Comparative Effectiveness and Safety of Moderate-Intensity Pravastatin Versus Atorvastatin in Patients with Dyslipidemia: A Retrospective Cohort Study Using a Common Data Model of Multicenter Electronic Health Records in South Korea

Sung Wan Chun; Hae Jin Kim; Ji A Seo; Suk Chon; Sung Eun Kim; Jung Hwa Jung; Sang Soo Kim; Hyejin Lee; Sanghoon Shin; So Hun Kim; Dughyun Choi; Hyeong Kyu Park; Soo-Kyung Kim; Ji-Hwan Bae; In-Kyung Jeong

doi:10.5551/jat.65345

Abstract

Aim: To compare the effectiveness and safety of moderate-intensity pravastatin 40 mg/day and atorvastatin 10 mg/day in patients with dyslipidemia.

Methods: We conducted a retrospective cohort study using electronic health records of 19 million patients across 14 secondary/tertiary hospitals, standardized to a Common Data Model. New users of pravastatin (40 mg/day) and atorvastatin (10 mg/day) were identified. Six distinct cohorts were used to assess the comparative effectiveness in preventing major adverse cardiovascular events (MACE) and the risks of new-onset diabetes mellitus (NODM), myalgia or rhabdomyolysis, and hepatotoxicity (measured by aspartate aminotransferase [AST]/alanine aminotransferase [ALT]). Propensity score matching (PSM) was applied to each cohort for effectiveness and safety analyses, followed by a meta-analysis of hospital-specific results.

Results: After PSM, patients were equally assigned to the pravastatin and atorvastatin groups for primary (n = 2,688/group) and secondary MACE prevention (n = 1,258/group) and to assess the risk of NODM (n = 2,391/group), new-onset myalgia or rhabdomyolysis (n = 11,799/group), and hepatotoxicity (AST, n = 4,034/group; ALT, n = 3,655/group). No significant differences were observed in the hazard ratios (HRs) for primary (HR = 0.84; 95% CI, 0.59-1.20) and secondary MACE prevention (HR = 0.89; 95% CI, 0.68-1.16). Similarly, no significant difference was observed in the risk of NODM (HR, 0.99; 95% CI, 0.79-1.23). The risk of new-onset myalgia/rhabdomyolysis (HR = 0.82, 95% CI, 0.69-0.96) and the incidence of abnormal elevations in AST levels (2.35% vs. 3.37%, p＜0.05) were significantly lower in the pravastatin group.

Conclusion: Moderate-intensity pravastatin (40 mg/day) showed comparable effectiveness to moderate-intensity atorvastatin (10 mg/day) in preventing MACE with a more favorable safety profile.

Trial registration number: KCT0009248 (CRIS).

Introduction

Dyslipidemia is recognized globally as a major risk factor for cardiovascular disease (CVD), imposing a significant public health burden in many countries, including South Korea^1-3). Statins have been established as the cornerstone of dyslipidemia management because of their demonstrated effectiveness in lowering low-density lipoprotein cholesterol (LDL-C) levels, consequently reducing the risk of CVD^4-7). However, statin therapy also entails associated risks, including new-onset diabetes mellitus (NODM), statin-associated muscle symptoms, and elevated liver aminotransferase (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST])^8-10).

Several studies have reported that statins vary in their effectiveness and safety, owing to their distinct pharmacological properties^{4, 8-12)}. This variability is critical for clinical decision making, thus necessitating a tailored approach that aligns with each patient’s health profile and risk factors^13-16). Moreover, the differential impact of medication adherence on clinical outcomes emphasizes the importance of these pharmacological distinctions^{17, 18)}. Patients generally show higher compliance with treatments that have a lower burden of adverse events, which ultimately enhances the health outcomes over time. Therefore, selecting the most suitable statin therapy for patients with dyslipidemia requires careful assessment of the balance between effectiveness and safety, as well as consideration of the implications for adherence¹⁹⁾. Pravastatin, a first-in-class statin, has been commonly prescribed for the treatment of dyslipidemia in South Korea for many years. Despite its widespread use, only a few studies have so far thoroughly evaluated its effectiveness and safety in clinical practice. There is a need for evidence to support the judicious use of pravastatin relative to its pharmacological alternatives.

We aimed to compare the comprehensive clinical effectiveness and safety of moderate-intensity pravastatin versus moderate-intensity atorvastatin, one of the most frequently prescribed statins in South Korea, using a common data model (CDM) of electronic health records (EHRs) from 14 medical centers.

Methods

Data Source

This study (trial registration: KCT0009248 [Korean Clinical Research Information Service, CRiS]) included retrospective cohort data from approximately 19 million patients across 14 secondary or tertiary hospitals in South Korea, which were then converted to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). The following hospitals were included in this study: 1. Ajou University Medical Center CDM (AUMC: 2,765,795 patients), 2. CHA University Bundang Medical Center CDM (CHAMC; 2,363,386 patients), 3. Ewha Womans University Mokdong Hospital CDM, 4. Ewha Womans University Seoul Hospital CDM (EUMC; 1,667,671 patients included in the Mokdong Seoul integrated database), 5. Gyeongsang National University Hospital CDM (GNUH; 626,663 patients), 6. Inha University Hospital CDM (INHA, 1,978,186 patients), 7. Kangdong Sacred Heart Hospital CDM (KDH; 1,978,186 patients), 8. Kyung Hee University Medical Center CDM (KHMC; 1,168,640 patients), 9. Kyung Hee University Hospital at Gangdong CDM (KHNMC; 1,168,640 patients), 10. Korea University Ansan Hospital CDM (KUMC; 1,537,665 patients), 11. Pusan National University Hospital CDM (PNUH; 1,753,001 patients), 12. Soonchunhyang University Hospital Bucheon CDM (SCHBC, 1,301,117 patients), 13. Soonchunhyang University Hospital Cheonan CDM (SCHCA; 987,701 patients); 14. Soonchunhyang University Hospital Seoul CDM (SCHSU: 987,701 patients) (Supplementary Table 1). All databases consist of de-identified, patient-level electronic health record data converted into CDM standard vocabulary, enabling network-wide results through distributed research networks using a uniform analysis program among collaborating organizations^{20, 21)}.

Supplementary Table 1.Data usage period and institutional review board approval number by medical center

No.	Medical center	Data usage period	IRB Approval number
1	Ajou University Medical Center	1994/01 ~ 2022/12	AJIRB-DB-2023-180
2	CHA University Bundang Medical Center	2006/02 ~ 2019/05	CHAMC 2023-04-021
3	Ewha Womans University Mokdong Hospital	2001/01 ~ 2021/12	EUMC 2023-04-047
4	Ewha Womans University Seoul Hospital	2001/01 ~ 2021/12	SEUMC 2023-04-023
5	Gyeongsang National University Hospital	2009/10 ~ 2022/04	GNUH 2023-04-010
6	Inha University Hospital	1996/01 ~ 2019/05	2023-02-030
7	Kangdong Sacred Heart Hospital	1986/11 ~ 2022/09	KANGDONG 2023-04-002
8	Kyung Hee University Medical Center	2008/01 ~ 2022/02	KHUH 2023-04-025
9	Kyung Hee University Hospital at Gangdong	2006/06 ~ 2022/31	KHNMC 2023-04-009
10	Korea University Ansan Hospital	2002/01 ~ 2020/12	2023AS0093
11	Pusan National University Hospital	2011/02 ~ 2019/08	2304-001-136
12	Soonchunhyang University Hospital Bucheon	2001/02 ~ 2021/05	SCHBC 2023-04-013
13	Soonchunhyang University Hospital Cheonan	2006/06 ~ 2021/05	SCHCA 2023-04-044
14	Soonchunhyang University Hospital Seoul	2003/05 ~ 2021/05	SCHUH 2023-04-006

Abbreviation: IRB, institutional review board

Study Design and Population

An active-comparator new-user design was used to assess the comparative effectiveness and safety of moderate-intensity pravastatin 40 mg/day and atorvastatin 10 mg/day in patients with dyslipidemia. We selected all patients aged ≥ 18 years with a prescription of moderate-intensity pravastatin 40 mg/day or atorvastatin 10 mg/day from January 1, 2006, to August 31, 2022 (the end of data availability). The date of the first prescription was defined as the cohort entry date (CED). We only included patients who had a continuous observational period ≥ 365 days before CED.

To rigorously assess the comparative effectiveness of primary and secondary prevention of major adverse cardiovascular events (MACE), as well as the comparative risks of NODM, we constituted three distinct cohorts, each tailored to a specific objective by additionally selecting patients. The definitions of each indicator are summarized in Supplementary Table 2.

Supplementary Table 2.Definition of covariates and study outcomes

Diagnosis	ICD-10-CM, ICD-10-PCS or definition	Diagnostic definition
Inclusion/exclusion criteria
Cancer	C00-C99, D00-D48	Admission or outpatient department ≥ 1
Human immunodeficiency virus	B20-23	Admission or outpatient department ≥ 1
Solid organ transplant	Z94.0, Z94.1, Z94.2, Z94.4, Z94.5, Z94.7	Admission or outpatient department ≥ 1
Acute myocardial infarction	I21	Admission or outpatient department ≥ 1
Ischemic stroke	I63-64, I69.3	Admission or outpatient department ≥ 1
Heart failure	I50	Admission or outpatient department ≥ 1
Coronary revascularization	M6551, M6552, M6554, M6561, M6562, OA640, OA648, OA649	Admission or outpatient department ≥ 1
Diabetes Mellitus	E10-E14	Admission or outpatient department ≥ 1 or prescription of oral hypoglycemic agent ≥ 1, or medical record of glycated hemoglobin1c (HbA1c) level below 6.5% ≥ 1
Myalgia or rhabdomyolysis	M62.82, M79.1	Admission or outpatient department ≥ 1, or medical record of creatine kinase level upper 675 IU/L for female, 850 IU/L for male ≥ 1
Chronic liver disease	B18	Admission or outpatient department ≥ 1
Hepatitis B/C	B16-17	Admission or outpatient department ≥ 1
Toxic liver disease	K71	Admission or outpatient department ≥ 1
Hepatocellular carcinoma	C22.0	Admission or outpatient department ≥ 1
Comorbidities
Angina pectoris	I20	Admission or outpatient department ≥ 1
Atrial fibrillation	I48	Admission or outpatient department ≥ 1
Chronic atrial fibrillation	I48.2	Admission or outpatient department ≥ 1
Chronic liver disease	B18, K70, K76.0	Admission or outpatient department ≥ 1
Congenital heart disease	Q20.0, Q21, Q22, Q23.0, Q24, Q25, Q26.0, Q27.0, Q28.0	Admission or outpatient department ≥ 1
Chronic obstructive pulmonary disease	J44	Admission or outpatient department ≥ 1
Coronary artery disease	I22	Admission or outpatient department ≥ 1
Diabetes Mellitus	E10-E14	Admission or outpatient department ≥ 1
Hypertension	I10, I15	Admission or outpatient department ≥ 1
Peripheral vascular disease	I70, I73.1, I73.8, I77.1, I79.0, I79.2, K55.1, K55.8, K55.9	Admission or outpatient department ≥ 1
Renal impairment	N17-19	Admission or outpatient department ≥ 1
Rheumatic heart disease	I01, I02.0, I05-09	Admission or outpatient department ≥ 1
Venous thromboembolism	I74	Admission or outpatient department ≥ 1
Scores
CHA₂DS₂-VASc score	Heart failure (1 point), hypertension (1 point), age ≥ 75 years (2 points), diabetes (1 point), previous stroke/systemic embolism/ transient ischemic attack (2 points), vascular disease (prior myocardial infarction or peripheral artery disease, 1 point) and female sex (1 point)
Outcomes
Acute myocardial infarction	I21	Admission ≥ 1 and a procedure code for PCI or CABG and duration of hospitalization ≥ 3 days.
Ischemic stroke	I63-64, I69.3	Admission ≥ 1 and a procedure code for brain CT or MRI and duration of hospitalization ≥ 3
Heart failure	I50	Admission ≥ 1
Coronary revascularization	M6551, M6552, M6554, M6561, M6562, OA640, OA648, OA649	Admission ≥ 1
Diabetes Mellitus	E10-E14	Admission or outpatient department ≥ 1 or prescription of oral hypoglycemic agent ≥ 1, or medical record of glycated hemoglobin1c (HbA1c) level below 6.5% ≥ 1
Myalgia or rhabdomyolysis	M62.82, M79.1	Admission or outpatient department ≥ 1, or medical record of creatine kinase level upper 675 IU/L for female, 850 IU/L for male ≥ 1

Abbreviation: CABG, coronary artery bypass graft; CT, computed tomography; MRI, magnetic resonance imaging; PCI, percutaneous coronary intervention

Patients were excluded if they received a prescription of any other statins (fluvastatin, lovastatin, pitavastatin, and rosuvastatin), including crossover among the study drugs (moderate-intensity pravastatin and atorvastatin), within 365 days before and 180 days after the CED. We also excluded patients who received a different dosage of pravastatin (40 mg/day) or atorvastatin (10 mg/day) within 365 days before and 180 days after CED. The index date was defined as 180 days after CED (Supplementary Fig.1). Additionally, we excluded patients who had a diagnosis or procedure code for cancer, human immunodeficiency virus, or solid organ transplantation before the index date (Supplementary Table 2).

Supplementary Fig.1. Study design

^＊Alcohol status and smoking status were assessed during the one-year period before the cohort entry date.

^†Number of emergency department visits, number of hospitalizations, number of outpatient visits, number of cardiologist visits,number of endocrinologist visits, and number of neurologist visits, were assessed during the one-year period before the cohort entry date.

^‡Medical history of atrial fibrillation, cancer (excluding non-melanoma skin cancer), Charlson Comorbidity Index, chronic kidney disease (stage 3 or higher) chronic liver disease, chronic obstructive pulmonary disease, coronary artery disease, heart failure, hyperlipidemia, hypertension, inflammatory bowel disease, obesity, peripheral vascular disease, psoriasis, stroke or transient ischemic attack, type 2 diabetes mellitus, and venous thromboembolism were assessed during the one-year period before the cohort entry date.

^§History of prescription of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, antiarrhythmic drugs, anticoagulants, antiplatelets, beta blockers, calcium channel blockers, chronic obstructive pulmonary disease maintenance medications, cyclooxygenase-2 selective inhibitors, diuretics, insulin, lipid-lowering drugs, non-insulin diabetes medications, non-steroidal anti-inflammatorydrugs, nitrates, opioids, and other hormonal agents/hormonereplacement therapy were assessed during the one-year period before the cohort entry date.

^|Earliest occurrence of predefined outcomes, switching or discontinuation of study drugs, death, or end of the study period

^¶Earliest occurrence of predefined outcomes, switching or discontinuation of study drugs, death,the end of the 180-day follow-up, or end of the study period

Abbreviations: MACE, major adverse cardiovascular events; NODM, new-onset diabetes mellitus; HbA1c, glycated hemoglobin

For the cohort assessing the effectiveness of primary prevention of MACE, we excluded anypatients who were diagnosed with acute myocardial infarction, ischemic stroke, heart failure, or a procedure code for coronary artery revascularization before the index date. In contrast, for the secondary prevention cohort, only patients with a documented history of MACE before the index date were included. To assess the risk of NODM, we included only those patients without a prior diagnosis of type 2 diabetes mellitus (T2DM), no prescription for diabetes-related medications such as oral hypoglycemic agents (OHAs) or insulin, and no records for glycated hemoglobin (HbA1c) level ≥ 6.5% before the index date (Supplementary Fig.1A).

