This retrospective cohort study used data from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS), details of which have been described elsewhere . The NHIS has provided a general national health screening program since 1995, and a health screening program for transitional ages, aimed at individuals aged 40 and 66 years, since 2007. The general health screening program is applied at least once every 2 years for the entire population of Korean adults aged ≥40 years; the participation rate was 74.8% in 2014. NHIS-HEALS incorporates information from these health screening programs .
The NHIS-HEALS database comprised 514,866 subjects (aged 40–79 years, 54.2% males) at baseline (2002–2003) who were randomly selected by simple random sampling using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and represented 10% of all national health screening participants (N = 5,148,695) in 2002 and 2003. Participants were followed up from 2002 to 2015 and data constructed in 2015. Variables included social and economic qualifications, medical check-up results, healthcare usage and survival status linked to national death certificates . The healthcare usage database included information on records of inpatient and outpatient usage (diagnosis, procedures, and prescriptions). Diagnoses were coded according to the International Classification of Disease, Tenth Revision (ICD-10) .
Korean national guidelines  based on the risk stratification of NCEP-ATP III, categorized risk groups to very high-risk, high-risk, moderate-risk and low-risk and recommended LDL-C treatment goals dependent on risk assessment: very high-risk < 70 mg/dL, high-risk < 100 mg/dL, moderate-risk < 130 mg/dL, and low-risk < 160 mg/dL. Very high-risk consisted of ACS, stroke and TIA, and PAD; high-risk consisted of carotid artery disease, abdominal aortic aneurysm, and DM. According to guidelines, PAD and other AAD (including carotid artery disease and abdominal aortic aneurysm) were separated to adjust different LDL-C target goal. ICD-10 codes and related procedures for risk stratification were listed in Table 1.
From the NHIS-HEALS database, patients with LDL-C measurements during 2007–2013 were included. Although data on participants’ total cholesterol levels are available from 2002, data for triglyceride, HDL-C and LDL-C levels are available for the health screening program for transitional ages from 2007, and for general national health screening programs from 2009. Patients with LDL-C measurement < 10 mg/dL during 2007–2013 were excluded. Subjects with a high-risk of CVD including stroke, ACS, CHD, PAD, DM and AAD were identified using ICD-10 codes and related procedures (Table 1) and classified into two groups: 1) known high-risk patients, 2) newly defined high-risk patients (Fig. 1).
Subjects previously identified as having a high-risk for CVD, prior to measurement of LDL-C levels, were categorized as “known high-risk patients.” The index date is the first LDL-C testing date during the study period. Definition of high-risk status was required to be made in the previous year including the index date. Subjects categorized as “newly defined high-risk” were identified according to the following criteria: 1) patients with more than two LDL-C measurements, and 2) patients who were newly diagnosed or underwent procedures for high-risk CVD between two LDL-C measurements. As LDL-C levels were available from 2007, patients with new cases of each disease could be defined as having at least 5 years of disease-free periods. For subjects with newly defined high-risk disease, the earliest date of visit regarding high-risk disease was defined as the index date. Here is an example of the group definition. If a subject had five LDL-C measurements during the follow up period and there was a first diagnosis of DM prior to the first LDL-C measurement, he or she was defined as a known high-risk patient for DM; on the other hand, there was a first ACS diagnosis between the third and fourth LDL-C measurements, he or she was defined as a newly diagnosed high-risk patient for ACS.
Outcome variables: LDL-C goal attainment
Target LDL-C levels were defined by the 2018 Korean guidelines . For patients with stroke, ACS, CHD or PAD, defined as the very high-risk group, the target level was < 70 mg/dL. For patients with DM or AAD, defined as high-risk group, the target level was < 100 mg/dL. When patients with DM or AAD had other concurrent high-risk diseases—stroke, ACS, CHD or PAD—these patients were stratified into the subgroups “DM with high-risk of CVD” and “AAD with high-risk of CVD” for outcome analysis, because their target level was < 70 mg/dL as very high-risk group. To determine LDL-C target achievement, LDL-C levels at the index date and LDL-C levels after the index date were used for known high-risk patients and newly defined high-risk patients, respectively.
LDL-C goal attainment by reduction rates were defined by 2013 ACC/AHA guidelines: > 50% reduction in baseline LDL-C for high-intensity statin and 30 to < 50% for moderate-intensity statin; guidelines recommend high-intensity statin therapy in patients with ASCVD or those with DM aged > 45 years . In the present study, the two LDL-C levels just before and after the index date of newly defined high-risk patients were used to calculate changes in LDL-C levels. On average, the interval for the two LDL-C tests was approximately 1 year, due to government policy for providing the health screening program.
Assessment of statin use
Statins included atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Statin therapy intensity was classified as high-intensity (atorvastatin 40–80 mg, rosuvastatin 20 mg), moderate-intensity (atorvastatin 10–20 mg, fluvastatin 40–80 mg, lovastatin 40 mg, pitavastatin 2–4 mg, pravastatin 40 mg, rosuvastatin 5–10 mg, simvastatin 20–40 mg), and low-intensity (fluvastatin 20–40 mg, lovastatin 20 mg, pitavastatin 1 mg, pravastatin 5–20 mg, simvastatin 5–10 mg), according to generic name and dose.
Statin exposure was assessed on or within 30 days before the index date using the prescription date and duration in known high-risk patients. For newly defined high-risk patients, whether exposure to statin took place from 30 days before to 90 days after the index date, using prescription dates and duration was assessed. Subjects were classified by their statin use history, as existing users if receiving statins at the time of the index date or within 6 months before the index date, or new users if there was no record of statin use for 6 months prior to the index date.
General characteristics including age, sex, body mass index (BMI), waist circumference, smoking, presence of diabetes, presence of hypertension, systolic and diastolic blood pressure measurements, fasting blood glucose levels, total cholesterol, triglyceride, HDL-C and LDL-C, are presented as mean and standard deviation (SD) for continuous variables and as frequency and proportion for categorical variables.
The proportion of patients attaining target LDL-C levels was calculated by dividing the number of patients with LDL-C level less than target level by the total number of patients. The proportion of patients with > 50% reduction of LDL-C levels was calculated by dividing the number of patients with > 50% reduction of LDL-C from the previous LDL-C level by the total number of patients. All LDL-C measurements from the index date were included to identify annual trend. Data were analyzed by disease status: stroke, ACS, CHD, PAD, DM and AAD. Data were analyzed using SAS Enterprise Guide 7.1 (SAS Institute, Cary, North Carolina, USA).