Bisphosphonates, IBS and diet, CRP test for infection, Randomisation

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INSIDE HEALTH

Programme 11.

TX:  14.03.17  1530-1600

PRESENTER:  MARK PORTER

PRODUCER:  ERIKA WRIGHT

Porter

Coming up today:  Irritable Bowel Syndrome and a new service for helping people with IBS that hasn’t responded to the standard treatments and it all centres on what and how you eat.

A finger prick test that can tell whether you need antibiotics.  It’s been more than two years since NICE endorsed the use of CRP testing to help doctors assess people with chest infections.  So why is hardly anyone using the technology?

And I eat humble pie, having been castigated for getting clinical trial terminology mixed up.

But first, osteoporosis, and new research suggesting that the bisphosphonate family of drugs – currently the first line treatment for the condition – may actually weaken rather than strengthen bones.  It was a tiny study, including just 16 people, but it hit the headlines.  The team from Imperial College London found that the bones of people with osteoporosis given bisphosphonates contained lots of tiny faults or micro fractures that made them weaker than the bones of people with untreated osteoporosis.  The drugs are taken by hundreds of thousands of people in the UK and the resulting media coverage has caused concern.

Peter Selby is Professor of Metabolic Bone Disease at the University of Manchester and joins us on the internet from Manchester Royal Infirmary.  Peter, it’s no wonder people are worried, these drugs are supposed to strengthen weakened bone and protect against fractures.

Selby

I think that’s a real concern.  And I think for some years now we’ve known that when we’ve been treating people with this type of drug we’ve been walking a little bit of a tightrope.  So on the one hand we’re very anxious to stop the body breaking down bone, losing bone too quickly, but on the other hand we realise that this particular type of drug – the bisphosphonates – do build up in bone over time and as they build up what they potentially do is stop the body healing bone.  So normally as you go through life you get little bits of damage to bone that the body will be able to cut out and replace with new bone.  But if you’ve blocked the body’s ability to do that that damage can build up and can lead to the bone becoming more fragile.  So it is a bit of a paradox but I think it’s understandable why it comes about.

Porter

So what’s going wrong in this study, is it a time effect – if you take these drugs for too long does that make the bones more brittle?

Selby

I think that’s what’s going on here and it’s quite interesting – if you look at the patients who were on bisphosphonates in the study a lot of them have been on for a long period of time – eight or nine years – and I think what is happening is these drugs are building up over that period of time and allowing damage to accumulate in the bone.  Whereas if we treat people for much shorter lengths of time, which is what we’ve been tending to do more recently, then the risk of damage accumulating in the bone is minimal.

Porter

So what is the optimum duration do we think?

Selby

We don’t have firm research evidence and that’s an important area that we do need to look at but most people think somewhere between about three and five years.  And we would often say if you’re having injected bisphosphonates, so that’s drugs like zoledronic acid, then three years treatment is the point at which you need to review whether the benefits of treatment still outweigh the risks.  Or with the oral treatments perhaps five years the same question.  And there may be some people you would consider treatment has had a good effect, the risk of fracture has decreased substantially and therefore the risks of continuing treatment outweigh the benefits.  There may be other people who are at very high risk of fracture and you would still, despite the findings of this study, want to continue because you think the benefits of treatment will continue to outweigh the risks.

Porter

One would hope Peter that that sort of decision is based firmly on evidence but I get the impression that this study was only a small one but there isn’t a lot of evidence out there is there?

Selby

No I think you’re absolutely right and I think one of the problems that we have is that when you’re looking at developing a drug a lot of effort gets put in to initial development of a drug and people look at the way it’s used.  However, what has happened as these drugs have been in use now for over 20 years people have realised that these long term effects are perhaps more predominant than might have been the case.  And the impetus for a lot of research does come in looking at new drugs, rather than looking at what we do with something that’s actually a well-established treatment.  So you perhaps raise a real criticism of how we research the use of medicines in that we’re very good at rigorously looking at things before we put them into use, we’re less good at critically evaluating their use through the lifetime of the drug.

