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Healthcare Utilization and Statin Re‐Initiation Among Medicare Beneficiaries With a History of Myocardial Infarction

Background Contact with the healthcare system represents an opportunity for individuals who discontinue statins to re‐initiate treatment. To help identify opportunities for healthcare providers to emphasize the risk‐lowering benefits accrued through restarting statins, we determined the types of healthcare utilization associated with statin re‐initiation among patients with history of a myocardial infarction. Methods and Results Medicare beneficiaries with a statin pharmacy fill claim within 30 days of hospital discharge for a myocardial infarction in 2007 to 2012 (n=158 795) were followed for 182 days postdischarge to identify treatment discontinuation, defined as 60 continuous days without statins (n=24 461). Re‐initiation was defined as a statin fill within 365 days of the discontinuation date (n=13 136). Using a case‐crossover study design and each beneficiary as their own control, healthcare utilization during 0 to 14 days before statin re‐initiation (case period) was compared with healthcare utilization 30 to 44 days before statin re‐initiation (control period). The mean age of beneficiaries was 75.4 years; 52.8% were women and 81.9% were white. For routine healthcare utilization, the odds ratio (95% confidence interval) for statin re‐initiation associated with lipid panel testing was 2.65 (1.93–3.65), outpatient primary care was 1.31 (1.23–1.40), and outpatient cardiologist care was 1.38 (1.28–1.50). For acute healthcare utilization, the odds ratio (95% confidence interval) for statin re‐initiation associated with emergency department visits was 1.77 (1.31–2.40), coronary heart disease (CHD) hospitalizations was 3.16 (2.41–4.14) and non–coronary heart disease hospitalizations was 1.73 (1.49–2.01). Conclusions The weaker association of routine versus acute healthcare utilization with statin re‐initiation suggests missed opportunities to reinforce the importance of statin therapy for secondary prevention.

patients discontinue this treatment within 1 year. [6][7][8] However, many patients who discontinue statins frequently reinitiate therapy. [9][10][11] Among Medicare beneficiaries who discontinued statin treatment following a myocardial infarction, 53.7% re-initiated therapy within 1 year. 12 Data from patients in Canada in the late 1990s and early 2000s indicate that healthcare utilization including lipid panel testing and visiting the physician who initially prescribed their statin was associated with treatment re-initiation. 10 Contemporary US-based data on healthcare encounters associated with re-initiating statins are limited. Determining whether statins are re-initiated following specific types of healthcare encounters may identify opportunities to reinforce the importance of statin therapy for secondary prevention. In the current study, we identified healthcare utilization associated with statin re-initiation among Medicare beneficiaries who were hospitalized for a myocardial infarction (MI) and had discontinued treatment. 13,14 Methods Data used in this study are available from the Centers for Medicare and Medicaid Services. Other study information is available from the corresponding author.

Study Population
We conducted a case-crossover study of Medicare beneficiaries with a history of MI who discontinued and subsequently re-initiated statin therapy. Medicare is a federal health insurance program that covers adults aged 65 years and older as well as younger adults with disabilities or end-stage renal disease in the United States. We identified all beneficiaries with a hospitalization claim for a MI between January 1, 2007 and December 31, 2012 (n=918 464). MI hospitalizations were identified using the International Classification of Disease, Ninth Revision (ICD-9) coding system (410.xx in any discharge diagnosis position except 410.x2, which indicates a subsequent episode of care) from Medicare Part A in-hospital claims. 15 We restricted analyses to beneficiaries who had consistent demographic information, were ≥66 and <110 years of age, had Medicare Part A (inhospital), Part B (outpatient), and Part D (pharmacy) coverage without Part C (Medicare Advantage) coverage and were alive at least 730 days following hospital discharge for a MI (Figure 1). We excluded beneficiaries <66 years of age because Medicare beneficiaries <65 years of age represent a select population with disabilities or end-stage renal disease and we used a 1-year baseline period to assess covariates. We excluded beneficiaries with inconsistent demographic data because this suggests that multiple individuals were linked to the same beneficiary identification number. Additionally, beneficiaries were required to live in the United States from 365 days before admission for their MI through 730 days postdischarge, not to have hospice care from 365 days before their MI hospitalization through 730 days postdischarge, and not to have skilled nursing facility care from MI discharge through 730 days postdischarge. We excluded beneficiaries who received hospice or skilled nursing facility care because there are gaps in the prescription claims during these periods. We also excluded beneficiaries who did not fill a statin prescription within 30 days following hospital discharge for MI. Each patient's first eligible inpatient MI hospitalization claim was defined as their index MI. After these criteria were applied, the study population included 158 795 beneficiaries. 12 Beneficiaries were followed to identify statin discontinuation within 182 days postdischarge for their index MI hospitalization. Discontinuation of statin therapy was defined as having a 60-day continuous period with no statin supply. The date that a beneficiary had 60 continuous days with no days of supply for statins was assigned as their discontinuation date. Statin pills remaining from prescriptions filled before the MI hospital admission were included in a beneficiary's statin supply following hospital discharge. Additionally, if a beneficiary had statin pills remaining from a prescription when a refill occurred, the existing statin supply was added to the new statin fill. Statin re-initiation was evaluated during the 365 days following the discontinuation date. Beneficiaries who had a Part D claim for a statin during this period were categorized as having re-initiated statins. Of the 158 795 Medicare beneficiaries who met the inclusion criteria and filled a statin prescription within 30 days of discharge for their index MI, 24 461 (15.4%) beneficiaries discontinued treatment for at least 60 continuous days in the 182 days

