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Long-Term Effects of Doxazosin, Finasteride and Combination Therapy on Quality of Life in Men with Benign Prostatic Hyperplasia
Long-Term Effects of Doxazosin, Finasteride and Combination Therapy on Quality of Life in Men with Benign Prostatic Hyperplasia Chyng-Wen Fwu,*,† Paul W. Eggers,† Steven A. Kaplan,‡ Ziya Kirkali,† Jeannette Y. Lee† and John W. Kusek† From Social & Scientific Systems, Inc., Silver Spring (CWF), and Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (PWE, ZK, JWK), Maryland, Weill Cornell Medical College, Cornell University, New York, New York (SAK), and Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (JYL)
Purpose: We examined the effects of doxazosin, finasteride and combination therapy among men with benign prostatic hyperplasia on quality of life assessed with MOS-SF-36 (Medical Outcomes Study Short-Form 36) and 2 disease specific instruments (BII, benign prostatic hyperplasia Impact Index and I-PSS-QoL, International Prostate Symptom Score-QoL) during 4 years. Materials and Methods: The MTOPS (Medical Therapy of Prostatic Symptoms) study was a multicenter, randomized, double-blind, placebo controlled clinical trial with a primary outcome of time to benign prostatic hyperplasia progression. Change in quality of life was a secondary outcome. A total of 2,872 men enrolled in the MTOPS study who had 3 baseline quality of life measures and at least 1 followup measure by any of the quality of life instruments were analyzed. Results: Compared with men assigned to placebo, men assigned to doxazosin and combination experienced a statistically significant improvement in the BII at year 4. Men assigned to each of the drug groups also experienced a significant improvement in the I-PSS-QoL compared with those assigned to placebo. Considering longitudinal changes during 4 years, a significant improvement in BII and I-PSS-QoL scores was observed in men assigned to the drug groups compared with those assigned to placebo. However, there were no significant differences for the MOS-SF-36 subscales and summary scores when drug groups were compared with the placebo group. Conclusions: The quality of life of men treated with doxazosin, finasteride, and the drugs combined generally improved when assessed with the BII and the I-PSS-QoL compared with those treated with placebo. Quality of life did not show improvement when measured by the MOS-SF-36. Key Words: lower urinary tract symptoms, prostatic hyperplasia, quality of life, doxazosin, finasteride LOWER urinary tract symptoms associated with BPH are common, costly to treat and bothersome, and they negatively impact quality of life.1–3 In the last 2 decades the usual treatment of symptomatic BPH changed markedly from surgery to drug therapy.4 This is
a result of a substantial number of randomized clinical trials of 2 classes of drugs, 5␣-reductase inhibitors and ␣-adrenergic receptor blockers, which have shown them to reduce symptoms and/or progression of BPH significantly.5,6 While the severity and wors-
0022-5347/13/1901-0187/0 THE JOURNAL OF UROLOGY® © 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2013.01.061 Vol. 190, 187-193, July 2013 RESEARCH, INC. Printed in U.S.A.
AND
Abbreviations and Acronyms AUA-SI ⫽ American Urological Association symptom index BII ⫽ Benign Prostatic Hyperplasia Impact Index BPH ⫽ benign prostatic hyperplasia I-PSS ⫽ International Prostate Symptom Score LUTS ⫽ lower urinary tract symptoms MCS ⫽ Mental Component Summary MOS-SF-36 ⫽ Medical Outcomes Study Short-Form 36 PCS ⫽ Physical Component Summary QoL ⫽ quality of life Accepted for publication January 17, 2013. Study received institutional review board approval. * Correspondence: Social & Scientific Systems, Inc., 8757 Georgia Ave., 12th floor, Silver Spring, Maryland 20910 (telephone: 301-628-0342; FAX: 301-628-0301; e-mail: [email protected]). Supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (HHSN 276201200161U). † Nothing to disclose. ‡ Financial interest and/or other relationship with Merck, Pfizer, Astellas and Olympus.
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 368 and 369.
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ening (progression) of LUTS are clinically important outcomes among men with BPH, their impact on QoL is also important. Despite a number of reports of the effects of drug therapy on QoL in men with BPH,7–10 few studies have been long-term.11 The MTOPS study was a multicenter, randomized, double-blind, placebo controlled clinical trial designed to determine whether finasteride combined with doxazosin, finasteride alone, or doxazosin alone would significantly reduce the clinical progression of BPH compared with placebo.12,13 QoL associated with treatment was a secondary outcome. We report the effect of drug therapy, compared with placebo and with each other, on QoL assessed by general and disease specific instruments over 4 years.
METHODS Study Design The design and primary results of the MTOPS Study have been published previously.5,12,13 Men were eligible for the study if they were at least 50 years old, had an AUA-SI score of 8 to 30, a maximal urinary flow rate of 4 to 15 ml per second, and a minimum voided volume of 125 ml. After screening, 3,047 men were equally randomized to placebo, 4 or 8 mg doxazosin, 5 mg finasteride, or combination therapy. The primary outcome was clinical progression of BPH. Change over time in QoL was a secondary outcome. Selfreported QoL was assessed at baseline and every 3 months thereafter by the BII and the I-PSS-QoL, and annually by the MOS-SF-36. Clinical and demographic information also was obtained at baseline. The trial was approved by the appropriate institutional review boards. Written informed consent was obtained from all study participants. The MTOPS study found that combination therapy, finasteride alone, and doxazosin alone significantly reduced the risk of clinical progression of BPH and significantly improved (decreased) symptoms assessed by the AUA-SI, compared with placebo. In this secondary analysis of QoL, we analyzed men enrolled in the trial who had 3 baseline QoL measures and at least 1 followup measure by any of the QoL instruments.
QoL Measures General QoL was assessed by the MOS-SF-36.14 This instrument assesses 8 dimensions (measured by subscales) of health during the previous month, including physical functioning, role limitations due to physical problems, bodily pain, general health perception, vitality, social function, role limitations due to emotional problems and mental health. Two summary scales, the Mental Component Summary and the Physical Component Summary, are scored from norm based methods that standardize both scores to a mean of 50 and a SD of 10. The range of scores for each subscale and the summary scales is 0 to 100, with higher scores indicating better QoL. We also assessed QoL by 2 disease specific instruments, the BII and the I-PSS-QoL. The BII is a 4-item questionnaire that measures the health impact of LUTS during the last month, including physical discomfort, worry about health, symptom bother and frequency of symptoms that interfere
with performance of usual activities.15,16 The range of possible scores of the BII is 0 to 13, with a higher score indicating a greater negative impact of BPH symptoms. The I-PSSQoL is measured by a single question, “If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?” with a higher score indicating poorer QoL. Possible responses are 0 — delighted, 1—pleased, 2—mostly satisfied, 3—mixed, 4 —mostly dissatisfied, 5— unhappy and 6 —terrible.17
Statistical Analysis Statistical analyses were performed according to randomized treatment group (intent to treat). The characteristics of study participants at baseline were categorized by treatment group. Means (with SDs) for continuous variables and percentage distributions for categorical variables were calculated. Changes in the MOS-SF-36 subscales and the PCS and the MCS, the BII, and the I-PSS-QoL were assessed from baseline to followup year 4 for each of the drug groups and were compared with the change observed in the placebo group for the same time interval. Differences in changes from baseline to followup year 4 between the drug groups and the placebo group were assessed using nonparametric Wilcoxon rank sum test for all interval or ordinal scores. The effect sizes of changes between comparison groups were assessed with Cohen’s d, a measure of the magnitude of a treatment effect.18 Cohen’s d was calculated as the difference of the means (mean change score in the drug group minus mean change score in the placebo group) divided by the pooled SD of both groups at baseline. A zero value for a Cohen’s d indicates no effect, whereas a value between 0.2 and 0.5 is considered a small effect.18 In addition to the point comparison at 4 years, we also used the nonparametric WeiLachin test to compare longitudinal changes in scores from each of the QoL measures between each drug group and the placebo group during a 4-year period.19 We also compared longitudinal changes in QoL between drug groups (combination therapy vs doxazosin, combination therapy vs finasteride, and doxazosin vs finasteride) over 4 years. A total of 114 (4%) of the men we studied completed both the BII and the I-PSS-QoL, but not the MOS-SF-36, at least once during followup. We performed a sensitivity analysis by excluding those men who had not completed a followup MOS-SF-36 to assess whether those participants would influence our findings. To address the possible impact of missing followup data, we also performed analysis using the last observation carried forward (LOCF) and compared results with analyses using only available data when change at year 4 was considered. All tests of statistical significance were 2-sided with a Bonferroni adjusted criterion of a p value of less than 0.008 (6 pairwise comparisons in this analysis). All analyses were conducted using SAS® for Windows® software, version 9.2.
