Statins, Statins Everywhere

The health of America is in trouble. Life expectancy is noticeably lower than in other developed nations, 15% of the country lives precariously without health insurance, and the launch of Obamacare was so badly botched that this much-needed health reform is in serious jeopardy. Not to worry, though, the American Heart Association and the American College of Cardiology have a plan that will rescue the health of the nation: put a third of US citizens on statins – that ought to do it!

The new guidelines, released last month was widely reported in the UK press. The Mail misleadingly called the publication a new study rather than a set of guidelines, while the BBC gave a more measured view, including a revealing statistic that roughly half the expert panel had financial ties to the makers of cardiovascular drugs. What is worse, while the panel’s conflicts of interest appear to be clearly presented, with neither the chair nor co-chairs having conflicts, the superb investigative journalist Jeanne Lenzer has discovered that the chair in particular has been rather misleading with declaring his own interests. The protestation from the AHA spokesperson Dr George Mensah that ‘It is practically impossible to find a large group of outside experts in the field who have no relationships to industry’ is hard to swallow. In a country with as many specialists as the US? There were only 15 members on the panel – is it really that hard to find experts without financial ties? Or is it harder to tell some Key Opinion Leaders that their much vaunted opinions are not welcome since they are too close to industry?

The major change to the guidelines is that there is less emphasis on absolute levels of cholesterol, and a new category for treatment in those aged 40-75 with an estimated 10 year cardiovascular risk of 7.5%. Current UK guidelines recommend treatment at 20% risk, but NICE say they are looking at the same evidence as the US, before publishing new guidance next year. Despite the important debate in the medical press about overmedicalisation – spearheaded by the BMJ’s excellent Too Much Medicine series – we can expect a lowering of treatment thresholds when NICE issues its verdict.

The problem with the way we present guidelines, though, is that they are far too black and white, when the world of medicine we inhabit with our patients is generally full of grey. The question we should be asking is not what the threshold should be for treatment, but how to empower patients to make their own, informed decisions – because ultimately, the level of risk a patient is prepared to accept before they take a tablet is a personal decision, and a panel of experts has no authority to tell patients what risk they should, or should not take.

If we use the 7.5% cut-off, for instance, and assume that taking a statin for 10 years would lead to a 50% reduction in significant cardiovascular events (which is likely to be a gross over-estimate). This means that 3.75% of patients would avoid an event by taking the drug – call it 4% for ease of maths – and 96% would not benefit. The number needed to treat (nnt) is therefore 25 to avoid one event. What will our patients think about this? Surely that is entirely subjective and not for experts to dictate? One patient may have seen a close family member affected by a devastating stroke and might think any ability to reduce the risk of stroke is an opportunity to be grasped, another might consider the 3650 tablets they would have to swallow over 10 years and wonder if a 1 in 25 risk is really worth trying to avoid. In reality, the benefits of statins are much smaller than a 50% reduction, and so the nnt for low risk patients is likely to be 50, 100 or even higher.

We need a different approach to guidelines, one based on nnt, and the corresponding number needed to harm (nnh) (like this excellent calculator from ClinRisk Ltd. There should be a lower level below which the NHS says treatment is not justified on the grounds of either harm or rationing, and then a range of nnt and nnh based on individual risk. Expert panels should analyse the evidence to provide these figures, not to tell people what to do, and doctors and their patients can be given the freedom and flexibility of a large area of grey,  in which they can personalise treatment and truly empower patient choice. The experts and policy-makers won’t like it though – because it involves trusting patients, and we’ve never quite mastered how to do that.

This article was originally published in Pulse magazine (free registration required)

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!

Intrinsa? Intrinsically Wrong

Few of us will have noticed the change in status of the testosterone patch Intrinsa last October. As a GP I have no patients who have been affected by it, and while a treatment for the controversial diagnosis of Female Sexual Dysfunction might be significant for a small number of women, it is hardly a life-threatening condition or a major public health priority. However, we would do well to take note, because it heralds a new low in the behaviour of the pharmaceutical industry as they try to maximise profit, and has implications not only for the resources of the NHS, but also patient safety.

