Primary prevention of cardiovascular diseases among hypercholesterolemic Japanese with a low dose of pravastatin

doi:10.1016/j.atherosclerosissup.2007.02.003

Atherosclerosis Supplements

Volume 8, Issue 2, August 2007, Pages 13-17

https://doi.org/10.1016/j.atherosclerosissup.2007.02.003 Get rights and content

Abstract

The MEGA Study was Japan's first primary prevention trial of cardiovascular disease (CVD) by cholesterol lowering with low-dose pravastatin. Included were postmenopausal women aged ≤70 years and men aged 40–70 years with mildly elevated total cholesterol (TC) level 220–270 mg/dL. In all, 8214 outpatients were randomly assigned to receive diet alone or diet plus pravastatin 10–20 mg/day for an average follow-up of 5.3 years. The primary endpoint was a composite of fatal and nonfatal MI, angina, cardiac and sudden death, and coronary revascularization.

TC was reduced by 11.5% in the diet plus pravastatin group versus 2.1% in the diet alone group. LDL-C was reduced by 18% and 3.2% in the two groups, respectively. TC was reduced to <220 mg/dL and LDL-C to <130 mg/dL in patients in the diet plus pravastatin group. There was a significant 33% reduction of the primary endpoint in the diet plus pravastatin group compared with the diet alone group.

Notable findings of the MEGA Study included the observation that despite pravastatin's modest LDL-C reductions in this low-risk population, a 33% reduction of CHD events was achieved. Even though 68% of patients were women, who have been traditionally considered at less risk than men, significant CHD risk reduction was observed across all groups.

Introduction

The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study [1] was Japan's first primary prevention trial of cardiovascular disease (CVD) by cholesterol lowering with low-dose pravastatin. The MEGA Study was also designed to evaluate the long-term safety of pravastatin therapy in Japanese patients. Major inclusion criteria were men aged 40–70 years and postmenopausal women aged ≤70 years with mildly elevated total cholesterol (TC) level 220–270 mg/dL. Main exclusion criteria were history of atherosclerotic disease, cancer, and familial hypercholesterolemia. Written informed consent was obtained from all patients.

Section snippets

Study design

The MEGA Study was conducted in outpatients and followed a prospective, randomized, open-labeled blinded endpoints (PROBE) design. The primary endpoint was a composite of coronary heart disease (CHD) events such as fatal and nonfatal myocardial infarction (MI), cardiac/sudden death, angina, and arterial surgery/angioplasty. Secondary endpoints included stroke, CHD plus cerebral infarction (CI) of atherosclerotic origin, all CV events, and total mortality. Patients were randomly assigned to diet

Results

Baseline characteristics in the two groups were comparable (Table 1). Overall, women accounted for a higher percentage (68%) than men; 42% of patients had hypertension and 21% diabetes mellitus (DM). Patients generally had moderately elevated TC and low-density lipoprotein cholesterol (LDL-C) levels. Notably, they had high high-density lipoprotein cholesterol (HDL-C) levels. Triglycerides (TG) were in normal range and lipoprotein (a) was slightly elevated.

The time-course of average change of

Subgroups analysis

Analysis of the incidence rate of stroke at 5 years showed that fatal and nonfatal stroke was reduced by 35% (P = 0.034); NNT was 180. Ischemic stroke was also reduced by 42%; NNT was 205. No significant increase was noted in hemorrhagic stroke.

Analysis of the influence of sex on incidence of major CV events and total mortality revealed that pravastatin was equally beneficial in men and women without any interaction observed [3]. Risk reductions in women were noted with aging; the results

Which patients should receive pravastatin?

At what baseline level of LDL-C should pravastatin be started? When subjects were divided into those with LDL-C levels <150, 150–165, and >165 mg/dL, the incidence of CHD and CI was reduced by 16% (P = NS), 43% (P = 0.03), and 41% (P = 0.03) in the three tertiles, respectively. Therefore regardless of severity of hypercholesterolemia, patients with LDL-C ≥150 mg/dL may expect to derive benefit from pravastatin in terms of suppressing their risk of developing CVD. Indeed, a 30-mg/dL reduction of LDL-C

Notable findings of the MEGA Study

Notable findings of the MEGA Study included the observation that despite its less dramatic LDL-C reductions compared with those seen in other large-scale statins trials, similar reductions of CHD incidence were achieved. In the MEGA Study's low-risk population, a 33% reduction of CHD events was achieved by pravastatin. Also in MEGA, patients had high HDL-C and low TG levels at baseline. Even though 68% of patients were women, who have been traditionally considered at less risk than men,

Conflict of interest

None.

Acknowledgement

This research was funded by Sankyo Co., Ltd. The study sponsor had no involvement in the conduct, findings, and interpretation of this study.

