Impact of increasing adherence to disease-modifying therapies on healthcare resource utilization and direct medical and indirect work loss costs for patients with multiple sclerosis

Abstract

Objectives:

To estimate the effect of adherence to disease-modifying therapies (DMTs) among patients with multiple sclerosis (MS) on healthcare resource utilization (HRU) and costs, and model the impact of a 10 percentage point increase in adherence on these outcomes.

Methods:

Employed patients, 18–64 years old, with ≥2 MS diagnoses and ≥1 DMT claim during January 1, 2002 to September 30, 2012 were identified from a large commercially-insured US claims database. Adherence was measured as proportion of days covered (PDC) during follow-up. Multivariate regression analyses were conducted to estimate the effect of adherence on HRU related to urgent care (i.e., inpatient or emergency room visit), days of work loss, direct medical cost, and indirect work loss costs. Model coefficients were used to evaluate the impact of a 10 percentage point increase in adherence on the outcomes.

Results:

A total of 1510 patients were included (mean age = 43.4 years, 64% female). Patients with higher adherence had lower HRU, fewer days of work loss, and lower direct and indirect costs. A 10 percentage point increase in adherence significantly decreased the likelihood of an inpatient or emergency room visit by 9–19%, days of work loss by 3–8%, and direct and indirect costs by 3–5%, depending on the follow-up period (all p < 0.01).

Conclusions:

Increasing DMT adherence was found to significantly decrease urgent-care HRU, days of work loss, and direct and indirect costs among patients with MS.

• Multiple sclerosis
• Medication adherence
• Disease-modifying therapies
• Direct cost
• Indirect cost
• Work loss

Introduction

Multiple sclerosis (MS), a chronic, degenerative disease of the central nervous system, is estimated to affect over 550,000 individuals in the US and 2.3 million people worldwide1^,2. While the progression of disease varies across patients, MS becomes an increasingly disabling disease due to the progressive impairment of cognitive and neurologic functions.

The economic impact associated with MS is substantial3. Since the onset of the disease typically occurs between the ages of 20–50 years, it can have a considerable impact on the work productivity, earning potential, and employment status of affected individuals. A recent study found that the MS population was ∼3-times more likely to not be employed in a given year than a non-MS population1. It has been estimated that 55–80% of individuals with MS retire early after their diagnosis; the work ability varies with MS sub-types4^,5. Furthermore, the disabling nature of MS imposes a considerable indirect cost burden on employers6. A previous study on the cost of disability and medically-related absenteeism found that such indirect costs were over 4-times higher in employed individuals with MS compared to those of matched employees without MS7. Additionally, MS leads to increased healthcare costs, which have been estimated to be 5-times higher in an MS population than a non-MS population, after controlling for key chronic conditions1.

While there is no cure for MS, disease-modifying therapies (DMTs) effectively slow disease progression and reduce the severity of symptoms8–10. Previous research has suggested that initiation of DMTs following diagnosis can lead to significant direct medical and indirect cost savings11^,12. Adherence to therapy is important in order to achieve clinical benefits; however, adherence is challenging because of the need for long-term therapy in a chronic disease such as MS13^,14. Despite evidence of improved outcomes with DMTs, the real-world adherence to DMTs ranged from 41–88%15. Several studies have demonstrated that poor adherence to DMTs negatively impacts health outcomes, with significant subsequent medical and indirect costs among patients with MS12^,16^,17. Retrospective database studies have suggested that poor adherence, defined using medication possession ratio (MPR < 80–85%), was associated with a higher risk of relapse and hospitalization15^,16. Poor adherence was also found to be associated with higher medical costs and indirect costs16^,18^,19.

While studies examining the association of healthcare resource utilization (HRU) and medical and work productivity costs in patients who are non-adherent to DMTs compared to those who are adherent are available16–18, the data examined were old and did not include newer DMTs. Additionally, to the best of our knowledge, no study has predicted the incremental effect of increasing DMT adherence on the above outcomes. We, therefore, conducted a retrospective observational study to estimate the effect of DMT adherence on urgent-care HRU and direct medical and indirect work loss costs in patients with MS based on data up to March 2013. In addition, we created predictive equations to model the impact of an increase in adherence on these outcomes.

