 | with Norman Swan
Monday 30 June 2003
'Polypill' Summary:
Researchers in Britain are suggesting that the so-called 'Polypill' has the potential to cut down heart attacks and stroke significantly. Transcript:
Norman Swan: Today on The Health Report, more detail than you’ve had in the media so far on a story that broke on Friday, namely on a ‘polypill’, which, if people over 55 were to take every day, could cut heart attacks and stroke dramatically, and extend life expectancy significantly.
If you were to believe some of the reporting, the pill exists already and is being trialled, but that in fact is not the case. It is though, worth digging further into this radical proposal to see whether something that sounds too good to be true, is.
The series of papers in The British Medical Journal float an idea, a concept, based in large part on what are called meta-analyses: reviews of the combined best evidence from all the trials on a given topic around the world.
The proposal is to develop a pill which has six components: a cholesterol-lowering medication, one of the family called statins; three commonly-used blood pressure lowering drugs at half dose; low-dose aspirin which makes platelets less sticky and therefore blood clots less likely, and folic acid, which lowers a relatively newly recognised risk factor in the blood called homocysteine.
The critics aren’t going to take this lying down because it means treating otherwise healthy people with potentially harmful medications. Will there truly be a nett benefit both healthwise and economically?
The team which put forward the evidence was led by Nick Wald, who’s Professor of Environmental and Preventive Medicine at the Wolfson Institute of Preventive Medicine at the University of London.
Nick Wald is used to leading with the chin on controversial issues. He was the one who first proposed, amidst a lot of scepticism, the triple blood screening test in pregnancy for Down’s Syndrome, which has now become the standard almost world-wide.
So his track record isn’t bad.
I spoke to Nick Wald over the weekend, and asked him to justify the medications he’d chosen to make up this polypill of the future, and especially why he thinks it should include three drugs for blood pressure at half dose.
Nick Wald: The reason for that is that they’re associated with side effects which can be troublesome, but by using half dose, you substantially reduce the frequency of those side effects, and by using three, you have an additive or synergistic effect on efficacy. So it maximises efficacy and minimises side effects on blood pressure lowering.
There’s one statin that lowers LDL cholesterol, folic acid lowers homocysteine, and aspirin lowers platelet stickiness.
Norman Swan: Which was the most important component? I mean if you had to have one rather than all the others, which was the most important.
Nick Wald: With respect to heart disease, it’s the statin, easily, and with respect to stroke, it’s the three blood pressure lowering agents. The statin can lower heart disease by about 60% and the blood pressure lowering ones can reduce stroke by about 60%. They dominate in terms of risk reduction but by adding the others, you can get in respect of heart disease, from about 60% to 88% reduction, and with respect to stroke, from 60% to about 80%.
Norman Swan: Let’s just look at the evidence a little bit more closely. If you take for example aspirin, my understanding of the evidence for low dose aspirin is that people have retreated from their enthusiasm of a few years ago, and the recommendation for aspirin was really men over 50 at high risk of coronary heart disease, or who already had coronary heart disease, and that the risk of, say, a haemorrhagic stroke, a bleed into the brain, was too high to recommend it to healthy men over the age of 50. So aren’t you taking an undue risk by putting aspirin in there?
Nick Wald: No, for I think two reasons. One is a meta-analysis of all the low dose aspirin trials shows a clear nett benefit, certainly from age 55, where the majority of strokes are going to be thrombotic strokes, and where the aspirin has a big effect on thrombotic strokes.
Norman Swan: Thrombotic meaning there’s a clot.
Nick Wald: There’s a clot, yes. It is true that there will be an increase in haemorrhagic strokes, but the nett effect is clearly in favour.
Norman Swan: And you’ve made a jump to saying we should be taking folic acid when there really aren’t any randomised control trials yet showing that if you do reduce homocysteine, you get a benefit in terms of heart disease, although there are lots of other studies which suggest there is a link.
Nick Wald: That’s correct. Of all the risk factors, the evidence on homocysteine reduction producing risk is the weakest. The others are all very well demonstrated with randomised trials. But the evidence on homocysteine reduction comes largely from the epidemiological evidence which could be affected by bias, confounding.
Norman Swan: Professor Wald argues that the evidence for homocysteine being a true causative factor in heart disease is strongly supported by studies in people with an abnormal enzyme involved in folic acid metabolism. This genetic defect gives them high homocysteine levels and high rates of heart disease.
