A Comparative Study of Nicardipine and Pindolol as Second-line Treabnents in Essential Hypertension o PEN1TILAl, E KANNIAINEN
2
,
A
JOUNELA 2 AND
M
HUIKK0 3
'Paijat-Hame Central Hospital, Lahti, Finland; 'Lansi-Pohja Central Hospital, Kemi, Finland; "Mikkeli Central Hospital, Mikkeli, Finland
A controlled, randomized, single-blind, parallel-group study compared the effects of nicardipine hydrochloride/ hydrochlorothiazide (HCTZ) with those of pindolollHCTZ in treatment of essential hypertension. The study included 43 patients aged 30 - 64 years with supine diastolic blood pressures between 95 and 125 mmHg at baseline. Patients initially received 50 mg/day HCTZ for 6 weeks and those patients whose diastolic blood pressure remained at or above 90 mmHg at week 6 (n = 29) completed a 6-week comparative phase in which they were given, in addition, either 30 mg nicardipine hydrochloride or 5 mg pindolol three times daily. Nicardipine was more effective than pindolol as a second-line treatment in controlling blood pressure but, because patients who were treated with nicardipinelHCTZ had higher baseline blood pressures, significance was lost when results were adjusted for the baseline blood pressure values. Treatment was described as 'very good' by 71.4% of patientsin the nicardipine/ HCTZ group and by 53.9% of those in the pindolollHCTZ group; thus, both second-line antihypertensives were well accepted. Although 45% of patients in of each treatment group reported treatment-related adverse events, none experienced postural hypotension and no adverse event was unexpected.
218
KEY WORDS:
NICARDIPINE; PINDOLOL; HYDROCHLOROTHIAZIDE;
ANTIHYPERTENSIVES; HYPERTENSION
INTRODUCTION hypertensive effect of a nicardipine/thiazide combination is at least equal to that of the more traditional combination of a thiazide with a ~-blocker, nicardipine may be preferable to a ~-blocker as a second-line antihypertensive agent for the many patients whose blood pressure is unsuccessfully controlled by a thiazide alone. The present study was designed to compare the efficacy of two treatment combinations by assigning patients whose blood pressure was not effectively controlled by hydrochlorothiazide (HCTZ) alone to treatment with either nicardipine or pindolol in addition to HCTZ.
The thiazide diuretics are still regarded as effective, well-tolerated first-line treatments for mild to moderate hypertension, although their potentially harmful biochemical effects, i.e. potassium-losing properties, are cause for some concern.':" The mechanism by which the thiazides lower blood pressure has not been precisely defined: in part they act by reducing the circulating volume and promoting sodium excretion in the urine. The thiazides may also have non-diuretic properties, acting as vasodilators or modulators of the balance between intracellular and extracellular sodium concentrations. :l In approximately 80% of patients with mild to moderate hypertension, i.e. diastolic blood pressure 95 - 125 mmHg inclusive, blood pressure is adequately controlled using a thiazide alone; however, in the remaining 20% a second antihypertensive agent, traditionally a ~-receptor antagonist, is necessary. Use of~ blockers requires caution in some patients, particularly in those with obstructive airway disease, compromised myocardial function, or peripheral vascular disease. Recent evidence has suggested that essential hypertension is associated with an increase in intracellular calcium concentrations and, therefore, calcium channel blockers by inhibiting the entry of calcium into the cells may modulate the cell ular mechanisms underlying hypertension.' Nicardipine, a dihydropyridine antagonist of intracellular, slow-channel calcium influx, is a well-tolerated antihypertensive and is at least as effective as the ~-blockers atenolol and propranolol. ",r, There is also some evidence that patients with ischaemic heart disease can tolerate nicardipine better than the ~-blocker propranoloJ.7 Provided that the anti-
PATIENTS AND METHODS PATIENTS A total of 43 patients aged between 21 and 70 years who had been diagnosed as suffering from essential hypertension characterized by a supine diastolic blood pressure of between 95 and 125 mmHg were included in the study. Exclusion criteria were as follows: sensitivity to ~-blockers or thiazides; pregnancy or lactation; congestive heart failure; atrioventricular block or other dysrhythmia; recent history of myocardial infarction; insulindependent diabetes; and obstructive airway disease.