Patients and methods

Data source

A retrospective observational study was conducted using OptumHealth Reporting and Insights database, an administrative claims database containing longitudinal information from 1999–2013 for over 18 million privately-insured individuals employed by 82 US-based companies. These companies are geographically dispersed across the US and operate in a broad array of industries (e.g., financial services, manufacturing, telecommunications, energy, and food and beverage). The claims database contains de-identified information and is fully compliant with the Health Insurance Portability and Accountability Act (HIPAA) of 1996. Data recorded for the current study included patients’ demographic information, monthly enrollment history, medical and pharmacy claims, and short- and long-term disability claims. Medical claims included the date of service, place of service, primary and secondary diagnosis codes (i.e., International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes), services provided (i.e., Current Procedural Terminology (CPT-4), Healthcare Common Procedure Coding System (HCPCS), or ICD-9-CM procedure code), and amounts charged and paid. Pharmacy claims included prescription fill date, National Drug Code (NDC), days of drug supply, and amounts charged and paid. Short- and long-term disability claims and salary information were available for 42 of the 82 companies, which accounts for ∼5 million employees.

Sample selection

The study sample was selected from primary beneficiaries aged 18–64 years with available disability data and at least two distinct medical claims with a corresponding diagnosis of MS (ICD-9-CM code 340.xx), who had at least one claim (medical or pharmacy) for a DMT between January 1, 2002 and September 30, 2012 following MS diagnosis. The earliest claim for a DMT following the first MS diagnosis was identified as the index date for the study. Patients with at least 6 months of continuous eligibility prior to the index date (baseline period) and following the index date (follow-up period) were eligible. Patients with a DMT claim during the baseline period and those enrolled in a capitated or health maintenance organization (HMO) plan on the index date were excluded from the study. The following DMTs were available during the study period and were identified using NDC and HCPCS codes: fingolimod (oral, Gilenya®, Novartis Pharmaceuticals Corporation, East Hanover, NJ), glatiramer acetate (oral, Copaxone®, Teva Pharmaceuticals, Petach Tikva, Israel), interferon beta-1a (intramuscular (IM), Avonex®, Biogen Idec, Cambridge, MA; subcutaneous (SC), Rebif®, Merck Serono SA, Genf, Switzerland), interferon beta-1b (SC, Betaseron®, Bayer Healthcare, Leverkusen, Germany; SC, Extavia®, Novartis Pharma AG, Basel, Switzerland), mitoxantrone (intravenous (IV), Novantrone®, Serono, Inc, Rockland, MA), natalizumab (IV, Tysabri®, Biogen Idec, Cambridge, MA), and teriflunomide (oral, Aubagio®, Genzyme Corporation, Cambridge, MA).

Patient characteristics

Demographic and clinical characteristics of the patients were measured during the baseline period. Age at the index date, gender, comorbidities, and time from first MS diagnosis to DMT treatment initiation were assessed. Baseline comorbidities included select mental health conditions (i.e., anxiety, bipolar, depressive disorders) and chronic pain conditions (i.e., arthritis, back or neck pain, fibromyalgia, migraine), as well as Charlson Comorbidity Index (CCI)18^,20.

Definition of adherence and persistence

Adherence and persistence to DMTs were measured using medication administration or dispensing claims from both pharmacy and medical claims data. Medication availability was determined by the prescription fill date and days supply from the pharmacy claims. As medical claims did not contain information on days of supply for DMTs with IV, IM, or SC routes of administration, the recommended dosage on the drug label was used to calculate the days of supply21. All DMTs, as opposed to individual DMTs, were considered when measuring adherence and persistence.

