Introduction
Colchicine, extracted from the colchicum autumnale plant, is one of the most ancient anti-inflammatory medications still used nowadays. Its major mechanism of action relies on inhibition of tubulin polymerization and of the inflammasome. Despite its potential gastro-intestinal side effects, colchicine is a safe anti-inflammatory medication that has traditionally been used for the treatment of gout and Familial Mediterranean Fever (FMF). It has recently been shown to reduce the risk of ischemic cardiovascular events in patients with coronary artery disease. In the context of pericardium-related diseases, colchicine has proven useful in the setting of acute and recurrent pericarditis. Its impact on constrictive pericarditis and post-pericardiotomy syndrome remains to be clarified. This expert review will provide an overview of the major available data with regards to the use of colchicine for the treatment of pericardial diseases. These data are summarized in Table 1.

Table 1

Study	Year of Publication	Sample size and indication	Design	Intervention	Endpoints	Main results
COPE	2005	N=120 with a first episode of acute pericarditis (idiopathic, viral, PPS, and connective tissue diseases)	Prospective, randomized, open-label design	Aspirin vs. Aspirin + colchicine (1.0 to 2.0 mg for the first day as a loading dose, followed by 0.5 to 1.0 mg/d for 3 months) Corticosteroids were used in patients with aspirin contraindications or intolerance	The primary end point was recurrence rate at 18 months	Colchicine (on top of standard therapy with Aspirin) significantly reduced the recurrence rate compared to Aspirin alone (recurrence rates at 18 months were, respectively, 10.7% vs. 32.3%; P=0.004; number needed to treat of 5) Colchicine (vs. Placebo) also symptom persistence at 72 hours (respectively, 11.7% versus 36.7%; P=0.003)
ICAP	2013	N=240 with acute pericarditis	Multicenter, double-blind trial	Colchicine (at a dose of 0.5 mg twice daily for 3 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 at 18 months	Colchicine reduced the risk of recurrent pericarditis at 18 months compared to placebo (16.7% vs 37.5%, P<0.001, number needed to treat of 4 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)
CORE	2005	N=84 with a first episode of recurrent pericarditis	Prospective, randomized, open-label trial	Conventional treatment with aspirin alone vs. conventional treatment + colchicine (1.0-2.0 mg the first day and then 0.5-1.0 mg/d for 6 months) Corticosteroids were used in patients with aspirin contraindications or intolerance	The primary end point was the recurrence rate	Colchicine significantly decreased the recurrence rate at 18 months: 24.0% vs 50.6%; P = 0.02; number needed to treat = 4.0; Colchicine also reduced symptom persistence at 72 hours (10% vs 31%; P = 0.03)
CORP	2011	N=120 with a first recurrence of pericarditis	Double-blind, placebo-controlled and multi-center trial	In addition to conventional treatment, patients were randomly assigned to receive either 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	The primary study end point was the recurrence rate at 18 months	At 18 months, the recurrence rate was 24% in the colchicine group and 55% in the placebo group, relative risk reduction, 0.56 (95% CI, 0.27 to 0.73), number needed to treat of 3
CORP- 2	2014	N=360 adult patients with multiple recurrences of pericarditis (≥2)	Prospective, randomized, double-blind, placebo-controlled multicenter trial	Colchicine (0.5 mg twice daily for 6 months for patients weighing more than 70 kg or 0.5 mg once daily for patients weighing 70 kg or less) in addition to conventional anti-inflammatory treatment with aspirin, ibuprofen, or indomethacin	The primary outcome was recurrent pericarditis in the intention-to-treat population	Colchicine was more effective than placebo in preventing recurrent episodes of pericarditis, relative risk 0.49; 95% CI 0.24-0.65; P=0.0009 and number needed to treat of 5
COPPS	2010	N=360 enrolled on day 3 post cardiac surgery	Multicentre, double-blind, randomized trial	Placebo vs. colchicine (1.0 mg twice daily for the first day followed by a maintenance dose of 0.5 mg twice daily for 1 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	Colchicine significantly reduced the incidence of the PPS at 12 months compared with placebo respectively, 8.9 vs. 21.1%; P = 0.002; number needed to treat of 8
COPPS-2	2014	N=360 consecutive candidates for cardiac surgery enrolled	Double-blind, placebo-controlled multi-center trial	Placebo vs. 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 1 month after surgery	The primary efficacy endpoint was the occurrence of PPS within 3 months	Colchicine was associated with reduction of PPS compared to placebo, 19.4% and 29.4% respectively, number needed to treat of 10

