In stable CAD with type 2 diabetes, adding ticagrelor to aspirin reduced CV events but increased major bleeding

Although an industry-funded trial found little net benefit overall from adding ticagrelor to aspirin, it's possible that some patients with higher ischemic risk and low bleeding risk could benefit, according to an ACP Journal Club commentary.


The THEMIS study was an industry-funded trial that randomized patients with diabetes and stable coronary artery disease (CAD), including some with previous percutaneous coronary intervention (PCI), to ticagrelor plus aspirin or placebo plus aspirin. It found ticagrelor to be associated with a small improvement in the primary efficacy outcome, which was a composite of cardiovascular (CV) death, myocardial infarction (MI), or stroke, but also an increase in the primary safety outcome of major bleeding.

The results of the overall THEMIS study were published in the Oct. 3, 2019, New England Journal of Medicine. The subgroup analysis of patients with previous PCI was published in the Sept. 28, 2019, issue of The Lancet. The following commentary by Dominic L. Raco, MD, FACP, was published in the ACP Journal Club section of the Jan. 21 Annals of Internal Medicine.

Although it is well-established that antiplatelet therapy (APT) reduces the risk for ischemic events in patients with CV disease, the intensity of APT for specific patients must be balanced by their ischemic vs bleeding risks. The CURE trial found a 2.1% absolute risk reduction (ARR) in a composite of death, MI, or stroke by adding clopidogrel to aspirin for 1 year in patients with acute coronary syndrome (ACS). This was offset by a 1% absolute risk increase (ARI) in major bleeding, which still resulted in a net clinical benefit. Subsequent studies have intensified APT or extended its duration to try to define subgroups of patients who would have the greatest net clinical benefit. For example, PEGASUS-TIMI 54 found a net clinical benefit in extending therapy with aspirin plus ticagrelor beyond 1 year in patients with previous MI.

THEMIS added ticagrelor to aspirin in patients with type 2 diabetes who had known CAD but had never had an MI. Adherence to APT was limited; about 30% of patients stopped ticagrelor/placebo over a median 40 months of follow-up. Adding ticagrelor reduced the composite of death, MI, or stroke (ARR 0.8%) with an offsetting increase in major bleeding (ARI 1.2%), resulting in little net clinical benefit for the average patient in THEMIS. This doesn't exclude the possibility that some patients with higher ischemic risk and low bleeding risk would benefit from adding ticagrelor. For example, the 11,154 patients in THEMIS who had previous PCI had a net clinical benefit with ticagrelor added to baseline aspirin.

Several attempts have been made to develop scores to predict which patients would have the greatest net clinical benefit from more intensive and prolonged APT. The dual APT (DAPT) score initially seemed promising, but like other scores, it did not predict which patients would benefit from extended-duration DAPT when tested in a large, real-world patient population. Physicians must assimilate available data while using clinical judgment and shared decision making to prescribe the optimal APT intensity and duration depending on a specific patient's ischemic vs bleeding risks. For example, clinicians should consider adding ticagrelor for patients with diabetes who had recurrent ischemic events while using aspirin alone. In addition, APT should be reassessed periodically as patients' ischemic and bleeding risks fluctuate.

Several trials have compared APT in patients with ACS. In PLATO, ticagrelor reduced a composite of death, MI, or stroke (ARR 1.9%) compared with clopidogrel. Ticagrelor also reduced CV and overall mortality with a minimal increase in major bleeding (ARI 0.4%). TRITON-TIMI 38 found that prasugrel vs clopidogrel had a 2.2% ARR in the composite of death, MI, or stroke, but no mortality benefit, mainly due to increased bleeding. Without a head-to-head trial, many clinicians opted to use ticagrelor because of a perceived greater net clinical benefit, although some felt that prasugrel was the more potent antiplatelet agent. The open-label ISAR-REACT 5 trial, which was done mainly in centers in Germany, took almost 5 years to randomize 4018 patients with an ACS. It tested the hypothesis that a ticagrelor treatment strategy was superior to a prasugrel strategy. Given the previous trial results, experts speculated that ISAR-REACT 5 would be neutral or yield a small advantage for ticagrelor. Surprisingly, it found a 2.4% ARR in death, MI, or stroke in favor of prasugrel, with no increase in major bleeding. Previous trials consistently found that reducing ischemic events with more intensive APT came at a cost of increased bleeding, making the distinct results in ISAR-REACT 5 challenging to rationalize. It is also difficult to explain how the ARR for the primary composite outcome in ISAR-REACT 5 would be as large as that obtained when ticagrelor or prasugrel was being compared with clopidogrel. It is uncertain whether ISAR-REACT 5 will change the class 1 recommendation for use of ticagrelor or prasugrel in patients with an ACS. A blinded comparative trial with many more centers is needed to provide a generalizable, optimal APT strategy for patients with an ACS.