STUDY DESIGN AND TREATMENT The trial was conducted in accordance with the Declaration of Helsinki. The first stage of the study consisted of a 6-week run-in period during which the patients were treated orally with 50 mg/day HCTZ. At the end of this 6-
219
investigator interaction with a 95% confidence level.
week period, those patients whose supine diastolic blood pressure remained at or above 90 mmHg (but below 120 mmHg) were assigned according to a predetermined randomization schedule to 6 weeks' treatment with either 30 mg nicardipine or 5 mg pindolol both given three times daily, in addition to the continued HCTZ therapy. Blood pressure, pulse rate and any adverse events reported by the patients were recorded at 2-week intervals during the 6 weeks' combined treatment period. Blood pressure was determined with a random-zero sphygmomanometer by a blinded observer who, on each occasion, made two consecutive readings of supine blood pressure followed by a single reading of standing blood pressure; diastolic blood pressure was recorded at the disappearance of the fifth Korotkoff sound. At the end of the 6 weeks' combined treatment period, both the physicians and the patients assessed the efficacy of the treatment, and the physicians also assessed any adverse events that occurred. Full laboratory investigations (haematology and clinical chemistry) were performed at the beginning and end of the trial and, in addition, 12-lead electrocardiogram recordings were made at the beginning of the run-in period and repeated at the final visit on completion of 6 weeks' combined treatment.
RESULTS The distribution of supine diastolic blood pressure at entry was significantly (P < 0.001) different in the two treatment groups (Table 1). Baseline mean blood pressure measurements obtained from patients in the nicardi pinel HCTZ treatment group were statistically significantly (P < 0.05) higher than measurements from patients in the pindolol/HCTZ group. In other respects, however, the two treatment groups were comparable.
EFFICACY Patients were excluded from efficacy analysis because of protocol violations or premature withdrawals: in the nicardipine/HCTZ treatment group one patient because of a diuretic-related problem and one because of a study drug-related adverse event; in the pindolol/HCTZ treatment group one patient because of conjunctivitis and one because of a study drug-related adverse event. Of the 29 patients included in the efficacy analysis, 15 were in the nicardipine treatment group and 14 in the pindolol treatment group. The characteristics of these patients are summarized in Table 1. Supine and standing mean diastolic and systolic blood pressures at baseline and at the end of the 6-week treatment period are shown in Tables 2 and 3, respectively. Except for standing diastolic blood pressure for the pindolol/HCTZ treatment group, both of the second-line treatments produced significant reductions in systolic and diastolic blood pressures compared with baseline values. The reduction in mean supine diastolic pressure produced by nicardipine/HCTZ was significantly (P = 0.02) greater than that produced by pindolol/HCTZ, i.e. 15.1mmHg versus 5.7
STATISTICAL ANALYSIS Blood pressure and pulse rate were analysed at baseline and the change from baseline to endpoint was analysed using a two-way analysis of variance model that included the effects of treatment, investigator and treatment by investigator interaction. In addition, to account for the significant difference in baseline blood pressures and pulse rates in patients in the two treatment groups, an analysis of covariance was performed with the baseline value as the covariate and including the effects of treatment, investigator and treatment by
220
Demographic data for 29 patients with essential hypertension ineffectively controlled with 50 mg/day hydrochlorothiazide (HCTZ) and suosequentty treated with 50 mg/day HCTZ plus either 30 mg nicardipine hydrochloride three times daily or 5 mg pindolol three times daily for 6 weeks
Characteristic
Nicardipine treatment group
Pindolol treatment group
P-value a
No. of patients 10
7
Female
5
7
Prior antihypertensive treatment
6
7
0.28
Tobacco smokers
4
1
0.78
90 - < 100
6
9
100 - < 110
6
4
2 110
3
1
Male
0.28
Baseline supine diastolic pressure (mmHg)
< 0.01
Age (years) Median
46
46
Range
30- 64
37 - 63
83
80
0.89
Body weight (kg) Median Median history of hypertension (years)
5.8
2.3
0.36 0.12
Baseline mean (± SD) blood pressure (rnrnl-lq)> Supine
163 ± 14/ 104 ± 8
145 ± 14/ 97 ± 7
0.003/0.02
Standing
158 ± 16/ 109 ± 10
138 ± 15/ 101 ± 9
0.003/0.04
aBetween-treatment P-values are from analysis of variance or Grizzle - Starmer - Koch weighted least squares analysis of treatment, investigator and treatment by investigator effects. bEstimated means, are least squares means from analysis of variance.
