Body Mass Index and Risk for Mental Stress Induced Ischemia in Coronary Artery Disease.

Acute emotionally reactive mental stress (MS) can provoke prognostically relevant deficits in cardiac function and myocardial perfusion, and chronic inflammation increases risk for this ischemic phenomenon. We have described parasympathetic withdrawal and generation of inflammatory factors in MS. Adiposity is also associated with elevated markers of chronic inflammation. High body mass index (BMI) is frequently used as a surrogate for assessment of excess adiposity, and associated with traditional CAD risk factors, and CAD mortality. BMI is also associated with autonomic dysregulation, adipose tissue derived proinflammatory cytokines, which are also attendant to emotion provoked myocardial ischemia. Thus, we sought to determine if body mass index (BMI) contributes to risk of developing myocardial ischemia provoked by mental stress. We performed a prospective interventional study in a cohort of 161 patients with stable CAD. They completed an assessment of myocardial blood flow with single photon emission computed tomography (SPECT) simultaneously during 2 conditions: laboratory mental stress and at rest. Multivariate logistic regression determined the independent contribution of BMI to the occurrence of mental-stress induced ischemia. Mean age was 65.6 ±9.0 years; 87.0% had a history of hypertension, and 28.6% had diabetes. Mean BMI was 30.4 ± 4.7. Prevalence of mental stress ischemia was 39.8%. BMI was an independent predictor of mental stress ischemia, OR=1.10, 95% CI [1.01-1.18] for one-point increase in BMI and OR=1.53, 95% CI [1.06-2.21] for a 4.7 point increase in BMI (one standard deviation beyond the cohort BMI mean), p=0.025 for all. These data suggest that BMI may serve as an independent risk marker for mental stress ischemia. The factors attendant with greater BMI, which include autonomic dysregulation and inflammation, may represent pathways by which high BMI contribute to this risk and serve as a conceptual construct to replicate these findings in larger CAD populations.

Age-related macular degeneration and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: To determine whether age-related macular degeneration (AMD) is a risk indicator for coronary heart disease (CHD) and cardiovascular disease (CVD) events independent of other known risk factors in a multi-ethnic cohort. DESIGN: Population-based prospective cohort study. PARTICIPANTS: A diverse population sample of 6233 men and women aged 45 to 84 years without known CVD from the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: Participants in the MESA had retinal photographs taken between 2002 and 2003. Photographs were evaluated for AMD. Incident CHD and CVD events were ascertained during clinical follow-up visits for up to 8 years after the retinal images were taken. MAIN OUTCOME MEASURES: Incident CHD and CVD events. RESULTS: Of the 6814 persons at risk of CHD, there were 893 participants with early AMD (13.1%) and 27 patients (0.5%) at baseline. Over a mean follow-up period of 5.4 years, there was no statistically significant difference in incident CHD or CVD between the AMD and non-AMD groups (5.0% vs. 3.9%, P = 0.13 for CHD and 6.6% vs. 5.5%, P = 0.19 for CVD). In Cox regression models adjusting for CVD risk factors, there was no significant relationship between presence of any AMD and any CHD/CVD events (hazard ratio 0.99; 95% confidence interval, 0.74-1.33; P = 0.97). No significant association was found between subgroups of early AMD or late AMD and incident CHD/CVD events. CONCLUSIONS: In persons without a history of CVD, AMD was not associated with an increased risk of CHD or CVD.

Autonomic contribution to endothelin-1 increase during laboratory anger-recall stress in patients with coronary artery disease.

In coronary artery disease (CAD), endothelin-1 (ET-1) is released by activated macrophages and thereby contributes to coronary plaque rupture and triggered cardiac events. The multifactorial regulation of ET-1 includes stimulated release by cytokines and autonomic factors. Laboratory stress provokes alteration in autonomic tone and prolonged ET-1 mediated endothelial dysfunction. The objective of the study is to determine the autonomic contribution to an increase in ET-1 in response to laboratory stress in patients with CAD. Patients (n = 88) with chronic stable CAD instrumented with hemodynamic monitor, digital electrocardiogram (ECG) monitor and indwelling catheter for blood sampling completed a laboratory protocol that included initial rest (30 min), baseline (BL: 10 min), and anger recall stress (AR: 8 min). Change from BL to AR was determined for (a) parasympathetic activity (by spectral analysis of ECG); (b) sympathetic activity (by circulating catecholamines); and (c) ET-1. AR provoked increases from BL in catecholamines, and a decrease in parasympathetic activity. Multivariate analysis with change in parasympathetic activity and catecholamines, while controlling for age and use of ß-blockers, revealed a significant odds ratio (OR = 3.27, 95% CI 1.03, 10.41 P = 0.04) for an increase in ET-1 associated with parasympathetic withdrawal; no other variables were significant. The predominant influence of parasympathetic activity on anger/stress-provoked increase in ET-1 is consistent with the cholinergic antiinflammatory pathway. Future examination of autonomic influences on atherosclerotic leukocytes, endothelial cell function and the dynamics of ET-1 are warranted.