Intrinsa is a testosterone patch, and was one of the few such products licensed for use in women. In October 2012 Warner Chilcott, the company that held the rights to market Intrinsa, took the unusual step of voluntarily withdrawing its product licence ‘for commercial reasons’. Given the high costs involved in obtaining a product licence in the first place, it is hard to see how this could bring commercial benefit – until you follow the story a bit further.

Ben Bryant of The Daily Telegraph has been drawing attention to the activities of the pharmaceutical industry in a series of articles in the last two months, and has highlighted the situation with Intrinsa in his latest article. What Warner Chilcott have done is to maximise profit by exploiting the financial regulations surrounding licensed and unlicensed medicines – with the former having to abide by an agreed price cap while the latter exists in the mysterious world of the unregulated ‘specials’ market, where the drug company can charge whatever they want – frequently at outrageously high prices.

Within a month of the change, the ‘last batch’ of Intrinsa (sufficient for ‘the foreseeable future’) was acquired by another company HFA Healthcare, who were quick to point out their altruistic motive to ‘ensure continuity of medication for patients,’ but rather more reticent about mentioning the price hike – from £26 per pack to £395 per pack.

We have been here before with far more significant drugs – Epanutin was acquired by Flynn Pharma last year, with a 23-fold rise in the price and a great deal of worry for patients. What is new about is scenario, however, is the loss of the licence. A Licence is not just a mechanism to allow the pharmaceutical company to promote its product; it is a source of protection for both the doctor and patient. It provides security that a medicine has been properly tested, has safety data approved by an independent body (in this case the European Medicines Agency), and has been deemed to be effective in treating the condition in question. It is the medical equivalent of a Kite Mark.

The absence of a licence means prescribing a drug off-label. Doctors are used to doing this where treatment is required and no licensed product exists – the patient cannot always wait for the time-consuming processes involved – but this is because a licence has never existed, not because it has been withdrawn for purely commercial reasons. When a doctor does prescribe off-label in this way a doctor has to take extra responsibilities, or, to quote the MHRA:

The responsibility that falls on healthcare professionals when prescribing an unlicensed medicine or a medicine off-label may be greater than when prescribing a licensed medicine within the terms of its licence.

Put crudely, if something goes wrong you can’t sue the drug company as the medicine was used in a way that they did not recommend. The patient is more likely to sue the doctor, or not be able to get compensation at all if there is a problem; the drug company is able to wash its hands, and say ‘nothing to do with us.’ It is the equivalent of selling an electrical appliance, but withholding its 1 year warranty ‘on commercial grounds’, only the patient isn’t able to shop elsewhere, since there is no other licensed product to turn to.

Withdrawing a licence is not just a matter of finances, a way of a company balancing its books or a headache for the NHS drug budget – it is a patient safety issue first and foremost and this practice needs to be investigated and stopped in its tracks before the industry tries it out again – this time with a drug that really matters.

The Bizarre, Unpredictable and Shameful World of Drug Pricing

In recent months I have become so used to being bashed over the head by press releases from the Department of Health, that I have developed an almost Pavlovian response – the head bows, the shoulders go down, I duck for cover.

So it was only while peering carefully from a place of safety that I was pleasantly surprised by one of their latest pronouncements – to give NICE new responsibilities to look at fair pricing for pharmaceuticals.  For all its imperfections, NICE has been one of the best developments in the NHS in recent years. It has brought some much-needed clarity to prescribing guidelines and a degree of protection from the seemingly irresistible lure of the latest best thing to be marketed by the pharmaceutical industry. It can only be a good thing for NICE to be more involved in helping to bring common sense, and the needs of the NHS, to bear upon drug pricing.

In fact, I think it is such a good idea, that I would like to make some suggestions for how they could take things even further – by looking at some of the bizarre, irrational and often downright scandalous anomalies that exist within the drug tariff.

Take nebivolol, for instance, an important beta-blocker for some cardiac patients. It comes in both 2.5mg and 5mg tablets – how can it possibly make sense that the half-strength tablet costs the NHS over 30 times as much as its stronger counterpart? The anti-depressant paroxetine is similar – the multiplication factor is less extreme, with the 10mg tablet being only 6 times more expensive than its 20mg cousin, but the illogicality and blatant unfairness is the same.