To assess the comparative risk of new-onset myalgia, rhabdomyolysis, and hepatotoxicity, we created distinct cohorts. We included all patients aged ≥ 18 years with a prescription of moderate-intensity pravastatin 40 mg/day or atorvastatin 10 mg/day during the data availability period. We excluded patients who received a prescription for other statins or a different dosage of pravastatin 40 mg/day or atorvastatin 10 mg/day within 365 days before the CED. The index date was defined as 1 d after CED. We excluded any patients who had a diagnosis or procedure code for cancer, human immunodeficiency virus, or solid organ transplantation before the index date (Supplementary Table 2).

To assess the risk of new-onset myalgia or rhabdomyolysis, we excluded any patients with a diagnosis code for myalgia or rhabdomyolysis, or those who had a medical record of creatine kinase levels exceeding 5×the upper limit of normal (ULN) at any time before the index date, defined as ≥ 675 IU/L for females and ≥ 850 IU/L for males. For the hepatotoxicity cohort, we excluded patients who had a diagnosis code for chronic liver disease, hepatitis B or C, autoimmune hepatitis, hepatocellular carcinoma, or those with a medical record of AST or ALT levels exceeding 3×the ULN at any time before the index date. Patients without any medical records of AST or ALT levels before the index date or during the follow-up period were also excluded (Supplementary Fig.1B and 1C, Supplementary Table 2).

The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, was performed according to ethics committee approval, and was approved by the institutional review board (IRB) of each participating center; IRB approval numbers for each institution are listed in Supplementary Table 1.

Exposure

The moderate-intensity therapy groups were defined as follows: patients prescribed pravastatin 40 mg/day at the CED were classified into the pravastatin group, and those prescribed atorvastatin 10 mg/day at the CED were classified into the atorvastatin group.

Outcome Definitions

Effectiveness of Primary and Secondary Prevention of MACE

The primary endpoint was the composite of MACE, defined as acute myocardial infarction, ischemic stroke, hospitalization due to heart failure, coronary artery revascularization, or all-cause mortality²²⁾. The secondary endpoints were the individual components of the MACEs composite (Supplementary Table 2).

We also calculated the rate of change in the LDL-C levels during the observation period for patients in the pravastatin and atorvastatin groups included in cohorts to assess the comparative effectiveness of MACE primary and secondary prevention, as follows: [(LDL-C level during follow-up/LDL-C level at baseline) – 1]×100. The baseline LDL-C level was defined as the LDL-C level recorded at the time closest to the CED before CED. LDL-C level during follow-up was defined as the mean LDL-C level recorded during the respective follow-up periods. The rate of change in the LDL-C level was assessed at intervals from the start of follow-up: within 1 year, 1-2 years, 2-3 years, 3-4 years, 4-5 years, 5-6 years, and beyond 6 years.

Risk of NODM and New-Onset Myalgia or Rhabdomyolysis

NODM was defined as the occurrence of one of the following events: a diagnosis code for T2DM, an HbA1c level ≥ 6.5%, or a prescription for an OHA (Supplementary Table 2).

New-onset myalgia or rhabdomyolysis was defined as the occurrence of one of the following events: a diagnosis code for myalgia or rhabdomyolysis or a medical record of creatine kinase levels exceeding 5×the ULN (Supplementary Table 2).

Hepatotoxicity

Hepatotoxicity was assessed based on the proportion of abnormal AST and ALT levels. To assess hepatotoxicity, the proportion of abnormal values was defined as the number of patients with abnormal ALT or AST values divided by the number of patients included in the cohort. The number of patients with abnormal values recorded for ALT or AST was defined as cases in which AST or ALT levels were ＞3× the ULN during the observation period²³⁾. The proportions of patients with abnormal AST and ALT levels were calculated separately.

Follow-Up Time

To assess the comparative effectiveness of the primary and secondary prevention of MACE, and the risk of NODM and new-onset myalgia or rhabdomyolysis, patients included in each cohort were followed from the index date until censoring at the first occurrence of either the outcome of interest, drug discontinuation or switching, death, or the end of the study period.

For the assessment of hepatotoxicity, patients were followed up from the index date until censoring at the first occurrence of either the outcome of interest, drug discontinuation or switching, death, the end of the 180-day follow-up, or the end of the study period.

Drug discontinuation was defined as the end of exposure to the drug of interest, allowing for a 30-day gap between consecutive prescriptions. Drug switching was defined as a change to an alternative statin or alteration in dosage during the observation period.

Covariates

We defined the use of baseline medication as claiming a prescription 365 days before the CED. The baseline medications of interest were anti-arrhythmic drugs, anticoagulants, antidepressant drugs, antihypertensive drugs, antiplatelets, antirheumatic drugs, drugs for treating chronic obstructive pulmonary disease (COPD), corticosteroids, insulin, lipid-lowering drugs, narcotic analgesics, non-steroidal anti-inflammatory drugs, OHAs, and other hormonal agents or hormone replacement therapy.

Baseline comorbidities were defined as having a diagnosis code 365 days before CED. The baseline comorbidities of interest were angina pectoris, atrial fibrillation, chronic atrial fibrillation, chronic liver disease, congenital heart disease, COPD, coronary artery disease, T2DM, hypertension, peripheral vascular disease, renal impairment, rheumatic heart disease, and venous thromboembolism. To indirectly consider the frailty of patients, we defined the Charlson Comorbidity Index (CCI) score, calculated using a validated method, as a covariate²⁴⁾.

Statistical Analysis

Descriptive statistics were used to present the patient characteristics in the pravastatin and atorvastatin groups. To mitigate baseline differences between the two statin therapy groups, we conducted propensity score matching (PSM) with the nearest neighbor matching method, the caliper, a parameter of the range of matching, limited to 0.2 times the standard deviation of the propensity score distribution²⁵⁾. If the standardized mean difference (SMD) was equal to or less than 0.1, it was deemed indicative of comparable baseline characteristics between the two groups²⁶⁾. To compare the effectiveness of primary and secondary prevention of MACE, along with the risk of NODM and new-onset myalgia or rhabdomyolysis, we used three methods as follows: the Cox proportional hazard model was used to estimate the hazard ratios (HR) with the atorvastatin group as the reference, Kaplan-Meier curves were used for estimating the cumulative incidence with log-rank test for testing the significant difference of cumulative incidence, and linear regression was used for estimating the absolute rate difference for each outcome between the groups. We calculated the 95% confidence intervals (CIs) for HR and absolute rate difference. Additionally, we used a two-sample t-test (or Welch test) to assess whether there were statistically significant differences in the rate of change in LDL-C levels over time among patients included in the cohort to assess the comparative effectiveness of the primary and secondary prevention of MACE who were continuously treated with each statin. We used the Cchi-squared test to examine between-group differences. As a sensitivity analysis, we additionally applied the inverse probability of treatment weighting (IPTW) method to further account for potential residual confounding and assess the robustness of our findings. To mitigate the influence of extreme weights, we implemented the 5% and 10% trimming approaches, excluding observations with extreme propensity score weights. The balance between groups was assessed using the SMD criterion, with values ≤ 0.1 indicating an adequate balance in baseline covariates. The primary and secondary outcomes were analyzed using weighted Cox proportional hazard models and weighted linear regression models to estimate absolute rate differences. Statistical significance was assessed using a one-sided significance level of 0.05.

Meta-Analysis

All analyses were conducted using the same analytical R script on a dataset within each hospital, which was transformed into CDM. This approach ensured that data remained within each hospital, with only the results shared, thereby guaranteeing uniform analyses across all databases. The results from each hospital were then aggregated using fixed- and random-effects meta-analyseis.

All analyses were performed using the R statistical software program (version 4.2.2; R Foundation for Statistical Computing).

Results

Baseline Characteristics

Among 19,329,921 patients in the CDM of 14 secondary or tertiary hospitals from January 1, 2006, to August 31, 2022, six cohorts were constituted for different objectives. For the cohort comparing the effectiveness of primary prevention of MACE, 2,688 patients were eligible for both the pravastatin and atorvastatin groups. In the secondary prevention of MACE, 1,258 patients were eligible for both the pravastatin and atorvastatin groups. To compare the risk of NODM, 2,391 patients were included in both the pravastatin and atorvastatin groups. To assess the risk of new-onset myalgia or rhabdomyolysis, 11,799 patients were eligible for inclusion in both groups. Regarding the assessment of comparative hepatotoxicity, 4,034 patients were included in both the pravastatin and atorvastatin groups based on AST levels and 3,655 patients were included based on ALT levels (Fig.1). Baseline covariates were predominantly balanced after PSM, except for the department of care, which remained at SMD ＞0.1 in several cohorts (Table 1).

Fig.1. Patient disposition in six distinct cohorts

^＊The cohort entry date was defined as the first date of prescription for pravastatin 40 mg/day or atorvastatin 10 mg/day.

^†The index date was defined as 180 days after the cohort entry date.

^‡The index date was defined as one day after the cohort entry date.

^§Liver diseases included chronic liver disease, hepatitis B or C, autoimmune hepatitis, and hepatocellular carcinoma.

Abbreviations: AUMC, Ajou University Medical Center; CHAMC, Bundang CHA Medical Center; EUMC, Ewha Womans University Medical Hospital; GNUH, Gyeongsang National University Hospital; INHA, Inha University Hospital; KDH, Kangdong Sacred Heart Hospital; KHMC, Kyung Hee Medical Center; KHNMC, Kangdong Kyung Hee University Medical Center; KUMC, Korea University Medical Center in Ansan; PNUH, Pusan National University Hospital; SCHBC, Soonchunhyang University Bucheon Hospital; SCHCA, Soonchunhyang University Cheonan Hospital; SCHSU, Soonchunhyang University Seoul Hospital; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

Table 1.Baseline characteristics before and after propensity score matching in six distinct cohorts

A) Cohort to assess the comparative effectiveness of primary prevention of major adverse cardiovascular events
Characteristic	Before PSM			After PSM
Characteristic	Pravastatin group (N = 2,688)	Atorvastatin group (N = 25,578)	SMD	Pravastatin group N = 2,688	Atorvastatin group (N = 2,688)	SMD
Male, n (%)	1,439 (53.5)	13,330 (52.1)	0.03	1,439 (53.5)	1,459 (54.3)	0.02
Age, years, mean±SD	56.5±12.5	57.9±12.9	0.11	56.5±12.5	56.7±13.0	0.02
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.1±0.4	0.1±0.4	0.02	0.1±0.4	0.1±0.4	0.01
Hospital admissions	0.2±0.6	0.2±0.7	0.07	0.2±0.6	0.2±0.6	＜0.01
Outpatient visits	6.3±7.3	6.3±8.2	0.00	6.3±7.3	6.2±7.1	0.01
Department of care, n (%)
Cardiology	495 (18.4)	5,211 (20.4)	0.28	495 (18.4)	425 (15.8)	0.07
Endocrinology	802 (29.8)	6,292 (24.6)	0.37	802 (29.8)	736 (27.4)	0.06
Neurology	223 (8.3)	2,773 (10.8)	0.28	223 (8.3)	289 (10.8)	0.09
Other	316 (11.8)	6,298 (24.6)	0.39	316 (11.8)	386 (14.4)	0.08
Comorbidities, n (%)
Angina pectoris	124 (4.6)	1,132 (4.4)	0.01	124 (4.6)	127 (4.7)	0.01
Atrial fibrillation	3 (0.1)	19 (0.1)	0.01	3 (0.1)	2 (0.1)	0.01
Chronic atrial fibrillation	0 (0.0)	9 (0.0)	0.03	0 (0.0)	0 (0.0)	-
Chronic liver disease	113 (4.2)	888 (3.5)	0.04	113 (4.2)	125 (4.7)	0.02
Congenital heart disease	1 (0.0)	23 (0.1)	0.02	1 (0.0)	2 (0.1)	0.02
Chronic obstructive pulmonary disease	20 (0.7)	324 (1.3)	0.05	20 (0.7)	20 (0.7)	＜0.01
Coronary artery disease	4 (0.1)	21 (0.1)	0.02	4 (0.1)	4 (0.1)	＜0.01
Diabetes mellitus	900 (33.5)	7,122 (27.8)	0.12	900 (33.5)	912 (33.9)	＜0.01
Hypertension	1,320 (49.1)	12,093 (47.3)	0.04	1,320 (49.1)	1,318 (49.0)	＜0.01
Peripheral vascular disease	157 (5.8)	1,523 (6.0)	0.01	157 (5.8)	157 (5.8)	＜0.01
Renal impairment	80 (3.0)	1,323 (5.2)	0.11	80 (3.0)	77 (2.9)	0.01
Rheumatic heart disease	9 (0.3)	119 (0.5)	0.02	9 (0.3)	6 (0.2)	0.02
Venous thromboembolism	4 (0.1)	44 (0.2)	0.01	4 (0.1)	5 (0.2)	0.01
Charlson comorbidity index score, mean±SD	0.1±0.3	0.1±0.3	0.00	0.1±0.3	0.1±0.3	0.00
Comedication, n (%)
Anti-arrhythmic drugs	90 (3.3)	687 (2.7)	0.04	90 (3.3)	82 (3.1)	0.02
Anticoagulants	118 (4.4)	1,105 (4.3)	0.00	118 (4.4)	110 (4.1)	0.02
Antidepressants	181 (6.7)	1,654 (6.5)	0.01	181 (6.7)	168 (6.2)	0.02
Antihypertensives	1,236 (46.0)	11,129 (43.5)	0.05	1,236 (46.0)	1,210 (45.0)	0.02
Antiplatelets	397 (14.8)	2,993 (11.7)	0.09	397 (14.8)	388 (14.4)	0.01
Antirheumatic	42 (1.6)	444 (1.7)	0.01	42 (1.6)	49 (1.8)	0.02
Chronic obstructive pulmonary disease drugs	159 (5.9)	1,816 (7.1)	0.05	159 (5.9)	152 (5.7)	0.01
Corticosteroids	150 (5.6)	1,870 (7.3)	0.02	150 (5.6)	142 (5.3)	0.02
Insulin	185 (6.9)	1,642 (6.4)	0.02	185 (6.9)	180 (6.7)	0.01
Lipid-lowering drugs	278 (10.3)	1,443 (5.6)	0.17	278 (10.3)	280 (10.4)	0.00
Narcotic analgesics	198 (7.4)	1,918 (7.5)	0.01	198 (7.4)	195 (7.3)	0.00
Non-steroidal anti-inflammatory drugs	788 (29.3)	7,199 (28.1)	0.03	788 (29.3)	796 (29.6)	0.01
Oral hypoglycaemic agent	764 (28.4)	5,706 (22.3)	0.14	764 (28.4)	766 (28.5)	0.00
Other hormonal agents /Hormone replacement therapy	183 (6.8)	2,099 (8.2)	0.05	183 (6.8)	180 (6.7)	0.00

