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Alfuzosin for treatment of benign prostatichypertrophy

ADDRESSES: Urology Service, Bicêtre Hospital, 78 Avenue duGeneral Leclare, 94270 Kremlin-Bicêtre, (Prof A. Jardin, MD, HBensadoun, MD) and Synthelabo Recherche, Paris (M. C

Delauche-Cavallier, MD, P Attatli, MD) France.*Clinical centres: Prof B. Debré, Paris, France; Prof A. De Nicola,

Pavia, Italy; Prof B Gattegno, Paris, France; Prof J. P Sarramon,Toulouse, France; Prof J. Cinqualbre, Strasbourg, France; Dr R. D

Fourcade, Auxerre, France; Prof P. Colombeau, Limoges, France, Prof A.Martelli, Bologna, Italy; Dr A. Suhler, Cannes, France; Prof F. Richard,Paris, France; Prof M. Rampal, Marseille, France; Prof J. Toubol, Nice,France; Prof J M. Buzelin, Nantes, France; Dr P. Henry, France; Prof A.Leriche, St Genis Laval, France; Dr F. Jurascheck, Mulhouse, France;Prof M. Le Guillou, Bordeaux, France; Prof J. Ducassou, Marseille,France; Prof H Navratil, Nîmes, France; Prof D. Grasset, Montpellier,France; Prof W. Schutz, München, Germany; Prof H. Whitfield, London,UK, DrT. Stephenson, Cardiff, UK, Prof G. Chisholm, Edinburgh, UK; DrG. Rossignol, Toulouse, France; Dr A. Levallois, Avignon, France; ProfW. Von Niederhausern, Lausanne, Switzerland; Dr E. Schramek,Aix-en-Provence, France; Prof P. Perrin, Lyon, France; Dr P Coloby,Pontoise, France; and Dr A. Tenaillon, Albi, France.

Coordinating centre: Prof A. Jardin, Dr H. Bensadoun (Hôpital deBicêtre), Dr S. Brossel, Dr J. P. Sauvanet, Dr P. Attali, Dr F. Regnier, DrM C. Delauche-Cavallier (Synthelabo Recherche).Correspondence to Prof A. Jardin.

To assess the long-term efficacy and safety ofalfuzosin, a selective &agr;1-adrenergic antagonist, 518symptomatic patients with benign prostatichypertrophy (BPH) were randomised to receivedeither alfuzosin (daily dose 7·5-10 mg) or placebofor 6 months. Obstructive and irritative symptoms,assessed according to the Boyarsky scale,significantly improved in the alfuzosin groupcompared with the placebo group (p=0·0004).Fewer patients in the alfuzosin group than in the

placebo group dropped out due to lack of efficacy(6·8% vs 14·6%, p=0·004) and the prevalence ofspontaneous acute urine retention was lower in thealfuzosin group (0·4% vs 2·6%, p=0·04). By 6months, mean urinary flow rates had increased

(p<0&middot;05) and residual volume had decreased

(p=0&middot;017) in the alfuzosin group, although the twogroups were broadly similar with respect to increasein peak flow rate. The overall incidence of adverseevents was similar in the two groups, which led to thewithdrawal of 10&middot;8% and 9&middot;0% of patients,respectively. The findings emphasise the magnitudeof the placebo response in symptomatic patientswith BPH and show that treatment with &agr;1adrenergic antagonist drugs provides long-lastingimprovement in such patients.

Introduction

The prevalence of histological benign prostatichypertrophy (BPH) increases from about 8% in the fourthdecade of life to 90% in the ninth.! The condition is oftenassociated with troublesome micturition disorders, whichare related to infravesical obstruction. Surgery (open ortransurethral resection) is usually indicated if these aresevere. However, whether the prostatic adenoma causesthese voiding symptoms, especially in men aged over 60, isnot always easy to demonstrate.

