The benefits of statin therapy in reducing cardiovascular (CV) events are immense. In numerous studies, lowering low-density lipoprotein cholesterol (LDL-C) levels with statin therapy has been shown to reduce rates of major adverse CV events, such as myocardial infarction (MI) and stroke.1-5 Furthermore, randomized controlled studies have also demonstrated that treatment with high-intensity statins compared with low-/moderate-intensity statins (including all other statins and doses not listed below) is associated with increased CV outcomes benefit.6
The 2013 American College of Cardiology (ACC) and American Heart Association (AHA) guidelines focus on lowering LDL-C levels using statin therapies to reduce the risk for atherosclerotic CV disease (ASCVD) events.7 High-intensity statins are defined as statin doses that reduce LDL-C by ≥50%, including atorvastatin 40 mg and 80 mg, and rosuvastatin 20 mg and 40 mg. The ACC/AHA guidelines identify 4 statin benefit groups for whom treatment with statins resulted in a net patient benefit.7 In 3 of the 4 statin benefit groups, the use of high-intensity statins is recommended for (1) patients with clinical ASCVD who are aged ≤75 years; (2) patients with primary elevations of LDL-C levels ≥190 mg/dL; and (3) patients with diabetes aged 40 to 75 years, with LDL-C of 70 mg/dL to 189 mg/dL and an estimated 10-year ASCVD risk of ≥7.5% (defined as nonfatal MI, coronary heart disease [CHD] death, and nonfatal or fatal stroke).7
Historically, physician adherence to published dyslipidemia management guidelines has been suboptimal.8 Therefore, it is likely that patients will receive low-/moderate-intensity statin treatment or continue to not receive therapy, thereby foregoing the potential benefits of high-intensity statin therapy.7,9,10 Insights into CV outcomes in these scenarios would be invaluable; however, real-world evidence on the outcomes of high-intensity statin therapy compared with low-/moderate-intensity therapy or nonstatin therapy in the 3 statin benefit groups is currently limited.
The purpose of this study was to focus on patients with clinical ASCVD (statin benefit group 1) who are at highest risk for CV events among the 3 statin benefit groups. Specifically, our objective was to use historical data from primarily before the release of the 2013 ACC/AHA guidelines to evaluate the demographic characteristics, clinical and economic outcomes, and treatment patterns of patients with clinical ASCVD who initiated high-intensity versus low-/moderate-intensity statin therapy or nonstatin therapy.
In this retrospective, observational cohort study, we deidentified data in accordance with all applicable Health Insurance Portability and Accountability Act requirements; therefore, Institutional Review Board approval was not required.
We used medical and pharmacy administrative claims, as well as laboratory results, between January 1, 2006, and June 30, 2014, from the HealthCore Integrated Research Database, a large data repository of health plan enrollee information from 14 geographically diverse US health plans, to obtain clinical and economic data on patients who initiated high-intensity or low-/moderate-intensity statin therapies or those who did not use statin therapy. The index date was defined as the first claim for a statin for patients in the statin cohorts, or as the earliest diagnosis date for ASCVD for the nonstatin cohort. Patients between the ages of 21 and 75 years with ≥12 months of preindex and ≥3 months of postindex (including index date) continuous enrollment and at least 1 ASCVD condition were eligible for inclusion. The baseline period was defined as the 1-year period before the index date, whereas the follow-up period included all of the available time after (and including) the index date. All available data before the index date were used to identify patients with ASCVD.
For the purpose of this study, we adopted the ACC/AHA definition of clinical ASCVD, which includes those with acute coronary syndrome (ACS), CHD (eg, MI, angina, and coronary artery stenosis), as well as stroke or transient ischemic attack (TIA) and peripheral arterial disease. Individual ASCVD conditions were identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes and procedure codes in the Current Procedural Terminology (CPT; fourth edition) Healthcare Common Procedure Coding System Level II. We ensured that the selected codes represented conditions in which statins would be indicated. A complete list of codes is provided in the Appendix Table 1 at the end of this article. Patients with ischemic stroke and a history of atrial fibrillation or valvular disease were excluded, because the cause of the stroke may not be atherogenic. In addition, patients with previous use of lipid-lowering therapy in the baseline period, or those who had initiated multiple statin therapies on the index date, were excluded from the analysis.