References (4)

H. Nakamura et al.
Primary prevention of cardiovascular disease in Japan: results of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) randomized study with pravastatin
Lancet
(2006)
National Cholesterol Education Program. Report of the Expert Panel on Detection, Evaluation, and Treatment of High...

There are more references available in the full text version of this article.

Cited by (16)

Adequate enrollment of women in cardiovascular drug trials and the need for sex-specific assessment and reporting
2022, American Heart Journal Plus: Cardiology Research and Practice
Cardiovascular disease (CVD) is the leading cause of death for women in the United States and globally. There is an abundance of evidence-based trials evaluating the efficacy of drug therapies to reduce morbidity and mortality in CVD. Additionally, there are well-established influences of sex, through a variety of mechanisms, on pharmacologic treatments in CVD. Despite this, the majority of drug trials are not powered to evaluate sex-specific outcomes, and much of the data that exists is gathered post hoc and through meta-analysis. The FDA established a committee in 1993 to increase the enrollment of women in clinical trials to improve this situation. Several authors, reviewing committees, and professional societies have highlighted the importance of sex-specific analysis and reporting. Despite these statements, there has not been a major improvement in representation or reporting. There are ongoing efforts to assess trial design, female representation on steering committees, and clinical trial processes to improve the representation of women.
This review will describe the pharmacologic basis for the need for sex-specific assessment of cardiovascular drug therapies. It will also review the sex-specific reporting of landmark drug trials in hypertension, coronary artery disease (CAD), hyperlipidemia, and heart failure (HF). In reporting enrollment of women, several therapeutic areas like antihypertensives and newer anticoagulation trials fare better than therapeutics for HF and acute coronary syndromes. Further, drug trials and cardiometabolic or lifestyle intervention trials had a higher percentage of female participants than the device or procedural trials.
Consensus statement on management of dyslipidemia in Indian subjects
2014, Indian Heart Journal
Citation Excerpt :
However, it is noteworthy that in most of the larges-scale statin trials, the observed benefit on CV risk reduction was directly proportional to the reduction in LDL-C,251 suggesting that it may be possibleto achieve a similar degree of CV event reduction with lower dosages of statins in Asian populations. Indeed, in the MEGA (Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese) trial enrolling 7832 individuals, 10–20 mg pravastatin every day resulted in 33% reduction in CHD events as compared to diet alone.252 Exaggerated statin response in Asians also raises concerns of increased risk of adverse effects.
Statin clinical trial (REALITY) for prostate cancer: An over 15-year wait is finally over thanks to a dietary supplement
2011, Urologic Clinics of North America
Citation Excerpt :
It is expected that compliant participants will experience a 20% to 35% LDL-cholesterol reduction. Active surveillance patients will be followed for at least 1 year and have at least 2 biopsies in this 12-month period.54,55 The level of LDL is not predictive for response, and therefore will not be an eligibility criterion.
Cholesterol absorption and synthesis markers in individuals with and without a CHD event during pravastatin therapy: Insights from the PROSPER trial
2010, Journal of Lipid Research
Cholesterol homeostasis, defined as the balance between absorption and synthesis, influences circulating cholesterol concentrations and subsequent coronary heart disease (CHD) risk. Statin therapy targets the rate-limiting enzyme in cholesterol biosynthesis and is efficacious in lowering CHD events and mortality. Nonetheless, CHD events still occur in some treated patients. To address differences in outcome during pravastatin therapy (40 mg/day), plasma markers of cholesterol synthesis (desmosterol, lathosterol) and fractional cholesterol absorption (campesterol, sitosterol) were measured, baseline and on treatment, in the Prospective Study of Pravastatin in the Elderly at Risk trial participants with (cases, n = 223) and without (controls, n = 257) a CHD event. Pravastatin therapy decreased plasma LDL-cholesterol and triglycerides and increased HDL-cholesterol concentrations to a similar extent in cases and controls. Decreased concentrations of the cholesterol synthesis markers desmosterol (−12% and −11%) and lathosterol (−50% and −56%) and increased concentrations of the cholesterol absorption markers campesterol (48% and 51%) and sitosterol (25% and 26%) were observed on treatment, but the magnitude of change was similar between cases and controls. These data suggest that decreases in cholesterol synthesis in response to pravastatin treatment were accompanied by modest compensatory increases in fractional cholesterol absorption. The magnitude of these alterations were similar between cases and controls and do not explain differences in outcomes with pravastatin treatment.
HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis
2023, Cochrane Database of Systematic Reviews
Challenges in Optimizing Lipid Management in Women
2022, Cardiovascular Drugs and Therapy

View all citing articles on Scopus

View full text