Sex differences among patients with high risk receiving Ticagrelor with or without Aspirin after percutaneous coronary intervention: a subgroup analysis of the TWILIGHT randomized clinical trial

Selected in JAMA Cardiology by M. Alasnag , Y. Hanfi

This is a prespecified secondary sub-analysis of the TWILIGHT trial that seeks to shed light on the association of the different baseline risk factors, namely advanced age and significant renal dysfunction, with a higher bleeding risk in women.

Reviewers

Mirvat Alasnag

@mirvatalasnag

Interventional cardiologist / Cardiologist

King Fahd Armed Forces Hospital - Jeddah, Saudi Arabia

Yasmin Hanfi

Department of cardiology, Dallah Hospital - Riyadh, Saudi Arabia

Our Comment

Why this study? – the rationale/objective

To date, there have been numerous trials evaluating the most appropriate duration of dual anti-platelet therapy (DAPT) in individuals who had undergone percutaneous coronary interventions (PCI). The risk of bleeding is usually weighed against that of ischemia specifically with the use of the more potent P2Y12 inhibitors such as Ticagrelor. As noted by previously published data from the GLOBAL-LEADERS and the sex-based analysis from the RISK-PCI trials, the risk of bleeding is of particular concern in women^1-2.

Another study, Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention (TWILIGHT), concluded that monotherapy with a potent P2Y12 inhibitor after a short period of DAPT compared with continued DAPT leads to a reduction in bleeding without an increase in ischemic events in those who are at a high risk for either bleeding or ischemic events³. This is a prespecified secondary sub-analysis of the TWILIGHT trial that seeks to shed light on the association of the different baseline risk factors, namely advanced age and significant renal dysfunction, with a higher bleeding risk in women. It is plausible that independent biological factors impact this risk as well as cardiovascular outcomes in women.

How was it executed? – the methodology

The TWILIGHT study was a multicentric investigator-initiated, placebo-controlled randomized trial conducted in 187 sites internationally. The enrolled population was at high risk for ischemia or bleeding, with at least one high-risk angiographic feature, and one high clinical risk. Randomization occurred after a three-month run-in period. Only those who remained adherent to the DAPT regimen prescribed at discharge, which consisted of Ticagrelor 90 mg twice daily and Aspirin 81-100 mg once daily, and those with no major adverse events after the index PCI with drug-eluting stents, were included. At this point, patients were randomized to either Tricagrelor plus Aspirin or Ticagrelor plus placebo for an additional 12 months.

After the 12 months of protocol-mandated therapy, patients were maintained on the antiplatelet regimen at the discretion of their treating physician. A final telephone completed the follow-up after an additional 3 months.

The primary endpoint was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. The primary ischemic endpoint was a composite of death, myocardial infarction (MI), or stroke. Secondary bleeding and ischemic endpoints were reported. MI was defined according to the third universal definition, and revascularization and stent thrombosis were also included in the analysis.

What is the main result?

A total of 7,119 were randomized with a mean age of 63.9 years. Only 23.9 % of those randomized were women. Women were older (65.5 years vs 63.4 years), with a significantly higher prevalence of chronic kidney disease (CKD) (21.2 % vs 14.7 %) and anemia. The index PCI was more likely for an acute coronary syndrome (ACS). Fewer women had prior MI, PCI, or coronary artery bypass grafting. The angiographic features were similar including chronic total occlusions or bifurcation stenting. Women had shorter and smaller diameter stents. The primary bleeding endpoint occurred more often in women than men, attributable to the higher risk baseline characteristics. After multivariate adjustment, incremental bleeding risk associated with female sex was not significant (adjusted HR, 1.20; 95 % CI). Even after multivariate adjustment, the ischemic endpoints were similar in both sexes including a composite of death, MI, or stroke, and the individual endpoints of all-cause death, cardiovascular death, MI; ischemic stroke, and definite or probable stent thrombosis.

DAPT regimens and the balance between bleeding & ischemic risk

DAPT regimens and the balance between bleeding & ischemic risk

Critical reading and the relevance for clinical practice:

Firstly, although this was a pre-specified analysis of sex differences of the TWILIGHT study, the total number of women remained very low, not permitting definitive conclusions on the impact of individual baseline characteristics on bleeding or ischemic outcomes. Nevertheless, women had anemia, CKD and were older. Since an indication for oral anticoagulation (e.g. atrial fibrillation ), which contributes to bleeding risk, was excluded in this cohort, results of this analysis cannot be extended to such patients. The angiographic features were similar, suggesting a well-balanced enrollment. Although the stent length and diameter were smaller, this did not translate into higher stent thrombosis or other ischemic endpoints including MI. Since this was a high-risk population (higher incidence of ACS), the results cannot be expanded for the broader population in women, particularly those with stable disease.

Furthermore, since this was not a sex-stratified randomization at the outset of enrollment, conclusions on the sex-based differences between Ticagrelor monotherapy or combination of Ticagrelor plus Aspirin cannot be ascertained. The follow-up was limited to 12 months and one wonders whether the risk of bleeding will be consistent thereafter. Data from multiple previous studies suggest that those with an ACS have a higher risk of future events making it important to understand the efficacy of monotherapy in women beyond 12 months.

It is critical to interpret these results as hypothesis-generating only with a vision to conduct randomized trials for women only to determine the safety and efficacy endpoints of the various DAPT regimens. In addition, it would be important to understand the weight of individual clinical characteristics on the bleeding risk.

References:

1. Chichareon P, Modolo R, Kerkmeijer L, et al. Association of sex with outcomes in patients undergoing percutaneous coronary intervention: a subgroup analysis of the GLOBAL LEADERS randomized clinical trial.JAMA Cardiol. 2020;5(1): 21-29. doi:10.1001/jamacardio.2019.42964.
2. Mrdovic I, Savic L, Asanin M, et al. Sex-related analysis of short- and long-term clinical outcomes and bleeding among patients treated with primary percutaneous coronary intervention: an evaluation of the RISK-PCI data. Can J Cardiol. 2013;29(9): 1097-1103. doi:10.1016/j.cjca.2012.11.013
3. Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med. 2019;381(21):2032-2042. doi:10. 1056/NEJMoa1908419