ICAP

Published

Imazio M, et al. "A Randomized Trial of Colchicine for Acute Pericarditis". The New England Journal of Medicine. 2013. 369(16):1522-1528.
PubMed • Full text • PDF

Clinical Question

In patients experiencing their first episode of acute pericarditis, does colchicine reduce the rate of incessant or recurrent pericarditis when compared placebo?

Bottom Line

In patients experiencing their first episode of acute pericarditis, the addition of colchicine to NSAID or glucocorticoid therapy significantly reduces the rate of incessant or recurrent pericarditis.

Major Points

Pericarditis therapies include NSAIDs, glucocorticoids, and colchicine, although few trials exist to guide their use. The unblinded COPE trial (2005) suggested colchicine's efficacy in the first episode of pericarditis. The blinded CORP trial (2011) demonstrated the benefit of colchicine in recurrent pericarditis. No blinded, large RCT using colchicine had been performed in individuals with their first episode of pericarditis, however.

The 2013 Investigation on Colchicine for Acute Pericarditis (ICAP) trial randomized 280 patients in Italy with their first episode of acute pericarditis not due to bacterial infection or malignancy to three months of colchicine or placebo; all patients also received NSAID or prednisone therapy. With a mean follow up of 1.9 years, the colchicine arm had a significant reduction in the primary outcome of incessant or recurrent pericarditis (16.7% vs. 37.5%), higher remission at one week (85.0% vs. 58.3%), and fewer hospitalizations (5.0% vs. 14.2%). Rates of adverse events were similar in both groups.

Treatment of colchicine-resistant, steroid-dependent recurrent pericarditis was evaluated in AIRTRIP (2016).

Guidelines

ESC Pericardial disease management (2015, adapted)

• Treatment for pericarditis:
  • Aspirin/NSAIDs plus adjunctive colchicine as first-line therapy (class I level A)
  • Corticosteroids are not recommended as first-line therapy (class III level C)
    • Low-dose corticosteroids can be considered if contraindication or failure of aspirin/NSAIDs and colchicine and if infection is excluded or if another indication (e.g., autoimmune disease) (class IIa level C)

Design

• Multicenter, randomized, double-blind, placebo-controlled study
• N=280
  • Colchicine (n=120)
  • Placebo (n=120)
• Setting: 5 centers in Italy
• Enrollment: 2005-2010
• Mean follow-up: 22.6 months
• Analysis: Intention-to-treat
• Primary outcome: Incessant or recurrent pericarditis

Population

Inclusion Criteria

• ≥18 years old
• First episode of acute pericarditis deemed idiopathic, viral, post-cardiac injury, or connective-tissue disease related
• ≥2 of the following:
  • Chest pain that is sharp and pleuritic in nature improved by sitting up and leaning forward
  • Pericardial friction rub
  • Widespread ST-segment elevation or PR depression on EKG
  • New or worsening pericardial effusion

Exclusion Criteria

• Tuberculous pericarditis
• Neoplastic pericarditis
• Purulent pericarditis
• Severe liver disease or aminotransferase levels ≥1.5x ULN
• Serum creatinine >2.5 mg/dL (>221 umol/L)
• Skeletal myopathy or CK >ULN
• Blood dyscrasia
• IBD
• Hypersensitivity to colchicine or other contraindication to its use
• Life expectancy ≤18 months
• Pregnancy or lactation
• Women of childbearing potential not using contraception
• Evidence of myopericarditis as evidenced by elevation in serum troponin

Baseline Characteristics

From the colchicine group.

• Demographics: Age 53.5 years, male 59.2%
• Etiology: Idiopathic 76.7%, post-cardiac injury 20.8%, connective tissue disease 2.5%
• Clinical findings: Pericardiac chest pain 100%, rub 36.7%, ST-elevation 29.2%, pericardial effusion 63.3% (large 2.5%), tamponade 1.7%, elevated CRP 70.8%
• Medications: ASA 71.7%, ibuprofen 20.0%, prednisone 8.3%

Interventions

• Randomization to:
  • Colchicine: Colchicine 1 mg PO daily for 3 months (if weight ≤70kg or symptoms, decrease to 0.5 mg PO daily)
  • Placebo
• All patients were treated with aspirin 800 mg or ibuprofen 600 mg PO q8h for 7-10 days with taper over the next month
• If NSAID contraindicated, prednisone was substituted at 0.2-0.5 mg/kg/day for 14 days with "gradual tapering"
• All patients were treated with a PPI

Outcomes

Comparisons are placebo vs. colchicine.

Primary Outcomes

Incessant or recurrent pericarditis

Incessant defined as persistent or a symptom-free interval <6 weeks

37.5% vs. 16.7% (P<0.001; NNT 5)

Secondary Outcomes

Persistent symptoms at 72 hours

40% vs. 19.2% (P=0.001; NNT 5)

Remission at 1 week

58.3% vs. 85.0% (P<0.001; NNT 4)

Incessant pericarditis

16.7% vs. 7.5% (P=0.046; NNT 11)

Recurrent pericarditis

20.8% vs. 9.2% (P=0.02; NNT 9)

Recurrences/patient: 0.52 vs. 0.21 (P=0.001)

Time to first recurrence: 17.7 vs. 24.7 weeks (P<0.001)

Cardiac tamponade

2.5% vs. 0% (P=0.25)

Constrictive pericarditis

0.8% vs. 0% (P=1.00)

Pericarditis-related hospitalization

14.2% vs. 5.0% (P=0.02; NNT 11)

Adverse Events

Any

10.0% vs. 11.7% (P=0.84)

Serious: 0% vs. 0%

Discontinuation: 8.3% vs. 11.7% (P=0.52)

GI disease: 8.3% vs. 9.2% (P=0.67)

Diarrhea, nausea, cramping, abdominal pain, or vomiting.

Hepatotoxicity: 0.8% vs. 1.7% (no statistics provided)

ALT or AST higher than reference range

Myotoxicity: 0% vs. 0%

Alopecia: 0.8% vs. 0.8%

Criticisms

• Unclear effectiveness in those with liver or renal dysfunction or those with elevated troponins
• Unclear effectiveness in bacterial and neoplasia-related pericarditis
• Given the location of trial, there may have been an unusual amount of familial mediterranean fever provoking autoinflammatory pericarditis. It's unclear to what extent this limits generalizability.

Funding

• Azienda Sanitaria Locale 3 of Turin
• Acarpia Pharmaceuticals