The Polypill – Holy Grail or Fool’s Alchemy?

The Daily Express headline of an all-conquering Polypill waiting in the wings, ready to save thousands of lives and rescue the NHS finances, has become almost an annual event. This year’s offering is no disappointment, and its particularly misleading headline –Ten pence pill could help you live 8 years longer was rewarded with a front page spread.

The study that provided this exciting headline was based in India, and compared the use of a single combination pill with usual care for patients with established heart disease, or felt to be at risk of heart disease. The combination pill contained aspirin, simvastatin for lowering cholesterol, and two blood pressure drugs – lisinopril and either atenolol (a beta-blocker) or hydrochlorothiazide (a diuretic). Far from showing any reduction in heart problems, however, the study actually only demonstrated  increased adherence to medication in the treatment group, and a modest reduction in systolic blood pressure and LDL cholesterol compared with the control group. There was also the slightly awkward bias in the study whereby the treatment group received their medication for free, while the control group had to pay for any medication they received – a factor which could surely account for all the study findings at a stroke.

Whenever I hear of yet another study involving the Polypill, I find myself wondering why on earth they bother. Even if they finally break the mould and actually demonstrate benefit that means something to patients – rather than just improving the numbers that doctors measure – are GPs and their patients really going to want to start taking the 4 in 1 pill?

If you needed to be on that exact combination of tablets then there is no doubt that to swallow one pill rather than 4 would make life easier, but does this outweigh the downsides of coupling together 4 very different drugs into one preparation? None of these tablets will make a patient feel any better – they are only used to reduce the risk of something happening in the future, such as a heart attack or a stroke. The biggest issue when starting them, therefore, is side effects. No side effects is the goal, but what are the chances of someone having no side effects if they start 4 drugs all at once? And if they do get a side effect, how are they to know which tablet is causing it?

Some side effects are typical for a type of drug, an irritating cough can occur with lisinopril for instance, and so the doctor may well be able to guess the culprit – but a side effect with even one component in the Polypill will mean having to divide it into its constituent parts and start again. The prospect of having to unpick this magic medicine on a regular basis does not fill me with enthusiasm.

Then there is the need to respond to the ever-changing face of medicine. Aspirin, for instance, was used extensively in patients who were thought to be at risk of heart disease, but more recently the advice has changed to only use it in those with established disease. In fact the twists and turns of advice for this particular drug has an extensive history which caused me to write an early post in this blog. All it would take would be for the advice to change once more, and patients on the Polypill would need to be recalled, with their medicines changed, resulting in all the attendant uncertainty, anxiety and confusion that inevitably accompanies changes in medication.

The current direction of travel in healthcare is towards personalised medicine, with an emphasis on tailoring a drug cocktail to match the exact physiological needs of an individual’s biology. While I would prefer that there was an equal focus on tailoring medications to an individual person’s informed choice and preference, it can only be a good thing to try to personalise treatment in this way. The Polypill seeks to take us in the opposite direction and I remain deeply sceptical about any benefit it may have for our society.

The researchers behind this work are boundless in their enthusiasm, however, and so future studies will no doubt pop up from time to time  – well, at least it keeps a journalist employed at The Daily Express!

Antibiotics for Back Pain – Break-through or False Dawn?

The headlines on back pain this week are hard to ignore. The Guardian, not known for its sensationalist health claims, chose:

Antibiotics could cure 40% of chronic back pain patients.

It’s enough to make a GP sit up and take notice – I can only imagine what I might think if I was living with pain that my doctors had long since given up on.

The newspapers have caught up on an article published in the European Spine Journal in February (funny how these things lie quietly in the medical literature and then all the papers find them at once!) The article was the findings of a Danish trial examining the use of antibiotics in the treatment of long-standing low back pain, and the results are certainly promising – with significant improvement in pain in the treatment group versus placebo. There is a good rationale behind why antibiotics might work, as well as MRI scan findings that should help in the selection of patients who could benefit. The study has been very well critiqued here by Neil O’Connell. I would recommend reading his paper, as I don’t think I can better his analysis.

The key question is what the medical establishment now does with the findings – we need to tread very carefully. At the moment this is the result of a single research group in a relatively small study. For all we know this may have been caused by a statistical blip, an unseen bias, or even scientific fraud (I have absolutely no reason to think it is fraud, but we should never be so naive as to not consider this as possible, until findings have been replicated elsewhere). The results certainly justify a large, multi-centre trial to fully evaluate the hypothesis.

