Adherence to Statins and LDL-Cholesterol Goal Attainment

Objectives:

To examine the relationship between low-density lipoprotein cholesterol (LDL-C) goal attainment and adherence to statin medications in patients with coronary artery disease (CAD).

Study Design: Cross-sectional study of CAD patients 18 years of age or older in an integrated healthcare system.

Methods: Patients dispensed 2 or more statin prescriptions between May 2009 and May 2010, were identified. Medication possession ratio (MPR) was calculated to estimate adherence. The LDL-C value closest to May 27, 2010, was used to determine goal. Adherence and LDL-C goal were defined as 80% or greater MPR and less than 100 mg/dL or less than 70 mg/dL, respectively. Electronic medical records were used to identify patient demographics and clinical information. Logistic regression was used to estimate the effect of these factors on goal attainment.

Results: A total of 67,100 CAD patients were identified. Overall, 85.8% had LDL-C less than 100 mg/dL, 32.4% had LDL less than 70 mg/dL, and 79.8% were adherent to their statin medication. Over 65% of patients not at LDL-C goal less than 100 mg/dL were adherent. Among patients with LDL-C less than 100 mg/dL, 17.9% were not adherent. Increasing medication adherence was associated with improved LDL-C levels. Adherence to statins, male sex, Asian and Hispanic race/ethnicity, a higher number of concurrent prescriptions, higher Charlson Comorbidity Index, and hypertension were associated with LDL-C goal attainment.

Conclusions: Incorporating LDL-C levels and medication adherence at the point of care allows providers to focus interventions to address either adherence challenges or the need for medication titration in an effort to improve LDL-C goal attainment and ultimately reduce morbidity and mortality.

Am J Manag Care. 2014;20(4):e105-e112

Low-density lipoprotein cholesterol (LDL-C) goal attainment is essential in coronary artery disease (CAD) patients to reduce morbidity and mortality of recurrent clinical events. We examined the association between LDL-C goal attainment and adherence to statins among CAD patients.

• Adherence to statin therapy was strongly associated with LDL-C goal attainment.

• Patients not at goal (<100 mg/dL) are more likely to be black (compared with white) and utilize more healthcare services such as the emergency department and inpatient stays.

• Many patients not adherent to their statin medication had LDL-C levels less than 100 mg/dL, suggesting that 80% adherence level may not be necessary to achieve this LDL-C goal.

Cardiovascular disease is the leading cause of death in the United States with 1 out of 5 deaths attributable specifically to coronary artery disease (CAD). Each year, approximately 635,000 people in the United States will have a new coronary attack and 280,000 will have a recurrence.¹ Patients living with CAD have an increased risk of a recurrent coronary event,^2-4 which can lead to disability or death. In addition, in 2008, CAD had an estimated total national economic burden of $190.3 billion.¹

To reduce the risk of recurrent events, the National Cholesterol Education Program (NCEP) recommends a low-density lipoprotein cholesterol (LDL-C) goal level of less than 100 mg/dL for patients with CAD through the use of lipid-lowering drugs such as hydroxymethylglutaryl-CoA reductase inhibitors (statins),⁵ and studies have shown that those who have reached this goal have lower rates of recurrence and mortality.^6-9 Despite their efficacy, the use of these drugs in CAD patients has been shown to be suboptimal.^10-12

Although studies have focused separately on LDL-C levels as well as adherence to statins among CAD patients, little is known about how adherence directly affects lipid levels in this population. We examined the association between LDL-C goal attainment and adherence to statins among CAD patients. By understanding the association of adherence and LDL-C goal attainment status, it will be possible to target the appropriate populations to ultimately improve patient treatment and outcomes.

METHODSStudy Setting and Population

This study was conducted at Kaiser Permanente Southern California (KPSC), an integrated healthcare system that provides care to approximately 3.5 million members across 10 counties in Southern California. The Institutional Review Board at KPSC approved this study.

The source population was identified from the KPSC CAD Registry, which identifies patients with CADrelated International Statistical Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes from hospitalization and outpatient and inpatient CAD-related ICD-9-CM procedure codes (available upon request). The registry includes “risk equivalent” atherosclerotic cardiovascular diseases including ischemic stroke, peripheral arterial disease, and abdominal aortic aneurysm. Deceased members and those living in skilled nursing facilities are excluded from the registry.

