Delving Into Adherence With Multiple Sclerosis Therapies

Adherence is defined as conforming to the recommendations made by the provider with respect to timing, dosage, and frequency of medication taking,¹ and following these recommendations is important for patients with multiple sclerosis (MS) to fully benefit from disease-modifying therapies (DMTs). Adherence is commonly assessed by medication possession ratio (MPR), a calculation based on the number of medication claims during a period of time. Patients with an MPR of 80% or higher are generally considered adherent.²

A 1-year study examining patient adherence in several disease states found that female patients with MS have an MPR of 76.6%, and male patients have an MPR of 69.6%.³ These numbers are in line with those for hypertension (female/male MPR; 68.8%/70.5%), hyperlipidemia (67.6%/70.8%), osteoporosis (65.1%/61.7%), and cancer (69.2%/61.0%), and substantially greater than those for depression (58.0%/59.7%), diabetes (50.2%/54.9%), and asthma/chronic obstructive pulmonary disease (32.2%/31.0%).³ Across MS disease states, adherence rates tend to be lower in minorities; in patients of lower socioeconomic status; and in those where multiple conditions, drugs, or doses are involved.³

A study examining claims data for a cohort of 2446 patients with MS demonstrated that improved outcomes in MS are associated with an MPR equal to or higher than 80%, with adherent patients with MS being 37% less likely to be hospitalized and 29% less likely to relapse.⁴ Because adherence is associated with improved outcomes, it is notable that Ashvigala et al reported that patients taking an oral therapy for MS (fingolimod) had an MPR ≥80% for two-thirds (67%) of patients versus averages ranging from 42% to 54% for patients taking any one of 4 injectable therapies for MS.⁵

Barriers to Adherence

Fear of injection. Patients are often required to take DMTs by self-injection or by infusion, which may cause anxiety and fear, leading them to avoid the treatment.⁶ Patients may also turn to a family member or friend to give them the injection, and such dependence on another person for treatment may become a problem if the individual is unavailable. ⁶

Oral treatments are easier to take with fewer side effects compared with injectable DMTs, which can be associated with flu-like symptoms and injection site reactions. One study examined MPR and continuation of therapy for several MS DMTs, including fingolimod, which is taken orally, and the injectable DMTs, interferon beta-1b (INF-1b), intramuscular interferon beta-1a, subcutaneous interferon beta-1a, and glatiramer acetate.5 This study found that patients taking fingolimod had the highest MPR and the lowest number of patients discontinuing compared with the other treatments.⁵

Unrealistic expectations. Because there is no cure for MS, treatment is life-long but DMTs serve to prevent and treat symptoms and relapse. Some patients may have unrealistic expectations of the treatment and perceive that it is not working when symptoms persist or new ones develop.⁷ A study conducted by Mohr and colleagues found that patients in health care delivery settings showed unrealistic expectations of their treatment with INF-1b.8 More than half (57%) were unrealistically optimistic about lowering their attack rate and a third (34%) were unrealistically optimistic about improving their functional status.

Adverse events. Patients’ experience of adverse events can deter them from continuing with therapy. Flushing, tachycardia, and dyspnea may occur after injection of glatiramer acetate, which is self-administered by subcutaneous injection. This experience may result in an unwillingness to continue with the therapy.⁷ Lipoatrophy or disfiguring skin abnormalities are also associated with glatiramer acetate and may also lead to discontinuation of therapy.⁹

Depression. It is estimated that almost half of patients with MS also have depression.^10,11 A study conducted by Tarrants and colleagues examined the effect of comorbid depression on adherence to DMTs.¹² Patients with MS with or without diagnosis of depression in the last 6 months were compared. Patients with MS and depression had a 10% lower MPR score than patients without depression, suggesting that comorbid depression is associated with decreased patient adherence. Other barriers to adherence include complacency, treatment fatigue, deterioration of injection skills, forgetting to inject because of disease-related memory deficits, and lack of medical coverage or financial circumstances preventing access to therapy.⁷

Improving Adherence

The results of a 16-year follow-up study comparing IFN-1b with placebo show the potential importance of long-term adherence to DMT.¹³ In the original study, patients received placebo (n = 123), IFN-1b at a dose of 50 µg (n = 125) or 250 µg (n = 124).¹⁴ Mortality rates for the 260 patients in the follow-up study were lower in the 50-µg group (5.4%) and in the 250-µg group (8.3%) than for those in the original placebo group (18.3%).¹³

A successful relationship between health care provider and patient, setting realistic expectations, successfully dealing with injection anxiety, coping with adverse events,⁷ and making the injection process easier for patients are some ways that adherence can be improved. A study evaluated a ready-to-use, single-use autoinjector for self-administration of subcutaneous interferon beta-1a. After 12 weeks, patients were asked about the ease of use of the autoinjector. Most patients (more than 74%) rated the autoinjector as easy to use and convenient, and thought it simplified injections, suggesting an improved injection experience.¹⁵

According to Bianca Weinstock-Guttman, MD, professor in the department of neurology at University at Buffalo, The State University of New York, and author of a publication on new and emerging therapies for relapsing-remitting MS, to “improve adherence to DMTs and outcomes associated with long-term DMT use, recent attention has focused on the development of DMTs with improved tolerability and efficacy and those that are orally administered or require less frequent administration.”¹⁶

The table below details rates of discontinuation for 3 orally administered therapies. Rates of discontinuation are similar for patients receiving placebo and treatment.

