comparison of withdrawing antihypertensive therapy between diuretics and angiotensin converting...

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Comparison of withdrawing antihypertensive therapy between diuretics and angiotensin converting enzyme inhibitors in essential hypertensives One hundred thirteen patients with essential hypertension receiving single or multiple antihypertensive agents were enrolled in the study. All had had mild to severe hypertension before treatment, but their diastolic blood pressure (DBP) at study entry was lower than 90 mm Hg for all measurements. In half of the subjects, non-thiaride diuretics (n = 35) or angiotensin-converting enzyme inhibitors (ACEI, R = 37) were discontinued, and their remaining drugs were maintained throughout the study. The other patients (n = 41) continued all their medications. Forty-one percent of subjects remained normotensive for 12 months after withdrawal of diuretics, and 37% of patients with ACEI discontinuation remained normotensive, although the recurrence of hypertension after withdrawal of ACEI tended to be earlier than its recurrence after withdrawal of diuretics. Serum uric acid and creatinine concentration decreased after diuretic withdrawal, but not after ACEI withdrawal. Diuretic withdrawal resulted in an increase in serum potassium, but ACEI withdrawal induced a decrease in serum potassium. Withdrawal of diuretics or ACEI both significantly reduced plasma renin activity. The present study may be indicative of the ability to withdraw some medications in many patients being treated with multiple antihypertensive agents. (AM HEART J 1992;124:1574.) Yutaka Takata, PhD, MD,“, b Takayuki Yoshizumi, MD,a Yasuo Ito, MD,a Michio Ueno, MD,a Akira Tsukashima, MD,a Masanori Iwase, MD,” Kazuo Kobayashi, MD,b and Masatoshi Fujishima, MDb Fukuoka, Japan Diuretics and angiotensin I converting enzyme in- hibitors (ACEI) have been a mainstay of treatment for essential hypertension1 In contrast to the scant metabolic side effects of ACEIl, 2diuretics are known to cause adverse biochemical effects such as hyper- uricemia, l* 2 hyperlipidemia, 3 hyperglycemia,4 and hypokalemia.5 On the other hand, a persistent dry cough6 occurs frequently in subjects receiving ACEI. Therefore discontinuation or reduction in the dose of diuretics and ACE1 should be considered to lessen the undesirable side effects in patients with essential hypertension with prolonged hypertension control. Although a number of studies7, 8 have examined the effects of withdrawing diuretics in hypertensive pa- From “the First Division of Internal Medicine, National Fukuoka Central Hospital; and bthe Second Department of Internal Medicine, Faculty of Medicine, Kyushu University. Received for publication Jan. 10. 1992; accepted July 6, 1992. Reprint requests: Dr. Yutaka Takata, Department of Internal Medicine. Kyushu Dental College, Manazuru 2-6-l. Kokura-kita-ku. Kitakyushu City, 803. Japan. 4/l/41298 tients, little work has been done to study the with- drawal of ACEIg-l2 and non-thiazide diuretics. More- over, few studies have examined the influence of the type of treatment on the response to its withdrawal. We present the results of a prospective study com- paring withdrawal of non-thiazide diuretics and ACE1 conducted in the hypertension clinic at our hospital. The aims of this study were (1) to compare the ef- fect of antihypertensive drug withdrawal between non-thiazide diuretics and ACE1 in essential hyper- tensive patients; (2) to determine whether the with- drawal of diuretics or ACE1 could reduce the delete- rious effects on serum potassium, uric acid, glucose, and lipid; and (3) to examine how well blood pressure would remain under control after discontinuation of the drugs. METHODS One hundred thirteen patients with essential hyperten- sive aged 36 to 81 years, who had been receiving single or multiple antihypertensive agents, were enrolled in the 1574

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Comparison of withdrawing antihypertensive therapy between diuretics and angiotensin converting enzyme inhibitors in essential hypertensives

One hundred thirteen patients with essential hypertension receiving single or multiple antihypertensive agents were enrolled in the study. All had had mild to severe hypertension before treatment, but their diastolic blood pressure (DBP) at study entry was lower than 90 mm Hg for all measurements. In half of the subjects, non-thiaride diuretics (n = 35) or angiotensin-converting enzyme inhibitors (ACEI, R = 37) were discontinued, and their remaining drugs were maintained throughout the study. The other patients (n = 41) continued all their medications. Forty-one percent of subjects remained normotensive for 12 months after withdrawal of diuretics, and 37% of patients with ACEI discontinuation remained normotensive, although the recurrence of hypertension after withdrawal of ACEI tended to be earlier than its recurrence after withdrawal of diuretics. Serum uric acid and creatinine concentration decreased after diuretic withdrawal, but not after ACEI withdrawal. Diuretic withdrawal resulted in an increase in serum potassium, but ACEI withdrawal induced a decrease in serum potassium. Withdrawal of diuretics or ACEI both significantly reduced plasma renin activity. The present study may be indicative of the ability to withdraw some medications in many patients being treated with multiple antihypertensive agents. (AM HEART J 1992;124:1574.)