RESULTS Of the 3,047 men randomized in the MTOPS Study 2,915 (96%) completed the MOS-SF-36, the BII and the I-PSS-QoL at baseline, and 2,872 had at least 1 acceptable followup measure of QoL and were included in the present analysis. During the study period response rates were 90%, 88%, 86% and 71%
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Table 1. Baseline demographic and clinical characteristics of men with baseline and at least 1 followup value of QoL measures Overall No. pts Mean ⫾ SD pt age No. race/ethnicity (%): White Black Hispanic Other No. education (grade level last completed) (%): Grade 1–12 1–4 Yrs college Post-undergraduate Mean Mean Mean Mean Mean Mean
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
SD SD SD SD SD SD
AUA symptom score ml prostate vol ml/sec max urinary flow rate ml post-void residual ng/ml serum prostate specific antigen mg/dl serum creatinine
Mean ⫾ SD MOS-SF-36 subscales: Physical functioning Role limitation due to physical problems Bodily pain General health perception Vitality Social function Role limitation due to emotional problems Mental health Mean ⫾ SD MOS-SF-36 summary scores: PCS MCS Mean ⫾ SD BII Mean ⫾ SD I-PSS-QoL
Placebo
2,872 62.6 ⫾ 7.3
Demographic 698 62.5 ⫾ 7.6
2,380 (82.9) 248 (8.6) 204 (7.1) 40 (1.4) 838 (29.2) 1,246 (43.4) 788 (27.4) 16.8 ⫾ 5.9 36.4 ⫾ 19.9 10.5 ⫾ 2.6 68.0 ⫾ 83.5 2.3 ⫾ 2.1 1.1 ⫾ 0.2
580 (83.1) 63 (9.0) 46 (6.6) 9 (1.3) 213 (30.5) 300 (43.0) 185 (26.5) Clinical 16.7 ⫾ 5.9 35.3 ⫾ 19.0 10.5 ⫾ 2.7 69.9 ⫾ 82.3 2.3 ⫾ 2.1 1.1 ⫾ 0.2 Quality of Life
Doxazosin
Finasteride
Combination
712 62.7 ⫾ 7.3
723 62.5 ⫾ 7.3
739 62.6 ⫾ 7.1
589 (82.7) 63 (8.9) 52 (7.3) 8 (1.1)
607 (84.0) 56 (7.8) 43 (6.0) 17 (2.4)
604 (81.7) 66 (8.9) 63 (8.5) 6 (0.8)
207 (29.1) 298 (41.9) 207 (29.1)
212 (29.3) 303 (41.9) 208 (28.8)
206 (27.9) 345 (46.7) 188 (25.4)
16.9 ⫾ 5.9 36.9 ⫾ 21.6 10.3 ⫾ 2.6 68.9 ⫾ 89.2 2.4 ⫾ 2.2 1.1 ⫾ 0.2
17.1 ⫾ 6.0 36.9 ⫾ 20.7 10.5 ⫾ 2.6 66.2 ⫾ 81.0 2.3 ⫾ 2.1 1.1 ⫾ 0.2
16.7 ⫾ 5.8 36.3 ⫾ 18.4 10.6 ⫾ 2.5 67.0 ⫾ 81.6 2.3 ⫾ 2.0 1.1 ⫾ 0.2
83.9 ⫾ 19.3 81.2 ⫾ 31.7 76.8 ⫾ 21.0 74.4 ⫾ 17.3 65.5 ⫾ 18.9 88.8 ⫾ 18.7 84.8 ⫾ 29.9 79.8 ⫾ 15.4
84.1 ⫾ 19.1 82.5 ⫾ 31.5 78.2 ⫾ 19.9 74.9 ⫾ 17.1 65.6 ⫾ 18.6 89.4 ⫾ 17.7 86.2 ⫾ 28.8 80.1 ⫾ 15.0
84.1 ⫾ 18.9 81.7 ⫾ 31.4 76.5 ⫾ 21.4 74.1 ⫾ 17.4 64.7 ⫾ 18.9 88.3 ⫾ 19.1 85.3 ⫾ 29.6 79.8 ⫾ 16.1
83.7 ⫾ 19.6 79.3 ⫾ 32.8 75.6 ⫾ 21.4 74.0 ⫾ 17.1 65.6 ⫾ 19.2 88.2 ⫾ 19.4 84.6 ⫾ 29.6 79.2 ⫾ 15.4
83.5 ⫾ 19.7 81.4 ⫾ 31.2 76.7 ⫾ 21.2 74.5 ⫾ 17.4 66.0 ⫾ 18.8 89.4 ⫾ 18.6 83.0 ⫾ 31.5 80.1 ⫾ 15.2
49.5 ⫾ 52.9 ⫾ 3.9 ⫾ 3.0 ⫾
49.9 ⫾ 53.1 ⫾ 3.9 ⫾ 2.9 ⫾
49.5 ⫾ 52.8 ⫾ 3.9 ⫾ 3.0 ⫾
49.2 ⫾ 52.8 ⫾ 4.0 ⫾ 3.1 ⫾
49.6 ⫾ 52.9 ⫾ 3.8 ⫾ 3.0 ⫾
8.3 8.5 2.7 1.3
(2,051 of 2,872) for the MOS-SF-36, and 91%, 89%, 86%, and 76% (2,192 of 2,872) for the BII and the I-PSS-QoL, at year 1, year 2, year 3 and year 4 of followup, respectively. Selected baseline demographic and clinical characteristics, and QoL measures of the men we studied overall and by treatment group are shown in table 1. They were on average 62.6 (SD 7.3) years of age, were well educated (43.4% with college and 27.4% with post-undergraduate education), had a median AUA-SI score of 16, and were predominantly nonHispanic whites (82.9%) with a median baseline PCS score of 51.6, MCS score of 55.5, BII score of 3, and I-PSS-QoL score of 3. There were no significant differences in baseline demographic and clinical characteristics of the men we studied compared with all men enrolled in the trial (data not shown). Baseline characteristics did not differ significantly by treatment group. Medical Outcomes Study Short-Form 36 Changes in the MOS-SF-36 subscales and summary scales scores from baseline to year 4 of followup by treatment group are shown in table 2. A statistically
8.2 8.2 2.7 1.4
8.5 8.8 2.6 1.3
8.2 8.3 2.7 1.3
8.2 8.5 2.7 1.3
significant reduction (worsening) was observed for the subscales of physical functioning, role limitations due to physical problems, bodily pain, general health perception and vitality in all treatment groups, except bodily pain in men assigned to finasteride. Changes in social function and role limitations due to emotional problems varied. No significant change was observed in mental health in any treatment group. The subscale with the greatest reduction was role limitations due to physical problems. The decrease was greatest in the placebo group (⫺8.83, 95% CI ⫺12.09 to ⫺5.58) and least in finasteride (⫺6.97, ⫺10.19 to ⫺3.74). There also were significant decreases in the PCS score in each of the treatment groups (placebo ⫺2.63, 95% CI ⫺3.33 to ⫺1.92; combination therapy ⫺2.49, ⫺3.19 to ⫺1.80; doxazosin ⫺2.34, ⫺2.98 to ⫺1.71; finasteride ⫺1.61, ⫺2.30 to ⫺0.91). In contrast, the MCS score did not change significantly during the same period. Table 3 shows the differences in mean change in QoL measures between each of the drug groups and the placebo group from baseline to year 4. The dif-
