Description of the condition
Pericarditis is the inflammation of the pericardium, the membranous sac surrounding the heart. Acute pericarditis is idiopathic without an obvious aetiology in 80% to 90% of cases but has a presumed viral origin (Dudzinski 2012). Other causes include tuberculosis, or bacterial and neoplastic diseases that are more common in low-income countries (Zayas 1995).
Recurrent pericarditis is both the most common and most troublesome complication of acute pericarditis and is mostly idiopathic. This is because the exact cause of the recurrence of pericarditis is not known, but appears to be autoimmune as indicated by the presence of autoantibodies and response to steroids (Cantarini 2013). There are two types of recurrent pericarditis, intermittent or incessant. In the incessant type, discontinuation of non-steroidal anti-inflammatory therapy (NSAIDs) usually causes a relapse in less than six weeks. In the intermittent type, people have varying symptom-free intervals, usually longer than six weeks, without therapy (Soler-Soler 2004).
The actual incidence of acute pericarditis in unknown, but it is estimated to be 28 cases per 100,000 population/year (Imazio 2008a). It is responsible for 4% of all causes of chest pain (Launbjerg 1996) and 0.1% of all hospitalisations (Pölzl 2011). Recurrent pericarditis can occur in up to 20% to 30% of people who have experienced acute pericarditis (Fowler 1990; Adler 1998); this figure increases to 50% after the first recurrence (Imazio 2005a). The rate of recurrence varies and can be a single episode in some people; however, other people can experience more frequent episodes over many years. Almost 45% of people experience two episodes, 40% have between three and five episodes, and 10% have more than five episodes (Soler-Soler 2004; Shabetai 2005).
Presentation and diagnosis
The manifestation of acute pericarditis is a pleuritic chest pain with a sign or symptom marking the activity of the disease, such as fever, a pericardial rub, electrocardiography (ECG) changes (a widespread ST-segment elevation or PR-segment depression), pericardial effusion and raised inflammatory markers (erythrocyte sedimentation rate or C-reactive protein (CRP)) (Spodick 2003; Troughton 2004). Acute pericarditis is diagnosed if at least two of these manifestations are met (Dudzinski 2012).
Recurrent pericarditis is a repeat episode of acute pericarditis and can have similar symptoms, although it tends to be milder (Soler-Soler 2004; Adler 2011). There are no uniform diagnostic criteria for recurrent pericarditis (Imazio 2007); however, observational studies identified pleuritic chest pain, increased CRP and ECG changes as the minimum criteria for diagnosing a recurrent episode of acute pericarditis (Brucato 2006; Khandaker 2010).
The first relapse usually occurs within 18 months after the initial pericarditis episode (Imazio 2005; Imazio 2005a). However, people can have many relapses that manifest as severe chest pain lasting from several hours to several days. These painful and disabling episodes impair quality of life and cause a severe clinical problem (Soler-Soler 2004).
Acute and recurrent pericarditis can be complicated by life-threatening consequences, such as pericardial effusion, tamponade or constriction, which may increase mortality (Soler-Soler 2004; Dudzinski 2012). These complications can occur in up to 3.5% of people in recurrent pericarditis and even more frequently in people with acute pericarditis (Imazio 2007). However, in the long term, complications are rare and the prognosis of recurrent pericarditis is good (Brucato 2006).
Description of the intervention
Treatment aims to manage the acute episode of pericarditis and to then prevent subsequent recurrences. For a long time, high-dose steroids were the mainstay of treatment. Yet, high-dose steroids caused numerous serious adverse effects (Shabetai 2005), and their prolonged use has actually worsened the prognosis by increasing the recurrence rate of pericarditis and lengthening the course of the disease (Artom 2005; Imazio 2005; Imazio 2008). Therefore, identifying interventions with a safer adverse effect profiles was essential in order avoid worsening the natural course of recurrent pericarditis in other ways.
Episodes of pericarditis are currently treated with aspirin or other NSAIDs and with steroids for refractory cases (Maisch 2004; Soler-Soler 2004). Colchicine has been used for the prevention of recurrences (Brucato 2006a).
Colchicine has anti-inflammatory actions and antiproliferative effects (Robert 2009). It inhibits many of the functions of neutrophils, such as the adhesion to endothelium and the release of a chemotactic factor from neutrophil lysosomes (Nuki 2008).
Colchicine is considered a safe treatment (Imazio 2007); however, in high doses, it has many toxic effects and, in addition, it has a narrow therapeutic window (Robert 2009). The maximum therapeutic dose is 4 mg/24 hours, while a fatal dose can be as low as 7 mg/24 hours with a higher fatality rate if it the dose exceeds 0.5 mg/kg (Niel 2006; Finkelstein 2010). Overdose is associated with gastrointestinal, hepatic, renal, neuromuscular and cerebral toxicity; bone marrow damage; and high mortality (Nuki 2008; Finkelstein 2010). Colchicine is excreted mainly by the liver after 20 to 40 hours (Niel 2006) and can accumulate in people with advanced liver disease (Rudi 1994).
The recommended dose of colchicine used in gout and in recurrent pericarditis is 1 mg/day by oral administration (Adolph 1990; Adler 1998). Analgesia with colchicine is evident within 12 to 14 hours of oral administration (Imazio 2009). The most common adverse effects of the therapeutic dose are nausea, vomiting, diarrhoea and abdominal pain (Niel 2006).
How the intervention might work
Colchicine is used in treating several inflammatory diseases such as gout and familial Mediterranean fever (FMF) (Famaey 1988; Niel 2006). Considering the possible autoimmune inflammatory pathophysiology of recurrent pericarditis (Caforio 2010; Cantarini 2013), and its response to immunosuppressive and anti-inflammatory treatment (Marcolongo 1995), it is deemed acceptable and logical to determine the effects of colchicine in the management of recurrent pericarditis.
Why it is important to do this review
People with recurrent pericarditis can have a number of relapses over many years causing severe chest pain. These episodes of pain limit both the functionality of patients and their quality of life causing both a social and psychological burden for the patients and an economical burden on the hospitals taking care of them (Soler-Soler 2004). The high incidence of recurrent pericarditis in almost one-third of patients with acute pericarditis increases this burden. Therefore, there is a need to find and examine therapies that decrease the number of recurrences.
Observational studies have shown that colchicine might be effective in treating recurrent pericarditis (Rodríguez de la Serna 1987; Guindo 1990; Millaire 1994; Soler-Soler 2004; Imazio 2005; Brucato 2006a). However, randomised controlled trials have only recently studied the effect of colchicine on pericarditis. Therefore, there is a need to systematically assess and critically appraise these trials in order to obtain a more definite clinical answer for both patients and clinicians dealing with recurrent pericarditis.
A similar review has been published in the BMJ Heart journal (Imazio 2012). The main differences in our review are that we will not include postcardiac injury syndromes due to the different aetiology and pathophysiology from acute or recurrent pericarditis. In addition, trials of acute pericarditis will be analysed separately from trials of recurrent pericarditis. Any differences between our review and the Heart journal review will be mentioned explicitly in the full review in the section 'Agreements and disagreements with other studies or reviews'.