Lest any doctor get wise to the fact that lower strength tablets might be more expensive, we have the opposite situation with omeprazole. For most drugs it is more expensive to prescribe two low dose tablets than a single tablet of a higher dose, but 40mg omeprazole is twice as expensive as the equivalent dose in 20mg tablets. I have to ask my patients to swallow their pills twice as often, but most are more than willing once they realise it is the scarce resources of the NHS which are at stake.

Even if I prescribe the drug perfectly, price inflation can still happen in the most unpredictable way before the medicine leaves the pharmacy. The breast cancer drug letrozole is a prime example. It is only given as a 2.5mg dose, so what could possibly go wrong? Well, it turns out that pack sizes can make all the difference. If the drug is issued in packs of 14 the price is £1.89, while packs of 28 cost a staggering £73.24. What is going on here? A pharmacist who is on the ball and gives 2 packs of 14 will be saving the NHS nearly £70 a time – but if they all did that then how come the packs of 28 would manage to sell?

How am I meant to know all of this? Can I remember it all, each and every time I prescribe? Even if I could – do we want doctors to have to learn the prices of drugs? Wouldn’t we rather they spent their time keeping up to date with real medicine instead?

There can only be one reason why these pricing anomalies occur – bombard and bamboozle doctors enough with confusing prices and some of them won’t notice, leading to vast sums of money bleeding its way into the coffers of big pharma. It is a marketing strategy that is not unfamiliar to anyone who pays a utility bill; price plans are so bewildering that the companies rely on many of us making the wrong choice and paying over the odds. The Government has become wise to this and is trying its best to limit the number of price plans companies can offer.  If the Government can protect the voting public in this way then it should do the same for the NHS and start limiting the marketing opportunities of the pharmaceutical industry.

NICE should be involved in changing this. I have a simple formula to suggest to them, and it goes like this: Every drug should have an agreed, fair price for its lowest dose, and as you double the dose, you double the price. What could be simpler? There would be no more bizarre pricing arrangements, nor could a drug rep boast that their product has a fixed pricing regime whilst their rival’s does not – nor could the tariff be changed at the whim of the company once my patients are established on their treatment.

Everyone would know where they were, every drug would be fair. Simples.

I am very grateful to our pharmacist at Binscombe, Rebecca Huish, for helping me research this post, which was originally published in Pulse magazine (access through free registration).

Quick Post: Best not wash your pills down with grapefruit juice

Food-related health scares usually involve a tenuous link with either cancer or heart disease, and the associated headlines warning us to avoid the offending substance, or eat it by the bucket-load, are usually best ignored. The recent news reports concerning grapefruit juice, however, are worth heeding.

Grapefruit juice is good for our health, being low in fat and high in both fibre and Vitamin C. It does, however, contain a chemical which can affect the way our bodies handle certain medications – in particular some statin drugs used for cholesterol, and blood pressure tablets called calcium channel blockers. The result of this is that the tablet stays in the system much longer than it should, and to wash your pills down with a glass of grapefruit juice could have the same effect as taking an over-dose. While doctors do know about this problem, it probably needs to show up on the radar more often both for doctors and their patients.

The list of medications affected can be found here, and a pharmacist would be the best source of information for anyone who wants to check if their own tablets are affected.

Finally, I do feel obliged to make a declaration of interests here: I really do not like grapefruit – I wonder how I’d feel if it were orange juice?

The Marketing of Epanutin – Re-energising a Product for an Underserved Population, or Big Pharma Behaving Badly?

Imagine if you will that, through no fault of your own, your life depends on Widgets. You need to have a Widget at all times – in fact a constant supply of them as a Widget is only good for a day. If you run out of Widgets there is a real risk that something terrible will happen.

