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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #166385
Title: POWER SHORTAGE: CLINICAL TRIALS TESTING IN THE "HOMOCYSTEINE HYPOTHESIS" AGAINST A BACKGROUND OF FOLIC ACID-FORTIFIED CEREAL GRAIN FLOUR

Author
item BOSTOM, ANDREW - RHODE ISLAND HOSPITAL
item SELHUB, JACOB - TUFTS-HNRCA
item JACQUES, PAUL - TUFTS-HNRCA
item ROSENBERG, IRWIN - TUFTS-HNRCA

Submitted to: Annals of Internal Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/1/2001
Publication Date: 7/1/2001
Citation: Bostom, A.G., Selhub, J., Jacques, P.F., Rosenberg, I.H. 2001. Power shortage: clinical trials testing in the "homocysteine hypothesis" against a background of folic acid-fortified cereal grain flour. Annals Of Internal Medicine. 135:133-137.

Interpretive Summary: Large randomized, controlled trials of total homocysteine lowering therapy for the potential reduction of cardiovascular disease outcomes are ongoing in the United States and Canada. These trials are the Vitamin Intervention for Stroke Prevention (VISP) trial, the Women's Antioxidant Cardiovascular Disease Study (WACS), and the Heart Outcomes Prevention Evaluation (HOPE2). However, the dramatic effect of policies mandating fortification of cereal grain flour products with folic acid may reduce the statistical power of these trials. All three trials assume that the active treatment groups will achieve the same mean effects of total homocysteine lowering therapy as those reported in the absence of folic acid fortified cereal grain flour. This paper examines this assumption using data from studies of total homocysteine-lowering therapy in U.S. and Canadian patients with cardiovascular disease who were exposed to products made with folic acid fortified cereal grain flour. These data showed that the VISP trial, HOPE2, and WACS will probably achieve only approximately 20-25% of the projected treatment effects of mean total homocysteine lowering therapy (1.0 to 1.5 micromole/L vs. 4.0 to 6.0 micromole/L. As a result, all three trials will be substantially underpowered to test the specific hypotheses of total homocysteine-lowering therapy identified a priori. In contrast, renal transplant recipients have a persistent excess prevalence of hyperhomocysteinemia in the era of fortification but remain very responsive to supraphysiologic doses of folic acid based supplementation (mean reduction in total homocysteine level, 5.0 to 6.0 micromole/L. Therefore, unlike other populations with normal renal function that are at high risk for cardiovascular disease but are profoundly affected by fortification efforts, renal transplant recipients continue to merit serious consideration for a controlled trial of the "homocysteine hypothesis."

Technical Abstract: Large trials of total homocysteine (tHcy) 'lowering therapy for the potential reduction of cardiovascular disease (CVD) outcomes are ongoing in the US and Canada. These trials are the Vitamin Intervention for Stroke Prevention (VISP) trial, the Women's Antioxidant Cardiovascular Disease Study (WACS), and the Heart Outcomes Prevention Evaluation (HOPE2). However, the dramatic effect of folic acid fortification of enriched cereal grain products may reduce the statistical power of these trials. All three trials assume that the treatment groups will achieve the same ean effects of tHcy-lowering therapy as those reported in the absence of folic acid-fortification. This paper examines theis assumption using data from studies of tHcy-lowering therapy in patients with CVD who were exposed to folic acid fortification. Based on patients exposed to fortification, these 3 trials will probably achieve only about 20-25% of the projected treatment effects of tHcy-lowering therapy. As a result, all 3 trials will be substantially underpowered to test the specific hypotheses of tHcy-lowering therapy identified a priori. Incontrast, renal transplant recipients still have an excess prevalence of hyperhomocysteinemia in the era of fortification by remain very responsive to high doses of folic acid-based supplementation. Therefore, unlike other populations affected by fortification, renal transplant recipients continue to merit serious consideration for a trial of the homocysteine hypothesis.