Burden of Changes in Pill Appearance for Patients Receiving Generic Cardiovascular Medications After Myocardial Infarction

Context Generic medications are not required to have a similar appearance to brand-name medications or each other even though they are therapeutically interchangeable. Contribution Thirty percent of patients initiating treatment with a generic cardiovascular drug in 3 therapeutic classes after hospitalization for myocardial infarction had a change in medication shape or color. These changes were associated with nonpersistent use of the medications. Caution Clinical outcomes were not assessed. Implication Changes in the physical appearance of medications may be associated with gaps in patients' medication use. The Editors Generic drugs are essential to the treatment of cardiovascular disease. They are available in nearly every class of relevant medicationsincluding antihypertensive, lipid-lowering, anticoagulant, antiplatelet, and antiarrhythmic agentsand are inexpensive for patients and payors (1). The U.S. Food and Drug Administration (FDA) certifies qualifying generic drugs as being interchangeable with their brand-name counterparts on the basis of bioequivalence testing (2). Individual studies (3) and meta-analyses (4) show that patients who receive generic and brand-name drugs achieve equivalent clinical outcomes. Patients who reduce out-of-pocket spending by using generic drugs are more likely to adhere to their medication regimens (5, 6), which can improve cardiovascular outcomes (7, 8). Thus, most policymakers, physicians (9), and payors (which use tiered formularies that incentivize patients to fill prescriptions with generic drugs) encourage the use of generic drugs. The U.S. Government Accountability Office found that generic drugs contributed to more than $1 trillion in savings to the U.S. health care system in the past decade (10). Generic drugs may be therapeutically interchangeable, but they are not required to look the same as their brand-name counterparts (11) or other generic versions of the same product (12), in part for historical reasons (13). Yet, pill appearance can be an important driver of patients' health care experience (14). Pill color mediates patients' clinical response to medication (15), and changes in pill appearance contribute to patient confusion and medical error (16, 17). Changes in the appearance of medications used to treat chronic conditions may lead to nonadherence and negative health outcomes (18, 19). We have shown that changes in pill color among otherwise bioequivalent antiepileptic drugs were associated with a nearly 30% increased odds of nonpersistent use of medication (20). One half of patients with cardiovascular disease or its major risk factors adhere poorly to their prescribed medications (21), even in the year after myocardial infarction (MI) (22). Contributors include patient factors (23); providers (24); and routine aspects of health care delivery, such as medication burden (25). The association between nonadherence to cardiovascular medications and negative patient outcomes has been well-documented (2628). To improve adherence to cardiovascular medications, investigators have eliminated drug copayments (29), enhanced the use of cardiac rehabilitation programs (30), and implemented direct patient education (31). However, even effective interventions show incomplete results and these programs are costly, limiting their applicability. We identified a cohort of patients who had an MI and followed their refill habits for 1 year to assess the effect of variations in the color and shape of the cardiovascular medications dispensed to them. We also assessed the relationship between such changes in pill appearance and patients' persistence to their prescribed regimens during this sensitive time. Methods Research Design We did 2 analyses of patients initiating treatment with -blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin IIreceptor blockers (ARBs), or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) after hospital discharge for MI. First, we did a cohort study to evaluate the incidence of changes in color and shape among the generic medications dispensed after MI. We then used a nested casecontrol design to determine whether the odds of nonpersistence increased after a change in pill appearance (Figure). Adherence and persistence are similar concepts; however, our study technically measured persistence, which is the time from initiation to discontinuation of therapy (32). The Institutional Review Board at Brigham and Women's Hospital (Boston, Massachusetts) approved these studies. Figure. Organization of cohort and nested casecontrol studies. MI = myocardial infarction. * No history in the prior 6 mo of receiving any drugs in the same therapeutic class. Control patients were selected from members of the cohort who were receiving the same class of drugs as case patients; were still under observation when case patients discontinued their index medication; and were further