The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study
Bibliographic record
Abstract
AIMS: Clinical trials have established the value of clopidogrel therapy in a wide spectrum of patients with cardiovascular diseases. Both loss- and gain-of-function single nucleotide variants of CYP2C19 genes have been identified that affect clopidogrel metabolism and anti-platelet response. We sought to determine the impact of CYP2C19 polymorphisms on ischaemic and bleeding events. METHODS AND RESULTS: A subset of patients from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who consented to genotyping was analysed. Patients with clinically evident cardiovascular disease or multiple risk factors were enrolled in the trial. The rates of ischaemic and bleeding events were compared between carriers and non-carriers of loss-of-function and gain-of-function alleles in patients randomized to clopidogrel vs. placebo. A total of 4819 patients were genotyped and available for the analysis. Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischaemic events. However, clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers: 36.1% (240/665) vs. 42.5% (681/1601) in non-carriers, HR: 0.80, 95% CI: 0.69-0.93, P = 0.003 (genotype/treatment interaction, P-value = 0.023). The CYP2C19 gain-of-function alleles did not affect ischaemic or bleeding endpoints. CONCLUSION: No relationship was seen between CYP2C19 status and ischaemic outcomes in stable patients treated with clopidogrel. There was, however, significantly less bleeding with clopidogrel in carriers of the loss-of-function allele, suggesting less anti-platelet response. Although several prior studies, including mainly stented patients, have emphasized the relationship between CYP2C19 loss-of-function alleles and efficacy of clopidogrel, this study of stable patients establishes a potential link with reduced bleeding complications. CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov number, NCT00050817.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".