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Table 2. Change from baseline to year 4 in QoL measures Placebo No. pts Mean change MOS-SF-36 subscales (95% CI): Physical functioning Role limitation due to physical problems Bodily pain General health perception Vitality Social function Role limitation due to emotional problems Mental health Mean change MOS-SF-36 summary scores (95% CI): PCS MCS No. pts Mean change BII (95% CI) Mean change I-PSS-QoL (95% CI)
484
Doxazosin General instrument 526
Finasteride
Combination
506
535
⫺3.47 (⫺4.86 to ⫺2.08) ⫺7.90 (⫺10.96 to ⫺4.85) ⫺4.31 (⫺6.20 to ⫺2.43) ⫺2.75 (⫺3.91 to ⫺1.60) ⫺1.78 (⫺3.10 to ⫺0.45) ⫺1.02 (⫺2.78 to 0.74) ⫺2.22 (⫺5.33 to 0.90) 0.66 (⫺0.59 to 1.90)
⫺2.89 (⫺4.47 to ⫺1.32) ⫺6.97 (⫺10.19 to ⫺3.74) ⫺1.96 (⫺3.96 to 0.03) ⫺2.99 (⫺4.29 to ⫺1.68) ⫺2.74 (⫺4.20 to ⫺1.28) ⫺2.15 (⫺4.01 to ⫺0.29) ⫺5.02 (⫺8.03 to ⫺2.00) ⫺0.07 (⫺1.37 to 1.23)
⫺3.80 (⫺5.37 to ⫺2.23) ⫺8.55 (⫺11.65 to ⫺5.45) ⫺4.33 (⫺6.23 to ⫺2.43) ⫺3.71 (⫺5.04 to ⫺2.38) ⫺3.75 (⫺5.23 to ⫺2.27) ⫺3.64 (⫺5.49 to ⫺1.80) ⫺2.37 (⫺5.37 to 0.63) ⫺0.22 (⫺1.44 to 1.00)
⫺2.63 (⫺3.33 to ⫺1.92) ⫺2.34 (⫺2.98 to ⫺1.71) ⫺0.54 (⫺1.24 to 0.17) 0.40 (⫺0.35 to 1.14) Disease specific instruments 517 565 ⫺1.18 (⫺1.40 to ⫺0.96) ⫺1.59 (⫺1.80 to ⫺1.38) ⫺0.80 (⫺0.91 to ⫺0.68) ⫺1.18 (⫺1.28 to ⫺1.08)
⫺1.61 (⫺2.30 to ⫺0.91) ⫺0.59 (⫺1.32 to 0.14)
⫺2.49 (⫺3.19 to ⫺1.80) ⫺0.33 (⫺1.04 to 0.38)
539 ⫺1.45 (⫺1.67 to ⫺1.23) ⫺1.05 (⫺1.15 to ⫺0.95)
571 ⫺1.71 (⫺1.92 to ⫺1.50) ⫺1.26 (⫺1.37 to ⫺1.15)
⫺5.09 (⫺6.86 to ⫺3.32) ⫺8.83 (⫺12.09 to ⫺5.58) ⫺5.27 (⫺7.22 to ⫺3.33) ⫺3.41 (⫺4.75 to ⫺2.06) ⫺3.51 (⫺5.05 to ⫺1.97) ⫺2.45 (⫺4.23 to ⫺0.68) ⫺7.51 (⫺10.51 to ⫺4.51) 0.23 (⫺1.03 to 1.49)
Positive change scores in MOS-SF-36 indicate improved QoL during followup. Negative change scores in BII and I-PSS-QoL indicate improved QoL during followup.
ferences in changes for MOS-SF-36 subscales and summary scores between drug groups and placebo group were not statistically significant. Similarly, neither significant differences nor important effect sizes of the subscales and summary scores were observed when drug groups were compared with each other at year 4 (data not shown). Figure 1, A shows the pattern of mean change in PCS score from baseline to year 4 for each treatment group. Compared with men assigned to finasteride, those assigned to doxazosin or combination therapy had a statistically significant greater mean decrease in PCS scores during the 4-year period longitudinally. In contrast, the mean change in MCS scores was small in all treatment groups, with a range of ⫺0.59 to 0.40, with no significant differences between treatment groups (fig. 1, B). BII and I-PSS-QoL The mean decreases (improvement) in BII from baseline to year 4 among men assigned to combination therapy, doxazosin, finasteride and placebo were ⫺1.71 (95% CI ⫺1.92 to ⫺1.50), ⫺1.59 (⫺1.80 to ⫺1.38), ⫺1.45 (⫺1.67 to ⫺1.23) and ⫺1.18 (⫺1.40 to ⫺0.96), respectively (table 2). Compared with men assigned to placebo, those assigned to doxazosin (difference of change ⫺0.41, 95% CI ⫺0.72 to ⫺0.11) and combination therapy (⫺0.53, ⫺0.83 to ⫺0.22) experienced a statistically significant but small improvement (Cohen’s d ⫽ ⫺0.2) in BII at year 4 (table 3). However, no significant differences between drug groups were observed at year 4 (data not shown). As shown in figure 2, A, the mean BII score decrease (improvement) was greatest for each treatment group during the first 3 months after randomization and varied little thereafter.
The mean decreases (improvement) in the I-PSSQoL score from baseline to year 4 in men assigned to combination therapy, doxazosin, finasteride and placebo were ⫺1.26 (95% CI ⫺1.37 to ⫺1.15), ⫺1.18 (⫺1.28 to ⫺1.08), ⫺1.05 (⫺1.15 to ⫺0.95) and ⫺0.80 (⫺0.91 to ⫺0.68), respectively (table 2). Men assigned to each of the drug groups experienced a significant improvement in I-PSS-QoL score compared with those assigned to placebo at year 4, although the effect size was small, with Cohen’s d ranging from ⫺0.2 to ⫺0.4 (table 3). The improvement in the I-PSS-QoL was significantly greater in men assigned to combination therapy and doxazosin, compared with those assigned to finasteride, over time (fig. 2, B). Our findings were not changed significantly when only men who had completed the MOS-SF-36 during followup were considered. Changes at year 4 by treatment group also were similar when data were analyzed using the LOCF.
DISCUSSION This is the first and largest study of the long-term effects of commonly used drugs to treat men with BPH on QoL compared with placebo. In addition, this is the first report of a clinical trial of drug therapy in men with BPH that assessed QoL using the MOS-SF-36. Because drug treatment, most often an ␣-adrenergic receptor blocker and/or a 5␣-reductase inhibitor of these men is often lifelong after diagnosis, it is important to consider how these drugs may affect QoL during an extended period of time. At baseline, QoL was relatively well preserved in the men enrolled in the MTOPS Study whom we examined.