Clinical Perspective
What Is New?
• Among Medicare beneficiaries who had a history of myocardial infarction and who discontinued statins, recent healthcare utilization was associated with statin re-initiation. • The types of healthcare utilization most strongly associated with statin re-initiation were coronary heart disease hospitalizations followed by lipid panel testing, emergency department visits, and noncoronary heart disease hospitalizations. • Outpatient primary care and cardiology office visits were also associated with statin re-initiation, but associations of office visits with statin re-initiation were weaker than associations with acute care.
What Are the Clinical Implications?
• Among patients who discontinue treatment, contact with the health system and healthcare professionals may increase the likelihood that a patient re-initiates statin therapy. • Opportunities exist to emphasize the importance of continued statin treatment at routine healthcare encounters. postdischarge ( Figure 2). Analyses included the 13 136 (53.7%) beneficiaries who re-initiated statins in the 365 days following their date of discontinuation. The University of Alabama at Birmingham Institutional Review Board governing human subject research and the Centers for Medicare and Medicaid Services Privacy Board approved the study. The requirement for informed consent was waived.

Case-Crossover Study Design
A case-crossover study design is an efficient and effective method for evaluating whether a transient exposure is associated with an acute outcome ( Figure 2). 16 The current analysis assessed the exposures of lipid panel testing, outpatient care visits, and acute care visits with the outcome  . Study design schematic. Using the case-crossover study design, each beneficiary who reinitiated statin therapy within 365 days of discontinuation was their own control. For the primary analysis, healthcare utilization (exposure) during the 0 to 14 days before statin re-initiation (case period) was compared with healthcare utilization 30 to 44 days before statin re-initiation (control period).
of statin re-initiation. Because exposure information for each beneficiary at the time of statin re-initiation is compared with his/her own prior exposure experience, each person is their own control. This self-matching eliminates confounding by risk factors that do not change over the study period within individuals but differ between individuals (eg, sex, obesity, socioeconomic status). 17 In the primary analysis, the case and control periods included the 14 days and 30 to 44 days before statin re-initiation, respectively. A sensitivity analysis was performed using the 7 days and 30 to 37 days before statin re-initiation for the case and control periods, respectively.

Beneficiary Characteristics
Medicare beneficiaries' demographics (age, race/ethnicity, sex, low-income subsidy, area-level median income), characteristics before the index MI hospitalization (cardiologist care, diabetes mellitus, stroke, chronic kidney disease, heart failure, CHD, statin use and nonstatin lipid-lowering medication use), characteristics during the MI hospitalization (length of hospitalization, coronary stent insertion, newly diagnosed heart failure, diabetes mellitus, or chronic kidney disease), characteristics following the MI hospitalization (initial statin intensity filled, last intensity filled before discontinuation) and the index hospitalization admission and discharge dates were assessed using enrollment and claims data. Age at the time of index MI hospitalization, discharge was categorized as 66 to 69, 70 to 74, 75 to 79, 80 to 84, and ≥85 years old. Race/ethnicity was categorized as non-Hispanic white, non-Hispanic black, Hispanic, Asian, and Other. Lowincome status was defined by receipt of a low-income subsidy for Part D or dual Medicare/Medicaid eligibility in the 365-day baseline period or 182 days following hospital discharge. Arealevel median income, derived from zip codes linked to US Census data, was categorized into quartiles. Diabetes mellitus, stroke, chronic kidney disease, heart failure, CHD, statin use, and nonstatin lipid-lowering medication use before the MI hospitalization were defined as having diagnosis codes for these health problems or a claim filed in the 365 days before the admission date. New diagnoses of diabetes mellitus, chronic kidney disease, and heart failure, defined as having a diagnosis code for these health problems on the same claim as the index MI hospitalization, were determined among beneficiaries without prior evidence of each specified condition. Detailed definitions are provided in Data S1. Length of hospitalization was calculated as the difference in days between the hospital discharge and admission dates.
Statin intensity was categorized as low, moderate, and high consistent with the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. 1 We categorized statin intensity using the first statin filled within 30 days of hospital discharge and, separately, the last statin filled before discontinuation.