matched on age (5 y), sex, and the number of dispensings of the index medication. Data Synthesis and Analysis Data Sources We collected medical and pharmacy data from the UnitedHealth research database, a commercial insurance database covering more than 14 million persons annually. The database describes all participants, their demographic information, and the enrollment status of their health plan and includes inpatient and outpatient medical encounters (coded using the International Classification of Diseases, Ninth Revision, Clinical Modification, and Current Procedural Terminology, Fourth Edition) and filling prescriptions, including the National Drug Code numbers, quantity dispensed, and days' supply. Data were available from January 2006 through June 2012. We then linked pharmacy claims data by National Drug Code number to FDB MedKnowledge (formerly the First Databank National Drug Data File), which contains information on formulation (for example, capsule, tablet, or suspension), dose, color, and shape. Cohort Identification The study cohort consisted of patients aged 18 years or older discharged after MI (index hospitalization) between 1 July 2006 and 31 June 2011 who newly initiated treatment with a generic version of a -blocker, ACEI, ARB, or statin within 90 days of discharge. A diagnosis of MI was identified by a principal or secondary discharge diagnosis code 410.x2 with a 3- to 180-day length of stay. Previous research showed that this algorithm had a high positive predictive value (97%), sensitivity (96%), and specificity (99%) for MI (33). Patients were required to have at least 6 months of continuous insurance enrollment before discharge and at least 12 months of continuous enrollment after discharge. We required that dispensed medications be in pill form (tablet or capsule) and have at least 2 generic versions available on the U.S. market (Appendix Table 1, shows the list of eligible medications and when this second criterion was met). A prescription was newly initiated if no prescriptions were filled for any drug in the same therapeutic class in the 6 months before treatment initiation. For patients who initiated treatment with more than 1 therapeutic drug class, each eligible episode of treatment initiation was evaluated separately; thus, patients could have up to 3 cohort entries. Appendix Table 1. Study Drugs Leading to Inclusion in Cohort Patients were followed for 12 months after MI discharge and were censored if they were hospitalized for a subsequent MI, switched to a different drug in the same therapeutic class, or discontinued treatment with the index medication. Discontinuation was defined as a gap of 31 days or longer after the end of the days supplied in the last fill. Covariates We extracted the following information from the database: demographic characteristics (age at index hospital discharge and sex), characteristics of index hospitalization (whether a patient had coronary artery bypass grafting, placement of a percutaneous coronary stent, or percutaneous coronary angioplasty), coexisting illnesses (such as congestive heart failure, chronic obstructive pulmonary disease, diabetes, and previous MI or stroke), prior medication use (ACEIs, ARBs, -blockers, statins, clopidogrel, and warfarin), and use of health care services (the number of distinct medications filled, hospitalizations, inpatient days, and physician visits). The latter 3 categories were assessed during the 6 months before the index hospitalization for MI. In the absence of recorded diagnosis or procedure code, the covariate value was 0. Cohort Study of the Effect of Pill Appearance We expressed rates of changes in color and shape during follow-up as the number of changes (defined as a refill discordant in color or shape) divided by the total number of filled prescriptions. We calculated these rates for each therapeutic class separately and overall. We further distinguished whether changes in medication color or shape between refills were related to changes in dose strength. For the overall calculation, we combined all treatment episodes and determined the rates of nonpersistence on the patient level, with treatment episode as the unit of analysis. We compared patients with at least 1 change in pill appearance unrelated to change in dose with patients who did not have such changes by using chi-square and t tests, as appropriate. We further explored the associations between rates of change with the covariates by fitting a generalized estimating equation with logit link function and binary distributed errors. We adjusted for all covariates in the analysis. Nested CaseControl Analysis To evaluate the association between changes in pill appearance and medication discontinuation, we identified members of the cohort who discontinued treatment with each index medication (case patients). The 31-day gap required for discontinuation was shortened to 7 days and extended to 60 days in sensitivity analyses. Because we censored members of the cohort when they discontinued