LRC-CPPT and MRFIT Content Points: MRFIT confirmed results from one of the earlier primary-prevention trials, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT).20 The LRC-CPPT was a randomized, double-blind, placebo-controlled trial of diet plus cholestyramine vs diet and placebo in 3,806 asymptomatic men with type II hyperlipidemia. At seven year’s follow-up, there was a 19% total reduction in coronary events and a 24% reduction in CHD deaths. These two trials allowed epidemiologists to establish the clinical basis for reducing cholesterol to reduce overall event rates from coronary heart disease. The expected results of lipid-lowering efforts can be stated as follows: Each 1% reduction in total cholesterol is associated with a 3% reduction in CHD events.

4S results: Effects on lipids Content Points: Recently published results of three landmark clinical trials with HMG-CoA reductase inhibitors (statins) have provided nearly indisputable proof that aggressive lipid lowering can reduce cardiovascular and overall mortality. The next few slides briefly examine the lipid reductions seen in three important trials. This slide looks at the lipid reductions achieved in the Scandinavian Simvastatin Survival Study (4S).21 This was a secondary prevention trial reported in 1995, and involved 4,444 patients who had either angina or a previous MI, plus high cholesterol levels. After five years, substantial changes in lipid levels occurred with simvastatin therapy. Total cholesterol was reduced 25%, LDL-C by 35%, and triglycerides by 10%. HDL-C increased by 8%.

4S results: Effects on study outcomes Content Points: In the 4S trial, reduction in risk of total mortality was significantly reduced by 30%. This was largely attributable to a 42% reduction in the risk of CHD mortality. The risk of major coronary events was reduced by 34%.

WOSCOPS results: Effects on lipids Content Points: The second landmark statin trial was the West of Scotland Coronary Prevention Study (WOSCOPS), also published in 1995.22 This trial was a primary prevention study of cholesterol lowering in 6,595 high-risk, middle-aged men with no history of myocardial infarction. The therapeutic agent used was pravastatin. At study end, pravastatin lowered total cholesterol by 20% and LDL-C by 26%. Triglycerides were reduced by 12%, and there was a 5% increase in HDL-C.

WOSCOPS results: Effects on study outcomes Content Points: Statin therapy using pravastatin in the WOSCOPS trial was associated with a 31% decrease in recurrent coronary morbidity, and a 22% reduction in the overall risk of death. There was also a 33% reduction in risk of definite and suspected CHD death.

CARE results: Effects on lipids Content Points: The third statin trial was the Cholesterol and Recurrent Events (CARE) trial.23 This was also a secondary prevention trial, and it assessed the benefits of lowering cholesterol with pravastatin in 4,159 post-MI patients with total cholesterol levels less than 240 mg/dL. This study was significant because it studied patients with only average cholesterol levels, and in whom there was a history of coronary heart disease. Those individuals with CHD and cholesterol levels less than 240 mg/dL represent a large portion of the patient population. The following lipid changes were observed: Total cholesterol was reduced 20%. LDL-C was also reduced (28%), as were triglycerides (14%). HDL-C was increased 5%.

CARE results: Effect on study outcomes Content Points: A 24% reduction in the CARE study’s primary endpoint of CHD death or nonfatal MI was observed. There was also a 25% reduction in risk of fatal or nonfatal myocardial infarction, and a 27% reduction in need for coronary revascularization. It is interesting to note that in CARE, risk reduction was greatest (35%) for patients with baseline LDL-C levels greater than 150 mg/dL. The risk reduction was also significant (26%) in patients with baseline LDL-C concentrations of 125 to 150 mg/dL.

Clinical challenge in cardiovascular risk intervention management Content Points: How aggressively should you approach the task of lowering LDL-C in your patients? Or, is a moderate approach the prudent approach? The next few slides address these issues using data from trials looking at reducing the progression of atherosclerotic lesions in patients in the years following coronary artery bypass surgery.

Post-CABG: Impact of aggressive vs moderate approach to lowering LDL-C Content Points: This slide describes the trial design of a study to determine whether an aggressive rather than a moderate approach to reducing LDL-C is more effective in blunting the progression of atherosclerotic lesions in saphenous vein grafts (SVGs).24 The study sample included 1,351 participants who were one to 11 years post-CABG. Each of the men in the study had at least two patent SVGs, and each woman participant had at least one. The LDL-C levels were 130 to 175 mg/dL after being on a diet. Participants were randomized and blinded to the intensity of treatment which consisted of lovastatin at 40 to 80 mg/day plus or minus cholestyramine (2.5 to 5 g/day). The goal was to reach an aggressive target LDL-C of less than 85 mg/dL, and a moderate target LDL-C of 130 to 140 mg/dL.

Post-CABG: Impact of aggressive vs moderate approach to lowering LDL-C Content Points: The study outcomes were a mean per-patient percent of grafts with significant progression in SVG greater than a 0.6 mm change. The secondary endpoint was the occurrence of new occlusions and lesions plus lumen narrowing.

Post-CABG: Aggressive vs moderate LDL-C reduction Content Points: This slide examines the LDL-C reductions achieved with moderate and aggressive treatment strategies. The mean daily dose of lovastatin was 76 mg in the aggressively treated group, and 30% were prescribed 8 g of cholestyramine. The mean LDL-C during the study ranged from 93 to 96 mg/dL. In the moderately treated group the mean daily dose of lovastatin was 40 mg, and 5% of the patients were prescribed cholestyramine. The mean LDL-C was considerably higher, and ranged from 134 to 135 mg/dL during the study.

Post-CABG angiographic outcomes Content Points: In all study parameters, there was consistently greater benefit in the group of patients who were treated aggressively. Note the statistically significant reductions in the primary endpoint of substantial progression and in the secondary endpoints of new occlusions, new lesions, and changes in minimum and mean lumen diameter.

Post-CABG: Event rates by cholesterol group Content Points: This slide plots the event rates by cholesterol group. There was a 29% reduction in revascularization, PTCA, or CABG in the aggressively treated group. Note that there was no significant difference in the first 21⁄2 years, but that the curves progressively diverged in the last two years of the study.

Post-CABG study summary Content Points: The overall study conclusions are shown here. Aggressive treatment resulted in decreased rates of progression, new occlusions, new lesions, and decreases in mean lumen narrowing. In addition, as seen on the previous slide, revascularization rates were decreased by 29%. The primary conclusion is that by achieving a mean LDL-C of 95 mg/dL, there is greater benefit than if the patient carries a mean LDL-C of 135 mg/dL. This also supports the NCEP recommendations of a target LDL-C of less than 100 mg/dL in patients with coronary heart disease.