Thankfully you know someone who makes just the Widget you need. His name is Phil, and he says he makes Widgets because he cares about you. Then one day Phil writes to you and tells you he won’t be able to sell you Widgets any more, but not to worry as you will be able to get them from someone he knows called Fred. In fact, you don’t need to worry at all because, although Fred will call them Gizmos, they are actually still Widgets under a different name – that is because Phil will still be making them just as before; he will sell them to Fred who will then label the Widgets as Gizmos and sell them to you.

It takes a little while to adjust to this news – Widgets are something you depend upon after all. You trust Phil, though, and reconcile yourself to using Gizmos instead of Widgets and order your first supply from Fred – only to find that where a supply of Widgets cost just 66p, the same number of Gizmos will set you back over £15.

It’s the sort of behaviour we might expect to find in the back-street supply of illegal drugs – but what if a Widget is actually an important anti-epilepsy medication, while Phil and Fred are the Pharmaceutical companies Pfizer and Flynn Pharma? For that is exactly what has happened.

Pfizer have long been the manufacturers and distributors of Epanutin (generic name Phenytoin), one of the oldest drugs used in the treatment of epilepsy. On 24th September 2012 they agreed to transfer the marketing authorisation rights of Epanutin Capsules to Flynn Pharma. All GPs received a letter from Flynn Pharma advising us of the change, and the fact that we will have to change the prescriptions of all our patients on ‘Epanutin Capsules’ to read instead ‘Phenytoin Sodium Flynn hard capsules’. This is annoying in itself as it requires unnecessary work to make the switch, and no doubt some patients will be concerned or confused by the change. The letter was reassuring, however, as the new drug is exactly like the old one – so exactly in fact that it is still being made by the same people at the same site in the same way, only the packaging has changed.

What Flynn Pharma neglected to mention, however, was the price hike – from £0.66 to £15.74 for a packet of 28 capsules. How can this possibly be justified? Flynn Pharma’s website states that:

At Flynn Pharma, we aim to rediscover tried and trusted branded pharmaceutical products. We re-energise products for underserved patient populations

Epanutin is not a drug that needs to be re-energised. Doctors know how it works and, until recently, where to get it from. The ‘underserved patient population’ in question does not need this drug to be rediscovered or remarketed, what it does need is a reliable, trustworthy source of supply. No other justification for the change has been presented to me and, unless there is some crucial piece of the puzzle I am not party to, the only justification I can see is Big Pharma wanting to make new money out of an old drug.

Of course, it won’t be the patient paying the extra cost, but the tired old, uncomplaining all-absorbing NHS. And I will have to go along with it; my options are very limited. No-one else is makes the capsules. There is a liquid version, but the doses are not equivalent. While there is a tablet form which is cheaper, there is a caution in the British National Formulary which states that changing from capsules to tablets could possibly cause problems in some patients. If there is one drug I don’t want to mess about with it is phenytoin. Minor changes in dose can lead to major differences in blood levels, which could trigger a seizure. For a patient with epilepsy a single seizure, as well as being unpleasant and potentially hazardous, can mean losing your driving licence for 12 months. No matter how angry I feel about this, or how low I feel the risks to be, the stakes are too high for me to ask any of my patients to change their medication without very good reason.

I don’t know how this change has been allowed to happen, but I would like to find out. Which organisation fights for the NHS here? The Medicines and Healthcare products Regulatory Agency (MHRA) decides if a drug can be licensed, but not if the NHS can afford it. The National Institute for Clinical Excellence advises doctors on which treatments can be afforded, and which offer best value for money, but does not seem to have a role in price-setting. If there is a body that is responsible for protecting the NHS from this sort of behaviour then I can only conclude that they are not doing their job properly – and if there isn’t, then there jolly well should be!

Early Diagnosis of Dementia – Cui Bono?

The Roman Senator and Lawyer Cicero famously popularised one of the most fundamental legal arguments in criminal debate: Cui Bono – ‘who benefits?’ The logic of the argument is that you will often get to the perpetrator of a crime if you start to ask yourself who it is that is its greatest beneficiary.

The Government’s National Dementia Strategy is hardly a crime – there is much to be praised and welcomed within its 102 pages – but the emphasis on early diagnosis leaves me feeling decidedly uneasy, and when I apply Cicero’s method to the situation I start to understand why this might be.