Depression predicts elevated endothelin-1 in patients with coronary artery disease.

OBJECTIVE: To examine the relationship of depression severity to circulating endothelin-1 (ET-1), which has previously been linked to plaque rupture and postacute coronary syndrome (ACS) survival. Depression carries an independent two- to four-fold increased risk of early morbidity and mortality after ACS. The pathway(s) linking depression to event-free survival remains to be determined. METHODS: Patients with documented history of coronary artery disease (n = 101) provided a resting morning blood sample that was assayed for ET-1, and they completed the Beck Depression Inventory (BDI). ET-1 was treated as a log-transformed continuous variable (logET-1), and as a dichotomous variable using a post-ACS risk threshold previously reported (≥1.16 fmol/mL). RESULTS: BDI score was related to logET-1 in both unadjusted and adjusted models. In addition, unadjusted and adjusted logistic regression models with dichotomous ET-1 revealed that, for each point increase in BDI score, there was approximately a 14% increased likelihood of being at or above ET-1 risk threshold. Secondary logistic regression models demonstrated a >3.5-fold likelihood of being at or above this risk threshold in association with a BDI score of ≥10. CONCLUSIONS: Depression symptom severity predicts ET-1 elevation that has previously been linked to post-ACS survival, with the greatest risk of elevation among those patients with worse depression symptoms. This link may identify a vulnerability to triggered ACS and poorer survival associated with depression. Future research should establish whether the observed relationship of depressive symptoms to ET-1 level mediates the link between depression and survival.

Common genetic variation in multiple metabolic pathways influences susceptibility to low HDL-cholesterol and coronary heart disease.

A low level of HDL-C is the most common plasma lipid abnormality observed in men with established coronary heart disease (CHD). To identify allelic variants associated with susceptibility to low HDL-C and CHD, we examined 60 candidate genes with key roles in HDL metabolism, insulin resistance, and inflammation using samples from the Veterans Affairs HDL Intervention Trial (VA-HIT; cases, n = 699) and the Framingham Offspring Study (FOS; controls, n = 705). VA-HIT was designed to examine the benefits of HDL-raising with gemfibrozil in men with low HDL-C (≤40 mg/dl) and established CHD. After adjustment for multiple testing within each gene, single-nucleotide polymorphisms (SNP) significantly associated with case status were identified in the genes encoding LIPC (rs4775065, P < 0.0001); CETP (rs5882, P = 0.0002); RXRA (rs11185660, P = 0.0021); ABCA1 (rs2249891, P = 0.0126); ABCC6 (rs150468, P = 0.0206; rs212077, P = 0.0443); CUBN (rs7893395, P = 0.0246); APOA2 (rs3813627, P = 0.0324); SELP (rs732314, P = 0.0376); and APOC4 (rs10413089, P = 0.0425). Included among the novel findings of this study are the identification of susceptibility alleles for low HDL-C/CHD risk in the genes encoding CUBN and RXRA, and the observation that genetic variation in SELP may influence CHD risk through its effects on HDL.

Tendency to angry rumination predicts stress-provoked endothelin-1 increase in patients with coronary artery disease.

