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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。 * 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。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。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。此外，以下患者也被排除在外：(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。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。活性藥物包含兩種片劑，一種是含有50毫克氫氯噻嗪和0.1毫克利血平的複方片劑，每日兩次服用。另一種是25毫克鹽酸肼屈嗪，每日三次服用（JAMA，1970年8月17日，第213卷，第7期）。如果舒張壓持續高於90毫米汞柱，則後一種藥物的劑量增加至每日三次，每次50毫克。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。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。如有需要，可安排額外的追蹤。
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月期間入組，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。除可評估事件外的其他損失：因其他疾病導致的死亡。四名患者死於與高血壓無關的疾病。兩名患者屬於對照組。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。這兩名患者均進行了屍檢。藥物毒性導致的死亡。 ♥ 治療組有兩名患者出現疑似藥物毒性反應。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。
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。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。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。 6名患者搬離了診所所在地區。 2名患者因參與研究的診所關閉而失訪。 4名患者重新回到私人醫師處接受治療。 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。 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。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。
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。 ♥與心血管疾病相關的死亡。 ♥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。 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。或 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）。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。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。
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 overafive-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 whoseinitial diastolic blood pressure averaged 90 through 114 mm Hg. Pian 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 1144 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.