The issue I have with early diagnosis of dementia is that it is not the same as prompt diagnosis. Prompt diagnosis relates to someone with symptoms, who is seeking to know what is the cause of the problem, and where delay in reaching an understanding of their situation (ie a diagnosis) is never a good thing. That does not, however, mean that early diagnosis is always a good thing – since this also involves encouraging people with mild or no symptoms to look for early signs of the disease and to seek treatment.

In the strategy document there are compelling anecdotes about patients who have suffered with dementia for prolonged periods who have asked for medical help but had huge delays in receiving it, and the Government is right that this is unacceptable. However, whenever I hear about the dementia strategy in the news, or receive updates from our commissioning group about plans to implement it, the main emphases often seem to be on training for GPs so that we can recognise the early signs, and screening older people to test their memory. So the anecdotes tell us that diagnosis in patients who are already presenting to their GP is often not prompt enough, but the solution is to make the diagnosis more often.

So Cui Bono when it comes to early diagnosis?

The Pharmaceutical Industry: Without doubt the major beneficiaries of early diagnosis are the companies who manufacture the drugs used in the treatment of dementia. Most people with a diagnosis of dementia will end up on them, and many will stay on them for all or most of the rest of their lives. If a patient is diagnosed a year earlier then the drug company will profit from an extra year of prescriptions. If more people are diagnosed, then their client base will increase accordingly. Pharmaceutical companies need to look to their future market, and old age and dementia are reliably expanding year-on-year, so it makes sense that companies are investing heavily in this area. This is not necessarily a bad thing – I am not against businesses making a profit – but the question is, will all these extra prescriptions be to the benefit of patients?

The Politicians: A second clear set of winners from this drive for early diagnosis are the politicians. Dementia affects many of us one way or another, and causes most of us anxiety as we look to the future, and so there is high political capital to be made from seeming to be at the forefront of improving the lot of dementia care. What is more, were a high-profile politician to question the value of early diagnosis, there would be significant risk that they would be misunderstood or misquoted, and the damaging headlines accusing them of ageism would be easy to foresee. There are easy political wins to be gained here, also. There is little cost to declaring that GPs need better training, or investing in a computerised screening tool, and this allows our political leaders to sidestep the real issues of under-investment in nursing and social care for older people.

The Experts: While I have every respect for my specialist colleagues in the field of dementia care, I am concerned that we are overly reliant on the opinions and enthusiasm of experts in the developement of medical strategies and guidelines. The field of old age psychiatry has been much neglected by the medical profession over the years, and now that there are treatments for dementia it is finally coming of age and gaining the attention it deserves. It would take a bold consultant psychiatrist indeed to publicly question the wisdom of early diagnosis – it really would be biting off the hand that feeds. While it would be foolish to develop a strategy without receiving input from clinical experts, we must be more willing to question their objectivity and critically appraise their judgements.

The Patients: Ultimately, this is all to the good if everything is to the benefit of patients, but herein lies my problem – I am yet to be convinced that early diagnosis (as opposed to prompt diagnosis) is of any benefit at all. The medications which are prescribed do not alter the course of the disease. They effectively turn the clock back an average of six months, and it makes no difference whether we make this adjustment now or in two years time – the end position will be the same.

There are two main reasons why I might not pursue a referral in a patient who was possible early signs of dementia. The first, and most important, is resistance from the patient – and who can blame them. Attaching a diagnostic label turns a person into a patient, and often this comes with significant personal cost; we should only recommend this when the benefits clearly out-weigh this cost. While we must keep trying to reduce the stigma associated with dementia, we have to acknowledge that for many it remains a frightening and distressing diagnosis and should not attach it lightly.

I would not stand in the way of a referral for dementia, but the second reason why I lack enthusiasm for it is that the service currently available to me is just not good enough. It is woefully underfunded and the worthy people involved in dementia care are spread far too thinly. There is insufficient support available from dementia specialist nurses, little family support and education and inadequate social care. As a consequence a referral is often reduced to an infrequent clinic review and a decision about medication.

