Edwin J. Whitney

Relation Between Baseline and On-Treatment Lipid Parameters and First Acute Major Coronary Events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)

BACKGROUND The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is the first primary-prevention study in a cohort with average total cholesterol (TC) and LDL cholesterol (LDL-C) and below-average HDL cholesterol (HDL-C). Treatment with lovastatin (20 to 40 mg/d) resulted in a 25% reduction in LDL-C and a 6% increase in HDL-C, as well as a 37% reduction in risk for first acute major coronary event (AMCE), defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. This article describes the relation between baseline and on-treatment lipid and apolipoprotein (apo) parameters and subsequent risk for AMCEs. METHODS AND RESULTS With all available data from the entire 6605-patient cohort, a prespecified Cox backward stepwise regression model identified outcome predictors, and logistic regression models examined the relation between lipid variables and AMCE risk. Baseline LDL-C, HDL-C, and apoB were significant predictors of AMCE; only on-treatment apoB and the ratio of apoB to apoAI were predictive of subsequent risk; on-treatment LDL-C was not. When event rates were examined across tertiles of baseline lipids, a consistent benefit of treatment with lovastatin was observed. CONCLUSIONS Persons with average TC and LDL-C levels and below-average HDL-C may obtain significant clinical benefit from primary-prevention lipid modification. On-treatment apoB, especially when combined with apoAI to form the apoB/AI ratio, may be a more accurate predictor than LDL-C of risk for first AMCE.

A Randomized Trial of a Strategy for Increasing High-Density Lipoprotein Cholesterol Levels: Effects on Progression of Coronary Heart Disease and Clinical Events

