這是篇很古老的研究. 1967年刊登於 JAMA. 研究計畫原本要做五年. 但在進行三年後. 在血壓較高(DBP 115-129 mmHg)的亞組 subgroup. 實驗組和對照組出現明顯疾病差異. 基於醫療倫理考量. 研究提前終止. 之後這組患者繼續接受當時高血壓的常規治療.
舒張壓 115-129 mmHg. 1964年4月開始收案. 1967年5月結束.
舒張壓 90-114 mmHg. 1964年4月開始收案. 1968年9月停止收案. 1969年10月結束.
血壓 90-114 mmHg 的這組. 完整的實驗進行五年. 最早收案的患者觀察了 5.5年. 在研究計畫晚期才收案的患者至少觀察 1 年. 對照組(安慰劑組)平均的觀察時間是 3.9 年.
這段是廢話.
為何會有關於退伍軍人的醫療研究. 主要是美國對於退伍軍人提供醫療服務, 有完整的醫療紀錄可供追溯. 退伍軍人醫療保健的起源可以追溯到150年前1946年1月，第293號公共法案設立了退伍軍人事務部內科和外科，以及包括退伍軍人誌願服務在內的眾多其他項目，旨在為退伍軍人提供更優質的服務。該法案透過改革公務員制度、建立醫學研究機構以及將退伍軍人醫院與醫學院校聯繫起來，使退伍軍人醫療水平與私人醫療機構比肩，從而幫助退伍軍人事務部招募和留住頂尖的醫療人才。
美國退伍軍人健康管理局 (VHA) 是美國最大的綜合醫療保健系統，在1,380 個醫療保健機構（包括 170 個 VA 醫療中心和 1,193 個不同複雜程度的門診護理點 (VHA 門診診所)）為超過 910 萬名參加 VA 醫療保健計劃的退伍軍人提供 醫療服務。VHA有11萬3千位醫療學員. 1萬6千位附屬醫院教職員.
筆記
1. 實驗設計很有趣. 在還沒開始進行對照實驗前, 先評估病患是否適合作為被研究的對象. 所有收納病患先接受兩個月安慰劑治療(沒給降血壓藥物), 安慰劑中添加核黃素 Riboflavin (5 mg), 核黃素會隨小便排出體外. 尿液檢查會出現螢光反應. 如果病患沒有按時吃藥. 尿液就不會出現螢光. 還要測試病患是否能按時間回診(可靠度). 或按醫囑服藥(藥物剩下是否數量超過10%). 不配合的個案在隨機分組前就會被排除. 另外舒張壓<90 或 >129 (太低太高)也都被排除
2. 實驗原本從 1964 年4月開始收案. 原本計畫做到 1969年10月. 但因為實驗組與對照組出現明顯差異. 實驗提前在 1967年5月終止
註解/縮寫/定義
1. malignant hypertension 定義. 血壓超過 200/120 合併標的器官損傷
標的器官損傷包括腎損傷(急性腎衰竭). 腦損傷(高血壓腦病變).眼睛損傷(嚴重視網膜病變合併視乳突水腫. 出血. 或有滲出物)
Rapid injury to the kidneys (acute renal failure), brain (hypertensive encephalopathy), and eyes (severe retinopathy with papilledema, hemorrhages, or exudates)
2. Morbid Events 英文不難理解. 但翻譯成中文有點難. 暫時翻譯為發病事件
2. Morbid Events 英文不難理解. 但翻譯成中文有點難. 暫時翻譯為發病事件
3. CHF 充血性心衰竭
4. 實驗組有吃 losartan(可加上其他類型降血壓藥物). 對照組有吃其他降血壓藥物(不給予ACEI or ARB)
一群143名舒張壓（診間測量）平均在115至129 mmHg之間的男性高血壓患者被隨機分配實驗組(使用losartan +/- 其他降血壓藥物)或對照組(安慰劑 + 扣除 ARB/ACEI的其他類型降血壓藥物)
實驗組 吃兩種藥物A錠 hydrochlorothiazide/reserpine + B錠 hydralazine + 其他降血壓藥物.
