Lipid-related markers and cardiovascular disease prediction

Abstract

Context: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated.

Objective: To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction.

Design, setting, and participants: Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years).

Main outcome measures: Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk.

Results: The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.

Conclusion: In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

Figure 1. Changes in Cardiovascular Disease Risk Discrimination and Reclassification When Replacing Cholesterol Markers With Lipid-Related Markers

The model analyzed patients with conventional risk factors of age, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol (HDL-C), each of which were included as individual linear terms. The models were stratified by sex. Overall, the C-index for a model containing conventional cardiovascular disease (CVD) risk factors was 0.7244 (95% CI, 0.7200–0.7289). The net reclassification improvement analysis was calculated only for participants in studies that had at least 10 years of follow-up. ^aP<.001 for comparison against the model containing conventional risk factors. ^bP<.05 for comparison against the model containing conventional risk factors.

Figure 2. Changes in Cardiovascular Disease Risk Discrimination and Classification After Adding Lipid-Related Markers

The model containing conventional risk factors include age, systolic blood pressure, smoking status, history of diabetes, total and high-density lipoprotein cholesterol (HDL-C), each included as individual linear terms. Models were stratified by sex. ^aNet reclassification improvement was calculated only for participants in studies with at least 10 years of follow-up. Change in C-index adding lipoprotein(a) greater than 30 mg/dL was 0.0001 (95% CI, −0.0001 to 0.0003). ^bTriglyceride values were log-transformed. ^cP<.05 for comparison against model containing conventional risk factors. ^dP<.001 for comparison against model containing conventional risk factors. ^eLipoprotein(a) was modeled nonlinearly by including linear and quadratic terms of log-transformed lipoprotein(a).

Figure 3. Modeling of Reclassification per 100 000 People Initially Screened With Conventional Risk Factors and Then Additional Targeted Assessment of Lipid-Related Markers

Conventional risk factors were age, smoking status, systolic blood pressure, history of diabetes, total and high-density lipoprotein cholesterol (stratified by sex). ^aFollowing Adult Treatment Panel III (ATP-III) guidelines, this model assumes that people who should receive statins are those at a 20% or higher predicted 10-year cardiovascular disease (CVD) risk and other people (eg, those with diabetes) who merit statins irrespective of predicted 10-year CVD risk. People reporting statin use at baseline were also assumed to merit statin allocation.