Lipid Research Clinics Coronary Primary Prevention Trial Research Articles

Low-Density Lipoprotein Cholesterol Reduction and Prevention of Cardiovascular Disease

Low-Density Lipoprotein Cholesterol Reduction and Prevention of Cardiovascular Disease

Does Cholesterol Reduction with Cholestyramine Prevent Coronary Heart Disease among Individuals with Prehypertension?

Background: There have been few treatment studies examining whether risk factor modification among individuals with prehypertension (120–139/80–89 mm Hg) is beneficial in reducing clinical measures of cardiovascular disease.Methods: We examined the effect of cholesterol reduction with cholestyramine on coronary heart disease (CHD) among prehypertensive men in a secondary analysis of the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT). 828 participants were randomized to placebo and 853 to cholestyramine. The two outcomes were definite CHD (i.e., death and/or definite non-fatal myocardial infarction (MI)), and any CHD (i.e., definite CHD death and/or definite non-fatal MI and/or suspect CHD death and/or suspect MI).Results: Cholestyramine use was associated with a 22% reduced risk of any CHD among prehypertensive men, Hazard ratio [HR] = 0.78; 95% Confidence Interval [CI]: 0.59 – 1.03, and absolute risk reduction of 3.2% (p = 0.05). The number needed to treat was 31.Conclusion: Interven...

The Economics of Hypercholesterolemia and Lipid-Lowering Therapy: A Brief Historical Tour

The first formal economic evaluation of a lipid-lowering intervention was conducted almost 20 years ago. The field exploded in the mid-1980s following the publication of findings from the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), in which the bile-acid sequestrant, cholestyramine, was reported to reduce the incidence of coronary artery disease in adults with significant elevations in cholesterol. Almost all of the early pharmacoeconomic studies that followed focused on this agent. Later in the decade, the introduction of lovastatin, the first 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (or “statin”), revolutionized the treatment of hypercholesterolemia, as it was significantly more effective than earlier agents (as were the other statins that followed it). Pharmacoeconomic studies of the statins generally have reported that, despite their higher cost, they are significantly more cost-effective than bile acid sequestrants. Recent long-term clinical trials, such as the West of Scotland Coronary Prevention Study (WOSCOPS) and the Scandinavian Simvastatin Survival Study (4S), have provided firm evidence of the benefits of the statins in both the primary and secondary prevention of coronary artery disease. Formal economic evaluations were incorporated into most of these end-point studies—in contrast to morbidity and mortality trials of earlier lipid-lowering agents—and results from these evaluations are just now becoming available. The availability of primary economic data derived directly from large-scale, long-term clinical trials raises important questions about the future role of modeling in this area.

Primary Prevention of Coronary Heart Disease With Drug Therapy

The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) 1,2 was a landmark clinical trial that showed that lowering of the serum cholesterol level by cholestyramine therapy significantly decreased the risk for coronary heart disease (CHD). This trial provided the critical proof for the cholesterol-CHD hypothesis and, thereby, made possible the initiation of the National Cholesterol Education Program. A reduction in CHD rates by cholestyramine therapy was not accompanied by demonstrable serious side effects during the 7-year study period. However, in spite of a reduction in both new-onset CHD and deaths from CHD by cholestyramine treatment, there was not a statistically significant decrease in total mortality; this was because an apparent increase in trauma mortality offset the decrease in CHD deaths. The apparent increase in trauma mortality, it must be noted, was not statistically significant. Cholestyramine therapy in this trial also did not significantly predispose to tumor formation. Although total

Primary prevention of coronary heart disease with drug therapy. Safety and total mortality issues

The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) 1,2 was a landmark clinical trial that showed that lowering of the serum cholesterol level by cholestyramine therapy significantly decreased the risk for coronary heart disease (CHD). This trial provided the critical proof for the cholesterol-CHD hypothesis and, thereby, made possible the initiation of the National Cholesterol Education Program. A reduction in CHD rates by cholestyramine therapy was not accompanied by demonstrable serious side effects during the 7-year study period. However, in spite of a reduction in both new-onset CHD and deaths from CHD by cholestyramine treatment, there was not a statistically significant decrease in total mortality; this was because an apparent increase in trauma mortality offset the decrease in CHD deaths. The apparent increase in trauma mortality, it must be noted, was not statistically significant. Cholestyramine therapy in this trial also did not significantly predispose to tumor formation. Although total