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Table 3. Difference of change from baseline to year 4 between drug groups and placebo in QoL measures Difference of change (95% CI)
p Value*
Cohen’s d
1.62 (⫺0.63 to 3.87) 0.93 (⫺3.53 to 5.39) 0.96 (⫺1.75 to 3.67) 0.66 (⫺1.11 to 2.43) 1.73 (⫺0.30 to 3.76) 1.43 (⫺1.07 to 3.93) 5.29 (0.96 to 9.62) 0.42 (⫺1.35 to 2.20) 0.28 (⫺0.67 to 1.23) 0.93 (⫺0.09 to 1.96) ⫺0.41 (⫺0.72 to ⫺0.11) ⫺0.39 (⫺0.54 to ⫺0.23) Finasteride vs placebo ([mean in finasteride] minus [mean in placebo])
0.70 0.91 0.44 0.72 0.16 0.09 0.08 0.58 0.68 0.04 0.008 ⬍0.001
0.1 0.0 0.0 0.0 0.1 0.1 0.2 0.0 0.0 0.1 ⫺0.2 ⫺0.3
2.20 (⫺0.17 to 4.57) 1.87 (⫺2.71 to 6.44) 3.31 (0.52 to 6.10) 0.42 (⫺1.45 to 2.30) 0.77 (⫺1.35 to 2.89) 0.30 (⫺2.27 to 2.88) 2.49 (⫺1.76 to 6.74) ⫺0.31 (⫺2.12 to 1.50) 1.02 (0.03 to 2.01) ⫺0.05 (⫺1.07 to 0.96) ⫺0.27 (⫺0.59 to 0.04) ⫺0.26 (⫺0.41 to ⫺0.10) Combination vs placebo ([mean in combination] minus [mean in placebo])
0.05 0.46 0.013 0.72 0.25 0.50 0.17 0.76 0.013 0.98 0.05 ⬍0.001
0.1 0.1 0.2 0.0 0.0 0.0 0.1 0.0 0.1 0.0 ⫺0.1 ⫺0.2
0.70 0.86 0.51 0.68 0.88 0.53 0.05 0.76 0.91 0.58 0.002 ⬍0.001
0.1 0.0 0.0 0.0 0.0 ⫺0.1 0.2 0.0 0.0 0.0 ⫺0.2 ⫺0.4
Doxazosin vs placebo ([mean in doxazosin] minus [mean in placebo]) MOS-SF-36 subscales: Physical functioning Role limitation due to physical problems Bodily pain General health perception Vitality Social function Role limitation due to emotional problems Mental health MOS-SF-36 PCS MOS-SF-36 MCS BII I-PSS-QoL MOS-SF-36 subscales: Physical functioning Role limitation due to physical problems Bodily pain General health perception Vitality Social function Role limitation due to emotional problems Mental health MOS-SF-36 PCS MOS-SF-36 MCS BII I-PSS-QoL MOS-SF-36 subscales: Physical functioning Role limitation due to physical problems Bodily pain General health perception Vitality Social function Role limitation due to emotional problems Mental health MOS-SF-36 PCS MOS-SF-36 MCS BII I-PSS-QoL
1.29 (⫺1.06 to 3.65) 0.28 (⫺4.21 to 4.77) 0.94 (⫺1.78 to 3.67) ⫺0.30 (⫺2.19 to 1.60) ⫺0.24 (⫺2.37 to 1.90) ⫺1.19 (⫺3.75 to 1.37) 5.13 (0.89 to 9.38) ⫺0.45 (⫺2.21 to 1.30) 0.13 (⫺0.86 to 1.12) 0.20 (⫺0.80 to 1.20) ⫺0.53 (⫺0.83 to ⫺0.22) ⫺0.47 (⫺0.62 to ⫺0.31)
Positive differences and Cohen’s d in MOS-SF-36 indicate a better QoL change in the drug treatment group vs placebo group. Negative differences and Cohen’s d in BII and I-PSS-QoL indicate a better QoL change in the drug treatment group vs placebo group. * Wilcoxon rank-sum test.
Study participants had a mean MCS score above the population mean of 50 and a mean PCS score of nearly that value. After 4 years of followup, men assigned to all treatment groups, including placebo, experienced a significant but small decrease in PCS but not MCS scores. However, men assigned to the drug groups did not experience a significant change in any of the 8 subscales of the MOS-SF-36, the PCS, or the MCS compared with those assigned to placebo, suggesting that these drugs, used singly or combined, may neither adversely nor beneficially affect QoL. At 4 years after treatment assignment, there also was no significant difference in change in these measures when drug groups (doxazosin, finasteride and combination therapy) were compared. Although men assigned to drug
treatment each showed a significant improvement in the I-PSS-QoL after 4 years compared with placebo, the effect size was small. Differences in the improvement in the BII for the doxazosin and combination therapy groups (but not the finasteride group) were statistically significant compared with improvement in the BII for placebo at 4 years. The effect size was small, with no significant differences between drug groups at 4 years. However, significant improvements in longitudinal changes in both BII and I-PSS-QoL scores were observed in men assigned to the drug groups compared to placebo. It is noteworthy that the amount of improvement of QoL in all treatment groups we observed, including placebo, has previously been shown to be clinically significant.20
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A
year 1
year 2
year 3
MOS-SF-36 Mental Component Summary
B
MOS-SF-36 Physical Component Summary baseline
baseline
year 4
year 1
year 2
year 3
year 4
601 631 626 664
585 621 605 647
484 526 506 535
2.00
0.00
0.00
-2.00
Finasteride vs. doxazosin: p=0.005 Finasteride vs. combinaon: p<0.001 -2.00
-4.00 Placebo Doxazosin Finasteride Combinaon
698 712 723 739
626 641 648 661
PLACEBO
601 631 626 664
DOXAZOSIN
585 621 605 647
Placebo Doxazosin Finasteride Combinaon
484 526 506 535
FINASTERIDE
698 712 723 739
626 641 648 661
PLACEBO
COMBINATION
DOXAZOSIN
FINASTERIDE
COMBINATION
Figure 1. Mean change from baseline in quality of life measures over time in MOS-SF-36 Physical Component Summary and MOS-SF-36 Mental Component Summary. Wei-Lachin test of stochastic ordering was used to determine p values for all followup visit measurements.
patients with BPH and in epidemiological studies of LUTS.21–24 Both the BII and the I-PSS-QoL have been used as secondary outcomes in a number of clinical trials of drug therapy for BPH.7,11,25,26 As expected, we found both of these measures to be more sensitive to change than the MOS-SF-36 because both were developed to capture domains of QoL directly related to LUTS. Previous studies have reported significant improvements of the BII as a result of treatment with finasteride compared with placebo in shortterm (12 months) clinical trials,25,26 and during 4 years in a clinical trial of dutasteride, tamsulosin and combination therapy.11 The strengths of our study were the large sample size, long duration of followup, use of general and disease specific measures of QoL, analysis by intent to treat, a comparison (placebo) group, high rates of followup (assessment of QoL), and evaluation of 2 drugs
Despite the finding of a significant benefit of each drug on clinical progression of BPH in the MTOPS Study (an increase in AUA-SI score was the most common component of this composite outcome),5 we did not observe a comparable improvement in QoL as assessed by the PCS and the MCS when drug groups were compared with placebo. The absence of improvement of the MOS-SF-36 summary scores following drug treatment despite improvement of the AUA-SI suggests that this instrument likely does not capture the urological aspects of QoL of men with LUTS. Alternatively, the absence of significant improvement in overall QoL in drug treatment groups compared with placebo determined by the MOS-SF-36 may be a result of the adverse effects of the drugs, including dizziness, postural hypotension, asthenia, erectile dysfunction, decreased libido, abnormal ejaculation, among others. Previously, the MOS-SF-36 has been used as an outcome measure for invasive but not drug therapy in BII
A
I-PSS-QoL
B
0.00
0.00 PLACEBO
DOXAZOSIN
FINASTERIDE
COMBINATION
PLACEBO
DOXAZOSIN
FINASTERIDE
COMBINATION
Doxazosin vs. placebo: p<0.001 Finasteride vs. placebo: p=0.005 Combinaon vs. placebo: p<0.001 -1.00
-1.00
Doxazosin vs. placebo, finasteride vs. placebo, combinaon vs. placebo, finasteride vs. combinaon, finasteride vs. doxazosin: p<0.001 -2.00 Placebo Doxazosin Finasteride Combinaon
698 712 723 739
633 645 653 670
616 640 636 670
591 626 614 653
516 565 539 571
-2.00 Placebo Doxazosin Finasteride Combinaon
698 712 723 739
633 646 654 670
615 640 637 670
592 625 614 653
517 565 539 571
Figure 2. Mean change from baseline in quality of life measures over time in BII and I-PSS-QoL. Wei-Lachin test of stochastic ordering was used to determine p values for all followup visit measurements.
DRUG THERAPY FOR BENIGN PROSTATIC HYPERPLASIA AND QUALITY OF LIFE
commonly used (singly or combined) to treat BPH. We recognize that the generalizability of our findings may be limited because most of the men we studied were white and many were relatively well educated.
CONCLUSIONS QoL in men with BPH, as measured by disease specific QoL instruments, the BII and the I-PSSQoL, improved in men assigned to finasteride alone,
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doxazosin alone, and combination therapy compared with those assigned to placebo. No significant change in QoL was observed when a general measure, the MOS-SF-36, was used. QoL improved significantly during 4 years in men assigned to the doxazosin and combination therapy groups compared with those assigned to finasteride only when assessed with the I-PSS-QoL. QoL in men with BPH should be assessed with instruments specific to that disease.
