British JouInal of Urology (1992), 70, Suppl 1,22-26 0 1992 British Journal of Urology
Use of Terazosin in the Medical Treatment of Benign Prostatic Hyperplasia: Experience in Italy F. DI SILVER10 Department of Urology, University of Rome- La Sapienza, Rome, Italy
Summary-The purpose of this multicentre, randomised, placebo-controlled, double-blind study was to verify the safety and efficacy of terazosin, an alpha, adrenergic blocker, in patients with benign prostatic hyperplasia (BPH). This study involved 137 patients who were randomly assigned to receive either a designed dose of terazosin (2,5or 10 mg) or placebo. Response to treatment was measured objectively by uroflowmetric determinations. Subjective evaluation was based o n the investigator's assessment of each patient's symptoms. The safety of this agent was monitored by haematological tests and urinalysis. In addition, systolic and diastolic blood pressures and pulse rates were recorded during each visit. The treatment of BPH with terazosin produced a significant improvement in mean flow rate and peak flow rate; there were no statistically significant differences in the analysis of symptomatic responses between the groups of patients treated with terazosin or placebo). Moreover, the safety of this alpha, blocker was thoroughly tested and clinically proven.
The clinical symptoms associated with benign prostatic hyperplasia (BPH) result from a combination of dynamic and mechanical obstructive components. The dynamic component involves smooth muscle tone in the prostatic urethra and capsule and its effect on infravesical resistance (Bartsch et al., 1983; Berry et al., 1984). The mechanical component is the physical presence of an enlarged mass of prostatic tissue. The smooth muscle tone is dependent on the activation of alpha-adrenergic receptors, which are found in the bladder neck, prostatic urethra and prostatic capsule. These receptors are predominantly the alpha, type. The binding and functional properties of these adrenoceptors were studied in men with symptomatic BPH to clarify their role in the development of human prostatic disease. Moreover, Caine (1984; 1986a; 1986b) demonstrated a permanent stimulation of these receptors in BPH. The pharmacological rationale for treating BPH with alpha-adrenergic blockers is based on the finding that alpha-adrenergic blockers relax the dynamic component. Double-blind studies have shown that both phenoxybenzamine (a non-selective alpha, and alpha, blocking agent) (Brooks et
22
al., 1983; Griffiths and Schroder, 1984; Ferrie and Paterson, 1987) and prazosin (an alpha-selective blocking agent) (Hedlund et al., 1983; Stanaszek et al, 1983) significantly improved the obstructive symptoms of BPH. Phenoxybenzamine has been associated with significant toxicity; prazosin appears to be equally effective but associated with only few side effects. Terazosin is an alpha, adrenergic blocking agent, structurally similar to prazosin, with antihypertensive activity. Animal studies have suggested that terazosin exerts its antihypertensive effect by producing peripheral vasodilation via a blockade of alpha, adrenergic receptors (Lepor et al., 1988). The advantages of terazosin are its effectiveness achieved with only once-daily dosing and its selective alpha, antagonist activity. Laboratory assessments have demonstrated that this drug completely antagonises phenylephrine-induced contractions in the human prostate (Lepor et al., 1988). To determine the safety and efficacy of terazosin in the treatment of symptomatic BPH, a multicentre, randomised, placebo-controlled, doubleblind, parallel study was performed.
