健保免除部分負擔者

2026-09-03 09:27

幾個月前. 櫃台問我為何某個患者不用部分負擔. 我覺得有點納悶. 後來進入系統查看. 發現是百歲人瑞. 系統自動判定免除部分負擔. 

健保署-免除所有部分負擔者 113-01-30 更新 

發布日期 112-07-27 更新日期 113-01-30
按全民健康保險法第48條規定，保險對象因重大傷病、分娩及於山地離島地區就醫時，免自行負擔費用。

依全民健康保險法第49條及其施行細則第63條第1項規定，低收入戶成員之就醫部分負擔，係由中央社政主管機關編列預算支應。

依全民健康保險施行細則第63條第2項規定，全民健康保險法第10條第1項第6款第1目榮民、榮民遺眷之家戶代表之就醫部分負擔，係由國軍退除役官兵輔導委員會編列預算支應。

一、法定或公告免部分負擔者：
(一)重大傷病、分娩及於山地離島地區就醫者(註：山地離島地區一覽表)。
(二)經離島地區院所轉診至臺灣本島當次之門診或急診者。

(註：84年4月28日衛署健保字第84024016號)
(三)健保卡上註記「榮」字的榮民、榮民遺眷之家戶代表。
(四)健保卡上註記「福」字的低收入戶。
(五)百歲人瑞。

(註：85年1月3日衛署健保字第84076121號)
二、其他單位補助部分負擔者：
(一)3歲以下兒童。(註：衛生福利部社會及家庭署)
(二)登記列管結核病患至指定特約醫院就醫。(註：衛生福利部疾病管制署)
(三)勞保被保險人因職業傷病就醫。(註：勞動部勞工保險局)
(四)持「油症患者就診卡」或健保卡上註記「油症」身分之多氯聯苯中毒者(以下稱油症患者)：第一代油症患者之門、急診及住院；第二代油症患者之門、急診就醫。(註：衛生福利部國民健康署)
(五)服役期間持有役男身分證之替代役役男(含一般替代役役男及第一階段、第二階段研發替代役役男)。(註：內政部役政署)

內科-JAMA 1970 Effects of Treatment on Morbidity in Hypertension IT. Results in Patients With Diastolic Blood Pressure Averaging 90 Through 114 mm Hg

2026-09-02 13:21
這項研究從 1964年4月開始, 有523位退伍軍人(皆男性)納入研究, 初始舒張壓 90-129 mmHg. 原本實驗預計做五年. 但經過三年的試驗 發現其中初始舒張壓 115-129 這個 subgroup 已經明顯發現對照組(沒接受降壓治療)發生心血管疾病的比例明顯高於實驗組(有降壓治療). 所以提前終止試驗(1967年5月終止). 另一個 subgroup 舒張壓落在 90-114 mmHg 仍按照最初計畫. 繼續進行至 1969年 (舒張壓平均在90至114 mmHg 的 subgroup 有 380 人)


重點整理
1. 380人經過隨機分配到實驗組與對照組. 實驗組五年內發生不良事件的估計風險從55%降低至18%。

對照組有35名患者發生致命性不良事件，而治療組僅有9名患者發生此類事件。

對照組有19例死亡與高血壓或動脈粥狀硬化有關，而活性治療組有8例死亡。

除不良事件外，對照組有20名患者出現持續性舒張壓≥125 mmHg。

治療在預防充血性心臟衰竭和中風方面比預防冠狀動脈疾病併發症更有效。


獲益程度與隨機分組前的血壓水準有關。


在本刊先前發表的一篇文章中，退伍軍人事務部抗高血壓藥物合作研究小組 報告了抗高血壓藥物對中重度高血壓患者發病率的益處。
這些患者的初始舒張壓平均為 115 至 129 mmHg，他們被隨機分配到一項前瞻性雙盲試驗中，分別接受活性抗高血壓藥物治療和安慰劑治療。


對照組有 27 名患者發生了可評估的事件，而接受活性抗高血壓藥物治療組僅有 2 名患者發生此類事件。


這項顯著的治療效益結果與其他類似嚴重程度高血壓患者的前瞻性試驗結果一致。


然而，對於輕度高血壓，目前尚缺乏或幾乎沒有關於抗高血壓藥物治療價值的對照數據。解決這個問題至關重要，不僅因為輕度高血壓患者數量龐大，還因為藥物治療的潛在益處，尤其是在這部分高血壓患者中，一直備受質疑。 *


本報告介紹了一項前瞻性對照試驗的結果，該試驗旨在研究藥物治療對380例輕度或中度高血壓患者的發病率和死亡率的影響，這些患者的初始血壓水平為200%。 舒張壓平均值為 90 至 114 mmHg。


研究方案：
該臨床試驗納入了 523 名男性退伍軍人，他們在未接受降血壓治療的情況下，舒張壓平均值為 90 至 129 mmHg。


患者隨機分組於 1964 年 4 月開始。
然而，1967 年 5 月，由於隨機分組前舒張壓平均值為 115 至 129 mmHg 的 143 名患者亞組的研究被終止。


如前所述，終止該組研究的原因是，與治療組相比，對照組的併發症發生率較高，這表明治療效果在較早時就已非常顯著（P < 0.001）。


然而，在隨機分組前舒張壓平均值低於 115 mmHg 的患者中，當時並未觀察到如此顯著的差異。這些患者持續參與隨機試驗至1969年，也是本文的研究對象。


實驗設計已在先前的報告中描述。 *




註解/縮寫
1. moderately severe hypertension 中度嚴重高血壓: 初始舒張壓平均為 115 至 129 mmHg
2. lesser severe hypertension 輕度嚴重高血壓: 初始舒張壓 90-114 mmHg
3. Terminating morbid events 個案因發病而終止繼續實驗. 這些發病個案會列入實驗結果. 但在發病之後等於抵達實驗終點. 病患若還存活. 應脫離實驗. 接受常規治療(例如. 若一開始是被分配到對照組. 沒吃降壓藥物. 此時應該接受符合當時醫療常規的治療)


Effects of Treatment onMorbidity in HypertensionIT. Results in Patients With Diastolic Blood PressureAveraging 90 Through 114 mm HgVeterans Administration Cooperative Study Group on Antihypertensive Agents
（JAMA，1970年8月17日，第213卷，第7期）

底下中文使用google翻譯
治療對高血壓患者發生率的影響。舒張壓平均值在 90 至 114 mmHg 之間的患者的結果。退伍軍人事務部抗高血壓藥物合作研究組

380名舒張壓平均在90至114 mmHg之間的男性高血壓患者被隨機分配到活性降血壓藥組或安慰劑組。

治療後，五年內發生不良事件的估計風險從55%降低至18%。

對照組有35名患者發生致命性不良事件，而治療組僅有9名患者發生此類事件。

對照組有19例死亡與高血壓或動脈粥狀硬化有關，而活性治療組有8例死亡。

除不良事件外，對照組有20名患者出現持續性舒張壓≥125 mmHg。

治療在預防充血性心臟衰竭和中風方面比預防冠狀動脈疾病併發症更有效。


獲益程度與隨機分組前的血壓水準有關。


在本刊先前發表的一篇文章中，退伍軍人事務部抗高血壓藥物合作研究小組 報告了抗高血壓藥物對中重度高血壓患者發病率的益處。
這些患者的初始舒張壓平均為 115 至 129 mmHg，他們被隨機分配到一項前瞻性雙盲試驗中，分別接受活性抗高血壓藥物治療和安慰劑治療。


對照組有 27 名患者發生了可評估的事件，而接受活性抗高血壓藥物治療組僅有 2 名患者發生此類事件。


這項顯著的治療效益結果與其他類似嚴重程度高血壓患者的前瞻性試驗結果一致。


然而，對於輕度高血壓，目前尚缺乏或幾乎沒有關於抗高血壓藥物治療價值的對照數據。解決這個問題至關重要，不僅因為輕度高血壓患者數量龐大，還因為藥物治療的潛在益處，尤其是在這部分高血壓患者中，一直備受質疑。 *


本報告介紹了一項前瞻性對照試驗的結果，該試驗旨在研究藥物治療對380例輕度或中度高血壓患者的發病率和死亡率的影響，這些患者的初始血壓水平為200%。 舒張壓平均值為 90 至 114 mmHg。


研究方法
收案條件

該臨床試驗納入了 523 名男性退伍軍人，他們在未接受降血壓治療的情況下，舒張壓平均值為 90 至 129 mmHg。患者隨機分組於 1964 年 4 月開始。
然而，1967 年 5 月，由於隨機分組前舒張壓平均值為 115 至 129 mmHg 的 143 名患者亞組的研究被終止。如前所述，終止該組研究的原因是，與治療組相比，對照組的併發症發生率較高，這表明治療效果在較早時就已非常顯著（P < 0.001）。

然而，在隨機分組前舒張壓平均值低於 115 mmHg 的患者中，當時並未觀察到如此顯著的差異。這些患者持續參與隨機試驗至1969年，也是本文的研究對象。
最初，所有患者均住院接受高血壓的診斷和嚴重程度評估。住院第四至第六天舒張壓平均值在90至129 mmHg之間的患者被納入後續追蹤。在此期間舒張壓平均值低於90 mmHg或高於129 mmHg的患者被排除在外。

舒張壓太高. 應給予降壓治療. 不適合進行對照實驗

舒張壓90以下. 發生高血壓併發症機率低. 所以被排除

住院後，患者進入為期兩至四個月的隨機分組前觀察期☂，期間服用安慰劑或降血壓藥。在觀察期最後兩次門診就診中舒張壓平均值在90至129 mmHg之間的患者，若無其他排除原因，則被納入試驗。血壓由醫師測量，患者取坐姿。

排除條件

除舒張壓外，其他將患者排除在試驗之外的原因詳見其他報告。這些原因包括

先前有嚴重高血壓併發症病史，例如腦出血或蜘蛛網膜下腔出血、高血壓性視網膜病變、動脈夾層或腎衰竭，但不包括動脈粥狀硬化併發症，例如冠狀動脈疾病或腦血管血栓形成。

(1) 可透過手術治癒的高血壓患者；

(2) 患有其他致命性疾病(例如惡性腫瘤)的患者；

(3) 不願或無法返回診所的患者；以及 

(4) 缺乏動力或不配合或不可靠的患者。

如何評估個案是否適合被納入研究. 

這段不是這篇研究原文的內容. 是另一篇研究報告提到的. 正式實驗前兩個月. 尚未被隨機分配前. 所有受試者都給予兩個月安慰劑治療. 安慰劑裡面加入核黃素. 核黃素會從尿液排出. 因此檢視尿液是否出現螢光. 就可以知道個案是否有遵循醫囑吃藥. 另外. 門診約診時間沒按時回診. 代表個案不太可靠. 也會被排除. 

門診隨機分組前的觀察期為進一步檢驗患者的可靠性提供了機會。安慰劑中添加了核黃素，核黃素可使尿液呈現明亮的黃色螢光。每次就診時，都會在紫外光下檢查尿液樣本。此外，每次就診時均進行藥片計數。只有在隨機分組前觀察期內連續兩次就診時，尿液均顯示螢光且藥片計數均在規定範圍內，患者才能被納入隨機試驗。被納入試驗的患者隨後被隨機雙盲分配至活性藥物組或安慰劑組。

降血壓藥物有兩種. 

1. 50 mg hydrochlorothiazide/0.1 mg reserpine 複方. BID

2. hydralazine hydrochloride 25 mg TID, 若降壓效果不好(治療後的舒張壓仍>90 mmHg). 則改為 50mg TID

Active drugs consisted of two types of tablets, one being a combination tablet containing 50 mg hydrochlorothiazide and 0.1 mg_ reserpine which was given twice daily. The other was 25 mg of hydralazine hydrochloride given three times daily. The latter medication was raised to 50 mg three times daily if the diastolic blood pressure remained at 90 mm Hgorhigher.

顯然，安慰劑組幾乎所有患者的劑量都增加到了這個水平。如果出現低血壓反應或其他不良反應，則應減少劑量。對照組患者服用與活性藥物在口味和外觀上完全相同的安慰劑。所有患者均可接受必要的症狀治療，包括降血壓藥物以外的其他藥物。

隨機分組後，患者在前兩個月每月進行一次門診隨訪，之後每兩個月隨訪一次。年度檢查包括病史採集、身體檢查、胸部X光檢查、心電圖檢查、相關血液生化分析和腎功能檢查。如有需要，可安排額外的追蹤。進行相關的血液化學分析和腎功能檢查。

病患特徵：

本試驗隨機納入380位舒張壓平均值在90至114 mmHg之間的病患。

其中186例接受活性藥物治療，194例接受安慰劑治療。

表1和表2顯示，兩組患者在所列變數方面具有可比性。

對照組和治療組的中位年齡分別為49.2歲和48.1歲，平均年齡分別為52.0歲和50.5歲。

黑人患者在對照組中佔42%，在治療組佔41%。

在隨機分組前出院觀察期內，患者在診所測得的平均血壓，對照組為165.1/104.7 mmHg，治療組為162.1/103.8 mmHg。

對照組和治療組患者在腎功能檢查結果、空腹血糖值、血清膽固醇值、尿酸水平以及透過X光片和心電圖評估的左心室擴大方面均無顯著差異。

兩組患者在所有測量因子上均具有可比性。

觀察期：

患者於1964年4月至1968年9月期間收案，研究於1969年10月終止。

因此，最早入組的患者觀察了5.5年，最晚入組的患者至少觀察了1年。

若不計入失訪和終止研究，對照組的平均潛在觀察期為3.9年，治療組為3.7年。然而，由於下文所述的舒張壓升高導致的失訪和終止研究，隨機分組後的實際觀察期為對照組3.3年，治療組3.2年。

血壓變化：

治療組患者的收縮壓和舒張壓均迅速且顯著下降，並在整個試驗期間維持在較低水平。

圖1顯示了治療組和對照組患者在觀察期第四個月的血壓變化。

與隨機分組前觀察期記錄的水平相比，對照組患者的收縮壓平均升高了4.2 mmHg，而治療組患者的平均收縮壓平均下降了27.2 mmHg。

在同一時期，對照組患者的舒張壓平均增加了1.2 mmHg，而治療組患者的平均舒張壓平均下降了17.4 mmHg。

如圖1所示，血壓變化的分佈表明，與對照組相比，治療組患者的血壓變化曲線明顯向左偏移，進入「下降」區域。

此外，個體反應差異也很明顯，尤其是在收縮壓方面。

因其他原因退出研究：

Losses Other Than Assessable Events 

1. Deaths Due to Unrelated Conditions

2. Losses Due to Drug Toxicity

Deaths Due to Unrelated Conditions- 四名患者死於與高血壓無關的疾病

對照組兩人。一名患者死於屍檢證實的全身性癌症，另一名患者死於膀胱癌繼發的尿毒症。

治療組中一名患者死於顱骨骨折後發生的硬腦膜下血腫，另一名患者則死於青黴素過敏反應。

Losses Due to Drug Toxicity: 治療組有兩人疑似藥物產生嚴重不良反應而退出實驗

第一名患者出現眼眶水腫，伴隨發燒不適。胸部X光片顯示肺部浸潤。未見皮膚炎或關節炎。儘管抗核抗體檢測呈陽性，但血液中未發現狼瘡細胞。由於懷疑肼屈嗪可能會引起狼瘡綜合徵，因此停用了方案藥物。

第二名患者在開始積極藥物治療一個月後出現紫斑。醫院檢查結果（包括切片）符合過敏性紫斑症的診斷。停用方案治療兩週後，紫斑皮損消退，但在重新開始服用活性藥物三天後復發。因此，停止了方案治療。

Drop-Outs 退出研究 

在380名隨機分組的患者中，有56名（15%）在試驗過程中退出研究。

Fifty-six or 15% of the 380 randomized patients were classified as drop-outs during the course of the trial. 

其中27名患者被隨機分配到安慰劑組，29名患者被隨機分配到活性藥物組。

Of this number 27 had been randomized to receive placebos and 29 to receive active drugs. 

退出研究前的平均追蹤時間為17.6個月，最短少於1個月，最長49個月。 

The average period of followup prior to dropping out was 17.6 months with a range from less than 1 month to 49 months. 

6名患者搬離了診所所在地區。 

Six patients moved away from the area of the clinic. 

2名患者因參與研究的診所關閉而失聯。 

Two were lost from follow-up because of closure of one participating clinic.