OBJECTIVE: To determine whether a tendency to angry rumination predicts anger recall (AR) stress-provoked increase in endothelin (ET)-1 among patients with coronary heart disease (CHD). METHODS: Patients with chronic stable CHD (n = 105) completed a five-item measure of tendency to angry rumination (DAB-VR) and underwent a laboratory AR stress protocol (15-minute resting baseline [BL], 8-minute AR). Blood samples drawn at end of BL and AR were assayed for ET-1. Change in ET-1 from BL to AR (increase versus decrease/no change) was treated dichotomously in multivariate logistic regression models, including DAB-VR score and potential confounders, to evaluate the contribution of DAB-VR to the prediction of change in ET-1. RESULTS: In the multivariate model, DAB-VR score significantly predicted ET-1 increase (odds ratio, 1.34; 95% confidence interval, 1.10-1.1.63; p = .004), controlling for age, history of diabetes, hypercholesterolemia, rate pressure product, use of beta blockers, and statins. CONCLUSIONS: A tendency to angry rumination independently predicted AR stress-provoked ET-1 increase among patients with CHD. Given the involvement of ET-1 in plaque rupture, anger rumination tendency may identify vulnerability to anger-triggered acute coronary syndrome through prolongation of initial anger mobilization. The contribution of ruminative thinking to sustained poststress ET-1 elevation and the synergistic relationship of ET-1 during emotional stress with norepinephrine and nitric oxide remain to be explored.

Efficacy of gemfibrozil in the primary prevention of atrial fibrillation in a large randomized controlled trial.

BACKGROUND: Peroxisome proliferator-activated receptor alpha (PPARalpha) activators reduce inflammation and oxidative stress. Inflammation plays an important role in the initiation and maintenance of atrial fibrillation (AF). It has been suggested that PPARalpha activators may have antiarrhythmic properties, but no clinical data exist. The objective of this study was to investigate whether the PPARalpha activator gemfibrozil prevents or delays the development of AF in patients with coronary heart disease. METHODS: We retrospectively analyzed the electrocardiograms (ECGs) performed in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial, a multicenter, randomized, double-blinded, secondary prevention trial of gemfibrozil and matching placebo. The ECGs were performed annually or biannually and when clinically indicated. Participants who were in AF on baseline ECG were excluded from the present analysis. Relative risk for AF was calculated from Cox regression with death as a competing risk factor. RESULTS: A total of 12,605 ECGs from 2,130 participants were interpreted (5.9 +/- 2.1 ECGs per participant, range 2-20). At baseline, the gemfibrozil (n = 1,070) and placebo (n = 1,060) groups were well matched. Mean age was 64.1 +/- 7.1 years. Over 4.4 +/- 1.5 years of follow-up, 123 (5.8%) participants developed new AF. There was no difference in AF incidence between the gemfibrozil and placebo groups (64/1,070 vs 59/1,060, respectively; P = .33). In Cox regression, the risk of AF was similar between the 2 study groups (hazard ratio 1.04, 95% CI 0.73-1.49, P = .82). CONCLUSIONS: In this post hoc analysis of a multicenter, double-blinded, randomized controlled trial, the PPARalpha activator gemfibrozil did not reduce the 4-year incidence of AF among men with coronary heart disease.

Noninvasive detection of risk for emotion-provoked myocardial ischemia.

OBJECTIVES: To test an easily administered, noninvasive technology to identify vulnerability to mental stress ischemia. BACKGROUND: Myocardial ischemia provoked by emotional stress (MSI) in patients with stable coronary artery disease (CAD) predicts major adverse cardiac events. A clinically useful tool to risk stratify patients on this factor is not available. METHODS: Patients with documented CAD (n = 68) underwent single photon emission CT myocardial perfusion imaging concurrent with pulse wave amplitude assessment by peripheral arterial tonometry (PAT) during a mental stress protocol of sequential rest and anger stress periods. Heart rate and blood pressure were assessed, and blood was drawn for catecholamine assay, during rest and stress. MSI was defined by the presence of a new perfusion defect during anger stress (n = 26) and the ratio of stress to rest PAT response was calculated. RESULTS: Patients with MSI had a significantly lower PAT ratio than those without MSI (0.76 +/- 0.04 versus 0.91 +/- 0.05, p = .03). An ROC curve for optimum sensitivity/specificity of PAT ratio as an index of MSI produced a sensitivity of 0.62 and a specificity of 0.63. Among patients taking angiotensin converting enzyme (ACE) inhibitors, the sensitivity and specificity of the test increased to 0.86 and 0.73, respectively; 90% of patients without MSI were correctly identified. CONCLUSIONS: PAT in concert with ACE inhibition may provide a useful approach to assess risk for MSI. Future studies should help determine how best to utilize this approach for risk assessment in the clinical setting.

Cardiovascular events with increased lipoprotein-associated phospholipase A(2) and low high-density lipoprotein-cholesterol: the Veterans Affairs HDL Intervention Trial.

