- Email: [email protected]
The Effect of Doxazosin, Finasteride and Combination Therapy on Nocturia in Men With Benign Prostatic Hyperplasia
The Effect of Doxazosin, Finasteride and Combination Therapy on Nocturia in Men With Benign Prostatic Hyperplasia Theodore M. Johnson, II,*,† Pamela K. Burrows,‡ John W. Kusek,‡ Leroy M. Nyberg,‡ J. Lisa Tenover,‡ Herbert Lepor§ and Claus G. Roehrborn储 for the Medical Therapy of Prostatic Symptoms Research Group From the Birmingham/Atlanta Geriatric Research, Education, and Clinical Center, Atlanta Veterans Affairs Medical Center, Decatur (TMJ), Division of Geriatric Medicine and Gerontology, Department of Medicine (TMJ, JLT), and Emory University Center for Health in Aging (TMJ), Emory University, Atlanta, Georgia, George Washington University Biostatistics Center, Rockville, Maryland (PKB), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (JWK, LMN), Departments of Urology and Pharmacology, New York University Medical Center, New York, New York (HL), and the Department of Urology, University of Texas Southwestern, Dallas, Texas (CGR)
Purpose: We evaluated the effectiveness of single or combination drug therapy on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Materials and Methods: A total of 3,047 men with lower urinary tract symptoms/benign prostatic hyperplasia enrolled in the Medical Therapy of Prostatic Symptoms trial were randomly assigned to receive doxazosin alone, finasteride alone, combination therapy or placebo. Treatment effectiveness was assessed according to intent to treat by mean reduction in self-reported nightly nocturia at 1 and 4 years. A subgroup analysis by age (younger than 70 vs 70 years old or older) was also performed. Results: Of the men 2,583 reported 1 or more episodes of nocturia and finished 12 or more months of the trial. Mean nocturia was similar in all groups at baseline. Mean nocturia was reduced at 1 year by 0.35, 0.40, 0.54 and 0.58 in the placebo, finasteride, doxazosin and combination groups, respectively. Reductions with doxazosin and combination therapy were statistically greater than with placebo (p ⬍0.05). At 4 years nocturia was also significantly reduced in patients treated with doxazosin and combination therapy (p ⬍0.05 vs placebo). In men older than 70 years (495) all drugs significantly reduced nocturia at 1 year (finasteride 0.29, doxazosin 0.46 and combination 0.42) compared to placebo (0.11, p ⬍0.05). Conclusions: Doxazosin and combination therapy reduced nocturia more than placebo, but the net benefit of active drug compared to placebo was often modest with a net difference of less than 0.20 fewer nightly nocturia episodes at 1 and 4 years. Findings in men 70 years old or older were similar, with an even smaller effect observed for finasteride. Key Words: nocturia, prostatic hyperplasia, adrenergic alpha-antagonists, finasteride
octuria, waking at night from sleep to void, is a common and bothersome symptom associated with accidental falls and resulting in poor sleep.1 Nocturia results from primary sleep disorders, the overproduction of urine at night (nocturnal polyuria) and/or conditions resulting in low voided volumes (eg BPH, detrusor overactivity).2 Men with BPH often rate nocturia as their most bothersome LUTS.3
N
Submitted for publication February 12, 2007. Complete list of MTOPS Research Group investigators is found in reference 16. Supported by cooperative agreements from the National Institute of Diabetes and Digestive and Kidney Diseases U01 DK49977, U01 DK46416, U01 DK41418, U01 DK46429, U01 DK46431, U01 DK46437, U01 DK46468, U01 DK46472, U01 DK49880, U01 DK49912, U01 DK49951, U01 DK49954, U01 DK49960, U01 DK49963, U01 DK49971 and U01 49980, and funding from the National Center for Minority Health and Health Disparities, National Institutes of Health. Additional support provided by Merck and Pfizer. Presented at annual meeting of American Urological Association, Anaheim, California, May 19 –24, 2007. * Correspondence: Atlanta Veterans Affairs Medical Center, Birmingham/Atlanta Geriatric Research, Education, and Clinical Cen-
0022-5347/07/1785-2045/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
Although studies have examined drug therapy for nocturia in men, the short duration of treatment, absence of a placebo group, or consideration of only single agent therapy are limitations.4,5 The Department of Veterans Affairs Coter, 508/11B, 1670 Clairmont Rd., Decatur, Georgia 30033 (telephone: 404-728-7775; FAX: 404-417-2912; † Financial interest and/or other relationship with Ferring and Boehringer-Ingelheim. ‡ Nothing to disclose. § Financial interest and/or other relationship with Threshold, Zentaris, Watson and Med Reviews. 储 Financial interest and/or other relationship with the Cancer and Leukemia Group B Clinical Trial Group, Aeterna Zentaris, Spectrum Pharmaceuticals, Pfizer, GlaxoSmithKline, sanofi aventis, Lilly Icos, Veterans Affairs Corporate Studies, National Institute of Diabetes and Digestive and Kidney Diseases, Urologix and Southwest Oncology Group.
For another article on a related topic see page 2213.
Editor’s Note: This article is the fourth of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 2226 and 2227.
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Vol. 178, 2045-2051, November 2007 Printed in U.S.A. DOI:10.1016/j.juro.2007.07.013
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EFFECT OF MEDICAL THERAPY ON NOCTURIA IN MEN WITH PROSTATIC SYMPTOMS
operative Studies Benign Prostatic Hyperplasia Study demonstrated that terazosin and terazosin plus finasteride reduced mean nocturia by 0.7 and 0.4 episodes, respectively, compared to a 0.3 episode reduction for participants receiving placebo only.6 The VA CSP BPH trial was limited by its short duration (1 year of therapy) and that study participants from Veterans Affairs might not be representative of the greater population of men at large.7 We examined the impact of long-term effects of doxazosin, finasteride and combination therapy on nocturia on men enrolled in the MTOPS study, a large, multicenter randomized, double-blind, placebo controlled trial.8 Additional analyses of subgroups by age (older vs younger) and degree of nocturia (1 or more or 2 or more) were conducted because of the relationship between age and LUTS, and the association between more frequent nocturia and greater bother. MATERIALS AND METHODS The study design and primary results of the MTOPS study have been previously published.8,9 The primary outcome measure was a composite end point of clinical progression of BPH, defined as a 4 point or greater increase in AUA-7 SI, acute urinary retention, urinary incontinence, recurrent urinary tract infection or renal insufficiency from BPH.10 Men were eligible for the MTOPS study if they were 50 years old or older, had an AUA-7 SI of 8 to 30 (or 8 or more for the 116 pilot study participants) and a peak uroflow of 4 to 15 ml per second on a 125 ml or larger void. Participants with a prior medical or surgical intervention for BPH, a blood pressure of less than 90/70 mm Hg, or a serum PSA 10 ng/ml or greater were excluded from analysis. There were 3,047 men randomly assigned equally to placebo, doxazosin (titrated within a month to 8 mg and reduced to 4 mg if the 8 mg dose could not be tolerated), finasteride (5 mg) or combination therapy. Men unable to tolerate finasteride or doxazosin at a dose of 4 mg or greater stopped the drug, and were followed for primary and secondary outcomes. Assessment of Nocturia The outcome for this analysis was change in self-reported nocturia. Men were included if they reported 1 or more nocturia episode at baseline in response to the AUA-7 SI question, “In the last week, how often did you most typically get up at night from the time you went to bed at night until the time you got up in the morning? (0, 1, 2, 3, 4 and 5 or more times).” Change in self-reported nocturia from baseline at 1 and 4-year followup and at both points is reported by randomized treatment assignment (intent to treat). The proportion of men with a change in nocturia from baseline defined as improved (a decrease of 1 or more episodes), no