Of course, if we swamp the system with a swathe of new patients this might improve the service in time, as resources would have to be poured in to resolve the inevitable crisis. Crisis management, however, is one thing that is never to the benefit of patients.

Where is the Evidence?

I had one of my increasingly rare encounters with a representative from the pharmaceutical industry this afternoon. As usual, it left me wondering when our society will have the courage to stand up to the giants of the industry, and insist that they show some real evidence before they are allowed to market their products.

The drug in question is a new form of pain-killer called Tapentadol. I was quite interested to hear about this product since I had only come across it for the first time three days earlier, and it seemed worthwhile finding out a bit more. The drug is a morphine-like pain-killer, and the major selling point is that it has a novel, dual mode of action. Pain can be classed as nociceptive (standard, hit your thumb with a hammer type pain) and neuropathic (pain caused by over sensitive pain nerves, as occurs for instance after a bout of shingles). We already have drugs that can work on each type of pain, and these include Oxycodone (which is similar to morphine and good for your broken thumb), and Duloxetine, which works on neuropathic pain. ‘All the power of Oxycodone and Duloxetine wrapped up in one molecule!’ the Rep proudly informed me.

Well, if it has the combined strength of two drugs, is it not reasonable to expect it to be more effective than one of those drugs on its own? Apparently not. The best data she could show me was that Tapentadol was no less effective than Oxycodone.

‘I thought you said it was more effective?’ I asked her.

‘Oh it is, it has a dual mode of action.’ she replied.

‘But this just shows it’s no worse.’

‘But we know it is more effective.’

‘And how do we know this?’

‘The consultants at St George’s are using it.’

Well, much as I am sure I respect the consultants at St George’s, this is not what I would call evidence-based medicine.

When a Drug Rep shows you data you can be sure of one thing – it is the best data they have in favour of their drug. What you have to worry about is the data out there that they are not showing you. If this was the best she had in terms of efficacy, then this drug is not yet ready to convince me about its novel new dual mode of action.

It’s at times like this that I am glad of organisations like NICE which will look at whether these new agents really are what they claim to be – and even the PCT which gives increasingly tight guidance on what should usually be prescribed on the grounds of cost-effectiveness. Whilst we might not like being told what we can and cannot do, these organisations stop doctors jumping on the latest bandwagon and are some of our best defences against being hoodwinked by the pharmaceutical industry.

Hmmm, I seem to have strayed into politics. Well, sometimes you just have to do these things. Rant over.

Forgotten where you put the vitamin pills? Don’t worry too much just yet!

Alzheimer’s Disease is a serious problem in the UK. Devastating for sufferers and family alike, it is destined to place an ever-increasing financial burden on our ailing state, as our ageing population inevitably leads to more elderly people succumbing to this most debilitating illness. As our society has at last started to be concerned about this historically neglected condition, a headline such as: “A 10p Vitamin B pill a day from middle age may ward off Alzheimer’s” on the front page of The Daily Mail this morning is bound to catch the eye. It was also reported by both The Telegraph and The Independent  if they are more your cup of tea, with the former actually bolder in its claims than The Mail, changing the word ‘may’ for the rather more definitive ‘can’.

As ever with these claims, we have to make the often disappointing journey beyond the headlines. Whenever I read about new health claims my first thought is: ‘Will it do any harm?’, followed by: ‘Will it do any good?’, and finally: ‘Is it worth the effort?’

So what of harm? Well the proposed treatment is with vitamins – doesn’t sound too bad does it? Probably not – except these are high dose vitamins. Very high dose in fact. The 10p pill in question involves B vitamins and folic acid, some in  doses of up to fifteen times the Recommended Daily Amount (RDA). Now that’s not necessarily harmful – the RDA is a minimum recommendation to ensure sufficient intake of a vitamin, not a maximum safe limit. Indeed, some vitamins seem very innocuous in large amounts (Vitamin C seems to be a mild laxative, but not much else) but we cannot assume they are all harmless – Vitamin A, for instance, is highly toxic to the liver in over-dose; the researchers in this study concede that high dose Vitamin B12 might accelerate cancer; while Vitamin B6 can  cause nerve damage (although this is only proven at doses 25 times higher still than in this study). So I don’t want to jump on this bandwagon without at least seeing some data on harms. The newspapers make no comment on whether or not this data is available, and unfortunately I don’t have access to the original paper, so for the moment I will have to be content with a word of caution.

