Adherence and compliance remain low for most medication

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1 Gaps in Treatment, Treatment Resumption, and Cost Sharing At a Glance Practical Implications e160 Author Information e164 Full text and PDF Original Research Teresa B. Gibson, PhD; A. Mark Fendrick, MD; Justin Gatwood, MPH; and Michael E. Chernew, PhD Adherence and compliance remain low for most medication classes utilized in the treatment of chronic illness. 1,2 While much attention has been paid to factors related to treatment continuation and discontinuation, little evidence exists related to gaps in therapy and, in particular, the rate of reinitiation of therapy following a sizable gap in treatment. We focus on reinitiation rates of therapy in one of the most widely used prescription medication classes in the United States. Between 1999 and 2008, cholesterol-lowering agents were one of the top medication classes utilized by adults in the United States; for those 60 years and older they were the single-most utilized class of prescription drugs. 3 A widely accepted treatment for high cholesterol, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) remain the predominant therapy and their use continues to grow. 4 Furthermore, it is well documented that adherence to statins improves cardiac outcomes, reducing the risk of coronary heart disease related events (the Scandinavian Simvastatin Survival Study, 5 the Long-Term Intervention with Pravastatin in Ischaemic Disease Study, 6 the West of Scotland Coronary Prevention Study, 7 and the Air Force/Texas Coronary Atherosclerosis Prevention Study 8 ). In spite of such support for continued use, numerous studies have shown that adherence to statins remains low, with many patients experiencing significant gaps in therapy: rates of statin treatment persistence after 1 year range from 35% to 72%. 1,9-11 Discontinuation contributes to these suboptimal use rates, and has been shown to limit the effectiveness of treatment and increase the risk of coronary heart disease related morbidity and mortality Explanations for statin discontinuation given by patients have included adverse effects, beliefs about medications, and running out of medication. 15 However, McGinnis and colleagues reported that a majority of patients had no documented motivation for discontinuing treatment. 10 Recent investigations have suggested that statin adherence may also ABSTRACT Objectives: To describe the rate of return to statin therapy after an observed stoppage and to examine whether patient cost sharing plays a role in the resumption of therapy. Study Design: We conducted a retrospective, observational study of a cohort of commercially insured patients with a treatment gap in statin therapy. Methods: The 2006 to 2009 prescription drug and medical claims experience of individuals aged 18 to 64 years who fi lled at least 2 statin prescriptions was included. Treatment gaps were defi ned as at least 90 days without statin medications. To analyze the association between cost sharing and fi lling behavior within 1 year of discontinuation we estimated an alternative-specifi c conditional logit model, including cost-sharing prices faced for alternatives (brand, generic, no fi ll). Models controlled for sociodemographic characteristics, health status, and time. Results: Nearly half (42.5%) of patients with at least a 90-day gap in statin therapy did not return to treatment within the next year. Patients discontinuing branded statins were more likely to return to treatment (61.6%) than patients discontinuing generic statins (54.4%) (P <.01). Most patients reinitiating treatment returned to the type of medication (brand or generic) initially discontinued. Higher patient cost sharing, for both brand and generic medications, was associated with lower odds of a subsequent prescription fi ll (adjusted odds ratio = 0.989; 95% confi dence interval: ). Conclusions: Intermittent treatment stoppages with statins are common, they may last for several months, and only half of patients return to treatment. Assistance or interventions by providers and pharmacists to help reconnect patients with needed treatment may lead to improvements in the persistence of therapy. (Am J Pharm Benefi ts. 2012;4(6):e159-e165) Vol. 4, No. 6 The American Journal of Pharmacy Benefi ts e159

2 n Gibson Fendrick Gatwood Chernew PRACTICAL IMPLICATIONS For patients who have intentionally stopped their statin therapy, the odds of resuming use is, in part, influenced by the level of their cost burden. n n n While statin use is highly prevalent, interruptions in therapy are common and may appear early in the treatment process. Most patients that eventually resume therapy return to the same type of medication (generic or brand) they had stopped taking. Physicians and pharmacists need to be aware of the potential for stoppages in therapy and aid in the continuation of treatment, as most patients with a stoppage returned to statin use. be linked to levels of cost sharing the price faced by a patient to fill a medication within the patient population. In several