Concomitant PAD does not influence ticagrelor’s effects in T2D patients with atherosclerosis

In a prespecified analysis of the THEMIS trial, the efficacy and safety of ticagrelor plus aspirin versus placebo in patients with T2D and coronary artery disease were consistent regardless of concomitant peripheral artery disease (PAD).

This summary is based on the publication of Bonaca MP, Bhatt DL, Simon T, et al. - Limb Outcomes With Ticagrelor Plus Aspirin in Patients With Diabetes Mellitus and Atherosclerosis. J Am Coll Cardiol. 2024 Apr 30;83(17):1627-1636. doi: 10.1016/j.jacc.2024.03.377

Introduction and methods

Background

Patients with T2D are at increased risk of developing peripheral artery disease (PAD) and therefore of experiencing major adverse limb events than those with no T2D. Previously, ticagrelor, in combination with aspirin, reduced the risk of acute limb ischemia (ALI) by almost 50% in patients with prior MI and concomitant PAD [1]. In patients with T2D and stable coronary artery disease (CAD), ticagrelor lowered the risk of ischemic CV events but increased the rate of major bleeding events compared with placebo, as shown by the THEMIS (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus) trial [2]. The effects of ticagrelor on limb ischemic events in T2D patients with both CAD and PAD (i.e., polyvascular disease) are unknown.

Aim of the study

In a prespecified analysis of the THEMIS trial, the authors assessed the effects of ticagrelor on limb ischemic events in T2D patients with CAD, with or with no concomitant PAD.

Methods

In the THEMIS trial, 19,220 patients aged ≥50 years with T2D and stable CAD, but no history of MI or stroke, were randomized to ticagrelor (initial dose: 90 mg; after interim protocol amendment: 60 mg) twice daily or placebo, in addition to low-dose aspirin. Exclusion criteria included a high bleeding risk. Median follow-up duration was 3.3 years (Q1–Q3: 2.8–3.8). At baseline, 1687 patients (8.8%) had a history of PAD.

Outcomes

The study’s primary efficacy endpoint was a composite outcome of MACE, defined as CV death, MI, or stroke. The primary safety endpoint was major bleeding events based on the TIMI (Thrombolysis In Myocardial Infarction) criteria. In the current analysis, the primary limb ischemic event endpoint was a composite outcome of ALI, major amputation of a vascular etiology, or peripheral revascularization.

Main results

Risks of MACE and limb ischemic events

• In the placebo group, patients with concomitant PAD had a higher risk of MACE after 3 years than those with no PAD (10.7% vs. 7.3%; HR: 1.48; 95%CI: 1.20–1.81; P<0.001).
• Placebo-treated patients with PAD had a greatly increased risk of the primary limb ischemic event endpoint compared with those with no PAD (9.5% vs. 0.8%; HR: 10.67; 95%CI: 7.90–14.40; P<0.001), which was largely driven by an increased rate of peripheral revascularization procedures (8.9% vs. 0.8%; HR: 10.54; 95%CI: 7.72–14.38; P<0.001).

Effect of ticagrelor by PAD status

• Ticagrelor treatment reduced the frequency of limb ischemic events compared with placebo (1.3% vs. 1.6%; HR: 0.77; 95%CI: 0.61–0.96; P=0.022), with significantly reduced rates of peripheral revascularization (1.2% vs. 1.5%; HR: 0.79; 95%CI: 0.62–0.99; P=0.044) and ALI (0.04% vs. 0.16%; HR: 0.24; 95%CI: 0.08–0.70; P=0.009).
• The treatment effect of ticagrelor versus placebo on limb ischemic events was similar in patients with PAD (7.6% vs. 9.5%; HR: 0.80; 95%CI: 0.58–1.11) and those with no PAD (0.7% vs. 0.8%; HR: 0.76; 95%CI: 0.55–1.05; P for interaction=0.81). The absolute risk difference was numerically, albeit not statistically significantly, greater in patients with PAD than those with no PAD (–1.9% vs. –0.1%; P for interaction=0.25).
• The PAD status at baseline also did not influence the treatment effects of ticagrelor versus placebo on the primary limb ischemic event endpoint components of ALI, major amputation of a vascular etiology, and peripheral revascularization (all P for interaction≥0.16) or MACE (P for interaction=0.40).
• Ticagrelor increased the risk of TIMI major bleeding events compared with placebo in patients with no PAD (2.7% vs. 1.2%; HR: 2.41; 95%CI: 1.87–3.11) but not those with PAD (2.4% vs. 1.8%; HR: 1.62; 95%CI: 0.77–3.39), with no significant interaction by PAD status (P=0.45).

Conclusion

In this prespecified analysis of the THEMIS trial, patients with T2D, stable CAD, and concomitant PAD had higher risks of MACE and limb ischemic events than those with no PAD. Treatment with ticagrelor, in addition to aspirin, decreased these risks compared with placebo, regardless of concomitant PAD. The PAD status at baseline also did not influence the risk of major bleeding events with ticagrelor versus placebo.

The authors point out that “the cumulative incidence of limb ischemic events at 3 years in patients with PAD was similar in magnitude to the risk of MACE, [which] should underscore the importance of considering [major adverse limb events] as an equal if not dominant risk in patients with PAD and CAD overall and when assessing the impact of optimal medical therapy.”

Find this article online at J Am Coll Cardiol.

References

1. Bonaca MP, Bhatt DL, Storey RF, et al. Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease. J Am Coll Cardiol. 2016;67:2719–2728. https://doi.org/10.1016/j.jacc.2016.03.524
2. Steg PG, Bhatt DL, Simon T, et al. Ticagrelor in patients with stable coronary disease and diabetes. N Engl J Med. 2019;381:1309–1320. https://doi.org/10.1056/NEJMoa1908077