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Nonsteroidal Anti-inflammatory Drug Treatment for Postoperative Pericardial Effusion: A Multicenter Randomized, Double-Blind Trial

Philippe Meurin, MD; Jean Yves Tabet, MD; Gabriel Thabut, MD, PhD; Pascal Cristofini, MD; Titi Farrokhi, MD; Michel Fischbach, MD; Bernard Pierre, MD; Ahmed Ben Driss, MD, PhD; Nathalie Renaud, MD; Marie Christine Iliou, MD; Hélène Weber, MD, French Society of Cardiology
[+] Article and Author Information

For a list of all study investigators, see the Appendix.


From Les Grands Prés (CRCB), Villeneuve Saint Denis; Bichat Hospital and Broussais Hospital Paris; Bligny Hospital, Briis-sous-Forges; Centre de Réadaptation Château Lemoine, Cenon; and IRIS, Marcy l'Étoile, France.


Acknowledgment: The authors thank Dr. Anissa Bouzamondo from the French Society of Cardiology; Pr. Guilmet and members of the Association Chirurgicale pour le Développement et l'Amélioration des Techniques de Dépistage et de Traitement des Maladies Cardiovasculaires; all the investigators, who worked with enthusiasm and for free; and all the patients in the study, especially those who underwent surgery.

Grant Support: By the French Society of Cardiology and Association Chirurgicale pour le Développement et l'Amélioration des Techniques de Dépistage et de Traitement des Maladies Cardiovasculaires.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-1710.

Reproducible Research Statement:Study protocol, statistical code, and data set: Available from Dr. Meurin (e-mail, philippemeurin@hotmail.com).

Requests for Single Reprints: Philippe Meurin, MD, Les Grands Prés, 27 rue Sainte Christine, 77174 Villeneuve Saint Denis, France; e-mail, philippemeurin@hotmail.com.

Current Author Addresses: Drs. Meurin, Tabet, Renaud, Ben Driss, and Weber: Les Grands Prés, 27 rue Sainte Christine, 77174 Villeneuve Saint Denis, France.

Dr. Thabut: Service de pneumologie, Hôpital Bichat, 46 rue Huchard, 75018 Paris, France.

Drs. Cristofini and Iliou: Hôpital Broussais, 96 rue Didot, 75014 Paris, France.

Dr. Farrokhi: Hôpital Bligny, 91640 Briis-sous-Forges, France.

Dr. Fischbach: Château Lemoine, 70 Rue du Maréchal Galliéni, 33150 Cenon, France.

Dr. Pierre: IRIS, 271 Rue des Sources, 69280, Marcy l'étoile, France.

Author Contributions:Conception and design: P. Meurin, J.Y. Tabet, A. Ben Driss, M.C. Iliou, H. Weber.

Analysis and interpretation of the data: P. Meurin, J.Y. Tabet, G. Thabut, T. Farrokhi, M. Fischbach, B. Pierre, A. Ben Driss, H. Weber.

Drafting of the article: B. Pierre, A. Ben Driss, N. Renaud.

Critical revision of the article for important intellectual content: P. Meurin, J.Y. Tabet, G. Thabut, P. Cristofini, T. Farrokhi, M. Fischbach, B. Pierre, A. Ben Driss, M.C. Iliou, H. Weber.

Final approval of the article: P. Meurin, J.Y. Tabet, G. Thabut, P. Cristofini, M. Fischbach, B. Pierre, A. Ben Driss, M.C. Iliou, H. Weber.

Provision of study materials or patients: P. Meurin, J.Y. Tabet, P. Cristofini, M. Fischbach, B. Pierre, A. Ben Driss, M.C. Iliou, H. Weber.

Statistical expertise: J.Y. Tabet, G. Thabut, A. Ben Driss.

Administrative, technical, or logistic support: P. Meurin, P. Cristofini, T. Farrokhi, M. Fischbach, B. Pierre, A. Ben Driss, H. Weber.

Collection and assembly of data: P. Meurin, J.Y. Tabet, P. Cristofini, T. Farrokhi, M. Fischbach, B. Pierre, A. Ben Driss, N. Renaud, M.C. Iliou, H. Weber.


Ann Intern Med. 2010;152(3):137-143. doi:10.7326/0003-4819-152-3-201002020-00004
Text Size: A A A

Background: The incidence of asymptomatic pericardial effusion is high after cardiac surgery. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed in this setting, but no study has assessed their efficacy.

Objective: To assess whether the NSAID diclofenac is effective in reducing postoperative pericardial effusion volume.

Design: Multicenter randomized, double-blind, placebo-controlled study. (Clinical trials.gov registration number: NCT00247052)

Setting: 5 postoperative cardiac rehabilitation centers.

Patients: 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.