Figure 1

Patients eligible for this study included all adult members 18 years or older in the registry as of May 27, 2010, with 12 months of continuous prior enrollment. Patients were included if they had filled at least 2 statin prescriptions (simvastatin or a combination of simvastatin and ezetimibe) and had at least 1 LDL-C result in this time period. Patients with rhabdomyolysis, creatinine kinase greater than 10,000 IU/L, allergy or intolerance to statins, and those without continuous membership or drug benefits between May 2009 and May 2010, were excluded. A total of 67,100 members were eligible and included in this analysis ().

Data Collection and Measures

Information on patient demographics including age, gender, race/ethnicity, and clinical information including laboratory tests, prescription medications, healthcare utilization and comorbidities were extracted from health plan electronic databases. When multiple LDL-C measurements were present, the most recent measurement in the study period was extracted. LDL-C goal attainment was defined according to guidelines by the NCEP⁵ as less than 100 mg/dL and the optional goal of less than 70 mg/dL for these high-risk patients.

Information on healthcare utilization during the study period included the number of unique prescription medications (based on the generic product identified subclass), the numbers of clinic and emergency department (ED) visits and number of hospital admissions. The Deyo adaptation of the Charlson Comorbidity Index (CCI) was determined using ICD-9-CM diagnosis codes from inpatient and outpatient encounters as an overall measure of disease burden.¹³

Pharmacy fill data were extracted for each eligible individual and a medication possession ratio (MPR) was calculated looking back 400 days from May 27, 2010, as the sum of the days of supply divided by the total number of days between the first dispense date and May 27, 2010, when the most recent prescription was overdue. If the most recent prescription was not overdue, then MPR was calculated as the sum of the days of supply, excluding the last refill, divided by the total number of days between the first dispense date and last dispense date. The most recent refill was disregarded when the prescription was not overdue to avoid inflating the MPR. Adherence was defined as MPR 80% or greater, as suggested by previous studies.^4,14

Statistical Analysis

Descriptive statistics (means and proportions) were used to present patient characteristics categorized by LDLC goal attainment (<100 mg/dL; optional <70 mg/dL). Mean LDL-C levels were calculated according to various levels of adherence. Logistic regression was used to estimate the effect of adherence on LDL-C goal attainment controlling for multiple patient characteristics including adherence to statin medication, age, gender, race/ethnicity, concomitant medication use, utilization of healthcare services, CCI, and hypertension. All statistical analysis was performed using SAS version 9.2 (SAS Institute, Cary, North Carolina).

RESULTS

Table 1

Characteristics of the study population stratified by LDL-C goal attainment are shown in . Nearly 86% of the population reached the LDL-C goal of less than 100 mg/dL; 32.4% reached the optional goal of LDL-C less than 70 mg/dL; and 79.8% of the population was adherent to their statin medication (MPR ≥80%). Patients at goal had higher adherence rates (LDL-C <100 mg/dL: 82.1% vs 66.0%; LDL-C <70 mg/dL: 84.3% vs 77.7%) and lower mean LDL-C values (LDL-C <100 mg/dL: 73.4 mg/ dL vs 121.0 mg/dL; LDL-C <70 mg/dL: 57.3 mg/dL vs 91.1 mg/dL) compared with those not at goal. Patients achieving LDL-C of less than 100 mg/dL and LDL-C less than 70 mg/dL were more likely to be taking lower-dose statins and more medications compared with those not at medicagoal. In general, patients at goal were also sicker, with a higher CCI score and higher percentages of diabetes, hypertension, and prior myocardial infarction (MI). Patients achieving LDL-C less than 100 mg/dL had slightly lower utilization of hospitalizations and ED visits in the past year while patients achieving LDL-C less than 70 mg/dL had higher utilization of hospitalizations and ED visits compared with those not at goal.

Figure 2

Figure 3

In this population of patients chronically taking statin medications, increasing adherence as determined by MPR was associated with improved LDL-C levels. LDL-C goal attainment had a positive association with increasing adherence, but goal attainment leveled off once adherence was over 86% (). Men were consistently more adherent than women, and adherence increased with age ().

