Aernoud Fiolet

306 Chapter 12 From a biological point of view, we expected that patients using atorvastatin and simvastatin would have increased odds for developing myalgia, as a consequence of CYP3A4 isoenzyme competition of colchicine and those statins. However, use of CYP3A4 iosenzyme inhibiting statins was not associated with increase odds for intolerance and the odds for myalgia were in fact the opposite direction as expected. In addition, patients using rosuvastatin had more than three times the odds of experiencing myalgia as compared to any of the other statins. Rosuvastatin is the only statin that is metabolized via the CYP2C9 isoenzyme and CYP2C19 isoenzyme. These cytochromes are not affected by colchicine. With the present data, we cannot distinguish whether these increased odds represent any other pharmacokinetic mechanism not considered before. The current findings may become increasingly relevant as the body of evidence of the protective effects of colchicine in cardiovascular disease expands. Several randomized controlled trials have reported clinical relevant relative risk reductions for major adverse cardiovascular outcomes in patients with acute and chronic coronary syndromes. In addition, multiple international initiatives are investigating its purpose in a broad array of atherosclerotic disease, among which are patients with cerebrovascular disease. 25 Although the perceived side effects described in this cohort are mostly benign, all care providers should be familiar with such symptoms, regardless of the population the drug is introduced to. Knowledge of such data could contribute to drug compliance and recognition of drug related symptoms. We acknowledge several limitations of our study. Most importantly, these data were part of an open-label run-in phase and thus not placebo-controlled. Although patients were offered a re-challenge, perceived side effects could not be attributed to the drug solely and absolute proportions might be overestimated. Second, we did not formally asses compliance with pill-counts or serum colchicine levels, which further could contribute to overestimation of reported side effects. Future pharmacokinetic and pharmacodynamic studies could contribute to understanding some of the interactions that we observed. Lastly, analyzing outcomes in a more granular level reduced event numbers, which increased risk for type II statistical errors due to limited power.