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Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial
To evaluate the efficacy and tolerability of the selective alpha1-adrenergic antagonist doxazosin and the 5-alpha-reductase inhibitor finasteride, alone and in combination, for the symptomatic treatment of benign prostatic hyperplasia.
In a prospective, double-blind, placebo-controlled trial, 1095 men aged 50 to 80 years were randomized to treatment for 52 weeks with doxazosin, finasteride, the combination of doxazosin and finasteride, or placebo. The dose of finasteride (or its matched placebo) was 5 mg/day. Doxazosin (or its matched placebo) was initiated at 1 mg/day, and titrated up to a maximum of 8 mg/day over approximately 10 weeks according to the response of the maximal urinary flow rate (Qmax) and International Prostate Symptom Score (IPSS). The IPSS and Qmax were assessed at baseline and at weeks 10, 14, 26, 39, and 52 or at the endpoint.
An intent-to-treat analysis of 1007 men showed doxazosin and doxazosin plus finasteride combination therapy produced statistically significant improvements in total IPSS and Qmax compared with placebo and finasteride alone (P <0.05). Finasteride alone was not significantly different statistically from placebo with respect to total IPSS and Qmax. All treatments were generally well tolerated.
Doxazosin was effective in improving urinary symptoms and urinary flow rate in men with benign prostatic hyperplasia, and was more effective than finasteride alone or placebo. The addition of finasteride did not provide further benefit to that achieved with doxazosin alone.
Benign prostatic hyperplasia (BPH) is among the most common conditions associated with aging in men, affecting 50% of those between the ages of 50 and 60 years, and as many as 90% of those older than 80 years of age.
The condition is characterized by cell proliferation in the transition zone of the prostate and increased tone in the smooth muscle of the prostate and bladder neck that can contribute to urethral obstruction.
Pharmacologic treatment offers the potential for clinically significant symptom improvement with fewer, less-serious, and reversible side effects compared with surgery.
Selective alpha1-blockers, such as doxazosin, terazosin, and tamsulosin, block alpha1-adrenoceptors in the prostate and bladder neck, inhibiting sympathetic stimulation of prostatic smooth muscle, thereby reducing prostatic tone and relieving urinary obstruction in men with BPH. These agents improve obstructive and irritative BPH symptoms and improve urinary flow, usually within 1 to 2 weeks of treatment.
Finasteride is a 5-alpha-reductase inhibitor that interrupts the conversion of testosterone into 5-alpha-dihydrotestosterone. Finasteride has been demonstrated to reduce prostate size, and, in many placebo-controlled studies, but not the U.S. Veterans Affairs (VA) Cooperative Study,
Recent studies have indicated that finasteride reduces the risk of developing acute urinary retention (AUR) and the need for transurethral resection of the prostate (TURP) in men with moderate to severe lower urinary tract symptoms and an enlarged prostate by digital rectal examination (DRE) by 57% and 55%, respectively.
Few studies have compared the effects of selective alpha-blocker/5-alpha-reductase inhibitor combinations in BPH treatment. One multicenter study comparing terazosin, finasteride, their combination, and placebo in 1229 men with BPH found terazosin and terazosin plus finasteride, but not finasteride alone, to be effective compared with placebo.
We conducted the Prospective European Doxazosin and Combination Therapy (PREDICT) trial—the largest randomized European trial of alpha-blocker therapy for BPH—to evaluate the efficacy and safety of doxazosin and finasteride, alone and in combination, and placebo in the symptomatic treatment of BPH.
Material and methods
The PREDICT trial was a prospective, randomized, double-blind, placebo-controlled, 52-week trial conducted in 90 European study centers. A single-blind, 2-week placebo run-in phase was followed by a 52-week double-blind treatment phase during which subjects received either doxazosin, finasteride, doxazosin plus finasteride, or placebo. After the placebo run-in phase, patients who requalified according to the inclusion criteria were randomized. The treatment phase included a 10-week titration period for subjects taking doxazosin. Urinary flow and urinary symptoms were assessed at screening and baseline and weeks 10, 14, 26, 39, and 52 or at the endpoint. Blood pressure (BP), heart rate, and adverse events were recorded at every study visit (ie, efficacy visits and at weeks 2, 6, and 18). Electrocardiography, standard laboratory tests, and serum prostate-specific antigen (PSA) measurement were performed at screening and at the final visit.