221
Mean (:r SO) diastolic blood pressure measurements for 29 patients with essential hypertension ineffectively controlled with 50 mg/day hydrochlorothiazide (HCTZ) and subsequently treated with 50 mglday HCTZ plus either 30 mg nicardipine hydrochloride or 5 mg pindolol three times daily for 6 weeks
Blood pressure (mmHg) Treatment
Baseline
After treatment"
P-valueb
P-value c
Supine Nicardipine/HCTZ Pindoiol/HCTZ
104.2 ± 8 97.0 ± 7
89.1 ± 10 91.3 ± 10
0.0001 0.04
0.02
Standing . Nicardipine/HCTZ Pindoiol/HCTZ
108.6 ± 10 100.9 ± 9
95.1 ± 15 99.2±15
0.04 0.29
0.04
aMeans of analysis of variance without adjustment for baseline. P-values for change from baseline from analysis of covariance considering effects oftreatment, investigator and their interaction with the baseline value used as a covariate.
b
cP-value between treatments.
patients and 'fair' in two (14.3%) patients. The overall efficacy of pindolol was rated by the physicians as 'very good' in 8/13 (61.5%) patients, 'fair' in three (23.1 %) patients and 'poor' in two (15.4%) patients. The overall efficacy ofnicardipine was rated as 'very good' by 10 (71.4%) patients, 'good' by two (14.3%) patients and 'fair' by two (14.3%) patients. The overall efficacy of pindolol was rated as 'very good' by seven (53.9%) patients, 'good' by five (38.5%) patients and 'poor' by the remaining one (7.7%) patient. Overall twoway analysis of variance showed that the differences in the distribution of the responses attributable to treatment were not statistically significant.
mmHg, respectively. For standing diastolic blood pressure, the corresponding reductions were 13.5 mmHg for nicardipine/HCTZ and only 1.7 mmHg for pindolol/HCTZ (P = 0.04). The difference in baseline blood pressures was so great that the post-treatment blood pressures in the two groups were very similar (standing diastolic blood pressure 95.1 mmHg for nicardipine/HCTZ-treated patients versus 99.2 mmHg for pindolol/HCTZ-treated patients). The blood pressure changes in both treatment groups, adjusted for the differing baseline values, are shown in Figs 1 and 2;the differences between treatment groups were not significant after this adjustment had been made. Almost all of the patients responded well to the study medications. The physicians rated nicardipine's overall efficacy as 'very good' in 8/14 (57.1 %) patients, 'good' in four (28.6%)
ADVERSE EVENTS As might have been expected from the
222
TASLE3 Mean (± SO) systolic blood pressure measurements for 29 patients with essential hypertension ineffectively controUed with 50 mg/day hydrochlorothiazide (HCTZ) and subsequently treated with 50 mg/day HCTZplus either 30 mg nicardipine hydrochloride or 5 mg pindolol three times daily for 6 weeks
Blood pressure After treatment"
P·value b
P-valuec
163.2 ± 14 145.2 ± 14
143.1 ± 14 134.4 ± 14
0.001 0.001
0.09
157.8 ± 16 138.2 ± 15
139.8 ± 18 132.8 ± 18
0.04 0.03
0.08
Treatment
Baseline
Supine Nicardipine/HCTZ Pindolol/HCTZ Standing Nicardipine/HCTZ Pindolol/HCTZ
"Means of analysis of variance without adjustment for baseline. b P-values for change from baseline from analysis of covariance considering effects oftreatment, investigator and their interaction with the baseline value used as a covariate. cP-value between treatments.
