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Keywords:

  • BPH;
  • α-blocker;
  • alfuzosin;
  • pooled analysis;
  • randomized controlled trial

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

OBJECTIVES

To examine the efficacy and safety of a once-daily formulation of alfuzosin in a pooled analysis of three parallel, randomized, double-blind, placebo-controlled 3-month studies of patients with lower urinary tract symptoms (LUTS) consistent with clinical benign prostatic hyperplasia.

PATIENTS AND METHODS

Patients were randomized to receive alfuzosin, 10 mg once-daily (473) or placebo (482) for 12 weeks. Primary efficacy criteria were improvements in the International Prostate Symptom Score (IPSS) and peak urinary flow rate (PFR).

RESULTS

Alfuzosin significantly improved the mean (sd) IPSS, by − 6.0 (5.1) vs − 4.2 (5.7) with placebo (P < 0.005) and the PFR, by + 2.3 (3.8) vs + 1.1 (3.1) ml/s with placebo (P < 0.001), irrespective of prostate size. The significant improvement in LUTS included the irritative and the obstructive subscore of the IPSS and the nocturia criterion; the PFR increased rapidly and significantly, from the first visit (14 days). The quality-of-life score also improved significantly in alfuzosin-treated patients. Alfuzosin was well tolerated; the number of withdrawals for adverse events was comparable in both treatment groups. The most frequently reported adverse event was dizziness (placebo 2.9%, alfuzosin 6.1%). There were no significant changes in blood pressure with alfuzosin compared with placebo, including in elderly and hypertensive patients. Sexual adverse events were rare (abnormal ejaculation, 0.6%).

CONCLUSIONS

The once-daily formulation of alfuzosin, administered at 10 mg with no dose titration is effective, with a good safety profile, especially in elderly and hypertensive patients.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Worldwide, α1-blockers are recommended for the treatment of BPH by clinical guidelines [1]. Doxazosin and terazosin have traditionally been used in the management of BPH but these agents are primarily antihypertensive, and are associated with significant changes in blood pressure and an increased incidence of postural symptoms [2]. Newer α-blockers, e.g. tamsulosin and alfuzosin (a quinazoline derivative), are as effective as classical α-blockers at relieving the symptoms of BPH, but have an improved cardiovascular tolerability [2,3], and are thus prescribed with no initial dose titration.

Alfuzosin is marketed exclusively for the treatment of LUTS and clinical BPH. Two bio-equivalent formulations were previously available, a standard immediate-release form (2.5 mg, three times daily) and a sustained-release form (5 mg, twice daily). The efficacy and safety of both have been confirmed in well-designed placebo-controlled studies [4,5]. Alfuzosin acts from the first dose, maintains symptom relief for up to 3 years and its good safety profile on cardiovascular function and sexual function has been established [4,6–9]. A once-daily formulation has been recently developed to improve patient convenience and provide an optimal coverage of the dosing interval with no major plasma concentration fluctuations [10].

We report the pooled efficacy and safety results from three parallel studies with nearly identical protocols of alfuzosin 10 mg once-daily vs placebo for a 3-month treatment. The pooled analysis permits stratification of clinical trial data by patient age, hypertensive status and prostate size.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Three studies with similar design, inclusion and exclusion criteria were conducted with alfuzosin 10 mg once-daily in North America and Europe; two of the studies were reported previously [11,12]. All studies consisted of a 1-month placebo run-in phase and a 3-month, randomized, double-blind, placebo-controlled phase followed by an open-label extension period for up to 24 months. In study 1, inclusion criteria had to be met at both the screening (28 days) and inclusion (0 day) visits. In study 2 and 3, inclusion criteria had to be met exclusively at 28 days; patients did not have to re-qualify at the time of randomization. All patients provided written informed consent, and the study protocols were approved by the ethics committee of participating countries and/or institutions.

Patient selection

This pooled analysis focused on patients taking alfuzosin 10 mg or placebo in the three studies, including men aged > 50 years with a history of LUTS consistent with clinical BPH for ≥ 6 months and who had an IPSS of ≥ 13 points, a peak urinary flow rate (PFR) of 5–12 mL/s (with a voided volume of ≥ 150 mL), a residual urine volume of ≤ 350 mL, and a bother score (IPSS question 8) of ≥ 3 points at both the initial and 28-day visits. No threshold level for prostate size was specified.

