LDL Cholesterol Response and Statin Adherence Among High-Risk Patients Initiating Treatment

ABSTRACT

Objectives: The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol treatment guideline recommends monitoring percent reduction in low-density lipoprotein cholesterol (LDL-C) among patients initiating statins as an indication of response and adherence. We examined LDL-C reduction and statin adherence among high-risk patients initiating statins in a real-world setting.

Study Design: Retrospective cohort study.

Methods: The study population included Kaiser Permanente Georgia members (n = 1066) with a history of coronary heart disease or risk equivalent(s) initiating statins in 2011. Percent change in LDL-C was defined using measurements before and 60 to 450 days after statin initiation. Statin adherence was defined by proportion of days covered, categorized as high (≥80%), intermediate (50%-79%), and low (<50%).

Results: Overall, 58.4% of patients failed to achieve a ≥30% LDL-C reduction after statin initiation. The prevalences of high, intermediate, and low statin adherence were 41.3%, 23.2%, and 35.6%, respectively. Of patients with high adherence, 42.3% did not achieve a ≥30% reduction in LDL-C compared with 54.7% and 79.7% of those with intermediate and low statin adherence, respectively. After multivariable adjustment, and compared with those with high adherence, the risk ratios for not achieving a ≥30% LDL-C reduction were 1.31 (95% CI, 1.13-1.52) and 1.88 (95% CI, 1.67-2.11), for those with intermediate and low adherence. Women and African Americans were less likely to have high adherence, whereas having cardiologist visits was associated with high adherence.

Conclusions: In a real-world setting, many patients did not achieve a 30% or larger LDL-C reduction. These data support the ACC/AHA recommendation to monitor LDL-C response among patients initiating statins.

Am J Manag Care. 2016;22(3):e106-e115

Take-Away Points

• Using real-world clinical data, our study demonstrated that nonadherence to statins was very common (>50%) among high-risk patients initiating statins. Nonadherence was associated with suboptimal low-density lipoprotein cholesterol (LDL-C) reduction.
• Even among patients with high adherence, a small LDL-C response (<30%) to statins was very common.
• LDL-C should be monitored following statin initiation to identify suboptimal LDL-C response and medication nonadherence.

Reducing low-density lipoprotein cholesterol (LDL-C) has long been a central component of coronary heart disease (CHD) risk reduction, particularly among high-risk individuals.¹ The use of statins has increased markedly among US adults over the past 2 decades and this has been recognized as a major contributor to the decline in CHD in the US population.² However, despite the increased use of statins, substantial treatment gaps persist.

The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults³ noted that the magnitude of LDL-C reduction (30%-50% and ≥50% reductions for patients initiating moderate-intensity and high-intensity statins, respectively) should be used as a means to identify patients who may not be sufficiently adherent to their statin. This percent reduction is largely based on findings from meta-analyses of randomized controlled trials of statin therapy.⁴ However, patients in randomized trials represent select groups and there are limited data describing the reduction in LDL-C observed for patients initiating statins in real-world settings. Additionally, low statin adherence is common, and the degree to which low statin adherence accounts for smaller than expected reductions in LDL-C among patients with high-CHD risk is not well studied.^5-7

We conducted a retrospective cohort study of high-risk patients to examine LDL-C response following the initiation of statin treatment. Additionally, we investigated the contribution of statin adherence to achievement of a 30% or larger reduction in LDL-C following statin initiation. As part of these analyses, we determined the factors associated with statin nonadherence and the factors beyond adherence that were associated with failure to achieve a 30% or larger reduction in LDL-C following statin initiation.

METHODS

Data Source

The current study was conducted at Kaiser Permanente Georgia (KPGA), an integrated healthcare delivery system serving approximately 235,000 members in the greater metropolitan Atlanta area. KPGA maintains comprehensive electronic medical records (EMRs) and other electronic databases that capture nearly 100% of their members’ health services utilization. Members of KPGA are highly representative of its service areas.⁸

Study Population

We included KPGA patients who initiated a statin in 2011 (Figure 1). The date of each patient’s first statin fill in 2011 was defined as their “index date.” The “baseline period” was defined as the 365 days prior to the index date. The “follow-up period” was defined as the time between the index date and a patients’ last available LDL-C measurement on or before March 31, 2012.

