8,171 women were randomized into the antioxidant arms of the trial, with a mean age of 60.6 years (SD=8.8). Of these, 5,238 (64%) had a prior cardiovascular event, and 2,933 (36%) had three or more CVD risk factors. Mean BMI was 30.3 (SD=6.7), and 1,269 women (16%) were current smokers, 1,564 (19%) had diabetes, 6,137 (75%) had a history of hypertension, and 5,950 (73%) had a history of high cholesterol at baseline. There were no statistically significant differences in baseline characteristics between the randomized groups, except history of high cholesterol by beta-carotene ().
Comparison of baseline characteristics by randomized groups in the Women’s Antioxidant Cardiovascular Study.*
During the average 9.4 year follow-up, 1,450 women experienced a confirmed CVD event, including 274 MIs, 298 strokes, 889 coronary revascularization procedures, and 395 cardiovascular deaths, with some experiencing more than one event. 995 women died during follow-up.
There was no effect of vitamin C on the primary combined endpoint, with a relative risk (RR) of 1.02 (95% confidence interval (CI)=0.92-1.13, p=0.71) (). Cumulative incidence curves showed no variation of the effect over time (), and the test for proportionality of the RR over time was not significant. Individual components of the primary end point also did not differ significantly, although there was some suggestion of a benefit for ischemic stroke. When participants were censored upon noncompliance, results were similar (RR=0.95, 95% CI=0.83-1.09, p=0.47). There were no significant effects of randomized vitamin C on the primary end point in any cardiovascular risk factor subgroup considered ().
Relative risk of cardiovascular outcomes by randomized antioxidant intervention group in the Women’s Antioxidant Cardiovascular Study.*
Figure 2 Cumulative incidence of major vascular disease (myocardial infarction, stroke, coronary revascularization, or cardiovascular death), by randomized antioxidant intervention in the Women’s Antioxidant Cardiovascular Study (WACS). P-value is from (more ...)
Relative risk of major cardiovascular outcomes by randomized intervention within subgroups in the Women’s Antioxidant Cardiovascular Study.*
No differences were seen in the primary end point by randomized vitamin E assignment (RR=0.94, 95% CI = 0.85-1.04, p=0.23) ( and ), with no significant variation in the relative risk over time. We found a non-significant 16% reduction in total stroke, comprised of a 21% reduction in ischemic stroke (p=0.06) and an increase in hemorrhagic stroke based on small numbers. There was an overall 10% reduction in the combination of MI, stroke and CVD death, with a suggestion of a decrease (p=0.08) in benefit over time. No difference in total mortality by vitamin E group was found.
Censoring participants upon noncompliance led to a significant 13% reduction in the primary endpoint (RR=0.87, 95% CI = 0.76-0.99, p=0.04). Reductions in secondary study endpoints were also stronger, with a 22% reduction in MI (RR=0.78, 95% CI = 0.58-1.06, p=0.11), a 27% reduction in stroke (RR=0.73, 95% CI = 0.54-0.98, p=0.04), and a 9% reduction in CVD mortality (RR=0.91, 95% CI = 0.66-1.25, p=0.55). There was a 23% reduction in the combination of MI, stroke or CVD death (RR=0.77, 95% CI = 0.64-0.92, p=0.005). Among those with prior CVD the active vitamin E group experienced fewer major CVD events (RR=0.89, 95% CI = 0.79-1.00, p=0.04, p for interaction = 0.07) ().
For beta-carotene, there was no difference in the primary end point (RR=1.02, 95% CI = 0.92-1.13, p=0.71) ( and ), with no variation over time. There were no significant treatment effects on individual secondary endpoints. There was a non-significant 14% increase in CVD mortality in the active group, with a significant decline over time in the effect on CVD deaths (p=0.04), but no difference in total mortality. When participants were censored upon noncompliance, the effect on the primary endpoint remained non-significant (RR for major vascular disease = 1.09, 95% CI = 0.96-1.24, p=0.18), but an increase in CVD mortality appeared to emerge (RR=1.48, 95% CI = 1.08-2.02, p=0.02).
No statistically significant subgroup effects were seen for the primary endpoint. In particular, in the pre-specified subgroup of smokers, we did not find any elevation in the risk of the primary endpoint () or any of the individual components (data not shown).
Combinations of antioxidants
There were no significant two-way or three-way interactions among the agents for the primary endpoint. The effects for each of the combinations of active agents compared to the group with all three placebos is shown in (right). There were also no interactions for the secondary endpoints of MI or cardiovascular death. For stroke, we found a significant two-way interaction between vitamins C and E (p=0.03). Those in the active groups for both agents experienced fewer strokes compared to those in the placebo group for both agents (RR=0.69, 95% CI = 0.49-0.98, p=0.04) (, left).
Figure 3 Relative risk (RR) of major cardiovascular disease by eight combinations of all three active antioxidant assignments relative to the all placebo group (right); or of stroke by combinations of active vitamin C and vitamin E assignments relative to the (more ...)
We examined reports of bleeding (including gastrointestinal bleeds, hematuria, easy bruising, epistaxis), of gastrointestinal symptoms (including peptic ulcer, gastric upset, nausea, constipation, diarrhea), or of fatigue or drowsiness. There were no statistically significant differences by any of the randomized antioxidant groups except for a small increase in reports of symptoms suggestive of gastric upset among those in the active beta-carotene group (2785 vs. 2717 reports, RR=1.06, 95% CI = 1.00-1.11, p=0.05).