change or worse (an increase of 1 or more episodes) is presented for each treatment groups. The reduction in mean nocturia analysis was then repeated for 2 subgroups, that is participants with 2 or more episodes of nocturia at baseline, and participants 70 years old or older and younger than 70. Statistical Analysis SAS® 8.20 was used for statistical analyses. Spearman correlations were performed to determine if prostate size by ultrasound or PSA was correlated with nocturia. Continuous variables were compared using the Wilcoxon rank sum test and categorical variables were compared using a chi-square test. The Wei-Lachin procedure, an extension of the Wilcoxon sum test that adjusts for correlation in a patient over time, was used to compare the mean change in nocturia episodes. Nominal 2-sided p values were reported. For this analysis p ⬍0.05 was considered significant without adjustment for multiple comparisons. RESULTS Of the 3,047 men at baseline 2% reported no nocturia, whereas 24%, 34%, 24%, 10% and 5% reported having 1, 2, 3, 4 and 5 or more episodes, respectively. Of men with 1 or more episodes of nocturia at baseline 2,583 (87%) were followed for at least 1 year and constitute the sample for the main analyses. Table 1 shows selected demographic and clinical characteristics of the entire sample by treatment assignment, and table 2 shows the older and younger subgroups. While results for men in the different treatment arms were similar, there were some differences. Maximum urinary flow rate was significantly different by treatment allocation for those younger than 70 years (0.4 to 0.5 ml per second lower in doxazosin group, p ⫽ 0.04). In addition, for the younger participants there was a time vs treatment interaction (the effect of these 2 interventions was different depending on what time was examined) with respect to doxazosin and finasteride. In the older subgroup there was a trend toward higher AUA-7 SI scores in certain groups (scores 0.6 to 1.6 points higher in doxazosin and combination groups, p ⫽ 0.06). In the subgroup analyses participants differed with respect to baseline characteristics. Compared to their younger counterparts the 70 years old or older subgroup had a larger prostate (p ⬍0.001), greater PVR (p ⫽ 0.020), higher PSA (p ⬍0.001), lower total AUA-7 SI score (p ⬍0.001) and were more likely to be white (p ⫽ 0.02). Those men with 2 or more episodes of nocturia (1,926) differed from those with 1 episode (657) in that they were older (61.8 vs 63.2, p ⬍0.001) and less often white (89.4% vs 82.8%, p ⬍0.001), and they
TABLE 1. Baseline characteristics of entire study population by treatment assignment (nocturia 1 or more) followed for at least 1 year
No. pts Mean pt age ⫾ SD % White Mean nocturia report ⫾ SD Mean AUA 7 SI score ⫾ SD Mean gm prostate vol ⫾ SD Mean ml/sec max flow ⫾ SD Mean cc PVR ⫾ SD Mean ng/ml PSA ⫾ SD
Placebo
Doxazosin
Finasteride
Combination
All
628 62.8 ⫾ 7.5 84.1 2.3 ⫾ 1.1 16.7 ⫾ 5.9 35.3 ⫾ 19.2 10.5 ⫾ 2.7 70 ⫾ 80 2.4 ⫾ 2.1
649 62.8 ⫾ 7.3 84.9 2.3 ⫾ 1.1 17.0 ⫾ 5.8 37.3 ⫾ 22.0 10.2 ⫾ 2.6 71 ⫾ 89 2.4 ⫾ 2.2
653 62.6 ⫾ 7.3 85.5 2.4 ⫾ 1.1 17.2 ⫾ 5.9 36.6 ⫾ 20.8 10.5 ⫾ 2.6 64 ⫾ 75 2.3 ⫾ 2.1
653 62.9 ⫾ 7.0 83.5 2.3 ⫾ 1.1 16.8 ⫾ 5.8 36.8 ⫾ 19.3 10.6 ⫾ 2.6 71 ⫾ 84 2.4 ⫾ 2.0
2,583 62.8 ⫾ 7.3 84.5 2.3 ⫾ 1.1 16.9 ⫾ 5.9 36.5 ⫾ 20.4 10.5 ⫾ 2.6 69 ⫾ 82 2.4 ⫾ 2.1
73.7 ⫾ 3.1 87.9* 2.4 ⫾ 1.1 15.6 ⫾ 5.6* 43.8 ⫾ 24.7* 10.3 ⫾ 2.5 75 ⫾ 83* 3.1 ⫾ 2.3* 60.2 ⫾ 5.3 83.7 2.3 ⫾ 1.1 17.3 ⫾ 5.9 34.8 ⫾ 18.8 10.5 ⫾ 2.6 67 ⫾ 82 2.2 ⫾ 2.0 73.9 ⫾ 2.9 90.4 2.4 ⫾ 1.1 15.6 ⫾ 5.5† 44.2 ⫾ 22.4 10.6 ⫾ 2.3 81 ⫾ 94 3.2 ⫾ 2.5 * Differences by age: white (chi-square p ⫽ 0.02), PVR (Wilcoxon p ⫽ 0.020), prostate volume, PSA and AUA-7 SI (Wilcoxon p ⬍0.001). † Trend toward difference by group (Wilcoxon p ⬍0.06). ‡ Difference by group (Wilcoxon p ⬍0.04).
60.6 ⫾ 5.3 82.0 2.3 ⫾ 1.1 17.1 ⫾ 5.9 35.2 ⫾ 18.2 10.6 ⫾ 2.6‡ 68 ⫾ 82 2.2 ⫾ 1.9 73.6 ⫾ 3.1 91.3 2.4 ⫾ 1.1 15.0 ⫾ 5.7† 42.7 ⫾ 23.3 10.0 ⫾ 2.5 73 ⫾ 77 2.9 ⫾ 2.3 60.1 ⫾ 5.3 84.1 2.4 ⫾ 1.1 17.7 ⫾ 5.9 35.2 ⫾ 20.0 10.7 ⫾ 2.6‡ 62 ⫾ 74 2.1 ⫾ 1.9 60.2 ⫾ 5.4 84.6 2.3 ⫾ 1.1 17.1 ⫾ 5.9 34.7 ⫾ 18.2 10.2 ⫾ 2.7‡ 69 ⫾ 90 2.3 ⫾ 2.1 Mean pt age ⫾ SD % White Mean nocturia report ⫾ SD Mean AUA 7 SI score ⫾ SD Mean gm prostate vol ⫾ SD Mean ml/sec max flow ⫾ SD Mean cc PVR ⫾ SD Mean ng/ml PSA ⫾ SD
60.0 ⫾ 5.4 84.0 2.3 ⫾ 1.2 17.2 ⫾ 5.9 34.0 ⫾ 18.8 10.6 ⫾ 2.7‡ 71 ⫾ 82 2.2 ⫾ 2.0
73.8 ⫾ 3.4 84.3 2.3 ⫾ 1.1 14.9 ⫾ 5.6† 40.5 ⫾ 20.2 10.3 ⫾ 2.6 70 ⫾ 74 3.1 ⫾ 2.3
73.4 ⫾ 3.0 85.9 2.5 ⫾ 1.1 16.6 ⫾ 5.6† 48 ⫾ 31 10.3 ⫾ 2.4 78 ⫾ 86 3.0 ⫾ 2.3
Younger Than 70 Yrs 70 Yrs or Older
Combination
Younger Than 70 Yrs 70 Yrs or Older
Finasteride
Younger Than 70 Yrs 70 Yrs or Older
Doxazosin
Younger Than 70 Yrs 70 Yrs or Older
Placebo
Younger Than 70 Yrs
TABLE 2. Baseline characteristics of study participants by age and treatment assignment (nocturia 1 or more) followed for at least 1 year
All
70 Yrs or Older
EFFECT OF MEDICAL THERAPY ON NOCTURIA IN MEN WITH PROSTATIC SYMPTOMS
2047
had a lower maximum urinary flow rate (10.7 vs 10.4 ml per second, p ⫽ 0.004). While the AUA-7 SI was higher, as anticipated, for those with 2 or more episodes of nocturia (14.3 to 17.8, p ⬍0.001), mean PVR and PSA were not different. The mean change in nocturia by treatment assignment at 1 and 4 years as well as subgroup analyses are shown in table 3. At 1 year mean nocturia in the placebo and finasteride groups decreased by 0.35 and 0.40 episodes, respectively, whereas the reduction in the doxazosin and combination therapy groups was 0.54 and 0.58 episodes, respectively (p ⬍0.05 for doxazosin and combination vs either placebo or finasteride). Similar reductions in the mean number of episodes were observed over 4 years of followup and at both time points (p ⬍0.05 for doxazosin and combination vs placebo). In the younger subgroup no treatments by year 4 were statistically different from placebo. In men 70 years old or older each drug treatment group had a statistically significant reduction in mean episodes of nocturia (p ⬍0.05) at 1 year (doxazosin 0.46, finasteride 0.29 and combination 0.42) compared to placebo (0.11) and similar reductions were observed at year 4. With respect to the 1-year outcomes for the participants with 2 or more nocturia episodes, the mean number of nocturia episodes in the placebo and finasteride groups was reduced by 0.61 and 0.60 episodes, respectively, whereas the reduction in the doxazosin and combination therapy groups was 0.77 and 0.80 episodes, respectively (p ⬍0.05 for doxazosin and combination vs either placebo or finasteride). Mean reductions in nocturia were similar at 4 years yet there were no longer statistical differences among treatments. The figure shows the percentage of participants with improved status, with no change or worse condition at 1 and 4 years. Doxazosin (47.2% had 1 or more episode reduction) and combination therapy (47.9% had reduction) demonstrated statistically greater percentages of participants with improvement compared to finasteride (38.7%) and placebo (35.8%). The net difference in percentages of those who had improvement (doxazosin or combination vs placebo) was 11% to 12% of the men at 1 year and 4% to 7% of the men at 4 years. For the whole sample neither baseline prostate volume nor baseline PSA was significantly associated with nocturia (p ⫽ 0.40 and 0.60, respectively). DISCUSSION This secondary data analysis of a randomized, doubleblinded, placebo controlled trial demonstrated that participants with LUTS believed to be due to BPH who received doxazosin with or without finasteride had significant reductions in nocturia. The mean reduction in nocturia for doxazosin or combination therapy varied between 0.4 and 0.8 episodes, which may or may not represent a meaningful change.11 Doxazosin and combination therapy were statistically superior to placebo in nearly every analysis of those with 1 or more nocturia episodes at baseline, except for the subgroup of age less than 70 years at 4 years. The mean reduction in nocturia with finasteride varied from 0.3 to 0.7 episodes. Only for men 70 years old or older and only at 1 year was reduction in nocturia with finasteride statistically greater than the response with placebo. In all