4名患者重新回到私人醫師處接受治療。 

Four returned to the care of their private physicians. 

15名患者在退出研究前報告了副作用。其中9名患者正在接受藥物治療，6名患者正在服用安慰劑。 

Fifteen complained of side effects prior to dropping out. 

Nineof these patients had been receiving drugs, and six were taking placebos.

5名患者有嚴重的精神或酒精成癮問題，以致無法繼續進行試驗方案治療。

其餘患者的退出原因無法確定。

Five patients had psychiatric or alcoholic problems of such severity as to make continued protocol treatment impractical. In the remaining patients the reason for drop-out could not be determined. 

值得注意的是，3名服用安慰劑的患者在退出研究前發生了非終止性不良事件。

It should be noted that three of the patients taking placebos sustained nonterminating morbid events prior to their dropping out. 

Assessable Morbid Events 可評估的併發症事件

兩位未參與試驗的會診醫師審查了報告發生可評估併發症事件的病患記錄。除與左心室肥厚的心電圖表現或心臟擴大的X光錶現相關的事件外，所有可評估的事件均經過審查，這些事件將在後續報告中闡述。除方案治療類型和血壓水平外，所有與每項器質性併發症相關的可用數據均提交給審查人員，審查人員根據方案中給出的定義（參見文末可評估事件列表）對事件的發生和分類作出的決定被採納為最終決定。

表3按主要類別總結了可評估的事件。 

380名隨機分組的患者中有98名發生了此類事件，其中對照組76名，治療組22名。在這些事件中，20名對照組患者出現了血壓升高。 舒張壓在三次不同的門診中均超過 124 mmHg，且持續 3 週或更長時間。由於這些患者僅因持續性血壓升高而非器質性併發症而退出試驗，因此他們將不被納入後續評估治療預防不良事件有效性的分析。

其餘 78 例患者出現器質性併發症，情況如下：

對照組 194 例患者中有 56 例（佔 28.9%），治療組 186 例患者中有 22 例（佔 11.8%）。

治療獲益最顯著的證據體現在A類事件（方案中定義的需要將病人從研究中移除的高血壓併發症）的發生率。

治療組無A類事件發生，而對照組有14例。

其中包括5例A類死亡（表4）和9例其他A類事件（表5）。

即使加上其他心血管（B類）死亡和治療失敗，結果仍然令人矚目：

對照組194例患者中有35例（18.09%）發生此類事件，而治療組186例患者中僅有9例（4.8%）發生此類事件（表3）。

治療在預防終止性器質性併發症的有效性（對照組和治療組併發症發生率差除以對照組的併發症發生率）為73%（表3）。

終止試驗的決定是基於這些有利的證據，並輔以下文所述的生命表分析，這些分析表明治療獲益持續存在，並非僅集中在治療的最初一兩年。

終止事件 Terminating Events.  

與心血管疾病相關的死亡 DEATHS RELATED TO CARDIOVASCULAR DisEASE.

27例患者死於高血壓或動脈粥狀硬化併發症，其中19例發生在對照組，8例發生在治療組（表4）。 

5例死亡與A類或高血壓事件相關（參見文末可評估事件列表），其中4例為腦出血，1例為主動脈剝離動脈瘤，且皆發生在對照組。 

Five deaths associated with class A or hypertensive events (see list of assessable events at the end of the communication) were cerebral hemorrhage in four and dissecting aortic aneurysm in one, all occurring in the control group of patients. 

B類事件導致的死亡主要與冠狀動脈疾病有關。安慰劑組11例患者和治療組6例患者有記錄在案的心肌梗塞或猝死。 腦血管血栓形成（而非出血）是3例對照組患者和1例治療組患者的死因。其餘的 治療組的死亡病例為 ure。 ☝ * ur 與動脈粥狀硬化性腦血管破裂有關☂：事故被診斷為主動脈粥狀硬化性動脈瘤。

Deaths resulting from class B events were associated predominantly with coronary artery disease. Eleven patients in the placebo group and 6 in the treated group hadeither a documented myocardial infarction or a ☜sudden death.☝ Cerebrovascular thrombosis as opposed to hemorrhage was the cause of death in three contro] patients andin one treated patient. The remaining death in the treated group was caused by a rupture of an ather osclerotic aneurysm of the aorta.

Other Class A Events A 類嚴重事件

對照組有 9 位患者發生非致命性 A 類事件，而治療組則無此類事件（表 5）。

其中 5 例患者患有充血性心臟衰竭，無法透過服用洋地黃、限制鈉攝取和間歇性使用利尿劑來控制。其餘 4 例患者分別出現以下併發症各 1 例：主動脈夾層動脈瘤、蜘蛛網膜下腔出血、多發性條紋視網膜出血及伴隨神經系統症狀的急性高血壓腦病變。

其他終止事件

另有8例患者出現其他器質性併發症，這些併發症雖然不符合A類事件的標準，但嚴重程度足以終止方案治療，其中7例來自對照組。這些併發症列於表5「治療失敗」小標題下，臨床表現為血栓形成而非出血，但導致患者病情嚴重到無法就診。另有2例對照組患者因單發性視網膜出血而排除研究，其中1例伴隨提示急性高血壓腦病變的症狀，另1例伴隨疑似早期視乳頭水腫。剩餘的1例對照組患者出現氮血症惡化。治療組中有1例患者因心肌梗塞後出現低血壓而無法耐受降血壓治療方案，因此排除出研究。值得注意的是，在17例非致命性終止事件（A類及其他）中，16例發生在對照組，僅1例發生在治療組（表5）。

Nonterminating (Class B) Events.非終止性（B類）事件

B類事件包含無需或僅需暫時中止方案治療的器質性併發症（請參閱文末列出的可評估事件清單）。客觀可證實的動脈粥狀硬化併發症是B類事件的主要類型，但此類別也包括對常規治療（除降血壓藥物外）有效的充血性心臟衰竭以及某些較輕的腎臟疾病表現。

Nonterminating (Class B) Events. Class B events include organic complications which require no or only temporary suspensionof protocol treatment (see list of assessable events listed at the end of the communication). Objectively demonstrable atherosclerotic complications predominate as class B events, but the category also includes congestive heart failure responsive to routine therapy other than administration of antihypertensive drugs and certain less severe manifestations of renal disease. 

非致命性B類事件發生在21位對照組患者和13位治療組患者（表6）。 6例患者出現充血性心臟衰竭，可透過地高辛和短期利尿劑控制。值得注意的是，這6例患者皆在對照組。此外，對照組非終止性腦血管意外的發生率是治療組的兩倍。然而，接受治療的患者中有 5 例發生了非致命性心肌梗塞，而對照組中只有 2 例。兩組患者的心房顫動和傳導缺陷發生率基本上相同。

Nonfatal class B events occurred in 21 of the control patients and in 13 of the treated patients (Table 6). Six patients developed congestive heart failure controllable by digitalis and short-term administration of diuretics. It is noteworthy that all six of these patients were in the control group. Also, the incidence of nonterminating cerebrovascular accidents was twice as great in the control as in the treated patients. However, nonfatal myocardial infarction occurred in five of the treated patients as opposed to two of the control group. Theincidence of atrial fibrillation and conduction defects was essentially the same in the two groups.

生命表分析－使用生命表方法（圖 2）可以更精確地分析治療獲益。此方法具有以下優點：（1）它校正了患者入組時間不同，因此觀察時間長短不一的情況；（2）該方法校正了對照組和治療組之間觀察失訪率的差異；（3）最重要的是，它確定了治療獲益是早期出現、晚期出現還是持續存在。對照組和治療組之間的距離衡量了益處程度。從圖 2 可以清楚看出，治療獲益在早期就已顯現，並持續了整個五年的追蹤期。治療組中終止事件或所有發病事件的生命表分析表明，治療益處的程度較低。結果表明，隨著時間的推移，獲益逐漸增加。例如，就所有發病事件而言，可以看出，三年時對照組的估計累積發生率是治療組的兩倍。這表明，三年時治療的有效率約為50%。五年時，兩條曲線之間的差異顯著增大，顯示隨著時間的推移，獲益程度不斷提高。具體而言，五年時對照組的累積發生率上升至55%。相較之下，治療組五年時的發生率僅18%。因此，可以估計，五年內治療預防了37%的發病（55%減去18%），這代表了67%的有效率（37/55）。五年時，對照組的標準誤為6.3%，治療組為4.0%。 55% 和 18% 這兩個比率之間的差異具有統計意義，t 值為 5.0，具有高度統計意義。粗略估計得出，觀察到的 67% 有效率的置信區間為 49% 至 81%。治療與其他因素的關係－與診斷類別的關係。 ♥根據診斷類別將事件分類（表 7），檢視與治療相關的發病事件發生率具有重要意義。因此，在對照組和治療組中，充血性心臟衰竭的盛行率為 11:0，腎功能惡化的盛行率為 3:0，加速性高血壓（高血壓性視網膜病變或腦病變）的盛行率為 4:0。腦血管併發症的數量似乎也受到治療的顯著影響，因為對照組與治療組患者的腦血管事件發生率比為20:5，而對於更嚴重或致命性腦血管事件，該比值為12:1。另一方面，由冠狀動脈疾病（心肌梗塞或猝死）引起的可評估事件在兩組中幾乎相同，對照組為13例，治療組為11例，儘管對照組的致命性冠狀動脈事件略多。與隨機分組前血壓的關係：♥治療的益處在初始血壓水平較高的患者中最為明顯。就舒張壓而言，隨機分組前舒張壓平均值在105至114 mmHg之間的患者的治療有效率達到75%，而舒張壓平均值在90至104 mmHg之間的患者的治療有效率僅為35%（表8）。收縮壓方面也觀察到了類似的趨勢，儘管程度稍輕。初始收縮壓平均值在 165 mmHg 及以上的患者中，治療有效率達 64%，而初始收縮壓較低的患者組治療有效率僅為 40%。與年齡的關係。 ♥大多數患者在… 不良事件多見於老年組。在56例發生不良事件的對照組患者中，41例在入組時年齡為50歲或以上，而僅有15例年齡低於50歲。治療組患者的年齡分佈也類似。治療有效率在年輕組和老年組大致相同（表9）。然而，由於50歲以下患者的不良事件發生率較低，因此不能像老年患者那樣對其治療有效率的估計抱持同樣的信心。與種族的關係：黑人患者的不良事件發生率並不高於其他種族患者。事實上，在對照組中，黑人患者的不良事件發生率略低，為25.9%，而其他患者的發生率為31.0%。治療組患者也觀察到了類似的關係（表9）。兩個種族組的治療有效率基本上相同。副作用：治療組患者經常需要調整劑量，因為會出現低血壓和其他症狀。後續報告將對這些及其他副作用進行全面分析。上文已描述了兩名因藥物毒性而退出研究的患者。此外，本報告僅考慮需要從治療方案中移除利血平或氫氯噻嗪的副作用。共有29名患者因副作用而停止服用利血平、氫氯噻嗪或其安慰劑。利血平和氫氯噻嗪以複方片劑形式給藥。為了避免因疑似這兩種藥物之一引起的副作用而導致患者退出研究，研究方案允許用僅含利血平或氫氯噻嗪的片劑替代，從而避免使用引起不良反應的藥物。參與研究的醫生可提出申請取得這些特殊片劑。對照組患者則服用外觀相似的安慰劑片劑，醫師不知道替代的片劑是活性藥物還是安慰劑。在29名患者中，大多數患者需要更換特殊片劑是由於疑似利血平引起的副作用。 12名患者出現精神憂鬱。然而，其中只有7名患者接受了活性藥物治療，其餘5名患者被隨機分配接受安慰劑。 10名患者出現消化性潰瘍，其中6名患者服用活性藥物，4名患者服用安慰劑。 2名患者因陽痿而更換了藥物；這2名患者中，1名被隨機分配接受安慰劑治療。其餘6名患者均接受了活性藥物治療。他們的副作用包括嗜睡、嚴重鼻塞、痛風、疑似由低血壓引起的癲癇發作以及葡萄糖耐受試驗結果異常。

評論

對於隨機分組前收縮壓高於 164 mmHg 或舒張壓高於 104 mmHg 的患者，治療效果顯著。對於血壓低於上述水平的患者，對照組和治療組之間的併發症發生率差異不太明顯。這可能是由於輕度高血壓患者的器質性併發症出現緩慢，正如血壓低於 165/105 mmHg 的患者此類併發症發生率顯著降低所表明的那樣。正如預期的那樣，老年患者的器質性併發症發生率高於年輕患者。值得注意的是，治療能有效降低老年患者的併發症發生率。儘管治療效果在 50 歲以上和 50 歲以下患者中基本相同，但由於對照組和治療組患者的併發症發生率均較低，因此年輕組的治療效果並不十分顯著。然而，需要指出的是，在20名對照組患者中，有14名患者因舒張壓持續高於124 mmHg而被排除出研究，他們並未被計入發生併發症的病例。治療在預防高血壓併發症方面最為有效，但在預防動脈粥狀硬化併發症（尤其是與冠狀動脈疾病相關的併發症）方面效果最差。充血性心臟衰竭、腎損傷、腦血管出血和高血壓加速進展等併發症僅發生在對照組。另一方面，對照組和治療組患者冠狀動脈疾病相關併發症的發生率基本上相同。由於動脈粥狀硬化是一個漸進的過程，因此在預防心肌梗塞和猝死方面未觀察到療效並不能作為治療無效的證據。鑑於在預防高血壓併發症方面已取得的良好證據，本研究無需繼續進行。如果追蹤時間較長，且更早開始服用降血壓藥，或許能顯示出顯著差異。患者平均年齡為51歲，高血壓可能在隨機分組前已存在多年。因此，冠狀動脈粥狀硬化在入組時可能已相當嚴重。需要對更精準的人群進行進一步試驗，以確定降血壓治療是否有助於預防冠狀動脈疾病。值得注意的是，本研究中初始舒張壓平均為 90 至 114 mmHg 的患者結果，與先前報告的初始舒張壓平均為 115 至 129 mmHg 的患者結果進行了比較。 ☂ 在後一組患者中，治療效益迅速顯現。該組對照組患者在平均僅 15.7 個月的隨機分組後追蹤期內，有 38% 的患者發生了可評估的事件，而治療組患者的比例僅為 3%。在本研究中，舒張壓水平較低的患者需要更長的追蹤期才能證實治療的顯著效益。根據初始舒張壓水平劃分的兩組患者，其事件類型的分佈也存在差異。在初始舒張壓水平為 115 至 129 mmHg 的對照組患者中，高血壓性視網膜病變伴隨加速性高血壓是最常見的併發症。在本系列研究中，腦血管疾病、充血性心臟衰竭和冠狀動脈疾病是對照組最常見的併發症。在先前報告的高舒張壓患者係列中，4例對照組死亡患者中有3例死於主動脈剝離或破裂，而低舒張壓患者係列中最常見的死亡原因是中風、心肌梗塞和猝死。需要強調的是，本研究針對的是經過篩選的族群。在隨機分組前的觀察期內，透過藥片計數、尿液螢光試驗結果以及門診就診不規則等方法，識別並排除了許多不配合或不可靠的患者。顯然，如果患者族群的配合度沒有經過如此嚴格的篩選，治療效果將會大打折扣。該研究族群的限制在於，它排除了女性患者以及住院第四至第六天舒張壓平均值低於90 mmHg的不穩定型高血壓患者。此外，50歲以下族群的併發症發生率相對較低。需要進一步研究來評估治療不穩定型高血壓以及預防動脈粥狀硬化併發症（尤其是冠狀動脈疾病）的有效性。這類研究似乎需要納入更多年輕患者。在本研究報告的舒張壓較低患者係列病例中，需要更長的追蹤期才能證實治療的顯著益處。根據初始舒張壓水平劃分的兩組患者，其事件類型分佈也存在差異。在初始舒張壓 115 至 129 mmHg 的對照組患者中，高血壓性視網膜病變伴隨加速性高血壓是最常見的併發症。而在本研究系列中，對照組最常見的併發症是腦血管疾病、充血性心臟衰竭和冠狀動脈疾病。在先前報告的舒張壓較高患者係列中，4 例死亡的對照組患者中，3 例死於主動脈夾層或破裂性主動脈瘤；而在舒張壓較低患者係列中，最常見的死亡原因是中風、心肌梗塞和猝死。需要強調的是，本研究針對的是特定族群。在隨機分組前的觀察期內，研究人員根據藥片計數、尿液螢光檢測結果以及門診就診不規則等情況，識別並剔除了許多不配合且不可靠的患者。顯然，如果患者族群在配合度方面選擇不夠嚴格，治療效果會大打折扣。此外，研究族群也受到限制，因為它排除了女性患者以及住院第四至第六天舒張壓平均值低於90 mmHg的不穩定型高血壓患者。最後，50歲以下族群的併發症發生率相對較低。需要進一步的研究來評估治療不穩定型高血壓以及預防動脈粥狀硬化併發症（尤其是冠狀動脈疾病）的有效性。這類研究似乎需要納入更多年輕患者。在本研究報告的舒張壓較低患者係列病例中，需要更長的追蹤期才能證實治療的顯著益處。根據初始舒張壓水平劃分的兩組患者，其事件類型分佈也存在差異。在初始舒張壓 115 至 129 mmHg 的對照組患者中，高血壓性視網膜病變伴隨加速性高血壓是最常見的併發症。而在本研究系列中，對照組最常見的併發症是腦血管疾病、充血性心臟衰竭和冠狀動脈疾病。在先前報告的舒張壓較高患者係列中，4 例死亡的對照組患者中，3 例死於主動脈夾層或破裂性主動脈瘤；而在舒張壓較低患者係列中，最常見的死亡原因是中風、心肌梗塞和猝死。需要強調的是，本研究針對的是特定族群。在隨機分組前的觀察期內，研究人員根據藥片計數、尿液螢光檢測結果以及門診就診不規則等情況，識別並剔除了許多不配合且不可靠的患者。顯然，如果患者族群在配合度方面選擇不夠嚴格，治療效果會大打折扣。此外，研究族群也受到限制，因為它排除了女性患者以及住院第四至第六天舒張壓平均值低於90 mmHg的不穩定型高血壓患者。最後，50歲以下族群的併發症發生率相對較低。需要進一步的研究來評估治療不穩定型高血壓以及預防動脈粥狀硬化併發症（尤其是冠狀動脈疾病）的有效性。這類研究似乎需要納入更多年輕患者。三例死亡病例由主動脈剝離或破裂性主動脈瘤引起，而舒張壓較低的患者係列中最常見的死亡原因是中風、心肌梗塞和猝死。需要強調的是，本研究針對的是特定族群。在隨機分組前的觀察期內，透過藥片計數、尿液螢光試驗結果以及門診就診不規則等方法，識別並排除了許多不配合或不可靠的患者。顯然，如果患者配合度較低，治療效果會大打折扣。此外，本研究族群仍有局限性，排除了女性患者以及住院第四至第六天舒張壓平均值低於90 mmHg的不穩定型高血壓患者。最後，50歲以下族群的併發症發生率相對較低。未來需要進行更多研究，以評估治療不穩定型高血壓以及預防動脈粥狀硬化併發症（尤其是冠狀動脈疾病）的有效性。這類研究似乎需要更多年輕患者。三例死亡病例由主動脈剝離或破裂性主動脈瘤引起，而舒張壓較低的患者係列中最常見的死亡原因是中風、心肌梗塞和猝死。需要強調的是，本研究針對的是特定族群。在隨機分組前的觀察期內，透過藥片計數、尿液螢光試驗結果以及門診就診不規則等方法，識別並排除了許多不配合或不可靠的患者。顯然，如果患者配合度較低，治療效果會大打折扣。此外，本研究族群仍有局限性，排除了女性患者以及住院第四至第六天舒張壓平均值低於90 mmHg的不穩定型高血壓患者。最後，50歲以下族群的併發症發生率相對較低。未來需要進行更多研究，以評估治療不穩定型高血壓以及預防動脈粥狀硬化併發症（尤其是冠狀動脈疾病）的有效性。這類研究似乎需要更多年輕患者。 可以對這些患者進行長期追蹤。然而，在本研究的範圍內，目前的結果幾乎可以肯定地表明，抗高血壓藥物治療是有益的。目前的結果，連同先前報告的初始舒張壓為 115 至 129 mmHg 的患者的結果，清楚地表明血壓越高，此類治療的益處就越大。在接受治療的患者中，某些併發症，例如充血性心臟衰竭、高血壓性視網膜病變、中風和腎功能惡化，均減少或基本消除。此外，治療也阻止了舒張壓升高到顯著增加高血壓併發症風險的程度。治療在預防這種進展方面的有效性體現在，儘管約 10% 的對照組患者出現了持續性舒張壓升高超過 124 mmHg 的情況，但在治療組中完全沒有出現這種情況。