The problem is that we already have the technology to evaluate back pain with an MRI scan, and the antibiotics are established and inexpensive drugs. The temptation for doctors to agree to treat their patients with antibiotics ‘to see if it works’ will be very great – especially for patients in whom nothing else is working. We must resist this, as there are two equal and opposite dangers if we do not.

The first is that this turns out to be an erroneous finding, and thousands of patients are unnecessarily investigated, treated and harmed before, years down the line, the hypothesis is finally refuted and practice reverts to normal. The history of medicine is littered with examples of this – from the horrors of frontal lobotomies in the 50’s, to unnecessary tonsillectomies in the 70’s, or the over-use of aspirin in primary prevention of heart disease and stroke as recently as the last decade. It can be quite a task to put the Pandora’s box of over-treatment back where it came from once it has been unleashed.

The second danger is that this really is a break-through. That it is the Helicobacter pylori moment in the treatment of back pain (Helicobacter is the bacterium responsible for the majority of stomach ulcers and its discovery and treatment has revolutionised the management of this condition). If this is so, then we need robust evidence to establish this new way of thinking so that the majority of people can benefit. If treatment starts to become commonplace without evidence then it could remain the territory of private clinics and maverick surgeons who are more focused on pleasing their patients than practicing robustly evidenced medicine. NICE may never approve it, or take several more years to do so than it should, and many patients may miss out in the long run.

So what to do if you have back pain? Well, for now it is best to watch this space with interest. We really do not know at this stage if you would benefit from antibiotics or not. If a clinical trial starts, seriously consider enrolling on it – so that you can play your part in answering what is clearly a pressing clinical question.

Quick Post – Aspirin in the news again

 

I think I might start counting how many times aspirin hits the headlines in 2012 – twice so far and I am sure there will be more to come! Today’s news is a re-analysis of whether or not  the drug can reduce the risk of cancer. Interesting, worthy of further research, but not something that is going to send me running to the pharmacy just yet.

Why the scepticism? Well, three reasons. Firstly, the studies that were analysed were all designed to look at the risk of heart disease, not cancer – this is an important factor as it means the findings are much more likely to be due to chance than had the study been about cancer in the first place. Secondly, if the findings are true, 1000 people need to be treated for 3 to 5 years for 3 people to avoid getting a cancer. That’s a lot of people taking aspirin who were never going to get cancer anyway. And thirdly because there is bound to be another headline later this year about why taking aspirin is not such a good idea – but maybe there I have crossed the line between healthy scepticism and downright cynicism!

 

The Life and Times of Aspirin (a drug that just can’t keep out of the News)

If you are going to keep a medical blog, you will need to write about aspirin sooner or later. The medical profession’s love affair with this oldest of pharmaceutical agents has had more twists and turns to it than even Elizabeth Taylor and Richard Burton could achieve. One moment it is a wonder-drug that we should all be taking, the next it is at the centre of the latest health scare to hit the headlines. The last twenty-four months have been no exception.  The Telegraph, for instance,  has published several articles – some of which have eloquently expounded its potential benefits , such as cutting the risk of bowel cancer, and that all people over 45 should be taking it; while others have argued that it is of no benefit at all  in healthy people who are healthy, and – the latest concern published only last week – that it might be linked to blindness.

Aspirin certainly has a long history. It was first purified as acetylsalicylic acid in 1856, and acquired the trade name Aspirin in 1899. Bayer, the company who first marketed it, obviously had a less efficient patent department in the 19th century than they do these days, as they lost the exclusive right to sell the drug under the Aspirin brand – and so it became the widely used name by any manufacturer. Its popularity grew in the Spanish Flu epidemic, as it proved to be one of the few medicines at the time that actually worked, and it remained unopposed in the anti-inflammatory market until the development of paracetamol and ibuprofen in the 1950’s and 60’s. This might have signalled its demise, but by the 1980’s this multi-faceted drug was found to have anti-platelet properties that meant it could work to prevent blood clots from forming – opening up a huge market in the area of prevention of stroke and heart attack.

