Using the hypertriglyceridemic recall group of the Princeton School Family Study, we assessed the effectiveness and ramifications of family sampling based on hypertriglyceridemic probands and examined whether within-family correlations of lipids and lipoproteins outlast the period of shared common household environments. Thirty-two pediatric and 35 adult probands (who had fasting plasma triglyceride in the ninety-fifth percentile or above on initial sampling at visit 1) and their first-degree relatives were studied; 19 of the 32 pediatric probands (59%) had top-quartile triglyceride levels at the Family Study visit, and 14 (44%) were still in the ninety-fifth percentile triglyceride level. Twenty of 35 adult probands (57%) retained triglyceride in the ninety-fifth percentile or above at the Family Study visit, while 30 (86%) had topquartile triglyceride levels. Among the 67 probands, more subjects than expected had elevated total and low-density lipoprotein (LDL) cholesterol; probands were underand overrepresented in the top and bottom quartiles, respectively, of the high-density lipoprotein (HDL) cholesterol distribution. Twenty-one percent and 12% of the hypertriglyceridemic probands' siblings and offspring, respectively, also had triglyceride above the ageand sex-specific ninety-fifth percentile; siblings' and offspring's total and LDL cholesterol were shifted toward higher values. In adult relatives of hypertriglyceridemic probands, a parabolic relationship between triglycerides and LDL cholesterol, positive in the lowest triglyceride tertile and inverse in the top tertile, was observed. This suggests uncoupling of very low density lipoprotein-LDL precursor-product relationships in hypertriglyceridemic subjects. All lipid and lipoprotein correlations

OBJECTIVES The purpose of the study was to assess the effect of lipid reduction with pravastatin on hospital admissions in middle-aged men with hypercholesterolemia in the West of Scotland Coronary Prevention Study.BACKGROUND A prospective, randomized controlled trial was undertaken in primary care centers in the West of Scotland.METHODS A total of 6,595 participants randomized to receive pravastatin 40 mg or placebo daily were followed up for a mean of 4.9 years (range 3.5 to 6.1 years). Analysis of hospital admissions was undertaken according to the "intention to treat" principle both for cardiovascular diseases and noncardiovascular diseases (including malignant neoplasms, psychiatric diagnoses, trauma and other causes). A secondary analysis of hospitalization in patients who were greater than or equal to 75% compliant was performed.RESULTS During the trial, 2,198 (33%) of the 6,595 men were admitted to hospital on 4,333 occasions, of which 1,234 (28%) were for cardiovascular causes. Pravastatin reduced the number of subjects requiring hospital admission for cardiovascular causes by 21% (95% CI [confidence interval] 9 to 31, p = 0.0008) overall, and by 27% (95% CI 15 to 38) in compliant participants. The number of admissions per 1,000 subject-years for cardiovascular disease was reduced by 10.8 (95% CI 4 to 17.4, p = 0.0013) in all subjects, and by 15.6 (95% CI 8.3 to 23, p < 0.0001) in compliant participants. Pravastatin had no significant influence on hospital admission for any noncardiovascular diagnostic category. There were 13.4 fewer admissions per 1,000 subject years for all causes in the pravastatin-treated group (95% CI -0.4 to 27.3, p = 0.076). No significant difference in duration of hospital stay was found between the pravastatin and placebo patients in any diagnostic group.CONCLUSIONS Pravastatin therapy reduced the burden of hospital admissions for cardiovascular disease, without any adverse effect on noncardiovascular hospitalization. (J Am Coll Cardiol 1999;33:909-15) (C) 1999 by the American College of Cardiology.

