OBJECTIVES: To investigate if the effect of cardiac computed tomography (CT) vs. invasive coronary angiography (ICA) on cardiovascular events differs based on smoking status. MATERIALS AND METHODS: This pre-specified subgroup analysis of the pragmatic, prospective, multicentre, randomised DISCHARGE trial (NCT02400229) involved 3561 patients with suspected coronary artery disease (CAD). The primary endpoint was major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarction, or stroke). Secondary endpoints included an expanded MACE composite (MACE, transient ischaemic attack, or major procedure-related complications). RESULTS: Of 3445 randomised patients with smoking data (mean age 59.1 years + / - 9.7, 1151 men), at 3.5-year follow-up, the effect of CT vs. ICA on MACE was consistent across smoking groups (p for interaction = 0.98). The percutaneous coronary intervention rate was significantly lower with a CT-first strategy in smokers and former smokers (p = 0.01 for both). A CT-first strategy reduced the hazard of major procedure-related complications (HR: 0.21, 95% CI: 0.03, 0.81; p = 0.045) across smoking groups. In current smokers, the expanded MACE composite was lower in the CT- compared to the ICA-first strategy (2.3% (8) vs 6.0% (18), HR: 0.38; 95% CI: 0.17, 0.88). The rate of non-obstructive CAD was significantly higher in all three smoking groups in the CT-first strategy. CONCLUSION: For patients with stable chest pain referred for ICA, the clinical outcomes of CT were consistent across smoking status. The CT-first approach led to a higher detection rate of non-obstructive CAD and fewer major procedure-related complications in smokers. CLINICAL RELEVANCE STATEMENT: This pre-specified sub-analysis of the DISCHARGE trial confirms that a CT-first strategy in patients with stable chest pain referred for invasive coronary angiography with an intermediate pre-test probability of coronary artery disease is as effective as and safer than invasive coronary angiography, irrespective of smoking status. TRIAL REGISTRATION: ClinicalTrials.gov NCT02400229. KEY POINTS: • No randomised studies have assessed smoking status on CT effectiveness in symptomatic patients referred for invasive coronary angiography. • A CT-first strategy results in comparable adverse events, fewer complications, and increased coronary artery disease detection, irrespective of smoking status. • A CT-first strategy is safe and effective for stable chest pain patients with intermediate pre-test probability for CAD, including never smokers.

Administrative Centre Health Care District of Southwestern Finland Turku Finland

Bavarian Cancer Registry Bavarian Health and Food Safety Authority Munich Germany

Berlin Institute of Health at Charité Universitätsmedizin Berlin Berlin Germany

Berlin University Alliance Berlin Germany

Center of Advanced Research in Multimodality Cardiac Imaging CardioMed Medical Center Targu Mures Romania

Centro de Investigacion Biomedica en Red Madrid Spain

County Clinical Emergency Hospital Targu Mures Targu Mures Romania

Department of Biomedical Sciences Humanitas University and IRCCS Humanitas Research Hospital Milan Italy

Department of Cardiology Aintree University Hospital Liverpool UK

Department of Cardiology Alb Fils Kliniken Göppingen Germany

Department of Cardiology Basurto Hospital Bilbao Spain

Department of Cardiology Centro Hospitalar de Vila Nova de Gaia Espinho Vila Nova de Gaia Portugal

Department of Cardiology Copenhagen University Hospital Amager and Hvidovre Hvidovre Denmark

Department of Cardiology Copenhagen University Hospital Rigshospitalet and Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Department of Cardiology Herlev Gentofte Hospital Hellerup Denmark

Department of Cardiology Hospital of Lithuanian University of Health Sciences Kaunas Lithuania

Department of Cardiology Hospital Universitario Vall d'Hebron Institut de Recerca Universitat Autònoma de Barcelona Barcelona Spain

Department of Cardiology Institute for Cardiovascular Diseases of Vojvodina Novi Sad Serbia

Department of Cardiology Internal Medicine Clinic Clinical Hospital Center Zemun Belgrade Serbia

