Curr Med Res Opin Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
Current Medical Research and Opinion
Vol. 4, No. 8, 1977
A preliminary controlled evaluation of the antihypertensive effect of indapamide
P. Turner,* M.D.,B.Sc., F.R.C.P., G. N. Volans, M.D., B.Sc., M.R.C.P., and
H. J. Rogers, Ph.D., M.R.C.P. Departments of Clinical Pharmacology, St. Bartholomew’s Hospital,* and Guy’s Hospital, London, England
Curr. Med. Res. Opin., (1977), 4, 596.
Received: 10th February 1977
Summary A controlled, single-blind trial w a s carried out in 10 hypertensive patients to compare the effectiveness of a single daily dose (2.5 mg to 5 mg) of indapamide with that of placebo. Blood pressure was measured with a bias-fvee sphygmomanometer. Indapamide produced a signijicant reduction in mean systolic and diastolic pressures in both supine and erect positions. It was generally well tolerated: f e w side-effects were reportedandno signijcant changes were noted in laboratory tests. It is concluded that further long-term studies of indapamide are indicated in larger numbers of patients. Key words: Indapamide
-
antih.vpertensive agents - hypertensioii
Introduction Indapamidet, chloro-4-N (methyl 2 indolinyl-1) sulphamoyl-3 benzamide, has recently been introduced for the management of essential hypertension. When used in a single daily dosage of 2.5 mg, indapamide exerts a progressive antihypertensive effect comparable in potency to thiazide diuretic agents, but is without their adverse effects, such as significant diuresis and consequent electrolyte disturbances.2.3,5.7 The mechanism of action and good clinical tolerance of indapamide may be attributable to a predominantly specific local action on the arteriolar wall, demonstrated in vifro4 and after repeated doses in vivo’ through a reduction in the vascular reactivity to vasopressor stimuli. The present study was undertaken to assess further the role of indapamide in the treatment of hypertension under conditions where some of the many variables inherent in blood pressure measurements were carefully controlled. The trial design comprised a 2-week placebo baseline period followed by a 12-week period of drug administration, after which placebo tablets were substituted. A bias-free sphygmomanometer was used throughout.
Patients and methods Fourteen newly diagnosed or previously treated but poorly controlled hypertensive patients, referred as out-patients for further investigation of their hypertension, t‘Natrilex’, trade mark Servier 596
Curr Med Res Opin Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
P. Turner, G . N. Volans and H. J. Rogers
entered into the trial. Patients with overt congestive heart failure, severe renal insufficiency or who were pregnant were excluded. At entry, all patients were clinically assessed with measurements of body weight, lying and erect systolic and diastolic blood pressures, and lying and erect pulse rates. Laboratory investigations were undertaken for haematological, renal and hepatic status, glycaemia (random), uricaemia and electrolyte balance. Any existing antihypertensives or medications necessitated by their medical condition were continued in unchanged dosage. The first phase of the trial consisted of a 2-week administration of 1 matched placebo tablet daily to obtain a baseline against which the activity of indapamide could be evaluated. One tablet (2.5 mg) af indapamide daily was then prescribed for a 12-week period, either as the sole treatment or combined with the patient’s existing antihypertensive therapy. The patients returned at approximately 2-weekly intervals for assessment of blood pressure, tolerance to treatment, and laboratory investigations. After 12 weeks of treatment, aplacebotablet was substituted, unknown to the patients, and continued until such time as the blood pressure levels were considered t o require treatment intervention. This was defined as a blood pressure above normal for the patient’s age, according to the Royal Society of Actuaries. Blood pressure was measured throughout with a London School of Hygiene sphygmomanometer to avoid observer bias. On completion of this study, the mean changes after indapamide administration were compared with the mean placebo baseline values by paired ‘t’ tests.