HomeCirculationVol. 100, No. 25Baseline Cholesterol Level and Magnitude of Coronary Event Reduction in Diabetic Patients With Myocardial Infarction Free AccessOtherPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessOtherPDF/EPUBBaseline Cholesterol Level and Magnitude of Coronary Event Reduction in Diabetic Patients With Myocardial Infarction Dr Colin Johnston Dr Colin JohnstonDr Colin Johnston Consultant Physician and Endocrinologist Department of Endocrinology, Hemel Hempstead General Hospital, Hemel Hempstead, Herts, UK Search for more papers by this author Originally published21 Dec 1999https://doi.org/10.1161/01.CIR.100.25.e154Circulation. 1999;100:e154To the Editor:It would be very helpful if we were able to see further analysis of the study by Goldberg et al.1 The analysis presented was for the group as a whole, which included significant variations in baseline cholesterol levels. It would be helpful if we could see an analysis similar to that performed in the LIPID study2 looking at the outcome in relation to differences in the baseline cholesterol level. Although I suspect the number of end points may affect the statistical analysis, clinicians should be able to see the raw data and draw their own conclusions. The LIPID study demonstrated statistical benefit in treating all levels of cholesterol, but there appeared to be significant differences in the numbers needed to treat, and this would have a significant impact on health economics. References 1 Goldberg RB, Mellies MJ, Sacks FM, Moyé LA, Howard BV, Howard WJ, Davis BR, Cole TG, Pfeffer MA, Braunwald E, for the CARE Investigators. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol And Recurrent Events (CARE) Trial. Circulation.1998; 98:2513–2519.CrossrefMedlineGoogle Scholar2 Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Studies Group. N Engl J Med.1998; 339:1349–1357.CrossrefMedlineGoogle ScholarcirculationahaCirculationCirculationCirculation0009-73221524-4539Lippincott Williams & WilkinsResponseSacks Frank M., MD, Pfeffer Marc A., MD, PhD, Braunwald Eugene, MD, Goldberg Ronald B., MD, Mellies Margot J., MD, Moyé Lemuel A., MD, PhD, Davis Barry R., MD, PhD, Howard Barbara V., PhD, Howard Wm. James, MD, and Cole Thomas G., PhD21121999Dr Colin Johnston is interested in whether baseline cholesterol concentrations are related to the magnitude of coronary event reduction in diabetic patients with myocardial infarction and suggests that data from the CARE population may be useful. Coronary event rates in diabetics are strongly related to serum cholesterol concentration, and therefore fewer patients may be needed to be treated to prevent an event. Although we agree that the question is important, we have not analyzed this relationship in the diabetic patients in the CARE trial because of the small size of this subgroup (586 patients). We point out that the LIPID trial also has not reported this relationship in diabetic patients. The CARE and LIPID investigators are engaged in an analysis that combines the data from these 2 similar studies of pravastatin in secondary prevention, and the total number of diabetic patients is 1444. This larger population has better potential than either individual study to give a reliable answer to the issue of risk reduction in relation to pretreatment cholesterol concentrations in diabetic patients. Previous Back to top Next FiguresReferencesRelatedDetails December 21, 1999Vol 100, Issue 25 Advertisement Article InformationMetrics Copyright © 1999 by American Heart Associationhttps://doi.org/10.1161/01.CIR.100.25.e154 Originally publishedDecember 21, 1999 PDF download Advertisement

BACKGROUND:Although diabetes is a major risk factor for coronary heart disease (CHD), little information is available on the effects of lipid lowering in diabetic patients. We determined whether lipid-lowering treatment with pravastatin prevents recurrent cardiovascular events in diabetic patients with CHD and average cholesterol levels.METHODS AND RESULTS:The Cholesterol And Recurrent Events (CARE) trial, a 5-year trial that compared the effect of pravastatin and placebo, included 586 patients (14.1%) with clinical diagnoses of diabetes. The participants with diabetes were older, more obese, and more hypertensive. The mean baseline lipid concentrations in the group with diabetes--136 mg/dL LDL cholesterol, 38 mg/dL HDL cholesterol, and 164 mg/dL triglycerides--were similar to those in the nondiabetic group. LDL cholesterol reduction by pravastatin was similar (27% and 28%) in the diabetic and nondiabetic groups, respectively. In the placebo group, the diabetic patients suffered more recurrent coronary events (CHD death, nonfatal myocardial infarction [MI], CABG, and PTCA) than did the nondiabetic patients (37% versus 25%). Pravastatin treatment reduced the absolute risk of coronary events for the diabetic and nondiabetic patients by 8.1% and 5.2% and the relative risk by 25% (P=0.05) and 23% (P<0.001), respectively. Pravastatin reduced the relative risk for revascularization procedures by 32% (P=0.04) in the diabetic patients. In the 3553 patients who were not diagnosed as diabetic, 342 had impaired fasting glucose at entry defined by the American Diabetes Association as 110 to 125 mg/dL. These nondiabetic patients with impaired fasting glucose had a higher rate of recurrent coronary events than those with normal fasting glucose (eg, 13% versus 10% for nonfatal MI). Recurrence rates tended to be lower in the pravastatin compared with placebo group (eg, -50%, P=0.05 for nonfatal MI).CONCLUSIONS:Diabetic patients and nondiabetic patients with impaired fasting glucose are at high risk of recurrent coronary events that can be substantially reduced by pravastatin treatment.