OBJECTIVE: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), a proinflammatory enzyme that predominantly circulates with low-density lipoprotein (LDL), has been shown in general populations to predict cardiovascular (CV) events. We sought to determine whether increased Lp-PLA(2) would also predict CV events in the absence of high LDL-cholesterol (LDL-C), in a population with low high-density lipoprotein-cholesterol (HDL-C). METHODS AND RESULTS: Plasma Lp-PLA(2) activity was measured at baseline and after 6 months on-trial in 1451 men with low HDL-C (mean, 32 mg/dL) and low LDL-C (mean 110 mg/dL), randomized to either placebo or gemfibrozil therapy in the Veterans Affairs HDL Intervention Trial (VA-HIT). Over a quartile range of increasing Lp-PLA(2) there was a significant increase in LDL-C and decrease in HDL-C (P < 0.0001), and an increased percentage of myocardial infarction (MI), stroke, or CHD death (P=0.03 for trend). In Cox models, adjusted for major CV risk factors, a 1-SD increase in Lp-PLA(2) was associated with a significant increase in CV events (hazard ratio [HR] 1.17 95% CI 1.04 to 1.32). Although gemfibrozil reduced Lp-PLA(2) only modestly (6.6%), at higher levels of Lp-PLA(2) gemfibrozil produced a significant reduction in CV events. CONCLUSIONS: In VA-HIT, a population with low HDL-C and LDL-C, high Lp-PLA(2) independently predicted CV events that were reduced by gemfibrozil.

Relation of gemfibrozil treatment and high-density lipoprotein subpopulation profile with cardiovascular events in the Veterans Affairs High-Density Lipoprotein Intervention Trial.

The significant cardiovascular disease (CVD) event reduction in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) could not be fully explained by the 6% increase in high-density lipoprotein (HDL) cholesterol with the fibrate gemfibrozil. We examined whether measurement of HDL subpopulations provided additional information relative to CVD risk reduction. The HDL subpopulations were characterized by 2-dimensional gel electrophoresis in subjects who were treated with gemfibrozil (n = 754) or placebo (n = 741). In this study, samples obtained at the 3-month visit were used; and data were analyzed prospectively using CVD events (coronary heart disease death, myocardial infarction, or stroke) during the 5.1 years of follow-up. Analyses in the gemfibrozil arm showed that subjects with recurrent CVD events had significantly higher prebeta-1 and had significantly lower alpha-1 and alpha-2 HDL levels than those without such events. Prebeta-1 level was a significant positive predictor; alpha-1 and alpha-2 levels were significant negative risk factors for future CVD events. alpha-2 level was superior to HDL cholesterol level in CVD-risk assessment after adjustment for established risk factors. Gemfibrozil treatment was associated with 3% to 6% decreases in the small, lipid-poor prebeta-1 HDL and in the large, lipid-rich alpha-1 and alpha-2 HDL and with increases in the small alpha-3 (3%) and prealpha-3 (16%) HDLs. Although the use of gemfibrozil has been associated with reduction in CVD events in VA-HIT, HDL subpopulation analysis indicates that gemfibrozil-mediated improvement in CVD risk might not be the result of its effects on HDL. It is quite possible that much of the cardiovascular benefits of gemfibrozil are due to a much wider spectrum of effects on metabolic processes that is not reflected by changes in blood lipids and HDL subpopulations.

Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial.

BACKGROUND: Changes in conventional lipid risk factors with gemfibrozil treatment only partially explain the reductions in coronary heart disease (CHD) events experienced by men in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). We examined whether measurement of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle subclasses provides additional information relative to CHD risk reduction. METHODS AND RESULTS: This is a prospective nested case-control study of 364 men with a new CHD event (nonfatal myocardial infarction or cardiac death) during a 5.1-year (median) follow-up and 697 age-matched controls. Nuclear magnetic resonance (NMR) spectroscopy was used to quantify levels of LDL and HDL particle subclasses and mean particle sizes in plasma obtained at baseline and after 7 months of treatment with gemfibrozil or placebo. Odds ratios for a 1-SD increment of each lipoprotein variable were calculated with adjusted logistic regression models. Gemfibrozil treatment increased LDL size and lowered numbers of LDL particles (-5%) while raising numbers of HDL particles (10%) and small HDL subclass particles (21%). Concentrations of these LDL and HDL particles achieved with gemfibrozil were significant, independent predictors of new CHD events. For total LDL and HDL particles, odds ratios predicting CHD benefit were 1.28 (95% CI, 1.12 to 1.47) and 0.71 (95% CI, 0.61 to 0.81), respectively. Mean LDL and HDL particle sizes were not associated with CHD events. CONCLUSIONS: The effects of gemfibrozil on NMR-measured LDL and HDL particle subclasses, which are not reflected by conventional lipoprotein cholesterol measures, help to explain the demonstrated benefit of this therapy in patients with low HDL cholesterol.