To be eligible for this analysis, KPGA patients had to have: 1) been 18 years or older on January 1, 2011; 2) not been pregnant during the time between their index date and March 31, 2012; 3) filled at least 1 statin in 2011; 4) continuous health plan enrollment with drug benefits during the baseline and follow-up periods; 5) an LDL-C measurement performed at least 60 days following the index statin fill (for patients with statin prescriptions containing 30 days of supply [>120 and 180 days following the index date for patients receiving 60 and 90 days of supply, respectively]) but on or before March 31, 2012; 6) at least 1 LDL-C measurement during the baseline period; and 7) data on all National Cholesterol Education Program Adult Treatment Panel III (ATP III) risk factors (ie, age, total cholesterol, high-density lipoprotein cholesterol [HDL-C], systolic blood pressure, antihypertensive medication use, smoking, history of CHD, history of diabetes, peripheral artery disease and abdominal aortic aneurysm) from the baseline period.

We excluded patients with any statin fills during the baseline period and restricted our analysis to high-risk patients (ie, those with a history of CHD or a CHD risk equivalent). CHD risk equivalents included diabetes, history of stroke, a 10-year CHD risk greater than 20% based on the Framingham Risk Score, and other forms of symptomatic atherosclerotic disease including peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease.¹

Statin adherence. Statin adherence was defined using the proportion of days covered (PDC). We calculated the PDC as the cumulative number of days for which the patient had a statin available to take between their first fill in 2011 and their last LDL-C measurement during follow-up divided by the total number of days in this interval. The days of supply for statins that each patient had was a cumulative sum of days’ supply from all statin medications regardless of whether the patient changed statin dose or type. In several prior studies of medication adherence using pharmacy fill data, patients with medications available to take on 80% or more days have been categorized as adherent.^9-11 Adherence based on this cut point for cardiovascular disease—related conditions has been associated with improved outcomes.^12-14 Additionally, the 80% threshold for defining high adherence is recommended by CMS, the Pharmacy Quality Alliance, and the National Quality Forum.^15-18 We categorized adherence as high (PDC ≥80%), intermediate (PDC 50%-79%), or low (PDC <50%).^12,19,20 We used PDC to define medication adherence because it provides more conservative estimates than the medication possession ratio.²¹

LDL-C levels. Total cholesterol, HDL-C, and triglycerides were measured at KPGA laboratories as part of a lipid panel following standard measurement procedures. The LDL-C measures were direct measures or calculated using the Friedewald equation.²² Percent change in LDL-C was calculated as the difference between baseline and follow-up LDL-C divided by baseline LDL-C (defined using measurements before and 60 to 450 days after statin initiation). Our primary outcome was having a small reduction in LDL-C, defined as a change in LDL-C less than 30%. A secondary outcome—uncontrolled LDL-C&mdash;was defined as an LDL-C 100 mg/dL or greater at the last LDL-C measured on or before March 31, 2012. It is important to note that although the LDL-C target of less than 100 mg/dL is no longer recommended by the 2013 ACC/AHA cholesterol treatment guideline,³ it is included in this analysis as a secondary outcome for comparison purposes.

Study Variables

Study variables were chosen according to a conceptual framework²³ describing how factors interact to influence medication adherence.

Patient factors. Demographic information (ie, age, sex, self-reported race) was obtained from Kaiser Permanente’s EMR database. Area-level income was determined by matching patients’ geocoded addresses to 2010 Census data at the census tract level. Smoking status was obtained from the EMR as a self-reported response to whether patients currently smoke cigarettes. History of CHD, diabetes, stroke/carotid disease, and peripheral artery disease (PAD) or abdominal aneurysm were defined by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes obtained from KPGA’s claims database. In addition, hospitalizations during the baseline period were enumerated as a measure of patient health. Medication characteristics (ie, number of medications dispensed, type of statin, statin dose titration, number of statin refills, and use of a high-dose statin) were obtained from the KPGA pharmacy database. Statin type was defined based on the fill most recent to, and preceding, the last LDL-C measurement during follow-up. Statin titration was defined as an upward change in statin dose equivalents (eAppendix Table 1 [eAppendices available at www.ajmc.com]).^24-26 High-intensity statins were defined as 80 mg of simvastatin, 40 or 80 mg of atorvastatin, or 20 or 40 mg of rosuvastatin, according to the 2013 ACC/AHA cholesterol treatment guideline.³

