全民健康保險研究資料庫HMG-CoA Reductase Inhibitors處方型態及用藥安全性分析：自藥品交互作用觀點探討

Abstract

It’s known that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins for short, are widely used for the treatment of hypercholesterolemia and have demonstrated efficacy for primary and secondary prevention of coronary heart disease (CHD). They are safe and usually well tolerated. The most frequently reported adverse events, including gastrointestinal disturbances, liver enzyme elevation, and muscle pain/weakness, are usually mild and there is almost no need to interrupt the therapy. Nevertheless, rhabdomyolysis is a quite severe adverse effect, though rare, and is related to the dosage of statins. Furthermore, statins are metabolized mainly by CYP system. The risk of rhabdomyolysis will be increased by drugs that share the same metabolic pathway. In this thesis, the prescribing patterns of statins and statin-drug interactions in outpatient are analyzed through the National Health Insurance Research Database in Taiwan. The relative risk of rhabdomyolysis and the incidence rate of mild muscular side effects are also examined. All cohort datasets within year 2002, total 200,000 patients, are included. The statin-drug interactions are analyzed not only on the same prescription but among different prescriptions of a person. The prescribing patterns are expressed in terms of person-time, cumulative using days per year, prescribed daily doses (PDD), the prevalence of potentially severe statin-drug interactions, and the duration of combination use. Using persons not taking statins as a control, a case-control study was performed to exam the relative risk of rhabdomyolysis in patients on statins. As for the incidence rates of mild muscular side effects, five different groups are selected and compared with each other. The rates are calculated by using case numbers as the numerator and time interval of drug used as the denominator. The study shows that atorvastatin was the most frequently prescribed statin. The average cumulative using days per year of statins are about 120 days. The prevalence of statin-drug interactions is 18.5 %, and 60 % of the total interactions are prescribed by the same doctors. Diltiazem and gemfibrozil were the two most frequently prescribed drugs that combined with statins, and cyclosporine is the drug that has the longest duration of combination. PDDs of statins in combination was not significant different from those in single use. Patients on statin therapy are much older than the general population and have higher incidence of underlying circulatory and endocrine diseases (p < 0.05). In this study, no of rhabdomyolysis was detected in statin users. After controlling the predisposing factors such as age, gender, duration for exposing to drug, DM and hypothyroidism, the incidence of mild muscular side effects for statin users was 1.6 times (95 % CI 1.3, 1.9; p < 0.0001) of those not using statins, and the odds ratio in fibrate users was even higher (OR 2.7; 95 % CI 1.9, 3.8; p < 0.0001). Drug-drug interactions easily occur for drugs metabolized via CYP3A isoenzyme under polypharmacy. Atorvastatin and simvastatin that are metabolized by CYP3A, are the two most frequently prescribed statins in our research. Around 40 % of interactions are difficult to detect due to patients’ habits of doctor shopping. Although there is no rhabdomyolysis was detected in our study in patients using statins, statin’s monotherapy increased the risk of muscular side effects. It is important to monitor the use of statins and provide proper patient education. Small sample size and short duration to follow up are the limitations of this study. That National Health Research Institutes (NHRI) set a new database of patients on lipid lowering drugs and further longitudinal studies on the use of statins are recommended.