instances, higher levels of cost sharing have been shown to adversely affect adherence to statin medications As many health plans offer differential copayments for generic and brand name medications, patients typically face a range of brand and generic cost alternatives among statins. However, statins are not entirely interchangeable; for a specific patient, treatment outcomes may differ among statins. This study has 2 aims. First, we describe the rate of return to statin treatment after an observed stoppage and the type of medication resumed. Second, we analyze whether patient cost sharing plays a role in the resumption of therapy within the subsequent year. To our knowledge this investigation will be the first to assess the purchasing decisions of patients restarting statin therapy after an initial discontinuation while taking into consideration the potential role that cost sharing may play in the decision to do so. METHODS Data Source This analysis was based on data from the 2006 through 2009 Truven Health MarketScan Commercial Claims and Encounters Database. The Commercial Claims and Encounters Database represents the healthcare experience of tens of millions of active employees, retired employees, and their dependents annually who obtain healthcare insurance from medium- and large-sized firms, including linked inpatient and outpatient medical claims, outpatient prescription drug claims, and enrollment information. Study Population We examined the utilization patterns of adult patients aged 18 to 64 years who filled at least 2 statin prescriptions from January 1, 2007, through September 30, 2008, with the second prescription filled within 30 days of exhausting the days supply of the previous prescription. Patients with any indication of pregnancy during the study time frame were excluded. Starting with the first observed fill, we determined whether the patient had medication available on any given day based on the days supplied in each prescription fill. If a patient filled a subsequent statin prescription before the days supplied of the previous prescription ended, the days supplied for the new prescription were appended to the end date of the previous prescription to maximize the number of days medication was available. We identified the beginning of a gap in adherence when the days of available medications ended without a subsequent prescription fill. We found patients with a 90-day or larger gap in statin medication coverage. For these patients the index date was defined as the end of the 90-day gap, which was the date 90 days after the last day of statin coverage. Patients were included if they were continuously enrolled from at least 1 year before the first statin fill to at least 1 year after the index date. The type of prescription on the last claim before the gap (brand or generic) was recorded. Within 1 year, 3 alternatives existed for each patient: no statin filled, filled with a brand name statin, and filled with a generic statin. We also analyzed patients with a 180-day or larger gap in statin medication coverage using similar methods. Statistical Analysis Each patient faced 3 filling alternatives (no fill, brand, and generic). To analyze the association between cost sharing and these alternatives we estimated an alternative-specific conditional logit model (McFadden s choice logit). 20 The relevant cost-sharing amounts were applied to each alternative (alternative-specific characteristics). For example, the generic statin cost-sharing amount the patient faced in their plan was applied to the generic treatment alternative; the brand name costsharing amount the patient faced in their plan was applied to the brand name treatment alternative; no fill was zero ($0). Other covariates included sociodemographic characteristics, health plan type, health status, and office visit cost-sharing amounts. Based on the model results we calculated the effects of cost sharing for each treatment on the probability of selecting each treatment alternative. 21 Measures The key explanatory variables were the patient out-ofpocket cost-sharing amounts in effect on the index date e160 The American Journal of Pharmacy Benefits November/December 2012

3 Treatment Gaps and Cost Sharing Table 1. Patient Characteristics 90-Day Gap (N = 122,886) 180-Day Gap (N = 62,851) Brand name copayment, $ (SD) (11.84) (11.93) Generic copayment, $ (SD) 6.23 (3.37) 6.29 (3.32) Office visit copayment, $ (SD) (9.77) (9.95) Age group Age (%) Age (%) Age (%) Female (%) Employee (vs spouse/dependent) (%) Urban residence (%) Census region North east region (%) North central region (%) South region (%) West region (%) Median income in zip code, $ (SD) 47,695 ( ) 47,589 ( ) Health status (lagged 1 year) Charlson Comorbidity Index (SD) 0.58 (1.03) 0.57 (1.02) Number of psychiatric diagnostic groupings (SD) 0.17 (0.52) 0.18 (0.53) Index quarter 2Q 2007 (%) Q 2007 (%) Q 2007 (%) Q 2008 (%) Q 2008 (%) Q 2008 (%) Last medication filled before gap Brand name medication (%) Generic medication (%) SD indicates standard deviation; Q, quarter. for each alternative (brand, generic, no