The presence of CHD or CHD risk equivalents were defined by ICD-9-CM diagnostic codes during the baseline period and published algorithms (eAppendix Table 2). For patients without CHD or risk equivalents, the Framingham CHD risk score was calculated using the ATP III point scoring system and measurements from the patients’ EMRs from the baseline period.¹

Provider factor. Patients’ cardiologist visits were assessed during the follow-up period.

Statistical Analysis

Patient characteristics and percent change in LDL-C were calculated overall and by level of statin adherence. Risk ratios for a reduction in LDL-C <30% and uncontrolled LDL-C associated with low and intermediate versus high statin adherence, were calculated separately using log-binomial regression mod&shy;els with 3 levels of adjustment. An initial model adjusted for age, race, and sex. A second model included additional adjustment for area-level income, smoking, diabetes, history of stroke/carotid disease, Framingham 10-year CHD risk score of less than 20%, history of PAD or abdominal aneurysm, type of statin, number of medications, use of a high-dose statin, titration of statin dose, and cardiologist care. A final model additionally included adjustment for baseline LDL-C.

We conducted sensitivity analyses to examine the robustness of the findings. We examined the adjusted relative risk of a small LDL-C reduction (<30%) associated with statin adherence, restricting the cohort to: 1) patients with a 30-day supply for their initial statin fill, and 2) restricting the cohort to patients with at least 2 measurements of LDL-C measures during the follow-up period (and defining a small reduction in LDL-C as less than 30% on each of the last 2 measurements). Additionally, we calculated adjusted risk ratios for having intermediate/low statin adherence (PDC <80% vs ≥80%). Statistical analyses were conducted using SAS version 9.1.3 (SAS Institute, Cary, North Carolina).

RESULTS

Patient Characteristics

A total of 1066 KPGA patients with CHD or risk equivalents who initiated statin therapy in 2011 were included in our primary analysis. Older patients were more likely, whereas females and African-Americans were less likely, to have high adherence to statins (Table 1). Also, patients with an area-level income of $75,000 or more, a history of CHD, taking at least 10 different medications, with a cardiologist visit during follow-up, titration to their statin dose during follow-up, and with at least 1 statin refill in 2011 were more likely to have high adherence to statins.

Statin Adherence and Reduction in LDL-C

Over a median follow-up time of 213 days, 58.4% of patients failed to achieve at least a 30% reduction in LDL-C. Mean LDL-C reductions of 55.9 mg/dL (SD = 34.6 mg/dL), 44.6 mg/dL (SD = 35.8 mg/dL), and 21.0 mg/dL (SD = 37.1 mg/dL) were achieved for patients with high, intermediate, and low statin adherence, respectively (Figure 2). Small LDL-C reductions (<30%) were observed for 42.3%, 54.7%, and 79.7% of participants with high, intermediate, and low statin adherence, respectively (Table 2). After multivariable adjustment, relative to high adherence, intermediate adherence was associated with a 31% (risk ratio [RR], 1.31; 95% CI, 1.13-1.52) increased risk of a small LDL-C reduction, and low adherence was associated with an 88% (RR, 1.88; 95% CI, 1.67-2.11) increased risk of a small LDL-C reduction. The associations were consistent when we restricted the study cohort to patients with 30-day statin prescriptions (eAppendix Table 3) and when we required a reduction in LDL-C <30% on the last 2 measurements during follow-up (eAppendix Table 4).

Other Factors Associated With a Reduction in LDL-C <30%

In age, race, and sex-adjusted models, African Americans and patients who were taking pravastatin were more likely to have a small reduction in LDL-C compared with whites and patients taking simvastatin, respectively (eAppendix Table 5). Conversely, patients with baseline LDL-C 100 mg/dL or greater and those who had their statin dose titrated during follow-up were less likely to have a small reduction in LDL-C compared with patients with baseline LDL-C less than 100 mg/dL and those who did not have their statin dose titrated, respectively. In the full multivariable adjusted model, African American race was no longer independently associated with a small reduction in LDL-C.

