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

3-Hydroxy-3-methylglutaryl coenzyme A reductase抑制劑（HMG-CoA reductase抑制劑，簡稱statins）臨床上用於降血脂與預防心血管疾病，一般而言，安全性高且病患耐受度佳。最常見的副作用為腸胃道不舒服、肝指數上升及肌肉酸痛或無力，這些副作用通常輕微，少有導致需停藥的情況。然而，橫紋肌溶解症（rhabdomyolysis）在被報告過的肌肉副作用中，發生率通常不高，但一旦發生卻相當嚴重，且其發生與否與statins類藥品劑量成正相關，這對大多透過Cytochrome P450（CYP）系統代謝的statins而言，容易與同由CYP系統代謝或易影響CYP活性的藥品間產生交互作用，使得statins血中濃度上升而引發橫紋肌溶解的危機。 本研究利用全民健康保險研究資料庫分析statins門診處方型態，及處方中具潛在藥品交互作用之開方情形，另外，在安全性之探討上，則針對橫紋肌溶解的危險率以及肌肉相關副作用發生率做分析。 研究中所使用的為2002年承保抽樣歸人檔，將四組共20萬人一起納入分析。在處方型態分析上有別於以往只著重在單張處方的藥品交互作用，本研究中的藥品交互作用含括同一病患的所有用藥，主要是以人次來表達，並且計算平均年使用日數、平均日劑量、具潛在交互作用藥品併用盛行率及併用時間。利用case-control方式分析有使用statins類藥品的病患發生橫紋肌溶解相對於沒有使用者的危險率。在肌肉相關副作用發生率上，分成五組來分析：無使用statins及fibrates、單用fibrates、單用statins、有併用交互作用藥品、單看併用statins及fibrates交互作用等，以發生副作用病患數為分子，藥品使用時間為分母，計算各組發生率並加以比較。 研究結果顯示，atorvastatin是門診中開方比例最高的藥品，所有statins的平均年使用日數大約120天，交互作用盛行率為18.5 %，有60 %的併用為同位醫師開出。最常被併用的藥品為diltiazem，其次是gemfibrozil，而平均併用時間最長的藥品為cyclosporine，在併用情形下statins的平均日劑量降低的幅度無臨床意義。在病患基本特性上，使用statins病患比起門診有就醫紀錄者年齡明顯偏高，在心血管及內分泌疾病上明顯較多（p < 0.05）。 在使用statins的病患中，並未偵測到發生橫紋肌溶解的病症。而肌肉相關副作用發生率的分析上，在控制了年齡、性別、藥品使用時間、糖尿病、甲狀腺功能低下的因素後，使用statins的病患是未使用者發生副作用的危險性之1.6倍（95 % CI 1.3，1.9；p < 0.0001），甚至使用fibrates的病患之危險性更高（OR 2.7；95 % CI 1.9，3.8；p < 0.0001）。 經由CYP3A代謝的藥品在多種藥品同時併用下容易產生藥品交互作用，本研究中使用率最高的atorvastatin及simvastatin，就是由CYP3A途徑代謝，而研究中所有交互作用，有四成比例非由同一醫師開出，這與病患到處就醫習慣相關，使得醫療人員在交互作用的偵測上更加困難。雖在本研究中未發現橫紋肌溶解的案例，但單獨使用statins類藥品即有增加肌肉相關副作用的危險性，因此在此類藥品的使用上，小心監測及適當衛教相當重要。 在藥品使用安全性的研究上，受限於樣本數太小及研究時距不夠長的問題，未來研究可考慮跨時性研究設計及建議國衛院擴增使用降血脂藥品族群為主題的資料庫。

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.