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, Danny Chan, Hani Ali, Nina Wilkinson, Nicola Howe, Elaine McColl, Jared Thornton, Alexander von Wilamowitz-Moellendorff, Eva-Maria Holstein, Graham Burns, Andrew Fisher, Deborah Stocken, Anthony De Soyza, APPLE COPD-ICON2 Trial Investigators, Vijay Kunadian, Danny Chan, Hani Ali, Nina Wilkinson, Nicola Howe, Elaine McColl, Jared Thornton, Alexander von Wilamowitz-Moellendorff, Eva-Maria Holstein, Graham Burns, Andrew Fisher, Deborah Stocken, Anthony De Soyza, APPLE COPD-ICON2 Trial Investigators

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 inflammation, 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 inflammatory markers, CIMT, non-invasive measures of vascular stiffness, quality of life using questionnaires (EuroQol-five dimensions-five 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 scientific sessions and published in peer-reviewed journals.

Trial registration number: ISRCTN43245574; Pre-results.

Keywords: cardiology; chronic airways disease; coronary heart disease; ischaemic heart disease.

Conflict of interest statement

Competing interests: None declared.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1
Figure 1
APPLE COPD study flow chart. CIMT, carotid intima-media thickness; FEV1, forced expiratory volume in 1s; FVC, forced vital capacity; hsCRP, high-sensitivity C reactive protein; IL-6, interleukin-6; MPO, myeloperoxidase; PIC, patients’ identification centre; TNF, tumour necrosis factor.