B) Cohort to assess the comparative effectiveness of secondary prevention of major adverse cardiovascular event
Characteristic	Before PSM			After PSM
Characteristic	Pravastatin group N = 1,258	Atorvastatin group N = 10,461	SMD	Pravastatin group N = 1,258	Atorvastatin group N = 1,258	SMD
Male, n (%)	726 (57.7)	6,381 (61.0)	0.07	726 (57.7)	746 (59.3)	0.03
Age, years, mean±SD	64.4±11.5	65.5±12.1	0.09	64.4±11.5	64.6±11.8	0.02
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.2±0.5	0.2±0.5	0.08	0.2±0.5	0.2±0.5	0.00
Hospital admissions	0.3±0.6	0.4±0.9	0.21	0.3±0.6	0.3±0.6	0.01
Outpatient visits	6.3±8.6	5.8±8.4	0.06	6.3±8.6	6.2±6.9	0.02
Department of care, n (%)
Cardiology	346 (27.5)	3,785 (36.2)	0.39	346 (27.5)	338 (26.9)	0.01
Endocrinology	44 (3.5)	376 (3.6)	0.39	44 (3.5)	56 (4.5)	0.05
Neurology	400 (31.8)	3,486 (33.3)	0.41	400 (31.8)	394 (31.3)	0.01
Other	49 (3.9)	1,057 (10.1)	0.43	49 (3.9)	48 (3.8)	0.01
Comorbidities, n (%)
Angina pectoris	182 (14.5)	1,839 (17.6)	0.09	182 (14.5)	182 (14.5)	＜0.01
Atrial fibrillation	1 (0.1)	17 (0.2)	0.02	1 (0.1)	1 (0.1)	＜0.01
Chronic atrial fibrillation	2 (0.2)	14 (0.1)	0.01	2 (0.2)	2 (0.2)	＜0.01
Chronic liver disease	11 (0.9)	126 (1.2)	0.03	11 (0.9)	14 (1.1)	0.02
Congenital heart disease	1 (0.1)	23 (0.2)	0.04	1 (0.1)	1 (0.1)	＜0.01
Chronic obstructive pulmonary disease	9 (0.7)	165 (1.6)	0.08	9 (0.7)	11 (0.9)	0.02
Coronary artery disease	11 (0.9)	63 (0.6)	0.03	11 (0.9)	4 (0.3)	0.07
Diabetes mellitus	258 (20.5)	2,235 (21.4)	0.02	258 (20.5)	257 (20.4)	0.00
Hypertension	897 (71.3)	7,003 (66.9)	0.09	897 (71.3)	916 (72.8)	0.03
Peripheral vascular disease	139 (11.0)	1,570 (15.0)	0.12	139 (11.0)	136 (10.8)	0.01
Renal impairment	28 (2.2)	457 (4.4)	0.12	28 (2.2)	31 (2.5)	0.02
Rheumatic heart disease	11 (0.9)	128 (1.2)	0.03	11 (0.9)	15 (1.2)	0.03
Venous thromboembolism	1 (0.1)	8 (0.1)	0.00	1 (0.1)	0 (0.0)	0.04
Charlson comorbidity index score, mean±SD	0.1±0.3	0.1±0.4	0.12	0.1±0.3	0.1±0.4	0.03
Concomitant drugs, n (%)
Anti-arrhythmic drugs	86 (6.8)	671 (6.4)	0.02	86 (6.8)	82 (6.5)	0.01
Anticoagulants	191 (15.2)	1,677 (16.0)	0.02	191 (15.2)	207 (16.5)	0.04
Antidepressants	138 (11.0)	882 (8.4)	0.09	138 (11.0)	141 (11.2)	0.01
Antihypertensives	863 (68.6)	6,498 (62.1)	0.14	863 (68.6)	853 (67.8)	0.02
Antiplatelets	689 (54.8)	5,205 (49.8)	0.10	689 (54.8)	668 (53.1)	0.03
Antirheumatic	14 (1.1)	103 (1.0)	0.01	14 (1.1)	12 (1.0)	0.02
Chronic obstructive pulmonary disease drugs	84 (6.7)	680 (6.5)	0.01	84 (6.7)	73 (5.8)	0.04
Corticosteroids	55 (4.4)	505 (4.8)	0.02	11 (0.9)	11 (0.9)	＜0.01
Insulin	33 (2.6)	439 (4.2)	0.09	33 (2.6)	40 (3.2)	0.03
Lipid-lowering drugs	60 (4.8)	438 (4.2)	0.03	60 (4.8)	63 (5.0)	0.01
Narcotic analgesics	56 (4.5)	704 (6.7)	0.10	56 (4.5)	62 (4.9)	0.02
Non-steroidal anti-inflammatory drugs	720 (57.2)	5,647 (54.0)	0.07	720 (57.2)	718 (57.1)	0.00
Oral hypoglycemic agent	229 (18.2)	1,705 (16.3)	0.05	229 (18.2)	224 (17.8)	0.01
Other hormonal agents /Hormone replacement therapy	54 (4.3)	629 (6.0)	0.08	54 (4.3)	51 (4.1)	0.01

C) Cohort to assess the comparative risk of new-onset diabetes mellitus
Characteristic	Before PSM			After PSM
Characteristic	Pravastatin group N = 2,391	Atorvastatin group N = 22,557	SMD	Pravastatin group N = 2,391	Atorvastatin group N = 2,391	SMD
Male, n (%)	1,245 (52.1)	11,803 (52.3)	0.01	1,245 (52.1)	1,256 (52.5)	0.01
Age, years, mean±SD	59.3±12.7	60.1±13.3	0.06	59.3±12.7	59.1±13.2	0.02
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.2±0.4	0.2±0.4	0.01	0.2±0.4	0.2±0.4	0.00
Hospital admissions	0.2±0.5	0.2±0.7	0.10	0.2±0.5	0.2±0.6	0.03
Outpatient visits	5.8±7.9	5.6±7.1	0.03	5.8±7.9	6.0±9.7	0.02
Department of care, n (%)
Cardiology	627 (26.2)	6,736 (29.9)	0.34	627 (26.2)	618 (25.8)	0.01
Endocrinology	194 (8.1)	1,224 (5.4)	0.38	194 (8.1)	134 (5.6)	0.10
Neurology	469 (19.6)	4,839 (21.5)	0.35	469 (19.6)	506 (21.2)	0.04
Other	296 (12.4)	5,499 (24.4)	0.41	296 (12.4)	324 (13.6)	0.04
Comorbidities, n (%)
Angina pectoris	226 (9.5)	1,956 (8.7)	0.03	226 (9.5)	234 (9.8)	0.01
Atrial fibrillation	4 (0.2)	28 (0.1)	0.01	4 (0.2)	2 (0.1)	0.02
Chronic atrial fibrillation	2 (0.1)	19 (0.1)	＜0.01	2 (0.1)	3 (0.1)	0.01
Chronic liver disease	67 (2.8)	483 (2.1)	0.04	67 (2.8)	67 (2.8)	＜0.01
Congenital heart disease	1 (0.0)	38 (0.2)	0.04	1 (0.0)	1 (0.0)	＜0.01
Chronic obstructive pulmonary disease	17 (0.7)	312 (1.4)	0.07	17 (0.7)	19 (0.8)	0.01
Coronary artery disease	7 (0.3)	54 (0.2)	0.01	7 (0.3)	7 (0.3)	＜0.01
Diabetes mellitus	0 (0.0)	0 (0.0)	-	0 (0.0)	0 (0.0)	＜0.01
Hypertension	1,351 (56.5)	11,888 (52.7)	0.08	1,351 (56.5)	1,409 (58.9)	0.05
Peripheral vascular disease	161 (6.7)	1,717 (7.6)	0.03	161 (6.7)	173 (7.2)	0.02
Renal impairment	51 (2.1)	891 (3.9)	0.11	51 (2.1)	58 (2.4)	0.02
Rheumatic heart disease	14 (0.6)	181 (0.8)	0.03	14 (0.6)	15 (0.6)	0.01
Venous thromboembolism	3 (0.1)	39 (0.2)	0.01	3 (0.1)	1 (0.0)	0.03
Charlson comorbidity index score, mean±SD	0.1±0.3	0.1±0.3	0.04	0.1±0.3	0.1±0.3	0.00
Concomitant drugs, n (%)
Anti-arrhythmic drugs	120 (5.0)	886 (3.9)	0.05	120 (5.0)	105 (4.4)	0.03
Anticoagulants	201 (8.4)	1,741 (7.7)	0.03	201 (8.4)	191 (8.0)	0.02
Antidepressants	197 (8.2)	1,602 (7.1)	0.04	197 (8.2)	227 (9.5)	0.04
Antihypertensives	1,286 (53.8)	11,080 (49.1)	0.09	1,286 (53.8)	1,328 (55.5)	0.04
Antiplatelets	663 (27.7)	4,986 (22.1)	0.13	663 (27.7)	642 (26.9)	0.02
Antirheumatic	28 (1.2)	277 (1.2)	0.01	28 (1.2)	32 (1.3)	0.02
Chronic obstructive pulmonary disease drugs	141 (5.9)	1,502 (6.7)	0.03	141 (5.9)	148 (6.2)	0.01
Corticosteroids	119 (5.0)	1,432 (6.3)	0.06	119 (5.0)	134 (5.6)	0.03
Insulin	0 (0.0)	0 (0.0)	-	0 (0.0)	0 (0.0)	-
Lipid-lowering drugs	139 (5.8)	955 (4.2)	0.07	139 (5.8)	152 (6.4)	0.02
Narcotic analgesics	154 (6.4)	1,496 (6.6)	0.01	154 (6.4)	155 (6.5)	0.00
Non-steroidal anti-inflammatory drugs	914 (38.2)	7,858 (34.8)	0.07	914 (38.2)	892 (37.3)	0.02
Oral hypoglycaemic agent	0 (0.0)	0 (0.0)	-	0 (0.0)	0 (0.0)	-
Other hormonal agents /Hormone replacement therapy	132 (5.5)	1,531 (6.8)	0.05	132 (5.5)	154 (6.4)	0.04

D) Cohort to assess the comparative risk of new-onset myalgia or rhabdomyolysis
Characteristic	Before PSM			After PSM
Characteristic	Pravastatin group N = 11,799	Atorvastatin group N = 124,621	SMD	Pravastatin group N = 11,799	Atorvastatin group N = 11,799	SMD
Male, n (%)	5,486 (46.5)	58,476 (46.9)	0.01	5,486 (46.5)	5,508 (46.7)	＜0.01
Age, years, mean±SD	59.3±12.8	61.4±13.3	0.16	59.3±12.8	59.4±13.2	＜0.01
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.2±0.5	0.2±0.6	0.05	0.2±0.5	0.2±0.7	0.01
Hospital admissions	0.3±1.0	0.4±1.3	0.13	0.3±1.0	0.3±0.8	＜0.01
Outpatient visits	4.3±7.1	3.4±6.1	0.13	4.3±7.1	4.3±7.7	＜0.01
Department of care, n (%)
Cardiology	1,871 (15.9)	22,272 (17.9)	0.05	1,871 (15.9)	1,749 (14.8)	0.03
Endocrinology	2,155 (18.3)	18,125 (14.5)	0.24	2,155 (18.3)	1,869 (15.8)	0.08
Neurology	1,358 (11.5)	15,006 (12.0)	0.07	1,358 (11.5)	1,582 (13.4)	0.08
Other	2,169 (18.4)	42,839 (34.4)	0.31	2,169 (18.4)	2,300 (19.5)	0.04
Comorbidities, n (%)
Angina pectoris	690 (5.8)	7,005 (5.6)	0.01	690 (5.8)	676 (5.7)	0.01
Atrial fibrillation	8 (0.1)	59 (0.0)	0.01	8 (0.1)	4 (0.0)	0.02
Chronic atrial fibrillation	4 (0.0)	75 (0.1)	0.01	4 (0.0)	4 (0.0)	＜0.01
Chronic liver disease	420 (3.6)	3,667 (2.9)	0.04	420 (3.6)	422 (3.6)	＜0.01
Congenital heart disease	5 (0.0)	132 (0.1)	0.02	5 (0.0)	3 (0.0)	0.01
Chronic obstructive pulmonary disease	146 (1.2)	2,359 (1.9)	0.05	146 (1.2)	143 (1.2)	＜0.01
Coronary artery disease	29 (0.2)	160 (0.1)	0.03	29 (0.2)	23 (0.2)	0.01
Diabetes mellitus	2,838 (24.1)	27,392 (22.0)	0.05	2,838 (24.1)	2,924 (24.8)	0.02
Hypertension	5,429 (46.0)	55,197 (44.3)	0.04	5,429 (46.0)	5,510 (46.7)	0.01
Peripheral vascular disease	807 (6.8)	8,447 (6.8)	＜0.01	807 (6.8)	793 (6.7)	0.01
Renal impairment	413 (3.5)	7,343 (5.9)	0.11	413 (3.5)	452 (3.8)	0.02
Rheumatic heart disease	51 (0.4)	606 (0.5)	0.01	51 (0.4)	32 (0.3)	0.03
Venous thromboembolism	18 (0.2)	243 (0.2)	0.01	18 (0.2)	22 (0.2)	0.01
Charlson comorbidity index score, mean±SD	0.1±0.5	0.1±0.5	0.01	0.11±0.5	0.1±0.5	0.02
Concomitant drugs, n (%)
Anti-arrhythmic drugs	432 (3.7)	4,369 (3.5)	0.01	432 (3.7)	407 (3.4)	0.01
Anticoagulants	886 (7.5)	10,550 (8.5)	0.04	886 (7.5)	850 (7.2)	0.01
Antidepressants	940 (8.0)	9,728 (7.8)	0.01	940 (8.0)	924 (7.8)	0.01
Antihypertensives	4,894 (41.5)	45,988 (36.9)	0.09	4,894 (41.5)	4,903 (41.6)	＜0.01
Antiplatelets	2,271 (19.2)	18,202 (14.6)	0.12	2,271 (19.2)	2,322 (19.7)	0.01
Antirheumatic	505 (4.3)	4,782 (3.8)	0.02	505 (4.3)	502 (4.3)	＜0.01
Chronic obstructive pulmonary disease drugs	921 (7.8)	11,418 (9.2)	0.05	921 (7.8)	884 (7.5)	0.01
Corticosteroids	873 (7.4)	11,278 (9.0)	0.06	873 (7.4)	858 (7.3)	0.01
Insulin	637 (5.4)	7,516 (6.0)	0.03	637 (5.4)	654 (5.5)	0.01
Lipid-lowering drugs	874 (7.4)	4,502 (3.6)	0.17	874 (7.4)	865 (7.3)	＜0.01
Narcotic analgesics	1,495 (12.7)	20,920 (16.8)	0.12	1495 (12.7)	1,491 (12.6)	＜0.01
Non-steroidal anti-inflammatory drugs	4,712 (39.9)	47,099 (37.8)	0.04	4712 (39.9)	4,634 (39.3)	0.01
Oral hypoglycaemic agent	2,237 (19.0)	18,300 (14.7)	0.11	2237 (19.0)	2,316 (19.6)	0.02
Other hormonal agents /Hormone replacement therapy	1,327 (11.2)	17,460 (14.0)	0.08	1327 (11.2)	1,265 (10.7)	0.02