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EFFECT OF MEDICAL THERAPY ON NOCTURIA IN MEN WITH PROSTATIC SYMPTOMS TABLE 3. Change in nocturia from baseline
Completing at least 1 yr with 1 or more episodes of nocturia at baseline: Yr 1 Yr 4 Younger than 70 yrs:‡ Yr 1 Yr 4 70 Yrs old or older: Yr 1 Yr 4 All ages with 2⫹ nocturia episodes at baseline: Yr 1 Yr 4
No. Placebo (mean change)
No. Doxazosin (mean change)
No. Finasteride (mean change)
No. Combination (mean change)
628 (⫺0.35) 488 (⫺0.38)
649 (⫺0.54)*,† 533 (⫺0.53)*
653 (⫺0.40) 516 (⫺0.42)
653 (⫺0.58)*,† 528 (⫺0.55)
501 (⫺0.41) 389 (⫺0.46)
521 (⫺0.56)*,† 428 (⫺0.52)
527 (⫺0.43) 417 (⫺0.45)
539 (⫺0.61)*,† 442 (⫺0.58)
127 (⫺0.11) 99 (⫺0.08)
128 (⫺0.46)* 105 (⫺0.59)*
126 (⫺0.29)* 99 (⫺0.29)
114 (⫺0.42)* 89 (⫺0.40)*
459 (⫺0.61) 354 (⫺0.66)
484 (⫺0.77)*,† 393 (⫺0.77)
496 (⫺0.60) 385 (⫺0.68)
487 (⫺0.80)*,† 393 (⫺0.79)
* p ⬍0.05 vs placebo. † p ⬍0.05 vs finasteride. ‡ Treatment vs time interaction for men younger than 70 years who were allocated to doxazosin compared to those allocated to finasteride.
other analyses there was no benefit of finasteride compared to placebo. While combination therapy was efficacious for nocturia, in no analysis was combination therapy statistically better than doxazosin alone. For whatever reasons those men allocated to the placebo group might have reduced nocturia (participant expectations, increased attention to symptoms resulting in behavioral changes, regression to the mean), this effect was smaller in men 70 years old or older. This finding suggests that watchful waiting of nocturia in older adults might not be a successful strategy. While older study participants had, as expected, higher PSA values, larger prostate volume and larger PVR, they also unexpectedly had lower AUA-7 SI scores, similar uroflow rates and similar nocturia reports. These latter values normally worsen with aging.12,13 Because of the placebo controlled, double-blind trial design, each active treatment arm can be compared to placebo. These net reductions in mean nocturia (effect of active drug minus placebo group response) were often small, mainly because of the robust placebo effect. The net reduction in mean nocturia with doxazosin (alone or in combination) vs placebo was modest, ranging from 0.1 to 0.3 episodes for most groups (those 70 years old or older at 4 years had a 0.5 advantage with doxazosin compared to placebo). Because the clinical significance of a 0.1 to 0.3 mean nightly reduction is somewhat elusive, the percentage of participants reporting a decrease in nocturia of 1 episode or more at 1 year was analyzed. Of those on placebo 35.8% and of those on doxazosin 47.2% had at least 1 less episode of nocturia, which yields a marginal benefit of 11%. The 4-year results (40.4% of those on placebo and 44.7% of those on doxazosin for a marginal benefit of 4%) are less impressive. The nocturia reductions for doxazosin here are comparable to other published data on ␣-blockers. In a recent 12week study of 879 men with overactive bladder, the ␣-blocker tamsulosin reduced nocturia by a mean of 0.5 episodes (compared to 0.3 episodes for placebo, not significant). In that study combination therapy with tamsulosin and tolterodine resulted in a mean nocturia reduction of approximately 0.6 episodes, p ⫽ 0.02, vs placebo.14 In the Veterans Affairs Cooperative Study of Medical Treatment of BPH, terazosin reduced mean nocturia by 0.7 episodes (placebo 0.4 episode reduction).7 In another study with a different methodology (open label administration followed by
placebo controlled double-blind washout for responders), terazosin yielded a mean nocturia reduction of 1.0 episodes followed by a mean increase of 0.5 episodes with washout.15 These analyses have several important, practical ramifications. On average, men who have BPH will likely have fewer episodes of nocturia with ␣-blocker treatment. A good proportion, although not a majority, will report getting up an average of 1 less time each night. While finasteride may have benefits for several BPH outcomes it will not generally reduce nocturia. Older men may have a slightly greater benefit with finasteride, relative to placebo, for nocturia. In addition, finasteride and ␣-blockers combined offered no statistical advantage compared to ␣-blockers alone for nocturia. It remains to be seen if other 5␣-reductase inhibitors have superior efficacy for nocturia reduction. As demonstrated elsewhere the nocturia reduction from ␣-blockers in men with LUTS/BPH is rather modest, particularly when considering the net effect compared to placebo.7 These results are likely superior to average results in clinical practice as research trials have monitored compliance with therapy in a population selected for the best chance to benefit. There may be a need in clinical practice to look for and perhaps treat additional causes of nocturia. The strengths of this secondary data analysis include large sample size, use of a standard, validated instrument to assess nocturia, long-term followup and the use of the placebo group. Even with these strengths the limitations of this study should be mentioned. The study was not designed to specifically look at nocturia, although most men enrolled had nocturia (98%). Additionally, men were neither evaluated nor specifically treated for polyuria syndromes, which are an important cause of nocturia. The main outcome measure of nocturia is an estimated, selfreported average and no diary data were available. While self-reported nocturia has been validated against diaries16 and 24-hour monitoring,17 some studies have shown that these nocturia self-reports differ from diaries.18 In the VA CSP BPH trial the reliability of self-reported nocturia at baseline and after 2 weeks of placebo was strong with a 0.71 correlation. For 93% of participants nocturia was identical or differed by only 1 episode.7 These problems with self-reported nocturia make this analysis less
EFFECT OF MEDICAL THERAPY ON NOCTURIA IN MEN WITH PROSTATIC SYMPTOMS
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Percentage of participants having worse, no change or improved nocturia relative to baseline by treatment group. Report of worse nocturia is 1 or more additional episodes of nocturia at 1 year compared to initial self-report at baseline. Improve represents decrease in nocturia self-report by 1 or more episodes. A, outcomes at 1 year (chi-square 37.9, p ⬍0.001). B, outcomes at 4 years (chi-square 13.6, p ⬍0.001). For both comparisons df ⫽ 6.