Three hundred and eighty male hypertensive patients with diastolic blood pressures averaging 90 to 114 mmHg were randomlyassigned to either active antihypertensive agents or placebos. The estimated risk of developing a morbid event overa 5-year period was reduced from 55% to 18% by treatment. Terminating morbid events occurred in 35 patients of the control group as comparedto 9 patients in the treated group. Nineteen deaths related to hypertension or atherosclerosis occurred in the control group and 8 in the actively treated group. In addition to morbid events, 20 control patients developed persistent diastolic levels of 125 mm Hg or higher. Treatment was moreeffective in preventing congestive heartfailure and stroke than in preventing the complicationsof coronary artery disease. The degree of benefit wasrelatedto the level of prerandomization blood pressure.




In a previous publication in this journal the Veterans Administration Cooperative Study Group on Antihypertensive Agents reported on the beneficial effects of antihypertensive drugs on morbidity in patients with moderately severe hypertension. These were patients with initial diastolic blood pressures averaging 115 through 129 mm Hg who had been randomized into a prospective double-blind trial of active antihypertensive drugs vs placebos. Twenty-seven patients developed assessable events in the control group as compared to two patients in the group receiving active antihypertensive agents. This striking result favoring treatment was in agreement. with the results of other prospective trials?? in patients with hypertension of similar severity. In hypertension of lesser severity, however, there are little or no controlled data available on the value of antihypertensive drug therapy. Resolution of this question is of great importance not only because of the large numberof patients with mild hypertension but also because the potential benefits of drug treatment have been questioned especially in this group of hypertensive patients.* The present report presents the results of a prospective, controlled trial of drug treatment on morbidity and mortality in a group of 380 patients with mild or moderate hypertension whose initial diastolic blood pressure averaged 90 through 114 mm Hg.

Plan of investigation

The clinical trial included 523 male veterans who, while not receiving antihypertensive treatment, exhibited diastolic blood pressures averaging 90 through 129 mm Hg. Randomization of patients began int April 1964.

However, in May 1967, the study was terminated in the subgroup of 143 patients whose diastolic blood pressures averaged 115 through 129 mm Hgprior to randomization. Termination of the study of this group as previously reported☂ was necessitated by the high incidence of morbid events in the control as compared to the treated patients, demonstrating at a relatively early date a highly significant (P < 0.001) effect of treatment. Such a significant difference was not evident at the time, however, in the patients whose diastolic blood pressures averaged below 115 mm Hg prior to randomization. These latter patients were continued in the randomized trial until 1969 and are the subject of the present communication. The experimental design has been described in previous reports.'* Initially all patients were hospitalized for diagnosis and evaluation of the severity of their hypertension. Patients whose diastolic blood pressure averaged 90 through 129 mm Hg during the fourth through sixth hospital day were accepted for further follow-up. Patients whose diastolic averages fell below 90 mm Hg or rose above 129 mm Hg during this period of hospitalization were excluded. Following hospitalization the patients entered a prerandomization observation period of two to four months☂ duration during which time they received placebos of antihypertensive agents. The patients whose diastolic blood pressures during the last two clinic visits of the observation period averaged 90 through 129 mm Hg were entered into the trial, providing there were no other reasons for exclusion. Blood pressure was measured by a physician with the patient in a sitting position. Other reasons for excluding patients from the trial, in addition to diastolic blood pressure, are detailed in other reports.☂☂> Such reasons included a history of a severe hypertensive complication such as a cerebral or subarachnoid hemorrhage, hypertensive neuroretinopathy, dissecting aneurysm, or renal failure, but did not include atherosclerotic complications such as coronary artery disease or cerebrovascular thrombosis. Also excluded were (1) patients with surgically curable hypertension, (2) with unrelated fatal diseases such as malignant tumors, (3) those unwilling or unable to return to clinic, and (4) poorly motivated or otherwise uncooperative or unreliable patients. The outpatient prerandomization observation period provided a further opportunity to check on the reliability of the patients. Riboflavin, which produces bright yellow fluorescence of the urine, was incorporated in the placebos. At each clinic visit a urine specimen was examined under ultraviolet light. In addition, pill counts were made at each clinic visit. No patient wa accepted into the randomized trial unless the urine exhibited fluorescence andthepill counts were within a stipulated range, at each of two successive visits during the prerandomization observation period. Accepted patients were then randomly assigned double-blind to either active drugs or placebos. Active drugs consisted of two types of tablets, one being a combination tablet containing 50 mg hydrochlorothiazide and 0.1 mg_ reserpine which was given twice daily. The other was 25 mg of hydralazine hydrochloride given three times JAMA, Aug 17, 1970 © Vol 213, No 7 daily. The latter medication was raised to 50 mg three times daily if the diastolic blood pressure remained at 90 mm Hgorhigher. Obviously, practically all of the patients in the placebo group had their ☜doses☝ raised to this level. Provision was made for reduction of doses if hypotensive reactions or other disturbing side effects occurred. Patients in the control group received placebos identical in taste and appearanceto the active drugs. Indicated symptomatic treatment, including drugs other than antihypertensive agents, was permitted in all patients. Postrandomization clinic visits were at monthly intervals for the first two months and at bimonthly intervals thereafter. Annual examinations included taking a history and a physical examination, roentgenogram of the chest, electrocardiogram, pertinent chemical analyses of the blood, and renal function tests. Additional interim visits could be scheduled when indicated.

Characteristics of Patients Three hundred and eighty patients with diastolic blood pressures averaging 90 through 114 mm Hg were randomized into the trial. Of this number, 186 received active drugs while 194 were given placebos. Tables 1 and 2 indicate that the two groups were comparable according to the indicated variables. The median ages were 49.2 and 48.1 years and the average ages were 52.0 and 50.5 years in the control and treatment groups, respectively. Negro patients comprised 42%, of the control group and 41% of the treated group. Blood pressure as measured in the clinic during the posthospitalization observation period prior to randomization averaged 165.1/104.7 mm Hg in the control group and 162.1/103.8 mm Hg in the treated patients. There were no significant differences between the control and treated patients with regard to findings from renal function tests, fasting blood sugar value, serum cholesterol value, uric acid level, and left ventricular enlargement as assessed by x-ray films and electrocardiography. By all factors measured the two groups were comparable. Duration of Observation Patients were entered into the trial from April 1964 to September 1968, and the study was terminated in October 1969. Thus, the earliest entrants were observed for 5.5 years and the latest entrants for a minimum of 1 year. The average potential duration of observation, disregarding losses and terminations, was 3.9 years for the control group and 3.7 years for the treated patients. However, because of the losses and terminations due to elevated diastolic blood pressure described below, the actual duration of postrandomization observation was 3.3 years for the control group and 3.2 years for the treated patients.

Changes in Blood Pressure Systolic and diastolic blood pressure fell promptly and significantly in the treated patients and remained at reduced levels throughout the trial. The changes in blood pressure at the fourth month of observation in the treated and control patients are depicted in Fig 1. The mean change in systolic blood pressure was an increase of 4.2 mm Hg in the control group and a fall of 27.2 mm Hgin the treated patients from the levels recorded during the prerandomization observation period. The mean change in diastolic blood pressure was a rise of 1.2 mm Hgin the control patients and a fall of 17.4 mm Hgin the treated group during this same interval. The distribution of the changes in blood pressure as shown in Fig 1 indicates a marked shift to the left into the ☜decrease☝ zone for the treated patients as compared to the control group. Also apparent is the wide variation in individual responses particularly with regard to systolic blood pressure. Losses Other Than Assessable Events Deaths Due to Unrelated Conditions._Four patients died of disorders unrelated to hypertension. Two of the patients were in the control group. One died of generalized carcinomatosis demonstrated at autopsy and the other of uremia secondary to carcinoma of the urinary bladder. One patient in the treated group died of a subdural hematomafollowing a skull fracture and another of penicillin anaphylaxis. Postmortem examination was carried out in both of these patients. Losses Due to Drug Toxicity.♥ Twopatients in the treatment group developed reactions thought to be due to drug toxicity. The first patient developed orbital edema with fever and malaise. Roentgenogram of the chest revealed infiltrates in the lungs. There was no dermatitis or arthritis. Lupus cells were not found in the blood although the antinuclear antibody test was positive. Protocol drugs were discontinued because of the possibility of lupus syndrome associated with hydralazine. The second patient developed purpura one month after beginning active drug treatment. Findings from examination in the hospital, including biopsy, were consistent with anaphylactoid purpura. The purpuric lesions cleared two weeks after protocol treatment was discontinued and reappeared within three days after administration of active drugs began again. Protocol treatment was, therefore, discontinued.

Drop-Outs.♥Fifty-six or 15% of the 380 randomized patients were classified as drop-outs during the course of the trial. Of this number 27 had been randomized to receive placebos and 29 to receive active drugs. The average period of followup prior to dropping out was 17.6 months with a range from less than 1 month to 49 months. Six patients moved away from the area of the clinic. Two were lost from follow-up because of closure of one participating clinic. Four returned to the care of their private physicians. Fifteen 1146 complained of side effects prior to dropping out. Nineof these patients had been receiving drugs, and six were taking placebos. Five patients had psychiatric or alcoholic problems of such severity as to make continued protocol treatment impractical. In the remaining patients the reason for drop-out could not be determined. It should be noted that three of the patients taking placebos sustained nonterminating morbid events prior to their dropping out.

Assessable Morbid Events The records of the patients reported as having assessable morbid events were reviewed by two consulting physicians who had not participated in thetrial. All assessable events were reviewed except those related to the development of electrocardiographic signs of left ventricular hypertrophy or of roentgenographic evidence of cardiac enlargement, which will be reported in a subsequent communication. All available data pertaining to each organic complication, except the type of protocol treatment and the level of blood pressure, were presented to the reviewers and their decisions regarding the occurrence and classification of an event according to the definitions given in the protocol (see list of assessable events at the end of the communication) were accepted as final. Table 3 summarizes the assessable events by major categories. Such events occurred in 98 of the 380 randomized patients, 76 in the control group and 22 in the treated patients. Of this number 20 control patients developed an increase in diastolic blood pressure to levels exceeding 124 mm Hg on three separate clinic visits and persisting for 3 weeks or longer. Since these patients were removed from the trial only because of persistent blood pressure elevations and not for an organic complication, they will not be included in the subsequent assessment of effectiveness of treatment in preventing morbid events, The remaining 78 patients had organic complications subdivided as follows: 56 of 194 or 28.9% of the control group and 22 of 186 or 11.8% of the treated patients. The most striking evidence of benefit of treatment was manifested in the count of class A events (hypertensive complications defined in the protocol which required removal of the patient from the study.' There were none among the treated patients but 14 among the controls. These included five class A deaths (Table 4) plus nine other class A events (Table 5). When other cardiovascular (class B) deaths and treatment failures were added, the comparisons were still impressive, 35 of 194 patients or 18.09% amongst the controls and only 9 of 186 or 4.8% in the treated group (Table 3). The effectiveness of treatment (difference in percent incidence of complications between control and treated groups divided by the percent incidence in the control group) in preventing terminating organic complications was 73% (Table 3). The decision to discontinuethetrial wasbased onthis favorable evidence supplemented by the life-table analyses described below which suggested that the benefit of treatment was continuing through time and was not solely concentrated in the first year or two of treatment. Terminating Events. ♥ DEATHS RELATED TO CARDIOVASCULAR DisEASE.♥Twenty-seven patients died of hypertensive or atherosclerotic complications, 19 occurring in the control group and 8 in the treated patients (Table 4). Five deaths associated with class A or hypertensive events (see list of assessable events at the end of the communication) were cerebral hemorrhage in four and dissecting aortic aneurysm in one, all occurring in the control group of patients. Deaths resulting from class B events were eh Ol eee eo . Ree Oo © OG e;ooo0d0 | Axor associated predominantly with coronary artery disease. Eleven patients in the placebo group and 6 in the treated group hadeither a documented myocardial infarction or a ☜sudden death.☝ Cerebrovascular thrombosis as opposed to hemorrhage was the cause of death in three contro] patients andin one treated patient. The remaining death in the treated group was ure.☝ * ur we associated with caused by a rupture of an ather- cerebrovascu☂: ccidents diagnosed osclerotic aneurysm of the aorta. Oruer Crass A Events.♥Nine patients in the control group as opposed to none in the treated group developed nonfatal class A events (Table 5). Five of the patients had congestive heart failure which could not be controlled by administration of digitalis, sodium restriction, and the intermittent administration of diuretics. In the four remaining patients there was one instance of each of the following complications: dissecting aortic aneurysm, subarachnoid hemorrhage, multiple striate retinal hemorrhages, and acute hypertensive encephalopathy with accompanying neurological signs. OTHER TERMINATING EVENTS.♥ Additional organic complications, which did not fulfill the criteria for class A events but which were nevertheless of sufficient severity to require terminating protocol treatment occurred in eight patients of which seven were in the control group. These are listed in Table 5 under the subtitle ☁☁treatment fail clinically as tor mbosis rather than hemorrhage but which resulted in such severe inc::pacity that the patients were urable to attend the clinic. Two additional control patients were removed from the study because «* the appearance of a single st: ate retinal hemorrhage associated in one with symptoms suggesting acute hypertensive encephalopathy, and, in the other, with questionable early papilledema. The remaining control patient exhibited increasing azotemia. One patient in the treated group was removed from the study because of hypotension following a myocardial infarction which resulted in his inability to tolerate the antihypertensive regimen. It is neteworthy that of the 17 nonfatal terminating events (class A and others) 16 occurred in the control group and only one in the treated patient (Table 5). Nonterminating (Class B) Events. ♥Class B events include organic complications which require no or only temporary suspension of protocol treatment (see list of assessable events listed at the end of the communication). Objectively demonstrable atherosclerotic complications predominate as class B events, but the category also includes congestive heart failure responsive to routine therapy other than administration of antihypertensive drugs and certain less severe manifestations of renal disease. Nonfatal class B events occurred in 21 of the control patients and in 13 of the treated patients (Table 6). Six patients developed congestive heart failure controllable by digitalis and short-term administration of diuretics. It is noteworthy that all six of these patients were in the control group. Also, the incidence of nonterminating cerebrovascular accidents was twice as great in the control as in the treated patients. However, nonfatal myocardial infarction occurred in five of the treated patients as opposed to two of the control group. Theincidence of atrial fibrillation and conduction defects was essentially the same in the two groups.