The study protocol for the PREDICT trial was approved by the appropriate institutional ethics committees at each study center and was conducted in accordance with the revised Declaration of Helsinki (Hong Kong 1989) and local laws and regulations relevant to the use of new and approved therapeutic agents. All participants provided written informed consent before entering the study.
The initial visit comprised a complete medical history, including duration of symptoms; a complete medical examination, including DRE, and sitting and standing BP, heart rate, and body weight measurements; electrocardiography; standard laboratory testing, (chemistry, hematology, and urinalysis); urine cytology; PSA testing; and urinary flow rate measurement. Concomitant therapy with anticholinergics, cholinergics, other alpha-blockers, calcium channel blockers, antiandrogens, other 5-alpha-reductase inhibitors, and plant extract preparations was prohibited during the study. Diuretic and beta-blocker dosages were stable for 4 weeks before the initial screening and were maintained during the study.
The subjects were men aged 50 to 80 years with BPH and a total International Prostate Symptom Score (IPSS) of 12 or greater, Qmax of 5 mL/s or greater but 15 mL/s or less in a total voided volume of 150 mL or greater, and an enlarged prostate as determined by DRE. The prostate volume was estimated by the DRE to the nearest 5 g. Individuals who had undergone previous prostate surgery or other invasive procedures for treating BPH or who had prostate cancer or a PSA level exceeding 10 ng/mL were excluded. To exclude the presence of prostate cancer further, men with a PSA of 4.1 to 10 ng/mL had to provide at least two forms of documentation: (a) negative DRE findings (within the past 3 months); (b) negative transrectal ultrasound findings (within the past 3 months); or (c) negative biopsy findings (within the past 4 weeks) or negative results on all three tests if all were performed. Other criteria for exclusion included lower urinary tract symptoms or reduced urinary flow rates resulting from a condition other than BPH; large bladder diverticulum, bladder stones, recurrent urinary tract infection, or two or more episodes of AUR requiring catheterization within the year before study entry; residual urine volumes greater than 200 mL; or active urinary tract infection. Men diagnosed as having serious diseases or a history of drug or alcohol abuse were excluded, as were those with a history of sensitivity to alpha-adrenergic blocking agents, quinazolines, or finasteride. Men with hypotension (sitting BP less than 95/60 mm Hg) or orthostatic hypotension (greater than a 20-mm Hg decrease in systolic BP [SBP] when changing from a supine to standing position) were excluded.
Subjects were instructed to take the study medication (or matched placebo) once daily, preferably around 8:00 am. Doxazosin was initiated at 1 mg/day, and finasteride was initiated at 5 mg/day. Doxazosin was titrated to 2 mg/day at the end of week 2 and to 4 mg/day at the end of week 6. At the end of week 10, the 4-mg dose was maintained in subjects who met the following two criteria: (a) total IPSS had decreased by 30% or more from baseline, and (b) Qmax had increased by 3 mL/s or more from baseline. For subjects who did not meet these goals, the doxazosin dose was increased to 8 mg/day and maintained for the remaining 42 weeks. Doses were reduced to the next lower dose if the SBP/diastolic BP (DBP) fell to less than 90/60 mm Hg or tolerability was limited. Subjects unable to tolerate a 2-mg/day dose of doxazosin were withdrawn. Finasteride therapy was maintained at 5 mg throughout the study.
Urinary flow was assessed using the Dantec Urodyn 1000 rotating flowmeter. Overall urinary symptoms and subscores for obstructive and irritative symptoms were assessed using the IPSS in its culturally and linguistically validated translations in the subjects’ native language.
BP, heart rate, and all adverse events, whether voluntarily reported by the subject or observed by the investigator, were recorded on the case report forms at each study visit.
Two Steering Committee members conducted a blinded post-hoc clinical review of the occurrence of AUR and/or TURP up to 30 days after study completion. The relevant pages of the case report forms, with the treatment assignment and patient identifiers blacked out, were reviewed.