Context Most trials that address lipid management focus on reducing low-density lipoprotein (LDL) cholesterol levels rather than increasing high-density lipoprotein (HDL) cholesterol levels. Contribution In this double-blind trial, 143 military retirees with low HDL cholesterol levels and coronary artery disease were randomly assigned to placebo or aggressive HDL cholesterolincreasing therapy with gemfibrozil, niacin, and cholestyramine for 30 months. All participants received diet and exercise counseling. Compared with the placebo group, the treated group had a 20% decrease in total cholesterol level; a 36% increase in HDL cholesterol level; less focal coronary stenosis; fewer total cardiovascular events; and more flushing, skin rashes, and abdominal symptoms. Cautions The small trial had limited ability to assess clinical outcomes. The Editors Large epidemiologic studies have repeatedly demonstrated that cardiovascular risk increases proportionally with increasing total cholesterol and low-density lipoprotein (LDL) cholesterol levels and decreasing high-density lipoprotein (HDL) cholesterol levels (1, 2). Although many studies have documented that statins, drugs that primarily reduce LDL cholesterol levels, significantly reduce the risk for cardiovascular events (3-7), prospective studies that examine the clinical effects of increasing HDL cholesterol levels have been more limited. The Coronary Drug Project first reported evidence of a mortality benefit in patients treated with niacin; however, the difference was seen long after withdrawal of the study drug, making the mechanism of benefit less clear (8). The Helsinki Heart Study (9) examined the use of gemfibrozil in primary prevention. Coronary events were reduced by 34%, but the increase in HDL cholesterol level was modest (only 11%). The Bezafibrate Infarction Prevention Trial failed to show a reduction in cardiovascular events in the composite population, although a recent reanalysis of the data suggests an improved outcome in patients experiencing a greater increase in HDL cholesterol level (10). The Veterans Affairs HDL Intervention Trial (VA-HIT) (11) demonstrated a modest reduction in coronary events when gemfibrozil was used in patients with normal levels of LDL cholesterol and low levels of HDL cholesterol. The authors ascribed most of the reduction in clinical events to the improvement in HDL cholesterol, although the overall improvement was only approximately 6% with drug therapy. More recently, a combination of a statin (simvastatin) with niacin was found to favorably modify both HDL cholesterol and LDL cholesterol levels and reduce cardiovascular events compared with both placebo therapy and underlying treatment with antioxidants in a cohort of 160 patients with coronary disease (12). Despite a significant increase in mean HDL cholesterol levels, the overwhelming treatment effect in this study was the reduction in LDL cholesterol level (42% in the treatment group). The most suggestive evidence of benefit from an increase in HDL cholesterol level has come from trials assessing the effect on coronary stenosis. Trials of quantitative angiography after monotherapy with fibrates (13), as well as combinations of medications that both reduce LDL cholesterol levels and increase HDL cholesterol levels (14-18), have shown an attenuation in angiographic progression. Nissen and colleagues (19) recently took this theory a step further by demonstrating that an infusion of a recombinant form of HDL, apolipoprotein A-I Milano, can lead to regression of angiographic stenosis as assessed by intravascular ultrasonography. We undertook the Armed Forces Regression Study (AFREGS) in 1993 to determine whether coronary atherosclerosis, assessed by quantitative coronary angiography and clinical coronary events, would improve when combination drug therapy focused on increasing HDL cholesterol levels in a sample of patients with fairly normal LDL cholesterol levels and low HDL cholesterol levels. A pilot study by Whitney and colleagues (20) showed the feasibility of this trial design, and the safety of using these drugs in combination has been previously established (21). Methods Patients Participants living within a 150-mile radius of Wilford Hall Medical Center in San Antonio, Texas, who could provide written informed consent were eligible for enrollment. We recruited men and women younger than 76 years of age who had established or suspected coronary artery disease (positive results on an exercise treadmill test or classic angina) and did not have unstable symptoms. We allowed LDL cholesterol levels up to 4.1 mmol/L (160 mg/dL) with HDL cholesterol levels less than 1.0 mmol/L (40 mg/dL) after adherence to the American Heart Association (AHA) step II diet for at least 6 months. We set no lower limit to either HDL cholesterol or LDL cholesterol level. Each patient was required to have measurable stenosis between 30% and 80% of the luminal diameter within the coronary tree by caliper inspection. Patients with stenosis greater than 80% were eligible if they had a favorable prognosis based on functional testing (ability to exercise for >9 minutes on a full Bruce protocol exercise treadmill test). Exclusions included a major vascular event (myocardial infarction, cerebrovascular accident, coronary artery bypass grafting, or other coronary catheterbased intervention) within 6 months, a history of congestive heart failure (other than in the setting of myocardial infarction), or a left ventricular ejection fraction less than 0.4 on ventriculography. Other exclusion criteria included alcohol or substance abuse within the past year, uncontrolled arrhythmias, resistant hypertension, diabetes, uncontrolled gout, uncontrolled thyroid disease, liver or gall bladder disease, renal dysfunction (creatinine concentration > 176.8 mol/L [>2.0 mg/dL] or proteinuria greater than 2+ by dipstick or 500 mg/24 h), uncontrolled peptic ulcer disease, or pancreatic disorders. In addition, we excluded patients taking any lipid-modifying medications within 4 weeks of randomization, heparin or coumarin-type anticoagulants, long-term oral corticosteroid therapy, or other immunosuppressive agents. We also excluded patients if they had hypersensitivity to or history of intolerance that required cessation of therapy for any component of gemfibrozil, nicotinic acid, cholestyramine, aspirin, or nitrates. Other exclusion criteria were the potential for childbearing, technically inadequate coronary arteriography for stenosis quantification, or any serious condition that we thought would compromise participation in the study or preclude survival for the duration of the study. We thoroughly informed participants of the details of the study. Each patient voluntarily enrolled and signed an informed consent statement that the Wilford Hall Medical Center Institutional Review Board reviewed and approved. From screening laboratory records, we identified 1290 participant candidates and invited them to participate (Figure 1). Of the 847 patients who attended the introductory briefing, 671 met LDL cholesterol and HDL cholesterol entry criteria on fasting lipid analysis. Of the 269 participants who eventually provided informed consent, 55 subsequently withdrew for personal reasons, most commonly citing a fear of cardiac catheterization, and an additional 27 met an exclusion criterion. Of the 187 participants who completed the 6-month lifestyle modification phase and underwent coronary angiography, 44 were excluded after initial coronary arteriography; 27 had extensive coronary disease necessitating revascularization (percutaneous coronary intervention in 3 patients and coronary artery bypass grafting in 24 patients), and 17 had insignificant coronary disease on angiography. Thus, we eventually randomly assigned 143 patients (11% of those initially contacted) to either pharmacologic therapy or placebo. Figure 1. Flow of patients through the study. Protocol After inclusion and exclusion criteria were met, a 6- to 8-month run-in period was performed to ensure that patients could adhere to the prescribed diet. During this phase, all patients received diet counseling from a study dietitian, exercise guidance from an exercise specialist, and smoking cessation advice. All study participants committed to attending a bimonthly food show for training in the AHA step II diet, with reinforcing presentations from the dietitian, exercise specialist, and cardiologist that discussed cardiac risk factor modification. We randomly assigned each participant by using a computer-generated randomization schedule. The central pharmacy held the code, and the information was not shared with physicians or patients until the completion of the protocol. Patients were randomly assigned to 1 of 2 treatment groups: pharmacologic therapy with gemfibrozil, niacin, and cholestyramine or conventional therapy. The goal of therapy was to increase HDL cholesterol level by at least 25%. The study was double-blind and placebo-controlled. The pharmaceutical company prepared all medications and placebos, and the central pharmacy dispensed them at 30-day intervals. The pharmacologic therapy group began receiving gemfibrozil, 600 mg twice per day. Short-acting niacin was added in the third month at a dosage of 250 mg/d and was titrated to 3000 mg/d as tolerated. Cholestyramine was added in the sixth month, and the dosage was titrated to 16 g/d as tolerated. The conventional therapy group was maintained on the AHA step II diet and applicable matching placebos for the duration of the investigation. If LDL cholesterol levels exceeded 4.14 mmol/L (160 mg/dL) during the trial, cholestyramine was administered in an open-label fashion. Participants visited 1 clinic on a monthly basis for the duration of the study. At each monthly visit, clinicians measured vital signs and weight, counted unused study drugs, reviewed changes in medications or medical status, provided ne