The validity of estimating heart disease reduction from a framingham logistic equation

We compared two ways in which a logistic equation could be used to estimate the number of heart disease events prevented after lowering blood cholesterol levels. Men were selected from an Australian population survey who met the entry criteria of the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT). The numbers of heart disease events expected over 7.4 years were calculated from the logistic equation after reducing the men's blood cholesterol by the amounts achieved in the LRC-CPPT placebo and treatment groups (our simulated placebo and treatment groups). The number of events prevented was calculated as the absolute difference between the simulated groups (9.48 per 1000 men per 7.4 years) and the percentage difference of the simulated groups multiplied by the observed incidence rate in the LRC-CPPT placebo group (13.66 per 1000 men per 7.4 years). The second estimate was closer to that observed in the LRC-CPPT (17.10 per 1000 men per 7.4 years), and we recommend this approach in cost-effectiveness studies.

Comparison of an Aggressive (U.S.) and a Less Aggressive (Canadian) Policy for Cholesterol Screening and Treatment

To determine the point at which adverse quality-of-life effects engendered by an aggressive cholesterol-lowering strategy dictate the use of a less aggressive approach. Decision analysis was used to compare the effects of the National Cholesterol Education Program (NCEP) guidelines, an aggressive program, with those of the Canadian Task Force on the Periodic Health Examination (CTF) guidelines, a more conservative program. Quality-adjusted life expectancy was calculated for a theoretical cohort of middle-aged men treated according to each program using Markov cohort analysis. Guidelines were applied to the population of the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), under the assumption that cholesterol levels had the distribution of the age- and sex-matched general population. Outcomes were calculated using a three-state (health, coronary heart disease, and death) Markov model. State transition probabilities were calculated using bivariate (age and cholesterol) proportional hazards and logistic regression functions. The result was a "toss-up"; the number of expected quality-adjusted life years was similar for both programs at all time intervals, although the conservative program was consistently slightly favored. The result was very sensitive to the disutility of dietary therapy (threshold value, 0.0014 compared with the baseline estimate of 0.02) but was also affected by the time frame of the analysis and the rate at which adverse effects of treatment decline. Even small disutilities associated with treatment may outweight the benefits of aggressive cholesterol-lowering strategies. Research should be directed toward measuring these disutilities and finding ways to reduce their size. Incorporation of the disutility of treatment into policy formulation may result in less interventionist and less costly policies.

Compliance as an Explanatory Variable in Clinical Trials

Abstract The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) measured the effectiveness of the drug cholestyramine for lowering cholesterol levels. The patients in the study were measured for compliance (the proportion of the intended dose actually taken) and for cholesterol decrease. The compliance-response regression for the Treatment group shows a smooth increasing effect of the drug in cholesterol level with increasing compliance. However, a similar, though less dramatic, compliance-response regression is seen in the Control group. This article investigates the recovery of the true dose-response curve from the Treatment and Control compliance-response curves. A simple model is proposed, analyzed, and applied to the LRC-CPPT data. Under this model, part but not all of the true dose-response curve can be estimated.

Compliance as an Explanatory Variable in Clinical Trials

Abstract The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) measured the effectiveness of the drug cholestyramine for lowering cholesterol levels. The patients in the study were measured for compliance (the proportion of the intended dose actually taken) and for cholesterol decrease. The compliance-response regression for the Treatment group shows a smooth increasing effect of the drug in cholesterol level with increasing compliance. However, a similar, though less dramatic, compliance-response regression is seen in the Control group. This article investigates the recovery of the true dose-response curve from the Treatment and Control compliance-response curves. A simple model is proposed, analyzed, and applied to the LRC-CPPT data. Under this model, part but not all of the true dose-response curve can be estimated.

