Presenter: Massimo Imazio, MD, FESC COlchicine for Post-Pericardiotomy Syndrome (COPPS) and Post-Operative Atrial Fibrillation (POAF) prevention study: a multicenter, double-blind randomized controlled trial. Presenter: Massimo Imazio, MD, FESC on behalf of the COPPS Investigators E-mail: massimo_imazio@yahoo.it The COPPS-POAF study is a prospective, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of colchicine for the prevention of post-operative atrial fibrillation. This is the first trial to test colchicine for POAF prevention. Cardiology Dpt. Maria Vittoria Hospital, ASLTO2, Torino, Italy

Role of the Funding Source: Disclosure: None Role of the Funding Source: Independent study founded and performed within the Italian National Healthcare System. Approval by the relevant institutional ethical review boards, written informed consent by participants. The steering committee designed and oversaw the trial. All data were received, checked, and analyzed independently at the Coordinating Centre (Cardiology Dpt, Maria Vittoria Hospital, Torino, Italy) following blinded adjudication of clinical events and side effects. Acarpia Lda (Madeira, Portugal) provided supply of drug/placebo as unrestricted grant. There are no conflits of interest to disclose. The trial was an independent study founded and performed within the Italian National Healthcare System. The research protocol was approved by the relevant institutional review boards or ethics committees and all participants gave written informed consent. The steering committee designed and oversaw the trial and had the final decision on the contents of the manuscript. All data were received, checked, and analyzed independently at the Coordinating Centre at the Cardiology Department, Maria Vittoria Hospital, Torino, Italy following blinded adjudication of clinical events and side effects. Acarpia Lda (Madeira, Portugal) provided supply of drug/placebo as unrestricted grant.

Background Postoperative atrial fibrillation (POAF) is commom after cardiac surgery (10%-65%), depending on the surgery type, patient features, definition of arrhythmia, and surveillance*; Inflammation and pericarditis may be contributing factors for POAF; both are potentially affected by antiinflammatory drugs and colchicine, which has been shown to be safe and efficacious for pericarditis prevention° POAF is a common complication following cardiac surgery. Inflammation and pericarditis may be important contributing factors for POAF. Colchicine that is efficacious for pericarditis prevention and treatemt may be a tool for its prevention. *Ann Intern Med. 2001;135:1061–1073; °CORP trial- Ann Intern Med. 2011;155:409-414

Halonen J et al. JAMA 2007;297:1562-7

Halonen J et al. JAMA 2007;297:1562-7 5

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Prospective, double-blind design. Herz. 2002;27:791-4 p=NS Prospective, double-blind design. 163 patients; colchicine 1.5mg/day for 1 month 52/163 (31%) excluded (complications, intolerance, non-compliance) PPS at 3 months (placebo vs. colchicine: 14/64 vs.5/47; p= NS) The COPPS trial was designed to assess the efficacy and safety of colchicine for the primary prevention of the PPS. This possible indication was tested for the first time in a preliminary prospective, open-label, randomized trial of colchicine (1.5mg/day) compared to placebo beginning on the third postoperative day in 163 patients who underwent cardiac surgery. Fifty-two of the 163 (31.9%) initial patients were excluded because of post-operative complications, non-compliance, or gastrointestinal side effects. PPS was diagnosed in 19 of 111 patients (17.1%) who completed the study: 5/47 (10.6%) in the colchicine group and 14/64 (21.9%) in the placebo group. The difference showed a possible trend toward statistical significance (p<0.135), however, these results can be considered only as preliminary, because of the limited sample size, the relatively short follow-up (3 months), and the lack of an intention-to treat analysis.

COPPS study questions Is colchicine efficacious and safe to prevent: The post-pericardiotomy syndrome? Post-operative effusions (pericardial and/or pleural)? Post-operative atrial fibrillation?

COPPS-POAF study Objective To evaluate the efficacy and safety of colchicine for the prevention of post-operative atrial fibrillation; Specific condition to test: occurrence of POAF on intervention (from the 3rd post-operative day). The aim of the study is to evaluate the efficacy and safety of colchicine for POAF prevention.

Study design and setting Design: Prospective, randomized, double-blind, placebo-controlled, multicenter trial; Setting: 6 general hospital in North of Italy- urban areas (Maria Vittoria Hospital, Torino; Ospedali Riuniti, Bergamo; Mauriziano Hospital, Torino; Niguarda Hospital, Milano; San Maurizio Regional Hospital,Bolzano; and Ospedale degli Infermi, Rivoli); The trial is a prospective, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of colchicine.

Inclusion/Exclusion Criteria Inclusion criteria. All consecutive patients undergoing cardiac surgery were recruited. Eligible patients had no contraindication to colchicine, were able to provide informed consent, and had no unfavourable short-term outlook. Inclusion criteria were: candidate for cardiac surgery, age ≥18 years, informed consent. All patients had to be willing and able to give informed consent and able to comply with the study procedures and follow-up. Exclusion criteria. Patients meeting any of the following exclusion criteria were not eligible for the study: known severe liver disease or current transaminases >1.5 times the upper normal limit, current serum creatinine above 2.5 mg/dl, known myopathy or elevated baseline preoperative creatine kinase (CK), known blood dyscrasias or gastrointestinal disease, pregnant and lactating women or women of childbearing potential not protected by a contraception method, known hypersensitivity to colchicine, current treatment with colchicine for any indications. For the COPPS POAF substudy, POAF events limited to days 1 and 2 were excluded from the analysis because the effect of colchicine could not be evaluated (the drug was administered starting on day 3). The protocol excluded patients with chronic AF and those with persistent POAF on day 3 before starting colchicine.

