Research Clinics Coronary Primary Prevention Research Articles

Generalizing Clinical Trial Results to a Target Population

The external validity of the estimated treatment effect from a clinical trial is in doubt when there are effect modifiers whose distribution in the target population differs from that in the trial. Adjusting an estimated treatment effect from a trial to predict its likely value for the target population is a process known as generalization. We review classical and contemporary approaches to this problem. The traditional method is post-stratification, or the reweighting of stratum-specific treatment effect estimates by population distribution proportions. Contemporary methods employ stratification or weighting techniques based on estimates of the probability that an individual is included in the trial, akin to the propensity score. These methods are more flexible in that they readily accommodate continuous effect modifiers. Estimating the probabilities, however, requires in principle that one have individual-level population data, which are seldom available for pharmaceutical trials. When the effect modifiers are all discrete, the post-stratification and probability-weighting approaches give essentially the same estimates. Naïvely computed standard errors with the contemporary methods may be inflated. We illustrate and compare generalization methods in a simulation and using data from the Lipids Research Clinics Coronary Primary Prevention Trial and the New York School Choice Experiment.

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 …

High-capacity selective uptake of cholesteryl ester from native LDL during macrophage foam cell formation

Macrophage foam cells are a defining pathologic feature of atherosclerotic lesions. Recent studies have demonstrated that at high concentrations associated with hypercholesterolemia, native LDL induces macrophage lipid accumulation. LDL particles are taken up by macrophages as part of bulk fluid pinocytosis. However, the uptake and metabolism of cholesterol from native LDL during foam cell formation has not been clearly defined. Previous reports have suggested that selective cholesteryl ester (CE) uptake might contribute to cholesterol uptake from LDL independently of particle endocytosis. In this study we demonstrate that the majority of macrophage LDL-derived cholesterol is acquired by selective CE uptake in excess of LDL pinocytosis and degradation. Macrophage selective CE uptake does not saturate at high LDL concentrations and is not down-regulated during cholesterol accumulation. In contrast to CE uptake, macrophages exhibit little selective uptake of free cholesterol (FC) from LDL. Following selective uptake from LDL, CE is rapidly hydrolyzed by a novel chloroquine-sensitive pathway. FC released from LDL-derived CE hydrolysis is largely effluxed from cells but also is subject to ACAT-mediated reesterification. These results indicate that selective CE uptake plays a major role in macrophage metabolism of LDL.

Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study

The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile (P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not significantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a significant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add significant information about CHD risk. In addition, the cholesterol content in Lp(a) is not a significant predictor of CHD risk.

Lipoprotein(a) levels and long-term cardiovascular risk in the contemporary era of statin therapy

Lipoprotein(a) [Lp(a)] has enhanced atherothrombotic properties. The ability of Lp(a) levels to predict adverse cardiovascular outcomes in patients undergoing coronary angiography has not been examined. The relationship between serum Lp(a) levels and both the extent of angiographic disease and 3-year incidence of major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, and coronary revascularization) was investigated in 2,769 patients who underwent coronary angiography [median Lp(a) 16.4 mg/dl, elevated levels (≥30 mg/dl) in 38%]. An elevated Lp(a) was associated with a 2.3-fold [95% confidence interval (CI), 1.7-3.2, P < 0.001] greater likelihood of having a significant angiographic stenosis and 1.5-fold (95 CI, 1.3-1.7, P < 0.001) greater chance of three-vessel disease. Lp(a)≥30 mg/dl was associated with a greater rate of MACE (41.8 vs. 35.8%, P = 0.005), primarily due to a greater need for coronary revascularization (30.9 vs. 26.0%, P = 0.02). A relationship between Lp(a) levels and cardiovascular outcome was observed in patients with an LDL cholesterol (LDL-C) ≥70-100 mg/dl (P = 0.049) and >100 mg/dl (P = 0.02), but not <70 mg/dl (P = 0.77). Polymorphisms of Lp(a) were also associated with both plasma Lp(a) levels and coronary stenosis, but not a greater rate of MACE. Lp(a) levels correlate with the extent of obstructive disease and predict the need for coronary revascularization in subjects with suboptimal LDL-C control. This supports the need to intensify lipid management in patients with elevated Lp(a) levels.

Low-Density Lipoprotein Cholesterol Reduction and Prevention of Cardiovascular Disease

Low-Density Lipoprotein Cholesterol Reduction and Prevention of Cardiovascular Disease

The emerging role of high-density lipoprotein cholesterol in hypertension trials

Population Health Research Institute,McMaster University, Hamilton Health Sciences, Hamilton, CanadaCorrespondence to Fabio Angeli, MD, Department of Cardiology, ClinicalResearch Unit ‘Preventive Cardiology’, Hospital Santa Maria della Misericordia,06156 Perugia, ItalyTel: +39 075 5782213; fax: +39 075 5782214; e-mail: fangeli@cardionet.it

Apo[a] size and PNR explain African American-Caucasian differences in allele-specific apo[a] levels for small but not large apo[a

Apolipoprotein [a] (apo[a]) gene size is a major predictor of lipoprotein [a] level. To determine genetic predictors of allele-specific apo[a] levels beyond gene size, we evaluated the upstream C/T and pentanucleotide repeat (PNR) polymorphisms. We determined apo[a] sizes, allele-specific apo[a] levels, and C/T and PNR in 215 Caucasians and 139 African Americans. For Caucasians, apo[a] size affected allele-specific levels substantially greater in subjects with apo[a] < 24 K4; for African Americans, the size effect was smaller than in Caucasians, <24 K4, but did not decrease at higher repeats. In both groups, the level decreased with increasing size of the other allele. Controlling for apo[a] sizes, PNR decreased allele-specific apo[a] levels in Caucasians with increasing PNR > 8. In a multiple regression model, apo[a] allele size and size and expression of the other apo[a] allele (and PNR > 8 for Caucasians) significantly predicted allele-specific apo[a] levels. For a common PNR 8 allele, predicted values were similar in the two ethnicities for small size apo[a]. Allele-specific apo[a] levels were influenced by the other allele size and expression. Observed differences between Caucasians and African Americans in allele-specific apo[a] levels were explained for small apo[a] sizes by the other allele size and PNR; the ethnicity differences remain unexplained for larger sizes.

Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy, part IV: The 1984 Coronary Primary Prevention Trial ends it—almost

As of the early 1980s, despite the wealth of evidence from experimental animal models, the extensive epidemiologic evidence, the powerful genetic evidence, and the strongly suggestive clinical intervention trial results, most clinicians still remained unpersuaded regarding the relevance of the lipid hypothesis. What was needed was a well-designed, large-scale, long-term, double-blind study demonstrating a statistically significant impact of treatment on coronary heart disease events. The National Institutes of Health (NIH) had laid the groundwork for such a study as early as 1970, but the study was not completed and the results published until 1984. This study, the Coronary Primary Prevention Trial, showed that treatment with a bile acid binding resin reduced major coronary events in hypercholesterolemic men by 19%, with a P value of 0.05. The NIH followed this up with a national Consensus Development Conference on Lowering Blood Cholesterol to Prevent Heart Disease. For the first time, the NIH now went on record advocating screening for hypercholesterolemia and urging aggressive treatment for those at high risk. The Institute initiated a national cooperative program to that end, the National Cholesterol Education Program. For the first time, preventing coronary heart disease became a national public health goal.

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 Effect of Cholesterol Reduction With Cholestyramine on Renal Function

Epidemiological studies suggest that dyslipidemia is an independent risk factor for the development of renal insufficiency in otherwise healthy individuals. Yet, data on the effect of cholesterol reduction are lacking in this population. We performed a secondary analysis of a large existing cohort to determine whether treatment with cholestyramine improved renal function compared with placebo. A total of 3,603 middle-aged men from the Lipid Research Clinics Coronary Primary Prevention Trial comprised the study group: 1,806 men were randomly assigned to treatment with cholestyramine, and 1,797 men, placebo. The primary outcome is difference in glomerular filtration rates between the 2 groups. A total of 1,806 men were randomly assigned to treatment with cholestyramine, and 1,797 men, placebo. For the entire group, the estimated mean difference in glomerular filtration rates between the cholestyramine and placebo groups was 0.39 mL/min/1.73 m2 (0.007 mL/s/1.73 m2; P = 0.28) during a follow-up period of more than 8 years. Cholesterol reduction with cholestyramine treatment did not meaningfully affect renal function compared with placebo in the present analysis. Prospective intervention trials are needed to determine whether decreasing serum cholesterol levels benefits kidney function in otherwise healthy individuals.

Bile Acid Synthesis in Humans Has a Rapid Diurnal Variation That Is Asynchronous With Cholesterol Synthesis

The conversion of cholesterol to bile acids by the liver is an important regulator of body cholesterol homeostasis. In rodents, both cholesterol and bile acid synthesis have marked diurnal rhythms that peak synchronously at midnight. The aim of this study was to establish whether such diurnal rhythms are also present in healthy humans. Serum levels of the markers 7alpha-hydroxy-4-cholesten-3-one (C4) monitoring bile acid biosynthesis and lathosterol reflecting cholesterol synthesis were determined at 90-minute intervals in 8 human volunteers during standardized dietary conditions. Serum C4 showed 2 distinct peaks (2- to 4-fold above baseline) during a 24-hour period, the first at 1:00 pm and the second at 9:00 pm. During the night, C4 levels declined, and they returned to baseline levels the next morning. In contrast, serum lathosterol levels peaked at night, between midnight and 4:00 am. The diurnal changes of C4 were not synchronous with serum lipid changes or with the postprandial increase in serum bile acids and were maintained in cholecystectomized subjects. Bile acid synthesis in humans has a diurnal rhythm, with 2 peaks during the daytime, that is opposite from the circadian rhythm of cholesterol synthesis. This is completely different from the pattern in rodents and indicates the presence of an important species variation in the regulation of cholesterol homeostasis.

Thematic Review Series: The Immune System and Atherogenesis. Molecular mechanisms regulating monocyte recruitment in atherosclerosis

Cardiovascular disease, a progressive disorder characterized by the accumulation of lipids in the artery wall, is a leading cause of death in Western societies. One of the initial events in atherogenesis involves the recruitment of inflammatory cells from the circulation into the developing lesion. Studies during the past decade have underscored the role of inflammatory mediators in disease initiation and progression. Critical progress has been made in our understanding of the complex mechanisms by which monocytes, macrophages, and T-cells accumulate in atherosclerotic plaques. Experimental research has identified several candidate adhesion proteins and chemokines that are critically involved in the recruitment process, and encouraging data provide a mechanistic framework for new therapeutic targets. This review provides an overview of our current understanding of the mechanisms that direct the recruitment of monocytes to, and their retention in, atherosclerotic lesions.

Measurement Error in Covariates in the Marginal Hazards Model for Multivariate Failure Time Data

We consider measurement error in covariates in the marginal hazards model for multivariate failure time data. We explore the bias implications of normal additive measurement error without assuming a distribution for the underlying true covariate. To correct measurement-error-induced bias in the regression coefficient of the marginal model, we propose to apply the SIMEX procedure and demonstrate its large and small sample properties for both known and estimated measurement error variance. We illustrate this method using the Lipid Research Clinics Coronary Primary Prevention Trial data with total cholesterol as the covariate measured with error and time until angina and time until nonfatal myocardial infarction as the correlated outcomes of interest.

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.