References

    1. Healthcare Commission. Clearing the air. A national study of chronic obstructive pulmonary disease. London: Healthcare Commission, 2006.
    1. Ghoorah K, De Soyza A, Kunadian V. Increased cardiovascular risk in patients with chronic obstructive pulmonary disease and the potential mechanisms linking the two conditions: a review. Cardiol Rev 2013;21:196–202. 10.1097/CRD.0b013e318279e907
    1. Antonelli Incalzi R, Fuso L, De Rosa M, et al. . Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. Eur Respir J 1997;10:2794–800. 10.1183/09031936.97.10122794
    1. Curkendall SM, DeLuise C, Jones JK, et al. . Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol 2006;16:63–70. 10.1016/j.annepidem.2005.04.008
    1. Mannino DM, Thorn D, Swensen A, et al. . Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J 2008;32:962–9. 10.1183/09031936.00012408
    1. Mapel DW, Dedrick D, Davis K. Trends and cardiovascular co-morbidities of COPD patients in the Veterans Administration Medical System, 1991-1999. COPD 2005;2:35–41. 10.1081/COPD-200050671
    1. Rubinsztajn R, Chazan R. [Mortality and comorbidity in hospitalized chronic obstructive pulmonary disease patients]. Pneumonol Alergol Pol 2011;79:343–6.
    1. Sode BF, Dahl M, Nordestgaard BG. Myocardial infarction and other co-morbidities in patients with chronic obstructive pulmonary disease: a Danish nationwide study of 7.4 million individuals. Eur Heart J 2011;32:2365–75. 10.1093/eurheartj/ehr338
    1. Anthonisen NR, Connett JE, Enright PL, et al. . Hospitalizations and mortality in the Lung Health Study. Am J Respir Crit Care Med 2002;166:333–9. 10.1164/rccm.2110093
    1. Halpin DM, Decramer M, Celli B, et al. . Risk of nonlower respiratory serious adverse events following COPD exacerbations in the 4-year UPLIFT® trial. Lung 2011;189:261–8. 10.1007/s00408-011-9301-8
    1. Agarwal S, Rokadia H, Senn T, et al. . Burden of cardiovascular disease in chronic obstructive pulmonary disease. Am J Prev Med 2014;47:105–14. 10.1016/j.amepre.2014.03.014
    1. Williams MC, Murchison JT, Edwards LD, et al. . Coronary artery calcification is increased in patients with COPD and associated with increased morbidity and mortality. Thorax 2014;69:718–23. 10.1136/thoraxjnl-2012-203151
    1. Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357:2482–94. 10.1056/NEJMra071014
    1. Maclay JD, McAllister DA, Johnston S, et al. . Increased platelet activation in patients with stable and acute exacerbation of COPD. Thorax 2011;66:769–74. 10.1136/thx.2010.157529
    1. Vestbo J, Anderson JA, Brook RD, et al. . Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. Lancet 2016;387:1817–26. 10.1016/S0140-6736(16)30069-1
    1. Vestbo J, Anderson J, Brook RD, et al. . The study to understand mortality and morbidity in COPD (SUMMIT) study protocol. Eur Respir J 2013;41:1017–22. 10.1183/09031936.00087312
    1. Brook RD, Anderson JA, Calverley PM, et al. . Cardiovascular outcomes with an inhaled beta2-agonist/corticosteroid in patients with COPD at high cardiovascular risk. Heart 2017;103:1536–42. 10.1136/heartjnl-2016-310897
    1. Vandvik PO, Lincoff AM, Gore JM, et al. . Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl):e637S–68. 10.1378/chest.11-2306
    1. Pitchford SC. Novel uses for anti-platelet agents as anti-inflammatory drugs. Br J Pharmacol 2007;152:987–1002. 10.1038/sj.bjp.0707364
    1. Nylander S, Schulz R. Effects of P2Y12 receptor antagonists beyond platelet inhibition–comparison of ticagrelor with thienopyridines. Br J Pharmacol 2016;173:1163–78. 10.1111/bph.13429
    1. Storey RF, James SK, Siegbahn A, et al. . Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets 2014;25:517–25. 10.3109/09537104.2013.842965
    1. Alsharif KF, Thomas MR, Judge HM, et al. . Ticagrelor potentiates adenosine-induced stimulation of neutrophil chemotaxis and phagocytosis. Vascul Pharmacol 2015;71:201–7. 10.1016/j.vph.2015.02.006
    1. Butler K, Maya J, Teng R. Effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease patients. Curr Med Res Opin 2013;29:569–77. 10.1185/03007995.2013.781502
    1. Andell P, James SK, Cannon CP, et al. . Ticagrelor versus clopidogrel in patients with acute coronary syndromes and chronic obstructive pulmonary disease: an analysis from the platelet inhibition and patient outcomes (PLATO) Trial. J Am Heart Assoc 2015;4:e002490 10.1161/JAHA.115.002490
    1. Harrison MT, Short P, Williamson PA, et al. . Thrombocytosis is associated with increased short and long term mortality after exacerbation of chronic obstructive pulmonary disease: a role for antiplatelet therapy? Thorax 2014;69:609–15. 10.1136/thoraxjnl-2013-203996
    1. Wilson SJ, Newby DE, Dawson D, et al. . Duration of dual antiplatelet therapy in acute coronary syndrome. Heart 2017;103:573–80. 10.1136/heartjnl-2016-309871
    1. Steg PG, Huber K, Andreotti F, et al. . Bleeding in acute coronary syndromes and percutaneous coronary interventions: position paper by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 2011;32:1854–64. 10.1093/eurheartj/ehr204
    1. Chesebro JH, Knatterud G, Roberts R, et al. . Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987;76:142–54. 10.1161/01.CIR.76.1.142