23
TERAZOSIN IN TREATMENT OF BPH: EXPERIENCE IN ITALY
Patients and Methods
visit (every 2 weeks). Tests included measurement of peak and average flow rates. Residual urine The study was conducted in two phases: (1) a 4- volumes were also determined by catheterisation. week, single-blind, placebo lead-in period, and (2) a For the patient to be enrolled in the study, peak 2-month, double-blind treatment period. The pla- flow rate had to be < 12 ml/s and the voided volume cebo lead-in period allowed us to perform baseline had to be at least 100 ml. measurements and to identify patients who were Objective evaluation of response was based on suitable for the study. The double-blind, placebo- changes in the urine flow rate over baseline. controlled phase of the study allowed us to evaluate Subjective evaluation of response was based on the the safety and efficacy of terazosin in the treatment investigator’s global assessment of each patient’s of BPH with objective and subjective parameters. symptoms. Symptoms were assessed with the use of At the end of the placebo lead-in period, patients methods recommended by the Food and Drug were randomly assigned to receive either a desig- Administration (FDA) ; these methods were also nated dose of terazosin (2, 5 or 10 mg) or placebo delineated by Boyarsky et al. (1977). for the duration of the study. The safety of the treatment was monitored by Patients randomised to the terazosin group haematological tests and urinalysis. In addition, received ,an initial dose of 1 mg of the drug for the systolic and diastolic blood pressures and pulse first day only. The patients then took a 2 mg tablet rates were recorded during each visit. daily for the next 13 days. Patients randomised to the 2mg dosage remained at this level for the Statistical plan remaining 6 weeks. Patients randomised to the The efficacy of treatment was evaluated by statisti5 mg and 10 mg groups received 5 mg daily for the cal procedures. Peak and average urinary flow rates next 2 weeks. Then, the first group continued the were the primary efficacy variables. Changes in 5 mg dose for the remaining 4 weeks, while the peak and average urinary flow rates from baseline second group changed to a dose of 10 mg. in the 3 groups of patients receiving terazosin were On the basis of a medical history, a physical compared with rates in the placebo group by the examination (which included digital palpation of use of Dunnett’s t test with a significance level of the prostate), uroflowmetric determinations and P=0.05. The 3 groups receiving terazosin were also an ultrasonic measurement of prostatic size, 137 compared with the placebo group by the use of the patients with BPH were randomised to receive least squares means at the 5Xlevel. Changes in treatment. The patients were required to be residual urine volume from baseline to the end of normotensive, not taking any antihypertensive treatment were similarly analysed. Safety was medications, and to have a sitting diastolic blood evaluated by blood pressure measurements, pulse pressure < 1 15 mm Hg. The demographic data for rates, laboratory test results and the patients’ rethe patients entered into screening are summarised ports of adverse events. in Table 1. Table 1 Age (year) Distribution of Efficacy-Evaluable Randomised Patients Receiving Terazosin versus Placebo
2mg
5mg
lOmg
A total of 162 patients were enrolled in the study during the screening visit. Of these, 25 (15%) were not randomised to receive treatment; therefore, they are not included in the analyses of safety and efficacy in Table 2.
63.2 45 77
63.4 47 78
60.8 45 80
Table 2 Distribution and Evaluability Status of 137 Randomised Patients Enrolled During Screening Visit
Terazosin Placebo
Mean 63.6 Minimum 46 Maximum 79
Results
Screening examinations of the prostate by digital palpation showed that the majority of patients had moderately enlarged prostates, with no differences between the randomised treatment groups. The response to treatment was measured objectively by uroflowmetric determinations during each
Treatment group
No. No. (%)evaluable No. not randomised for eficacy evaluable
Placebo Terazosin, 2 mg Terazosin, 5 mg Terazosin, 10 mg
35 34 36 32
32 (91) 32 (94) 34 (94) 30 (94)
3 2 2 2
24
BRITISH JOURNAL OF UROLOGY
Peakflow rate At baseline, there was no statistically significant difference in mean peak flow rate between the treatment groups. The mean peak flow rates at baseline (V3) and the final visit (V7), and the mean change from baseline are summarised in Table 3. An analysis of the mean change from baseline showed no differences between the treatment groups overall (P = 0.068, F test). Table 3
Summary of Uncorrected Mean Peak Flow Rates (ml/s) for Efficacy-Evaluable Patients at Baseline (V3) a n d Final Visit (V7), a n d Mean Change from Baseline
Treatment group
V3
V7
Mean change
Mean change (%)
Placebo Terazosin, 2 mg Terazosin, 5 mg Terazosin, 10 mg
8.8 8.8 8.3 8.4
10.0 11.1 11.2 10.8
1.2 2.4 2.9 2.4
16.6 32.5 39.4 32.2
There was a significant difference in the least squares means (at the 5% level without adjustment for multiple testing) between placebo and 5mg terazosin (P=0.012, t test). There was no evidence of a difference between the treatments in percentage change from baseline (P = 0.1 10, F test). There was a significant difference in the least squares means between placebo and 5 mg terazosin. The percentage change in the placebo group was higher than would be expected (17%), and although the percentage change in the terazosin groups was twice that seen in the placebo group (ie.,3473, there was no statistically significant difference between them.
