應用觀察性研究探討藥物使用與發生巴金森氏症之相關性以降血脂藥物(statin)及降血壓藥物為例

Abstract

巴金森氏症是老年常見之退化性疾病，其致病機轉多元而不明，牽涉基因，環境因素及兩者之間的交互作用；由於目前未有治療藥物能阻斷疾病進展、即多巴胺細胞死亡，有越來越多流行病學研究針對常見藥物使用，探討其對巴金森氏症發生的風險。 使用次級資料庫進行藥物療效與安全性評估日益普遍，亦為研究相關題材可貴及有效率的資源，但因為其觀察性質，缺乏臨床試驗隨機分配的特性，目前多數研究仍受到一些限制；大多數研究使用”未使用藥物者”(nonuser)當作對照組進行研究而未考慮藥物處方的適應症 (或禁忌症)常造成適應症干擾(confounding by indication)，使用與未使用藥物者在疾病嚴重程度，就醫型態，生活習慣或疾病預後常有很大的差別，而這些差別多與所欲研究的結果(outcome)相關，且是在次級資料庫中無法測量且難以控制的，若藥物的適應症是研究疾病的危險因子之一或研究疾病正好是研究藥物的所欲療效，或者與欲探討疾病共享同一危險因子(如血壓、血脂)，造成的誤差將更加嚴重。 本論文提出常見藥物使用與巴金森氏症之兩個研究，使用限制研究族群策略來選取研究對照組可以降低適應症干擾所造成的誤差，：第一個研究利用本國健保局對降血脂藥物給付中，達標即停藥的規定，研究開始使用降血脂藥物statin族群，用藥與停藥發生巴金森氏症的風險，本研究發現，相對於停藥，繼續使用親脂性降血脂藥物能降低巴金森氏病的發生風險達58%(HR:0.42, 95%C.I.:0.27–0.64)，而親水性降血脂藥物則未有保護效果，而親脂性降血脂藥物使用並未發現有劑量累積效應；第二個研究限制於高血壓診斷病患，探討不同類型高血壓藥物與巴金森氏症發生的風險，本篇研究發現，在平均約4.6年的追蹤時間，相對於乙型阻斷劑的使用，DHP類及中樞性鈣離子阻斷劑的使用能減少巴金森氏症的發生風險(aHR:0.71; 95% CI, 0.57–0.90)，此效果有劑量累積的效應，使用其他種類降血壓藥物ACEI及ARB在累積高劑量時有潛在保護效果。 持續使用親脂性降血壓藥物statin及DHP類鈣離子阻斷劑可能減少巴金森氏症的發生，未來需要大型長期性追蹤的研究來驗證其保護效果。

Parkinson disease (PD) is a common neurodegenerative disorder for which causes are diverse and mostly unknown. Given that there is no mechanism-based treatment to ameliorate dopaminergic neuron loss; agents that can attenuate or modify disease processes may play a role in halting the degeneration process of PD. While using administrative databases to investigate the association of drug use and PD is increasing, concerns arise from the observational nature of the research. Without randomization, the comparison between drug users with nonusers would cause bias from confounding by indication because these two groups of population differed substantially in terms of disease severity, lifestyle factors, patterns of medical utilization, and even physicians’ perspective of their prognosis, which are all associated with the determinant of the outcome. Current literatures studying the use of chronic medications, statin and anti-hypertensive medications, and the risk of Parkinson’s disease (PD) used nonuser as comparison group and demonstrated inconsistent results. To minimize possible confounding by indication in current literature, we propose two studies that different restriction strategies are used in design to include a relatively homogeneous population. In study one, among the 43,810 statin initiators, continuation of lipophilic statins was associated with a decreased risk of PD (hazard ratio, HR:0.42, 95%C.I.:0.27–0.64) as compared with statin discontinuation. There was no association between hydrophilic statins and occurrence of PD. Long-term use of statins, either lipophilic or hydrophilic, was not significantly associated with PD. In the second study, among 65,001 hypertensive patients with a mean follow-up period of 4.6 years, use of dihydropyridine CCBs, but not non-dihydropyridine CCBs, was associated with a reduced risk of PD (aHR:0.71; 95% CI, 0.57–0.90). There was no association between the use of ACEIs (aHR = 0.80 [0.64–1.00]) or ARBs (aHR = 0.86 [0.69–1.08]) with PD. A potentially decreased association was only found for higher cumulative use of ACEIs (HR = 0.52 [0.34–0.80]) and ARBs (HR = 0.52 [0.33–0.80]). Continuation of lipophilic statin therapy was associated with a decreased incidence of PD as compared to discontinuation in statin users. Also, centrally-acting dihydropyridine CCB use and high cumulative doses of ACEIs and ARBs may associate with a decreased incidence of PD in hypertensive patients. Further long-term follow-up studies are needed to confirm the potential beneficial effects.