Extended Ticagrelor Monotherapy After Stenting Misses Endpoint

August 27, 2018

MUNICH — A novel antiplatelet regimen of extended ticagrelor monotherapy with aspirin added just for the first month after stenting narrowly failed to show superiority over standard treatment in the GLOBAL LEADERS trial.

The trial was presented here at the European Society of Cardiology (ESC) Congress 2018  by Patrick Serruys, MD, Erasmus Medical Center, Rotterdam, the Netherlands, and simultaneously published in The Lancet

In the study, ticagrelor in combination with aspirin for 1 month followed by ticagrelor alone for 23 months was not superior to standard 1-year dual antiplatelet therapy followed by 1 year of aspirin monotherapy in terms of the composite endpoint of all-cause mortality or new Q-wave myocardial infarction at 2 years. Major bleeding was similar between the two groups.

However, at 1 year there was a clear reduction of the primary endpoint in the ticagrelor group, and there was an issue with adherence to ticagrelor in the second year;  this could have contributed to the less impressive result at 2 years, Serruys noted. Deutsches Herzzentrum, Munich, Germany

"The idea behind that concept was to try and replace aspirin for secondary prevention by a drug which is more specific and reliable antiplatelet therapy," Serruys told theheart.org | Medscape Cardiology.  

"Aspirin has become a classic therapy for everyone with heart disease — the combination of aspirin and other antiplatelet therapy in the field of PCI [percutaneous coronary intervention] and stenting is somewhat of a historical accident. But aspirin is quite nonspecific and does cause a lot of bleeding," he said. "We believe that if a potent antiplatelet drug like ticagrelor is used it may be possible to drop the aspirin."

"We were very close to showing superiority," Serruys added. "The upper 95% confidence limit was 1.01. If we had stopped at 1 year we would have had a positive trial. But ticagrelor will not get approval for this based on this study, unfortunately, because the 1-year timepoint wasn't the primary endpoint. Overall, our results do not support a change to standard clinical practice, and we need more convincing data."

Designated discussant Adnan Kastrati, MD, Deutsches Herzzentrum, Munich, Germany, described the GLOBAL LEADERS trial as a "well-designed and -conducted study." 

"It is a formally negative trial that may have a positive impact on the overall value of ticagrelor therapy in patients with coronary artery disease and PCI," Kastrati added.

Commenting for theheart.org | Medscape Cardiology, Freek Verheugt, MD, OLVG Amsterdam, the Netherlands, who was chair of the data safety monitoring committee of the trial, said, "I believe the strategy of using a strong antiplatelet therapy like ticagrelor without aspirin is a good one. But this trial was probably a little too complicated."

The investigators were trying to answer three questions, he said: (1) Can we do without aspirin? (2) Can we also give ticagrelor to stable patients (the trial included both stable and unstable patients)? (3) Can we extend ticagrelor for 2 years?

"And they had a very hard endpoint — all-cause mortality and new Q-wave MI [myocardial infarction]," Verheugt said. "To attempt all that was very courageous but perhaps a little too ambitious for one trial with limited funds. But they were very unlucky — they were very close to showing superiority.

"It seems from the data that 1 year of ticagrelor is enough. If they had stopped the trial at 1 year it would have been highly positive. The trial was open label and doctors stopped using ticagrelor in the second year."  

There were no safety issues, which was "very reassuring," he added.

"I do believe that when we use ticagrelor or prasugrel, they are such strong antiplatelet drugs we do not need aspirin. That is my personal view," Verheugt concluded. "But we need the data to confirm this. There will be other studies no doubt with a shorter follow-up and a double-blind design so physicians will be more likely to continue experimental treatment for the whole time."

The study involved 15,968 patients undergoing PCI with a biolimus A9-eluting stent for stable coronary artery disease or acute coronary syndromes.

They were randomly assigned in an open-label design to 75 to 100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy (experimental arm), or standard dual antiplatelet therapy with 75 to 100 mg aspirin daily plus either 75 mg clopidogrel daily (for patients with stable coronary artery disease) or 90 mg ticagrelor twice daily (for patients with acute coronary syndromes) for 12 months, followed by aspirin monotherapy for 12 months (control arm).

The primary endpoint (a composite of all-cause mortality or new Q-wave MI at 2 years) occurred in fewer patients in the experimental group, but this finding did not quite reach statistical significance.  There was no difference in major bleeding, which was the key secondary safety endpoint.

Table. GLOBAL LEADERS: Main Results at 2 Years  

Endpoint Experimental Group (%) Control Group (%) Rate Ratio (95% Confidence Interval) P Value
Death or new Q-wave MI 3.81 4.37 0.87 (0.75 - 1.01) .073
Bleeding Academic Research Consortium grade 3 or 5 bleeding 2.04 2.12 0.97 (0.78 - 1.20) .77


Adherence to ticagrelor was an issue, particularly in the second year of the trial.  

In the first year, 18% of patients in the experimental group and 15% of those in the control group with acute coronary syndrome (and so receiving ticagrelor) did not adhere to the drug.  By the end of the second year — which was a comparison of ticagrelor monotherapy (experimental arm) with aspirin monotherapy (control) — 22% of patients in the experimental group had stopped taking ticagrelor compared with 7% of controls who had stopped taking aspirin.

The most common reason for stopping ticagrelor was the occurrence of dyspnea, a known adverse effect of the drug.

Serruys commented: "Every time there was an event like another PCI, bleeding, or dyspnea, the physician was supposed to restart the treatment 1 month later, but that often didn't take place so adherence fell in the ticagrelor arm. Also, as this was an open-label trial, the physician knew which therapy was being given, and they might have thought it was unnecessary to continue ticagrelor in the second year."  

In an accompanying Comment in The Lancet, Deepak Bhatt, MD, Brigham and Women's Hospital,  Boston, Massachusetts, notes that strategies to de-escalate the duration or intensity of dual antiplatelet therapy are of interest for reducing bleeding risk.

Bhatt says that while practice should not be changed on the basis of this trial's results, this does not mean that current recommended therapy cannot be improved upon.

"The best way to optimize the balance between reduction of the risk of ischemic events and avoidance of bleeding risk could be to use biological assays or simple risk scores to establish the ideal intensity and duration of antithrombotic therapy in individual patients," he suggests. "Thus, the field of tailoring therapy remains ripe for investigation."

GLOBAL LEADERS trial was an investigator-initiated trial sponsored by the European Clinical Research Institute, which received funding from Biosensors International, AstraZeneca, and the Medicines Company. Serruys has received personal fees from Abbot Laboratories, AstraZeneca, Biotronik, Cardialysis, GLG Research, Medtronic, Sino Medical Sciences Technology, Société Europa Digital Publishing, Stentys France, Svelte Medical Systems, Philips/Volcano, St Jude Medical, Qualimed, and Xeltis, outside the submitted work. Batt's disclosures are available with the Lancet publication.

European Society of Cardiology (ESC) Congress 2018. Presented August 27, 2018.

Lancet. Published online August 27, 2018. Abstract. Comment

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