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Review | Clinician's Corner

Lipoprotein(a) Concentration and the Risk of Coronary Heart Disease, Stroke, and Nonvascular Mortality

The Emerging Risk Factors Collaboration*
JAMA. 2009;302(4):412-423. doi:10.1001/jama.2009.1063.
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Published online

Context Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein–like particle, may be associated with risk of coronary heart disease (CHD) and stroke.

Objective To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes.

Study Selection Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators.

Data Extraction Individual records were provided for each of 126 634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22 076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline.

Data Synthesis Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer.

Conclusion Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.

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Figures

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Figure 1. Literature Search and Study Selection
Graphic Jump Location

Lp(a) indicates lipoprotein(a).

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Figure 2. Risk Ratios for Coronary Heart Disease, Ischemic Stroke, or Nonvascular Death by Quantile of Usual Lp(a) Level
Graphic Jump Location

Lp(a) indicates lipoprotein(a); MI, myocardial infarction. Sizes of data markers are proportional to the inverse of the variance of the risk ratios. Confidence intervals (CIs) were calculated using a floating absolute risk technique. Studies involving fewer than 10 cases of any outcome were excluded from the analysis of that outcome.
aFurther adjustment for usual levels of systolic blood pressure, smoking status, history of diabetes, body mass index, and total cholesterol. The x- and y-axes are shown on a log scale. Lowest quantiles are referents.

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Figure 3. Risk Ratios for Vascular and Nonvascular Outcomes per 3.5-Fold (1-SD) Higher Usual Lp(a) Level, Adjusted for Cardiovascular Risk Factors
Graphic Jump Location

Lp(a) indicates lipoprotein(a); MI, myocardial infarction; CI, confidence interval. Sizes of data markers are proportional to the inverse of the variance of the risk ratios. Risk ratios are adjusted for age, usual levels of systolic blood pressure, smoking status, history of diabetes, body mass index, and total cholesterol and are stratified, where appropriate, by sex and study group. Studies involving fewer than 10 cases of any outcome were excluded from the analysis of that outcome.
aSubtotals do not add to the total number of coronary heart disease outcomes because some nested case-control studies did not subdivide outcomes into coronary death or nonfatal MI.

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Figure 4. Risk Ratios for Coronary Heart Disease per 3.5-Fold (1-SD) Higher Usual Lp(a) Level, by Age and Thirds of Individual Characteristics
Graphic Jump Location

Lp(a) indicates lipoprotein(a); HDL-C, high-density lipoprotein cholesterol; CI, confidence interval. Sizes of data markers are proportional to the inverse of the variance of the risk ratios. Risk ratios are adjusted for age, usual levels of systolic blood pressure, smoking status, history of diabetes, body mass index, and total cholesterol and are stratified, where appropriate, by sex and study group. Studies with fewer than 3 cases per stratum were excluded from analyses.
aBody mass index is calculated as weight in kilograms divided by height in meters squared.
bCorrection for the cholesterol content of Lp(a) was made by subtracting estimated Lp(a) cholesterol values from total cholesterol; Lp(a) cholesterol was estimated from Lp(a) total mass using the following equation: Lp(a) − cholesterol (mg/dL) = 0.15 × Lp(a) (mg/dL) + 1.24.73

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