TiCAB: Ticagrelor No Better Than Aspirin 1-Year Post-CABG

Patrice Wendling

November 27, 2018

CHICAGO — Monotherapy with ticagrelor (Brilinta, AstraZeneca) instead of aspirin showed no signal for benefit and similar bleeding risk 1 year after coronary artery bypass grafting (CABG) in the TiCAB trial.

The event rate for the primary end point of cardiovascular death, myocardial infarction (MI), stroke, or repeat revascularization was 9.7% with ticagrelor and 8.2% with aspirin (hazard ratio, 1.19; 95% CI, 0.87 - 1.62; = .27).

There were no trends for benefit with ticagrelor in any subgroup, investigator Heribert Schunkert, MD, German Heart Center Munich, reported in a late-breaking science session at the American Heart Association (AHA) 2018 Scientific Sessions.

It was hypothesized that more intensive platelet inhibition might reduce the risk for graft failure, which peaks in the first year and is associated with major adverse events, he said.

In the DACAB trial, presented at AHA 2017, dual-antiplatelet therapy (DAPT) with ticagrelor plus aspirin significantly improved saphenous vein graft patency 1 year after CABG compared with aspirin alone. There was no benefit with ticagrelor monotherapy, however, and observers questioned the correlation between 1-year graft patency and subsequent clinical events.

The double-blind, phase 3 Study Comparing Ticagrelor With Aspirin for Prevention of Vascular Events in Patients Undergoing CABG (TiCAB), carried out in 26 centers, compared ticagrelor 90 mg twice daily with aspirin 100 mg once daily for up to 1 year after CABG. Patients had to have an indication for CABG surgery and three-vessel disease, or left main stenosis, or two-vessel disease with impaired ejection fraction (<50%).

Although AstraZeneca cancelled the contract with the German Heart Center in September 2016, the trial continued with in-house funding but ultimately was stopped early for futility after a March 2018 interim analysis of about half of the planned 3760 patients, Schunkert noted.

Most of the 1859 patients evaluable were male (85%), had triple-vessel disease (92%), and stable angina (69%). Adherence to study medication was 85% in both groups at the end of the study, he said.

The ticagrelor and aspirin groups had similar rates of the individual secondary end points of CV death (1.2% vs 1.4%; P = .68), MI (2.1% vs 3.4%; = .12), stroke (3.2% vs 2.6%; P = .49), and revascularization (5.0% vs 3.9%; P = .28).

All-cause death was also similar in the two groups (2.4% vs 2.5%; .89).

"The data safety monitoring board suggested stopping the trial because even if the other half of the patients were very different, there was no chance to turn this trial into a positive result," Schunkert observed.

Major bleeding events, defined by Bleeding Academic Research Consortium (BARC) criteria 3 to 5 events, occurred at similar rates with ticagrelor and aspirin (3.7% vs 3.2%; HR, 1.17; 95% CI, 0.71 - 1.92; P = .53).

This is notably because there's "a lot of concern about the safety of ticagrelor in bypass surgery and we now can see that concern relates to dual therapy rather than monotherapy," said Robert Storey, DM, University of Sheffield, United Kingdom, who was invited to discuss the results.

Although TiCAB was underpowered for the primary end point and the aspirin group had a surprisingly low event rate, he noted that ticagrelor monotherapy has failed to show superiority over aspirin monotherapy in large randomized trials, such as GLOBAL LEADERS and SOCRATES.

"The question is whether a larger study in this population is now warranted. I will argue on numerous strands of evidence that this study is sufficient to demonstrate a lack of superiority of ticagrelor monotherapy compared with aspirin," Storey said.

Large clinical outcomes trials of DAPT after bypass surgery are warranted, he said, as current evidence favors a DAPT strategy for achieving greater reductions in CV events, albeit at the expense of higher bleeding rates.

Importantly, these post-CABG outcome studies should consider the effects of opiates on absorption of oral P2Y12 receptor inhibitors, suggested Storey. Aspirin has the advantage of being absorbed from the stomach, even after surgery in patients receiving drugs like fentanyl, he said, whereas absorption of ticagrelor and other P2Y12 inhibitors is from the intestine and can be delayed by opiates.

"This is potentially an issue in the onset of action of ticagrelor in this postoperative study, which could have disadvantaged it and may even have been the cause of the slight excess of early events," Storey said.

Notably, labeling for all three oral P2Y12 inhibitors — ticagrelor, clopidogrel (Plavix, Bristol-Myers Squibb), and prasugrel (Effient, Lilly/Daiichi-Sankyo) — was updated in 2018 to include information that the coadministration of opioid agonists delays and reduces their absorption and suggested that clinicians "consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists."

The study was sponsored by Deutsches Herzzentrum München and partially funded by a grant from AstraZeneca. Schunkert reports receiving a research grant from AstraZeneca; honoraria from AstraZeneca, Bayer Vital, Merck Sharp & Dohme, Novartis, Servier, Sanofi, Boehringer Ingelheim, Daiichi-Sankyo, Amgen, and Pfizer; and serving as a consultant/advisory board member for AstraZeneca, Amgen, Merck Sharp & Dohme, Boehringer Ingelheim, Daiichi-Sankyo, Servier, and Bayer Vital. Storey reports receiving a research grant and honoraria from and consulting for AstraZeneca; consulting for Avacta, Idorsia, Bayer, BMS/Pfizer, Haemonetics, Novartis, and Thromboserin; and receiving a research grant from and consulting for PlaqueTec.

American Heart Association (AHA) Scientific Sessions 2018: Abstract 19561. Presented November 11, 2018.

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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