Yutaka Takata, PhD, MD,“, b Takayuki Yoshizumi, MD,a Yasuo Ito, MD,a

Michio Ueno, MD,a Akira Tsukashima, MD,a Masanori Iwase, MD,”

Kazuo Kobayashi, MD,b and Masatoshi Fujishima, MDb Fukuoka, Japan

Diuretics and angiotensin I converting enzyme in- hibitors (ACEI) have been a mainstay of treatment for essential hypertension1 In contrast to the scant metabolic side effects of ACEIl, 2 diuretics are known to cause adverse biochemical effects such as hyper- uricemia, l* 2 hyperlipidemia, 3 hyperglycemia,4 and hypokalemia.5 On the other hand, a persistent dry cough6 occurs frequently in subjects receiving ACEI. Therefore discontinuation or reduction in the dose of diuretics and ACE1 should be considered to lessen the undesirable side effects in patients with essential hypertension with prolonged hypertension control. Although a number of studies7, 8 have examined the effects of withdrawing diuretics in hypertensive pa-

From “the First Division of Internal Medicine, National Fukuoka Central Hospital; and bthe Second Department of Internal Medicine, Faculty of Medicine, Kyushu University.

Received for publication Jan. 10. 1992; accepted July 6, 1992.

Reprint requests: Dr. Yutaka Takata, Department of Internal Medicine. Kyushu Dental College, Manazuru 2-6-l. Kokura-kita-ku. Kitakyushu City, 803. Japan.

4/l/41298

tients, little work has been done to study the with- drawal of ACEIg-l2 and non-thiazide diuretics. More- over, few studies have examined the influence of the type of treatment on the response to its withdrawal. We present the results of a prospective study com- paring withdrawal of non-thiazide diuretics and ACE1 conducted in the hypertension clinic at our hospital.

The aims of this study were (1) to compare the ef- fect of antihypertensive drug withdrawal between non-thiazide diuretics and ACE1 in essential hyper- tensive patients; (2) to determine whether the with- drawal of diuretics or ACE1 could reduce the delete- rious effects on serum potassium, uric acid, glucose, and lipid; and (3) to examine how well blood pressure would remain under control after discontinuation of the drugs.

METHODS

One hundred thirteen patients with essential hyperten- sive aged 36 to 81 years, who had been receiving single or multiple antihypertensive agents, were enrolled in the

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Number 6 Withdrawal of diuretics and ACEIs in hypertension 1575

study. The study was performed after approval by the In- stitutional Human Investigations Committee, and in- formed consent was obtained from each subject after the nature of the procedure had been fully explained. All pa- tients had mild to severe hypertension as evidenced by an average diastolic blood pressure (DBP) between 90 and 124 mm Hg before treatment. Electrocardiograms, fundoscopic examination, and a urine examination were done. The di- agnosis of essential hypertension was made for cases of hy- pertension without any associated abnormal renal, endo- crinologic, or metabolic findings. Patients with heart fail- ure, malignant hypertension, or recent cardiovascular or cerebrovascular complications were excluded. During the study period, the patients were seen in our Hypertension Clinic at l-month intervals. Symptoms and side effects of the drugs were monitored at each visit.

All patients were receiving either diuretics (n = 53) or ACE1 (n = 60). The most common diuretic used was inda- pamide, 1 rng/day (Sumitomo Pharmaceutical Co. Ltd., Osaka, Japan) (n = 43); some patients received mefruside 25 mg/day (Yoshitomi Pharmaceutical Co. Ltd., Osaka, Japan) (n = 10). ACEIs were enalapril, 5 mg/day (Merck- Banyu Pharmaceutical Co. Ltd., Tokyo, Japan) (n = 34), or alacepril,‘” 50 mg/day (Dai-Nippon Pharmaceutical Co. Ltd., Osaka, Japan) (n = 26). The number of patients re- ceiving other antihypertensive therapies than diuretics or ACEIs were 48 for diuretic and 50 for ACE1 groups, indi- cating that most subjects had been given multiple antihy- pertensive agents. The patients receiving a single agent were only five for diuretic and 10 for ACE1 groups.