But there is a risk in extrapolating from studies where all they’ve done is observed a group of people, some of whom have high homocysteine levels, and some of whom don’t, and watched what’s happened to them over the years. And that risk is exemplified by hormone replacement therapy where such observational studies showed that women on HRT had less heart disease, stroke, and possibly even dementia.
Yet when they did a randomised trial, comparing HRT with placebo, which eliminates as many sources of error as possible, HRT turned out either to be harmful or of no benefit.
But Nick Wald doesn’t think folate supplementation is going to be the same story.
Nick Wald: No, that’s right, because I think with hormone replacement therapy, it really was uncertain as to whether the HRT was protective, or whether the women who took HRT were at low risk. That was the genuine uncertainty that required a randomised trial. Similarly, the evidence on beta carotene and vitamin E was a situation where the observational evidence could either indicate a causal relationship or an indirect effect where there wasn’t a causal link, and randomised trials there have shown that neither beta carotene nor vitamin E, have any protective effects. So I think if it wasn’t for this genetic marker, providing this investigative tool, I’d be equally uncertain, but I think given the evidence on the genetic enzyme defect, the evidence is actually very persuasive.
Now I accept that some people will want to wait until the randomised trials are completed, and so be it. The only problem with the randomised trials is the expected effect of homocysteine reduction is relatively modest compared to the statins and blood pressure lowering, so they’ll have to be extremely large, and there is a risk that intermediate sized studies which don’t show a significant result, will be interpreted as negative, when in fact if they were larger, they’d be positive and fit in with the expected estimate.
Norman Swan: And you’re confident that folic acid’s not going to turn out like beta carotene to be actually harmful, to be blocking the effects of the recent studies suggesting that beta carotene actively blocks the effects of fruit and vegetables.
Nick Wald: I must say I’m sceptical of that interpretation. I was sceptical of beta carotene being as protective as people made out years ago, and I’m now similarly sceptical that it’s actually harmful. I think it’s more likely than not, irrelevant to either. So I do remain rather agnostic. I’m not saying that they may not be a risk to beta carotene, but at the moment I’m not persuaded that they are. But I think the point that you make is valid. There was prior suggestion that it was protective, and there’s now no evidence for that. I don’t think that’s likely to apply to folic acid homocysteine and cardiovascular disease.
Norman Swan: How many people over the age of 55 would have to take this pill on a daily basis for one person to be saved from a heart attack or a stroke?
Nick Wald: Three.
Norman Swan: Three?
Nick Wald: Yes.
Norman Swan: That’s extraordinary.
Nick Wald: Yes, it is. If you take 100 people, one third of them, about 35 people, will stand to benefit, and on average those people would have about 12 years of additional life; it’s a very big effect. It’s simply a reflection of how important heart attack/strokes are in curtailing life expectation in our society. The ultimate benefits of this is going to be reduced in absolute terms, because heart disease and strokes are reducing anyway in Australia and Britain and America, but the proportional benefit will still be similar. It will be about one in three will benefit.
Norman Swan: And how many people would be taking the pill for one to be harmed by it?
Nick Wald: In terms of serious harm, it will be very few. It will be of the order of one in 1,000 or less.
Norman Swan: So 1,000 people would have to take the pill on a daily basis for one to be seriously harmed, in other words a haemorrhagic stroke, presumably?
Nick Wald: Of the order of that, yes. But there will be some such cases. It’s not a total win-win situation. But the trade-off is easily in favour of benefit.
Norman Swan: And what about other diseases, like cancer?
Nick Wald: Well there’s no indication from any of these, either folic acid or the blood pressure lowering drugs, or the statins, you know, cholesterol lowering; there was a while, 15 years ago when people thought the cholesterol lowering might be associated with cancer, but that really has been clearly put to rest. There’s no evidence at all for it, and considerable evidence against it.
Norman Swan: So you believe that they all cause mortality, in other words, there’s not going to be a trade-off apart from, say haemorrhagic stroke that the total mortality in this group of people taking this pill, will go down?
Nick Wald: Yes, it will go down. Although looking at total mortality the impact – I mean it will be quite big compared to looking at all cause mortality if you were to avoid breast cancer, because that only accounts for about 5% of deaths in all women. Here you’re looking at a group of diseases that account for a third of deaths in all people. So it will have a demonstrable benefit in terms of all cause mortality. But it will get diluted because at the end of the day you’re reducing 80% of a third of all deaths. So something like a quarter.
