One-time assessment of 3 biomarkers predicts lifetime CVD risk in women

In a prospective cohort study among ~28,000 initially healthy US women, a single combined measurement of hs-CRP, LDL-c, and Lp(a) levels predicted incident MACE over the next 30 years.

This summary is based on the publication of Ridker PM, Moorthy MV, Cook NR, et al. - Inflammation, Cholesterol, Lipoprotein(a), and 30-Year Cardiovascular Outcomes in Women. N Engl J Med. 2024 Aug 31 [Online ahead of print]. doi: 10.1056/NEJMoa2405182

Introduction and methods

Background

In addition to LDL-c, hs-CRP and Lp(a) are emerging as targets for CVD interventions [1-5]. However, data on the long-term risk of ASCVD associated with these biomarkers, alone or in combination, are limited. Moreover, this long-term risk poses a major concern for women, in whom CVD remains underdiagnosed and undertreated.

Aim of the study

The authors investigated whether one-time measurement of hs-CRP, LDL-c, and Lp(a) levels is a useful method to evaluate lifetime CVD risk in women.

Methods

In a prospective cohort study, data were collected from 27,939 healthy, female health professionals who were enrolled in the Women’s Health Study in the USA from 1992 through 1995 and were subsequently followed for 30 years. At baseline, hs-CRP, LDL-c, and Lp(a) levels were measured in a single blood sample. Median follow-up time was 27.4 years (IQR: 22.6–28.5).

Outcome

The primary endpoint was the first occurrence of MACE, defined as a composite outcome of incident MI, incident stroke, coronary revascularization, or CV death.

Main results

• During follow-up, 3662 first MACE occurred.
• For all 3 biomarkers, quintiles of increasing baseline levels predicted 30-year MACE risk. When comparing quintile 5 of a baseline biomarker level with quintile 1, the covariable-adjusted HR for the primary endpoint was 1.70 (95%CI: 1.52–1.90) for hs-CRP, 1.36 (95%CI: 1.23–1.52) for LDL-c, and 1.33 (95%CI: 1.21–1.47) for Lp(a).
• The effects of hs-CRP and LDL-c levels on MACE risk reduced slightly over time, whereas no risk attenuation was observed for Lp(a) levels during follow-up.
• Cumulative incidence curves adjusted for age and competing risk showed an increasing probability of incident MACE with each higher quintile of the hs-CRP or LDL-c levels. However, for the third biomarker, 30-year MACE risk was elevated primarily in participants with an Lp(a) level in quintile 5.
• Each biomarker contributed independently to predicting overall MACE risk, but the greatest spread for risk was obtained in models in which all 3 biomarkers were combined. The covariable-adjusted HR for the primary endpoint was 1.0 for participants with no biomarker levels in quintile 5 (reference group), 1.27 (95%CI: 1.19–1.37) for those with 1 biomarker level in quintile 5, 1.66 (95%CI: 1.51–1.83) for those with 2 biomarker levels in quintile 5, and 2.63 (95%CI: 2.16–3.19) for those with 3 biomarker levels in quintile 5.
• Comparable results were found for the risks of CHD and stroke.

Conclusion

In this prospective cohort study among ~28,000 initially healthy US women, a single combined measurement of hs-CRP, LDL-c, and Lp(a) levels predicted incident MACE over the next 30 years. The 3 biomarkers independently predicted MACE risk, but their combination provided the greatest spread for long-term risk stratification. The 30-year risk of MACE increased with each quintile of the hs-CRP or LDL-c levels. For Lp(a), however, this risk was increased primarily in the highest quintile. The authors conclude “these data strongly support the need for efforts to extend strategies for the primary prevention of atherosclerotic events well beyond traditional 10-year estimates of risk.”

Find this article online at N Engl J Med.

Watch a video by Paul Ridker on this study

References

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2. Ridker PM, Lei L, Louie MJ, et al. Inflammation and cholesterol as predictors of cardiovascular events among 13 970 contemporary high-risk patients with statin intolerance. Circulation 2024; 149: 28-35.
3. Arnold N, Blaum C, Goßling A, et al. C-reactive protein modifies lipoprotein(a)-related risk for coronary heart disease: the BiomarCaRE project. Eur Heart J 2024; 45: 1043-54.
4. Puri R, Nissen SE, Arsenault BJ, et al. Effect of C-reactive protein on lipoprotein(a)-associated cardiovascular risk in optimally treated patients with high-risk vascular disease. a prespecified secondary analysis of the ACCELERATE Trial. JAMA Cardiol 2020; 5: 1136-43.
5. Zhang W, Speiser JL, Ye F, et al. High-sensitivity C-reactive protein modifies the cardiovascular risk of lipoprotein(a): Multi-Ethnic Study of Atherosclerosis. J Am Coll Cardiol 2021; 78: 1083-94.