The L162V polymorphism at the peroxisome proliferator activated receptor alpha locus modulates the risk of cardiovascular events associated with insulin resistance and diabetes mellitus: the Veterans Affairs HDL Intervention Trial (VA-HIT).

BACKGROUND: The Veterans Affairs HDL Intervention Trial (VA-HIT) showed that gemfibrozil, which activates peroxisome proliferator-activator receptor alpha (PPARalpha), significantly reduced the risk of cardiovascular (CV) events in men with low HDL cholesterol (< 40 mg/dl) and established coronary heart disease. Treatment was particularly beneficial in those with insulin resistance (IR) or diabetes mellitus (DM). We hypothesized that the association between a functional polymorphism at the PPARA locus (L162V) and the risk of a CV event, as well as response to fibrate therapy, might be greatest in those with either IR or DM (DM/IR) in VA-HIT. METHODS AND RESULTS: A total of 827 men (placebo, n = 413; gemfibrozil, n = 414) from the VA-HIT were genotyped. This population included a high proportion of subjects with DM/IR. In VA-HIT, the PPARA V162 allele was associated with reduced levels of HDL cholesterol and the presence of DM/IR at baseline. It was also associated with reduced risk of CV events in those with DM/IR but not in those with neither (DM/IR *PPARA genotype, P = 0.005). Among subjects with DM/IR, treatment with gemfibrozil reduced CV events in non-carriers from 29.9 to 17.8% and carriers of the V162 allele from 14.7 to 4.8%. In contrast, carriers of the V162 allele with no DM/IR who were treated with gemfibrozil experienced significantly more CV events than did those who received placebo (20.6% versus 13.6%; P = 0.01). CONCLUSIONS: The effect of the L162V polymorphism at the PPARA locus on CV risk depends on the presence of DM/IR. Among subjects treated with gemfibrozil, the V162 allele was associated not only with reduced CV risk in subjects with DM/IR, but also with significantly increased CV risk in the absence of these traits, identifying this genetic variant as a potential marker for predicting which subjects may have a favorable response to fibrate therapy.

LpA-I, LpA-I:A-II HDL and CHD-risk: The Framingham Offspring Study and the Veterans Affairs HDL Intervention Trial.

OBJECTIVE: We tested the hypothesis that concentrations of LpA-I and/or LpA-I:A-II HDL subclasses are significantly associated with CHD prevalence and recurrent cardiovascular events. METHODS: LpA-I levels were determined by differential electroimmunoassay in male participants with (n = 169) and without CHD (n = 850) from the Framingham Offspring Study (FOS) and in male participants with CHD from the placebo arm of the Veterans Affairs HDL Intervention Trial (VA-HIT) (n = 741). Data were analyzed cross-sectionally (FOS) and prospectively (VA-HIT) and were adjusted for established lipid and non-lipid CHD risk factors. RESULTS: We observed slightly but significantly higher LpA-I levels in CHD cases compared to all or to HDL-C-matched controls and slightly but significantly higher LpA-I:A-II levels in CHD cases compared to HDL-C-matched controls it the FOS. Neither LpA-I nor LpA-I:A-II levels were significantly different between groups with and without recurrent cardiovascular events in the VA-HIT. No significant differences were observed in LpA-I and LpA-I:A-II levels in low HDL-C (< or = 40 mg/dl) subjects with CHD (VA-HIT, n = 711) and without CHD (FOS, n = 373). Plasma LpA-I concentration had a positive correlation with the large LpA-I HDL particle (alpha-1) but no correlation with the small LpA-I HDL particle (prebeta-1). LpA-I:A-II concentration had a positive correlation with the large (alpha-2) and an inverse correlation with the small (alpha-3) LpA-I:A-II HDL particles. CONCLUSION: Our data do not support the hypothesis that CHD prevalence (FOS) or recurrence of cardiovascular events (VA-HIT) are associated with significant reductions in the concentrations of LpA-I and/or LpA-I:A-II HDL subclasses.

