Description of the condition
Cardiovascular disease (CVD) is the leading cause of death worldwide (WHO 2011). CVD is a class of diseases that affect the heart and blood vessels. CVD includes coronary heart disease and cerebrovascular disease, both diseases of the blood vessels supplying the heart or brain with oxygenated blood. One important pathophysiologic mechanism of CVD is the development of atherosclerotic lesions, so called 'plaques' (Libby 2013; Shah 2003; Shah 2009). These lesions may cause chronic ischemia and subsequent organ damage leading, for example, to heart failure. However, such plaques may also rupture and cause acute thrombotic events such as myocardial infarctions or strokes (Libby 2013; Shah 2003; Shah 2009). The mechanisms leading to destabilization of atherosclerotic plaques and subsequent rupture are not completely understood, but inflammatory processes seem to play an important role (Libby 2013; Shah 2009). This is based on observations that inflammatory cells concentrate at ruptured plaques (Carr 1997; Libby 2013), and there is strong evidence that raised blood levels of inflammatory markers (C-reactive protein) are associated with increased risk of coronary events (Emerging Risk Factors Collaboration 2010).
Description of the intervention
Colchicine is a very old, inexpensive drug with strong anti-inflammatory effects (Niel 2006; Terkeltaub 2009). Extracts from autumn crocus (Colchicum autumnale) have been used for centuries to treat acute gout (Cocco 2010; Rodnan 1970; Terkeltaub 2009). In the 18th century, an alkaloid was identified as the active pharmaceutical ingredient of this plant, which became known as colchicine and which since then has been widely used for treatment of gout (Rodnan 1970; Schlesinger 2004).
In addition to gout, colchicine is also used for treatment of several other diseases, including familial Mediterranean fever (FMF), Behçet's disease, primary biliary cirrhosis, and pericarditis (Cocco 2010; Terkeltaub 2009). The complex molecular and cellular mechanisms of action of colchicine and its pharmacological properties have recently been systematically reviewed by Terkeltaub 2009. While the mechanism of action against diverse diseases is not completely understood, over recent years the understanding of how and under what circumstances colchicine can be used to treat diverse clinical conditions has continuously evolved (Terkeltaub 2009). Colchicine's anti-inflammatory action is strongly related to its effects on leukocytes by modifying their adhesion, migration, cytokine production and secretion (Cronstein 2006; Niel 2006; Terkeltaub 2009).
Colchicine has a relatively narrow therapeutic window and high interindividual pharmacokinetic variability (Niel 2006; Terkeltaub 2009; Yang 2010). Despite its widespread use in treatment of gout, evidence is limited allowing assessment of the optimal dosage of colchicine for this condition. A Cochrane review published in 2006 identified only a single randomized controlled trial (RCT) comparing colchicine to placebo (with 42 participants) and no trial comparing colchicine to non-steroidal anti-inflammatory drugs (NSAIDs) or to other treatments (Schlesinger 2006). In this trial, acute gout was treated with a regimen of 1 mg of oral colchicine followed by 0.5 mg every two hours until symptoms were relieved or adverse effects occurred. The participants received a mean dose of 6.7 mg colchicine and all those in the active treatment group had gastrointestinal side effects (diarrhea or vomiting), while five control participants developed nausea but without diarrhea or vomiting (Ahern 1987). A recent RCT including 185 participants explored the comparative effectiveness of such a high-dose treatment for acute gout (here 4.8 mg over six hours, i.e. 1.2 mg initially and 0.6 mg every hour) with a low-dose regimen (1.8 mg over one hour, i.e. 1.2 mg initially and 0.6 mg one hour later) and with placebo (Terkeltaub 2010). The gout-related benefits of treatment (pain reduction) were similar in both active treatment regimens. However, while with the high-dose regimen 77% of participants had diarrhea (19% severe), 77% nausea, and 17% vomiting, with low-dose treatment 23% of participants had diarrhea (none severe), 4% nausea and none had vomiting (placebo: 14%, 5%, 0% respectively). Serious adverse events did not occur in this study.
Low-dose colchicine for the treatment and prevention of pericarditis has been shown to be effective in several RCTs without providing indications of severe adverse effects occurring in the first six months of treatment (Imazio 2012). The daily dose used in five trials was 0.5 to 1.0 mg and 1.5 mg/day in one trial. Among 684 participants with a maximum follow-up of six months, gastrointestinal intolerance was the most frequent side effect and no severe adverse events were reported (Imazio 2012).
In people at increased risk for cardiovascular events, low-dose colchicine treatment is a novel and non-standard treatment approach. It has been evaluated as continuous treatment over six months in doses of 0.5 mg/day (Nidorf 2013), and 1 mg/day (Deftereos 2013). An earlier trial used colchicine after coronary angioplasty at a dose of 1.2 mg/day over six months (O'Keefe 1992). Side effects in these studies were predominantly gastrointestinal, with other reported adverse effects including myalgia, myositis, and muscle cramps, and a small number of cases of increased creatine kinase levels, rash, accelerated hair loss, alopecia, itch, peripheral neuritis, and death (Deftereos 2013; Nidorf 2013; O'Keefe 1992).
How the intervention might work
Colchicine might inhibit the inflammatory mechanisms leading to the development or destabilization of atherosclerotic plaques. Colchicine treatment was associated with a decrease of high-sensitivity C-reactive protein in people with stable coronary artery disease (Nidorf 2007), but this was not observed in a randomized trial of participants with acute coronary syndrome or acute stroke (Raju 2012).
However, recently published results from RCTs on prevention of cardiovascular events suggest a considerable benefit of low-dose colchicine treatment in people at increased risk for cardiovascular events (Deftereos 2013; Nidorf 2013). Nidorf 2013 analyzed in a RCT with blinded outcome assessment 532 participants with stable coronary disease who were treated with colchicine 0.5 mg/day or no colchicine. Median follow-up was three years. The primary outcome (a combined endpoint of acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke) was significantly reduced with colchicine treatment (hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.18 to 0.59; P < 0.001; number needed to treat for an additional beneficial outcome (NNTB): 11). Deftereos 2013 analyzed in a placebo-controlled, double-blinded study 222 participants with diabetes undergoing a percutaneous coronary intervention (PCI) with a bare-metal stent (BMS). Colchicine treatment (1 mg/day) over six months significantly reduced the risk for in-stent restenoses (odds ratio (OR) 0.38, 95% CI 0.18 to 0.79, P = 0.007, NNTB: 6).
Why it is important to do this review
While recent studies (Deftereos 2013; Nidorf 2013) suggest a considerable benefit of low-dose colchicine treatment, their results are inconsistent with previous findings where no benefit for prevention of restenosis after coronary angioplasty was demonstrated (O'Keefe 1992).
There is thus far no systematic review of the available evidence on the effects of colchicine treatment on cardiovascular events that would allow a valid assessment of the potential long-term benefits and harms of this intervention for primary or secondary prevention of cardiovascular events.