Life-Table Analysis.-The benefit of treatment is more precisely analyzed using life-table methods (Fig 2). This method has the following advantages: (1) it adjusts for the fact that patients enter the study at different times and thus are observed for varying lengths of time; (2) the method adjusts for any differences in losses to observation between the control and treated groups; and (3) most important, it determines whether the benefit of treatment occurs early or late or is continuing through time. The distance separating the control and treatment lines is a measure of the degree of benefit. It is clear from Fig 2 that the benefit of treatment manifested itself early and continued throughout the entire five years of follow-up. The life-table analysis of either terminating or all morbid events indicates that the benefit increased with time. For example, with respect to ☜all morbid events☝ it may be seen that at three years the estimated cumulative incidence of morbidity in the control group is twice as great as in the treated patients. This suggests that treatment was about 50% effective at three years. At five years the spread between the two curves was substantially greater indicating an increasing degree of benefit with the passage of time. Specifically, at five years the cumulative incidence rate of events for the control group rises to 55%. By contrast, for the treated group the indicated incidence of events at five years is only 18%. It can be estimated, therefore, that over a five-year period treatment prevented 37% morbidity (55% minus 18%), and this represents a 67% effectiveness (37/55). The standarderrors at five years were 6.3% for the control patients and 4.0% for the treated group. The significance of the difference between the two rates of 55% and 18% yielded a t-value of 5.0 which is highly significant. A crude estimate gave confidence limits of 49% to 81% for the observed 67% effectiveness. Relationship of Treatment to Other Factors.-RELATIONSHIP TO Discnostic Catecories.♥It is revealing to examine the incidence of morbid events as related to treatment when the events are classified according to diagnostic categories (Table 7). Thus, in the control vs the treated groups, the prevalence of congestive heart failure was 11:0, of renal deterioration 3:0, and of ☜accelerated☝ hypertension (hypertensive neuroretinopathy or encephalopathy) 4:0. The number of cerebrovascular complications also seemed to be considerably influenced by treatment since the ratio of cerebrovascular events in the control vs treated patients was 20:5, and, of the more severe or terminating cerebrovascular events, it was 12:1. On the other hand, assessable events caused by coronary artery disease (myocardial infarction or sudden death) were nearly the same in the two groups, 13 in the control and 11 in the treated, although fatal coronary events were somewhat greater in the control group. RELATIONSHIP TO PRERANDOMIZATION BLoop PressurE.♥The beneficial effect of treatment was most evident in the patients with higher initial levels of blood pressure. With respect to diastolic blood pressure the effectiveness of treatment was 75% in the patients with prerandomization diastolic blood pressure averaging 105 through 114 mm Hg as opposed to only 35% in the group averaging 90 through 104 mm Hg (Table 8). A similar although somewhat less striking trend was noted with respect to systolic blood pressure, the effectiveness of treatment being 64% in patients with initial systolic levels averaging 165 mm Hg and above as opposed to 40% in the group with lower initial systolic blood pressure. RELATIONSHIP TO AGE.♥The majority of the patients developing morbid events were in the older age group. Of the 56 control patients developing morbid events 41 were 50 years of age or older at the time of admission to the study, while only 15 were below age 50. A similar distribution was found with respect to the treated patients. The percent effectiveness of treatment was approximately the same in the younger and older groups (Table 9). However, because of the lower number of events in the patients below age 50 the estimated effectiveness of treatment cannot be accepted with the same degree of confidence as in the older patients. RELATIONSHIP TO RaAce.♥The incidence of morbid events was no greater in Negro patients. In fact, in the control group the incidence of events was slightly lower in Negroes, 25.9% as opposed to 31.0% of the other patients. A similar relationship was noted in the treated patients (Table 9). The percent effectiveness of treatment was essentially the same in the two racial groups. Side Effects In the treated group of patients dosage adjustments frequently were required because of hypotensive and other symptoms. A complete analysis of these and other side effects will be made in a subsequent communication. The two patients lost to protocol because of drug toxicity have been described above. In addition, in the present report only those side effects requiring removal of either reserpine or hydrochlorothiazide from the treatment regimen will be considered. Administration of either reserpine or hydrochlorothiazide or their placebos was withdrawn because of side effect in 29 patients. Reserpine and hydrochlorothiazide were administered combined in a single tablet. In order to avoid losses to protocol because of side effects presumably caused by one or the other of the two agents, provision was made to permit substitution of a tablet which contained either reserpine or hydrochlorothiazide alone and omitted the offending medication. These special tablets were made available on request of a participating physician. Similarappearing placebo tablets were made available for the control patients and the physician did not know whether the substitution represented active drugs or placebos. In the majority of the 29 patients substitution of the special tablet was necessitated by presumed reserpine-induced side effects. Mental depression occurred in 12 patients. However, only seven of these patients had been receiving active drugs while the remaining five had been randomly selected to receive placebos. Ten patients developed peptic ulcer of which six had been taking active drugs and four placebos. In two patients substitution was made because of impotence; one of these two had been randomly selected to receive the placebo regimen. The remaining six patients all were receiving active treatment. Their side effects included sleepiness, severe nasal stuffiness, gout, seizures presumably caused by hypotension, and abnormal results from the glucose tolerance test.

Comment

The effectiveness of treatment was clearly demonstrated in the patients with prerandomization systolic blood pressures above 164 or diastolic pressure above 104 mm Hg. The difference in the incidence of morbid events between control and treated patients was less clear cut in the patients with blood pressures below these levels. This may be due to the fact that organic complications appear slowly in mild hypertension as indicated by the considerably☂ lower incidence of such events in patients with blood pressures below 165/105 mm Hg. As would be expected, a greater incidence of organic complications occurred in the older than in the younger patients. Of considerable importance is the observation that treatment was found to be effective in reducing the number of such complications in these older patients. Although the indicated effectiveness of treatment was essentially the same in patients above and below age 50 years, the results were not as convincing in the younger group because of the low incidence of morbid events in both the control and treated patients. It should be mentioned, however, that in the group of 20 control patients, not counted as having morbid events but who were removed from the study because of persistent elevation of diastolic blood pressure greater than 124 mm Hg, 14 so removed were below 50 years of age. Treatment was most effective in preventing hypertensive complications and least effective in preventing atherosclerotic complications, particularly those associated with coronary artery disease. Complications such as congestive heart failure, renal damage, cerebrovascular hemorrhage, and accelerated hypertension occurred only in the control group. On the other hand, the incidence of complications associated with coronary artery disease was essentially the same in the control and treated patients. Because of the gradual progression of atherosclerosis, the negative result with regard to prevention of myocardial infarction and sudden death cannot be taken as evidence that treatment is ineffective. Continuation of the present study was not justified because of the favorable evidence with regard to prevention of hypertensive complications. If follow-up had been longer, and if administration of antihypertensive drugs had been started at an earlier age, a significant difference might have been demonstrated. The average age of the patients was 51 years and hypertension could have been present for many years prior to randomization. Atherosclerosis of the coronary arteries, therefore, may have been well established at the timeof entrance into the study. Further trials are needed in a more selected population to determine whether antihypertensive treatment helps prevent coronary artery disease. It is of interest to compare the results of the present series of patients whose initial diastolic blood pressures averaged 90 through 114 mm Hg with the results previously reported in the patients whose diastolic blood pressures at the beginning of study averaged 115 through 129 mm Hg.☂ The benefit of treatment was quickly manifested in the latter series. Thirty-eight percent of the control patients in that series developed assessable events over an average period of only 15.7 months of postrandomization follow-up, whereas such events occurred in only 3% of the treated patients. A considerably longer period of follow-up was required to demonstrate a significant benefit of treatment in the presently reported series of patients with lower levels of diastolic blood pressure. The distribution as to type of events also was different in the two groups of patients divided according to level of initial diastolic blood pressure. In the control patients with initial diastolic levels of 115 through 129 mm Hg accelerated hypertension with hypertensive neuroretinopathy was the most frequent complication. In the present series cerebrovascular disease, congestive heart failure, and coronary artery disease were the most frequent morbid events occurring in the control group. Of the four control patients who died in the previously reported series of patients with high diastolic pressures, three deaths were caused by dissecting or ruptured aortic aneurysm whereas the most commoncauses of death in the series of patients with lower diastolic pressures were strokes, myocardial infarcts, and sudden death. It should be emphasized that the present study dealt with a selected population. Many uncooperative and unreliable patients were identified and eliminated from thetrial on the basis of pill counts, urine fluorescence test results, and irregularity of clinic attendance during a prerandomization observation period. Treatment obviously would not have been as effective in a group of patients less carefully selected with regard to their desire to cooperate. The population was further limited in that it excluded female patients and patients with labile hypertension whose diastolic blood pressures averaged lower than 90 mm Hgduringthe fourth through the sixth day of hospitalization. Finally, the incidence of morbid events in the group below age 50 was relatively low. Further studies are needed to evaluate the effectiveness of treatment in labile hypertension and in the prevention of atherosclerotic complications, particularly coronary artery disease. Such studies would seem to require larger numbers of younger patients who can be followed up for long periods of time. Within the limits defined by this study, however, the present results leave little doubt that antihypertensive drug treatment is beneficial. The present results together with those previously reported in patients with initial diastolic blood pressures of 115 through 129 mm Hg! indicate clearly that the higher the level of blood pressure the greater the degree of benefit of such therapy. Certain complications such as congestive heart failure, hypertensive neuroretinopathy,' strokes, and renal deterioration were reduced or essentially eliminated in the treated patients. In addition, treatment prevented elevation of diastolic blood pressure to levels where the risk of developing hypertensive complications is greatly increased. The effectiveness of the treatment in preventing such progression is indicated by the fact that while persistent elevation of diastolic blood pressure exceeding 124 mm Hg occurred in approximately 10% of the control patients, they were completely absent in the treated group.

內科-腎臟-Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy September 20, 2001

2026-09-01 11:27 

這篇是相當久遠的研究. 2001年刊登在 NEJM

Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy  NEJM September 20, 2001
Abstract
Background
Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin–angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II–receptor antagonist losartan in patients with type 2 diabetes and nephropathy.
Methods
A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease.
Results
A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo).
Conclusions
Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.
Interruption of the renin–angiotensin system with angiotensin-I–converting enzyme inhibitors slows the progression of renal disease both in patients with type 1 diabetes and in nondiabetic patients who have overt nephropathy.1–3 However, postponing end-stage renal disease in patients with type 2 diabetes, the leading cause of chronic renal failure in many countries, remains an elusive goal. We undertook a study in patients with type 2 diabetes and nephropathy in order to determine whether the angiotensin-II–receptor antagonist losartan, alone or in combination with conventional antihypertensive therapy, would increase the time to a doubling of the serum creatinine concentration, the onset of end-stage renal disease, or death. In addition, we assessed the effects of losartan and placebo on the following secondary end points: a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease.
Methods
Study Design
The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study was an investigator-initiated, multinational, double-blind, randomized, placebo-controlled study designed to evaluate the renoprotective effects of losartan in 1513 patients with type 2 diabetes and nephropathy. The study design has been described previously.4 In brief, 250 centers in 28 countries in Asia, Europe, Central America, South America, and North America participated. The study protocol was approved by the institutional review board of each center, and all patients gave written informed consent. The study was overseen by steering and safety committees, each of which contained one nonvoting member who was an employee of the sponsoring pharmaceutical company. The steering committee oversaw the study design, the conduct of the trial, and the management and analysis of the data. A writing subcommittee of the steering committee prepared this report. An independent end-points committee whose members were unaware of the patients' treatment assignments reviewed the data to determine which patients had reached the end points.
We planned to complete the study 3.5 years after the last patient underwent randomization, which would have resulted in a mean follow-up time of 4.5 years. However, the study was discontinued early (February 10, 2001) by a unanimous vote of the steering committee, whose members were unaware of the treatment assignments. Their decision was based on new evidence suggesting that angiotensin-I–converting enzyme inhibitors, which were excluded by design from the study, may be effective in reducing the incidence of cardiovascular events in patients with renal impairment, including those with diabetes.5 Therefore, the results reported here represent a mean follow-up time of 3.4 years (range, 2.3 to 4.6).
Patients
The study involved male and female patients, ranging in age from 31 to 70 years, who had received diagnoses of type 2 diabetes and nephropathy. Nephropathy was defined by the presence on two occasions of a ratio of urinary albumin (measured in milligrams per liter) to urinary creatinine (measured in grams per liter) from a first morning specimen of at least 300 (or a rate of urinary protein excretion of at least 0.5 g per day) and serum creatinine values between 1.3 and 3.0 mg per deciliter (115 and 265 μmol per liter), with a lower limit of 1.5 mg per deciliter (133 μmol per liter) for male patients weighing more than 60 kg. Patients were excluded if they had received a diagnosis of type 1 diabetes or nondiabetic renal disease, including renal-artery stenosis. We also excluded patients who had had a myocardial infarction or had undergone coronary-artery bypass grafting within the previous month, who had had a cerebrovascular accident or had undergone percutaneous transluminal coronary angioplasty within the previous six months, who had had a transient ischemic attack within the previous year, or who had any history of heart failure before enrollment.4
Treatment
During the six-week screening phase, patients with hypertension continued to receive their standard antihypertensive therapy. If they had been taking angiotensin-I–converting enzyme inhibitors or angiotensin-II–receptor antagonists, however, these medications were discontinued and replaced by alternative open-label medications (diuretics, calcium-channel antagonists, alpha- or beta-blockers, centrally acting agents, or some combination of these types of medication). Patients were stratified according to their base-line level of proteinuria (a urinary albumin-to-creatinine ratio <2000 or ≥2000) and randomly assigned to receive either losartan (50 mg) or placebo once daily, along with conventional antihypertensive therapy. After four weeks, the dose of losartan or placebo was increased to 100 mg or the placebo equivalent once daily if the trough blood pressure with the patient sitting was above the target level of a systolic blood pressure of less than 140 mm Hg and a diastolic blood pressure of less than 90 mm Hg. After an additional eight weeks, antihypertensive agents of the types described above (but not angiotensin-I–converting enzyme inhibitors or angiotensin-II–receptor antagonists) were added or their doses increased to achieve the target blood pressure.
Throughout the study, patients received the standard of care for the treatment of diabetes, including measurements of glycosylated hemoglobin and fasting serum glucose concentrations. Visits were scheduled every three months, or more often if necessary, to monitor the blood pressure and laboratory measurements and to assess whether adverse events had occurred or end points had been reached. Patients who discontinued the study drugs early had follow-up visits every three months until the end of the study; at these visits, the primary and secondary end points reached were recorded, the blood pressure was measured, and laboratory measurements were performed. Those who could not return for clinic visits or a family member was contacted by telephone to determine whether they had reached the end points of the initiation of dialysis, renal transplantation, or death.
Outcome Measures
The primary efficacy measure was the time to the first event of the composite end point of a doubling of the serum creatinine concentration, end-stage renal disease, or death. The doubling of the serum creatinine concentration was defined as the first serum creatinine value that was twice the base-line value, as confirmed by a second serum creatinine value obtained at least four weeks after the initial doubling. End-stage renal disease was defined by the need for long-term dialysis or renal transplantation. The prespecified secondary end point, morbidity and mortality from cardiovascular causes, was a composite of myocardial infarction, stroke, first hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, or death from cardiovascular causes. Analyses of the components of both the primary and secondary composite end points were also prespecified. Other secondary end points included the progression of renal disease6 and changes in the level of proteinuria.
Statistical Analysis
Analyses of the primary and secondary end points were performed according to the intention-to-treat principle; we included data from all randomized patients (with the exception of three patients who were lost to follow-up), from the time of randomization through the date of study termination. In a second, per-protocol analysis, we excluded patients who violated the criteria for inclusion and exclusion and censored patients' data 14 days after they permanently discontinued the study medication. A Cox regression model7 that included the base-line level of proteinuria as a stratification factor and the geographic region as a covariate was used to determine the hazard ratio for the primary end point and its 95 percent confidence interval. The risk reduction was calculated as 100 percent × (1 – hazard ratio). In analyses of nonfatal end points, data for the patients who had died were considered to have been censored. Event curves are based on Kaplan–Meier analysis.8 We examined the effect of differences between the groups in the control of blood pressure by adding the mean arterial pressure during treatment as a time-dependent covariate in the Cox model and comparing the effect of losartan estimated by this model with that estimated by the primary analysis.
The analyses of the progression of renal disease and changes in the level of proteinuria were based on an on-treatment approach. For the analysis of the progression of renal disease, we compared the slopes of the reciprocal of the serum creatinine concentration6 of the two treatment groups using a linear random-effects model. Changes in the level of proteinuria in the two groups were compared by means of a mixed-effects model9 whose terms included the treatment at each point and the base-line level of proteinuria.
Because one interim analysis used a stopping boundary that was based on an alpha spending function of the O'Brien–Fleming type,10 a critical P value of 0.048 was required for the primary hypothesis. For other outcomes, a P value of less than 0.05 was considered to indicate statistical significance. All statistical tests were two-sided.
Results
A total of 1513 patients were randomly assigned to receive losartan or placebo once daily, along with conventional antihypertensive therapy as needed but excluding angiotensin-I–converting enzyme inhibitors and angiotensin-II–receptor antagonists. The daily dose of losartan ranged from 50 to 100 mg, with 71 percent of the patients receiving 100 mg. The base-line characteristics were similar in the two groups (Table 1). More patients discontinued the study treatment in the placebo group (53.5 percent) than in the losartan group (46.5 percent). Adverse clinical events resulted in discontinuation in 17.2 percent of the patients in the losartan group, as compared with 21.7 percent of those in the placebo group. Increased serum concentrations of creatinine or potassium led to the discontinuation of the study medication in 1.5 percent and 1.1 percent, respectively, of the patients in the losartan group, as compared with 1.2 percent and 0.5 percent of the patients in the placebo group. A total of 7.5 percent of the patients in the losartan group and 7.8 percent of those in the placebo group withdrew their consent. We were able to determine the status of all patients (except for three patients in the losartan group who could not be contacted) with respect to dialysis, transplantation, and death.