Department of Cardiology Liverpool University Hospital NHS FT Liverpool UK

Department of Cardiology Medical Academy Lithuanian University of Health Sciences Kaunas Lithuania

Department of Cardiology Motol University Hospital Prague Czech Republic

Department of Cardiology Nordsjællands Hospital University of Copenhagen Copenhagen Denmark

Department of Cardiology Paul Stradins Clinical University Hospital Riga Latvia

Department of Cardiology Provincial Specialist Hospital in Wroclaw Wroclaw Poland

Department of Cardiology Southeastern Health and Social Care Trust Belfast UK

Department of Cardiology St Vincent's University Hospital Dublin Ireland

Department of Cardiology University of Leipzig Heart Centre Leipzig Germany

Department of Clinical Epidemiology and Applied Biostatistics Universitätsklinikum Tübingen Tübingen Germany

Department of Clinical Internal Anesthesiologic and Cardiovascular Sciences Sapienza University of Rome Rome Italy

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Internal Medicine 3 Department of Cardiology Innsbruck Medical University Innsbruck Austria

Department of Internal Medicine Clinic of Cardiology George Emil Palade University of Medicine Pharmacy Science and Technology Targu Mures Romania

Department of Public Health Section for Health Services Research University of Copenhagen Copenhagen Denmark

Department of Radiological Sciences Sapienza University of Rome Rome Italy

Department of Radiology Aintree University Hospital Liverpool UK

Department of Radiology and Neuroradiology SS Annunziata Hospital Taranto Italy

Department of Radiology Basurto Hospital Bilbao Spain

Department of Radiology Charité Universitätsmedizin Berlin Freie Universität Berlin and Humboldt Universität Zu Berlin Berlin Germany

Department of Radiology Copenhagen University Hospital Rigshospitalet and Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Department of Radiology Innsbruck Medical University Innsbruck Austria

Department of Radiology Kaunas Clinics Institute of Cardiology Lithuanian University of Health Sciences Kaunas Lithuania

Department of Radiology Medical Imaging Center Semmelweis University Budapest Hungary

Department of Radiology Motol University Hospital Prague Czech Republic

Department of Radiology Provincial Specialist Hospital in Wroclaw Wroclaw Poland

Department of Radiology St Vincent's University Hospital Dublin Ireland

Department of Radiology University of Cagliari Cagliari CA Italy

Department of Radiology University of Leipzig Heart Centre Leipzig Germany

Deutsches Herzzentrum Der Charité Berlin Germany

Deutsches Herzzentrum der Charité Department of Cardiology and Angiology Campus Virchow Klinikum Augustenburger Platz 1 13353 Berlin Germany

Deutsches Herzzentrum Der Charité Partner Site Berlin Berlin Germany

Deutsches Herzzentrum Der Charité Partner Site Berlin Germany

Duke Clinical Research Institute Duke University School of Medicine Durham NC USA

ECRIN ERIC Paris France

Edge Hill University Ormskirk UK

Faculty of Medicine University of Belgrade Belgrade Serbia

Faculty of Medicine University of Latvia Riga Latvia

Faculty of Medicine University of Novi Sad Novi Sad Serbia

Golden Jubilee National Hospital Clydebank UK

Heart and Vascular Center Semmelweis University Budapest Hungary

Heart Center Turku University Hospital and University of Turku Turku Finland

Institute of Biometry and Clinical Epidemiology Charité Universitätsmedizin Berlin Freie Universität Berlin and Humboldt Universität Zu Berlin Berlin Germany

Institute of Public Health Charité Universitätsmedizin Berlin Freie Universität Berlin and Humboldt Universität Zu Berlin Berlin Germany

Liverpool Centre for Cardiovascular Studies University of Liverpool Liverpool UK

National Institute of Cardiology Warsaw Poland

School of Cardiovascular and Metabolic Health University of Glasgow Glasgow UK

School of Medicine University College Dublin Dublin Ireland

Turku PET Centre Turku University Hospital and University of Turku Turku Finland

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ClinicalTrials.gov
NCT02400229