對照組 吃安慰劑 placebo + 其他降血壓藥物
對照組發生了27例嚴重併發症，而實驗組僅有2例。
對照組有4例死亡，實驗組無死亡病例。
對照組的其他併發症包括
1. 三級或四級高血壓視網膜病變、充血性心臟衰竭、氮質血症加重、腦血管血栓形成、短暫性腦缺血發作、腦出血、心肌梗塞和嚴重高血壓。
實驗組的嚴重併發症包括
1例腦血管血栓形成和1例多重藥物毒性(副作用)
舒張壓平均為 115 毫米汞柱或以上的男性患者屬於高風險族群，抗高血壓治療對他們有顯著的益處。
抗高血壓藥物治療在惡性高血壓(定義在開頭)中的價值已得到充分證實。然而，其在預防輕度高血壓患者的發病率和死亡率方面的有效性仍存在爭議。需要進行充分對照的前瞻性研究來評估原發性高血壓患者的這個問題。 1963年，退伍軍人事務部抗高血壓藥物合作研究小組啟動了一項此類研究。
收案與排除
所有患者均住院進行初步檢查。男性患者若在住院期間第4至6天的平均舒張壓在90至129 mmHg之間（未經治療），則考慮納入隨機分組前的試驗期。
所有患者均住院進行初步檢查。男性患者若在住院期間第4至6天的平均舒張壓在90至129 mmHg之間（未經治療），則考慮納入隨機分組前的試驗期。
(這篇研究則是取其中血壓 115-129 mmHg的 subgroup 亞組)
嚴重程度評估分為五個類別. 包括平均舒張壓與四個標的器官損傷程度
視神經眼底、腦、心臟和腎臟中臨床可檢測到的高血壓損傷程度。
損害嚴重程度 0-4 分. 0分是無可偵測到的異常, 4分是最嚴重標的器官變化
(最後計算總分時. 平均舒張壓分數與視神經損傷程度加權乘以2)
*' 將平均舒張壓評分和視神經眼底損害嚴重程度評分乘以2後，將每個類別的評分相加，得到總嚴重程度指數。
總分 2 至 7 分的患者被歸類為輕度，8 至 15 分的患者被歸類為中度，16 分及以上的患者被歸類為重度，重度患者被排除在試驗之外。
排除條件
1. 重度高血壓
排除條件
1. 重度高血壓
2. 可手術治癒的高血壓(例如腎動脈狹窄)
3. 洗腎患者
4. 伴隨致命疾病（如癌症）的患者。
5. 視神經眼底出血、滲出或視乳頭水腫、
6. 有腦出血 ICH 或蛛網膜下腔出血史 SAH
7. 動脈剝離/動脈瘤
8. 對digitalis 及 mercurial diuretics 治療無效的CHF患者
9. 病患主動想退出(希望返回私人醫生就診)
10. 因地理位置或其他原因無法定期到診所就診的患者
11. 可靠性存疑的患者，例如酗酒者、流浪漢和缺乏動力的患者
隨機分組前試驗期 (評估病患是否遵從醫囑. 按時服藥,沒給losartan)
出院後，所有收案病患都進入為期兩至四個月的隨機分組前試驗期☂。
他們接受兩種安慰劑，醫生知道但病人不知道，並每月到診所就診一次。
其中一種安慰劑中添加了核黃素（5毫克）。
核黃素會使尿液在紫外光下呈現黃色螢光。
每次就診時，都會檢查尿液樣本的螢光狀況。
患者需歸還所有藥物瓶，並清點藥片評估患者的服藥可靠性。
為符合入組條件，患者需連續兩次門診就診均無違規行為。
違規行為包括未按時赴約、尿液未顯示螢光，或藥片數量（兩種安慰劑中的任何一種）超出可接受範圍。
可接受範圍的上限定義為：
歸還的藥片數量不超過按處方服用所有劑量後計算剩餘藥片數量的10%；
下限定義為：歸還的藥片數量少於計算剩餘藥片數量的5片。
近一半收納的患者在隨機分組前因未能通過上述可靠性測試而被排除。
此外，試驗期間舒張壓（坐位）平均值低於 90 或高於 129 mmHg 的患者也被排除在外。
因此，最終決定是否接受患者參與研究，是基於個案可靠性以及試驗期間在診所測定的舒張壓高低
隨機分組後時期
在隨機分組時，打開一個密封信封，將患者隨機分配到兩種治療方案之一：活性降血壓藥物組或對照組。
統計學家使用隨機數字表來決定分組。
根據嚴重程度評分，輕度高血壓患者與中度高血壓患者分別進行分層隨機分組。(避免輕症集中到某一組)
採用雙盲技術，使用一系列複雜的代碼來掩蓋隨機分組的治療方案，並使活性藥物和安慰劑外觀相同。
然而，血壓水平和副作用使得維持這種雙盲研究變得困難且不完美。
(吃藥之後一直沒降血壓. 醫師或病患可以猜到自己吃安慰劑)
活性藥物有兩種
A錠是複方. B錠是單方.
B錠有兩種劑量 25mg 及 50mg
tablet A bid: hydrochlorothiazide 50 mg + reserpine 0.1mg
tablet B tid: hydralazine hydrochloride 25mg 及 50mg
特殊A錠:
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
藥物劑量
實驗組. 第一次門診開 A錠 bid + B錠25mg tid * 一個月
一個月後回診若舒張壓仍 > 90 mmHg 則調整B錠劑量. A錠 bid + B錠 50mg tid.