Table 1
Base-Line Characteristics of the Patients.
Blood Pressure
At base line, 93.5 percent of the patients (92.3 percent in the losartan group and 94.6 percent in the placebo group) were receiving antihypertensive therapy. An additional 3 percent of the patients had hypertension but were not receiving antihypertensive therapy. The trough blood pressure declined progressively during the course of the study. The trough blood pressure at base line averaged 152/82 mm Hg in the losartan group and 153/82 mm Hg in the placebo group; the mean arterial pressure was 105.5 mm Hg in the losartan group and 106.0 mm Hg in the placebo group (P=0.38); and the pulse pressure was 69.4 mm Hg in the losartan group and 70.8 mm Hg in the placebo group (P=0.13). At one year, the values averaged 146/78 mm Hg in the losartan group and 150/80 mm Hg in the placebo group (mean arterial pressure, 100.9 mm Hg and 103.1 mm Hg, respectively [P<0.001]; pulse pressure, 67.8 mm Hg and 69.8 mm Hg, respectively [P=0.05]); at two years, the values were 143/77 mm Hg and 144/77 mm Hg, respectively (mean arterial pressure, 99.1 mm Hg and 99.7 mm Hg, respectively [P=0.38]; pulse pressure, 66.2 mm Hg and 67.1 mm Hg, respectively [P=0.37]); and at the end of the study they were 140/74 mm Hg and 142/74 mm Hg, respectively (mean arterial pressure, 95.9 mm Hg and 96.8 mm Hg, respectively [P=0.59]; pulse pressure, 66.7 mm Hg and 67.4 mm Hg, respectively [P=0.77]). The various classes of conventional antihypertensive drugs that were used before and during the study are listed in Table 2.

Table 2
Use of Conventional Antihypertensive Medications at Base Line and during Study Treatment.
Primary Outcomes
According to the intention-to-treat analysis, the primary composite end point of a doubling of the serum creatinine concentration, end-stage renal disease, or death was reached in 327 patients in the losartan group (43.5 percent), as compared with 359 in the placebo group (47.1 percent) (Figure 1A). Treatment with losartan resulted in a 16 percent reduction in the risk of the primary composite end point (P=0.02) (Table 3). The decrease in risk remained essentially unchanged (15 percent) after adjustment for blood pressure (P=0.03). Furthermore, according to the per-protocol analysis, among the patients who continued to receive their assigned study treatment, losartan conferred a 22 percent reduction in the risk of the primary composite end point (P=0.008).

Figure 1

Kaplan–Meier Curves of the Percentage of Patients with the Primary Composite End Point (Panel A) and Its Individual Components, a Doubling of the Serum Creatinine Concentration (Panel B), End-Stage Renal Disease (Panel C), and the Combined End Point of End-Stage Renal Disease or Death (Panel D).

Table 3
Incidence of the Primary Composite End Point and Its Components.
The intention-to-treat analyses of the individual components of the primary composite end point are also shown in Table 3. The risk of a doubling of the serum creatinine concentration was 25 percent lower in the losartan group than in the placebo group (P=0.006) (Figure 1B). Losartan also reduced the risk of end-stage renal disease by 28 percent (P=0.002) (Figure 1C). Approximately 20 percent of the patients died, but there was no significant difference in mortality between the two groups (P=0.88). The risk of the combined end point of end-stage renal disease or death was 20 percent lower in the losartan group than in the placebo group (P=0.01) (Figure 1D and Table 3). The reductions in the risk of end-stage renal disease and of end-stage renal disease or death changed little after correction for blood pressure (26 percent, P=0.007, and 19 percent, P=0.02, respectively).
Secondary Outcomes
There was no significant difference between the losartan group and the placebo group in the composite end point of morbidity and mortality from cardiovascular causes. Approximately one third of the patients had a fatal or nonfatal cardiovascular event (247 in the losartan group [32.9 percent] and 268 in the placebo group [35.2 percent]; risk reduction, 10 percent; P=0.26). There were no significant differences in the rates of most of the cardiovascular end points; the exception was the first hospitalization with heart failure (89 patients in the losartan group [11.9 percent], as compared with 127 in the placebo group [16.7 percent]), for which the risk was reduced by 32 percent (P=0.005) (Figure 2). There was a difference between the number of myocardial infarctions in the losartan group (50 patients [6.7 percent]) and the number in the placebo group (68 patients [8.9 percent]; risk reduction, 28 percent), but this difference was not statistically significant (P=0.08).

Figure 2

Kaplan–Meier Curves of the Percentage of Patients with a First Hospitalization for Heart Failure in the Losartan and Placebo Groups.
Losartan also led to an average reduction in the level of proteinuria (the urinary albumin-to-creatinine ratio) of 35 percent, whereas in the patients in the placebo group, the urinary albumin-to-creatinine ratio tended to increase (P<0.001 for the overall treatment effect) (Figure 3). Losartan reduced the rate of decline in renal function, as assessed by the reciprocal of the serum creatinine concentration, by 18 percent (median slope, –0.056 dl per milligram per year in the losartan group, as compared with –0.069 dl per milligram per year in the placebo group; P=0.01). Likewise, losartan was associated with a 15.2 percent reduction in the estimated decline in the glomerular filtration rate (median rate of decline, 4.4 ml per minute per 1.73 m2 of body-surface area per year in the losartan group, as compared with 5.2 ml per minute per 1.73 m2 per year in the placebo group; P=0.01).12,13 These reductions in the rate of decline are far smaller than those reported for captopril as compared with placebo in patients with type 1 diabetes nearly a decade ago.1

Figure 3

Median Changes from Base Line in the Level of Proteinuria.
Discussion
Our study establishes that losartan, along with conventional antihypertensive treatment as needed, confers strong renal protection in patients with type 2 diabetes and nephropathy. The risk of the primary end point, a composite of a doubling of the serum creatinine concentration, end-stage renal disease, or death from any cause, was reduced by 16 percent with losartan. The primary benefit appeared to be the effect on the renal components of this composite end point. In particular, the risk of end-stage renal disease was reduced by 28 percent with losartan during an average follow-up of 3.4 years. Extrapolating from the observed data, we estimate that this reduction corresponds to an average delay of two years in the need for dialysis or transplantation. The risk of a doubling of the serum creatinine concentration was also reduced by 25 percent with losartan. The difference between the slopes of the reciprocals of the serum creatinine values and the lower level of proteinuria provide further evidence of global renal protection with losartan.
There was a small, time-averaged difference in the trough blood pressure between the losartan group and the placebo group. We cannot exclude the possibility that this small difference had a beneficial effect on the renal outcomes. However, statistical analysis that corrected for these small differences confirmed that the renal protection conferred by losartan exceeded that attributable to any small differences in blood pressure. This study extends our knowledge of the efficacy of antihypertensive therapy in patients with type 2 diabetes and nephropathy. Previous studies involving angiotensin-I–converting enzyme inhibitors have demonstrated beneficial effects on proteinuria but have not demonstrated the superiority of blockade of the renin–angiotensin system in slowing the progression to end-stage renal disease over nonblockade forms of therapy.14–20 Indeed, studies of the effects of angiotensin-I–converting enzyme inhibitors on the progression of renal disease and end-stage renal failure have yielded conflicting results.14,15,20–24 Therefore, in the absence of a direct comparison between angiotensin-I–converting enzyme inhibitors and angiotensin II antagonists, any extrapolation from the results obtained with different classes of drugs is speculative at best.
The benefits of losartan were observed among our patients, many of whom were already receiving other therapies, such as aspirin, beta-blockers, and lipid-lowering agents, as part of sound medical practice. Similarly, simultaneous therapy with calcium-channel antagonists did not detract from the beneficial effects of losartan, despite the recent controversy regarding the role of calcium-channel antagonists in the protection of the kidneys and the heart.25–27 In this regard, it should be noted that in related studies in patients with type 1 and type 2 diabetes,1,28,29 the benefits of captopril or irbesartan were not tested in the presence of concurrent calcium-channel–antagonist therapy. Furthermore, calcium-channel antagonists have been shown to augment the production of angiotensin II,30 a response that may be counteracted by concomitant angiotensin-II–receptor blockade.
There was no significant difference between the losartan group and the placebo group in the composite secondary end point of morbidity and mortality from cardiovascular causes. This similarity of incidence may have resulted in part from the relatively small sample and the strict criteria for enrollment that excluded patients at high risk for cardiovascular events including heart failure. We did find a significant difference in favor of losartan with regard to the rate of a first hospitalization for heart failure, a component of this secondary composite end point. This finding in patients without clinical heart failure at base line accords well with findings from the Studies of Left Ventricular Dysfunction Prevention study.31 That study, however, did not include patients with impaired renal function. The Heart Outcomes Prevention Evaluation (HOPE) Study32 and its substudy of patients with diabetes, MICRO-HOPE,20 showed benefits of angiotensin-I–converting enzyme inhibition in terms of the signs and symptoms of heart failure but failed to show significant differences in hospitalizations for heart failure. Furthermore, the evaluation of a subgroup of the HOPE population with renal insufficiency5 did not show a significant effect on this outcome. Our findings suggest that angiotensin II blockade in patients with renal disease decreases the risk of overt heart failure resulting in hospitalization.
In this population, losartan (plus conventional antihypertensive therapy) demonstrated excellent tolerability, similar to that of placebo (plus conventional antihypertensive therapy), as evidenced by the similar numbers of patients in the two groups in whom the study treatment was discontinued because of adverse events. The addition of losartan to a conventional antihypertensive treatment regimen did not increase the incidence of adverse events.
End-stage renal disease continues to be a worldwide public health concern. Recent estimates by the National Institutes of Health indicate that diabetes represents the single largest cause of end-stage renal disease, accounting for approximately 40 percent of all cases in the United States between 1994 and 1998.33 Furthermore, the incidence of end-stage renal disease in patients with type 2 diabetes is rising sharply in many regions of the world and is expected to double by 2010. The annual costs associated with end-stage renal disease in the United States reached $12 billion in 1998 and are expected to surpass $28 billion by 2010.34 Preventing or delaying the progression of diabetic nephropathy is therefore an essential management goal. We believe our findings go a long way toward achieving this goal and may also have an important economic effect.

In summary, losartan led to significant improvement in renal outcomes that was beyond that attributable to blood-pressure control in patients with type 2 diabetes and nephropathy.

內科-1972 Circulation: Effects of Treatment on Morbidity in Hypertension III 年齡-舒張壓, 過去病史. 副作用進一步分析

2026-09-01 10:10AM

Effects of Treatment on Morbidityin Hypertension III. Influence of Age, Diastolic Pressure,and Prior Cardiovascular Disease; 

Further Analysis of Side Effect
Circulation, Volume XLV, May 1972

筆記

1. 降血壓藥物無法減少心肌梗塞與猝死機率(這項有點反直覺)

2. 隨機分組前血壓值: 醫生在隨機分組前最後兩次門診就診期間測量血壓的平均值。

但目前關於血壓測量. 建議使用家中血壓為主(避免白袍症干擾)

3. 50歲以下. 若無心血管風險. 降血壓治療沒有效益. 

註釋與縮寫

1. morbid events 可翻譯為發病事件. 罹病事件. 不良事件 .併發症事件

2. CHF 充血性心衰竭

3. CVR異常: cardio-vascular-renal abnormalities

3. 亞組 subgroup. 將治療組與對照組依照特定條件在

(下面中文使用 GOOGLE 翻譯)
摘要

THE VETERANS Administration Coop-erative Study Group 提供了退伍軍人事務部合作研究的補充數據，該研究納入了194名對照組男性患者和186名治療組男性患者，這些患者的初始舒張壓平均值為90-114 mmHg。

排除條件, 先前有其他高血壓嚴重併發症病史的患者, 包括下列

1. 腦出血或蜘蛛網膜下腔出血

2. 需要持續使用利尿劑的持續性充血性心臟衰竭、

3. 高血壓加速期

4. 急性高血壓腦病變

研究檢視了以下隨機分組前存在的危險因子與疾病發作率和治療效果之間的關係：

(1) 心血管腎臟 (CVR) 異常，其盛行率高於一般高血壓患者族群；

(2) 舒張壓；

(3) 年齡。

疾病發作率 Attack rates 和治療效果 effective-ness of treatment 均與隨機分組前存在的這些危險因子的數量呈正相關。

年齡和入組時是否有CVR異常似乎對後續疾病發作率有顯著影響，而入組血壓水平對疾病發作率的影響相對較小。

另一方面，「治療效果」似乎最受初始血壓水平的影響。

入組前舒張壓在 90 至 104 mmHg 範​​圍內的患者，除非入組時有心血管風險異常或年齡超過 50 歲，否則從治療中獲益甚微。

需要更長的追蹤期來評估治療在低風險亞組的價值。

在副作用方面，治療組輕度低血鉀、高尿酸血症和空腹血糖升高的發生率顯著高於對照組。

應權衡這些及其他副作用與治療低風險高血壓患者預期獲益之間的利弊。

THE VETERANS Administration Coop-erative Study Group 一項隨機、雙盲臨床試驗的結果，該試驗納入了194名對照組男性患者和186名治療組男性患者，初始舒張壓平均為90至114 mmHg，並進行了長達5.5年（平均3.3年）的前瞻性隨訪。 治療藥物為 hydrochlorothiazide, reserpine, hydralazine.