Value of high-density lipoprotein (HDL) subpopulations in predicting recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial.

OBJECTIVE: To test the hypothesis whether determination of high-density lipoprotein (HDL) subpopulations provides more power to predict recurrent cardiovascular disease (CVD) events (nonfatal myocardial infarction, coronary heart disease death, and stroke) than traditional risk factors in the Veterans Affairs HDL Intervention Trial (VA-HIT). METHODS AND RESULTS: Apolipoprotein A-I (apoA-I)-containing HDL subpopulations were quantitatively determined by nondenaturing 2D gel electrophoresis. Hazard ratios of recurrent CVD events were calculated by comparing VA-HIT subjects with (n=398) and without (n=1097) such events. Subjects with new CVD events had significantly lower HDL-C, apoA-I, and large cholesterol-rich HDL particle (alpha-1, alpha-2, pre-alpha-1, and pre-alpha-2) levels, significantly higher triglyceride, and small poorly lipidated HDL particle (pre-beta-1 and alpha-3) levels than subjects without such events. Multivariate analyses indicated that alpha-1 and alpha-2 particle levels were significant negative risk factors, whereas alpha-3 level was a significant positive risk factor for new CVD events. Pre-beta-1 level was a significant risk factor for new CVD events only in univariate analysis. A forward selection model indicated that alpha-1 was the most significant risk factor for recurrent CVD events among HDL particles. CONCLUSIONS: An altered HDL subpopulation profile marked with low alpha-1 and alpha-2 levels and a high alpha-3 level in coronary heart disease patients indicated an elevated risk for new CVD events. Moreover, alpha-1 and alpha-2 levels were superior to HDL-C levels in risk assessment in patients with low HDL-C in VA-HIT.

Long term clinical trials: how much information do participants retain from the informed consent process?

Previous studies report mixed results about how much information study participants actually can read, understand and retain after completing the informed consent process; fewer studies have examined disparities in the retention and recall of information by patient factors, such as age, education, and race. Not retaining or being able to recall information from the informed consent process has potentially important ethical and legal implications and consequences for research quality and integrity, especially when found in populations that commonly are underserved or underrepresented in clinical trials. To determine how much basic knowledge participants finishing a five-year, multi-center, double-blinded randomized, placebo-controlled clinical trial had about the study, participants (n=1,789) were asked at their final follow-up visit three multiple-choice questions: (1) the study's purpose; (2) the name of the medication under investigation; (3) the main side effect of the medication. The associations between knowledge of these fundamental details and participant social and demographic factors were investigated. A majority of participants correctly recalled the study's purpose (64.7%) and medication (79.6%), but few correctly reported the main side effect (31.1%). In spite of relatively high recall for study purpose and medication, disparities by age, education and race exist. Increasing age was significantly associated with higher odds of incorrectly recalling both the study purpose and the name of the study medication. Likewise those with less than a high school education were more likely to incorrectly identify the study's purpose and the name of the study medication. Black and other non-white race or ethnic groups were more than two and a half times as likely to incorrectly identify the study's purpose. These findings suggest that even the most basic information may not be understood or retained by important subgroups of patients enrolled in clinical trials. Implementing effective strategies, such as additional time and effort for consent or repetition of study information, may be necessary in order to assure ethical and valid consent.

Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial.