The change from baseline to final visit was significantly different between treatments (P= 0.042, F test), and Dunnett’s t test showed a significant difference between placebo and 10 mg terazosin (P
Use of Terazosin in the Medical Treatment of Benign Prostatic Hyperplasia: Experience in Italy F. DI SILVER10 Department of Urology, University of Rome- La Sapienza, Rome, Italy
Summary-The purpose of this multicentre, randomised, placebo-controlled, double-blind study was to verify the safety and efficacy of terazosin, an alpha, adrenergic blocker, in patients with benign prostatic hyperplasia (BPH). This study involved 137 patients who were randomly assigned to receive either a designed dose of terazosin (2,5or 10 mg) or placebo. Response to treatment was measured objectively by uroflowmetric determinations. Subjective evaluation was based o n the investigator's assessment of each patient's symptoms. The safety of this agent was monitored by haematological tests and urinalysis. In addition, systolic and diastolic blood pressures and pulse rates were recorded during each visit. The treatment of BPH with terazosin produced a significant improvement in mean flow rate and peak flow rate; there were no statistically significant differences in the analysis of symptomatic responses between the groups of patients treated with terazosin or placebo). Moreover, the safety of this alpha, blocker was thoroughly tested and clinically proven.
The clinical symptoms associated with benign prostatic hyperplasia (BPH) result from a combination of dynamic and mechanical obstructive components. The dynamic component involves smooth muscle tone in the prostatic urethra and capsule and its effect on infravesical resistance (Bartsch et al., 1983; Berry et al., 1984). The mechanical component is the physical presence of an enlarged mass of prostatic tissue. The smooth muscle tone is dependent on the activation of alpha-adrenergic receptors, which are found in the bladder neck, prostatic urethra and prostatic capsule. These receptors are predominantly the alpha, type. The binding and functional properties of these adrenoceptors were studied in men with symptomatic BPH to clarify their role in the development of human prostatic disease. Moreover, Caine (1984; 1986a; 1986b) demonstrated a permanent stimulation of these receptors in BPH. The pharmacological rationale for treating BPH with alpha-adrenergic blockers is based on the finding that alpha-adrenergic blockers relax the dynamic component. Double-blind studies have shown that both phenoxybenzamine (a non-selective alpha, and alpha, blocking agent) (Brooks et
22
al., 1983; Griffiths and Schroder, 1984; Ferrie and Paterson, 1987) and prazosin (an alpha-selective blocking agent) (Hedlund et al., 1983; Stanaszek et al, 1983) significantly improved the obstructive symptoms of BPH. Phenoxybenzamine has been associated with significant toxicity; prazosin appears to be equally effective but associated with only few side effects. Terazosin is an alpha, adrenergic blocking agent, structurally similar to prazosin, with antihypertensive activity. Animal studies have suggested that terazosin exerts its antihypertensive effect by producing peripheral vasodilation via a blockade of alpha, adrenergic receptors (Lepor et al., 1988). The advantages of terazosin are its effectiveness achieved with only once-daily dosing and its selective alpha, antagonist activity. Laboratory assessments have demonstrated that this drug completely antagonises phenylephrine-induced contractions in the human prostate (Lepor et al., 1988). To determine the safety and efficacy of terazosin in the treatment of symptomatic BPH, a multicentre, randomised, placebo-controlled, doubleblind, parallel study was performed.