特殊A錠
為了避免個案因藥物不良反應而退出實驗. 提供兩種特殊A錠
1. 僅 hydrohydrochlorothiazide 單方: 適合憂鬱症.活動性消化道潰瘍, 或其他因 reserpine 所致不良反應
2. 僅 reserpine 單方: 適合高血糖或痛風患者
The other contained reserpine without hydrochlorothiazide for toxicity associated with the latter, such as hyperglycemia or
acute gout. These special A tablets were available
in both active and placebo forms.
回診時間
患者在隨機分組後的前兩個月每月到診所就診一次，之後每兩個月就診一次。
每次就診時均進行藥片計數，並隔次進行尿液螢光檢測。
年度體檢包括全面的身體檢查、胸部X光檢查、心電圖、血液生化檢查和腎功能檢查。
除已知的有效降血壓藥物外，所有患者均接受一般醫療護理和症狀治療。
患者特徵
這篇研究僅納入在隨機分組前最後兩次門診就診期間舒張壓平均值在 115 至 129 mmHg 之間的患者(血壓90-114的個案. 於1970年另發表一篇研究)。對於這一高風險族群，研究於 1967 年 5 月提前終止。
這篇研究僅納入在隨機分組前最後兩次門診就診期間舒張壓平均值在 115 至 129 mmHg 之間的患者(血壓90-114的個案. 於1970年另發表一篇研究)。對於這一高風險族群，研究於 1967 年 5 月提前終止。
實驗終止
由於舒張壓在 115 mmHg 及以上時風險率顯著升高，且此類患者的臨床病程似乎受到降血壓藥物治療的正面影響，因此研究提前終止。此後，該高風險族群的所有患者均接受了積極治療。
這篇研究共收案143 例。
70 例在隨機試驗期間接受了安慰劑治療，73 例接受了活性降血壓藥物治療。
他們的平均年齡為 51 歲，年齡範圍為 30 至 73 歲。
平均體重為 483.5 公斤（184 磅）。
77 名患者為黑人，66 名患者為白人。
對照組和活性治療組在年齡、體重、已知高血壓病程或高血壓家族史方面均無顯著差異（表 1 和表 2）。
實驗組的黑人患者和糖尿病患者人數多於對照組，但差異無統計意義。
兩組患者的各項嚴重程度指標，例如住院和門診血壓、眼底檢查、心臟、中樞神經系統和腎臟異常等，基本上都相似。
收案及終止研究時間
1964 年 4 月至 1966 年 12 月共收納 143 例
所有患者的觀察期均於 1967 年 5 月結束
個案觀察期存在相當大的差異(主要是收案時間的影響)
有 38% 的患者接受了兩年或兩年以上的觀察。
研究中，對照組患者隨機分組後階段的平均持續時間為15.7個月，實驗組為20.7個月。
對照組有26位患者隨機分組後追蹤時間少於一年，而實驗組僅有15例。
對照組有23位患者的隨機分組後追蹤時間超過兩年，而實驗組則有32例。
對照組患者追蹤時間較短的原因是該組發生終止事件的病例較多。
由於兩組的平均追蹤時間有差異. 理論上. 追蹤時間越長. 隨著老化發生的疾病就會更多. 對於實驗組來說. 由於實驗組平均追蹤時間多了 5 個月. 兩組的發病事件會受影響. 實驗組假性增加. 對照組假性減少. 所以最後分析風險降低的比例. 需要用統計學公式校正時間差帶來的影響
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.
藥物劑量調整
實驗組73例.
45例 A錠(50mg/0.1mg) BID + B錠50mg TID
其他 28 例因不同問題而降低劑量
SLE 無個案
兩例使用特殊A錠 bid + B錠 50mg tid(一例憂鬱症.另一例高血糖)
對照組70例
66例接受標準劑量(個案以為自己吃的是活性藥物. 實際上吃的是安慰劑)
兩例患者因疑似 Hydralazine 引起的副作用而減少了B片的劑量
2例患者因憂鬱症而改用特製A片安慰劑
(註, 對照組服用的是安慰劑. 並無活性藥物. 但個案以為自己有吃活性藥物. 所以將一些症狀歸責於藥物引起的副作用. 這也是為何醫療研究必須有對照組的原因)
退出研究
♥共有12例患者退出研究，佔8.4%。
隨機分組後的前兩個月內發生了9例退出。
其中7例隨機分配至對照組，5例隨機分配至實驗組。
實驗組和對照組的退出研究人數大致相等。
血壓變化：
♥實驗組的收縮壓和舒張壓迅速且顯著下降，並在整個試驗期間保持在較低水平。
表5顯示了患者坐位時記錄的舒張壓的前瞻性趨勢。
經過24個月的活性藥物治療，與隨機分組前相比，診室血壓平均下降了43 mmHg（收縮壓）和29.7 mmHg（舒張壓）。
相較之下，對照組患者在隨機分組後平均血壓水準並沒有顯著變化（表3）。
圖示顯示了個體變化的分佈。與對照組相比，治療組患者的血壓變化明顯向左偏移至☁☜☁下降☝區域。這種顯著變化在收縮壓和舒張壓的變化中均有體現。個體反應的差異也很明顯。
可評估的發病事件 Assessable Morbid Events
如表4所示，對照組有27例患者發生可評估的發病事件，而實驗組僅有2例。
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 developmentof 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.
