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Lipoprotein(a) and cardiovascular disease: prediction, attributable risk fraction and estimating benefits from novel interventions

By Paul Welsh, Claire Welsh, Carlos A Celis-Morales, Rosemary Brown, Lyn D Ferguson, Patrick B Mark, James Lewsey, Stuart R Gray, Donald M. Lyall, Jason MR Gill, Jill Pell, James A de Lemos, Peter Willeit, Naveed Sattar

Posted 01 Apr 2020
medRxiv DOI: 10.1101/2020.03.30.20043554

BackgroundLipoprotein (a) (Lp(a)) is a CVD risk factor amenable to intervention and might help guide risk prediction. ObjectivesTo investigate the population attributable fraction due to elevated Lp(a) and its utility in risk prediction. MethodsUsing a prospective cohort study, 413,724 participants from UK Biobank, associations of serum Lp(a) with composite fatal/nonfatal CVD (n=10,065 events), fatal CVD (n=3247), coronary heart disease (n=16,649), ischaemic stroke (n=3191), and peripheral vascular disease (n=2716) were compared using Cox models. Predictive utility was determined by C-index changes. The population attributable fraction was estimated. ResultsMedian Lp(a) was 19.7nmol/L (interquartile interval 7.6-75.3nmol/L). 20.8% had Lp(a) values >100nmol/L; 9.2% had values >175nmol/L. After adjustment for classical risk factors, in participants with no baseline CVD and not taking a statin, 1 standard deviation increment in log Lp(a) was associated with a HR for fatal/nonfatal CVD of 1.09 (95%CI 1.07-1.11). Associations were similar for fatal CVD, coronary heart disease, and peripheral vascular disease. Adding Lp(a) to a prediction model containing traditional CVD risk factors improved the C-index by +0.0017 (95% CI 0.0009, 0.0026). We estimated that having Lp(a) values >100nmol/L accounts for 5.7% of CVD events in the whole cohort. We modelled that an ongoing trial to lower Lp(a) in patients with CVD and Lp(a) above [~]175nmol/L may reduce CVD risk by 20.3%, assuming causality, and an achieved Lp(a) reduction of 80%. ConclusionsPopulation screening for elevated Lp(a) may help to predict CVD and target Lp(a) lowering drugs, if such drugs prove efficacious, to those with markedly elevated levels.

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