Table 2

Results of the multivariable logistic analysis are presented in . Patients who were adherent to their statin medication were much more likely to be at LDL-C goal than patients who were not adherent (LDL-C <100 mg/dL: odds ratio [OR], 2.24; 95% confidence interval [CI], 2.13-2.35; LDL-C <70 mg/dL: OR, 1.55; 95% CI, 1.48-1.62). Other patient characteristics associated with LDL-C goal attainment of less than 100 mg/dL included increased age, male sex, and Hispanic and Asian race/ethnicity (compared with whites). Patients prescribed more medications, and who had higher CCI scores, and who had hypertension, were more likely to have LDL-C less than 100 mg/dL. In contrast, black patients with CAD had lower odds of LDL-C less than 100 mg/dL compared with whites. Patients with more hospitalizations and ED visits in the prior year were also less likely to have LDLC of less 100 mg/dL. Results of the multivariable logistic regression analysis using LDL-C goal attainment of less than 70 mg/dL were similar although age and ED visits were no longer significantly associated with LDL-C goal attainment and patients who were hospitalized were more likely to be at LDL-C goal of less than 70 mg/dL.

DISCUSSION

In this study of patients with CAD in a large integrated healthcare system, 85.9% of patients were at the recommended LDL-C goal of less than 100 mg/dL and 79.8% were adherent to their statin medication. Among patients who were not at LDL-C goal, 66.0% were adherent while 17.9% of patients who were at goal were not adherent (defined as MPR <80%) to their statin medication. Adherence to statin medication, older age, male sex, Hispanic and Asian race/ethnicity, ambulatory utilization, higher CCI scores, and hypertension were associated with a higher likelihood of LDL-C goal attainment.

Overall, our study found higher rates of LDL-C goal attainment and secondary adherence to statin medications than many previous reports.^11,15-17 However, we required 2 statin prescriptions during the study window in order to calculate the MPR, which may have resulted in a more adherent population. Additionally, there has been an ongoing effort within KPSC in recent years to achieve LDL-C goal levels in all patients through more stringent monitoring of medications and cholesterol levels. Healthcare providers offer medication therapy, education, and drug information to patients utilizing evidence-based guidelines, standardized practices, and tools to optimize pharmacologic efficacy and improve clinical outcomes. Providers are trained to identify barriers and offer solutions to help patients use medications correctly. In addition, patients who are overdue for refills or who have low adherence to taking certain medications receive telephone outreach. When looking at LDL-C goal attainment, Nag et al found that older age, hypertension, and a greater number of medication classes had a higher likelihood of goal attainment, which is in line with our findings.¹⁸ These results seem to suggest that patients who were older and had more comorbidities may have been more vigilant about taking medications due to increased perceived risk.

A substantial proportion of patients in our study who were not at goal were adherent, suggesting that these patients may have needed their medication adjusted. On the other hand, the patients who were not adherent and not at goal may have faced medication use and adherence challenges, and healthcare providers need to address those issues. Our finding that many patients not adherent to their statin medication had LDL-C levels less than 100 mg/dL warrants further investigation. It is possible that clinicians are titrating through nonadherence, although the design of our study did not allow us to analyze this specifically, or that an 80% adherence level to statin medication is not necessary to achieve optimal LDL-C levels. Throughout the literature, 80% has been the widely used cutoff to determine adherence to statin medications. This level of adherence has been associated with lower healthcare utilization,¹⁹ and it has been shown that patients with hypertension who are at least 80% adherent to antihypertensive therapy have better control of their blood pressure. ²⁰ However, studies suggest that an adherence rate of 80% is not necessarily the optimal cutoff point in every population.^21-23 Karve et al looked at adherence to medications and its association with hospitalization in patients with schizophrenia, diabetes, hypertension, hyperlipidemia, and congestive heart failure. They determined that the optimal cutoff point that predicted disease-specific hospitalizations varied from 63% to 89%, depending on the disease.²¹ In a study involving heart failure patients, it was found that 88% was the level of adherence to all prescription medications needed to predict event-free survival. ²³ Even low exposure—defined as medication possession between 1 and 365 days in a 2-year period&mdash;to a bundle of cardioprotective medications in a population of patients with diabetes and/or CAD was found to reduce risk of hospitalization for MI or stroke by 15 events per 1000 person-years.²⁴ In our study, among patients who were at goal (LDL-C <100 mg/dL), 17.9% were not adherent to their statin medications, according the 80% cutoff point. Additionally, the mean LDL-C level in those with adherence rates as low as 26% to 35% was approximately 100 mg/dL. Though further studies are needed to determine what the most appropriate cutoff would be, these data suggest that it may be possible to achieve optimal LDL-C levels without 80% adherence to statin medications in CAD patients. Furthermore, in a setting of finite resources, it appears that focusing medication adherence efforts on patients who have adherence rates of 0% to 55% may have larger LDL improvement benefit than efforts focused on the group with greater than 55% adherence. The determination of an adequate cutoff value would be important for correctly identifying adherent and nonadherent patients, and implementing the most appropriate intervention.

