Pericarditis is probably the most common form of pericardial disease. The management of pericardial diseases is primarily based on expert opinion, but recently, clinical trials have been planned and realized to test specific therapeutic questions. The main questions addressed include: 1) is colchicine efficacious and safe for the treatment and prevention of pericarditis; 2) is colchicine or diclofenac efficacious for the treatment of postoperative effusions; 3) is adjunctive steroid therapy efficacious and safe for the treatment of tuberculous pericarditis and prevention of constrictive pericarditis? The aim of this Expert Analysis article is to summarize the clinical implications of the multicenter trials in pericarditis.

Clinical Trials on Colchicine for Pericarditis

Colchicine has been traditionally administered for the treatment and prevention of gouty attacks for centuries. More recently, following its efficacy and safety in the treatment and prevention of attacks of poliserositis in familial Mediterranean fever (FMF), the drug has been adopted for the treatment and prevention of recurrences of pericarditis.¹ The first randomized trial was a single-centre, open-label, randomized trial (COlchicine for acute PEricarditis [COPE] trial) published in 2005.² A total of 120 patients (mean age 56.9+/-18.8 years, 54 males) with a first episode of acute pericarditis (idiopathic, viral, post-pericardiotomy syndromes, and connective tissue diseases) were randomly assigned to conventional treatment with aspirin (group I) or conventional treatment plus colchicine 1.0 to 2.0 mg for the first day and then 0.5 to 1.0 mg/d for three months (group II). Corticosteroid therapy was restricted to patients with aspirin contraindications or intolerance. The primary end point was recurrence rate. During the 2873 patient-month follow-up, colchicine significantly reduced the recurrence rate (recurrence rates at 18 months were, respectively, 10.7% vs. 32.3%; P = 0.004; number needed to treat [NNT] = 5) and symptom persistence at 72 hours (respectively, 11.7% vs. 36.7%; P = 0.003). After multivariate analysis, corticosteroid use (odds ratio [OR] 4.30, 95% confidence interval [CI] 1.21 to 15.25; P = 0.024) was an independent risk factor for recurrences. Colchicine was discontinued in five cases (8.3%) because of diarrhea. No serious adverse effects were observed. A subsequent multicenter, double-blind, randomized trial (ICAP trial) has more recently confirmed these findings.³ The ICAP trial was a multicenter, double-blind trial in which eligible adults with acute pericarditis were randomly assigned to receive either colchicine (at a dose of 0.5 mg twice daily for three months for patients weighing >70 kg or 0.5 mg once daily for patients weighing ≤70 kg) or placebo in addition to conventional anti-inflammatory therapy with aspirin or ibuprofen. The primary study outcome was incessant or recurrent pericarditis. A total of 240 patients were enrolled, and 120 were randomly assigned to each of the two study groups. The primary outcome occurred in 20 patients (16.7%) in the colchicine group and 45 patients (37.5%) in the placebo group (relative risk reduction in the colchicine group, 0.56; 95% CI, 0.30 to 0.72; NNT = 4; P <0.001). Colchicine reduced the rate of symptom persistence at 72 hours (19.2% vs. 40.0%, P = 0.001), the number of recurrences per patient (0.21 vs. 0.52, P = 0.001), and the hospitalization rate (5.0% vs. 14.2%, P = 0.02). Colchicine also improved the remission rate at one week (85.0% vs. 58.3%, P <0.001). Overall adverse effects and rates of study-drug discontinuation were similar in the two study groups. No serious adverse events were observed.

Similar efficacy and safety has also been demonstrated for patients with a first recurrence of pericarditis^4,5 or multiple recurrences.⁶ Taken together, these data (Tables 1 and 2) indicate that colchicine should be considered as a first choice in adjunct to conventional anti-inflammatory therapy for pericarditis in order to hasten the response to medical therapy and reduce the recurrence risk. The drug is safe when administered at the recommended doses and should be given without a loading dose in order to improve adherence (e.g., 0.5 mg twice daily for patients of >70 kg and 0.5 mg once daily if patients <70 kg). The proposed treatment length is three months for acute pericarditis and six months for recurrences. The most common side effect is diarrhea reported in 5-10% of cases and reversible with dose reduction of drug withdrawal. The main contraindication to colchicine is severe renal or hepatic impairment or hypersensitivity to colchicine. In the absence of a compelling indication (e.g., FMF), the drug should be avoided during pregnancy. Dose adjustment (halving the dose) should be considered for the elderly and children and with concomitant use of a P-glycoprotein (P-gp) or strong CYP3A4 inhibitor. Colchicine is contraindicated in case of concomitant use of a P-glycoprotein (P-gp) or strong CYP3A4 inhibitor in presence of renal or hepatic impairment.

