Aernoud Fiolet

304 Chapter 12 DISCUSSION This prospective study assessed early intolerance to colchicine 0.5mg once daily in just over 4,000 patients with coronary disease. The most notable observations include the following: First,we found that odds for intolerance are seen in one out eleven patients and that perceived side effects comprise a wide array of symptoms, with gastro-intestinal upset, myalgia and fatigue most often reported. Second, when investigating common demographical andmedical characteristics, female sexwas most distinctly associated with intolerance with an odds ratio just over one-and-a-half. Third, statin use in general was not associated with intolerance due to any side effects, but CYP3A4 isoenzyme inhibiting statins were counterintuitively associated with almost two thirds lower odds for myalgia. The 8.9% intolerance observed in this study compared to half the proportion of patients that ceased trail medication in the complete cohort of the Colchicine Cardiovascular Outcomes Trial (COLCOT). 9 This trial investigated the same dose colchicine in patients with recent myocardial infarction and reported discontinuation by 18.4% of patients in the active treatment arm as compared to 18.7% in the placebo arm. The trial did not report on reasons for discontinuation, specific symptomatology, distinction between early or late discontinuation or re- challenges. The high proportion of drug discontinuation in patients assigned to the placebo arm probably represents a partial nocebo effect. 13 The proportion of intolerant patients found in our study is similar as the numbers reported in the open-label Colchicine for Aute Pericarditis Trial (COPS) (8.3%) and is lower than was reported in the placebo-controlled Investigation on Colchicine for Acute Pericarditis trial (ICAP) (10.8%), although both trials used higher doses colchicine (1 mg once daily) and no difference in intolerance between colchicine and placebo was found in the ICAP trial. 14,15 In patients without established cardiovascular disease such as those treated with the drug for Familial Mediterranean Fever, often using doses of 1-2 mg colchicine daily, proportion of intolerance may be as high as 18.8%. 16 Meta-analyses on colchicine in a broad spectrum of patients report pooled estimates of intolerance of 8.9% to 13.2%, although these numbers do not take in account early versus late intolerance. 5 When compared to other drugs commonly used in patients with cardiovascular disease, the proportion of intolerance we found for colchicine is lower than general intolerance reported for statins (10 to 15%) and higher than general intolerance