There are several limitations to our study. We used pharmacy prescription refill information to calculate medication adherence, which indicates that a patient picked up their medication, but we do not know if they are actually taking the medication as prescribed. However, pharmacy fill data have been shown to be comparable to self-reports of adherence,25,26 and although pill splitting is a common phenomenon, it is typically more common with single-source medications due to cost. Furthermore, at the time of this study, simvastatin was generic; therefore, it was inexpensive and available at a generic copay for all strengths. It is possible that there was pill splitting with simvastatin-ezetimibe, but this would have been captured in the days of supply/daily dose fields in our pharmacy management information system. Additionally, only 15.1% of the patients with CAD were prescribed simvastatin-ezetimibe in this study, and we only included patients with drug benefits. Therefore, we do not believe pill splitting is a likely to have impacted the findings in this study. Patients could have been misclassified as nonadherent if they obtained their medications at a non-KPSC pharmacy, which would not be captured in our electronic systems. However, it is unlikely as more than 90% of KPSC members have a drug benefit that covers all or a portion of their medication costs, providing a financial incentive to use only KP pharmacies.

Furthermore, we excluded patients without pharmacy benefits. We did not assess the prescribing physician and patient relationship (physician specialty, inpatient, or outpatient setting), which also may have an influence on medication adherence. We included only 1 LDL-C value during the study period, and did not assess the length of time on the statin medication. We used MPR, one of the most common methods to estimate a patient’s adherence to medication using administrative databases. An inherent limitation to MPR is that it can only be calculated for patients with at least 2 dispenses. Thus, our study does not include the primary nonadherence population (those patients who did not fill their prescription the first time) and those who only filled the prescription once.

Lastly, the population we looked at had high adherence rates and high proportions at LDL-C goal. Given that KPSC is a managed care organization, our results may not be generalizable to other populations. However, the KPSC population has been shown to be generalizable to the Southern California population. The extremely poor and highly educated were only marginally underrepresented among KPSC members in 2010 compared with the general population living in Southern California. ²⁷ Finally, this was a cross-sectional analysis, and we were not able to determine whether goal attainment or use of high dose statins has more benefit on clinical outcomes.

To our knowledge, the association between adherence to statin medications and LDL-C values has not been widely studied. Adherence was strongly associated with LDL-C goal attainment and LDL-C values. By examining LDL-C levels along with medication adherence levels, healthcare providers and health systems can focus their interventions to address either patient adherence challenges or the need for medication titration. The incorporation of effective point-of-care strategies—such as standardization and coordination of use of evidence-based guidelines, adherence tools embedded in the EMR, disease registries, and active outreach for the management of CAD patients&mdash;are vital for improving LDL-C goal attainment.Author Affiliations: Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA (MDC, I-LAL, KR); Kaiser Permanente Pharmacy Analytical Service, Downey, CA (SSV, TCC); Kaiser Permanente, Southern California Permanente Medical Group, Pasadena, CA (KRG); West Los Angeles Medical Center, Southern California Kaiser Permanente, Los Angeles, CA (RDS).

Source of Funding: None reported. Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (SSV, I-LAL, TCC, KG, KR); acquisition of data (SSV); analysis and interpretation of data (MDC, I-LAL, TCC, KG, KR); drafting of the manuscript (MDC); critical revision of the manuscript for important intellectual content (MDC, I-LAL, TCC, KG, RDS, KR); statistical analysis (I-LAL, KR); administrative, technical, or logistic support (SSV, RDS); supervision (KR).

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