療效與藥物經濟學評估之系列研究

Abstract

背景 降血壓藥物治療能夠有效預防高血壓所造成的併發症。但目前醫學界對於何種降壓藥是最適當的第一線藥物並無完全一致的共識。針對臨床上降血壓藥物實際處方情形的了解，能夠幫助我們來改善對高血壓病患的治療成效。本論文的目的，首先希望探討台灣目前對單純高血壓患者的降壓藥物處方型態和趨勢，並且和國際上主要的高血壓臨床指引之建議做比較；然後我們進一步利用全民健康保險資料庫來進行效果研究 (outcome research)，探討不同種類的降壓藥物是否對預防高血壓患者併發中風的效果會有差異。 方法 首先我們利用全民健保資料庫20萬人抽樣歸人檔 (1997至2004年)，從其中找出6,536位年齡在30歲以上，並且在1998年之後新診斷暨治療的單純高血壓病患，分析他們在1998至2004年間的所有降血壓藥物處方情形。 此外我們利用全民健保資料庫100萬人抽樣歸人檔來建立一個回溯型世代研究 (retrospective cohort study)，以進行降血壓藥物的效果研究。在1999年至2004年間，共有29,759位年齡在30歲以上之新診斷暨治療的單純高血壓病患。我們利用「時間相依之Cox比例危險模型 (time-dependent Cox’s proportional hazards model)」來分析他們併發中風的風險性。 結果 我們發現國內新診斷單純高血壓病患的降壓藥物處方情形隨著其年齡、性別及就醫院所層級而有所不同。不論是單一降血壓藥物處方或是併用多重降壓藥物之處方，鈣離子阻斷劑 (calcium channel blocker) 是處方頻率最高之藥物；其次是乙型交感神經阻斷劑 (beta-blocker)。雖然利尿劑之費用最便宜，但它在單一降血壓藥物處方中之處方頻率僅8.3%；在全體降壓藥物處方中之處方頻率也只有19.9%。而血管升壓素受器阻斷劑 (angiotensin receptor blocker) 的處方率卻隨著時間遞增。利用多變數羅吉斯回歸分析控制相關變因後發現：醫學中心或區域醫院之醫師開出較多之血管升壓素受器阻斷劑的處方。 在探討不同種類之降壓藥物對預防高血壓併發中風的效果研究當中，這29,759位新診斷暨治療的高血壓病患在6年追蹤期間當中，總共有1,078個病人發生中風，其中包括654位缺血性中風患者。經校正過各危險因子後發現：藥物順從性低、年紀愈大、男性、合併糖尿病或心臟病之患者，有較高的中風風險。不同種類的降壓藥物並未被發現有中風風險的差異。但在進一步的分組分析當中，我們觀察到使用乙型交感神經阻斷劑的單純高血壓患者相對於沒有使用該類降壓藥者，具有較高之缺血性中風風險 (hazard ratio：1.3，95%信賴區間：1.0-1.6，P = 0.046)。 結論 我們的研究結果顯示台灣國內目前對高血壓之藥物治療的實際情況，距成本效果 (cost-effectiveness) 的目標仍有相當之差距；換句話說，在高血壓之藥物治療上仍有相當的改善空間。服藥順從性差是決定高血壓患者發生中風併發症的關鍵因素。本研究雖然沒有發現不同種類的降壓藥物會造成併發全體中風風險之差異性，但卻顯示使用乙型交感神經阻斷劑可能和較高的缺血性中風有關聯。這部分的因果關係仍需進一步的研究來加以否證。

BACKGROUND Although antihypertensive pharmacotherapy is widely considered to reduce the premature mortalities and comorbidities associated with hypertension, no consensus has yet been reached as to the appropriate choice of first-line medication. Knowledge of existing prescription patterns in the treatment of newly-diagnosed hypertension can provide useful information for improving clinical practice in this field. The aims of this dissertation are to determine the prescription patterns and time trends for antihypertensive medication in newly-diagnosed cases of uncomplicated hypertension in Taiwan and to compare these with current clinical guidelines. Furthermore, we conducted an outcome research to assess the risk of stroke associated with various antihypertensive drugs among previously uncomplicated hypertensive patients. METHODS First, a total of 6,536 newly-diagnosed patients with uncomplicated hypertension, aged over 30 years, were identified from the representative 200,000-person sample in the computerized reimbursement database of the National Health Insurance in Taiwan. These patients were followed from 1998 to 2004 with all diagnoses, prescription data and medication charges being retrieved for subsequent analysis. For the outcome research of antihypertensive treatment, another retrospective cohort study was undertaken, covering the period from 1997 to 2004, on a 1,000,000-person random sample obtained from Taiwan's National Health Insurance reimbursement database. Between January 1999 and December 2004, 29,759 patients aged 30 years or older were identified as newly-diagnosed uncomplicated hypertensive cases. They were followed up until the end of 2004. A time-dependent Cox’s proportional hazards model was specified to analyze the risk of stroke development. RESULTS Prescription patterns varied by age, gender and clinical facilities, with mono-therapies being found to be dominant in the first year, albeit declining over time. Calcium channel blockers and beta-blockers were the most frequently prescribed antihypertensive drugs, either alone or in combinations. Although least expensive, the prescription rates of diuretics were low, at 8.3% for mono-therapies and 19.9% overall. The prescription rate for angiotensin receptor blockers was elevated considerably over time. After controlling for other related factors by multiple logistic regression analysis, angiotensin receptor blockers were found to be prescribed mainly by medical centers or regional hospitals. Among the 29,759 uncomplicated hypertensive patients in the 1,000,000-person random sample of NHI reimbursement database, 1,078 new cases of stroke were identified and followed up for at least one month during the study period, including 654 ischemic stroke cases. After adjustment for various risk factors, the hazard ratio of developing stroke was significantly higher for poor medication compliance (hazard ratio 1.5-1.9), old age, male, and comorbid diabetes mellitus and/or other heart diseases. Different categories of antihypertensive medications were not associated with differential effects on stroke development. In the subsequent analysis, we found that patients receiving pharmacotherapy with beta-blockers were 1.3 (95% confidence interval 1.0-1.6) times more likely to develop ischemic stroke than those who had been treated with other types of antihypertensive medication. CONCLUSIONS The above findings indicate the existence of a gap between current clinical practice and the desired goal of cost-effectiveness in antihypertensive treatment in our country, which should be corrected. Poor medication compliance is a key determinant of developing stroke among hypertensive patients. Our research suggests that there has been no differential effect of antihypertensive medication on overall risk of stroke, whereas beta-blockers might be associated with more ischemic stroke. Further studies are needed to corroborate this hypothesis.