Diuretic therapies in low renin and normal renin essential hypertension This study was designed to compare the effectiveness oJ spironolactone, hydrochlorothiazide, and combined spironolactone-hydrochlorothiazide therapy in patients with low renin and those with normal renin essential hypertension. Patients with low renin hypertension had a greater hypotensive response to each regimen (p < 0.001). Low renin patients responded equally to both spironolactone and to hydrochlorothiazide, and in low renin but not in normal renin patients reduction oJ blood press ure correlated with weight loss. These results suggest that a volume Jactor, not specijically related to increased mineralocorticoid production, contributes to the pathogenesis oJ low ren in essential hypertension.
Charles S. Brooks, M.D.,* Curtis A. Johnson, Pharm.D., Jane M. Kotchen, M.D., and Theodore A. Kotchen, M.D. Lexington, Ky. Departments oJ Medicine and Community Medicine, College oJ Medicine and College oJ Pharmacy, University oJ Kentucky
Although it is well documented that approximately 25% of patients with essential hypertension have suppressed plasma renin activity (PRA), the mechanism of renin suppression has not been defined in most of these patients. 9 Expanded extracellular fluid volumes have been measured by several but not by all investigators. 9 Based on bioassay for mineralocorticoid activity in urine of patients with low renin hypertension (LREH) and low salivary sodium-potassium ratios, it has been suggested
Supported in part by Grant HL 15528 and Nephrology·Urology Training Program AM 05701, both from the National Institutes of Health, and by a grant from the Eagles' Max Baer Heart Fund. Received for publication Feb. 2, 1977. Accepted for publication March I, 1977. Reprint requests to: Theodore A. Kotchen, M.D., Department of Medicine, University of Kentucky College of Medicine, Lexington, Ky.40506. 'Present address: Department of Medicine, University of Missouri Medical Center and Veterans Administration Hospital, Columbia, Mo. 65201.
14
that LREH may be related to increased production of a mineralocorticoid. l , 17 Indeed, inappropriate aldosterone production may occur in some of these patients,IO and in a relatively small number of patients with LREH increased production of other mineralocorticoids has been demonstrated.5, 13-18 Additional indirect evidence has been interpreted to indicate that LREH may be a disease of mineralocorticoid excess. Compared with patients with normal renin essential hypertension (NREH), patients with LREH have a greater hypotensive response to both an inhibitor of adrenal steroid biosynthesis (aminoglutethimide) and to spironolactone, a mineralocorticoid antagonist. 6. 7, 19, 23 It has also been reported that high-dose spironolactone therapy (400 mg/ day) is more effective than thiazide therapy in lowering blood pressure of patients with LREH.12, 20 Other reports indicate that low renin patients are more responsive to all diuretic therapies than
Diuretics in low and normal renin hypertension
Volume 22 Number I
15
Table I. Mean (±SE) drug dosages at the end of each treatment period and mean weight loss durmg each treatment period in patients with NREH and LREH Type hypertension
Drug dose (mg/day) NREH LREH Weight loss (kg) NREH LREH
Spir
HCTZ
Spir-HCTZ (twice daily)
Spir-HCTZ (once daily)
159 ± 20 (16)* 128 ± 20 (9)
114 ± 13 (16) 111 ± 11 (9)
133 ± Ilt (12) 129 ± 21 (7)
106 ± 10 (12) 100 ± 13 (8)
1.08 ± 0.15 0.60 ± 0.29
1.42 ± 0.14 1.26±0.19
1.85 ± 0.27 1.83 ± 0.28
1.66 ± 0.18 2.52 ± 0.18
*Numbers in parentheses refer to number of patients. tDose refers to each drug in the combination.
normal renin patients,2. 21 which suggests that the greater responses to aminoglutethimide and spiranolactone do not necessarily reftect increased mineralocorticoid praduction. Unlike that in patients with primary aldosteranism, increased in vitra binding of steroids in plasma of patients with LREH to mineralocorticoid receptors has not been observed. 3 The purpose of our report is to describe the results of our double-blind crossover study designed to compare the effectiveness of spiranolactone (Spir), hydrachlorothiazide (HCTZ), and combined Spir-HCTZ therapy in patients with LREH and NREH. Methods
Essential hypertension was diagnosed on the basis of history , physical examination, urinalysis, measurement of creatinine cIearance, serum Na+, K+, CI-, and CÜ 2 concentrations,
rapid-sequence intravenous pyelogram, and, in selected patients, measurement of 24-hr urine vanillylmandelic acid (VMA) excretion and renal angiography. Patients with secondary hypertension, serum creatinine concentration above 1.5 mg/dl, hyper- or hypokalemia, congestive heart failure, or malignant hypertension and patients receiving estragen therapy were excIuded. We 4 have published our protocol for identifying patients with LREH. Briefty, PRA was measured after an overnight fast, before, and 4 hr after the combined stimulus of 80 mg furosemide given orally and the upright posture in 30 patients with essential hypertension and in 16 normotensive control subjects who were matched for age, sex, and race. Before
6.0
5.0
.::....
