A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events.

BACKGROUND: The high-density lipoprotein (HDL) cholesterol level is a strong predictor of cardiovascular events in epidemiologic studies. Until recently, it has been less extensively studied as a therapeutic target. OBJECTIVE: To assess the angiographic and clinical effects of a pharmacologic strategy to increase HDL cholesterol levels. DESIGN: Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1996. SETTING: Outpatient specialty clinic of a large U.S. military medical center. PARTICIPANTS: 143 military retirees younger than 76 years of age with low HDL cholesterol levels and angiographically evident coronary disease. INTERVENTION: Gemfibrozil, niacin, and cholestyramine or corresponding placebos, with aggressive dietary and lifestyle intervention at baseline. MEASUREMENTS: Change from baseline to 30 months and a composite measure of clinical events that included hospitalization for angina, myocardial infarction, transient ischemic attack and stroke, death, and cardiovascular procedures. RESULTS: At baseline, mean (+/-SD) lipid values were as follows: total cholesterol, 5.1 +/- 0.8 mmol/L (196 +/- 31 mg/dL); low-density lipoprotein (LDL) cholesterol, 3.3 +/- 0.7 mmol/L (128 +/- 27 mg/dL); and HDL cholesterol, 0.9 +/- 0.2 mmol/L (34 +/- 6 mg/dL). Compared with placebo, the pharmacologically treated group experienced a 20% (95% CI, 14.8% to 24.3%) decrease in total cholesterol level, a 36% (CI, 28.4% to 43.5%) increase in HDL cholesterol level, a 26% (CI, 19.1% to 33.7%) decrease in LDL cholesterol level, and a 50% (CI, 40.5% to 59.2%) reduction in triglyceride levels. Focal coronary stenosis increased by 1.4% in the placebo group but decreased by 0.8% in the drug group (difference, -2.2 percentage points [CI, -4.2 to -0.1 percentage points]). A composite cardiovascular event end point was reached in 26% of patients in the placebo group and 13% of those in the drug group (difference, 13.7 percentage points [CI, 0.9 to 26.5 percentage points]). Side effects, particularly flushing and gastrointestinal intolerance, were more common in the drug group but rarely led to withdrawal from the study. LIMITATIONS: The study was small and used a composite clinical outcome. Whether improvements in angiographic findings were due to reductions in LDL cholesterol or increases in HDL cholesterol was not established. Flushing may have led to inadvertent unblinding in patients who were randomly assigned to active study drugs. CONCLUSIONS: A combination regimen aimed at increasing HDL cholesterol levels improves cholesterol profiles, helps prevent angiographic progression of coronary stenosis, and may prevent cardiovascular events in some people who exercise regularly and eat low-fat diets.

The effect of gemfibrozil, niacin and cholestyramine combination therapy on metabolic syndrome in the Armed Forces Regression Study.

INTRODUCTION: Metabolic syndrome is a powerful predictor of cardiovascular events independent of overt diabetes. Dietary restriction and weight loss modify metabolic syndrome components. This study addresses whether combination pharmacologic therapy focused on dyslipidemia provides additional benefit. METHODS: This study examines the effect of 1 year of gemfibrozil, niacin and cholestyramine therapy on a baseline of aggressive dietary and lifestyle intervention in 143 clinically stable, nondiabetic patients with coronary disease, randomized into a double-blind, placebo-controlled trial. RESULTS: Cohort characteristics included age 63 ± 7 years, 92% men, 43% with previous myocardial infarction, systolic blood pressure 139 ± 17 mm Hg, triglycerides 168 ± 81 mg/dL and high-density lipoprotein cholesterol 34 ± 6 mg/dL. The mean number of metabolic syndrome components decreased from 2.2 ± 0.9 to 1.5 ± 1.1, P < 0.001, and metabolic syndrome prevalence decreased from 38% to 18% (P < 0.001) for the entire cohort. In the lifestyle intervention and placebo group, the mean number of metabolic syndrome components decreased from 2.2 ± 0.9 to 1.9 ± 1.1 (P = 0.01), and prevalence of metabolic syndrome decreased from 44% to 30% (P = 0.15). A far more marked change was observed with lifestyle intervention and pharmacologic therapy: abnormal metabolic components decreased from 2.2 ± 0.9 to 1.0 ± 1.0 (P < 0.001), and prevalence of metabolic syndrome decreased from 32% to 6% (P < 0.001). CONCLUSIONS: The combination of gemfibrozil, niacin and cholestyramine has profound, beneficial effects on the components of metabolic syndrome. These benefits are additive to those seen with aggressive diet and lifestyle modification.

Impact of increases in high-density lipoprotein cholesterol on cardiovascular outcomes during the armed forces regression study.

