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

內科-1967 JAMA- Effects of Treatment on Morbidity in Hypertension

2026-09-01 08:49AM

這是篇很古老的研究. 1967年刊登於 JAMA

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。

退伍軍人健康管理局

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淘汰. 另外舒張壓<90 或 >129 (太低太高)也都被排除

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).

(pdf)Effects of Treatment onMorbidity in Hypertension Results in Patients With Diastolic Blood Pressures Averaging 115 Through 129 mm HgVeterans Administration Cooperative Study Group on Antihypertensive Agents

JAMA, Dec 11, 1967

下面中文使用 google 翻譯
治療對舒張壓平均值在 115 至 129 mmHg 之間的高血壓患者發病率的影響 退伍軍人事務部抗高血壓藥物合作研究組
JAMA，1967年12月11日


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治療組(使用降血壓藥物)或對照組(只給安慰劑)

hydrochlorothiazide plus reserpine plus hydralazine hydrochloride) or placebo treatment.

安慰劑組發生了27例嚴重併發症，而活性治療組僅有2例。

安慰劑組有4例死亡，活性治療組無死亡病例。

安慰劑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。

活性治療組的嚴重併發症包括

1例腦血管血栓形成和1例多藥中毒。

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。研究的設計，包括為確保患者遵守方案和避免脫落而採取的預防措施，已在先前的報告中有所描述。本報告主要關注患者所獲得的研究結果。


調查計劃
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。嚴重程度評估分為五個類別。這些類別包括住院期間的平均舒張壓以及以下四個目標器官（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。每個類別的損害嚴重程度均以0（無可偵測到的異常）至4（最嚴重的改變）的等級進行評分。嚴重程度分級標準已在其他文獻中詳細描述。 *' 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。

本研究也排除了可手術治癒的高血壓、尿毒症以及伴隨致命疾病（如癌症）的患者。

視神經眼底出血、滲出或視乳頭水腫、有腦出血或蛛網膜下腔出血史、主動脈夾層動脈瘤或對洋地黃和汞利尿劑無效的充血性心臟衰竭的患者也被排除在外。

其他排除標準包括：

希望返回私人醫生就診的患者、因地理位置或其他原因無法定期到診所就診的患者，以及可靠性存疑的患者，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)

出院後，病患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，是基於可靠性以及試驗期間在診所測定的舒張壓水平。

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安慰劑組。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。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。

活性藥物製成兩種片劑，如下：A片含有50毫克氫氯噻嗪和0.1毫克利血平，B片含有鹽酸肼屈嗪。 B片有兩種規格，分別為25毫克和50毫克。安慰劑的配製與每種活性藥物片劑相對應。


治療開始時，患者可選擇服用A片（每日兩次，每次一片）加25毫克B片（每日三次，每次一片），或服用安慰劑。下次就診時，B片的劑量增加至50毫克。因此，隨機分配至活性治療組的患者的常規維持每日劑量為：氫氯噻嗪100毫克、利血平0.2毫克和鹽酸肼屈嗪150毫克。然而，如果出現低血壓反應或其他嚴重副作用，劑量可減少至可耐受的水平。為了進一步減少藥物 毒性造成的損失，可根據要求提供兩種特殊的A片。一種含有氫氯噻嗪，但不含利血平，適用於出現憂鬱、活動性消化性潰瘍或其他利血平相關嚴重副作用的患者。另一種含有利血平，但不含氫氯噻嗪，適用於氫氯噻嗪相關的毒性反應，例如高血糖或急性痛風。這些特殊的A片有活性藥物和安慰劑兩種形式。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。如有需要，可安排額外的追蹤。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
本報告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。對於這一高風險族群，研究於 1967 年 5 月終止。隨機分組前舒張壓較低的患者仍在研究中，相關結果將在後續報告中闡述。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。 ⁴ 隨機分組的高危險群患者總數為 143 例。其中，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。安慰劑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）。活性治療組的黑人患者和糖尿病患者人數多於安慰劑組，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。 143 名患者於 1964 年 4 月至 1966 年 12 月期間入組本研究。所有患者的觀察期均於 1967 年 5 月結束。因此，觀察期存在相當大的差異（表 3）。儘管如此，仍有 38% 的患者接受了兩年或兩年以上的觀察。研究中，安慰劑組患者隨機分組後階段的平均持續時間為15.7個月，活性藥物組為20.7個月。安慰劑組有26位患者隨機分組後追蹤時間少於一年，而活性藥物組僅有15例。安慰劑組有23位患者的隨機分組後追蹤時間超過兩年，而活性藥物組則有32例。安慰劑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。