REFERENCES 1. Wei JT, Calhoun E and Jacobsen SJ: Urologic Diseases in America Project: benign prostatic hyperplasia. J Urol, suppl., 2008; 179: S75. 2. Parsons JK: Benign prostatic hyperplasia and male lower urinary tract symptoms: epidemiology and risk factors. Curr Bladder Dysfunct Rep 2010; 5: 212. 3. Barry MJ: Evaluation of symptoms and quality of life in men with benign prostatic hyperplasia. Urology 2001; 58: 25. 4. Elterman DS, Barkin J and Kaplan SA: Optimizing the management of benign prostatic hyperplasia. Ther Adv Urol 2012; 4: 77. 5. McConnell JD, Roehrborn CG, Bautista OM 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. 6. Roehrborn CG, Siami P, Barkin J et al: The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol 2008; 179: 616. 7. Barry MJ, Williford WO, Chang Y 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? J Urol 1995; 154: 1770.
10. Lepor H, Williford WO, Barry MJ et al: The impact of medical therapy on bother due to symptoms, quality of life and global outcome, and factors predicting response. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. J Urol 1998; 160: 1358. 11. Montorsi F, Henkel T, Geboers A et al: Effect of dutasteride, tamsulosin and the combination on patient-reported quality of life and treatment satisfaction in men with moderate-to-severe benign prostatic hyperplasia: 4-year data from the CombAT study. Int J Clin Pract 2010; 64: 1042. 12. Kusek JW, Ahrens A, Burrows PK et al: Recruitment for a clinical trial of drug treatment for benign prostatic hyperplasia. Urology 2002; 59: 63. 13. Bautista OM, Kusek JW, Nyberg LM et al: Study design of the Medical Therapy of Prostatic Symptoms (MTOPS) trial. Control Clin Trials 2003; 24: 224. 14. Ware JE, Snow KK, Kosinski M et al: SF-36 Health Survey Manual and Interpretation Guide. Boston: The Health Institute, New England Medical Center 1993. 15. Barry MJ, Fowler FJ Jr, O’Leary MP 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.
8. Batista-Miranda JE, Diez MD, Bertran PA et al: Quality-of-life assessment in patients with benign prostatic hyperplasia: effects of various interventions. Pharmacoeconomics 2001; 19: 1079.
16. Barry MJ, Fowler FJ Jr, O’Leary MP et al: Measuring disease-specific health status in men with benign prostatic hyperplasia. Measurement Committee of The American Urological Association. Med Care 1995; 33: AS145.
9. Fourcade RO, Lacoin F, Rouprêt M et al: Outcomes and general health-related quality of life among patients medically treated in general daily practice for lower urinary tract symptoms due to benign prostatic hyperplasia. World J Urol 2012; 30: 419.
17. Barry MJ, Adolfsson J, Batista JE et al: Measuring symptoms and health impact of benign prostatic hyperplasia and its treatments. In: 4th International Consultation on Benign Prostatic Hyperplasia. Edited by L Denis, K Griffiths, S Khoury et al. Plymouth, UK: Plymbridge Distributors, Ltd. 1998; p 265.
18. Cohen J: Statistical Power Analysis for the Behavioral Sciences, 2nd ed. Hillsdale, New Jersey: Lawrence Erlbaum Associates, Inc. 1988. 19. Lachin JM: Some large-sample distribution-free estimators and tests for multivariate partially incomplete data from two populations. Stat Med 1992; 11: 1151. 20. Barry MJ, Cantor A and Roehrborn CG: Relationships among participant International Prostate Symptom Score and Benign Prostatic Hyperplasia Impact Index changes and global ratings of change in a trial of phytotherapy for men with lower urinary tract symptoms. J Urol 2013; 189: 987. 21. Carter A, Sells H, Speakman M et al: Quality of life changes following KTP/Nd:YAG laser treatment of the prostate and TURP. Eur Urol 1999; 36: 92. 22. Roberts RO, Jacobsen SJ, Rhodes T et al: Natural history of prostatism: impaired health states in men with lower urinary tract symptoms. J Urol 1997; 157: 1711. 23. Welch G, Weinger K and Barry MJ: Quality-of-life impact of lower urinary tract symptom severity: results from the Health Professionals Follow-up Study. Urology 2002; 59: 245. 24. Engström G, Henningsohn L, Walker-Engström ML et al: Impact on quality of life of different lower urinary tract symptoms in men measured by means of the SF 36 questionnaire. Scand J Urol Nephrol 2006; 40: 485. 25. Byrnes CA, Morton AS, Liss CL et al: Efficacy, tolerability, and effect on health-related quality of life of finasteride versus placebo in men with symptomatic benign prostatic hyperplasia: a community based study. CUSP Investigators. Community based study of Proscar. Clin Ther 1995; 17: 956. 26. Tenover JL, Pagano GA, Morton AS et al: Efficacy and tolerability of finasteride in symptomatic benign prostatic hyperplasia: a primary care study. Primary Care Investigator Study Group. Clin Ther 1997; 19: 243.
Purpose: We examined the effects of doxazosin, finasteride and combination therapy among men with benign prostatic hyperplasia on quality of life assessed with MOS-SF-36 (Medical Outcomes Study Short-Form 36) and 2 disease specific instruments (BII, benign prostatic hyperplasia Impact Index and I-PSS-QoL, International Prostate Symptom Score-QoL) during 4 years. Materials and Methods: The MTOPS (Medical Therapy of Prostatic Symptoms) study was a multicenter, randomized, double-blind, placebo controlled clinical trial with a primary outcome of time to benign prostatic hyperplasia progression. Change in quality of life was a secondary outcome. A total of 2,872 men enrolled in the MTOPS study who had 3 baseline quality of life measures and at least 1 followup measure by any of the quality of life instruments were analyzed. Results: Compared with men assigned to placebo, men assigned to doxazosin and combination experienced a statistically significant improvement in the BII at year 4. Men assigned to each of the drug groups also experienced a significant improvement in the I-PSS-QoL compared with those assigned to placebo. Considering longitudinal changes during 4 years, a significant improvement in BII and I-PSS-QoL scores was observed in men assigned to the drug groups compared with those assigned to placebo. However, there were no significant differences for the MOS-SF-36 subscales and summary scores when drug groups were compared with the placebo group. Conclusions: The quality of life of men treated with doxazosin, finasteride, and the drugs combined generally improved when assessed with the BII and the I-PSS-QoL compared with those treated with placebo. Quality of life did not show improvement when measured by the MOS-SF-36. Key Words: lower urinary tract symptoms, prostatic hyperplasia, quality of life, doxazosin, finasteride LOWER urinary tract symptoms associated with BPH are common, costly to treat and bothersome, and they negatively impact quality of life.1–3 In the last 2 decades the usual treatment of symptomatic BPH changed markedly from surgery to drug therapy.4 This is
a result of a substantial number of randomized clinical trials of 2 classes of drugs, 5␣-reductase inhibitors and ␣-adrenergic receptor blockers, which have shown them to reduce symptoms and/or progression of BPH significantly.5,6 While the severity and wors-
0022-5347/13/1901-0187/0 THE JOURNAL OF UROLOGY® © 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2013.01.061 Vol. 190, 187-193, July 2013 RESEARCH, INC. Printed in U.S.A.
AND
Abbreviations and Acronyms AUA-SI ⫽ American Urological Association symptom index BII ⫽ Benign Prostatic Hyperplasia Impact Index BPH ⫽ benign prostatic hyperplasia I-PSS ⫽ International Prostate Symptom Score LUTS ⫽ lower urinary tract symptoms MCS ⫽ Mental Component Summary MOS-SF-36 ⫽ Medical Outcomes Study Short-Form 36 PCS ⫽ Physical Component Summary QoL ⫽ quality of life Accepted for publication January 17, 2013. Study received institutional review board approval. * Correspondence: Social & Scientific Systems, Inc., 8757 Georgia Ave., 12th floor, Silver Spring, Maryland 20910 (telephone: 301-628-0342; FAX: 301-628-0301; e-mail: [email protected]). Supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (HHSN 276201200161U). † Nothing to disclose. ‡ Financial interest and/or other relationship with Merck, Pfizer, Astellas and Olympus.