E) Cohort to assess comparative hepatotoxicity (aspartate aminotransferase level)
Characteristic	Before PSM			After PSM
Characteristic	Pravastatin group (N = 4,034)	Atorvastatin group (N = 50,589)	SMD	Pravastatin group (N = 4,034)	Atorvastatin group (N = 4,034)	SMD
Male, n (%)	1,884 (46.7)	23,224 (45.9)	0.02	1,884 (46.7)	1,883 (46.7)	＜0.01
Age, years, mean±SD	58.6±12.9	61.9±13.7	0.24	58.6±12.9	58.7±13.3	＜0.01
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.2±0.4	0.3±0.4	0.10	0.2±0.4	0.2±0.4	＜0.01
Hospital admissions	0.4±0.5	0.5±0.5	0.33	0.4±0.5	0.4±0.5	0.01
Outpatient visits	0.9±0.2	0.9±0.3	0.12	0.9±0.2	0.9±0.2	＜0.01
Department of care, n (%)
Cardiology	238 (10.1)	3,075 (7.9)	＜0.01	238 (10.1)	301 (12.8)	0.06
Endocrinology	815 (34.4)	7,448 (19.2)	0.15	815 (34.4)	767 (32.6)	0.03
Neurology	458 (19.3)	6,674 (17.2)	0.06	458 (19.3)	399 (16.9)	0.05
Other	857 (36.2)	21,654 (55.7)	0.48	857 (36.2)	888 (37.7)	0.02
Comorbidities, n (%)
Angina pectoris	189 (4.7)	2,676 (5.3)	0.03	189 (4.7)	184 (4.6)	＜0.01
Atrial fibrillation	3 (0.1)	25 (0.0)	0.01	3 (0.1)	4 (0.1)	＜0.01
Chronic atrial fibrillation	0 (0.0)	25 (0.0)	0.03	0 (0.0)	0 (0.0)	-
Chronic liver disease	0 (0.0)	0 (0.0)	-	0 (0.0)	0 (0.0)	-
Congenital heart disease	1 (0.0)	53 (0.1)	0.03	1 (0.0)	0 (0.0)	0.02
Chronic obstructive pulmonary disease	74 (1.8)	1,333 (2.6)	0.05	74 (1.8)	69 (1.7)	＜0.01
Coronary artery disease	10 (0.2)	67 (0.1)	0.03	10 (0.2)	8 (0.2)	0.01
Diabetes mellitus	1,342 (33.3)	14,835 (29.3)	0.09	1,342 (33.3)	392 (37.0)	0.08
Hypertension	962 (23.8)	13,422 (26.5)	0.06	962 (23.8)	948 (23.5)	＜0.01
Peripheral vascular disease	313 (7.8)	3,792 (7.5)	0.01	313 (7.8)	283 (7.0)	0.03
Renal impairment	244 (6.0)	4,812 (9.5)	0.13	244 (6.0)	249 (6.2)	＜0.01
Rheumatic heart disease	18 (0.4)	277 (0.5)	0.01	18 (0.4)	17 (0.4)	＜0.01
Venous thromboembolism	11 (0.3)	136 (0.3)	＜0.01	11 (0.3)	12 (0.3)	＜0.01
Charlson comorbidity index Score, mean±SD	0.1±0.6	0.1±0.6	0.01	0.1±0.6	0.1±0.5	0.03
Comedication, n (%)
Anti-arrhythmic drugs	123 (3.0)	2,180 (4.3)	0.07	123 (3.0)	124 (3.1)	＜0.01
Anticoagulants	422 (10.5)	6,678 (13.2)	0.09	422 (10.5)	433 (10.7)	＜0.01
Antidepressants	1,587 (39.3)	20,438 (40.4)	0.02	1,587 (39.3)	1,600 (39.7)	＜0.01
Antihypertensives	502 (12.4)	4,347 (8.6)	0.13	502 (12.4)	473 (11.7)	0.02
Antiplatelets	616 (15.3)	6,970 (13.8)	0.04	616 (15.3)	611 (15.1)	＜0.01
Antirheumatic	298 (7.4)	2,789 (5.5)	0.08	298 (7.4)	275 (6.8)	0.02
Chronic obstructive pulmonary disease drugs	375 (9.3)	6,352 (12.6)	0.11	375 (9.3)	351 (8.7)	0.02
Corticosteroids	429 (10.6)	6,579 (13.0)	0.07	429 (10.6)	456 (11.3)	0.02
Insulin	353 (8.8)	4,752 (9.4)	0.02	353 (8.8)	373 (9.2)	0.02
Lipid-lowering drugs	355 (8.8)	1,932 (3.8)	0.21	355 (8.8)	325 (8.1)	0.03
Narcotic analgesics	762 (18.9)	13,041 (25.8)	0.17	762 (18.9)	729 (18.1)	0.02
Non-steroidal anti-inflammatory drugs	1,729 (42.9)	22,202 (43.9)	0.02	1,729 (42.9)	1,648 (40.9)	0.04
Oral hypoglycaemic agent	991 (24.6)	8,970 (17.7)	0.17	991 (24.6)	996 (24.7)	＜0.01
Other hormonal agents /Hormone replacement therapy	751 (18.6)	10,518 (20.8)	0.06	751 (18.6)	718 (17.8)	0.02

F) Cohort to assess comparative hepatotoxicity (alanine aminotransferase level)
Characteristic	Before PSM			After PSM
Characteristic	Pravastatin group (N = 3,655)	Atorvastatin group (N = 46,850)	SMD	Pravastatin group (N = 3,655)	Atorvastatin group (N = 3,655)	SMD
Male, n (%)	1,744 (47.7)	21,689 (46.3)	0.03	1,744 (47.7)	1,800 (49.2)	0.03
Age, years, mean±SD	58.9±13.0	61.8±13.8	0.22	58.9±13.0	58.6±13.4	0.02
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.2±0.4	0.3±0.4	0.09	0.2±0.4	0.2±0.4	＜0.01
Hospital admissions	0.4±0.5	0.5±0.5	0.31	0.4±0.5	0.4±0.5	0.02
Outpatient visits	0.9±0.3	0.9±0.3	0.11	0.9±0.3	0.9±0.3	＜0.01
Department of care, n (%)
Cardiology	225 (11.3)	2,608 (7.4)	0.03	225 (11.3)	273 (13.7)	0.05
Endocrinology	704 (35.4)	6,415 (18.2)	0.15	704 (35.4)	652 (32.8)	0.04
Neurology	387 (19.4)	6,141 (17.5)	0.08	387 (19.4)	371 (18.7)	0.01
Other	674 (33.9)	20,017 (56.9)	0.55	674 (33.9)	693 (34.8)	0.01
Comorbidities, n (%)
Angina pectoris	175 (4.8)	2,357 (5.0)	0.01	175 (4.8)	165 (4.5)	0.01
Atrial fibrillation	3 (0.1)	25 (0.1)	0.01	3 (0.1)	4 (0.1)	＜0.01
Chronic atrial fibrillation	0 (0.0)	22 (0.0)	0.03	0 (0.0)	0 (0.0)	＜0.01
Chronic liver disease	0 (0.0)	0 (0.0)	-	0 (0.0)	0 (0.0)	-
Congenital heart disease	1 (0.0)	51 (0.1)	0.03	1 (0.0)	0 (0.0)	0.02
Chronic obstructive pulmonary disease	72 (2.0)	1259 (2.7)	0.05	72 (2.0)	59 (1.6)	0.03
Coronary artery disease	10 (0.3)	67 (0.1)	0.03	10 (0.3)	7 (0.2)	0.02
Diabetes mellitus	1,265 (34.6)	13,644 (29.1)	0.12	1,265 (34.6)	397 (41.1)	0.13
Hypertension	858 (23.5)	12,189 (26.0)	0.06	858 (23.5)	852 (23.3)	＜0.01
Peripheral vascular disease	278 (7.6)	3,434 (7.3)	0.01	278 (7.6)	265 (7.3)	0.01
Renal impairment	238 (6.5)	4,514 (9.6)	0.12	238 (6.5)	233 (6.4)	＜0.01
Rheumatic heart disease	17 (0.5)	260 (0.6)	0.01	17 (0.5)	23 (0.6)	0.02
Venous thromboembolism	10 (0.3)	134 (0.3)	＜0.01	10 (0.3)	9 (0.2)	＜0.01
Charlson comorbidity index Score, mean±SD	0.1±0.6	0.1±0.6	＜0.01	0.1±0.6	0.1±0.5	0.01
Comedication, n (%)
Anti-arrhythmic drugs	112 (3.1)	1,943 (4.1)	0.06	112 (3.1)	111 (3.0)	＜0.01
Anticoagulants	408 (11.2)	6,430 (13.7)	0.08	408 (11.2)	381 (10.4)	0.02
Antidepressants	1,470 (40.2)	18,824 (40.2)	＜0.01	1,470 (40.2)	1,471 (40.2)	0.001
Antihypertensives	456 (12.5)	4,030 (8.6)	0.13	456 (12.5)	426 (11.7)	0.03
Antiplatelets	560 (15.3)	6,261 (13.4)	0.06	560 (15.3)	584 (16.0)	0.02
Antirheumatic	279 (7.6)	2,478 (5.3)	0.10	279 (7.6)	252 (6.9)	0.03
Chronic obstructive pulmonary disease drugs	348 (9.5)	5,994 (12.8)	0.10	348 (9.5)	326 (8.9)	0.02
Corticosteroids	398 (10.9)	6,023 (12.9)	0.06	398 (10.9)	388 (10.6)	＜0.01
Insulin	334 (9.1)	4,407 (9.4)	＜0.01	334 (9.1)	345 (9.4)	0.01
Lipid-lowering drugs	290 (7.9)	1,768 (3.8)	0.18	290 (7.9)	280 (7.7)	0.01
Narcotic analgesics	704 (19.3)	12,250 (26.1)	0.17	704 (19.3)	686 (18.8)	0.01
Non-steroidal anti-inflammatory drugs	1,590 (43.5)	20,495 (43.7)	＜0.01	1,590 (43.5)	1,562 (42.7)	0.02
Oral hypoglycaemic agent	940 (25.7)	8,267 (17.6)	0.2	940 (25.7)	969 (26.5)	0.02
Other hormonal agents /Hormone replacement therapy	700 (19.2)	9,878 (21.1)	0.05	700 (19.2)	684 (18.7)	0.01

Abbreviation: PSM, propensity score matching; SD, standard deviation; SMD, standardized mean difference

Effectiveness of Primary Prevention and Secondary Prevention of MACE

The incidence rate of the composite of MACE (primary prevention) was numerically lower in the pravastatin group than in the atorvastatin group (5.38 events per 1,000 person-years vs. 6.44 events per 1,000 person-years). However, there was no statistically significant difference in the risk of MACE between the two groups (HR, 0.84; 95% CI, 0.59-1.20) (Fig.2A). Additionally, no significant between-group differences were observed in either the cumulative incidence or absolute rate difference for the primary prevention of MACE (Fig.2B, Supplementary Table 3).

Fig.2. Forest plot and Kaplan-Meier curve for the primary prevention of MACE, the secondary prevention of MACE, new-onset diabetes mellitus, and new-onset myalgia and rhabdomyolysis

^＊The incidence rate was calculated per 1,000 person-years.

Abbreviations: HR, hazard ratio; CI, confidence interval; MACE, major cardiovascular event; AUMC, Ajou University Medical Center; CHAMC, Bundang CHA Medical Center; EUMC, Ewha Womans University Medical Hospital; GNUH, Gyeongsang National University Hospital; INHA, Inha University Hospital; KDH, Kangdong Sacred Heart Hospital; KHMC, Kyung Hee Medical Center; KHNMC, Kangdong Kyung Hee University Medical Center; KUMC, Korea University Medical Center in Ansan; PNUH, Pusan National University Hospital; SCHBC, Soonchunhyang University Bucheon Hospital; SCHCA, Soonchunhyang University Cheonan Hospital; SCHSU, Soonchunhyang University Seoul Hospital; Chi, Chi square test; df, degrees of freedom

Supplementary Table 3.Absolute rate differences in outcomes between the pravastatin group and atorvastatin group

Outcomes	Absolute rate difference [95% CI]^＊	p-value^†
Primary prevention of MACE	-1.06 [-3.06; 0.95]	0.301
Secondary prevention of MACE	-1.90 [-6.78; 2.99]	0.447
New-onset diabetes mellitus	-1.21 [-4.75; 2.32]	0.501
Myalgia and/or rhabdomyolysis	-1.00 [-1.77; -0.22]	0.012

^＊Calculated per 1,000 person-years.

^†The p-value was calculated using a z-test (or Wald test).

Abbreviation: MACE, major cardiovascular event; CI, confidence interval

Similar outcomes were observed in the cohort to assess the comparative effectiveness of secondary prevention of MACE (Fig.2C and 2D, Supplementary Table 3). Forest plots of the incidence rates and hazard ratios of individual endpoints included in the composite of MACE in the cohorts to assess the effectiveness of primary prevention of MACE and secondary prevention of MACE are presented in Supplementary Figs.2 and 3.

Supplementary Fig.2. Forest plots of incidence rates and hazard ratios of individual endpoints included in the composite of MACE in cohort to assessthe effectiveness of primary prevention of MACE

^＊Incidence rate was calculated per 1,000 person-years.

Abbreviations: HR, hazard ratio; CI, confidence interval; MACE, major cardiovascular event; AUMC, Ajou University Medical Center; CHAMC, Bundang CHAMedical Center; EUMC, Ewha Womans University Medical Hospital; GNUH, Gyeongsang National University Hospital; INHA, Inha University Hospital; KDH, Kangdong Sacred Heart Hospital; KHMC, Kyung Hee Medical Center; KHNMC, Kangdong Kyung Hee University Medical Center; KUMC, Korea University MedicalCenter in Ansan; PNUH , Pusan National University Hospital; SCHBC, Soonchunhyang University Bucheon Hospital; SCHCA, Soonchunhyang University Cheonan Hospital; SCHSU, Soonchunhyang University Seoul Hospital; Chi, Chisquare-test; df, degrees of freedom.

Supplementary Fig.3. Forest plots of incidence rates and hazard ratios of individual endpoints included in the composite of MACE in cohort to assess the effectiveness of secondary prevention of MACE

^＊Incidence rate was calculated per 1,000 person-years.

Abbreviations: HR, hazard ratio; CI, confidence interval; MACE, major cardiovascular event; AUMC, Ajou University Medical Center; CHAMC, Bundang CHAMedical Center; EUMC, Ewha Womans University Medical Hospital; GNUH, Gyeongsang National University Hospital; INHA, Inha University Hospital; KDH, Kangdong Sacred Heart Hospital; KHMC, Kyung Hee Medical Center; KHNMC, Kangdong Kyung Hee University Medical Center; KUMC, Korea University MedicalCenter in Ansan; PNUH , Pusan National University Hospital; SCHBC, Soonchunhyang University Bucheon Hospital; SCHCA, Soonchunhyang University Cheonan Hospital; SCHSU, Soonchunhyang University Seoul Hospital; Chi, Chisquare-test; df, degrees of freedom.

At baseline, LDL-C levels were comparable between the pravastatin and atorvastatin groups in both the primary (134.15±36.08 mg/dL vs. 131.83±36.84 mg/dL) and secondary prevention cohorts (123.58±34.91 mg/dL vs. 116.61±35.34 mg/dL) (Supplementary Tables 4 and 5). In each cohort, both treatment groups exhibited a statistically significant reduction in LDL-C levels within the first year of follow-up. Notably, beyond the 1-year time point, there were no significant differences in the rate of LDL-C reduction between the two groups.

