Extra Ticagrelor Benefit When PAD Complicates CAD, Diabetes: THEMIS

September 03, 2020

When peripheral artery disease (PAD) is known to accompany coronary artery disease (CAD) in people with diabetes, their already elevated risk of peripheral ischemic events rises even further. But so does the degree of protection conferred by addition of the antiplatelet drug ticagrelor (Brilinta, AstraZeneca) to daily low-dose aspirin, suggests a subanalysis of the THEMIS trial.

As previously reported, THEMIS saw a moderate but significant reduction in risk for cardiovascular death, myocardial infarction (MI), or stroke over an average of 40 months in more than 19,000 patients with diabetes and stable CAD randomly assigned to receive ticagrelor on top of low-dose aspirin or aspirin alone.

But there was also a jump in major bleeding complications on the chronic dual-antiplatelet therapy (DAPT), despite the trial's exclusion of patients at increased bleeding risk or who need anticoagulation.

Now a THEMIS subanalysis illustrates the steep climb in risk faced by patients with diabetes and CAD who are also recognized to have PAD.

Among patients on aspirin monotherapy in the control group, those with known PAD showed almost a 50% higher risk of cardiac events and a 73% increased risk of death compared to those without PAD, not to mention a 10-fold higher risk of limb ischemic events (LIE), defined as acute limb ischemia, peripheral revascularization, or major amputation of vascular etiology.

Hazard Ratio (HR)a for Outcomes Among 9601 Patients on Aspirin Plus Placebo in THEMIS, PAD vs No PAD

End Points

HR (95% CI)

Major adverse cardiac events

1.48 (1.20 - 1.81)

Death from any cause

1.73 (1.38 - 2.17)

Limb ischemic events

10.67 (7.90 - 14.40)

Peripheral revascularization

10.54 (7.72 - 14.38)

Major amputation of vascular etiology

9.96 (3.74 - 26.55)

Acute limb ischemia

5.61 (2.08 - 15.18)

aAll HRs, P < .001

But in ticagrelor-treated patients compared with the control group, the risk of LIE went down a significant 23% independently of whether patients had known PAD. The benefit was by more than 50% for major adverse limb events (MALE), a composite of prospectively adjudicated acute limb ischemia or amputation of vascular etiology; by more than 20% for peripheral revascularization; and by 76% for acute limb ischemia.

"So we see consistency amongst all of these components of adverse limb outcomes in the overall population," said Marc P. Bonaca, MD, MPH, University of Colorado School of Medicine, Aurora, when presenting the THEMIS substudy September 1 during the virtual European Society of Cardiology (ESC) Congress 2020.

"Those benefits were consistent regardless of PAD status at baseline," he said. "And because the risks were so high in those with PAD, their absolute benefit was greater over the course of the trial."

Limb Ischemic Outcomes at 3 Years, Ticagrelor vs Placebo, in 19,220 Patients

End Point

Placebo (%)

Ticagrelor (%)

HR (95% CI)




0.77 (0.61 - 0.96) P = .022

Peripheral revascularization



0.79 (0.62 - 0.99)

Acute limb ischemia



0.24 (0.08 - 0.70)

Major amputation of vascular etiology



0.63 (0.28 - 1.38)




0.45 (0.23 - 0.86)

The findings suggest that THEMIS-like patients with PAD may represent "a population that gets particular benefit from ticagrelor, as part of chronic DAPT, for both cardiovascular and peripheral vascular outcomes," Bonaca said.

THEMIS overall had shown a primary efficacy end point benefit that was somewhat canceled by an increased risk of bleeding; there was no significant difference in the exploratory end point of "net clinical benefit." But another substudy that had been reported at about the same time showed a significant net clinical benefit from ticagrelor among the patient subgroup with a history of percutaneous coronary intervention (PCI), Bonaca observed for theheart.org | Medscape Cardiology.

The current analysis highlights yet another "decision point" for THEMIS-like patients, in this case those with PAD, he said in an interview. It suggests a potential opportunity to go beyond ticagrelor's labeling, which indicates the drug for reducing MI and stroke. "There's actually a real benefit for limb outcomes."

Importantly, he said, in an analysis that stratified patients by their PAD status, those with known PAD — with their dramatically higher baseline risk — showed about a 2 percentage-point absolute advantage for LIE.

"As you weigh the potential benefits against the potential risks of bleeding for the patient with coronary disease, PAD, and diabetes, they're going to get a bigger benefit — if you look at the global metrics of benefit for the limbs, heart, and brain — than a patient without PAD," he said.

Rates of Limb Ischemic Events, Ticagrelor vs Placebo, by PAD Statusa

Population Cohorts

Placebo (%)

Ticagrelor (%)

HR (95% CI)

LIE overall, n = 19,220



0.77 (0.61 - 0.96)

LIE with PAD, n = 1687



0.80 (0.58 - 1.11)

LIE with no PAD, n = 17,533



0.76 (0.55 - 1.05)

a P = .81 for interaction between presence of known PAD and treatment-group effect on ischemic limb events

Patients with diabetes and polyvascular disease that includes PAD certainly need antithrombotic therapy beyond a single antiplatelet agent, "because these patients have such high risk," agreed Aaron W. Aday, MD, MSc, Vanderbilt University Medical Center, Nashville, Tennessee, in an interview with theheart.org | Medscape Cardiology.

But he hasn't generally been a proponent of DAPT in that setting. "For me, COMPASS was very practice changing," said Aday, who wasn't part of THEMIS.

In the COMPASS trial, reported and covered in these pages 3 years ago, low-dose rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals) when added to low-dose aspirin led to a 28% drop in risk for cardiovascular death, stroke, or MI, and a 46% reduced risk for major adverse limb events (P = .005 for both benefits). But there was also a 61% increase in major bleeding on rivaroxaban plus aspirin (P = .009).

Aday said he uses low-dose rivaroxaban with aspirin routinely in his patients with PAD, especially "those who are very symptomatic or who've had prior interventions, and certainly in those who have symptomatic disease in other vascular beds."

The current THEMIS findings are "intriguing," he said, but added he wants to see the analysis fleshed out in publication before making further judgment.

Still, "there are some patients for whom, for whatever reason, maybe rivaroxaban is not the right drug," he said. They have renal insufficiency or some other contraindication, or maybe cost is an issue.

"I'm not comfortable leaving them on just antiplatelet monotherapy" So perhaps ticagrelor plus aspirin would be "a reasonable option" to consider for such patients. But compared with the COMPASS regimen, "is this an equivalent option? Is it superior or inferior? I think we'll need to see more data," Aday said.

Bonaca cautions that the THEMIS analysis says nothing about ticagrelor's risk vs benefit in such patients with prior peripheral endovascular or surgical intervention and should not be interpreted as suggesting those patients will benefit.

"Not only do we not know the efficacy in that setting, we don't know the safety, what the bleeding would be like," he said. "And I think that really requires a dedicated study."

THEMIS was funded by AstraZeneca. Bonaca reported institutional grant support from Amgen, AstraZeneca, Bayer Janssen, and Merck. Aday reported payment for consulting from OptumCare.

European Society of Cardiology Congress 2020: Late Breaking Science in Cardiovascular Pharmacotherapy. Presented September 1, 2020.

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