1 Kunadian V, et al. BMJ Open 2018;8:e020713. doi:10.1136/bmjopen-2017-020713 Open Access Antiplatelet therapy in the primary prevention of cardiovascular disease in patients with chronic obstructive pulmonary disease: protocol of a randomised controlled proof-of-concept trial (APPLE COPD-ICON 2) Vijay Kunadian, 1,2 Danny Chan, 1,2 Hani Ali, 1,2 Nina Wilkinson, 3 Nicola Howe, 4 Elaine McColl, 3 Jared Thornton, 4 Alexander von Wilamowitz-Moellendorff, 4 Eva-Maria Holstein, 4 Graham Burns, 5 Andrew Fisher, 1,2 Deborah Stocken, 6 Anthony De Soyza, 1,2 On behalf of APPLE COPD-ICON2 Trial Investigators To cite: Kunadian V, Chan D, Ali H, et al. Antiplatelet therapy in the primary prevention of cardiovascular disease in patients with chronic obstructive pulmonary disease: protocol of a randomised controlled proof-of-concept trial (APPLE COPD-ICON 2). BMJ Open 2018;8:e020713. doi:10.1136/ bmjopen-2017-020713 ► Prepublication history and additional material for this paper are available online. To view these fles, please visit the journal online (http://dx.doi. org/10.1136/bmjopen-2017- 020713). Received 21 November 2017 Revised 5 March 2018 Accepted 10 April 2018 For numbered affliations see end of article. Correspondence to Dr Vijay Kunadian; vijay.kunadian@newcastle.ac.uk Protocol ABSTRACT Introduction The antiplatelet therapy in the primary prevention of cardiovascular disease in patients with chronic obstructive pulmonary disease (APPLE COPD- ICON2) trial is a prospective 2×2 factorial, double-blinded proof-of-concept randomised controlled trial targeting patients with chronic obstructive pulmonary disease (COPD) at high risk of cardiovascular disease. The primary goal of this trial is to investigate if treatment with antiplatelet therapy will produce the required response in platelet function measured using the Multiplate test in patients with COPD. Methods and analysis Patients with COPD are screened for eligibility using inclusion and exclusion criteria. Eligible patients are randomised and allocated into one of four groups to receive aspirin plus placebo, ticagrelor plus placebo, aspirin plus ticagrelor or placebo only. Markers of systemic infammation, platelet reactivity, arterial stiffness, carotid intima-media thickness (CIMT), lung function and quality of life questionnaires are assessed. The primary outcome consists of inhibition (binary response) of aspirin and ADP-induced platelet function at 6 months. Secondary outcomes include changes in infammatory markers, CIMT, non-invasive measures of vascular stiffness, quality of life using questionnaires (EuroQol–fve dimensions–fve levels of perceived problems (EQ5D-5L), St. George’s COPD questionnaire) and to record occurrence of repeat hospitalisation, angina, myocardial infarction or death from baseline to 6 months. Safety outcomes will be rates of major and minor bleeding, forced expiratory volume in 1 s, forced vital capacity and Medical Research Council dyspnoea scale. Ethics and dissemination The study was approved by the North East-Tyne and Wear South Research Ethics Committee (15/NE/0155). Findings of the study will be presented in scientifc sessions and published in peer- reviewed journals. Trial registration number ISRCTN43245574; Pre-results. INTRODUCTION  Chronic obstructive pulmonary disease (COPD) is a significant burden on the National Health Service. It is estimated to affect 3 million people within the UK, with approximately 2 million patients remaining undiagnosed. 1 We previously examined the evidence for increased cardiovascular (CV) disease risk in patients with COPD. We have reported possible mechanisms linking these two chronic conditions, discussed possible predictors or markers of poor outcomes among patients diagnosed with both COPD Strengths and limitations of this study ► Our study will consist of patients who have not been previously targeted in clinical cardiovascular research. ► We therefore hope to gather as much information as possible regarding the cardiovascular status of these high-risk patients with chronic obstructive pulmonary disease (COPD) in this proof-of-concept trial. ► Our study consists of patients with COPD who have not previously been diagnosed with coronary artery disease (CAD) and yet are at higher risk of CAD, myocardial infarction and excess mortality. ► The fndings of this study will provide us with de- tailed information regarding this patient cohort that will enable us to very carefully plan a future large- scale multicentre primary prevention study using antiplatelet therapy in patients with COPD at risk of future cardiovascular events. ► This trial is not powered to evaluate hard end points such as death or myocardial infarction. on 21 June 2018 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2017-020713 on 26 May 2018. Downloaded from