- 學位論文
探討內科藥物用於肺阻塞病人之肺高壓保護及治療效果
Evaluating the Protective Effect and Medical Effectiveness of Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease
摘要
研究背景與目的： 肺高壓是一種罕見但卻致命的血液動力學不穩定狀態，在台灣，因為肺阻塞引起的肺高壓是最常見的。然而治療肺高壓的藥物在此病人族群並沒有足夠的證據支持使用，目前只有長期的氧氣治療可改善病人症狀以及死亡率。因此本研究為回溯性世代追蹤研究，將探討是否有其他臨床使用內科藥物具有保護效果或療效，可降低此族群肺高壓發生率以及改善肺高壓引起症狀。經由文獻回顧與探討藥品特性後，採用statins (一種常見降血脂藥物)作為探討藥品進行後續的研究。 研究方法： 本研究使用台灣全民健保資料庫全人口檔以及多重死因檔(2002年至2017年)，進行兩部分的研究。第一部分為在肺阻塞病人族群，探討statins的肺高壓保護效果。第二部份為在肺阻塞病人後續產生肺高壓族群，探討statins的療效。第一部分納入新診斷肺阻塞病人，依照有無使用statins進行分組，並利用傾向分數進行一比一配對平衡兩組的基本特質。主要結果為比較兩組觀察五年的肺高壓發生率。統計方法使用Cox proportional hazard model計算風險值並找出危險因子。並使用Fine and Gray competing risk model校正競爭死亡因子。次族群分析探討statins的效果是否具有劑量與時間依賴性。第二部份納入因肺阻塞後續產生肺高壓的病人，依照有無使用statins進行分組，並進行傾向分數配對。主要結果為比較兩組觀察五年的因肺高壓死亡率。結果統計方法與第一部分相同。 研究結果： 第一部分共納入41,168 位肺阻塞病人，使用statins相較於沒有使用組可顯著地減少 22% 的肺高壓發生率。(Subdistribution hazard ratio:0.78, 95% CI:0.65-0.94, P=0.010) 在第二部份共納入1,325位肺阻塞後續產生肺高壓病人，根據結果使用statins相較於沒有使用組可顯著地降低 22%的肺高壓相關死亡率(adjusted HR:0.78, 95% CI:0.62-0.98, P=0.036)。在次族群分析發現當病人總累積statins劑量大於180個定義每日劑量後以及使用超過一年，statin的保護效果與療效具有顯著的劑量與時間依賴效果。 研究結論：Statins對於肺阻塞肺病相關肺高壓，具有潛在的好處。能降低肺阻塞病人肺高壓的發生率以及發生肺高壓後的相關死亡率。並且此好處具有劑量與時間依賴性。此外年紀大於60、男性、較低薪資、心衰竭是相關的危險因子。
並列摘要
Background and objective: Pulmonary hypertension (PH) is a pathophysiologic and hemodynamic imbalance condition. In the Taiwan prevalence survey, the patients with PH due to chronic obstructive pulmonary disease (COPD) (group 3) is the most common PH. However, the current medical treatments of PH including supportive therapy and new specific drug in group 3 is lack of evidence and the efficacy is still uncertain. Therefore, we performed a nationwide, population-based, retrospective cohort study to explore the protective effect and effectiveness of other medical treatments in this patients group. After reviewing the literature and the property of repurposing medical treatments, the statins which known as cholesterol-lowering drugs are selected to performed the study. Methods: The study used the medical record of full population-database and multiple cause of death data from the Taiwan National Health Insurance program from 2002.01.01 to 2017.12.31. The study conducted a two-part study. The part I study included new diagnosed COPD patients and divided into two groups according to whether taking statins or not. We used the 1:1 propensity score to match the statins user group and statins non-user group. The primary outcome is the incidence rate of PH between the two groups. The Cox proportional hazard model was conducted to analyze the hazard ratio and two-tail p-value was 0.05. The Fine and Gray competing risk model was used to adjust the competing risk with to estimate the subdistribution hazard ratios. (sHR) The part II study included new diagnosed PH due to COPD patients. Then the same as the part I study, patients were divided into two groups according statins exposure and performed a propensity score matching. The primary outcome was mortality related to PH. The statistically analyses were the same as part I study. Results: The part I identified 41,168 COPD patients. Compared to statins non-user, statins users had significantly lower 22% risk of PH. (sHR:0.78, 95% CI:0.65-0.94, P=0.010) The part II included 1,325 PH due to COPD patients. In primary outcome, statins user group significantly reduced 22% risk of mortality related to PH (adjusted HR:0.78, 95% CI:0.62-0.98, P=0.036) compared to no-use groups. The subgroup analysis in both two parts presented that the statins protective effect and effectiveness showed the protective effect from PH until patients used statins over 180 cumulative defined daily doses and more than one year. Conclusion: The finding of the study suggested that statins has potential benefits for PH related to COPD. Statins can reduce the incidence of PH and the mortality related to PH. Moreover, this benefit is dose-dependently and time-dependently. The age over 60 year-olds, male, low income, heart failure, and COPD severity are the risk factors in both incidence and mortality.