Clinics Coronary Primary Prevention Trial Research Articles

Adjusting for adherence in randomized trials when adherence is measured as a continuous variable: An application to the Lipid Research Clinics Coronary Primary Prevention Trial.

Clinicians and patients may be more interested in per-protocol effect estimates than intention-to-treat effect estimates from randomized trials. However, per-protocol effect estimates may be biased due to insufficient adjustment for prognostic factors that predict adherence. Adjustment for this bias is possible when appropriate methods, such as inverse probability weighting, are used. But, when adherence is measured as a continuous variable, constructing these weights can be challenging. In the placebo arm of the Lipid Research Clinics Coronary Primary Prevention Trial, we estimated the 7-year cumulative incidence of coronary heart disease under 100% adherence and 0% adherence to placebo. We used dose-response discrete-hazards models with inverse probability weighting to adjust for pre- and post-randomization covariates. We considered several continuous distributions for constructing the inverse probability weights. The risk difference estimate for 100% adherence compared with 0% adherence ranged from -7.7 to -6.1 percentage points without adjustment for baseline and post-baseline covariates, and ranged from -1.8 to 2.2 percentage points with adjustment using inverse probability weights, depending on the dose-response model and inverse probability weight distribution used. Methods which appropriately adjust for time-varying post-randomization variables can explain away much of the bias in the "effect" of adherence to placebo. When considering continuous adherence, investigators should consider several models as estimates may be sensitive to the model chosen.

Who Resembles a Scientific Leader-Jack or Jill? How Implicit Bias Could Influence Research Grant Funding.

When women advance in medicine, so does women’s health. In cardiology, women have led major research studies examining and confirming sex differences in cardiovascular disease risk factors, manifestations, and outcomes, providing essential data for evidence-based approaches to women’s heart health. The inclusion of women in cardiovascular research studies paralleled the entry of women physicians into cardiology. When women were absent as principal investigators, women were also missing from the tens of thousands of participants in the early cardiovascular prevention trials, including the Coronary Drug Project, Physicians Health Study, Lipid Research Clinics Coronary Primary Prevention Trial, and Multiple Risk Factors Intervention Trial (so-called MR FIT). Given the association between women entering cardiology and research in women’s heart health, it is worrisome that women comprise <20% of cardiologists (the lowest percentage among internal medicine subspecialties).1 Furthermore, although female cardiologists are more likely than their male peers to practice in academic settings where most research is conducted (43% versus 34%), they are less likely in these settings to be involved in research2 or achieve the rank of full professor,1 and more likely to report lower levels of career attainment.2 Because conducting research as an independent investigator is …

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...

Prevention Conference VI: Diabetes and Cardiovascular Disease: executive summary: conference proceeding for healthcare professionals from a special writing group of the American Heart Association.

The American Heart Association (AHA) sponsored a scientific conference entitled “Prevention VI: Diabetes and Cardiovascular Disease” on January 18 to 20, 2001, in Orlando, Fla. The purpose of this conference was to create a report that would assist the AHA in the development of an agenda to reduce cardiovascular diseases (CVDs) that are associated with diabetes. The report has been developed by working group sections. The topics to be covered by each working group were introduced by a series of presentations, and this was followed by an extensive discussion of a team of working group members. The primary objectives of this meeting were as follows: The key findings of each working group are presented in this Executive Summary of the conference. The full conference report with references is available online at http://www.circulationaha.org in the May 7, 2002, issue of Circulation . The prevalence of diabetes in the United States is increasing rapidly, and individuals with diabetes are at high risk for cardiovascular disorders that affect the heart, brain, and peripheral vessels. Although CVD accompanying diabetes is on the rise, many unanswered questions remain concerning the temporal relations between diabetes and CVD, the contributions of conventional risk factors, and the role of diabetes-specific risk factors. Almost 35 million Americans—20% …

Why some patients respond poorly to statins and how this might be remedied.

