Discrimination and Net Reclassification of Cardiovascular Risk With Lipoprotein(a): Prospective 15-Year Outcomes in the Bruneck Study

Study Questions:

Some epidemiological studies have shown that lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular disease (CVD). Does the Lp(a) level modify or improve clinical CVD risk assessment?


In 1995, Lp(a) was measured in 826 men and women (age range, representing 45-84 years) from the general community in Bruneck, Italy. Incidence of CVD was recorded over 15 years of follow-up.


In models adjusted for Framingham (FRS) and Reynolds Risk Score (RRS) variables, the hazard ratio for incident CVD was 1.37 per 1-standard deviation (SD) higher Lp(a) level (SD, 32 mg/dl), and 2.37, comparing the top fifth quintile versus other quintiles. The addition of Lp(a) to RRS increased the c-index by 0.016. Of the 502 subjects who remained free of CVD, 82 were correctly reclassified to a lower risk category and 49 were reclassified to higher 15-year risk categories: <7.5%, 7.5-<15%, 15-<30%, ≥30% (p < 0.001). Of the 148 subjects who developed CVD (15.0 per 1,000 person-years), 18 were correctly reclassified to a higher risk category and 17 were reclassified to a lower category. In subjects at intermediate risk (15-30% predicted 15-year risk of CVD), the net reclassification improvement afforded by Lp(a) was 22.5% for noncases, 17.1% for cases, and 39.6% overall. Allele-specific Lp(a) levels did not add to the predictive ability of FRS or RRS, nor to Lp(a). The change in c-index was similar in those who were nondiabetic at baseline.


Elevated Lp(a) predicts 15-year CVD outcomes and improves CVD risk prediction. These findings suggest that Lp(a) levels may be used in risk assessment of subjects in the general community, particularly in intermediate-risk groups.


Adding Lp(a) to the FRS and RRS improved both discrimination and reclassification of CVD risk over a prospective 15-year follow-up in an unselected elderly Italian population. The findings are modestly more robust than previous studies. The clinical utility of basing clinical management decisions on Lp(a) measurements for primary prevention of CV events awaits evaluation in prospective clinical trials. High Lp(a) is the most common lipid abnormality associated with a family history of premature CVD, yet the lipid moiety improved the c-index of the RRS, which includes the family history of CVD before age 60 years. Also, the improvement was more powerful when stroke was used for the endpoint. Lp(a) levels are not affected by diet, exercise, or statins. A novel Lp(a) anti-sense that reduces the level by about 95% is in early development.

Clinical Topics: Dyslipidemia, Prevention, Advanced Lipid Testing, Lipid Metabolism, Diet

Keywords: Stroke, Follow-Up Studies, Lipoprotein(a), Risk Factors, Diet, Risk Assessment, Primary Prevention

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