Adherence was assessed using two measures: the proportion of days covered (PDC) and the medication possession ratio (MPR). PDC was calculated as the proportion of days in the 6-, 12-, 24-, and 36-month follow-up periods during which the patient had at least one DMT available. MPR was calculated as the number of days when the patient had at least one DMT available divided by the number of days between the first fill and the last refill (plus the days of supply of the last refill) during the follow-up periods. For both measures, a ratio of 1 indicated perfect adherence, while a ratio lower than 1 indicated lapses in prescription filling. Previous literature has described adherence levels below 80% as non-adherent behavior22.

Persistence was measured as the time-to-discontinuation of DMT following the index date. Discontinuation was defined as a gap of at least 60 days between the end of a DMT prescription and the date of the next prescription, if any. The patient’s persistence on treatment was represented by the duration of time between the index date and discontinuation.

Healthcare resource utilization and costs

HRU and direct and indirect costs were analyzed in the baseline period and up to 3 years following DMT initiation, with estimates presented at 12, 24, and 36 months during follow-up. Direct HRU included urgent care (i.e., inpatient or emergency room) and outpatient visits. It was calculated based on claims for the corresponding services and was further categorized by place of service, type of service, and provider type. Indirect HRU was calculated based on the duration of claims for short- and long-term disability, as well as days of work loss from medically-related absenteeism. Days of work loss from medically-related absenteeism were calculated by summing days of urgent care (i.e., inpatient and emergency room) visits, and half days for outpatient visits occurring during the traditional work week, including days missed to qualify for disability benefit. Total days of work loss were the sum of total disability days and days of work loss from medically-related absenteeism.

Direct medical costs were calculated based on the amounts paid to the providers for services or prescription drugs (e.g., reimbursements to healthcare providers for inpatient or outpatient visits, ancillary services, and prescription drug costs). The costs of DMTs were excluded from direct costs calculations18. Indirect costs were assessed using insurance payments for disability claims, as well as the estimated costs to the employer from days of work loss associated with the use of medical services. The work loss costs to the employer were estimated using the employee’s daily wage reported by the employers. Wages were inflated to 2012 dollars using the All Items component of the Consumer Price Index and all costs were inflated to 2012 dollars using the Medical Care component of the Consumer Price Index23.

MS-related HRU and costs were assessed using claims with a corresponding diagnosis for MS. Use of treatments for the relief of common symptoms of MS was also evaluated. These treatments included anti-convulsants, anti-diuretics, corticosteroids, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), phosphodiesterase-5 inhibitors, anti-cholinergics, selective serotonin re-uptake inhibitors (SSRIs), stimulants, tricyclic anti-depressants, and urinary anti-spasmodics.

Statistical analyses

The baseline characteristics of the patients included in the study were described using counts and proportions for categorical variables and means (standard deviations (SD)) for continuous variables. Adherence and persistence of patients on the DMTs were described at 6-, 12-, 24-, and 36-month follow-up periods. The annualized HRU and direct and indirect costs for the patients included in the study were calculated and presented by adherence level (categorized as PDC <40%, 40–79%, and ≥80%) during the 12-, 24-, and 36-month follow-up periods. Statistical significance of differences between the PDC <40% and PDC ≥80% was calculated using the Wilcoxon rank sum test.

The effect of adherence on HRU and direct and indirect costs during the 12-, 24-, and 36-month follow-up periods was assessed using multivariate regression analyses, adjusting for baseline characteristics. The effect on direct HRU was assessed by estimating the likelihood of having at least one urgent care visit, i.e., inpatient or emergency room visit, using logistic regression. For the analysis of days of work loss, a negative binomial multivariate regression was used. A generalized linear model with a log link function and gamma distribution was used to study the effect of adherence on direct and indirect costs. A predictive model for each outcome was then created based on the regression coefficients. The impact of an increase in a patient’s adherence on the outcomes was estimated by applying the coefficients from the above multivariate regression analyses to each patient’s baseline characteristics and increasing the follow-up period adherence by 10 percentage points. Adherence was capped at 100% in these models. The difference between the observed and the estimated outcomes represented the incremental effect of a 10 percentage point increase in adherence. Statistical significance of differences was calculated using the Wilcoxon signed rank test. The incremental impact of increasing adherence was estimated for the overall study sample. For the 12-month follow-up period, the incremental impact of increasing adherence on direct costs was also estimated for a-priori selected sub-groups of patients, including patients without any disability days during the baseline period, without a general comorbidity (i.e., CCI = 0), male patients, and those with adherence ≥ 80%.