E ....
..
co c
4.0
3.0
a:: 0..
2.0
1.0
0 HYPERTENSIVES
NORMALS
(0=30)
(0=16)
Fig. 1. Mean (± SE) PRA before and after furosemide in hypertensive patients and normotensive control subjects. (From Brooks, C. S., Talwalker, R. T., and Kotchen, T. A.: J. Clin. Endocrinol. Metab. 44: 322- 329, 1977.
furosemide, mean PRA in normotensive contral subjects (0.9 ng/ml/hr ± 0.2*) and patients with essential hypertension (0.9 ng/ ml/hr ± 0.2) did not differ (Fig. 1). After furasemide, PRA increased in both control subjects and hypertensive patients (p < 0.001). Mean PRA of patients with essential hypertension (1.9 ng/ml/hr ± 0.3), however, was (p < 0.05) lower than that of normotensive contral subjects (3.1 ng/ml/hr ± 0.5). PRA was undetectable both before and after furo'Standard errOL
16
Brooks et al.
Clinical Pharmacology and Therapeutics
Table 11. Average (±SE) computed mean arterial blood pressure and PRA in contral periods and du ring drug therapy in NREH and LREH Type hypertension
Spir
Contra/
HCTZ
Control
Spir-HCTZ (twice daily)
± I ± 3
118 ± I 111 ± 2
124 ± 2 122 ± 3
115± 108 ± I
125 ± 3 119 ± 4
114 ± I 105 ± I
± 0.4 ± 0.1
3.5 ± 0.6 1.8 ± 0.3
0.9 ± 0.2 0.4 ± 0.2
5.0 ± 0.9 2.3 ± 0.6
0.8 ± 0.3 0.2 ± 0.1
Contra/
Mean arterial pressure NREH 122 LREH 128 PRA (ng/ml/hr) NREH 1.5 0.2 LREH
(mm Hg)
Table 111. Decrease oi mean arte rial pressure (±SE) and body weight, comparing measurements on final day oi therapy with contral va lues Type hypertension
Spir
Blood pressure decrease (mm Hg) NREH 6.3 ± 2.3 LREH 24.6 ± 2.6 Weight lass (kg) NREH 1.09 ± 0.41 LREH 0.50 ± 0.77
HCTZ
9.7 ± 2.8 18.9 ± 2.9 1.34 ± 0.41 1.73 ± 0.59
semide in one 65-yr-old black normotensive man, but in all the other normotensive subjects the lowest PRA after furosemide was 0.8 ng/ mi/hr. Nine of the 30 patients (30%) with essential hypertension had stimulated PRA lower than this value, and these patients were designated as having low renin essential hypertension. When patients with low renin hypertension and those with normal renin hypertension were compared, mean arterial pressure (126 mm Hg ± 4 and 123 mm Hg ± 3) and age (45 yr ± 2 and 49 yr ± 2) were similar (p > 0.3) in both groups. Of the low renin patients, 89% were black; 48% of normal renin patients were black (p < 0.05). Men comprised 21 % of low renin and 24% of normal renin patients. Serum creatinine of normotensive control subjects, patients with LREH, and patients with NREH did not differ (p > 0.7). Urine sodium excretion (4- hr) following furosemide also did not differ among the three groups (p > 0.5). Twenty-five of the 30 patients (16 NREH; 9 LREH) entered the clinical protocol designed to
12.9 ± 1.9 10.2 ± 2.1
compare HCTZ, Spir, and combination SpirHCTZ therapy. The first phase of the study was conducted according to a double-blind, crossover protocol. Two 6-wk active drug periods were each preceded by a 4-wk placebo period. Patients received either Spir or HCTZ during the drug periods . Each drug was administered twice daily with the initial dose being 25 mg twice daily. On subsequent visits the dosage was increased as necessary by one tablet (25 mg) twice daily if blood pressure was greater than 140/90 mm Hg. The maximum total daily dose of each drug was 200 mg. Patients continued without interruption into the second phase of the study which consisted of a 4-wk placebo period followed by a 6-wk period of combination therapy with Spir-HCTZ administered twice daily, followed by another 4-wk placebo period and then Spir-HCTZ administered once daily for 6 wk. In half the patients, treatment with the once-daily regimen preceded the twice-daily regimen. Treatment was initiated with one tab let twice daily (containing 25 mg Spir and 25 mg HCTZ) or two tab lets daily, and the dosage was progressively increased if blood pressure was higher than 140/90 mm Hg. Patients were seen every other week during each control period, for the first 2 wk of each treatment period, and then weekly for the duration of each treatment period. Blood pressure was measured with the patient in the sitting position with a mercury manometer three times each visit at 5-min intervals. Mean arterial pressure was ca1culated as one-third of the pulse pressure plus the diastolic pressure. The average of the three mean blood pressure determinations was taken as a single value to represent each visit. Blood was collected at the end of
