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(Hypertension. 1995;25:1042-1044.)
© 1995 American Heart Association, Inc.

Articles

Reduction of Salt Intake During Converting Enzyme Inhibitor Treatment Compared With Addition of a Thiazide

Donald R. J. Singer; Nirmala D. Markandu; Francesco P. Cappuccio; Michelle A. Miller; Giuseppe A. Sagnella; Graham A. MacGregor

From the Blood Pressure Unit, Department of Medicine, St George's Hospital Medical School (D.S., N.M., F.C., M.M., G.S., G.M.), London; the Department of Public Health Policy, London School of Hygiene and Tropical Medicine (F.C.); and the Heart Sciences Centre, National Heart and Lung Institute, Harefield Hospital (Middlesex), UK.

Correspondence to Dr D.R.J. Singer, Blood Pressure Unit, Department of Medicine, St George's Hospital Medical School, London SW17 0RE, UK.

	Abstract

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Abstract A moderate reduction in salt intake lowers blood pressure in individuals with hypertension and improves blood pressure control in those taking a converting enzyme inhibitor. However, it is unclear how effective reduction of salt intake is compared with addition of other drugs, in particular, thiazide diuretics. We directly compared the separate effects on blood pressure of reducing sodium intake or adding a thiazide diuretic in the presence of a converting enzyme inhibitor in a double-blind, randomized, crossover study. We studied 11 subjects with essential hypertension who had been taking 25 mg captopril twice daily for at least 1 month. In the double-blind study, after 1 month of captopril alone, supine blood pressure was 151±5/95±4 (SEM) mm Hg. With the addition of 25 mg hydrochlorothiazide once daily for 1 month, blood pressure fell to 137±5/87±3 mm Hg. When a moderate reduction in salt intake (from 206±26 to 109±20 mmol urinary sodium/24 h) was added to captopril for 1 month, blood pressure was reduced by a similar amount (to 137±4/90±3 mm Hg). Plasma potassium fell during the diuretic treatment (3.9±0.1 to 3.7±0.1 mmol/L, P<.05) but increased nonsignificantly during salt reduction (3.9±0.1 to 4.1±0.2 mmol/L). These results clearly demonstrate that moderate salt reduction, which can be easily achieved, is as effective as a thiazide diuretic in lowering blood pressure in the presence of a converting enzyme inhibitor and has the particular advantage that plasma potassium does not decrease. We recommend that all patients on a converting enzyme inhibitor be advised to reduce their dietary salt intake. This would lead to improved blood pressure control and avoids the need for thiazide treatment in many patients.

Key Words: hypertension, sodium-dependent • diet, sodium-restricted • renin • angiotensin-converting enzyme inhibitors • aldosterone • diuretics, thiazide

	Introduction

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The combination of an angiotensin-converting enzyme (ACE) inhibitor with sodium restriction^{1 2 3} or a thiazide diuretic^{3 4 5} is effective treatment in both essential hypertension and heart failure. However, treatment with thiazides alone is associated with adverse metabolic effects, including a reduction in serum potassium levels,⁵ as well as other side effects, including impotence⁶ and arrhythmias.⁷ Treatment with an ACE inhibitor alone tends to increase blood potassium levels mildly.⁵ In individuals with renal disease or hyporeninemic hypoaldosteronism who are receiving ACE inhibitor treatment, blood potassium levels should be monitored more frequently because the increase in blood potassium may be greater and because preexisting hyperkalemia may be exacerbated. Although the fall in plasma potassium with a thiazide alone is therefore less severe when the thiazide is combined with an ACE inhibitor, a clinically important reduction in potassium levels may still occur.⁵ However, it is unclear whether sodium restriction is as effective as a thiazide diuretic when added to a converting enzyme inhibitor.⁸

We therefore compared in a double-blind study in the same subjects with essential hypertension already on treatment with an ACE inhibitor the effects on blood pressure (BP) and on plasma potassium of addition of a thiazide to the effects of a moderate reduction in dietary sodium intake.

	Methods

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Subjects were referred by local general practitioners to the Blood Pressure Unit. They had uncomplicated essential hypertension and were accustomed to having their BP measured under standardized conditions. All subjects had been taking 25 mg captopril twice daily for at least 1 month before entry to the study, to which they gave written informed consent. Subjects with other significant disease or who were on any additional treatment were excluded from the study. Eleven subjects (8 male, 3 female; 9 white, 2 black) with average supine BP 12 hours after treatment of 162±4/105±2 mm Hg (±SEM) and mean age of 55 years (range, 47 to 69) entered and completed the study, which was approved by the local hospital ethics committee.

