Clopidogrel is commonly prescribed for secondary prevention of ACS. The drug has to be converted to its active metabolite before it can take effect (as a P2Y12 platelet inhibitor). This requires the hepatic enzyme cytochrome P450 2C19 (CYP2C19) – an enzyme that is subject to genetic polymorphism. The presence of one or more loss-of-function (LOF) alleles of CYP2C19 results in ‘poor metabolisers’ and ‘intermediate metabolisers’ who are unable to activate clopidogrel.

This study set out to determine the prevalence of common CYP2C19 polymorphisms in a British–South Asian population and correlate these with recurrent myocardial infarction risk in participants prescribed clopidogrel.

DNA samples from more than 44,000 volunteers were analysed. This group had a high prevalence (57%) of intermediate or poor CYP2C19 metabolisers, with at least one LOF CYP2C19 allele.  Of note, the prevalence of poor metabolisers carrying two CYP2C19 LOF alleles was 13%.  Previously reported proportions for European and Central/South Asian populations have been 2.4% and 8.2%, respectively.

Sixty-nine percent of the cohort who were diagnosed with an acute myocardial infarction were prescribed clopidogrel. Poor metabolizers were significantly more likely to have a recurrent myocardial infarction (OR: 3.1; P = 0.019). In fact, there was a clear gradient of increased risk of recurrent myocardial infarction with increased LOF burden.

The results of this study underline the potential importance of pharmacogenetic (PGx) testing so that the genotype is known before the prescription is issued and adjustments can be made. The alternative would be to prescribe non-CYP2C19 dependent platelet inhibitors such as prasugrel or ticagrelor for everyone but the costs may be too great.

Actionable drug-genome interactions are not uncommon and routine PGx testing services have been advocated  commenting on the findings Professor David Wright said:

“This is why all services need to be delivered in a culturally competent manner. PGx evidence is biased towards the white European population and may not translate to other populations. If the profession is to assume responsibility for PGx testing it will need to ensure that all patient groups are aware of its potential limitations when their DNA is taken. I would hope that any software providing guidance following PGx testing will be routinely updated with such evidence as it would be impossible for any individual to be able to remember these differences.”

Professor Wright (University of Leicester) leads a research team focused on design and implementation of routine pharmacogenomics (PGx) services in community pharmacy.

Reference

Magavern E, Jacobs B, Warren H, et al. CYP2C19 Genotype Prevalence and Association With Recurrent Myocardial Infarction in British–South Asians Treated With Clopidogrel. JACC Adv. null2023, 0 (0) .https://doi.org/10.1016/j.jacadv.2023.100573

Why pharmacogenomics matters to community pharmacy

Pharmacogenomic testing is an important step in improving the safety of drug treatment and delivering better outcomes for patients. Professor Wright explains that traditional prescribing is for the ‘average’ patient but 20 per cent of patients are at either end of the normal distribution and are not ‘average’. They may need different doses or even different drugs to get the best effects. “What pharmacogenomics does is gives us that extra piece of information to say actually they might not want this drug, this is likely to cause a side effect or actually they need a high dose or a low dose or you just need to monitor them more carefully”, he explains. The best way to deliver this is through a pharmacy-led service, integrated into the primary care system, he says.

Designing a pharmacogenomic service

Designing and evaluating PGx services requires multidisciplinary input from patients, doctors and pharmacists. This process was described in a poster, based on research led by Tim Rendell (Head of Pharmacy for Day Lewis Pharmacy) that was presented at the 80th FIP World Congress in Seville.¹

The test itself requires only collection of a DNA sample using a cheek swab and is “simpler than a covid test”. However, the way that the results are communicated is critical and, building on multidisciplinary discussions, a training package for community pharmacy has now been developed. “It’s not about them needing to understand exactly which base pairs in the DNA are different and why those base pairs cause this change in metabolism further down the route …….. It’s all about confidence. It’s all about demystifying the very clever, very complex science for the healthcare professional and for the patient so we make the right sort of decisions”, says Professor Wright.

Making pharmacogenomics work in practice

Actionable drug-genome interactions (DGIs) are found in one in five tests and this makes the processes of obtaining informed consent for testing and follow-up of test results particularly important, says Professor Wright. Patient can have a number of concerns about how the DNA results will be used and stored. “If you want to get the most out of the test you communicate at the start, you communicate at the end and then you make sure that the right changes are made to therapy and the patient’s expectations are managed through the process”, he says.