Diuretics in low and normal renin hypertension
Valurne 22 Number I
Spir-HCTZ
Control
(once daily)
124 ± 4 118 ± 2
111 ± 2 103 ± 1
1.9 ± 0.7 0.5 ± 0.4
7.8 ± 1.0 7.7 ± 1.3
each contral and treatment period for determination of PRA, and serum potassium and uric acid concentrations. PRA was also determined after 4 wk of therapy in each study period. PRA after 4 and 6 wk did not differ significantly, and for analysis these measurements were averaged to give a single value. Serum potassium and uric acid concentrations were measured with an AutoAnalyzer, and PRA was measured by the radioimmunoassy pracedure of Haber and associates. lI Analysis of variance was used to compare the statistical significance of group differences and treatment differences. Two group comparisons were made with the Student's t test. A p value of 0.05 or more was not considered to indicate statistical significance. Results
Among NREH patients and among LREH patients, the final doses of each drug regimen did not differ significantly (Table I). The final dosages of Spir alone, HCTZ alone, and combined Spir-HCTZ (once or twice daily) did not differ in NREH and LREH patients. Table II lists the average computed mean arterial blood pressures during control and treatment periods . Overall, in the control periods, blood pressure of patients with NREH and LREH did not differ. Among patients with NREH, Spir alone had a small but significant hypotensive effect (p < 0.005). HCTZ and Spir-HCTZ, given either once or twice daily, had a greater hypotensive effect than Spir alone (p < 0.01), and with each of these three regimens the effect on blood pressure did not differ. Blood pressure was lowered by each of the treatment regimens in patients with LREH
17
(p < 0.001), and in these patients there were no significant differences among treatments. In patients with LREH, average me an blood pressure during each treatment period was lower than that in those with NREH (p < 0.001); overall change in blood pressure from pretreatment contral values was greater (p < 0.001) in patients with LREH (Fig. 2). Based upon blood pressure measurements in the control period and at the final visit of each treatment period, the responses of LREH patients on Spir and HCTZ were greater (p < 0.001 and p < 0.05, respectively) than the responses of NREH patients (Table II1). In LREH patients, blood pressures at the end of each of the two treatment periods did not differ significantly. In NREH patients, also, the responses to Spir and HCTZ did not differ when evaluated by comparison of blood pressures at the end of the treatment period. On each regimen, both graups of patients demonstrated significant weight loss (Table I). The mean weight loss on each regimen did not differ between patients with LREH and NREH. Among NREH patients, the overall mean weight loss during treatment with Spir alone or HCTZ alone did not differ, but during treatment periods with combined therapy (either once or twice daily) overall weight loss was greater than that with Spir alone (p < 0.05). In LREH patients, mean weight loss over the 6 wk of therapy with HCTZ alone and with combined therapy (once or twice daily) was greater than that with Spir alone (p < 0.05). By comparing pretreatment weight with weight measured on the final visit of each drug period, weight loss of low renin patients after Spir and HCTZ did not differ (Table II1). In patients with NREH, change in weight did not correlate with change in blood pressure during treatment with Spir (r = 0.17; P > 0.12), HCTZ Cr = 0.08; p > 0.45), or Spir-HCTZ Cr = 0.14; P > 0.33). In patients with LREH, during the Spir period there was a significant correlation between change in weight and change in blood pressure Cr = 0.41; P < 0.005); on HCTZ there was a suggestive although not statistically significant correlation Cr = 0.29; P < 0.06), and on Spir-HCTZ there was no correlation (p > 0.2).
