Aernoud Fiolet

82 Chapter 3 effect on all-cause mortality (relative risk, 0.94; 95% CI, 0.82–1.09) with only low to moderate quality of evidence available. The risk for myocardial infarction was reduced but with limited evidence and wide CIs (relative risk, 0.20; 95% CI, 0.07– 0.57; 2 trials). There appeared to be no effect of colchicine on total adverse events, although gastrointestinal intolerance was increased. In a meta-analysis focusing only on the 5 trials that included 1301 patients with cardiovascular disease (coronary artery disease, acute coronary syndrome or stroke, postangioplasty or congestive heart failure), the combined data showed a reduced incidence of composite cardiovascular outcomes by ~60% (risk ratio, 0.44; 95% CI, 0.28–0.69) in patients treated with colchicine. 45 SAFETY AND LONG-TERM USE OF COLCHICINE IN STABLE CORONARY DISEASE Continuous administration of colchicine has beenused fordecades in the secondary prevention of a range of inflammatory conditions, most notably gout and familial Mediterranean fever, providingmuch information on tolerability and toxicity. 46,47,48 Five to ten percent of patients experience early mild gastrointestinal side effects when treatment is initiated at 0.5 mg daily, which often settles spontaneously. The overall rate of late intolerance to colchicine is low and similar to both low-dose aspirin and statin therapy. 49,50 A review by the US Food and Drug Administration revealed that colchicine is well tolerated when used in therapeutic doses and adjusted for renal and/or hepatic insufficiency. Even with long-term treatment, adverse events other than gastrointestinal toxicities are seen in <15% of patients, and they occur most often with inappropriate dosing in those with renal of hepatic insufficiency, in interactionwith other drugs, orwhen overdosing. Severe hematologic disturbances (eg, leukopenia, agranulocytosis, pancytopenia) are rare and seem to be related to high daily doses in patients with end-stage renal impairment. 51,52,53,54 Drugs that have an inhibitory effect on the P-glycoprotein or cytochrome P450 3A4 system or that compete in metabolism by this enzyme may cause an increase in colchicine levels and subsequently lead to toxic effects, particularly in the presence of a generally decreased metabolism or excretion such as in hepatic or renal failure. 54,55,56 Clarithromycin seems to be the most clinically relevant agent in this regard. 57,58,59