All significance tests were two-sided, and the differences were considered significant at p < 0.05. All statistical analyses were performed using SAS software version 9.3 (SAS Institute, Cary, NC).

Results

Sample selection

Of ∼5 million primary beneficiaries with available disability data, 1510 patients met the study selection criteria, as shown in the flow diagram in Figure 1. Of these patients, 85% (n = 1284) had continuous eligibility for 12 months after the index date and were included in the 12-month follow-up analysis; 64% (n = 967) were included in the 24-month follow-up and 48% (n = 731) were included in the 36-month follow-up.

Figure 1. Flow diagram showing the selection of patients included in the study. MS, multiple sclerosis; DMT, disease-modifying therapy; HMO, health maintenance organization.

Baseline demographic and clinical characteristics

The baseline demographic and clinical characteristics of the included patients are presented in Table 1. The patients were, on average, 43.4 years old (SD = 10.1) on the index date, and 64% of patients were female. Among the selected mental health comorbidities and chronic pain conditions, the most common comorbidity was back or neck pain (29%), followed by depressive disorders (7%). The mean CCI was 0.4 (SD = 0.8), and the most common comorbidity within the CCI measurement was cerebrovascular disease (9%). The median time from first MS diagnosis to DMT initiation was 86 days (IQR = 31–387). Forty-eight per cent of patients initiated DMT on interferon beta-1a (n = 718), 36% on glatiramer acetate (n = 543), and 11% on interferon beta-1b (n = 169). The remaining patients initiated treatment on natalizumab (3%; n = 51), mitoxantrone (1%; n = 17), and fingolimod (1%; n = 12).

Table 1. Baseline demographics and clinical characteristics of patients with MS included in the study (n = 1510).

Characteristics	n (%)*
Age at index date, years, mean (SD)	43.4 (10.1)
Female	961 (64)
Baseline comorbidities
Select mental health comorbidities
Anxiety disorders	77 (5)
Bipolar disorders	13 (1)
Depressive disorders	110 (7)
Select painful conditions
Arthritis	45 (3)
Back or neck pain	445 (29)
Fibromyalgia	57 (4)
Migraine	85 (6)
Charlson Comorbidity Index, mean (SD)	0.4 (0.8)
Myocardial infarction	4 (0)
Congestive heart failure	10 (1)
Peripheral vascular disease	7 (0)
Cerebrovascular disease	130 (9)
Dementia	4 (0)
Chronic pulmonary disease	46 (3)
Rheumatologic disease	19 (1)
Peptic ulcer disease	1 (0)
Liver disease	9 (1)
Diabetes	61 (4)
Diabetes with chronic complications	8 (1)
Hemiplegia or paraplegia	74 (5)
Renal disease	3 (0)
Any malignancy including leukemia   and lymphoma	33 (2)
Moderate or severe liver disease	0 (0)
Metastatic solid tumor	3 (0)
AIDS	2 (0)
Time from first MS diagnosis to treatment initiation, days, median (IQR)	86 (31–387)

n, number of patients; SD, standard deviation; MS, multiple sclerosis; AIDS, acquired immunodeficiency syndrome; IQR, interquartile range.

*Data are numbers (%) unless otherwise indicated.

Adherence, persistence, and discontinuation

Figure 2 summarizes adherence, persistence, and discontinuation at 6, 12, 24, and 36 months during the follow-up period. Adherence to DMTs among patients with MS included in the study declined as the duration of follow-up period increased. The mean adherence measured using PDC was 82% (SD = 22%) at 6 months following treatment initiation and declined to 67% (SD = 29%) at 36 months of follow-up. Overall, the average MPR was 79% (SD = 21%). In terms of persistence, within the first 6 months following DMT initiation, only 4% of the patients discontinued therapy, while 42% had discontinued by 36 months. The average persistence on therapy was 394 days (SD = 279) for those patients who discontinued DMT therapy during the 36-month follow-up period.

