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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://doi.org/10.1056/NEJMoa2405182

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 proportional-hazards models comparing quintiles 2–5 with quintile 1 (reference), with death from other causes as a competing risk. Models were adjusted for age, then further for blood pressure, smoking status, and diabetes, and finally for the other two biomarkers simultaneously; all analyses also controlled for the randomly assigned WHS treatment group. Alternative Fine–Gray competing-risk models were used. A sensitivity analysis censored follow-up at the time of the first-reported statin prescription (statin use was not entered as a covariate).

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

Baseline Characteristics

CharacteristicComorbiditiesQualifying Event
Hypertension25
Diabetes2.5
Smoker12

Arms

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

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
First major adverse cardiovascular event (composite of MI, coronary revascularization, stroke, or death from cardiovascular causes)PrimaryReference: lowest quintile (Q1) of each biomarkerQ5 vs Q1, covariable-adjusted: CRP HR 1.70 (95% CI, 1.52–1.90); LDL HR 1.36 (95% CI, 1.23–1.52); Lp(a) HR 1.33 (95% CI, 1.21–1.47)1.7
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
Not reportedAdverseNo adverse event data extracted for this trial

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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