Lowering Plasma Homocysteine Levels Reduces Coronary Restenosis: Cath Lab Digest talks with researcher Guido Schnyder, MD

Why is homocysteine important? In 1969, McCully linked elevated plasma homocysteine levels with vascular disease. He reported extensive arterial thrombosis and arteriosclerosis in two children with homocystinuria (a disease where the patients have very high levels of homocysteine and die at an early age of coronary artery disease (CAD) or strokes).¹ After his discovery, researchers started to look into homocysteine as a possible new cardiovascular risk factor, with the hypothesis that even a slightly elevated homocysteine level might be a negative factor for patients, inducing coronary artery disease. The last 10 years have seen a multitude of cross-sectional studies looking at homocysteine levels and the incidence of CAD. These studies showed, with few exceptions, that the higher the homocysteine level, the higher the risk of having CAD. Despite those findings, the pathogenesis of homocysteine-induced vascular damage is still not clearly understood. Nonetheless, several hypotheses have been suggested: 1. Elevated homocysteine levels increase the risk of thrombosis, also within the arterial wall, inducing changes typical of arteriosclerosis. 2. There is also increasing evidence that the primary mechanism may be oxidative-endothelial injury and dysfunction. Elevated homocysteine levels not only increase the generation of hydrogen peroxide but also decrease its degradation by impairing intracellular endothelial antioxidant enzymes, thus rendering nitric oxide more susceptible to oxidative inactivation. 3. Furthermore, plasma homocysteine levels promote lipid peroxidation oxidizing LDL-cholesterol (the so-called bad cholesterol). Lipid peroxidation also enhances platelet-derived growth factor gene expression and receptor formation, inducing smooth muscle cell proliferation and extracellular matrix formation in the arterial wall. All this promotes buildup of plaque and the development of atherosclerosis. But besides the cross-sectional studies that merely associated homocysteine with CAD and the possible pathophysiologic mechanisms, there is no proof that homocysteine is not just a marker or by-product of CAD rather than an actual cardiovascular risk factor. The question that always arises is: Is atherosclerosis inducing a higher homocysteine level or is a higher homocysteine level inducing atherosclerosis? To really answer that question, long-term studies that look at the effects of lowering homocysteine on primary or secondary prevention have to be done. Half the patients receive treatment that lowers homocysteine levels and the other half a placebo. After five, ten and twenty years, you see whether patients that were treated have higher rates of death, MI, strokes and so on. Several such studies are currently under way, with the first results expected in about three to five years. Our group chose a different approach, studying a disease sharing some common pathophysiologic mechanisms with atherosclerosis. We focused on the effect of lowering homocysteine levels on restenosis after coronary angioplasty (Schnyder G, Roffi M, Pin R, et al. Decreased Rate of Coronary Restenosis After Lowering of Plasma Homocysteine Levels. NEJM. Nov 29 2001;345: 1593“1600). Coronary angioplasty is a wonderful procedure, but with one major drawback at 6 months restenosis. If you consider that worldwide, a little over one million angioplasties are performed each year, and 20“40% of those patients develop restenosis, we’re talking about a serious problem. Restenosis has been described as being a modern plague. It really puts a tremendous burden on healthcare costs. As an interventional cardiologist, I am familiar with the literature on restenosis and I have a great interest in new cardiovascular risk factors, especially homocysteine. Reading about some of the homocysteine-related mechanisms possibly promoting the development of atherosclerosis, I started to put two and two together and realized that elevated levels of homocysteine might also promote restenosis. Restenosis results from recoil, excessive smooth muscle cells and collagen deposition as well as neointimal hyperplasia, what we commonly call scar tissue. While atherosclerosis is related to the deposit of oxidized LDL in the arterial wall, the homocysteine-induced lipid peroxidation theory might be a common mechanism to both diseases. Our hypothesis was that homocysteine was responsible for some of the excessive scar production at the site treated with angioplasty. Our initial work focused on a possible correlation between restenosis and homocysteine levels. We found that patients with homocysteine levels below 9 micromol/L had about a 50% lower rate of restenosis than patients with homocysteine levels above 9 micromol/L. Do we know why homocysteine levels become elevated? Yes. Homocysteine is metabolized from methionine, an essential amino acid. Homocysteine is then either remethylated into methionine or catabolized into cystine, which is excreted in the urine. 