Urinary obstruction in BPH caused by an enlargedprostate is partly anatomical, (the physical presence of thehyperplastic tissue), but is also partly due to the tone of theprostatic smooth muscle.2 The proximal urethra containssympathetic nerves,3 and there are a-adrenergic receptors(predominantly of the al sub-type4) in the stroma and in thecapsule of the prostate.5 Pharmacological stimulation ofthese receptors causes smooth-muscle contraction and anincrease in the perfusion pressure of the urethra.6

Furthermore, the sensitivity of BPH tissue to (X-antagonistssuch as phenylephrine is greater than that of normal prostatetissue? Chronic bladder outlet obstruction has beenassociated with bladder detrusor instability, which can bedemonstrated in about 70% of patients with prostatism.8,9

There is evidence that the normal P-type response toadrenergic stimulation is replaced by that of an a-type,leading to detrusor muscle contraction and irritative

symptoms.loImprovements in symptoms and/or urodynamics have

followed treatment with phenoxybenzamine,l1-13prazosin,8,14 indoramin,9,15,16 terazosin,17,18 and alfuzosin.19The medium and long-term efficacy of such ot-adrenoceptorantagonists has not yet been substantiated except in oneopen 4-month study with terazosin:17 most trials have dealtwith short-term efficacy. Thus, the precise role of

excadrenergic antagonists in the treatment of symptomaticBPH needs to be clarified in long-term properly-designedplacebo-controlled clinical trials.

Alfuzosin, a quinazoline derivative, is a selective

antagonist of al-adrenergic receptors. In laboratory animalsthis drug relaxes the isolated urethra contracted bya-adrenergic agonists or sympathetic nervous stimulation;additionally, alfuzosin reduces resting urethral pressure andinhibits urethral hypertonia induced by sympatheticnervous stimulation .2021 In patients with neurogenicbladder dysfunction intravenous alfuzosin reduces urethralpressure.22 The aim of this large clinical study was to assessthe long-term efficacy and safety of alfuzosin in

symptomatic patients with BPH.

Patients and methods

Patients

The study was undertaken in 32 centres in five Europeancountries between May, 1985, and December, 1987. Patients of anyage with symptoms of BPH were considered for entry into the

study. Patients were eligible if their Boyarsky score23 was at least 6.This score was the sum of the scores for each symptom; scores

ranged from 0 (absent) to 3 (maximum severity). The symptomsassessed were nocturia, daytime frequency, hesitancy, terminal

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TABLE I-CLINICAL CHARACTERISTICS AT BASELINE

Values are mean (SD)

dribbling, sensation of incomplete bladder emptying, urgency, andpoor quality of the stream.

Patients were excluded if they had concomitant urologicaldisorders, neurological disturbances, or severe cardiac, renal, orhepatic failure; if they had had a myocardial infarction within theprevious 6 months; or if they were taking drugs likely to interferewith the study medication-eg, drugs acting at a-receptors orP-receptors.

Eligible patients were randomised at each centre to receive eitheralfuzosin or placebo capsules of identical appearance for 6 months(for 3 months in 2 centres). The dose was 2-5 mg every 8 h (7-5mg/day); this daily dose was given from the first day, without anyprogressive increase, for 14 days. The evening dose could then bedoubled (10 mg/day) depending on the therapeutic response andtolerance. The optimum regimen was maintained throughout thetrial.

Methods

Symptoms were assessed by the investigator (Boyarsky score) atday 0 and at weeks 2, 6, 13, 20, and 26. Urinary flow rates andresidual urine volume (assessed with ultrasonography) were

measured before treatment and during weeks 6, 13, and 26 in thosecentres that had adequate equipment (ie, 20 and 19 centres,

respectively). Peak flow rate, voided volume, and voiding time weremeasured; mean flow rate was calculated subsequently as voidedvolume - voiding time. Data were included in the analysis only if apre-treatment assessment and at least one other assessment duringtreatment had been done and if the voided volume was more than100 ml. All the flow-rate curves were read blind by one of us (A. J.)at the end of the study. The size of the prostate was evaluated bytransrectal ultrasonography before treatment and during weeks 13

706 s

Fig 1-Percentage of patients improved at the end of the6-month treatment with alfuzosin (hatched columns) orplacebo (open columns).