events during treatment with nicardipine/ HCTZ. Of these events, nine were familiar calcium antagonist effects: tachycardia/ palpitations in five patients; flushing in three patients; and oedema in one patient. The other 13 adverse events were dry mouth in two patients and angina pectoris, dry mouth, dizziness, hyperkinesia, paraesthesia, sweating, vertigo, gastro-intestinal pain, vomiting, increased coughing, an upper respiratory infection and eczema in one patient each. A total of 10 patients in the pindolol/HCTZ treatment group reported 21 adverse events. Among these were familiar 13-blocker effects: vivid dreams occured in three patients; and tiredness in three patients. The other 15 adverse events were hypotension, dizziness, increased sweating, central nervous system disorders
pharmacological profiles of nicardipine and pindolol, mean pulse rate increased slightly, but not significantly, during treatment with nicardipine/HCTZ from 75.2 beats/min to 80.7 beats/min and fell significantly (P = 0.0001) during treatment with pindolol from 83.4 beats/min to 72.2 beats/min. During treatment with HCTZ alone, there were only three reports of a drug-related adverse event - headache on each occasion. The incidence of adverse events was considerably higher during the second-line combined treatments than during the run-in period with HCTZ alone: 14% during the HCTZ treatment period versus 45% during either nicardipine/ HCTZ or pindolol/HCTZ treatment. Most of the reported adverse events could be directly related to nicardipine and pindolol. A total of 12 patients reported 22 adverse
223
0 OJ
.s
- -& -
Pindolol/HCTZ
--a--
Nicardipine/HCTZ
-2
Qi Ul
2
,
A
JOUNELA 2 AND
M
HUIKK0 3
'Paijat-Hame Central Hospital, Lahti, Finland; 'Lansi-Pohja Central Hospital, Kemi, Finland; "Mikkeli Central Hospital, Mikkeli, Finland
A controlled, randomized, single-blind, parallel-group study compared the effects of nicardipine hydrochloride/ hydrochlorothiazide (HCTZ) with those of pindolollHCTZ in treatment of essential hypertension. The study included 43 patients aged 30 - 64 years with supine diastolic blood pressures between 95 and 125 mmHg at baseline. Patients initially received 50 mg/day HCTZ for 6 weeks and those patients whose diastolic blood pressure remained at or above 90 mmHg at week 6 (n = 29) completed a 6-week comparative phase in which they were given, in addition, either 30 mg nicardipine hydrochloride or 5 mg pindolol three times daily. Nicardipine was more effective than pindolol as a second-line treatment in controlling blood pressure but, because patients who were treated with nicardipinelHCTZ had higher baseline blood pressures, significance was lost when results were adjusted for the baseline blood pressure values. Treatment was described as 'very good' by 71.4% of patientsin the nicardipine/ HCTZ group and by 53.9% of those in the pindolollHCTZ group; thus, both second-line antihypertensives were well accepted. Although 45% of patients in of each treatment group reported treatment-related adverse events, none experienced postural hypotension and no adverse event was unexpected.
218
KEY WORDS:
NICARDIPINE; PINDOLOL; HYDROCHLOROTHIAZIDE;
ANTIHYPERTENSIVES; HYPERTENSION
INTRODUCTION hypertensive effect of a nicardipine/thiazide combination is at least equal to that of the more traditional combination of a thiazide with a ~-blocker, nicardipine may be preferable to a ~-blocker as a second-line antihypertensive agent for the many patients whose blood pressure is unsuccessfully controlled by a thiazide alone. The present study was designed to compare the efficacy of two treatment combinations by assigning patients whose blood pressure was not effectively controlled by hydrochlorothiazide (HCTZ) alone to treatment with either nicardipine or pindolol in addition to HCTZ.