1. About 12-14% of patients have an increased level of homocysteine because of genetic reasons. They have a deficiency in some of the enzymes that are needed to metabolize homocysteine into cystine or methionine. 2. It can also result from a lack of certain vitamins in the food, such as folic acid, vitamin B12 and vitamin B6. These vitamins are co-enzymes that play an essential role in the metabolization of homocysteine. 3. A third possibility lies in the renal processing of homocysteine, which is mainly excreted through the kidneys. Therefore, patients with decreased renal function have higher levels of homocysteine. This is probably also the reason why patients with renal failure are at a higher risk of developing CAD, because these patients tend to have a higher homocysteine level. Once we realized that there was a correlation between high homocysteine levels and restenosis, the next logical step was to try to reduce restenosis rates by lowering homocysteine levels. This can be done with three vitamins: folic acid, B12 and B6. Our study medication was: 1 milligram of folic acid 400 micrograms of vitamin B12 10 milligrams of vitamin B6 This formulation was not just a wild guess on our part. It’s based on previous research from other groups who tried to find out the ideal dosage of these three vitamins in order to have a maximal lowering effect on homocysteine levels. We decided to use what seemed to be the maximal dosage offering the maximal effect, without inducing any side effects. The study included 205 patients who were randomized in a double-blind fashion. One group got the vitamin formulation and the other group got a placebo. Both groups of patients were treated for a total of six months after having angioplasty. Patients were then restudied with a new angiogram. We measured the difference in the inner lumen of the vessel immediately after the procedure and at 6 months follow-up to see if any re-narrowing had occurred and whether the vitamin treatment had any benefit. It obviously did, reducing the rate of restenosis by almost 50%. Did lesion type or vessel size have any bearing on the success of this treatment? Both study groups were comparable in terms of lesion type, vessel size and adjunctive therapies. At the AHA 2001 Anaheim conference, we presented the encouraging effect of this therapy in small vessels. Small vessels are a real problem in our field. For vessels larger than 3 mm, stents have tremendously reduced the rate of restenosis, as has radiotherapy. The emergence of coated stents to deliver rapamycin or other drugs locally also shows promising results. However, in small vessels, there’s currently not much we can offer to our patients. The rate of restenosis in small vessels remains around 50%. A less than 3 mm vessel with 2 mm of scar tissue will be much more flow-limited than a 4-5 mm diameter vessel with the same 2 mm of scar tissue. It is encouraging to realize that with a simple vitamin combination, we can also reduce the amount of scar tissue in small vessels. People have asked me if the vitamin treatment is going to replace stents or radiotherapy, but I think this question is the wrong way to look at the results. This treatment is really just one more tool in our battle against restenosis. How long should patients continue to take the vitamin combination post-intervention? We treated our patients for 6 months, about the time it takes for restenosis to develop. It’s really only 6 months that we’ve looked at in our research, and we have no idea if taking this treatment for a longer time would help the patient. The question I am often asked is whether the vitamin treatment has any beneficial effects on the development of atherosclerotic plaque. There’s just no answer yet to that question. We have to wait for the results of the double-blind placebo-controlled trials, which should be available in about 3-5 years. Considering the absence of any side effects and the potential benefit, should we wait for those results or should we take the vitamin treatment? If, at 3-5 years out, the study results are positive, well, we would be a few years ahead in fighting the disease. If the results are negative, we could just stop. However, I think it’s up to every patient and physician to make their own decision. There are no side effects? We had one patient that had a slight itching, so he decided to discontinue the study medication. The itching resolved right away. Maybe it’s linked to the treatment, maybe not. But we did not find any serious side effects. The literature in general shows that if you take less than 5 milligrams of folic acid in