PGx services are well-developed in some other countries. He suggests that in the UK PGx testing could be built into the New Medicine Service (NMS) for specified drugs.

Evidence for pharmacogenomic services

A growing number of studies is now providing evidence for the benefits of pharmacogenomics testing (PGx) services. The PREPARE (PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions) study has shown what can be achieved in a well-conducted, multicentre trial. Now there are two critical gaps to be addressed. The first is the need for a service that tackles polypharmacy rather than single drugs. The second is working out how to incorporate PGx testing into services and make it part of the system. “I want to actually put it into the real world and show the benefit in the real world with a proper system set up”, says Professor Wright.

Reference

1. Rendell T, Barnett J, Wright D, Scott S. Pharmacogenomics: co-designing a community pharmacy testing service in England. Poster CPS-078. Presented at 80^th FIP World Congress, Seville Spain Sep2022

So far studies involving antidepressants, warfarin and clopidogrel have demonstrated the effectiveness and cost-effectiveness of testing services. “It’s kind of common sense if you know that one in five times you get the right drug for a patient more quickly – more quickly than you would have done – and therefore they go to back to the GP less frequently – then there’s some savings to be had”, says Professor Wright.

Recently the PREPARE (PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions) study was completed. This involved centres in several European countries. So far, “what’s been presented are what’s very encouraging and positive results from a well-conducted trial”, he says. In this study centres tackled single drugs “they didn’t do multi-testing which is what we tend to do so that you get the additional benefits of all the other drugs being checked at the same time”, he says.  There are now about 120 drugs for which PGx testing can be done so it is possible that people receiving multiple drug therapy will have several potential actionable drug-genome interactions (DGIs).

At present there are two critical gaps. The first is the need for a service that tackles polypharmacy rather than single drugs. The second is working out how to incorporate PGx testing into services and make it part of the system. “I want to actually put it into the real world – and that’s what the MRC guidance is all about – and show the benefit in the real world with a proper system set up”, says Professor Wright.

A further trial is now required “because the world is complex and because putting a test into the system is not that easy”, he says. By definition, in a trial the people involved have all “signed up” and are committed to the service but this does not reflect the way that services operate in the real world. “So, what they’ve done is shown the benefits if it’s done beautifully and perfectly – my job as a health services researcher is then to translate that into the real world and into real practice and still show the benefits are maintained as a result”, he explains.

Regarding funding for a future PGX testing services, Professor Wright says that he would want to see it as part of the national [community pharmacy] contract. “I think it’s probably one of the most sensible things we could add into the national contract because it really works across the different professions and really integrates us into the system. But for that to happen we need that evidence so that’s why I want the trial, that’s why I want to have some real guidance on how to train the pharmacists to do this, how to set the service up appropriately, how to build those relationships and then run it out. So, you know the NHS says anything that has a cost per QALY of less than twenty thousand pounds it can afford …..  that’s the measure we have to use – so we need to do this trial on a set group of patients, demonstrate the cost per QALY and then we go back via Community Pharmacy England …… to say, ‘Here’s your evidence’.”

The next steps will involve putting in a grant application to do the feasibility testing. “We’ve done the listening; we’ve looked at the literature. We’re now ready to set up and run a small service and test it and then run the big trial and get the evidence – and I don’t think it should take that long – purely because we’ve done all the groundwork”, he says.

Professor Wright’s message to pharmacists is: “This is our role; this is how we put ourselves on the map and this is how we show patients that we are the scientists on the high street – and we have that academic expertise to help [them to] get the most out of their medicines”.

Read and watch the full series on our website or on YouTube.

Professor David Wright BPharm, PGCHE, PhD FRPharmS is Head of the School of Healthcare, University of Leicester.

He also holds the position of Professor of Clinical Pharmacy at the University of Bergen, Norway.

GPs could order pharmacogenomics (PGx) tests much like any other biochemical test, but unlike other tests patients have many concerns and questions about PGx tests. Professor Wright explains:

“The patient concerns are …. Are you going to tell me who my dad is?  Are you going to tell me what my life expectancy is? Are you going tell me what disease I’ve got coming down the road?” …… So, you know, when you’ve got a patient [and say] ‘I need to take your DNA’ there’s all these concerns in their heads that you’ve got to overcome before you can actually take the DNA”, he says. Proper informed consent is critical. Patients from deprived areas are very often worried about this information going to the police or being used to solve crimes and then being recorded on a national database.  “So, there’s all these things we’ve got to think about as healthcare professionals so that we can reassure the patient that the bit of DNA we’re taking …. will only tell us about their medicines and nothing else and certainly that data will be secure [and] it will not be given to anybody else”, he says.

