. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology. 2011;77(11):1061–7.

  56. 56.

    Khatri B. Fingolimod in the treatment of relapsing–remitting multiple sclerosis: long-term experience and an update on the clinical evidence. Ther Adv Neurol Disord. 2016;9:130–47.

  57. 57.

    Hatcher SE, Waubant E, Nourbakhsh B, et al. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol. 2016;73:790–4. https://doi.org/10.1001/jamaneurol.2016.0826.

  58. 58.

    Clerico M, Artusi CA, Di Liberto A, et al. Natalizumab in multiple sclerosis: long-term management. Int J Mol Sci. 2017. https://doi.org/10.3390/ijms18050940.

  59. 59.

    Kister I. Disease-modifying therapies can be safely discontinued in an individual with stable relapsing-remitting MS—Yes. Mult Scler J. 2017;23:1188–90.

  60. 60.

    Tobin WO, Weinshenker BG. Disease-modifying therapies can be safely discontinued in an individual with stable relapsing-remitting MS—NO. Mult Scler J. 2017;23:1190–2. https://doi.org/10.1177/1352458517709957.

  61. 61.

    Kingwell E, van der Kop M, Zhao Y, et al. Relative mortality and survival in multiple sclerosis: findings from British Columbia. Canada. J Neurol Neurosurg Psychiatry. 2012;83:61–6. https://doi.org/10.1136/jnnp-2011-300616.

Download references

Acknowledgements

The authors gratefully acknowledge the BCMS clinic neurologists who contributed to the study through patient examination and data collection (current members at the time of data extraction are listed here, by primary clinic): University of British Columbia (UBC) MS Clinic: A. Traboulsee, MD, FRCPC (UBC Hospital MS Clinic Director and Head of the UBC MS Programs); A-L. Sayao, MD, FRCPC; V. Devonshire, MD, FRCPC; S. Hashimoto, MD, FRCPC (UBC and Victoria MS Clinics); J. Hooge, MD, FRCPC (UBC and Prince George MS Clinic); L. Kastrukoff, MD, FRCPC (UBC and Prince George MS Clinic); J. Oger, MD, FRCPC. Kelowna MS Clinic: D. Adams, MD, FRCPC; D. Craig, MD, FRCPC; S. Meckling, MD, FRCPC. Prince George MS Clinic: L. Daly, MD, FRCPC. Victoria MS Clinic: O. Hrebicek, MD, FRCPC; D. Parton, MD, FRCPC; K. Atwell-Pope, MD, FRCPC. The authors also thank Tom Duggan, Feng Zhu, and the Pharmacoepidemiology in MS Research Group (https://epims.med.ubc.ca/) for research support at UBC. We are indebted to all of the people with MS who contributed the data used in this study. The views expressed in this study do not necessarily reflect the views of each individual acknowledged.

The BeAMS Study Group (the long-term Benefits and Adverse effects of beta-interferon for Multiple Sclerosis): A. Shirani, Y. Zhao, C. Evans, M.L. van der Kop, G. Gustafson, J. Petkau, J. Oger. Role: Facilitated gaining funding applications and creation of the study cohort used in the simulation-related analyses in the current manuscript. Funding: Canadian Institutes of Health Research (CIHR) [MOP-93646] and the US National MS Society [#RG 4202-A-2]; 2009-12; Principal Investigator: Helen Tremlett.

Author information

All authors contributed to the study conception and design. Data analyses and modeling were performed by Natalie Schwehr. The first draft of the manuscript was written by Natalie Schwehr and all authors commented on later versions of the manuscript. All authors read and approved the final manuscript.

Correspondence to Natalie A. Schwehr.

Ethics declarations

Conflict of interest

Natalie Schwehr, Karen Kuntz, Eva Enns, Nathan Shippee, Elaine Kingwell, Helen Tremlett, Adam Carpenter, and Mary Butler have no conflicts of interest that are directly relevant to the contents of this article. Eva Enns has received consulting fees from ViiV Healthcare for work unrelated to this manuscript. Helen Tremlett is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. Current research support was received from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, the Multiple Sclerosis Society of Canada, and the Multiple Sclerosis Scientific Research Foundation. In addition, in the last 5 years, she has received research support from the Multiple Sclerosis Society of Canada (Don Paty Career Development Award); the Michael Smith Foundation for Health Research (Scholar Award), and the UK MS Trust; speaker honoraria and/or travel expenses to attend continuing medical education (CME) conferences from the Consortium of MS Centers (2013, 2018), the National MS Society (2014, 2016, 2018), European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (2013, 2014, 2015, 2016, 2017, 2018, 2019), Biogen Idec (2014), and American Academy of Neurology (2013, 2014, 2015, 2016, 2019). All speaker honoraria are either declined or donated to an MS charity or to an unrestricted grant for use by Helen Tremlett’s research group. Adam Carpenter has received research funding for participation in clinical trials involving medications (interferon-β, natalizumab) discussed in this manuscript.

Funding

Natalie Schwehr received funding that partially supported this project, i.e. a Thesis Research Travel Grant from the University of Minnesota and 3 months of support as an Advanced Research Program Scholar under the University of Minnesota’s NIH Clinical and Translational Science Award (UL1TR002494). The funding sources played no role in the design, methods, data, or interpretation of the results of the study.

Ethical approval

Ethical approval was gained from the University of Minnesota Institutional Review Board and the UBC Clinical Research Ethics Board.

Data availability

Simulation model parameters were derived from analyses of a patient cohort (access to these data are restricted to on-site in Vancouver, BC, Canada) and published literature. The resulting parameters are presented in the Methods section and in the accompanying tables.

Additional information

Members of “The BeAMS Study group” are listed in the Acknowledgement section.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 23 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schwehr, N.A., Kuntz, K.M., Enns, E.A. et al. Informing Medication Discontinuation Decisions among Older Adults with Relapsing-Onset Multiple Sclerosis. Drugs Aging (2020) doi:10.1007/s40266-019-00741-1

Download citation