Correspondence

The Effect of Pravastatin on Coronary Events after Myocardial Infarction

N Engl J Med 1997; 336:961-962March 27, 1997

Article

To the Editor:

The long-awaited results of the Cholesterol and Recurrent Events (CARE) trial (Oct. 3 issue)1 confirm and extend the results of the virtually unbroken string of coronary disease prevention trials demonstrating the efficacy of substantial reductions in low-density lipoprotein (LDL) cholesterol in preventing coronary heart disease (notably with respect to secondary prevention). Since the reduction in risk in this study was proportional to base-line levels of LDL cholesterol, with benefit being confined to patients with higher pretreatment LDL levels (who were therefore at higher risk), even if the levels fell within the normal range, these findings are both reassuring and logical.

As gerontologists, however, we must add an important caveat in interpreting the results of the study. Whereas an encouraging number of older subjects participated (as well as a substantial proportion of women), none were truly elderly at entry (75 years of age is a useful lower limit in defining that term). Hence, future trials must explicitly focus on those older than 75 in order for physicians to individualize therapeutic regimens most precisely for their oldest patients. Such patients are at highest risk for coronary heart disease by virtue of their age but also may derive the least benefit from cholesterol reduction, especially as the upper limit of the human life span is approached and competing risks (including those of intervention) loom ever larger in the treatment-decision analysis.2

In addition, careful reading of this report suggests that the CARE study may (perhaps unintentionally) have addressed yet another issue that has confounded clinicians and policymakers alike — namely, the implications of the increased risk of death among patients with very low levels of cholesterol (total, LDL, and at the lowest levels, high-density lipoprotein cholesterol as well), a risk that is evident in the J-shaped curvilinear relation between cholesterol level and mortality from all causes (including cardiovascular causes).3 On a clinical level, this increased risk is most apparent in hospitalized patients, among whom a low or decreasing cholesterol level is associated with morbidity, complications, costs, and mortality.4

But what of patients with low cholesterol levels and coronary heart disease? Will their already high risk of morbidity and mortality be further increased if average or low LDL cholesterol levels are lowered even more with diet and drug intervention? Here, the results of the CARE study should be reassuring. Whereas the risks of coronary events and mortality were not lowered by a diet and pravastatin regimen that resulted in a reduction in LDL cholesterol levels below an initial level of less than 125 mg per deciliter, neither were they increased.

William R. Hazzard, M.D.
Walter H. Ettinger, Jr., M.D.
Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC 27157

4 References

1. 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;335:1001-1009
   Full Text | Web of Science | Medline

2. 2

   Welch HG, Albertsen PC, Nease RF, Bubolz TA, Wasson JH. Estimating treatment benefits for the elderly: the effect of competing risks. Ann Intern Med 1996;124:577-584
   Web of Science | Medline

3. 3

   Harris T, Feldman JJ, Kleinman JC, Ettinger WH Jr, Makuc DM, Schatzkin AG. The low cholesterol-mortality association in a national cohort. J Clin Epidemiol 1992;45:595-601
   CrossRef | Web of Science | Medline

4. 4

   Noel MA, Smith TK, Ettinger WH. Characteristics and outcomes of hospitalized older patients who develop hypocholesterolemia. J Am Geriatr Soc 1991;39:455-461
   Web of Science | Medline

To the Editor:

In the study by Sacks et al., the reduction in deaths from coronary disease and nonfatal events in patients with normal and seminormal cholesterol levels is impressive. However, the greater number of cases of breast cancer in the intervention group as compared with the control group (12 vs. 1) needs careful evaluation. Cholesterol is involved in the biosynthesis of sex-steroid hormones. A low cholesterol level is not likely to be a cause of breast cancer, given the low cholesterol levels and low rates of breast cancer in China and Japan. It is also unlikely that lowering cholesterol by nonpharmacologic means is associated with an increased risk of breast cancer, due to the absence of such an effect in other studies.

The effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the metabolism of sex-steroid hormone in postmenopausal women should be further evaluated, because it is highly likely that many more women will be treated with these drugs. Post-marketing surveillance and case–control studies of older women with breast cancer and matched controls could provide a fairly rapid and reassuring answer to the question of whether the increased risk of breast cancer is associated with long-term use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

Baruch Modan, M.D.
Chaim Sheba Medical Center, Tel Hashomer 52621, Israel

Lewis H. Kuller, M.D., Dr.P.H.
University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15642

To the Editor:

The CARE study reported a significant reduction in the incidence of coronary events among patients with a history of acute myocardial infarction and total cholesterol levels of less than 240 mg per deciliter and LDL cholesterol levels above 125 mg per deciliter. However, the range in the lengths of time between acute myocardial infarction and randomization (3 to 20 months) was relatively wide and might have influenced the results of the study. It is known that mortality is higher in the first year after patients hospitalized for acute myocardial infarction are discharged than in the following years.1

We hope the authors can supply survival analyses in subgroups according to the interval between acute myocardial infarction and randomization, so that it can be determined whether early administration of pravastatin after acute myocardial infarction increases the survival benefit and whether the beneficial effect starts earlier in patients so treated than in those treated later during the course of coronary disease. Such data will help answer a very important question: What is the optimal length of time after acute myocardial infarction to start cholesterol-lowering treatment?

Ilan Auerbach, M.D.
Solomon Behar, M.D.
Michael Motro, M.D.
Chaim Sheba Medical Center, Tel Hashomer 52621, Israel

1 References

1. 1

   Behar S, Barbash GI, Copel L, Gottlieb S, Goldbourt U. Improved survival of hospitalized patients with acute myocardial infarction from 1981-1983 to 1992 in Israel. Coron Artery Dis 1994;5:1001-1007
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: In response to Hazzard and Ettinger: the CARE study has the oldest population among cholesterol-treatment trials, with patients reaching 80 years by the end of the trial. Among the 1116 patients who were 65 to 75 years old at entry (70 to 80 years at the end of the trial), pravastatin reduced fatal coronary events and nonfatal myocardial infarctions by 32 percent, as compared with a 19 percent reduction among those less than 65 years at entry (the difference in risk reduction between the age groups was not significant). Since the older patients had a higher rate of events, the absolute reduction was also greater than that in the younger patients (5.2 percent vs 2.1 percent). Although a clinical trial in patients in their 80s would be needed to evaluate the potential benefit directly, current data indicate that the benefit is just as great in older patients as in younger patients, if not greater.

Modan and Kuller, citing data from international studies and clinical trials, agree with our view that neither cholesterol levels nor cholesterol treatment is likely to be causally associated with breast cancer. Pravastatin does not increase serum levels of estradiol or other sex steroids1 : if anything, a decrease would have been expected on the basis of its ability to inhibit the synthesis of cholesterol, the metabolic precursor of estradiol. We agree on the need for long-term clinical data and will be collecting information on cancer in the women in the trial for an additional five years.

In response to Auerbach et al.: the patients in the CARE study who were enrolled between 3 and 6 months after myocardial infarction had the same reduction in coronary events (24 percent) as the patients who were enrolled from 7 to 20 months after infarction. The trial was not designed to address whether starting cholesterol-lowering treatment during hospitalization for acute myocardial infarction would enhance the benefit of such therapy. This important issue needs to be tested in a specific trial. However, in the absence of direct data, we recommend that cholesterol-lowering treatment be started as soon as possible after myocardial infarction. Clinically, what is important is to begin treatment in a timely manner and then do everything possible to encourage adherence to therapy, since the benefit increases with every year of treatment.

Frank M. Sacks, M.D.
Marc A. Pfeffer, M.D., Ph.D.
Eugene Braunwald, M.D.
Brigham and Women's Hospital, Boston, MA 02115

1 References

1. 1

   Dobs AS, Sarma PS, Schteingart D. Long-term endocrine function in hypercholesterolemic patients treated with pravastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Metabolism 1993;42:1146-1152
   CrossRef | Web of Science | Medline