Review of clinical trials: proving the lipid hypothesis

The Lipid Hypothesis, which states that lowering blood cholesterol levels should significantly reduce the incidence of coronary heart disease (CHD), has been repeatedly tested in primary and secondary intervention trials. Viewed as a whole, it is apparent that the incidence of CHD in treated groups decreased in proportion to the degree of plasma cholesterol reduction. An early study at the Wadsworth Hospital in Los Angeles showed that a diet high in polyunsaturated fat and low in cholesterol reduced the incidence of CHD. The Oslo study of diet and smoking intervention demonstrated a significant decrease in CHD concomitant with a 13% reduction in serum cholesterol achieved through a low saturated-fat diet and cessation of smoking. In the World Health Organization primary prevention trial, clofibrate reduced serum cholesterol by 9% and first clinical episodes of myocardial infarction by 20%. There was a 37% rise in total mortality, but no causal link with clofibrate has been found, and this was not significant when corrected for age at death. A secondary trial, the Coronary Drug Project, demonstrated that oestrogen and dextrothyroxine were clearly toxic. In this trial, niacin produced a 10% fall in serum cholesterol and mortality was 11% lower than in the placebo group after long-term follow-up. The Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT) found an 8% reduction in plasma cholesterol and a 19% reduction in the incidence of CHD in the group treated with cholestyramine compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

The Purity of Cholestyramine Resin-Reply

In Reply. — We are pleased to respond to the questions about Questran raised by Dr Goldstein by assuring him that (1) the cholestyramine resin used in the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) was not contaminated, (2) currently marketed Questran is free of contamination, and (3) although a temporal association between cholestyramine resin and certain tumors has been observed, a causal relationship has not been established after more than 20 years of commercial availability and several hundred thousand patient-years of therapy dispensed. The questions asked by Dr Goldstein appear to arise from the fact that, in April 1988, Bristol Laboratories initiated a recall because it determined that certain batches of bulk cholestyramine resin supplied by Rohm & Haas and used in the production of Questran contained very low levels of the agricultural chemicals dichlorodiphenyldichloroethylene and dichlorobenzophenone. These chemicals are related to the manufacture of a pesticide (dicofol)

Reduction in coronary heart disease: clinical and anatomical considerations.

Coronary artery bypass surgery, percutaneous transluminal coronary angioplasty and thrombolytic therapy in acute myocardial infarction have relieved symptoms, preserved myocardium, and prolonged life but have not modified the progression of atherosclerosis in the coronary arteries. In the last 10 years, however, progress has been made in establishing the cholesterol-atherogenesis hypothesis. Epidemiologic studies have demonstrated that the higher the total plasma cholesterol and low density lipoprotein cholesterol (LDL-C), the greater the risk that coronary artery disease will develop. Recently, clinical trials including the Coronary Drug Project, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), and the Helsinki Heart Study provided evidence that lowering cholesterol reduces the frequency of fatal and nonfatal coronary events. In addition, the National Heart, Lung, and Blood Institute (NHLBI) Type II Coronary Intervention Study and the Cholesterol Lowering Atherosclerosis Study demonstrated that lowering of cholesterol was associated with a decreased incidence of progression of coronary disease, as well as with the potential for reduction in the atherosclerotic plaque. Beneficial effects of diet and lifestyle changes also have an important effect on atherosclerosis. The impact of lowering cholesterol has been limited primarily by pharmacologic programs which lower cholesterol only 10-20% and are associated with a high incidence of intolerable side effects. With the recent introduction of the HmG co-A reductase inhibitors and their more profound effect on serum lipids, it may be possible to further promote plaque regression. The future of all these interventions, however, must still be assessed by overall mortality; studies to date have demonstrated beneficial effects on cardiovascular mortality but age-adjusted total mortality has remained unchanged. Future management of patients with acute and chronic coronary artery disease will involve a collaboration of cardiologists, endocrinologists, and epidemiologists to coordinate screening, recognition, and treatment of this disease.

