PPIs, Aspirin and cancer, Radiotherapy and smoking - 有声 - Intermediate level


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Porter

Coming up in today’s programme: Radiotherapy – it’s a crucial part of modern cancer treatment, so why does it get so little attention compared to other therapies like drugs? An injustice one of our listeners thinks Inside Health should address. So we do by visiting the department where she works.

Smoking – we all know it’s detrimental to health but new research highlights just how important it is for patients undergoing radiotherapy to kick their habit. Radiation and tobacco making particularly poor bedfellows.

And we’ve an update on the latest research into using daily low dose aspirin to protect against cancer – so called chemo-prevention.

But first, growing concerns about the widespread use of PPIs – the acid suppressing family of drugs that includes omeprazole and lansoprazole used to treat indigestion, and now among the most prescribed drugs in the world.

Since their introduction in the ‘80s the number of people taking a PPI in the UK has soared from around 1 in 500 in 1990, to over 1 in 10 today. And while NICE advises limiting courses of treatment to weeks in typical cases of heartburn, most people, myself included, take them for months or years. But at what cost to our health? Well, PPIs have now been linked to a number of problems – ranging from fragile bones to an early grave. Dr Margaret McCartney has been looking at the evidence.

McCartney

So I remember when these drugs were brought in and it was quite exciting at the time, they were very powerful drugs. And because they were very expensive they were mainly prescribed by specialists in hospitals and it took a few years before they were rolled out to people, like me, GPs prescribing them, but of course you don’t get something for nothing and lots of people have raised concerns about some side effects, quite rare side effects so uncommon that you only really pick up in a population, day to day most people put up with these tablets pretty well. So in 2003 there was concerns that people who were taking PPIs long term had a higher risk of a nasty gastric infection called clostridium and since then there was also another concern that people were at higher risk of another infection – pneumonia. In 2006 people started to notice that long term use of PPIs led to a higher risk of lower magnesium in the blood. And then there was a concern that this might lead to hip fractures, to the bones being thinner than you would expect. We’ve also had concern about a type of kidney disease and there’s now been at least two studies saying that there is an increase in mortality, death rates, when people are taking PPIs in the longer term. There’s also been a study that seems to have found an association between long term PPI taking and an increased risk of being diagnosed with dementia.

Porter

The one that’s going to catch people’s eye there obviously is that if you take a long term PPI you’re more likely to die earlier.

McCartney

Well yes, so this was a big study, an enormous cohort study, that was published earlier this year in BMJ Open, looking at a core of army and military service veterans who’d been taking PPIs for a long time. And the researchers found that for every 500 people taking these drugs for a year there was one extra death that they say would not have otherwise occurred. Now there’s big problems with this kind of study, I absolutely think it’s important that we should pay attention to it but what we don’t know is why people were being prescribed them. Were they being prescribed them because they were already ill with another disorder that was then going to cause their demise or were these tablets somehow leading to their death? That’s what we don’t know and we don’t have a study that tells us that we can reduce death rates if we take people off them or if we don’t prescribe them, that’s the problem.

Porter

Because is there a plausible mechanism to explain why there might be these associations? You can imagine with things like clostridium difficile – C. diff – that we’re affecting the acidity in the gut and that might have an impact on the bacteria that live there for instance. But people dying early, non-specifically, seems odd.

McCartney

Well the cause hasn’t been established, nobody really knows. One theory is that it may change the chemical balances in your body, particularly magnesium, which we need for our hearts and for our lungs and for our brains, so it could be something like that. But the bottom line is we just don’t know. And what’s really important to note is that these big cohort studies tell us there’s an association, it tells us there’s a link but it doesn’t tell us what is cause and what is effect.

Porter

Looking at your own practice, I presume like any other GP you’re prescribing an awful lot of these?

McCartney

Well we are, there’s absolutely no question about that and I do wonder if we’re prescribing more of them because they actually work quite well. So of course if you have gastric symptoms that’s caused by too much alcohol, being overweight, smoking, the motivation to perhaps change your lifestyle when you’ve got a drug that works so well perhaps isn’t there. And so they have become very popular drugs and of course the more popular they are the more widely they’re prescribed, the more you’re going to see relatively rare side effects becoming more common.

Porter

Margaret McCartney.

Dr Matthew Banks is Consultant Gastroenterologist at University College London Hospital NHS Trust.

Banks

If you have a look at the evidence we know that up to 70% of patients on PPIs don’t have a very clear indication. Not only that when patients come into hospital approximately 20% of them are taking PPIs when they arrive, when they’re there 40% are prescribed PPIs and when they leave 50% are on PPIs. But not only that if you have a look through the notes of those patients 90% of them haven’t got a clear indication.

