Measurement of lipoprotein (a) in the evaluation and management of cardiovascular disease is considered experimental, investigational and unproven.
The following is a summary of the key literature to date.
Lipoprotein A as a Predictor of Cardiovascular Risk
Numerous prospective cohort studies and systematic reviews have evaluated lipoprotein (a) (lp[a]) as a cardiovascular risk factor. The following are representative prospective trials drawn from the extensive literature on this topic.
The Emerging Risk Factors Collaboration published a patient-level meta-analysis of 37 prospective cohort studies enrolling 154,544 individuals. (1) Risk prediction was examined for a variety of traditional and non-traditional lipid markers. For lp(a), evidence from 24 studies on 133,502 individuals reported that lp(a) was an independent risk factor for reduced cardiovascular risk, with an adjusted hazard ratio for cardiovascular events of 1.13 (95% CI: 1.09-1.18). The addition of lp(a) to traditional risk factors resulted in a small improvement in risk prediction, with an increase in the C-statistic of approximately 0.002. On reclassification analysis, there was no significant improvement in the net reclassification index (0.05%, 95% CI: -0.59 to 0.70).
A systematic review by Genser et al. (2) included 67 prospective studies on 181,683 individuals that evaluated the risk of cardiovascular disease associated with lp(a). Pooled analysis was performed on 37 studies that reported the endpoints of cardiovascular events. When grouped by design and populations, the relative risks for these studies, comparing the uppermost and lowest strata of lp(a), ranged from 1.64-2.37. The relative risk (RR) for cardiovascular events was higher in patients with previous cardiovascular disease compared to patients without previous disease. There were no significant associations found between lp(a) levels, overall mortality, or stroke.
The Lipid Research Clinics (LRC) Coronary Primary Prevention Trial, one of the first large-scale, RCTs of cholesterol-lowering therapy, measured initial lp(a) levels and reported that lp(a) was an independent risk factor for coronary artery disease (CAD) when controlled for other lipid and non-lipid risk factors. (3) As part of the Framingham offspring study, lp(a) levels were measured in 2,191 asymptomatic men between the ages of 20 and 54 years. (4) After a mean follow-up of 15 years, there were 129 coronary heart disease events, including myocardial infarction (MI), coronary insufficiency, angina, or sudden cardiac death. Comparing the lp(a) levels of these patients with the other participants, the authors concluded that elevated lp(a) was an independent risk factor for the development of premature coronary heart disease (i.e., before age 55 years). The Atherosclerosis Risk in Communities Study (ARIC) study evaluated the predictive ability of lp(a) in 12,000 middle-aged individuals free of CAD at baseline who were followed up for 10 years. (5) The lp(a) levels were significantly higher among patients who developed CAD compared with those who did not, and lp(a) levels were an independent predictor of CAD above traditional lipid measures.
Kamstrup and colleagues (6) analyzed data from the Copenhagen City Heart Study, which followed up 9,330 individuals from the Copenhagen general population over a period of 10 years. This study reported a graded increase in risk of cardiac events with increasing lp(a) levels. At extreme levels of lp(a) above the 95th percentile, the adjusted hazard ratio for MI was 3.6 (95% CI: 1.7–7.7) for women and 3.7 (95% CI: 1.7–8.0) in men. Tzoulaki and colleagues (7) reported data from the Edinburgh Artery Study, which was a population cohort study that followed up 1,592 individuals for a mean of 17 years. These authors reported that lp(a) was an independent predictor of MI, with an odds ratio of 1.49 (95% CI: 1.0–2.2) for the highest one-third versus the lowest one-third.
Zakai and co-workers (8) evaluated 13 potential biomarkers for independent predictive ability compared to established risk factors, using data from 4,510 individuals followed up for 9 years in the Cardiovascular Health Study. The lp(a) was 1 of 7 biomarkers that had incremental predictive ability above established risk factors. The adjusted hazard ratio for each standard deviation increase in lp(a) was 1.07 (95% CI: 1.0-1.12).
Some studies, however, have failed to demonstrate such a relationship. In the Physicians’ Health Study, initial lp(a) levels in the 296 participants who subsequently experienced MI were compared with lp(a) levels in matched controls who remained free from CAD. (9) The authors found that the distribution of lp(a) levels between the groups was identical. The European Concerted Action on Thrombosis and Disabilities (ECAT) study, a trial of secondary prevention, evaluated lp(a) as a risk factor for coronary events in 2,800 patients with known angina pectoris. (10) In this study, lp(a) levels were not significantly different among patients who did and did not have subsequent events, suggesting that lp(a) levels were not useful risk markers in this population.