Significant differences (two-sided chi-square test) between alfuzosinand placebo for nocturia (A), day-time frequency (B), hesitancy (C), andfeeling of incomplete bladder emptying (F) (p<0’05); for urgency (E)(p<001), and for quality of the stream (G) (p<0 001) D=termmal

dnbblmg. n =no of patients in each group with initial score >1 for thesymptom.

TABLE II-CHANGES IN URINARY FLOW RATES

Values are mean flow rates (SD) m ml/s*p< 0 01, tp< 0 05 (alfuzosin vs placebo, two-sided Wilcoxon test)

and 26 in all patients of 1 centre preselected because it had adequateequipment to do such a measurement.

Heart rate, blood pressure (supine and erect), and subjectiveadverse events (without prompting) were recorded at each visit, androutine laboratory investigations (blood count, erythrocytesedimentation rate, blood glucose, serum creatinine, aspartateaminotransferase, alanine aminotransferase, alkaline phosphatase,total bilirubin, prostatic acid phosphatase, total protein) weremonitored on day 0 and during weeks 13 and 26. Overallassessments of efficacy and safety were made by patients andinvestigators.

Statistics

The calculation of the population size needed for the study wasbased on symptomatic improvement as the primary criterion ofefficacy. With a placebo effect of 50-60% and an expectedsymptomatic improvement of 15% in favour of alfuzosin, a

minimum of 222 patients in each group was necessary to obtain astatistical significance with Ot and j3 risks equal to 5%. According tothe protocol, 500 patients were to be included in the study-ie, 250patients per treatment group. Patients were sequentially allocated tothe treatment group. The randomisation was balanced withincentres. Data from all patients were included in the intention-to-treat statistical analysis. The principal analysis was at endpoint week26. Additionally, sensitivity analyses at each visit were done formean and peak flow measurements to assess the robustness of theresults. All tests were two-sided. The most recent available datawere used for patients who dropped out. In addition to the endpointanalysis of the total Boyarsky score, patients were given a symptomscore. Patients were regarded as clinically improved if their

symptom score decreased by at least 1 point; only patients with ascore of at least 1 at baseline were included in this descriptiveanalysis. Pearson’s (chi-square) test was used for comparisons offrequencies, and a one-way analysis of variance and/or the

equivalent non-parametric Wilcoxon test for quantitative or ordinal

12. T

Fig 2-Changes in peak flow rate in patients with severe BPH(initial peak flow rate <10 mils).

Alfuzosin (.) n=38, placebo (0) n=59 p <- 05 at weeks 6 and 13(alfuzosin vs placebo) Vertical bars= SD

1459

Fig 3-Changes in residual urine volume in alfuzosin (.) andplacebo (0) groups.

p<0 05 (alfuzosin vs placebo) at week 26. Vertical bars=SD.

variables. An additional analysis was carried out at the end of thestudy for descriptive purposes in patients with initial peak flow ratesof less than 10 ml/s.

Results

518 patients entered the study. The clinical and

demographic characteristics of the two groups were broadlysimilar at entry (table l). 162 patients withdrew from thestudy-70 (27-9%) in the alfuzosin group and 92 (34-5%) inthe placebo group (p>0-l), mean delay until withdrawalwas 165 days and 135 days, respectively. There weresignificantly more withdrawals owing to lack of efficacy inthe placebo group than in the alfuzosin group (14-6% vs6-8%, p = 0-004). 7 patients (2-6%) in the placebo group and1 (0-4%) in the alfuzosin group withdrew because of acuteurinary retention (p = 0-04). The numbers of patients whowithdrew for adverse events or lack of cooperation, or whowere lost to follow-up were similar in the two groups.The decrease in mean (SD) total Boyarsky score in the

alfuzosin group-from 9-5 (0-2) to 5-5 (0-2)-wassignificantly greater than that in the placebo group (9-4 [0-2]to 64 [0-2]) (p=0-0004). The additional descriptiveevaluation symptom-by-symptom among patients with aninitial score of at least 1 showed that alfuzosin was moreeffective than placebo (p < 0-05) (fig 1) for all symptoms ofBPH other than terminal dribbling. The improvement wasseen early and was maintained throughout treatment.