Copyright © 1998 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514 1998;98;2513-2519 Circulation and Eugene Braunwald Howard, William James Howard, Barry R. Davis, Thomas G. Cole, Marc A. Pfeffer Ronald B. Goldberg, Margot J. Mellies, Frank M. Sacks, Lemuel A. Moyé, Barbara V. Trial Levels : Subgroup Analyses in the Cholesterol And Recurrent Events (CARE) Glucose-Intolerant Myocardial Infarction Survivors With Average Cholesterol Cardiovascular Events and Their Reduction With Pravastatin in Diabetic and http://circ.ahajournals.org/cgi/content/full/98/23/2513 located on the World Wide Web at: The online version of this article, along with updated information and services, is

The West of Scotland Coronary Prevention Study recently demonstrated the benefits of pravastatin therapy in the prevention of coronary heart disease events in middle-aged hypercholesterolemic men without prior myocardial infarction. We present an analysis of the influence of baseline risk factors on coronary events and total mortality in the trial, and their interaction with therapy, using the Cox proportional hazards model. The multivariate predictors of fatal or nonfatal coronary events were treatment allocation (pravastatin or placebo), current smoking, diabetes mellitus, nitrate consumption, minor electrocardiographic abnormalities, angina pectoris, family history of premature coronary death, widowhood, blood pressure, and total cholesterol/high density lipoprotein cholesterol ratio. Independent of other risk factors, pravastatin reduced the risk of definite coronary heart disease death or nonfatal myocardial infarction by 32% (95% confidence interval 17 to 44, p = 0.0001), definite or suspected coronary heart disease death by 35% (3 to 56, p = 0.035), cardiovascular death by 33% (4 to 53, p = 0.027), coronary revascularization procedures by 38% (11 to 56, p = 0.009), and all-cause mortality by 24% (2 to 41, p = 0.037). The 5-year risk of fatal or nonfatal myocardial infarction, calculated using the predictors identified in the Cox analysis, ranged from <4.4% in the lowest quartile of risk to >9.6% in the highest quartile. The proportional benefit achieved by pravastatin was independent of other risk factors; hence, the absolute benefit of therapy was greatest in subjects with the highest baseline risk. Such subjects can be identified easily in the population and deserve high priority for treatment. (C) 1997 by Excerpta Medica, Inc.

Recent landmark studies using hydroxy-methyl-glutaryl-Co-enzyme A reductase inhibitors (HMG-CoA reductase inhibitors or statins), specifically, pravastatin and simvastatin, have led to dramatic changes in medical practice. These clinical trials have demonstrated that clinicians can impact coronary morbidity and mortality in primary (pravastatin) and secondary (pravastatin, simvastatin) prevention settings, including post-infarct patients with ‘normal’ cholesterol levels (pravastatin). The clinical benefit can be seen irrespective of risk factors at baseline and in women, the elderly and diabetics.