We stratified statin initiators into high-intensity statin initiators (ie, patients using atorvastatin 40 mg or 80 mg, rosuvastatin 20 mg or 40 mg, or simvastatin 80 mg) and low-/moderate-intensity statin initiators (ie, patients starting all other statins and doses). Patients with clinical ASCVD (group 1) who did not have a claim for a statin during the study period were assigned to the “no statin therapy” group.
CV event rates and mortality were assessed via inpatient or emergency department claims with relevant ICD-9-CM diagnosis and procedure codes and through linking to Social Security Death Index (SSDI) records over the entire follow-up period for each patient. The CV outcomes included nonfatal and fatal events, including MI, unstable angina, stroke, coronary revascularization, and TIA. Mortality was based on observed death from SSDI records or a hospital discharge status of “deceased” from claims, and was considered CV-related if the patient had ≥1 inpatient stays or emergency department visits with a CV event as a primary diagnosis within 30 days before or on the date of death.
Healthcare resource utilization and costs were assessed over a 1-year follow-up period among patients with ≥12-month postindex continuous enrollment. Medical encounters were considered to be CV-related if the claims contained ICD-9-CM diagnosis or procedure codes or CPT codes for CV outcomes and related procedures. Similarly, pharmacy claims for statins, combination statins, and nonstatin lipid-lowering medications were considered as CV-related pharmacy dispensing.
Treatment patterns were assessed among the patients with ≥12-months postindex continuous enrollment. Treatment discontinuation was defined as exceeding the “permissible gap” between fills (45 days past the last supply date of index statin fill during the follow-up period). Restarting therapy was defined as ≥1 refills of the index statin after the discontinuation of the index statin during follow up. Proportion of days covered (PDC) was used to measure adherence and was defined as the number of days during follow-up on which the patient had the index statin (or statin of similar intensity) available based on prescription claims, divided by the number of days in the follow-up period. The patients were categorized as adherent if the PDC was ≥80%.
Switching therapy was defined as the receipt of a nonindex drug of interest with no further refills of the index statin therapy. Switching to similar or different intensity statins, as well as combination statin therapy and nonstatin lipid-lowering drugs, was determined.
LDL-C level was assessed at baseline for the subset of patients with available laboratory results. The laboratory result closest to and preceding the index date was used. For follow-up, the result closest to and preceding the index date plus 365 days was used. Consistent with the National Cholesterol Education Program Adult Treatment Panel III clinical guidelines that were available during the study,11 goal attainment was defined using those guidelines.11,12 Changes in laboratory values (from preindex to the end of 12 months postindex) were determined.
To improve baseline balance before the comparison of the follow-up outcomes, propensity score matching of high-intensity versus low-/moderate-intensity statin users was performed. For this purpose, the subgroup of statin users was stratified into 5 mutually exclusive ASCVD groups based on the clinical categories of ACS (MI or unstable angina requiring hospitalization within 12 months before the index date); CHD with a history of MI of >12 months; CHD without a history of MI; ischemic stroke; and peripheral arterial disease.
Matching was performed separately within each of the 5 subgroups to obtain the matched samples, which were then pooled for analysis. For the propensity score model, 1:1 nearest-neighbor matching was used with caliper width equal to 0.2 of the standard deviation (SD) of the logit of the propensity score,13 and was performed with the R statistical software package (R Development Core Team, R Foundation for Statistical Computing; Vienna, Austria). Balance before and after matching was assessed using standardized mean differences14 and statistical testing. A list of variables included in the propensity score model is available in the Appendix, Table 2 at the end of this article.
Descriptive statistics were used to report the baseline and follow-up characteristics. Chi-square tests were used to determine any statistical difference across categorical variables; t-tests were used for continuous variables, including costs. Multivariable generalized linear models with a log link and gamma distribution15 were used for the analysis of cost outcomes. Comparisons were made across the 2 statin user cohorts and 1 non–statin user cohort at baseline, and across the high-intensity statin cohort and the low-/moderate-intensity statin cohort in the postmatch sample during follow-up. These statistical analyses were performed using SAS version 9.4 (SAS Institute; Cary, NC).
