If we are to believe the conclusion of Professor K. H. Bonaa, leader of the recent NORVIT trial, the homocysteine hypothesis is now dead, and patients who’ve had myocardial infarctions should not take B vitamins. If they do, the data suggest they’re at higher risk of second MI or stroke, and further, increased risk of cancer. The question is, should we believe Prof. Bonaa?
The NORVIT study was presented orally at the European Society of Cardiology Congress 2005 (see report at left). The data have not yet been published in a peer-reviewed journal. Yet the surprising results were well publicized, and like the reaction to similar news earlier this year that supplemental vitamin E increased mortality, physicians are now told to advise patients against B vitamins. In light of the overall evidence, this NORVIT-driven recommendation is questionable.
Hyperhomocysteinemia has been shown to promote restenosis in models of atherosclerosis. Several clinical trials also show high homocysteine (Hcy) is associated with restenosis after angioplasty or stenting. In one study, folate markedly reduced restenosis, from 37.6% among controls to 19.6%. in treated patients (Schnyder G, et al. Ann Med. 2003; 35(3): 156–163). In another, folic acid and vitamin B12 improved vascular endothelial function in patients with CHD (Chambers JC. Circulation. 2000 Nov 14; 102(20): 2479–2483).
NORVIT patients had all had MIs within 7 days of participation. Standard treatment in such patients usually consists of intensive drug therapy, including high-dose statins and drugs to lower C-reactive protein. In NORVIT, about 90% of subjects were on aspirin and beta-blockers; about 80% were on statins.
Concurrent drug therapy is one of several confounding variables in NORVIT. Many common drugs, including lipid-lowering fibrates, niacin, hydrochlorothiazide, methotrexate, levodopa, and anticonvulsants can raise Hcy. The oral presentation of the NORVIT study did not include baseline data on how many subjects were taking any of these medications. Similarly, there was no information on diet and lifestyle factors or concurrent disorders, though we know all of these can affect Hcy and folate. Smoking raises Hcy, as does coffee, both of which are popular in Norway. Alcohol and aspirin lower folic acid levels. Hcy also correlates with creatinine level, and in patients with chronic renal failure, high Hcy is resistant to folic acid or vitamin therapy.
NORVIT randomized subjects into 4 groups in a 2 × 2 factorial design: (1) folic acid + vitamin B6; (2) folic acid alone; (3) vitamin B6 alone; (4) placebo. Dosages were folic acid at 0.8 mg/day (with vitamin B12 at 0.4 mg/day) and vitamin B6 at 40 mg/day. I, and others, question whether NORVIT was sufficiently powered to reach statistically significant conclusions.
In order to support healthy remethylation patterns, one of two primary mechanisms thought to underlie folate’s proposed CV benefits, folate alone is insufficient and must be accompanied by adequate B12. The 28% drop in Hcy achieved in groups 1 and 2 is probably inadequate to impact CV event rates. A decrease in Hcy level to 7–8 μmol/L should be the target goal (Miller AL, Kelley GS. Alt Med Rev. 1997; 2(4): 234–254), but this was not a defined target in NORVIT.
Baseline pre-MI Hcy data were not provided in the preliminary NORVIT report, yet we know that Hcy rises significantly for up to one week after MI, and may be associated with a healing response as much as representing a prognostic marker. Without knowing the pre-MI baselines, it is difficult to estimate a reasonable expectation for B vitamin therapy in this cohort. What we do know is, Hcy values over 10 μmol/L increase the possibility of long term all-cause mortality after a non-ST segment elevation acute coronary event (Facila L, et al. Int J Cardiol. 2005 Apr 20; 100(2): 275–279).
The NORVIT report did not specify what forms of folic acid, vitamins B12 and B6 were used, nor any authentication of their potency. Enzyme deficiencies (the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene) and liver disease can result in inability to convert folic acid into its biologically active form. If a significant number of NORVIT patients were poor converters, the net effect of folate on CV function could be compromised.
Dr. Bonaa commented, “the results of the NORVIT trial are important because they tell doctors that prescribing high doses of B vitamins will not prevent heart disease or stroke. B vitamins should be prescribed only to patients who have B vitamin deficiency diseases.” He went on to state “The homocysteine hypothesis is dead.” God must be jealous!
Extrapolating the results of NORVIT, a secondary prevention trial, to stable patient populations who’ve not had MIs is beyond arrogant. It is irresponsible and reprehensible. Clinical and epidemiological studies in the past two decades show that elevated Hcy is at least a modest independent predictor for atherosclerosis, cardiovascular disease and stroke in the general population, supporting the “homocysteine hypothesis,” though causality and precise pathophysiological mechanism(s) remain unproven.
Bear in mind that folic acid does many things besides reducing Hcy. For one, it increases nitric oxide in endothelial cells. In a recent double-blind study of people with CHD, folic acid (30 mg per day) improved coronary blood flow as measured by PET scan. The improvement was especially enhanced in areas of the heart that had shown reduced blood flow prior to supplementation. Folic acid supplementation also significantly lowered blood pressure (Tawakol A, et al. J Am Coll Cardiol. 2005; 45: 1580–1584).
Readers are referred to a recent analysis of 12 large-scale randomized trials of B-vitamin supplementation and risk of CVD (Clark R. Semin Vasc Med. 2005 May; 5(2): 215–222). Taken together, these trials involve over 50,000 patients. A meta-analysis of these, and other trials, totaling over 100,000 patients, should have adequate power to definitively determine whether Hcy-lowering B vitamin supplements can reduce CVD and prevent all-cause mortality and morbidity.
Miller and Kelley have recommended that at least 800 mcg of folate and 800 mcg of B12 should be taken to support healthy re-methylation. An additional 100 mg daily of Vitamin B6 should be taken to support homocysteine’s trans-sulfuration pathway. Trimethylglycine (500–6000 mg daily) and S-adenosyl-methionine (SAMe) (200–800 mg daily) may be needed along with higher doses of folate B12 and B6 to achieve an optimal Hcy level of 7–8 μmol/L. Healthy Hcy metabolism is critical for endogenous production of a host of essential compounds in the body, including carnitine, taurine, glucosamine sulfate, coenzyme Q10, and melatonin.
While the NORVIT data warrants serious attention, the rumors of homocysteine’s death are greatly exaggerated. I believe that inexpensive, well-tolerated Hcy-lowering treatment should still be considered a rational approach in patients with high Hcy baselines who are at high risk of MI and stroke.
Michael Traub, ND, is past-president of the American Association of Naturopathic Physicians. He practices in Kailua-Kona, Hawaii.