Urinary flow rates were assessed in 234 patients (102alfuzosin, 132 placebo) whose characteristics were similar to

TABLE III-MOST COMMON ADVERSE EVENTS

TABLE IV-OVERALL THERAPEUTIC EFFECT

Values are % of patients in improvement category*p=0 00001, tp=0 0 002 (alfuzosin vs placebo, two-sided chi square test)

those of the total study population. Mean baseline values forpeak and mean flow rates were similar in the two groups(table II). There were substantial increases in flow rates fromthe first assessment (week 6) in the alfuzosin group and thesewere maintained throughout treatment. At endpoint week26 there was a significant difference between groups in meanflow rates (p<0’05) but not in peak flow rates (p>0-01)(table II). There were larger improvements in flow rates inboth treatment groups in those patients whose initial

peak-flow rate was less than 10 ml/s (fig 2) (alfuzosin, n = 38,mean [SD] peak flow rates at baseline 7-2 [0’3] ml/s and atweek 26 10-3 [0’7] ml/s; placebo, n = 59, 6-7 [0.3], 9-1 [0’6]; --p=0-18). Residual urine volume was measured in 189

patients (86 alfuzosin, 103 placebo) whose characteristicswere again similar to those of the total study population.Mean (SD) residual urine volume significantly decreased inthe alfuzosin group (from 80 1 [8 &deg; 34] to 49.3 [6’1] ml at week26) compared with the placebo group (from 87-8 [7’1] to79-5 [10’7]) (p=0-017) (fig 3). Neither treatment affectedthe size of the prostate, measured in 15 patients from eachgroup.Compared with placebo, there were small, but significant,

reductions in erect and supine mean systolic and diastolicblood pressures (BP); the maximum mean (SD) change was3-9 (1-3) mm Hg for erect systolic BP. There were nosignificant abnormalities during routine laboratory testing.

91 patients (36-3%) receiving alfuzosin and 97 (36-3%)receiving placebo experienced adverse events; the mostfrequent of these are shown in table III. The overall

incidence, nature, and severity were broadly similar in thetwo groups. However, during the first 2 weeks of treatment,vasodilatatory effects were more common in the alfuzosingroup (8-4% 3-8%). 27 patients (10-8%) receivingalfuzosin and 24 (9-0%) receiving placebo withdrew becauseof adverse events. Vasodilatatory effects (ie, dizziness,headache, postural hypotension) were the main adverseevents leading to therapy discontinuation in both groups.

In their overall assessments, patients and investigatorsjudged that the therapeutic effect of alfuzosin was betterthan that of placebo and that the tolerability of the twotreatments was similar (table IV).

Discussion

Symptomatic BPH can be treated by surgery or

pharmacological agents (hormonal therapy, inhibition ofgrowth factors) to reduce prostatic volume, or the tone of theprostatic smooth muscle can be decreased to relieve thevoiding symptoms. Surgery is regarded as the besttreatment for patients with prostatic outflow obstruction,24despite significant mortality25 and reoperation26 rates.

However, not all symptomatic patients with BPH needsurgical treatment.The demonstration of long-term improvement in voiding

symptoms in BPH is impaired by numerous practical

1460

TABLE V-PLACEBO-CONTROLLED CLINICAL TRIALS EVALUATING A-ADREN ERG I C BLOCKERS IN SYMPTOMATIC BPH

*Mean initial value/mean fmal value .

PBZ= phenoxybenzamme, PRZ=prazosn, ALF =alfuzosm, IND indoramine, ND = not done, GI = global improvement (efficacy)tsignificant difference between placebo and drug groups$Results for patients takmg 20 mg twice daily&sect;Subgroup of patients with initial peak flow rate < 10 0 mils

difficulties-ie, the variability of symptoms with time,interindividual variability, a substantial placebo effect, andexpected high drop-out rate. Therefore, clinical trialsshould include a large number of patients, and have arandomised, placebo-controlled, matched group design. Inour study, we took these requirements into account.

