Limb Outcomes With Ticagrelor Plus Aspirin in Patients With Diabetes Mellitus and Atherosclerosis

Marc P Bonaca; Deepak L Bhatt; Tabassome Simon; Kim Michael Fox; Shamir Mehta; Robert A Harrington; Lawrence A Leiter; Warren H Capell; Claes Held; Anders Himmelmann; Wilhelm Ridderstråle; Jersey Chen; Jane J Lee; Yang Song; Marielle Andersson; Jayne Prats; Mikhail Kosiborod; Darren K McGuire; Ph Gabriel Steg

doi:10.1016/j.jacc.2024.03.377

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.

Authors

Marc P Bonaca¹, Deepak L Bhatt², Tabassome Simon³, Kim Michael Fox⁴, Shamir Mehta⁵, Robert A Harrington⁶, Lawrence A Leiter⁷, Warren H Capell⁸, Claes Held⁹, Anders Himmelmann¹⁰, Wilhelm Ridderstråle¹⁰, Jersey Chen¹⁰, Jane J Lee¹¹, Yang Song¹¹, Marielle Andersson¹⁰, Jayne Prats¹², Mikhail Kosiborod¹³, Darren K McGuire¹⁴, Ph Gabriel Steg¹⁵

Affiliations

¹ University of Colorado, CPC Clinical Research, Aurora, Colorado, USA. Electronic address: Marc.Bonaca@cpcmed.org.
² Mount Sinai Heart, Icahn School of Medicine at Mount Sinai Health System, New York, New York, USA.
³ Department of Clinical Pharmacology and Clinical Research, Research Platform of East of Paris (URCEST-CRCEST-CRB.APHPSU), Assistance Publique Hopitaux de Paris (APHP), Sorbonne Universite, FACT (French Alliance for Cardiovascular Trials), Paris, France.
⁴ The National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London, United Kingdom.
⁵ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
⁶ Weill Cornell Medicine, New York, New York, USA.
⁷ Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
⁸ University of Colorado, CPC Clinical Research, Aurora, Colorado, USA.
⁹ Department of Medical Sciences, Cardiology, Uppsala University, Uppsala Clinical Research Center, Uppsala, Sweden.
¹⁰ AstraZeneca BioPharmaceuticals R&D, Late-stage Development, Cardiovascular, Renal and Metabolic, Gothenburg, Sweden.
¹¹ Baim Institute for Clinical Research, Boston, Massachusetts, USA.
¹² Elysis LLC, Carlisle, Massachusetts, USA.
¹³ Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, Missouri, USA.
¹⁴ University of Texas Southwestern Medical Center, and Parkland Health and Hospital System, Dallas, Texas, USA.
¹⁵ French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148, Paris, France.

PMID: 38658101
DOI: 10.1016/j.jacc.2024.03.377

Abstract

Background: Ticagrelor reduced major adverse cardiovascular events (MACE) and increased bleeding in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease. Limb events including revascularization, acute limb ischemia (ALI), and amputation are major morbidities in patients with T2DM and atherosclerosis.

Objectives: This study sought to determine the effect of ticagrelor on limb events.

Methods: Patients were randomized to ticagrelor or placebo on top of aspirin and followed for a median of 3 years. MACE (cardiovascular death, myocardial infarction, or stroke), limb events (ALI, amputation, revascularization), and bleeding were adjudicated by an independent and blinded clinical events committee. The presence of peripheral artery disease (PAD) was reported at baseline.

Results: Of 19,220 patients randomized, 1,687 (8.8%) had PAD at baseline. In patients receiving placebo, PAD was associated with higher MACE (10.7% vs 7.3%; HR: 1.48; P < 0.001) and limb (9.5% vs 0.8%; HR: 10.67; P < 0.001) risk. Ticagrelor reduced limb events (1.6% vs 1.3%; HR: 0.77; 95% CI: 0.61-0.96; P = 0.022) with significant reductions for revascularization (HR: 0.79; 95% CI: 0.62-0.99; P = 0.044) and ALI (HR: 0.24; 95% CI: 0.08-0.70; P = 0.009). The benefit was consistent with or without PAD (HR: 0.80; 95% CI: 0.58-1.11; and HR: 0.76; 95% CI: 0.55-1.05, respectively; P_interaction = 0.81). There was no effect modification of ticagrelor vs placebo based on PAD for MACE (P_interaction = 0.40) or TIMI major bleeding (P_interaction = 0.3239).

Conclusions: Patients with T2DM and atherosclerosis are at high risk of limb events. Ticagrelor decreased this risk, but increased bleeding. Future trials evaluating the combination of ticagrelor and aspirin would further elucidate the benefit/risk of such therapy in patients with PAD, including those without coronary artery disease. (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus [THEMIS]: NCT01991795).

Keywords: Long-term ticagrelor; myocardial infarction; real-world evidence.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aspirin* / administration & dosage
Aspirin* / therapeutic use
Atherosclerosis / drug therapy
Diabetes Mellitus, Type 2* / complications
Diabetes Mellitus, Type 2* / drug therapy
Double-Blind Method
Drug Therapy, Combination
Female
Humans
Ischemia / prevention & control
Male
Middle Aged
Peripheral Arterial Disease / drug therapy
Platelet Aggregation Inhibitors* / administration & dosage
Platelet Aggregation Inhibitors* / therapeutic use
Ticagrelor* / administration & dosage
Ticagrelor* / therapeutic use
Treatment Outcome

Substances

Aspirin
Platelet Aggregation Inhibitors
Ticagrelor

Associated data

ClinicalTrials.gov/NCT01991795