Aims To assess the additional benefit gained from high compliance in the West of Scotland Coronary Prevention Study and to examine cases where withdrawal from trial medication was due to an adverse event.Methods The incidence of definite coronary heart disease or non-fatal myocardial infarction, cardiovascular mortality, definite or suspect coronary heart disease death or non-fatal myocardial infarction, the need for coronary revascularization procedures, all-cause mortality and incident cancers were measured in the entire cohort and compared with the high compliance group. The adverse events associated with withdrawal were coded by body system.Results In subjects with compliance greater than or equal to 75%, treatment with pravastatin resulted in a 38% risk reduction for definite coronary heart disease death or non-fatal myocardial infarction and for cardiovascular mortality, a 46% reduction in risk or coronary revascularization and a 32% risk reduction (P = 0.015) for all-cause mortality.Conclusions The analysis of the effect of pravastatin in the subgroup of high compliers to randomized medication demonstrated a substantial increase in the estimated risk reductions in comparison with that achieved in the intention-to-treat analysis. This result has significant implications for the motivation of high compliance among patients and for the assessment of the cost-effectiveness of treatment.

Background We assessed the potential benefit of treatment for low-risk and high-risk groups in the West of Scotland Coronary Prevention Study (WOSCOPS) population, and compared the benefits of primary and secondary prevention of coronary heart disease (CHD) by lipid lowering with the benefits of blood pressure reduction in the primary prevention of stroke.Methods We did a subgroup analysis of placebo-treated men in the WOSCOPS population by age, vascular disease at trial entry, and other established risk factors. We also compared WOSCOPS findings with those of the Scandinavian Simvastatin Survival Study (4S) and the Medical Research Council (MRC) trial of treatment for mild to moderate hypertension in middle-aged men. The WOSCOPS population comprised 6595 men aged 45-64 years with no history of myocardial infarction (MI) and plasma total cholesterol concentrations of 6 . 5-8 . 0 mmol/L at initial screening. Participants were randomly allocated pravastatin (40 mg daily) or placebo, and followed up for an average of 4 . 9 years.Findings Coronary event rates at 5 years in the WOSCOPS placebo group were higher than 10% (the recommended treatment threshold) in men with pre-existing vascular disease and in those 55 years or older without symptoms least one other low in men with hypercholesterolaemia but no other risk factor: 3 . 5% (95% CI 1 . 3-5 . 7) for men aged 45-54 years and 5 . 3% (2 . 7-8 . 0) for men aged 55-64 years. Three times more men had to be treated for 5 years to prevent one endpoint in WOSCOPS than in 4S, By contrast, two to four times fewer men with hyperlipidaemia were treated to save one coronary event in WOSCOPS than hypertensives to save one stroke in the MRC trial. These differences persisted after adjustment for the low-risk status of many of the patients with hypertension who took part in the MRC trial.Interpretation There were a substantial number of men whose risk of a coronary event was more than 10% at 5 years in the WOSCOPS cohort, The absolute benefit of pravastatin treatment of hyperlipidaemia is less in the primary prevention of CHD than in secondary prevention, but is similar to that for primary prevention of stroke by treatment of mild to moderate hypertension in middle-aged men.

The Prospective Pravastatin Pooling (PPP) project is a pooled evaluation of 3 large, placebo-controlled, randomized trials of cholesterol-lowering treatment with pravastarin. It is designed to more reliably evaluate the effect of treatment on coronary and all-cause mortality and on total coronary artery disease (CAD) events for specific populations of interest, including women and the elderly. The trials—Long-Term Intervention With Pravastatin in Ischemic Disease trial, the Cholesterol and Recurrent Events trial, and the West of Scotland Coronary Prevention Study—each have common design features, including drug, dose, and duration. The project prospectively defines the objectives, end points, and analytic plans in a protocol developed before results are known of any individual trial. More than 2,000 (or 10%) of the participants in the pooled data set are women, 1,841 are aged ≥70 years at trial entry, and >6,000 have a total cholesterol <5.5 mmol/L (213 mg/dl). The mean low-density lipoprotein cholesterol level is 4.2 mmol/L (162 mg/dl). The mean blood pressure level is 134/81 mm Hg and 20% are current smokers. Half of the PPP participants have had a prior myocardial infarction. More than 7% have a history of diabetes and 26% have a history of hypertension. PPP is projected to have data on about 1,100 CAD deaths, 500 non-CAD deaths, and >1,000 cancers by study completion. Based on a pooled population of 19,768 patients, with approximately 1,600 deaths and 100,000 patient-years of follow-up, PPP should have good power to examine the effects of treatment on total mortality, CAD mortality, and cancer incidence, and ta determine effects on total CAD events in important subgroups including the elderly, women, diabetics, and those with lower serum cholesterol levels (<5.5 mmol/L [213 mg/dl]).

