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.