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 368 and 369.
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ening (progression) of LUTS are clinically important outcomes among men with BPH, their impact on QoL is also important. Despite a number of reports of the effects of drug therapy on QoL in men with BPH,7–10 few studies have been long-term.11 The MTOPS study was a multicenter, randomized, double-blind, placebo controlled clinical trial designed to determine whether finasteride combined with doxazosin, finasteride alone, or doxazosin alone would significantly reduce the clinical progression of BPH compared with placebo.12,13 QoL associated with treatment was a secondary outcome. We report the effect of drug therapy, compared with placebo and with each other, on QoL assessed by general and disease specific instruments over 4 years.
METHODS Study Design The design and primary results of the MTOPS Study have been published previously.5,12,13 Men were eligible for the study if they were at least 50 years old, had an AUA-SI score of 8 to 30, a maximal urinary flow rate of 4 to 15 ml per second, and a minimum voided volume of 125 ml. After screening, 3,047 men were equally randomized to placebo, 4 or 8 mg doxazosin, 5 mg finasteride, or combination therapy. The primary outcome was clinical progression of BPH. Change over time in QoL was a secondary outcome. Selfreported QoL was assessed at baseline and every 3 months thereafter by the BII and the I-PSS-QoL, and annually by the MOS-SF-36. Clinical and demographic information also was obtained at baseline. The trial was approved by the appropriate institutional review boards. Written informed consent was obtained from all study participants. The MTOPS study found that combination therapy, finasteride alone, and doxazosin alone significantly reduced the risk of clinical progression of BPH and significantly improved (decreased) symptoms assessed by the AUA-SI, compared with placebo. In this secondary analysis of QoL, we analyzed men enrolled in the trial who had 3 baseline QoL measures and at least 1 followup measure by any of the QoL instruments.
QoL Measures General QoL was assessed by the MOS-SF-36.14 This instrument assesses 8 dimensions (measured by subscales) of health during the previous month, including physical functioning, role limitations due to physical problems, bodily pain, general health perception, vitality, social function, role limitations due to emotional problems and mental health. Two summary scales, the Mental Component Summary and the Physical Component Summary, are scored from norm based methods that standardize both scores to a mean of 50 and a SD of 10. The range of scores for each subscale and the summary scales is 0 to 100, with higher scores indicating better QoL. We also assessed QoL by 2 disease specific instruments, the BII and the I-PSS-QoL. The BII is a 4-item questionnaire that measures the health impact of LUTS during the last month, including physical discomfort, worry about health, symptom bother and frequency of symptoms that interfere
with performance of usual activities.15,16 The range of possible scores of the BII is 0 to 13, with a higher score indicating a greater negative impact of BPH symptoms. The I-PSSQoL is measured by a single question, “If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?” with a higher score indicating poorer QoL. Possible responses are 0 — delighted, 1—pleased, 2—mostly satisfied, 3—mixed, 4 —mostly dissatisfied, 5— unhappy and 6 —terrible.17
Statistical Analysis Statistical analyses were performed according to randomized treatment group (intent to treat). The characteristics of study participants at baseline were categorized by treatment group. Means (with SDs) for continuous variables and percentage distributions for categorical variables were calculated. Changes in the MOS-SF-36 subscales and the PCS and the MCS, the BII, and the I-PSS-QoL were assessed from baseline to followup year 4 for each of the drug groups and were compared with the change observed in the placebo group for the same time interval. Differences in changes from baseline to followup year 4 between the drug groups and the placebo group were assessed using nonparametric Wilcoxon rank sum test for all interval or ordinal scores. The effect sizes of changes between comparison groups were assessed with Cohen’s d, a measure of the magnitude of a treatment effect.18 Cohen’s d was calculated as the difference of the means (mean change score in the drug group minus mean change score in the placebo group) divided by the pooled SD of both groups at baseline. A zero value for a Cohen’s d indicates no effect, whereas a value between 0.2 and 0.5 is considered a small effect.18 In addition to the point comparison at 4 years, we also used the nonparametric WeiLachin test to compare longitudinal changes in scores from each of the QoL measures between each drug group and the placebo group during a 4-year period.19 We also compared longitudinal changes in QoL between drug groups (combination therapy vs doxazosin, combination therapy vs finasteride, and doxazosin vs finasteride) over 4 years. A total of 114 (4%) of the men we studied completed both the BII and the I-PSS-QoL, but not the MOS-SF-36, at least once during followup. We performed a sensitivity analysis by excluding those men who had not completed a followup MOS-SF-36 to assess whether those participants would influence our findings. To address the possible impact of missing followup data, we also performed analysis using the last observation carried forward (LOCF) and compared results with analyses using only available data when change at year 4 was considered. All tests of statistical significance were 2-sided with a Bonferroni adjusted criterion of a p value of less than 0.008 (6 pairwise comparisons in this analysis). All analyses were conducted using SAS® for Windows® software, version 9.2.
RESULTS Of the 3,047 men randomized in the MTOPS Study 2,915 (96%) completed the MOS-SF-36, the BII and the I-PSS-QoL at baseline, and 2,872 had at least 1 acceptable followup measure of QoL and were included in the present analysis. During the study period response rates were 90%, 88%, 86% and 71%