治療方案調整。在 隨機分配至活性降血壓藥物組的73例患者中，45例在整個研究期間均接受了標準維持劑量的氫氯噻嗪（50 mg加利血平0.1 mg，每日兩次）和鹽酸肼屈嗪（50 mg，每日三次）。其餘患者則因標準方案下血壓偏低或出現嚴重頭痛或疲倦等副作用而減少了劑量。未發生系統性紅斑狼瘡病例。 2例患者改用特製A片，1例因憂鬱症，另1例因高血糖反應。 70例安慰劑組患者中有66例接受了標準維持劑量。 2例患者因疑似肼屈嗪引起的副作用而減少了B片的劑量。另有2例患者因憂鬱症而改用特製A片安慰劑。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例脫落。其中7例隨機分配至安慰劑組，5例隨機分配至活性藥物組。因此，脫落率較低，且活性藥物組和安慰劑組的脫落人數大致相等。血壓變化：♥活性藥物治療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，安慰劑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。與安慰劑組相比，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。可評估的不良事件 如表4所示，安慰劑組有27例患者發生可評估的不良事件，而活性藥物組僅有2例。使用卡方檢驗，並假設治療無效，該結果在P<0.001水平上具有統計意義。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例安慰劑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，安慰劑組有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，安慰劑組為21例，而活性治療組為1例。安慰劑組患者的終止事件。 ♥表5列出了21例因併發症而需要停止方案指定治療的安慰劑組患者。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例安慰劑組患者和1位活性藥物治療組患者。安慰劑組中有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。安慰劑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，安慰劑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，儘管隨機分配到安慰劑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安慰劑組的三分之一。 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安慰劑組。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

Plan of Investigation 

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. 4 The total number of high-risk patients ran7 domized 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. J 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.