Porter

And if you do stop treatment the effects of the drugs continue for a while afterwards don’t they?

Selby

Well that’s the whole reason that we’re having this discussion.  I think when we first got the bisphosphonates we thought they would be like a drug you’d use to treat blood pressure – once you stopped it the effect would wear off – but because they do stick to the surface of the bone the effect is going to continue after you’ve stopped treatment for probably some years.

Porter

What would your take home message be to anybody who’s on bisphosphonates listening because I suspect there’s an awful lot of people out there who have been on these drugs for longer than three to five years?

Selby

I don’t think for any individual person there should be great concern but if you have been on for longer than three to five years you need to discuss with your doctor whether the time has come for your use of bisphosphonate treatment to be reviewed because it will differ for each individual.

Porter

Professor Peter Selby.  And examples of bisphosphonates include alendronate, ibandronate and risedronate.  More details on the Inside Health page of the Radio 4 website.

As a GP I’m required to attend a lot of lectures and meetings every year in order to keep up-to-date, which is how I ended up at a seminar being given by the team behind a new specialist service in Gloucestershire for treating people with refractory IBS – that’s IBS that has not responded to the normal treatments.   As many as one in five of the UK adult population will be affected by IBS to some degree and it can be a difficult condition to manage.  Although there are number of medicines that can help, there is no one panacea and results are often disappointing.

This new approach, which is used by other centres across the UK too, focusses on encouraging healthy eating practices and dietary change involving a group of starches and sugars known as FODMAPs.  But first it is important to be sure of the diagnosis.

Alex di Mambro is Consultant Gastroenterologist and Clinical Lead for Nutrition at Gloucestershire Hospitals NHS Foundation Trust.

Mambro

I am always surprised most of us don’t suffer from more IBS symptoms because actually we lead such chaotic lifestyles and most of us are running around, busy, unable to maintain regular eating habits, we snack irregularly, we miss breakfast, we don’t exercise regularly and actually stress plays a huge role in IBS symptoms. 

Porter

Because the bowel is a much more complex organ that people give it credit for.  What’s the classic story of somebody who comes along to your clinic?

Mambro

Usually I’m seeing the patients who are not responding well to first line treatment.  So they will have had their diagnosis of IBS by their GP, they will have been suffering from diarrhoea symptoms, constipation symptoms, often a mixture of both.  They’ll get abdominal bloating, pain relieved by going to the toilet, often quite predominantly morning symptoms, women often get worse symptoms around their cycle as well.

Porter

Because if someone is thought to have IBS they’ve got a change in their bowel habit, they’ve got bloating – what else might it be that would worry you as a clinician?

Mambro

So there are certain things with IBS that you shouldn’t have.  In general, not always but in general, IBS doesn’t occur at night, you don’t get diarrhoea at night with IBS, so you don’t get what we call nocturnal symptoms.  You also don’t bleed with IBS.  And you don’t have changes on your blood tests, okay?  So we always check people for inflammatory disease, GPs are very good now at excluding coeliac disease, for instance, excluding inflammatory disease with raised inflammatory markers or anaemia.

Porter

Things like ulcerative colitis and Crohn’s disease?

Mambro

Absolutely, so Crohn’s disease, ulcerative colitis and as a gastroenterologist those are the things that I want to see in clinic and I want to see them rapidly and I want to get them to the right test at the right time.  But likewise I don’t want to do that at the expense of all my IBS patients who are also struggling and suffering.

Porter

So the GP has made a diagnosis of IBS but on what basis?

Mambro

Years ago it may be that if you were concerned you didn’t have the diagnosis right, we actually had to endoscope these people, we actually had to clear their bowels out and actually put a camera inside them and maybe even biopsy their bowel.  Nowadays we actually don’t have to do that, we now have the ability to perform something called a faecal calprotectin and this is a stool test.  So the patient will send in a simple stool test via their GP to our service here, we analyse that for a biomarker of inflammation.  So faecal calprotectin is essentially something released by inflammatory cells that are in the bowel.  And if that’s negative it’s very sensitive so it excludes an inflammatory process going on.  And that means the GP and the patient feel a lot more confident that they’ve got the diagnosis right and they can actually get them to the right place at the right time.

