多巴胺促效劑之處方型態分析及其對巴金森氏病病人心臟瓣膜病變的影響

Abstract

背景 2001-2007年間陸續有文獻指出，巴金森氏病治療藥物中麥角鹼類多巴胺促效劑可能導致病人心臟瓣膜疾病危險性上升。 目的 經由分析國內某醫學中心使用多巴胺促效劑的處方型態，及病人心臟超音波瓣膜之變化，以評估國人使用pergolide的安全性及瓣膜病變之臨床意義。 方法 第一部分，根據國內某醫學中心門診藥品開方資料庫，回溯性分析多巴胺促效劑處方型態與使用劑量的分布情形。第二部分，收納使用麥角鹼及非麥角鹼類多巴胺促效劑的巴金森氏病病人，以及經年齡配對的非巴金森氏病受試者，接受心臟超音波檢查，紀錄瓣膜逆流程度、瓣膜增厚及是否有限制性瓣膜病變，分析三組受試者之間心臟超音波檢查結果的差異。除此之外，考慮到此心臟瓣膜病變對於巴金森氏病病人臨床意義，使用MLHFQ心衰竭問卷來評估病人臨床症狀。最後以多變項統計分析來探討各影響因子。 結果 由國內某醫學中心處方資料庫的分析發現，而2007年pergolide使用量有明顯的減少，且換藥人數比起往年則有大幅度的增加。 本研究共分析12444筆pergolide的處方，在2003至2007年間，pergolide的使用人數，因有其他兩種多巴胺促效劑ropinirole及pramipexole的上市，並無明顯增加，且在多巴胺促效劑的使用上，係非麥角鹼衍生物為主流。國人使用pergolide最常見的劑量為0.75 mg/day，且為整體劑量分布之中位數，只有1.1%處方超過2.0 mg/day的劑量，遠低於仿單建議劑量。在2007年3月後，pergolide的使用者有48.8%（78/160）有換藥行為，其換藥成功者達84.6%（66/78），但仍有12人因副作用或療效不佳又換回原pergolide使用。轉換劑量則以pergolide：pramipexole：ropinirole＝1：2：4最為常見。 共有37位維持pergolide使用的病人進入第二部份觀察性研究，另外還包括34位服用非麥角鹼類巴金森氏病病人及41位經年齡及心血管疾病配對的對照者。 使用pergolide的病人共有37位，男性25位，女性12位，平均年齡為66.8±10.0歲，平均患病年數為8.8年，pergolide平均每日劑量為0.85 mg/day，平均使用時間為51.2個月，平均累積劑量為1058.24 mg。 任何一個瓣膜具有中度以上瓣膜逆流的發生率在pergolide組、Non-ergot組與對照組分別為21.6%、2.9%及7.3%，年齡及pergolide的使用與此發生率有顯著的相關性。三尖瓣tenting area的平均值在pergolide組、Non-ergot組與對照組分別為 0.25、0.21及0.19 cm2，高血壓及pergolide的使用是導致三尖瓣tenting area升高的獨立危險因子。低劑量pergolide的使用下，心臟瓣膜病變的發生與pergolide使用劑量沒有相關。而心衰竭問卷總分的平均值在pergolide組、Non-ergot組與對照組分別為6.4、4.5及2.8，患病年齡較輕及左多巴胺使用劑量較高的病人，量表總分越高。 結論 國人使用pergolide的每日劑量遠低於歐美，甚至低於亞洲其他國家。非麥角鹼類衍生物取代麥角鹼類衍生物成為新處方巴金森氏病病人治療中使用多巴胺促效劑的主流。雖然心臟瓣膜病變的發生率與pergolide的使用有正相關，但觀察到之病人瓣膜逆流的程度為初期癥象，臨床表現均無明顯的心衰竭症狀，其臨床嚴重度皆不顯著，然而在大規模研究或前瞻性分析進一步確定國內使用pergolide的安全性之前，對使用pergolide病人仍建議應定期以心臟超音波檢查追蹤其心臟瓣膜變化。

Background Recently published literatures indicated that ergot-derived dopamine receptor agonists, often used in the treatment of Parkinson's disease, have been associated with an increased risk of valvular heart disease. Objective To evaluate the safety issue of pergolide use in patients with Parkinson disease（PD）in Taiwan by analyzing the drug utilization and echocardiographic data of patients. Methods For the first part, the drug utilization and dosage distribution of dopamine agonists prescriptions treated in patients with Parkinson disease（PD）in a medical center during 2000 and 2007 were analyzed based on the hospital pharmacy database For th second part, patients with PD using ergot and non-ergot dopamine agonists were included, respectively. Forty-one subjects without PD matched with age were served as controls. All subjects underwent transthoracic echo-Doppler examinations. Aortic, mitral, tricuspid and pulmonary regurgitation and mitral valvular thicknesses as well as tenting area and distance of the mitral and tricuspid valve were assessed. Minnesota Living with Heart Failure Questionnaire (MLHFQ) was used to assess the potential clinical presentation of valvulopathy of patients. Multiple regression anlysis was used to assess the correlation between factors. Results The amount of pergolide used during 2003-2006 did not have any significant change, since there were two other dopamine agonists available on market after year 2002. However, there was a significant decresed in pergolide drug withdrawal from the market by FDA. Among 12444 prescriptions, the most often daily dose of pergolide is 0.75 mg/day, and only 1.1% prescriptions is higher than 2.0 mg/day. Since March 2007, 78 out of 160（48.8%）patients with pergolide opted to switched to a nonergot dopamine agonist. Overall, 12 of 78 patients（15.4%）experienced adverse events suggestive of over- or unedertreatment and reverted to pergolide.The most often used dose conversion ratio in these patients was pergolide：pramipexole：ropinirole＝1：2：4. 71 patients with PD（37 were taking pergolide and 34 were taking non-ergot derivatives）and 41 controls were included in the observational study. Among 37 pergolide users ( 25 male, 12 female ), mean age was 66.8±10.0 y/o, mean duration of illness was 8.8 years, mean daily dose of pergolide was 0.85 mg/day, mean duration of treatment was 51.2 months, and mean cumulative dose was 1058.24 mg. Regurgitation (grade 2 to 3) in any valve was found with significantly higher frequency in patients taking pergolide (21.6%) but not in patients taking non-ergot dopamine agonists (2.9%), as compared with control subjects (7.3%). The mean tricuspid tenting area in Ergot group, Non-ergot group was 0.25 cm2、0.21 cm2, respectively, and both were significantly higher than that in control group ( 0.19 cm2). There was no significant correlation between cardiovalvulopathy and pergolide dose after adjusted for potential confounding factors. Mean MLHFQ score in Ergot group, Non-ergot group and control was 6.4, 4.5 and 2.8, respectively. Among the variables examined, early onset of illness and levodopa daily dose were independent factors predicting the MLHFQ scores. Conclusion Mean daily dose of pergolide using in PD patients in Taiwan is much lower than that reported in the literature. Although the use of pergolide is associated with an increased risk of cardiac valvulopathy, the symptoms caused by heart valvular regurgitation are not clinically significant in most of our study population. Before the safety issues is clarified in further large scale or prospective studies, regular echocardiography follow up is needed in PD patients using pergolide .