Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Aggressive lowering of LDL cholesterol level delayed progression of atherosclerosis

ACP J Club. 1997 Jul-Aug;127:2. doi:10.7326/ACPJC-1997-127-1-002

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Source Citation

The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med. 1997 Jan 16;336:153-62.


Abstract

Objective

To compare aggressive lowering of low-density lipoprotein (LDL) cholesterol levels with moderate lowering to delay progression of atherosclerosis in saphenous vein coronary grafts and to compare low-dose anticoagulation therapy with placebo to reduce obstruction of bypass grafts.

Design

Randomized controlled trial with a mean duration of 4.3 years. A 2 × 2 factorial design was used.

Setting

7 clinical centers in the United States.

Patients

1351 patients who were 21 to 74 years of age (mean age 62 y, 92% men) with 2 patent saphenous vein grafts with stenosis < 75%. Inclusion criteria were LDL cholesterol levels of 3.4 to 4.5 mmol/L and an ejection fraction of not less than 30%. Follow-up was 98%.

Intervention

Patients were allocated to aggressive treatment (n = 676) or moderate treatment (n = 675) to lower LDL cholesterol levels. Lovastatin, 40 to 80 mg/d, was given as aggressive treatment compared with 2.5 to 5 mg/d as moderate treatment. Cholestyramine, 8 g/d, was added if LDL cholesterol levels remained elevated. The target LDL cholesterol level was 2.2 mmol/L in patients receiving aggressive treatment and 3.6 mmol/L in patients receiving moderate treatment. Patients also received anticoagulation therapy with warfarin, 1 mg/d at entry, and increased to a total dose of 4 mg/d (n = 674) or placebo (n = 677). The international normalized ratio was kept < 2.0.

Main outcome measures

Per-patient percentage of initially patent major grafts that had substantial progression of atherosclerosis (defined as a decrease of ≥ 0.6 mm in lumen diameter). Clinical outcomes were a composite end point of death, myocardial infarction (MI), stroke, bypass surgery, or angioplasty; these events were also considered individually.

Main results

Analysis was by intention to treat. During follow-up, the mean LDL cholesterol level ranged from 2.4 to 2.5 mmol/L with aggressive treatment and from 3.4 to 3.5 mmol/L with moderate treatment. The per-patient percentage of grafts with substantial progression of atherosclerosis was lower in patients who received aggressive treatment than in those who received moderate treatment (27% vs 39%, P < 0.001). Angiographic outcomes did not differ for patients receiving warfarin as compared with those receiving placebo. Composite and individual clinical end points did not differ between aggressive and moderate treatment or between warfarin and placebo.

Conclusions

Aggressive reduction of LDL cholesterol level delayed the progression of atherosclerosis in grafts but did not reduce the incidence of clinical events. Warfarin therapy conferred no benefit.

Sources of funding: National Heart, Lung, and Blood Institute and Merck & Company.

For article reprint: Post CABG Coordinating Center, Maryland Medical Research Institute, 600 Wyndhurst Avenue, Baltimore, MD 21210, USA. FAX 410-323-8622.


Commentary

In the Post Coronary Artery Bypass Graft Trial, aggressive modification of lipid levels improved the appearance of saphenous vein grafts on angiography after a mean of 4.3 years but had no effect on clinical outcome. Low-dose warfarin produced no demonstrable effect. These results are consistent with previously reported trials, but several caveats should be noted.

The failure of low-dose warfarin to provide a measurable benefit in this trial does not prove that other regimens are ineffective. The positive results obtained with aggressive lipid modification must also be interpreted with caution. The goal of treatment is to reduce adverse clinical events to acceptable risk and cost levels, not to improve the results of angiography. Although encouraging trends for improvement in clinical end points were seen with aggressive lipid modification, none achieved the criterion for significance set by the investigators.

Moreover, the benefits of aggressive lipid modification may not apply to patients who were excluded from or poorly represented in the trial. All participants were younger than 75 years of age, had LDL cholesterol levels between 3.4 and 4.5 mmol/L on a step 1 diet, and had an ejection fraction of 30% or greater. Patients with serious medical conditions, including recent MI, were excluded. Only 8% of patients were women, and only 6% were nonwhite. The recently reported increase in breast cancer among women who received a cholesterol-lowering statin drug (1) serves as a reminder that it is hazardous to conclude that lipid lowering is safe or effective for members of any group until that group has been adequately studied.

The failure of this trial to show a significant reduction in clinical events with anticoagulation or aggressive lipid modification was disappointing. Nonetheless, I interpret the superior angiographic appearance in the group treated with aggressive lipid modification as evidence in support of cholesterol reduction for selected patients after saphenous vein aortocoronary bypass.

William C. Taylor, MD
Beth Israel Deaconess Medical CenterBoston, Massachusetts, USA


Reference

1. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-9.