Men with previous prostate surgery, a history of postural hypotension or syncope, concomitant use of medications that might alter voiding pattern, and clinically relevant biochemical abnormalities (aspartate or alanine aminotransferases more than twice the upper limit of normal range, blood creatine ≥ 150 µmol/L, PSA > 10 ng/mL) were excluded from the study. Patients with a serum PSA of 4–10 ng/mL had to have prostate cancer excluded to the satisfaction of the investigator. Men treated with α1-blockers in the month preceding the study or androgens, antiandrogens, 5α-reductase inhibitors and LHRH analogues in the 3 months before the study were also excluded.

Any improvement in LUTS and quality of life (QoL) were assessed 28 days before, 0 and at 28, 56 and 84 days of treatment using the IPSS and the bother question. Uroflowmetry curves were assessed (Dantec Urodyn 1000, Denmark) at 28 days before, and at 0, 14, 28, 56 and 84 days. The PFR was determined by a central interpreter unaware of origin and applying the 2-s rule. Prostate size was measured by TRUS using a standardized protocol and the volume formula for an ellipsoid. Cardiovascular safety was evaluated by monitoring systolic and diastolic blood pressures with the patient supine and after 5 min upright. Any adverse events spontaneously reported by the patient or observed by the investigator during clinical examination were recorded. Routine blood and chemistry tests were performed before inclusion and at the end of the trial.

Statistical analysis

Data were analysed for the intention-to-treat population that included all randomized patients receiving at least one dose of the study drug and having at least one IPSS after the baseline evaluation. Repeated-measures analysis using the ‘last observation carried forward’ method was also used. The two primary efficacy variables, IPSS and PFR, were analysed using Student's t-test. Any qualitative improvement in the bother score was analysed using the chi-square or Fisher's exact test. Safety was analysed on the exposed population (patients who received at least one dose of medication during the study). Adverse events and cardiovascular variables were described in the overall population, in elderly (≥ 65 years) and hypertensive patients (i.e. those with a history of hypertension at baseline).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

In the three studies, 955 patients with BPH were randomized to receive alfuzosin (473) or placebo (482) for 84 days. At baseline, the clinical characteristics of the patients were comparable in both treatment groups (Table 1).

Table 1.  The baseline demographics and clinical characteristics, with the change from baseline to study end (84 days) in the IPSS and subscores, PFR and QoL index in patients receiving alfuzosin or placebo
VariablePlaceboAlfuzosin
Mean (range) age, years  63.7 (49–85)  64.6 (49–92)
≥  65 years, n (%)270 (56)246 (52)
< 65 years, n (%)212 (44)226 (48)
Mean (range):
duration of LUTS, months  55.8 (6–341)  54.1 (5–360)
prostatic volume, mL  36.8 (15–90)  36.8 (10–110)
Hypertensive, n (%)
Yes142 (29.5)132 (27.9)
No340 (70.5)341 (72.1)
Mean (range) IPSS  17.9 (2–33)  17.8 (4–27)
Mild, n (%)  13 (2.7)    7 (1.5)
Moderate, n (%)306 (63.5)309 (65.5)
Severe, n (%)163 (33.8)156 (33.1)
Mean (range)
PFR, mL/s    9.6 (2–31)    9.6 (4–27)
QoL index    3.5 (1–6)    3.6 (1–6)
Outcome at 84 days, mean (sd):
IPSS
Baseline  18.8 (4.4)  18.7 (4.6)
Endpoint  14.6 (6.8)  12.7 (6.1)
Absolute change −  4.2 (5.7) −  6.0 (5.1)
P vs placebo< 0.001
Irritative subscore
Baseline    7.7 (2.5)    7.9 (2.8)
Endpoint    6.1 (3.0)    5.6 (2.8)
Absolute change −  1.6 (2.7) −  2.3 (2.8)
P vs placebo< 0.001
Obstructive subscore
Baseline  11.1 (3.2)  10.9 (3.5)
Endpoint    8.2 (4.5)    7.1 (4.1)
Absolute change −  2.9 (3.9) −  3.8 (3.7)
P vs placebo< 0.001
Nocturia criterion
Baseline    3.4 (0.7)    3.6 (0.8)
Endpoint    2.6 (1.0)    2.5 (1.1)
Absolute change −  0.8 (1.0) −  1.1 (1.0)
P vs placebo    0.04
PFR, mL/s
Baseline    8.8 (1.9)    8.8 (1.9)
Endpoint    9.9 (3.1)   11.2 (4.0)
Absolute change    1.1 (3.1)    2.3 (3.8)
P vs placebo< 0.001
Bother score (QoL)
Baseline    3.6 (1.0)    3.6 (1.0)
Endpoint    2.9 (1.3)    2.6 (1.2)
Absolute change −  0.7 (1.1) −  1.0 (1.1)
P vs placebo< 0.001

