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PARIS -- Ticagrelor (Brilinta) as part of a dual antiplatelet therapy (DAPT) regimen didn't improve net outcomes for stable coronary artery disease (CAD) among type 2 diabetes patients, except perhaps in the setting of percutaneous coronary intervention (PCI), the THEMIS trial showed.

Adding the potent antiplatelet agent to aspirin reduced cardiovascular (CV) death, myocardial infarction (MI), or stroke (7.7% vs 8.5%, HR 0.90, 95% CI 0.81-0.99), reported Deepak Bhatt, MD, MPH, of Brigham and Women's Hospital and Harvard Medical School in Boston, at the European Society of Cardiology (ESC) congress and online in the .

But it also increased TIMI major bleeding (2.2% vs 1.0%, HR 2.32, 95% CI 1.82-2.94) and intracranial hemorrhage (0.7% vs 0.5%, HR 1.71, 95% CI 1.18- 2.48) over aspirin alone, albeit without more fatal bleeding (0.2% vs 0.1%, P=0.11).

The combined effect was neutral for the exploratory composite outcome of "irreversible harm" (death from any cause, MI, stroke, fatal bleeding, or intracranial hemorrhage 10.1% vs 10.8%, HR 0.93, 95% CI 0.86-1.02).

ESC session study discussant Colin Baigent, MD, of Oxford University in England, actually calculated 12 major bleeds for every eight events prevented.

"This is a consistent story: when we add an antiplatelet agent for risk reduction, we increase the risk of bleeding," noted Richard Kovacs, MD, of Indiana University in Indianapolis and president of the American College of Cardiology.

is the final part of a largely-disappointing PARTHENON development program for ticagrelor, he noted. "It hasn't changed practice. ...Will the main THEMIS trial change clinical practice? In my opinion, no."

Who to Treat?

However, the trial had a prespecified substudy in patients with a history of PCI -- THEMIS-PCI -- that signaled who might benefit.

Among the 11,154 patients with prior PCI (58% of the total 19,220 in THEMIS), ticagrelor-based DAPT had a relative 15% lower relative risk of CV death, MI, or stroke (7.3% vs 8.6%, HR 0.85, P=0.013).

Bleeding risk was still elevated (2.0% vs 1.1% TIMI major), but ticagrelor improved net clinical benefit in preventing irreversible harms (9.3% vs 11.0%, HR 0.85, 95% CI 0.75–0.95, P=0.012 for interaction by prior PCI status).

PCI in itself isn't likely the reason for the benefit, but rather an easy shorthand for finding those patients who have already tolerated DAPT to prevent stent thrombosis after the procedure, Bhatt suggested at an ESC press conference for the late-breaking clinical trial session.

Kovacs suggested that the balance here "seems to indicate that they have enough risk reduction to warrant accepting the increased risk of bleeding."

Baigent was not so generous.

"I don't think we should be paying too much attention to the attempt to find net benefit by referring to interactions. Why would we pick out a particular interaction for PCI when it was not statistically significant in the primary outcome?" he said.

The only significant interaction between treatment effect and subgroup was actually for proton pump inhibitor use, Baigent noted. "And in fact, if you go back to PEGASUS, there was no interaction there by PCI, at least for the primary outcome. There is no reason really to be focusing on PCI taking from the main results. Ticagrelor probably doesn't work better."

"But can we find patients where there is a bigger net benefit?" Baigent posited.

In primary prevention trials, the same things that predict risk of bleeding also predict the benefit of ischemic event prevention, he noted. "If you try and find patients who are at higher risk of ischemic events but lower risk of bleeding, they are so few and far between in predictive terms that you can't do it."

Duration of Treatment

THEMIS randomized patients to twice daily ticagrelor (90 mg for the 73.9% enrolled before a protocol change to 60 mg) or placebo atop aspirin. Participants were ages ≥50, had type 2 diabetes treated pharmacologically for at least 6 months, with stable CAD, and at least one of the following: a history of PCI or of coronary artery bypass grafting, or documentation of ≥50% angiographic stenosis in at least one coronary artery.

Treatment continued for a median 40 months, which Kovacs noted was even longer than the extended regimen in the DAPT trial, which went for 18 months.

Now for a THEMIS-like, older, diabetes patient with a stent, he said he would push toward longer duration DAPT, possibly beyond 18 months, he suggested.

"This is a significant proportion of patients," he noted, and "an increasingly important population as we deal with more and more diabetic patients."

Co-author Robert Harrington, MD, of Stanford University in California and president of the American Heart Association, agreed that the findings argue for longer duration DAPT in type 2 diabetes, regardless of the agent used.

The opposite message came from Eric Bates, MD, of the University of Michigan in Ann Arbor, in an accompanying the NEJM paper.

"In patients with type 2 diabetes, aspirin has a proven role for the secondary prevention of cardiovascular events, but the evidence base is growing against additional roles for antiplatelet therapy," he noted, pointing to ASCEND, the diabetes subgroup in the DAPT trial, and PEGASUS.

"But for most patients with type 2 diabetes and known coronary disease who fit the THEMIS enrollment criteria, the addition of ticagrelor to aspirin is not recommended," he said.

Kovacs also cautioned that the results may not be generalizable to all other DAPT drug combinations. "Is one DAPT strategy better than the other? You would have to compare head-to-head in this population."

Meanwhile, individualization of the decision is likely to be key, he added. "It is not only the scientific data but also the conversation with the patient -- do they want to accept, with their particular goals of therapy and their values, the higher bleeding risk? It's not for everybody, but it appears to be for some."