18
Brooks et al.
Clinical Pharmacology and Therapeutics
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Charles S. Brooks, M.D.,* Curtis A. Johnson, Pharm.D., Jane M. Kotchen, M.D., and Theodore A. Kotchen, M.D. Lexington, Ky. Departments oJ Medicine and Community Medicine, College oJ Medicine and College oJ Pharmacy, University oJ Kentucky
Although it is well documented that approximately 25% of patients with essential hypertension have suppressed plasma renin activity (PRA), the mechanism of renin suppression has not been defined in most of these patients. 9 Expanded extracellular fluid volumes have been measured by several but not by all investigators. 9 Based on bioassay for mineralocorticoid activity in urine of patients with low renin hypertension (LREH) and low salivary sodium-potassium ratios, it has been suggested
Supported in part by Grant HL 15528 and Nephrology·Urology Training Program AM 05701, both from the National Institutes of Health, and by a grant from the Eagles' Max Baer Heart Fund. Received for publication Feb. 2, 1977. Accepted for publication March I, 1977. Reprint requests to: Theodore A. Kotchen, M.D., Department of Medicine, University of Kentucky College of Medicine, Lexington, Ky.40506. 'Present address: Department of Medicine, University of Missouri Medical Center and Veterans Administration Hospital, Columbia, Mo. 65201.
14
that LREH may be related to increased production of a mineralocorticoid. l , 17 Indeed, inappropriate aldosterone production may occur in some of these patients,IO and in a relatively small number of patients with LREH increased production of other mineralocorticoids has been demonstrated.5, 13-18 Additional indirect evidence has been interpreted to indicate that LREH may be a disease of mineralocorticoid excess. Compared with patients with normal renin essential hypertension (NREH), patients with LREH have a greater hypotensive response to both an inhibitor of adrenal steroid biosynthesis (aminoglutethimide) and to spironolactone, a mineralocorticoid antagonist. 6. 7, 19, 23 It has also been reported that high-dose spironolactone therapy (400 mg/ day) is more effective than thiazide therapy in lowering blood pressure of patients with LREH.12, 20 Other reports indicate that low renin patients are more responsive to all diuretic therapies than
Diuretics in low and normal renin hypertension
Volume 22 Number I
15
Table I. Mean (±SE) drug dosages at the end of each treatment period and mean weight loss durmg each treatment period in patients with NREH and LREH Type hypertension
Drug dose (mg/day) NREH LREH Weight loss (kg) NREH LREH
Spir
HCTZ
Spir-HCTZ (twice daily)
Spir-HCTZ (once daily)
159 ± 20 (16)* 128 ± 20 (9)
114 ± 13 (16) 111 ± 11 (9)
133 ± Ilt (12) 129 ± 21 (7)
106 ± 10 (12) 100 ± 13 (8)
1.08 ± 0.15 0.60 ± 0.29
1.42 ± 0.14 1.26±0.19
1.85 ± 0.27 1.83 ± 0.28
1.66 ± 0.18 2.52 ± 0.18
*Numbers in parentheses refer to number of patients. tDose refers to each drug in the combination.
normal renin patients,2. 21 which suggests that the greater responses to aminoglutethimide and spiranolactone do not necessarily reftect increased mineralocorticoid praduction. Unlike that in patients with primary aldosteranism, increased in vitra binding of steroids in plasma of patients with LREH to mineralocorticoid receptors has not been observed. 3 The purpose of our report is to describe the results of our double-blind crossover study designed to compare the effectiveness of spiranolactone (Spir), hydrachlorothiazide (HCTZ), and combined Spir-HCTZ therapy in patients with LREH and NREH. Methods
Essential hypertension was diagnosed on the basis of history , physical examination, urinalysis, measurement of creatinine cIearance, serum Na+, K+, CI-, and CÜ 2 concentrations,
rapid-sequence intravenous pyelogram, and, in selected patients, measurement of 24-hr urine vanillylmandelic acid (VMA) excretion and renal angiography. Patients with secondary hypertension, serum creatinine concentration above 1.5 mg/dl, hyper- or hypokalemia, congestive heart failure, or malignant hypertension and patients receiving estragen therapy were excIuded. We 4 have published our protocol for identifying patients with LREH. Briefty, PRA was measured after an overnight fast, before, and 4 hr after the combined stimulus of 80 mg furosemide given orally and the upright posture in 30 patients with essential hypertension and in 16 normotensive control subjects who were matched for age, sex, and race. Before
6.0
5.0
.::....
