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Nonsteroidal anti-inflammatory drug treatment for postoperative pericardial effusion: A multicenter randomized, double-blind trial

Meurin P, Tabet JY, Thabut G, Cristofini P, Farrokhi T, Fischbach M, Pierre B, Driss AB, Renaud N, Iliou MC, Weber H; French Society of Cardiology. Ann Intern Med 2010 Feb 2;152(3):137-43.

Post-cardiac injury syndrome develops within days to months after cardiac, pericardial injury or both. It resembles the post-myocardial infarction syndrome, both appearing to be variants of a common immunopathic process. Unlike post-myocardial infarction syndrome, post-cardiac injury syndrome acutely provokes a greater anti-heart antibody response (anti-sarcolemmal and anti-fibrillary), probably related to more extensive release of antigenic material [1]. Pericardial effusion after cardiac surgery is common and its size and site are related to the type of surgery, periprocedural medications, and individual response to surgical trauma. Cardiac tamponade after open heart surgery is more common following valve surgery (73%) than coronary artery bypass grafting (CABG) alone (24%) and may be related to the preoperative use of anticoagulants [2].

Most cases of cardiac tamponade occur more than 7 days after surgery, and may develop slowly, without clear-cut clinical signs [2,3]. This is a major concern because patients often have already been discharged from the hospital by that time. In the retrospective analysis of Ashikhmina et al [4] out of 21,416 patients that underwent cardiac surgery 327 (1.5%) had pericardial effusion. Clinical features of tamponade were documented in 138 patients (42%). Effusions were evacuated by echocardiography-guided pericardiocentesis (n = 169, 52%) or surgical drainage (n = 75, 23%). Effusion resolved after left thoracocentesis for pleural effusion in 3 patients (1%); 67 patients (20%) were treated conservatively. In 13 cases (4%), recurrent effusion required drainage after initial pericardiocentesis. Independent risk factors for effusion were larger body surface area, pulmonary thromboembolism, hypertension, immunosuppression, renal failure, urgency of operation, cardiac operation other than coronary artery bypass grafting, and prolonged cardiopulmonary bypass. Previous cardiac surgery is associated with lower risk of effusion.

Cardiac tamponade after cardiac surgery may also be caused by intrapericardial haematoma which most often spontaneously resolved but may also require urgent evacuation. Constrictive pericarditis may also occur after cardiac surgery. Warfarin administration in patients with early postoperative pericardial effusion imposes the greatest risk, particularly in those who did not undergo pericardiocentesis and drainage of the effusion [5].

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to reduce the size of asymptomatic postoperative pericardial effusions (in 77% of the patients in one large study (3]). However, only one previous study [6] has shown the efficacy of NSAIDs for this condition and since patients who have recently had heart surgery are fragile, it is important to understand the balance of risks and benefits for this treatment. Although NSAIDs are usually given for only a short time to patients with pericardial effusions, they can cause serious adverse effects, such as upper gastrointestinal tract bleeding or perforation [7], but also myocardial infarction, acute heart failure, and acute renal failure [8].
Myocardial Disease

Summary of the paper

In the February issue of the Annals of Internal Medicine, Meurin and the colleagues from the French Society of Cardiology [9] have published results of their randomized trial on the NSAIDs Treatment for Postoperative Pericardial Effusion, performed in 5 French postoperative cardiac rehabilitation centres. They evaluated 196 patients at high risk for tamponade because of moderate to large persistent pericardial effusion (grade 2, 3, or 4 on a scale of 0 to 4, as measured by echocardiography) more than 7 days after cardiac surgery. The patients were randomly assigned at each site in blocks of 4 to diclofenac, 50 mg, or placebo twice daily for 14 days. The main end point was change in effusion grade after 14 days of treatment. Secondary end points included frequency of late cardiac tamponade. The initial mean pericardial effusion grade was 2.58 (SD, 0.73) for the placebo group and 2.75 (SD, 0.81) for the diclofenac group. The 2 groups showed similar mean decreases from baseline after treatment (-1.08 grades [SD, 1.20] for the placebo group vs. -1.36 (SD, 1.25) for the diclofenac group). The mean difference between groups was -0.28 grade (95% CI,  -0.63 to 0.06 grade; P=0.105). Eleven cases of late cardiac tamponade occurred in the placebo group and 9 in the diclofenac group (P=0.64). These differences persisted after adjustment for grade of pericardial effusion at baseline, treatment site, and type of surgery. Therefore, in this trial, the use of diclofenac, 100 mg/d, did not significantly reduce the size of pericardial effusions or the risk for late cardiac tamponade. Moreover, this study confirms that moderate to large pericardial effusion (grade 2, 3, or 4) occurring 7 to 30 days after cardiac surgery is a severe condition because 10.2% of these patients required pericardiocentesis in the 14 days after they enrolled in the study.