Of the 273,308 patients with ASCVD meeting the inclusion criteria (see Appendix, Tables 3a and 3b at the end of this article), there were 24,106 (8.8%) high-intensity statin initiators, 80,543 (29.5%) low-/moderate-intensity statin initiators, and 168,659 (61.7%) non–statin users. As anticipated, the demographic and clinical characteristics were different between the 3 cohorts (Table 1). The mean age of the high-intensity statin initiators was 56.6 years (SD, 9.17) compared with 57.4 years (SD, 9.41) and 53.6 years (SD, 12.01) for patients initiating low-/moderate-intensity and no statin therapy, respectively (P <.001). Female patients made up 43.9% of the total population and constituted 26.7% of the high-intensity initiators, 39.4% of the lower-intensity statin initiators, and 48.5% of the non–statin users.
Among patients initiating high-intensity statins, 48% received their prescription from a cardiologist compared with 32.7% of patients initiating low-/moderate-intensity statins. The proportion of patients with ACS was greater among high-intensity statin users (55.3%) than low-/moderate-intensity statin initiators (29.7%; P <.001). Among patients who were not using any statin therapy, only 24.4% had ACS. By contrast, the proportion of patients with ischemic stroke was highest in the non–statin users cohort (25.3% vs 8.8% in high-intensity statin users and 16.9% in low-/moderate-intensity statin users). Type 1 or 2 diabetes was reported in 24.9% of the high-intensity statin users and in 26.8% of the low-/moderate-intensity statin users compared with 19.6% of the non–statin users (P <.001).
The matching process resulted in 23,340 pairs of high-intensity statin and low-/moderate-intensity statin initiators, whose baseline demographic, clinical, and economic characteristics were well-balanced (see Appendix, Table 4 at the end of this article). For all outcomes except CV event incidence and mortality, patients with ≤12 months of follow-up enrollment were removed after matching, which resulted in a sample size of 16,793 high-intensity statin initiators and 16,964 low-/moderate-intensity statin initiators for those outcomes.
Treatment discontinuation rates among the high-intensity statin and low-/moderate-intensity statin initiators were 81.1% and 82%, respectively, over 12 months of follow-up (Table 2). The mean adherence rates as measured by PDC were 0.5 (SD, 0.35) in both groups, and similar fractions of patients were classified as adherent (27.0% vs 26.4%, respectively; P = .181).
Switching to a nonindex statin of similar intensity was more common among low-/moderate-intensity statin initiators (18.7%) than high-intensity statin initiators (10.4%; P <.001). Switching to a nonindex statin with different intensity occurred more frequently among patients in the high-intensity statin initiator group (28.5%) than in the low-/moderate-intensity statin initiators (16.5%; P <.001). The proportions of patients restarting an index statin treatment were slightly different for the high-intensity statin and low-/moderate-intensity statin groups (37% vs 34.3%, respectively; P <.001).
Between 15% and 17% of patients had ≥1 LDL-C laboratory results during the baseline period (Table 3). The most recent preindex mean laboratory values were 119.1 mg/dL (SD, 42.04) and 123.7 mg/dL (SD, 37.01), respectively, for the high-intensity statin and low-/moderate-intensity statin treatment initiators (P <.001). Similar proportions of patients had at least 1 LDL-C laboratory result at 1 year postindex; the mean LDL-C was 79.3 mg/dL (SD, 34.11) for the high-intensity statin group and 88.1 mg/dL (SD, 31.78) for the low-/moderate-intensity statin initiators (P <.001). A larger proportion of high-intensity statin initiators (79.9%) than low-/moderate-intensity statin initiators (70.2%) achieved LDL-C <100 mg/dL (P <.001).
The mean length of follow-up for the treatment groups was approximately 865 days (SD, 656.7) and 876 days (SD, 657.5), respectively, for the high-intensity statin and low-/moderate-intensity statin initiators (Table 4). Approximately 16% of the patients had CV events during follow-up. Specifically, approximately 8% of patients in each treatment group had an MI event; the incidence rates (per 1000 person-years) were 39.9 among high-intensity statin initiators and 32.7 for low-/moderate-intensity statin initiators.
The proportion of patients who had at least 1 MI event was highest in the ACS subgroup (data not shown). In addition, approximately 8% of the patients in either cohort had ≥1 unstable angina events in the emergency department or the inpatient setting, and approximately 3% of the patients in either cohort had an ischemic stroke or TIA event. Per 1000 person-years, the all-cause mortality incidence rates for the high-intensity statin and low-/moderate-intensity statin initiators were 11.2 and 9.7, respectively, and the CV-related mortality rates were 1.5 and 1, respectively (Table 4).