Supplementary Table 4.Time-course of percent changes in LDL-C level throughout the follow-up period in the cohort to assess the comparative effectiveness of primary prevention of MACE

	Pravastatin group			Atorvastatin group			P-value
	Patients	LDL-C level, mg/ dL mean (SD)	Percent change from baseline to follow-up visits, mean (SD)^＊	Patients	LDL-C level, mg/ dL mean (SD)	Percent change from baseline to follow-up visits, mean (SD)^＊	P-value
0 (Index date)	1428	134.15 (36.08)	-	1398	131.83 (36.84)	-	0.092^†
Within 1 year	892	100.17 (26.48)	23.1 (28.51)	774	88.39 (23.19)	31.18 (24.53)	0.047^‡
1~2 years	720	98.12 (27.29)	24.39 (26.59)	613	90.36 (27.34)	27.45 (29.18)	0.210^‡
2~3 years	611	98.42 (28.95)	25.04 (24.67)	548	92.68 (28.56)	26.94 (26.88)	0.703^‡
3~4 years	511	97.47 (29.82)	25.26 (27.66)	492	91.26 (27.1)	25.94 (28.52)	0.367^‡
4~5 years	433	96.07 (28.44)	26.87 (24.25)	445	91.67 (26.65)	25.22 (29.6)	0.164^‡
5~6 years	355	96.52 (29.66)	27.78 (25.97)	415	93.95 (35.69)	24.67 (35.82)	0.776^‡
After 6 years	439	95.49 (29.34)	26.96 (29.32)	464	88.67 (25.61)	27.53 (30.12)	0.047^‡

^＊Calculated by [(LDL-C levels recorded during the follow-up / LDL-C level at baseline LDL-C) – 1]×100.

^†P-value was calculated using the T-test to assess whether there was a significant difference in the mean LDL-C levels between the two groups at baseline.

^‡P-values were calculated using either a T-test or Mann-Whitney U test, as appropriate, to assess the significance of differences in the percent change in LDL-C levels between the two groups at each time point.

Abbreviation: LDL-C, low density lipoprotein cholesterol; MACE, major cardiovascular event; SD, standard deviation

Supplementary Table 5.Time-course of percent changes in LDL-C level throughout the follow-up period in the cohort to assess the comparative effectiveness of secondary prevention of MACE

	Pravastatin group			Atorvastatin group			P-value
	Patients	LDL-C level, mg/ dL mean (SD)	Percent change from baseline to follow-up visits, mean (SD)^＊	Patients	LDL-C level, mg/ dL mean (SD)	Percent change from baseline to follow-up visits, mean (SD)^†	P-value
0 (Index date)	380	123.58 (34.91)	0.004^†	472	116.61 (35.34)	-	0.004^†
Within 1 year	146	91.69 (25.05)	0.433^‡	176	79.75 (18.63)	26.39 (24.78)	0.433^‡
1~2 years	158	98.49 (28.05)	0.094^‡	174	84.9 (29.38)	23.04 (28.83)	0.094^‡
2~3 years	140	94.76 (24.84)	0.949^‡	142	85.74 (22.82)	21.57 (30.05)	0.949^‡
3~4 years	120	95.04 (29.77)	0.521^‡	149	85.7 (24.19)	21.44 (31.9)	0.521^‡
4~5 years	107	87.52 (28.2)	0.241^‡	119	83.23 (24.77)	22.43 (28.79)	0.241^‡
5~6 years	97	88.73 (27.91)	0.031^‡	117	84.68 (25.32)	21.45 (27.95)	0.031^‡
After 6 years	141	85.34 (27.36)	0.299^‡	171	80.64 (25.91)	26.14 (30.06)	0.299^‡

^＊Calculated by [(LDL-C levels recorded during the follow-up / LDL-C level at baseline LDL-C) – 1]×100.

^†P-value was calculated using the T-test to assess whether there was a significant difference in the mean LDL-C levels between the two groups at baseline.

Abbreviation: LDL-C, low density lipoprotein cholesterol; MACE, major cardiovascular event; SD, standard deviation

Risk of NODM and New-Onset Myalgia or Rhabdomyolysis

The incidence rate per 1,000 person-years for NODM was 15.89 in the pravastatin group and 17.11 in the atorvastatin group (Fig.2E). There was no statistically significant difference in the risk of NODM between the two groups (HR, 0.99; 95% CI, 0.79-1.23) (Fig.2E). Additionally, no significant differences were observed in the cumulative incidence and absolute rate differences of NODM between the two treatment groups (Fig.2F, Supplementary Table 3).

The incidence rates per 1,000 person-years were 4.35 in the pravastatin group and 5.34 in the atorvastatin group, respectively (Fig.2G). The risk of new-onset myalgia or rhabdomyolysis was significantly lower with the pravastatin group than with the atorvastatin group (HR, 0.82; 95% CI, 0.69-0.96) (Fig.2G). Furthermore, the cumulative incidence and absolute rate differences of new-onset myalgia and rhabdomyolysis were significantly lower in the pravastatin group (Fig.2H, Supplementary Table 3).

Hepatotoxicity

The proportion of patients with abnormal AST levels was significantly lower in the pravastatin group than in the atorvastatin group (2.35% vs. 3.37%, P = 0.008). In contrast, there was no difference in the proportion of patients with abnormal ALT levels between the pravastatin and atorvastatin groups (2.87% vs. 3.06%; P = 0.679) (Table 2).

Table 2.Abnormal aspartate aminotransferase and alanine aminotransferase levels in the pravastatin group versus the atorvastatin group during the observation period

Abnormal proportion	Pravastatin group		Atorvastatin group		P-value^＊
Abnormal proportion	N	%	N	(%)	P-value^＊
Aspartate aminotransferase (N = 4,034)	95	2.35	136	3.37	0.008
Alanine aminotransferase (N = 3,655)	105	2.87	112	3.06	0.679

^＊proportions of patients with abnormal AST and ALT levels between the two statin therapy groups were compared using the chi-square test. Abbreviation: AST, aspartate aminotransferase; ALT, alanine aminotransferase level

Sensitivity Analysis

To assess the robustness of our findings, we conducted a sensitivity analysis using IPTW. The results of the IPTW analysis were generally consistent with those of the main analysis, with similar effect estimates observed for the effectiveness of primary and secondary prevention of MACE, as well as the risks of NODM and new-onset myalgia or rhabdomyolysis (Supplementary Tables 6, 7, 8 and 9, and Supplementary Figs.4 and 5).

Supplementary Table 6.Baseline characteristics before and after inverse probability of treatment weighting in four distinct cohorts (5% trimming)

A) Cohort to assess the comparative effectiveness of primary prevention of major adverse cardiovascular events
Characteristic	Before IPTW			After IPTW
Characteristic	Pravastatin group (N = 2,688)	Atorvastatin group (N = 25,578)	SMD	Pravastatin group (N = 25290.2)	Atorvastatin group (N = 25358.0)	SMD
Male, n (%)	1,439 (53.5)	13,330 (52.1)	0.03	13279.3 (52.5)	13100.4 (51.7)	0.02
Age, years, mean±SD	56.5±12.5	57.9±12.9	0.11	57.0±12.4	57.6±12.8	0.05
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.1±0.4	0.1±0.4	0.02	0.1±0.4	0.1±0.4	＜0.01
Hospital admissions	0.2±0.6	0.2±0.7	0.07	0.2±0.5	0.2±0.6	0.04
Outpatient visits	6.3±7.3	6.3±8.2	0.00	6.2±7.7	5.9±5.9	0.03
Department of care, n (%)
Cardiology	495 (18.4)	5,211 (20.4)	0.28	5445.7 (27.9)	5352.2 (25.9)	0.01
Endocrinology	802 (29.8)	6,292 (24.6)	0.37	8304.7 (42.6)	6395.6 (30.9)	0.17
Neurology	223 (8.3)	2,773 (10.8)	0.28	2640.7 (13.5)	2676.0 (12.9)	＜0.01
Other	316 (11.8)	6,298 (24.6)	0.39	3123.3 (16.0)	6254.7 (30.2)	0.32
Comorbidities, n (%)
Angina pectoris	124 (4.6)	1,132 (4.4)	0.01	1110.9 (4.4)	1131.8 (4.5)	＜0.01
Atrial fibrillation	3 (0.1)	19 (0.1)	0.01	22.7 (0.1)	16.9 (0.1)	0.01
Chronic atrial fibrillation	0 (0.0)	9 (0.0)	0.03	0 (0.0)	0 (0.0)	-
Chronic liver disease	113 (4.2)	888 (3.5)	0.04	945.8 (3.7)	862.7 (3.4)	0.02
Congenital heart disease	1 (0.0)	23 (0.1)	0.02	0.0 (0.0)	10.6 (0.0)	0.03
Chronic obstructive pulmonary disease	20 (0.7)	324 (1.3)	0.05	218.7 (0.9)	220.3 (0.9)	＜0.01
Coronary artery disease	4 (0.1)	21 (0.1)	0.02	18.7 (0.1)	19.7 (0.1)	＜0.01
Diabetes mellitus	900 (33.5)	7,122 (27.8)	0.12	7322.6 (29.0)	6855.9 (27.0)	0.04
Hypertension	1,320 (49.1)	12,093 (47.3)	0.04	11764.4 (46.5)	11757.9 (46.4)	＜0.01
Peripheral vascular disease	157 (5.8)	1,523 (6.0)	0.01	1406.5 (5.6)	1468.4 (5.8)	0.01
Renal impairment	80 (3.0)	1,323 (5.2)	0.11	910.4 (3.6)	901.8 (3.6)	＜0.01
Rheumatic heart disease	9 (0.3)	119 (0.5)	0.02	128.7 (0.5)	100.9 (0.4)	0.02
Venous thromboembolism	4 (0.1)	44 (0.2)	0.01	50.0 (0.2)	40.6 (0.2)	0.01
Charlson comorbidity index score, mean±SD	0.1±0.3	0.1±0.3	0.00	0.1±0.3	0.1±0.3	＜0.01
Comedication, n (%)
Anti-arrhythmic drugs	90 (3.3)	687 (2.7)	0.04	500.1 (2.0)	669.5 (2.6)	0.04
Anticoagulants	118 (4.4)	1,105 (4.3)	0.00	975.1 (3.9)	1066.2 (4.2)	0.02
Antidepressants	181 (6.7)	1,654 (6.5)	0.01	1601.9 (6.3)	1639.4 (6.5)	0.01
Antihypertensives	1,236 (46.0)	11,129 (43.5)	0.05	10948.5 (43.3)	10812.1 (42.6)	0.01
Antiplatelets	397 (14.8)	2,993 (11.7)	0.09	2833.1 (11.2)	2843.9 (11.2)	＜0.01
Antirheumatic	42 (1.6)	444 (1.7)	0.01	455.5 (1.8)	431.4 (1.7)	0.01
Chronic obstructive pulmonary disease drugs	159 (5.9)	1,816 (7.1)	0.05	1642.4 (6.5)	1667.9 (6.6)	＜0.01
Corticosteroids	150 (5.6)	1,870 (7.3)	0.02	1582.0 (6.3)	1631.6 (6.4)	0.01
Insulin	185 (6.9)	1,642 (6.4)	0.02	1613.3 (6.4)	1576.6 (6.2)	0.01
Lipid-lowering drugs	278 (10.3)	1,443 (5.6)	0.17	1397.1 (5.5)	1126.8 (4.4)	0.05
Narcotic analgesics	198 (7.4)	1,918 (7.5)	0.01	1798.0 (7.1)	1866.7 (7.4)	0.01
Non-steroidal anti-inflammatory drugs	788 (29.3)	7,199 (28.1)	0.03	6886.2 (27.2)	7067.9 (27.9)	0.01
Oral hypoglycaemic agent	764 (28.4)	5,706 (22.3)	0.14	5924.6 (23.4)	5480.4 (21.6)	0.04
Other hormonal agents /Hormone replacement therapy	183 (6.8)	2,099 (8.2)	0.05	1863.9 (7.4)	1974.0 (7.8)	0.02

B) Cohort to assess the comparative effectiveness of secondary prevention of major adverse cardiovascular event
Characteristic	Before IPTW			After IPTW
Characteristic	Pravastatin group (N = 1,258)	Atorvastatin group (N = 10,461)	SMD	Pravastatin group (N = 11537.7)	Atorvastatin group (N = 10585.4)	SMD
Male, n (%)	726 (57.7)	6,381 (61.0)	0.07	7226.4 (62.6)	6398.4 (60.4)	0.05
Age, years, mean±SD	64.4±11.5	65.5±12.1	0.09	64.9±11.9	65.3±12.1	0.03
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.2±0.5	0.2±0.5	0.08	0.2±0.5	0.2±0.5	0.05
Hospital admissions	0.3±0.6	0.4±0.9	0.21	0.4±0.7	0.4±0.7	0.02
Outpatient visits	6.3±8.6	5.8±8.4	0.06	5.8±7.5	5.7±8.0	0.01
Department of care, n (%)
Cardiology	346 (27.5)	3,785 (36.2)	0.39	4038.0 (43.8)	3845.6 (43.5)	0.03
Endocrinology	44 (3.5)	376 (3.6)	0.39	698.7 (7.6)	375.0 (4.2)	0.12
Neurology	400 (31.8)	3,486 (33.3)	0.41	4088.8 (44.3)	3560.6 (40.3)	0.04
Other	49 (3.9)	1,057 (10.1)	0.43	403.7 (4.4)	1054.6 (11.9)	0.26
Comorbidities, n (%)
Angina pectoris	182 (14.5)	1,839 (17.6)	0.09	2304.0 (20.0)	1846.7 (17.4)	0.07
Atrial fibrillation	1 (0.1)	17 (0.2)	0.02	18.8 (0.2)	13.0 (0.1)	0.01
Chronic atrial fibrillation	2 (0.2)	14 (0.1)	0.01	15.9 (0.1)	16.0 (0.2)	＜0.01
Chronic liver disease	11 (0.9)	126 (1.2)	0.03	216.6 (1.9)	120.5 (1.1)	0.06
Congenital heart disease	1 (0.1)	23 (0.2)	0.04	43.2 (0.4)	19.0 (0.2)	0.04
Chronic obstructive pulmonary disease	9 (0.7)	165 (1.6)	0.08	109.5 (0.9)	135.6 (1.3)	0.03
Coronary artery disease	11 (0.9)	63 (0.6)	0.03	60.4 (0.5)	71.9 (0.7)	0.02
Diabetes mellitus	258 (20.5)	2,235 (21.4)	0.02	2533.4 (22.0)	2134.7 (20.2)	0.04
Hypertension	897 (71.3)	7,003 (66.9)	0.09	7999.6 (69.3)	7087.4 (67.0)	0.05
Peripheral vascular disease	139 (11.0)	1,570 (15.0)	0.12	2249.2 (19.5)	1507.6 (14.2)	0.14
Renal impairment	28 (2.2)	457 (4.4)	0.12	370.4 (3.2)	379.5 (3.6)	0.02
Rheumatic heart disease	11 (0.9)	128 (1.2)	0.03	139.2 (1.2)	118.9 (1.1)	0.01
Venous thromboembolism	1 (0.1)	8 (0.1)	0.00	4.1 (0.0)	6.4 (0.1)	0.01
Charlson comorbidity index score, mean±SD	0.1±0.3	0.1±0.4	0.12	0.1±0.4	0.1±0.4	0.03
Concomitant drugs, n (%)
Anti-arrhythmic drugs	86 (6.8)	671 (6.4)	0.02	734.9 (6.4)	625.4 (5.9)	0.02
Anticoagulants	191 (15.2)	1,677 (16.0)	0.02	1959.6 (17.0)	1622.2 (15.3)	0.05
Antidepressants	138 (11.0)	882 (8.4)	0.09	949.2 (8.2)	895.1 (8.5)	0.01
Antihypertensives	863 (68.6)	6,498 (62.1)	0.14	7559.0 (65.5)	6610.8 (62.5)	0.06
Antiplatelets	689 (54.8)	5,205 (49.8)	0.10	5543.7 (48.0)	5311.7 (50.2)	0.04
Antirheumatic	14 (1.1)	103 (1.0)	0.01	105.1 (0.9)	96.3 (0.9)	＜0.01
Chronic obstructive pulmonary disease drugs	84 (6.7)	680 (6.5)	0.01	697.4 (6.0)	650.7 (6.1)	＜0.01
Corticosteroids	55 (4.4)	505 (4.8)	0.02	585.7 (5.1)	482.3 (4.6)	0.02
Insulin	33 (2.6)	439 (4.2)	0.09	503.9 (4.4)	384.4 (3.6)	0.04
Lipid-lowering drugs	60 (4.8)	438 (4.2)	0.03	698.6 (6.1)	455.4 (4.3)	0.08
Narcotic analgesics	56 (4.5)	704 (6.7)	0.10	822.4 (7.1)	624.5 (5.9)	0.05
Non-steroidal anti-inflammatory drugs	720 (57.2)	5,647 (54.0)	0.07	6117.1 (53.0)	5754.5 (54.4)	0.03
Oral hypoglycemic agent	229 (18.2)	1,705 (16.3)	0.05	2014.6 (17.5)	1677.6 (15.8)	0.04
Other hormonal agents /Hormone replacement therapy	54 (4.3)	629 (6.0)	0.08	762.9 (6.6)	564.7 (5.3)	0.05