Efficacy

Improvements in the IPSS were significantly greater in the alfuzosin than in the placebo group at all visits (Fig. 1A and Table 1). Improvements in the IPSS in the alfuzosin group were unrelated to prostate size at baseline, with mean (sd) values for < 30 mL of − 5.4 (5.2), 30–40 mL, − 5.6 (5.1) and > 40 mL, − 5.7 (4.9). The percentage of patients with an improvement of ≥ 3 points in the IPSS was significantly greater among patients receiving alfuzosin (76%) than placebo (61.5%, P < 0.001).

imageimageimage

Figure 1. The mean (95% CI) change from baseline in patients receiving alfuzosin (red squares) or placebo (green circles) in: A, the overall IPSS at 28, 56 and 84 days of treatment; B, PFR at 14, 28, 56 and 84 days of treatment; C, the irritative (a), obstructive (b) and nocturia (c) subscores at 28, 56 and 84 days of treatment.

Both irritative and obstructive symptoms were significantly improved in patients receiving alfuzosin than placebo (Table 1 and Fig. 1C). Alfuzosin was also associated with a significant improvement in the nocturia criterion, at − 1.1 (1.0), vs placebo, at − 0.8 (1.0) (P = 0.04; Table 1 and Fig. 1Cc).

The PFR was significantly greater (P < 0.005) in the alfuzosin than in the placebo group at 14, 28 and 84 days. (Table 1 and Fig. 1B). As with the changes in IPSS, the improvements in PFR associated with alfuzosin were unrelated to prostate size at baseline, at 1.8 (3.5), 1.7 (3.9) and 1.9 (3.7) mL/s, respectively, for the three groups.

The bother score was significantly improved from baseline to the endpoint in alfuzosin-treated patients when compared with placebo, at − 1.0 vs. − 0.7 (P < 0.001; Table 1).

Safety

Alfuzosin was well tolerated; the number of study withdrawals was similar in both treatment groups (placebo, 42, 8.7%; alfuzosin 45, 9.5%). Of all patients, 41.6% and 35.9% experienced at least one adverse event in the alfuzosin and placebo groups, respectively. There was no first-dose effect compared with placebo. Dizziness was the most commonly reported adverse event (Table 2), and asthenia/fatigue was similarly reported in both treatment groups. Two patients (0.4%) experienced hypotension and one (0.2%) syncope with alfuzosin, compared with none in the placebo group. Alfuzosin was also well tolerated in frail patients; the proportion of patients experiencing adverse events potentially related to vasodilatation (i.e. dizziness, hypotension, malaise/syncope) was comparable in elderly (15/226, 6.6%) and younger patients (14/246, 5.7%); the results were similar with hypertensive (11/132, 8.3%) and normotensive patients (18/341, 5.3%).

Table 2.  Treatment-emergent adverse events (≥ 1%) of the exposed population
Adverse event, n (%)PlaceboAlfuzosin
Dizziness14 (2.9)25 (5.3)
Respiratory tract infection  4 (0.8)14 (3.0)
Headache10 (2.1)14 (3.0)
Asthenia/fatigue11 (2.2)13 (2.7)
Influenza-like symptoms12 (2.5)  9 (1.9)
Pain  4 (0.8)  7 (1.5)
Bronchitis  3 (0.6)  7 (1.5)
Sinusitis  7 (1.5)  7 (1.5)
Rhinitis  9 (1.9)  7 (1.5)
Impotence  3 (0.6)  7 (1.5)
Back pain  7 (1.5)  6 (1.3)
Inflicted injury  2 (0.4)  6 (1.3)
Pharyngitis  2 (0.4)  5 (1.1)
Arthralgia  6 (1.2)  4 (0.8)
Diarrhoea10 (2.1)  3 (0.6)
Hypertension  6 (1.2)  2 (0.4)
UTI  7 (1.5)  2 (0.4)

Sexual adverse events were rare with alfuzosin (impotence, 1.5%; ejaculation failure, 0.6%) and with placebo (impotence, 0.6%). Lastly, two patients had acute urinary retention in the placebo group (0.4%), compared with none in the alfuzosin group. There were no statistically significant changes in blood pressure with alfuzosin or placebo, including in elderly and hypertensive patients (Table 3). In particular, the percentage of patients with an asymptomatic orthostatic hypotension defined by a decrease in systolic blood pressure of ≥ 20 mmHg when standing was comparable in both treatment groups.

Table 3.  The initial value and change in blood pressure (BP) in the whole population, and categorized as elderly (≥ 65 years) or hypertensive
GroupNMean (sd) BP, mmHgNo. with AOH*
SystolicDiastolic
  • *

    asymptomatic orthostatic hypotension, i.e. an asymptomatic decrease in systolic blood pressure of ≥ 20 mmHg when changing to upright.

