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20 July 2020
Lipoprotein(a): a marker of residual cardiovascular risk
Lipoprotein(a) may offer prognostic value when assessing the risk of recurrent cardiovascular events, according to this real-world analysis of secondary prevention patients.
Liu HH, Cao YX, Jin JL et al. Association of lipoprotein(a) levels with recurrent events in patients with coronary artery disease. Heart 2020; doi:10.1136/heartjnl-2020-316586.
Objective: To investigate the impact of admission lipoprotein(a) level on the risk for recurrent cardiovascular events in a real-world cohort of patients with coronary artery disease (CAD).
Study design: Multicentre, prospective study
Study population: 7,562 patients (mean age 57.3 years, 73.9% male, 77.1% with prior revascularisation) who had angiography-diagnosed CAD and experienced a first cardiovascular event were included in the study. Baseline medications included statins (78%), aspirin (74%), a P2Y12 inhibitor (54%), and beta-blockers (44%).
Mains study variables: •Recurrent cardiovascular events, defined as a composite of cardiovascular death, non-fatal myocardial infarction, and stroke. •Lipoprotein(a) level at admission for the recurrent cardiovascular event, categorised by tertiles: <8.88 mg/dL (n=2520), 8.88–26.44 mg/dL (n=2521) and ≥26.45 mg/dL (n=2521)
Methods: Event-free survival rates for each tertile were calculated using Kaplan-Meier analysis and compared by the log-rank test. The association between admission lipoprotein(a) level and risk for recurrent cardiovascular events was investigated using multivariate Cox regression analysis, with adjustment for age, sex, current smoking, diabetes, hypertension, left ventricular ejection fraction, revascularisation (percutaneous coronary intervention/coronary artery bypass grafting), triglyceride, low-density lipoprotein cholesterol, high-sensitivity C-reactive protein, glycated haemoglobin and baseline statin use.
Main results:

There were 680 recurrent cardiovascular events over a mean follow-up of 61.4±19.6 months, representing 17.5 events per 1000 person-years. Patients with a recurrent cardiovascular event had significantly higher admission lipoprotein(a) levels: 20.58 mg/dL vs 14.95 mg/dL in those without events, p<0.001. <br>
Regression analysis showed that lipoprotein(a) was independently associated with the risk of recurrent cardiovascular events (Table 1). Each 1 standard deviation increment in admission lipoprotein(a) was associated with 23% (10% to 38%) increase in the risk of recurrent cardiovascular events (p<0.001). 

Table 1. Admission lipoprotein(a) and recurrent cardiovascular events (RCVEs)


Tertile 1

(<8.88 mg/dL)

Tertile 2

(8.88–26.44 mg/dL)

Tertile 3

(≥26.45 mg/dL)

RCVEs/1000 person-years

(95% CI)

12.9 (8.6 to 17.2)

19.0 (13.7 to 24.3)

20.6 (15.3 to 26.7)

Hazard ratio               (95% CI)


1.69 (1.21 to 2.36)*

2.01 (1.44 to 2.80)**

*p<0.05; ** p<0.001

Furthermore, addition of admission lipoprotein(a) to established cardiovascular risk factors in the SMART risk score model significantly improved risk stratification for recurrent cardiovascular events (p<0.001).

Authors’ conclusion: Circulating lipoprotein(a) concentration was a useful predictor for the risk of recurrent cardiovascular events in real-world treated patients with CAD, providing additional information concerning the future clinical application of lipoprotein(a).


Multiple epidemiologic, genetic, and Mendelian randomization studies have demonstrated that higher lipoprotein(a) levels are associated with an increased risk of atherosclerotic cardiovascular disease and calcified aortic stenosis (1). The strength of the evidence has established lipoprotein(a) as an independent genetically-inherited causal risk factor for cardiovascular disease.  Whether lipoprotein(a) has prognostic value in predicting recurrent cardiovascular events in patients with CAD was uncertain. 

The results of this study in a real-world CAD patient population receiving best-evidence based preventive treatment (most were on a statin, aspirin, a P2Y12 inhibitor and a beta-blocker) showed that the admission lipoprotein(a) level was significantly associated with risk for recurrent cardiovascular events. When standardised, each 1 standard deviation increment in admission lipoprotein(a) was associated with 23% increase in the risk of recurrent cardiovascular events (p<0.001). This association persisted even after adjustment for established cardiovascular risk factors. Moreover, inclusion of the admission lipoprotein(a) level in the SMART Risk Score model (2), showed significant improvement in risk classification. 

In conclusion, the findings from this study lend support to consideration of lipoprotein(a) as a residual cardiovascular risk factor, as suggested by a previous study (3). Taken together, these data provide further impetus for novel treatments targeting elevated lipoprotein(a) to address this unmet clinical need. 


References 1. Gencer B, Kronenberg F, Stroes ES, Mach F. Lipoprotein(a): the revenant. Eur Heart J 2017;38:1553-60. 2. Dorresteijn JAN, Visseren FLJ, Wassink AMJ, et al. Development and validation of a prediction rule for recurrent vascular events based on a cohort study of patients with arterial disease: the smart risk score. Heart 2013;99:866–72.3. Shah NP, Wang Q, Wolski KE, et al. The role of lipoprotein (a) as a marker of residual risk in patients with diabetes and established cardiovascular disease on optimal medical therapy: post hoc analysis of ACCELERATE. Diabetes Care 2020;43(2): e22-e24.
Key words Lipoprotein(a); residual cardiovascular risk factor; real-world data