Association of Chronic Obstructive Pulmonary Disease with Morbidity and Mortality in Patients with Peripheral Artery Disease: Insights from the EUCLID Trial

Abstract

Background: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of developing lower extremity peripheral artery disease (PAD) and suffering PAD-related morbidity and mortality. However, the effect and burden of COPD on patients with PAD is less well defined. This post hoc analysis from EUCLID aimed to analyze the risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with PAD and concomitant COPD compared with those without COPD, and to describe the adverse events specific to patients with COPD.

Methods: EUCLID randomized 13,885 patients with symptomatic PAD to monotherapy with either ticagrelor or clopidogrel for the prevention of MACE. In this analysis, MACE, MALE, mortality, and adverse events were compared between groups with and without COPD using unadjusted and adjusted Cox proportional hazards model.

Results: Of the 13,883 patients with COPD status available at baseline, 11% (n=1538) had COPD. Patients with COPD had a higher risk of MACE (6.02 vs 4.29 events/100 patient-years; p<0.001) due to a significantly higher risk of myocardial infarction (MI) (3.55 vs 1.85 events/100 patient-years; p<0.001) when compared with patients without COPD. These risks persisted after adjustment (MACE: adjusted hazard ratio (aHR) 1.30, 95% confidence interval [CI] 1.11-1.52; p<0.001; MI: aHR 1.45, 95% CI 1.18-1.77; p<0.001). However, patients with COPD did not have an increased risk of MALE or major bleeding. Patients with COPD were more frequently hospitalized for dyspnea and pneumonia (2.66 vs 0.9 events/100 patient-years; aHR 2.77, 95% CI 2.12-3.63; p<0.001) and more frequently discontinued study drug prematurely (19.36 vs 12.54 events/100 patient-years; p<0.001; aHR 1.34, 95% CI 1.22-1.47; p<0.001).

Conclusion: In patients with comorbid PAD and COPD, the risks of MACE, respiratory-related adverse events, and premature study drug discontinuation were higher when compared with patients without COPD.

Registration: ClinicalTrials.gov: NCT01732822.

Keywords: chronic obstructive pulmonary disease; major adverse cardiovascular events; peripheral artery disease.

Conflict of interest statement

FWR: Grants from AstraZeneca during the conduct of the study; personal fees from Merck Research Labs, GSK, Sanofi, Novartis, Lilly, Rhythm, Tolerion, NovoNordisk, UCB, AstraZeneca, Merck KGaA, Janssen, Sarepta, Eidos, Phathom, Amgen, honoraria from Athira Pharma, Spencer Health Solutions, and DataVant outside the submitted work; and ownership in HunterRockhold, Inc, equity in GlaxoSmithKline, Athira, Spencer Health Solutions, DataVant. JSB: Institutional research grants from Astra Zeneca, National Heart, Lung, and Blood Institute, and American Heart Association; Consulting fees from Amgen, Janssen, Merck, Takeda. JIB: Consultation for and prior employment with AstraZeneca. FGRF: Member of advisory boards for AstraZeneca, Bayer, Merck. WRH: Grant support from Amgen, grant support from NIH and grants to CPC from Bayer, Janssen, Amgen. BGK: Employee of AstraZeneca. LN: Honorarium/other from Pluristem, AnGes, Bayer. KWM: Personal fees from Abbott, grants from Afferent, AHA, grants, personal fees from Amgen, personal fees from Anthos, grants from Apple, Inc, grants, personal fees from AstraZeneca, personal fees from Baim Institute, grants, personal fees from Bayer, personal fees from Boehringer Ingelheim, grants from Cardiva Medical, Inc, personal fees from CSL Behring, grants from Eidos, personal fees from Elsevier, grants from Ferring, grants from Gilead, grants from Google (Verily), personal fees from Inova, personal fees from Intermountain Health, grants, personal fees from Johnson & Johnson, grants from Luitpold, personal fees from Medscape, grants from Medtronic, grants from Merck, personal fees from Mount Sinai, personal fees from Mundi Pharma, personal fees from Myokardia, grants, personal fees from NIH, grants, personal fees from Novartis, personal fees from Novo Nordisk, personal fees from Otsuka, personal fees from Portola, personal fees from Regeneron, grants from Sanifit, grants, personal fees from Sanofi, personal fees from SmartMedics, grants from St. Jude, personal fees from Theravance; more disclosure information is available at https://profiles.stanford.edu/kenneth-mahaffey?tab=research-and-scholarship. JKQ: Research grants from The Health Foundation, MRC, GlaxoSmithKline, Bayer, Boehringer Ingelheim, British Lung Foundation, Chiesi, AstraZeneca, Insmed and Asthma UK outside the submitted work; Honorarium/personal fees from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Bayer, Insmed. MRP: Institutional research grants from AstraZeneca, CSL, HeartFlow, Janssen Research; Personal and grants from Bayer. WSJ: Research Grants from Boehringer Ingelheim, Doris Duke Charitable Foundation, National Institutes of Health, Patient-Centered Outcomes Research Institute; Honorarium/other from Bayer, Bristol-Myers Squibb, Janssen Pharmaceuticals. The authors report no other conflicts of interest in this work.

© 2021 Galani et al.

Figures

Figure 1

Inclusion criteria for EUCLID trial. This figure highlights the inclusion criteria of patients for both the EUCLID trial and this COPD-focused post hoc analysis of the EUCLID trial.

Figure 2

Kaplan–Meier plot of primary endpoint by history of COPD. The rate of occurrence of the primary endpoint (composite of cardiovascular death, myocardial infarction and ischemic stroke) is greater in patients with a history of COPD, compared to PAD patients without baseline COPD.

Figure 3

Association between baseline COPD and clinical outcomes. This forest plot highlights the primary efficacy outcomes (MACE and MALE), secondary endpoints of interest (all-cause mortality), safety endpoints (TIMI major bleed), and serious adverse events (all-cause hospitalizations, hospitalization for dyspnea or pneumonia, premature study drug discontinuation).