The advent of the statins, competitive inhibitors of HMG CoA reductase and thus of cholesterol synthesis, has revolutionized the treatment and prevention of coronary heart disease. The reduction in coronary heart disease events in dyslipidaemic subjects largely reflects the extent to which these drugs lower LDL cholesterol, although additional mechanisms have been proposed in normolipidaemic individuals. A meta-analysis of the five major statin trials showed an overall reduction in LDL cholesterol of 28%, which resulted in a 31% decrease in coronary heart disease events. The latter value is 10% less than expected from the decrease in LDL cholesterol that occurred, judging from the Proportional Hazards analysis of the Lipid Research Clinics Coronary Primary Prevention Trial (CPPT) where cholestyramine was used to lower LDL. This discrepancy may reflect differences in design and duration between the CPPT and statin trials but does not support the notion that statins reduce coronary heart disease events by actions (‘pleiotropic effects’) which are additional to their LDL-lowering properties. Hence any factors which adversely affect the latter would be expected to diminish the benefits of statin therapy in the prevention of coronary heart disease, at least in hypercholesterolaemic subjects.

Cost-Effectiveness Analysis for Statin Therapies in the Primary Prevention of Coronary Heart Disease in Italy

The objective of this analysis was to compare the costs, benefits and cost effectiveness of two dosage regimens of cerivastatin (0.2 and 0.4 mg/day) with Italian National Health Service (NHS) reimbursed comparative statins in the primary prevention of coronary heart disease in Italy. This study is part of a broader analysis undertaken in five European countries. A cost-effectiveness analysis (CEA) was performed, as the interventions have the same treatment objectives but vary in terms of magnitude of effectiveness. This CEA compared alternative treatments both in the NHS and from societal perspectives. A coronary heart disease risk assessment model, based on intervention study data from the Lipid Research Clinics Coronary Primary Prevention Trial, was used. This was augmented with demographic, disease, life expectancy, pharmacological and economic data for patients with coronary heart disease in Italy. In terms of average cost effectiveness, our analysis showed that cerivastatin 0.2 mg/day compared favourably with pravastatin 20 mg/day, and compared similarly with simvastatin 20 mg/day in all age groups studied. The study also demonstrated that cerivastatin 0.4 mg/day compared favourably with both simvastatin 40 mg/day and pravastatin 20 mg/day. These results were consistent for both the NHS and societal perspective.The incremental cost per life-year gained [in 1998 Italian lire (L)] of simvastatin versus cerivastatin ranged from about L40 million [or Euro (Eur)20 658] to greater than L650 million (or Eur335 697). Cerivastatin 0.2 mg/day was more cost-effective than pravastatin 20 mg/day, while the incremental cost per life-year gained for cerivastatin 0.4 mg/day versus pravastatin 20 mg/day ranged from L11.1 million (or Eur5733) to L31.8 million (or Eur16 423) in the three age groups (35 to 39 years, 50 to 54 years and 65 to 69 years) for both perspectives. The results of this study showed that in primary prevention, average cost-effectiveness ratios of cerivastatin compared favourably with those of the other pharmacological interventions available on the Italian market.

Do triglycerides provide meaningful information about heart disease risk?

Prior research suggests that adding triglyceride determinations to measurements of total cholesterol and cholesterol subfractions may improve the prediction of coronary heart disease (CHD). To determine the additional value of measuring triglyceride levels, in addition to cholesterol levels and subfractions, for predicting CHD. A set of secondary analyses of previously reported studies. We performed secondary analyses of data from the Multiple Risk Factor Intervention Trial, the Lipid Research Clinics Coronary Primary Prevention Trial, and the Lipid Research Clinics Prevalence and Mortality Follow-Up Study. Predictor variables included the levels of fasting triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and fasting blood glucose; age; blood pressure; cigarette smoking; body mass index; and postmenopausal estrogen use. Analytic methods included Cox proportional hazards models, calculation of stratified crude incidence rates, and measurement of the area under the receiver operating characteristic curve. Outcome variables were fatal and nonfatal myocardial infarctions. With few exceptions, no significant interactions between cholesterol subfractions and triglyceride levels were found and receiver operating characteristic curve analyses revealed that triglyceride measurements did not improve discrimination between those subjects who did and did not suffer CHD events. In men, categorical analyses employing both triglyceride and cholesterol levels were similar to those using cholesterol categories alone. In the one study of women, those subjects with both a high-risk cholesterol profile and high triglyceride levels were more likely to have a CHD event, though this finding was based on fewer subjects and CHD events. These data suggest that, in men, measurement of serum triglyceride levels does not provide clinically meaningful information about CHD risk beyond that obtainable by measurement of serum cholesterol subfractions alone.

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.

