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 Morbidityin Hypertension

2026-09-01 10:10AM
Effects of Treatment on Morbidityin Hypertension
Circulation, Volume XLV, May 1972


(下面中文使用 GOOGLE 翻譯)
退伍軍人事務部合作研究小組先前報告了一項隨機、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。 治療方案為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疾病的風險從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。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列出了以隨機分組年齡劃分的研究期間併發症發生率。如預期，主要併發症的發生率隨年齡增加而增加。

在對照組中，50歲以下患者的併發症發生率為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。

治療預防不良事件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%；

在50-59歲年齡組中，治療有效率達68%；

在60歲以上患者中，治療有效率達54%。

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。

後者在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。

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。

 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。 ¹ 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。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。由於在試驗的前 3 年裡，一些醫院用餐後 2 小時血糖取代了空腹血糖 (FBS)，因此有關空腹血糖 (FBS) 的數據並不完整。由於在試驗的前 3 年裡，一些醫院用餐後 2 小時血糖取代了空腹血糖 (FBS)，因此有關空腹血糖 (FBS) 的數據並不完整。

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⁶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。

T HE 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 sharplyreduced 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, 20control 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 and20.5% 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 thecontrol group, 15.2% of the patients under age50 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年-高血壓研究

2026-09-01 08:49AM

Effects of Treatment on Morbidity in Hypertension

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 placebo-treated 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.1-6 However, its  effectiveness in preventing morbidity and mortality in less severe forms of hypertension has been disputed.7-9 Adequately controlled, prospective studies are needed to evaluate this question in patients with essential hypertension.11 An investigation of this type was initiated 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 avoidance of dropouts, has been described in a previous communication.10 The present report is concerned with the results obtained in the patients without signs of accelerated hypertension at admis-sion whose diastolic blood pressures prior to treat-ment averaged 115 through 129 mm Hg.

Plan of Investigation

All patients were hospitalized for the initial work-up. 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 prerandomization trial 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.11 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 summed to 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 the trial.

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 for exclusion included the inability to attend clinic visits regularly, as well as unreliable patient profiles such as individuals with alcoholism, vagrancy, or low motivation.

Prerandomization Trial Period: After hospital discharge, patients underwent a two-to-four-month prerandomization trial phase, receiving two physician-known placebos while attending monthly clinic visits.

Riboflavin (5 mg) was added to a placebo to cause yellow urine fluorescence under UV light, monitored at each visit alongside tablet counts from returned bottles to check patient reliability. Patients needed two consecutive visits without "violations"—missed appointments, lack of urine fluorescence, or unacceptable tablet counts (defined as returning more than 10% above or 5 tablets below the expected number). Nearly half of the prospective patients were excluded before randomization for failing these reliability checks.