Ahead of World Stroke Day, David Budd, CEO of genedrive plc, underscores the growing role of pharmacogenetics in personalised medicine and how its application can decrease the odds of secondary cerebrovascular disease.
Key insights:
- Routine use of pharmacogenetics in stroke patient management offers the best chance to guarantee efficacy of secondary prevention measures, avoiding thousands of unnecessary deaths every year.
- Clopidogrel is a single anti-thrombotic agent treatment for ischaemic stroke, but for those carrying CYP2C19*2 or CYP2C19*3 loss-of-function alleles, clopidogrel has no discernable clinical benefits.
- Customised treatment with clopidogrel or an alternative for those resistant to its effects, as guided by pharmacogenetics, could significantly reduce the risk of future cerebrovascular infarctions.
The value of pharmacogenetics in personalised medicine is indisputable. Few would argue against the merits of being able to confidently treat patients with the medications best suited to both their clinical requirements and their body’s genetic ability to respond appropriately to them. But sadly, the availability of pharmacogenetic testing – despite its myriad of benefits – is still to be realised, while sufferers of a variety of illnesses continue to receive suboptimal treatment, unbeknown to their care providers.
This is a poor outcome for patients, the NHS, and society as a whole. The health and economic burden of additional morbidity and avoidable adverse drug reactions affects us all.
So where should we be looking to press the case for increased use of pharmacogenetic testing? A primary candidate is stroke, as it is the second leading cause of death worldwide, and fourth in the UK. The routine use of pharmacogenetics in stroke patient management offers the best chance to guarantee efficacy of secondary prevention measures, avoiding thousands of unnecessary deaths every year.
Genetic variants render many prescribed medications ineffective or dangerous
It is believed that most prescription medicines are effective in only 30% to 50% of people. The reason for such a low percentage is that some genetic traits lead to resistance or amplification of the intended therapeutic effects of certain medications.
For example, variants in the 5-HTTLPR allele have been linked to varying responses to selective serotonin reuptake inhibitors; those carrying the 5-HTTLPR SS variant are less likely to respond to the anti-depressant, diminishing any discernible clinical benefit of taking it.
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In addition to negating the effects of some medications, genetic variants can predispose patients to harm on exposure to certain drugs. Adverse drug reactions are believed to occur in up to one fifth of hospital inpatients, account for 6.5% of hospital admissions, and cost the NHS £380 million each year. Genetic variations can confer susceptibility to particular adverse reactions, such as the MT-RNRI m.1555A>G variant, which causes permanent hearing loss following exposure to gentamicin. These are largely avoidable using rapid pharmacogenetic tests at the patient bedside.
Rapid pharmacogenetics involves quick point-of-care testing for specific genetic variants that indicate whether a patient is likely to receive the intended clinical benefits of a particular medication. This is entirely distinct from genetics testing as a predictor of inherited disease, which comes with an abundance of ethical considerations far beyond the scope of our proposed indication.
Strokes cost the NHS more than £3 billion every year
There are more than 100,000 strokes in the UK every year, resulting in 38,000 deaths and long-term disability for two-thirds of survivors. While the estimated annual cost to the NHS is £3.4 billion, when taking into consideration the societal cost (loss of productivity in stroke victims of working age, unpaid carer hours, and so forth) the total actual cost to the economy is believed to be an astonishing £26 billion annually.
Following a stroke, secondary prevention medications are prescribed to reduce the risk of future events. One of these is clopidogrel, an anti-platelet agent that lowers the risk of secondary thrombosis by impairing platelet aggregation via indirect effects on vascular inflammation and endothelial function.
Point-of-care tests fit well with recommendations for genotyping patients prior to administering clopidogrel. Genetics laboratories remain distant from patients and may have up to two-week turnaround times, whereas treatment should be prescribed within 24 hours. Genedrive's CYP2C19 kit aims to deliver a result in less than an hour. If you want to have a genetic result within a day, you need a device near a patient.
The National Institution of Clinical Excellence (NICE) and the British National Formulary (BNF) recommends treatment with clopidogrel as a single anti-thrombotic agent following ischaemic stroke, but for those carrying CYP2C19*2 or CYP2C19*3 loss-of-function alleles, clopidogrel has no discernable clinical benefits, leaving them vulnerable to composite cerebrovascular events.
Clopidogrel is a crucial stroke secondary prevention measure
Clopidogrel is a prodrug, relying on the CYP2C19 liver enzyme for activation before it can exert its intended effect.
Up to one in five people are unable to convert clopidogrel into its active form, rendering it ineffective. Identifying these one in five patients on arrival in accident and emergency is an opportunity to transform their medical management. Those resistant to clopidogrel can be given an appropriate alternative, such as aspirin combined with dipyridamole, or Ticagrelor. This drug, while linked to higher bleeding rates and costs, is still potentially lifesaving when given to the right people.
The clinical benefit of CYP2C19 genotyping is well documented in scientific literature when it comes to protecting against new strokes or myocardial infarction. Recently, genedrive’s CYP2C19 ID testing kit, which identifies people carrying the loss-of-function mutation conferring inadequate metabolisation of clopidogrel, has been included in NICE’s recent DAP programme – a testament to its recognised potential for enhancing treatment.
Pharmacogenetic testing could revolutionise stroke outcomes
The Royal College of Physicians and the British Pharmacological Society publicly support the case for the speedy introduction of widespread pharmacogenetic testing across the UK. It already has an established role in cancer and heart disease treatments and has the potential to also reform the management of cerebrovascular disease.
Customised treatment with clopidogrel or an alternative for those resistant to its effects, as guided by pharmacogenetics, could significantly reduce the risk of future cerebrovascular infarctions.
During a time of unprecedented pressure on the NHS, stripping out the cost of ineffective prescriptions and reducing the burden of avoidable illness and adverse drug reactions could present a substantial cost-saving opportunity, in addition to optimising the efficacy and safety of the care each individual patient receives.