C) Cohort to assess the comparative risk of new-onset diabetes mellitus
Characteristic	Before IPTW			After IPTW
Characteristic	Pravastatin group (N = 2,391)	Atorvastatin group (N = 22,557)	SMD	Pravastatin group (N = 22413.2)	Atorvastatin group (N = 22470.1)	SMD
Male, n (%)	1,245 (52.1)	11,803 (52.3)	0.01	11995.8 (53.5)	11681.8 (52.0)	0.03
Age, years, mean±SD	59.3±12.7	60.1±13.3	0.06	58.5±12.8	59.9±13.2	0.11
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.2±0.4	0.2±0.4	0.01	0.1±0.4	0.1±0.4	0.01
Hospital admissions	0.2±0.5	0.2±0.7	0.10	0.2±0.5	0.2±0.5	0.03
Outpatient visits	5.8±7.9	5.6±7.1	0.03	5.7±8.8	5.5±6.7	0.02
Department of care, n (%)
Cardiology	627 (26.2)	6,736 (29.9)	0.34	6694.8 (38.3)	6935.1 (37.4)	0.02
Endocrinology	194 (8.1)	1,224 (5.4)	0.38	2865.7 (16.4)	1202.8 (6.5)	0.26
Neurology	469 (19.6)	4,839 (21.5)	0.35	4984.0 (28.5)	4815.4 (26.0)	0.02
Other	296 (12.4)	5,499 (24.4)	0.41	2943.8 (16.8)	5572.7 (30.1)	0.30
Comorbidities, n (%)
Angina pectoris	226 (9.5)	1,956 (8.7)	0.03	2101.5 (9.4)	1953.0 (8.7)	0.02
Atrial fibrillation	4 (0.2)	28 (0.1)	0.01	22.2 (0.1)	30.6 (0.1)	0.01
Chronic atrial fibrillation	2 (0.1)	19 (0.1)	＜0.01	21.7 (0.1)	21.0 (0.1)	＜0.01
Chronic liver disease	67 (2.8)	483 (2.1)	0.04	594.3 (2.7)	460.5 (2.0)	0.04
Congenital heart disease	1 (0.0)	38 (0.2)	0.04	0.0 (0.0)	12.6 (0.1)	0.03
Chronic obstructive pulmonary disease	17 (0.7)	312 (1.4)	0.07	220.9 (1.0)	246.4 (1.1)	0.01
Coronary artery disease	7 (0.3)	54 (0.2)	0.01	47.5 (0.2)	59.3 (0.3)	0.01
Diabetes mellitus	0 (0.0)	0 (0.0)	-	0 (0.0)	0 (0.0)	-
Hypertension	1,351 (56.5)	11,888 (52.7)	0.08	11576.2 (51.6)	11756.6 (52.3)	0.01
Peripheral vascular disease	161 (6.7)	1,717 (7.6)	0.03	1718.5 (7.7)	1592.8 (7.1)	0.02
Renal impairment	51 (2.1)	891 (3.9)	0.11	674.4 (3.0)	684.4 (3.0)	＜0.01
Rheumatic heart disease	14 (0.6)	181 (0.8)	0.03	166.9 (0.7)	163.9 (0.7)	＜0.01
Venous thromboembolism	3 (0.1)	39 (0.2)	0.01	36.7 (0.2)	34.6 (0.2)	＜0.01
Charlson comorbidity index score, mean±SD	0.1±0.3	0.1±0.3	0.04	0.1±0.3	0.1±0.3	＜0.01
Concomitant drugs, n (%)
Anti-arrhythmic drugs	120 (5.0)	886 (3.9)	0.05	646.4 (2.9)	831.1 (3.7)	0.05
Anticoagulants	201 (8.4)	1,741 (7.7)	0.03	1609.8 (7.2)	1648.8 (7.3)	0.01
Antidepressants	197 (8.2)	1,602 (7.1)	0.04	1421.9 (6.3)	1613.0 (7.2)	0.03
Antihypertensives	1,286 (53.8)	11,080 (49.1)	0.09	10956.4 (48.9)	10980.4 (48.9)	＜0.01
Antiplatelets	663 (27.7)	4,986 (22.1)	0.13	4267.6 (19.0)	4991.2 (22.2)	0.08
Antirheumatic	28 (1.2)	277 (1.2)	0.01	277.1 (1.2)	280.9 (1.2)	＜0.01
Chronic obstructive pulmonary disease drugs	141 (5.9)	1,502 (6.7)	0.03	1333.7 (6.0)	1422.1 (6.3)	0.02
Corticosteroids	119 (5.0)	1,432 (6.3)	0.06	1195.1 (5.3)	1330.9 (5.9)	0.03
Insulin	0 (0.0)	0 (0.0)	-	0 (0.0)	0 (0.0)	-
Lipid-lowering drugs	139 (5.8)	955 (4.2)	0.07	1358.5 (6.1)	935.6 (4.2)	0.09
Narcotic analgesics	154 (6.4)	1,496 (6.6)	0.01	1453.6 (6.5)	1423.4 (6.3)	0.01
Non-steroidal anti-inflammatory drugs	914 (38.2)	7,858 (34.8)	0.07	7129.2 (31.8)	7870.9 (35.0)	0.07
Oral hypoglycaemic agent	0 (0.0)	0 (0.0)	-	0 (0.0)	0 (0.0)	-
Other hormonal agents /Hormone replacement therapy	132 (5.5)	1,531 (6.8)	0.05	1378.2 (6.1)	1441.9 (6.4)	0.01

D) Cohort to assess the comparative risk of new-onset myalgia or rhabdomyolysis
Characteristic	Before IPTW			After IPTW
Characteristic	Pravastatin group (N = 11,799)	Atorvastatin group (N = 124,621)	SMD	Pravastatin group (N = 121064.3)	Atorvastatin group (N = 122496.9)	SMD
Male, n (%)	5,486 (46.5)	58,476 (46.9)	0.01	57774.5 (47.7)	56616.9 (46.2)	0.03
Age, years, mean±SD	59.3±12.8	61.4±13.3	0.16	60.1±12.8	61.1±13.2	0.08
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.2±0.5	0.2±0.6	0.05	0.2±0.6	0.2±0.6	0.03
Hospital admissions	0.3±1.0	0.4±1.3	0.13	0.3±0.9	0.3±0.8	0.04
Outpatient visits	4.3±7.1	3.4±6.1	0.13	3.7±5.3	3.4±5.7	0.05
Department of care, n (%)
Cardiology	1,871 (15.9)	22,272 (17.9)	0.05	21119.0 (23.0)	22868.0 (23.4)	0.03
Endocrinology	2,155 (18.3)	18,125 (14.5)	0.24	27470.1 (29.9)	18296.7 (18.7)	0.20
Neurology	1,358 (11.5)	15,006 (12.0)	0.07	16331.4 (17.8)	14993.1 (15.3)	0.04
Other	2,169 (18.4)	42,839 (34.4)	0.31	26804.6 (29.2)	41688.8 (42.6)	0.27
Comorbidities, n (%)
Angina pectoris	690 (5.8)	7,005 (5.6)	0.01	6971.2 (5.8)	6840.5 (5.6)	0.01
Atrial fibrillation	8 (0.1)	59 (0.0)	0.01	45.2 (0.0)	57.9 (0.0)	0.01
Chronic atrial fibrillation	4 (0.0)	75 (0.1)	0.01	85.9 (0.1)	67.8 (0.1)	0.01
Chronic liver disease	420 (3.6)	3,667 (2.9)	0.04	4029.9 (3.3)	3510.7 (2.9)	0.03
Congenital heart disease	5 (0.0)	132 (0.1)	0.02	16.2 (0.0)	73.8 (0.1)	0.02
Chronic obstructive pulmonary disease	146 (1.2)	2,359 (1.9)	0.05	2132.5 (1.8)	2039.0 (1.7)	0.01
Coronary artery disease	29 (0.2)	160 (0.1)	0.03	111.1 (0.1)	158.7 (0.1)	0.01
Diabetes mellitus	2,838 (24.1)	27,392 (22.0)	0.05	27135.7 (22.4)	25873.1 (21.1)	0.03
Hypertension	5,429 (46.0)	55,197 (44.3)	0.04	51517.9 (42.6)	52851.7 (43.1)	0.01
Peripheral vascular disease	807 (6.8)	8,447 (6.8)	＜0.01	8490.8 (7.0)	7985.2 (6.5)	0.02
Renal impairment	413 (3.5)	7,343 (5.9)	0.11	5038.0 (4.2)	5365.6 (4.4)	0.01
Rheumatic heart disease	51 (0.4)	606 (0.5)	0.01	591.3 (0.5)	589.4 (0.5)	＜0.01
Venous thromboembolism	18 (0.2)	243 (0.2)	0.01	269.1 (0.2)	211.6 (0.2)	0.01
Charlson comorbidity index score, mean±SD	0.1±0.5	0.1±0.5	0.01	0.1±0.5	0.1±0.5	＜0.01
Concomitant drugs, n (%)
Anti-arrhythmic drugs	432 (3.7)	4,369 (3.5)	0.01	3623.2 (3.0)	4165.7 (3.4)	0.02
Anticoagulants	886 (7.5)	10,550 (8.5)	0.04	8736.1 (7.2)	9573.3 (7.8)	0.02
Antidepressants	940 (8.0)	9,728 (7.8)	0.01	8941.6 (7.4)	9518.9 (7.8)	0.02
Antihypertensives	4,894 (41.5)	45,988 (36.9)	0.09	44510.8 (36.8)	44599.5 (36.4)	0.01
Antiplatelets	2,271 (19.2)	18,202 (14.6)	0.12	16280.3 (13.4)	17670.2 (14.4)	0.03
Antirheumatic	505 (4.3)	4,782 (3.8)	0.02	4590.4 (3.8)	4837.9 (3.9)	0.01
Chronic obstructive pulmonary disease drugs	921 (7.8)	11,418 (9.2)	0.05	10535.2 (8.7)	10771.8 (8.8)	＜0.01
Corticosteroids	873 (7.4)	11,278 (9.0)	0.06	10751.8 (8.9)	10509.9 (8.6)	0.01
Insulin	637 (5.4)	7,516 (6.0)	0.03	7793.6 (6.4)	6963.5 (5.7)	0.03
Lipid-lowering drugs	874 (7.4)	4,502 (3.6)	0.17	5377.8 (4.4)	3485.8 (2.8)	0.09
Narcotic analgesics	1,495 (12.7)	20,920 (16.8)	0.12	18026.4 (14.9)	19418.8 (15.9)	0.03
Non-steroidal anti-inflammatory drugs	4,712 (39.9)	47,099 (37.8)	0.04	43594.1 (36.0)	45836.6 (37.4)	0.03
Oral hypoglycaemic agent	2,237 (19.0)	18,300 (14.7)	0.11	19195.0 (15.9)	17354.3 (14.2)	0.05
Other hormonal agents /Hormone replacement therapy	1,327 (11.2)	17,460 (14.0)	0.08	15924.1 (13.2)	16209.9 (13.2)	＜0.01

Abbreviation: IPTW, inverse probability of treatment weighting; SD, standard deviation; SMD, standardized mean difference

Supplementary Table 7.Baseline characteristics before and after inverse probability of treatment weighting in four distinct cohorts (10% trimming)

