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Etiology

Lipoprotein(a) was not associated with risk for acute myocardial infarction in U.S. men

ACP J Club. 1994 Mar-April;120:54. doi:10.7326/ACPJC-1994-120-2-054


Source Citation

Ridker PM, Hennekens CH, Stampfer MJ. A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA. 1993 Nov 10;270:2195-9.


Abstract

Objective

To determine whether lipoprotein(a) [Lp(a)] is a risk factor for acute myocardial infarction (MI).

Design

Nested case-control study within the Physicians' Health Study, a randomized, double-blind, placebo-controlled trial of aspirin and β-carotene for prevention of cardiovascular disease and cancer. Mean follow-up was 60 months.

Setting

United States.

Participants

296 predominantly white, male physicians, aged 40 to 84 years, who had returned a baseline blood sample in the Physicians' Health Study and had an MI after randomization were matched to 296 control participants for age, smoking status, and time since randomization.

Assessment of risk factors

Collected plasma was assayed for total Lp(a) level for each participant; investigators and laboratory personnel were blinded to case or control status. Baseline cardiovascular risk factors including height, weight, blood pressure, parental history of MI before the age of 60 years, presence of diabetes mellitus, and frequency of exercise were provided for each participant. Total and high-density lipoprotein cholesterol levels were measured.

Main outcome measure

First confirmed acute MI.

Main results

The distribution of Lp(a) levels among cases was the same as among controls (P > 0.2). When case values were separated into Lp(a) quintiles as defined by values from the controls, no association was noted between Lp(a) level and risk for MI. Risk for a first MI for men in the highest quintile of Lp(a) level was the same as that for men in the lowest quintile (relative risk [RR] 1.07, 95% CI 0.65 to 1.76). The lack of association remained after controlling for randomized treatment assignment, lipid parameters, and other cardiovascular risk factors (RR for the highest quintile 0.83, CI 0.36 to 1.89). The power of the study to detect a 2-fold increase in RR for MI associated with the top half of the control distribution was > 99%.

Conclusion

Lipoprotein(a) was not an independent risk factor for acute myocardial infarction in a cohort of white North American male physicians.

Sources of funding: National Institutes of Health; American Heart Association; Merck Sharp & Dohme.

For article reprint: Dr. P.M. Ridker, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Boston, MA 02215-1204, USA. FAX 617-277-4981.


Commentary

Since it was first described in the 1960s, Lp(a) has rapidly become the darling of many lipidologists for several reasons. First, many cross-sectional studies during the past 25 years found that white men have increased Lp(a) levels after an MI. This association appeared to be independent of other risk factors, including increased levels of other lipids. Second, several lines of evidence suggest that Lp(a) may be a genetic marker or closely linked to one. Third, Lp(a) levels vary little over time in a person, a desirable attribute in light of the proposed use of Lp(a) measurement as a screening test. Finally, Lp(a) shares structural and physiologic similarities with plasminogen, which is compatible with the long-sought association between lipoproteins and thrombosis.

Some health care workers have even recommended screening for Lp(a) despite the high cost of the test ($30), the absence of effective treatment, and the lack of evidence that decreasing Lp(a) prevents heart disease. This enthusiasm should be dampened considerably by the prospective study of Ridker and colleagues, which shows no association between Lp(a) and the risk for MI in white North American men.

The immediate clinical importance of this report is that it leaves no rationale for screening for Lp(a). The scientific implications are that additional cohorts, not confounded by a randomized trial design, should be studied. It is premature to dismiss Lp(a) as a risk factor because associations may exist in other geographic areas, in other ethnic groups, in women, or in persons with more extreme elevations of Lp(a) where the excess risk is expected. Recently, multiple isoforms of Lp(a) have been identified, only some of which may prove to be atherogenic. The Lp(a) chapter of cardiovascular disease is not closed.

Elizabeth Barrett-Connor, MD
University of California, San DiegoLa Jolla, California, USA