A sample size of 1000 subjects (250 per treatment group) was calculated as sufficient to detect a difference of 1 mL/s in Qmax between the groups, assuming a standard deviation of 4.0 mL/s, a two-tailed 5% significance level, and a power of 80% against a type II error. Efficacy data were analyzed using an analysis of covariance model that included effects for treatment, center (pooled by country), and treatment-by-center interaction with baseline as covariate. Least-squares mean changes ± standard error adjusted for baseline are presented. An efficacy intent-to-treat (ITT) analysis was performed for all men who had a baseline assessment and at least one follow-up assessment of IPSS or Qmax and who took at least one dose of double-blind study medication. If a subject discontinued early, a last-observation-carried-forward algorithm was used for the endpoint analysis. Pair-wise treatment comparisons were made only if the overall F-test for treatment effect was significant (P <0.05). All statistical tests were two-tailed with a 5% level of significance for treatment effects. Men who took at least one dose of double-blind study medication were included in the ITT safety assessment group. Adverse events were analyzed using two-tailed Fisher’s exact tests.
Of 1378 men screened, 1095 men were randomized to treatment. The baseline characteristics were not significantly different statistically among the four treatment groups except for Qmax, for which the maximal among-treatment group difference was approximately 0.6 mL/s (Table I). These differences were accounted for in the analysis of the data by adjusting for the baseline values. At baseline, for all groups combined, the mean age was 64 years, mean IPSS was 17.2, mean Qmax was 10.5 mL/s, mean PSA was 2.6 ng/mL, and mean prostate volume was 36.3 g. The baseline parameters, endpoint values, and changes from baseline (least-squares mean ± standard error for IPSS and Qmax; mean ± standard deviation for PSA) are listed in Table I.
Of those randomized, 1094 took at least one dose of double-blind study drug and were evaluated for safety. Of the 1007 subjects included in the ITT efficacy analyses (patients with baseline assessment and at least one follow-up assessment of IPSS or Qmax and who had taken at least one dose of double-blind study medication), 999 were analyzable for IPSS and 961 were for urinary flow. The study was completed by 771 subjects (71%), with an even distribution among the four groups. Table II summarizes the study discontinuations for each treatment group.
TABLE IISummary for all randomized subjects for discontinuation from study by treatment group
For the ITT efficacy population, the mean final dose of doxazosin was 6.4 mg/day in the doxazosin monotherapy group and 6.1 mg/day in the combination-therapy group. The distribution of doxazosin dose at the subjects’ final visit for doxazosin monotherapy and combination therapy groups, respectively, was 8 mg for 63.2% and 57.0%; 4 mg for 31.2% and 35.5%; 2 mg for 4.8% and 6.0%; and 1 mg for 0.8% and 1.5%.
Maximal urinary flow rate
Both doxazosin and doxazosin plus finasteride groups experienced statistically significant improvements in Qmax from baseline to endpoint compared with placebo (P ≤0.0001) and finasteride monotherapy (P ≤0.0001; Fig. 1). No statistically significant differences were observed between the finasteride and placebo groups or between the doxazosin and doxazosin plus finasteride groups.
Doxazosin and doxazosin plus finasteride both demonstrated statistically significant improvements in total IPSS from baseline to endpoint compared with placebo (P ≤0.0001) and finasteride alone (P <0.01; Fig. 1). No statistically significant difference was noted between the doxazosin and doxazosin plus finasteride groups or between the finasteride and placebo groups.
Subscores of IPSS
Treatment with doxazosin and doxazosin plus finasteride resulted in significantly greater improvements statistically in both obstructive and irritative symptoms compared with placebo or finasteride (Fig. 1). Finasteride produced significantly greater improvements statistically in obstructive symptoms at endpoint (P <0.05), but not in irritative symptoms, compared with placebo. The doxazosin plus finasteride combination did not result in further improvement at endpoint in either obstructive or irritative subscores compared with doxazosin alone.
Selected urologic events
AUR and TURP were generally uncommon in the PREDICT trial (Table III). Both AUR and TURP occurred more frequently in the placebo group than in any active treatment group. The incidence of AUR or TURP was 2.6% for placebo, 1.9% for finasteride, 0.4% for doxazosin, and 0% for doxazosin plus finasteride.
