Data from the PEGASUS-TIMI 54 trial indicate that the use of aspirin plus ticagrelor (Brilinta, AstraZeneca) in patients with prior myocardial infarction and concomitant peripheral arterial disease is associated with a risk reduction in major adverse cardiovascular events and ischaemic lower limb events.
Writing in the Journal of the American College of Cardiology (JACC), Marc Bonaca (Brigham and Women’s Heart Hospital & Vascular Centre, Boston, USA) and others report that the presence of concomitant peripheral arterial disease in patients with coronary artery disease is associated with an increased risk of ischaemic events (further to that associated with coronary artery disease alone). They add that this risk of ischaemic events with peripheral arterial disease “is further complicated by its association with increased bleeding risk”. The authors explain the diseased vasculature that is associated with peripheral arterial disease may mean that patients with the condition “may be more prone to injury or procedural complications leading to bleeding” and note that a significantly increased risk of bleeding has been observed in studies of “potent antithrombotic strategies” for the prevention of peripheral arterial disease.
Therefore, Bonaca et al reviewed data from the PEGASUS-TIMI 54 trial (Prevention of cardiovascular events in patients with prior heart attack using ticagrelor compared to placebo on a background of aspirin–thrombolysis in myocardial infarction 54), which found that adding ticagrelor to aspirin to patients with a history of myocardial infarction was associated with a significant reduction in ischaemic events but also with a significant increase in major bleeding, to determine whether the presence of peripheral arterial disease affected the benefits of ticagreglor seen in the study. They also evaluated the effect of ticagrelor therapy on the rate of major adverse limbs events.
Of the 21,162 patients enrolled in the PEGASUS-TIMI 54 trial, 1,143 (5%) had known peripheral arterial disease at randomisation. Of these, 404 were randomised to receive placebo, 368 were randomised to receive ticagrelor 60mg, and 371 were randomised to receive ticagrelor 90mg (all patients were already receiving low-dose aspirin). The authors report that within the placebo group, at three years, patients with peripheral arterial disease at baseline had a “more than two-fold increase in the rate of major adverse cardiovascular events (MACE)” compared with the placebo group patients without peripheral arterial disease. They add that patients with peripheral arterial disease had a higher risk of MACE even after adjusting for differences in baseline characteristics.
Bonaca et al comment that there was no heterogeneity in the relative risk reduction with ticagrelor for MACE in patients based on the presence of peripheral arterial disease at baseline. They add, “However, by nature of their greater absolute risk, patients with peripheral arterial disease had a numerically greater absolute risk reduction at three years (4.1%) relative to those without peripheral arterial disease (1%). The efficacy versus placebo was generally similar for the two doses of ticagrelor, but of note the 60mg dose resulted in a significant reduction in cardiovascular mortality, which drove a reduction in all-cause mortality (p=0.0074).”
Furthermore, in the overall study population, ticagrelor (pooled doses) was associated with a significant reduction in major adverse ischaemic limb events (p=0.026) compared with placebo, “with a numerically greater relative risk reduction with the 90mg dose (p>0.005) relative to the 60mg dose (p=0.33),” the authors comment.
Bonaca et al conclude: “The current study suggests that dual antiplatelet therapy with aspirin and ticagrelor may be efficacious for acute limb ischaemia if studied in larger, higher risk cohorts. In addition, the reduction in the exploratory endpoint of peripheral revascularisation for ischaemia also supports potential antithrombotic benefits of ticagrelor on the limb circulation.” The authors add that the ongoing study EUCLID (A study comparing cardiovascular effects of ticagrelor and clopidogrel in patients with peripheral artery disease) will further explore, as a secondary endpoint, whether “potent antiplatelet therapy can reduce elective revascularisation for claudication”.