Norman Swan: And just finally, it’s the selection of the group of people, I mean this is men and women over the age of 55 regardless of their risk of heart disease. This is the general population.
Nick Wald: Yes, this is very important, and it’s the one that’s going to be most controversial. Many cardiologists feel that you’ve got to identify a person’s individual risk profile, on the basis of the risk factors. And then try and tailor the treatment according to the risk factor. We think this is a mistake. The main determinant of risk is either having existing disease, diabetes or one’s age. Influencing the risk by the extent of the risk factor, cholesterol, blood pressure, really only modifies it to a relatively small extent. However, those are the things you have to intervene on to reverse risk, because you can’t change a person’s age, but you can change the factors that are involved in the mechanism of the disease and that should be applied to all people not influenced by the risk factor per se. That’s backed up by the evidence that whatever the cholesterol level or blood pressure you have, if you lower it, you’ll lower risk. There isn’t a threshhold. Years ago there was thought to be a threshhold that if your cholesterol was below a certain level, there was no benefit in lowering it further. Similarly for blood pressure. And that is not the case, there is a continuous straight-line proportional relationship, so the lower the better, and given that there’s no point in finding just a high group and treating those and ignoring people in the middle group, say.
Norman Swan: Now if somebody was listening to us and they didn’t like taking tablets, they’d say Well why don’t I just eat more healthily, get a bit of exercise, lose weight, cut down on a bit of alcohol, won’t I get all the same benefits?
Nick Wald: No you wouldn’t. They would if they could have essentially a completely natural diet from childhood, with low salt, low fat, but that is completely impractical in our modern society and by changing one’s diet in middle-age, even to a considerable extent, you’ll only be able to lower your blood cholesterol by about 5% or 10%. Take a statin, you can lower it by 20% or 30% easily. So quantitatively, the pharmacological effects of these agents is much greater than the effects you could achieve by reasonable lifestyle changes. That’s going to be a bit upsetting to a lot of people who’ve pushed lifestyle changes for years, but it is a clear fact, and many trials, randomised trials, in which people were encouraged to change their diet, exercise more, reduce weight and so on, really had very little effect on the risk factors, let alone on disease end points.
Norman Swan: I notice you’ve patented it and trademarked ‘polypill’, have you got a queue of pharmaceutical companies waiting to actually put their drugs in your preparation?
Nick Wald: No, we haven’t, and we are at the moment looking to partner with an appropriate pharmaceutical company who could fund the trials that would be needed to produce the pill and market it. And that’s a tricky job actually, it’s not straightforward because this is not a straightforward new pharmaceutical agents, the kind that the Pfizers and the Merck Sharp & Dohmes like, and it’s also not a straight generic, it’s not just producing an old drug that everyone’s used to prescribing, it’s a kind of intermediate drug between a generic and a new chemical entity which would need formulation, going through the trials and marketing, and I don’t think it’ll be that easy to find the right commercial sponsor. But that’s what we’re trying to do.
Norman Swan: And the cost trade-off is worth it?
Nick Wald: Yes, we haven’t done a formal economic analysis, and it’s actually quite complicated because you’d have to take into account the extra years of life, the savings in terms of other drugs used, the savings in terms of by-pass operations and angioplasties and we haven’t done that yet, but we will, want and need to do. But in simple terms, the overall conclusion is going to be extremely clear-cut, provided the daily cost of this pill is not too great, not much more than a dollar a day, then it’s going to be an economic winner. If it was going to be ten times that then it would be quite a different story, and we’re very much hoping that we could partner with a company that would go for the low-cost end so it would be the interests of national health services and so on to encourage the use of this drug. We don’t want there to be a financial obstacle.
Norman Swan: Nick Wald, who’s Professor of Environmental and Preventive Medicine at the Wolfson Institute of Preventive Medicine at the University of London.
References:
Wald N J and Law M R A strategy to reduce cardiovascular disease by more than 80% British Medical Journal 2003;326:1419
Law M R et al Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis British Medical Journal 2003;326:1423
Law M R et al Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials British Medical Journal 2003;326:1427
Rodgers A. A cure for cardiovascular disease? (Editorial) British Medical Journal 2003;326:1407-1408 Guests: Dr Nick Wald
Professor of Environmental and Preventive Medicine,
Wolfson Institute of Preventive Medicine,
University of London,
London, U.K. Producer :
Brigitte Seega
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