Comparison of the effects of diuretic therapy and low sodium intake in isolated systolic hypertension

Comparison of the Effects of Diuretic Therapy and Low Sodium Intake in Isolated Systolic Hypertension

ANDREAS P. NIARCHOS, M.D. DAVID L. WEINSTEIN, B.S. JOHN H. LARAGH, M.D. New York. New York

From the Hypertension Center and Department of Medicine, New York Hospital-Cornell University Medical Center, New York, New York. This work was supported by Grant HL-18323 from the National Institutes of Health, Bethesda, Maryland. Requests for reprints should be addressed to Dr. Andreas P. Niarchos, Hypertension Center (K400) New York Hospital-Cornell University Medical Center, 525 East 68th Street, New York, New York 10021. Manuscript accepted June 19, 1984.

Of 103 patients with isolated systolic hypertension, 71 were treated with diuretics and another 32 with low-sodium diet. In the 71 who were treated with diuretics, body weight decreased from 69.46 f 1.47 to 66.60 f 1.45 kg (p
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TABLE I

Comparison of Control Data and Percent Changes in All Diuretic- and Low-Sodium Diet-Treated Patients with Isolated Systolic Hypertension Diuretic Therapy

Low-Sodium Diet

Data before Therapy Number of patients Sex (male/female) Age (years) Weight (kg) Heart rate (beats/minute) Systolic blood pressure

71

29142 64.5 f 2 69.48 f 1.47 76 f 3 178f2

(mm Hg) Diastolic blood pressure

89f

(mm Hg) Plasma renin activity (ng/ml/ hour) Urinary aldosterone (pg/24 hours) Urinary sodium (meq/24 hours)

1

1.78 f 0.30 10f

1

92 f

10’

Percent Changes with Therapy Weight -1.22 f 0.34 +8f2* Heart rate -14f 1’ Systolic blood pressure Diastolic blood pressure -2fl Plasma renin activity +584 f 42’ Urinary aldosterone +159 f 42’ Urinary sodium +60 f 31’ l

32 12/20 62 f 4 71.18 f 2.50 77 f 2 174f2 90f

1

2.25 f 0.33 9fl 143 f

-1.40 f -3f2 -11 f -3.5 f +90 f +68 f -66 f

10

0.23 1 2 30 16 20t

p <0.05 or less, unpaired t test.

7 As expected.

of the lack of prospective therapeutic trials or because treatment was &sociated with intolerable or even serious side effects when it was attempted [ 121. The therapeutic approach to isolated systolic hypertension so far has been either empiric using the stepped-care approach [ 1,131 or based on the hemodynamic characteristics of the disease [ 14,151. The last therapy [ 151 takes into consideration the findings that younger patients have an increased cardiac output and consequently ought to be treated with a beta-adrenergic receptor blocking drug and that older patients maintain isolated systolic hypertension by an increased impedence to flow as a result of decreased aortic compliance and increased peripheral resistance and consequently ought to be treated with a vasodilator drug [ 12,151. This approach however, based on the agerelated hemodynamic characteristics of systolic hypertension, may not be as appropriate as initially thought because there are younger patients with isolated systolic hypertension in whom impedence to flow might be increased and-vice versa-older patients in whom an increased cardiac output is also present [ 161. Although the hemodynamic approach in the treatment of isolated systolic hypertension has been emphasized [ 151, and