Results Of the 14 patients initially included in the study, 3 did not attend for follow-up and 1 was withdrawn because of a partial nephrectomy due to pre-existing hydronephrosis. Four males and 6 females with an age range of 25 to 62 years (mean 46 years) completed the study. Eight of the patients received indapamide alone and the other 2 patients received indapamide in combination with propranolol. Additional medications consisted of amitriptyline (25 mg) in 1 depressed patient, and medazepam and amitriptyline in another. Blood pressure Figure 1 and Table I show the mean changes in blood pressure associated with the 1 0 3 2 week period of indapamide and the two periods of placebo administrations for all of the patients. Mean baseline blood pressures after the initial 2-week placebo period were 175/105 mmHg supine and 169/109 mmHg erect. After addition of indapamide, the antihypertensive efficacy was apparent after the first 2 weeks, and by the end of indapamide administration significant mean reductions in systolic and diastolic pressures were seen. The mean reductions obtained were in the order of 32/19 mmHg lying and 37/16 mmHg in the erect position. On stopping indapamide, mean pressure gradually 597
A preliminary controlled evaluation of the antihypertensiveeffect of indapamide
Figure 1. Changes in erect and supine blood pressure after treatment with placebo and indapamide: mean (fS.D.) values
/&
Curr Med Res Opin Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
n-10
2oo?nfo
n -5
n=10
n=10
w i Systolic
***
Diastolic
60 0
4
'
1
4
1
1
1
8 '-12
1
1
16
kIndaparnide*[h Placebo Placebo
1
1
20 ' Weeks
0
4
8
12
16
4
LIndapamide *I4 Placebo Placebo
20
Weeks
Note: *p < 0.01,**p< 0.005,***p < 0.001
Table I. Mean (fS.D.) blood pressure response to treatment in 10 patients completing trial
Entry
After 2 weeks placebo
After 10&2 weeks indapamide
Erect Systolic Diastolic
175.40126.97 106.6Of 14.63
169.10131.65 108.80f15.35
132.40116.82** 93.30+12.58**
Supine Systolic Diastolic
171.30f31.61 103.80116.67
175.10f23.65 104.60f14.64
142.70117.51 *** 85.80112.47**
Blood pressure (mmHg)
**p < 0.005, ***p < 0.001
increased, with a mean rise of 616 mmHg after 4 weeks. In 4 patients, erect blood pressures had achieved baseline values after 4 weeks of placebo administration. In the other 6 patients, however, blood pressure returned to pre-treatment values in 2 598
Curr Med Res Opin Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
P. Turner, G . N. Volans and H. J . Rogers
after 6 to 8 weeks of placebo, while lower erect blood pressure values were maintained in the other 4 patients for 10 to 12 weeks of placebo. In 1 female patient, the dose of indapamide was reduced to 1 tablet (2.5 mg) on alternate days because of giddiness on standing which developed within a few days of active treatment. Her blood pressure was found to be 122/84 mmHg supine and 99/78 mmHg standing, with a postural increase in heart rate from 78 to 90 beats per minute. However, following the dose reduction, her pressure increased over 2 weeks to 128/115 mmHg supine and 1 10/97 mmHg standing, and the dose was, therefore, raised to the original 1 tablet daily without a return of postural giddiness and with pressures of 103/81 mmHg supine and 115189 mmHg standing. In 4 patients, the dose of indapamide was increased to 2 tablets (5.0 mg daily) during the 12-week treatment period, and in 1 of the patients receiving propranolol on entry, the dose of propranolol was reduced after the addition of indapamide to the drug regimen. In 2 other patients, 80 mg oxprenolol b.d. was successfully added to indapamide to achieve good blood pressure control. On an individual basis, 6 of the 10 patients responded to indapamide. Adequate control was achieved if the erect systolic pressure was reduced to 120 to 140 mmHg and the diastolic to 80 to 100 mmHg. Of the 4 non-responders, 2 had adequate falls in systolic pressure and 1 had achieved a diastolic pressure of 95 mmHg. In 2 of these non-responders, the dose of indapamide was increased to 5 mg daily, without further benefit. Body weight There was no significant change in the body weight of the patients throughout the trial period, although body weight measurements were not taken in all subjects.
