Two New Cholesterol Trials: The Soup Thickens
By Jonathan Abrams, MD
At the november 1997 american heart association Scientific Sessions, two long-awaited clinical trials using statins were reported. These studies fill in several gaps in our present approach to healthy individuals as well as coronary patients with dyslipidemia. The trialsLong-term Intervention with Pravastatin in Ischemic Disease (LIPID) and the Airforce/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)conclusively demonstrate that aggressive cholesterol lowering with statins saves lives, prevents heart attacks and unstable angina, and decreases coronary revascularization rates. When added to the list of other major clinical trials over the past three years (i.e., 4S, Western Scotland, CARE), the existing database of more than 30,000 patients randomized to a statin or placebo is overwhelmingly positive in appropriately selected individuals.
LIPID Trial
The LIPID trial was carried out in Australia and New Zealand in 87 hospitals and enrolled 9014 individuals (17% women) randomized to 40 mg of pravastatin or placebo between 1990 and 1992. The group was followed through September 1997, at which time the study was stopped because of evidence that active treatment reduced all major coronary events. Average follow-up was six years. The primary end point was coronary artery death; secondary end points included non-fatal myocardial infarction (MI), stroke, total mortality, and revascularization rates.
LIPID is a secondary prevention trial, enrolling individuals with a prior MI (2/3) or unstable angina (1/3) no less than three months or more than three years prior to randomization. All subjects were on a diet for eight weeks before trial entry. Entry lipid criteria were cholesterol 155-270 mg/dL and triglycerides less than 445. The mean baseline values were total cholesterol 218, LDL-C 150, HDL-C and triglycerides 161. During the study, lipid levels decreased with an 18% decline in cholesterol, a 25% reduction in LDL-C, a 12% reduction in triglycerides, and a 6% increase in HDL-C (mean values at 5 years).
The primary end point of CAD mortality showed a 24% reduction (P = 0.0004). Other important end points included a 23% reduction in total mortality, a 23% reduction in fatal CAD and non-fatal MI, a 20% reduction in stroke, a 24% decrease in revascularization procedures, and a 29% decrease in total MI (all highly significant). There was no obvious downside to the therapy and, specifically, no increase in cancer. Asymptomatic elevations of liver enzymes were more frequent in pravastatin patients.
In summary, pravastatin resulted in major reductions in death and all CAD end points in the largest reported statin trial to date. Baseline lipid levels were slightly above the U.S. population mean values and would be considered by most physicians as unremarkable.
AFCAPS/TexCAPS Trial
The AFCAPS/TexCAPS trial enrolled 6605 healthy individuals (15% women) who were free of clinical CAD and randomized to lovastatin or placebo. Follow-up was a mean of 4.8 years, at which time the study was stopped because of clear-cut benefits in the lovastatin cohort. Subjects had to be on a diet and exercise program prior to randomization. Entry lipid levels included an LDL-C of 130-190 mg/dL, HDL-C less than 50 mg/dL, and a total cholesterol/HDL ratio of less than five. Lova-statin dosing began with 20 mg and could be increased to 40 mg; target LDL-C was 110 mg/dL. Approximately one-half of the active-treated patients required the higher dose; the mean study dose was 30 mg. The primary end point was acute MI or unstable angina. Secondary end points included coronary revascularization, any MI, unstable angina, any cardiovascular or coronary event, or death. Tertiary end points were safety-related and included total mortality, cancer, and non-CV death. The age for eligible men was 45-73 and 55-73 for eligible women; the average age was 58 (men, 57; women, 63). Eighty-nine percent of enrollees were white, 7% were Hispanic, and 3% were black. This was a healthy population with only 12% smokers, 2% diabetics, and 22% hypertensives. Thirty-five percent had an HDL-C less than 30. Mean baseline lipids for the cohort was cholesterol of 221, LDL-C of 150, and HDL-C of 37.