OBJECTIVE: We have previously reported that genetic variation at the cholesteryl ester transfer protein (CETP) TaqIB locus is correlated with plasma lipid levels and coronary heart disease (CHD) risk in the Framingham Offspring Study (FOS). In FOS, the B2 allele was associated with increased levels of high density lipoprotein (HDL) cholesterol (HDL-C), decreased CETP activity, and reduced CHD risk for men having the B2B2 genotype. The present study was undertaken to further define the relationship between this polymorphism and CHD risk at the population level. METHODS AND RESULTS: We tested for associations between the CETP TaqIB genotype and plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in 852 men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to explore the potential benefits of raising HDL levels in men having established CHD with low HDL-C (< or =40 mg/dL) as their primary lipid abnormality. In VA-HIT, 13.9% of the men had the B2B2 genotype relative to 19.1% of the men in FOS (-27%, P<0.03), whereas more men in VA-HIT had the B1B1 genotype (15%, P<0.05). Similar to our finding in FOS, B2B2 men in VA-HIT had the highest mean level of HDL-C (32.6+/-4.8 mg/dL), followed by B1B2 men (32.0+/-5.3 mg/dL), and, last, by B1B1 men (30.9+/-4.9 mg/dL). Interestingly, B1B1 men, who had the least favorable plasma lipid profile at baseline, had the greatest triglyceride-lowering response to gemfibrozil (-34%, P=0.006). CETP TaqIB genotype was also associated with the risk of CHD end points in VA-HIT, with an adjusted risk ratio of 0.52 for B2B2 men (P=0.08). CONCLUSIONS: Our data demonstrate that in men with CHD and HDL deficiency, the CETP TaqI B2B2 genotype is (1) significantly reduced and (2) associated with higher levels of plasma HDL-C and lower CHD risk. Together with our earlier report, these results support the concept that increased HDL-C levels, resulting from reduced CETP activity, are associated with decreased CHD risk.

Cost-effectiveness of gemfibrozil for coronary heart disease patients with low levels of high-density lipoprotein cholesterol: the Department of Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial.

BACKGROUND: Although numerous clinical trials and economic analyses have established the efficacy and cost-effectiveness of lowering cholesterol for the prevention of coronary heart disease, there are few data on the role of raising high-density lipoprotein cholesterol (HDL-C) levels and lowering triglyceride levels. The US Department of Veterans Affairs (VA) Cooperative Studies Program HDL-C Intervention Trial (VA-HIT) was a multicenter, randomized trial of gemfibrozil, an agent that raised HDL-C levels and lowered triglyceride levels, yet had no effect on low-density lipoprotein cholesterol (LDL-C) levels. The study showed that gemfibrozil therapy significantly reduced major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in patients with coronary heart disease, low HDL-C levels, and low LDL-C levels. OBJECTIVE: To report the results of a cost-effectiveness study based on the results of the VA-HIT. METHODS: The cost per year of life gained with gemfibrozil therapy was calculated. Hazard functions were estimated, and the resulting probabilities were used in a Markov model simulation to estimate the effect of gemfibrozil on life expectancy and costs over a simulated lifetime. Sensitivity analyses were used to account for uncertainty. RESULTS: Using the prices of gemfibrozil that were negotiated by the VA, gemfibrozil was cost saving. Using drug prices found outside the VA, a quality-adjusted life-year saved by gemfibrozil therapy cost between $6300 and $17 100. CONCLUSIONS: Gemfibrozil reduces major cardiovascular events in male coronary heart disease patients with low levels of HDL-C and low levels of LDL-C and would result in cost saving at annual drug costs of $100 or less in 1998 dollars. Even at the higher drug prices represented by the average wholesale price in the United States, the cost of a life-year saved is well below the threshold that would be deemed cost-effective. To our knowledge, this is the first economic analysis based on clinical trial data to assess the cost-effectiveness of raising HDL-C levels and lowering triglyceride levels in a setting in which LDL-C levels were not lowered.

Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT).

BACKGROUND: Diabetes mellitus, impaired fasting glucose level, or insulin resistance are associated with increased risk of cardiovascular disease. OBJECTIVES: To determine the efficacy of gemfibrozil in subjects with varying levels of glucose tolerance or hyperinsulinemia and to examine the association between diabetes status and glucose and insulin levels and risk of cardiovascular outcomes. METHODS: Subgroup analyses from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial, a randomized controlled trial that enrolled 2531 men with coronary heart disease (CHD), a high-density lipoprotein cholesterol level of 40 mg/dL or less (/=271 pmol/L) was associated with a 31% increased risk of events (P =.03). Gemfibrozil was effective in persons with diabetes (risk reduction for composite end point, 32%; P =.004). The reduction in CHD death was 41% (HR, 0.59; 95% CI, 0.39-0.91; P =.02). Among individuals without diabetes, gemfibrozil was most efficacious for those in the highest fasting plasma insulin level quartile (risk reduction, 35%; P =.04). CONCLUSION: In men with CHD and a low high-density lipoprotein cholesterol level, gemfibrozil use was associated with a reduction in major cardiovascular events in persons with diabetes and in nondiabetic subjects with a high fasting plasma insulin level.

Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT).