Some researchers have hypothesized that there is a stronger relationship between lp(a) and stroke than for coronary heart disease. Similar to the situation with cardiac disease, the majority of prospective studies, but not all, have indicated that lp(a) is an independent risk factor for stroke. In 1 prospective cohort study, Rigal and co-workers (11) reported that an elevated lp(a) level was an independent predictor of ischemic stroke in men (OR: 3.55; 95% CI: 1.33–9.48) but not in women (OR: 0.42; 95% CI: 0.12–1.26). In the ARIC prospective cohort study of 14,221 participants, (12) elevated lp(a) was a significant independent predictor of stroke in African-American women (RR: 1.84; 95% CI: 1.05-3.07) and white women (RR: 2.42; 95% CI: 1.30–4.53) but not in African-American men (RR: 1.72; 95% CI: 0.86–3.48) or white men (RR: 1.18; 95% CI: 0.47–2.90).
There also may be a relationship between lp(a) as a cardiovascular risk factor and hormone status in women. Suk Danik et al. (13) reported the risk of a first cardiovascular event over a 10-year period in 27,736 women enrolled in the Women’s Health Study. After controlling for standard cardiovascular risk factors, lp(a) was an independent predictor of risk in women who were not taking hormonal replacement therapy (HR: 1.77; 95% CI: 1.36–2.30, p<0.0001). However, for women who were taking hormonal replacement therapy, lp(a) levels were not a significant independent predictor of cardiovascular risk (HR: 1.13; 95% CI: 0.84–1.53, p=0.18).
Several meta-analyses have also examined the relationship between lp(a) levels and cardiovascular risk. Bennet et al. (14) synthesized the results of 31 prospective studies with at least 1 year of follow-up and that reported data on cardiovascular death and nonfatal MI. The combined results revealed a significant positive relationship between lp(a) and cardiovascular risk, with an odds ratio for patients with lp(a) in the top-third compared to those in the bottom-third of 1.45 (95% CI: 1.32–1.58). This analysis reported a moderately high degree of heterogeneity in the included studies (I2=43%), reflecting the fact that not all studies reported a significant positive association.
Smolders et al. summarized evidence from observational studies on the relationship between lp(a) and stroke. (15) Five prospective cohort studies and 23 case-control studies were included in this meta-analysis. Results from prospective cohort studies, lp(a) added a modest amount of incremental predictive information (combined RR for the highest one-third of lp(a): 1.22; 95% CI: 1.04–1.43). From case-control studies, an elevated lp(a) level was also associated with an increased risk of stroke (combined OR 2.39; 95% CI: 1.57–3.63).
A patient-level meta-analysis of 36 prospective studies published between 1970 and 2009 included 126,634 participants. (16) Overall, the independent association of lp(a) with vascular disease was consistent across studies but modest in size. The combined risk ratio, adjusted for age, sex, and traditional lipid risk factor, was 1.13 (95% CI: 1.09–1.18) for coronary heart disease and 1.10 (95% CI: 1.02–1.18) for ischemic stroke. There was no association of lp(a) levels with mortality.
Genetic studies have examined the association of various genetic loci with lp(a) levels, and Mendelian randomization studies have examined whether lp(a) is likely to be causative for CAD. In one such study, (17) there were 3 separate loci identified for increased lp(a) levels. Genetic variants were identified at 2 of these loci that were independently associated with coronary disease (OR: 1.70; 95% CI: 1.49–1.95, and OR: 1.92; 95% CI: 1.48–2.49). This finding strongly implies that elevated lp(a) levels are causative of coronary disease, as opposed to simply being associated.
Lipoprotein A as Treatment Target
There is a lack of evidence to determine whether lp(a) can be used as a target of treatment. Several randomized studies of lipid-lowering therapy have included measurements of lp(a) as an intermediate outcome measurement. While these studies have demonstrated that lp(a) levels are reduced in patients receiving statin therapy, the data are inadequate to demonstrate how this laboratory test can be used to improve patient management. (18, 19)
A large amount of epidemiologic evidence has determined that lp(a) is an independent risk factor for cardiovascular disease. The overall degree of risk associated with lp(a) levels appears to be modest, and the degree of risk may be mediated by other factors such as LDL levels and/or hormonal status. There is considerable uncertainty regarding the clinical utility of measuring lp(a), specifically how knowledge of lp(a) levels can be used in clinical care of patients who are being evaluated for lipid disorders. There is scant evidence on the use of lp(a) as a treatment target for patients with hyperlipidemia. The available evidence is insufficient related to impact on clinical outcomes; testing for lp(a) is considered experimental, investigational and unproven.
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