A) Cohort to assess the comparative effectiveness of primary prevention of major adverse cardiovascular events
Characteristic	Before IPTW			After IPTW
Characteristic	Pravastatin group (N = 2,688)	Atorvastatin group (N = 25,578)	SMD	Pravastatin group (N = 22274.3)	Atorvastatin group (N = 22556.6)	SMD
Male, n (%)	1,439 (53.5)	13,330 (52.1)	0.03	11720.1 (52.6)	11633.2 (51.6)	0.02
Age, years, mean±SD	56.5±12.5	57.9±12.9	0.11	57.0±12.3	57.5±12.8	0.04
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.1±0.4	0.1±0.4	0.02	0.1±0.4	0.1±0.4	0.02
Hospital admissions	0.2±0.6	0.2±0.7	0.07	0.2±0.5	0.2±0.6	0.05
Outpatient visits	6.3±7.3	6.3±8.2	0.00	5.9±5.8	5.9±5.7	＜0.01
Department of care, n (%)
Cardiology	495 (18.4)	5,211 (20.4)	0.28	4898.2 (28.0)	4925.4 (26.4)	＜0.01
Endocrinology	802 (29.8)	6,292 (24.6)	0.37	7460.0 (42.6)	5658.0 (30.3)	0.19
Neurology	223 (8.3)	2,773 (10.8)	0.28	2335.6 (13.3)	2379.3 (12.7)	＜0.01
Other	316 (11.8)	6,298 (24.6)	0.39	2822.3 (16.1)	5728.8 (30.6)	0.33
Comorbidities, n (%)
Angina pectoris	124 (4.6)	1,132 (4.4)	0.01	1017.2 (4.6)	1024.2 (4.5)	＜0.01
Atrial fibrillation	3 (0.1)	19 (0.1)	0.01	16.3 (0.1)	13.3 (0.1)	0.01
Chronic atrial fibrillation	0 (0.0)	9 (0.0)	0.03	0 (0.0)	0 (0.0)	-
Chronic liver disease	113 (4.2)	888 (3.5)	0.04	806.2 (3.6)	763.7 (3.4)	0.01
Congenital heart disease	1 (0.0)	23 (0.1)	0.02	0.0 (0.0)	6.4 (0.0)	0.02
Chronic obstructive pulmonary disease	20 (0.7)	324 (1.3)	0.05	170.0 (0.8)	177.1 (0.8)	＜0.01
Coronary artery disease	4 (0.1)	21 (0.1)	0.02	7.1 (0.0)	12.5 (0.1)	0.01
Diabetes mellitus	900 (33.5)	7,122 (27.8)	0.12	6384.4 (28.7)	6026.5 (26.7)	0.04
Hypertension	1,320 (49.1)	12,093 (47.3)	0.04	10313.0 (46.3)	10398.8 (46.1)	＜0.01
Peripheral vascular disease	157 (5.8)	1,523 (6.0)	0.01	1157.6 (5.2)	1285.1 (5.7)	0.02
Renal impairment	80 (3.0)	1,323 (5.2)	0.11	690.5 (3.1)	754.7 (3.3)	0.01
Rheumatic heart disease	9 (0.3)	119 (0.5)	0.02	83.4 (0.4)	86.9 (0.4)	＜0.01
Venous thromboembolism	4 (0.1)	44 (0.2)	0.01	50.0 (0.2)	39.4 (0.2)	0.01
Charlson comorbidity index score, mean±SD	0.1±0.3	0.1±0.3	0.00	0.1±0.3	0.1±0.3	＜0.01
Comedication, n (%)
Anti-arrhythmic drugs	90 (3.3)	687 (2.7)	0.04	422.0 (1.9)	583.7 (2.6)	0.05
Anticoagulants	118 (4.4)	1,105 (4.3)	0.00	768.9 (3.5)	954.0 (4.2)	0.04
Antidepressants	181 (6.7)	1,654 (6.5)	0.01	1438.7 (6.5)	1476.6 (6.5)	＜0.01
Antihypertensives	1,236 (46.0)	11,129 (43.5)	0.05	9540.0 (42.8)	9566.7 (42.4)	0.01
Antiplatelets	397 (14.8)	2,993 (11.7)	0.09	2328.8 (10.5)	2469.7 (10.9)	0.02
Antirheumatic	42 (1.6)	444 (1.7)	0.01	386.1 (1.7)	398.4 (1.8)	＜0.01
Chronic obstructive pulmonary disease drugs	159 (5.9)	1,816 (7.1)	0.05	1403.3 (6.3)	1453.8 (6.4)	0.01
Corticosteroids	150 (5.6)	1,870 (7.3)	0.02	1366.8 (6.1)	1411.9 (6.3)	0.01
Insulin	185 (6.9)	1,642 (6.4)	0.02	1417.8 (6.4)	1376.1 (6.1)	0.01
Lipid-lowering drugs	278 (10.3)	1,443 (5.6)	0.17	1124.6 (5.0)	827.8 (3.7)	0.07
Narcotic analgesics	198 (7.4)	1,918 (7.5)	0.01	1574.0 (7.1)	1666.1 (7.4)	0.01
Non-steroidal anti-inflammatory drugs	788 (29.3)	7,199 (28.1)	0.03	6002.8 (26.9)	6256.4 (27.7)	0.02
Oral hypoglycaemic agent	764 (28.4)	5,706 (22.3)	0.14	5175.0 (23.2)	4824.2 (21.4)	0.04
Other hormonal agents /Hormone replacement therapy	183 (6.8)	2,099 (8.2)	0.05	1532.6 (6.9)	1744.0 (7.7)	0.03

B) Cohort to assess the comparative effectiveness of secondary prevention of major adverse cardiovascular event
Characteristic	Before IPTW			After IPTW
Characteristic	Pravastatin group (N = 1,258)	Atorvastatin group (N = 10,461)	SMD	Pravastatin group (N = 9318.4)	Atorvastatin group (N = 9460.0)	SMD
Male, n (%)	726 (57.7)	6,381 (61.0)	0.07	5790.1 (62.1)	5726.2 (60.5)	0.03
Age, years, mean±SD	64.4±11.5	65.5±12.1	0.09	65.1±11.9	65.3±12.0	0.02
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.2±0.5	0.2±0.5	0.08	0.2±0.5	0.2±0.5	0.05
Hospital admissions	0.3±0.6	0.4±0.9	0.21	0.4±0.7	0.4±0.7	＜0.01
Outpatient visits	6.3±8.6	5.8±8.4	0.06	5.7±7.8	5.6±7.7	0.01
Department of care, n (%)
Cardiology	346 (27.5)	3,785 (36.2)	0.39	3164.4 (42.3)	3463.7 (43.5)	0.06
Endocrinology	44 (3.5)	376 (3.6)	0.39	478.6 (6.4)	319.2 (4.0)	0.09
Neurology	400 (31.8)	3,486 (33.3)	0.41	3453.8 (46.2)	3216.4 (40.4)	0.06
Other	49 (3.9)	1,057 (10.1)	0.43	385.1 (5.1)	957.3 (12.0)	0.23
Comorbidities, n (%)
Angina pectoris	182 (14.5)	1,839 (17.6)	0.09	1984.9 (21.3)	1657.3 (17.5)	0.10
Atrial fibrillation	1 (0.1)	17 (0.2)	0.02	18.8 (0.2)	13.0 (0.1)	0.02
Chronic atrial fibrillation	2 (0.2)	14 (0.1)	0.01	15.9 (0.2)	16.0 (0.2)	＜0.01
Chronic liver disease	11 (0.9)	126 (1.2)	0.03	216.6 (2.3)	110.3 (1.2)	0.09
Congenital heart disease	1 (0.1)	23 (0.2)	0.04	43.2 (0.5)	16.0 (0.2)	0.05
Chronic obstructive pulmonary disease	9 (0.7)	165 (1.6)	0.08	109.5 (1.2)	121.1 (1.3)	0.01
Coronary artery disease	11 (0.9)	63 (0.6)	0.03	48.6 (0.5)	71.9 (0.8)	0.03
Diabetes mellitus	258 (20.5)	2,235 (21.4)	0.02	1898.7 (20.4)	1864.2 (19.7)	0.02
Hypertension	897 (71.3)	7,003 (66.9)	0.09	6454.5 (69.3)	6312.9 (66.7)	0.05
Peripheral vascular disease	139 (11.0)	1,570 (15.0)	0.12	1674.1 (18.0)	1357.3 (14.3)	0.10
Renal impairment	28 (2.2)	457 (4.4)	0.12	293.8 (3.2)	314.0 (3.3)	0.01
Rheumatic heart disease	11 (0.9)	128 (1.2)	0.03	72.5 (0.8)	105.0 (1.1)	0.03
Venous thromboembolism	1 (0.1)	8 (0.1)	0.00	4.1 (0.0)	6.4 (0.1)	0.01
Charlson comorbidity index score, mean±SD	0.1±0.3	0.1±0.4	0.12	0.1±0.4	0.1±0.4	0.03
Concomitant drugs, n (%)
Anti-arrhythmic drugs	86 (6.8)	671 (6.4)	0.02	640.8 (6.9)	555.1 (5.9)	0.04
Anticoagulants	191 (15.2)	1,677 (16.0)	0.02	1675.9 (18.0)	1445.7 (15.3)	0.07
Antidepressants	138 (11.0)	882 (8.4)	0.09	817.9 (8.8)	786.1 (8.3)	0.02
Antihypertensives	863 (68.6)	6,498 (62.1)	0.14	6098.9 (65.4)	5897.6 (62.3)	0.07
Antiplatelets	689 (54.8)	5,205 (49.8)	0.10	4494.5 (48.2)	4779.7 (50.5)	0.05
Antirheumatic	14 (1.1)	103 (1.0)	0.01	98.2 (1.1)	91.5 (1.0)	0.01
Chronic obstructive pulmonary disease drugs	84 (6.7)	680 (6.5)	0.01	607.0 (6.5)	568.0 (6.0)	0.02
Corticosteroids	55 (4.4)	505 (4.8)	0.02	448.4 (4.8)	426.7 (4.5)	0.01
Insulin	33 (2.6)	439 (4.2)	0.09	354.7 (3.8)	317.1 (3.4)	0.02
Lipid-lowering drugs	60 (4.8)	438 (4.2)	0.03	550.2 (5.9)	405.4 (4.3)	0.07
Narcotic analgesics	56 (4.5)	704 (6.7)	0.10	472.6 (5.1)	540.0 (5.7)	0.03
Non-steroidal anti-inflammatory drugs	720 (57.2)	5,647 (54.0)	0.07	4933.7 (52.9)	5180.3 (54.8)	0.04
Oral hypoglycemic agent	229 (18.2)	1,705 (16.3)	0.05	1452.7 (15.6)	1481.3 (15.7)	＜0.01
Other hormonal agents /Hormone replacement therapy	54 (4.3)	629 (6.0)	0.08	467.1 (5.0)	487.1 (5.1)	0.01

C) Cohort to assess the comparative risk of new-onset diabetes mellitus
Characteristic	Before IPTW			After IPTW
Characteristic	Pravastatin group (N = 2,391)	Atorvastatin group (N = 22,557)	SMD	Pravastatin group (N = 19390.6)	Atorvastatin group (N = 20016.1)	SMD
Male, n (%)	1,245 (52.1)	11,803 (52.3)	0.01	10345.1 (53.4)	10358.8 (51.8)	0.03
Age, years, mean±SD	59.3±12.7	60.1±13.3	0.06	58.6±12.6	59.9±13.2	0.11
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.2±0.4	0.2±0.4	0.01	0.1±0.4	0.1±0.4	0.02
Hospital admissions	0.2±0.5	0.2±0.7	0.10	0.2±0.5	0.2±0.5	0.02
Outpatient visits	5.8±7.9	5.6±7.1	0.03	5.7±9.3	5.5±6.6	0.03
Department of care, n (%)
Cardiology	627 (26.2)	6,736 (29.9)	0.34	5676.1 (37.4)	6277.1 (37.6)	0.05
Endocrinology	194 (8.1)	1,224 (5.4)	0.38	2426.6 (16.0)	1067.4 (6.4)	0.25
Neurology	469 (19.6)	4,839 (21.5)	0.35	4315.7 (28.4)	4381.1 (26.2)	0.01
Other	296 (12.4)	5,499 (24.4)	0.41	2772.8 (18.3)	4981.3 (29.8)	0.27
Comorbidities, n (%)
Angina pectoris	226 (9.5)	1,956 (8.7)	0.03	1926.5 (9.9)	1749.9 (8.7)	0.04
Atrial fibrillation	4 (0.2)	28 (0.1)	0.01	22.2 (0.1)	22.5 (0.1)	＜0.01
Chronic atrial fibrillation	2 (0.1)	19 (0.1)	＜0.01	21.7 (0.1)	21.0 (0.1)	＜0.01
Chronic liver disease	67 (2.8)	483 (2.1)	0.04	530.2 (2.7)	401.9 (2.0)	0.05
Congenital heart disease	1 (0.0)	38 (0.2)	0.04	0.0 (0.0)	8.5 (0.0)	0.03
Chronic obstructive pulmonary disease	17 (0.7)	312 (1.4)	0.07	191.2 (1.0)	206.7 (1.0)	0.01
Coronary artery disease	7 (0.3)	54 (0.2)	0.01	47.5 (0.2)	59.3 (0.3)	0.01
Diabetes mellitus	0 (0.0)	0 (0.0)	-	0 (0.0)	0 (0.0)	-
Hypertension	1,351 (56.5)	11,888 (52.7)	0.08	9983.7 (51.5)	10467.1 (52.3)	0.02
Peripheral vascular disease	161 (6.7)	1,717 (7.6)	0.03	1438.0 (7.4)	1427.3 (7.1)	0.01
Renal impairment	51 (2.1)	891 (3.9)	0.11	578.2 (3.0)	585.7 (2.9)	＜0.01
Rheumatic heart disease	14 (0.6)	181 (0.8)	0.03	161.9 (0.8)	145.9 (0.7)	0.01
Venous thromboembolism	3 (0.1)	39 (0.2)	0.01	36.7 (0.2)	32.5 (0.2)	0.01
Charlson comorbidity index score, mean±SD	0.1±0.3	0.1±0.3	0.04	0.1±0.3	0.1±0.3	＜0.01
Concomitant drugs, n (%)
Anti-arrhythmic drugs	120 (5.0)	886 (3.9)	0.05	545.4 (2.8)	734.4 (3.7)	0.05
Anticoagulants	201 (8.4)	1,741 (7.7)	0.03	1438.5 (7.4)	1491.7 (7.5)	＜0.01
Antidepressants	197 (8.2)	1,602 (7.1)	0.04	1220.8 (6.3)	1451.4 (7.3)	0.04
Antihypertensives	1,286 (53.8)	11,080 (49.1)	0.09	9415.5 (48.6)	9784.1 (48.9)	0.01
Antiplatelets	663 (27.7)	4,986 (22.1)	0.13	3530.8 (18.2)	4450.4 (22.2)	0.10
Antirheumatic	28 (1.2)	277 (1.2)	0.01	230.4 (1.2)	251.9 (1.3)	0.01
Chronic obstructive pulmonary disease drugs	141 (5.9)	1,502 (6.7)	0.03	1177.1 (6.1)	1262.4 (6.3)	0.01
Corticosteroids	119 (5.0)	1,432 (6.3)	0.06	995.8 (5.1)	1171.2 (5.9)	0.03
Insulin	0 (0.0)	0 (0.0)	-	0 (0.0)	0 (0.0)	-
Lipid-lowering drugs	139 (5.8)	955 (4.2)	0.07	1273.3 (6.6)	807.3 (4.0)	0.11
Narcotic analgesics	154 (6.4)	1,496 (6.6)	0.01	1215.7 (6.3)	1274.4 (6.4)	0
Non-steroidal anti-inflammatory drugs	914 (38.2)	7,858 (34.8)	0.07	6176.5 (31.9)	7021.9 (35.1)	0.07
Oral hypoglycaemic agent	0 (0.0)	0 (0.0)	-	0 (0.0)	0 (0.0)	-
Other hormonal agents /Hormone replacement therapy	132 (5.5)	1,531 (6.8)	0.05	1120.8 (5.8)	1275.1 (6.4)	0.03