fill). For example, the brand name and generic statin cost-sharing amounts represented the statin copayment or coinsurance amount that a patient faced under their specific employer s plan. When measured in this way, a price was determined for branded and generic statins in the patient s health plan even if the patient did not fill both types of statin prescriptions, because the copayment is a function of the plan. Other explanatory variables (that were not alternative specific) were measured at the index date and included sociodemographic characteristics (age, gender, urban [vs rural] residence, US Census region, employee [vs spouse or dependent]), median income in the patient s zip code of residence (via the US Census files), and health plan type (indemnity, preferred provider organization vs other plan types [eg, health maintenance organization, point of service plan]). Health status variables were measured in the year prior to the index date and included: the Charlson Comorbidity Index, an aggregate measure based on diagnoses associated with 19 conditions with a range from 0 to ; the number of psychiatric diagnostic groupings; 12 mental health comorbidities including alcohol use disorders, other substance use disorders, depression, bipolar disorder, and schizophrenia 23 ; and the number of non-statin prescriptions filled in the year prior to the index date (disease burden and medication management Vol. 4, No. 6 The American Journal of Pharmacy Benefits e161

4 n Gibson Fendrick Gatwood Chernew Figure. Treatment Alternative in the Year Following a 90-Day Gap % of Patients % 9.7% 38.4% Stopped Brand (n = 61,165) 4.5% 49.9% 45.6% Stopped Generic (n = 61,721) burden). Physician visit cost-sharing amounts for the patient s health plan were also included. An indicator variable for the quarter of the index date (eg, fourth quarter 2007) was included in the models, as was a fixed effect for the employer to account for any time-invariant characteristics common to all employees of an employer. RESULTS We found 724,837 patients aged 18 to 64 years with no indication of pregnancy who filled a second statin prescription within 30 days of exhausting the days supply of the first prescription. These patients were continuously enrolled at least 1 year before the first statin fill. Of these patients, 185,737 (25.6%) had at least a 90-day gap in statin medication treatment at some point in our study period. Of the patients with a 90-day gap, 122,886 (66.2%) were continuously enrolled at least 1 year after the index date (could be followed at least 1 year after the index date, ie, the date at the end of the 90-day gap) and comprise the main patient sample. Patient characteristics for the 90-day gap and 180-day gap cohorts were similar (Table 1). Slightly over half of the patients were aged 55 to 64 years, slightly less than half were female, and about two-thirds were employees (vs spouses and dependents). Almost half resided in the South Census region (a reflection of the composition of the convenience sample). Serious comorbidities were not highly prevalent (mean Charlson Comorbidity Index was well under 1 and the average number of psychiatric diagnostic groupings was 0.17). On average, patients filled prescriptions for slightly more than 6 non-statin prescription medications in the year prior to the index date. Filled brand Filled generic No fill Brand name copayments were $20 per fill and generic copayments were approximately $6 per fill, on average. Office visit cost sharing was slightly over $15 per visit. Approximately half (49.8%) of the patients filled a brand name medication before the treatment gap, and half filled a generic medication (50.2%) before the treatment gap. Nearly half (42.5%) of patients with at least a 90-day gap in statin therapy did not return to treatment within the next year. Patients discontinuing branded statins were significantly more likely to return to treatment (61.6%) than patients discontinuing a generic statin (54.4%) (P <.01). If a patient returned to treatment within the next year, for the most part, they tended to return to the type of treatment that they were on prior to the gap in care. For example, of the patients with a gap after a generic prescription fill, 49.9% filled a generic prescription within a year, and 4.5% filled a brand name prescription (Figure). Results from the alternative specific conditional logit model showed that higher cost sharing was associated with lower odds of filling a statin prescription after a gap in treatment (Table 2). While prices for brand and generic medications from each patient s plan were entered separately in the model, a single marginal effect of an increase in cost sharing was obtained, and higher cost sharing was associated with a reduction in the odds of augmentation (adjusted odds ratio = 0.989; 95% confidence interval: for all patients). Finally, we estimated the effects of a change in cost sharing varying the prices of brand and generic statins 1 at a time on the probability of no fill within 1 year (Table 3). At a $5 brand name copayment the probability of no fill within 1 year was 40.6%, while at $45 the probability of no fill rose to 45.7%, a 12.6% increase. Varying the generic copayments from $5 to the maximum found in the data of $25 showed a smaller estimated increase in the probability of no fill, from 42.4% to 45.1%. We repeated the analysis using a 180-day gap in treatment and found similar patterns of resumption and in the costsharing effects. e162 The American Journal of Pharmacy Benefits November/December 2012