Patients whose DBP at all measurements had been lower than 90 mm Hg for 2 months and whose average DBP was less than 90 mm Hg for 6 months were candidates for with- drawal of the diuretic or ACEI. The diuretic medication was discontinued in 35 patients receiving diuretics, while it was continued in the remaining 18 whose DBP also met the same criteria. Similarly, given the same criteria for with- drawal of drug therapy (DBP less than 90 mm Hg at any recording for 2 months and an average DBP less than 90 mm Hg for 6 months), 37 patients with essential hyperten- sion discontinued the ACE1 antihypertensive medication and 23 patients continued their medication. The selection of patients to either stop or continue their diuretic or ACE1 therapy was done at random. Although subjects were ran- domly allocated to the two groups of patients withdrawn and not withdrawn, many patients who were allocated to the not withdrawn group desired the withdrawal of drugs, causing inequality in the number of patients between the groups.

Twelve of 60 patients in the ACE1 study had a dry cough as a side effect of treatment with the ACEI. The antihy- pertensive drugs other than diuretics and ACE1 were maintained at the same dosage throughout the study. The remaining therapies for the diuretic withdrawal study were mainly calcium antagonists (for example, slow release nifedipine), p-blockers (for example, propranolol), and ACEIs (for example, enalapril). Those for the ACE1 with- drawal study were calcium antagonists, P-blockers, and di-

uretics (for example, indapamide). The statistical analysis did not indicate that these associated antihypertensive drugs could influence the number of patients who were re- instated and the length of time to reinstatement.

Blood pressure (BP) and pulse rate were recorded monthly before and after withdrawing the diuretics or ACEI. The BP measurements with a standard sphygmo- manometer and blood sampling were performed after the patients had been sitting for 5 minutes or longer. The level at which the Korotkoff sounds disappeared was taken as the DBP. The diuretic or ACE1 was reinstated if the DBP at two readings was 95 mm Hg or higher on different occa- sions. A DBP of 105 mm Hg or higher necessitated imme- diate reinstatement of the medication. The number of pa- tients who were reinstated because their DBP levels were greater than 95 mm Hg on two occasions were 13 for diuretic withdrawal and 14 for ACE1 withdrawal. The re- maining patients, four for the diuretic group and five for the ACE1 group, were reinstated because of a DBP higher than 105 mm Hg. Most patients who were not given rein- statement remained normotensive (BP less than 95 mm Hg) for 12 months after withdrawal (eight for the diuretic group, and nine for the ACE1 group), but some patients had a single reading of DBP higher than 95 mm Hg and lower than 105 mm Hg (four for the diuretic group and two for the ACE1 group).

Laboratory measurements were performed before and several months after withdrawal of the medication. These measurements included the following: serum electrolytes (Na, K, Cl), total cholesterol, triglyceride, fasting glucose, high-density lipoprotein, total protein, creatinine, and blood nitrogen (BUN), as well as plasma norepinephrine (PNE), epinephrine (PE), renin activity (PRA), and al- dosterone concentration (PAC). PNE and PE samples maintained at -80’ C were measured by diphenyl ethyl- enediamine methods with high-performance liquid chro- matography (SRL Co. Ltd., Tokyo, Japan). PRA and PAC were determined by a radioimmunoassay technique.

All data are presented as mean 5 SEM. Differences were examined with paired and unpaired Student’s t tests where appropriate, and categorical variables were compared us- ing the chi square test. The proportions remaining nor- motensive without readministration of the diuretic or ACE1 were compared using the 2 test. Results were considered to be significant when the p value was less than 0.05.

