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WHS Biomarkers

Inflammation, Cholesterol, Lipoprotein(a), and 30-Year Cardiovascular Outcomes in Women

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Year of Publication: 2024

Authors: Ridker PM, Moorthy MV, Cook NR, ..., Buring JE

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2024;391:2087–2097. doi:10.1056/NEJMoa2405182

Link: https://clinicaltrials.gov/ct2/show/NCT00000479

Clinical Question

Do baseline levels of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) predict cardiovascular outcomes over 30 years in initially healthy women?

Bottom Line

Baseline high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels independently predicted 30-year cardiovascular risk in healthy women, with the highest risk observed when all three biomarkers were elevated.

Major Points

  • 30-year prospective follow-up of 27,939 initially healthy U.S. women enrolled in the Women’s Health Study
  • High-sensitivity CRP, LDL cholesterol, and lipoprotein(a) each independently predicted cardiovascular risk
  • Greatest risk was among women with all three biomarkers in the highest quintile (HR 2.63; 95% CI, 2.16–3.19)
  • Hazard ratios attenuated slightly over time for CRP and LDL, but not lipoprotein(a)
  • Supports use of combined biomarker stratification for long-term risk prediction

Design

Study Type: Prospective cohort study

Randomization:

Enrollment Period: 1992–1995

Follow-up Duration: 30 years

Centers: 1

Countries: USA

Sample Size: 27939

Analysis: Cause-specific Cox models, Fine–Gray competing risk models, stratified by quintile, adjusted for covariates and statin use in sensitivity analyses

Inclusion Criteria

  • Initially healthy female health professionals
  • Enrolled in Women’s Health Study between 1992–1995
  • Provided baseline blood sample for biomarker assay

Exclusion Criteria

  • Pre-existing cardiovascular disease at baseline
  • Missing biomarker data

Arms

FieldWomen with baseline biomarker data
InterventionObservational follow-up with no intervention
Duration30 years

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
First major adverse cardiovascular event (MI, revascularization, stroke, or CV death)PrimaryReference: lowest quintile of each biomarkerCRP: HR 1.70; LDL: HR 1.36; Lp(a): HR 1.33 (Q5 vs Q1)
Combined effect of all 3 biomarkers in highest quintileSecondaryNo biomarker in Q5HR 2.63 (95% CI 2.16–3.19)2.63
Individual risk for stroke with all 3 biomarkers in Q5SecondaryNo biomarker in Q5HR 1.68 (95% CI 1.14–2.48)1.68
Individual risk for coronary heart disease with all 3 biomarkers in Q5SecondaryNo biomarker in Q5HR 3.71 (95% CI 2.94–4.68)3.71

Subgroup Analysis

Stratified analyses by number of biomarkers in highest quintile, quintile-based risk curves, and biomarker interactions confirmed additive independent predictive effects

Criticisms

  • Limited racial diversity (94% White participants)
  • Female-only cohort limits generalizability to men
  • Confidence intervals not adjusted for multiplicity
  • No repeated biomarker measurements over 30 years

Funding

National Institutes of Health (HL043851, HL080467, HL099355, CA047988, CA182913)

Based on: WHS Biomarkers (The New England Journal of Medicine, 2024)

Authors: Ridker PM, Moorthy MV, Cook NR, ..., Buring JE

Citation: N Engl J Med 2024;391:2087–2097. doi:10.1056/NEJMoa2405182

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