Air force/texas coronary atherosclerosis prevention study (afcaps/texcaps): Additional perspectives on tolerability of long-term treatment with lovastatin

This study presents the long-term safety data from AFCAPS/TexCAPS, the first primary prevention trial to demonstrate that men and women with average levels of low-density lipoprotein cholesterol (LDL-C) and below average levels of high-density lipoprotein cholesterol (HDL-C) can significantly benefit from long-term treatment to lower LDL-C; lovastatin 20 to 40 mg/day reduced the risk of a first acute major coronary event (fatal or nonfatal myocardial infarction, unstable angina, or sudden death) by 37% (p = 0.00008). This double-blind randomized, placebo-controlled trial, in 6,605 generally healthy middle-aged and older men and women, had prespecified end point and cancer analyses. All analyses were intention-to-treat. Safety monitoring included history, physical examination, and laboratory studies (including hepatic transaminases and creatine phosphokinase [CPK]). All participants, even those who discontinued treatment, were contacted annually for vital status, cardiovascular events, and cancer history. After an average of 5.2 years of follow-up, there were 157 deaths (80 receiving lovastatin and 77 receiving placebo; relative risk [RR] 1.04; 95% confidence interval [CI] 0.76 to 1.42; p = 0.82); of which 115 were noncardiovascular (RR 1.21; CI 0.84 to 1.74; p = 0.31), and of these, 82 were due to cancer (RR 1.41; CI 0.91 to 2.19; p = 0.13). There were no significant differences between treatment groups in overall cancer rates, discontinuations for noncardiovascular adverse experiences, or clinically important elevations of hepatic transaminases or CPK. Among those who used cytochrome P450 isoform (CYP3A4) inhibitors, there were no treatment group differences in the frequency of clinically important muscle-related adverse events. Treatment with lovastatin 20 to 40 mg daily for primary prevention of coronary heart disease was well tolerated and reduced the risk of first acute coronary events without increasing the risk of either noncardiovascular mortality or cancer.

Design & Rationale of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)