Figure 2. Adherence, persistence, and discontinuation at 6, 12, 24, and 36 months during follow-up for patients with MS initiating DMT. MS, multiple sclerosis; DMT, disease-modifying therapy; PDC, proportion of days covered; n, number of patients.

Healthcare resource utilization and costs during the follow-up periods

Table 2 summarizes annualized HRU for the 12-, 24-, and 36-month follow-up periods. MS patients with higher DMT adherence had lower urgent-care HRU during each follow-up period. During the 12-month follow-up period, patients with adherence ≥80% had significantly fewer inpatient and emergency room visits compared to those with adherence <40% (both p < 0.01). Similarly, the number of total days of work loss and days of disability were significantly lower among those with ≥80% adherence than among those with adherence <40% (both p < 0.01). The number of outpatient visits and days of medically-related absenteeism were not significantly different between the two groups during follow-up (both p > 0.05).

Table 2. Annualized healthcare resource utilization by adherence level in 12-, 24-, and 36-month follow-up periods for patients with MS initiating DMT.

	12-month follow-up (n = 1284)				24-month follow-up (n = 967)				36-month follow-up (n = 731)
	PDC adherence level				PDC adherence level				PDC adherence level
				p Value				p Value				p Value
	<40%	40–79%	≥80%	<40% vs	<40%	40–79%	≥80%	<40% vs	<40%	40–79%	≥80%	<40% vs
Outcomes	n = 155	n = 302	n = 827	≥80%	n = 187	n = 265	n = 515	≥80%	n = 162	n = 225	n = 344	≥80%
Direct healthcare resource utilization, mean (SD)
Inpatient visits	0.4 (1.6)	0.4 (1.9)	0.1 (0.7)	<0.001	0.4 (1.6)	0.3 (1.8)	0.1 (0.5)	<0.001	0.5 (2.4)	0.2 (1.2)	0.1 (0.6)	<0.001
Emergency room visits	17.4 (15.9)	16.8 (14.6)	16.1 (13.3)	0.003	15.6 (18.2)	16.6 (18.7)	15.3 (17.0)	<0.001	15.5 (21.4)	15.7 (18.4)	15.3 (20.8)	0.002
Outpatient visits	0.7 (1.3)	0.7 (1.7)	0.5 (1.4)	0.969	0.8 (2.1)	0.6 (1.6)	0.4 (1.7)	0.903	0.7 (2.3)	0.5 (1.6)	0.4 (2.1)	0.827
Indirect work loss, mean (SD)
Total days of work loss	53.5 (87.7)	54.0 (89.0)	34.1 (68.8)	0.005	55.9 (126.3)	55.4 (126.6)	27.9 (13.9)	<0.001	57.2 (157.7)	43.9 (135.7)	30.0 (51.7)	<0.001
Disability days	42.6 (90.8)	44.8 (91.6)	25.3 (70.2)	0.006	46.0 (59.9)	46.5 (59.8)	19.4 (15.5)	<0.001	47.2 (162.6)	35.5 (139.7)	21.3 (54.0)	0.003
Medically-related absenteeism days	10.9 (15.3)	9.2 (10.7)	8.9 (10.2)	0.837	9.9 (17.0)	9.0 (17.3)	8.5 (11.9)	0.514	10.0 (25.8)	8.3 (12.4)	8.6 (14.9)	0.329

MS, multiple sclerosis; DMT, disease-modifying therapy; n, number of patients; PDC, proportion of days covered; SD, standard deviation.

Figure 3 summarizes annualized direct costs and indirect costs by DMT adherence level. The total direct (medical and pharmacy) and indirect costs decreased with increasing adherence in each follow-up period. During the 12-month follow-up period, the total average direct and indirect costs were higher among patients with <40% adherence compared to those with ≥80% adherence to DMTs ($22,280 (SD = $31,247) vs $13,970 (SD = $21,289)). Similar trends were observed for each category of costs evaluated separately, as well as for each follow-up period, with the exception of pharmacy costs during the 36-month follow-up period which were higher for those with ≥80% adherence (<40% adherence = $2114 (SD = $5291) vs ≥80% adherence = $2382 (SD = $7472)).