Primary Exposures
We assessed claims for lipid panel testing, outpatient primary care visits, outpatient cardiologist care, and emergency department visits during the case and control periods for each beneficiary. We also assessed claims for non-CHD and CHD hospitalizations with discharge dates during these periods. We grouped the lipid panel testing, outpatient primary care visits, and outpatient cardiologist care visits as routine healthcare utilization and emergency department visits and CHD and non-CHD hospitalizations as acute healthcare utilization. The diagnosis and procedure codes used to define these types of healthcare utilization are provided in Data S1.

Statistical Analysis
Summary statistics comparing demographic factors among Medicare beneficiaries with MI and included and excluded from the current study were calculated as frequencies and percentages for categorical variables and mean and SD for continuous variables. Beneficiary characteristics before, during, and after the MI hospitalization were also described using frequencies and percentages for categorical variables and mean and SD or median with 25th and 75th percentiles for continuous variables among those included in the study population. Conditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for statin re-initiation associated with the occurrence of each exposure, including lipid panel testing, outpatient primary care visits, outpatient cardiologist care visits, emergency department visits, non-CHD hospitalization, and CHD hospitalization, during the 14 days (case period) compared with 30 to 44 days (control period) before statin re-initiation. This is the standard approach for matched case-control studies, except instead of case participants matched to control participants, the case and control periods were paired within the same Medicare beneficiary. 17 ORs were calculated for the overall population and within subgroups defined by history of statin use before the index MI hospitalization, race/ ethnicity, age (<75 and ≥75 years old), sex, and statin intensity discontinued. For assessing the statistical significance of differences in associations between healthcare utilization and statin re-initiation across subgroups, models were conducted using a main effects indicator variable for the healthcare utilization factors (eg, lipid panel) and a product term between the healthcare utilization factor and subgroup (eg, lipid panel*age group). The main effect term for the subgroup (eg, age group) was not included because it did not vary between the case and control periods. In a sensitivity analysis, the models described above were repeated for healthcare utilization during the 7 days (case period) compared with 30 to 37 days (control period) before statin reinitiation. P≤0.05 were considered statistically significant. Analyses were conducted using SAS version 9.3 (SAS Institute, Cary, NC).

Characteristics of Medicare Beneficiaries Who Re-Initiated Statins
Beneficiaries who met all study inclusion criteria were younger and less likely to have low-income Part D subsidy than those who were excluded (Table S1). Beneficiaries who re-initiated statins had an average age of 75.4 years, 52.8% were women, and 81.9% were non-Hispanic white (Table 1). Before the MI hospitalization, 37.2% of beneficiaries had a history of diabetes mellitus and 52.6% had a history of CHD. Statin and nonstatin lipid-lowering medications were being used before the index MI hospitalization by 50.9% and 15.0% of beneficiaries, respectively. The median length of MI hospitalization was 5 days. Overall, 60.2% of beneficiaries initially filled a moderate-intensity statin within 30 days postdischarge, and 32.9% initially filled a high-intensity statin. Also, 7.1%, 60.5%, and 32.4% of beneficiaries' last fill before discontinuation was for a low-, moderate-, and high-intensity dosage, respectively.

