Having blasted onto the scene back in 2010 to provide a novel alternative to the previous standard of care in anticoagulation, direct oral anticoagulants (DOACs) have since become an attractive treatment option for prescribers and patients (Chen et al, 2020). However, as with all treatments, DOACs are not without their side effects.
In a new development, the Medicines and Healthcare products Regulatory Agency (MHRA) recently announced its intention to work with Genomics England to analyse patients' experiences of side effects reported from the use of DOACs. This will take place as part of a genetic biobank version of the Yellow Card adverse events reporting scheme, and will make use of gene sequencing to analyse the ways in which a person's genetic make-up may influence their response to DOACs (Clews, 2024).
The genetic biobank, which operates alongside the Yellow Card scheme and is thought to be first in the world, facilitates patient-reported suspected adverse effects of medicines and medical devices. It then stores genetic data and samples with the aim of identifying whether genetic traits are linked to the adverse reactions patients have experienced.
DOACs
Cardiac arrhythmias represent a significant burden, affecting morbidity and mortality (Gheorghe-Andrei et al, 2018). Atrial fibrillation (AF) is the most common arrhythmia, and prevalence not only increases but roughly doubles with every decade of age (Eftekhari et al, 2021). AF can lead to thromboembolic stroke as clots in AF arise as a result of slow blood flow in the atria, which leads to a hypercoagulable state (Steffel et al, 2018).
This state requires the use of anticoagulation, which does not fall into the anti-arrhythmic drug category, but is crucial in reducing the incidence of life-changing strokes in people with AF (Eftekhari et al, 2021). Anticoagulation includes either the traditional mainstay, warfarin (a vitamin K antagonist), or DOACs, which include rivaroxaban, apixaban, edoxaban or betrixaban, which are oral direct factor Xa inhibitors, and dabigatran, which is a direct thrombin inhibitor (Chen et al, 2020).
According to the National Institute for Health and Care Excellence (NICE) (2021a), when recommending an anticoagulation treatment option, DOACs, which act directly on the clotting cascade (rather than indirectly as warfarin does (Eftekhari et al, 2021), should be recommended in people with AF who have a CHA2DS2-VASc score of 2 or above, taking into account bleeding risk and other relevant guidelines such as shared decision-making (NICE, 2021b) and the British National Formulary, particularly for contraindications such as valvular AF and severe kidney failure (Eftekhari et al, 2021).
The CHA2DS2-VASc system provides a way to calculate stroke risk with a low threshold (one or more points) for anticoagulation (Eftekhari et al, 2021).
Genomic medicine
Patients in England who are being treated with DOACs and who do experience excessive bleeding are being asked by the MHRA to submit Yellow Card reports of this experience (Clews, 2024). These patients, as well as any others who have reported experiencing side effects of DOACs in the past, may be contacted by the MHRA to provide a blood sample for storage in the biobank. The sample would then be genetically sequenced, and de-identified before being added to the National Genomic Research Library for analysis (Clews, 2024).
The Yellow Card biobank is thought to be the first of its kind in the world, and the inclusion of DOACs marks its second phase, as the goal of achieving personalised medicine continues to progress (Clews, 2024).
Genomic medicine has been taking great strides since the first human genome was sequenced, taking 13 years and costing in excess of £1.5 billion of public funding (Robinson, 2017). This was an international research effort to sequence and map all of the genes, collectively known as the genome, of the species. The Human Genome Project ran from 1990 to 2003, giving us the ability to read the genetic blueprint for building a human for the first time in history. This was followed by the 100 000 Genomes Project from 2012 to 2018, which was the first initiative led by Genomics England and, as the name would suggest, saw 100 000 genomes sequenced in 6 years (Mendes, 2019).
Conclusion
It is hoped that the MHRA's recent move to include DOACs in the Yellow Card biobank scheme and analyse individual samples to determine the genetic role of patient responses to DOACs will help to improve and tailor treatment options offered to prevent thromboembolic stroke in people living with AF.
The developments outlined in this article all form part of an effort to move away from the previous model of one-size-fits-all medicine, towards the person-centred approach of precision medicine, allowing for a more targeted understanding of the role played by a person's genetics in the development of disease, their treatment and their individual responses to treatment.
The goal is to eventually integrate genomics into mainstream healthcare, tailoring prevention and treatment to each individual.