E ....
..
co c
4.0
3.0
a:: 0..
2.0
1.0
0 HYPERTENSIVES
NORMALS
(0=30)
(0=16)
Fig. 1. Mean (± SE) PRA before and after furosemide in hypertensive patients and normotensive control subjects. (From Brooks, C. S., Talwalker, R. T., and Kotchen, T. A.: J. Clin. Endocrinol. Metab. 44: 322- 329, 1977.
furosemide, mean PRA in normotensive contral subjects (0.9 ng/ml/hr ± 0.2*) and patients with essential hypertension (0.9 ng/ ml/hr ± 0.2) did not differ (Fig. 1). After furasemide, PRA increased in both control subjects and hypertensive patients (p < 0.001). Mean PRA of patients with essential hypertension (1.9 ng/ml/hr ± 0.3), however, was (p < 0.05) lower than that of normotensive contral subjects (3.1 ng/ml/hr ± 0.5). PRA was undetectable both before and after furo'Standard errOL
16
Brooks et al.
Clinical Pharmacology and Therapeutics
Table 11. Average (±SE) computed mean arterial blood pressure and PRA in contral periods and du ring drug therapy in NREH and LREH Type hypertension
Spir
Contra/
HCTZ
Control
Spir-HCTZ (twice daily)
± I ± 3
118 ± I 111 ± 2
124 ± 2 122 ± 3
115± 108 ± I
125 ± 3 119 ± 4
114 ± I 105 ± I
± 0.4 ± 0.1
3.5 ± 0.6 1.8 ± 0.3
0.9 ± 0.2 0.4 ± 0.2
5.0 ± 0.9 2.3 ± 0.6
0.8 ± 0.3 0.2 ± 0.1
Contra/
Mean arterial pressure NREH 122 LREH 128 PRA (ng/ml/hr) NREH 1.5 0.2 LREH
(mm Hg)
Table 111. Decrease oi mean arte rial pressure (±SE) and body weight, comparing measurements on final day oi therapy with contral va lues Type hypertension
Spir
Blood pressure decrease (mm Hg) NREH 6.3 ± 2.3 LREH 24.6 ± 2.6 Weight lass (kg) NREH 1.09 ± 0.41 LREH 0.50 ± 0.77
HCTZ
9.7 ± 2.8 18.9 ± 2.9 1.34 ± 0.41 1.73 ± 0.59
semide in one 65-yr-old black normotensive man, but in all the other normotensive subjects the lowest PRA after furosemide was 0.8 ng/ mi/hr. Nine of the 30 patients (30%) with essential hypertension had stimulated PRA lower than this value, and these patients were designated as having low renin essential hypertension. When patients with low renin hypertension and those with normal renin hypertension were compared, mean arterial pressure (126 mm Hg ± 4 and 123 mm Hg ± 3) and age (45 yr ± 2 and 49 yr ± 2) were similar (p > 0.3) in both groups. Of the low renin patients, 89% were black; 48% of normal renin patients were black (p < 0.05). Men comprised 21 % of low renin and 24% of normal renin patients. Serum creatinine of normotensive control subjects, patients with LREH, and patients with NREH did not differ (p > 0.7). Urine sodium excretion (4- hr) following furosemide also did not differ among the three groups (p > 0.5). Twenty-five of the 30 patients (16 NREH; 9 LREH) entered the clinical protocol designed to
12.9 ± 1.9 10.2 ± 2.1
compare HCTZ, Spir, and combination SpirHCTZ therapy. The first phase of the study was conducted according to a double-blind, crossover protocol. Two 6-wk active drug periods were each preceded by a 4-wk placebo period. Patients received either Spir or HCTZ during the drug periods . Each drug was administered twice daily with the initial dose being 25 mg twice daily. On subsequent visits the dosage was increased as necessary by one tablet (25 mg) twice daily if blood pressure was greater than 140/90 mm Hg. The maximum total daily dose of each drug was 200 mg. Patients continued without interruption into the second phase of the study which consisted of a 4-wk placebo period followed by a 6-wk period of combination therapy with Spir-HCTZ administered twice daily, followed by another 4-wk placebo period and then Spir-HCTZ administered once daily for 6 wk. In half the patients, treatment with the once-daily regimen preceded the twice-daily regimen. Treatment was initiated with one tab let twice daily (containing 25 mg Spir and 25 mg HCTZ) or two tab lets daily, and the dosage was progressively increased if blood pressure was higher than 140/90 mm Hg. Patients were seen every other week during each control period, for the first 2 wk of each treatment period, and then weekly for the duration of each treatment period. Blood pressure was measured with the patient in the sitting position with a mercury manometer three times each visit at 5-min intervals. Mean arterial pressure was ca1culated as one-third of the pulse pressure plus the diastolic pressure. The average of the three mean blood pressure determinations was taken as a single value to represent each visit. Blood was collected at the end of