對照組有19例死於心血管疾病，治療組有8例。生命表分析表明，治療使5年內發生致命或非致命性發病事件 morbid events 的風險從55%降低至18%。接受治療的患者中，充血性心臟衰竭、中風和進行性腎損傷的發生率顯著降低或消失。

然而，對照組和治療組的心肌梗塞和猝死發生率基本上相同。除可評估的併發症外，對照組有20位患者出現持續性舒張壓升高（≥125 mmHg），而治療組無一例出現這種情況。

在試驗報告中，患者在隨機分組前心血管異常的盛行率特徵描述不完整。本報告旨在確定既往心血管損傷與治療效果之間的關係。此外，本報告也比原始論文更詳細地分析了年齡和血壓的影響。本報告和初始報告中給出的隨機分組前血壓值代表醫生在隨機分組前最後兩次門診就診期間測量血壓的平均值。

最後，本報告還提供了有關副作用和劑量調整的補充數據。

年齡的影響：

初始報告中所給的中位年齡為：對照組49.2歲，治療組48.1歲。補充數據見表1。

對照組有51%的患者年齡小於50歲，治療組有55%的患者年齡小於50歲。

約四分之一的患者年齡在50-59歲之間。 

60歲以上年齡組佔對照組的22.1%，佔治療組的20.5%，其中年齡最大的患者為75歲。

不同年齡組的隨機分組前血壓如表2。

收縮壓與年齡呈正相關，40歲以下患者的平均收縮壓為154 mmHg，並隨年齡增長而升高，70-75歲年齡組的平均收縮壓為178 mmHg。

然而，各年齡層的平均舒張壓基本上相同。對照組及治療組患者的血壓無顯著差異。(分組前舒張壓)

已知高血壓病程的資料顯示，48%的患者確診高血壓病程為5年或以上，29%的患者確診高血壓病程為9年或以上。高血壓病程較長的患者盛行率相對較高，部分原因可能是年齡分佈，部分原因可能是樣本僅包含「固定型」高血壓患者，即住院第四至第六天舒張壓平均值≥90 mmHg的患者。

表3列出了隨機分組後, 五年研究期間以年齡劃分的併發症 morbid events 發生率。如預期，主要併發症 morbid events 的發生率隨年齡增加而增加。

在對照組中(做為疾病背景值)，50歲以下患者的併發症 morbid events 發生率為15.2%，而59歲以上患者的併發症發生率為62.8%。

在治療組中，這兩個年齡組的併發症 morbid events 發生率分別為6.9%和28.9%。

治療似乎對所有年齡層均有效。

治療預防併發症 morbid events 的有效性是透過比較對照組和治療組患者主要併發症發生率的年齡百分比差異，再除以對照組患者的發生率百分比來估算的（表3）。

在50歲以下的亞組中，治療有效率達55%(15.2% → 6.9%)

在50-59歲年齡組中，治療有效率達68%(26.9%→8.7%

在60歲以上患者中，治療有效率達54%(62.8%→28.9%)

表4顯示了年齡與發病事件類型之間的關係。

在對照組中，年齡最大的患者組最常見的併發症是腦血管意外和充血性心臟衰竭。

充血性心臟衰竭在60歲以下人群中並不常見。

然而，高血壓惡化或進行性腎損傷主要發生於50歲以下的對照組患者。

冠狀動脈疾病在所有年齡層中均有發生，但在60歲及以上患者的發生率較高（表1、4）。

與其他類別不同，冠狀動脈疾病的併發症似乎不受治療的影響。

(這個有點反直覺. 但實驗數據是降壓治療無法降低心肌梗塞或猝死機率)

既往心血管異常的影響：

表5總結了隨機分組前發現的心血管-腎臟異常的盛行率。

在眼底分級時，「高血壓性」和「硬化性」改變是分別評估的。

[註: 以靜脈直徑做對照. 計算動脈直徑與靜脈直徑比例. 動脈越細(狹窄越嚴重). 比值越小. 動脈小於靜脈直徑 50%. 稱為2級改變]

1級高血壓性改變定義為小動脈管徑可能減小，動靜脈比值約為1:2；

2級高血壓性改變則表示小動脈管徑明顯減小，動靜脈比值小於1:2，甚至細如絲線。

由於1級改變與正常變化難以區分且變異性較大，因此僅報告2級變化。

此類改變在31%的對照組患者和25%的治療組患者中出現。

 2級硬化性改變（而非高血壓性改變）定義為散在的顯著動靜脈缺損或小動脈節段不對稱不規則。

此類改變在24%的患者中出現。

分析了背景特徵以確定是否存在心臟、中樞神經系統或腎臟異常。

所有在上述任何目標器官系統中，嚴重程度評分大於零的患者均被納入研究，但以下情況除外：頭痛（如果這是唯一的CNS異常）和劇烈活動後呼吸困難（如果這是唯一的心臟異常）；眼底評分也不納入研究。

納入標準包括：

日常活動呼吸困難、心絞痛、左心室擴大（LVE）、X光片顯示心臟擴大、除頭痛以外的其他神經系統症狀或腎臟評分大於零。

根據這些標準，對照組中有55%的患者和治療組中有60%的患者在主要目標器官系統中表現出一種或多種異常（表5）。

採用Ungerleider標準，透過標準胸部後前位X光片確定心臟擴大。

根據這些標準，隨機分組前，對照組中有 22% 的患者和治療組中有 28% 的患者被認為有心臟擴大。

左心室擴大 (LVE) 的心電圖標準要求患者同時出現電壓變化（V1 或 V2 導聯的 S 波和 V3 或 V4 導聯的 R 波 > 35 mm）以及 I、aVI 和 V1 或 V2* 導聯的 T 波平坦、雙相或倒置。

在隨機分組前，對照組和治療組中各有 16% 的患者符合這些 LVE 標準。

腎損傷分級如下。

1級腎臟病變包括以下任兩項：

三次獨立過夜尿液收集的比重均≤1.020；

任一尿液樣本中蛋白尿≥1+；

以及2小時混合尿液樣本中酚磺酞（PSP）排泄率≤45%。

2級腎臟病變包括以下任兩項：

比重≤1.015；三次每日尿液樣本中蛋白尿≥1+；

以及PSP排泄率≤30%。 

3級腎臟病變指上述三項全部符合。 

4級腎臟病變指有氮質血症。

對照組和治療組中1級和2級腎臟病變的發生率相同，分別為12%和2%（表5）。

所有患者均未出現3級腎臟病變。

對照組有4例患者，治療組有3例患者的血中尿素氮濃度在25至32 mg/100 ml範圍內。然而，這4例患者的血清肌酸酐值正常，且在隨機分組後未發生不良事件。

其餘3例患者中，1例死於膀胱癌，1例發生充血性心臟衰竭，另1例最初患有慢性腎絲球腎炎（GN），血清肌酸酐為2.4 mg/1100 ml，後因舒張壓升高而退出試驗。 

5例患者（對照組2例，治療組3例）被診斷為原發性腎臟疾病。

其中4例診斷為慢性腎絲球腎炎，1例診斷為雙側髓質海綿腎。

兩名慢性腎絲球腎炎對照組患者中，一名因舒張壓升高（見上文）而退出研究，另一名患者則發生腦血栓。

三名接受積極治療的原發性腎病患者均未發生不良事件。

研究納入了一些先前發生過重大事件的患者。 

380名患者中，7%（對照組和治療組各佔一半）在隨機分組前曾發生心肌梗塞。

對照組有6%的患者，治療組有9%的患者曾經有心臟衰竭病史，但在隨機分組時未出現充血性心臟衰竭。

對照組和治療組中各有5%的患者被臨床診斷為腦血栓。

先前有其他高血壓嚴重併發症病史的患者，例如腦出血或蜘蛛網膜下腔出血、需要持續使用利尿劑的持續性充血性心臟衰竭、高血壓加速期或急性高血壓腦病變，均未納入本試驗。

老年患者心血管腎臟異常的發生率較高（表6）。 

50歲以下患者中，46%出現一種或多種異常，而50-59歲年齡組的比例為65%，59歲以上患者中這一比例為78%。

既往心血管損傷顯著增加了隨機分組後發生不良事件的風險（表7）。

在隨機分組前已發生心肌梗塞、充血性心臟衰竭或腦血栓的患者中，隨機分組後，對照組和治療組的後續主要併發症發生率分別為53%和26%。

在隨機分組前無重大併發症但有心臟、中樞神經或腎臟損傷的患者中，對照組後續不良事件發生率為33%，治療組為8%。對於隨機分組前有異常的合併亞組，治療有效率達64%（表7）。

在無異常的對照組患者中，不良事件發生率較低。

在本子樣本中，對照組患者發生嚴重併發症的比例為16%，而治療組為8%。儘管差異無統計學意義，但治療有效率達50%的趨勢與先前有異常的患者組相似。

需要強調的是，20名對照組患者在發生任何不良事件之前就因舒張壓升高至124 mmHg以上且持續3週或更長時間而被排除出試驗。 這20名患者中有7名在隨機分組前的門診舒張壓低於105 mmHg。 20名患者中有15名年齡小於50歲；20名患者中有10名沒有心臟、中樞神經或腎臟異常的證據。由於在這種舒張壓水平下，若不進行治療，發生後續事件的風險極高⁴，因此在發生不良事件之前將這些患者排除在外，可能導致所有亞組（尤其是50歲以下亞組和無心臟、中樞神經系統或腎臟異常的亞組）的治療效果被低估。在隨機試驗期間發生的27例死亡病例中，17例死亡與心肌梗塞相關或猝死；其中11例發生在對照組，6例發生在治療組。關於這17例患者的其他危險因素，對照組中有6例，治療組中有2例在隨機分組前血清膽固醇高於260 mg/100 ml。對照組有2位患者，治療組有1位患者的空腹血糖值高於110 μg/100 ml。在所有猝死患者中，年度檢查均未發現低血鉀的證據。 11名對照組患者出現充血性心臟衰竭。其中5例為復發，6例為首次發作，發生在隨機分組後。儘管17名治療組患者在隨機分組前有充血性心臟衰竭病史，但在隨機分組後均未復發。

影響治療效果的因素：

由於舒張壓程度、年齡、考慮到先前心血管異常對發病事件發生率的影響，評估這些因素各種組合的影響顯得特別重要。將患者群體細分為若干小亞組會增加觀察率因隨機波動而出現較大誤差的可能性。因此，我們採用多元迴歸技術來估計發病率，該技術類似於曲線擬合，可以平滑觀察資料中的一些隨機波動。多元迴歸技術同樣可以為較大的亞組（所有具有特定危險因子的患者）提供更精確的估計值。因此，該技術已被用於重新計算先前描述的亞組的發病率，例如，年輕組與老年組。表 8 第一部分列出了這些改進後的估計值。當然，計算出的「治療效果」在某種程度上有所修正。就風險因素組合而言，結果表明，無論是否存在明顯的心血管腎臟疾病，也無論年齡大小，舒張壓在 105-114 mmHg 的亞組中，治療獲益最大（表 8，圖 1）。

治療效果最差的兩個亞組是：

初始舒張壓低於 105 mmHg 且無心血管、中樞神經系統或

腎臟異常的患者；以及 50 歲以下且血壓水平相似的患者。

當然，這些結果可能受到相對較短的追蹤期的顯著影響。表 9 顯示了三種風險因子的整體盛行率與發病率和治療效果之間的關係，而與風險因子的類型無關。當不存在危險因子時，疾病發作率和治療效果均最低；隨著危險因子盛行率的增加，發作率和治療效果也逐漸提高。

副作用：

初步報告顯示，兩名接受治療的患者因疑似毒性反應而退出試驗，其中一名患者出現過敏性紫斑，另一名患者疑似患有狼瘡綜合徵，但尚未確診。此外，還有30名患者因疑似藥物相關副作用而停用了疑似致病藥物或其安慰劑。其中12名患者出現憂鬱症狀，7名在治療組，5名在對照組。 10名患者出現消化性潰瘍；其中6名服用活性藥物，4名服用安慰劑。兩名患者（一名服用活性藥物，另一名服用安慰劑）因陽痿而改變了治療方案。其餘6名患者均接受活性藥物治療。

其副作用包括嗜睡、嚴重鼻塞、痛風、可能由低血壓引起的癲癇發作以及葡萄糖耐受試驗異常。

生化副作用：低血鉀症。如表10所示，隨機分組前，對照組和治療組患者的血清鉀濃度分佈幾乎相同，對照組和治療組分別只有1%和2%的患者血清鉀濃度低於正常值。然而，在第一次年度檢查時，治療組的血清鉀水平百分比分佈向低值偏移，而對照組基本上保持不變。 1年後，對照組和治療組分別有2%和23%的患者血清鉀濃度低於正常值。然而，治療組中僅有1%的患者血清鉀濃度低於2.5 mEq/L。第二次年度檢查也觀察到了類似的趨勢，儘管治療組中沒有患者的血清鉀水平低於2.5 mEq/L。在完成兩次年度檢查的患者中，在第一次年度檢查時血清鉀水平低於3.5 mEq/L的23名治療組患者中，約有一半在第二次年度檢查時仍存在低鉀血症。在首次年度檢查中，5名血清鉀值低於正常值的患者接受了補鉀治療。其中3名患者在第二次年度檢查中血清鉀值恢復正常，而2名患者仍存在輕度低血鉀症。

血清尿酸：

初次檢查時，對照組13%的患者和治療組11%的患者尿酸值達到或超過8.0 mg/100 ml（表11）。在首次年度檢查中，尿酸水平達到或超過8.0 mg/100 ml的患者在對照組中佔16%，在治療組中佔30%；在第二次年度檢查中，對照組和治療組的比例分別為19%和25%。在40名治療一年後出現高尿酸血症的患者中，有18名患者在第二次年度檢查時尿酸水平仍達到或超過8.0 mg/100 ml。在首次年度檢查中，5名尿酸水平升高的患者分別接受了別嘌醇或丙磺舒治療；在第二次年度檢查中，3名患者的尿酸水平仍然升高，2名患者的尿酸水平降至8.0mg/100ml以下。如前所述，2名接受積極治療的患者在隨機分組後出現了首次痛風發作。

在首次年度檢查時血清鉀濃度低於 3.5 mEq/L 的 23 例接受治療的患者中，約有一半在第二次年度檢查時仍有低血鉀。首次年度檢查時血清鉀水平低於正常值的 5 例患者接受了鉀補充劑治療。其中 3 例在第二次年度檢查時血清鉀濃度恢復正常，而 2 例仍有輕度低血鉀。血清尿酸：在初次檢查時，對照組中有 13% 的患者和治療組中有 11% 的患者尿酸濃度達到或超過 8.0 mg/100 ml（表 11）。在首次年度檢查時，尿酸水平達到或超過 8.0 mg/100 ml 的患者在對照組中佔 16%，在治療組中佔 30%；在第二次年度檢查時，對照組和治療組的相應比例分別為 19% 和 25%。在接受治療一年後出現高尿酸血症的40例患者中，18例在第二次年度檢查時尿酸水準仍為8.0 mg/100 ml或更高。在第一次年度檢查時尿酸升高的5例患者分別接受了別嘌醇或丙磺舒治療；在第二次年度檢查時，3例患者的尿酸水平仍然升高，2例患者的尿酸水平降至8.0 mg/100 ml以下。如前所述，2例接受積極治療的患者在隨機分組後出現了首次痛風發作。

