EvidenceHealthVitaminsSupplementsCardiometabolic
Multivitamins & Cardiovascular Disease in Men
- Study type:
- Large randomised, double‑blind, placebo‑controlled primary prevention trial in male physicians
- Topic:
- Daily multivitamin use and cardiovascular disease in middle‑aged and older men
- Added:
- 2026-01-10
- Status:
- published
Strength of evidence
Very low – strong randomisation and blinding with clinically relevant endpoints, but no true Null‑control arm and heavy reliance on diagnostic criteria and composite endpoints; under WorthDay's strict evidence criteria this remains hypothesis‑generating and does not provide a hard causal proof.
Source
Sesso HD, et al. Multivitamins in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA. 2012;308(17):1751–1760.
Open original studyIn this 11‑year randomised trial, over 14,000 male physicians took either a daily multivitamin (Centrum Silver) or a placebo. Despite long‑term use, multivitamins did not reduce heart attacks, strokes, cardiovascular deaths or overall mortality compared with placebo. Under WorthDay's criteria, the trial cannot establish causality, but it strongly fails to support the idea that a standard multivitamin protects well‑nourished men from major cardiovascular events.
Key findings
- 14,641 male U.S. physicians (≥50 years) were randomised to daily multivitamin vs placebo and followed for a median of 11.2 years.
- The primary composite endpoint (non‑fatal myocardial infarction, non‑fatal stroke, cardiovascular death) occurred at virtually the same rate in both groups (HR ≈ 1.01; 95 % CI around 0.91–1.10).
- There was no significant effect on individual endpoints (myocardial infarction, stroke), on cardiovascular mortality, or on all‑cause mortality.
- Absolute differences in event rates between the multivitamin and placebo groups were extremely small and clinically trivial, suggesting no meaningful protection in this well‑nourished population.
- According to WorthDay's evidence criteria, the study uses diagnostically defined, composite clinical endpoints without a true Null‑control arm; it therefore offers only very low‑quality evidence for causality but a strong negative signal against any major protective effect of standard multivitamin use in such men.
Background
- Multivitamins are widely marketed as a simple insurance policy against chronic disease, including heart attacks and strokes. Observational studies have sometimes suggested benefits, but such designs are prone to healthy‑user bias and confounding. The Physicians' Health Study II (PHS II) was designed as a large randomised, double‑blind, placebo‑controlled trial to test directly whether long‑term daily multivitamin use reduces major cardiovascular events in apparently well‑nourished male physicians.
Methods
- Species / population: 14,641 male U.S. physicians aged 50 years or older, including 754 men with pre‑existing cardiovascular disease at baseline. Design: Randomised, double‑blind, placebo‑controlled primary prevention trial. Intervention: A daily commercial multivitamin (Centrum Silver) vs an identical‑appearing placebo. Follow‑up: Randomisation began in the late 1990s with a median follow‑up of 11.2 years. Endpoints (as defined by the investigators): Primary endpoint: composite of non‑fatal myocardial infarction, non‑fatal stroke, and cardiovascular death. Secondary endpoints: total myocardial infarction, total stroke, cardiovascular mortality, and all‑cause mortality, plus various additional cardiovascular outcomes. All events were ascertained through medical records and adjudication committees, i.e. via diagnostic and classification procedures rather than purely direct, unfiltered observation.
Results
- No reduction in major cardiovascular events: The incidence of the primary composite endpoint was virtually identical in the multivitamin and placebo groups. Hazard ratio (HR) for multivitamin vs placebo was about 1.01, with a 95 % confidence interval roughly from 0.91 to 1.10, clearly crossing 1.0 and excluding any large benefit. No significant effect on individual cardiovascular outcomes: Non‑fatal myocardial infarction and non‑fatal stroke occurred at similar rates in both groups. Cardiovascular mortality did not differ meaningfully between multivitamin and placebo. No reduction in total mortality: All‑cause mortality was not significantly different between the two arms; any absolute differences were numerically tiny and clinically trivial. Subgroup and secondary analyses did not reveal a robust cardioprotective signal in any major subgroup of these male physicians. Under a conventional evidence hierarchy, PHS II is considered a strong negative trial: it provides little to no support for the notion that a daily multivitamin meaningfully prevents cardiovascular events in already well‑nourished men.
Interpretation
- From a WorthDay perspective, S0031 sends a clear practical message: In a large, long‑term randomised trial of mostly healthy, well‑fed male doctors, a standard daily multivitamin did not reduce heart attacks, strokes or deaths compared with placebo. The intuitive idea that a multivitamin acts as a cardioprotective "safety net" is not supported by these data for this population. At the same time, WorthDay applies stricter evidence criteria than conventional hierarchies and therefore highlights important limitations: No true Null‑control arm: All participants ingested a daily capsule (either multivitamin or placebo). Under WorthDay's logic, this prevents a clean separation of intervention effects from any generic capsule‑ or expectation‑related effects. Diagnostic endpoints: Myocardial infarction, stroke and cardiovascular death are identified via complex diagnostic protocols, classification rules and documentation, not by simple, direct mechanical observation. By WorthDay's definitions, these are "soft" endpoints once they are used for strong causal medical claims. Composite endpoints and relative effects: The primary endpoint combines several different clinical events, and results are reported mainly as hazard ratios. Absolute risk differences, which are crucial for assessing real‑world relevance, are very small. Consequently, while the trial strongly argues against any major protective effect of daily multivitamins in this particular group, it does not, under WorthDay's strict criteria, provide high‑quality causal proof. Instead, it is best seen as: A large, well‑conducted but diagnostically framed intervention study, which fails to show any clinically meaningful cardiovascular benefit from routine multivitamin use in well‑nourished male physicians.
Limitations
- Selective population: Male physicians in the U.S. are not representative of the general population; they tend to have higher baseline health awareness, medical access and nutritional status.
- No assessment of true deficiency states: The trial does not focus on individuals with documented vitamin or mineral deficiencies; effects in genuinely deficient or malnourished groups were not tested.
- Diagnostic, not purely observational endpoints: Event classification relies on medical diagnostics and coding schemes, which WorthDay regards as indirect and assumption‑laden.
- No Null‑control: There is no group without any capsule intake; potential expectation‑ or capsule‑related effects are not separated from the specific effects of the multivitamin formulation.
WorthDay perspective
- S0031 supports a cautious view of routine multivitamin supplementation in already well‑nourished adults: the best available randomised data in this group do not show a reduction in heart attacks, strokes or deaths.
- For WorthDay, this means that "multivitamin for heart protection" should not be presented as an evidence‑based strategy in such populations.
- Instead, the emphasis should remain on primary foods, lifestyle, sleep, stress and movement, while acknowledging that – in strictly tested settings – standard multivitamin pills have not delivered the promised cardiovascular benefits.
Permalink: https://www.worth-day.com/science-compass/s0031-multivitamins-cardiovascular-disease-in-men
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