Table 1: Main Features of Recent Clinical Trials for the Treatment of Acute and Recurrent Pericarditis

Study	Setting	Patients	Intervention	Main result
ICAP 2013°	Acute pericarditis	240	placebo or colchicine* (at a dose of 0.5 mg twice daily for three months for patients weighing >70 kg or 0.5 mg once daily for patients weighing ≤70 kg).	Reduction by 56% of the risk of incessant or recurrent pericarditis in the colchicine group at 18 months.
CORP 2011	First recurrence	120	placebo or colchicine*, 1.0 to 2.0 mg on the first day followed by a maintenance dose of 0.5 to 1.0 mg/d, for 6 months.	Reduction by 56% of the risk of recurrent pericarditis in the colchicine group at 18 months.
CORP-2 2014°	Multiple recurrences	240	placebo or colchicine* (at a dose of 0.5 mg twice daily for six months for patients weighing >70 kg or 0.5 mg once daily for patients weighing ≤70 kg).	Reduction by 49% of the risk of recurrent pericarditis in the colchicine group at 18 months.
COPPS 2010	Postoperative prevention of PPS (from postoperative day 3)	360	placebo or colchicine (1.0 mg twice daily for the first day followed by a maintenance dose of 0.5 mg twice daily for one month in patients ≥70 kg, and halved doses for patients <70 kg or intolerant to the highest dose).	Reduction by 58% of the risk of developing PPS at 12 months.
COPPS-2 2014°	Preoperative prevention of PPS (from 48 to 72 hours before cardiac surgery)		placebo or colchicine (0.5 mg twice daily in patients ≥70 kg or 0.5 mg once daily in patients <70 kg) starting between 48 and 72 hours before surgery and continued for one month after surgery.	Reduction by 34% of the risk of developing PPS at three months.

Table 2: Recommendations on the Use of Colchicine for Acute and Recurrent Pericarditis

Indication	Dosing	Loading Dose	Treatment Duration	Recommendation
Acute pericarditis	0.5 mg twice daily for patients weighing >70 kg or 0.5 mg once daily for patients weighing ≤70 kg	No	3 months	Class I, LOE A
First recurrence	0.5 mg twice daily for patients weighing >70 kg or 0.5 mg once daily for patients weighing ≤70 kg	No	6 months	Class I, LOE A
Multiple recurrences	0.5 mg twice daily for patients weighing >70 kg or 0.5 mg once daily for patients weighing ≤70 kg	No	6 months	Class I, LOE A

Clinical Trials on Colchicine for Postoperative Complications

Colchicine use has also been suggested for the prevention of the post-pericardiotomy syndrome. In the COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS) trial,⁸ on the third postoperative day, 360 patients (mean age 65.7 ± 12.3 years, 66% males), 180 in each treatment arm, were randomized to receive placebo or colchicine (1.0 mg twice daily for the first day followed by a maintenance dose of 0.5 mg twice daily for one month in patients ≥70 kg, and halved doses for patients <70 kg or intolerant to the highest dose). The primary efficacy endpoint was the incidence of PPS at 12 months. Secondary endpoint was the combined rate of disease-related hospitalization, cardiac tamponade, constrictive pericarditis, and relapses. Baseline characteristics were well balanced between the study groups. Colchicine significantly reduced the incidence of the PPS at 12 months compared with placebo (respectively, 8.9 vs. 21.1%; P = 0.002; NNT = 8). Colchicine also reduced the secondary endpoint (respectively, 0.6 vs. 5.0%; P = 0.024). The rate of side effects (mainly related to gastrointestinal intolerance) was similar in the colchicine and placebo groups (respectively, 8.9 vs. 5.0%; P = 0.212). These results were also confirmed in the COPPS-2 trial⁹ when colchicine was given before surgery. The main differences between the two trials were: 1) colchicine was given without a loading dose in COPPS-2, 2) in COPPS-2, colchicine was provided 48 to 72 hours before surgery in order to better prevent postoperative atrial fibrillation (POAF); 3) in COPPS-2, colchicine did not prevent POAF and postoperative effusions as in the COPPS¹⁰ because of an increased risk of gastrointestinal side effects and drug withdrawal that can be explained with the possible interaction with other perioperative drugs (e.g., proton pump inhibitors, antibiotics) that could have similar gastrointestinal side effects.