Overall
Placebo478137.7 (16.9)  82.6 (9.6)  8 (1.7)
Δ   −  1.3 (14.7) −  2.0 (10.0) 
Alfuzosin469136.3 (16.5)  81.9 (9.8)10 (2.1)
Δ   −  2.1 (14.7) −  0.9 (8.7) 
Elderly
Placebo209142.0 (16.9)  82.7 (9.4)  2 (1.0)
Δ   −  1.7 (15.1) −  0.2 (9.0) 
Alfuzosin224138.2 (16.7)  81.4 (9.9)  5 (2.2)
Δ   −  1.3 (15.3) −  1.4 (10.0) 
Hypertensive
Placebo141147.2 (18.1)  87.6 (10.7)  5 (3.5)
Δ   −  2.6 (17.0) −  1.8 (9.1) 
Alfuzosin130142.7 (15.8)  85.5 (9.7)  1 (0.8)
Δ   −  2.1 (17.6) −  2.4 (10.4) 

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

This pooled analysis of three phase III, double-blind, placebo-controlled studies shows that alfuzosin is effective and safe for treating men with BPH, including elderly (≥ 65 years) and hypertensive patients. The drug produced a clinically significant therapeutic effect, as shown by improvements in LUTS (as assessed by the IPSS) and PFR, irrespective of prostate size. These clinical improvements are consistent with results obtained with other α1-blockers [2,13,14]. Alfuzosin improved both obstructive and irritative subscores, especially the nocturia criterion, and this was reflected by improvements in the QoL index scores.

The efficacy of α1-blockers for treating BPH has been well documented [2]. Despite similar efficacy, α1-blockers have different adverse-event profiles, with newer agents such as alfuzosin having improved safety [3]. Many adverse events associated with α1-blockers are secondary to blood pressure lowering (e.g. dizziness and orthostatic hypotension) [2]. The incidence of such events has been shown to be two to three times more common with terazosin and doxazosin than with placebo [12,13,15]. In this pooled analysis of alfuzosin administered with no initial dose titration, relatively few patients had vasodilatory-related adverse events. In addition, there were no clinically relevant changes in systolic and diastolic blood pressure with alfuzosin, including in elderly and hypertensive patients.

The efficacy and cardiovascular safety profile associated with alfuzosin reinforces its clinical uroselectivity and is consistent with previous results [3,4,8]. These findings are also comparable to those observed with tamsulosin, another clinically uroselective α-blocker [11,16].

There were no first-dose adverse events with alfuzosin, confirming that the drug can be administered at a therapeutic dose from the first day of treatment, with no initial dose titration. In cases of poor compliance or interruption to therapy, patients can restart their treatment with no safety concerns.

The incidence of abnormal ejaculation was particularly low (three, 0.6%) and this is consistent with previous experience with alfuzosin. In a previous analysis of patients enrolled in randomized, double-blind studies, no ejaculatory disorders were reported in 536 patients receiving alfuzosin 2.5 mg three times daily or 407 on alfuzosin 5 mg twice daily [17]. In contrast, two 13-week placebo-controlled studies showed that abnormal ejaculation occurred in 6% and 18%, and 11% and 18%, of patients receiving tamsulosin 0.4 mg and 0.8 mg, respectively [14,18]. Tamsulosin has an affinity for α1A-receptors (thought to be important in contraction of the vas deferens [19] and seminal vesicle [20]; this selective α1A-blocking activity may therefore be one of the mechanisms by which tamsulosin compromises ejaculation.

In the present study the overall incidence of withdrawals because of adverse events was comparable among both treatment groups (placebo 8.7%, alfuzosin 9.5%) and with tamsulosin over a similar exposure [19]. The reported incidence of study withdrawals with terazosin and doxazosin is higher than that for alfuzosin and tamsulosin, despite the use of dose titration [2,13,15]. However, a direct comparison of the incidence of adverse events and study withdrawals between trials is difficult given the different baseline patient characteristics, methods of collecting information and study duration of independent studies.

BPH is a condition that affects millions of men worldwide and as life expectancy increases, more men are expected to seek treatment for LUTS associated with BPH. The results of the present study confirm that alfuzosin 10 mg once-daily provides effective relief from the symptoms of BPH, and has a good safety profile for both cardiovascular and sexual function. The safe use of alfuzosin in elderly and hypertensive patients was also confirmed. For the medical management of men with BPH, alfuzosin 10 mg once daily is an effective, well-tolerated and convenient treatment option.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
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Abbreviations
PFR

peak urinary flow rate

QoL

quality of life.