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Synopsis: Data confirm Lp(a) as an important coronary artery disease risk factor, and emphasize the point that their study used fresh serum samples as opposed to most of the data literature, which measured stored and frozen serum or plasma.
Source: von Eckardstein A, et al. J Am Coll Cardiol. 2001;37:434-439.
Lipoprotein (a) has been a controversial risk factor for coronary artery disease (CAD) for many years, with varying recommendations as to whether Lp(a) should be measured in risk stratification for CAD. This is an interesting moiety, consisting of a cholesteryl ester apoB particle, with an additional glycoprotein, apo(a), which homologous to plasminogen. This latter feature is believed to be responsible for the proatherogenic and proathrombotic characteristics of Lp(a). Elevations of Lp(a) have been correlated with increased CAD risk; however, it is not generally recommended to assay individuals for it, as data are conflicting and drug therapy to lower Lp(a) is difficult. Furthermore, there are no prospective studies showing that decreasing Lp(a) would improve outcomes. This report represents a substudy of the PROCAM study (Prospective Cardiovascular Münster), a long-term primary prevention study of 34,000 employees in Germany, recruited between 1979 and 1985. Ten-year follow-up data from a recently analyzed cohort of 5333 men, age 35-65 at entry, are now available. The Lp(a) data relate to a subgroup of 820 men who had Lp(a) measurements obtained from fresh serum. CAD risk factors and lipid levels were used to assess the role of the interaction of Lp(a) and traditional risk factors in predicting major CAD events. During the 10-year follow-up, 44 major coronary events occurred, including nonfatal MI, fatal MI, and stroke. The CAD risk factor profile of men with events was worse than those who did not have an event over 10 years. In addition, the median Lp(a) level was higher in those with events than in men without events (0.09 g/L vs 0.04 g/L; P = .05). Major CAD events were significantly increased in the highest quintile of baseline Lp(a), eg, a level greater than 0.17 g/L. For those individuals with a level greater than 0.2 g/L, there was almost a 3-fold increase risk of having a coronary event over the next 10 years. There was an adverse interaction of elevated Lp(a) on events with elevated LDL-C, low HDL-C, and hypertension. After correction of total LDL-C levels to take into account the cholesterol contained in the Lp(a) fraction, high Lp(a) levels actually increased risk in all men, irrespective of baseline LDL-C. An elevated Lp(a) did not increase risk in smokers or in individuals with elevated triglyceride levels, but it did impart risk in the absence of these risk factors. An Lp(a) level greater than 0.2 g/L was a risk marker for events in all men who were the top 40% of global CAD risk; in the majority of individuals with a more benign risk profile, Lp(a) elevations did not impart hazard. Eckardstein and associates conclude that their data confirm Lp(a) as an important CAD risk factor, and they emphasize the point that their study used fresh serum samples as opposed to most of the data in the literature, which measured stored and frozen serum or plasma. They suggest that assay difficulties may be the reason why Lp(a) has not always correlated with CAD risk. As in other studies, elevated Lp(a) increased risk in men with an elevated LDL-C but not in men with less than 160 mg/dL. Individuals with hypertension or low HDL-C were also at considerably higher risk with high Lp(a) concentrations. In summary, Lp(a) was a significant predictive risk factor in individuals with the greatest burden of overall CAD risk. Eckardstein et al state, "because Lp(a) increases the risk of coronary events strongly depending on the presence of additional coronary risk factors, it is imperative to strictly control additional risk factors in individuals with elevated Lp(a)."
Comment by Jonathan Abrams, MD
These data further support the argument that measurements of Lp(a) may be useful in primary prevention and suggest that in fresh plasma samples a level of 0.2 g/L or more increases CAD risk, particularly if the individual has other CAD risk factors present, such as an LDL-C above 160, low HDL, or hypertension. The suggestion that fresh samples may be more useful than frozen plasma could explain some of the discrepancies in the literature regarding this controversial matter. It does not appear that routine measurements of Lp(a) are indicated for prevention of CAD. Some lipid experts routinely use this assay, but the vast majority of physicians do not, nor do national guidelines support routine use of Lp(a) testing. However, when one is considering initiating pharmacologic therapy, such as a statin, a fibrate, or niacin, the measurement of Lp(a) may be useful in decision making. Statin therapy and estrogens lower Lp(a). However, there are no data to support that efforts to decrease levels of this compound are useful. Nevertheless, presence of high Lp(a) should trigger increased vigilance and a lower threshold for prescribing preventive measures, particularly drug therapy.