    1. Mehran R, Rao SV, Bhatt DL, et al. . Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736–47. 10.1161/CIRCULATIONAHA.110.009449
    1. Jakl M, Sevcik R, Fatorova I, et al. . High on-treatment platelet reactivity: risk factors and 5-year outcomes in patients with acute myocardial infarction. Anatol J Cardiol 2017;17:113–8. 10.14744/AnatolJCardiol.2016.7042
    1. Campo G, Pavasini R, Pollina A, et al. . On-treatment platelet reactivity in patients with chronic obstructive pulmonary disease undergoing percutaneous coronary intervention. Thorax 2014;69:80–1. 10.1136/thoraxjnl-2013-203608
    1. Floyd CN, Ferro A. Mechanisms of aspirin resistance. Pharmacol Ther 2014;141:69–78. 10.1016/j.pharmthera.2013.08.005
    1. Guirguis-Blake JM, Evans CV, Senger CA, et al. . Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. preventive services task force. Ann Intern Med 2016;164:804–13. 10.7326/M15-2113
    1. Sibbing D, Braun S, Jawansky S, et al. . Assessment of ADP-induced platelet aggregation with light transmission aggregometry and multiple electrode platelet aggregometry before and after clopidogrel treatment. Thromb Haemost 2008;99:121–6. 10.1160/TH07-07-0478
    1. Kawase Ishihara K, Kokubo Y, Yokota C, et al. . Effect of plasma fibrinogen, high-sensitive C-reactive protein, and cigarette smoking on carotid atherosclerosis: the suita study. J Stroke Cerebrovasc Dis 2015;24:2385–9. 10.1016/j.jstrokecerebrovasdis.2015.06.039
    1. Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003;107:1514–9. 10.1161/01.CIR.0000056767.69054.B3
    1. Andreas S, Anker SD, Scanlon PD, et al. . Neurohumoral activation as a link to systemic manifestations of chronic lung disease. Chest 2005;128:3618–24. 10.1378/chest.128.5.3618
    1. Agustí A. Systemic effects of chronic obstructive pulmonary disease: what we know and what we don’t know (but should). Proc Am Thorac Soc 2007;4:522–5. 10.1513/pats.200701-004FM
    1. Karadag F, Karul AB, Cildag O, et al. . Biomarkers of systemic inflammation in stable and exacerbation phases of COPD. Lung 2008;186:403–9. 10.1007/s00408-008-9106-6
    1. Kaźmierczak M, Ciebiada M, Pękala-Wojciechowska A, et al. . Evaluation of markers of inflammation and oxidative stress in copd patients with or without cardiovascular comorbidities. Heart Lung Circ 2015;24:817–23. 10.1016/j.hlc.2015.01.019
    1. Fimognari FL, Scarlata S, Conte ME, et al. . Mechanisms of atherothrombosis in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2008;3:89–96.
    1. Vlachopoulos C, Aznaouridis K, Stefanadis C. Aortic stiffness for cardiovascular risk prediction: just measure it, just do it!. J Am Coll Cardiol 2014;63:647–9. 10.1016/j.jacc.2013.10.040
    1. Mills NL, Miller JJ, Anand A, et al. . Increased arterial stiffness in patients with chronic obstructive pulmonary disease: a mechanism for increased cardiovascular risk. Thorax 2008;63:306–11. 10.1136/thx.2007.083493
    1. McAllister DA, Maclay JD, Mills NL, et al. . Arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:1208–14. 10.1164/rccm.200707-1080OC
    1. Fisk M, Mäki Petäjä K, Gale N, et al. . Abstract 12457: carotid intima-media thickness and aortic stiffness are elevated in Chronic Obstructive Pulmonary Disease (COPD) subjects compared to controls and not associated with systemic inflammation. Circulation 2015;132(Suppl 3):A12457.
    1. Vanfleteren LE, Spruit MA, Groenen MT, et al. . Arterial stiffness in patients with COPD: the role of systemic inflammation and the effects of pulmonary rehabilitation. Eur Respir J 2014;43:1306–15. 10.1183/09031936.00169313
    1. Mitchell GF. Arterial stiffness and wave reflection: biomarkers of cardiovascular risk. Artery Res 2009;3:56–64. 10.1016/j.artres.2009.02.002
    1. Mitchell GF. Arterial stiffness: insights from Framingham and Iceland. Curr Opin Nephrol Hypertens 2015;24:1–7. 10.1097/MNH.0000000000000092
    1. Safar ME, Nilsson PM, Blacher J, et al. . Pulse pressure, arterial stiffness, and end-organ damage. Curr Hypertens Rep 2012;14:339–44. 10.1007/s11906-012-0272-9
    1. Kim SJ, Yoon DW, Lee EJ, et al. . Carotid atherosclerosis in patients with untreated chronic obstructive pulmonary disease. Int J Tuberc Lung Dis 2011;15:1265–70. 10.5588/ijtld.10.0680
    1. Zamzam MA, Azab NY, El Wahsh RA, et al. . Quality of life in COPD patients. Egypt J Chest Dis Tuberc 2012;61:281–9. 10.1016/j.ejcdt.2012.08.012
    1. Jones PW, Brusselle G, Dal Negro RW, et al. . Health-related quality of life in patients by COPD severity within primary care in Europe. Respir Med 2011;105:57–66. 10.1016/j.rmed.2010.09.004
    1. Hinz A, Kohlmann T, Stöbel-Richter Y, et al. . The quality of life questionnaire EQ-5D-5L: psychometric properties and normative values for the general German population. Qual Life Res 2014;23:443–7. 10.1007/s11136-013-0498-2
    1. Jung SH. Randomized phase II trials with a prospective control. Stat Med 2008;27:568–83. 10.1002/sim.2961
    1. Perl L, Zemer-Wassercug N, Rechavia E, et al. . Comparison of platelet inhibition by prasugrel versus ticagrelor over time in patients with acute myocardial infarction. J Thromb Thrombolysis 2015;39:1–7. 10.1007/s11239-014-1119-9

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