Actuality

… here.  This – I’m going to chop a few things for my omelette today.

Porter

Sylvie Miller is one the patients who has benefitted from the new IBS service.

Miller

I used to live in fear of the pain, it’s like a knife in my bowels, very, very painful.  I’ve had this for nearly 20 years now but I’ve been to see many doctors, nothing worked.  And finally last year went to see Dr di Mambro.  She sent me to a dietician, Claire, and she said you’re going to have to go on a very strict diet for six weeks.

Oldale

My name’s Claire Oldale, I’m dietetic lead for the Refractory IBS service here.  Many patients really do struggle without a regular eating pattern, maybe due to their lifestyle or due to their symptoms if their symptoms are particularly bad in the morning they’re struggling to get breakfast in but also in terms of specific diet, I’m looking particularly at fermentable starches and sugars because those are very clearly linked to IBS symptoms.

Porter

Now this is the so-called FODMAPs, which is very much in vogue in the dietary world at the moment.  What does it mean?

Oldale

FODMAP in itself is an acronym, it stands for Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols.  Now nobody needs to remember that.  Essentially it’s a group of starches and sugars that many patients will struggle to digest.  So they’re present in certain grains within the diet, certain fruits, certain vegetables, certain dairy products and also certain sweeteners.  A particular group of artificial sweeteners that maybe contributing factors and those are the sweeteners which end in ol, so sorbitol, maltitol, xylitol, those are part of the polyol group which also occur naturally in certain fruits and vegetables but can be artificially added to things like chewing gum.

Peck

My name is Lisa Peck and I’ve been suffering with IBS over the last two or three years.  At the moment there’s an awful lot of information and companies promoting diets and what I wanted to do was to have something that had some research behind it rather than starting on something that might have helped some people but wasn’t really proven.

Porter

How was it explained to you by the dietician?

Peck

It was explained to me as a diet of excluding anything that might ferment in the bowel, that may cause these bowel changes and it is quite a difficult diet to follow.  I couldn’t have done it on my own.

Oldale

We have a very structured approach to managing the low FODMAP diet, it’s not just a diet, it’s not a diet for life, it’s a nutritional investigation, if you like, and it’s a three stage approach.  So we look at a very strict exclusion of high FODMAP containing foods for up to six weeks in the first instance, followed by a process of rechallenging with all of those FODMAP foods if some improvement has taken place because what an exclusion demonstrates that some of those foods within the total exclusion have been helpful but we need to identify which ones because it’s very unlikely that patients react to all FODMAPs within the diet.  There’s up to six different groups of FODMAPs, it may be that the patients only react to two or three and we need to identify which they are.

Porter

So then you’ll reintroduce them and if the symptoms recur?

Oldale

Then we have our answer.

Porter

What are the common culprits in your experience?

Oldale

It does vary very much.  For many patients it tends to be things like wheat, things like onion and garlic, perhaps also things like cauliflower, broccoli – things like that.

Porter

What proportion of people that you see get better on that initial exclusion phase

Oldale

What we’re seeing in terms of our data within the service is that up to 75% of people are seeing some degree of improvement if not complete resolution of their symptoms following the low FODMAP exclusion.

Miller

When I started going on the FODMAP I introduced beetroot because I used to have a lot of beetroot and beetroot immediately gave me pain the next day.  I reintroduced apple.  I think it’s the first thing I reintroduced and immediately I had pain, which was a catastrophe because I love apples.  Orange I can’t have.  Garlic I never eat but I tried it in the diet and yes it doesn’t agree with me at all.  Avocado I cannot have.  The things that I like that are good for me are eggs, Brussels sprouts, French beans, salad, carrots, tomatoes, I can have yoghurt, doesn’t bother me at all.  They’ve been a great help because once I started that no more pain but now that’s it, I’m not afraid anymore.