precise but not biased (nocturia estimates should not vary by treatment assignment). For the 5% of the sample who reported 5 or more nocturia episodes, there could be a ceiling effect (those reducing from 7 to 5 nightly nocturia episodes, for instance, would be erroneously captured as no change). Other studies in which respondents were of-
fered more response choices for nocturia (0 through 10) demonstrated that only 1% of respondents had 6 or more episodes of nocturia.19 Therefore, this ceiling effect might be minimal. Lastly, the lack of a standardized, accepted quality of life measure specific for nocturia is a limitation.20
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EFFECT OF MEDICAL THERAPY ON NOCTURIA IN MEN WITH PROSTATIC SYMPTOMS
CONCLUSIONS Doxazosin alone or in combination with finasteride reduced episodes of nocturia in men with BPH to a greater extent than did placebo or finasteride alone. Doxazosin treatment reduced nocturia by 0.4 to 0.8 episodes depending on the specific analysis. The net advantage in the main analysis for doxazosin compared to placebo was a mean reduction of 0.2 nocturia episodes. Four-year data were similar to the 1-year results. In contrast to the parent study analyses in which finasteride demonstrated benefit with respect to a combined clinical end point for BPH, nocturia reductions with finasteride were not statistically greater than those with placebo (except in 1 subanalysis for participants 70 years old or older at only 1 year). The combination of finasteride and doxazosin was not superior to doxazosin alone in reducing nocturia.
Abbreviations and Acronyms AUA-7 SI ⫽ American Urological Association 7 Symptom Inventory BPH ⫽ benign prostatic hyperplasia LUTS ⫽ lower urinary tract symptoms MTOPS ⫽ Medical Treatment of Prostatic Symptoms PSA ⫽ prostate specific antigen PVR ⫽ post-void residual VA CSP BPH trial ⫽ Veterans Affairs Cooperative Study of BPH Trial
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REFERENCES 1.
2. 3.
4.
5.
6.
7.
van Kerrebroeck P, Abrams P, Chaikin D, Donovan J, Fonda D, Jackson S et al: The standardisation of terminology in nocturia: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21: 179. Weiss JP and Blaivas JG: Nocturia. Curr Urol Rep 2003; 4: 362. DuBeau CE, Yalla SV and Resnick NM: Implications of the most bothersome prostatism symptom for clinical care and outcomes research. J Am Geriatr Soc 1995; 43: 985. Gourova LW, van de Beek C, Spigt MG, Nieman FH and van Kerrebroeck PE: Predictive factors for nocturia in elderly men: a cross-sectional study in 21 general practices. BJU Int 2006; 97: 528. Nishino Y, Masue T, Miwa K, Takahashi Y, Ishihara S and Deguchi T: Comparison of two alpha1-adrenoceptor antagonists, naftopidil and tamsulosin hydrochloride, in the treatment of lower urinary tract symptoms with benign prostatic hyperplasia: a randomized crossover study. BJU Int 2006; 97: 747. Johnson TM 2nd, Jones K, Williford WO, Kutner MH, Issa MM and Lepor H: Changes in nocturia from medical treatment of benign prostatic hyperplasia: secondary analysis of the Department of Veterans Affairs Cooperative Study Trial. J Urol 2003; 170: 145. Lepor H, Williford WO, Barry MJ, Brawer MK, Dixon CM, Gormley G et al: The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med 1996; 335: 533.
19.
20.
McConnell J, Roehrborn C, Bautista O, Andriole GJ, Dixon C, Kusek J et al: The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349: 2387. Bautista OM, Kusek JW, Nyberg LM, McConnell JD, Bain RP, Miller G et al: Study design of the Medical Therapy of Prostatic Symptoms (MTOPS) trial. Control Clin Trials 2003; 24: 224. Barry MJ, Fowler FJ Jr, O’Leary MP, Bruskewitz RC, Holtgrewe HL, Mebust WK et al: The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992; 148: 1549. Wein A: Editorial comment. J Urol 2006; 175: 1434. Drach G, Ignatoff J and Layton T: Peak urinary flow rate: observations in female subjects and comparison to male subjects. J Urol 1979; 122: 215. Tikkinen KA, Tammela TL, Huhtala H and Auvinen A: Is nocturia equally common among men and women? A population based study in Finland. J Urol 2006; 175: 596. Kaplan SA, Roehrborn CG, Rovner ES, Bavendam T and Guan Z: Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder. JAMA 2006; 296: 2319. Debruyne FM, Witjes WP, Fitzpatrick J, Kirby R, Kirk D and Prezioso D: The international terazosin trial: a multicentre study of the long-term efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia. The ITT Group. Eur Urol 1996; 30: 369. Abrams P and Klevmark B: Frequency volume charts: an indispensable part of lower urinary tract assessment. Scand J Urol Nephrol, suppl., 1996; 179: 47. Matzkin H, Greenstein A, Prager-Geller T, Sofer M and Braf Z: Do reported micturition symptoms on the American Urological Association Questionnaire correlate with 24-hour home uroflowmetry recordings? J Urol 1996; 155: 197. Blanker MH, Bohnen AM, Groeneveld FP, Bernsen RM, Prins A and Ruud Bosch JL: Normal voiding patterns and determinants of increased diurnal and nocturnal voiding frequency in elderly men. J Urol 2000; 164: 1201. Johnson TM 2nd, Sattin RW, Parmelee P, Fultz NH and Ouslander JG: Evaluating potentially modifiable risk factors for prevalent and incident nocturia in older adults. J Am Geriatr Soc 2005; 53: 1011. Abraham L, Hareendran A, Mills IW, Martin ML, Abrams P, Drake MJ et al: Development and validation of a qualityof-life measure for men with nocturia. Urology 2004; 63: 481.
EDITORIAL COMMENT The authors have performed a secondary analysis of the MTOPS trial with emphasis on the outcomes of treatment of nocturia with doxazosin alone, finasteride alone, combination therapy or placebo. The principle outcomes instrument was patient self-report of nocturia. Notwithstanding this obvious limitation (the lack of diary data to substantiate outcomes based on patient recall), the large size of the database combined with a detailed analysis regarding correlation of nocturia self-report and diary data afford the reader valuable insight as to expectations for nocturia treatment efficacy using ␣-blockers, 5␣-reductase inhibitors or a combination thereof. The take home message is that treatment of nocturia in unselected patients using monotherapy or combination therapy for prostatic obstruction yields minimal, albeit statistically significant, benefit compared with placebo.1,2 The likeliest hope for nocturia improvement in
EFFECT OF MEDICAL THERAPY ON NOCTURIA IN MEN WITH PROSTATIC SYMPTOMS this series occurred in men treated with doxazosin alone who were 70 years old or older (0.5 decrease in episodes of nocturia compared with placebo at 4 years). Combination therapy and finasteride alone conferred no statistical advantage compared to doxazosin alone in the treatment of nocturia. It is worth noting that patients were not treated according to a classification scheme which may have selected more appropriate candidates with nocturia for therapy. For example, any of the treatment arms presented may have demonstrated improved outcomes had patients with nocturia been selected for low bladder capacity as opposed to nocturnal polyuria or global polyuria. The authors correctly point out that the MTOPS trial was not designed to treat nocturia per se, although the majority of men studied had
2051
nocturia. The limitations and value of this subanalysis are clearly reviewed by the authors. Jeffrey P. Weiss Department of Urology Weill Medical College of Cornell University New York, New York 1.