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ET AL

the possible pathogenetic role of the renin-angiotensin system and its importance in selecting therapy for isolated systolic hypertension have been reported [ 17-201, the effects of long-term diuretic therapy in comparison with those of low-sodium diet and their relation to the renin-sodium profiles have not yet been investigated in patients with isolated systolic hypertension. PATIENTS AND METHODS Patients. One hundred and three patients with isolated systolic hypertension were prospectively investigated. Their age ranged from 32 to 78 years. Of the 103 patients, 41 were men and the remaining 82 were women. isolated systolic hypertension was defined as systolic blood pressure greater than 180 mm Hg and diastolic blood pressure less than 90 mm Hg on at least two examinations. Patients with known causes of isolated systolic hypertension such as anemia, hyperthyroidism, arteriovenous fistulas, aortic insufficiency, and coarctation of the aorta were excluded from the study. Patients with systolic hypertension caused by clinically obvious and angiographicaiiy severe and obstructive atherosclerosis or Takayasu’s disease were not included in this study. Patients who had complications (stroke, heart failure, renal failure) and patients with diabetes mellitus and isolated systolic hypertension [21] were also excluded from this study, as were those with borderline hypertension, that is, systolic blood pressure between 140 and 159 mm Hg. In addition, in order to avoid racial differences in the response to diuretics or low-sodium diet, black patients were excluded from this study. Methods. All patients were investigated prospectively in a similar manner in the untreated state; if a candidate for this study was receiving treatment, it was discontinued for at least three weeks before entrance into the study. The 103 patients were divided according to the treatment they received into two groups, a diuretic-treated group and a low-sodium diettreated group. The age, sex distribution, baseline blood pressure, and renin-sodium profiles were similar in the two groups, with the exception of 24-hour urinary sodium excretion, which was higher in the diet-treated group (Table I). Diuretic-treated group: This group included 7 1 patients who were treated with diuretics and were investigated as outpatients. On the day of the beginning of the study, patients were examined in the seated position. Three blood pressure readings were obtained by the usual mercury column cuff sphygmomanometer, and the values were averaged. Pulse rate and weight were also checked. Blood was drawn for the usual blood chemical studies and plasma renin activity, which was measured by radioimmunoassay [22]. The concurrent 24-hour urine collection (from the previous day until the ITIOrning of the examination) was analyzed for sodium, potaSSiUm, protein, creatinine, and aldosterone levels [23]. Treatment was begun with chlorothaiidone, 25 mg every other day and then 25 mg daily up to 50 mg daily. Patients were examined every two months, but renin-sodium profiling was repeated six months after therapy was begun. Therefore, the data on diuretic therapy were obtained six months after di-

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DIURETICS VERSUS LOW SALT IN SYSTOLIC HYPERTENSION-NIARCHOS

uretic therapy was begun. The effects of diuretic therapy were then analyzed according to the renin status of the patient and according to the response of the systolic blood pressure to diuretic therapy. The 71 diuretic-treated patients were classified as follows according to their pretreatment renin level: low renin (n = 48) normal renin (n = 18) and high renin (n = 5). Furthermore, if the systolic blood pressure decreased by at least 10 mm Hg, patients were classified as responders to diuretic therapy, and if by less, as nonresponders. Their pretreatment characteristics are summarized in Table II. To avoid diurnal variations in blood pressure or renin, all patients were seen in the morning. Low-sodlum dlet-treated group: This group included 32 patients not previously treated who were advised to begin a low-sodium diet. They were followed as outpatients and were investigated exactly the same as the diuretiotreated patients, with the exception that they were instructed to begin a lowsalt diet by providing them with a list of the salt content of the most common foods. Patients were advised to continue a stable potassium intake. No antihypertensive drugs were given during the period of the low-sodium diet. The renin status of the low-salt diet-treated group was as follows: 12 patients were in the low-renin group, 18 were in the normal-renin group, and the remaining four patients were in the high-renin group. Their pretreatment characteristics are summarized in Table I and Table Ill. The duration of lowsodium diet was 5 f 0.4 months, when blood pressure measurement and renin-sodium profiling were repeated. Statlstlcal Analysls. The paired or unpaired t test, as appropriate, was used to compare differences between pretreatment data and those obtained with treatment or between different groups. A p value of less than 0.05 was accepted as significant. Correlation coefficients were calculated by the method of Spearman. Data are given as mean f SEM. RESULTS Effects of Dluretlc Treatment. When all patients were analyzed together, that is, regardless of the systolic blood pressure response, diuretic therapy significantly decreased body weight from 69.46 f 1.47 to 68.60 i 1.46 kg (by 0.93 f 0.27 kg, p <0.0005) and systolic

blood pressure from 178 f 2 to 152 f 2 mm Hg (p <0.005). Diastolic blood pressure did not decrease significantly (from 89 f 1 to 87 f 2 mm Hg), whereas heart rate increased slightly but significantly from 76 f 3 to 82 f 3 beats per minute (p <0.025). Plasma renin activity increased from 1.78 f 0.30 to 7.32 f 1.78 ng/ml per hour (p <0.005) and urinary aldosterone from 10 f 1 to 23 f 4 pg per 24 hours (p
24-hour urinary sodium excretion increased from 92 f 10 to 140 f 30 meq, this change was not significant. In all patients, the change in systolic blood pressure was not significantly

related to the age of the patient (r or to control weight (r = -0.04) or to control urinary sodium excretion (r = -0.23,O.lO > p >0.05) or urinary aldosterone (r = 0.08). The strongest correlation existed between the control pulse pressure and the change in the systolic blood pressure (r = -0.39, = 0.14)

