CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Sanjay Kaul, MD*,
Andrew A. Zadeh, MD and
Prediman K. Shah, MD
* Cedars–Sinai Medical Center, Cardiology, South Professional Tower, Room 5536, 8700 Beverly Boulevard, Los Angeles, California 90048-1804 (Email: kaul{at}cshs.org).
The data from the 3 largest completed trials of homocysteine lowering with folic acid and vitamin B12 with or without vitamin B6 (VISP [Vitamin Intervention for Stroke Prevention] [1], NORVIT [Norwegian Vitamin Trial] [2], and HOPE-2 [Heart Outcomes Prevention Evaluation] [3]) consistently demonstrate no treatment benefit in patients with established vascular disease. These trials primarily evaluated white, middle-aged patients exposed to folate-fortified food (70% in HOPE-2, 100% in VISP) with only mild increases in homocysteine levels (<15 µmol/l). We agree that homocysteine-lowering therapy might potentially still prove to be beneficial in populations other than those studied—for example, in Southeast Asian patients where homocysteine levels typically exceed 15 µmol/l related to genetic or dietary factors, as suggested by Dr. Akhtar. However, subgroup analyses of the NORVIT and HOPE-2 trials provide useful insights. In 40% of patients in the NORVIT trial with a baseline homocysteine level above 13 µmol/l (mean homocysteine level was 17.4 µmol/l in this subgroup), homocysteine-lowering therapy provided no benefit. Similarly, no treatment benefit was observed among patients in the upper fifth of the baseline homocysteine distribution ( 19.7 µmol/l) in HOPE-2. It is quite possible that this lack of benefit may be related to inadequate statistical power in these subgroups. Thus, whether homocysteine-lowering therapy is going to be beneficial cannot be answered definitively until prospective, randomized trials are conducted in these populations. Ongoing large trials that are currently exploring these issues and the planned meta-analyses of all trials (12 trials involving about 52,000 participants with adequate statistical power, 7 in populations without fortification, and 5 in populations with fortification) (4) might help answer remaining relevant clinical questions.
With regards to folate therapy and in-stent restenosis, we do mention in our article (5) (p. 916) that slight, but not significant, benefits were observed in patients with elevated homocysteine levels (27.2% vs. 31.7%; p = NS).
A causal link between recent trends toward a lower rate of death from stroke in the U.S. and Canada and the fortification of food with folic acid remains speculative, as many other factors may have contributed to the decline (6).
Finally, we agree with Dr. Akhtar that a major obstacle to developing tools that address health problems of people in developing countries is the so-called 10/90 problem, whereby 90% of health research expenditure is targeted at problems affecting only 10% of the world’s population. Investment in health, both at the individual country level and at a global level, should therefore be encouraged to provide the necessary resources to develop these tools and enhance public health.
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1. Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial JAMA 2004;291:565-575.[Abstract/Free Full Text]2. Bønaa KH, Njølstad I, Ueland PM, et al. NORVIT Trial Investigators Homocysteine lowering and cardiovascular events after acute myocardial infarction N Engl J Med 2006;354:1578-1588.[Abstract/Free Full Text] 3. Lonn E, Yusuf S, Arnold MJ, et al. Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators Homocysteine lowering with folic acid and B vitamins in vascular disease N Engl J Med 2006;354:1567-1577.[Abstract/Free Full Text] 4. B-Vitamin Treatment Trialists’ Collaboration Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials Am Heart J 2006;151:282-287.[CrossRef][Web of Science][Medline] 5. Kaul S, Zadeh AA, Shah PK. Homocysteine hypothesis for atherothrombotic cardiovascular disease: not validated J Am Coll Cardiol 2006;48:914-923.[Abstract/Free Full Text] 6. Yang Q, Botto LD, Erickson JD, et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002 Circulation 2006;113:1335-1343.[Abstract/Free Full Text]
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