Colchicine Profile
Colchicine is a lipid-soluble drug. It is characterized by a bioavailability of 44%, a peak plasma concentration reached one hour after oral intake, CYP3A4-related metabolism, and predominant excretion by the liver (only 10-20% being excreted by the kidneys). Colchicine should not be administered chronically in patients with an estimated glomerular filtration rate less than 30 ml/min/1.73 m² or during treatment with a powerful CYP3A4 inhibitor. It exerts its anti-inflammatory action through binding to tubulin and inhibition of microtubule polymerization leading to reduced inflammasome activation and blunted pro-inflammatory cytokine release. Colchicine concentrates preferentially in white blood cells, thus resulting in anti-inflammatory effects at low doses. Colchicine's mechanism of action is summarized in Figure 1.

Figure 1

Acute and Recurrent Pericarditis
The benefit of colchicine is well established in acute viral or idiopathic pericarditis as well as in recurrent pericarditis. The COPE (COlchicine for acute PEricarditis) prospective, randomized, open-label trial, which included patients with a first episode of acute pericarditis, showed that colchicine, in addition to conventional anti-inflammatory therapy, significantly reduced symptoms at 72 hours (11.7% vs. 36.7%; p=0.003).¹ In addition, the recurrences of pericarditis at 18 months were significantly less frequent in patients under colchicine when compared to placebo (10.7% vs. 32.3%, respectively; p=0.004 and number needed to treat (NNT) to prevent one recurrence = 5).¹

The ICAP (Investigation on Colchicine for Acute Pericarditis) trial was a randomized, double-blind trial comparing the effects of colchicine versus placebo in patients with a first episode of acute pericarditis.² In the ICAP trial, colchicine reduced the risk of recurrent pericarditis at 18 months compared to placebo (16.7% vs. 37.5%, P<0.001 with relative risk reduction of 0.56; and 95% confidence interval (CI), 0.30 to 0.72), NNT of 4. Colchicine also 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 number of hospitalizations (5.0% vs. 14.2%, p=0.02) versus placebo.²

The CORE (COlchicine for REcurrent Pericarditis) study was an open-label prospective trial in which patients with a first recurrence of acute pericarditis were randomized to receive either aspirin alone or aspirin plus colchicine (1 mg per day) for 6 months.³ The association of aspirin plus colchicine demonstrated a significant reduction in the rate of recurrent events at 18 months compared with aspirin alone (24.0% vs. 50.6% respectively, p=0.02) after a mean follow-up of 20 months.³

The Colchicine for Recurrent Pericarditis (CORP) study was a multi-center controlled randomized trial involving 120 patients with recurrent pericarditis, in which the association of colchicine plus aspirin/non-steroidal anti-inflammatory drugs (NSAIDs) showed a significant reduction in recurrent events at 18 months in comparison with aspirin/NSAIDs alone (relative risk reduction, 0.56 (95% CI, 0.27 to 0.73); NNT=3).⁴ In addition, colchicine reduced the persistence of symptoms at 72 hours (relative risk reduction, 0.56 (CI, 0.27 to 0.74); increased the remission rate at 1 week, and prolonged the time to subsequent recurrence.⁴

Finally, the CORP-2 (Efficacy and Safety of Colchicine for Treatment of Multiple Recurrences of Pericarditis) trial investigated the effects of colchicine on top of conventional anti-inflammatory therapy for recurrent pericarditis, and demonstrated that, in patients with two or more episodes of recurrences, the addition of colchicine to aspirin/NSAIDs was more effective than aspirin/NSAIDs alone in preventing future episodes (relative risk 0.49; 95% CI 0.24-0.65; p=0.0009).⁵

