Will GLOBAL LEADERS Change Dual Antiplatelet Therapy Regimens?

Adnan Kastrati, MD; Christopher B. Granger, MD


September 06, 2018

Christopher B. Granger, MD: I'm Christopher Granger from Duke University, and we're here at the European Society of Cardiology Congress with Adnan Kastrati from Munich. Thank you for hosting us. We're here today to discuss one of the important trials that was presented at the meeting and published in the Lancet—the GLOBAL LEADERS trial.[1]

The background for this includes the fact that various combinations of antiplatelet therapy have been shown to have different benefits and risks in patients after acute coronary syndrome (ACS) and stenting. There has been intense interest in coming up with a more focused approach, including limiting the use of aspirin in some situations where we're treating people with ACS, for example, who are on anticoagulant therapy for atrial fibrillation. We have data from PLATO suggesting that lower-dose aspirin was associated with better effectiveness of ticagrelor.[2]

This trial addressed important questions regarding the use of ticagrelor more consistently after stenting and ACS, dropping the aspirin after a certain period of time, and extending the duration of ticagrelor. Could you describe the design and the population?

Stable and Acute Patients, Complex Design

Adnan Kastrati, MD: Thank you very much for this opportunity. I'm happy to be here. I was not personally involved in the trial, but I was the discussant and gave some comments yesterday [at this meeting].

I don't think that, for the moment, it will change my practice, but it will give us a lot of confidence in the monotherapy.

The GLOBAL LEADERS trial was a very large trial with 16,000 patients. It was not a company-sponsored trial. It was an investigator-initiated trial with the financial support of both drug and stent companies.

It had very broad inclusion criteria—it included both stable and ACS patients. The primary endpoint was a composite of all-cause mortality and Q-wave myocardial infarction. The authors assumed incidence of the primary endpoint at 2 years of 5%, which was a little bit higher than what they actually found in the control group. They also were expecting at least a 20% reduction with a new regimen of treatment that was evaluated in this trial.

Of the 16,000 patients, half of them had acute syndromes and the other half had stable coronary artery disease. They used one specific type of stents with biodegradable polymer, which probably reflected the fact that the company financially supported the trial. It was also interesting to see that they used the full dose of the ticagrelor (90 mg twice daily) for the whole time and in both groups—stable and ACS patients.

The control group regimen was different for stable and ACS patients because the stable patients had only clopidogrel and aspirin, and ACS patients had the same ticagrelor [for 12 months followed by aspirin monotherapy for 12 months]. The experimental group for both ACS patients and the stable angina pectoralis patients had the same treatment, which was ticagrelor for 2 years—the whole study period—and only 1 month of aspirin after stenting.

The main result, the primary endpoint, was not significantly different. There was a trend and the P value was .07, but it was not formally significant. Interestingly, the bleeding rate was the same in both groups—experimental and control—at about 2% over 2 years.

Furthermore, the treatment effect was consistent between the groups of stable coronary artery disease patients and acute coronary artery disease patients. There was an interesting finding, which was shown in the supplemental material of the publication, showing that bleeding was higher in the experimental group in the stable coronary artery disease patients. The ACS patients didn't have an increase in bleeding with ticagrelor therapy, likely because ticagrelor was present in the control group.

Granger: That's interesting, isn't it? In the 50% that had ACS, basically the comparison was ticagrelor with 1 month of aspirin and then ticagrelor alone versus ticagrelor plus aspirin. When one looks simply at the 1-year results, I think there are a couple of important findings there. It did reach nominal statistical significance for a reduction in the primary outcome at 1 year and there was decreased bleeding, as you point out, in the ACS population. These are very interesting findings, and mortality was going in the right direction.

ACS Group Most Interesting

Kastrati: For me, the most interesting group is the ACS group. First, it was very courageous to leave out aspirin in this group because these patients are at the highest risk for ischemic events and stent thrombosis. This is also the group that benefits from therapy in the sense that they can get rid of the aspirin, having the same ticagrelor therapy over the study period. The problem is exactly what you said: In 1 year it was a significant result. The question is whether we need longer than that.

Granger: Let's tease this out a little bit. You gave the commentary, which was excellent and well balanced, and Deepak Bhatt wrote the editorial in the Lancet.[3] To be appropriate and conventional, we need to say that [the overall results] did not show that this novel approach was better than our traditional approach for management of this broad population of patients. There were some really interesting findings, including that at 1 year you could have less bleeding and a tendency for better efficacy with ticagrelor alone versus ticagrelor plus aspirin for most of that time. Equally important, there wasn't much benefit in this broad population continuing ticagrelor alone beyond a year, compared with simply the 1 year of treatment.

Kastrati: Yes, exactly. That's the question. As I said before, it is a really complex trial design because on the one side it was the regimen, it was the kind of therapy evaluated. On top of that, the investigators also evaluated the length, which is not the length of therapy we are giving to most of our patients.

Granger: Some people have said that it was courageous, but maybe even so ambitious as to be a bit more complicated than it needed to be to address any of those questions. Nonetheless, this is a really ambitious and important set of data. Did the choice of stent have any effect?

Kastrati: I don't think so because it is a second-generation stent, but it's one of the first second-generation drug-eluting stents. It doesn't have the benefits or the favors of a thin-strut stent. It is a stainless-steel stent. I don't think it had [any effects].

Granger: What do you think about the results of the trial in terms of the overall implications? Will this change your practice?

Kastrati: I don't think that, for the moment, it will change my practice, but it will give us a lot of confidence in the monotherapy, which [we have not had]. We have been together in the session about ACS with the indication for anticoagulation. It's a very challenging area, and if you have this much evidence for monotherapy in this critical subset of patients, you have more [information] for deciding therapy.

Aspirin's Role Weakened

Granger: For example, let's say someone has a very high risk of bleeding or has had a lot of gastrointestinal bleeding or maybe an intolerance to aspirin. Would this give you some reassurance that ticagrelor alone is probably okay?

There was a trend for reduced mortality... If you put together PLATO and this trial, you'll get a significant result.

Kastrati: Yes. Chris, you know that the position of aspirin is not as strong as it was before. We have the WOEST trial that got rid of aspirin in patients needing anticoagulation.[4] You have had here two trials for primary and secondary prevention. There were subsets of patients where aspirin didn't work as we wanted or believed it to work. I think that a few years from now, we'll talk less about aspirin.

Granger: Maybe we'll find out with further research, including individual patient characteristics that may help us to refine this combination of antithrombotic therapy.

Kastrati: I want to highlight that there was a trend for reduced mortality, which, for me, is important. If you put together [data from] PLATO,[2] PEGASUS,[5] and this trial, you'll get a significant result. If we put the existing evidence together, it is suggesting that there is something true in this reduction of mortality, which should be tested in a larger trial. If you have this favor, you get more confidence for the treatment.

Another aspect is the low adherence, which was present in more than 20% of the patients. This is not new for ticagrelor; we have had it in other trials.

Granger: Right. I think it was pretty typical of what you'd expect in this type of trial.

Kastrati: In 20% or 30%, you know you get this. There are side effects, but when you stop treatment, you don't have them anymore. It's another thing to have bleeding complications—to have GI bleeding, which is not like dyspnea, for example. I said also during my comments that we should interpret the results as achieved despite this low adherence to ticagrelor.

Granger: Exactly. Well, it's great to have the opportunity to review this with you after having freshly interpreted this at the European Society of Cardiology Congress.

Adnan, I'd like to thank you for a terrific discussion, and I'd like to thank our audience for being with us today.


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