使用卡方檢驗，並假設治療無效，P<0.001 具有統計意義。
如果考慮12例患者退出研究的可能影響，並做出最不利的假設，即假設7例對照組患者如果繼續留在研究中就不會發生任何可計數的事件，而5例活性藥物組患者每人都會發生一次可計數的事件（這種情況極不可能發生！），那麼結果將為27比7。但即使這樣，保守假設☜結果☝在0.001水準上具有統計意義。當死亡和A級高血壓併發症合併計算時，對照組有14例患者發生此類事件，而接受降血壓藥物治療的患者組則無此類事件發生。包括死亡、A級事件和其他治療失敗在內的終止事件總數，對照組為21例，而活性治療組為1例。對照組患者的終止事件。 ♥表5列出了21例因併發症而需要停止方案指定治療的對照組患者。這些患者的平均年齡為55.2歲，比隨機分組總人口的平均年齡大4歲。其中13例終止事件發生在白人患者中，8例發生在黑人患者。 21例患者隨機分組前的平均診室血壓為196.9/121.5 mmHg，略高於所有高風險族群的平均收縮壓。從隨機分組到終止事件發生的最短時間為2個月，最長為26個月，平均為11個月。終止事件均勻分佈於15家參與醫院，其中14家醫院報告了1例或多例事件。共有4例死亡，均與心血管疾病相關。其中2例為主動脈剝離，1例為腹主動脈瘤破裂，1例為家中猝死（表5）。後1例猝死未進行屍檢。主動脈剝離的診斷在手術探查或屍檢中得到證實。腹主動脈瘤破裂伴隨致命性出血的診斷在屍檢中得到證實。 2. A類事件是指方案中定義的需要使用已知活性藥物治療並永久停止方案指定治療的高血壓併發症。這些事件包括：眼底鏡檢查顯示3級或4級高血壓視網膜病變（多條條紋狀出血或軟性滲出）。 超過一個象限（或雙側視乳頭水腫）；血中尿素氮（BUN）倍增至 60 mg/100 cc 以上；主動脈夾層動脈瘤；腦血管出血而非血栓形成；蛛網膜下腔出血；儘管使用洋地黃和汞利尿劑，充血性心臟夾層動脈瘤；腦血管出血而非血栓形成；蛛網膜下腔出血；儘管使用洋地黃和汞利尿劑，充血性心力衰竭 mmHg mmHg mmHg mm張壓在三次中三張中均升高至 1430 mmHg mmHg mmHg mmH或更高。由兩名參與者和兩名顧問組成的四人小組審查了發生終止事件的患者的病例史。該小組確定每個病例是否符合方案中定義的 A 類事件標準。未完全符合這些標準的終止事件被歸類為治療失敗，如下所述。共有 10 例 A 類事件，患者皆存活。其中兩例被認為是不可逆的，八例在積極降血壓治療後證實可逆。其中一例可逆事件為腦血管出血，表現為偏癱、頸項強直、血性黃褐色腦脊髓液。另一例發生於一名氮質血症患者，其腎功能迅速惡化。 八例可逆的A級事件中有七例出現3級或4級視盤改變。兩例出現紋狀體出血及視乳頭水腫。另兩例可見雙側多發紋狀體出血及棉絮狀滲出物；兩例同時出現雙側紋狀體出血及難治性充血性心臟衰竭；第七例患者雙側出現紋狀體出血，但無滲出物（表5）。剩餘一例可逆的A級事件與嚴重高血壓相關，再次入院期間舒張壓平均為136 mmHg。 3. 治療失敗是指不符合方案中定義的任何A類事件具體標準的事件。然而，由於併發症被認為危及生命，因此停用了方案藥物，並開始使用已知的降血壓藥物進行治療。 7例終止安慰劑治療的患者被歸類為治療失敗。其中2例患者的視盤可見多條條紋狀出血和軟性滲出，但這些患者也患有糖尿病。視網膜病變可能主要與高血壓有關，因為在這兩例病例中，開始使用已知降血壓藥物治療後兩個月內，眼底病變都已消退。在第三例非糖尿病患者中，僅觀察到一處棉絮狀滲出，未見條紋狀出血。另有2例患者被歸類為治療失敗，因為其在門診記錄的舒張壓經常高於140 mmHg，但在再次入院期間平均低於130 mmHg 。此外，一名34歲患者因既往正常的血中尿素氮（BUN）和血清肌酸酐水平在年度檢查時分別升高至28 mg/100 cc和3 mg/100 cc而被停止方案治療。最終治療失敗的原因是腦血管意外，診斷為血栓形成而非出血，但導致患者完全喪失勞動能力，無法返回診所。積極治療患者的終止事件。 ♥在73名接受活性藥物治療的患者中，唯一一例終止事件發生在一名出現多種藥物毒性的患者身上。在終止治療前五個月，該患者的血糖值為450 mg/100 cc，血清鉀值為2.5 mEq/L。當改用僅含利血平的特殊A片後，這兩項異常都消失。然而，五個月後，他出現了精神憂鬱。非終止性（B類）不良事件。 ♥ B類事件（表6）與A類事件不同，是指無需永久停止方案治療的事件。發生B類事件的患者可使用已知的降血壓藥物治療長達六個月，之後必須重新開始方案治療。 B類事件包括與動脈粥狀硬化相關的器質性併發症，例如腦血管血栓形成（與被視為A類事件的出血不同）或心肌梗塞。對常規洋地黃或汞劑治療有效且無需使用降血壓藥物的充血性心臟衰竭也被歸類為B類事件。