2.
Kaplan SA, McConnell JD, Roehrborn CG, Meehan AG, Lee MW, Noble WR et al: Combination therapy with doxazosin and finasteride for benign prostatic hyperplasia in patients with lower urinary tract symptoms and a baseline total prostate volume of 25 ml or greater. J Urol 2006; 175: 217. Logan YT and Belgeri MT: Monotherapy versus combination drug therapy for the treatment of benign prostatic hyperplasia. Am J Geriatr Pharmacother 2005; 3: 103.
Purpose: We evaluated the effectiveness of single or combination drug therapy on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Materials and Methods: A total of 3,047 men with lower urinary tract symptoms/benign prostatic hyperplasia enrolled in the Medical Therapy of Prostatic Symptoms trial were randomly assigned to receive doxazosin alone, finasteride alone, combination therapy or placebo. Treatment effectiveness was assessed according to intent to treat by mean reduction in self-reported nightly nocturia at 1 and 4 years. A subgroup analysis by age (younger than 70 vs 70 years old or older) was also performed. Results: Of the men 2,583 reported 1 or more episodes of nocturia and finished 12 or more months of the trial. Mean nocturia was similar in all groups at baseline. Mean nocturia was reduced at 1 year by 0.35, 0.40, 0.54 and 0.58 in the placebo, finasteride, doxazosin and combination groups, respectively. Reductions with doxazosin and combination therapy were statistically greater than with placebo (p ⬍0.05). At 4 years nocturia was also significantly reduced in patients treated with doxazosin and combination therapy (p ⬍0.05 vs placebo). In men older than 70 years (495) all drugs significantly reduced nocturia at 1 year (finasteride 0.29, doxazosin 0.46 and combination 0.42) compared to placebo (0.11, p ⬍0.05). Conclusions: Doxazosin and combination therapy reduced nocturia more than placebo, but the net benefit of active drug compared to placebo was often modest with a net difference of less than 0.20 fewer nightly nocturia episodes at 1 and 4 years. Findings in men 70 years old or older were similar, with an even smaller effect observed for finasteride. Key Words: nocturia, prostatic hyperplasia, adrenergic alpha-antagonists, finasteride
octuria, waking at night from sleep to void, is a common and bothersome symptom associated with accidental falls and resulting in poor sleep.1 Nocturia results from primary sleep disorders, the overproduction of urine at night (nocturnal polyuria) and/or conditions resulting in low voided volumes (eg BPH, detrusor overactivity).2 Men with BPH often rate nocturia as their most bothersome LUTS.3
N
Submitted for publication February 12, 2007. Complete list of MTOPS Research Group investigators is found in reference 16. Supported by cooperative agreements from the National Institute of Diabetes and Digestive and Kidney Diseases U01 DK49977, U01 DK46416, U01 DK41418, U01 DK46429, U01 DK46431, U01 DK46437, U01 DK46468, U01 DK46472, U01 DK49880, U01 DK49912, U01 DK49951, U01 DK49954, U01 DK49960, U01 DK49963, U01 DK49971 and U01 49980, and funding from the National Center for Minority Health and Health Disparities, National Institutes of Health. Additional support provided by Merck and Pfizer. Presented at annual meeting of American Urological Association, Anaheim, California, May 19 –24, 2007. * Correspondence: Atlanta Veterans Affairs Medical Center, Birmingham/Atlanta Geriatric Research, Education, and Clinical Cen-
0022-5347/07/1785-2045/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
Although studies have examined drug therapy for nocturia in men, the short duration of treatment, absence of a placebo group, or consideration of only single agent therapy are limitations.4,5 The Department of Veterans Affairs Coter, 508/11B, 1670 Clairmont Rd., Decatur, Georgia 30033 (telephone: 404-728-7775; FAX: 404-417-2912; † Financial interest and/or other relationship with Ferring and Boehringer-Ingelheim. ‡ Nothing to disclose. § Financial interest and/or other relationship with Threshold, Zentaris, Watson and Med Reviews. 储 Financial interest and/or other relationship with the Cancer and Leukemia Group B Clinical Trial Group, Aeterna Zentaris, Spectrum Pharmaceuticals, Pfizer, GlaxoSmithKline, sanofi aventis, Lilly Icos, Veterans Affairs Corporate Studies, National Institute of Diabetes and Digestive and Kidney Diseases, Urologix and Southwest Oncology Group.
For another article on a related topic see page 2213.
Editor’s Note: This article is the fourth of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 2226 and 2227.
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Vol. 178, 2045-2051, November 2007 Printed in U.S.A. DOI:10.1016/j.juro.2007.07.013
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EFFECT OF MEDICAL THERAPY ON NOCTURIA IN MEN WITH PROSTATIC SYMPTOMS
operative Studies Benign Prostatic Hyperplasia Study demonstrated that terazosin and terazosin plus finasteride reduced mean nocturia by 0.7 and 0.4 episodes, respectively, compared to a 0.3 episode reduction for participants receiving placebo only.6 The VA CSP BPH trial was limited by its short duration (1 year of therapy) and that study participants from Veterans Affairs might not be representative of the greater population of men at large.7 We examined the impact of long-term effects of doxazosin, finasteride and combination therapy on nocturia on men enrolled in the MTOPS study, a large, multicenter randomized, double-blind, placebo controlled trial.8 Additional analyses of subgroups by age (older vs younger) and degree of nocturia (1 or more or 2 or more) were conducted because of the relationship between age and LUTS, and the association between more frequent nocturia and greater bother. MATERIALS AND METHODS The study design and primary results of the MTOPS study have been previously published.8,9 The primary outcome measure was a composite end point of clinical progression of BPH, defined as a 4 point or greater increase in AUA-7 SI, acute urinary retention, urinary incontinence, recurrent urinary tract infection or renal insufficiency from BPH.10 Men were eligible for the MTOPS study if they were 50 years old or older, had an AUA-7 SI of 8 to 30 (or 8 or more for the 116 pilot study participants) and a peak uroflow of 4 to 15 ml per second on a 125 ml or larger void. Participants with a prior medical or surgical intervention for BPH, a blood pressure of less than 90/70 mm Hg, or a serum PSA 10 ng/ml or greater were excluded from analysis. There were 3,047 men randomly assigned equally to placebo, doxazosin (titrated within a month to 8 mg and reduced to 4 mg if the 8 mg dose could not be tolerated), finasteride (5 mg) or combination therapy. Men unable to tolerate finasteride or doxazosin at a dose of 4 mg or greater stopped the drug, and were followed for primary and secondary outcomes. Assessment of Nocturia The outcome for this analysis was change in self-reported nocturia. Men were included if they reported 1 or more nocturia episode at baseline in response to the AUA-7 SI question, “In the last week, how often did you most typically get up at night from the time you went to bed at night until the time you got up in the morning? (0, 1, 2, 3, 4 and 5 or more times).” Change in self-reported nocturia from baseline at 1 and 4-year followup and at both points is reported by randomized treatment assignment (intent to treat). The proportion of men with a change in nocturia from baseline defined as improved (a decrease of 1 or more episodes), no