Similar negative results were showed in the Post-Operative Pericardial Effusion (POPE-2) trial presented at the 2014 European Society of Cardiology (ESC) Congress; colchicine did not reduce late postoperative effusions. Negative results were also reported for the use of diclofenac in the POPE trial.¹¹ In the POPE trial, 96 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 seven days after cardiac surgery were randomly assigned to diclofenac, 50 mg, or placebo twice daily for 14 days in five postoperative cardiac rehabilitation centers. In this trial, diclofenac neither reduced the size of the effusions nor prevented late cardiac tamponade.¹¹

Clinical Trials for Tuberculous Pericarditis

Tuberculous pericarditis is the most common cause of pericardial diseases in countries with a high prevalence of tuberculosis. In the recently published Investigation of the Management of Pericarditis (IMPI) trial,¹² the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy were evaluated in patients with tuberculous pericarditis. Using a 2-by-2 factorial design, 1,400 adults with definite or probable tuberculous pericarditis were randomized to either prednisolone or placebo for six weeks and to either M. indicus pranii or placebo, administered in five injections over the course of three months. Two-thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio [HR], 0.95; 95% CI, 0.77 to 1.18; P = 0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; HR, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; HR, 0.56; 95% CI, 0.36 to 0.87; P = 0.009) and hospitalization (20.7% vs. 25.2%; HR, 0.79; 95% CI, 0.63 to 0.99; P = 0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; HR, 3.27; 95% CI, 1.07 to 10.03; P = 0.03, and 1.8% vs. 0.5%; HR, 3.69; 95% CI, 1.03 to 13.24; P = 0.03, respectively), owing mainly to an increase in HIV-associated cancer.¹²

Clinical Implications

Colchicine has been demonstrated to be a first-line adjunctive drug for the treatment and prevention of pericarditis in the absence of contraindications (Level of Evidence A). In the perioperative setting, colchicine may prevent the post-pericardiotomy syndrome, but preoperative use may be characterized by an increased risk of gastrointestinal side effects. Adjunctive steroids may reduce the risk of constrictive pericarditis in tuberculous pericarditis, but increased risk of HIV-associated cancer limit its applicability to patients without HIV-infection.

References

1. Imazio M, Brucato A, Trinchero R, Spodick D, Adler Y. Colchicine for pericarditis: hype or hope? Eur Heart J 2009;30:532-9.
2. Imazio M, Bobbio M, Cecchi E, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation 2005;112:2012-6.
3. Imazio M, Brucato A, Cemin R, et al. A randomized trial of colchicine for acute pericarditis. N Engl J Med 2013;369:1522-8.
4. Imazio M, Bobbio M, Cecchi E, et al. Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Arch Intern Med 2005;165:1987-91.
5. Imazio M, Brucato A, Cemin R, et al. Colchicine for recurrent pericarditis (CORP): a randomized trial. Ann Intern Med 2011;155:409-14.
6. Imazio M, Belli R, Brucato A, et al. Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial. Lancet 2014;383:2232-7.
7. Finkelstein Y, Shemesh J, Mahlab K, et al. Colchicine for the prevention of postpericardiotomy syndrome. Herz 2002;27:791-4.
8. Imazio M, Trinchero R, Brucato A, et al. COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial. Eur Heart J 2010;31:2749-54.
9. Imazio M, Brucato A, Ferrazzi P, et al. Colchicine for prevention of postpericardiotomy syndrome and postoperative atrial fibrillation: the COPPS-2 randomized clinical trial. JAMA 2014;312:1016-23.
10. Imazio M, Brucato A, Ferrazzi P, et al. Colchicine reduces postoperative atrial fibrillation: results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) atrial fibrillation substudy. Circulation 2011;124:2290-5.
11. Meurin P, Tabet JY, Thabut G, et al. Nonsteroidal anti-inflammatory drug treatment for postoperative pericardial effusion: a multicenter randomized, double-blind trial. Ann Intern Med 2010;152:137-43.
12. Mayosi BM, Ntsekhe M, Bosch J, et al. Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis. N Engl J Med 2014;371:1121-30.

Keywords: Adrenal Cortex Hormones, Anti-Bacterial Agents, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Atrial Fibrillation, Cardiac Surgical Procedures, Cardiac Tamponade, Colchicine, Connective Tissue Diseases, Diarrhea, Diclofenac, Double-Blind Method, Echocardiography, Familial Mediterranean Fever, HIV Infections, Ibuprofen, Immunotherapy, Incidence, Longitudinal Studies, Multivariate Analysis, Mycobacterium, ATP Binding Cassette Transporter, Subfamily B, Member 1, Pericardial Effusion, Pericardiectomy, Pericardiocentesis, Pericarditis, Pericarditis, Constrictive, Pericarditis, Tuberculous, Phosphatidylethanolamines, Postpericardiotomy Syndrome, Prednisolone, Pregnancy, Prevalence, Proton Pump Inhibitors, Recurrence, Rehabilitation Centers, Risk, Risk Factors

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