Clinical Characteristics and Unmet Need Among Patients with Atherosclerotic Cardiovascular Disease Stratified by Statin Use

Abstract

Background

The American College of Cardiology (ACC)/American Heart Association (AHA) 2013 guidelines for blood cholesterol treatment recommend high-intensity statins for adults with atherosclerotic cardiovascular disease (ASCVD). Currently, little is known about the real-world patient characteristics of ASCVD, as well as the clinical and economic consequences of different treatment options for this disease.

Objectives

To compare the demographic, clinical, and economic characteristics of patients with clinical ASCVD who started therapy with high-intensity statins, low-/moderate-intensity statins, or no statins in usual-care settings based on data primarily before the release of the ACC/AHA 2013 guidelines.

Methods

This retrospective, observational cohort study used claims data from US commercial health plans from January 2006 to June 2014 to identify patients with ASCVD (ie, acute coronary syndrome, coronary heart disease, ischemic stroke, or peripheral arterial disease). High-intensity, low-/moderate-intensity statin users and non–statin users were selected based on the presence of a corresponding prescription fill. The index date was defined as the first statin fill date for the statin cohorts and the earliest eligibility date for clinical ASCVD for the non–statin users group. The follow-up outcomes, including treatment patterns, cardiovascular (CV) events, and healthcare utilization and costs, were assessed after matching the high-intensity statin and low-/moderate-intensity statin initiators.

Results

A total of 273,308 patients with ASCVD were included in the study; of these, 104,649 were statin initiators and 168,659 non–statin users. Only 8.8% (N = 24,106) of the total population initiated high-intensity statins. Patient adherence (defined as proportion of days covered ≥80%) to statin therapy was low in the matched high-intensity statin and low-/moderate-intensity statin cohorts (27.0% vs 26.4%, respectively). Approximately 16% of the patients in either of the matched cohorts had at least 1 CV event during the available follow-up period.

Conclusion

The low percentage of patients who initiated high-intensity statin therapy, low adherence to statin therapy, and high rates of CV events during the follow-up period suggest a substantial unmet need among patients with ASCVD in the real-world setting. The demographic and clinical heterogeneity across the cohorts suggests significant variability in physician perception of the appropriate use of statins and may provide an opportunity to improve care and health outcomes in these high-risk patients.

KEY POINTS

• ▸Current cholesterol treatment guidelines recommend high-intensity statins for adults with atherosclerotic cardiovascular disease (ASCVD).
• ▸Using claims data, this retrospective study compared outcomes in patients with clinical ASCVD who used high-intensity versus low-/moderate-intensity statin therapy.
• ▸Only 38% of the 273,308 patients with ASCVD initiated statin therapy in this study, and only 8.8% used high-intensity statins.
• ▸Overall, 25.3% of patients who did not use statins had ischemic stroke versus 16.9% in low-/moderate-intensity statin users, and 8.8% in high-intensity statin users.
• ▸Approximately 16% of the patients in either of the statin cohorts had at least 1 CV event during follow-up.
• ▸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.
• ▸This study shows that in patients who are prescribed statins, the doses are rarely titrated, and adherence continues to be suboptimal.
• ▸These findings suggest that a significant paradigm shift must occur in statin utilization in patients with ASCVD to improve outcomes.

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 increaded 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.

Methods

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 online in the Appendix, Table 1 (see AHDBonline.com). 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.

Outcome Metrics

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 (see www.AHDBonline.com).

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).

Results

Of the 273,308 patients with ASCVD meeting the inclusion criteria (see Appendix, Tables 3a and 3b, at www.AHDBonline.com), 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.

Table 1.