Paul O’Connor, MD, director of the MS Clinic and MS Research and the Evoked Potentials Laboratory at St. Michael’s Hospital in Ontario, Canada, and author of a study²⁰ examining adherence to MS DMTs, stated there are “a number of reasons why adherence to therapies of proven value might be low. These drugs don’t work in everyone, and some patients may stop them because they don’t feel they are experiencing benefits. In some cases, patients may stop treatment because of side effects. It is important that patients understand the need for continuing treatment in order to prevent some of the long-term consequences of MS.”²¹ Study coauthor Tara Gomes, MHSc, added that this “study shows that adherence to treatment with DMTs is low, which is concerning given their proven effectiveness in slowing the progression of MS. We need to increase the appreciation of the long-term benefits of these medications to ensure that MS patients are receiving the best treatment available.” ²¹

References:

1. Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health. 2008;11(1):44-47.

2. Fairman K, Motheral B. Evaluating medication adherence: which measure is right for your program? J Managed Care Pharm. 2000;6(6):499-504.

3. Rolnick SJ, Pawloski PA, Hedblom BD, Asche SE, Bruzek RJ. Patient characteristics associated with medication adherence. Clin Med Res. 2013;11(2):54-65.

4. Tan H, Cai Q, Agarwal S, Stephenson JJ, Kamat S. Impact of adherence to disease-modifying therapies on clinical and economic outcomes among patients with multiple sclerosis. Adv Ther. 2011;28(1):51-61.

5. Agashivala N, Wu N, Abouzaid S, et al. Compliance to fingolimod and other disease modifying treatments in multiple sclerosis patients, a retrospective cohort study. BMC Neurol. 2013;13:138.

6. Cox D, Stone J. Managing self-injection difficulties in patients with relapsing-remitting multiple sclerosis. J Neurosci Nurs. 2006;38(3):167-171.

7. Costello K, Kennedy P, Scanzillo J. Recognizing nonadherence in patients with multiple sclerosis and maintaining treatment adherence in the long term. Medscape J Med. 2008;10(9):225.

8. Mohr DC, Goodkin DE, Likosky W, et al. Therapeutic expectations of patients with multiple sclerosis upon initiating interferon beta-1b: relationship to adherence to treatment. Mult Scler. 1996;2(5):222-226.

9. Edgar CM, Brunet DG, Fenton P, McBride EV, Green P. Lipoatrophy in patients with multiple sclerosis on glatiramer acetate. Can J Neurol Sci. 2004;31(1):58-63. 10. Marrie RA, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. The burden of mental comorbidity in multiple sclerosis: frequent, underdiagnosed, and undertreated. Mult Scler. 2009;15(3):385-392.

11. Sadovnick AD, Remick RA, Allen J, et al. Depression and multiple sclerosis. Neurology. 1996;46(3):628-632.

12. Tarrants M, Oleen-Burkey M, Castelli-Haley J, Lage MJ. The impact of comorbid depression on adherence to therapy for multiple sclerosis. Mult Scler Int. 2011;2011:271321.

13. Ebers GC, Traboulsee A, Li D, et al. Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial. J Neurol Neurosurg Psychiatry. 2010;81(8):907-912.

14. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology. 1993;43(4):655-661.

15. Wray S, Armstrong R, Herrman C, et al. Results from the single-use autoinjector for self-administration of subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis (MOSAIC) study. Expert Opin Drug Deliv. 2011;8(12):1543-1553.

16. Weinstock-Guttman B. An update on new and emerging therapies for relapsing-remitting multiple sclerosis. Am J Manag Care. 2013;19(suppl 17):s343-s354.

17. O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-1303.

18. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401.

19. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098-1107.

20. Wong J, Gomes T, Mamdani M, Manno M, O’Connor PW. Adherence to multiple sclerosis disease-modifying therapies in Ontario is low. Can J Neurol Sci. 2011;38(3):429-433.

21. Medical News Today. In Multiple Sclerosis, Less Than Half Of Patients Continually Adhere To Drug Therapies For Treatment: Study. May 11, 2011.