除上述終止事件中所描述的患者外，試驗期間還有7例患者出現B級併發症（表6）。這些事件發生在6例對照組患者和1位活性藥物治療組患者。對照組中有2例患者發生心肌梗塞，並伴隨診斷性心電圖和血清轉氨酶改變。另有2例患者發生充血性心臟衰竭，經洋地黃治療後症狀及徵兆消失。第5例患者被診斷為腦血管血栓形成，第6例患者反覆出現短暫性左側偏癱。活性藥物治療組中唯一發生的B級事件是一名68歲男性，其血壓偏低，伴隨左側偏癱。評論：雖然原發性高血壓通常被認為是一種緩慢進展的疾病，但這些男性患者的診室舒張壓≥115 mmHg，似乎並非如此。對照組出現嚴重併發症的發生率極高，尤其是早期眼底鏡下可見加速性高血壓的表現。類似的發生率也出現在其他組別。 Wolff 和 Lindeman* 報告稱，在為期兩年的觀察期內，對照組患者出現嚴重高血壓併發症的比例較低。他們將部分原因歸因於其診所的患者群體主要為低收入黑人。然而，在本報告中，儘管隨機分配到對照組的白人和黑人人數相等，但白人高血壓併發症的比例高於黑人。先前關於抗高血壓藥物治療原發性高血壓療效的大多數報告均未包含隨機對照組。 Hodge 等人* 以拒絕接受治療的患者作為對照組。他們發現，在 1 至 8 年的觀察期內，治療組 2 級高血壓性視網膜病變患者的死亡率降低了 50%。 Leishman* 的未治療患者是指那些拒絕接受交感神經切除術或被認為不適合接受該手術的患者。他發現，治療組的發病率和死亡率降低了三分之二。 Hood及其同事☂*使用非隨機未治療對照組得出結論，治療可顯著降低原發性高血壓患者的死亡率。 Wolff和Lindeman對87名患者進行了一項前瞻性隨機對照研究。 12%的患者失訪。在為期兩年的研究中，治療組患者的併發症發生率僅為對照組的三分之一。 Hamilton☂將61名診室舒張壓平均≥110 mmHg的患者隨機分配至活性治療組及對照組。其中30名患者接受了降血壓藥物治療，31名患者未接受治療。在為期八年的追蹤期間，16名未治療組患者出現併發症，主要為中風，而治療組僅有5名患者出現併發症。在治療組中，有4名患者血壓控制不佳。若排除這4名患者，治療組僅有1名患者出現嚴重併發症。先前研究以及本報告提供的證據幾乎可以肯定，對於診室舒張壓≥115 mmHg的原發性高血壓患者，抗高血壓藥物治療具有顯著價值。大多數這類患者似乎可以透過噻嗪類利尿劑、利血平和肼屈嗪*的聯合用藥得到有效控制，且這些藥物均無需進行大幅度的劑量調整。
除上述終止事件中所描述的患者外，試驗期間還有7例患者出現B級併發症（表6）。這些事件發生在6例對照組患者和1位活性藥物治療組患者。對照組中有2例患者發生心肌梗塞，並伴隨診斷性心電圖和血清轉氨酶改變。另有2例患者發生充血性心臟衰竭，經洋地黃治療後症狀及徵兆消失。第5例患者被診斷為腦血管血栓形成，第6例患者反覆出現短暫性左側偏癱。活性藥物治療組中唯一發生的B級事件是一名68歲男性，其血壓偏低，伴隨左側偏癱。評論：雖然原發性高血壓通常被認為是一種緩慢進展的疾病，但這些男性患者的診室舒張壓≥115 mmHg，似乎並非如此。對照組出現嚴重併發症的發生率極高，尤其是早期眼底鏡下可見加速性高血壓的表現。類似的發生率也出現在其他組別。 Wolff 和 Lindeman* 報告稱，在為期兩年的觀察期內，對照組患者出現嚴重高血壓併發症的比例較低。他們將部分原因歸因於其診所的患者群體主要為低收入黑人。然而，在本報告中，儘管隨機分配到對照組的白人和黑人人數相等，但白人高血壓併發症的比例高於黑人。先前關於抗高血壓藥物治療原發性高血壓療效的大多數報告均未包含隨機對照組。 Hodge 等人* 以拒絕接受治療的患者作為對照組。他們發現，在 1 至 8 年的觀察期內，治療組 2 級高血壓性視網膜病變患者的死亡率降低了 50%。 Leishman* 的未治療患者是指那些拒絕接受交感神經切除術或被認為不適合接受該手術的患者。他發現，治療組的發病率和死亡率降低了三分之二。 Hood及其同事☂*使用非隨機未治療對照組得出結論，治療可顯著降低原發性高血壓患者的死亡率。 Wolff和Lindeman對87名患者進行了一項前瞻性隨機對照研究。 12%的患者失訪。在為期兩年的研究中，治療組患者的併發症發生率僅為對照組的三分之一。 Hamilton☂將61名診室舒張壓平均≥110 mmHg的患者隨機分配至活性治療組及對照組。其中30名患者接受了降血壓藥物治療，31名患者未接受治療。在為期八年的追蹤期間，16名未治療組患者出現併發症，主要為中風，而治療組僅有5名患者出現併發症。在治療組中，有4名患者血壓控制不佳。若排除這4名患者，治療組僅有1名患者出現嚴重併發症。先前研究以及本報告提供的證據幾乎可以肯定，對於診室舒張壓≥115 mmHg的原發性高血壓患者，抗高血壓藥物治療具有顯著價值。大多數這類患者似乎可以透過噻嗪類利尿劑、利血平和肼屈嗪*的聯合用藥得到有效控制，且這些藥物均無需進行大幅度的劑量調整。
A group of 143 male hypertensive patients with diastolic blood pressures (at the clinic) averaging between
115 and 129 mm Hg were randomly assigned to either
active (hydrochlorothiazide plus reserpine plus hydralazine hydrochloride) or placebo treatment. Twenty-seven
severe, complicating events developed in the placebotreated patients as compared to two in the active group.
Four deaths occurred in the placebo-treated group and
none in the actively treated patients. Other complications
in the placebo group included grade 3 or 4 hypertensive
