http://orcid.org/0000-0003-3521-8395
Figures
Abstract
Objective
Whether a low-density lipoprotein cholesterol (LDL-C) goal is essential in secondary prevention is still being debated. The aim of our study was to investigate whether achieving particular LDL-C level goals is associated with the reduction in the risk of major adverse cardiac events (MACEs) in patients with atherosclerotic cardiovascular diseases (ASCVD) on statin therapy.
Methods and results
From January 2010 to August 2014, a total of 4099 patients with ASCVD in the Taiwan Secondary Prevention for patients with AtheRosCLErotic disease (T-SPARCLE) registry were analyzed. The risk of a MACE was lower in patients with LDL-C level under control at < 100 mg/dL by statins than in patients with LDL-C level ≥100 mg/dL whether on statin therapy (hazard ratio [HR] 1.66, 95% confidence interval [CI] 1.04‒2.63, p = 0.03) or not (HR 2.04, 95% CI 1.06‒3.94, p = 0.03). In multivariate Cox model analyses, statin intensity had no significant predictive value, and LDL-C ≥ 100 mg/dL was associated with a slight but not significant trend toward increased risk of MACEs (HR 1.41, 95% CI 0.96‒2.07, p = 0.08).
Citation: Yeh Y-T, Yin W-H, Tseng W-K, Lin F-J, Yeh H-I, Chen J-W, et al. (2017) Lipid lowering therapy in patients with atherosclerotic cardiovascular diseases: Which matters in the real world? Statin intensity or low-density lipoprotein cholesterol level? ‒ Data from a multicenter registry cohort study in Taiwan. PLoS ONE 12(10): e0186861. https://doi.org/10.1371/journal.pone.0186861
Editor: Katriina Aalto-Setala, University of Tampere, FINLAND
Received: May 8, 2017; Accepted: October 9, 2017; Published: October 26, 2017
Copyright: © 2017 Yeh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The Taiwan Consortium of Lipid and Atherosclerosis is sponsored by the Taiwan Society of Lipids & Atherosclerosis since 2009 and Taiwan Ministry of Science and Technology since 2012 (Project code: NRPB-TR11: 100-2325-B-002-075). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death worldwide, and patients with known ASCVD (especially those with concurrent dyslipidemia) are at high risk for cardiovascular (CV) events [1]. Lipid modification, particularly lowering of low-density lipoprotein cholesterol (LDL-C) with statin therapy, is one of the cornerstones of prevention and treatment for ASCVD. Statins have been shown in multiple large trials and meta-analyses to reduce CV events in patients with ASCVD [2–9]. This is known as secondary prevention.
For a long while, the level at which LDL-C should be controlled has been debated. High-intensity statin therapy has been shown in multiple studies to improve outcomes of patients with ASCVD [10,11]. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines strongly recommended a fixed-dose strategy of high-intensity statin therapy because most of the studies confirming the efficacy of cholesterol reduction in secondary prevention used a single fixed-dose statin to lower LDL-C levels. And the guidelines made no recommendation for or against specific LDL-C target levels in patients with clinical ASCVD because no randomized controlled study has been conducted to evaluate the titration of statin dosage to achieve specific LDL-C level goals [12]. Since the randomized controlled trials completed to date are unable to answer the question of whether an LDL-C level should be achieved, real-world data from a cohort of patients with ASCVD on statin therapy targeting a specific LDL-C level would be extremely helpful to address this question.
In Taiwan, the National Health Insurance (NHI) covers almost all citizens’ medical expenditures, including expenditures on statin therapy. Based on the NHI revised payment regulation in 2008, the target LDL-C level for secondary prevention is 100 mg/dL and clinicians need to decrease dosage and maintain a minimally-required statin dose once the target level is reached. Therefore, the NHI payment regulation has made patients with ASCVD in Taiwan into basically a cohort on LDL-C goal-directed statin therapy, giving us the opportunity to investigate whether an achieved LDL-C level affects cardiovascular (CV) outcome in patients with ASCVD. Consequently, our study aimed to evaluate whether achieving a specific LDL-C level with statin therapy has an effect on CV outcome in patients with ASCVD.
Methods
Study design and setting
The study was conducted using the data from the Taiwan Secondary Prevention for patients with AtheRosCLErotic disease (T-SPARCLE) registry. The T-SPARCLE registry is a multicenter prospective observational registry collecting patients with symptomatic ASCVD at 14 medical sites across Taiwan. The study protocol and previous analysis of the registry have been published previously [13–16]. In this study, we included patients who were treated between January 2010 and August 2014 and had follow-up data as of March 2015.
