Ticagrelor may not be superior to clopidogrel in ACS patients undergoing PCI

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The use of ticagrelor in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) was not associated with a significant difference in the risk of net adverse clinical events (NACE), a study published in the Journal of the American Medical Association (JAMA) has found.

The retrospective cohort study by Seng Chan You (Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea) and colleagues sought to determine the association of ticagrelor versus clopidogrel with ischaemic and haemorrhagic events in patients undergoing PCI for ACS in clinical practice.

The current American and European guidelines recommend the use of ticagrelor with aspirin in preference to clopidogrel for patients with ACS, largely based upon the Platelet Inhibition and Patient Outcomes (PLATO) trial which demonstrated that ticagrelor was more effective than clopidogrel in patients with ACS. However, You and colleagues note that questions remain over the greater effectiveness of ticagrelor compared with clopidogrel, with recent observational studies and open-label RCTs suggesting that ticagrelor is associated with better outcomes compared with clopidogrel in clinical practice.

Researchers used two US electronic health record–based databases and one nationwide South Korean database from November 2011 to March 2019, with patients matched using a large-scale propensity score algorithm. The final follow-up date was March 2019.

The primary end point was NACE at 12 months, composed of ischaemic events (recurrent myocardial infarction, revascularization, or ischaemic stroke) and haemorrhagic events (haemorrhagic stroke or gastrointestinal bleeding). Secondary outcomes included NACE or mortality, all-cause mortality, ischaemic events, haemorrhagic events, individual components of the primary outcome, and dyspnoea at 12 months. The database-level hazard ratios (HRs) were pooled to calculate summary HRs by random-effects meta-analysis.

A total of 183,579 patients across the three databases were included in the analysis—43,578 in the ticagrelor group, and 140,001 in the clopidogrel group. You and colleagues reported that the one-year risk of NACE was not significantly different between ticagrelor and clopidogrel (15.1% vs. 14.6% p=0.06) after propensity score matching. Additionally, they report that there was also no significant difference in the risk of all-cause mortality (2% for ticagrelor vs. 2.1% for clopidogrel p=0.74) or ischaemic events (13.5% for ticagrelor vs. 13.4% for clopidogrel p=0.32). The risks of haemorrhagic events (2.1% for ticagrelor vs. 1.6% for clopidogrel p=0.001) and dyspnoea (27.3% for ticagrelor vs, 22.6% for clopidogrel p<0.001) were significantly higher in the ticagrelor group.

Discussing the findings, the study team posits several possible explanations for the lack of a significant difference in risk of NACE for patients treated with the two drugs, including the potential for residual confounding, drug adherence and the overall improvement in clinical outcomes of patients with coronary diseases. They note: “The overall improvement in the clinical outcomes of patients with coronary diseases may be another possible explanation for the diminished benefit of ticagrelor in the modern era; in particular, this may be driven by progress in the use of drug-eluting stents and post-stenting care. More than 60% of the study population in PLATO, who were treated using PCI, received bare metal stents, and most of the remaining patients received first-generation drug-eluting stents. The recent clinical trials, which reported comparable thrombotic event rates between the ticagrelor and clopidogrel groups, mostly used second-generation drug-eluting stents, which might have reduced the need for a stronger P2Y12 inhibitor. In addition, it may be that despite the finding from a single trial, ticagrelor is not more effective than clopidogrel.”

Seng Chan You

The study was developed and executed by the OHDSI community, a multi-stakeholder, interdisciplinary collaboration that works to bring out the value of health data through large-scale analytics. All solutions are open-source, and links to the study protocol, code and results are posted in the paper. All analyses are performed at the individual sites, meaning no patient-level data needed to be shared and patient privacy could be maintained.

“Interventional cardiology has achieved numerous advances at a rapid pace. There is no guarantee that the results of the single large trial a decade ago are still valid in contemporary real-world clinical practice.” said Seng Chan You. “Recently, POPular AGE and TICA-KOREA study have already demonstrated that clopidogrel can be a favourable alternative to ticagrelor in European elderlies and Korean patients with ACS, who are usually underrepresented in randomized clinical trials including PLATO. Our study suggest that this may be true for overall patients with ACS who underwent PCI.”


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