CXCR2 Inhibition – a novel approach to treating CoronAry heart DiseAse (CICADA): study protocol for a randomised controlled trial

Abstract Background There is emerging evidence of the central role of neutrophils in both atherosclerotic plaque formation and rupture. Patients with lower neutrophil counts following acute coronary syndromes tend to have a greater coronary flow reserve, which is a strong predictor of long-term cardiovascular health. But so far, no data are available regarding the impact of neutrophil inhibition on cardiovascular clinical or surrogate endpoints. Therefore, the aim of this study is to investigate the effects of AZD5069, a cysteine-X-cysteine chemokine receptor 2 (CXCR2) inhibitor, on coronary flow reserve and coronary structure and function in patients with coronary artery disease. Methods/Design Ninety subjects with coronary artery disease undergoing percutaneous coronary intervention will be included in this investigator-driven, randomised, placebo-controlled, double-blind, phase IIa, single-centre study. Participants will be randomised to receive either AZD5069 (40 mg) administered orally twice daily or placebo for 24 weeks. Change in coronary flow reserve as determined by 13N-ammonia positron emission tomography-computed tomography will be the primary outcome. Change in the inflammatory component of coronary plaque structure and the backward expansion wave, an invasive coronary physiological measure of diastolic function, will be assessed as secondary outcomes. Discussion Cardiovascular surrogate parameters, such as coronary flow reserve, may provide insights into the potential mechanisms of the cardiovascular effects of CXCR2 inhibitors. Currently, ongoing trials do not specifically focus on neutrophil function as a target of intervention, and we therefore believe that our study will contribute to a better understanding of the role of neutrophil-mediated inflammation in coronary artery disease. Trial registration EudraCT, 2016-000775-24 . Registered on 22 July 2016. International Standard Randomised Controlled Trial Number, ISRCTN48328178 . Registered on 25 February 2016

Colchicine and Cardiovascular Outcomes: A Critical Appraisal of Recent Studies

Purpose of review: Recent studies have demonstrated an important role for inflammation in the pathogenesis of atherosclerotic cardiovascular disease. Several studies have investigated the efficacy of colchicine (a widely used and safe anti-inflammatory drug) in patients with atherosclerosis. This review explains the rationale for the use of colchicine in this setting, and critically appraises recent outcomes trials. Recent findings: Two large randomised-controlled trials LoDoCo2 (included patients with chronic coronary syndromes) and COLCOT (acute coronary syndromes) have demonstrated reductions in atherosclerotic cardiovascular events, but not mortality. A smaller study (COPS) found no beneficial effect of colchicine but was probably underpowered. Summary: Colchicine is effective at reducing cardiovascular events in chronic and acute coronary syndromes, although reductions in all-cause mortality have not been demonstrated during the period of follow up in trials to date. Mild gastrointestinal symptoms are the most commonly reported adverse effects, although in well-designed randomised controlled trials these are relatively uncommon