change or worse (an increase of 1 or more episodes) is presented for each treatment groups. The reduction in mean nocturia analysis was then repeated for 2 subgroups, that is participants with 2 or more episodes of nocturia at baseline, and participants 70 years old or older and younger than 70. Statistical Analysis SAS® 8.20 was used for statistical analyses. Spearman correlations were performed to determine if prostate size by ultrasound or PSA was correlated with nocturia. Continuous variables were compared using the Wilcoxon rank sum test and categorical variables were compared using a chi-square test. The Wei-Lachin procedure, an extension of the Wilcoxon sum test that adjusts for correlation in a patient over time, was used to compare the mean change in nocturia episodes. Nominal 2-sided p values were reported. For this analysis p ⬍0.05 was considered significant without adjustment for multiple comparisons. RESULTS Of the 3,047 men at baseline 2% reported no nocturia, whereas 24%, 34%, 24%, 10% and 5% reported having 1, 2, 3, 4 and 5 or more episodes, respectively. Of men with 1 or more episodes of nocturia at baseline 2,583 (87%) were followed for at least 1 year and constitute the sample for the main analyses. Table 1 shows selected demographic and clinical characteristics of the entire sample by treatment assignment, and table 2 shows the older and younger subgroups. While results for men in the different treatment arms were similar, there were some differences. Maximum urinary flow rate was significantly different by treatment allocation for those younger than 70 years (0.4 to 0.5 ml per second lower in doxazosin group, p ⫽ 0.04). In addition, for the younger participants there was a time vs treatment interaction (the effect of these 2 interventions was different depending on what time was examined) with respect to doxazosin and finasteride. In the older subgroup there was a trend toward higher AUA-7 SI scores in certain groups (scores 0.6 to 1.6 points higher in doxazosin and combination groups, p ⫽ 0.06). In the subgroup analyses participants differed with respect to baseline characteristics. Compared to their younger counterparts the 70 years old or older subgroup had a larger prostate (p ⬍0.001), greater PVR (p ⫽ 0.020), higher PSA (p ⬍0.001), lower total AUA-7 SI score (p ⬍0.001) and were more likely to be white (p ⫽ 0.02). Those men with 2 or more episodes of nocturia (1,926) differed from those with 1 episode (657) in that they were older (61.8 vs 63.2, p ⬍0.001) and less often white (89.4% vs 82.8%, p ⬍0.001), and they
TABLE 1. Baseline characteristics of entire study population by treatment assignment (nocturia 1 or more) followed for at least 1 year
No. pts Mean pt age ⫾ SD % White Mean nocturia report ⫾ SD Mean AUA 7 SI score ⫾ SD Mean gm prostate vol ⫾ SD Mean ml/sec max flow ⫾ SD Mean cc PVR ⫾ SD Mean ng/ml PSA ⫾ SD
Placebo
Doxazosin
Finasteride
Combination
All
628 62.8 ⫾ 7.5 84.1 2.3 ⫾ 1.1 16.7 ⫾ 5.9 35.3 ⫾ 19.2 10.5 ⫾ 2.7 70 ⫾ 80 2.4 ⫾ 2.1
649 62.8 ⫾ 7.3 84.9 2.3 ⫾ 1.1 17.0 ⫾ 5.8 37.3 ⫾ 22.0 10.2 ⫾ 2.6 71 ⫾ 89 2.4 ⫾ 2.2
653 62.6 ⫾ 7.3 85.5 2.4 ⫾ 1.1 17.2 ⫾ 5.9 36.6 ⫾ 20.8 10.5 ⫾ 2.6 64 ⫾ 75 2.3 ⫾ 2.1
653 62.9 ⫾ 7.0 83.5 2.3 ⫾ 1.1 16.8 ⫾ 5.8 36.8 ⫾ 19.3 10.6 ⫾ 2.6 71 ⫾ 84 2.4 ⫾ 2.0
2,583 62.8 ⫾ 7.3 84.5 2.3 ⫾ 1.1 16.9 ⫾ 5.9 36.5 ⫾ 20.4 10.5 ⫾ 2.6 69 ⫾ 82 2.4 ⫾ 2.1
73.7 ⫾ 3.1 87.9* 2.4 ⫾ 1.1 15.6 ⫾ 5.6* 43.8 ⫾ 24.7* 10.3 ⫾ 2.5 75 ⫾ 83* 3.1 ⫾ 2.3* 60.2 ⫾ 5.3 83.7 2.3 ⫾ 1.1 17.3 ⫾ 5.9 34.8 ⫾ 18.8 10.5 ⫾ 2.6 67 ⫾ 82 2.2 ⫾ 2.0 73.9 ⫾ 2.9 90.4 2.4 ⫾ 1.1 15.6 ⫾ 5.5† 44.2 ⫾ 22.4 10.6 ⫾ 2.3 81 ⫾ 94 3.2 ⫾ 2.5 * Differences by age: white (chi-square p ⫽ 0.02), PVR (Wilcoxon p ⫽ 0.020), prostate volume, PSA and AUA-7 SI (Wilcoxon p ⬍0.001). † Trend toward difference by group (Wilcoxon p ⬍0.06). ‡ Difference by group (Wilcoxon p ⬍0.04).
60.6 ⫾ 5.3 82.0 2.3 ⫾ 1.1 17.1 ⫾ 5.9 35.2 ⫾ 18.2 10.6 ⫾ 2.6‡ 68 ⫾ 82 2.2 ⫾ 1.9 73.6 ⫾ 3.1 91.3 2.4 ⫾ 1.1 15.0 ⫾ 5.7† 42.7 ⫾ 23.3 10.0 ⫾ 2.5 73 ⫾ 77 2.9 ⫾ 2.3 60.1 ⫾ 5.3 84.1 2.4 ⫾ 1.1 17.7 ⫾ 5.9 35.2 ⫾ 20.0 10.7 ⫾ 2.6‡ 62 ⫾ 74 2.1 ⫾ 1.9 60.2 ⫾ 5.4 84.6 2.3 ⫾ 1.1 17.1 ⫾ 5.9 34.7 ⫾ 18.2 10.2 ⫾ 2.7‡ 69 ⫾ 90 2.3 ⫾ 2.1 Mean pt age ⫾ SD % White Mean nocturia report ⫾ SD Mean AUA 7 SI score ⫾ SD Mean gm prostate vol ⫾ SD Mean ml/sec max flow ⫾ SD Mean cc PVR ⫾ SD Mean ng/ml PSA ⫾ SD
60.0 ⫾ 5.4 84.0 2.3 ⫾ 1.2 17.2 ⫾ 5.9 34.0 ⫾ 18.8 10.6 ⫾ 2.7‡ 71 ⫾ 82 2.2 ⫾ 2.0
73.8 ⫾ 3.4 84.3 2.3 ⫾ 1.1 14.9 ⫾ 5.6† 40.5 ⫾ 20.2 10.3 ⫾ 2.6 70 ⫾ 74 3.1 ⫾ 2.3
73.4 ⫾ 3.0 85.9 2.5 ⫾ 1.1 16.6 ⫾ 5.6† 48 ⫾ 31 10.3 ⫾ 2.4 78 ⫾ 86 3.0 ⫾ 2.3
Younger Than 70 Yrs 70 Yrs or Older
Combination
Younger Than 70 Yrs 70 Yrs or Older
Finasteride
Younger Than 70 Yrs 70 Yrs or Older
Doxazosin
Younger Than 70 Yrs 70 Yrs or Older
Placebo
Younger Than 70 Yrs
TABLE 2. Baseline characteristics of study participants by age and treatment assignment (nocturia 1 or more) followed for at least 1 year
All
70 Yrs or Older
EFFECT OF MEDICAL THERAPY ON NOCTURIA IN MEN WITH PROSTATIC SYMPTOMS
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had a lower maximum urinary flow rate (10.7 vs 10.4 ml per second, p ⫽ 0.004). While the AUA-7 SI was higher, as anticipated, for those with 2 or more episodes of nocturia (14.3 to 17.8, p ⬍0.001), mean PVR and PSA were not different. The mean change in nocturia by treatment assignment at 1 and 4 years as well as subgroup analyses are shown in table 3. At 1 year mean nocturia in the placebo and finasteride groups decreased by 0.35 and 0.40 episodes, respectively, whereas the reduction in the doxazosin and combination therapy groups was 0.54 and 0.58 episodes, respectively (p ⬍0.05 for doxazosin and combination vs either placebo or finasteride). Similar reductions in the mean number of episodes were observed over 4 years of followup and at both time points (p ⬍0.05 for doxazosin and combination vs placebo). In the younger subgroup no treatments by year 4 were statistically different from placebo. In men 70 years old or older each drug treatment group had a statistically significant reduction in mean episodes of nocturia (p ⬍0.05) at 1 year (doxazosin 0.46, finasteride 0.29 and combination 0.42) compared to placebo (0.11) and similar reductions were observed at year 4. With respect to the 1-year outcomes for the participants with 2 or more nocturia episodes, the mean number of nocturia episodes in the placebo and finasteride groups was reduced by 0.61 and 0.60 episodes, respectively, whereas the reduction in the doxazosin and combination therapy groups was 0.77 and 0.80 episodes, respectively (p ⬍0.05 for doxazosin and combination vs either placebo or finasteride). Mean reductions in nocturia were similar at 4 years yet there were no longer statistical differences among treatments. The figure shows the percentage of participants with improved status, with no change or worse condition at 1 and 4 years. Doxazosin (47.2% had 1 or more episode reduction) and combination therapy (47.9% had reduction) demonstrated statistically greater percentages of participants with improvement compared to finasteride (38.7%) and placebo (35.8%). The net difference in percentages of those who had improvement (doxazosin or combination vs placebo) was 11% to 12% of the men at 1 year and 4% to 7% of the men at 4 years. For the whole sample neither baseline prostate volume nor baseline PSA was significantly associated with nocturia (p ⫽ 0.40 and 0.60, respectively). DISCUSSION This secondary data analysis of a randomized, doubleblinded, placebo controlled trial demonstrated that participants with LUTS believed to be due to BPH who received doxazosin with or without finasteride had significant reductions in nocturia. The mean reduction in nocturia for doxazosin or combination therapy varied between 0.4 and 0.8 episodes, which may or may not represent a meaningful change.11 Doxazosin and combination therapy were statistically superior to placebo in nearly every analysis of those with 1 or more nocturia episodes at baseline, except for the subgroup of age less than 70 years at 4 years. The mean reduction in nocturia with finasteride varied from 0.3 to 0.7 episodes. Only for men 70 years old or older and only at 1 year was reduction in nocturia with finasteride statistically greater than the response with placebo. In all