RESULTS

Fig. 1 shows the follow-up results of the study population. Among the 113 patients who originally entered the trial, 13 who were withdrawn from diuretics or ACE1 were dropped within 12 months for reasons unrelated to increased BP or cardiovascular complications. Twenty-nine of the patients in the di- uretic withdrawal study, 30 in the ACE1 withdrawal group, 18 of those with diuretic continuation, and 23 with ACE1 continuation were followed for 12 months

1576 Takata et al. December 1992

American Heart Journal

1 Diuje3tics 1 ) *2 I

I I I I

I I

1 I

I I

Withdrawn Not withdrawn Withdrawn Not withdrawn 37 23

I I I

12M follow Unavailable 12M follow Unavailable

29 for follow 30 for follow

I 6 I 7 I I I I

Drug free Diuretics normotensive reinstated normotensive reinstated

12 17

Within 3M 4-12M Within 3M 4-l 2M 6 11 16 3

Fig. 1. Follow-up of withdrawal study population. Numbers indicate patients within a category; M indi- cates months.

after initiation of the study. Of the 29 patients hav- ing discontinued the diuretic medication and com- pleted 12 months of follow-up, 12 (41%) remained normotensive for 12 months off treatment, while 17 met at least one criterion for recurrence of hyperten- sion. Six patients became hypertensive within 3 months, while the remaining 11 patients had a recur- rence of hypertension 4 to 12 months after at least a 3-month normotensive period. Two out of three sub- jects who had received a single diuretic medication and had discontinued the diuretic remained nor- motensive for 12 months.

Similarly, in 11 (37 % ) of 30 patients with ACE1 discontinuation, the DBP remained normotensive over 12 months of follow-up, while the remaining 19 patients required reinitiation of their ACE1 medica- tion, 16 patients within 3 months and three 4 to 12 months after withdrawal. The ACE1 was discontin- ued in six patients who received a single ACE1 med- ication. In three out of six patients with ACE1 discontinuation, the BP remained normotensive over 12 months. In 29 patients who completed the diuretic withdrawal study with a 12-month follow-up, 23 subjects received indapamide and six received mef- ruside. There was no difference in the ratio of rein- statement between the two groups. Likewise, restart- ing treatment did not depend on the specific drug withdrawal of enalapril versus alacepril. The ratios of those who remained normotensive for 1 to 3 months after withdrawal were significantly higher in the di-

uretic group than in the ACE1 group (p < O.Ol), but this difference disappeared thereafter (Fig. 2).

Clinical characteristics of the patients who re- mained normotensive for 12 months and those who required resumption of diuretic or ACE1 medication are listed in Table I. There was no significant differ- ence in any parameter between the subjects with and without resumption of either the diuretic or the ACEI. The prevalence of target organ damage as es- timated by left ventricular hypertrophy, fundoscopic examination, and proteinuria was also not signifi- cantly different in patients with persistent nor- motension and in those with a return of hypertension. Family history of hypertension and renin profiles showed no significant differences between groups.

Fig. 3 shows the BP and pulse rate before and 1 month after withdrawal of diuretics and ACEI. In patients not requiring readministration of either di- uretics or ACEI, the SBP and DBP did not signifi- cantly rise following withdrawal, while in those requiring resumption of the medication, both SBP and DBP were clearly increased (from 122.4 + 3.4/ 78.4 +- 1.9 mm Hg to 152.1 f 6.8/86.8 ? 2.6 mm Hg, p < 0.001, for the diuretic group; and from 129.7 t- &l/82.4 * 2.3mmHgto 149.7 + 5.2/94.6 + 2.1mm Hg, p < 0.001, for the ACE1 group). Pulse rates were not altered by the discontinuation of diuretics or ACE1 in any group. DBP 1 month after ACE1 with- drawal significantly differed between patients with and without readministration of ACEI, but the

Volume 124 Number 6 Withdrawal of diuretics and ACEI. in hypertension 1577

Months after withdrawal 0 3 6 9 12

c 100 B 2

K

5 2 .c 3

50 F .- ii B

i u Diuretics (n = 29) * p < 0.01

z ----A---- ACEI (n = 30)

x 0

Fig. 2. Percentage of patients remaining normotensive after withdrawal of diuretics (0) and ACE1 (A). *p < 0.01 comparing diuretic and ACE1 groups.

Table I. Clinical characteristics of patients with and without readministration of diuretics or ACEI

Diuretic ACEI

Continued Restarted Continued Restarted withdrawal diuretic withdrawal ACEI

Number 12 17 11 19 Age (yr) 63.8 t 3.0 60.5 k 2.8 64.3 + 3.2 57.2 + 2.0

Sex (F/M) 913 11/6 8/3 1118 Duration of hypertension (M)

107.4 i 23.3 125.8 k 26.9 85.9 + 13.4 78.1 k 15.0 Duration of drug administration (M)

72.5 + 23.2 73.1 + 17.8 46.7 + 14.5 44.4 + 14.0 BP pre initial medication (mm Hg)