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Table 1. Baseline demographic and clinical characteristics of men with baseline and at least 1 followup value of QoL measures Overall No. pts Mean ⫾ SD pt age No. race/ethnicity (%): White Black Hispanic Other No. education (grade level last completed) (%): Grade 1–12 1–4 Yrs college Post-undergraduate Mean Mean Mean Mean Mean Mean
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
SD SD SD SD SD SD
AUA symptom score ml prostate vol ml/sec max urinary flow rate ml post-void residual ng/ml serum prostate specific antigen mg/dl serum creatinine
Mean ⫾ SD MOS-SF-36 subscales: Physical functioning Role limitation due to physical problems Bodily pain General health perception Vitality Social function Role limitation due to emotional problems Mental health Mean ⫾ SD MOS-SF-36 summary scores: PCS MCS Mean ⫾ SD BII Mean ⫾ SD I-PSS-QoL
Placebo
2,872 62.6 ⫾ 7.3
Demographic 698 62.5 ⫾ 7.6
2,380 (82.9) 248 (8.6) 204 (7.1) 40 (1.4) 838 (29.2) 1,246 (43.4) 788 (27.4) 16.8 ⫾ 5.9 36.4 ⫾ 19.9 10.5 ⫾ 2.6 68.0 ⫾ 83.5 2.3 ⫾ 2.1 1.1 ⫾ 0.2
580 (83.1) 63 (9.0) 46 (6.6) 9 (1.3) 213 (30.5) 300 (43.0) 185 (26.5) Clinical 16.7 ⫾ 5.9 35.3 ⫾ 19.0 10.5 ⫾ 2.7 69.9 ⫾ 82.3 2.3 ⫾ 2.1 1.1 ⫾ 0.2 Quality of Life
Doxazosin
Finasteride
Combination
712 62.7 ⫾ 7.3
723 62.5 ⫾ 7.3
739 62.6 ⫾ 7.1
589 (82.7) 63 (8.9) 52 (7.3) 8 (1.1)
607 (84.0) 56 (7.8) 43 (6.0) 17 (2.4)
604 (81.7) 66 (8.9) 63 (8.5) 6 (0.8)
207 (29.1) 298 (41.9) 207 (29.1)
212 (29.3) 303 (41.9) 208 (28.8)
206 (27.9) 345 (46.7) 188 (25.4)
16.9 ⫾ 5.9 36.9 ⫾ 21.6 10.3 ⫾ 2.6 68.9 ⫾ 89.2 2.4 ⫾ 2.2 1.1 ⫾ 0.2
17.1 ⫾ 6.0 36.9 ⫾ 20.7 10.5 ⫾ 2.6 66.2 ⫾ 81.0 2.3 ⫾ 2.1 1.1 ⫾ 0.2
16.7 ⫾ 5.8 36.3 ⫾ 18.4 10.6 ⫾ 2.5 67.0 ⫾ 81.6 2.3 ⫾ 2.0 1.1 ⫾ 0.2
83.9 ⫾ 19.3 81.2 ⫾ 31.7 76.8 ⫾ 21.0 74.4 ⫾ 17.3 65.5 ⫾ 18.9 88.8 ⫾ 18.7 84.8 ⫾ 29.9 79.8 ⫾ 15.4
84.1 ⫾ 19.1 82.5 ⫾ 31.5 78.2 ⫾ 19.9 74.9 ⫾ 17.1 65.6 ⫾ 18.6 89.4 ⫾ 17.7 86.2 ⫾ 28.8 80.1 ⫾ 15.0
84.1 ⫾ 18.9 81.7 ⫾ 31.4 76.5 ⫾ 21.4 74.1 ⫾ 17.4 64.7 ⫾ 18.9 88.3 ⫾ 19.1 85.3 ⫾ 29.6 79.8 ⫾ 16.1
83.7 ⫾ 19.6 79.3 ⫾ 32.8 75.6 ⫾ 21.4 74.0 ⫾ 17.1 65.6 ⫾ 19.2 88.2 ⫾ 19.4 84.6 ⫾ 29.6 79.2 ⫾ 15.4
83.5 ⫾ 19.7 81.4 ⫾ 31.2 76.7 ⫾ 21.2 74.5 ⫾ 17.4 66.0 ⫾ 18.8 89.4 ⫾ 18.6 83.0 ⫾ 31.5 80.1 ⫾ 15.2
49.5 ⫾ 52.9 ⫾ 3.9 ⫾ 3.0 ⫾
49.9 ⫾ 53.1 ⫾ 3.9 ⫾ 2.9 ⫾
49.5 ⫾ 52.8 ⫾ 3.9 ⫾ 3.0 ⫾
49.2 ⫾ 52.8 ⫾ 4.0 ⫾ 3.1 ⫾
49.6 ⫾ 52.9 ⫾ 3.8 ⫾ 3.0 ⫾
8.3 8.5 2.7 1.3
(2,051 of 2,872) for the MOS-SF-36, and 91%, 89%, 86%, and 76% (2,192 of 2,872) for the BII and the I-PSS-QoL, at year 1, year 2, year 3 and year 4 of followup, respectively. Selected baseline demographic and clinical characteristics, and QoL measures of the men we studied overall and by treatment group are shown in table 1. They were on average 62.6 (SD 7.3) years of age, were well educated (43.4% with college and 27.4% with post-undergraduate education), had a median AUA-SI score of 16, and were predominantly nonHispanic whites (82.9%) with a median baseline PCS score of 51.6, MCS score of 55.5, BII score of 3, and I-PSS-QoL score of 3. There were no significant differences in baseline demographic and clinical characteristics of the men we studied compared with all men enrolled in the trial (data not shown). Baseline characteristics did not differ significantly by treatment group. Medical Outcomes Study Short-Form 36 Changes in the MOS-SF-36 subscales and summary scales scores from baseline to year 4 of followup by treatment group are shown in table 2. A statistically
8.2 8.2 2.7 1.4
8.5 8.8 2.6 1.3
8.2 8.3 2.7 1.3
8.2 8.5 2.7 1.3
significant reduction (worsening) was observed for the subscales of physical functioning, role limitations due to physical problems, bodily pain, general health perception and vitality in all treatment groups, except bodily pain in men assigned to finasteride. Changes in social function and role limitations due to emotional problems varied. No significant change was observed in mental health in any treatment group. The subscale with the greatest reduction was role limitations due to physical problems. The decrease was greatest in the placebo group (⫺8.83, 95% CI ⫺12.09 to ⫺5.58) and least in finasteride (⫺6.97, ⫺10.19 to ⫺3.74). There also were significant decreases in the PCS score in each of the treatment groups (placebo ⫺2.63, 95% CI ⫺3.33 to ⫺1.92; combination therapy ⫺2.49, ⫺3.19 to ⫺1.80; doxazosin ⫺2.34, ⫺2.98 to ⫺1.71; finasteride ⫺1.61, ⫺2.30 to ⫺0.91). In contrast, the MCS score did not change significantly during the same period. Table 3 shows the differences in mean change in QoL measures between each of the drug groups and the placebo group from baseline to year 4. The dif-
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DRUG THERAPY FOR BENIGN PROSTATIC HYPERPLASIA AND QUALITY OF LIFE
Table 2. Change from baseline to year 4 in QoL measures Placebo No. pts Mean change MOS-SF-36 subscales (95% CI): Physical functioning Role limitation due to physical problems Bodily pain General health perception Vitality Social function Role limitation due to emotional problems Mental health Mean change MOS-SF-36 summary scores (95% CI): PCS MCS No. pts Mean change BII (95% CI) Mean change I-PSS-QoL (95% CI)
484
Doxazosin General instrument 526
Finasteride
Combination
506
535
⫺3.47 (⫺4.86 to ⫺2.08) ⫺7.90 (⫺10.96 to ⫺4.85) ⫺4.31 (⫺6.20 to ⫺2.43) ⫺2.75 (⫺3.91 to ⫺1.60) ⫺1.78 (⫺3.10 to ⫺0.45) ⫺1.02 (⫺2.78 to 0.74) ⫺2.22 (⫺5.33 to 0.90) 0.66 (⫺0.59 to 1.90)
⫺2.89 (⫺4.47 to ⫺1.32) ⫺6.97 (⫺10.19 to ⫺3.74) ⫺1.96 (⫺3.96 to 0.03) ⫺2.99 (⫺4.29 to ⫺1.68) ⫺2.74 (⫺4.20 to ⫺1.28) ⫺2.15 (⫺4.01 to ⫺0.29) ⫺5.02 (⫺8.03 to ⫺2.00) ⫺0.07 (⫺1.37 to 1.23)
⫺3.80 (⫺5.37 to ⫺2.23) ⫺8.55 (⫺11.65 to ⫺5.45) ⫺4.33 (⫺6.23 to ⫺2.43) ⫺3.71 (⫺5.04 to ⫺2.38) ⫺3.75 (⫺5.23 to ⫺2.27) ⫺3.64 (⫺5.49 to ⫺1.80) ⫺2.37 (⫺5.37 to 0.63) ⫺0.22 (⫺1.44 to 1.00)
⫺2.63 (⫺3.33 to ⫺1.92) ⫺2.34 (⫺2.98 to ⫺1.71) ⫺0.54 (⫺1.24 to 0.17) 0.40 (⫺0.35 to 1.14) Disease specific instruments 517 565 ⫺1.18 (⫺1.40 to ⫺0.96) ⫺1.59 (⫺1.80 to ⫺1.38) ⫺0.80 (⫺0.91 to ⫺0.68) ⫺1.18 (⫺1.28 to ⫺1.08)
⫺1.61 (⫺2.30 to ⫺0.91) ⫺0.59 (⫺1.32 to 0.14)
⫺2.49 (⫺3.19 to ⫺1.80) ⫺0.33 (⫺1.04 to 0.38)
539 ⫺1.45 (⫺1.67 to ⫺1.23) ⫺1.05 (⫺1.15 to ⫺0.95)
571 ⫺1.71 (⫺1.92 to ⫺1.50) ⫺1.26 (⫺1.37 to ⫺1.15)
⫺5.09 (⫺6.86 to ⫺3.32) ⫺8.83 (⫺12.09 to ⫺5.58) ⫺5.27 (⫺7.22 to ⫺3.33) ⫺3.41 (⫺4.75 to ⫺2.06) ⫺3.51 (⫺5.05 to ⫺1.97) ⫺2.45 (⫺4.23 to ⫺0.68) ⫺7.51 (⫺10.51 to ⫺4.51) 0.23 (⫺1.03 to 1.49)
Positive change scores in MOS-SF-36 indicate improved QoL during followup. Negative change scores in BII and I-PSS-QoL indicate improved QoL during followup.