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EFFECT OF MEDICAL THERAPY ON NOCTURIA IN MEN WITH PROSTATIC SYMPTOMS TABLE 3. Change in nocturia from baseline
Completing at least 1 yr with 1 or more episodes of nocturia at baseline: Yr 1 Yr 4 Younger than 70 yrs:‡ Yr 1 Yr 4 70 Yrs old or older: Yr 1 Yr 4 All ages with 2⫹ nocturia episodes at baseline: Yr 1 Yr 4
No. Placebo (mean change)
No. Doxazosin (mean change)
No. Finasteride (mean change)
No. Combination (mean change)
628 (⫺0.35) 488 (⫺0.38)
649 (⫺0.54)*,† 533 (⫺0.53)*
653 (⫺0.40) 516 (⫺0.42)
653 (⫺0.58)*,† 528 (⫺0.55)
501 (⫺0.41) 389 (⫺0.46)
521 (⫺0.56)*,† 428 (⫺0.52)
527 (⫺0.43) 417 (⫺0.45)
539 (⫺0.61)*,† 442 (⫺0.58)
127 (⫺0.11) 99 (⫺0.08)
128 (⫺0.46)* 105 (⫺0.59)*
126 (⫺0.29)* 99 (⫺0.29)
114 (⫺0.42)* 89 (⫺0.40)*
459 (⫺0.61) 354 (⫺0.66)
484 (⫺0.77)*,† 393 (⫺0.77)
496 (⫺0.60) 385 (⫺0.68)
487 (⫺0.80)*,† 393 (⫺0.79)
* p ⬍0.05 vs placebo. † p ⬍0.05 vs finasteride. ‡ Treatment vs time interaction for men younger than 70 years who were allocated to doxazosin compared to those allocated to finasteride.
other analyses there was no benefit of finasteride compared to placebo. While combination therapy was efficacious for nocturia, in no analysis was combination therapy statistically better than doxazosin alone. For whatever reasons those men allocated to the placebo group might have reduced nocturia (participant expectations, increased attention to symptoms resulting in behavioral changes, regression to the mean), this effect was smaller in men 70 years old or older. This finding suggests that watchful waiting of nocturia in older adults might not be a successful strategy. While older study participants had, as expected, higher PSA values, larger prostate volume and larger PVR, they also unexpectedly had lower AUA-7 SI scores, similar uroflow rates and similar nocturia reports. These latter values normally worsen with aging.12,13 Because of the placebo controlled, double-blind trial design, each active treatment arm can be compared to placebo. These net reductions in mean nocturia (effect of active drug minus placebo group response) were often small, mainly because of the robust placebo effect. The net reduction in mean nocturia with doxazosin (alone or in combination) vs placebo was modest, ranging from 0.1 to 0.3 episodes for most groups (those 70 years old or older at 4 years had a 0.5 advantage with doxazosin compared to placebo). Because the clinical significance of a 0.1 to 0.3 mean nightly reduction is somewhat elusive, the percentage of participants reporting a decrease in nocturia of 1 episode or more at 1 year was analyzed. Of those on placebo 35.8% and of those on doxazosin 47.2% had at least 1 less episode of nocturia, which yields a marginal benefit of 11%. The 4-year results (40.4% of those on placebo and 44.7% of those on doxazosin for a marginal benefit of 4%) are less impressive. The nocturia reductions for doxazosin here are comparable to other published data on ␣-blockers. In a recent 12week study of 879 men with overactive bladder, the ␣-blocker tamsulosin reduced nocturia by a mean of 0.5 episodes (compared to 0.3 episodes for placebo, not significant). In that study combination therapy with tamsulosin and tolterodine resulted in a mean nocturia reduction of approximately 0.6 episodes, p ⫽ 0.02, vs placebo.14 In the Veterans Affairs Cooperative Study of Medical Treatment of BPH, terazosin reduced mean nocturia by 0.7 episodes (placebo 0.4 episode reduction).7 In another study with a different methodology (open label administration followed by
placebo controlled double-blind washout for responders), terazosin yielded a mean nocturia reduction of 1.0 episodes followed by a mean increase of 0.5 episodes with washout.15 These analyses have several important, practical ramifications. On average, men who have BPH will likely have fewer episodes of nocturia with ␣-blocker treatment. A good proportion, although not a majority, will report getting up an average of 1 less time each night. While finasteride may have benefits for several BPH outcomes it will not generally reduce nocturia. Older men may have a slightly greater benefit with finasteride, relative to placebo, for nocturia. In addition, finasteride and ␣-blockers combined offered no statistical advantage compared to ␣-blockers alone for nocturia. It remains to be seen if other 5␣-reductase inhibitors have superior efficacy for nocturia reduction. As demonstrated elsewhere the nocturia reduction from ␣-blockers in men with LUTS/BPH is rather modest, particularly when considering the net effect compared to placebo.7 These results are likely superior to average results in clinical practice as research trials have monitored compliance with therapy in a population selected for the best chance to benefit. There may be a need in clinical practice to look for and perhaps treat additional causes of nocturia. The strengths of this secondary data analysis include large sample size, use of a standard, validated instrument to assess nocturia, long-term followup and the use of the placebo group. Even with these strengths the limitations of this study should be mentioned. The study was not designed to specifically look at nocturia, although most men enrolled had nocturia (98%). Additionally, men were neither evaluated nor specifically treated for polyuria syndromes, which are an important cause of nocturia. The main outcome measure of nocturia is an estimated, selfreported average and no diary data were available. While self-reported nocturia has been validated against diaries16 and 24-hour monitoring,17 some studies have shown that these nocturia self-reports differ from diaries.18 In the VA CSP BPH trial the reliability of self-reported nocturia at baseline and after 2 weeks of placebo was strong with a 0.71 correlation. For 93% of participants nocturia was identical or differed by only 1 episode.7 These problems with self-reported nocturia make this analysis less
EFFECT OF MEDICAL THERAPY ON NOCTURIA IN MEN WITH PROSTATIC SYMPTOMS
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Percentage of participants having worse, no change or improved nocturia relative to baseline by treatment group. Report of worse nocturia is 1 or more additional episodes of nocturia at 1 year compared to initial self-report at baseline. Improve represents decrease in nocturia self-report by 1 or more episodes. A, outcomes at 1 year (chi-square 37.9, p ⬍0.001). B, outcomes at 4 years (chi-square 13.6, p ⬍0.001). For both comparisons df ⫽ 6.
