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. 2018 Nov 2;1(7):e185239.
doi: 10.1001/jamanetworkopen.2018.5239.

Polyvascular Disease and Risk of Major Adverse Cardiovascular Events in Peripheral Artery Disease: A Secondary Analysis of the EUCLID Trial

J Antonio Gutierrez  1 , Hillary Mulder  1 , W Schuyler Jones  1 , Frank W Rockhold  1 , Iris Baumgartner  2 , Jeffrey S Berger  3 , Juuso I Blomster  4 , F Gerry R Fowkes  5 , Peter Held  6   7 , Brian G Katona  8 , Kenneth W Mahaffey  9 , Lars Norgren  10 , William R Hiatt  11 , Manesh R Patel  1
Affiliations

Polyvascular Disease and Risk of Major Adverse Cardiovascular Events in Peripheral Artery Disease: A Secondary Analysis of the EUCLID Trial

J Antonio Gutierrez et al. JAMA Netw Open. .

Abstract

Importance: The effect of polyvascular disease on cardiovascular outcomes in the background of peripheral artery disease (PAD) is unclear.

Objective: To determine the risk of ischemic events (both cardiac and limb) among patients with PAD and polyvascular disease.

Design, setting, and participants: In this post hoc secondary analysis of the international Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, outcomes were compared among 13 885 enrolled patients with PAD alone, PAD + coronary artery disease (CAD), PAD + cerebrovascular disease (CVD), and PAD + CAD + CVD. Adjusted Cox proportional hazards regression models were implemented to determine the risk associated with polyvascular disease and outcomes, and intention-to-treat analysis was performed. The EUCLID trial was conducted from December 31, 2012, to March 7, 2014; the present post hoc analysis was performed from June 1, 2017, to February 5, 2018.

Interventions: EUCLID evaluated ticagrelor vs clopidogrel in preventing major adverse cardiac events (cardiovascular death, myocardial infarction [MI], or ischemic stroke) and major bleeding in patients with PAD.

Main outcomes and measures: The primary end point was a composite of cardiovascular death, MI, or ischemic stroke. Key secondary end points included the individual components of the primary end point and acute limb ischemia leading to hospitalization, major amputation, and lower-extremity revascularization. The primary end point of Thrombolysis in Myocardial Infarction (TIMI) major bleeding was also evaluated.

Results: The EUCLID trial randomized 13 885 patients with a median age of 66 years (interquartile range, 60-73 years), of whom 3888 (28.0%) were women. At baseline, 7804 patients (56.2%) had PAD alone; 2639 (19.0%) had PAD + CAD; 2049 (14.8%) had PAD + CVD; and 1393 (10.0%) had PAD + CAD + CVD. Compared with patients with isolated PAD, the adjusted hazard ratios (aHRs) for major adverse cardiac events were 1.34 (95% CI, 1.15-1.57; P < .001) for PAD + CVD, 1.65 (95% CI, 1.43-1.91; P < .001) for PAD + CAD, and 1.99 (95% CI, 1.69-2.34; P < .001) for PAD + CAD + CVD. The aHRs for lower-extremity revascularization were 1.17 (95% CI, 1.03-1.34; P = .01) for PAD + CAD, 1.17 (95% CI, 1.02-1.35; P = .02) for PAD + CVD, and 1.34 (95% CI, 1.15-1.57; P < .001) for PAD + CAD + CVD. Polyvascular disease was not associated with an increased risk of acute limb ischemia (aHR for PAD + CVD, 0.91; 95% CI, 0.62-1.34, P = .63; PAD + CAD, 0.93; 95% CI, 0.64-1.34, P = .69; and PAD + CAD + CVD, 0.98; 95% CI, 0.63-1.53, P = .93), major amputation (aHR for PAD + CVD, 0.83; 95% CI, 0.54-1.27, P = .40; PAD + CAD, 0.74; 95% CI, 0.47-1.16, P = .19; and PAD + CAD + CVD, 1.12; 95% CI, 0.69-1.80, P = .65), or TIMI major bleeding (PAD + CVD, 0.98; 0.66-1.44, P = .91; PAD + CAD, 1.04; 0.74-1.48, P = .81; and PAD + CAD + CVD, 0.96; 95% CI, 0.62-1.51, P = .88).