Throughout the study, all subjects continued taking 25 mg captopril (Capoten, Squibb) twice daily. After 1 month of their usual sodium intake, the subjects were advised to reduce their sodium intake to approximately 100 mmol/d for the rest of the study by not adding salt during cooking or at the table and by avoiding salt-laden foods. After an initial 2 weeks of reduced sodium intake, subjects entered the double-blind, double-placebo, randomized, crossover part of the study, in which they all underwent each of the following three 1-month periods of treatment: (1) 10 Slow Sodium (Ciba Laboratories) tablets per day (10 mmol sodium per tablet) and 25 mg hydrochlorothiazide once daily; (2) Slow Sodium placebo tablets (Ciba Laboratories, 10/d) and placebo hydrochlorothiazide once daily; and (3) 10 Slow Sodium tablets per day (10 mmol sodium per tablet) and placebo hydrochlorothiazide once daily. This allowed comparison in the sodium-replete state of captopril alone against captopril combined with hydrochlorothiazide. In addition, it allowed comparison with the combination of captopril and reduction in sodium intake of approximately 100 mmol/d.

BP was recorded 2 hours after the morning dose of tablets at the end of each month of treatment in the double-blind study with the use of semiautomatic ultrasound sphygmomanometers (Arteriosonde, Roche) with attached recorders.^{9 10} Blood samples were taken after 5 minutes of sitting rest, 2 hours after treatment at the end of each month in the double-blind study, for measurement of full blood count and blood biochemistry including plasma renin activity¹¹ and aldosterone.¹² Before each visit, subjects collected two consecutive 24-hour urine samples for measurement of 24-hour urinary electrolytes and creatinine and urine volume. Compliance with captopril, hydrochlorothiazide, Slow Sodium, and placebo treatment was checked by tablet count.

Mean arterial pressure was calculated as one third pulse pressure+diastolic pressure. Results are reported as mean±SEM unless otherwise indicated. Statistical analysis was performed by paired Student's t tests and one-way ANOVA, using the Statistical Package for Social Sciences of the North-Western Universities on the University of London computer. For the ANOVA, significant differences between paired data were assessed using t tests based on the variance derived from the ANOVA.

Based on the observed standard deviation for diastolic pressure within subjects of 7.6 mm Hg, this study had a power of 80% at the 5% level in a two-tailed test to detect a difference in supine diastolic pressure of 6 mm Hg between the periods of treatment when either a thiazide diuretic or a moderate reduction in dietary sodium intake was added to captopril treatment.

	Results

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Supine BP
In the 11 subjects, average supine BP 2 hours after treatment after 1 month of observation in the double-blind part of the study during captopril was 151±5/94±4 mm Hg (see the Table and Figure). Supine BP was significantly lower (ANOVA: F=5.44, P<.02) after 1 month of the addition of hydrochlorothiazide (137±5/87±3 mm Hg, P<.05 for systolic pressure versus captopril alone, Table) as well as after 1 month of reduced sodium intake (137±4/90±3 mm Hg, P<.05 for systolic pressure versus captopril alone, Table). The results for mean arterial pressure were similar (ANOVA: F=3.46, P=.051). The effects on standing BP during the study were similar to the effects on supine BP.

View this table: [in this window] [in a new window]   Table 1. Supine Blood Pressure and Plasma Potassium in 11 Subjects With Essential Hypertension at the End of Each Month of Treatment

View larger version (33K): [in this window] [in a new window]   Figure 1. Graphs show results for 24-hour urinary sodium excretion and 2 hours after treatment for supine blood pressure and plasma potassium in the double-blind study in 11 subjects with essential hypertension at the end of each month during (1) 25 mg captopril twice daily, (2) 25 mg captopril twice daily and moderate salt reduction, and (3) 25 mg captopril twice daily and 25 mg hydrochlorothiazide once daily. *P<.05 vs captopril alone; P<.05 vs captopril alone and vs captopril combined with moderate reduction in salt intake; **P<.01.

Urinary Sodium Excretion During the Double-Blind Study
At the end of 1 month of captopril alone, urinary sodium excretion was 193±14 mmol/24 h, with similar values at the end of 1 month of captopril and hydrochlorothiazide (206±26 mmol/24 h). After 1 month of captopril and reduced sodium intake, sodium excretion was reduced to 109±20 mmol/24 h (see the Figure).

