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Colchicine Reduces Postoperative Atrial Fibrillation

Results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) Atrial Fibrillation Substudy

Background

Immune-mediated forms of pericarditis are still poorly understood conditions 1-3. One of these is certainly the post-pericardiotomy syndrome  (PPS), a common complication of cardiac surgery, which can prolong recovery of the patient and duration of hospitalization, but also be significantly disabling and even life-threatening1. It has been hypothesized that PPS may relate to an non-sustained autoreactive reaction to pericardial autoantigens released after cardiac surgery, as well as a non-specific post-operative inflammatory status1. Thus, it is not surprising that PPS has recently been shown to be effectively prevented by a very old drug, colchicine, in the Colchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS) trial4.  Colchicine is an old drug, with anti-inflammatory and immunomodulatory effects. The premise of the COPPS substudy, recently published by Dr Imazio, is that the same inflammatory milieau could contribute to the onset of postoperative atrial fibrillation (POAF), and therefore that colchicine might also be effective in POAF prevention5.

Myocardial Disease


Summary

The aim of the Colchicine for the Prevention of the Post-Pericardiotomy Syndrome (COPPS) POAF substudy was to test the efficacy and safety of colchicine for the prevention of POAF after cardiac surgery.
The COPPS POAF substudy included 336 patients (mean age, 65.7±12.3 years; 69% male) of the COPPS trial, a multicenter, double-blind, randomized trial. Substudy patients were in sinus rhythm before starting the intervention (placebo/colchicine 1.0 mg twice daily starting on postoperative day 3 followed by a maintenance dose of 0.5 mg twice daily for 1 month in patients ≥70 kg, halved doses for patients <70 kg or intolerant to the highest dose). The substudy primary end point was the incidence of POAF on intervention at 1 month. Despite well-balanced baseline characteristics, patients on colchicine had a reduced incidence of POAF (12.0% versus 22.0%, respectively; P=0.021; relative risk reduction, 45%; number needed to treat, 11) with a shorter in-hospital stay (9.4±3.7 versus 10.3±4.3 days; P=0.040) and rehabilitation stay (12.1±6.1 versus 13.9±6.5 days; P=0.009). Side effects were similar in the study groups.
The authors’ conclusion was that colchicine seems safe and efficacious in the reduction of POAF with the potentiality of halving the complication and reducing the hospital stay.
Clinical Trial Registration— Unique identifier: NCT00128427.

Comments

The study by Imazio5 is very promising and in keeping with a number of well-conducted studies by the same group of researchers showing that colchicine prevents acute6, recurrent pericarditis7 and PPS4. The present study5 has limitations, in particular it is a post-hoc analysis on a small number of patients and needs confirmation on a larger, multicenter patient population. In addition, 43% of the POAF occurred before the onset of colchicine treatment. Since colchicine was started on postoperative day 3, it is unclear whether the drug would be equally effective in preventing POAF on day 1 or 2. To this end another study (such as starting colchicine before the operation) is needed to confirm efficacy as well as safety.
The only independent predictor of POAF risk was an increased (>45 mm) left atrial anteroposterior diameter by echocardiography. This is an important point. In fact, more data would be needed to clarify who are the surgical patients at risk of POAF development, to target possible preventive strategies to those at high risk. Of note, also perioperative beta-blocker use had a protective effect, and statistically more potent than colchicine5.
More experimental work is needed to understand the pathogenesis of POAF.  So far surgery-related pericardial inflammation, autonomic disturbance, changes in plasma volume regulation and ionic disturbance are all plausible causes, as well as atrial trauma and ischemia or even subepicardial atrial myocarditis triggering atrial fibrillation8. The relative importance of these factors or their combination may differ in distinct patient subsets. Similarly, more research should better clarify the mechanisms of action of colchicine in pericardial inflammatory conditions. Colchicine blocks microtubule assembly and can actively disrupt microtubules, in addition it suppresses the release of a c hemotactic factor from neutrophil lysosomes, leading to reduction in neutrophil activation, in endothelial cell adhesion and migration to injured tissues. In addition, colchicine might have an effect on the microtubules of atrial myocytes, which modulate the phosphorylation of calcium channels, possibly affecting the response of atrial myocytes with an anti-sympathetic activity.  

References





1. Erlich JF, Paz Z. Postpericardial injury syndrome: an autoimmune phenomenon. Clin Rev Allergy Immunol. 2010;38(2-3):156-8
2. Imazio M, Spodick DH, Brucato A, Trinchero R, Adler Y. Controversial issues in the management of pericardial diseases. Circulation. 2010;121:916–928.
3. Caforio ALP, A Brucato,  A Doria , G Brambilla, A Angelini , A Ghirardello, S Bottaro, F Tona, C Betterle, L Daliento, G Thiene, S Iliceto. Anti-heart and anti-intercalated disc autoantibodies: evidence for autoimmunity in idiopathic recurrent acute pericarditis. Heart, 2010; 96:779-84
4. Imazio M, Trinchero R, Brucato A, Rovere ME, Gandino A, Cemin R, Ferrua S, Maestroni S, Zingarelli E, Barosi A, Simon C, Sansone F, Patrini D, Vitali E, Ferrazzi P, Spodick DH, Adler Y; COPPS Investi- gators. COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo- controlled trial. Eur Heart J. 2010;31:2749–2754.
5. Massimo Imazio, MD; Antonio Brucato, MD; Paolo Ferrazzi, MD; Maria Elena Rovere, MD; Anna Gandino, MD; Roberto Cemin, MD; Stefania Ferrua, MD; Riccardo Belli, MD; Silvia Maestroni, MD; Caterina Simon, MD; Edoardo Zingarelli, MD; Alberto Barosi, MD; Fabrizio Sansone, MD; Davide Patrini, MD; Ettore Vitali, MD; Rita Trinchero, MD; David H. Spodick, MD; Yehuda Adler, MD; for the COPPS Investigators. Colchicine Reduces Postoperative Atrial Fibrillation. Results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) Atrial Fibrillation Substudy. Circulation. 2011;124:2290-2295.
6. Imazio M, Bobbio M, Cecchi E, Demarie D, Demichelis B, Pomari F, Moratti M, Gaschino G, Giammaria M, Ghisio A, Belli R, Trinchero R. Colchicine in addition to conventional therapy for acute pericarditis. Circulation. 2005;112:2012–2016.
7. Imazio M, Bobbio M, Cecchi E, Demarie D, Pomari F, Moratti M, Ghisio A, Belli R, Trinchero R. Colchicine as first choice therapy for recurrent pericarditis. Arch Intern Med. 2005;165:1987–1991.
8. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation.Circulation.1997 Aug 19;96(4):1180-4.
9. Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep. 2008;10:218–227.
10. Head BP, Patel HH, Roth DM, Murray F, Swaney JS, Niesman IR, Farquhar MG, Insel PA. Microtubules and actin microfilaments regulate lipid raft/caveolae localization of adenylyl cyclase signaling components. J Biol Chem. 2006;281:26391–26399.
11. Malan D, Gallo MP, Bedendi I, Biasin C, Levi RC, Alloatti G. Micro-tubules mobility affects the modulation of L-type I(Ca) by muscarinic and beta-adrenergic agonists in guinea-pig cardiac myocytes. J Mol Cell Cardiol. 2003;35:195–206.

Notes to editor


Presented by Alida LP Caforio, MD, PhD, FESC,
Cardiology, Dept of Cardiological Thoracic and Vascular Sciences, University of Padova, Italy.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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