In this review we examined an amount of 361 studies from 1977 to 2016. Of these studies we considered only 7 randomized controlled trials, including trials regarding PPS and pleural effusion after heart surgery. 5 of them were double blind multicenter randomized trials [8, 9, 10, 11], 1 was a triple blind multicenter randomized trial [12], 1 was a single center randomized trial. Follow up period was from 1 to 12 months. Only five patients got lost during the follow up of all studies. The groups did not differ in clinical characteristics and type of surgery.
The indication for pharmacological therapy was dependent upon PPS and postoperative pericardial effusion.
The seven prospective studies from 2002 to 2015 included 1677 patients (mean age 60,8, male 67,4 %). Control group received placebo. The weight–adjusted colchicine dosage was 0.5 mg in three studies and 1 mg in two studies. The duration of colchicine treatment was between 14 days and 30 days. It was started 48–72 hours before surgery [10], on 3rd postoperative day [8, 9], on day 7, 30 [11] and 3 weeks after heart surgery [12].
Indomethacin dosage was 25 mg 3 times/day for 3 days before surgery. Treatment duration lasted for six weeks after operation.
Dexamethasone dosage was 1 mg/Kg i.v. as a single intraoperative bolus.
Main Outcomes
Primary endpoints were related to reduction of pericardial and pleural effusion in all the studies examined, while there was no homogeneity with secondary endpoints in the study groups.
In Forest and Funnel plot statistical analysis upon primary endpoints was reported an overall effect size only in two studies (Fig. 1A, Fig. 1B).
Forest and Funnel plot for secondary endpoints demonstrated non significant effect size depending also on the heterogeneity of the pathologies involved (Fig. 2A, Fig. 2B).
Adverse effects contemplated gastrointestinal intolerance (GI), allergic reactions (AR), renal failure (RF), pancreatitis (PR), hepatotoxicity (HT), alopecia (AP), leucopenia (LP). Adverse effects ranged from 7–20%. Even in Adverse effects forest plot analysis doesn’t mean an homogeneity of demographics (Fig. 3).
Finkelstein et al., COPPS 2010 study, Copps 2014 study (all three studies referred to colchicine) and Inan et al. (Indomethacine) reported as results a reduction of PPS and PE, but POPE − 2 2015, Amoli et al. study and Bunge et al. (Dexamethasone) registered no reduction of PPS or PE.
In particular, Finkelstein et al. reported a prospective, randomized, double-blind design in which they demonstrated a better outcome for patients undergoing colchicine treatment [95% CI -0,86 (-1,96, 0,25)].
COOPS study reported a significant reduction of the incidence of the PPS at 12 months compared with placebo [95% CI -1,01 (-1.635 ,-0.383)] and the secondary endpoint including hospitalization, cardiac tamponade, constrictive pericarditis, and relapses at 18 months [95% CI -0,04 (-0,25, 0,17)]. The rates of side effects and drug withdrawal were similar in the colchicine and placebo groups although colchicine showed a trend towards an increased rate of both events. No severe side effects were recorded [95% CI 0,24 (0,03,0,44)].
In COOPS-2 trial a significant reduction of incidence of PPS was reported [95% CI -0,55 (-1,04, -0,06)]. As secondary endpoints only incidence of atrial fibrillation was sensibly reduced compared with the control group. No significant differences were recorded between the two groups [ 95% CI -0,04 (-0,25, 0,17)]. Adverse effects were more common in the Colchicine group, especially due to gastrointestinal events [95% CI 0,13 (-0,08, 0,34)].
In POPE- 2 investigation there was no difference between Colchicine group and control group [ 95% CI -0,38 (-1,00, 0,24)] for the incidence of PPS. Secondary endpoints were similar in two groups [ 95% CI 0,09 (-0,19, 0,37)].
In Amoli et al. trial no differences between the study groups were registered as primary endpoints [95% CI 0,36 (-0,30, 1,02)] and secondary endpoints [95% CI 0,02 (-0,30, 0,34)].
Inan et al. explored indomethacin effect on pericardial effusion when administered 7 days before surgery. Medication continued for six weeks after operation. We quote this study for its statistical features similar to the other in this review, but its low number of patients is a limit for a statistical comparison with other studies with a high number of patients enrolled. It is worth mentioning that during hospitalization and follow-up a significant positive difference was registered between the Indomethacin group and control group.
Bunge et al. trial compared 1 mg/kg single dose intraoperative dexamethasone with placebo group. No significant statistical data was recorded for primary prophylaxis on PPS [95% CI 0,50 (0,12, 0,88)]. Also for secondary endpoints there was no statistical significance [95% CI -0,03 (-0,18, 0,12)].
Finkelstein et al., COPPS 2010 study, Copps 2014 study (all three studies referred to colchicine) and Inan et al. (Indomethacin) reported as results a reduction of PPS and PE, but POPE − 2 2015, Amoli et al. study and Bunge et al. (Dexamethasone) registered no reduction of PPS or PE.
In Table 5 are reported characteristics of population study in order to potentially explore factors reducing or increasing the number of events. The analysis failed to show any significant triggering factor.
Instead, pre-operative pericardial effusion was identified as a factor able to impact on studies outcome. Indeed, in Table 6, between the different characteristics analyzed and reported, none of the other factors, despite pre-operative PE, have achieved an association with the heterogeneity between studies.