On the positive, does it work? Well the research sounds promising – it reduced shrinkage of the brain (seen on brain scans) over a 2 year period by an average of 30%. We know that there is a correlation between brain shrinkage and Alzheimer’s so this is likely to be beneficial. What does a 30% reduction mean though? Well, it does not mean that  those who took the vitamins ended up with brains 30% larger than those who did not take them. It is the shrinkage that was reduced. This means, for instance, that if the brains in the placebo group shrank by 10% in the 2 year period, then those in the Vitamin group would have shrunk by 7% – or would have been 3% larger – which might still be significant, but does not sound quite so impressive.

The next question we need to ask is, does the reduction in brain shrinkage seen in this study mean a reduction in the development of Alzheimer’s? Well there is good reason to think it does, but we cannot assume so. The problem with brain shrinkage is that it is a proxy marker for Alzheimer’s. A proxy marker is something that is associated with a disease, but is not the disease itself. Put it another way – I don’t care what size my brain is, I want to know how well it is going to work. It may be that the reduction in brain shrinkage seen in this study is nothing to do with Alzheimer’s but due to some other cause. For instance, were high dose vitamins to actually damage brain cells in a way that made them swell, there would be a reduction of brain shrinkage due to the vitamins causing a problem in the patients taking them rather than preventing one. I have no reason to think this might be the case, but we cannot assume that the effects seen in this study are due to a delay in the development of Alzheimer’s Disease on the basis of scan results alone.

A second possibility is that the effect brain shrinkage is due to a delay in the onset of Alzheimer’s, but to an extent that is not clinically relevant. This is an important distinction. There may be a statistically proven delay in the onset of Alzheimer’s – but if it the onset of the disease by only a week, would it be worth taking vitamins every day for that? If the reduction in brain shrinkage means that I am slightly better at remembering a list of names and addresses, but still have trouble knowing what year it is, or how to use the bathroom, what use is that to me? There is some evidence for a clinically useful outcome from the study – a subset of those who were tested (those with a high blood level of a chemical called homocysteine) performed better in a word recall test. However, this effect was not seen in other patients in the trial, and it was not the primary purpose of the study to test memory. For this reason the scientists behind the study are launching a new, larger, investigation, which will look at more clinically relevant outcomes. So the study is promising, there is good reason to think that it may lead to a useful strategy for preventing Alzheimer’s, but it is far from proven.

What is frustrating is the tendency for the scientists behind studies like this to get carried away with their own enthusiasm, and make claims that are beyond the evidence in their research. In this case, Dr Celeste de Jager of Oxford University, who led the trial, is quoted as saying that ‘the trial had “definitively” shown that the vitamins were a good way of preventing mental decline’. If this is an accurate quote and not a media distortion, then it is distinctly misleading.

So, is it worth the effort? Well, if it was the simple matter of taking standard doses of a vitamin tablet then it might well be worth it – I would have no concerns about harms, and it might just help – so why not? However, I would need a bit more persuading before taking the very high doses in this study – and there is no evidence that standard doses will make any difference at all, so for the moment I won’t be recommending that anyone heads for the health food shop just yet. Let’s wait for more research, and – no doubt – another eye-catching headline!

 

Tablets, tablets everywhere…

Friday morning’s radio brought with it a familiar scene: John Humphrys was interviewing a representative from the Royal College of General Practitioners about some newly published research. Having established the facts, he posed the inevitable question: ‘So what should people do? Get in touch with their GP I suppose?’, to which he received the somewhat panicked reply ‘Yes, but not all at once!’ Whilst I applaud her attempt to prevent hundreds of concerned patients from beating a path to my door, I do wonder how you are meant to approach this as a patient. If we are to not go ‘all at once’ we need to know when everyone else is going, and try to go at a different time – only I don’t know when anyone else will contact their GP. What if we all wait a month before going, and then still turn up all at once? How do I know where I am in the queue? While all these unanswerables were going through my head, I thought I had better listen to the rest of the article and find out what I was supposed to know about, in case anyone turned up at all. Six surgeries later and so far no-one has asked me about it, but maybe the people of Godalming are just too polite and are waiting for everyone else to go first – our former senior partner Chris Jagger always said our best asset was our patients!

