Homocysteine lowering does not reduce heart attack risk

by Crystal Phend

Homocysteine-lowering supplements do not help prevent further cardiovascular events in heart attack survivors, a large randomized trial affirmed.

The trial, which followed more than 12,000 heart attack survivors over nearly seven years, found that folic acid plus vitamin B12 effectively reduced homocysteine levels, but did not reduce major vascular events overall nor any other individual endpoint compared with placebo, reported Jane M. Armitage, BM BChBSc, MBBS, of the University of Oxford, England, and colleagues.

Despite concerns raised by other studies that folate may be linked to increased cancer risk, this was not seen in the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial, the authors noted in the June 23/30 issue of the Journal of the American Medical Association.

These results reinforce the lack of benefit for homocysteine-lowering supplements seen in other secondary prevention trials, such as the Western Norway B-Vitamin Intervention Trial (WENBIT), the HOPE-2 (Heart Outcomes Project Evaluation) study, the Norwegian Vitamin (NORVIT) trial, and others.

Some suggestive subgroup and meta-analyses of these prior trials had supported a potential protective effect against stroke, but the SEARCH trial was large enough to effectively resolve the issue with a prespecified stroke endpoint.

The SEARCH results showed nearly identical stroke rates in both groups — 4.5% among patients taking homocysteine-lowering vitamins and 4.4% in the placebo group (risk ratio 1.02, 95% CI 0.86 to 1.21).

Importantly, these results were seen in a British population not exposed to mandatory folic acid fortification in foods, giving the vitamins their best chance to shine, the researchers noted.

Taken together, it’s time to move on to what works, Armitage and colleagues said.

“These results highlight the importance of focusing on drug treatments (e.g., aspirin, statins, and antihypertensive therapy) and lifestyle changes (in particular, stopping smoking and avoiding excessive weight gain) that are of proven benefit, rather than lowering homocysteine with folic acid–based vitamin supplements, for the prevention of cardiovascular disease,” they wrote in JAMA.

Alice H. Lichtenstein, DSc, director of the Cardiovascular Nutrition Laboratory at Tufts University in Boston, agreed, calling the study the “final nail in the coffin” for homocysteine lowering.

“I think we have gone through a period of high hopes that vitamin E, beta carotene, and folate in supplemental form would decrease risk of cardiovascular disease,” she told MedPage Today. “After a whole series of studies we’ve found that is not the case, so we have to put more emphasis on what we know does work.”

The double-blinded SEARCH trial randomized 12,064 heart attack survivors treated at secondary care hospitals in the U.K. between 1998 and 2008 to treatment with 2 mg folic acid plus 1 mg vitamin B12 daily or a placebo.

After 6.7 years of follow-up, adherence in both groups was excellent at 84% and 85%, respectively.

As expected, homocysteine levels dropped by 28% in the supplement group (3.8 μmol/L lower than the placebo group) by the end of the study.

For the primary endpoint of the combined rate of first major coronary event (coronary death, MI, or coronary revascularization), fatal or nonfatal stroke, or noncoronary revascularization, the supplements held no advantage over placebo (25.5% versus 24.8%, RR 1.04, P=0.28).

The same was true for vitamins versus placebo in the secondary endpoints, including the following:

* Major coronary events (20.4% versus 19.6%, RR 1.05, 95% CI 0.97 to 1.13)
* Stroke (4.5% versus 4.4%, RR 1.02, 95% CI 0.86 to 1.21)
* Noncoronary revascularization (3.0% versus 2.5%, RR 1.18, 95% CI 0.95 to 1.46)
* Deaths attributed to vascular causes (9.6% versus 9.3%, RR 1.04, 95% CI 0.92 to 1.16)
* Death attributed to nonvascular causes (6.7% versus 6.5%, RR 1.04, 95% CI 0.90 to 1.19)
* Incidence of new nonmelanoma cancer overall (11.2% versus 10.6%, RR 1.07, 95% CI 0.96 to 1.19) or by specific site, including colorectal cancer (1.4% versus 1.5%, RR 0.95, 95% CI 0.71 to 1.27)

The trial also found no benefits for homocysteine-lowering with regard to cognitive impairment, hearing loss, fracture, or blood pressure.

Crystal Phend is a MedPage Today Senior Staff Writer.

Originally published in MedPage Today. Visit MedPageToday.com for more cardiology news.