Porter

And by a clear indication what you mean is some documented reason that you should be taking these drugs?

Banks

Absolutely, patients on ITU are often put on PPIs for no good reason.

Porter

Well there must be a reason.

Banks

Yes if they are very sick then they have a higher risk of developing ulcers and they are, for good reason, put on it but then they’re not reviewed when they come off ITU or discharged. So if a patient is put on a PPI for good reason, such as acid reflux, then they should be reviewed within four to eight weeks. And at that stage the treatment should be either discontinued or tapered off and then they should be re-reviewed.

Porter

But I know both from personal experience, I’ve been on these drugs on and off for eight years now for reflux, it’s about the only thing that seems to control my symptoms and I’ve got lots of patients who are just taking these drugs day in day out, there must be some people who need to continue taking these drugs. Are you happy? Do you think that’s safe?

Banks

Well the evidence for the risk of these drugs is not very clear and therefore the whole community, gastroenterologists, are a little bit worried about what they should be doing. By not clear there are risk associations and I just saw an article a few weeks ago about fizzy drinks reducing your life expectancy or making you older by five years and that may not have been because you’re on fizzy drinks, it may be because you never exercise or because you’re overweight, there are many other reasons. And that holds true with most of the studies that have been undertaken with PPIs. Yes there are lots of associations but we have no idea whether these are causative effects. So we don’t really know the dangers yet.

Porter

What about if I wanted to try coming off my PPI and have been on it for a long time, months or maybe even years? One of the problems you often hear discussed amongst doctors is that when you come off a PPI there’s some sort of rebound excess production of acid that makes your symptoms much, much worse and drives you back to the pills again. Is there any science behind that?

Banks

You’re describing patients who abruptly stop PPIs and then their perception is that their symptoms are far worse than they ever were and there is very little evidence for rebound and probably my belief is patients are experiencing symptoms as they had done before they went on to PPIs or they’ve picked up bad habits on PPIs, for example going to bed after a heavy meal or drinking too much alcohol, that they’re able to do when they’re on PPIs but not able to do before they started. And what I suggest with most patients is they slowly taper off the PPIs and get used to the feeling of some of their symptoms coming back and either to reduce the dose initially and then take alternate days for a week or so and then finally stop.

Porter

And what happens to these people if their symptoms do come back and affecting their quality of life on a day to day basic, presumably they’re going to have to go back on them aren’t they?

Banks

This is something that we need to discuss with the patients and we need to make it very clear there might be some long term side effects but as yet we don’t know. But there are alternatives, there are being careful with your diet, so food that’s fried or very high in oil or fat will increase the risk of acid reflux. There are certain irritants such as citrus, chillies and alcohol. Losing weight helps. And finally using Gaviscon relatively regularly or antacids, of which there are many on the market, probably all equally effective. So there are other alternatives.

Porter

If you’re looking after somebody who has significant reflux and you want them to be on a PPI long term are there any investigations, any monitoring, that we need to do to keep an eye on what’s going on?

Banks

So there are an increasing number of case reports with magnesium.

Porter

And this is an important salt which we can measure using a blood test.

Banks

It is but we do know there are very clear case reports of patients who had low magnesium on PPIs, having not had low magnesium before, stop the PPIs the magnesium returns to normal, restarted the PPIs and the magnesium dropped again. So I think there’s a causative effect there rather than an association. But it’s so rare you can’t justify monitoring everyone on PPIs, it would cost the earth and I don’t think it would be effective.

Porter

The other one that you often hear mentioned is Vitamin B12, that the reduction in acid somehow affects the absorption of that, is there any evidence for that?

Banks

There’s some evidence but again it’s conflicting. I’m not convinced with the body of evidence so far. And perhaps the only people you should possibly monitor are vegetarians or those who have low dietary intake of B12.

Porter

Who are going to be more at risk anyway.

Banks

Exactly.

Porter

Gastroenterologist Matthew Banks who has persuaded me to have another go at coming off my PPI.

But it’s not all bad news. One reason why PPIs are being prescribed so widely these days is that they are increasingly being used to protect the lining of the gut from other drugs. Drugs like aspirin. And combining a PPI with aspirin may have other benefits too.

A 10 year UK study – the ASPECT trial – is investigating whether the combination can reduce the long term risk of cancer of the oesophagus in people with Barrett’s syndrome – a condition where changes in the lining of the lower oesophagus resulting from acid reflux, that’s acid splashing up from the stomach, can occasionally turn cancerous.

Professor Janusz Jankowski is ASPECT’s lead investigator.

Jankowski

The best way to think about aspirin is like a speed regulator in a high speed truck. It stops the speed of the cycling of the cells getting out of control. And aspirin is an important physiological molecule which dampens the signalling generally within the cell.