retinopathy, congestive heart failure, increasing azotemia,
cerebrovascular thrombosis, transient ischemic attacks,
cerebral hemorrhage, myocardial infarction, and severely
elevated blood pressure. Severe complications in the
active-treatment group were one cerebrovascular thrombosis and one case of multiple drug toxicity. Male patients with diastolic blood pressures averaging 115 mm
Hg or above represent a high-risk group in which antihypertensive therapy exerts a significant beneficial effect.
The value of antihypertensive drug treatment in
malignant hypertension has been amply demonstrated.☂ However, its effectiveness in preventing morbidity and mortality in less severe forms of
hypertension has been disputed.☂® Adequately controlled, prospective studies are needed to evaluate
this question in patients with essential hypertension.☝ An investigation of this type wasinitiated by
the Veterans Administration Cooperative Study
Group on Antihypertensive Agents in 1963. The
design of the study, including the precautions employed to maintain adherence to protocol and
avoidanceof dropouts, has been described in a previous communication.'☂ The present report is con-
cerned with the results obtained in the patients
All patients were hospitalized for the initial workup. Male patients whose diastolic blood pressures
from the fourth through the sixth day of hospitalization averaged 90 through 129 mm Hg without
treatment were considered for admission to the
prerandomizationtrial period.
Severity was evaluated in five categories. These
were the average diastolic blood pressure during
hospitalization and the degree of clinically detectable hypertensive damage in the following four target organs: the optic fundi, the brain, heart, and
kidneys. Severity of damage in each category was
graded on a scale from 0 (no detectable abnormality) to 4 (most severe changes). The criteria used
for grading severity have been described in detail
elsewhere.*'
After doubling the scores for the average diastolic blood pressure and the severity of
damage to the optic fundi, the scores obtained in
each category were summedto obtain a total severity index. Patients with total scores of 2 through 7
were classified as mild, 8 through 15 as moderate,
and 16 or above as severe, the latter being excluded
from thetrial.