The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is a randomized, double-blind, placebo-controlled primary prevention trial. It is designed to test the hypothesis that in addition to a lipid-lowering diet, treatment with lovastatin is more effective than placebo in reducing acute major coronary events (i.e., sudden cardiac death, fatal and nonfatal myocardial infarction, and unstable angina) in a cohort with normal to mildly elevated total (180 to 264 mg/dl) and low-density lipoprotein (LDL) cholesterol (130 to 190 mg/dl) and low high-density lipoprotein (HDL) cholesterol (< or =45 mg/dl for men and < or =47 mg/dl for women). Two sites in Texas, Lackland Air Force Base in San Antonio and the University of North Texas Health Science Center in Fort Worth, will conduct the study. After at least 12 weeks of an American Heart Association Step 1 diet and 2 weeks placebo run-in, 6,605 men and women, ages 45 to 73 and 55 to 73 years, respectively, without clinical evidence of coronary heart disease, are randomized in equal numbers to either lovastatin (20 mg/day) or placebo. Study procedures maintain the blind, allowing titration of lovastatin from 20 to 40 mg/day to achieve an LDL cholesterol goal of < or = 110 mg/dl. All participants are followed until study completion, when 320 participants have had a primary end point or a minimum of 5 years after the last participant is randomized, whichever occurs last. All end points are adjudicated by an independent committee using prespecified criteria. Unique features of this trial are (1) the inclusion of unstable angina in the primary end point to reflect the increasing trend to treat coronary heart disease aggressively before a myocardial infarction has occurred, (2) aggressive pharmacologic intervention, with titration, to attain an LDL cholesterol goal less than the current National Cholesterol Education Panel guidelines for primary prevention, and (3) a cohort that includes women, the elderly, and those with mild to moderate hyperlipidemia and low HDL cholesterol. Compared with earlier studies, results will be applicable to a broader population and may help clarify the role of aggressive LDL cholesterol reduction measures in primary prevention. Treatment of this population is likely to realize the greatest cumulative long-term benefit in the prevention of acute major coronary events.

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.

Effect of lovastatin on cardiovascular resource utilization and costs in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) ☆

This cost-consequences analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study compares the costs of lovastatin treatment with the costs of cardiovascular hospitalizations and procedures. The cost of lovastatin treatment was defined as the average retail price and the cost of drug safety monitoring and adverse experiences. Costs were determined by actual rates of hospitalizations and procedures. Within a trial, lovastatin treatment cost approximately

Air force/Texas Coronary Atherosclerosis Prevention study (AFCAPS/TexCAPS): Baseline Characteristics and comparison with USA population

4,654/patient. Lovastatin treatment significantly reduced the cumulative rate of cardiovascular hospitalizations and procedures (p = 0.002). Over the duration of the study, the cumulative number of cardiovascular hospitalizations and related therapeutic procedures was significantly reduced by 29%. The time to first cardiovascular-related hospitalization or procedure was significantly extended by lovastatin (p = 0.002). Lovastatin reduced the frequency of cardiovascular hospitalization (28%), and cardiovascular therapeutic (32%) and diagnostic procedures (23%). Among therapeutic procedures, treatment reduced coronary artery bypass graft surgery by 19% and percutaneous transluminal coronary angioplasty by 37%. Total cardiovascular-related hospital days were reduced by 26% (p = 0.025). The between-group offset in direct medical costs was

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

524, which resulted in a 11% cost offset of lovastatin therapy over the mean study duration of 5.2 years. Lovastatin provides meaningful reductions in cardiovascular-related resource utilization and reductions in direct cardiovascular-related costs associated with the onset of coronary disease.

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

Background Results of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonstrated that treatment with lovastatin, in addition to modifications of diet and lifestyle, reduced the rate of first acute major coronary events compared with placebo in a cohort that included participants with average to mildly elevated total levels of cholesterol, and below average levels of high-density lipoprotein cholesterol, women, and elderly subjects. Objective To describe the baseline characteristics of the studys cohort. Design This was a double-blind, placebo-controlled, primary-prevention trial in which Americans with average to mildly elevated total levels of cholesterol [4.65–6.83 mmol/l (180–264 mg/dl)] and no clinical evidence of atherosclerotic cardiovascular disease were randomly allocated either 20–40 mg/day lovastatin or placebo in addition to a low-saturated fat, low-cholesterol diet. Baseline characteristics of the study cohort are described, and the characteristics of a USA reference population based upon NHANES III data are provided for comparison. Results The study includes 5608 men (85%) and 997 women (15%) with mean total cholesterol level 5.71 ± 0.54 mmol/l (221 ± 21 mg/dl), low-density lipoprotein cholesterol level 3.88 ± 0.44 mmol/l (150 ± 17 mg/dl), high-density lipoprotein cholesterol 0.96 ± 0.15 mmol/l (37 ± 6 mg/dl), and median triglyceride level 1.78 ± 0.86 mmol/l (158 ± 76 mg/dl). The mean age is 58 years (ranges 45–73 years for men and 55–73 years for women). The participants are 89% white, 7% Hispanic, and 3% black. Conclusion Results from AFCAPS/TexCAPS will be applicable to large segments of populations; in the USA alone, eight million share the demographic and baseline-lipid-level characteristics of the study cohort.

Impact of Increases in High-Density Lipoprotein Cholesterol on Cardiovascular Outcomes During 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.