空腹血糖。

由於在試驗的前3年中，部分醫院以餐後2小時血糖取代空腹血糖，因此空腹血糖（FBS）數據不完整。

在隨機分組前，對照組和治療組中空腹血糖（FBS）值≥110 mg/100 ml的盛行率基本相同（表12）。然而，隨機分組一年後，治療組的盛行率為20.8%，而對照組為15.6%；隨機分組兩年後，治療組的盛行率為30.0%，對照組為17.0%。在隨機分組前，治療組中有7.0%的患者FBS水平≥120 mg/100 ml；在第一次年度檢查時，這一比例為12.5%；在第二次年度檢查時，這一比例為14.6%。由於第一年和第二年追蹤結束時可供檢查的患者總數存在差異（表12），因此，數據分析僅使用完成了第一次和第二次年度檢查的患者作為分母。結果仍顯示，治療組中空腹血糖升高的患者比例高於對照組患者。治療組患者血清鉀降低與空腹血糖升高無顯著相關性。治療一年後，119例空腹血糖低於110 mg/100 ml的治療組患者平均血清鉀為3.91 mEq/L（標準差0.57 mEq/L），40例空腹血糖為110 mg/100 ml或更高的治療組患者平均血清鉀為3.89 m兩年後，兩組患者的血清鉀濃度分別為 4.04 ± 0.58 mEq/L 和 3.98 ± 0.91 mEq/L。

方案藥物劑量調整：

隨機分組時，治療組所有患者均接受氫氯噻嗪 50 mg 和利血平 0.1 mg 每日兩次合併肼屈嗪 25 mg 每日三次的治療方案。 * 顯然，與通常使用單一降血壓藥物的初始治療方案相比，這種治療方案會導致更高的副作用發生率。因此，當出現低血壓症狀或其他副作用時，可以減少劑量或停用三種藥物中的一種。從隨機分組的 380 名患者中抽取了 124 名患者作為樣本，檢查了他們的病歷，以確定劑量調整情況及其原因。樣本的選擇方式確保每個參與診所的樣本數量比例均衡，並涵蓋患者入組試驗的時間段。對照組中有 9 位（16%）患者調整了劑量，治療組中有 36 位（53%）患者調整了劑量（表 13）。

安慰劑組調整劑量的原因包括以下副作用：

頭痛、鼻塞、心絞痛、皮疹和多種不適症狀。治療組 36 例調整劑量的患者中有 28 例，其劑量減少的主要原因是出現低血壓症狀，如虛弱、嗜睡或暈厥，這些症狀通常伴隨舒張壓降至遠低於 90 mmHg 的水平。

在適當降低劑量後，這些症狀均有所緩解。

除低血壓症狀外，其他導致劑量調整的副作用包括 3 例心絞痛、3 例頭痛、一名患者出現緊張，另一名患者出現鼻塞。

因此，除低血壓導致劑量調整外，其他副作用的發生率在對照組和治療組之間無顯著差異。

如果治療開始時僅使用一種降血壓藥，低血壓症狀可能會少很多。

主觀副作用的發生率：

對同一組124名患者的主觀副作用進行了評估，評估依據是門診就診報告表上的醫生訪談清單。回顧了隨機分組前試驗期間最後兩次就診的報告以及所有隨機分組後的就診報告。可能由於不同門診醫師的價值判斷不同，不同醫院報告特定症狀的頻率有相當大的差異。由於每位患者始終由同一位醫生接診，因此將每位患者的隨機分組後時期與隨機分組前時期進行比較是合理的。對於任何特定患者，僅統計隨機分組後出現且在隨機分組前未記錄的副作用。

結果顯示，在隨機分配至安慰劑組的患者中，有相當數量的患者報告了特定的副作用。

例如，在隨機分組前未報告惡夢的52名對照組患者中，有6名在隨機分組後的某個時間報告了這種「副作用」（表14）。

對於惡夢、關節炎、心絞痛​​和頭痛這些特定症狀，對照組患者的發生率實際上高於治療組。

而對於憂鬱、皮疹、陽痿和其他「不適」等副作用，對照組和治療組的發生率幾乎相同。

對「副作用」發生率高的一個可能解釋是，醫生在隨機分組後可能更重視副作用訪談。

治療組患者發生頻率較高的副作用僅有嗜睡或疲倦、鼻塞、潰瘍症狀及首次出現任何不適症狀。

後者指的是隨機分組前沒有任何不適症狀，但在隨機分組後報告出現一種或多種副作用的患者。

此外，在達到適當的降血壓藥物維持劑量後，檢查副作用的發生率也十分重要。因此，表14中也列出了特定副作用的報告數據，但省略了隨機分組後前兩次訪視（僅包括第三次及以後的訪視）。

在這些後續訪視中，對照組和治療組患者報告的潰瘍症狀、嗜睡或疲勞以及鼻塞症狀的發生率差異無統計學意義。

值得注意的是，在這些追蹤期間，對照組患者報告心絞痛和頭痛的比例明顯高於治療組患者。

討論：

本研究中併發症的發生率高於高血壓患者整體族群的預期水準。原因可能包括：（1）入院時患有高血壓但住院第四至第六天舒張壓平均值低於90 mmHg的患者被排除在外；（2）超過一半的患者出現心血管或腎臟異常；（3）近30%的患者已知患有高血壓10年或更長時間。 (4) 雖然只有五分之一的患者年齡超過 60 歲，但這些患者卻佔了所有發病事件的一半。對照組中，初始舒張壓平均在 105-114 mmHg 的患者發生事件發生率高於初始舒張壓在 90-104 mmHg 的患者。治療效果在初始血壓較高的患者中更為顯著。本研究表明，既往心血管疾病顯著增加對照組發生事件的風險，並且在有限的觀察期內，有既往疾病史的患者治療效果更佳。由於治療組與對照組相比獲益明顯，因此必須終止試驗。由於無心血管疾病史的患者風險較低，因此追蹤時間過短，不足以觀察到大量事件，也無法在該亞組樣本中獲得對照組和治療組之間具有統計意義的差異。

然而，在「無異常」組中觀察到的50%的治療有效率與「異常」組中64%的有效率並無顯著差異，這與治療的保護作用相符。

本試驗的結果表明，有必要加大力度識別並持續為出現任何心血管損傷跡像或舒張壓平均值超過104 mmHg的患者提供充分的治療。

來自代表性人群調查的證據表明，許多高血壓患者要么不知道自己患有高血壓，要么沒有接受充分的治療。

然而，還需要更多證據來確定治療的益處是否大於其對低風險患者（例如輕度高血壓且無血管疾病證據的患者，特別是女性患者以及血壓波動性高血壓患者）的弊端。

目前所有可用的抗高血壓藥物都可能引起毒性反應，而副作用，特別是與噻嗪類及其相關利尿劑相關的生化改變，較為常見。

由於其他令人不安的副作用，通常需要調整劑量。雖然這些副作用的風險看似很小，但必須與預期獲益進行比較，尤其是在高血壓併發症風險也相對較低的患者中。然而，如果患者未接受治療，則應定期隨訪，以確定高血壓是否進展至更嚴重的階段。這種追蹤對於年輕患者尤其重要。

在本研究中，20名舒張壓嚴重升高的對照組患者中有15名年齡在50歲以下；其中7名患者的初始舒張壓低於105 mmHg。

在本研究的患者樣本中，抗高血壓治療似乎能有效降低高血壓相關併發症，但心肌梗塞和猝死除外。

這項結果並非一定與統計學證據相矛盾，即高血壓是冠心病發病率增加的「危險因子」之一。更大的樣本量或更長的追蹤期或許能夠揭示本研究中未發現的差異。此外，如果在高血壓早期階段就開始治療，或許能夠獲得更大的保護作用。為了解決這個問題，需要在不同的高血壓患者群體中進行治療試驗。需要對不同高血壓患者族群進行治療試驗，以解決這個問題。需要對不同高血壓患者族群進行治療試驗，以解決這個問題。

SUMMARYA

Additional data are presented from the Veterans Administration Cooperative Studywith respect to the 194 control and 186 treated male patients with initial diastolicblood pressures averaging 90-114 mm Hg. Attack rates and effectiveness of treatment were examined with respect to the following risk factors present at entry: 

(1) cardio-vascular-renal (CVR) abnormalities, the prevalence of which was higher than in thegeneral population of hypertensive patients; 

(2) diastolic blood pressure; and 

(3) age.Both attack rates and effectiveness of treatment increased directly with the number ofthese risk factors present at entry. 

Age and presence of CVR abnormalities at entryappeared to strongly influence subsequent attack rates, whereas entry level of bloodpressure had a relatively smaller effect on attack rates. On the other hand, "effective-ness of treatment" appeared to be most influenced by the initial level of blood pressure. Patients with prerandomization diastolic blood pressure in the range of 90 to104 mm Hg derived relatively little benefit from treatment unless they had CVR abnormalities at entry or were over 50 years of age. A longer period of follow-up wouldbe needed to assess the value of treatment in the lower risk subgroups.With respect to side effects, the incidence of mild hypokalemia, hyperuricemia, andelevated fasting blood sugar was significantly higher in the treated group. These andother side effects should be weighed against the benefit to be expected from treatinghypertensive patients at low risk.

THE VETERANS Administration Coop-erative Study Group previously reportedon the results of a randomized, double-blindclinical trial in 194 control and 186 treatedmale patients with initial diastolic bloodpressures averaging 90 through 114 mm Hgfollowed prospectively for periods up to 5.5years, average 3.3 years.1 Treatment consistedof a combination of hydrochlorothiazide,reserpine, and hydralazine. There were 19deaths related to cardiovascular disease in thecontrol group and eight in the treated series.Life table analysis indicated that the risk of amorbid event, fatal or nonfatal, over a 5-yearperiod was reduced from 55 to 18% bytreatment. Congestive heart failure, stroke,and progressive renal damage were sharply reduced or eliminated in the treated patients.However, the incidence of myocardial infarc-tion and sudden death was essentially thesame in the control and treated groups. Inaddition to assessable morbid events, 20 control patients versus none of the treatedgroup developed persistent diastolic elevationsof 125 mm Hg or higher.

In the trial report the patients wereincompletely characterized as to the preva-lence of cardiovascular abnormalities prior torandomization. The present report determinesthe relationship between prior cardiovasculardamage and the effectiveness of treatment.The influences of age and blood pressure alsoare analyzed in more detail than in theoriginal paper. The prerandomization bloodpressures given in this and in the initialreport1 represent the average of the readingstaken by the physician during the last twooutpatient visits preceding randomization.Finally, additional data with respect to sideeffect and dose modifications are presented.Influence of AgeThe median ages were given in the initialreport1 as 49.2 years for the control group and48.1 years for the treated series.Additional data are presented in table 1.Fifty-one percent of the control and 55% of thetreated group were less than 50 years of age.Approximately one fourth of the patients were in the 50-59-year age group. The 60 and aboveage group included 22.1% of the control and 20.5% of the treated patients, the oldest patientbeing 75 years of age.The prerandomization blood pressures forthe different age groups are shown in table 2.Systolic blood pressure was related directly toage, and averaged 154 mm Hg in the patientsunder 40 years of age and rose with age to 178mm Hg in the 70-75-year age group. Meandiastolic blood pressures, however, were es-sentially the same at all ages. There were nosignificant differences in blood pressure in thecontrol and treated patients.Information on the duration of knownhypertension indicated that 48% had recog-nized hypertension for 5 years or more, and29% had hypertension for 9 years or more. Therelatively high prevalence of hypertension oflong duration may be explained in part by theage distribution and in part by the fact thatthe sample included only patients with "fixed"hypertension, namely those with diastolicblood pressures averaging 90 mm Hg or morefrom the fourth through the sixth day ofhospitalization.The incidence of morbid events during thestudy by age at randomization is listed intable 3. As would be expected, the incidenceof major complications rose with age. In the control group, 15.2% of the patients under age 50 years developed morbid events followingrandomization as compared to 62.8% of thepatients above age 59 years. In the treatedpatients, the percentage incidence of morbidevents was 6.9 and 28.9%, respectively, in thesetwo age groups. Treatment appeared to beeffective in all age groups. The effectiveness of treatment in preventing morbid events wasestimated from the difference in the percent-age incidence of major complications between control and treated patients divided by thepercentage incidence in the control patients(table 3). 