Mambro

Some of these patients get so far down the line with their symptoms that they’re frightened to eat, they’re frightened to go out, they won’t drive anywhere in their car because they can’t guarantee they’ll make a toilet.  They become so debilitated by some of their more severe symptoms that actually by the time they get to us they really are struggling and that’s why the FODMAP is so important that’s done with dietetic support because if you send somebody out there with a piece of paper saying these are all your high fermentable carbohydrates cut them all out, well that might work to begin with but it’s very difficult to sustain, FODMAPs are found in all sorts of different food groups, and the patients often find that their symptoms get better, then recur, they become frightened of what foods they’re eating, some patients are then significantly losing weight, they’re struggling and psychologically their IBS is getting worse because they’re so anxious.  And actually that’s so prominent now and so well recognised that the NHS funds IBS focused cognitive behavioural therapy just for those IBS patients.

Porter

Symptoms aside, Alex, is there any damage, long term damage being done to the bowel?

Mambro

No and that’s very well recognised.  The bowel itself is normal, that’s really important for people to know.  If you have IBS your bowel is normal.  If I was to scope the bowel or scan the bowel I would see normal small bowel and normal colon. 

Porter

So if I’m following a diet which controls my symptoms and I have a weekend off and I get some symptoms that’s not doing me any harm, it’s causing me some grief.

Mambro

If you choose to go out and have really nice Italian food with your garlic and onion intolerance you’re going to feel a bit bloated and you might have a bit of a dodgy tummy the following day but as you go back and reduce your FODMAPs again those symptoms will resolve.  If you know that onions and garlic make you feel poorly because of your IBS symptoms it doesn’t mean you’re allergic to them.  And actually that’s what the FODMAP is about, it’s about giving people the power and the knowledge and the armour so that their symptoms do not dictate their life.

Porter

What happens to somebody who engages in the FODMAPs’ scheme, is very good, but doesn’t get a response, does that raise a red flag with you?

Mambro

Yeah it does.  So any patient who hasn’t responded in the way we would hope, and remember that sometimes it’s partial response or we give it a bit more time, but we do – we do monitor these patients quite carefully.  If a patient isn’t responding in the way we want generally I will see them quite quickly.  And I have to say in those patients – and we’re only talking about a small number – but in those patients I am more likely to then investigate further, so that I can make sure, 100%, that this bowel is normal.

Porter

Consultant gastroenterologist Alex di Mambro from the Refractory IBS service in Gloucestershire.  More information on our website.

Chest infections are another very common problem in general practice.  Most are viral and self-limiting but some are bacterial, require antibiotics and are much more serious.  Differentiating between the two, particularly in the early stages, can be tricky which is why NICE recommended the use of new desk top technology to measure C-reactive protein back in 2014.  CRP is a marker of inflammation with high levels suggesting a bacterial rather than a viral infection.  So why, more than two years after NICE endorsed the test, is it not being routinely used?  Indeed we struggled to find a GP practice that even has the new equipment.

Professor Mark Woodhead is National Clinical Adviser on pneumonia to the Department of Health.

Woodhead

The beauty of these new tests is a bit like somebody with diabetes doing a finger prick to test what their blood sugar is, you can do exactly the same for CRP – just a simple finger prick, put the blood sample in the machine during the consultation with the patient in the general practice which will produce the result within minutes to guide you while the patient is there.

Porter

Like all GPs I have access to CRP testing at the moment but that means taking a blood sample from the patient in the conventional way, sending it to our local laboratory and the result’s often not available for six to eight hours.  What you’re saying is that we could have desktop technology.