Figure 3. Annualized cost outcomes by adherence level in each follow-up period for patients with MS initiating DMT. †Costs in 2012 USD. MS, multiple sclerosis; DMT, disease-modifying therapy; PDC, proportion of days covered; n, number of patients.

Effect of DMT adherence on healthcare resource utilization and costs

Table 3 shows the estimated effect on HRU and costs of a 10 percentage point increase in DMT adherence during the 12-, 24-, and 36-month follow-up periods. After adjusting for age, gender, index year, and baseline days of work loss, MS-related direct costs, non-MS related direct costs, MS-related comorbidities, and CCI, increased adherence during each follow-up period was estimated to significantly decrease HRU and direct and indirect costs (all p < 0.01). At the 12-month follow-up period, a 10 percentage point increase in DMT adherence was estimated to significantly reduce the likelihood of an inpatient visit by 12.8% and of an emergency room visit by 8.9%, reducing the number of days of work loss by 3.6%, direct costs by 4.1%, and indirect costs by 2.9% (all p < 0.01). The same increase in DMT adherence was also estimated to significantly decrease HRU and costs in subsequent follow-up periods. The impact of increasing DMT adherence on the likelihood of having an inpatient or emergency room visit was lowest for the 12-month and highest for the 36-month follow-up period.

Table 3. Estimated effect on healthcare resource utilization and costs of a 10% increase in adherence at 12-, 24-, and 36-month follow-up periods for patients with MS initiating DMT.

	12-month follow-up (n = 1284)			24-month follow-up (n = 967)			36-month follow-up (n = 731)
Outcomes	Observed PDC	10% increase in PDC	Percent difference	Observed PDC	10% increase in PDC	Percent difference	Observed PDC	10% increase in PDC	Percent difference
Direct healthcare resource utilization, likelihood of having at least one:
Inpatient visit	10.7%	9.4%	−12.8%*	17.8%	14.7%	−17.4%*	24.8%	20.1%	−19.0%*
Emergency room visit	28.2%	25.7%	−8.9%*	41.5%	36.8%	−11.2%*	49.4%	40.2%	−18.6%*
Indirect work loss
Total days of work loss, mean (SD)	41.1 (76.9)	39.6 (74.9)	−3.6%*	81.6 (152.6)	75.4 (144.4)	−7.6%*	120.8 (226.6)	114 (218.0)	−5.6%*
Costs†
Direct costs, mean (SD)	$10,439	$10,012	−4.1%*	$21,032	$20,104	−4.4%*	$29,797	$28,540	−4.2%*
	($19,261)	($19,175)		($40,378)	($40,232)		($45,406)	($45,230)
Indirect costs, mean (SD)	$5,509	$5,349	−2.9%*	$11,194	$10,679	−4.6%*	$16,692	$16,074	−3.7%*
	($10,218)	($10,072)		($20,971)	($20,520)		($31,603)	($31,132)

*Statistically significant at p < 0.01.

†Costs in 2012 USD.

MS, multiple sclerosis; DMT, disease-modifying therapy; n, number of patients; PDC, proportion of days covered; SD, standard deviation.

The effect of a 10 percentage point increase in DMT adherence on direct costs was also observed in a-priori selected patient sub-groups. In the 12-month follow-up period, the impact of a 10 percentage point increase in DMT adherence on direct costs was larger for patients with adherence ≥80% compared to the overall study sample (−11.0% vs −4.1%). Direct costs were decreased by 4.6% patients without disability days during the baseline period, 4.9% for patients with no general comorbidities (CCI = 0), and by 5.8% for males, both of which are greater decreases compared to the decreases for the overall study population.