INTRODUCTION: high-density lipoprotein (HDL) cholesterol is a well-established inverse risk factor for cardiovascular disease. The extent to which cardiovascular risk can be modified through changes in HDL, however, is less clear. We further examined the role of aggressive HDL raising therapy on cardiovascular outcomes in the 143 patients enrolled in the Armed Forces Regression Study (AFREGS). METHODS: reanalysis of the AFREGS population. Patients with stable coronary disease were randomized to receive gemfibrozil, niacin, and cholestyramine in combination or matching placebos, on top of aggressive dietary and exercise modification for a 30-month period. Blood work was performed at baseline and repeated after 1 year of therapy. RESULTS: patients were divided into 3 groups based on their therapeutic response: no HDL increase, mild HDL increase, and large HDL increase (% change in HDL ≤ 0, ≤ the lower 2 tertiles of HDL increase, and > the upper tertile of HDL increase, respectively). A progressive decrease in cardiovascular events was noted across these groups (30.4%, 19.4%, and 3.2%, respectively, P = .01). Kaplan-Meier analysis according to percentage change in HDL demonstrated a similar improvement in event-free survival (P = .01). Proportional hazards modeling also demonstrated that increasing HDL predicted a lower hazard of cardiovascular events, even after adjusting for changes in low-density lipoprotein ([LDL] P < .01). For every 1% increase in HDL achieved, a 2% decrease in events was recognized. CONCLUSIONS: these data suggest that in a population of patients with stable atherosclerosis, the greater the percentage increase in HDL achieved, the greater the cardioprotective benefit. This further supports HDL raising as a beneficial therapeutic strategy.

Impact of fibrinogen levels on angiographic progression and 12-year survival in the armed forces regression study.

We assessed the role of fibrinogen levels on angiographic progression and long-term survival among 111 patients with coronary disease enrolled in the Armed Forces Regression Study (AFREGS). Baseline fibrinogen levels and quantitative coronary angiography were performed initially and at 30 months. Progression or nonregression of coronary disease was more prevalent in patients with high fibrinogen than patients with normal fibrinogen (66.1% vs 45.5%; P = .022). Twelve-year cardiovascular (CV) mortality was substantially higher if fibrinogen was elevated (17.9% vs 3.6%, P = .016). Among patients with elevated fibrinogen and angiographic progression or nonregression, there were 10 deaths and all were CV. Elevated levels of fibrinogen predict the angiographic progression of existing coronary disease and likelihood of CV death. Among patients with elevated levels of fibrinogen, angiographic progression identifies a significantly increased likelihood of a fatal CV event.

Effects of combination lipid therapy on coronary stenosis progression and clinical cardiovascular events in coronary disease patients with metabolic syndrome: a combined analysis of the Familial Atherosclerosis Treatment Study (FATS), the HDL-Atherosclerosis Treatment Study (HATS), and the Armed Forces Regression Study (AFREGS).

We examined the impact of metabolic syndrome (MS) on coronary stenosis progression and major cardiovascular (CV) events and investigated the mitigating effects of low-density lipoprotein (LDL) cholesterol lowering and LDL cholesterol lowering plus high-density lipoprotein (HDL) cholesterol increasing. This analysis combined individual patient data from 445 subjects who participated in 3 double-blinded, randomized, placebo-controlled trials (FATS, HATS, and AFREGS) comparing intensive lipid therapy to placebos on coronary stenosis progression by quantitative coronary angiography and on major CV events. The primary end points were change in mean proximal coronary diameter stenosis (Delta%S(prox)) over 3 years and the frequency of the predefined composite of coronary artery disease death, nonfatal myocardial infarction, stroke, and revascularization due to worsening ischemia. Patients with MS had 50% more rapid coronary stenosis progression and 64% increased CV event frequency compared to those without. More rapid coronary stenosis progression was significantly and independently associated with a 3.5-fold increased event risk (p <0.001). Combination lipid therapy significantly decreased stenosis progression by 83% (Delta%S(prox) 0.5 vs 2.9, p <0.001) in patients with MS and induced a small net regression in those without (Delta%S(prox) -0.3 vs 2.0, p <0.001). Combination therapy decreased the event rate by 54% (13% vs 28%, p = 0.03) in those with MS and by 82% (3% vs 17%, p = 0.002) without. On average, each 10% decrease in LDL cholesterol or 10% increase in HDL cholesterol was significantly associated with a 0.3 Delta%S(prox) decrease. Each 10% decrease in LDL cholesterol or 10% increase in HDL cholesterol was associated with 11% (p = 0.02) or 22% (p <0.001) event risk decrease. In conclusion, patients with MS have significantly more rapid coronary stenosis progression and a higher frequency of CV events. Greater stenosis progression rate is associated with a higher event rate. LDL cholesterol-lowering and HDL cholesterol-increasing therapies independently and significantly decrease coronary stenosis progression and decrease CV events.