Once the result is received it is important to take time to explain it to the patient. Because other parts of the health service work on a ‘no news is good news’ basis there is a tendency to think that if you are called to receive test results then there is bad news. However, one of the reasons it is important to communicate negative PGx results (where no genetic reason for altered response is found) is that evidence suggests medication adherence improves when patients understand that their treatment is individualised and is safe and appropriate for them. “If you want to get the most out of the test you communicate at the start, you communicate at the end and then you make sure that the right changes are made to therapy and the patient’s expectations are managed through the process”, says Professor Wright.

He recalls that some patients have been a little upset to find that there was no genetic cause for the side effects that they were experiencing. This was because their expectations had not been appropriately managed, he says. For GPs this could be a time-consuming process, especially as only one in five tests is likely to detect an actionable drug-genome interaction (DGI). “What they need to be able to do is say [to a patient], ‘Go to your pharmacist, ask for a test, let them talk to you about it and they can give me the result and discuss it, if need be. If not, they’ll just discuss it with you’”, suggests Professor Wright. Ideally, this is something that could fit into the New Medicine Service (NMS) and provide an additional piece of information, he suggests.

PGx services in other countries

Pharmacy-based PGx services have a “head of steam” in The Netherlands but one country where it is well-developed is Australia where a private service was set up.

Professor Wright explains: “The measure of success was that the doctors actually got to the point of saying to the patients, ‘Can you go to the pharmacist, get this test first and then I’ll prescribe for you’. Now there is a difference in Australia because patients are used to paying for their care ……. so therefore, it’s more acceptable for the doctor to say that”. In fact, the doctor might even explain that by doing the test first it might be possible to prescribe the right drug and dose for the patient first time and avoid trying three others first. What this shows is that “when the doctors see the benefits and see the results, they engage with it more”, he says.  He envisages a situation where every time a NMS interview was done for a patient with specified treatments, a PGx test could be ordered and charged to the surgery. Such a process could build a good working relationship between the community pharmacist and the prescriber and lead to better quality patient care.

Read and watch the full series on our website or on YouTube.

Professor David Wright BPharm, PGCHE, PhD FRPharmS is Head of the School of Healthcare, University of Leicester.

He also holds the position of Professor of Clinical Pharmacy at the University of Bergen, Norway.

The poster described work that was led by Tim Rendell, Head of Pharmacy for Day Lewis Pharmacy.

The MRC guidance on evaluation of complex interventions calls for collaboration between all the stakeholders in order to design and test a realistic intervention. In this case pharmacists, patients and GPs were invited to participate.  There was no disagreement that the service should be offered by community pharmacists, recalls Professor Wright. Both pharmacists and GPs said they had little training in the field and felt that they lacked knowledge about the technology and the underpinning science. However, “they recognised the benefits when they realised that this would mean that patients didn’t come back so often because they were given the right drug the first time and they were less likely to suffer side effects”, he says.  The group did not immediately realise that five patients would need to undergo testing to identify one actionable drug-genome interaction. Nevertheless, “there was clear positivity about the idea and the technology and also about the community pharmacies doing it”, he says.

Community pharmacists were concerned about time, space and the appropriateness of their consultation rooms for doing DNA testing. In fact, the test involves only a simple swab inside the cheek, often done by the patient. “It is simpler than a covid test”, notes Professor Wright.

“You do need to sit down with the patient and talk to them about what this means -what’s going to happen to their DNA, what’s not going to happen to the DNA. More importantly, reassure them what the result means”, he says. In the event of a positive result there could be another 50 medicines listed that a patient might receive in the future and it is important to make the patient aware of the risks and the importance of keeping the list for reference. “The test gives you information for life”, he emphasises.

During a visit to another country “I found that doctors were ordering the test more than once for the same patients. Your DNA doesn’t change”, says Professor Wright. This showed a lack of understanding of the technology and underlined the need for training.

Study participants also raised the importance of presenting the results in a way that they could be used and safe storage of data. In addition, the group recommended a ‘soft start’ on a small scale before rolling the scheme out this out on a large scale.

As a result of this work, it has been possible to design a training package for community pharmacy. It was clear that a properly integrated service needs to be set up from the beginning. There has to be agreement on how information will be communicated, which patients will be involved and how doctors and pharmacists will respond to the information received. “What we have learned is we don’t need to teach the science. We don’t need to go down to the detailed level. What we need to do is make sure they know how to respond to it and to treat the patient not the result”, he says.