Aspirin has had its problems along the way – like any drug that really works, it also has the potential to cause real side effects. In the 1980’s a strong association came to light between a rare, but potentially fatal, condition in children called Reye’s Syndrome. Although we cannot prove that aspirin was the major cause of this condition, there was a stong association and the incidence of this disease fell to a fifth of its previous level within five years of 1986, when it was recommended that aspirin should no longer be given to children under the age of 16.

For adults, the major risk of aspirin has always been bleeding from the stomach and stomach ulcers. This is well established, and the major reason to think twice before taking it. In a healthy individual the risk of bleeding is not great – it approximately doubles if you take aspirin, but if you double a small number then you still get a small number. The reason for considering this risk very carefully, however,  is that the benefits quoted for aspirin are also often very small. For instance, the benefit of taking aspirin in preventing colon cancer (from the article above) is quoted as a reduction of the risk of developing colon cancer by a quarter. The Professor who conducted the research recommended that people should take it in their 40’s and continue until 75. Well, according to Cancer Research UK the lifetime risk of developing colon cancer is 6.9% in a man and 5.4% in a woman, so if I reduce this by a quarter I would have figures of 5.2% and 4.1% respectively, which means that if 100 people took aspirin for 30 years, as recommended, we could expect between 1 and 2 of them to not get colon cancer who otherwise would have developed it – the other 98-99 either will get colon cancer despite the aspirin or would not get it anyway. Well that is a benefit – but it is a small benefit, and so the small extra risk of bleeding from the stomach starts to seem more important.

And what of the latest study showing a link with blindness? Well The Telegraph rightly points out that this is a an observational study, and so does not demonstrate any causal link. The researchers noticed that people who took aspirin regularly were twice as likely to develop an eye condition called wet macular degeneration (a serious eye condition that can cause blindness) than those who did not. There may be several explanations for this, however. For instance, people generally take aspirin for a good reason – such as a history of heart disease or stroke – and it could be that the causal link is more between these conditions and the eye condition, than the aspirin itself. We must always be very wary of drawing conclusions from observational studies – they are mostly useful as a guide for where to do further research.

Observational studies are rather like those ingenious geophysicists in Channel 4’s archeology programme Time Team. Walking up and down the dig site with their high-tech equipment (that looks unnervingly like an upturned television aerial) they produce exquisite pictures of coloured dots that help Tony Robinson and his team to know where to dig their trenches – but that is all they do. Until the trench is dug and they actually see what is under the ground the geophysics is only ever speculation. So with observational studies – they point us in the right direction, but rarely prove anything and so should rarely change our practice.

The main reason to take aspirin remains its effectiveness at reducing the risk of stroke and heart attack. This is well established, with hundreds of studies being conducted over the years, and it seems to reduce the risk both heart attacks and strokes by about 25% (follow this link for a good summary) and so the key question is – are you at risk? If your risk is high enough, then a 25% reduction will outweigh the risk of bleeding and you should take aspirin, but if you are at low risk then any benefit will be outweighed by the risk of side effects. For a person who has had a previous stroke or transient ischaemic attack (TIA, a temporary form of stroke), the risk of developing a new stroke has been calculated as 10.8% over a 29 month period. With aspirin this will come down to 8.3%. So if 100 people, who have had a previous stroke or TIA, take aspirin for 29 months between 2 and 3 of them will avoid having a stroke that would otherwise have happened. This compares with 1 or 2 over 30 years in the above example regarding colon cancer, and now this has clear benefits over the risk of bleeding.The figures are similar for people who have angina or have had a heart attack.

We used to think that the balance would also tip in favour of taking aspirin in people who have not yet developed heart disease or a stroke but who (by virtue of problems such as diabetes, high blood pressure, high cholesterol and so on) are at high risk of developing it. About 18 months ago it became apparent that the benefit of aspirin in these people is much lower than we expected, and probably just out-weighed by the risk of bleeding.This changed my practice and I spent the next few months saying to people: “You know that aspirin I recommended you should take? How do you feel about stopping it?”

So who should take aspirin? Three types of people should consider it: Those who have had a previous stroke or TIA; those who have a history of heart attack or angina; and finally a small group of people who are at risk of stroke because of a heart condition called Atrial Fibrillation who cannot take warfarin (which is usually more effective than aspirin in preventing stroke in this condition). For the rest of us? Well the story of aspirin is certain to have a few more twists and turns before it is finished – keep an eye on the news, but have your large pinch of salt handy!