Prematching Baseline: Demographic and Clinical Characteristics by Statin Intensity in Statin Benefit Group 1

Demographic and clinical characteristics	High-intensity statin initiators [A] (N = 24,106)	Low-/moderate-intensity statin initiators [B] (N = 80,543)	Non–statin users [C] (N = 168,659)	P value [A] vs [B]	P value [A] vs [C]
Female, N (%)	6448 (26.7)	31,753 (39.4)	81,743 (48.5)	<.001	<.001
Age at index, yrs, mean (SD)	56.6 (9.17)	57.4 (9.41)	53.6 (12.01)	<.001	<.001
Medicare Advantage, N (%)	2902 (12.0)	12,122 (15.1)	18,548 (11.0)	<.001	<.001
Prescribing physician specialty, N (%), selected
Cardiology	11,569 (48.0)	26,375 (32.7)	—	<.001	—
Family/general practice	3672 (15.2)	21,745 (27.0)	—	<.001	—
Internal medicine	3925 (16.3)	17,541 (21.8)	—	<.001	—
ASCVD group, hierarchical, mutually exclusive, N (%)
ACS	13,324 (55.3)	23,955 (29.7)	41,086 (24.4)	<.001	<.001
CHD with history of MI	1224 (5.1)	4616 (5.7)	11,908 (7.1)	<.001	<.001
CHD with no history of MI	6535 (27.1)	30,570 (38.0)	55,786 (33.1)	<.001	<.001
Ischemic stroke	2112 (8.8)	13,620 (16.9)	42,679 (25.3)	<.001	<.001
PAD	911 (3.7)	7782 (9.7)	17,200 (10.2)	<.001	<.001
Baseline comorbidities
Quan-Charlson Comorbidity Index, mean (SD)	1.9 (1.75)	2.0 (1.88)	2.2 (2.25)	.100	<.001
Congestive heart failure, N (%)	4339 (18.0)	13,233 (16.4)	23,843 (14.1)	<.001	<.001
Type 1 or 2 diabetes, N (%)	6011 (24.9)	21,603 (26.8)	33,094 (19.6)	<.001	<.001
Chronic kidney disease, N (%)	1475 (6.1)	5479 (6.8)	12,390 (7.3)	<.001	<.001
Anxiety, N (%)	2500 (10.4)	10,151 (12.6)	30,669 (18.2)	<.001	<.001
Depression, N (%)	2002 (8.3)	8406 (10.4)	24,695 (14.6)	<.001	<.001
Hypertension, N (%)	17,385 (70.3)	60,746 (72.3)	105,782 (60.2)	<.001	<.001
Obesity, N (%)	3720 (15.1)	11,606 (13.8)	25,278 (14.4)	<.001	.005
Baseline medication use, N (%)
Antihypertensive agents	11,838 (49.1)	47,361 (58.8)	74,055 (43.9)	<.001	<.001
Antidiabetic agents	3151 (13.1)	12,770 (15.9)	15,637 (9.3)	<.001	<.001
Prescription omega-3 fatty acids	179 (0.7)	795 (1.0)	1068 (0.6)	.001	.048
Antiplatelets/anticoagulants	3667 (15.2)	13,815 (17.2)	20,492 (12.1)	<.001	<.001
Peripheral arterial claudication medications	166 (0.7)	730 (0.9)	918 (0.5)	.001	.005

ACS indicates acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CHD, coronary heart disease; MI, myocardial infarction; PAD, peripheral arterial disease; SD, standard deviation.

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 www.AHDBonline.com). 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).

Table 2.

Postmatching Follow-Up: Statin Therapy Treatment Patterns Among Statin Users in Statin Benefit Group 1

Postindex treatment patterns	High-intensity statin initiators (N = 16,793)	Low-/moderate-intensity statin initiators (N = 16,964)	P value
Index medication groups, N (%)
Atorvastatin	11,957 (71.2)	3902 (23.0)	<.001
Rosuvastatin	2163 (12.9)	1412 (8.3)	<.001
Simvastatin	2673 (15.9)	8953 (52.8)	<.001
Others	0 (0)	2697 (15.9)	<.001
Discontinuation, N (%)	13,618 (81.1)	13,906 (82.0)	.037
PDC, mean (SD)	0.5 (0.35)	0.5 (0.35)	.008
Adherence (PDC ≥80%), N (%)	4534 (27.0)	4471 (26.4)	.181
Switching to a nonindex statin with similar intensity, N (%)	1749 (10.4)	3177 (18.7)	<.001
Switching to a nonindex statin with different intensity, N (%)	4789 (28.5)	2792 (16.5)	<.001
Switching to combination statin therapy and/or nonstatin lipid-lowering therapy, N (%)	2139 (12.7)	1857 (10.9)	<.001
Restart, N (%)	6209 (37.0)	5813 (34.3)	<.001

PDC indicates proportion of days covered; SD, standard deviation.