The differences in all-cause healthcare resource utilization and costs during follow-up across the cohorts were small but significant, with higher costs in the high-intensity statin cohort (mean costs, $22,581 vs $20,597, respectively; median, $9971 vs $8636, respectively; Table 5). The disease-related metrics followed a similar pattern. These trends were also observed in the generalized linear regression models, which accounted for cost skewness and indicated an increase in costs of 11% to 21% in the high-intensity statin cohort compared with the low-/moderate-intensity statin cohort (data not shown).
Based on historical statin utilization, the results of this study provide important insights into the projected patterns of statin use among patients qualifying for ACC/AHA statin benefit group 1 in a managed care setting. Overall, only 38% of patients with clinical ASCVD (group 1) initiated statin therapy in this study. Among patients receiving a statin, 23% used a high-intensity statin, with <10% of the entire patient population receiving this intensity level of a statin.
These findings suggest that a significant paradigm shift must occur in the use of these drugs among patients with ASCVD. However, historical evidence suggests that the delayed adoption of clinical management guidelines (based on factors such as clinical inertia, patient reluctance, and perceived risk) will result in patients not receiving guideline-recommended treatment in the near future.16-18 Although this gap is likely to remain for some time, small increases in statin uptake after the 2013 ACC/AHA guidelines changes have been reported.12,19,20
The increased use of high-intensity statins may require changes in how drug prescribing patterns are conceptualized (especially for those with ACS), such as starting treatment with high-intensity statins rather than starting with low-/moderate-intensity statins, and subsequently uptitrating, as is often suggested in medical practice (based on discussions with practicing cardiologists). In addition, the initiation of high-intensity statin therapy was considered unnecessary (based on discussions with practicing cardiologists), if LDL-C targets could be reached at lower doses according to the treat-to-target approach that was widely accepted before the publication of the 2013 ACC/AHA guidelines.
Widespread underutilization of high-intensity statins was evident, even though the benefits of starting with high-intensity statins had been demonstrated before the guidelines’ release.6 One study using a nationwide sample found that in 2007, 2008, or 2009, only 27% of Medicare beneficiaries had a first fill of a high-intensity statin after a hospital discharge for CHD, which increased to only 35% within 1 year of discharge.21 Multiple physician and patient factors (based on discussions with practicing cardiologists) tend to favor starting treatment at a low dose, such as clinical care protocols, patient intuition, and aversion to side effects (eg, muscle pain). These factors will likely continue to play a role even after the release of the 2013 ACC/AHA guidelines.
Our findings highlight several important differences in the demographic, clinical, and economic outcomes associated with the treatment of patients in statin benefit group 1 with high-intensity statins and low-/moderate-intensity statins, as well as with nonstatin agents. Male patients and patients with recent ACS were more likely to receive a high-intensity statin, and patients with ischemic stroke were less likely to receive high-intensity statins, despite evidence of reduced recurrent events among such patients.22
Patients between ages 21 and 39 years were less likely to start statin therapy, despite having ASCVD. Cardiologists prescribed the largest proportion of high-intensity statins, whereas family and general physicians accounted for a higher share of the low-/moderate-intensity statin prescriptions. Cardiologists may be more likely to see patients with more advanced and complex disease who have increased cardiac comorbidities, which may account for a part of this difference in prescribing patterns.
Certain baseline comorbidities, including heart failure and hypertension, were seen more frequently among statin initiators than in patients who were not taking a statin, whereas other comorbidities (in particular, patients with anxiety and depression) were more frequently observed among non–statin users. For patients with available lipid panel results, the baseline LDL-C levels were clinically similar across the cohorts.
After treatment initiation, we observed a high level of therapy discontinuation and low overall adherence in the high-intensity and the low-/moderate-intensity statin cohorts, as has been previously documented.23,24 This may suggest a need for better patient management and/or alternative treatments. Although statin treatment was associated with a reduction in mean LDL-C levels of approximately 25% in both cohorts (in the subgroup of patients with available lipid panel results), a substantial fraction of patients had a CV event during the follow-up period (up to 20% based on the composite CV outcome), highlighting the remaining unmet need in this patient population for better disease management.