Also excluded from the study were patients with
surgically curable hypertension, uremia, and concomitant fatal diseases such as carcinoma. Patients
with hemorrhages, exudates, or papilledema in the
optic fundi, history of cerebral or subarachnoid hemorrhage, dissecting aneurysm, or congestive heart
failure resistant to digitalis and mercurial diuretics
were excluded.
Additional exclusions included patients who wished to return to the care of their
private physicians, those who for geographical or other reasons would be unable to attendclinic regularly, and patients of dubious reliability such as
alcoholics, vagrants, and poorly motivated patients.
Prerandomization Trial Period.♥
Following discharge from the hospital, the patients entered a
prerandomization trial period of two to four
months☂ duration. They received two placebos,
known to the physician but not to the patient, and
were seen in theclinic at monthly intervals.
Riboflavin (5 mg) was incorporated into one of
the placebos. Riboflavin produces a yellow fluorescence of the urine when the latter is viewed under
ultraviolet light. At each visit, a urine specimen was
examined for fluorescence. Patients were required
to return all bottles of medication, at which time
the tablets were counted to assess the patient☂s
reliability. To qualify for admission to the study,
the patients were required to have no ☜violations☝
on two successiveclinic visits. A violation consisted
eitheroffailure to appear at the regularly scheduled
clinic appointment, or failure of the urine to exhibit fluorescence, or a tablet count (of either of the
two types of placebos) which was outside the acceptable range. The upper limit of the acceptable
range was defined as the return of no more than a
10% excess of the calculated numberof tablets remainingif all doses had been taken as prescribed,
while the lower limit was a return of five tablets less
than the same calculated number. Nearly one half
of the patients accepted into the trial period were
excluded prior to randomization because of failure
to pass the abovetests of reliability.
Also excluded were patients who during the trial
period exhibited diastolic blood pressures (while in
the sitting position) averaging below 90 or above
129 mm Hg. Thus, the final decision to accept the
patient into the study was based on bothreliability
and the level of diastolic blood pressure determined
in the clinic during thetrial period.
Postrandomization Period.
At the time of randomization, a sealed envelope was opened which
assigned the patient to one of two possible regimens♥active antihypertensive medications or their
placebos. A table of random numbers was utilized
by the statistician in determining the assignments.
Patients classified by severity scores as having mild
hypertension were randomized in a separate stratification from those with moderate hypertension.
The double-blind technique was employed by utilizing a series of complex code numbersto disguise
the identity of the randomized treatments and by
making active drugs and placebos identical in appearance. It is realized, however, that blood pressure levels and side effects made the maintenance
of such a double-blind study difficult and imperfect.
The active drugs were incorporated in the two
tablets as follows: tablet A contained 50 mg hydro- chlorothiazide plus 0.1 mg reserpine, and tablet B
contained hydralazine hydrochloride. Tablet B was
available in two strengths, 25 and 50 mg. Placebos
were madeup to correspond with each tablet of the
active drugs.
Treatment was begun with either tablet A, one
twice daily, plus the 25-mg tablet B, one tablet
three times daily, or else with the placebos of both
of these tablets. At the next visit, tablet B was
increased to the 50-mg strength. Thus, the regular
maintenance daily dose to patients randomized to
the active regimen was 100 mg of hydrochlorothiazide, 0.2 mg of reserpine, and 150 mg of hydralazine hydrochloride. However, if there were hypotensive reactions or other severe side effects, doses
could be reduced to a tolerable level.
In order to further minimize losses due to drug toxicity, two special A tablets were available on
request. One contained hydrochlorothiazide without reserpine for patients becoming depressed or
having active peptic ulcer or other reserpine-associated severe side effects. The other contained reserpine without hydrochlorothiazide for toxicity associated with the latter, such as hyperglycemia or
acute gout. These special A tablets were available
in both active and placebo forms.
The patients visited the clinic at monthly intervals for the first two months following randomization and at bimonthly intervals henceforth.
Additional interim visits were scheduled if needed.
Tablet counts were made at all clinic visits and
fluorescence tests of the urine were made at alternate visits. Annual examinations included complete
physical examination, roentgenogram of the chest,
electrocardiogram, blood chemistry, and renal function tests. General medical care measures and
symptomatic treatment, with the exception of
known active antihypertensive drugs, were employed in all patients.
Characteristics of Patients
Only the patients whose diastolic blood pressures
averaged 115 to 129 mm Hg during the last two
prerandomization clinic visits are included in the
present report. For this high-risk group the study
was ended in May 1967.
The patients with lower
prerandomization diastolic readings are continuing
in the study and will be reported on later.
The
study was terminated in the 115 mm Hg and above
group at an earlier date than expected when it
became apparent that the risk rate increased sharply at these levels of diastolic blood pressure and
that the clinical course of such patients appeared
to be favorably influenced by antihypertensive drug
treatment. Therefore, all patients in this high-risk group have since been
given active treatment.
The total number of
high-risk patients randomized was 143.