Backgrounds: Treatment of severe hypercholesterolemia often requires high-dose therapy with a hydroxymethylglutaryl-coenzyme A reductase inhibitor alone or in combination with bile acid-binding resin. We evaluated the efficacy and safety, of pravastatin, a new hydroxymethylglutaryl-coenzyme A reductase inhibitor with hydrophilic selectivity, alone and in combination with cholestyramine.Methods: Pravastatin was studied at doses of 20 or 40 mg twice daily alone or 20 mg twice daily with cholestyramine, 12 g twice daily, vs placebo in a randomized, double-blind multicenter study of 311 patients for 8 weeks and in continued therapy through 24 weeks.Results: After 8 weeks of therapy, pravastatin in a dosage of 20 mg twice daily reduced low-density lipoprotein cholesterol levels by 31%, whereas a dosage of 40 mg twice daily reduced low-density lipoprotein cholesterol levels by 38%. Cholestyramine, 24 g daily alone, reduced low-density lipoprotein cholesterol levels by 32%. Cholestyramine combined with 40 mg of pravastatin reduced the level by 51%. Pravastatin, 40 or 80 mg daily, reduced the triglyceride level by 13% to 19%, resin alone increased the triglyceride level by 21%, and no change was seen with combined therapy. High-density lipoprotein cholesterol levels increased by about 5% regardless of regimen. Similar effects were seen at 24 weeks. Symptoms reported were indistinguishable among placebo and pravastatin users and were less than with cholestyramine alone or cholestyramine in combination with pravastatin. Elevations of liver enzyme levels were small in all groups, indistinguishable between resin and pravastatin, and were highest when the two drugs were combined. Plasma creatine kinase levels did not increase in any treatment group.Conclusions: Pravastatin treatment of hypercholesterolemia is highly effective and well tolerated alone and in combination with bile acid-binding resin and shows no tendency to increase muscle enzyme levels.

This multicenter, double-blind, placebo-controlled, dose-response study was conducted in patients with primary hypercholesterolemia to examine the effects of pravastatin, a selective inhibitor of HMG-CoA reductase, on plasma lipids and lipoproteins. A total of 306 patients on cholesterol-lowering diets received twice daily doses of 5 mg, 10 mg, 20 mg pravastatin, or placebo for 12 weeks. Marked reductions in low density lipoprotein (LDL) cholesterol and total cholesterol were observed after 1 week of treatment; maximum lipid-lowering effects occurred at 4 weeks and were sustained for the duration of the trial. At week 12, pravastatin treatment resulted in dose-dependent mean reductions from baseline in LDL cholesterol of 17.5%, 22.9%, and 30.8% for the 3 doses tested (P <= 0001 compared with baseline and placebo). The reduction in LDL cholesterol was log-linear with respect to dose; each doubling of dose reduced LDL cholesterol an additional 6.5%. Dose-dependent reductions in total cholesterol from 12.9% to 23.3% also occurred (P <= 0.001). Triglycerides decreased by as much as 15.4% (P <= 0.001) and high-density lipoprotein (HDL) cholesterol increased approximately 7% (P <= 0.01), but these effects were not dose-dependent. No patient receiving pravastatin was discontinued during the 12-week trial. Transient episodes of rash and headache occurred. Slight increases in mean serum levels of ASAT and ALAT occurred, and 2% of both placebo- and pravastatin-treated patients reported myalgia although there was no clinically significant elevation of creatine kinase. These data indicate that pravastatin favorably affects all lipid parameters and is well tolerated.