A Prudent Approach to Control of Cholesterol Levels

Concern about serum cholesterol has become a national preoccupation. Recently, this pernicious substance has received even greater attention after announcement of the recommendations of the National Cholesterol Education Program. 1 This initiative represents the culmination of four decades of epidemiologic research that has demonstrated a nearly monotonic relationship between elevations of the serum cholesterol level and risk of atherosclerotic heart disease. Until recently, however, it was uncertain whether lowering of the serum cholesterol level would also lower cardiac risk. The results of the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) now confirm that in men with substantial elevations of plasma cholesterol levels, dietary and drug intervention can indeed reduce coronary morbidity and mortality. 2 The LRC-CPPT data, viewed as the linchpin in the cholesterol-coronary chain of evidence, have served as the catalyst for the National Cholesterol Education Program. The recommendations advise frequent screening of most adults and treatment of

Primary prevention of coronary heart disease by lowering lipids: Results and implications

Evidence to support the hypothesis that lowering total and low-density lipoprotein (LDL) cholesterol may reduce heart attacks and heart deaths has, until recently, not been available. Early primary prevention trials lacked definitive data on these “hard” end points. Since 1980, five primary prevention trials have attempted to demonstrate the benefit of lowering cholesterol. Three of these involved diet: the Osio Heart Trial and both the European and American Multiple Risk Factor Intervention Trials (MRFITs). Two involved lipid-lowering drugs: the European Clofibrate Primary Prevention Trial and the National Heart, Lung, and Blood Institute's recently concluded Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT). The Oiso Heart Trial suggested a benefit from the dietary reduction of cholesterol; results of the other studies of diet were equivocal. Although clofibrate did demonstrate a reduced incidence of heart attacks in the treated group, the cardiac mortality rate was not altered in this group. A significant increase in the all-cause mortality rate (other than ischemic heart disease) observed in this trial in treated subjects makes clofibrate difficult to recommend. The LRC-CPPT study, involving cholestyramine, has provided conclusive evidence concerning the benefits of lowering cholesterol: significant reductions were observed in all cardiovascular end points measured, including the development of angina and positive exercise stress tests, referral for bypass surgery, and the hard primary study end point heart attack and heart attack death.

Total Serum Cholesterol and Ischemic Heart Disease Risk in Clinical Trials and Observational Studies

Despite compelling evidence that elevated plasma total and low-density lipoprotein cholesterol plays a causal role in ischemic heart disease (IHD) (evidence derived from molecular biologic, genetic, animal experimental, and human observational studies), the results of individual clinical trials testing the lipid hypothesis have not been regarded as conclusive. Analyzed in aggregate, however, the trials results indicate a dose-response relationship between amount of cholesterol lowering and reduction of ischemic heart disease risk. This summary analysis predicted the quantitative measure of efficacy in the recently completed Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT). There was a quantitatively similar relationship between the amount of IHD risk reduction associated with amount of total plasma cholesterol reduction within the active drug (cholestyramine) treated group. Further, the risk function relating baseline level of total plasma cholesterol to ischemic heart disease incidence in community-based studies such as Framingham was so similar to the risk function of the LRC-CPPT placebo group that it accurately predicted the ischemic heart disease events in the trial. These findings in aggregate provide strong confirmation of the lipid hypothesis, indicate that lowering total plasma cholesterol in middle-aged hypercholesterolemic men will reduce ischemic heart disease risk, and suggest that some extrapolation of the results to lower levels of plasma cholesterol is appropriate. However, aggregate evidence that supports the lipid hypothesis should be distinguished from that required for intervention and treatment programs. Instituting the latter requires the review and evaluation of the evidence relating cholesterol levels and cholesterol reduction not only to ischemic heart disease, but also to other outcomes.(ABSTRACT TRUNCATED AT 250 WORDS)

The Lipid Research Clinics Coronary Primary Prevention Trial

To the Editor.— We would like to point out a discrepancy between the final report of the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) 1 and the report on the design and implementation of this trial. 2 In the article on planning, the following statements appear in Appendix D under the heading, Calculation of Sample Size: Since the time, magnitude, and cost of this study make it unlikely that it could ever be repeated, it was essential to be sure that any observed beneficial effect of cholesterol lowering was a real one. Therefore, alpha was set at 0.01 rather than the usual 0.05. However, when the results appear for the primary end points and all-cause mortality, they are reported in relation to a level of significance of.05. We are concerned by this apparent post-hoc relaxation of the α-level used to judge the statistical significance of the LRC-CPPT results. Despite

