Current evidence on the use of potent P2Y12 inhibitors in elective percutaneous coronary intervention

Dear Editor:

The recent study by Gallo et al. (Gallo) concludes that, in patients with chronic coronary syndrome (CCS) treated with percutaneous coronary intervention (PCI), the use of ticagrelor significantly reduces major adverse cardiovascular events and all-cause mortality at one year’s follow-up.¹ However, the routine use of these agents in CCS lacks solid support in current guidelines, which continue to regard clopidogrel as the standard of care due to insufficient evidence of net clinical benefits in this population.²

From a critical epidemiological perspective, the finding of a 57% reduction in all-cause mortality is pathophysiologically unlikely. This magnitude of benefit is not associated with a significant reduction in non-fatal myocardial infarction (AMI) or stroke (CVA), for which the confidence intervals are extremely wide.¹ The low number of AMI and CVA events, combined with these intervals, results in a degree of imprecision that suggests residual selection bias or analytical fragility rather than a consistent causal effect, particularly when ischaemic outcomes do not follow the same trend as mortality.

This dissociation suggests that the observed mortality may be influenced by unmeasured confounding factors or competing non-cardiovascular mortality, given that the clopidogrel group had a higher baseline burden of comorbidities.¹ Furthermore, in data derived from a 1:1 propensity score, the observations are matched and not independent. If a standard Cox model is applied without pair-stratification or without a robust variance estimate (such as a sandwich or pair-cluster model), there is a high risk of underestimating the variance, artificially narrowing the confidence intervals and obtaining excessively optimistic p-values.¹

Contrary to what has been reported, the THEMIS trial (Bhatt), involving more than 19,000 patients, did not demonstrate a reduction in overall mortality (p = 0.68).³ Furthermore, when adjusting for the risk of bleeding using the PRECISE-DAPT (Costa) scale, the ischaemic benefit is often outweighed by the risk of bleeding.⁴ Finally, the ALPHEUS (Silvain) trial has already shown that ticagrelor is not superior to clopidogrel in elective PCI.⁵ Therefore, the purported survival benefit must be interpreted with extreme caution; given the methodological limitations and the inconsistency with previous evidence, these findings should not even be regarded as a valid hypothesis for changing current clinical practice.

Funding

This letter to the editor has not received any external funding, whether public or private, for its production.