Therapy with NSAIDs has been previously considered useful for postoperative pericardial effusions that persist after the first postoperative week. Pericardial effusions and tamponade that occur early after surgery are usually related to surgical bleeding; however, late effusions and tamponade (which are much more frequent) have multiple causal mechanisms, and inflammation seems to play an important role. Postpericardiotomy syndrome may include fever, friction rubs, chest pain, pleuritis, and pericardial effusion. Therefore, use of an NSAID to treat late postoperative pericardial effusions seems logical, and it is common in daily practice (up to 77% of patients in several surveys [2,3,10]). However, patients who have valvular surgery routinely receive oral anticoagulants, and the combination of these agents with an NSAID could provoke gastrointestinal haemorrhage. In addition, use of an NSAID after CABG could promote atherothrombotic complications. Diclofenac was selected for this study because it is widely used and seems not to antagonize the irreversible platelet inhibition induced by aspirin [11], which is usually prescribed for these patients. However, the main limitation of the study is that it was underpowered to detect small beneficial effects from diclofenac or to evaluate adverse clinical events from the drug, because only 95 patients received the drug.

Although postoperative pericardial effusion is frequent and potentially severe, few randomized, controlled trials have examined treatment for this condition. Recommendation given in the ESC Guidelines to treat postoperative pericardial effusion with NSAIDs was based on the results of the double-blind, placebo-controlled, randomized study by Horneffer et al. [6] applying a 10-day course of ibuprofen or indomethacin. Of 1019 adult patients undergoing cardiac operations during a 14-month period, a diagnosis of postpericardiotomy syndrome was made in 187, and 149 were enrolled in the study. Diagnosis was based on the presence of at least two of the following: fever, anterior chest pain, and friction rub. Drug efficacy was defined as the resolution of at least two of these criteria within 48 hours of drug initiation. Ibuprofen and indomethacin were 90.2% and 88.7% effective, respectively, and both were significantly more effective than placebo (62.5%, p = 0.003). 

The occurrence of side effects, including nausea, vomiting, renal failure, and fluid retention, was low in all groups (13.1% for ibuprofen, 16.1% for indomethacin, and 16.7% for placebo [p = not significant). Length of hospital stay, incidence of ischemic events, and accumulation of significant pericardial effusions were similar in all groups. The results of this study suggested that both ibuprofen and indomethacin provide safe and effective symptomatic treatment for postpericardiotomy syndrome.
Aspirin [12] and diclofenac [13] were tested in clinical trials that examined prevention of the postcardiotomy syndrome (not treatment), but these trials included rather limited number of patients. A prospective, randomized, double-blind on primary prevention of postpericardiotomy syndrome was performed by Finkelstein et al [14] in 163 patients who underwent cardiac surgery in two centres in Israel between. On the 3rd postoperative day, the patients were randomly assigned to receive colchicine (1.5 mg/day) or placebo for 1 month. All were evaluated monthly for the first 3 postoperative months for development of postpericardiotomy syndrome. Of the 111 patients who completed the study, 47 (42.3%) received colchicine and 64 (57.7%) placebo. There was no statistically significant difference between the groups in clinical or surgical characteristics. The postpericardiotomy syndrome was diagnosed in 19 patients (17.1%), 5/47 cases (10.6%) in the colchicine group and 14/64 (21.9%) in the placebo group. However the study was underpowered and the difference showed only a trend toward statistical significance (p < 0.135). Therefore, colchicine is further being tested in an ongoing prevention trial of prevention (COPPS) [15].


