Original Investigation
Ticagrelor for Prevention of Ischemic Events After Myocardial Infarction in Patients With Peripheral Artery Disease

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Abstract

Background

Peripheral artery disease (PAD) is associated with heightened ischemic and bleeding risk in patients with prior myocardial infarction (MI).

Objectives

This study evaluated the efficacy and safety of ticagrelor on major cardiovascular (CV) events and major adverse limb events in patients with PAD and a prior MI.

Methods

PEGASUS-TIMI 54 (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) randomized 21,162 patients with prior MI (1 to 3 years) to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of low-dose aspirin. History of PAD was obtained at baseline. Occurrences of major adverse cardiovascular events (MACE) (defined as CV death, MI, or stroke) and major adverse limb events (MALE) (defined as acute limb ischemia or peripheral revascularization for ischemia) were recorded in follow-up.

Results

A total of 1,143 patients (5%) had known PAD. In the placebo arm, those with PAD (n = 404) had higher rates of MACE at 3 years than those without (n = 6,663; 19.3% vs. 8.4%; p < 0.001), which persisted after adjusting for baseline differences (adjusted hazard ratio: 1.60; 95% confidence interval: 1.20 to 2.13; p = 0.0013), and higher rates of acute limb ischemia (1.0% vs. 0.1%) and peripheral revascularization procedures (9.15% vs. 0.46%). Whereas the relative risk reduction in MACE with ticagrelor was consistent, regardless of PAD, patients with PAD had a greater absolute risk reduction of 4.1% (number needed to treat: 25) due to their higher absolute risk. The absolute excess of TIMI major bleeding was 0.12% (number needed to harm: 834). The 60-mg dose had particularly favorable outcomes for CV and all-cause mortality. Ticagrelor (pooled doses) reduced the risk of MALE (hazard ratio: 0.65; 95% confidence interval: 0.44 to 0.95; p = 0.026).

Conclusions

Among stable patients with prior MI, those with concomitant PAD have heightened ischemic risk. In these patients, ticagrelor reduced MACE, with a large absolute risk reduction, and MALE. (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS-TIMI 54]; NCT01225562)

Key Words

acute limb ischemia
major adverse cardiovascular events
major adverse limb events
peripheral arterial disease
ticagrelor

Abbreviations and Acronyms

ALI
acute limb ischemia
CABG
coronary artery bypass graft
CI
confidence interval
HR
hazard ratio
MACE
major adverse cardiovascular event(s)
MALE
major adverse limb event(s)
MI
myocardial infarction
PAD
peripheral artery disease
TIA
transient ischemic attack
TIMI
Thrombolysis In Myocardial Infarction

Cited by (0)

The TIMI Study Group has received significant research grant support from AstraZeneca. Dr. Bonaca has received consulting fees from AstraZeneca, Merck, Bayer, and Roche Diagnostics. Dr. Bhatt has served on the advisory board of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; has served on the Board of Directors of Boston VA Research Institute, and the Society of Cardiovascular Patient Care; is chair of the American Heart Association Quality Oversight Committee; has served on the data monitoring committees of Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and the Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); has served as deputy editor of Clinical Cardiology; has served as vice-chair of the NCDR-ACTION Registry Steering Committee; has served as the chair of the VA CART Research and Publications Committee; has received research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); is a site coinvestigator for Biotronik, Boston Scientific, and St. Jude Medical; is a trustee of the American College of Cardiology; and has performed unfunded research for FlowCo, PLx Pharma, and Takeda. Dr. Storey has received grants, personal fees, and travel support from AstraZeneca; and has received personal/consultancy fees from Aspen, PlaqueTec, Correvio, The Medicines Company, Medscape, and Thermo Fisher Scientific. Dr. Steg has received research grants from Merck, Sanofi, and Servier; and has served as a consultant or speaker for Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, CSL Behring, Daiichi-Sankyo-Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and The Medicines Company. Dr. Cohen has received grants and personal fees from AstraZeneca during the conduct of the study; outside of this study he has received personal fees from Merck, Janssen, Maquet, malpractice attorneys, Merck, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and Lilly; and has received grants from Janssen and Edwards Lifesciences. Dr. Nicolau has received speaker/consulting honoraria and/or research grant support from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Merck, Novartis, Pfizer, and Sanofi. Dr. López-Sendón has received research grants from AstraZeneca, Lilly/Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Novartis, and Servier; and has received honoraria from AstraZeneca, Lilly/Daiichi-Sankyo, Merck, and Sanofi. Dr. Dalby has received personal fees from AstraZeneca during the conduct of the study; and has received personal fees from Aspen, Bayer, Boehringer Ingelheim, DiscoveryHealth, Lilly, Novartis, Pfizer, Sanofi, and Servier outside of the submitted work. Dr. Aylward has received a research grant, has received honoraria for speaking, and served on the advisory board of AstraZeneca. Dr. Abola has received grants and modest personal/speaker fees from and served on the local advisory board for AstraZeneca during the conduct of the study; as an investigator in other ticagrelor trials has received modest personal fees as a member of the advisory board of and as a speaker for Pfizer; has received modest personal fees as speaker for Bayer, Boehringer Ingelheim, and Daiichi-Sankyo; and has received modest investigator fees from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, and Population Health Research Institute. Dr. Jensen is an employee of AstraZeneca. Dr. Held is an employee and stockholder of AstraZeneca. Dr. Braunwald has received institutional grant support from AstraZeneca. Dr. Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi-Sankyo, Eisai, Gilead, GlaxoSmithKline, Intarcia, Merck, Novartis, Poxel, Roche Diagnostics, Sanofi, and Takeda; and has served as a consultant for Alnylam, Amgen, AstraZeneca, Cubist, CVS Caremark, Intarcia, and Merck (all ≤$10,000/year). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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