Woodhead

That’s exactly right.  The NICE guidance doesn’t say to do this test on everybody with a respiratory infection because there will be patients that the GP sees where they’re absolutely confident this is a minor infection that will get better on its own, those patients don’t need a test and there’ll be occasional patients that the GP sees where they’re absolutely confident this patient’s very unwell with pneumonia and they need antibiotics and therefore those patients don’t need the test.  It’s the group in the middle where the GP’s just not quite sure where this test gives them that added confidence both not to prescribe and in other situations to prescribe.

Porter

Now CRP testing was recommended in the NICE guidance back in 2014, you chaired the committee that produced those guidelines and yet it’s not a test that’s being widely used.  Do you find it frustrating that the test hasn’t been more widely adopted?

Woodhead

Yes, the simple answer is I do feel frustrated and I guess we recognised when we made this recommendation that the uptake would not be quick or immediate unless the NHS found some way of rolling it out with some money behind it.  But I guess in the big picture of things this is not something that’s a high priority but may be it should be in the context of the problems that we see with the antibiotic resistance that result from giving antibiotics when they’re not needed.

Cross

What I really like is the fact the patients are satisfied, they’re happy to go away without a course of antibiotics.

Porter

Liz Cross is an Advanced Nurse Practitioner at Attenborough Surgery in Bushey, Hertfordshire and has seen a significant drop in antibiotic prescriptions for chest infections since introducing desktop CRP testing.

Cross

We’ve got generations of people where whenever they get a chesty cough, they get green phlegm, every single year they come in and they get a course of antibiotics and by doing that you’re reinforcing those strongly held beliefs that antibiotics are the answer and it’s going to get them better.  Now that’s very difficult when you’re sat there in front of somebody to challenge those beliefs without really upsetting the patient.  If they leave the consultation with an unmet need or if they’re not confident that you’ve made the right decision then you’re going to see them again in clinic.  Whereas when you add in the CRP finger prick blood test it gives them something objective, so you can say look I know you feel really grotty but this year you don’t need antibiotics and here’s the proof.

Porter

Does your experience of using the CRP suggest that people are less likely to come back?

Cross

I was really surprised.  Last year I did a small scale pilot, I just looked at patients coming in to my clinic and what I found was that antibiotics that I prescribed reduced by a third but more importantly I followed everybody up after 28 days and what I found was that my unplanned follow up appointments also dropped.  So patients weren’t coming back into clinic, they weren’t going to out-of-hours or A&E or to urgent care.  In your peak winter months if you can show that you’re freeing up appointments that’s a brilliant win for the NHS.

Porter

The equipment costs around £1200 to buy, and £3.50 for each test which only takes a couple of minutes.  But not everyone shares Liz Cross’s enthusiasm, including resident sceptic Dr Margaret McCartney.

McCartney

From my perspective I think this is actually tech that comes with not a huge amount of value.  When you go back and look at the trials, the most recent one that seems to have made the change in policy was a trial from the Netherlands and they had groups of doctors and patients and they looked at different ways of doing things.  As good as or better than doing a CRP test was a bit of training in enhanced communication skills, trying to share decisions, share uncertainty, give people really good information about why antibiotics weren’t necessary and that was as good as reducing antibiotic use as the CRP test.  And I think, from my personal perspective, I would prefer to use that rather than relying on a bit of kit and expensive kit.  They’ll say – the manufacturers say it only takes two minutes, well that’s 20% of the consultation time, that’s actually quite a lot of time.

Porter

But Margaret, two minutes may be a significant part of the consultation but it’s also quite time consuming trying to persuade people that they don’t really need antibiotics and if the CRP hastens that process is it not worthwhile?

McCartney

Well I suppose that these tests might be most useful if you had found out that you were a high prescriber of antibiotics and you perhaps wanted a little bit of backup, either for you or for your patients to know that you were doing the right thing in not prescribing.  Or it might be that if you work in a community which has been used over a long period of time to expecting lots of antibiotics for infections this might be the kind of thing that might possibly help to show people that actually they didn’t need them and they wouldn’t benefit from them.