The purpose of the training is to give community pharmacists the confidence to offer the test and the confidence to respond appropriately to it. “It’s not about them needing to understand exactly which base pairs in the DNA are different and why those base pairs cause this change in metabolism further down the route. Unfortunately, a lot of the training is focused on that. …….. It’s all about confidence. it’s all about demystifying the very clever, very complex science for the healthcare professional and for the patient so we make the right sort of decisions”, he concludes.

Reference

Rendell T, Barnett J, Wright D, Scott S.  Pharmacogenomics: co-designing a community pharmacy testing service in England. Poster CPS-078. Presented at 80^th FIP World Congress, Seville Spain Sep2022

Read and watch the full series on our website or on YouTube.

Professor David Wright BPharm, PGCHE, PhD FRPharmS is Head of the School of Healthcare, University of Leicester.

He also holds the position of Professor of Clinical Pharmacy at the University of Bergen, Norway.

Professor Wright leads studies concerned with improving the delivery of healthcare to patients and these often involve complex, multidisciplinary interventions. As such, these need to be developed and evaluated in accordance with Medical Research Council (MRC) guidance. It is not sensible to rush into short-term studies to test an idea – the so-called ‘ISLAGIATTs’ (‘it seemed like a good idea at the time’) approach, because they usually do not work. Far better, he says, to plan carefully.

“We need to listen to people, we need to learn from the literature [and] we need to sit down and co-design our intervention. And even when we’re all happy with it, [both] professionally and with the patients involved as well, we’ve then got to ….. feasibility test it – and that’s the bit I really enjoy”, he says. Only when the intervention has been refined and feasibility-tested is it time to undertake a randomised, controlled trial.

Professor Wright’s other role (as Head of the School of Healthcare)  is to manage the delivery of courses for a number of healthcare professionals including nurses, midwives, physiotherapists, operating department practitioners (ODPs) radiographers and the pharmacist prescribing team.  “What’s really interesting is seeing how those healthcare professionals are educated and trained compared to how pharmacists are educated and trained so I can see that these things all link up”, he says.

Why pharmacogenomics?

When first approached about the implementation of pharmacogenomics services by his colleague Dr Dhiren Bhatt, Professor Wright thought it was “futuristic” and was surprised to learn that services were already available in Australia, America, Canada and The Netherlands – but not in the UK.

“When I saw what it was, I was, like, blown over by it – really excited”, he recalls.

“Pharmacogenomics is clearly the next step. All pharmacogenomics is – is looking at someone’s DNA to work out what bits are different and therefore how that then affects how a patient’s drug should be prescribed. It took me a while to realise this, but we prescribe for the average patient. So, the BNF says the average patient will respond within this dose range with this drug and this is the best drug to start with.  But you know 20 per cent of people are either end of that normal distribution and they’re not average and therefore they might need a different drug or a different dose and what pharmacogenomics does is gives us that extra piece of information to say actually they might not want this drug, this is likely to cause a side effect or actually they need a high dose or a low dose or you just need to monitor them more carefully. So, it just gives us another piece in the jigsaw when we’re prescribing.” Furthermore, it improves patient safety and should lead to better outcomes more quickly, he adds.

Initially, he was concerned about how the DNA analysis could be done and interpreted but when he discovered that schemes are in place to do this and that “the software makes the recommendation – it says, for this patient, based on their DNA, you should be doing this – and that just blew me away”, he says.  He realised that it could become standard practice.

During a visit to Norway, where he holds a position of Professor Clinical Pharmacy at the University of Bergen, he discovered that PGx testing is routinely available to GPs. However, the service is little-used – GPs order on average one test per year.  “What that told me was that actually this isn’t something that GPs want to take on. This is an additional workload. …. If you look at the model in every other country, it’s pharmacist-delivered. So, for me, this is a real exciting opportunity for pharmacists to take centre stage, look after the patient, provide individualised care and work closely with GP. So, it’s no longer a service on the side, it’s a service integrated into the system to enhance patient care”, he says.

As part of this project a small-scale feasibility test in a mental health setting has just been completed, he adds.

Read and watch the full series on our website or on YouTube.

Professor David Wright BPharm, PGCHE, PhD FRPharmS is Head of the School of Healthcare, University of Leicester.

He also holds the position of Professor of Clinical Pharmacy at the University of Bergen, Norway.