Participants
The inclusion criteria were > 18 years old, stable symptomatic atherosclerotic diseases (i.e., coronary atherosclerosis, cerebral vascular disease, or peripheral atherosclerosis), and willingness to follow a National Cholesterol Education Program (NCEP) Therapeutic Lifestyle Change or similar cholesterol-lowering diet. Female patients receiving hormone therapy were included if they were maintained on a stable dose and regimen for at least 8 weeks prior to visit 1 and if they were willing to continue the same regimen throughout the study. Exclusion criteria included serious heart disease, New York Heart Association (NYHA) functional class ≥ III heart failure, life-threatening malignancy, treatment with immunosuppressive agents, unknown type of atherosclerotic vascular disease, taking two statins at enrollment, or any condition or situation which, in the opinion of the investigator, might be not suitable for this registry.
After enrollment, clinical information including medications and laboratory data were collected at every follow-up. Eligible patients who fulfilled the enrollment criteria would be followed every year for a total of 5 years and every 2 years thereafter. The study was approved by the Joint Institutional Review Board, Taiwan, for each participating hospital (JIRB number 09-S-015).
Main outcomes
The primary endpoint of this study was the occurrence of a first major adverse cardiovascular event (MACE) since enrollment. The MACE is a composite endpoint which includes cardiovascular death, nonfatal stroke (ischemic stroke, hemorrhagic stroke, transient ischemic attack [TIA], or vertebrobasilar insufficiency [VBI]), nonfatal myocardial infarction (MI, including non-ST-elevation MI or ST-elevation MI), or cardiac arrest with resuscitation. The follow-up duration was from enrollment to the occurrence of MACEs or till the last follow-up visit if no MACE occurred.
Statistical analysis
Patients were stratified into groups by different statin intensity, and baseline characteristics and incidence rates of MACEs were analyzed. Categorical variables are presented as percentage and continuous variables as mean ± standard deviation. Chi-square test was used to compare proportions among groups. Survival analysis was conducted among patients on therapy with different statin intensity, and multivariate Cox proportional hazards (PH) regression modeling was used to identify independent predictors of MACE occurrence while adjusting for the covariates. We further evaluated the risk of MACEs among patients based on distribution of statin use and LDL-C level at enrollment. Hazard ratio (HR) and 95% confidence interval (CI) were estimated. Under missing-at-random (MAR) assumption to handle the missing data, we used multiple imputation (by PROC MI procedure in SAS), which is considered the most effective way of treating missing data and may provide unbiased results with the least influence by the proportion and mechanism of missingness [17]. Multiple imputation acknowledges the uncertainty associated with the imputed values by generating a set of m plausible values (in this study, m = 5) for each unobserved data point, using alternative configurations of covariates. The imputation step resulted in five complete data sets, each with one unique estimate of the missing values. After imputation, we fit Cox proportional hazards model for each complete data set, and then used PROC MIANALYZE procedure in SAS to combine results from the five Cox models (the pooled standard error of the parameter estimate incorporates the uncertainty due to the missing data treatment). Data analyses were performed using the Statistical Analysis System (SAS) version 9.4 (SAS Institute, Cary, NC), and a 2-tailed p-value < 0.05 was considered statistically significant.
Results
From January 2010 to August 2014, a total of 5843 patients met the inclusion criteria, and 4099 of them were included in the final analysis (Fig 1). Of these 4099 patients, the majority (n = 2338, 57%) were on medium-intensity statins at enrollment, 1166 (28%) took no statin at all, and 1781 (43%) failed to achieve the target LDL-C level of < 100 mg/dL. Only a small proportion (n = 183, 4.5%) of the patients took high-intensity statins, reflecting the target-driven nature of the NHI policy on statin therapy. Interestingly, statins were prescribed in only 51% (389 out of 763) of those with prior ischemic stroke or transient ischemic attack. The distribution of patients according to statin intensity and other patient characteristics is presented in Table 1.
The study flowchart of T-SPARCLE registry.
The median follow-up duration was 2 years, and MACEs occurred in 109 patients. No significant difference in MACE incidence rates was found among statin intensity groups (Table 2). Patients on medium-intensity statins had a higher unadjusted incidence rate of nonfatal myocardial infarction.
