EvidenceHealthVitaminsSupplementsCardiometabolic
Antioxidant Vitamins & Cardiovascular Disease in High‑Risk Women
- Study type:
- Randomised, double‑blind, placebo‑controlled 2×2×2 factorial trial in high‑risk women
- Topic:
- Vitamins C, E and β‑carotene for secondary prevention of cardiovascular disease in women at high risk
- Added:
- 2026-01-11
- Status:
- published
Strength of evidence
Very low – robust RCT structure with long follow‑up, but no true Null‑control arm and diagnostically defined composite endpoints; under WorthDay's strict evidence criteria this yields only very low‑quality causal evidence, while strongly failing to support any cardioprotective effect of these antioxidant vitamins in this group.
Source
Cook NR, et al. A randomized factorial trial of vitamins C, E, and β-carotene in the secondary prevention of cardiovascular events in women: the WACS trial. Arch Intern Med. 2007;167(15):1610–1618.
Open original studyIn the Women's Antioxidant Cardiovascular Study (WACS), over 8,000 middle‑aged and older women with existing cardiovascular disease or multiple risk factors took vitamin C (500 mg/d), vitamin E (600 IU every other day), β‑carotene (50 mg every other day), or matching placebos for almost 10 years. None of the vitamins reduced heart attacks, strokes, coronary revascularisations or cardiovascular deaths. Under WorthDay's criteria, the trial remains hypothesis‑generating, but it offers no evidence that these antioxidant supplements improve clinical outcomes in high‑risk women.
Key findings
- 8,171 women aged ≥40 years with established cardiovascular disease or at least three major risk factors were enrolled.
- Participants were randomised in a 2×2×2 factorial design to vitamin C (500 mg/day), vitamin E (600 IU every other day), β‑carotene (50 mg every other day), alone or in combination, versus corresponding placebos.
- The primary composite endpoint (non‑fatal myocardial infarction, non‑fatal stroke, coronary revascularisation, or cardiovascular death) was not significantly reduced by any of the vitamin regimens; relative risks were all very close to 1.0 with confidence intervals spanning 1.0.
- No substantial effects were observed on all‑cause mortality or other major cardiovascular outcomes.
- Under WorthDay's criteria, the use of diagnostically defined clinical endpoints and the absence of a true Null‑control arm mean the study provides very low‑quality causal evidence, but it strongly argues against meaningful cardioprotective effects of these supplements in this population.
Background
- Women with established cardiovascular disease or multiple risk factors are a prime target group for preventive strategies, including vitamin supplements. Antioxidant vitamins C, E and β‑carotene have been promoted as potential protectors against oxidative vascular damage. The Women's Antioxidant Cardiovascular Study (WACS) was designed to test whether long‑term supplementation with these vitamins can reduce recurrent cardiovascular events in high‑risk women.
Methods
- Species / population: 8,171 female health professionals aged 40 years or older with either: documented cardiovascular disease (such as prior myocardial infarction, stroke or revascularisation), or at least three major cardiovascular risk factors. Design: Randomised, double‑blind, placebo‑controlled 2×2×2 factorial trial. Interventions: Vitamin C: 500 mg/day vs matching placebo. Vitamin E: 600 IU every other day vs matching placebo. β‑carotene: 50 mg every other day vs matching placebo. Participants were assigned to one of eight combinations (each vitamin active or placebo), allowing independent and combined effects to be estimated. Follow‑up: Mean follow‑up was approximately 9.4 years, providing long‑term exposure and event accrual. Endpoints (as defined by the investigators): Primary endpoint: first major cardiovascular event, defined as non‑fatal myocardial infarction, non‑fatal stroke, coronary revascularisation (such as bypass or angioplasty), or cardiovascular death. Secondary endpoints: individual components of the primary endpoint, all‑cause mortality, and other vascular outcomes. All events were identified and adjudicated through medical records and standard diagnostic procedures, meaning they relied on clinical diagnostics and coding rather than purely direct, mechanical observation.
Results
- No benefit of vitamin C: Vitamin C supplementation did not significantly reduce the risk of the primary composite endpoint. Relative risk estimates hovered around 1.0, with confidence intervals including 1.0, indicating no clear protective effect. No benefit of vitamin E: Vitamin E likewise failed to lower the incidence of major cardiovascular events. Relative risks were close to unity and statistically non‑significant. No benefit of β‑carotene: β‑carotene supplementation showed no meaningful reduction in the primary composite or its components. Again, estimated effects were near 1.0 with wide, non‑significant confidence intervals. No improvement in total mortality: All‑cause mortality was not convincingly reduced by any of the vitamin regimens. In summary, none of the three antioxidant vitamins – alone or in combination – improved clinical cardiovascular outcomes in this large group of high‑risk women.
Interpretation
- For WorthDay, S0033 is an important counter‑example to the marketing narrative that "antioxidant vitamin pills" are effective secondary prevention tools for heart disease: Over nearly a decade, high‑risk women taking vitamin C, vitamin E or β‑carotene did not experience fewer heart attacks, strokes, revascularisations or cardiovascular deaths than women taking placebos. This trial directly challenges the assumption that adding these supplements on top of usual care meaningfully reduces cardiovascular risk in such populations. Under WorthDay's strict evidence criteria, several caveats are highlighted: No true Null‑control arm: Every participant ingested capsules (active or placebo), which from a WorthDay perspective prevents full separation of generic capsule or expectation effects from the specific biochemical actions of the vitamins. Diagnostic endpoints: Major cardiovascular events are defined via clinical diagnostics, imaging, procedural codes and death certificates. By WorthDay's definitions, this reliance on diagnostic systems makes the endpoints "soft" once used for causal medical claims. Focus on relative measures and composites: Results mainly report relative risks for composite endpoints; absolute risk differences and their precision are modest, underscoring the lack of meaningful clinical impact. Even with these WorthDay‑based reservations, the overall pattern is robust: There is no signal that vitamins C, E or β‑carotene materially help high‑risk women avoid serious cardiovascular events. The study provides strong negative evidence against the idea that these antioxidant supplements are an effective secondary prevention strategy in this context.
Limitations
- Selective population of female health professionals; results may not generalise fully to all women with CVD, though they are directly relevant to health‑aware, well‑treated populations.
- The trial did not target women with demonstrated micronutrient deficiencies; potential effects in truly deficient individuals were not assessed.
- Endpoints rely on complex diagnostic and adjudication processes, which WorthDay regards as indirect and assumption‑laden.
- Lack of a true Null‑control group without any capsule intake; capsule‑related expectation effects cannot be entirely ruled out.
WorthDay perspective
- S0033 supports a critical view of antioxidant vitamin supplementation (C, E, β‑carotene) as a strategy for women who already have cardiovascular disease or are at very high risk.
- For WorthDay users, the key learning is: long‑term vitamin pills did not deliver fewer heart attacks or strokes in this large, controlled trial; relying on them as a core prevention strategy is not evidence‑based.
- WorthDay can instead emphasise lifestyle, nutrition quality, sleep, recovery and stress management, while highlighting that these specific supplements have failed to show clinical benefit in a rigorous test.
Permalink: https://www.worth-day.com/science-compass/s0033-antioxidant-vitamins-cardiovascular-disease-in-high-risk
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