TABLE IIIOccurrence of acute urinary retention and/or transurethral resection of the prostate according to treatment group
Treatment with doxazosin, finasteride, or doxazosin plus finasteride was generally well tolerated. Most adverse events were mild or moderate in severity. Similar percentages of subjects discontinued treatment because of adverse events in each group (doxazosin, 11.6%; finasteride, 13.6%; doxazosin plus finasteride, 12.6%; and placebo, 11.9%). Table IV shows the treatment-related adverse events that are known to occur with either doxazosin or finasteride. The side-effect distribution was as expected, with more doxazosin-exposed patients having asthenia, dizziness, and hypotension. More patients in the combination group had impotence. The syncope incidence was low in all groups. Congestive heart failure (including lung edema) was rare (doxazosin, 0.72%; finasteride, 0.37%; doxazosin plus finasteride, 0.70%; and placebo, 0%), as was myocardial infarction/ischemia (doxazosin, 0.36%; finasteride, 1.12%; doxazosin plus finasteride, 1.05%; and placebo, 0.74%). No statistically or clinically significant mean changes in sitting SBP and DBP occurred in normotensive subjects; the mean changes were less than 5 mm Hg for SBP and 3 mm Hg or less for DBP across all treatment groups and time periods. Among hypertensive subjects (sitting DBP 90 mm Hg or greater, sitting SBP 140 mm Hg or greater), doxazosin and doxazosin plus finasteride significantly lowered the sitting and standing SBP and DBP compared with placebo (P <0.05) and finasteride (P <0.05). The least-squares mean changes at endpoint in hypertensive subjects for sitting SBP/DBP for doxazosin (−11.8/−5.7 mm Hg) and doxazosin plus finasteride (−9.2/−5.6 mm Hg) were clinically significant. No significant mean changes in BP were observed in hypertensive subjects with finasteride (−5.7/−2.7 mm Hg) or placebo (−4.0/−2.1 mm Hg).
The results of the PREDICT trial demonstrate that in a European population of men with symptomatic BPH, the selective alpha1-blocker doxazosin is effective in improving urinary symptoms and urinary flow rate and more effective than finasteride alone or placebo. Barry et al.
Benign prostatic hyperplasia specific health status measures in clinical research how much change in the American Urological Association symptom index and the Benign Prostatic Hyperplasia Impact Index is perceptible to patients?.
demonstrated that an average 3-point reduction in American Urological Association symptom score was perceived by patients as “slight” improvement, and an average 8.8-point reduction was perceived as “marked” improvement. Patients in the PREDICT trial who received doxazosin had an average perceived improvement in symptom score that can be considered “markedly improved.” The addition of finasteride did not enhance the efficacy of doxazosin. In contrast, the therapeutic responses observed among subjects taking finasteride alone were not significantly different statistically from those observed with placebo. The average decrease from baseline by 6.6 points would, however, also represent a noticeable subjective improvement. These findings are consistent with the results of the only other 1-year randomized study, the VA trial, comparing the effects of the alpha-blocker terazosin alone and in combination with finasteride, with finasteride alone, and placebo in 1229 men with BPH.
is reaffirmed by the results of PREDICT as well as the VA study. Unlike the findings in other studies of finasteride in BPH, however, the limited effects of finasteride alone in the PREDICT and VA studies suggest potential limitations in the usefulness of 5-alpha-reductase inhibition in symptomatic BPH treatment in a broad population not selected for prostate size. Subsequent analysis of the VA study data, as well as data from other studies, appears to indicate that finasteride efficacy may be limited to men with enlarged prostates (greater than 40 cm3, greater than 50 cm3, or greater than 60 cm3)
Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group The impact of medical therapy on bother due to symptoms, quality of life and global outcome, and factors predicting response.
No comparable data for alpha-blockers have been available. In the PREDICT trial, at 1 year, the occurrence of AUR or TURP was lower in all active-treatment groups than in the placebo group. Although this was a post-hoc analysis, and some events may have been missed, the event rates in the finasteride and placebo groups were very similar to those observed at 1 year in the Proscar Long-term Efficacy and Safety Study and the Proscar Worldwide Efficacy and Safety Study.
The PREDICT trial, however, was neither specifically designed, nor statistically powered, to detect differences among the groups with regard to AUR or TURP. The Medical Therapy of Prostate Symptoms trial, a 5-year National Institutes of Health-sponsored study with a design similar to those of the PREDICT and the VA studies,
is likely to provide a definitive answer as to whether both 5-alpha-reductase inhibitors and alpha-blockers decrease the risk of AUR and TURP.