To evaluate the effect of achieving the target LDL-C level on MACE occurrence, we performed multivariate Cox PH regression analysis based on statin use status and LDL-C level reached at baseline (Table 3). Compared to those achieving the LDL-C target (< 100 mg/dL) with statins, patients with LDL-C level ≥ 100 mg/dL had more occurrences of MACEs no matter their statin use status (HR 1.66, 95% CI 1.04‒2.63, p = 0.03 for those on statins; HR 2.04, 95% CI 1.06‒3.94, p = 0.03 for those not on statins). On the other hand, for patients who achieved the LDL-C target level of < 100 mg/dL, there was no association between statin intensity and risk of MACEs (Table 4). The multivariate Cox PH model identified history of diabetes mellitus (DM), congestive heart failure, cigarette smoking, and chronic kidney disease as independent predictors of MACEs (Table 5). Statin intensity had no significant predictive value, and LDL-C ≥ 100 mg/dL was associated with a trend toward increased risk of MACEs, although the increase was not statistically significant (HR 1.41, 95% CI 0.96‒2.07, p = 0.08). After addition of an interaction term of statin use and LDL-C level, the multivariate-adjusted Cox model showed no significant interaction (P > 0.05).
Discussion
Principal findings
In this multicenter registry cohort study, we found that failure to achieve an LDL-C target level of < 100 mg/dL, irrespective of statin use, was associated with increased risk of MACEs in patients with ASCVD, and no specific statin intensity had a significant impact on CV outcome. Such findings highlight the importance of keeping LDL-C at goal levels instead of fixing statin intensity without having any specific LDL-C target level to reach.
Comparison with other studies
Multiple randomized controlled trials (RCTs) have demonstrated that (for patients with ASCVD) the risk of CV events is reduced more by fixed high-intensity statin treatment than fixed lower-dose statin treatment. This finding has resulted in the recommendation of fixed high-intensity statin strategy by the 2013 ACC/AHA guidelines. In these RCTs, high-intensity statin treatment and lower-intensity statin treatment achieved a mean LDL-C level of 67–79 and 97–102 mg/dL, respectively, and these levels differed by 23–30 mg/dL between the 2 groups [12]. In a meta-analysis of 26 RCTs and involving nearly 170,000 patients [18], each reduction in LDL-C level of 1 mmol/L (38.7 mg/dL) resulted in an approximately 22% relative reduction in risk of major vascular events, and there was no variation in the relative reduction of CV risk among these trials after adjusting for LDL-C reduction. This indicates that the reduction in CV risk is due primarily to LDL-C lowering. This conclusion is compatible with the one drawn in this real-world observational study.
In this study, the study population was a cohort of patients with ASCVD on treatment to lower LDL-C to target levels of < 100 mg/dL according to the National Health Insurance (NHI) regulations in Taiwan. Given the nature of this target-driven strategy, the mean achieved LDL-C levels did not differ much (range 97.6–102.7 mg/dL) among statin intensity groups. Since the reduction in CV risk is mainly driven by LDL-C lowering (relative risk reduction of 22% per 1 mmol/L [38.7 mg/dL] LDL-C reduction) according to the meta-analysis mentioned previously [18], it is therefore not surprising that statin intensity was not associated with the risk of MACEs in our study.
Some studies have demonstrated the additional benefit of combining a statin (e.g., simvastatin) with ezetimibe. IMPROVE-IT, a double-blind RCT, demonstrated that combination therapy further lowered the risk of CV events in patients having prior acute coronary syndrome [19]. A nationwide population study using the National Health Insurance Research Database in Taiwan (NHIRD-TW) showed an independent association between the combination therapy and a lower risk of MACEs in patients with DM [20]. In the T-SPARCLE registry, however, only a small proportion (< 5%) of the study population received other lipid-lowering agents in addition to statins, so we could not evaluate the effect of combination therapy on the risk of MACEs in this study.
Public health impact
The incidence and mortality of acute myocardial infarction (AMI) have continuously declined in developed western countries [21–23]. Improvements in thrombolysis, primary percutaneous coronary interventions (PCI), coronary artery bypass grafting (CABG), and concurrent antiplatelet and antithrombotic therapies, have contributed much to the reduction or control of established CV risk factors, such as hypertension, DM, and dyslipidemia. However, data from the NHIRD-TW showed the decrease in the incidence of ST-elevation myocardial infarction in Taiwan has been only modest compared to that in western countries [24]. Suboptimal control of CV risk factors might partly explain this difference. Based on data obtained from the T-SPARCLE registry, which includes subjects from 14 medical sites across Taiwan, 28% of patients with ASCVD took no statin drug and 43% failed to achieve the LDL-C goal of < 100 mg/dL. This implied that there is still substantial room for improvement in CV risk and outcome.