Discussion

This retrospective cohort study among employed patients with MS initiating DMTs demonstrated that patients with ≥ 80% adherence to DMTs had significantly lower urgent-care HRU and total days of work loss compared to those with < 40% adherence. Importantly, increasing adherence by 10 percentage points significantly reduced the likelihood of urgent care (i.e., inpatient and emergency room) visits, and decreased direct medical and indirect work productivity costs as well as the number of days of work loss among patients during the follow-up period.

The findings of the current study are comparable to prior ones17^,18. A study by Ivanova et al.18 among 648 employed patients with MS compared those with ≥80% adherence to those with <80% adherence (defined using MPR). This study demonstrated that patients with higher adherence had lower urgent care (i.e., inpatient and emergency room) visits over a 2-year period. Similar findings were obtained by Tan et al.17, who studied 2446 employed patients with MS initiating DMTs. The current study also demonstrated lower direct and indirect costs among patients with higher adherence compared to those with lower adherence, confirming the findings of earlier studies17^,18. Adherence to DMTs could be influenced by several factors including the MS sub-type, cognitive impairment, perceived lack of efficacy of the therapy, frequency of dosing, and adverse events associated with therapy24. Poor adherence with subsequently reduced efficacy of therapy and continued disease progression is associated with more frequent hospitalizations and emergency room visits resulting in increased costs17^,18.

The current study also identified significantly lower total number of days of work loss and disability among those with a higher adherence to DMTs during each follow-up period. Ivanova et al.18 also demonstrated similar findings; however, these were not statistically significant in their study (p > 0.05). Several reasons could account for this difference in findings; the current study compared outcomes between those with ≥ 80% adherence to DMTs and < 40% adherence, a group including patients with substantially poor adherence, while Ivanova et al. compared patients with ≥80% adherence to those with <80% adherence. Additionally, Ivanova et al. excluded patients who were on disability leave or had medically-related absenteeism for the entire 3-month period before the index date. This criterion potentially excluded patients with more severe stages of the disease, while the current study did not impose this criterion. Another difference is that the current study also included data for newer drugs with potentially improved safety and ease of administration likely resulting in improved adherence and efficacy of the treatment24.

Our findings demonstrate that a 10 percentage point increase in adherence to therapy could significantly reduce urgent-care HRU, days of work loss, and direct and indirect costs for MS patients. The current study also found that, with observed adherence, the total days of work loss at the 36-month follow-up was very high, ∼121 days, and a 10 percentage point increase in adherence led to an ∼6% reduction in the number of days of work loss. Furthermore, an increase in adherence led to a 4% reduction in direct medical and indirect costs. In addition to reducing urgent-care HRU and medical costs, our findings suggest that improved adherence could significantly reduce the indirect burden to employers, as employees with higher adherence will have a lower number of days of work loss (both disability and medically-related absenteeism days) and, hence, lower indirect costs.

Adherence to DMTs, measured using various definitions in the available studies, has generally been found to be sub-optimal among patients with MS15. The current study used PDC and MPR to measure adherence and also presented persistence of patients on DMTs to provide a comprehensive assessment of patient DMT use. We found that adherence decreased substantially over time, from 82% at 6 months of follow-up to 67% at 36 months of follow-up. We also observed that patients possessed their medication for an average of 79% of the days they were followed up in the study. Similar rates of adherence have been observed in earlier studies15^,25^,26. Furthermore, ∼42% of patients included in the current study were observed to discontinue therapy by 36 months after treatment initiation. This finding is similar to previous studies, which have reported almost 50% of the patients discontinuing treatment within the first few years of treatment initiation27–29.

Adherence to therapy may be affected by the type of DMT prescribed. In the current study, a majority of patients were initiated on DMTs administered subcutaneously. Although adherence by different DMTs prescribed was not assessed in our study, other studies have reported higher rates of adherence among patients initiated on IM interferon beta-1a compared to other injectable DMTs26^,30. In addition, two recent studies have found that an oral DMT for the treatment of relapsing form of MS, fingolimod, had higher rates of adherence and persistence compared to injectable or infused DMTs21^,31. The improved adherence observed could be explained partly by the convenience of the dosing schedule and side-effects32. As adherence to therapy among patients with MS has been reported to decline after the initiation of treatment, and sub-optimal adherence has been demonstrated to be associated with adverse clinical outcomes and subsequent higher costs, new therapies with different modes of administration, particularly oral therapies, may prove beneficial in reducing costs and improving outcomes.