The thiazide diuretics are still regarded as effective, well-tolerated first-line treatments for mild to moderate hypertension, although their potentially harmful biochemical effects, i.e. potassium-losing properties, are cause for some concern.':" The mechanism by which the thiazides lower blood pressure has not been precisely defined: in part they act by reducing the circulating volume and promoting sodium excretion in the urine. The thiazides may also have non-diuretic properties, acting as vasodilators or modulators of the balance between intracellular and extracellular sodium concentrations. :l In approximately 80% of patients with mild to moderate hypertension, i.e. diastolic blood pressure 95 - 125 mmHg inclusive, blood pressure is adequately controlled using a thiazide alone; however, in the remaining 20% a second antihypertensive agent, traditionally a ~-receptor antagonist, is necessary. Use of~ blockers requires caution in some patients, particularly in those with obstructive airway disease, compromised myocardial function, or peripheral vascular disease. Recent evidence has suggested that essential hypertension is associated with an increase in intracellular calcium concentrations and, therefore, calcium channel blockers by inhibiting the entry of calcium into the cells may modulate the cell ular mechanisms underlying hypertension.' Nicardipine, a dihydropyridine antagonist of intracellular, slow-channel calcium influx, is a well-tolerated antihypertensive and is at least as effective as the ~-blockers atenolol and propranolol. ",r, There is also some evidence that patients with ischaemic heart disease can tolerate nicardipine better than the ~-blocker propranoloJ.7 Provided that the anti-
PATIENTS AND METHODS PATIENTS A total of 43 patients aged between 21 and 70 years who had been diagnosed as suffering from essential hypertension characterized by a supine diastolic blood pressure of between 95 and 125 mmHg were included in the study. Exclusion criteria were as follows: sensitivity to ~-blockers or thiazides; pregnancy or lactation; congestive heart failure; atrioventricular block or other dysrhythmia; recent history of myocardial infarction; insulindependent diabetes; and obstructive airway disease.
STUDY DESIGN AND TREATMENT The trial was conducted in accordance with the Declaration of Helsinki. The first stage of the study consisted of a 6-week run-in period during which the patients were treated orally with 50 mg/day HCTZ. At the end of this 6-
219
investigator interaction with a 95% confidence level.
week period, those patients whose supine diastolic blood pressure remained at or above 90 mmHg (but below 120 mmHg) were assigned according to a predetermined randomization schedule to 6 weeks' treatment with either 30 mg nicardipine or 5 mg pindolol both given three times daily, in addition to the continued HCTZ therapy. Blood pressure, pulse rate and any adverse events reported by the patients were recorded at 2-week intervals during the 6 weeks' combined treatment period. Blood pressure was determined with a random-zero sphygmomanometer by a blinded observer who, on each occasion, made two consecutive readings of supine blood pressure followed by a single reading of standing blood pressure; diastolic blood pressure was recorded at the disappearance of the fifth Korotkoff sound. At the end of the 6 weeks' combined treatment period, both the physicians and the patients assessed the efficacy of the treatment, and the physicians also assessed any adverse events that occurred. Full laboratory investigations (haematology and clinical chemistry) were performed at the beginning and end of the trial and, in addition, 12-lead electrocardiogram recordings were made at the beginning of the run-in period and repeated at the final visit on completion of 6 weeks' combined treatment.
RESULTS The distribution of supine diastolic blood pressure at entry was significantly (P < 0.001) different in the two treatment groups (Table 1). Baseline mean blood pressure measurements obtained from patients in the nicardi pinel HCTZ treatment group were statistically significantly (P < 0.05) higher than measurements from patients in the pindolol/HCTZ group. In other respects, however, the two treatment groups were comparable.