Pulse rare A gradual decrease in supine pulse rate was seen during indapamide administration which reached significance at the end of the treatment period (p
Current Medical Research and Opinion
Vol. 4, No. 8, 1977
A preliminary controlled evaluation of the antihypertensive effect of indapamide
P. Turner,* M.D.,B.Sc., F.R.C.P., G. N. Volans, M.D., B.Sc., M.R.C.P., and
H. J. Rogers, Ph.D., M.R.C.P. Departments of Clinical Pharmacology, St. Bartholomew’s Hospital,* and Guy’s Hospital, London, England
Curr. Med. Res. Opin., (1977), 4, 596.
Received: 10th February 1977
Summary A controlled, single-blind trial w a s carried out in 10 hypertensive patients to compare the effectiveness of a single daily dose (2.5 mg to 5 mg) of indapamide with that of placebo. Blood pressure was measured with a bias-fvee sphygmomanometer. Indapamide produced a signijicant reduction in mean systolic and diastolic pressures in both supine and erect positions. It was generally well tolerated: f e w side-effects were reportedandno signijcant changes were noted in laboratory tests. It is concluded that further long-term studies of indapamide are indicated in larger numbers of patients. Key words: Indapamide
-
antih.vpertensive agents - hypertensioii
Introduction Indapamidet, chloro-4-N (methyl 2 indolinyl-1) sulphamoyl-3 benzamide, has recently been introduced for the management of essential hypertension. When used in a single daily dosage of 2.5 mg, indapamide exerts a progressive antihypertensive effect comparable in potency to thiazide diuretic agents, but is without their adverse effects, such as significant diuresis and consequent electrolyte disturbances.2.3,5.7 The mechanism of action and good clinical tolerance of indapamide may be attributable to a predominantly specific local action on the arteriolar wall, demonstrated in vifro4 and after repeated doses in vivo’ through a reduction in the vascular reactivity to vasopressor stimuli. The present study was undertaken to assess further the role of indapamide in the treatment of hypertension under conditions where some of the many variables inherent in blood pressure measurements were carefully controlled. The trial design comprised a 2-week placebo baseline period followed by a 12-week period of drug administration, after which placebo tablets were substituted. A bias-free sphygmomanometer was used throughout.
Patients and methods Fourteen newly diagnosed or previously treated but poorly controlled hypertensive patients, referred as out-patients for further investigation of their hypertension, t‘Natrilex’, trade mark Servier 596
Curr Med Res Opin Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
P. Turner, G . N. Volans and H. J. Rogers
entered into the trial. Patients with overt congestive heart failure, severe renal insufficiency or who were pregnant were excluded. At entry, all patients were clinically assessed with measurements of body weight, lying and erect systolic and diastolic blood pressures, and lying and erect pulse rates. Laboratory investigations were undertaken for haematological, renal and hepatic status, glycaemia (random), uricaemia and electrolyte balance. Any existing antihypertensives or medications necessitated by their medical condition were continued in unchanged dosage. The first phase of the trial consisted of a 2-week administration of 1 matched placebo tablet daily to obtain a baseline against which the activity of indapamide could be evaluated. One tablet (2.5 mg) af indapamide daily was then prescribed for a 12-week period, either as the sole treatment or combined with the patient’s existing antihypertensive therapy. The patients returned at approximately 2-weekly intervals for assessment of blood pressure, tolerance to treatment, and laboratory investigations. After 12 weeks of treatment, aplacebotablet was substituted, unknown to the patients, and continued until such time as the blood pressure levels were considered t o require treatment intervention. This was defined as a blood pressure above normal for the patient’s age, according to the Royal Society of Actuaries. Blood pressure was measured throughout with a London School of Hygiene sphygmomanometer to avoid observer bias. On completion of this study, the mean changes after indapamide administration were compared with the mean placebo baseline values by paired ‘t’ tests.