Healthcare Utilization and Statin Re-Initiation
In the 2 weeks before statin re-initiation, 1.1% of beneficiaries had claims for lipid panel testing, 21.9% had claims for outpatient primary care visits, 13.4% had claims for outpatient cardiology visits, 0.9% had claims for emergency department visits, 1.7% had claims for CHD hospitalizations, and 3.9% had claims for non-CHD hospitalizations. Comparing routine healthcare utilization during the 0 to 14 days (case period) with 30 to 44 days (control period) before statin re-initiation, the odds ratio (95% CI) for statin re-initiation associated with lipid panel testing was 2.65 (1.93-3.65), outpatient primary care was 1.31 (1.23-1.40), and outpatient cardiologist care was 1.38 (1.28-1.50). The OR (95% CI) for statin re-initiation associated with emergency department visits was 1.77 (1.31-2.40), CHD hospitalization was 3.16 (2.41-4.14), and non-CHD hospitalization was 1.73 (1.49-2.01) comparing these acute healthcare utilization during the 0 to 14 days (case period) with 30 to 44 days (control period) before statin re-initiation ( Table 2, top panel). These healthcare utilization factors were associated with statin re-initiation among those who were not taking (  Table S2). The ORs for the association between healthcare utilization and statin re-initiation were not statistically significantly different across strata of age, sex, and statin intensity discontinued (all P-interactions>0.05; Tables S3 through S5, respectively).
In the sensitivity analysis, lipid panel testing comparing 0 to 7 days (case period) with 30 to 37 days (control period), outpatient primary care visits, outpatient cardiologist care visits, emergency department visits, and CHD and non-CHD hospitalizations were associated with statin re-initiation ( Table 3, top panel). Outpatient cardiologist visit (P-interac-tion=0.008) and CHD hospitalization (P-interaction=0.046) had stronger associations with statin re-initiation in beneficiaries without compared with prior statin use (  Table S6). There were no statistically significant differences in healthcare utilization associated with statin reinitiation among beneficiaries grouped by age, sex, and statin intensity discontinued (all P-interactions>0.05; Tables S7 through S9, respectively).

Discussion
Recent healthcare utilization including lipid panel testing, outpatient primary care visits, outpatient cardiologist care visits, emergency department visits, and CHD and non-CHD hospitalizations were each associated with statin re-initiation. The strongest associations for statin re-initiation were with CHD hospitalizations followed by lipid panel testing, emergency department visits, and non-CHD hospitalizations; outpatient primary care and cardiology office visits were the most common healthcare encounters and had weaker associations with statin re-initiation. However, among those who re-initiated statin therapy, less than half had a claim for any healthcare encounters during the 2 weeks preceding statin re-initiation.
Statin treatment is a highly effective secondary prevention approach for reducing cardiovascular disease risk. A systematic review of 92 randomized controlled trials reported 23% to 38% lower odds of a major coronary event and 10% to 25% reduction in the odds of all-cause mortality among participants with history of cardiovascular disease who were randomized to statin therapy versus placebo. 18 However, statin discontinuation is common, with >25% of patients stopping treatment within 1 year of initiation. 8,10 Identifying factors that are associated with re-initiation in patients who discontinue therapy can help in developing approaches for increasing re-initiation rates. In turn, individuals who reinitiate treatment will continue to accrue risk reduction benefits over time. Results from the current study suggest that contact with the health system and healthcare professionals may increase the rates of statin re-initiation in those who discontinue therapy. These associations were observed for cardiovascular care (ie, outpatient cardiology visits and CHD hospitalizations) and other health system encounters (ie, outpatient primary care visits and non-CHD hospitalizations). Opportunities to emphasize the importance of continued statin treatment at routine healthcare encounters may be missed since statin re-initiation was more strongly associated with acute versus more common routine healthcare encounters, including emergency department visits and CHD and  non-CHD hospitalizations. Future studies should investigate approaches for incorporating patient counseling during routine care visits on the accrual of risk reduction benefits with statins. Statin re-initiation following discontinuation was common in this population of Medicare beneficiaries. In those who had a MI between 2007 and 2012 and filled a statin within 30 days of their hospital discharge (n=158 795), 15.4% discontinue treatment within 6 months. 12 Among this group who discontinue treatment, 53.7% re-initiated statins within 1 year, 12 suggesting that many individuals who discontinue will re-initiate statins following discontinuation. However, for many individuals it remains unclear why statins were reinitiated, since fewer than half of beneficiaries in the current study had a healthcare encounter in the 14 days before reinitiation.
Several studies have characterized the problem of statin discontinuation by identifying subgroups of patients who are at high risk for discontinuing treatment. 14,19-22 Few studies have described opportunities to re-initiate statins. Brookhart et al conducted a case-crossover study using data from 1997 through 2004 to investigate healthcare utilization associated with statin re-initiation in 129 167 new statin users from British Columbia, Canada who discontinued treatment for at least 90 days. Treatment was re-initiated in 48.0% of these individuals within 365 days of discontinuation. 10 Visiting the physician who wrote the patient's first statin prescription or another physician, lipid panel testing, and incident MI and other cardiovascular disease-related hospitalizations were strongly associated with statin re-initiation. 10 The current results are consistent with these previous findings and extend them by presenting contemporary data in a secondary prevention population and in subgroups defined by history of statin use before the MI hospitalization, race/ethnicity, age, sex, and statin intensity discontinued. The differences in statin re-initiation by history of statin use before the MI hospitalization and race/ethnicity help to identify specific populations to direct resources for increasing statin reinitiation.
The national sample of older US adults provides sufficient sample size to examine important subgroups (ie, history of statin use before a MI hospitalization, race/ethnicity, age, sex, statin intensity discontinued). Medicare beneficiaries who did not have full fee-for-service coverage and were less healthy (eg, those who died following MI and those in skilled nursing care) were excluded from the current analyses. Although the inclusion criteria resulted in a selected population, this allowed us to focus on the individuals likely to benefit from statin re-initiation. The case-crossover design permitted assessment of exposures that precipitated statin re-initiation. Confounding by unmeasured patient-level characteristics that do not change over time was accounted for using the self-controlled case-crossover design. However, unmeasured time-varying factors may have confounded the results. For example, changing perception of disease risk and statin benefits may cause a person to schedule a healthcare visit, or an event that occurs outside a physician's office may lead to lipid panel testing. Other time-varying exposures, such as cognitive, behavioral, and psychosocial factors, which could motivate individuals to re-initiate statins and might confound the association between healthcare utilization and statin re-initiation, were unavailable. In addition, we could not uniquely link lipid panel testing to ambulatory or inpatient visits or types of providers. The administrative database used in the current study did not permit the assessment of reasons that a patient discontinued statins or physician involvement in the decision. Additionally, beneficiaries might have had healthcare system contact that was not reimbursable and did not result in a claim submitted to Medicare (eg, prescription refills may have been requested through a telephone call to the physician's office or through an electronic messaging system). Last, prescription refills for which a reimbursement claim was not submitted are not present in Medicare claims.