combination with vitamin B12, then there are no side effects. With a dose of 1 milligram, we’re really on the safe side. Are there any patients that would not be candidates for this treatment? Since it has no serious side effects, theoretically everyone could take it. In theory, everyone could take it. There are some patients with Parkinson’s disease who take a drug that has only levodopa (dopamine). Most of the Parkinson’s drugs have levodopa and carbidopa. If you take drugs containing both types, then there’s no problem taking the vitamin treatment. If a patient is being treated only with levodopa, then they should talk to their physician. As a general rule, if you have Parkinson’s disease, I would first talk to my physician. Twenty-eight of your patients didn’t complete follow-up. You mentioned one had a problem with itching. Was there any kind of trend as to why the others did not complete the study? When a double-blind study with a new drug is performed, patients are often reluctant to participate, but when you show up and ask the patient if he’s willing to take sugar pills or vitamins, he immediately says yes. We actually had problems where we approached patients and in the same room was another patient who didn’t qualify for the study. These non-qualifying patients would also ask to participate, because they wanted to get the vitamin. This was the strength of the study, but also its weakness, because patients realized they had a 50% chance of getting a placebo. A lot of those 28 who didn’t complete follow-up called me at some point and said, Look, I want to take the vitamins, so I’m going to stop my medication and just go to the drugstore and get myself the vitamins. This was the main reason why patients stopped. A few continued to take the study medication, but then refused to have an angiogram done, which again, is fairly common in this kind of study. This treatment is dramatically less expensive than coated stents or brachytherapy. Yes. Then again, I wouldn’t put these three treatments that seem to prevent restenosis in competition. It’s unclear how much coated stents are going to cost, but probably a multiple of the price of a regular stent. Brachytherapy has also been difficult to put a number on, because you need several people standing in the room, including a radio-oncologist. But it’s expensive. The vitamin treatment is quite inexpensive and amounts to about $20-30 for 6 months. Our attitude is to give the therapy to all coronary angioplasty patients. If they come back with restenosis (in our study we still had 17% with restenosis), then brachytherapy would be an option. Later, when coated stents are available in the U.S., they will probably replace brachytherapy. But coated stents will most likely also be used for treating critical lesions, such as lesions in the left main, in the proximal LAD, bifurcation lesions, or lesions in diabetic patients. I don’t think that every patient is going to receive a coated stent for every lesion because it might just be too expensive. I believe these three treatments need to be used in combination and targeted to certain clinical situations. In regard to your study, you note that a reduction in the rate of restenosis was greatest in lesions treated only with balloon angioplasty. We performed a subanalysis in our study to see if there was a difference between balloon angioplasty-treated lesions and stented lesions. The purpose was to pinpoint the mechanism by which homocysteine-lowering therapy is reducing restenosis. Even though balloon angioplasty and stent patients can experience restenosis, the mechanism of restenosis is slightly different in those two treatments. Restenosis is a combination of recoil (elasticity of the vessel), negative remodeling (excessive scar material production in the vessel wall, growing inwardly) and excessive neointimal proliferation (proliferation of the innermost layer of the vessel wall). A stent prevents most recoil and negative remodeling. After stenting, the mechanism of restenosis takes place mainly in the endothelium or intima. There is excessive production of endothelial cells taking up space from the vessel lumen, which results in restenosis. For balloon angioplasty-treated lesions, both mechanisms take place: the increased production of endothelial cells, but also recoil and negative remodeling, which are not prevented in the absence of a stent. Realizing that homocysteine-lowering therapy seems to induce different rates of restenosis between patients treated with balloons versus stents, we are given a clue on how homocysteine therapy might work. It probably reduces both mechanisms. In patients treated with balloon angioplasty only, inhibition of both restenosis mechanisms by homocysteine-lowering therapy might double the effect of the therapy. With stents, only one mechanism causing restenosis (excessive