TABLE II

ET AL

Comparison of Patients with and without Response to Dluretlc Therapy Responders

Data before Diuretic Therapy Number of patients Sex (male/female) Age (years) Weight (kg) Heart rate (beats/minute) Systolic blood pressure (mm Hg) Diastolic blood pressure

60

p Valus 11

25735 65f 1 69.16 f 1.56 78 f 2 179 f 2 a9f

NOM-

1

417 62 f 71.16 f a0 f 172 f 91 f

3 4.16 3 5

NS NS NS NS

1

NS

(mm ffg) Plasma renin activity 1.23 f 0.21 3.06 f 0.75 <0.005 (ng/ml/hour) 10f 1 9f2 NS Urinary akfosterone &g/24 hours) 119f22 NS Urinary sodium (meq124 ai f 10 hours) Percent Changes Induced by Diuretic Therapy Weight -1.37 f 0.37 -0.71 f 0.87 NS Systolic blood pressure -17 f 1 -1 f2 <0.005 +692 f 215 +333 f 167 Plasma renin activity NS +171 ia9 NS Urinary aldosterone +154 f 48 Urinary sodium +a8 f 42 -6 f 30 0.10 > p >0.05

p p >0.05). In addition, renin and urinary aldosterone levels were significantly increased (Table IV), despite the lack of systolic blood pressure decrease. When the responders were compared with the nonresponders before diuretic therapy, only the difference

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5

6

4.57 4 5 2 0.80

<0.0005 -

NS

<0.0005 NS <0.0005 <0.005 <0.025

p Value

1 11 1

81 f 65%

0.13

1

10f

0.91 f

89 f

Titerspy

1

100 f -

13

26 f 6

7.34 f 2.93

84 f

68.88 f 1.87 81 f 2 149 f 2

p Value

NS -


<0.05

<0.0005

<0.005
136 f 64 f

8fl

2.01 f

88 f

16 2

0.15

1

67.16 f 2.96 79 f 3 174f3

l

0.28

2

patients.

41 8 -

14 f 2

3.95 f

87 f

66.46 f 2.90 82 f 3 151 f 3

<0.0005 -


<0.0005

NS

NS NS <0.0005

1

119f22 64 f 4

9f2

5

Therapy

0.99

78f -

11

18 f 3

6.3 f

91 f2

70.61 f 4.12 83 f 2 171 f 5

-

<0.025

<0.05 NS NS NS
a Value

0.01 > p >0.05 -

<0.005


NS

NS NS NS

p Value

5 4 1.17

9.30


21 f

75.32 f 81 f3 174f 92 f 6.22 f

Nonrespondsrs(n = 11)’ Diuretic

56f 16 58 f 6

3.06 f 0.75

91 f

9.31 3 5 2 1.40

14 f 4

76.60 f 80 f 168f 90 f 4.65 f

Control

Nonresponders

High Aenin (n = 4)’ Low&ciium Control Diet

71.16 f 4.16 80 f 3 172 f 5

162 f 38 -

<0.05

<0.0005 <0.0005 <0.0005 NS <0.0005

p Value

p value

3.45 3 3 2 0.28

<0.0005 -

Normal Resin (n = 16) Diuretic Control Therapy

Responders(n = 60)

146flf7 62 f 3

f f f f f

14f2

69.33 73 151 89 3.95

The nonresponders include ail five high-renin patients, four low-renin patients, and two normal-renin + Age was not significantly different.

(mm Hg) Plasma renin activity (ng/mi/hour) Urinary aidosterone @g/24 hours) Urinary sodium (meqI24 hours) Aget

1.88 2 3

Control

69.91 f 77 f 181 f

Low Renin (n = 44) Diuretic

f 3.49 f 2 f 3 f 2 f 0.15

8fl

70.36 75 172 90 2.22

Normal Renin (n = 16) Low-Sodium Control Diet

Responders

Effects of Diuretic Therapy in Isolated Systolic Hypertension

Weight (kg) Heart rate (beats/minute) Systolic blood pressure (mm Hg) Diastolic blood pressure

TABLE IV

l

Ail nonresponders had high renin levels. + Age was not significantly different.