Diuretics in low and normal renin hypertension
Valurne 22 Number I
Spir-HCTZ
Control
(once daily)
124 ± 4 118 ± 2
111 ± 2 103 ± 1
1.9 ± 0.7 0.5 ± 0.4
7.8 ± 1.0 7.7 ± 1.3
each contral and treatment period for determination of PRA, and serum potassium and uric acid concentrations. PRA was also determined after 4 wk of therapy in each study period. PRA after 4 and 6 wk did not differ significantly, and for analysis these measurements were averaged to give a single value. Serum potassium and uric acid concentrations were measured with an AutoAnalyzer, and PRA was measured by the radioimmunoassy pracedure of Haber and associates. lI Analysis of variance was used to compare the statistical significance of group differences and treatment differences. Two group comparisons were made with the Student's t test. A p value of 0.05 or more was not considered to indicate statistical significance. Results
Among NREH patients and among LREH patients, the final doses of each drug regimen did not differ significantly (Table I). The final dosages of Spir alone, HCTZ alone, and combined Spir-HCTZ (once or twice daily) did not differ in NREH and LREH patients. Table II lists the average computed mean arterial blood pressures during control and treatment periods . Overall, in the control periods, blood pressure of patients with NREH and LREH did not differ. Among patients with NREH, Spir alone had a small but significant hypotensive effect (p < 0.005). HCTZ and Spir-HCTZ, given either once or twice daily, had a greater hypotensive effect than Spir alone (p < 0.01), and with each of these three regimens the effect on blood pressure did not differ. Blood pressure was lowered by each of the treatment regimens in patients with LREH
17
(p < 0.001), and in these patients there were no significant differences among treatments. In patients with LREH, average me an blood pressure during each treatment period was lower than that in those with NREH (p < 0.001); overall change in blood pressure from pretreatment contral values was greater (p < 0.001) in patients with LREH (Fig. 2). Based upon blood pressure measurements in the control period and at the final visit of each treatment period, the responses of LREH patients on Spir and HCTZ were greater (p < 0.001 and p < 0.05, respectively) than the responses of NREH patients (Table II1). In LREH patients, blood pressures at the end of each of the two treatment periods did not differ significantly. In NREH patients, also, the responses to Spir and HCTZ did not differ when evaluated by comparison of blood pressures at the end of the treatment period. On each regimen, both graups of patients demonstrated significant weight loss (Table I). The mean weight loss on each regimen did not differ between patients with LREH and NREH. Among NREH patients, the overall mean weight loss during treatment with Spir alone or HCTZ alone did not differ, but during treatment periods with combined therapy (either once or twice daily) overall weight loss was greater than that with Spir alone (p < 0.05). In LREH patients, mean weight loss over the 6 wk of therapy with HCTZ alone and with combined therapy (once or twice daily) was greater than that with Spir alone (p < 0.05). By comparing pretreatment weight with weight measured on the final visit of each drug period, weight loss of low renin patients after Spir and HCTZ did not differ (Table II1). In patients with NREH, change in weight did not correlate with change in blood pressure during treatment with Spir (r = 0.17; P > 0.12), HCTZ Cr = 0.08; p > 0.45), or Spir-HCTZ Cr = 0.14; P > 0.33). In patients with LREH, during the Spir period there was a significant correlation between change in weight and change in blood pressure Cr = 0.41; P < 0.005); on HCTZ there was a suggestive although not statistically significant correlation Cr = 0.29; P < 0.06), and on Spir-HCTZ there was no correlation (p > 0.2).
18
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Clinical Pharmacology and Therapeutics
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