The findings of the current study on the effect of increasing adherence to DMT among patients with MS have important implications. Close collaboration should be encouraged between the patient and the provider to ensure patient’s concerns are dealt with appropriately and in a timely fashion24^,30. Patients should also be monitored for drug intake frequently. Establishment of programs for patients with educational sessions to increase awareness about the disease, reminders for missed drug refills, and individual or group counseling to increase adherence can prove beneficial33. Involvement of family members and strategies to improve adherence and prevent discontinuation should be incorporated in regular patient care. Furthermore, a prospective study evaluating the effect of an increase in adherence on healthcare resource use and costs would help to validate the current findings and provide insights on important steps patients and providers should take to improve adherence.

This study has several strengths. It evaluated the effect of increasing adherence to DMTs on HRU and direct medical and indirect work loss costs. As the study sample consisted of employed patients, it allowed the assessment of indirect costs related to work loss and disability payments. Lastly, adherence was measured using both PDC and MPR, along with the persistence to DMTs which allowed a comprehensive assessment of patient behavior in a real-world setting.

There are several limitations of this study. Because this is a retrospective study conducted using a healthcare claims database primarily collected for administrative purposes and lacking clinical details of disease characteristics, the MS disease sub-type could not be identified. Thus, HRU and costs outcomes could not be stratified by the severity of the disease. Another inherent limitation of a claims database study is the use of claims for the identification of the disease of interest and of comorbidities that could be subject to misdiagnosis or coding error. In regards to the indirect cost calculation, a limitation of the claims data is that there is no information on the work schedule of each employee. Thus, the analysis assumed that each employee maintained a traditional weekday and office hour schedule. Furthermore, this study analyzed direct medical costs and indirect costs from disability and medically-related absenteeism, but did not include any additional societal costs related to MS, such as caregiver burden, which may constitute a substantial burden to the family of patients with MS, or presenteeism, which may be an additional burden to employers. In addition, the analyses presented in the current study could not establish causality as adherence, and outcomes were measured for the same time periods. Finally, this study was limited to patients with MS who were privately employed and retained employment throughout the duration of the study, and, hence, the study findings may not be generalizable to all patients with MS in the US.

Conclusions

This study demonstrated that an increase in DMT adherence significantly decreased inpatient and emergency room visits, number of days of work loss, and direct and indirect costs among patients with MS initiating DMTs.

Transparency

Declaration of funding

This study was funded by Biogen Idec, Cambridge, MA.

Declaration of financial/other relationships

MC and MSD are employees of Analysis Group, Inc., a consulting company that has received research grants from Biogen Idec, including one for the current study. SY and MD were employees of Analysis Group at the time of the study. MF, BB, SS, and RI are employees of Biogen Idec.

Acknowledgments

The authors take full responsibility for the content of the paper. The authors thank Batool Haider (Analysis Group, Inc.) for writing support.

Previous presentations

Parts of the manuscript were presented as a poster at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 19th Annual International Meeting in Montreal, Canada, May 31–June 4, 2014. Yermakov S, Davis M, Calnan M, et al. Effect of Improving Adherence to Disease-Modifying Agents on Healthcare Resource Utilization and Medical Costs in Patients With Multiple Sclerosis (PND34). Parts of the manuscript were also presented at the 2014 Joint Americas Committee for Treatment and Research in Multiple Sclerosis–European Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS-ECTRIMS) Meeting in Boston, MA, September 10–13, 2014. Yermakov S, Davis M, Calnan M, et al. Impact of Improved Adherence to Disease-Modifying Therapies on Healthcare Resource Utilization and Medical Costs for Patients with Multiple Sclerosis (P029).