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).

Table 3.

Postmatching: Change in Lipid Levels and Goal Attainment Among Statin Users in Statin Benefit Group 1

Low-density lipoprotein cholesterol	High-intensity statin initiators (N = 16,793)	Low-/moderate-intensity statin initiators (N = 16,964)	P value
Patients with ≥1 laboratory results during baseline, N (%)	2586 (15.4)	2918 (17.2)	<.001
Most recent baseline (preinitiation) laboratory result (mg/dL) mean (SD)	119.1 (42.04)	123.7 (37.01)	<.001
Patients with LDL-C <100 mg/dL at most recent baseline laboratory result, N (%)	904 (35.0)	770 (26.4)	<.001
Patients with ≥1 laboratory results during 1-year follow-up, N (%)	4031 (24.0)	4271 (25.2)	.012
Most recent follow-up laboratory result (mg/dL), mean (SD)	79.3 (34.11)	88.1 (31.78)	<.001
Patients with LDL-C <100 mg/dL at 1-year follow-up, N (%)	3222 (79.9)	2999 (70.2)	<.001
Patients with ≥1 laboratory results during baseline and 1-year follow-up, N (%)	1668 (9.9)	1878 (11.1)	.001
Relative change in levels from baseline to 1-year follow-up, mean (SD), %	–25 (34)	–24 (29)	.472

LDL-C indicates low-density lipoprotein cholesterol; SD, standard deviation.

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.

Table 4.

Postmatching Follow-Up: Differences in CV Event Rates and Mortality Among Statin Users in Statin Benefit Group 1

Postindex CV events and mortalitya	High-intensity statin initiators (N = 23,340)	Low-/moderate-intensity statin initiators (N = 23,340)	P value
Follow-up length, days, mean (SD)	865.2 (656.73)	876.1 (657.47)	.073
Follow-up length, days, median	673	689
CV-related outcomes
Myocardial infarction
Patients with ≥1 events, N (%)	2044 (8.8)	1722 (7.4)	<.001
Incidence rate per 1000 person-years	39.9	32.7
Unstable angina in the inpatient/emergency department setting
Patients with ≥1 events, N (%)	1992 (8.5)	1816 (7.8)	.003
Incidence rate per 1000 person-years	39.0	34.8
Ischemic stroke
Patients with ≥1 events, N (%)	870 (3.7)	758 (3.2)	.005
Incidence rate per 1000 person-years	16.1	13.8
Transient ischemic attack
Patients with ≥1 events, N (%)	655 (2.8)	556 (2.4)	.004
Incidence rate per 1000 person-years	12.1	10.1
Coronary revascularization, including CABG and PCI
Patients with ≥1 events, N (%)	1765 (7.6)	1610 (6.9)	.006
Incidence rate per 1000 person-years	34.2	30.6
All-cause mortality,b N (%)	621 (2.7)	544 (2.3)	.022
Incidence rate per 1000 person-years	11.2	9.7
CV-related mortality using a claims-based algorithm,c N (%)	83 (0.4)	54 (0.2)	.013
Incidence rate per 1000 person-years	1.5	1.0
Composite CV outcome groupd
Patients with ≥1 events, N (%)	4777 (20.5)	4205 (18.0)	<.001
Incidence rate per 1000 person-years	103.1	87.0

^aPostindex CV events and mortality were reported for the duration of available follow-up, unless otherwise specified. CV event was defined as inpatient or emergency department visits with claims containing any of the codes related to the CV event of interest based on an ICD-9-CM diagnosis/procedure codes or CPT codes. An emergency department visit and inpatient stay in succession (without any gap in dates of service) was considered the same event.