Of note, for CV events, our findings are perhaps counterintuitive, suggesting no improvement in follow-up events for the high-intensity statin cohort relative to the low-/moderate-intensity statin cohort. A similar result was previously reported in a study that compared composite all-cause death and recurrent ACS outcomes between high-intensity and low-/moderate-intensity statin users who were covered by Medicare.25 In that study, patients who received high-intensity statins had a similar event likelihood (hazard ratio, 1.02; 95% confidence interval, 0.96-1.08) as patients who received low-/moderate-intensity statins.25
Regarding the event rates in our study, the results could be a reflection of the overall poor adherence to treatment and the likelihood that patients who were prescribed high-intensity statins by their cardiologist had greater overall disease risks. Information on risk factors is limited in claims data, and cardiologists’ decisions to prescribe patients high-intensity statins may reflect their access to additional information, such as weight, smoking status, ethnicity, family history, and clinical severity of the underlying ASCVD (eg, number of cardiac vessels affected or degree affected), among others, providing a more nuanced risk profile than claims data alone.
In some cases during the time period studied, health plans might have required specific prior authorizations or step edits for the initiation of high-intensity statin therapies that were not available in a generic formulation. In such cases, physicians tend to request authorizations for patients with more severe conditions, which could result in baseline and follow-up differences between patients receiving high-intensity statins and those receiving low-/moderate-intensity statins.
The study results must be interpreted with awareness of some important limitations, including those associated with analyses of claims data. Specific information that is not available in claims could have an effect on the study outcomes. In light of differences in our study results compared with previous randomized clinical trial evidence, it is possible that the absence of such additional risk factors introduced bias into the estimates. Although the propensity score-matching approach noticeably improved balance across the cohorts in all available claims-based patient characteristics, the counterintuitive patterns in CV event rates remained.
The assumptions underlying ASCVD risk calculation and the potential imprecise cause of death assignment via the claims-based CV mortality algorithm could have affected the CV mortality outcome (although both cohorts would presumably have been affected equally). Moreover, the potential difference between statistical and clinical significance, given the large sample sizes of our comparison groups, must be noted.
The results are based on a sample of commercially insured patients and may not be generalizable to patients with other types of insurance or no insurance. As is the case with all claims studies, the presence of a claim for a filled prescription does not indicate that the medication was consumed or that it was taken as prescribed, nor does the absence of a medication claim mean that no medication was taken.
Finally, the presence of a diagnosis code on a medical claim does not guarantee the positive presence of a disease, because the diagnosis code might have been incorrectly coded or included as a rule-out criterion. Conversely, the absence of a diagnosis code does not guarantee the absence of disease.
Overall statin use and the specific use of high-intensity statin doses remain low in patients with clinical ASCVD, which may result in unnecessary residual risk. In patients who are prescribed statins, the doses are rarely titrated, and adherence continues to be suboptimal. Even within a cohort of patients with ASCVD, the demographic and clinical characteristics were significantly different between the dosing intensities of statins prescribed and compared with patients who were not prescribed a statin. In addition, CV events occurred at substantial rates in all patients receiving a statin, suggesting a potential for improving patient health outcomes.
Additional therapies, such as the proprotein convertase subtilisin kexin type 9 (better known as PCSK9) inhibitors that have drawn considerable interest as an emerging treatment option for patients with ASCVD, may also be a consideration in patients who fail to reach their treatment goal despite receiving maximum tolerated doses of a statin. Future research should examine changes in prescribing patterns in populations after the 2013 ACC/AHA guidelines release date for new and existing statin and nonstatin lipid therapies, and their impact on clinical and economic outcomes.
Bernard B. Tulsi, MSc, an employee of HealthCore, provided writing and editorial support for this manuscript. Minor editorial and administrative support was provided by Rachel Wright, PhD, of Prime Medica Ltd, Knutsford, Cheshire, United Kingdom, and was funded by Sanofi and Regeneron Pharmaceuticals. We also wish to acknowledge Rita Samuel, MD, of Regeneron Pharmaceuticals, for providing a critical review of the manuscript.
Source of Funding
Funding for this study was provided by Sanofi US, Inc, and Regeneron Pharmaceuticals, Inc. The authors received no payment related to the development of this publication.
Author Disclosure Statement
Dr Huang, Dr Grabner, Dr Willey, and Dr Cziraky are employees of HealthCore, which was contracted by Regeneron Pharmaceuticals for this study; Dr Sanchez is an employee of and receives stock compensation from Regeneron Pharmaceuticals; Ms Palli was an employee of HealthCore during this study; Dr Power reported no conflicts of interest.
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