SBP 175.0 rt 5.6 171.9 + 5.4 185.3 f 7.4 174.6 -t 5.3 DBP 100.9 t 3.3 102.0 t 2.2 100.0 f 5.4 111.5 t 3.7

BP pre diuretic or ACEI (mm Hg) SBP 166.2 -+ 8.3 169.7 + 6.9 170.6 + 4.3 162.4 + 4.8 DBP 94.8 + 3.6 95.3 k 1.8 97.2 t 4.1 100.2 * 1.3

BP & PR before withdrawal SBP (mm Hg) 134.3 * 6.6 122.4 f 3.4 130.4 k 7.0 129.7 * 5.1 DBP (mm Hg) 83.0 t 1.7 78.0 t 1.9 76.7 r 2.5 82.4 t 2.3 PR (beats/min) 70.8 +- 2.4 69.3 k 2.8 66.2 t 2.4 72.2 + 2.4

LVH (+/-) 517 7110 219 7112

KW (11,/I) 3/2 316 l/l 3/4 Proteinuria (+/-) 2110 3/14 219 l/l8

BP, Blood pressure: SBP, systolic blood pressure; DBP, diastolic blood pressure; ACEI, angiotensin-converting enzyme inhibitor(s); PR, pulse rate; LVH, left ventricular bypertropby; KW, Keith-Wagener classification.

difference in SBP did not reach a statistical signifi- The effects of withdrawal of diuretics or ACE1 on cance. BP and pulse rate were unchanged for 12 laboratory findings are shown in Table II. Serum uric months in the patients who had no withdrawal of the acid concentration was decreased by diuretic with- diuretic or ACEI. drawal, but not by ACE1 withdrawal. Serum creati-

1578 Takata et al.

BP CmmHd 160

December 1992

American Heart Journal

120

100

80

60

PR (beats/min) 80

60 1

- P<o.ool

kTiair-

I I I I

B A B A Diuretics ACE1

Fig. 3. Blood pressures (bars) and pulse rates (circles and triangles) before (B) and 1 month after (A) withdrawal of diuretics or angiotensin-converting enzyme inhibitors (ACEI). Hatched bars and closed symbols indicate patients who required drug readministration during 12 months of follow-up; open bars and symbols indicate those who remained normotensive for 12 months. Data are shown as mean + SEM.

Table II. Serum uric acid (UA), blood urea nitrogen (BUN), creatinine (Cr), potassium (K), plasma renin activity (PRA), plasma aldosterone concentration (PAC), plasma norepinephrine (PNE), and plasma epinephrine (PE) before and several months after withdrawal of diuretic or ACE1

UA (mg/dl) BUN (mg/dl) Cr bg/dl) K (mEq/L)

Diuretic ACE:

Before After Before After withdrawal withdrawal withdrawal withdrawal

(n = 28) (n = 20) (n = 21) (n = 16)

6.7 + 0.3 6.0 t 0.2t 5.7 ? 0.3 5.9 i 0.3 18.3 * 1.0 17.4 ? 0.9 17.2 + 1.3 17.6 + 0.9 1.02 + 0.04 0.94 +- 0.05* 0.97 i- 0.06 0.97 + 0.06

4.0 -+ 0.1 4.3 t 0.1t 4.4 + 0.1 4.3 t 0.1*

PRA (ng/ml/hr) 6.0 + 2.0 1.5 f 0.4* 2.3 k 0.6 1.3 t 0.4t PAC (pg/ml) 97.9 t 13.2 85.2 t 11.7 61.2 + 7.9 81.3 i- 14.2 PNE (pg/ml) 0.41 5 0.05 0.43 + 0.05 0.41 f 0.05 0.48 +- 0.05 PE kg/ml) 0.029 * 0.005 0.028 k 0.006 0.024 t 0.004 0.026 + 0.005

Data are shown as mean i SEM. *p < 0.05, tp < 0.005, in comparison with the data before withdrawal.

nine was also lowered by diuretic discontinuation, rum potassium. The serum total cholesterol, triglyc- but not by ACE1 discontinuation. Diuretic with- eride, fasting glucose, sodium, and chloride were not drawal resulted in an increase in serum potassium, influenced by withdrawal of either drug. The dry whereas ACE1 withdrawal induced a decrease in se- cough as a side effect of the ACE1 disappeared within

Volume 124 Number 6 Withdrawal of diuretics and ACEIs in hypertension 1579

several days following discontinuation of treatment. Plasma hormone levels are also shown in Table II. Withdrawal of diuretics and ACE1 both significantly reduced PRA, although PAC, PNE, and PE were not altered following discontinuation of either treat- ment. No cardiovascular complication occurred dur- ing this study in any group.

