B Vitamins Do Not Lower Risk of Cardiovascular Events Among Transplant Recipients

Norra MacReady

November 05, 2009

November 5, 2009 (San Diego, California) — Lowering total plasma homocysteine levels in renal transplant recipients (RTRs) does not reduce their risk of cardiovascular events or all-cause mortality relative to a control group, according to Andrew G. Bostom, MD, associate professor of medicine at Rhode Island Hospital, Providence.

"There was no evidence of a treatment effect," Dr. Bostom said at a plenary session here at Renal Week 2009, the annual meeting of the American Society of Nephrology.

Observational studies involving thousands of patients going back more than 20 years have suggested an association between high levels of total homocysteine (tHcy) and an increased risk of coronary heart disease and other cardiovascular outcomes, said Dr. Bostom, This relationship has been seen in people with chronic renal insufficiency and end-stage renal disease, as well as stable RTRs and people without kidney disease.

The Folic Acid for Vascular Outcome Reduction in Transplantation Trial (FAVORIT) tested the effect of reducing tHcy levels in RTRs by adding high doses of folic acid, pyridoxine, and vitamin B12 to a standard multivitamin supplement. "About 24 million people in the United States have stage 3 or 4 chronic kidney disease, and we felt the data on the RTR population might be applicable to them as well," said Dr. Bostom, the principal investigator.

In FAVORIT, 4110 RTRs at 30 clinical sites across North America and Brazil were randomly assigned to either the high-dose or standard (low-dose) supplement. To be eligible, they had to have had a functioning renal allograft for at least 6 months and have tHcy levels of at least 11 μmol/L for women or 12 μmol/L for men. Homocysteine levels for people with normal renal function range from 6 to 12 μmol/L.

The 2 groups shared similar baseline characteristics, including mean age (52 years), sex distribution (37% women), and histories of stroke, hypertension, and diabetes. The primary endpoint was pooled arteriosclerotic cardiovascular disease (CVD) outcomes, including CVD death or nonfatal myocardial infarction, resuscitated sudden death, stroke, or need for an invasive procedure for coronary, peripheral, or renovascular disease. The planned follow-up period was 5 years, but the trial was halted early because of evidence of adverse effects after a median follow-up of 3.5 years.

At baseline, both groups had a mean tHcy level of 16.4 μmol/L. By year 4 of the study, mean tHcy levels for the high-dose and low-dose vitamin groups were 11.8 μmol/L and 15.9 μmol/L, respectively, "really in line with what we had predicted," Dr. Bostom said.

There was no difference in cardiovascular outcomes, he noted. At 3.5 years, there were 236 CVD events in the high-dose group and 252 events in the low-dose group. Despite their transplants, 149 patients in the high-dose group and 139 patients in the low-dose group had progressed to dialysis-dependent end-stage renal disease, and all-cause mortality in the high-dose and low-dose groups was 202 and 195, respectively. All in all, after adjusting for age, race, sex, smoking, systolic blood pressure, diabetes status, and cholesterol levels, the hazard ratio for CVD events for the high-dose vitamin group was 1.0, indicating no difference in risk.

Findings like these suggest that "the era of using pharmaceutical doses of B vitamins is nearly over," said Andrew A. House, MD, associate professor of medicine at the University of Western Ontario, London, Canada, who was not involved in FAVORIT.

In a study of people with diabetic nephropathy, Dr. House and his associates similarly found that B-vitamin supplementation did lower plasma tHcy levels but did not help clinical outcomes. In fact, supplementation was associated with a faster decline in estimated glomerular filtration rate — 3.9 mL/minute/year compared with 3.3 mL/minute/year in the placebo group (P = .008). "What was even more surprising was that the risk of stroke and myocardial infarction nearly doubled" among patients receiving the supplements, said Dr. House.

There are now "scores of well-conducted randomized clinical trials showing no benefit, and this one showing harm," he concluded. "I think we probably should discourage our patients from using B vitamins."

Dr. Bostom and Dr. House have disclosed no relevant financial relationships.

Renal Week 2009: American Society of Nephrology 2009 Annual Meeting: Abstract 7007. Presented October 30, 2009. Abstract SA-FC343. Presented October 31, 2009.

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