Statin Adherence and LDL-C Control

At the end of follow-up, 44.7% of patients had uncontrolled LDL-C (ie, LDL-C ≥100 mg/dL). The prevalence of uncontrolled LDL-C was 25.7%, 45.3%, and 66.5% among patients with high, intermediate, and low statin adherence, respectively (Table 2, bottom panel). After multivariable adjustment, and compared with high adherence, intermediate and low statin adherence were associated with a risk ratio for uncontrolled LDL-C of 1.64 (95% CI, 1.34-2.02) and 2.44 (95% CI, 2.06-2.89), respectively.

Factors Associated With Intermediate/Low Statin Adherence

In age, race, and sex-adjusted models, being aged at least 65 years, having a history of CHD, taking 5 to 9 or more than 10 medications, or seeing a cardiologist following statin initiation were each associated with a reduced risk of intermediate/low statin adherence (PDC <80%) (Table 3). Women, African Americans, and smokers were more likely to have intermediate/low statin adherence. After full multivariable adjustment, patients taking 10 or more medications at baseline and seeing a cardiologist during the follow-up period decreased the risk of intermediate/lower statin adherence and being female, African American, or hospitalized during the follow-up period increased the risk of intermediate/low adherence.

DISCUSSION

In this study, the majority of patients with CHD or CHD risk equivalents did not achieve a 30% or larger reduction in LDL-C approximately 1 year following statin initiation. Additionally, most patients had moderate or low statin adherence. We observed that adherence was strongly associated with LDL-C reduction, with about half of those with moderate adherence, and less than a quarter of those with low adherence, demonstrating a LDL-C reduction expected for a moderate intensity statin regimen. These findings show that statin nonadherence in real-world clinical care is very common and has a major impact on LDL-C reduction. Also, even among patients with high adherence, 42.3% failed to achieve a 30% reduction in LDL-C approximately 1 year following statin initiation.

The results from the current study highlight the role of statin nonadherence in suboptimal LDL-C reduction. Compared with those with high adherence, patients with low statin adherence were almost twice as likely to have a small (<30%) reduction in LDL-C, after adjusting for potential confounders. Although these results are consistent with previous research,^27-29 our study points to a uniquely important issue: in well-managed patients with access to healthcare and a comprehensive system of services aimed at providing easy and convenient means for filling prescriptions, statin adherence remains low.

The reasons for statin nonadherence are likely multi-factorial and include patient, provider, and health system factors.^30-34 Consistent with prior studies,^5,35 women and African Americans were more likely to have low statin adherence. Women may have more depressive symptoms, be less satisfied with communication with their healthcare provider, and/or have inadequate social support systems in place compared with men.³⁶ Racial differences in statin adherence may be due to patient health beliefs, social norms, preferences, knowledge about the benefits of statins, or patient—physician communication.³⁷ In the current study, patients who had a cardiologist visit during follow-up were less likely to have low statin adherence. We were not able to discern whether cardiologists are more active in monitoring and encouraging statin adherence or whether patients in this health system who see cardiologists are more motivated to be adherent. Finally, there may be reasons for nonadherence related to the statin treatment itself. Statin-related events, such as muscle aches or weakness, gastrointestinal symptoms, and liver enzyme abnormalities, are reported in 5% to 10% of patients in trials, and as high as 20% of patients in observational studies.³⁸ The role of patient intolerance as a contributor to poor adherence and discontinuation has not been fully characterized.

Even among patients with high adherence in the current study, a substantial proportion (42.3%) did not have a 30% reduction in LDL-C. Additionally, 25.7% of patients with high adherence did not achieve an LDL-C less than 100 mg/dL at the end of follow-up. The expectation of a 30% or larger reduction in LDL-C associated with low-moderate intensity statins is derived from a meta-analysis of randomized controlled trials.⁴ Given the strong graded association between higher on-treatment LDL-C and increased cardiovascular disease risk, the small reduction in LDL-C experienced by many patients—even for those with high adherence&mdash;represents an important clinical challenge.³⁹ However, reductions in LDL-C not reaching 30% may nevertheless be important in reducing the risk of cardiovascular events and associated morbidity and healthcare costs.^40-42 Future studies are needed to evaluate the excess cardiovascular disease risk, if any, associated with having a suboptimal reduction in LDL-C following the initiation of statins.