Cholesterol and coronary heart disease: Predicting risks in men by changes in levels and ratios: Bruce Kinosian, Henry Glick, Liliana Preiss, Katherine L. Puder. University of Pennsylvania, Philadelphia, PA; Columbia University, New York, NY; Sandoz Pharmaceuticals, East Hanover, NJ. J Investig Med 1995;43:443–50

Little is known about the relative ability of different measures of change in cholesterol to discriminate coronary heart disease risk. We evaluated this ability for changes in low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, LDL/HDL ratios, and total cholesterol/HDL ratios.We predicted risks of coronary heart disease using data from 3641 men in the Lipid Research Clinics Coronary Primary Prevention Trial. Treating these patients as a cohort, we estimated risks associated with changes in cholesterol levels independent of the patients' randomization group.Changes in LDL and HDL cholesterol when used in combination were each significant predictors of coronary heart disease risk (odds ratios [OR] for 10% increases, 1.15 and 0.84, respectively; P < 0.001). Changes in LDL/HDL and total cholesterol/HDL ratios had similar discriminating ability (OR for 10% increases, 1.17 and 1.21, respectively; P < 0.0001). In the best discriminating models, changes in ratios added information about risks to changes in LDL cholesterol, although changes in LDL cholesterol levels failed to add information to changes in ratios.Changes in total cholesterol/HDL and LDL/HDL ratios were better predictors of risk for coronary heart disease than were changes in LDL cholesterol levels alone. When assessed as percentage changes averaged during the first two months of intervention, they were among the best discriminators of risk. Clinicians selecting treatments for intervention should include among their considerations the treatment's effect on both LDL and HDL cholesterol rather than their effects on LDL cholesterol levels alone.

Triglyceride concentration and coronary heart disease

EDITOR,—We wish to respond to two letters concerning our paper.1 2 Despite the intuitive appeal of lowering triglyceride concentrations along with cholesterol concentrations when both are raised, there is no evidence that this strategy is more effective than targeting treatment at cholesterol alone. Even treatments that raise triglyceride concentrations reduce the risk of coronary heart disease in hypercholesterolaemic subjects. In the Lipid Research Clinics coronary primary prevention trial, treatment with diet and cholestyramine resulted in a 19% reduction in the risk of coronary …

Cost-effectiveness of medical nutrition therapy by registered dietitians for patients with hypercholesterolemia

COST-EFFECTIVENESS OF MEDICAL NUTRITION THERAPY BY REGISTERED DIETITIANS FOR PATIENTS WITH HYPERCHOLESTEROLEMIA. KLM. McGehee, RD, E.Q. Johnson, MS, RD, H.M. Rasmussen, MS, RD, N.R. Sahyoun, MS, RD, M.M. Lynch, MS, RD, R. Lobosco, RD, M. Carey, PhD, RD, J. Folkman, MS, RD, L. Gallagher, RD, N. Braunstein, MS, RD, J. Dwyer, DSc, RD, Massachusetts Dietetics Association, Plainville, MA. The Massachusetts Dietetic Association (MDA) implemented a state-wide retrospective quality assurance audit to determine the cost-effectiveness of medical nutrition therapy in patients with hypercholesterolemia (>200mg/dL). It is well established that hypercholesterolemia is a significant risk factor for coronary artery disease (CAD). Twenty-three sites across the state collected the data on 285 out-patients seen by a registered dietitian (RD) for a minimum of 2 visits. Patients on lipid lowering medications were excluded from the study. Of the 285 patients, 108 (38%) were male and 177 (62%) were female. The mean age was 51.4 years old (range=22-79). Results showed the average reduction in serum cholesterol was 9.0%, translating to an approximate 18% decrease in risk of CAD. ' Reduction in serum cholesterol levels correlated with increased time spent with the RD (r=0.188, p<0.001). The average cost per year for nutrition intervention with an RD was $163.00 for a mean of 3.9 visits (median=3.0). Yet an estimated annual cost for patients with hypercholesterolemia on drug therapy is $1450.00. According to the Surgeon General's Report (1988),the cost of treating heart disease in the United States is calculated to be $136 billion. Nutrition therapy should be considered the initial, cost-effective approach in medical management of patients with mild to moderate hypercholesterolernia . 'The Lipid Research Clinics Program. The lipid research clinics coronary primary prevention trial results: IL The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251:365-74.

Lipoprotein(a) levels and risk of coronary heart disease in men. The lipid Research Clinics Coronary Primary Prevention Trial

Lipoprotein(a) levels and risk of coronary heart disease in men. The lipid Research Clinics Coronary Primary Prevention Trial

Long-term benefit of cholesterol reduction

Source Citation Lipid Research Clinics Investigators. The Lipid Research Clinics Coronary Primary Prevention Trial. Results of 6 years of post-trial follow-up. Arch Intern Med. 1992 Jul;152:1399-410.