Limitations
Our study has several limitations. First, this is an observational cohort study. To directly compare a target-driven strategy to an intensity-driven strategy, we may need an RCT which randomizes the enrolled patients to groups based on each strategy. Second, our multivariate Cox PH model revealed a borderline association between LDL-C ≥ 100 mg/dL and increased risk of MACEs, and our study might be underpowered to detect such an association during a short follow-up period. Third, the relatively low patient numbers in the high-intensity and low-intensity groups might have increased the possibility of type II error. Fourth, data of statin therapy and LDL-C level were all collected at enrollment, and we didn’t have data of therapy discontinuation or modification during the follow-up period, which might have an impact on the outcomes. Fifth, the LDL-C target level in our study cohort was 100 mg/dL not 70 mg/dL, which has been a widely accepted target for patients with ASCVD and high CV risk in western countries. In Caucasians, because the benefit of LDL-C reduction is the same within the range 77–135 mg/dL,12 the more optimal treatment target would likely be 70 mg/dL rather than 100 mg/dL. However, there is always an argument that the Asian (compared to the Causcasian) population has less need to use a high-intensity statin or to achieve such a low LDL-C level for secondary prevention. For example, in the Secondary Prevention Cohort Study of the Japan Lipid Intervention Trial (J-LIT), it was found that regulating the serum LDL-C concentration to <120 mg/dL is a reasonable therapeutic strategy to reduce coronary heart disease progression in Japanese patients with prior history under low-dose statin treatment [25]. This issue can be further investigated only if the Taiwanese NHI payment regulation revises the LDL-C target level to < 70 mg/dL for secondary prevention in the future.
Conclusions
In the real world, for patients with ASCVD on statin therapy guided by a target-driven strategy, failure to control LDL-C levels to < 100 mg/dL was associated with higher risk of MACEs. Statin intensity alone had no significant impact on the risk of MACEs after multivariate adjustment.
Supporting information
S1 File. Supporting tables and figures.
Supporting tables and figures of T-SPARCLE registry.
https://doi.org/10.1371/journal.pone.0186861.s001
(PDF)
S2 File. Statistical data.
Statistical data of T-SPARCLE registry.
https://doi.org/10.1371/journal.pone.0186861.s002
(PDF)
Acknowledgments
We thank the Taiwan Society of Lipids & Atherosclerosis and Taiwan Ministry of Science and Technology for supporting this project. The following investigators are in the Taiwanese Secondary Prevention for Patients with AtheRosCLErotic disease (T-SPARCLE) Registry: Wei-Hsian Yin, Shao-Yuan Chuang (Institute of Population Sciences, National Health Research Institutes, Miaoli, Taiwan), Wei-Kung Tseng, Yen-Wen Wu, I-Chang Hsieh (Cardiology section, Department of Internal Medicine, Chang Gung Medical Foundation, Taipei, Taiwan), Tsung-Hsien Lin (Cardiology section, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan), Yi-Heng Li (Department of Internal Medicine, National Cheng Kung University Hospital and National Cheng Kung University, Tainan, Taiwan), Lien-Chi Huang (Department of Internal Medicine, Taipei City Hospital [Heping Fuyou Branch], Taipei, Taiwan), Hui-Heng Hsu (Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan), Kuo-Yang Wang (Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan), Kwo-Chang Ueng (Cardiology section, Department of Internal Medicine, Chung Shan Hospital, Taipei, Taiwan), Ching-Chang Fang (Division of Cardiology, Department of Internal Medicine, Tainan Municipal Hospital, Tainan, Taiwan), Wen-Harn Pan (Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan), Hung-I Yeh, Chau-Chung Wu, and Jaw-Wen Chen. The lead author of T-SPARCLE investigators is Chau-Chung Wu, the co-corresponding author of this article.