Intervention: Random assignment at each site in blocks of 4 to diclofenac, 50 mg, or placebo twice daily for 14 days.

Measurements: The main end point was change in effusion grade after 14 days of treatment. Secondary end points included frequency of late cardiac tamponade.

Results: 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.

Limitation: The sample was not large enough to find small beneficial effects of diclofenac or assess the cardiovascular tolerance of diclofenac.

Conclusion: In patients with pericardial effusion after cardiac surgery, diclofenac neither reduced the size of the effusions nor prevented late cardiac tamponade.

Primary Funding Source: French Society of Cardiology.

Figures

Grahic Jump Location
Figure.
Study flow diagram.

NSAID = nonsteroidal anti-inflammatory drug.

Grahic Jump Location

Tables

References

Letters

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Nonsteroidal Anti-inflammatory Drug Treatment for Postoperative Pericardial Effusion: A Multicenter Randomized, Double-Blind Trial
Posted on February 25, 2010
Amir Y. Shaikh
University of Massachusetts Medical School, Worcester, MA, USA
Conflict of Interest: None Declared

To The Editor: We appreciate Meurin and co-workers (1) initiative to assess the effectiveness of diclofenac to treat postoperative pericardial effusion. However before implying that physicians should stop prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) for postoperative pericardial effusion, some points should be considered. The first issue is the choice of NSAID. The 2004 European Society of Cardiology guidelines (2) suggest ibuprofen as the preferred NSAID for treatment of pericarditis because of its less detrimental side effect profile, favorable impact on coronary artery blood flow, and large dose range. For the prevention of postoperative pericardial effusion, diclofenac has been studied previously only in a single-center randomized prospective trial which demonstrated a favorable impact on the rate of significant pericardial effusion and C- reactive protein concentration in the diclofenac-treated group; however these differences were not statistically significant (3). The authors self-acknowledged that their study was underpowered to detect the beneficial effects of diclofenac. Hence, the abovementioned points suggest that before concluding that NSAIDS can play no role in management of postoperative pericardial effusion, use of ibuprofen and other NSAIDs should be subjected to study in adequately powered randomized controlled trials.

Another set of issues to consider is the dosing frequency, duration of treatment, and the time-interval between the surgery and initiation of NSAIDs. In the current study (1), the dose of diclofenac used was 50 mg twice daily. Considering that the half-life of diclofenac is 2 hours and the optimal serum drug concentration stays for 4 half lives, a dosing frequency of every 8 hours may have been more appropriate. The recommended maximal dose of this agent is a total daily dose of 150 mg. Treatment with a tapering dose of NSAIDs is recommended for weeks to months even after the disappearance of pericardial effusion (2). In the current study(1), the treatment duration of only 12.8 days may be expected to provide a lesser therapeutic effect and thus may have unfavorably impacted the primary endpoint. In addition, baseline echocardiography and initiation of diclofenac was done at a mean of 15.9 days postoperatively raising a concern if the treatment was significantly delayed rather than being initiated on day 7 postoperatively as per protocol. A median value of interval between the surgery and NSAID initiation would have answered the above concern excluding the outliers. Based on these considerations it would be inappropriate to conclude diclofenac failure without utilizing the maximum anti-inflammatory dosage, the optimal dosing frequency, optimal treatment duration, and timely initiation of the treatment.

Lastly, rather than stratifying the grades of pericardial effusion into localized or circumferential, the authors resulted the grades and localization separately (Table 2). The number of grade 4 effusions (23/98) and right atrial/ventricular loculated effusions (26/98) in the diclofenac group, even though statistically not significant, were higher than observed in the placebo group (14/98 and 17/98 respectively). Right-sided loculated effusions may lead to a higher incidence of cardiac tamponade as compared to effusions adjacent to the left heart chambers. Hence, it would be essential to know the percentage of grade 4 effusions that were right- sided and loculated as the results and implications may have been different. A statistically significant difference in patients with tamponade with baseline grade 3 pericardial effusions between the treatment and the placebo groups (Table 4) was observed but was not further discussed, thus raising a question of benefits of diclofenac in preventing tamponade in patients with baseline grade 3 postoperative pericardial effusions.