Conclusions and relevance: Compared with patients with PAD alone, the risk of major adverse cardiac events and lower-extremity revascularization increased with multiple vascular bed involvement. There was no clear increased risk of bleeding associated with polyvascular disease.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Jones has received funding through research grants to the Duke Clinical Research Institute from the American Heart Association, AstraZeneca, Boston Scientific, and Bristol-Myers Squibb. Dr Rockhold has received research grants from AstraZeneca, Patient-Centered Outcomes Research Institute (PCORI), the National Institutes of Health, ReNeuron, Luitpold, and Intarcia; consulting fees/honoraria from Amgen, AbbVie, Adverum, Biotechnologies, Novo Nordisk, GlaxoSmithKline, California Institute for Regenerative Medicine, PCORI, Merck, Eidos Therapeutics, UCB Biosciences, Research, Velicept Therapeutics, and Janssen; and has equity interest in GlaxoSmithKline. Dr Baumgartner has received steering committee fees from AstraZeneca, advisory board fees from Bayer and Sanofi, and research grants from Abbott Vascular, Cook Medical, Optimed, Terumo Medical, Promedics, Amgen, and Boston Scientific. Dr Berger has received advisory board fees from Janssen, Merck, and Takeda. Dr Blomster was employed by AstraZeneca at the time of the trial. Dr Fowkes receives consulting fees from Bayer and Merck. Dr Held was employed by AstraZeneca at the time of the trial. Dr Mahaffey has received consulting fees from BAROnova, Bayer, Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cubist, Eli Lilly, Epson, Forest Laboratories, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, MyoKardia, Omthera Pharmaceuticals, Portola Pharmaceuticals, Purdue Pharma, the Medicines Company, Theravance, Vindico, and WebMD; research grants from Amgen, Daiichi-Sankyo, Johnson & Johnson, Medtronic, Merck, St Jude Medical, and Tenax Therapeutics; and has equity interest in BioPrint Fitness. Dr Norgren has received steering committee fees from AstraZeneca, Bayer, AnGes MG, and Pluristem Therapeutics; advisory board fees from Cesca Therapeutics; consulting fees from Mitsubishi Tanabe Pharma; and research grants from AnGes MG and Mitsubishi Tanabe Pharma. Dr Hiatt has received research funding through CPC Clinical Research from AstraZeneca, Bayer, Jansen, and Pluristem. Dr Patel has received consulting fees from Bayer, Ortho-McNeil-Janssen, theheart.org, Ikaria, and Duke Continuing Medical Education; and research grants from AstraZeneca, Cardiovascular Systems Inc, HeartFlow, Janssen Research & Development, Maquet, Medtronic, and the National Heart, Lung, and Blood Institute. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Outcomes for the Efficacy End Points
Outcomes for the primary efficacy end point (composite of cardiovascular death, myocardial infarction, and ischemic stroke) (A), cardiovascular death (B), myocardial infarction (C), and ischemic stroke (D). CAD indicates coronary artery disease; CVD, cerebrovascular disease; and PAD, peripheral artery disease. For all panels P < .001.
Figure 2.
Figure 2.. Major Adverse Cardiac Events According to Polyvascular Disease Phenotype
Adjusted rates presented as events per 100 patient-years. Reference group was patients with peripheral artery disease (PAD) alone. The primary end point (composite of cardiovascular death, myocardial infarction, and ischemic stroke) was adjusted for age, weight, sex, estimated glomerular filtration rate (eGFR), baseline ankle-brachial index (ABI), randomized treatment, sex, inclusion criteria, geographic region, critical limb ischemia, diabetes (type 1 or 2), statin use before randomization, smoking status, prior major amputation, and prior minor amputation. Cardiovascular death was adjusted for age, weight, eGFR, baseline ABI, randomized treatment, sex, geographic region, critical limb ischemia, diabetes, use of statins before randomization, and prior minor amputation. Myocardial infarction was adjusted for age, eGFR, baseline ABI, randomized treatment, inclusion criteria, geographic region, diabetes, smoking status, and prior minor amputation. Ischemic stroke was adjusted for age, baseline ABI, randomized treatment, geographic region, diabetes, smoking status, and prior minor amputation. CAD indicates coronary artery disease; CVD, cerebrovascular disease; and HR, hazard ratio.
Figure 3.
Figure 3.. Major Adverse Limb Events and Safety Events According to Polyvascular Disease Phenotype
Adjusted rates presented as events per 100 patient-years. Reference group was patients with peripheral artery disease (PAD) alone. Acute limb ischemia was adjusted for baseline ankle-brachial index (ABI), randomized treatment, inclusion criteria, use of statins before randomization, and use of angiotensin receptor blockers before randomization. Lower-extremity revascularization was adjusted for baseline ABI, estimated glomerular filtration rate, inclusion criteria, diabetes (type 1 or 2), use of aspirin before randomization, use of clopidogrel before randomization, and smoking status. Amputation was adjusted for weight, baseline ABI, inclusion criteria, critical limb ischemia, diabetes, use of statins before randomization, prior major amputation, and prior minor amputation. Major bleeding was adjusted for age, randomized treatment, and geographic region. Minor bleeding was adjusted for age, baseline ABI, inclusion criteria, sex, randomized treatment, and geographic region. CAD indicates coronary artery disease; CVD, cerebrovascular disease; HR, hazard ratio; and TIMI, Thrombolysis in Myocardial Infarction.
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