Results
Lipid lowering was predictable, with an 18% reduction in cholesterol, 25% reduction in LDL-C, 15% decrease in triglycerides, and a 6% increase in HDL.
The primary and secondary end points at study termination included a 36% risk reduction for first acute coronary event (unstable angina or MI). Revascularizations decreased by 33%, unstable angina by 34%, total MI by 35%, total coronary events by 26%, and cardiovascular events by 24%all highly significant. The risk of an acute coronary event was decreased in a variety of prespecified categories; of interest, women had a 54% event reduction vs. 34% for men. Smokers achieved a 59% event reduction, hypertensives 43%, and diabetics 43%. Twenty-one percent of the patients were older than 65 years; the event reduction in this population was 29%. Treatment benefit in terms of curve separation appeared within the first year, with continuing separation of the event curves by five years.
Comments
The LIPID and AFCAP/TexCAP studies were both large population studies lasting up to six years that achieved virtually identical results. Baseline LDL-C and HDL-Cwere comparable; in general, these lipid profiles would be considered only mildly abnormal by contemporary standards. While the AFCAP/TexCAPS primary prevention trial enrolled individuals with a low HDL, mean HDL was only moderately depressed (37 mg/dL). Forty-two percent of the treatment group achieved the target LDL of less than 110, and 80% of this cohort reached an LDL-C level of less than 130 (the NCEP goal for individuals with 2 or more major coronary risk factors). The LIPID trial is also convincing, although it does not provide any surprises; previous secondary prevention trials, including 4S (high baseline LDL-C) and CARE (normal LDL-C), predicted the outcome of LIPID. The use of unstable angina as an enrollment criteria was unique in this study. Thus, this trial extends the use of statin therapy in individuals with CAD. The Texas study substantially strengthens the statin efficacy story in healthy individuals. The other major primary prevention trial was Western Scotland, which enrolled only men (many current or former smokers) who had a substantially higher LDL-C level at entry. It is gratifying that both new trials are positive across a broad array of CAD end points, including need for coronary revascularization.
In conclusion, there is now a robust and persuasive database supporting LDL cholesterol-lowering in the large majority of patients with CAD or normal subjects with mild or moderate dyslipidemiawith or without other CAD risk factors. These drugs induce substantial reduction in CAD risk, particularly recurrent MI, unstable angina, or need for coronary revascularization. The consistency of these trials with respect to the proportionate risk reduction is impressive. There are now sufficient data in women (i.e., 4S, CARE, LIPID, AFCAP/TexCAPS) and the elderly to confirm that lipid lowering is at least as effective in women as in men and is beneficial in older subjects. Of note, stroke rates were reduced by statin therapy in most of these trials; a recent meta-analysis confirms that LDL cholesterol lowering substantially reduces cerebrovascular accidents in populations free of overt cerebrovascular disease prior to entry. AFCAP/TexCAPS suggests that individuals at higher risk might achieve greater benefit; smokers, hypertensives, and diabetics had the greatest proportional event reduction. Thus, it remains appropriate to resave statins in higher risk, non-CAD individuals.
The remaining uncertainty regarding use of statins is in those individuals without evidence for vascular disease, whose LDL is in the normal range. While CARE indicated that the patient with a prior infarct and relatively normal lipid levels benefited from pravastatin, the higher LDL cutpoint in AFCAP/TexCAPS (when coupled with a low HDL) indicates that, in healthy people, significant dyslipidemia must be documented before statin treatment is considered. Clearly, in primary prevention, individuals with other CAD risk factors in addition to an elevated LDL-C or low HDL-C should be placed on lipid-lowering therapy after an appropriate diet trial. Virtually all patients with established CAD should be treated unless baseline lipids are well below average (e.g., total cholesterol < 200 mg/dL, LDL-C < 120).
Statin therapy of patients with prior myocardial ischemic events shows:
a. reduced total mortality.
b. reduced subsequent MI.
c. reduced stroke.
d. all of the above.
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