EFFICACY Patients were excluded from efficacy analysis because of protocol violations or premature withdrawals: in the nicardipine/HCTZ treatment group one patient because of a diuretic-related problem and one because of a study drug-related adverse event; in the pindolol/HCTZ treatment group one patient because of conjunctivitis and one because of a study drug-related adverse event. Of the 29 patients included in the efficacy analysis, 15 were in the nicardipine treatment group and 14 in the pindolol treatment group. The characteristics of these patients are summarized in Table 1. Supine and standing mean diastolic and systolic blood pressures at baseline and at the end of the 6-week treatment period are shown in Tables 2 and 3, respectively. Except for standing diastolic blood pressure for the pindolol/HCTZ treatment group, both of the second-line treatments produced significant reductions in systolic and diastolic blood pressures compared with baseline values. The reduction in mean supine diastolic pressure produced by nicardipine/HCTZ was significantly (P = 0.02) greater than that produced by pindolol/HCTZ, i.e. 15.1mmHg versus 5.7
STATISTICAL ANALYSIS Blood pressure and pulse rate were analysed at baseline and the change from baseline to endpoint was analysed using a two-way analysis of variance model that included the effects of treatment, investigator and treatment by investigator interaction. In addition, to account for the significant difference in baseline blood pressures and pulse rates in patients in the two treatment groups, an analysis of covariance was performed with the baseline value as the covariate and including the effects of treatment, investigator and treatment by
220
Demographic data for 29 patients with essential hypertension ineffectively controlled with 50 mg/day hydrochlorothiazide (HCTZ) and suosequentty treated with 50 mg/day HCTZ plus either 30 mg nicardipine hydrochloride three times daily or 5 mg pindolol three times daily for 6 weeks
Characteristic
Nicardipine treatment group
Pindolol treatment group
P-value a
No. of patients 10
7
Female
5
7
Prior antihypertensive treatment
6
7
0.28
Tobacco smokers
4
1
0.78
90 - < 100
6
9
100 - < 110
6
4
2 110
3
1
Male
0.28
Baseline supine diastolic pressure (mmHg)
< 0.01
Age (years) Median
46
46
Range
30- 64
37 - 63
83
80
0.89
Body weight (kg) Median Median history of hypertension (years)
5.8
2.3
0.36 0.12
Baseline mean (± SD) blood pressure (rnrnl-lq)> Supine
163 ± 14/ 104 ± 8
145 ± 14/ 97 ± 7
0.003/0.02
Standing
158 ± 16/ 109 ± 10
138 ± 15/ 101 ± 9
0.003/0.04
aBetween-treatment P-values are from analysis of variance or Grizzle - Starmer - Koch weighted least squares analysis of treatment, investigator and treatment by investigator effects. bEstimated means, are least squares means from analysis of variance.
221
Mean (:r SO) diastolic blood pressure measurements for 29 patients with essential hypertension ineffectively controlled with 50 mg/day hydrochlorothiazide (HCTZ) and subsequently treated with 50 mglday HCTZ plus either 30 mg nicardipine hydrochloride or 5 mg pindolol three times daily for 6 weeks
Blood pressure (mmHg) Treatment
Baseline
After treatment"
P-valueb
P-value c
Supine Nicardipine/HCTZ Pindoiol/HCTZ
104.2 ± 8 97.0 ± 7
89.1 ± 10 91.3 ± 10
0.0001 0.04
0.02
Standing . Nicardipine/HCTZ Pindoiol/HCTZ
108.6 ± 10 100.9 ± 9
95.1 ± 15 99.2±15
0.04 0.29
0.04
aMeans of analysis of variance without adjustment for baseline. P-values for change from baseline from analysis of covariance considering effects oftreatment, investigator and their interaction with the baseline value used as a covariate.
b
cP-value between treatments.