Commentary on the Published Results of the Lipid Research Clinics Coronary Primary Prevention Trial

THE LIPID Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) was a randomized double-blind clinical trial testing the efficacy of the cholesterollowering drug cholestyramine taken in conjunction with a cholesterol-lowering diet in reducing the risk of coronary heart disease (CHD) in asymptomatic middle-aged men with primary hypercholesterolemia. The CPPT trial results were described in detail in two recent articles inThe Journal.1,2The first article presented the results of the clinical trial itself, comparing the occurrence of cardiovascular disease in the two study groups: (1) cholestyramine plus diet and (2) placebo plus diet. The second article analyzed data from the two groups separately and within each group examined the relationship of lowering of levels of total cholesterol and of low-density lipoprotein-cholesterol (LDL-C) to the incidence of primary cardiovascular end points. The trial was well designed and superbly carried out. However, the reported conclusions seem to go beyond what is reasonably

Lipid Research Clinics Program

<h3>To the Editor.—</h3> The recent publication of the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) results¹inThe Journalwas met with considerable enthusiasm by the news media and the general public. Some misconceptions among these groups warrant a few basic clarifications for our patients. First, the LRC-CPPT cannot be used to support the still unproved notion that diet modification, by itself, has any statistically significant effect in prevention of coronary heart disease (CHD). The authors of the report themselves concede that, although other randomized trials of diet or drug therapy have shown trends toward lower incidence of CHD, "no single one of these studies is convincing." They further state that their own study "was not designed to assess directly whether cholesterol lowering by diet prevents CHD." The LRC-CPPT was a test of cholestyramine resin<i>v</i>placebo; both study groups followed the same diet. Second, the results of

Lipid Research Clinics Program

To the Editor.— The recent publication of the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) results 1 inThe Journalwas met with considerable enthusiasm by the news media and the general public. Some misconceptions among these groups warrant a few basic clarifications for our patients. First, the LRC-CPPT cannot be used to support the still unproved notion that diet modification, by itself, has any statistically significant effect in prevention of coronary heart disease (CHD). The authors of the report themselves concede that, although other randomized trials of diet or drug therapy have shown trends toward lower incidence of CHD, no single one of these studies is convincing. They further state that their own study not designed to assess directly whether cholesterol lowering by diet prevents CHD. The LRC-CPPT was a test of cholestyramine resin v placebo; both study groups followed the same diet. Second, the results of

Cholesterol and cardiovascular disease: An overview of lipid research clinics (LRC) epidemiologic studies as background for the LRC coronary primary prevention trial

The Lipid Research Clinics (LRC) Program has implemented an integrated series of observational epidemiologic, community-based studies that provide a frame of reference for the results of the LRC Coronary Primary Prevention Trial (CPPT). The observational studies were performed in 16 populations sampled in the United States, Canada, the Soviet Union and Israel. Findings based on data from more than 80,000 study participants indicate that atherogenic profiles of plasma total, low-density lipoprotein and high-density lipoprotein cholesterol levels are highly prevalent in middle-aged adults. The lipoprotein cholesterol fraction components are related to a wide range of demographic, behavioral, anthropometrie, medical status, drug utilization and hormonal factors, in addition to the well known major dietary and genetic determinants. The results of the LRC CPPT are directly applicable to high-risk, high total cholesterol, and high low-density lipoprotein cholesterol levels in middle-aged men. Considered jointly with the observational finding that the major burden of ischemic heart disease is associated with moderately elevated lipid levels, the LRC studies suggest that 2 concurrent approaches are necessary to achieve community control: approaches for high-risk person through individualized medical intervention and hygienic, population-oriented approaches toward achieving less atherogenic distributions of lipids and lipoproteins. With this combined approach, the current epidemic of ischemic heart disease can be controlled.