DISCUSSION

We compared the effect of withdrawing non-thi- azide diuretics and ACEI, which had been given to control hypertension for many years in patients with essential hypertension, and demonstrated that a similar percentage (40%) of patients remained nor- motensive for at least 12 months after discontinuing treatment with diuretics and ACEI, but the recur- rence of hypertension during the 12-month follow-up tended to be earlier with discontinuation of the ACE1 than with discontinuation of the diuretics. The pro- portion remaining normotensive following with- drawal of non-thiazide diuretics in the present study was similar to that from a previous report in which thiazide diuretics were used.s Although many pre- dictors of continued normotension after stopping therapy have been reported by several investigators, we failed to obtain significant differences with regard to age,i4! l5 sex,14 the degree of hypertensive organ damage,‘” pretreatment BP level,15* 17, i8 treated BP level,1g, 2o or duration of treatment.20* 21 Our observa- tions indicate that a significant elevation of SBP and DBP 1 month after withdrawal of diuretics and ACE1 may only predict the recurrence of hypertension. This finding is in agreement with that from Alderman et a1..22 who conducted a study in the general popu- lation.

The beneficial effects of withdrawal of thiazide di- uretic treatment on biochemical findings have been reported in several studies8* l5 The most important is the increase in serum potassium that accompanies withdrawal of thiazide and related diuretics.l In our study, a highly significant rise in serum potassium was observed after withdrawal of indapamide23> 24 or mefruside.25 Indapamide23B 24 is a sulfamoyl chlo- robenzamide compound that differs in having no thiazide ring but rather a methylindoline moiety. Al- though the lipid problems that have been frequently reported as side effects of thiazide diuretics may be less with indapamide26-28 and mefruside,2g hypokale- mia can appear with the use of indapamide26-28 and mefruside.2gv so The present finding that withdrawal of indapamide and mefruside raised serum potas- sium levels may confirm not only the side effect of hypokalemia, which is similar to that with thiazide diuretics, but also the reversal of hypokalemia with

stopping treatment. A reduction in serum uric acid is associated with thiazide withdrawal.‘3 l5 The decline in serum uric acid after discontinuation of the non- thiazide diuretics indapamide and mefruside may suggest that these types of diuretics possess a similar adverse effect on uric acid, which can be improved by withdrawing the treatment. The decrease in serum creatinine observed in the present trial suggests pos- sible reduced renal blood flow by indapamide and mefruside after long-term therapy, although Guez et al.27 did not find a significant increase in serum cre- atinine following treatment with indapamide. Lack of a decrease in serum total cholesterol, triglyceride, and glucose levels following withdrawal of diuretics in our study may be attributed to the relatively lower adverse effects on lipid and glucose metabolism of indapamide26*28 and mefruside.2g This observation may give these non-thiazide diuretics some advan- tage over thiazide as antihypertensive drugs. In con- trast to the withdrawal of diuretics, little change was seen in the laboratory data with ACE1 withdrawal, as reported by another laboratory.12 However, serum potassium decreases resulted from ACE1 discontinu- ation, suggesting the hyperkalemic effects of ACE131> 32 following long-term treatment. Increases in PRA due to treatment with ACE133-35 and diuret- ics33, 34 are well known, and decreases in PRA after the withdrawal of ACEI lo and diuretics36g 37 have also been reported previously.

Early recurrence of hypertension after ACE1 with- drawal and improvement in metabolic abnormalities following withdrawal of diuretics, but not of ACEI, might indicate that diuretic withdrawal may be pref- erable to ACE1 withdrawal in patients with essential hypertension having long-term control. The current study finding that approximately 40% of patients remained normotensive without any cardiovascular complications after discontinuation of diuretics and ACE1 suggests that once BP has been controlled, particularly if significant side effects exist, with- drawal of one of several antihypertensive drugs should be done to decrease side effects and to be cost-effective, although continued surveillance is nec- essary so that medications can be reinstituted if the BP rises, Nutritional therapy,38 with weight loss and sodium restriction, may promote the successful with- drawal of drug therapy. The present study may be indicative of our ability to withdraw some medica- tions in many patients being treated with multiple antihypertensive agents.

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