Treatment was 55% effective in the subsample below 50 years of age, 68% in the50-59-year age group, and 54% in the patientsaged 60 years and over.The relationship between age and type ofmorbid event is shown in table 4. In thecontrol group the most frequent complicationsin the oldest age group were cerebrovascularaccidents and congestive heart failure. Thelatter was uncommon below age 60 years.However, increasing hypertension or progres-sive renal damage occurred predominantly inthe control patients below age 50 years.Coronary artery disease occurred in all agegroups but its percentage incidence was morecommon in the patients aged 60 years or over(tables 1, 4). Unlike the other categories, thecomplications of coronary artery disease didnot appear to be affected by treatment.Influence of Prior CardiovascularAbnormalitiesThe prevalence of cardiovascular-renal ab-normalities found prior to randomization issummarized in table 5. In grading the opticfundi, "hypertensive" and "sclerotic" changeswere evaluated separately. Grade 1 hyperten-sive changes were defined as a probabledecrease in arteriolar caliber with an A-V ratioof approximately 1:2, while grade 2 changesindicated a definite decrease in arteriolarcaliber ranging from an A-V ratio less than 1:2to threadlike arterioles. Because of the difficul ty and variability in differentiating grade 1from niormal, only the grade 2 changes arereported. Such changes occurred in 31% of thecontrol and 25% of the treated patients. Grade2 sclerotic as opposed to hypertensive changeswere defined as scattered prominent A-V nicksor asymmetric irregularity of arteriolar seg-ments. Such changes were reported in 24% ofpatients.Backgound charactistics were analyzed todetermine the presence of cardiac, centralnervous system (CNS), or renal abnormal-ities. All patients with severity grades2 greaterthan zero with respect to any of these targetorgan systems were included with the follow-ing exceptions: headache, if this was the onlyCNS abnormality, and dyspnea on heavyeffort if it was the only cardiac abnormality; optic fundi scores also were not included.Patients with dyspnea on ordinary activity,angina, left ventricular enlargement (LVE),cardiomegaly by X-ray, neurologic symptomsother than headache, or renal score greaterthan zero were included. On the basis of thesecriteria, 55% of the control group and 60% ofthe treated patients exhibited one or moreabnormalities in the major target organsystems (table 5).Ungerleider criteria3 were used for deter-mining cardiomegaly from the standard poste-rior-anterior X-ray of the chest. By thesecriteria, 22% of the control group and 28% of the treated patients were considered to exhibitcardiomegaly prior to randomization.The electrocardiographic criteria for leftventricular enlargemenit (LVE) required thatthe patieint exhibit both voltage changes (S inV, or V, plus R in V, or V,, > 35 mm) and flat,biphasic, or negative T waves in leads I, aVI,and V, or V*;. Sixteeni percent of both thecontrol and treated groups exhibited LVE bythese criteria prior to randomization.Renal damage was graded as follows. Grade1 inicluded any two of the following: specificgravity of 1.020 or less in all of three separateovernight urine collections, proteinuria of 1+or more in any one of these speceimens, andphenosulfonphthalein (PSP) excretion of lessthan 45% in a pooled 2-hour specimen. Grade 2changes included any two of the following:specific gravity of 1.015 or less, proteinuria 1+or more in all of three daily specimens, andPSP excretion of 30% or less. Grade 3 indicatedall three of the above changes. Grade 4denoted the presence of azotemia.The frequency of grades 1 and 2 renalchanges was the same in control and treatedgroups with 12% exhibiting grade 1 and 2%exhibiting grade 2 changes (table 5). None ofthe patients exhibited grade 3 changes. Therewere four patients in the control group andthree in the treated series in whom the bloodurea nitrogen was reported as being in therange of 25 to 32 mg/ 100 ml. However, theserum creatinine value was normal in four ofthese patients, and they did not developmorbid events following randomization. Ofthe remaining three patients, one died of acarcinoma of the urinary bladder, anotherdeveloped congestive heart failure, while thethird, who had chronic glomerulonephritis(GN) with serum creatinine of 2.4 mg/1100 mlinitially, was later removed from the trialbecause of elevated diastolic blood pressure.Five patients, two in the control and threein the treated group, were diagnosed ashaving primary renal disease. Chronic glomer-ulonephritis was diagnosed in four andbilateral medullary sponge kidney in one. Oneof the two control patients with chronic GNwas removed because of elevated diastolic blood pressure (see above) while the otherdeveloped a cerebral thrombosis. In the threeactively treated patients with primary renaldisease there were no morbid events.Included in the study were some patientswho had previous major events. Seven percentof the 380 patienits, equally divided betweencontrol and treated groups, had sustained amyocardial infaretion prior to randomization.Six pereent of the control group and 9% of thetreated patients had a past history of cardiacdecompensation but were Inot in conigestiveheart failure at the time of randomizationi.Five percent of patients in both the controlanid treated groups had a clinical diagniosis ofcerebral thrombosis. Patients with a histoiy ofother major complications of hypertensionisuch as cerebral or subarachnoid hemorrhage,persistent congestive heart failure requiringcontiniuous diuretics, accelerated phase ofhypertensioni, or acute hypertensive enicepha-lopathy were not admitted into the trial.Cardiovascular-renal abnormalities weremore frequent in the older patients (table 6).In those under 50 years of age, 46% presentedwith one or more abnormalities as opposed to65% of the 50-59-year age group and 78,/ of thepatienits above age 59 years.The presence of prior cardiovascular dam-age greatly increased the risk of dexelopingnmorbid events followinig randomizationi (table]7). In the patients with either myocardialinfaretion, congestive heart failure, or cerebralthrombosis prior to ranidomization, subsequentmajor complications occurred in 53% of thecontrol and 26% of the treated group duringthe postrandomization period. In those witlevidence of cardiac, CNS, or renal damagebut without a major complication precedingranidomizationi, the incidenice of subsequentmorbid events was 33% in the control patientsanid 8% in the treated group. Effectixeniess oftreatment for the combined subsamples pre-senting with prerandomnization abnormnalitieswvas 64% (table 7).The incidence of morbid events xwas muehless in the control series of patients presenitingwithout abnormalities. In this subsample, 16%of the colntrol patienlts developed a major complication as opposed to 8% of the treated.The difference is not statistically significantalthough the trend indicating 50% effectivenessof treatment is similar to that found in thegroup with preexisting abnormalities.It should be emphasized that 20 controlpatients were removed from the trial prior toany morbid event because of elevations ofdiastolic pressures to more than 124 mm Hgwhich persisted for 3 weeks or longer.1 Sevenof the 20 patients had a prerandomizationclinic diastolic blood pressure lower than 105mm Hg. Fifteen of the 20 were less than 50years of age; 10 of the 20 had no evidence ofcardiac, CNS, or renal abnormality. Since atthis level of diastolic blood pressure the risk ofdeveloping subsequent events without treat-ment is very high,4 the removal of thesepatients prior to the development of a morbidevent probably resulted in an underestimateof the effectiveness of treatment in allsubgroups but especially in the subgroupunder age 50 years and the group presentingwithout cardiac, CNS, or renal abnormalities.Among the 27 fatalities occurring during therandomized trial, 17 deaths were associated with myocardial inifarction or occurred sud-denly; of these, 11 occurred in the controlgroup and six in the treated patients. Withrespect to other risk factors in these 17patients, six of the control and two of thetreated patients had prerandomization serumcholesterol levels greater than 260 mg/100 ml.Two control patienits and one treated patientexhibited fasting blood sugar levels above 110iig/ 100 ml. There was no evidence ofhypokalemia during the annual examinationsin any of the patients who had suddendeath.Congestive heart failure occurred in 11 ofthe control patients. In five it represented arecurrence, while in six the initial attackoccurred following randomization. Although17 of the treated patients had a history ofcongestive heart failure prior to randomiza-tion, none developed recurrences during thepostrandomization period.Influences on Therapeutic EffectivenessBecause of the separate effects of level ofdiastolic blood pressure,' age, and prior car-diovascular abnormalities on the incidence morbid events it seemed of initerest to assessthe influence of various combinations of thesefactors. Subdivision of the patient populationinto small subgroups increases the likelihoodof large errors in observed rates due torandom fluctuations. Therefore, rates wereestimated by the use of multiple regressiontechnics which, like curve fitting, smooth outsome of the random fluctuations in theobserved data.The multiple regression technic likewise canprovide improved estimates for the large subgroups (all patients presenting with agiven risk factor). Thus, the technic has beenused to restate the attack rates for subgroupspreviously described, e.g., the younger groupversus the older group. Such improved esti-mates are shown in the first section of table 8.Of course, the calculated "effectiveeness oftreatment" is modified to some degree.With regard to combinations of risk factorsthe results indicate that the greatest benefit oftreatment was achieved in the subgroups withdiastolic blood pressure of 105-114 mm Hg regardless of evident cardiovascular-renal dis-ease and irrespective of age (table 8, fig. 1).Treatment was least effective in two sub-groups: those with initial diastolic bloodpressure below 105 mm Hg and no cardiovas-cular, CNS, or renal abnormalities; and thosebelow age 50 years with similar levels of bloodpressure. These results, of course, may beconsiderably influenced by the relatively briefperiod of follow-up.Table 9 indicates attack rates and effective-ness of treatment in relation to prevalenice ofthe three risk factors at entiy irrespective of the type of risk factor. Both attack rates andeffectiveness of treatment are lowest when norisk factors are present anid increase progres-sively with increasing prevalence of riskfactors.Side EffectsThe initial report' indicated that twotreated patients w,ere removed from the trialbecause of presumed toxic reactioiis onebeing aniaphylactoid purpura. the other sus-pected, but unproveni, lupus syndrome. Inadditioni, there wvere 30 patienits in whom the suspected offending drug or its placebo wasdiscontinued because of presumed drug-relat-ed side effects. Twelve of these patientsdeveloped mental depression, of whom sevenwere in the treated group and five in thecontrol group. Ten patients developed pepticulcer; six had been taking active drugs andfour placebos. Two patients, one on activedrugs the other on placebos, had a change inregimen because of impotence. The remainingsix patients all were receiving active treat-ment. Their side effects included excessivesleepiness, severe nasal stuffiness, gout, sei-zures presumably caused by hypotension, andan abnormal glucose tolerance test.Biochemical Side EffectsHypokalemia. As indicated in table 10, thedistribution of serum potassium levels prior torandomization was nearly identical in thecontrol and treated patients with only 1% ofthe control and 2% of the treated patientsexhibiting subnormal values. At the firstannual examination, however, the percentdistributions in the treated group shiftedtoward lower values of serum K while thecontrol group remained essentially unchanged.At the end of 1 year, 2% of the control and 23%of the treated group exhibited subnormalvalues. However, only 1% of the treatedpatients exhibited a serum K level below 2.5mEq/liter. A similar trend was found at thesecond annual examination, although therewere no patients in the treated group who hada serum potassium level below 2.5 mEq/liter.Of the patients completing two annualexaminations, approximately half of the 23 treated patients who exhibited serum K levelsunder 3.5 mEq/liter at the first annualexamination remained hypokalemic at thesecond annual examination. Five of thepatients exhibiting subnormal serum K valuesat the first annual examination receivedpotassium supplements. Three of these exhib-ited normal serum K values at the secondannual examination, while two remainedmildly hypokalemic.Serum Uric Acid. At the initial examination,13% of the control group and 11% of thetreated patients exhibited uric acid levels of8.0 mg/100 ml or higher (table 11). At thefirst annual examination patients with eleva-tions of 8.0 mg/ 100 ml or higher accounted for16% in the control and 30% in the treated series;at the second annual examination the percent-ages were 19 in the control and 25 in thetreated. In the 40 treated patients exhibitinghyperuricemia after 1 year, 18 had uric acidlevels remaining at 8.0 mg/ 100 ml or higher atthe second annual examination. Five of thepatients exhibiting uric acid elevations at thefirst annual examination were placed on eitherallopurinol or probenecid; the uric acidremained elevated in three and fell below 8.0mg/ 100 ml in two at the second annualexamination. As indicated in the previousreport,' two actively treated patients experi-enced their first attack of gout during thepostrandomization period.Fasting Blood Sugar. The data with regardto fasting blood sugar (FBS) are incompletedue to the fact that the 2-hour postprandialblood sugar was substituted for FBS at a fewhospitals during the first 3 years of the trial.


The prevalence of FBS values of 110 mg/100ml or higher was essentially the same in thecontrol and treated groups prior to randomiza-tion (table 12). One year after randomization,however, the prevalence was 20.8% in thetreated series as compared to 15.6% in thecontrol, and 2 years after randomization it was30.0% in the treated and 17.0% in the controlpatients. FBS levels of 120 mg/100 ml werefound in 7.0% of the treated patients prior torandomization, 12.5% at the first annual, and14.6% at the second annual examination.Because of the difference in total patientsavailable for examination at the end of thefirst and second year of follow-up (table 12),the data also were analyzed using as denom-inators only the patients who completed boththe first and second annual examinations. Theresults still indicated a greater percentage ofpatients with elevated FBS in the treated ascompared to the control group of patients.There was no significant correlation be-tween reduction in serum K and the increase in FBS in the treated group of patients. Atter1 year of treatment mean serum K was 3.91 SD0.57 mEq/liter in 119 treated patients withFBS levels below 110 mg/100 ml and 3.89 SD0.57 mEq/liter in 40 treated patients with FBSlevels of 110 mg/100 ml or higher. After 2years, the serum K levels were 4.04 SD 0.58 and3.98 SD 0.91 mEq/liter, respectively, in the twogroups.Changes in Doses of Protocol DrugsAt the time of randomization a combinationof hydrochlorothiazide 50 mg and reserpine0.1 mg twice daily plus hydralazine 25 mgthree times daily5 were administered to allpatients in the treated group.* Obviously, thistherapeutic regimen will result in a higherincidence of side effects than the usual methodof initiating treatment with a single antihyper-tensive agent. Therefore, provision was made for reducing doses or for discontinuing one ofthe three drugs in the presence of hypotensivesymptoms or other side effects.A sample of 124 patients was taken of the380 randomized into the trial. Their caserecords were examined for modifications indoses and for the reason for the changes. Thesample was chosen in a way which wouldcontribute proportionate numbers from eachof the participating clinics and would span thetime period during which the patients wereentered into the trial.Doses were modified in nine (16%) of thecontrol sample and in 36 (53%) of the treatedsample (table 13). In the placebo group thereasons for changing doses included thefollowing side effects: headache, nasal stuffi-ness, angina, skin rash, and multiple com-plaints. In the treated group 28 of the 36patients whose regimens were modified hadtheir doses reduced mainly because of hypo-tensive symptoms of weakness, lethargy, orfaintness associated with a fall of diastolicblood pressure to levels usually well below 90mm Hg. These symptoms abated followingappropriate reductions in doses. Side effectsother than hypotensive symptoms leading tochanges in doses included angina in threepatients, headache in three, nervousness inone, anid nasal stuffiness in one patient. Thus,the incidence of side effects other thanhypotension leading to changes in doses wasnot significaintly different in the control andtreated groups. Hypotensive symptoms prob-ably would have been far less if treatment hadbeeni initiated with a single antihypertensiveagent.Incidence of Subjective Side EffectsSubjective side effects in the same subsam-ple of 124 patients were evaluated from aphysician's interview checklist contained onthe clinic visit report forms. The reports forthe last two visits during the prerandomiza-tion trial period and all postrandomizationvisits were reviewed.Probably because of different value judg-ments used by the various clinic physiciansthere was considerable variation from onehospital to another regarding the frequencywith which specific complaints were reported.Since the same physician always saw aparticular patient it seemed valid to comparethe postrandomization against the prerandom-ization period for each patient. In anyparticular patient only those side effects werecounted which were complained of solelyduring the postrandomization period andwhich were not nioted prior to randomization The results indicate a surprising number ofpatients complaining of specific side effects inthe group of patients randomized on placebos.For example, of 52 patients in the controlgroup who did not complain of nightmaresprior to randomization, six reported this "sideeffect" at some time following randomization(table 14). For the specific complaints ofnightmares, arthritis, angina, and headache,the incidence actually was greater in thecontrol group of patients than in the treatedgroup. The incidence was nearly equal forboth control and treated groups for the sideeffects of depression, skin rash, impotence,and "other complaints." A possible explanationfor the high incidence of "side effects" is thatthe physician may have paid more attention tothe side effects interview following randomi-zation.The only side effects occurring with greaterfrequency in the treated group of patientswere lethargy or weakness, nasal stuffiness,ulcer symptoms, and first appearance of anycomplaint. The latter refers to the patientswho had no complaints of any kind prior torandomization but who reported one or moreside effects following randomization.It also seemed important to examine theincidence of side effects after appropriatemaintainence doses of the antihypertensivedrugs had been obtained. Therefore, datarelating to the reporting of specific side effectsomitting the first two postrandomization visits(third and subsequent visits only) also arepresented in table 14. For these latter visitsthe reporting of complaints of ulcer symp-toms, lethargy or weakness, and nasal stuffi-ness were insignificantly differeint in thecontrol and treated groups of patients. It isinteresting that during these visits the report-ing of angina and headache was considerablyhigher for the control as compared to thetreated group of patients.DiscussionThe incidence of morbid events in thepresent study was higher than o7ould beexpected in the general population of hyper-tensive patients. The reasons for this probablyinclude the following: (1) patients withhypertension on admission but whose diastolicblood pressure averaged below 90 mm Hgduring the fourth through sixth day ofhospitalization were excluded; (2) more thanhalf of the patients presented with cardiovas-cular or renal abnormalities; (3) in almost 30%of the patients hypertension was known to bepresenit for 10 years or longer; and (4) while only one fifth of the patients were above 60years of age such patients contributed half ofthe morbid events.The incidence of morbid events in thecontrol group was greater in patients withinitial levels of diastolic blood pressureaveraging 105-114 mm Hg than in those with90-104 mm Hg at entry. The effectiveness oftreatment was much greater for those with thehigher initial blood pressure levels. In thepresent communication it is shown thatpreexisting cardiovascular disease markedlyincreases the risk of developing events in thecontrol group and that the effectiveness oftreatment over the limited period of observa-tion was greater in those with such evidenceof prior disease.Termination of the trial was necessitated bythe clear-cut evidence of benefit in the treatedgroup as compared to the controls. Since thepatients without evidence of cardiovasculardisease were at reduced risk, follow-up was oftoo brief duration for the occurrence of manyevents or to obtain a statistically significantdifference between control and treated groupsin this subsample. However, the observed 50%effectiveness of treatment in the "no abnor-mality" group, which was not substantiallydifferent from the 64% effectiveness found inthe group with abnormalities, is consistentwith a protective effect of treatment.The results of the present trial justify moreinten.;ive efforts to identify and maintainunder adequate treatment patients with anysigns of cardiovascular damage or withdiastolic blood pressure averaging in excess of104 mm Hg. Evidence from surveys carriedout in representative population groups"6indicate that many of these patients are eitherunaware of their hypertension or are notreceiving adequate treatment.Additional evidence will be required, how-ever, to determine whether the benefits oftreatment outweigh its disadvantages in lowerrisk patients, such as in those with mildhypertension and no evidence of vasculardisease, particularly in women, and in patientswith labile hypertension. Toxic reactions mayoccur with any of the presently availableCirculation, Volume XLV, May 1972aintihypertensive agents, and side effect, par-ticularly biochemical changes associated withthiazides and related diuretics, are relativelycommon. Modifications of doses often arerequired because of other disturbing sideeffects. While the risk associated with thesevarious side effects appears small, it must beconsidered in relation to the benefit to beexpected in treating patients whose risk ofdeveloping complications due to hypertensionalso is relatively low. If patients are nlottreated, however, they should be followedperiodically to determine whether the hyper-tenision progresses to a more severe stage.Such follow-up appears to be particularlyimportant in younger patients. In the presentstudy, 15 of the 20 control patients whosediastolic blood pressures became severelyelevated were below 50 years of age; sevenihad an initial diastolic blood pressure below105 mm Hg.In the present sample of patienits, antihy-pertenisive treatment appeared to be effectivein reducing the complications associated withhypertension except for myocardial inifarctionanid sudden death. This result is not niecessar-ily iniconsistent with the statistical evidencethat elevated blood pressure is one of the "riskfactors" associated with an increased inci-denice of coronary heart disease. It is possiblethat a larger sample size or a longer period offollow-up might have revealed differences notapparent in the presenit study. Also, a greaterdegree of protection might have beeni affordedif treatment had beeni instituted at an earlierstage of hypertension. Therapeutic trials areneeded in a different population of hyperten-siv'e patients in order to resolve this question