Results Of the 14 patients initially included in the study, 3 did not attend for follow-up and 1 was withdrawn because of a partial nephrectomy due to pre-existing hydronephrosis. Four males and 6 females with an age range of 25 to 62 years (mean 46 years) completed the study. Eight of the patients received indapamide alone and the other 2 patients received indapamide in combination with propranolol. Additional medications consisted of amitriptyline (25 mg) in 1 depressed patient, and medazepam and amitriptyline in another. Blood pressure Figure 1 and Table I show the mean changes in blood pressure associated with the 1 0 3 2 week period of indapamide and the two periods of placebo administrations for all of the patients. Mean baseline blood pressures after the initial 2-week placebo period were 175/105 mmHg supine and 169/109 mmHg erect. After addition of indapamide, the antihypertensive efficacy was apparent after the first 2 weeks, and by the end of indapamide administration significant mean reductions in systolic and diastolic pressures were seen. The mean reductions obtained were in the order of 32/19 mmHg lying and 37/16 mmHg in the erect position. On stopping indapamide, mean pressure gradually 597
A preliminary controlled evaluation of the antihypertensiveeffect of indapamide
Figure 1. Changes in erect and supine blood pressure after treatment with placebo and indapamide: mean (fS.D.) values
/&
Curr Med Res Opin Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
n-10
2oo?nfo
n -5
n=10
n=10
w i Systolic
***
Diastolic
60 0
4
'
1
4
1
1
1
8 '-12
1
1
16
kIndaparnide*[h Placebo Placebo
1
1
20 ' Weeks
0
4
8
12
16
4
LIndapamide *I4 Placebo Placebo
20
Weeks
Note: *p < 0.01,**p< 0.005,***p < 0.001
Table I. Mean (fS.D.) blood pressure response to treatment in 10 patients completing trial
Entry
After 2 weeks placebo
After 10&2 weeks indapamide
Erect Systolic Diastolic
175.40126.97 106.6Of 14.63
169.10131.65 108.80f15.35
132.40116.82** 93.30+12.58**
Supine Systolic Diastolic
171.30f31.61 103.80116.67
175.10f23.65 104.60f14.64
142.70117.51 *** 85.80112.47**
Blood pressure (mmHg)
**p < 0.005, ***p < 0.001
increased, with a mean rise of 616 mmHg after 4 weeks. In 4 patients, erect blood pressures had achieved baseline values after 4 weeks of placebo administration. In the other 6 patients, however, blood pressure returned to pre-treatment values in 2 598
Curr Med Res Opin Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
P. Turner, G . N. Volans and H. J . Rogers
after 6 to 8 weeks of placebo, while lower erect blood pressure values were maintained in the other 4 patients for 10 to 12 weeks of placebo. In 1 female patient, the dose of indapamide was reduced to 1 tablet (2.5 mg) on alternate days because of giddiness on standing which developed within a few days of active treatment. Her blood pressure was found to be 122/84 mmHg supine and 99/78 mmHg standing, with a postural increase in heart rate from 78 to 90 beats per minute. However, following the dose reduction, her pressure increased over 2 weeks to 128/115 mmHg supine and 1 10/97 mmHg standing, and the dose was, therefore, raised to the original 1 tablet daily without a return of postural giddiness and with pressures of 103/81 mmHg supine and 115189 mmHg standing. In 4 patients, the dose of indapamide was increased to 2 tablets (5.0 mg daily) during the 12-week treatment period, and in 1 of the patients receiving propranolol on entry, the dose of propranolol was reduced after the addition of indapamide to the drug regimen. In 2 other patients, 80 mg oxprenolol b.d. was successfully added to indapamide to achieve good blood pressure control. On an individual basis, 6 of the 10 patients responded to indapamide. Adequate control was achieved if the erect systolic pressure was reduced to 120 to 140 mmHg and the diastolic to 80 to 100 mmHg. Of the 4 non-responders, 2 had adequate falls in systolic pressure and 1 had achieved a diastolic pressure of 95 mmHg. In 2 of these non-responders, the dose of indapamide was increased to 5 mg daily, without further benefit. Body weight There was no significant change in the body weight of the patients throughout the trial period, although body weight measurements were not taken in all subjects.
Pulse rare A gradual decrease in supine pulse rate was seen during indapamide administration which reached significance at the end of the treatment period (p
