使用雙磷酸鹽藥物Alendronate與心房纖維顫動的風險探討：重疊式病例對照研究

Abstract

背景： 雙磷酸鹽類藥物可以有效降低骨質疏鬆症病人發生骨折的風險。2007年一篇臨床研究報告顯示使用雙磷酸鹽類藥物可能與心房纖維顫動發作有關。有許多觀察性研究以資料庫為分析對象來探討此一相關性，但是研究結果不一致。alendornate為廣泛使用的一種口服雙磷酸鹽類藥物，因此有必要去調查臨床上使用alendronate與心房纖維顫動發作之間的關係。 目的： 探討骨質疏鬆症的病人使用雙磷酸鹽類物alendronate與心房纖維顫動之間的相關性。 研究方法： 本研究為一回溯性重疊式病例對照研究，地點位在國立台灣大學醫學院附設醫院－臺灣北部的一間醫學中心。研究對象來源為2002年1月1日至2005年12月31日間，診斷有骨質疏鬆症的門診病人。透過完整病歷回顧，我們一共確認出218位心房纖維顫動發作的病例。接著從剩下的病人裡隨機配對出218位無心房纖維顫動的對照病人，配對條件為年紀(一年之內)、性別、降血壓藥物使用與index date(一年之內)。詳細記錄兩組病人alendronate的用藥史，並收集臨床相關資訊例如心血管病史、併用藥物、心臟超音波檢查與血脂數值等等。 研究結果： 病例組有35人(16.1%)、對照組有29人(13.3%)曾經使用alendronate治療骨質疏鬆症。經過控制高血壓、降血壓藥物的使用、甲狀腺亢進、左心房擴大與心衰竭後，結果顯示曾經使用alendronate的病人比起從未用過的病人，心房纖維顫動發病的相對風險為1.89 (95%CI 0.98-3.65)。過去使用alendronate的病人更會顯著提高發病的風險(RR=2.37, 95%CI 1.01-5.42)。心房纖維顫動的發病風險與alendronate累積劑量呈現正相關 (<2.4 gm [中位數] vs ≥2.4gm: RR=1.69 [95%CI 0.68-4.17] 與RR=2.10 [95%CI 0.87-5.07], 趨勢分析 p=0.05)。曾經使用alendronate的病人與持續性心房纖維顫動發病的相關性高於間歇性及暫時性心房纖維顫動 (持續性心房纖維顫動:RR=2.73 [95%CI 0.43-17.44]; 間歇性心房纖維顫動:RR=2.06 [95%CI 0.28-5.95]與暫時性心房纖維顫動:RR=1.28 [95%CI 0.85-4.99])。 結論： 曾經使用alendronate與心房纖維顫動發作有相關的趨勢，但尚未達到統計顯著水準。然而過去使用alendronate會明顯提高心房纖維顫動發作的風險。這樣的關係可能跟alendronate累積劑量以及越嚴重的發病情形有關。

Background: Bisphosphonates are well-known for effectively reducing risk of fracture in osteoporotic patinets. The concern of the use of bisphosphonates associating with atrial fibrillation (AF) has been raised since 2007. However, the results were conflicting from the observational studies, most of them were register-based. For the widespread using of alendronate, the most popular oral bisphosphonate, there is a necessity to investigate the relationship between alendronate and AF in clinical practice setting. Objective: The purpose of this study is to assess the association between AF and use of alendronate among osteoporotic patients. Design: Retrospective, nested case-control study. Setting: National Taiwan University Hospital (NTUH)－ a medical center in northern Taiwan. Participants: All patients visited the clinics at NTUH during the period from 2002/1/1 to 2005/12/31 with a diagnosis of osteoporosis. Methods: We identified 218 cases with confirmed incident AF through complete medical record review, and 218 control subjects, selected at a random from the remaining patients and matched on age (within 1 year), sex, use of anti-hypertensive medication, and index date (within 1 year). The detailed history of alendronate was documented. Other related information was also collected such as cardiovascular history, concomitant medications, echocardiogram and lipid profile etc. Results: 35 cases (16.1%) and 29 controls (13.3%) were ever use of alendronate for osteoporosis. The relative risk of ever use of alendronate compared with never-user was 1.89 (95%CI 0.98-3.65) after adjustment for hypertension, anti-hypertensive medication, hyperthyroidism, left atrial dilatation and heart failure. Past users had a higher adjusted relative risk of 2.37 (95%CI 1.01-5.42) compared with never user. There was a trend in AF according to the cumulative grams of alendronate (<2.4 gm [the median] vs ≥2.4gm: RR, 1.69 [95%CI 0.68-4.17] and 2.10 [95%CI 0.87-5.07], respectively, trend analysis p=0.05). The risk of sustained AF associated with alendronate ever use seemed to be higher than the risk of intermittent and transitory AF (sustained AF: RR, 2.73 [95%CI 0.43-17.44]; intermittent AF: 2.06 [95%CI 0.28-5.95]; and transitory AF: 1.28 [95%CI 0.85-4.99]). Conclusion: Ever use of alendronate was associated with an increased risk of incident AF in clinical practice, though it didn’t achieve statistical significance. However, past use of alendronate did significantly increase AF. The association might be dose-dependent and related to more severe events.