23
TERAZOSIN IN TREATMENT OF BPH: EXPERIENCE IN ITALY
Patients and Methods
visit (every 2 weeks). Tests included measurement of peak and average flow rates. Residual urine The study was conducted in two phases: (1) a 4- volumes were also determined by catheterisation. week, single-blind, placebo lead-in period, and (2) a For the patient to be enrolled in the study, peak 2-month, double-blind treatment period. The pla- flow rate had to be < 12 ml/s and the voided volume cebo lead-in period allowed us to perform baseline had to be at least 100 ml. measurements and to identify patients who were Objective evaluation of response was based on suitable for the study. The double-blind, placebo- changes in the urine flow rate over baseline. controlled phase of the study allowed us to evaluate Subjective evaluation of response was based on the the safety and efficacy of terazosin in the treatment investigator’s global assessment of each patient’s of BPH with objective and subjective parameters. symptoms. Symptoms were assessed with the use of At the end of the placebo lead-in period, patients methods recommended by the Food and Drug were randomly assigned to receive either a desig- Administration (FDA) ; these methods were also nated dose of terazosin (2, 5 or 10 mg) or placebo delineated by Boyarsky et al. (1977). for the duration of the study. The safety of the treatment was monitored by Patients randomised to the terazosin group haematological tests and urinalysis. In addition, received ,an initial dose of 1 mg of the drug for the systolic and diastolic blood pressures and pulse first day only. The patients then took a 2 mg tablet rates were recorded during each visit. daily for the next 13 days. Patients randomised to the 2mg dosage remained at this level for the Statistical plan remaining 6 weeks. Patients randomised to the The efficacy of treatment was evaluated by statisti5 mg and 10 mg groups received 5 mg daily for the cal procedures. Peak and average urinary flow rates next 2 weeks. Then, the first group continued the were the primary efficacy variables. Changes in 5 mg dose for the remaining 4 weeks, while the peak and average urinary flow rates from baseline second group changed to a dose of 10 mg. in the 3 groups of patients receiving terazosin were On the basis of a medical history, a physical compared with rates in the placebo group by the examination (which included digital palpation of use of Dunnett’s t test with a significance level of the prostate), uroflowmetric determinations and P=0.05. The 3 groups receiving terazosin were also an ultrasonic measurement of prostatic size, 137 compared with the placebo group by the use of the patients with BPH were randomised to receive least squares means at the 5Xlevel. Changes in treatment. The patients were required to be residual urine volume from baseline to the end of normotensive, not taking any antihypertensive treatment were similarly analysed. Safety was medications, and to have a sitting diastolic blood evaluated by blood pressure measurements, pulse pressure < 1 15 mm Hg. The demographic data for rates, laboratory test results and the patients’ rethe patients entered into screening are summarised ports of adverse events. in Table 1. Table 1 Age (year) Distribution of Efficacy-Evaluable Randomised Patients Receiving Terazosin versus Placebo
2mg
5mg
lOmg
A total of 162 patients were enrolled in the study during the screening visit. Of these, 25 (15%) were not randomised to receive treatment; therefore, they are not included in the analyses of safety and efficacy in Table 2.
63.2 45 77
63.4 47 78
60.8 45 80
Table 2 Distribution and Evaluability Status of 137 Randomised Patients Enrolled During Screening Visit
Terazosin Placebo
Mean 63.6 Minimum 46 Maximum 79
Results
Screening examinations of the prostate by digital palpation showed that the majority of patients had moderately enlarged prostates, with no differences between the randomised treatment groups. The response to treatment was measured objectively by uroflowmetric determinations during each
Treatment group
No. No. (%)evaluable No. not randomised for eficacy evaluable
Placebo Terazosin, 2 mg Terazosin, 5 mg Terazosin, 10 mg
35 34 36 32
32 (91) 32 (94) 34 (94) 30 (94)
3 2 2 2
24
BRITISH JOURNAL OF UROLOGY
Peakflow rate At baseline, there was no statistically significant difference in mean peak flow rate between the treatment groups. The mean peak flow rates at baseline (V3) and the final visit (V7), and the mean change from baseline are summarised in Table 3. An analysis of the mean change from baseline showed no differences between the treatment groups overall (P = 0.068, F test). Table 3
Summary of Uncorrected Mean Peak Flow Rates (ml/s) for Efficacy-Evaluable Patients at Baseline (V3) a n d Final Visit (V7), a n d Mean Change from Baseline
Treatment group
V3
V7
Mean change
Mean change (%)
Placebo Terazosin, 2 mg Terazosin, 5 mg Terazosin, 10 mg
8.8 8.8 8.3 8.4
10.0 11.1 11.2 10.8
1.2 2.4 2.9 2.4
16.6 32.5 39.4 32.2
There was a significant difference in the least squares means (at the 5% level without adjustment for multiple testing) between placebo and 5mg terazosin (P=0.012, t test). There was no evidence of a difference between the treatments in percentage change from baseline (P = 0.1 10, F test). There was a significant difference in the least squares means between placebo and 5 mg terazosin. The percentage change in the placebo group was higher than would be expected (17%), and although the percentage change in the terazosin groups was twice that seen in the placebo group (ie.,3473, there was no statistically significant difference between them.
The change from baseline to final visit was significantly different between treatments (P= 0.042, F test), and Dunnett’s t test showed a significant difference between placebo and 10 mg terazosin (P