References
- 1. Pekkanen J, Linn S, Heiss G, Suchindran CM, Leon A, Rifkind BM, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med. 1990; 322: 1700–7. pmid:2342536
- 2. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005; 366: 1267–78. pmid:16214597
- 3. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004; 350: 1495–504. pmid:15007110
- 4. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005; 294: 2437–45. pmid:16287954
- 5. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005; 352: 1425–35. pmid:15755765
- 6. Miura M, Yamasaki M, Uemura Y, Yoshikawa M, Miyauchi K, Tanaka H, et al. Effect of Statin Treatment and Low-Density Lipoprotein-Cholesterol on Short-Term Mortality in Acute Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention—Multicenter Registry From Tokyo CCU Network Database. Circ J. 2016; 80: 461–8 pmid:26658282
- 7. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996; 335: 1001–9. pmid:8801446
- 8. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383–9 pmid:7968073
- 9. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360: 7–22. pmid:12114036
- 10. Stoekenbroek RM, Boekholdt SM, Fayyad R, Laskey R, Tikkanen MJ, Pedersen TR, et al. High-dose atorvastatin is superior to moderate-dose simvastatin in preventing peripheral arterial disease. Heart. 2015; 101: 356–62. pmid:25595417
- 11. Pauriah M, Elder DH, Ogston S, Noman AY, Majeed A, Wyatt JC, et al. High-potency statin and ezetimibe use and mortality in survivors of an acute myocardial infarction: a population-based study. Heart. 2014; 100: 867–72. pmid:24553389
- 12. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129(25 Suppl 2): S1–45.
- 13. Lin TH, Chuang SY, Chu CY, Lee WH, Hsu PC, Su HM, et al. The impact of chronic kidney disease on lipid management and goal attainment in patients with atherosclerosis diseases in Taiwan. Int J Med Sci. 2014; 11: 381–8. pmid:24578616
- 14. Ho LT, Yin WH, Chuang SY, Tseng WK, Wu YW, Hsieh IC, et al. Determinants for achieving the LDL-C target of lipid control for secondary prevention of cardiovascular events in Taiwan. PloS One. 2015; 10: e0116513. pmid:25756522
- 15. Jeng JS, Yin WH, Huang CC, Chuang SY, Yeh HI, Fang CC, et al. Guideline-adherent therapy in patients with cardiovascular diseases in Taiwan. J Formos Med Assoc. 2015; 114: 1000–7. pmid:24275017
- 16. Yin WH, Wu CC, Chen JW. Registry of Lipid Control and the Use of Lipid-lowering Drugs for Secondary Prevention of Cardiovascular Events in Patients with Established Atherosclerotic Disease in Taiwan: Rationality and Methods. Int J Gerontol. 2012; 6:241–6.
- 17. Klebanoff MA, Cole SR. Use of multiple imputation in the epidemiologic literature. Am J Epidemiol. 2008; 168: 355–7. pmid:18591202
- 18. Cholesterol Treatment Trialists’ (CTT) Collaboration., Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010; 376: 1670–81. pmid:21067804
- 19. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015; 372: 2387–97. pmid:26039521
- 20. Chang SH, Wu LS, Lee CH, Kuo CT, Liu JR, Wen MS, et al. Simvastatin-ezetimibe combination therapy is associated with a lower rate of major adverse cardiac events in type 2 diabetics than high potency statins alone: A population-based dynamic cohort study. Int J Cardiol. 2015; 190: 20–5. pmid:25912112
- 21. Schmidt M, Jacobsen JB, Lash TL, Bøtker HE, Sørensen HT. 25 year trends in first time hospitalisation for acute myocardial infarction, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity: a Danish nationwide cohort study. BMJ 2012; 344: e356. pmid:22279115
- 22. Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS. Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med. 2010; 362: 2155–65. pmid:20558366
- 23. Lawesson SS, Alfredsson J, Fredrikson M, Swahn E. Time trends in STEMI—improved treatment and outcome but still a gender gap: a prospective observational cohort study from the SWEDEHEART register. BMJ open. 2012; 2: e000726. pmid:22457480
- 24. Yin WH, Lu TH, Chen KC, Cheng CF, Lee JC, Liang FW, et al. The temporal trends of incidence, treatment, and in-hospital mortality of acute myocardial infarction over 15years in a Taiwanese population. Int J Cardiol. 2016; 209: 103–13. pmid:26889592
- 25. Mabuchi H, Kita T, Matsuzaki M, Matsuzawa Y, Nakaya N, Oikawa S, et al. and the J-LIT Study Group. Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia and coronary heart disease–secondary prevention cohort study of the Japan Lipid Intervention Trial (J-LIT). Circ J. 2002; 66: 1096–1100. pmid:12499612