patients and 'fair' in two (14.3%) patients. The overall efficacy of pindolol was rated by the physicians as 'very good' in 8/13 (61.5%) patients, 'fair' in three (23.1 %) patients and 'poor' in two (15.4%) patients. The overall efficacy ofnicardipine was rated as 'very good' by 10 (71.4%) patients, 'good' by two (14.3%) patients and 'fair' by two (14.3%) patients. The overall efficacy of pindolol was rated as 'very good' by seven (53.9%) patients, 'good' by five (38.5%) patients and 'poor' by the remaining one (7.7%) patient. Overall twoway analysis of variance showed that the differences in the distribution of the responses attributable to treatment were not statistically significant.
mmHg, respectively. For standing diastolic blood pressure, the corresponding reductions were 13.5 mmHg for nicardipine/HCTZ and only 1.7 mmHg for pindolol/HCTZ (P = 0.04). The difference in baseline blood pressures was so great that the post-treatment blood pressures in the two groups were very similar (standing diastolic blood pressure 95.1 mmHg for nicardipine/HCTZ-treated patients versus 99.2 mmHg for pindolol/HCTZ-treated patients). The blood pressure changes in both treatment groups, adjusted for the differing baseline values, are shown in Figs 1 and 2;the differences between treatment groups were not significant after this adjustment had been made. Almost all of the patients responded well to the study medications. The physicians rated nicardipine's overall efficacy as 'very good' in 8/14 (57.1 %) patients, 'good' in four (28.6%)
ADVERSE EVENTS As might have been expected from the
222
TASLE3 Mean (± SO) systolic blood pressure measurements for 29 patients with essential hypertension ineffectively controUed with 50 mg/day hydrochlorothiazide (HCTZ) and subsequently treated with 50 mg/day HCTZplus either 30 mg nicardipine hydrochloride or 5 mg pindolol three times daily for 6 weeks
Blood pressure After treatment"
P·value b
P-valuec
163.2 ± 14 145.2 ± 14
143.1 ± 14 134.4 ± 14
0.001 0.001
0.09
157.8 ± 16 138.2 ± 15
139.8 ± 18 132.8 ± 18
0.04 0.03
0.08
Treatment
Baseline
Supine Nicardipine/HCTZ Pindolol/HCTZ Standing Nicardipine/HCTZ Pindolol/HCTZ
"Means of analysis of variance without adjustment for baseline. b P-values for change from baseline from analysis of covariance considering effects oftreatment, investigator and their interaction with the baseline value used as a covariate. cP-value between treatments.
events during treatment with nicardipine/ HCTZ. Of these events, nine were familiar calcium antagonist effects: tachycardia/ palpitations in five patients; flushing in three patients; and oedema in one patient. The other 13 adverse events were dry mouth in two patients and angina pectoris, dry mouth, dizziness, hyperkinesia, paraesthesia, sweating, vertigo, gastro-intestinal pain, vomiting, increased coughing, an upper respiratory infection and eczema in one patient each. A total of 10 patients in the pindolol/HCTZ treatment group reported 21 adverse events. Among these were familiar 13-blocker effects: vivid dreams occured in three patients; and tiredness in three patients. The other 15 adverse events were hypotension, dizziness, increased sweating, central nervous system disorders
pharmacological profiles of nicardipine and pindolol, mean pulse rate increased slightly, but not significantly, during treatment with nicardipine/HCTZ from 75.2 beats/min to 80.7 beats/min and fell significantly (P = 0.0001) during treatment with pindolol from 83.4 beats/min to 72.2 beats/min. During treatment with HCTZ alone, there were only three reports of a drug-related adverse event - headache on each occasion. The incidence of adverse events was considerably higher during the second-line combined treatments than during the run-in period with HCTZ alone: 14% during the HCTZ treatment period versus 45% during either nicardipine/ HCTZ or pindolol/HCTZ treatment. Most of the reported adverse events could be directly related to nicardipine and pindolol. A total of 12 patients reported 22 adverse
223
0 OJ
.s
- -& -
Pindolol/HCTZ
--a--
Nicardipine/HCTZ
-2
Qi Ul