All three active drug regimens were well tolerated, with discontinuation rates due to adverse events similar to that observed with placebo. The adverse effects were generally mild to moderate. Although impotence was approximately twice as common in the combination group as in the monotherapy groups, several factors may explain this occurrence. Impotence was not a planned study endpoint and is subject to variation in investigator-recorded terms. The incidence rates of impotence with doxazosin and combination therapy in the PREDICT trial are similar to those reported with terazosin (6%) and a finasteride plus terazosin combination (9%) in the VA trial.
The results of the PREDICT trial, the largest randomized European trial involving alpha-blocker therapy for BPH, demonstrate that doxazosin is effective in improving urinary symptoms and urinary flow rate in men with BPH and more effective than finasteride alone or placebo. The addition of finasteride did not provide additional benefit to that achieved with doxazosin alone.
The members of the Steering Committee were as follows: Roger S. Kirby, Chair, Georg Bartsch, Peter Boyle, Alain Jardin, and Claus Roehrborn.
The Principal Investigators were as follows: Belgium—Paul Reynders and Eric Wespes; France—Henri Bensadoun, Jacques Biserte, Henri Botto, Rémy Claude, Patrick Coloby, Pierre Costa, Pierre Coulange, Georges Fournier, Bernard Gattegno, Laurent Boccon Gibod, Pierre Girardot, Jean-Luc Jung, Jean Lalaude, Yves Lanson, Pierre-Marie Lugagne, Philippe Mangin, Maxime Robert, Jean-Pierre Sarramon, Thierry Schauvliege, Dominique Scharff, Michel Soulié, Armand Sul-her, Pierre Teillac, Jacques Toubol, and Guy Vallancien; Germany—Jürgen Albrecht, Peter Alken, Ralf Basting, Hermann Becker, Hans-Udo Eickenberg, Michael Freudenberg, Hans-Martin Guddat, Rudolf Hohenfellner, Henning Hüsch, Günther H. Jacobi, Peter Klinger, Klaus-Dieter Lauber, Hassan Meier-Mouhanna, Kurt G. Naber, Klaus Peter, Erwin W. Rugendorff, Detlev Russ, Hans-Joachim Schneider, Harald Schumacher, Wilfried Seibke, Jörg Sosna, Albert Spaeth, Georgios Vardakis, and Wolfgang Wagner; Italy—Carlo Andrisani, Rocco Battista, Franco Di Silverio, Michele Gallucci, Nicola Loreto, Alberto Mandressi, Enrico Pisani, Patrizio Rigatti, Francesco Rocco, Maurizio Turriziani, and Enzo Usai; The Netherlands—Karel Delaere, Gerald Dijkman, Ronald Janknegt, Tom Lock, Th. J. M. Schlatmann, Wim Witjes, and Anton Ypma; United Kingdom—Paul Abel, Paul Abrams, Christopher Michael Booth, John Boyd, Stephen James Brough, Christopher Chapple, Timothy Christmas, Malcolm Coptcoat, Anthony Doble, George Michael Flannigan, Nicholas George, David Anthony Gillatt, John Christopher Hammonds, Timothy Bruce Hargreave, Simon Charles Harrison, Anthony Hinchliffe, Roger Sinclair Kirby, David Kirk, Stuart Nigel Lloyd, Philip Nevill Matthews, Tomas Anthony McNicholas, Paul David Miller, Euan James Milroy, Robert John Morgan, Patrick John O’Boyle, Christopher Stephen Powell, Mark Anthony Scott, P. Julian Shah, G. N. A. Sibley, Timothy Robin Terry, and David Neill Tulloch.
The development of human benign prostatic hyperplasia with age.
☆A complete list of the Study Investigators can be found in the Appendix.
☆The PREDICT trial was funded by a grant from Pfizer Inc. Finasteride and matched placebo were provided by Merck and Co., Inc.
☆M. M. Cary, E. B. Grossman, and M. Sweeney are employees of Pfizer Inc., sponsor of the study and manufacturer of doxazosin. R. S. Kirby is a paid consultant with Pfizer Inc. C. G. Roehrborn has been an investigator for Pfizer Inc., the manufacturer of doxazosin, and for Merck, Sharpe, & Dohme, the manufacturer of finasteride.