neointimal hyperplasia) is present, because the other one (recoil and negative remodeling) has been treated with the stent (which is, of course, also true for the placebo group). Therefore, you have less of an effect in patients treated with stents. This doesn’t mean that the therapy is of no benefit in stented lesions. A subanalysis of our stented lesions, albeit not statistically significant, still shows a 31% restenosis rate reduction in favor of homocysteine-lowering therapy. So I would present this problem in a slightly different light and talk about the half-full glass rather than the half-empty one: despite the use of stents, which already reduce the rate of restenosis, homocysteine-lowering therapy still managed to reduce the rate of restenosis even more in this subgroup of patients. For a definite answer, one would have to design a study that only includes patients treated with stents. Where do you see the research heading? I think the next step is precisely to look at the differences between balloon and stents with regard to homocysteine-lowering therapy. Our study was not designed to answer that question, but the favorable trend also in stented lesions is promising. We basically have to design a study with more patients to have a definite answer. We did have a tremendous benefit with homocysteine-lowering therapy for 20 patients that were treated for restenotic lesions. This is another study that has to be done and specifically designed to answer that question. You received an overwhelming response to your article. ² I received somewhere between 1400 and 1700 emails, which took me almost two weeks of full-time work to answer. About half of those were physicians around the world asking for reprints, and the other half were from pharmacists, physicians, and patients, asking whether there is any formulation out there that replicates our study medication. In our study, the pharmacy at the University Hospital produced the vitamin and the placebo tablets. So we weren’t aware at the time of a commercially available formulation. No drug company supported the study, which made it tough to set up, but now that we managed to get it done, it’s been a blessing for us, because we’re really independent, and I think it’s given more credibility to the results. Nevertheless, pharmacists and physicians were asking, what should we prescribe? There’s no exact match to our formulation on the market right now. Immediately, what people can do is go to the drugstore, look at multivitamin formulations and put those together to more or less reproduce our formulation. There is also one company worth checking out. Pan American Laboratories (Covington, Louisiana) has all three vitamins in a supplement called Foltx®, which is nice. Their formulation has the exact relative proportion of all three vitamins but with an overall 2.5 higher dose. The advantage of Foltx is that in certain states it gets reimbursed by health insurance. Especially for physicians, that’s important information, since they can actually prescribe the drug, unlike the others, where the patient pays for it. For us, the extent of our study results have been somewhat surprising and it’s refreshing to realize there are still very simple solutions out there for complex problems. This treatment is inexpensive, has no serious side effects, is widely available and no one is making a lot of money with it. Most importantly, it seems to benefit our patients. Where did you conduct your research? This study was done in Bern, Switzerland, at the University Hospital in Bern. Professor Bernhard Meier, who was the first assistant to Andreas Gruentzig, is Director of the Cardiology Department. We have two cath labs with a volume of about 3000 diagnostic caths, of which a little over half are interventions. When compared to a lab in the U.S., this is somewhere between between a mid- and a large-size lab. I should mention that in Switzerland, the flour is not enriched with folic acid. In the United States, starting in January 1998, the FDA added 100 micrograms of folic acid to flour to prevent spina bifida in newborns, which is 10% of the amount we gave in our study. If we were to repeat the study here in the U.S., we would probably have slightly less impressive results, because the placebo patients would also receive some folic acid (100 micrograms = 0.1 milligrams) just by eating bread and pasta. But I think this is probably the only basic nutritional difference between the U.S. and the Swiss population. References 1. McCully KS. Vascular pathology of homcysteinemia: implication for the pathogenesis of arterosclerosis. Am J Pathol 1969;56:111-128. 2. Schnyder G, Roffi M, Pin R, et al. Decreased Rate of Coronary Restenosis After Lowering of Plasma Homocysteine Levels. NEJM. Nov 29 2001;345:1593“1600.

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