Other Variables
Plasma potassium was significantly lower after 1 month of the addition of hydrochlorothiazide (3.7±0.1 mmol/L) compared with captopril alone (P<.03, 3.9±0.1 mmol/L) as well as compared with captopril and reduced dietary sodium intake (P<.02, 4.1±0.2 mmol/L, Table). There were no significant changes between the double-blind treatment periods in weight, plasma sodium, uric acid, glucose, 24-hour urinary potassium and creatinine, or urine volume.

Plasma renin activity was significantly increased during addition of a thiazide (6.22±1.90 nmol angiotensin I [Ang I]/L per hour, P<.05) or moderate salt reduction (4.28±1.37 nmol Ang I/L per hour, P<.05) compared with captopril alone (3.36±1.18 nmol Ang I/L per hour). However, the increase in plasma renin activity was not associated with increased plasma aldosterone levels, indicating effective blockade of the renin system by captopril (captopril and thiazide, 292±62 pmol/L; captopril and salt reduction, 366±68 pmol/L; captopril alone, 369±60 pmol/L).

	Discussion

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The results of this double-blind, randomized, crossover study clearly demonstrate that a moderate reduction in salt intake is as effective in lowering BP as addition of a thiazide diuretic in subjects already taking a converting enzyme inhibitor. However, thiazide treatment but not salt reduction was associated with a significant reduction in plasma potassium.

Left ventricular hypertrophy, defined by echocardiographic criteria, occurs in approximately 30% of patients with established essential hypertension and is a better predictor of risk of cardiac death than coronary disease.¹³ Sudden arrhythmic death is an important cause of this increased mortality, and an increased prevalence of ventricular arrhythmias is well described in association with hypertensive left ventricular hypertrophy.^{14 15} Hypokalemia and thiazide treatment are predisposing factors for ventricular arrhythmias.⁷ Furthermore, diuretics may exacerbate exercise-associated hypokalemia.¹⁶ Additional evidence for a link between cardiac events and thiazide diuretics has come from a recent case-control study that reported an increased risk of cardiac arrest in hypertensive patients treated with higher doses of thiazide diuretics.¹⁷ Thus, reducing the need for thiazide diuretic treatment with the use of moderate salt reduction has advantages in reducing the risk of arrhythmias and of primary cardiac arrest and may be particularly important in patients with left ventricular hypertrophy.

We chose to study a sodium intake of approximately 200 mmol/d (sodium replete) with a reduced sodium intake of approximately 100 mmol/d first because epidemiological studies show that the average sodium intake during the sodium-replete periods of our study is typical of the usual sodium intake in many communities in the United Kingdom and elsewhere in the developed world. For example, in the Scottish heart health study,¹⁸ the average sodium intake reported in 3754 men was 192.8±76.7 (SD) mmol/24 h, and in the multinational Intersalt study of 10 079 adults,¹⁹ 34 of the 52 centers had average sodium excretion for males and females of greater than 150 mmol/24 h, and 19 of the 52 centers of greater than 170 mmol/24 h. Second, a number of studies now indicate that both in hospital practice^{10 20 21 22} and in the community,²³ this very moderate reduction in salt intake is easily achieved and well tolerated. The reduction in daily salt intake in the present study was very modest compared with the dietary recommendations recently published by the UK Department of Health.²⁴ These governmental guidelines will provide added incentive to the food industry to reduce the large amounts of salt added to many processed foods. This will make it easier for individuals to reduce their dietary salt intake and lower their BP further, as previous studies of reduced salt intake, particularly in conjunction with an ACE inhibitor,^{1 2 3} have shown that the effect on BP is related to the degree of salt reduction achieved.

We recommend that all patients taking a converting enzyme inhibitor should reduce their dietary sodium intake. This will have the major benefit of many patients being able to avoid the use of thiazide diuretics.

	Acknowledgments

 
This study was supported in part by a grant from ER Squibb & Sons Ltd (UK). D.R.J. Singer was a British Heart Foundation Intermediate Research Fellow (F201). We thank Dr David Lott of Ciba Laboratories for supplying Slow Sodium and matching placebo tablets.

Received July 7, 1994; first decision August 31, 1994; accepted January 18, 1995.

	References

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