The Lipid Research Clinics Coronary Primary Prevention Trial. Results of 6 years of post-trial follow-up. The Lipid Research Clinics Investigators

Participants in the Lipid Research Clinics Coronary Primary Prevention Trial, a randomized, cholesterol-lowering trial comparing cholestyramine (N = 1907) vs placebo (N = 1899) treatment in 35- and 59-year-old asymptomatic hypercholesterolemic men, conducted between 1973 and 1983, were followed up annually from 1985 until 1989. Post-trial treatment was not provided. Eleven predefined hypotheses pertaining to possible benefits and adverse effects of in-trial cholestyramine treatment were tested by standard statistical comparisons of the two original Coronary Primary Prevention Trial treatment groups (cholestyramine and placebo). Similar increasing proportions of cholestyramine and placebo used cholesterol-lowering drugs post-trial. After 13.4 years of in-trial plus post-trial follow-up, there were 13 (143 vs 156) fewer deaths in the cholestyramine group than in the placebo group. Although not statistically significant, the mortality hazard ratio (0.89) was similar to that in other cholesterol-lowering trials. This trend, a result of reduced coronary heart disease mortality, occurred despite a post-trial narrowing of the in-trial cholestyramine-placebo difference in coronary heart disease incidence from 32 (155 vs 187) to 16 (268 vs 284). The cholestyramine and placebo groups had similar 13.4-year mortality rates from cancer, other medical causes, and trauma and similar cancer incidence rates. However, 13.4-year incidences of benign colorectal tumors (50 vs 34), cancer of the buccal cavity and pharynx (eight vs two), gallbladder disease (68 vs 53), and gallbladder surgery (58 vs 40) were nonsignificantly increased in the cholestyramine group. Overall, 6 years of post-Coronary Primary Prevention Trial follow-up have not provided conclusive evidence of benefit or long-term toxicity of cholestyramine treatment beyond that evident at the cessation of the trial.

The Lipid Research Clinics Coronary Primary Prevention Trial

Plasma levels ofhigh-density lipoprotein cholesterol (HDL-C) atentryandsubsequent changes fromthese baseline levels were inversely predictive ofcoronaryheart disease (CHD)end points inhypercholesterolemic men followed for7to10yearsintheLipid Research Clinics Coronary Primary Prevention Trial, especially inthe1907participants receiving cholestyramine. Whenthe men inthis cohort were compared, each1mg/dl increment inbaseline HDL-C(mean44.3mg/dl) was associated with a 5.5%decrement inrisk CHD death ormyocardial infarction (Z= - 5.4), andeach1mg/dl increase frombaseline HDL-Clevels (mean increase = 1.6mg/dl) during the trial wasassociated with a4.4%risk reduction (Z= -2.2). Inthe1899participants receiving placebo, thecorresponding risk decrements were3.4%and1.1%.Although baseline HDL-Clevel (mean = 44.4mg/dl) remained asignificant risk predictor (Z= -3.8)intheplacebo cohort, increases inHDL- C(mean increase 0.5mg/dl) werenotsignificantly predictive ofCHD(Z= -0.6) unless suspect as well asdefinite endpoints were analyzed (Z= - 2.0). Whentheassociations between HDL-C (baseline pluschange) andincidence ofdefinite CHD endpoints within eachtreatment cohort were compared, their difference approached nominal significance (Z= 1.9).Theresults suggest asynergis- ticinteraction, inwhichcholestyramine treatment reduced CHDrisk mostsubstantially inmen main- taining thehighest HDL-Clevels. Circulation 74,No.6,1217-1225, 1986

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.

Using provisional diagnoses in monitoring a clinical trial

In clinical trials there is delay between the occurrence of an event and the recording of that event as an end point in the trial data base. Delays are especially likely if events are reviewed carefully to determine whether diagnostic criteria for end points are satisfied. As a result, the value of a statistic used to evaluate efficacy during a trial may differ from the value of that statistic based on the true end point status of all events which have already occurred. Simulating the process causing delays can be useful in evaluating interim efficacy data by providing a quantitative estimate of the uncertainty in a monitoring statistic. These ideas are illustrated using data from the Lipid Research Clinics Coronary Primary Prevention Trial.

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.