5 Treatment Gaps and Cost Sharing Table 2. Adjusted Odds Ratios of Cost-Sharing Amounts ($) on Treatment Resumption by Type of 90-Day Treatment Failure Model n Adjusted Odds Ratio a 95% CI P All 122, [ ] <.01 Stopped Brand 61, [ ] <.01 Stopped Generic 61, [ ] <.01 CI indicates confidence interval. a The adjusted odds ratio of cost-sharing amounts in dollars on treatment failure. DISCUSSION In this analysis of prolonged treatment gaps in statin therapy it was found that nearly half of patients did not return to treatment after an initial 90-day gap in therapy. These rates of return to treatment are consistent with a previous study by Brookhart et al assessing the resumption of statin therapy among a cohort of patients in British Columbia which found that 48% of patients resumed statin treatment after a 90-day gap. 24 As described, patients were more likely to re-initiate therapy on the type (brand or generic) of statin which had originally been prescribed for them. This suggests that these patients most likely refilled an existing, valid prescription for the statin they had been previously prescribed a pattern unlikely for those who had previously experienced adverse effects while taking the prescribed medication. Counterintuitively, individuals taking branded statins were significantly more likely to return to treatment than those who discontinued a generic statin, even though the average copayment for a branded agent was more than those for generic alternatives. Additionally, patient cost sharing, for those stopping treatment, was observed to play a role in the return to treatment, the probability of which was dependent on the level of copayment. The association between cost sharing and treatment resumption was not limited to brand name medications, but was also evident for patients who stopped a generic medication most returning to a generic. While no other study has examined the role of cost sharing in the resumption of statin therapy following a treatment gap, the size of the association between patient cost sharing and treatment resumption is smaller than the effects seen in studies examining the association between patient cost sharing and adherence. Even so, this is further evidence that cost burden is an important influence in the medication-taking decision process. It is important to note that in certain clinical circumstances (eg, adverse effect, drug-drug interactions, failure to reach cholesterol goal), those who appropriately stop a generic statin may require a higher-cost branded drug. This increase in patient cost sharing to allow a clinically indicated switch within the statin class may contribute to the lower return to therapy rates for those who discontinued a generic agent. In order to mitigate adverse clinical outcomes secondary to cost-related nonadherence, it has been suggested that the cost sharing for brand name medications might be lowered after an unsuccessful trial with an available generic option. This reward the good soldier approach maintains financial incentives to use generics initially, yet mitigates the concern that patients who do not clinically respond to generic agents would discontinue high-value drug classes altogether due to the additional financial burden associated with a branded, higher-tier prescription. 25 The good soldier benefit design concept differs from many step-edit or fail first programs in that after appropriate, initial medication use has been attempted, subsequent copayments for branded (or second/third step) drugs are then set below copayments for medications in the same tier. Since many patients did not reinitiate therapy after several months of nonadherence, it is possible that the gap in treatment may be explained by the patients inability to acquire the indicated statin. In some circumstances, patients may only be able to renew an expired prescription from the provider who initially prescribed the treatment a phenomenon that was previously observed to impact filling behavior. 24 For patients unable to see this provider, perhaps due to the cost of the visit or an inability to schedule an appointment in a timely manner, the number of days without treatment would accumulate. In the case of statins where a specialist may have originated treatment it is reasonable that a gap may accrue beyond the expiration date of the prescription before the patient is able to see the provider and obtain a prescription renewal. The relationship between renewal policies and treatment gaps warrants further study. The inability to ascertain precise reasons for discontinuation of therapy was one of the limiting factors of this analysis and a consequence of using administrative claims data. In addition, we could not determine the reasons why one compound was selected over another. Also, it was assumed that the filling of prescriptions meant that consumption of the drug took place, indicating adherent Vol. 4, No. 6 The American Journal of Pharmacy Benefits e163

