Homocysteine, Restenosis and Cardiovascular Risk Factors

Has it become clear that there’s a cause and effect role between homocysteine and restenosis? Up until now, the research community was trying to link homocysteine as a new cardiovascular risk factor in the development of atherosclerosis. Of course, with our most recent research, we haven’t shown anything that would prove that, but we were able to show that it might be an important risk factor for restenosis. Can you briefly review the results of your data on homocysteine? Based on the homocysteine research that had been done in the field of atherosclerosis, we started to believe homocysteine might be linked with the process of restenosis. The exact mechanisms by which elevated homocysteine levels impair vascular function and possibly influence outcome after coronary angioplasty are still not clearly understood. Nevertheless, several hypotheses have been suggested, including homocysteine-induced endothelial dysfunction, smooth muscle cell proliferation and extracellular matrix formation. That’s how we came up with the idea that homocysteine levels might be related to restenosis. First, we looked at the patient population and simply tried to link their homocysteine levels to their risk of having restenosis. Those findings were published a few years ago and clearly showed that a patient’s risk of restenosis was proportional to homocysteine levels. The logical next step was to medically lower homocysteine levels in order to influence the rate of restenosis. This can be done with three vitamins: folic acid, vitamin B12 and B6. The trial design was straightforward with a double blind randomization: one group received the vitamin treatment, the other a placebo. After successful coronary angioplasty, patients were followed for six months with a control angiogram for accurate restenosis assessment. The first study was published in the New England Journal of Medicine.¹ In our more recent publication, in the Journal of the American Medical Association,² we focused on clinical endpoints, which is ultimately what counts for the patient. Since we had some indication from our previous research that homocysteine-lowering therapy might work up to 6 months, we now faced the issue that maybe the therapy was just delaying the mechanism of restenosis. We worried that the initial benefit at 6 months might disappear after interruption of the B-vitamin treatment. To face this concern, we extended the clinical follow-up for another 6 months. The results remained very encouraging. The overall risk reduction at 6 months was 38% and was maintained at 12 months, with a 32% benefit in favor of the vitamin treatment. I think the conclusions are quite compelling. Lowering homocysteine seems to have a long term benefit after coronary angioplasty. One has to look at the event curves that separate after 8-10 weeks. They keep on separating for the first 6 months, and then stay parallel. There seems to be no additional benefit in continuing the vitamin treatment beyond six months for prevention of restenosis, which is known to take between 3-6 months. We also found a strong trend in favor of reducing myocardial infarction and death. Extending the treatment beyond 6 months might have increased the benefit with regard to those endpoints. Yet we can’t conclude from those findings whether patients would truly benefit with regard to these two strong endpoints (myocardial infarction and death) by extending the vitamin treatment beyond 6 months. Some labs used to measure homocysteine levels, but what happens now is that the physicians will just prescribe vitamins if they feel it might be beneficial. That’s exactly what we did. Homocysteine level wasn’t a criteria to be included in the study; we nevertheless measured homocysteine levels on the day of the procedure. It is a rather expensive test, somewhere between $150-200. Most hospitals collect samples and do the analysis once a week. So there’s not only a time issue, but also, looking at the subgroup of patients with so-called normal homocysteine levels, those patients still seemed to benefit from lowering their homocysteine. The benefit wasn’t as important for the normal-level patients as for those with higher homocysteine levels, but still they received a benefit. I think it makes a lot of sense, especially with regard to restenosis, not to bother about the absolute level and to treat all patients for a 6-month time period. With regard to a potential benefit in primary or secondary prevention of atherosclerosis, measuring homocysteine would make a lot of sense, to improve long term compliance. If a patient knows his level is high, he’s going to take his vitamins every day. If he does not know his level, he’s probably not going to. I recommend at least one measurement if homocysteine therapy is considered for long-term cardiovascular prevention, which by the way has not yet been proven of any benefit. Has there been any gender analysis? Nowadays, there are two beliefs with regard to homocysteine issue. Some physicians are convinced it is a new cardiovascular risk factor, while others say it is a marker, meaning that if your homocysteine is elevated, this is just a marker of the patient’s overall bad health. Therefore, it was very important to control our results for the traditional cardiovascular risk factors. We looked at gender issues along with all the other cardiovascular risk factors, and the benefit in women was similar to the one in the general population. Flour in the U.S. already contains folate (100 micrograms) as opposed to no folate in the flour in Switzerland, where the study took place. I would like to point out that this small amount of folate (100mg) has been implemented for women of childbearing age, who most likely have a different diet than the average older cardiac patient. Furthermore, 100mg is believed to be absorbed daily by those in the United States who have an average balanced diet. This intake amounts to 10 percent of the 1mg of folate and none of the vitamin B12 and B6 given to our patients. There is no basis for assuming that such an intake alone would be adequate to achieve the lower rate of restenosis seen in our study. While it will be important to have our results reproduced in a U.S.-based population, it would be unduly ethnocentric to exclude a beneficial treatment with virtually no side effects, based on speculation that it may be less applicable to U.S. patients. Furthermore, it would not surprised me if the average Swiss patient had a healthier diet than the average U.S. person. There are far fewer obese patients in Switzerland and our overall study baseline homocysteine levels were rather low, suggesting that the 100mg supplemented in the U.S. flour might be available to Swiss patient through an overall healthier diet. Is the benefit from the vitamins linked only to homocysteine levels? We cannot exclude the possibility that the benefit seen was not also influenced by other homocysteine-independent treatment effects. Specifically, folic acid likely improves nitric oxide availability independently of its homocysteine-lowering effect, and vitamin B6 deficiency appears to be an independent predictor of coronary artery disease and further has been shown to alter platelet function. Therefore a homocysteine-unrelated effect of folic acid, vitamin B12 or B6 could have contributed to the improvement seen in our study. Still, if I had to undergo coronary angioplasty, there’s no doubt I would take the vitamin treatment. It’s cheap and there are no side effects. What kind of research is going on with homocysteine right now? There are many ongoing trials, but some of the most promising are five multicenter, randomized, double blind, placebo-controlled trials looking at cardiovascular prevention. The Norwegian Vitamin Interventional Trial (NORVIT) and the Western Norway B-vitamin Intervention Trial (WENBIT) will assess the effects of homocysteine-lowering therapy in patients with coronary artery disease. The Vitamin Intervention for Stroke Prevention (VISP) study in the United States will report the effect of B vitamins on stroke recurrence in patients with cardiovascular disease. The Prevention with a Combined Inhibitor and Folate in Coronary Heart Disease (PACIFIC) study in Australia, and the Study of Effectiveness of Additional Reduction in Cholesterol and Homocysteine (SEARCH) in the United Kingdom will address similar issues. These five trials are really going to answer most of our questions and will tell whether we should implement homocysteine-lowering therapy on a large scale. I am, of course, biased in regard to homocysteine issues. I love the whole idea of a potential new cardiovascular risk factor, especially the fact that one can treat it in such a simple, inexpensive way that doesn’t trigger side effects. In a field dominated by complex and expensive devices and medications, I find our results extremely refreshing.