COPPS-POAF CONSORT Flow Diagram No patients lost to follow-up All patients analysed for outcomes CONSORT Flow Diagram of the trial.

Baseline features Baseline patient characteristics were similar between the 2 study groups.

COPPS POAF study primary end point Despite well-balanced baseline characteristics, patients on colchicine had a reduced incidence of POAF (12.0% versus 22.0%, respectively; P0.021; relative risk reduction, 45%; number needed to treat, 11) with a shorter in-hospital stay (9.43.7 versus 10.34.3 days; P0.040) and rehabilitation stay (12.16.1 versus 13.96.5 days; P0.009).

Kaplan-Meier POAF–free survival after postoperative day 3 according to treatment groups.

Clinical Characteristics Comparison Between Patients With and Without Postoperative Atrial Fibrillation (POAF) The following clinical features were more commonly recorded in patients with POAF on placebo/colchicine treatment compared with those without POAF (Table): left atrium anteroposterior diameter 45 mm (32.7% versus 15.3%; P0.004), surgery other than coronary artery bypass graft (63.6% versus 47.7%; P0.039), and the presence of pericardial effusion (27.3% versus 15.7%; P0.051). On the contrary, a lower perioperative use of -blockers (32.7% versus 55.5%; P0.003) and colchicine (36.4% versus 53.0%; P0.027) was recorded in patients with POAF compared with those without POAF. No significant differences were recorded in the perioperative use of amiodarone.

Hazard Ratios for POAF on Placebo/Colchicine Treatment in the Cox Proportional Hazards Model A dilated left atrium (hazard ratio 2.31; 95% confidence interval, 1.15– 4.63; P0.019) was identified as the only independent risk factor for POAF in multivariable analysis (Table ).

Side Effects and Drug Withdrawal Side effects were similar in the study groups.

COPPS study questions Is colchicine efficacious and safe to prevent: The post-pericardiotomy syndrome? Post-operative effusions (pericardial and/or pleural)? Post-operative atrial fibrillation? 20

COPPS trial: Main results NNT=8 The study end points with the RRR and NNT for the primary end point. Imazio M et al. Eur Heart J. 2010;31(22):2749-54

Colchicine reduces post-operative effusions °RRR -43.9% **RRR -52.3% *RRR -43.9% *p=0.019 **p=0.002 °p=0.017 Imazio M et al. Am Heart J. 2011;162:527-32.e1

Colchicine reduces post-operative atrial fibrillation RRR 45.5% * Imazio M et al. Circulation 2011; in press

Limitations Colchicine is not registered for the prevention of pericarditis in North America or Europe and its use as such is off-label; Our limited sample size might have precluded the identification of certain adverse effects; Colchicine was given starting on the postoperative day 3. On this basis, the potential beneficial effect of the drug is limited from postoperative day 3, with the potential to miss early POAF cases in the first 2 days; Only Caucasian adults (may not apply to paediatric populations and other ethnicities); Patients with transaminases elevation, or severe liver disease, elevated creatinine, and patients with myopathy, blood dyscrasias or gastrointestinal disease were excluded; Women who are pregnant, lactating, or women of childbearing potential without sufficient contraceptive protection were excluded. Our findings might not be generalizable to other settings or other patient populations. Although the results are encouraging, important issues need to be considered. The relatively small sample size is the first study limitation. This study shows the first evidence of colchicine efficacy for the prevention of POAF, requiring further confirmation and validation in multicenter studies. Further research should address whether alternative regimens providing the drug in the perioperative period (eg, starting the administration before the operation) may provide better prevention for either PPS or POAF. Both efficacy and safety should be evaluated in this setting.

Conclusions Following cardiac surgery, colchicine, as empiric anti-inflammatory therapy, appears to be an in-expensive and safe means to reduce the incidence of POAF and hospitalization length; to reduce the incidence of the PPS and post-operative effusions. Colchicine seems safe and efficacious in reducing the incidence of POAF after cardiac surgery. Such findings may be particularly important for clinical practice because colchicine might represent a cheap and relatively safe option for the prevention of both PPS and POAF, 2 common and troublesome complications of cardiac surgery that may increase management costs.

COPPS Steering Commitee, Recruiting centres and investigators Steering Committee: Chairman: Rita Trinchero, MD, Torino, Italy. Co-chairman and Principal Investigator: Massimo Imazio, MD. Torino. Italy. Nucleus Members of the Study Group on “Heart and Infectious diseases” of the Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO). COPPS recruiting centres and investigators: Cardiology Dpt, Maria Vittoria Hospital, Torino, Italy (Coordinating Centre; investigators: M.Imazio, A. Chinaglia, B. Demichelis, D. Forno, S. Ierna), Ospedali Riuniti, Bergamo, Italy (investigators: A. Brucato, S. Maestroni, C. Simon, D. Cumetti, P. Ferrazzi), Cardiac Surgery, Ospedale Mauriziano, Torino, Italy (investigators: M.E. Rovere, E. Zingarelli, F. Sansone), Ospedale Niguarda, Milano, Italy (investigators: A. Gandino, A. Barosi, D. Patrini, E. Vitali), Department of Cardiology, San Maurizio Regional Hospital, Bolzano, Italy (R. Cemin), Ospedale degli Infermi, Rivoli, Italy (S. Ferrua, M.R. Conte). Acknowledgements The most important acknowledgement is to the participants in the study and to the physicians, nurses, ethical committees, and administrative staff in hospitals who assisted with its conduct.

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