Aggressive Lowering of Cholesterol: An Increasingly Positive Story

ABSTRACT & COMMENTARY

Synoposis: Aggressive reduction of LDL-C (below 100 mg/dL) significantly reduced regression of graft atherosclerosis.

Source: The Post Coronary Artery Bypass Graft Trial Investigators. N Engl J Med 1997;336:153-162.
Saphenous vein grafts are well known to become obstructive over time, with occlusion rates of 30-50% by 10-12 years after CABG. The two dominant causes for graft disease are believed to be lipid deposition and progressive atherosclerosis within the grafts and thrombosis developing within the grafts themselves. The Post Coronary Artery Bypass Graft Trial investigators sought to establish whether aggressive cholesterol lowering, low-dose warfarin, or both could effect graft status and patency after 4-5 years of therapy.

They chose a relatively low-risk population who were stable and who had had CABG 1-11 years before entry. Subjects with a high LDL cholesterol (130-175 mg/dL) and triglycerides less than 300 mg/dL on a step 1 AHA diet were eligible. Male candidates had to have at least two patent vein grafts with no stenosis greater than 75%, and women were required to have one patent graft. Major exclusion criteria included unstable angina or MI within six months, low EF, likelihood of revascularization or death within five years, severe angina, or heart failure.

The study design was two-by-two factorial, resulting in four groups: aggressive cholesterol lowering, aiming for a target LDL cholesterol (LDL-C) of 60-85 mg/dL vs. moderate lowering (target of 130-140 mg/dL); or low-dose anticoagulation to maintain an INR less than 2.0 vs. placebo.

Baseline coronary and bypass graft angiograms were obtained with follow-up angiograms 4-5 years after enrollment, unless there was an interval study based on clinical grounds. Of 2300 patients screened, 1351 were initially enrolled; the primary angiographic analysis included 1192 patients with paired angiograms and 64 patients who died.

Study drugs included lovastatin, begun at 40 mg daily in the aggressive arm, increasing to 80 mg daily with the addition of cholestyramine if LDL-C did not fall below 95 mg/dL. In the moderate cholesterol-lowering cohort, lovastatin was started at 2.5 mg per day, increasing to 5 mg per day with or without cholestyramine, to reach a target LDL less than 130 mg/dL. Warfarin or placebo were given in 1 mg increments, increasing to 4 mg so long as the INR was below 2.0.

Quantitative angiography was performed and graded for five categories of stenosis severity. The primary end point of the study was a per-patient percentage of initially patent major grafts that developed substantial progression of atherosclerosis at the site of greatest change at follow-up. An intention-to-treat analysis was used. A composite clinical outcome was assessed using major cardiovascular end points, including myocardial infarction, stroke, or revascularization.

The four patient groups were comparable with respect to risk factors, medications, and lipid levels. More than 90% of the patients were male and white, with a mean age of 61.5 years. The mean baseline total cholesterol was 224-229 mg/dL, and mean LDL-C was 154-157 mg/dL, for the four groups.

Results

The mean follow-up was 4.3 years; 5% of the patients died, 78% had a scheduled second angiogram, and 10% had an angiogram because of symptoms before the study was completed.Lipid lowering was extremely effective. In the aggressive cohort, the total dose of lovastatin was almost 80 mg, with one-third also taking 8 g of choles tyramine per day. In the moderate-treatment group, a mean of 4 mg of lovastatin was used.

The LDL-C achieved by year 1 was 93 mg/dL in the aggressive-treatment subjects and 136 mg/dL in the moderate group; 66% of the aggressive group had a LDL below 100 mg/dL, whereas 60% of the moderate-treatment group were above 130 mg/dL. The mean LDL-C difference between the two groups was 40 mg/dL. The percentage decrease from baseline for aggressive therapy approached 40% and was 13-15% in the moderate-treatment group.

Warfarin Treatment: There was no effect of warfarin on graft status compared to placebo.

Lovastatin Therapy: 27% of individuals in the aggressive-treatment group reached the primary end point vs. 39% of the moderate-treatment group (P < 0.001). The number of graft occlusions or new lesions was significantly lower with aggressive vs. moderate LDL lowering; improvement in graft status was not noted (no regression). Combined clinical outcomes showed no difference between the two lipid-lowering groups, although there was a 29% lower rate of revascularization in the aggressive cohort (P = 0.03).

The authors conclude that aggressive reduction of LDL-C (below 100 mg/dL) significantly reduced progression of graft atherosclerosis, particularly when compared to a modest lowering of cholesterol of 15%. These data are concordant with the previously reported CLAS data and appear comparable with respect to angiographic changes to a number of coronary artery atherosclerosis regression trials.

Anticoagulation had no influence on progression of graft disease, although the authors point out that more vigorous anticoagulation might have been successful. In this trial, patients in the aggressive LDL treatment group had a 31% reduction in the mean per patient percentage of grafts showing progression of atherosclerosis.

The cumulative life table rates of events demonstrated a difference in revascularization rates that began approximately 2.5 years into the study, with the curves widening by study conclusion at 4.5 years. This suggests that longer treatment would have even greater effects on the need for revascularization, and possibly other clinical events as well.

COMMENT BY JONATHAN ABRAMS, MD

This trial, initially presented at the American College of Cardiology meeting in March 1996, provides further compelling evidence that vigorous lowering of LDL-C in patients with established atherosclerosis is imperative and results in impressive reductions of angiographic progression of disease, whether it be in the native coronary arteries or in bypass grafts.

The investigators are to be congratulated on their choice of an extremely aggressive LDL-C target of 85 mg/dL. The study began in 1989, one year after the release of the 1988 NCEP guidelines and long before any of the major statin trials were concluded, which indicates the foresight of the trial design. Furthermore, the use of extremely high-dose statin therapy was quite uncommon in 1989 and even today 80 mg/d of this drug, or a comparable dose of other statins, is most unusual.

It is important to recognize that this was a clinically low risk population at baseline, typical of many male bypass patients. Clinical outcomes were not different except for revascularization rates. This is likely due in part to the fact that patients had patent bypass grafts at entry to the study and were clinically stable; exclusion criteria eliminated patients with active or recent ischemic syndromes. Furthermore, only half of the patients had any graft disease at entry. Thus, it is unrealistic that there would be differences in mortality or infarction rates over the 4-5 year period. Nevertheless, the impressive reduction of graft atherosclerosis progression is compatible with considerable other regression trial data.

The time has come for all patients who have had coronary revascularization, angioplasty, or bypass surgery, to be carefully evaluated for their lipid status. Statin therapy is indicated with or without a resin to lower LDL-C to 100 mg/dl or less. The recently published CARE trial (Clin Cardiol Alert 1996;15:94-96) suggests that even for patients with relatively normal lipids who have had a prior myocardial infarction, such therapy is beneficial. It is clear that in 1997, any patient with established coronary artery disease should have their LDL-C maintained as close to 100 mg/dL as possible: lower is better.