The article related to a piece of research from the University of East Anglia and you can follow this link for more information from their website. The trial looked at a large number of people and the medications they were taking, and they wanted to see if there was a link with the development of dementia or mortality (how likely you are to die). Many medicines have what is known as an anticholinergic effect, either as the desired effect of the medicine or a side effect. This means that they block the effects of a chemical called acetylcholine, which we know is an important chemical in the brain that helps nerves to ‘talk’ to each other. This seems to be important in dementia, and certainly the tablets that have been shown to help dementia sufferers work by increasing the action of this chemical – so there is a logical reason to think that drugs that stop acetylcholine from working might increase the risk of dementia, and even death.

The researchers did indeed find an increased risk of both dementia and death in patients taking a combination of these medications, and that the stronger the anticholinergic effect the higher the associated risk. Some of these medicines, such as piriton  (an antihistamine) and oxybutynin (which is used for urinary incontinence) are useful and important medicines which are widely prescribed or purchased over the counter. On the face of it, this would seem to be a major concern, but it is important to look a bit deeper into the study before we draw any conclusions. There are three main cautions to consider.

The first is that the study looked at medicines that were prescribed to patients in the early 1990’s – around 20 years ago. Many of these medicines are no longer used these days, or are used very rarely, while newer medicines might be missing from the list simply because they were not around back then. The second is that there are 83 different medicines on the list, which makes it very difficult to draw conclusions about any particular drug. The authors of the study looked at the combination of medicines, and certainly the risk of any single tablet from the list seems to be very low – it is the combination of these drugs that causes the concern.

The most important caution with a study of this kind, however, is the issue of cause and effect. The study showed and association, but it could not say what caused the association. This was alluded to on the radio programme, but at the same time it was implied that taking these medicines caused a risk, which may not be true. What we know from the study is that people on several of these medicines are more likely to die and to develop dementia. We also know that people who are sent a telegram from the Queen are quite likely to die in the next few years, or show signs of dementia, by virtue of needing to reach their hundredth birthday before they receive such ann honour. There is an association between the telegram and death or dementia, but it would be foolish to imply that the telegram has caused these outcomes. The study also found that: ‘Those who were older, of lower social class, and with a greater number of health conditions tended to take the most anticholinergic drugs.’ This is not surprising, as medicines are not prescribed without a reason, and means that the cause of the higher incidence of dementia and death could have been older age, class distinctions, or due to having underlying health problems. It certainly seems likely that this caused a significant proportion to the findings. The question we want to know, and which is very difficult to prove, is whether the medicines also contributed to the risk of dementia and death, and whether by stopping them, or not prescribing them in the first place, we might improve the health of older people.

So what should we conclude? Well, if nothing else this study is a useful reminder that there is the potential for side effects from all medicines and we should think carefully about the benefits and harms of medicines before we use them. It is inevitable that older people can end up on many different medications at once, and we have always known that it is important to review medications regularly and to stop those which are not needed. It is helpful to be reminded that some over the counter drugs can have similar side effects to prescribed medicines, and that both our pharmacist and our doctor need to know about all the pills we are taking. We should especially be wary of using sedating drugs in older people (we know that sedation in the elderly is a bad idea from many other studies), and some of the medicines in this study (like piriton) can be sedating – so it seems sensible to choose non-sedating alternatives where these are available.

At the end of the day, however, it is a matter of looking at the benefits against the harms. If I can take a pill like oxybutynin for urinary urgency and incontinence, and it makes the difference between going out in confidence or staying trapped in the house because I am so worried about being away from a toilet, then for me there is no question that I would take it. On the other hand, if I could get the same result by switching to decaffeinated coffee… then maybe one less tablet is no bad thing!