According to the guidelines for the investigation of benignprostatic hypertrophy,23 patients in whom the urinary flowrates are more than 10 ml/s should not be included in a studyevaluating drug treatment for BPH. We did not retain thiscriterion because it would have lowered the rate ofrecruitment in a long-term study. Although we were able toexceed the minimum number of 500 patients required, only230 patients had flow-rate assessments, of whom only 41 %were defined as obstructed (peak flow rate < 10 ml/s).However, voiding symptoms in patients with BPH are anunreliable index of obstruction, and their severity in anindividual patient does not predict the likelihood of

progression with time."2’ The possibility that the prostateenlargement is not directly responsible for the voidingsymptoms in some patients cannot be excluded.The high drop-out rate was expected and accords with

that found in previous studies of shorter duration.8

Moreover, the drop-out rate due to lack of efficacy in ourstudy was significantly higher in controls. Additionally, wewould like to emphasise that the mean time untildiscontinuation was longer in patients receiving alfuzosinthan in those receiving placebo.Our finding that obstructive and irritative symptoms

improved in both treatment groups (improvements beingsignificantly more common in the alfuzosin group) accordswith the results of short-term studies of C’L1 blockers.

However, the studies are not comparable becauseassessment criteria of voiding symptoms differed from onetrial to another.The placebo response that we recorded is important:

30-50% of patients receiving placebo had long-term

improvement of at least one symptom and 40% of patientswere satisfied with their clinical improvement at the end ofthe study. Such a subjective placebo response has beenpreviously reported in short-term studies, even in moreseverely obstructed patients.The so-called "objective" criteria-ie, urinary flow rates

and residual urine measurement-should be assessed in

therapeutic trials of symptomatic BPH. Mean flow rateswere significantly increased by alfuzosin in our study andimprovements persisted throughout. That increases in peakflow rate in alfuzosin-treated patients were not statisticallydifferent from those in controls at 6 months could be partlydue to an increase in peak flow rate in the placebo group atweek 26. The absence of urodynamic evaluation in patientswhen they dropped out, and the higher drop-out rate in theplacebo group could also explain this finding.The magnitude of the flow-rate increases for the study

group as a whole is smaller than that reported in some otherstudies assessing (x-adrenergic antagonists, in which patientswere enrolled according to urodynamic evidence ofobstruction (table v). In our study, there was a similarincrease in flow rates in patients with comparableobstruction. It is noteworthy that the increase in flow rates inobstructed placebo-treated patients was not seen in othertherapeutic trials in which patients were selected on the basisof peak flow rate values. This placebo effect should be takeninto account in the evaluation of unselected symptomaticpatients with BPH. The decrease in residual volume withalfuzosin treatment that we recorded was similar to that

reported with phenoxybenzamine13 and prazosin.8,14We found that alfuzosin was tolerated well; the incidence

of adverse events was similar in the two groups, leading towithdrawal in about 10% of patients. Such a high rate ofwithdrawal for adverse events is usual in elderly patienttrials.Our study confirms the magnitude of the placebo

response and the benefit of treatment with a selective

1461

oti-adrenergic antagonist in a large number of symptomaticpatients with BPH, and highlights the need for long-termplacebo-controlled therapeutic trials. Furthermore, we haveshown that improvements can be safely maintained for atleast 6 months with alfuzosin. This drug would thereforeseem to be beneficial for patients awaiting surgery or forthose in whom surgery is not indicated and who requiretreatment for troublesome voiding symptoms. The lowoccurrence of acute urinary retention during alfuzosintreatment warrants further investigation of the drug inBPH.

This work was supported in part by Synthelabo Recherche. We thankMme S. Leroux and Mme C. Thevenot for technical assistance, Mr C.Martin for his comments, and Mr L. Darchy, Mr B. Orofiama, and Mr A.Zipfel for statistical analysis.

REFERENCES

1. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of humanprostatic hyperplasia with age. J Urol 1984; 132: 474-79.

2. Caine M. The present role of alpha-adrenergic blockers in the treatmentof benign prostatic hypertrophy. J Urol 1986; 136: 1-4.

3. Raezer DM, Wem AJ, Jacobowitz DJ, Corriere JN. Autonomicinnervation of canine urinary bladder. Urology 1973; 2: 211-21.