OBJECTIVE: To assess the effect of insulin resistance and the benefit of the fibrate, gemfibrozil, on the incidence of major cardiovascular events in subjects with low HDL cholesterol and a broad range of triglyceride values who participated in the Veterans Affairs High Density Lipoprotein Intervention Trial (VA-HIT). RESEARCH DESIGN AND METHODS: This intention-to-treat analysis, specified as a secondary objective in VA-HIT, determined using Cox proportional hazards models the 5-year combined incidence of nonfatal myocardial infarction, coronary heart disease (CHD) death, or stroke in relation to the presence or absence of insulin resistance (defined by the highest tertile of the homeostasis model assessment of insulin resistance, HOMA-IR) in conjunction with lower and higher levels of HDL cholesterol and triglycerides. The study population consisted of 2,283 men with known coronary heart disease (CHD), treated with either placebo or gemfibrozil, who could be subdivided into groups with diabetes with or without insulin resistance, with no diabetes but insulin resistance, and with neither diabetes nor insulin resistance. RESULTS: With insulin resistance there was a significantly higher relative risk (RR) of a cardiovascular event both with diabetes (RR of 1.62 with 95% CI of 1.28-2.06) and without diabetes (RR of 1.43 with 95% CI of 1.03-1.98) than without insulin resistance. Throughout both lower and higher ranges of HDL cholesterol and triglycerides, the rate of new cardiovascular events and the reduction of events with gemfibrozil was greater in subjects with insulin resistance than without, despite the finding that an increase in HDL cholesterol and a decrease in triglycerides with gemfibrozil was less with insulin resistance than without insulin resistance. CONCLUSIONS: Results show that in VA-HIT the occurrence of a new cardiovascular event and the benefit of fibrate therapy was much less dependent on levels of HDL cholesterol or triglycerides than on the presence or absence of insulin resistance.

Effect of gemfibrozil on change in renal function in men with moderate chronic renal insufficiency and coronary disease.

BACKGROUND: Limited data suggest that low levels of serum high-density lipoprotein cholesterol (HDL-C) and high levels of triglyceride-rich lipoproteins may be associated with more rapid rates of kidney function loss in individuals with chronic renal insufficiency (CRI). Although fibric acid derivatives increase serum HDL-C levels and decrease triglyceride levels, their effects on renal function are largely unknown. We conducted this study to determine whether gemfibrozil reduced rates of renal function loss in people with moderate CRI. METHODS: This was a post hoc subgroup analysis in the Veterans Affairs High-Density Lipoprotein Intervention Trial, a randomized double-blind trial of gemfibrozil versus placebo in 2,531 men with coronary disease, HDL-C levels of 40 mg/dL or less (< or =1.0 mmol/L), low-density lipoprotein cholesterol levels of 140 mg/dL or less (< or =3.6 mmol/L), and a range of triglyceride values. Moderate CRI is defined as estimated glomerular filtration rate (GFR) of 30 to 59.9 mL/min/1.73 m2 at baseline. Multivariate regression was used to calculate rates of decline in estimated GFR for individuals administered gemfibrozil or placebo, controlling for prospectively determined potential confounders. RESULTS: Change in renal function could be calculated in 1,981 individuals, of whom 399 individuals (20.2%) were eligible for inclusion. Among 399 study subjects, the rate of change in renal function in the gemfibrozil group during a median of 61 months was not significantly different from that in the placebo group (0.49 mL/min/1.73 m2/y faster; 95% confidence interval, 0.09 slower to 1.09 faster; P = 0.10). No clinically relevant effect of gemfibrozil on renal function was observed in groups defined by baseline lipid levels, kidney function, diabetic status, or other components of the metabolic syndrome. The incidence of transient (10% versus 4%; P = 0.01), but not sustained (9% versus 4%; P = 0.07), increases in serum creatinine levels of 0.5 mg/dL or greater (> or =44 micromol/L) was significantly greater in the gemfibrozil group. However, in 5 subjects with acute increases in serum creatinine levels, serum creatine kinase levels were significantly elevated as well, suggesting that myocyte toxicity may have been responsible. Even when these individuals were excluded, no clinically significant effect of gemfibrozil on kidney function was observed. CONCLUSION: Gemfibrozil does not appear to exert a clinically relevant effect on rates of kidney function loss in individuals with moderate CRI, low HDL-C levels, and concomitant coronary disease.