38 f -

124 f 15 64 f 2

f f f f f

16f

68.22 77 157 84 3.14

8f2

69.20 f 4.62 79 f 4 178f5 91 f2 1.04 f 0.12

Control

Low Renin (n = 12) Low-Sodium Diet

Effects of Low-Sodium Diet in Isolated Systolic Hypertension

Weight (kg) Heart rate (beats/minute) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Plasma renin activity (ng/mi/hour) Urinary aidosterone @g/24 hours) Urinary sodium (meq/24 hours) Aget

TABLE 111

DlU!4ETlCS VERSUS LOW SALT IN SYSTOLIC

in the level of plasma renin activity (1.23 f 0.21 ng/ml per hour in the responders and 3.06 f 0.75 ng/ml per hour in the nonresponders, Table II) was significant (p <0.005). In addition, all high-renin patients were nonresponders, but four (8 percent) of the 48 low-renin patients and two (12 percent of the 18 normal-renin patients were also nonresponders. The percent changes in the other variables (weight, renin, aldosterone, urinary sodium) induced by diuretic therapy in the responders and nonresponders are also compared in Table II. Although the changes were more marked in the responders, these differences were not significant, probably because of the wide variation of the data. Effects ot Low-Sodium Diet. in all patients (n = 32), the low-sodium diet decreased 24-hour urinary sodium excretion from 143 f 10 to 48 f 5 meq (p
HYPERTENSION-NIARCHOS

Systolic i3P

Diastolic

5r

ET AL

BP -I-

0 mm Hg

P
’

t m

1

Low

I P< 0.0 I

renin

+ P
m Normal renin

m High renin

from control

Flgure 7. Comparison of the effects of low sodium intake on systolic and diastolic blood pressure in low-, normal-, and high-renin isolated systolic hypertension.

weight and 24-hour urinary sodium reduction (Table Ill), the patients with low renin levels had the greatest percent increase in renin and aldosterone. The renin level during the low-sodium diet was the highest in the nonresponder high-renin patients because they had started from a higher baseline renin level (Table Ill). Comparlson of the Effects of Diuretic Therapy with the Effects of Low-Sodium Diet. The effects of diuretic therapy compared with the effects of low sodium diet in all patients are shown in Table I. Although the decreases in body weight and diastolic blood pressure were similar, the decrease in systolic blood pressure and the increase in renin and aldosterone were significantly greater in the diuretic-treated group. COMMENTS Role of Diuretic Therapy in Isolated Systolic Hypertension. The results of the present study show that diuretic therapy was effective in decreasing systolic blood pressure in the low- and normal-renin groups: in this respect, they confirm our previous findings in a smaller group of patients with isolated systolic hypertension [24]. On the other hand, diuretics were ineffective in the patients with high renin levels despite the concurrent reduction in body weight [25] and the increase in plasma renin activity and urinary aldosterone (Table IV), evidence that these patients took their diuretic. Although these findings have been previously reported in patients with combined systolic and diastolic hypertension [26], they nevertheless also confirm that high-renin isolated systolic hypertension is not re-

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sponsive to diuretics regardless of the age of the patient, since older patients were also included in the high-renin group in the present study. Normal systolic blood pressure (160 mm Hg or less) was not achieved with diuretic therapy in 20 percent of the patients with low and normal renin levels. This finding suggests that, in addition to volume, other mechanisms (arterial rigidity, possibly the high renin values induced by diuretic therapy, sympathetic nervous system) also maintain elevated systolic blood pressure, even in patients with low or normal renin levels, These possible mechanisms were not investigated further in the present study. An attempt should be made to decrease elevated systolic blood pressure as much as possible, since the level of the systolic blood pressure is significantly related to the incidence of stroke (91, left ventricular hypertrophy [27,2&I], coronary artery disease [ 71, and even mortality, not only in combined systolic and diastolic hypertension [6,7] but also in isolated systolic hypertension [ 21. On the other hand, the lack of a diuretic-induced hypotensive effect in 15 (20 percent) of the 71 patients in the present study precludes the use of diuretics as first-step therapy in all patients with isolated systolic hypertension. The usual diuretic-induced biochemical abnormalities [ 29-341 were also observed in this study, but they were without any clinical importance, at least during the period of this study. The main antihypertensive effect of diuretics is thought to be mediated via reduction of the extracellular fluid [35], which is usually accompanied by a decrease in body weight. However, in the nonresponders in the present study, weight reduction-although nonsignificant-did not affect the blood pressure. This has also been observed following the short-term administration of diuretics [36] and can be explained on the basis of an acute increase in peripheral resistance that compensates for the decrease in cardiac output. Other possible mechanisms to explain the hypotensive effect of diuretic therapy have also been proposed [37-391, but these were not investigated in the present study. In patients with systolic hypertension, Vardan et al [40] have studied the hemodynamic pattern of systolic blood pressure response to long-term diuretic therapy. They found that both stroke volume and peripheral resistance were decreased in patients with response to diuretic therapy. Thus, it appears that diuretic therapy affects not only volume but also vasoconstrictor mechanisms