^bAll-cause mortality was based on reported death in SSDI records or a hospital discharge status of “deceased” in claims.

^cMortality was considered CV-related if the patient had ≥1 inpatient stays or emergency department visits with a CV event as the primary diagnosis within 30 days before or on the date of death.

^dComposite CV outcome group included ACS, stroke, coronary revascularization, and CV-related mortality.

ACS indicates acute coronary syndrome; CABG, coronary artery bypass grafting; CPT, Current Procedural Terminology; CV, cardiovascular; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; PCI, percutaneous coronary intervention; SD, standard deviation; SSDI, Social Security Death Index.

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).

Table 5.

Postmatching: Healthcare Resource Utilization and Costs Among Statin Users (Follow-Up)

	Statin benefit group 1 patients
Healthcare resource utilization, costs per patient	High-intensity statin initiators (N = 16,793)	Low-/moderate-intensity statin initiators (N = 16,964)	P value
Postindex
All-cause utilization
Patients with ≥1 physician office visits, N (%)	16,522 (98.4)	16,737 (98.7)	.036
Physician office visits, mean (SD)	9.8 (8.31)	9.5 (8.03)	.001
Patients with ≥1 other outpatient visits, N (%)	16,234 (96.7)	16,338 (96.3)	.071
Other outpatient visits, mean (SD)	19.4 (24.20)	18.3 (22.54)	<.001
Patients with ≥1 emergency department visits, N (%)	4097 (24.4)	3946 (23.3)	.014
Emergency department visits, mean (SD)	0.4 (1.00)	0.4 (1.08)	.053
Patients with ≥1 inpatient hospitalizations, N (%)	4898 (29.2)	4575 (27.0)	<.001
Hospitalizations, mean (SD)	0.5 (1.00)	0.4 (1.04)	<.001
LOS of those with hospitalizations, mean (SD)	6.6 (13.05)	6.4 (12.91)	.469
Patients with ≥1 pharmacy dispensings, N (%)	16,793 (100.0)	16,964 (100.0)	—
Prescription fills, mean (SD)	45.9 (28.38)	44.0 (28.18)	<.001
Disease-related utilization
Patients with ≥1 physician office visits, N (%)	13,901 (82.8)	13,377 (78.9)	<.001
Patients with ≥1 other outpatient visits, N (%)	11,735 (69.9)	10,975 (64.7)	<.001
Patients with ≥1 emergency department visits, N (%)	1971 (11.7)	1728 (10.2)	<.001
Patients with ≥1 inpatient hospitalizations, N (%)	4273 (25.4)	3850 (22.7)	<.001
All-cause costs
Total medical, $	18,606 (40,817)	17,209 (39,767)	.001
Physician office, $	1471 (3731)	1352 (2849)	.001
Outpatient, $	6913 (16,148)	6526 (17,239)	.034
Emergency department, $	689 (2547)	654 (2483)	.209
Inpatient, $	9534 (32,679)	8676 (31,358)	.014
Pharmacy, $	3975 (4495)	3389 (4656)	<.001
Total, $	22,581 (41,938)	20,597 (40,841)	<.001
Median (IQR), $	9971 (5144–23,194)	8636 (4218–20,412)	—
Disease-related costs
Total medical, $	12,345 (33,344)	10,901 (32,087)	<.001
Physician office, $	510 (1102)	429 (707)	<.001
Other outpatient, $	3005 (8707)	2602 (8402)	<.001
Emergency department, $	362 (1856)	312 (1592)	.008
Inpatient, $	8467 (30,681)	7558 (29,678)	.006
Pharmacy, $	905 (733)	470 (571)	<.001
Total, $	13,250 (33,365)	11,371 (32,106)	<.001
Median (IQR), $	2974 (1210–11,107)	1961 (556–8241)	—

IQR indicates interquartile range; LOS, length of stay; SD, standard deviation.

Discussion

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.

Limitations

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.

Conclusion

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.