precise but not biased (nocturia estimates should not vary by treatment assignment). For the 5% of the sample who reported 5 or more nocturia episodes, there could be a ceiling effect (those reducing from 7 to 5 nightly nocturia episodes, for instance, would be erroneously captured as no change). Other studies in which respondents were of-
fered more response choices for nocturia (0 through 10) demonstrated that only 1% of respondents had 6 or more episodes of nocturia.19 Therefore, this ceiling effect might be minimal. Lastly, the lack of a standardized, accepted quality of life measure specific for nocturia is a limitation.20
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EFFECT OF MEDICAL THERAPY ON NOCTURIA IN MEN WITH PROSTATIC SYMPTOMS
CONCLUSIONS Doxazosin alone or in combination with finasteride reduced episodes of nocturia in men with BPH to a greater extent than did placebo or finasteride alone. Doxazosin treatment reduced nocturia by 0.4 to 0.8 episodes depending on the specific analysis. The net advantage in the main analysis for doxazosin compared to placebo was a mean reduction of 0.2 nocturia episodes. Four-year data were similar to the 1-year results. In contrast to the parent study analyses in which finasteride demonstrated benefit with respect to a combined clinical end point for BPH, nocturia reductions with finasteride were not statistically greater than those with placebo (except in 1 subanalysis for participants 70 years old or older at only 1 year). The combination of finasteride and doxazosin was not superior to doxazosin alone in reducing nocturia.
Abbreviations and Acronyms AUA-7 SI ⫽ American Urological Association 7 Symptom Inventory BPH ⫽ benign prostatic hyperplasia LUTS ⫽ lower urinary tract symptoms MTOPS ⫽ Medical Treatment of Prostatic Symptoms PSA ⫽ prostate specific antigen PVR ⫽ post-void residual VA CSP BPH trial ⫽ Veterans Affairs Cooperative Study of BPH Trial
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REFERENCES 1.
2. 3.
4.
5.
6.
7.
van Kerrebroeck P, Abrams P, Chaikin D, Donovan J, Fonda D, Jackson S et al: The standardisation of terminology in nocturia: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21: 179. Weiss JP and Blaivas JG: Nocturia. Curr Urol Rep 2003; 4: 362. DuBeau CE, Yalla SV and Resnick NM: Implications of the most bothersome prostatism symptom for clinical care and outcomes research. J Am Geriatr Soc 1995; 43: 985. Gourova LW, van de Beek C, Spigt MG, Nieman FH and van Kerrebroeck PE: Predictive factors for nocturia in elderly men: a cross-sectional study in 21 general practices. BJU Int 2006; 97: 528. Nishino Y, Masue T, Miwa K, Takahashi Y, Ishihara S and Deguchi T: Comparison of two alpha1-adrenoceptor antagonists, naftopidil and tamsulosin hydrochloride, in the treatment of lower urinary tract symptoms with benign prostatic hyperplasia: a randomized crossover study. BJU Int 2006; 97: 747. Johnson TM 2nd, Jones K, Williford WO, Kutner MH, Issa MM and Lepor H: Changes in nocturia from medical treatment of benign prostatic hyperplasia: secondary analysis of the Department of Veterans Affairs Cooperative Study Trial. J Urol 2003; 170: 145. Lepor H, Williford WO, Barry MJ, Brawer MK, Dixon CM, Gormley G et al: The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med 1996; 335: 533.
19.
20.
McConnell J, Roehrborn C, Bautista O, Andriole GJ, Dixon C, Kusek J et al: The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349: 2387. Bautista OM, Kusek JW, Nyberg LM, McConnell JD, Bain RP, Miller G et al: Study design of the Medical Therapy of Prostatic Symptoms (MTOPS) trial. Control Clin Trials 2003; 24: 224. Barry MJ, Fowler FJ Jr, O’Leary MP, Bruskewitz RC, Holtgrewe HL, Mebust WK et al: The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992; 148: 1549. Wein A: Editorial comment. J Urol 2006; 175: 1434. Drach G, Ignatoff J and Layton T: Peak urinary flow rate: observations in female subjects and comparison to male subjects. J Urol 1979; 122: 215. Tikkinen KA, Tammela TL, Huhtala H and Auvinen A: Is nocturia equally common among men and women? A population based study in Finland. J Urol 2006; 175: 596. Kaplan SA, Roehrborn CG, Rovner ES, Bavendam T and Guan Z: Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder. JAMA 2006; 296: 2319. Debruyne FM, Witjes WP, Fitzpatrick J, Kirby R, Kirk D and Prezioso D: The international terazosin trial: a multicentre study of the long-term efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia. The ITT Group. Eur Urol 1996; 30: 369. Abrams P and Klevmark B: Frequency volume charts: an indispensable part of lower urinary tract assessment. Scand J Urol Nephrol, suppl., 1996; 179: 47. Matzkin H, Greenstein A, Prager-Geller T, Sofer M and Braf Z: Do reported micturition symptoms on the American Urological Association Questionnaire correlate with 24-hour home uroflowmetry recordings? J Urol 1996; 155: 197. Blanker MH, Bohnen AM, Groeneveld FP, Bernsen RM, Prins A and Ruud Bosch JL: Normal voiding patterns and determinants of increased diurnal and nocturnal voiding frequency in elderly men. J Urol 2000; 164: 1201. Johnson TM 2nd, Sattin RW, Parmelee P, Fultz NH and Ouslander JG: Evaluating potentially modifiable risk factors for prevalent and incident nocturia in older adults. J Am Geriatr Soc 2005; 53: 1011. Abraham L, Hareendran A, Mills IW, Martin ML, Abrams P, Drake MJ et al: Development and validation of a qualityof-life measure for men with nocturia. Urology 2004; 63: 481.
EDITORIAL COMMENT The authors have performed a secondary analysis of the MTOPS trial with emphasis on the outcomes of treatment of nocturia with doxazosin alone, finasteride alone, combination therapy or placebo. The principle outcomes instrument was patient self-report of nocturia. Notwithstanding this obvious limitation (the lack of diary data to substantiate outcomes based on patient recall), the large size of the database combined with a detailed analysis regarding correlation of nocturia self-report and diary data afford the reader valuable insight as to expectations for nocturia treatment efficacy using ␣-blockers, 5␣-reductase inhibitors or a combination thereof. The take home message is that treatment of nocturia in unselected patients using monotherapy or combination therapy for prostatic obstruction yields minimal, albeit statistically significant, benefit compared with placebo.1,2 The likeliest hope for nocturia improvement in
EFFECT OF MEDICAL THERAPY ON NOCTURIA IN MEN WITH PROSTATIC SYMPTOMS this series occurred in men treated with doxazosin alone who were 70 years old or older (0.5 decrease in episodes of nocturia compared with placebo at 4 years). Combination therapy and finasteride alone conferred no statistical advantage compared to doxazosin alone in the treatment of nocturia. It is worth noting that patients were not treated according to a classification scheme which may have selected more appropriate candidates with nocturia for therapy. For example, any of the treatment arms presented may have demonstrated improved outcomes had patients with nocturia been selected for low bladder capacity as opposed to nocturnal polyuria or global polyuria. The authors correctly point out that the MTOPS trial was not designed to treat nocturia per se, although the majority of men studied had
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nocturia. The limitations and value of this subanalysis are clearly reviewed by the authors. Jeffrey P. Weiss Department of Urology Weill Medical College of Cornell University New York, New York 1.
2.
Kaplan SA, McConnell JD, Roehrborn CG, Meehan AG, Lee MW, Noble WR et al: Combination therapy with doxazosin and finasteride for benign prostatic hyperplasia in patients with lower urinary tract symptoms and a baseline total prostate volume of 25 ml or greater. J Urol 2006; 175: 217. Logan YT and Belgeri MT: Monotherapy versus combination drug therapy for the treatment of benign prostatic hyperplasia. Am J Geriatr Pharmacother 2005; 3: 103.