1411. Our finding that renin increased in the high-renin patients without any concurrent significant blood pressure decrease suggests that the baroreceptor mechanism is not of major importance in the increase of renin during diuretic therapy [42]. Other investigators have also shown that isolated systolic hypertension responds to diuretic therapy [ 431. 1066

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ET AL

Antihypertensive

Effect of Low Sodium Intake in Iso-

lated Systolic Hypertension.

The results of the present study show that a low-sodium diet also significantly decreased elevated systolic blood pressure in patients with isolated systolic hypertension with low and normal renin levels. Previous studies by other investigators have also shown that a low sodium intake decreases both the systolic and diastolic blood pressure in patients with mild to moderate combined systolic and diastolic hypertension [44] and in normotensive subjects [ 451. The mechanism by which a low-sodium diet lowers blood pressure is unclear and has not been investigated in detail, despite the numerous epidemiologic and clinical studies [46] that have ShDWn an association between sodium intake and blood pressure or a blood pressure reduction during low sodium intake. In the present study, the antihypertensive effect of a lowsodium diet was not related to the concurrent weight loss, although a fall in blood pressure with concurrent weight reduction but without salt reduction has been reported to occur in obese hypertensive patients [ 471. In our study, the decrease in systolic blood pressure produced by the low-sodium diet was related to the control plasma renin activity and control 24hour urinary sodium excretion; since both variables can be taken as indexes of volume status, our findings suggest that the systolic pressure response to a low-sodium diet was mediated via volume reduction [ 481, but other mechanisms cannot be excluded. From the various mechanisms (weight reduction, extracellular volume contraction, contraction of sodium space, blunting of baroreceptor function, decreased vascular response to vasoconstrictor stimuli, increased production of an endogenous vasodilator, reversal of the abnormality of the Na/K-ATPase pump, increase of natriuretic factor) that probably contribute to the antihypertensive effect of low sodium intake [48-531, the decrease in weight and alteration of the sympathetic nervous system and baroreflex function may at least partially explain the mode of action of low sodium intake in our patients with isolated systolic hypertension. In this regard, it is of interest to note that heart rate was not increased in our study by the low-sodium diet despite the significant decrease in systolic blood pressure. Moreover, diastolic blood pressure was only slightly decreased. These findings are in agreement with data from previous studies that have shown greater systolic blood pressure increases during high salt intake in comparison with concurrent diastolic increases because of a greater increase in cardiac output in comparison with the increase in peripheral resistance [54-561. Since the level of systolic blood pressure partially depends on cardiac output (heart rate, stroke volume) and stroke volume partially depends on total blood volume, it is conceivable that a volume reduction could explain the lowering of the systolic blood pressure

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DIURETICS VERSUS LOW SALT IN SYSTOLIC HYPERTENSION-NIARCHOS

by a low-sodium diet. In this respect, a low-sodium diet has the same antihypertensive and hormonal effects as diuretic therapy, but these are of a smaller magnitude (Table I). However, it should be mentioned here that other studies [57] have shown that moderate sodium restriction does not lower blood pressure in patients with mild hypertension. Therapeutic and Prognostic Implications. The results of the present study show that diuretic therapy or lowsodium diet decreases the mildly to moderately elevated systolic blood pressure in patients with isolated systolic hypertension and low or normal renin levels. High-renin patients may respond better to a beta-adrenergic blocker or converting enzyme inhibitor [ 17,20,58]. Furthermore, our data show that the response to antihypertensive therapy based on the renin-sodium profile

ET AL

in isolated systolic hypertension is similar to the response of combined systolic and diastolic hypertension, although the former is probably epidemiologically different [59]. Finally, as far as complications of isolated systolic hypertension are concerned, data from the Framingham [2] and other studies [60] show that untreated systolic hypertension increases cardiovascular morbidity and mortality. However, prospective and long-term therapeutic trials are needed to demonstrate the possible beneficial effects of long-term diuretic therapy or the long-term antihypertensive efficacy of and compliance with low sodium intake [61] in patients with isolated systolic hypertension, especially in view of the data from this and other recent studies [62] showing that the blood pressure response to a lowsodium diet is not uniform.

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