4. Hieble JP, Caine M, Zalaznik E. In vitro characterization of the

&agr;-adrenoceptors in human prostate. Eur J Pharmacol 1985; 107:

111-17.

5. Caine M, Raz S, Zeigler M. Adrenergic and cholinergic receptors in thehuman prostate, prostatic capsule and bladder neck. Br J Urol 1975; 47:193-202.

6. Awad SA, Downie JW. The adrenergic component in the proximalurethra. Uro Int 1977; 32: 192-97.

7. Kitada S, Kumazawa J. Pharmacological characteristics of smoothmuscle in benign prostatic hyperplasia and normal prostatic tissue. JUrol 1987; 138: 158-60.

8. Kirby RS, Coppinger SWC, Corcoran MO, Chapple CR, Flannigan M,Milroy EJG. Prazosin in the treatment of prostatic obstruction. Aplacebo controlled study. Br J Urol 1987; 60: 136-42.

9. Iacovou JW, Dunn M. Indoramin: an effective new drug in the

management of bladder outflow obstruction. Br J Urol 1987; 60:526-28.

10. Perlberg S, Came M. Adrenergic response of bladder muscle in prostaticobstruction. Its relation to detrusor instability. Urology 1982; 20:524-27.

11. Gerstenberg T, Blaabjerg J, Nielsen ML, Olausen S. Phenoxybenzaminereduces bladder outlet obstruction in benign prostatic hyperplasia. Aurodynamic investigation. Invest Urol 1980; 18: 29-31.

12. Came M, Pelberg S, Shapiro A. Phenoxybenzamine for benign prostatichypertrophy. Review of 200 cases. Urology 1981; 17: 542-46.

13. Abrams PH, Shah PJR, Stone R, Choa RG. Bladder outflow obstructiontreated with phenoxybenzamine. Br J Urol 1982; 54: 527-30.

14. Hedlung H, Anderson KE, Ek A. Effects of prazosin in patients withbenign prostatic obstruction. J Urol 1983; 130: 275-78.

15. Stott MA, Abrams PH. Indoramin in benign prostatic hypertrophy. Aplacebo controlled trial. J Urol 1989; 139: 464A.

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18. Lepor H, Knapp Maloney G, Wozniak Petrofsky J. The safety andefficacy of terazosin for the treatment of benign prostatic hyperplasia.Int J Clin Pharmacol Ther Toxicol 1989; 27: 392-97.

19. Ramsay JWA, Scott GI, Whitfield HN. A double-blind controlled trial ofa new &agr;1-blocking drug in the treatment of bladder outflow obstruction.Br J Urol 1985; 57: 657-59.

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operative complications. A cooperative study of 13 participatinginstitutions evaluating 3,885 patients. J Urol 1989; 141: 243-47.

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Identification of the causes of

persistent hyperuricaemia

ADDRESS. University of Queensland, Department of Medicine,Princess Alexandra Hospital, Brisbane, Queensland 4102,Australia (Prof B T. Emmerson, MD)

Accurate identification of the factors that contributeto hyperuricaemia in an individual may enable someof these factors to be modified, and lead to

permanent correction of the hyperuricaemia. Aprotocol is described which can supplement clinicalassessment. Measurement of the effects on serumurate and urinary urate excretion of a low-purine dietfor 7 days facilitates the identification of thecontributions made by urate production (eitherendogenous or from purine consumption) and renalunderexcretion of urate (either as a low urate

clearance in the absence of renal disease or due torenal glomerular insufficiency).

Introduction

Clinicians often encounter patients with persistenthyperuricaemia but may often find it difficult to decidewhom to reassure, whom to investigate, and whom to treat.Even when the hyperuricaemia is chronic or severe, somephysicians prefer to reassure patients that complications areunlikely to arise, whereas others will commence prolonged,potentially life-long treatment with a urate-lowering drug.The only alternative to this empirical approach is to identifythe cause or causes of the hyperuricaemia and to correctthem. However, while several factors are known to

contribute to hyperuricaemia-which essentially reflects animbalance between urate production and its elimination,mainly via the kidneys-it is often difficult to determine