References

1. Meurin P, Tabet JY, Thabut G, Cristofini P, Farrokhi T, Fischbach M et al. Nonsteroidal anti-inflammatory drug treatment for postoperative pericardial effusion. Ann Intern Med 2010;152:137-143

2. Seferovi PM, Risti AD, Erbel R, Rienmeuller R, Adler Y, Tomkowski WZ et al. The Task Force on the diagnosis and management of pericardial diseases of the European Society of Cardiology. Guidelines on the diagnosis and management of pericardial diseases. European Heart Journal 2004;25:587-610

3. 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;43:449-453

Conflict of Interest:

None declared

Re:Nonsteroidal Anti-inflammatory Drug Treatment for Postoperative Pericardial Effusion: A Multicenter Randomized, Double-Blind Trial
Posted on March 15, 2010
Philippe Meurin
Les Grands Pres, Villeneuve Saint Denis 77174 France
Conflict of Interest: None Declared

It is very important not to mix up acute pericarditis, post pericardiotomy syndrome (which are clinical syndromes) and post operative pericardial effusions (POPEs) which are usually asymptomatic. In deed, this confusion is the reason why non steroidal anti inflammatory drugs (NSAIDs) have been frequently prescribed to treat POPEs. Indeed, if the European Society of Cardiology recommends Ibuprofen (1), this is to treat acute pericarditis (not POPEs) and if a long treatment duration is recommended, this is to prevent recurrences, not to help to reduce the volume of the effusions (which was the aim of our study) or to prevent the incidence of late tamponades (which usually occur before post operative day 30).In our study, the post study follow up clearly shows that a longer treatment would have been useless, as only 2 patients required pericardial drainage after the end of the treatment.

The choice of the drug and of its posology can be extensively discussed with multiple references; we chose diclofenac: a very classical and effective NSAID, and 100mg per day is a dose widely used in daily life practice and recommended in Guidelines as the cardiovascular risk of the drug dramatically increases at a higher dose (2).

It is wrong to say that we acknowledge the fact that our study was underpowered to detect beneficial effects of diclofenac; the sample size was calculated (172 patients) and largely reached(196 patients); we only suggested that the sample was not large enough to find small beneficial effects (i.e clinically useless in these asymptomatic patients) or to detect groups of patients in which this treatment could have been helpful (for instance patients with an important inflammatory syndrome).

It is wrong to say that a previous study demonstrated a favorable impact on the rate of significant pericardial effusion; this study (3), that was already quoted in our article, examined pericardial effusions prevention (not treatment) did not demonstrate anything: "there was no statistically significant difference in the size of post operative pericardial effusion..." and was largely underpowered. The echocardiographic classification that we used has the great advantage to help to predict the occurrence of a late tamponade in 2 large clinical studies (4.5), one of them being multicentric(5).

Finally, in a negative study as ours, it is useless and probably harmful to try to find very small post-specified subgroups in which the NSAID could seem to be effective. For instance, contrarily to what was suggested in Dr Shaikh's comments, right sided loculated effusions did not lead to a higher incidence of tamponade in our study.

In conclusion, medical history is filled with widely applied therapeutic habits that replicate longstanding practices based upon theories that have no true scientific background. Thus, challenging doctor' s lifelong habits may be good for their patients. Our study, which was properly designed and conducted, is, so far, the only one dedicated to post operative pericardial effusion treatment. It clearly shows the absence of effectiveness of an NSAID. Furthermore, we have no conflict of interest and would have been very happy to publish a positive study but scientific facts must be admitted.

References

1- Maisch B, Seferovic PM, Ristic AD, Erbel R, Rienmuller R, Adlery et al. Guidelines on the diagnosis and management of pericardial diseases. Full text. The task force on the diagnosis and management of pericardial diseases of the European Society of Cardiology.Eur. Heart J. 2004;25:587- 610.

2- Gislason GH, Jacobsen S, Rasmussen JN, Rasmussen S, Buch P, Friberg J et al. Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal anti- inflammatory drugs after acute myocardial infarction.Circulation 2006;113;2906-13.

3- 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. 2002;43:449-53.

4- Meurin P, Weber H, Renaud N, Larrazet F, Tabet JY , Demolis P et al. Evolution of the post operative pericardial effusion after day 15. The problem of the late tamponade.Chest 2004;125:2182-87

5. Meurin P, Tabet JY, Thabut G, Cristofini P, Farrokhi T, Fischbach M et al. Nonsteroidal anti-inflammatory drug treatment for postoperative pericardial effusion. Ann Intern Med 2010;152:137-143

to the editor: in the Shaikh's letter, European Guidelines are misquoted: the first author is Maisch, not Seferovic.

Conflict of Interest:

None declared

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Summary for Patients

Treating Postoperative Pericardial Effusion With Nonsteroidal Anti-inflammatory Drug Therapy

The summary below is from the full report titled “Nonsteroidal Anti-inflammatory Drug Treatment for Postoperative Pericardial Effusion. A Multicenter Randomized, Double-Blind Trial.” It is in the 2 February 2010 issue of Annals of Internal Medicine (volume 152, pages 137-143). The authors are P. Meurin, J.Y. Tabet, G. Thabut, P. Cristofini, T. Farrokhi, M. Fischbach, B. Pierre, A. Ben Driss, N. Renaud, M.C. Iliou, and H. Weber, for the French Society of Cardiology.

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