Abstract Body (Do not enter title and authors here): Introduction:
In recent years, genetic interactions with drugs have been demonstrated to alter drug metabolism. Efforts such as PharmGKB and the Clinical Pharmacogenomics Implementation Consortium (CPIC) have developed recommendations to alter the use of several commonly prescribed drugs based on patient genotype. However, most prescriptions are still given without pharmacogenomic testing.
Objective: Demonstrate the real world implications of the use of pharmacogenomic testing through a retrospective study of clopidogrel prescriptions given without testing.
Methods:
We analyzed ~100K individuals with paired medical records and clinical grade exome sequencing data, from population health studies administered at multiple medical centers. We genotyped all individuals for CYP2C19 star alleles. We identified daily dosage of clopidogrel by processing the freetext prescription “sig” field with GPT-4. Then, we identified all instances of individuals with at least one prescription that is not in concordance with the CPIC clopidogrel use guidelines based on their CYP2C19 genotype (Bousman et al. 2023). We identified instances of thrombosis using a comprehensive codeset based on the medical records.
Results:
25% of individuals with a calculable daily dose of clopidogrel have a mismatch between the recommended clopidogrel dosage guideline based on their CYP2C19 genotype and their prescribed dose. 12% of these mismatched individuals are poor metabolizers (PM), who should not use clopidogrel at all. The remaining 88% are intermediate metabolizers (IM). PMs and IMs receiving clopidogrel are much more likely to experience thrombosis than other metabolizers. 25% of PMs experienced thrombosis after the initiation of clopidogrel, with 40% of these occurring in the first two months (vs normal metabolizers, binomial p-value = 0.001).
Conclusions:
As expected from a lack of testing and a high population frequency of pharmacogenomic variants, many patients are prescribed doses of clopidogrel that are too high given their subsequently derived pharmacogenomic information. There is at least a 38% excess of adverse events (as measured by thrombosis) in this group. At minimum, this testing could prevent 1 thrombosis event per every ~30 people prescribed clopidogrel, demonstrating tangible benefits of population-based pharmacogenomic testing.