Limb Outcomes With Ticagrelor Plus Aspirin in Diabetics With PAD/CAD

Quick Takes

  • Addition of ticagrelor to aspirin in patients with peripheral artery disease (PAD), diabetes, and atherosclerosis reduced adverse limb events.
  • This reduction came at the cost of increased bleeding.
  • Patients with PAD were poorly defined in this analysis, and future trials with better objective measures of PAD might identify a subset of patients with PAD for whom addition of ticagrelor might have a more favorable risk: benefit ratio.

Study Questions:

Since limb events are major drivers of morbidity in diabetic patients with peripheral (PAD) and coronary artery disease (CAD), does the addition of ticagrelor to background therapy of aspirin improve limb events?


In the THEMIS trial, 19,220 patients with type 2 diabetes and CAD were randomized to ticagrelor versus placebo on a background therapy of aspirin. A subset of 1,687 patients with documented PAD was identified. This identification included claudication, prior revascularization, or amputation. Ankle brachial indexes (ABIs) were not mandatory. This group was analyzed for ischemic limb events, major adverse cardiovascular events (MACE), and bleeding.


In patients who were receiving placebo, PAD was associated with higher MACE and limb risk. The patients in the ticagrelor arm had fewer limb events (absolute risk reduction of 0.3%) and less revascularization. Interestingly, the presence of PAD did not alter the effect of ticagrelor on MACE or on the increased bleeding risk.


Ticagrelor, when compared to placebo (in patients with diabetes and atherosclerosis) decreases limb events, but with an increased risk of bleeding. The benefit is small, but the study only loosely defined PAD by presence of claudication, prior revascularization, or amputation, so it is unclear which subpopulations, if any, would have a more favorable risk: benefit ratio given the increased rate of bleeding.


The idea that dual antiplatelet therapy (DAPT) might have a benefit for PAD is indeed intriguing. Since the presence of PAD, particularly in diabetics with known CAD, yields very high risk for MACE and limb events, this population of patients has potentially much to gain from effective therapies. This study gives a hint that there may be a benefit to DAPT in this population and that, in the right population, may have a benefit that outweighs the bleeding risk. While this analysis suggests there may be such a subset, the general classification of PAD by presence of claudication, revascularization, or amputation is very nonspecific. Quantification with ABIs would have been helpful in perhaps identifying a subgroup with particular benefit that may better outweigh the bleeding risk.

In the editorial comment, note is also made that the COMPASS trial did show a benefit of low-dose rivaroxaban in addition to aspirin in similar patients, with the suggestion that a strategy with rivaroxaban might be preferable to DAPT in this population until more specific data are obtained in future trials.

In the meantime, it is important to re-double our efforts in treating patients with diabetes and CAD with “a little claudication,” with a clear recognition of the dire consequences of anything other than the most aggressive of lipid therapy, antihypertensive therapy, diet, exercise, and smoking cessation. Future trials may give us clearer conclusions on the benefits of DAPT in this population.

Clinical Topics: Vascular Medicine, Atherosclerotic Disease (CAD/PAD)

Keywords: Diabetes Mellitus, Type 2, Peripheral Arterial Disease, Ticagrelor

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