In conclusion, the study of Meuring et al. is one step further in introduction of evidence-based medicine in the management of pericardial diseases and suggests that, until we have further data, clinicians should avoid the routine use of NSAIDs [9]. This is most probably especially true, in the absence of evidence of inflammation, such as elevated C-reactive protein levels or other symptoms. Furthermore, in the postoperative setting, corticosteroids plus colchicine may be the favoured choice to avoid negative interactions between NSAID and oral anticoagulant therapy [16]. However, careful monitoring of postoperative pericardial effusions is warranted, especially for large effusions. Redo surgery and pericardiectomy are very rarely needed. Primary prevention of postperiocardiotomy syndrome using short-term perioperative steroid treatment, intrapericardial treatment or colchicine should be also further evaluated.


References Part I

1. Maisch B, Seferovic PM, Ristic AD, et al. Task Force on the Diagnosis and Manage-ment of Pericardial Diseases of the European Society of Cardiology. Guidelines on the diagnosis and management of pericardial diseases. Executive summary. Eur Heart J 2004;25(7):587-610.
2. Kuvin JT, Harati NA, Pandian NG et al. Postoperative cardiac tamponade in the modern surgical era. Ann Thorac Surg 2002;74(4):1148-53.
3. Tsang TS, Barnes ME, Hayes SN, Freeman WK, Dearani JA, Butler SL, et al. Clinical and echocardiographic characteristics of significant pericardial effusions following cardiothoracic surgery and outcomes of echo-guided pericardiocentesis for management: Mayo Clinic experience, 1979-1998. Chest. 1999;116:322-31.
4. Ashikhmina EA, Schaff HV, Sinak LJ, Li Z, Dearani JA, Suri RM, Park SJ, Orszulak TA, Sundt TM 3rd. Pericardial effusion after cardiac surgery: risk factors, patient profiles, and contemporary management. Ann Thorac Surg 2010;89(1):112-8.
5. Matsuyama K, Matsumoto M, Sugita T et al. Clinical characteristics of patients with constrictive pericarditis after coronary bypass surgery. Jpn Circ J 2001;65(6):480-2.
6. Horneffer PJ, Miller RH, Pearson TA et al. The effective treatment of postpericardiotomy syndrome after cardiac operations. A randomized placebo-controlled trial. J Thorac Cardiovasc Surg 1990;100(2):292-6.

References Part II

7. Ong CK, Lirk P, Tan CH, Seymour RA. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res 2007;5:19-34.
8. Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA; American Heart Association. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115:1634-42.
9. Meurin P, Tabet JY, Thabut G, Cristofini P, Farrokhi T, Fischbach M, Pierre B, Driss AB, Renaud N, Iliou MC, Weber H; French Society of Cardiology. Nonsteroidal anti-inflammatory drug treatment for postoperative pericardial effusion: a multicenter randomized, double-blind trial. Ann Intern Med 2010;152(3):137-43.
10. Weitzman LB, Tinker WP, Kronzon I, Cohen ML, Glassman E, Spencer FC. The incidence and natural history of pericardial effusion after cardiac surgery—an echocardiographic study. Circulation 1984;69:506-11.
11. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345:1809-17.
12. Béland MJ, Paquet M, Gibbons JE, Tchervenkov CI, Dobell AR. Pericardial effusion after cardiac surgery in children and effects of aspirin for prevention. Am J Cardiol 1990;65:1238-41.
13. Niva M, Biancari F, Valkama J, Juvonen J, Satta J, Juvonen T. Effects of diclofenac in the prevention of pericardial effusion after coronary artery bypass surgery. A prospective, randomized study. J Cardiovasc Surg (Torino) 2002;43:449-53.
14. Finkelstein Y, Shemesh J, Mahlab K et al. Colchicine for the prevention of postpericardiotomy syndrome. Herz 2002;27:791-4.
15. Imazio M, Cecchi E, Demichelis B, Chinaglia A, Coda L, Ghisio A, Demarie D, Ierna S, Trinchero R; COPPS Investigators. Rationale and design of the COPPS trial: a randomised, placebo-controlled, multicentre study on the use of colchicine for the primary prevention of postpericardiotomy syndrome. J Cardiovasc Med (Hagerstown). 2007 Dec;8(12):1044-8.
16. Imazio M. Asymptomatic postoperative pericardial effusions: against the routine use of anti-inflammatory drug therapy. Ann Intern Med 2010;152(3):186-7.


Notes to editor

Presented by Arsen D. Ristić, MD, PhD, FESC, Associate Professor of Internal Medicine – Cardiology, Department of Cardiology of the Clinical Center of Serbia, Belgrade University School of Medicine, Koste Todorovića 8, 11000 Belgrade, Serbia
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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