Conclusions
Healthcare system encounters related to CHD as well as other conditions were associated with statin re-initiation among Medicare beneficiaries with history of MI. There was a weaker association of routine versus acute healthcare utilization with statin re-initiation. The current study indicates there are missed opportunities to reinforce the importance of statin therapy for secondary prevention in routine healthcare encounters.

Author Contributions
Study conception and design: Booth, Colantonio, Rosenson, Safford, Kilgore, Taylor, Dent, Monda, Muntner, Levitan; Acquisition, analysis or interpretation of data: Booth, Colantonio, Rosenson, Safford, Chen, Kilgore, Brown, Taylor, Dent, Monda, Muntner, Levitan; Statistical analysis: Booth, Chen, Levitan; Drafting of the article: Booth, Levitan; Critical revision of the article: Booth, Colantonio, Rosenson, Safford, Chen, Kilgore, Brown, Taylor, Dent, Monda, Muntner, Levitan; Chen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Sources of Funding
This research, including design and conduct of the study, analysis and interpretation of the data, and preparation of the article, was supported through an academic collaboration between University of Alabama at Birmingham and Amgen Inc. The funders provided comments on the design and interpretation of this work. The academic authors conducted all analyses and maintained the rights to publish this article.

Disclosures
Dr Rosenson receives advisory board fees from Amgen, C5, CVS Caremark, Regeneron, and Sanofi; institutional research grants from Akcea, Amgen, Astra Zeneca, Medicines Company, and Regeneron; honoraria for education from Akcea, Kowa, and Pfizer; and royalties from UptoDate, Inc. Dr Safford receives institutional research grants from Amgen and advisory board fees from Amgen. Dr Kilgore receives institutional research grants from Amgen. Dr Brown receives institutional research grants from Amgen and research support from Astra Zeneca and Omthera Pharmaceuticals.
Dr Taylor was employed at Amgen during the time this work was conducted. Dr Dent is an Amgen employee and stockholder. Dr Monda is an Amgen employee and stockholder. Dr Muntner receives research grants and advisory board fees from Amgen. Dr Levitan receives research grants and advisory board fees from Amgen and fees for scientific consulting for a research grant funded by Novartis. The remaining authors have no disclosures to report.    The Centers for Medicare and Medicaid Services requires cell counts of < 11 to be suppressed. † Indicates the association of the health utilization factor (exposure) with statin re-initiation (outcome) differs across race/ethnicities (p=0.026). 3.14 (2.33, 4.23) CHD: coronary heart disease. The association of the health utilization factors (exposure) with statin re-initiation (outcome) did not differ by age. The association of the health utilization factors (exposure) with statin re-initiation (outcome) did not differ by sex. Table S9. Odds ratio for statin re-initiation associated with healthcare utilization during the 0 to 7 days before statin re-initiation (case period) compared with 30 to 37 days (control period) before statin re-initiation by the statin intensity discontinued.
Type of healthcare utilization Case period Control period Odds ratio (95% confidence interval) N (%) N (%) Low statin intensity discontinued (N=930) Lipid panel testing