Dr. Armitage: I think it was the understanding that LDL, in order to become toxic, needs to become oxidized; if it's oxidized, it's taken up by the artery wall much more readily. Knowing that there are antioxidants within the diet, people got interested in whether these substances – particularly vitamin E, which circulates in the LDL particles – might be protective against toxicities.
Dr. Hutter: So that's why vitamin E got a lot of attention because it's the major one in the LDL particle.
Dr. Armitage: Yes, it seemed to be in the right sort of place. Beta carotene is also there to a lesser extent, although the beta carotene story in fact started really with cancer rather than coronary artery disease. As for these different supplements, often they were tested together; sometimes in cardiovascular trials sometimes in cancer trials.
Dr. Hutter: And I guess we should throw into the hopper that there are other trials that show antioxidants prevent vasoreactivity problems after glucose loading and things like that, so they seem to be a vasoactive species, too.
Dr. Armitage: Well, there was quite a lot of promising evidence that vitamin E in particular would work. When you look back in hindsight it doesn't look so convincing, but we were all very interested and really hopeful that vitamin E would be protective.
Dr. Hutter: So this led to trials.
Dr. Armitage: And this led to trials. One of the difficulties doing vitamin trials, of course, is that there is not a lot of money in it as far as the pharmaceutical industry is concerned (Slide 1). So, often what happens is that they're sort of added as a factorial design in a trial or done as a sort of cost-effective trial perhaps by mail as some of the more recent trials have been done. And there have been several large trials.[1-8]
 | Slide 1. |
Dr. Hutter: There have been about seven or eight trials that have been large. Could you summarize that information for us?
Dr. Armitage: I can summarize it to say that none of them have shown any cardiovascular benefit.
Dr. Hutter: And these are prospective randomized trials?
Dr. Armitage: Yes.
Dr. Hutter: Men and women?
Dr. Armitage: Yes, indeed, in a variety of high-risk and lower-risk populations (Slide 2). In our own Heart Protection Study,[5] there were 20,000 men and women on ordinary diets. They got a combination of vitamin E, vitamin C, and beta carotene in two capsules and no evidence of effect at all after 5 years.
 | Slide 2. |
Dr. Hutter: That was a huge trial.
Dr. Armitage: It was a 20,000-patient trial over 5 years, so a lot of information.
Dr. Hutter: And then there was a recent trial again in physicians...
Dr. Armitage: Indeed. Dr. Gaziano presented data at AHA 2008 (JAMA, in press), which was a randomized trial of 15,000 male physicians who took either vitamin E or vitamin C using two separate randomizations (Slide 3). But again, absolutely no evidence...
 | Slide 3. |
Dr. Hutter: No difference.
Dr. Armitage: ...of anything.
Dr. Hutter: Jane, do you think we should put that concept to rest now?
Dr. Armitage: I really think we do need to encourage our patients to stop buying these over-the-counter antioxidant or vitamins. There is no evidence of any benefit. They don't seem to be harmful, but it is wasting a huge amount of money.
Dr. Hutter: What about homocysteine? Why did that draw interest?
Dr. Armitage: Well, the original observation was that people who have a genetic defect and have very, very high homocysteine levels seem to be at risk of early vascular disease. That observation led people to look at homocysteine within the normal range and studies found that it was actually a good marker of heart disease; in particular, a marker of the risk of stroke.[9,10] That prompted a lot of studies over many years. We go back to the 1990s, the initial observational evidence suggested that a 25% lower homocysteine level was associated with huge differences — about a 60% lower risk of coronary events and strokes.[11-13]
Dr. Hutter: Sixty percent? Wow.
Dr. Armitage: In the early data, that's what it suggested. As the data have been looked at a little more carefully, particularly doing prospective observational studies — in other words only looking at where measurements have been done at baseline and people followed up over time — it doesn't seem to be as strong as that. More recent data suggest that for a 25% lower homocysteine there is about 10% less heart disease and about 20% less stroke.
Dr. Hutter: Isn't that an interesting comment in itself? More careful analysis, more sophisticated analysis, takes a 60% event reduction down to 10%.
Dr. Armitage: That's right, and we've seen this in other situations. And those studies were generally started when they thought the effects were bigger.
Dr. Hutter: Sure.
Dr. Armitage: So people set up trials to test a hypothesis, because B vitamins lower homocysteine very effectively. Several groups around the world set up trials in the '90s.
Dr. Hutter: How many trials have there been now?
Dr. Armitage: I think there have been six and then the most recent trial (Slide 4), the SEARCH Trial...
 | Slide 4. |
Dr. Hutter: In which you were a co-investigator.
Dr. Armitage: Yes and 12,000 patients were randomized and followed for almost 7 years.
Dr. Hutter: So long duration, large numbers.
Dr. Armitage: And a big difference in homocysteine (Slide 5). So they took folic acid plus vitamin B-12 or a dummy tablet. We saw almost a 30% difference in homocysteine, which was maintained over the 7 years.
 | Slide 5. |
Dr. Hutter: And the other trials also showed a marked reduction in homocysteine?
Dr. Armitage: Indeed. But the other trials didn't show benefit and our SEARCH data have added sort of half as much again and the overall effect is no effect at all on either coronary events or in stroke (Slide 6).
 | Slide 6. |
Dr. Hutter: Looking at all the trials: No benefit for cardiovascular complications whatsoever?
Dr. Armitage: No. But no evidence of any harm either. And that is important because folic acid is added to foods to try and protect against neural tube defects. So there have been concerns that the health policy of adding folate to food might have adverse effects particularly for older people. But there has been no evidence.
Dr. Hutter: Do you think we should put the treatment of elevated homocysteine to rest also?
Dr. Armitage: I think we should. We've given it a very good test and it's not come up trumps.
Dr. Hutter: Well, you just saved an awful lot of us an awful lot of money. We don't need to buy our vitamin E and other antioxidants, we don't need to buy the agents that lower homocysteine. We can save that money and put it to better use.
Dr. Armitage: And eat healthy diets: plenty of fruit and vegetables.
Dr. Hutter: Thank you, Jane. That was excellent. And thank you for joining us. I'm Dolph Hutter.
Source : http://www.medscape.com/viewarticle/587915
No comments:
Post a Comment