Modification in Treatment Regimens. Of the 73 patients randomized to active antihypertensive drugs, 45 received the standard maintenance doses of hydrochlorothiazide, 50 mg plus reserpine 0.1 mg twice daily, and hydralazine hydrochloride, 50 mg three times daily, throughout their participation in the study. Dosages were reduced in the remaining patients because of low blood pressure levels with the standard regimen or because of side effects such as severe headache or weakness. There were no cases of systemic lupus erythematosus. Two patients were transferred to the special A tablets, one because of depression and the other because of a hyperglycemic reaction. Sixty-six of the 70 placebo-treated patients received standard maintenance dosages. Reduced doses of tablet B were given to two patients because of presumed hydralazine-inducedside effects. Special tablet A placebos were substituted in two other patients because of depression. Dropouts.♥The total number of dropouts was 12 or 8.4%. Nine occurred during the first two months following randomization. Seven had been randomized to placebos and five to active drugs. Thus, the dropout rate was small and was approximately equally divided between the active- and placebo-treated patients. Changes in Blood Pressure.♥Systolic and diastolic blood pressures fell promptly and significantly in the actively treated patients and remained at these reduced levels throughout the trial. The prospective trends for diastolic blood pressure recorded with the patients in the sitting position are shown in Table 5. After 24 months of active treatment. the reduction from prerandomization levels of clinic blood pressure averages 43 mm Hg systolic and 29.7 mm Hg diastolic. By contrast, the placebotreated patients showed no significant changes in average blood pressure levels following randomization (Table 3). The distribution of individual changes are shown in the Figure. There is a marked shift to the left into the ☁☜☁decrease☝ zone for the treated patients as compared with the placebo group. This marked shift is evident for both systolic and diastolic changes. Also apparent is the wide variation in individual responses. Assessable Morbid Events As shown in Table 4 assessable morbid events occurred in 27 placebo-treated versus two actively treated patients. Using the chi-square test, and assuming that the treatment has no effect, this result is statistically significant at the P<.001 level. If the possible effect of the 12 patient dropouts is considered and the most adverse assumption made, namely, that the seven placebo-treated patients would have had no countable event if they had stayed in the study and the five patients taking active drugs each would have had a countable event (a most unlikely occurrence!), then the score would have been 27 to 7. But even this conservative hypothetical ☜result☝ is statistically significant at the .001 level. When deaths and class A hypertensive complications are combined, such events occurred in 14 placebo-treated patients as compared to none in the group receiving antihypertensive drugs. The total number of patients with terminating events, which includes deaths, class A events, and other treatment failures, was 21 in the placebo group versus one in the actively treated group. Terminating Events in Placebo-Treated Patients. ♥The 21 placebo-treated patients having complications which required discontinuation of the protocol assigned treatmentare listed in Table 5. The average age of these patients was 55.2 years, which was four years older than the average age of the total randomized population. Thirteen of the terminating events occurred in whites and eight in Negroes. The average clinic blood pressure of the 21 patients prior to randomization was 196.9/ 121.5 mm Hg, a slightly higher systolic average than that found in the entire group at risk. The shortest period from randomization to terminating event was 2 months, the longest 26 months and the average 11 months. Terminating events were well distributed among the 15 participating hospitals, 14 contributing one or more events. 1. There were four deaths, all of which were related to cardiovascular diseases. Dissecting aortic aneurysm occurred in two, ruptured abdominal aneurysm in one, and sudden death at home in one (Table 5). No autopsy was obtained in the latter instance. The diagnosis of dissecting aortic aneurysm wasverified either at surgical exploration or at autopsy. The diagnosis of ruptured abdominal aortic aneurysm with fatal hemorrhage was verified at autopsy. 2. Class A events were those hypertensive complications as defined in the protocol which required treatment with known active agents and permanent removal from protocol assigned therapy. They included the following: funduscopic evidence of grade 3 or 4 hypertensive retinopathy (multiple striate hemorrhages or soft exudates in more than one quadrant, or bilateral papilledema), doubling of blood urea nitrogen (BUN) to levels above 60 mg/100 cc; dissecting aortic aneurysm; cerebrovascular hemorrhage as opposed to thrombosis; subarachnoid hemorrhage; congestive heart failure persisting despite digitalis and mercurial diuretics; and elevation of diastolic blood pressures to 140 mm Hgor higher on three repeated visits and average rehospitalization diastolic pressure to 130 mm Hgorhigher. Thecase histories of patients having terminating events were reviewed by a panel of four members consisting of two participants and two consultants. The panel determined in each case whether the criteria for a class A event as defined in the protocol were fulfilled. Terminating events which did not fully meet these criteria were classified as treatment failures as described below. There were ten class A events in which the patients lived. Two of these were considered irreversible, and eight proved to be reversible following active antihypertensive treatment. Oneof theirreversible events was a cerebrovascular hemorrhage as evidenced by hemiplegia, stiff neck, and bloody and xanthrochromic spinalfluid. The other occurred in an azotemic patient whose renal function deteriorated rapidly.  Seven of the eight reversible class A events included grade 3 or 4 changes in the optic fundi. In two, striate hemorrhages and papilledema were present. In two others, multiple bilateral striate hemorrhages and cotton wool exudates were visualized; in two additional patients bilateral striate hemorrhages andresistant congestive heart failure were present simultaneously; and in the seventh patient, striate hemorrhages were presentbilaterally but without exudates (Table 5). The remaining reversible class A event was associated with severely elevated blood pressure, the diastolic pressure during rehospitalization averaging 136 mm Hg. 3. Treatment failures were those events which did not meet the specific criteria for any one class A event as defined in the protocol. Nevertheless, because the complications were considered to be life threatening, protocol drugs were removed and treatment instituted with known antihypertensive agents. Seven of the terminated placebo-treated patients were classified as treatment failures. In two, multiple striate hemorrhages and soft exudates were seen in the optic fundi, but these patients also had diabetes mellitus. That the retinopathy probably was primarily associated with hypertension is suggested by the fact that, in both instances, the changes in the fundi cleared within two months after initiation of treatment with known antihypertensive agents. In a third nondiabetic patient only one cotton wool exudate and no striate hemorrhages were observed. Two patients were classified as treatment failures because the diastolic blood pressures in the clinic were frequently recorded above 140 mm Hg but averaged below 130 mm Hg during rehospitalization. Additionally, a 34-year-old patient was removed from protocol therapy because previously normal levels of BUN and serum creatinine increased to 28 and 3 mg/100 cc respectively at the time of annual examination. The final treatment failure was a cerebrovascular accident diagnosed as thrombosis rather than hemorrhage, but which resulted in complete invalidism and inability to return to the clinic. Terminating Event in Actively Treated Patients.♥The single terminating events in the 73 patients who received active drugs occurred in a patient with multiple drug toxicity. Five months before termination the patient was found to have a blood glucose level of 450 mg/100 cc and a serum potassium value of 2.5 mEq/liter. Both abnormalities disappeared when the special A_ tablet containing only reserpine was substituted. However, five months later he had a mental depression. Nonterminating (Class B) Morbid Events.♥ Class B events (Table 6), as opposed to class A events, were those which did not require permanent discontinuation of protocol treatments. Patients with developing B events could be treated with known antihypertensive agents for as long as six months, after which, protocol treatment had to be reinstituted. Class B events included organic complications associated with atherosclerosis, such as cerebrovascular thrombosis (as constrasted to hemorrhage which was considered a class A event) or myocardial infarction. Congestive heart failure which responded to routine therapy with digitalis or mercurials and did not require antihypertensive agents also was classified as a B event. 

 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