Porter

Using your truck metaphor, it’s careering down a road from normality towards cancer and aspirin is applying the brake – is that a fair analogy?

Jankowski

Yes that’s exactly right, it slows down the cells so that they all start working in synchrony. The important aspect of aspirin is that there’s already quite compelling data, which has already been approved by the United States preventative services taskforce to give limited approval for low dose aspirin cancer prevention in people with heightened risk of colorectal cancer. And that’s a common condition that has high risk of going to cancer. The condition we’re studying is actually Barrett’s Oesophagus which has mild to moderate risk of going to cancer – 97-98% of people with Barrett’s Oesophagus will never have oesophageal cancer. So it’s a much more useful condition because it’s more generalizable to the population and that’s why we’re hoping – in fact I think the whole community in chemo prevention is hoping if we can get clear results in the ASPECT trial it actually will help national guidelines and policy change about how we prescribe low dose aspirin for the general population.

Porter

Earlier in the series we talked about using aspirin alongside acid suppressing drugs to protect the lining of the stomach against the side effects of aspirin, which can include quite significant bleeds, but that’s not why you’re using this combination together in the case of Barrett’s?

Jankowski

Partly true. The most important reason we’re using it is because the problem with oesophageal reflux is it’s abnormal acid coming up the oesophagus and causing the damage. So the premise of this study is actually to switch off the causative factor in the first place, which is the acid reflux disease and then actually deal with the aspirin as chemo prevention to actually slow down the process once it’s developed. But there is actually a good synergy between the two agents there where the Proton Pump Inhibitors also prevent the incidence of aspirin complications in the upper GI tract.

Porter

Because if aspirin was to prove effective in preventing cancer of the gullet in cases like this the downside would be at what price and the price is normally significant bleeds from the stomach, which can be fatal. But by prescribing with these anti-ulcer drugs, like omeprazole and lansoprazole and esomeprazole, have you actually negated that risk?

Jankowski

No not completely but we do decrease the risk by at least 50% and some of the studies say up to 85%.

Porter

Can you explain where you are at with your research now, when will we know?

Jankowski

The main findings of the ASPECT trial won’t be published until early or mid-next year but I can share some preliminary findings presented recently at the British Society of Gastroenterology. What we were able to show there is in a highly selected patients with Barrett’s Oesophagus when we followed up 100% of these patients at baseline who were randomised to aspirin we found out that 22% of these patients actually had the aspirin stopped in agreement with their local physician, simply because of increasing potential complications – peptic ulcer disease, gastrointestinal bleed, vomiting, nausea and in one or two cases haemorrhagic strokes.

Porter

I mean that’s a high proportion.

Jankowski

Oh absolutely. In the vast majority of these individuals, in fact the complications were mild to moderate, so stopping the aspirin they went back to relatively near normal life expectancy again. And in some of the individuals there was very serious complications indeed. In fact what was interesting from our preliminary results is that another 13% had other reasons for stopping aspirin, probably because they were tired of taking it, so this is only after five years you have to remember or maybe it was interfering with some of the other medications. So when you add that together after five years of taking aspirin 35% of our population were no longer on it and it’s a question of whether your glass is half full or half empty. Sixty five percent were still taking aspirin but we know to get the maximum benefits you need a minimum of five years, probably six years, and the average length for most of the case cohort studies shows that in fact probably 10 years is where you get your medium benefit from. So even if you do want to take aspirin most people run out of enthusiasm after a period of time. What we would like to do is trying to target who’s going to respond to aspirin better so we can actually give them therapies to actually maintain their enthusiasm.

Porter

Janusz Jankowski on using aspirin and PPIs to reduce the risk of cancer which, albeit exciting, has its fair share of problems too. And we will invite Janusz back when the final results of ASPECT are published next year. More details, as ever, on the Inside Health page of the Radio 4 website.

Now I’ve left the studio and I’m standing next to the fountain in the centre of Bart’s Hospital Square in London and I’ve come to see a Christine Usher. Christine emailed us, she’s the Head of Radiotherapy Physics here at the hospital, she emailed us after listening to our programme in the last series talking about thyroid cancer when the surgeon I interviewed made what she regarded as a throwaway comment that thyroid therapies were not like radiotherapy that cause lots of unpleasant side effects. She says that she can’t remember when we did a decent programme on radiotherapy, that’s because we’ve probably never done a programme on radiotherapy, and she says it’s about time we did and put that right. So we’ve come to Bart’s to meet Christine.

Usher

Hello Mark, welcome to our radiotherapy department. So this is one of our linear accelerators, so they’re high energy x-ray machines, they deliver x-rays a 1,000 more than a diagnostic x-ray would be that people might have a chest x-ray.

Porter