6 n Gibson Fendrick Gatwood Chernew Table 3. Copayments and the Probability of No Fill Within 1 Year Copayment ($) Probability of no brand statin fill within a year (%) Probability of no generic statin fill within a year (%) N/A N/A behavior; however, such precise action could not be accounted for. Additionally, since clinical data were not included in the analysis, treatment stoppages due to adverse effects or changes in disease severity could not be evaluated. The study also used a population of continuously enrolled patients who received healthcare coverage from their employer; therefore, these results may not be representative of those without similar levels of insurance or income, or for whom a larger share of their income is allocated to prescription medications or other healthcare costs. The results described suggest that close to half of patients who have discontinued statin therapy are unwilling or unlikely to return to treatment after a gap of 3 months or more. This has both methodological and clinical implications. From a methodological standpoint many studies define discontinuation of medication treatment as a 30-, 60-, or 90-day gap in coverage, and reported variations in the rate of return to therapy may be affected by the definition used to determine discontinuation. 26,27 Applying our 90- and 180-day definitions, the findings suggest that resumption is highly likely for many of these patients even those with longer gaps and such results remain consistent with previous analyses of medication use disruptions. 24 Our findings suggest that the design of studies associating discontinuation and outcomes needs to be informed by the potential for many patients to resume treatment after a sizable gap. From a clinical standpoint, since many clinical trials have demonstrated that the benefits of statins are more apparent after 2 years of therapy, the removal of such a gap is important to the patient s progress. As a substantial minority of the patients in our study did not return to therapy, the implication is that medication-independent factors led to the initial discontinuation; the identification of such contributing factors, including cost-related barriers, remains important. Both physicians and pharmacists need to be aware of the potential for intermittent treatment stoppages that may last for several months. Assistance or interventions by providers and pharmacists when treatment gaps occur including clinically targeted benefit design changes may help reconnect patients with needed treatment and lead to improvements in the persistence of therapy. Author Affiliations: From Truven Health (TBG, JG), Ann Arbor, MI; University of Michigan Medical School (AMF), Ann Arbor, MI; Harvard Medical School (MEC), Boston, MA. Funding Source: This project was funded by Pfizer, Inc. All opinions expressed are those of the authors. Author Disclosures: Dr Gibson and Mr Gatwood report employment with Truven Health, which received funds from Pfizer, Inc, to complete this work. Dr Fendrick reports having received consultancies from Abbott, ActiveHealth Management/Aetna, AstraZeneca, BlueCross BlueShield Association, Centers for Medicare & Medicaid Services, Genentech, GlaxoSmithKline, Health Alliance Plan, Aon Hewitt, Highmark BlueCross BlueShield, Integrated Benefits Institute, MedImpact Health- Care Systems, Inc, Merck and Co, National Business Coalition on Health, National Pharmaceutical Council, Pfizer Inc, POZEN, Inc, Regence BlueCross BlueShield of Oregon, sanofi-aventis, Thomson Reuters, TriZetto, and zansors. He has served on speaker s bureaus for Merck and Co and Pfizer Inc, and has conducted research for Abbot, AstraZeneca, Eli Lilly, Genentech, GlaxoSmithKline, Merck and Co, Novartis, Pfizer, Inc, and sanofi-aventis. Dr Chernew reports board memberships with Abbott, FairHealth, Massachusetts Medical Society, and Benefit-Based Designs; consultancies from TriZetto, AHIP, Hewitt, Genentech, Pfizer, and the VBID Institute; as well as payment for involvement in the preparation of this manuscript from Precision Health Economics, New America Foundation. Authorship Information: Concept and design (TBG, AMF); acquisition of data (TBG, AMF); analysis and interpretation of data (TBG, AMF, JG, MEC); drafting of the manuscript (TBG, AMF, JG, MEC); critical revision of the manuscript for important intellectual content (TBG, AMF, JG, MEC); statistical analysis (TBG, MEC); provision of study materials or patients (TBG); obtaining funding (TBG); administrative, technical, or logistic support (AMF); and supervision (TBG). Address correspondence to: Teresa B. Gibson, PhD, Truven Health Analytics, 777 E Eisenhower Pkwy, Ann Arbor, MI teresa.gibson@truvenhealth.com. REFERENCES 1. 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