Strengths and Limitations

Strengths of the current study include its diverse, real-world population of high-risk patients initiating statin therapy. Additionally, our study utilized EMR data that included pharmacy claims. In a recent unpublished survey, 95.1% of KPGA members reported that they never or rarely fill their prescriptions at non-network pharmacies (results obtained via personal communication with A. Owen-Smith, PhD). Therefore, our study likely reflects nearly complete capture of statins filled by patients.

Several potential limitations of the current study warrant mentioning. Our measure of statin adherence was based on pharmacy fill data and may not represent actual medication consumption.⁴³ Although only 13% of patients had their statin dose titrated during follow-up, it is possible that changes in statin dose or type during follow-up may have altered adherence estimates. Given the observational study design, confounding due to unmeasured risk factors may be present. The follow-up period was relatively short and we were not able to examine the long-term effects of statin nonadherence on percent change in LDL-C or CHD outcomes. Consistent with prior studies, a low percentage of patients initiated statins at high doses, which prevented us from studying LDL-C response to high-dose statins. Finally, it is possible that due to limitations of administrative data, some misclassification for study variables may be present.

CONCLUSIONS

More than half of patients with a high risk for CHD who are initiating statins demonstrated statin nonadherence, which was associated with failure to achieve at least a 30% reduction in LDL-C. Additionally, a substantial percentage of patients with high statin adherence still did not achieve a 30% reduction in LDL-C. The findings from our study support the 2013 ACC/AHA cholesterol treatment guideline that suggests monitoring LDL-C following initiation of statins for response and poor adherence. Author Affiliations: Kaiser Permanente Mid-Atlantic States, Mid-Atlantic Permanente Research Institute (SV), Rockville, MD; Department of Health Policy, Rollins School of Public Health, Emory University (PJJ), Atlanta, GA; Center for Observational Research, Amgen Inc (RK, JMW), Thousand Oaks, CA; Mount Sinai Cardiovascular Institute, Mount Sinai School of Medicine (MEF), New York, NY; and the Peter Munk Cardiac Centre, University of Toronto (MEF), Toronto, ON, Canada; Department of Epidemiology, University of Alabama at Birmingham School of Public Health (HY, PM), Birmingham, AL; and Department of Medicine, University of Alabama at Birmingham School of Medicine (MMS), Birmingham, AL.

Source of Funding: This research, including the design and conduct of the study, analysis, and interpretation of the data, was supported by Amgen, Inc.

Author Disclosures: Dr Vupputuri has received grant support from GlaxoSmithKline for other work. Drs Kilpatrick and Woolley were employees of Amgen Inc, which sells Repatha, a PCSK9 inhibitor that reduces LDL, and thus, may benefit from the results of this study. Dr Farkouh has previously received grant support from Merck for other work. Dr Yun has previously received grant support from the Agency for Healthcare Research and Quality for other work. Dr Safford has received grant support from Amgen Inc for other work, and served as a consultant for diaDexus. Dr Muntner has received grant support from Amgen Inc for this study and served on an advisory board for Amgen Inc. The remaining 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 (SV, HY, JMW, PM); acquisition of data (SV, PJJ); analysis and interpretation of data (SV, MEF, HY, JMW, PM, PJJ); drafting of the manuscript (SV, JMW); critical revision of the manuscript for important intellectual content (SV, MEF, HY, BER, JMW, PM); statistical analysis (SV, PJJ); obtaining funding (JMW, PM); administrative, technical, or logistic support (HY, BER); and supervision (SV, BER, PM).

REFERENCES

Address correspondence to: Suma Vupputuri, PhD, Kaiser Permanente Mid-Atlantic States, Mid-Atlantic Permanente Research Institute, 2101 East Jefferson St, 4W, Rockville, MD 20852. E-mail: Suma.Vupputuri@kp.org.

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