D) Cohort to assess the comparative risk of new-onset myalgia or rhabdomyolysis
Characteristic	Before IPTW			After IPTW
Characteristic	Pravastatin group (N = 11,799)	Atorvastatin group (N = 124,621)	SMD	Pravastatin group (N = 105679.9)	Atorvastatin group (N = 108998.7)	SMD
Male, n (%)	5,486 (46.5)	58,476 (46.9)	0.01	50236.1 (47.5)	50028.2 (45.9)	0.03
Age, years, mean±SD	59.3±12.8	61.4±13.3	0.16	59.9±12.8	61.0±13.1	0.08
Healthcare utilization, frequencies, mean±SD
Emergency department visits	0.2±0.5	0.2±0.6	0.05	0.2±0.6	0.2±0.6	0.03
Hospital admissions	0.3±1.0	0.4±1.3	0.13	0.3±0.8	0.3±0.8	0.03
Outpatient visits	4.3±7.1	3.4±6.1	0.13	3.6±5.2	3.4±5.6	0.05
Department of care, n (%)
Cardiology	1,871 (15.9)	22,272 (17.9)	0.05	19064.5 (23.6)	20967.4 (23.7)	0.03
Endocrinology	2,155 (18.3)	18,125 (14.5)	0.24	24255.1 (30.0)	16437.1 (18.6)	0.20
Neurology	1,358 (11.5)	15,006 (12.0)	0.07	13909.9 (17.2)	13620.8 (15.4)	0.02
Other	2,169 (18.4)	42,839 (34.4)	0.31	23580.3 (29.2)	37276.7 (42.2)	0.27
Comorbidities, n (%)
Angina pectoris	690 (5.8)	7,005 (5.6)	0.01	6256.9 (5.9)	6045.5 (5.5)	0.02
Atrial fibrillation	8 (0.1)	59 (0.0)	0.01	33.2 (0.0)	51.0 (0.0)	0.01
Chronic atrial fibrillation	4 (0.0)	75 (0.1)	0.01	85.9 (0.1)	63.6 (0.1)	0.01
Chronic liver disease	420 (3.6)	3,667 (2.9)	0.04	3669.7 (3.5)	3068.9 (2.8)	0.04
Congenital heart disease	5 (0.0)	132 (0.1)	0.02	16.2 (0.0)	59.3 (0.1)	0.02
Chronic obstructive pulmonary disease	146 (1.2)	2,359 (1.9)	0.05	1791.0 (1.7)	1750.4 (1.6)	0.01
Coronary artery disease	29 (0.2)	160 (0.1)	0.03	64.8 (0.1)	110.3 (0.1)	0.01
Diabetes mellitus	2,838 (24.1)	27,392 (22.0)	0.05	23662.0 (22.4)	22780.4 (20.9)	0.04
Hypertension	5,429 (46.0)	55,197 (44.3)	0.04	44200.4 (41.8)	46311.0 (42.5)	0.01
Peripheral vascular disease	807 (6.8)	8,447 (6.8)	＜0.01	7326.3 (6.9)	6899.7 (6.3)	0.02
Renal impairment	413 (3.5)	7,343 (5.9)	0.11	4199.2 (4.0)	4432.0 (4.1)	0.01
Rheumatic heart disease	51 (0.4)	606 (0.5)	0.01	537.8 (0.5)	527.8 (0.5)	＜0.01
Venous thromboembolism	18 (0.2)	243 (0.2)	0.01	269.1 (0.3)	184.9 (0.2)	0.02
Charlson comorbidity index score, mean±SD	0.1±0.5	0.1±0.5	0.01	0.1±0.5	0.1±0.5	＜0.01
Concomitant drugs, n (%)
Anti-arrhythmic drugs	432 (3.7)	4,369 (3.5)	0.01	3039.3 (2.9)	3695.4 (3.4)	0.03
Anticoagulants	886 (7.5)	10,550 (8.5)	0.04	7403.1 (7.0)	8373.3 (7.7)	0.03
Antidepressants	940 (8.0)	9,728 (7.8)	0.01	7884.3 (7.5)	8496.7 (7.8)	0.01
Antihypertensives	4,894 (41.5)	45,988 (36.9)	0.09	38405.9 (36.3)	39278.7 (36.0)	0.01
Antiplatelets	2,271 (19.2)	18,202 (14.6)	0.12	13640.2 (12.9)	15568.1 (14.3)	0.04
Antirheumatic	505 (4.3)	4,782 (3.8)	0.02	3889.9 (3.7)	4382.3 (4.0)	0.02
Chronic obstructive pulmonary disease drugs	921 (7.8)	11,418 (9.2)	0.05	8843.6 (8.4)	9544.7 (8.8)	0.01
Corticosteroids	873 (7.4)	11,278 (9.0)	0.06	9137.8 (8.6)	9305.0 (8.5)	＜0.01
Insulin	637 (5.4)	7,516 (6.0)	0.03	6551.8 (6.2)	6190.7 (5.7)	0.02
Lipid-lowering drugs	874 (7.4)	4,502 (3.6)	0.17	4719.0 (4.5)	2719.5 (2.5)	0.11
Narcotic analgesics	1,495 (12.7)	20,920 (16.8)	0.12	15939.6 (15.1)	17119.7 (15.7)	0.02
Non-steroidal anti-inflammatory drugs	4,712 (39.9)	47,099 (37.8)	0.04	37327.0 (35.3)	40607.8 (37.3)	0.04
Oral hypoglycaemic agent	2,237 (19.0)	18,300 (14.7)	0.11	16874.7 (16.0)	15257.9 (14.0)	0.06
Other hormonal agents /Hormone replacement therapy	1,327 (11.2)	17,460 (14.0)	0.08	13839.1 (13.1)	14311.0 (13.1)	＜0.01

Abbreviation: IPTW, inverse probability of treatment weighting; SD, standard deviation; SMD, standardized mean difference

Supplementary Table 8.Absolute rate differences in outcomes between the pravastatin group and atorvastatin group (5% trimming)

Outcomes	Absolute rate difference [95% CI]^＊	p-value^†
Primary prevention of MACE	-0.85 [-1.52; -0.18]	0.012
Secondary prevention of MACE	-6.25 [-8.37; -4.17]	＜0.001
New-onset diabetes mellitus	-0.98 [-2.19; 0.22]	0.108
Myalgia and/or rhabdomyolysis	-1.17 [-1.46; -0.89]	＜0.001

^＊Calculated per 1,000 person-years.

The p-value was calculated using a z-test (or Wald test).

Abbreviation: MACE, major cardiovascular event; CI, confidence interval

Supplementary Table 9.Absolute rate differences in outcomes between the pravastatin group and atorvastatin group (10% trimming)

Outcomes	Absolute rate difference [95% CI]^＊	p-value^†
Primary prevention of MACE	-1.19 [-1.88; -0.50]	0.001
Secondary prevention of MACE	-4.77 [-7.03; -2.52]	＜0.001
New-onset diabetes mellitus	-1.07 [-2.34; 0.19]	0.097
Myalgia and/or rhabdomyolysis	-1.21 [-1.51; -0.91]	＜0.001

^＊Calculated per 1,000 person-years.

^†The p-value was calculated using a z-test (or Wald test).

Abbreviation: MACE, major cardiovascular event; CI, confidence interval

Supplementary Fig.4. Forest plot for primary prevention of MACE, secondary prevention of MACE, new-onset diabetes mellitus, and new-onset myalgia and rhabdomyolysis (IPTW with 5% trimming)

^＊Incidence rate was calculated per 1,000 person-years.

Abbreviations: HR, hazard ratio; CI,confidence interval; MACE, major cardiovascular event; IPTW, inverse probability of treatment weighting; AUMC, Ajou University Medical Center; CHAMC, Bundang CHAMedical Center; EUMC, Ewha Womans UniversityMedical Hospital; GNUH, Gyeongsang National University Hospital; INHA, Inha University Hospital; KDH, Kangdong Sacred Heart Hospital; KHMC, Kyung Hee Medical Center; KHNMC, Kangdong Kyung Hee University Medical Center; KUMC, Korea University Medical Center in Ansan; PNUH, Pusan National University Hospital; SCHBC, Soonchunhyang University Bucheon Hospital; SCHCA, Soonchunhyang University Cheonan Hospital; SCHSU, Soonchunhyang University Seoul Hospital; Chi, Chi square-test; df, degrees of freedom

Supplementary Fig.5. Forest plot for primary prevention of MACE, secondary prevention of MACE, new-onset diabetes mellitus, and new-onset myalgia and rhabdomyolysis (IPTW with 10% trimming)

^＊Incidence rate was calculated per 1,000 person-years.

Discussion

In the current study conducted among patients with dyslipidemia in South Korea, moderate-intensity pravastatin 40 mg/day demonstrated non-inferiority to moderate-intensity atorvastatin 10 mg/day with respect to the composite outcomes of acute myocardial infarction, ischemic stroke, hospitalization for heart failure, coronary artery revascularization, and all-cause mortality in both primary and secondary prevention settings. Notably, the patients receiving moderate-intensity pravastatin had a lower risk of new-onset myalgia or rhabdomyolysis and a lower incidence of abnormal elevations in AST levels.

This study’s findings challenge the conventional view that higher-potency statins, such as atorvastatin at lower doses, provide greater cardiovascular risk reduction than less potent alternatives, such as pravastatin at higher doses⁵⁾. An analysis of lipid-lowering effects over varying durations of statin use showed that LDL-C level reductions were comparable among patients adhering to either statin for periods exceeding 2 years. These results suggest that the cardiovascular benefits of statin therapy may be more closely related to long-term adherence to the prescribed statin than to the specific statin used^{27, 28)}. Therefore, clinical practice should emphasize strategies that improve patient adherence to enhance the benefits of statin therapy in preventing adverse cardiovascular outcomes.

It is also important to clarify the rationale for selecting atorvastatin at 10 mg/day as the comparator in our study. Although atorvastatin is generally recognized as a high-potency statin, the 10 mg/day dose used in our analysis was considered a moderate‐intensity regimen when viewed in the context of South Korean clinical practice at the time of data collection. In South Korea, statin dosing has historically been determined according to a treat-to-target strategy rather than a fixed-dose intensity approach. Until November 2022, the 4^th edition of the Korean Guidelines for the Management of Dyslipidemia recommended an LDL-C target of ＜70 mg/dL for the highest-risk patients, including those requiring secondary prevention²⁹⁾. This guideline led to the frequent prescription of lower‐dose statins, such as atorvastatin 10 mg/day, as a common treatment approach³⁰⁾. With the introduction of the 5^th edition of the Korean guidelines in December 2022 ³¹⁾, the target LDL-C level was revised to ＜55 mg/dL for high-risk patients, aligned with the 2018 ACC/AHA and 2019 ESC recommendations^{5, 32)}. Consequently, high-intensity statin therapy has been commonly adopted in clinical practice since 2023. However, because our study data were collected prior to this revision, the therapeutic strategies reflected herein primarily represent an earlier treatment landscape. In selecting the comparator for pravastatin 40 mg/day, we aimed to match statins of equivalent intensity based on real-world prescription patterns in Korea, where atorvastatin 10 mg/day was the most commonly used dose.

Pravastatin and atorvastatin differ significantly in their pharmacokinetics and pharmacodynamics³³⁾, which may contribute to the variations in clinical outcomes observed in this study. The hydrophilicity of pravastatin may contribute to its reduced incidence of muscle-related adverse events, as it demonstrates lower passive diffusion into extrahepatic tissues, such as skeletal muscle. This observation aligns with the findings of the current study, wherein pravastatin users exhibited a significantly lower risk of new-onset myalgia or rhabdomyolysis than atorvastatin users. Previous studies corroborate this finding, suggesting that hydrophilic statins are generally associated with a lower incidence of muscle-related adverse effects than their lipophilic counterparts^{34, 35)}. Given the significant impact of muscle-related complications on the discontinuation of statin therapy, this observation is clinically important. Risk reductions in muscle-related adverse events can improve patient adherence to statin therapy, making pravastatin a potentially more favorable option for improving adherence and maintaining the long-term benefits of statin therapy.

Pravastatin, a hydrophilic statin predominantly metabolized via hepatic sulfation, minimizes interactions with the cytochrome P450 system, thereby reducing the risk of drug–drug interactions and hepatotoxicity. In contrast, atorvastatin is a lipophilic statin extensively processed by the CYP3A4 pathway, rendering it more susceptible to interactions with other medications³⁶⁾. Consistent with these differences, patients receiving pravastatin experienced fewer abnormal liver function events than those receiving atorvastatin. Although liver abnormalities can result from multiple factors, including unverified supplements, viral infections, alcohol use, and strenuous exercise^37-39), the lower hepatotoxicity observed with pravastatin is likely attributable to its hydrophilic nature and reduced protein-binding ability. These findings underscore a more favorable hepatic safety profile for pravastatin, which may be particularly advantageous for populations at increased risk of hepatic complications, such as the elderly population.

Additionally, the incidence of abnormal elevations in the AST levels was statistically lower in the pravastatin group than in the atorvastatin group. Although an elevation in the AST levels can result from causes other than hepatotoxicity, such as inflammation or stress on cells in the heart, muscles, and kidneys, this study could not determine the underlying causes of the higher AST levels observed in the atorvastatin group⁴⁰⁾. However, the lower incidence of MACE and new-onset myalgia or rhabdomyolysis in the pravastatin group may partially explain the reduced incidence of abnormal elevations in the AST levels in this group.

Regarding the risk of NODM, our results showed no significant difference between moderate-intensity pravastatin and atorvastatin, despite previous studies indicating that lipophilic statins can more readily penetrate extrahepatic cell membranes such as β-cells, adipocytes, and skeletal muscle cells, and increase the risk of elevated serum glucose levels^41-43). Our findings imply that the intensity of statin therapy, rather than its distinct pharmacological properties, may critically influence NODM. This perspective is supported by results from other studies that have indicated variability in the risk of NODM associated with the intensity of statins^44-46). This divergence may also stem from differences in the study design, population characteristics, and statin dosages.

This study was associated withd several limitations. First, the patients included in this study tended to have relatively severe acute-phase conditions. This is because the hospitals included in the CDM database are relatively large secondary or tertiary care hospitals, such as university and regional core hospitals. Therefore, the generalizability of the results should be considered during the assessments. Second, patient-level data linkages between hospitals are lacking. Therefore, long-term analyses imay be interrupted when patients move from one hospital to another. Third, as an observational and retrospective study, it was subject to inherent confounding bias. Confounders, such as smoking, drinking, BMI, and laboratory tests, which had missing values due to the characteristics of this retrospective study based on CDM, were not considered as covariates in PSM and IPTW, and this may have affected the study results.

In conclusion, among patients with dyslipidemia identified in the CDM of multicenter EHRs in South Korea, moderate-intensity pravastatin (40 mg/day) demonstrated comparable effectiveness to moderate-intensity atorvastatin (10 mg/day) in both the primary and secondary prevention of MACE, with a more favorable muscle and hepatic safety profile. These findings substantiate the clinical utility of pravastatin as a viable and effective treatment option, particularly for patients with increased susceptibility to adverse events associated with statin therapy. Future research should aim to confirm these results in diverse populations and investigate strategies to enhance the long-term adherence to statin therapy, ultimately improving the cardiovascular outcomes.

Conflict of Interest Disclosure

JAS received a research grant from the Chong Kun Dang Pharmaceutical. J-HB is a full-time employee of Daiichi Sankyo Korea and has no competing interests. The other authors have no conflicts of interest to declare.

Author Contributions

SWC, HJK, JAS, SC, SEK, JHJ, SSK, HL, SS, DC, HKP, S-KK, J-HB, and I-KJ contributed to the data acquisition and interpretation. SWC and J-HB conceived the design and wrote and revised the first draft of the manuscript. I-KJ contributed to the review and critical revision of the manuscript. All authors reviewed and approved the manuscript submitted for publication and agreed to be accountable for all aspects of the work and to ensure the accuracy and integrity of the publication.

Funding

This study was supported by a grant from Daiichi Sankyo (Seoul, Republic of Korea).

Acknowledgements

The authors thank EvidNet for assistance with statistical analysis. Nila Bhana MSc (Hons) and David P. Figgitt PhD, CMPP™, provided editorial assistance on behalf of the Content Ed Net Quest, Seoul, Republic of Korea. This study was supported by funding from Daiichi Sankyo Korea Co. Ltd., Seoul, Republic of Korea.

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