Porter

But it’s not just about reducing the total number of antibiotic prescriptions is it, there’s lot of ways of doing that, I mean it’s about making sure that people who require antibiotics get them and that those that don’t require them don’t get them, it’s about making sure the right people get the antibiotics.  Are you not convinced by the evidence from that because NICE certainly were?

McCartney

No I think NICE have said – and I’ll quote from you – consider a point of care test if after clinical assessment a diagnosis of pneumonia has not been made and it is not clear whether antibiotics should be prescribed.  Now you can define clear in a variety of ways but certainly NICE are not saying to use it for everyone, just where there’s reasonable or significant uncertainty.  It may be more useful for ruling out the need for antibiotics than it is to tell you who they should be used in.  And I think in clinical practice this test might have a variety of unintended outcomes that we haven’t quite captured and I think it will be really useful to get more information about how this could be used actually on the ground in a randomised controlled trial setting.

Porter

Thank you Margaret.  And on the subject of randomisation and trials you might be interested in this email from Inside Health listener Dr Adam Zacks:

Zacks (read)

Did Mark make a mistake when interviewing the team behind the RePhill study into whether air ambulances should give blood rather than saline to the critically injured?  He referred to putting the alternative infusions in two different sealed boxes as blinding, when I think he meant randomisation.  Margaret must be furious!

Porter

You have me bang to rights Adam – and here is the proof.

Clip – RePhill

Paramedic

We will open the boxes and inside we’ll either find saline or we’ll find freeze dried plasma and red blood cells.

Porter

So the decision to give fluid has already been made.  You then open the box to get your fluid but you don’t know what it’s going to be?

Paramedic

That’s exactly it, that’s exactly it.

Porter

And that’s the blinding of the trial?

Paramedic

Yeah.

So Margaret, were you thumping the radio?

McCartney

Yes Mark I’ve been incandescent all week but I know what you meant.

Porter

Well that’s part of the problem isn’t it, I mean I was talking to the person organising the trial and another member of the trial, we listened to it, no one picked up on my silly error because everybody knew what I really meant.  So Margaret, let’s clarify these terms so that we don’t mislead our listeners in future.

First of all, let’s start with randomisation.  What is it and why do we do it?

McCartney

Randomisation is when you don’t know what it is that you’re going to get and we really do this so that we’ve got fair comparative groups in a trial, we can compare the two groups that have got different treatments and work out was there a difference and then really try and say that the difference was down to the treatments that we give the two different groups.  So in the case of this RePhill study the paramedic or the patient didn’t know what the fluid being given was going to be, either a blood product or standard saline.  And either one was being randomly assigned to the patient.

Porter

So they just opened the box and whatever was in there they gave it, so they had no control over selecting what was happening.

McCartney

Yeah.

Porter

And that’s different from blinding, they might not be able to see what was in the box but that’s nothing to do with blinding.  Blinding is what and why do we do that?

McCartney

So blinding is different, it’s also called masking sometimes and that’s when you don’t know what you’ve got.  So you can be blinded, both the researcher and the patient or just one, and that means a trial can be either double blind, when nobody knows what treatment you got or just single blind when only the patient doesn’t know what they got.  And the reason why this is important is because knowing what you got can create bias, we can interpret our symptoms in different ways and we can be misled into reporting symptoms or signs that actually weren’t there in the first place.

Porter

So looking at this RePhill study if it was properly blinded the bags would have to be covered up so neither patient nor the paramedic knew whether they were giving clear liquid or blood products, that would be blinded?

McCartney

That’s right, you would have to have no idea what it is that you got.

Porter

Thank you very much Margaret.  And before Adam emails again, that of course would be double blind.

Just time to tell you about next week when we explore the cardiovascular implications of post-traumatic stress disorder – could it really be as bad for your heart as smoking 10 cigarettes a day?  And talking of hearts I will be answering a listener’s question about defibrillators in the community – has putting them in places like supermarkets, stations and airports saved many lives?

ENDS