Pharmacogenomics into practice - stroke services and a systems approach by Dr Richard Marigold, Consultant Stroke Physician and NIHR Hyperacute Stroke Research Centre Lead, University Hospital Southampton NHS Foundation Trust

1. Pharmacogenomics into practice – stroke services and a
systems wide approach
Dr Richard Marigold
Consultant Stroke Physician
Clinical and Hyperacute Stroke Research Centre Lead
University Hospital Southampton

2. Stroke in the UK • 116,000 hospital admissions in 2023
• 99,000 emergency cases
• 4th commonest cause of death and largest cause of long
term neurological disability, 2/3 of cases >65 years
• Costs £25 billion 2015, £75 billion by 2035
• But – things are substantially improving
• Thrombolysis 13% and mechanical thrombectomy rates
locally 5.7%
• NHS long term plan – aim 20% thrombolysis, 15%
thrombectomy
• Earlier physio and multidisciplinary team care on
designated stroke units
• Mortality 15%, 40% return to completely independent
living, 20% nursing home care, 40% moderate disability
needing assistance with ADLs

3. Stroke in Wessex
• 6000 ischaemic strokes in 2022
• Numbers rising by 1000 every 4 years
• 60% increase predicted by 2035
• Research active sites in Portsmouth, UHD, HHFT,
UHS
• Also support thrombectomy for patients from
Salisbury and Chichester

4. NIHR Hyper-acute stroke research centres (HSRCs) :
• Status awarded to Southampton General hospital, the team is led by Dr Richard Marigold
• 14 clinical trials since 2018 screened 1851 and recruited 651 patients
• HSRCs deliver acute stroke research requiring advanced neuro-imaging, specialist
interventional skills and rapid enrolment of patients
• Patients randomised and recruited within 9hrs of admission to hospital
• The accreditation, supported by the NIHR CRN Stroke Specialty, provides sites with increased
support to deliver complex interventions within the first nine hours of stroke onset.
• The marked impact these accredited centres have had on research performance and patient
outcomes, has recently been published in the Health Research Policy and Systems journal*
* https://health-policy-systems.biomedcentral.com/articles/10.1186/s12961-019-0417-2
Criteria for designation of Hyperacute Stroke Research Centres

5. Stroke at UHS • 1100 cases per year
• 13 bedded HASU
• 900 ischaemic strokes
• Current recruitment 9am-5pm during week but
planning to increase to out of hours with 24/7
thrombectomy autumn 2024
• 5.08 WTE research nurses

6. Breakthrough
stroke
Recurrence rates
• 1 year 11%
• 5yrs 26.4%
• 10yrs 39.2%
Reasons –
• Poor adherence to treatment
• Inadequately controlled or monitored risk factors –
eg hypertension / diabetes
• Lifestyle
• Unidentified atrial fibrillation or carotid stenosis
• Antiplatelet resistance

7. Clopidogrel
• 2nd generation thienopyridine
• Licenced for acute phase if patients are
aspirin allergic and main antiplatelet of
choice for long term secondary prevention
• Pro-drug metabolised to active form by
cytochrome p450-2C19 and essential for
inhibition of P2Y12 receptor leading to
platelet aggregation
• CYP2C19 highly polymorphic – over 30 loss
of function (LoF) alleles

8. CYP2C19 testing • Most evidence from East Asian populations
• Significant heterogeneity between studies
• Two cohort studies from UK – Torino et al
2019, Pilling et al 2021
• Meta-analysis (Pan et al) 15 studies, 11 from
China, 2 from UK
• CYPSC19 LOFA 12% vs no loss of alleles 5.8%
increased risk of recurrent stroke
• Increased risk of composite vascular events
13.7% vs 9.4%

9. Pilling LC et al BMJ Open 2021: 11: e53905
If applied to Wessex, could prevent 420 strokes per year,
saving £12 million to local health economy

10. NICE technology appraisal
DRAFT Recommendations published for consultation June 2023
Offer laboratory-based clopidogrel genotype testing, or the
Genomadix Cube point-of-care test if laboratory testing is not
possible, to people who have had an ischaemic stroke or transient
ischaemic attack if treatment with clopidogrel is being considered.

11. Strategic focus on personalised medicine in the NHS
NHS Long Term Plan (2019)
Patients will be offered more personalised therapeutic options due to
advances in precision medicine
WGS to improve diagnosis and access to personalised treatments e.g.
cancer
Focus on research and innovation e.g. linking genomic, clinical and
patient data and providing routes to new treatments
Genome UK – National Genomics Healthcare Strategy (2020)
Three pillars: diagnosis & personalised medicine, prevention, research
Incorporating the latest genomics advances into routine healthcare to
improve the diagnosis, stratification and treatment of disease
Accelerating genomic medicine in the NHS (2022)
Over next 5 years:
Embed genomics in NHS from primary/community through to
tertiary care
Deliver equitable genomic testing in Ca/RD and PGx to reduce
ADRs
Improve data/digital interoperability
Rapid implementation of research and innovation

12. Next steps Wessex based study to define:
• Define prevalence in local population and
differences in ethnicities
• Establish point of care testing using
Genomadix / Genedrive system
• Rapidly scale up to provide an ISDN wide
approach
• Follow 2022 CPIC guidelines for management
• Ticagrelor for those who are intermediate or
poor metabolisers (supported by 2023
National Stroke Guidelines)
• Continue clopidogrel for rapid or ultrarapid
metabolisers