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Antioxidant Vitamins Don't Provide CardioVascular Protection

Posted: Thursday, August 23, 2007

Taking vitamin C, vitamin E, or beta-carotene supplements had no apparent effect on the long-term risk of major cardiovascular events, including stroke or death, in a trial that randomized thousands of women considered at high cardiovascular (CV) risk and followed them for an average of about nine years.  

The Women's Antioxidant Cardiovascular Study (WACS), which had separate randomizations against placebos for each of the three supplements, also found no effects from vitamin combinations on the composite primary end point, although there was a suggestion of fewer strokes from taking both vitamin C and vitamin E.

"While additional research into combinations of agents, particularly for stroke, may be of interest, widespread use of these individual agents for cardiovascular protection does not appear warranted," conclude the authors, led by Dr Nancy R Cook (Brigham and Women's Hospital and Harvard Medical School, Boston, MA).

Their findings, are consistent with clinical-trial evidence against a cardioprotective effect from any of the three antioxidant vitamins. But the absence of harm from the supplements in the current study argues against suggestions in the literature that they — vitamin E and beta-carotene in particular — may increase mortality.

Cook emphasized that the WACS findings apply to supplements only. There is abundant observational and even some clinical-trial evidence that antioxidant vitamins from dietary sources are protective against CV disease, she said.

In the trial, 8171 women with a history of CV events or at least three CV risk factors were assigned to receive each of the three vitamins or corresponding placebos in three separate randomizations. The qualifying CV events were myocardial infarction (MI), angina, stroke, transient ischemic attack (TIA), or percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). The eligible risk factors included self-reported hypertension, "high cholesterol," or diabetes; obesity; smoking; and parental history of premature MI, according to the report.

Over a mean follow-up of 9.4 years, the rate of the primary end point of CV morbidity and mortality was 17.7% and of death from any cause was 12.2%; included in the primary end point were MI, stroke, PCI or CABG, and CV death. There were no noteworthy differences in adverse advents, according to the authors.

In multivariate analysis, none of the vitamins showed significant jumps or declines in relative risks for the primary end point or for its individual components, which were prespecified secondary end points. All-cause mortality was also consistently unaffected.

In other analyses, the group writes, no significant interactions between any of the vitamins were seen for the primary end point. Subjects who received both active vitamin C and active vitamin E had a 0.69 relative risk (p=0.04) of stroke, the only secondary end point showing such a significant effect, compared with those who received both corresponding placebos.

"We looked at a lot of interactions. I think our general feeling is that [the stroke finding] is probably a false positive," Cook said. "On the other hand, I wouldn't necessarily rule it out, and I think, if possible, it should be looked at in other studies."

Solely among the subjects who entered the study with a history of CV events, vitamin E appeared to lower the risk of subsequent CV events (p=0.04).

And a few other significant effects emerged when the analyses excluded participants who didn't comply with their supplement regimens. They included a reduced risk of the composite primary end point (p=0.04) and of stroke (p=0.04) with vitamin E and elevated CV mortality (p=0.02) with beta-carotene.

But because such ancillary findings weren't part of the trial's prospective design or weren't based on intention-to-treat analysis, Cook said, she and the other WACS investigators feel they probably don't carry much weight.

Practice Pearls
Oxidative damage may play a role in the development of cardiovascular disease, particularly through its effect on lipid peroxidation and DNA damage. In addition, free radicals may damage arterial endothelium, encourage thrombosis, and alter vasomotor function.
There were no overall effects of vitamin C, vitamin E, or beta-carotene alone or in combination on cardiovascular events among women at high risk for cardiovascular disease.

Source: Diabetes In Control: Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta-carotene in the secondary prevention of cardiovascular events in women: Results from the Women's Antioxidant Cardiovascular Study. Arch Intern Med 2007;167:1610-1618

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