Postpericardiotomy Syndrome
Postpericardiotomy syndrome (PPS) has been described in up to 40% of patients after cardiac surgery, and may develop within days or months after pericardial injury. The role of colchicine in PPS has been tested in the COPPS (COlchicine for the Prevention of the Post-pericardiotomy Syndrome) study, a double-blind, multi-center, randomized, placebo-controlled trial, where one month of colchicine therapy (started on day 3 after surgery) demonstrated a significant reduction in the incidence of PPS at 12 months compared with placebo (8.9 vs. 21.1%, respectively, p=0.002; NNT=8) without significant side effects.⁶

The COPPS-2 (COlchicine for prevention of the Post-pericardiotomy Syndrome and Post-operative Atrial Fibrillation) study had a design similar to that of COPPS except that colchicine was started 48-72 hours prior to the index cardiac surgery and was continued for a total of one month after surgery.⁷ In COPPS-2, preventive colchicine therapy was associated with a significant reduction in the incidence of PPS compared to placebo (19.4% and 29.4% respectively, 95% CI, 1.1%-18.7%; NNT = 10).⁷ Notably, there were no significant differences between colchicine and placebo for the secondary endpoints of post-operative atrial fibrillation (33.9% vs. 41.7%, respectively) or post-operative pericardial/pleural effusion (57.2% vs. 58.9%, respectively).⁷

Myopericarditis and Constrictive Pericarditis
There is no clearly demonstrated role for colchicine in cases of pericarditis with myocardial involvement, nor in the chronic calcific stage of constrictive pericarditis.⁸ Empiric use of colchicine could be considered in the setting of transient constriction accompanying acute pericarditis when there is concomitant evidence of systemic and/or pericardial inflammation including evidence of elevated inflammatory biomarkers (hs-CRP) or evidence of pericardial enhancement on cardiac imaging.⁸

Guidelines
The most recent guidelines from the European Society of Cardiology on the management of acute pericarditis recommend the use of colchicine as first-line therapy to improve the response to medical treatment and prevent recurrences.⁸ Colchicine (0.5 mg once daily in patients <70 kg or 0.5 mg BID in those ≥70 kg) is recommended for 3 months as an adjunct to aspirin/NDSAIDs therapy (Class I recommendation - Level of evidence A). Colchicine treatment for 6 months is recommended for recurrent pericarditis, with aspirin or NSAIDs administered until symptom relief (Class I recommendation - Level of evidence A). Colchicine has received a Class IIa recommendation - Level of evidence B for the management and prevention of PPS such that it should be considered for 1 month after cardiac surgery using weight-adjusted doses in the absence of contraindications. Finally, empiric anti-inflammatory therapy in the setting of transient or new diagnosis of constriction with concomitant evidence of pericardial inflammation has received a Class IIb recommendation - Level of evidence C.⁸

Conclusion
Colchicine is clearly efficacious for the treatment and prevention of acute and recurrent pericarditis and represents the cornerstone of therapy of these pericardial diseases. The safety and tolerability of colchicine has been demonstrated in large randomized cardiovascular trials.

References

1. 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.
2. Imazio M, Brucato A, Cemin R, et al. A randomized trial of colchicine for acute pericarditis. N Engl J Med 2013;369:1522-8.
3. 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.
4. Imazio M, Brucato A, Cemin R, et al. Colchicine for recurrent pericarditis (CORP): a randomized trial. Ann Intern Med 2011;155:409-14.
5. 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.
6. 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.
7. 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.
8. Adler Y, Charron P, Imazio M, et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The task force for the diagnosis and management of pericardial diseases of the European Society of Cardiology (ESC) Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2015;36:2921-64.

Clinical Topics: Pericardial Disease

Keywords: Colchicine, Pericarditis, Pericardium, Anti-Inflammatory Agents, Inflammation, Pericarditis, Constrictive, Aspirin

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