Of this
total, 70 received placebos, and 73 received
active antihypertensive
drugs during the randomization trial.
Their average age was 51 years with
a range of 30 to 73 years.
The average weight was
4 83.5 kg (184 Ib). Seventy-seven patients were
Negroes and 66 whites. There were no significant
differences with regard to
age, weight, duration of
known hypertension, or
family history of hypertension, between the placebo- and_ active-treatment groups (Tables 1 and 2). There were more Negro and diabetic patients in the actively treated than in the placebo
group, but the differences were not significant. The
various indices of severity such as hospital and
clinic blood pressure; funduscopic, cardiac, central
nervous system, and renal abnormalities were essentially similar in the two groups.
The 143 patients were admitted into the study
from April 1964 to December 1966. Observations
on all these patients ended in May 1967. Thus,
there is considerable variation in the duration of
observation (Table 3). Nevertheless, 38% of the
patients were observed for two years or more. The
duration of the postrandomization phase of the
study averaged 15.7 months for the placebo-treated
patients and 20.7 for the active-drug group. Twenty-six of the placebo patients were in the postrandomization period of the study for less than one
year as compared to 15 of the active group. Twenty-three placebo-treated patients exceeded a twoyear period of postrandomization follow-up as
opposed to 32 of the actively treated patients. The
briefer period of follow-up of the patients in the
placebo group was caused by the larger number
of terminating events which developed in this
group.
Seven patients, in addition to those described
above under terminating events, had class B complications during the course of the trial (Table 6).
These events occurred in six placebo-treated patients and in one actively treated. In the placebotreated group myocardial infarction accompanied
by diagnostic electrocardiographic and serum transaminase changes occurred in two patients. Congestive heart failure occurred in two others, the
symptoms and signs of which cleared following
treatment with digitalis. Cerebrovascular thrombosis was diagnosed in the fifth case, and the sixth
had repeated transient episodes of left-sided hemiparesis. The single class B event in the activetreatment group occurred in a 68-year-old man
who had hypotensive levels of blood pressure accompanied by a left-sided hemiparesis.
Comment
Although essential hypertension is generally regarded as a slowly progressive disorder, such did
not appear to be the case in these male patients
with clinic diastolic blood pressures of 115 mm Hg
or higher. An extremely high incidence of severe
complications, especially early funduscopic manifestations of accelerated hypertension occurred in
the placebo-treated group. A similar high incidence of severe hypertensive complications occurring in
placebo-treated patients sver a two-year period of
observation was reported by Wolff and Lindeman.'*
They attributed this in part to the fact that their
clinic populaticn was primarily a lower-income
Negro group. However, in the present report more
whites than Negroes had hypertensive complications despite equal numbers of each race randomized to placebos.
The majority of prior reports on the effects of
antihypertensive drug treatment in essential hypertension have not contained randomized control
groups. Hodgeet al'☂ utilized as their control the
patients who refused to undertake treatment. They
found a 50% reduction in mortality in the treated
group over a period of 1 to 8 years of observation
in patients with grade 2 hypertensive retinopathy.
Leishman☂s untreated patients were those who declined or who were considered unsuitable for sympathectomy.'' He found morbidity and mortality
reduced by two thirds in the treated group. Hood
and his associates☂* using a nonrandomized untreated control group concluded that mortality was
considerably reduced by treatment in essential
hypertension.
A prospective, randomized control study was
carried out by Wolff and Lindeman in 87 patients.'°
Twelve percent defaulted. Over a two-year period
the incidence or morbid events in the treated patients was one third of that observed in the placebo group. Hamilton'☂ alternately assigned 61 pa.
tients with clinic diastolic blood pressures averaging
110 mm Hg or higher to active treatment and
placebo. Thirty were treated with antihypertensive
agents and 31 were not. Over an eight-year period
of follow-up, 16 of the untreated patients had complications, primarily strokes, as compared to five
of the treated group. Of the latter, four exhibited
poor blood pressure control. If they are excluded.
only one of the treated patients had a severe complication.
The evidence provided by these earlier studies
plus the present report leaves little doubt as to
the value of antihypertensive drug therapy in essential hypertension associated with clinic diastolic
blood pressures of 115 mm Hg or more. It appears
that the majority of such patients can be managed
satisfactorily with combinations of thiazides, reserpine, and hydralazine,'* none of which require more
than minor dosage adjustments.
Generic and Trade Namesof Drugs
Hydralazine hydrochloride♥Apresoline Hydrochloride.
Hydrochlorothiazide♥Aquarius, Esidrix, Hvydril, Hydrodiuril.
Oretie.
Reserpine♥Rauloydin, Raurine, Rau-Sed. Reserpoid. Sandril.
Serfin, Serpasil, Serpate, Vio-Serpine
沒有留言:
張貼留言