Effect of <i>PON1</i> Q192R Genetic Polymorphism on Clopidogrel Efficacy and Cardiovascular Events in the Clopidogrel in the Unstable Angina to Prevent Recurrent Events Trial and the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events
Bibliographic record
Abstract
BACKGROUND: A recent report suggested that carriers of the Q allele of the PON1 Q192R polymorphism had decreased biotransformation of clopidogrel into its active metabolite and decreased efficacy of clopidogrel in preventing cardiovascular events. Furthermore, PON1 has been reported to have a central role in the antioxidant function of high-density lipoprotein, and the Q192R polymorphism has been previously associated with cardiovascular risk in patients not treated with clopidogrel. METHODS AND RESULTS: Patients (n=5059) from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) randomized trial that demonstrated benefits of clopidogrel versus placebo in preventing cardiovascular events in acute coronary syndromes were genotyped for the PON1 Q192R polymorphism. Clopidogrel compared with placebo significantly reduced the first primary efficacy outcome, irrespective of PON1 Q192R genotype (P=0.07 for heterogeneity). No association was observed between the Q192R polymorphism and cardiovascular events in the overall sample (hazard ratio [HR], 1.09 per allele; 95% confidence interval [CI], 0.95-1.24; P=0.23). However, an association was observed between the Q allele and increased cardiovascular events in the placebo group (HR, 1.23 per allele; 95% CI, 1.03-1.47; P=0.03) but not in the clopidogrel group (HR, 0.93 per allele; 95% CI, 0.76-1.13; P=0.46). In 1156 atrial fibrillation patients from the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events, there was no evidence of interaction between PON1 genotype and clopidogrel for any outcome or for an association between genotype and cardiovascular events. CONCLUSIONS: In conclusion, our study shows that PON1 Q192R genotype does not modify the efficacy and safety of clopidogrel in patients with acute coronary syndromes. Further studies are needed to confirm or refute the association of the Q allele with adverse cardiovascular events independent of clopidogrel in secondary prevention patients.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.003 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".