ferences in changes for MOS-SF-36 subscales and summary scores between drug groups and placebo group were not statistically significant. Similarly, neither significant differences nor important effect sizes of the subscales and summary scores were observed when drug groups were compared with each other at year 4 (data not shown). Figure 1, A shows the pattern of mean change in PCS score from baseline to year 4 for each treatment group. Compared with men assigned to finasteride, those assigned to doxazosin or combination therapy had a statistically significant greater mean decrease in PCS scores during the 4-year period longitudinally. In contrast, the mean change in MCS scores was small in all treatment groups, with a range of ⫺0.59 to 0.40, with no significant differences between treatment groups (fig. 1, B). BII and I-PSS-QoL The mean decreases (improvement) in BII from baseline to year 4 among men assigned to combination therapy, doxazosin, finasteride and placebo were ⫺1.71 (95% CI ⫺1.92 to ⫺1.50), ⫺1.59 (⫺1.80 to ⫺1.38), ⫺1.45 (⫺1.67 to ⫺1.23) and ⫺1.18 (⫺1.40 to ⫺0.96), respectively (table 2). Compared with men assigned to placebo, those assigned to doxazosin (difference of change ⫺0.41, 95% CI ⫺0.72 to ⫺0.11) and combination therapy (⫺0.53, ⫺0.83 to ⫺0.22) experienced a statistically significant but small improvement (Cohen’s d ⫽ ⫺0.2) in BII at year 4 (table 3). However, no significant differences between drug groups were observed at year 4 (data not shown). As shown in figure 2, A, the mean BII score decrease (improvement) was greatest for each treatment group during the first 3 months after randomization and varied little thereafter.
The mean decreases (improvement) in the I-PSSQoL score from baseline to year 4 in men assigned to combination therapy, doxazosin, finasteride and placebo were ⫺1.26 (95% CI ⫺1.37 to ⫺1.15), ⫺1.18 (⫺1.28 to ⫺1.08), ⫺1.05 (⫺1.15 to ⫺0.95) and ⫺0.80 (⫺0.91 to ⫺0.68), respectively (table 2). Men assigned to each of the drug groups experienced a significant improvement in I-PSS-QoL score compared with those assigned to placebo at year 4, although the effect size was small, with Cohen’s d ranging from ⫺0.2 to ⫺0.4 (table 3). The improvement in the I-PSS-QoL was significantly greater in men assigned to combination therapy and doxazosin, compared with those assigned to finasteride, over time (fig. 2, B). Our findings were not changed significantly when only men who had completed the MOS-SF-36 during followup were considered. Changes at year 4 by treatment group also were similar when data were analyzed using the LOCF.
DISCUSSION This is the first and largest study of the long-term effects of commonly used drugs to treat men with BPH on QoL compared with placebo. In addition, this is the first report of a clinical trial of drug therapy in men with BPH that assessed QoL using the MOS-SF-36. Because drug treatment, most often an ␣-adrenergic receptor blocker and/or a 5␣-reductase inhibitor of these men is often lifelong after diagnosis, it is important to consider how these drugs may affect QoL during an extended period of time. At baseline, QoL was relatively well preserved in the men enrolled in the MTOPS Study whom we examined.
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Table 3. Difference of change from baseline to year 4 between drug groups and placebo in QoL measures Difference of change (95% CI)
p Value*
Cohen’s d
1.62 (⫺0.63 to 3.87) 0.93 (⫺3.53 to 5.39) 0.96 (⫺1.75 to 3.67) 0.66 (⫺1.11 to 2.43) 1.73 (⫺0.30 to 3.76) 1.43 (⫺1.07 to 3.93) 5.29 (0.96 to 9.62) 0.42 (⫺1.35 to 2.20) 0.28 (⫺0.67 to 1.23) 0.93 (⫺0.09 to 1.96) ⫺0.41 (⫺0.72 to ⫺0.11) ⫺0.39 (⫺0.54 to ⫺0.23) Finasteride vs placebo ([mean in finasteride] minus [mean in placebo])
0.70 0.91 0.44 0.72 0.16 0.09 0.08 0.58 0.68 0.04 0.008 ⬍0.001
0.1 0.0 0.0 0.0 0.1 0.1 0.2 0.0 0.0 0.1 ⫺0.2 ⫺0.3
2.20 (⫺0.17 to 4.57) 1.87 (⫺2.71 to 6.44) 3.31 (0.52 to 6.10) 0.42 (⫺1.45 to 2.30) 0.77 (⫺1.35 to 2.89) 0.30 (⫺2.27 to 2.88) 2.49 (⫺1.76 to 6.74) ⫺0.31 (⫺2.12 to 1.50) 1.02 (0.03 to 2.01) ⫺0.05 (⫺1.07 to 0.96) ⫺0.27 (⫺0.59 to 0.04) ⫺0.26 (⫺0.41 to ⫺0.10) Combination vs placebo ([mean in combination] minus [mean in placebo])
0.05 0.46 0.013 0.72 0.25 0.50 0.17 0.76 0.013 0.98 0.05 ⬍0.001
0.1 0.1 0.2 0.0 0.0 0.0 0.1 0.0 0.1 0.0 ⫺0.1 ⫺0.2
0.70 0.86 0.51 0.68 0.88 0.53 0.05 0.76 0.91 0.58 0.002 ⬍0.001
0.1 0.0 0.0 0.0 0.0 ⫺0.1 0.2 0.0 0.0 0.0 ⫺0.2 ⫺0.4
Doxazosin vs placebo ([mean in doxazosin] minus [mean in placebo]) MOS-SF-36 subscales: Physical functioning Role limitation due to physical problems Bodily pain General health perception Vitality Social function Role limitation due to emotional problems Mental health MOS-SF-36 PCS MOS-SF-36 MCS BII I-PSS-QoL MOS-SF-36 subscales: Physical functioning Role limitation due to physical problems Bodily pain General health perception Vitality Social function Role limitation due to emotional problems Mental health MOS-SF-36 PCS MOS-SF-36 MCS BII I-PSS-QoL MOS-SF-36 subscales: Physical functioning Role limitation due to physical problems Bodily pain General health perception Vitality Social function Role limitation due to emotional problems Mental health MOS-SF-36 PCS MOS-SF-36 MCS BII I-PSS-QoL
1.29 (⫺1.06 to 3.65) 0.28 (⫺4.21 to 4.77) 0.94 (⫺1.78 to 3.67) ⫺0.30 (⫺2.19 to 1.60) ⫺0.24 (⫺2.37 to 1.90) ⫺1.19 (⫺3.75 to 1.37) 5.13 (0.89 to 9.38) ⫺0.45 (⫺2.21 to 1.30) 0.13 (⫺0.86 to 1.12) 0.20 (⫺0.80 to 1.20) ⫺0.53 (⫺0.83 to ⫺0.22) ⫺0.47 (⫺0.62 to ⫺0.31)
Positive differences and Cohen’s d in MOS-SF-36 indicate a better QoL change in the drug treatment group vs placebo group. Negative differences and Cohen’s d in BII and I-PSS-QoL indicate a better QoL change in the drug treatment group vs placebo group. * Wilcoxon rank-sum test.
Study participants had a mean MCS score above the population mean of 50 and a mean PCS score of nearly that value. After 4 years of followup, men assigned to all treatment groups, including placebo, experienced a significant but small decrease in PCS but not MCS scores. However, men assigned to the drug groups did not experience a significant change in any of the 8 subscales of the MOS-SF-36, the PCS, or the MCS compared with those assigned to placebo, suggesting that these drugs, used singly or combined, may neither adversely nor beneficially affect QoL. At 4 years after treatment assignment, there also was no significant difference in change in these measures when drug groups (doxazosin, finasteride and combination therapy) were compared. Although men assigned to drug
treatment each showed a significant improvement in the I-PSS-QoL after 4 years compared with placebo, the effect size was small. Differences in the improvement in the BII for the doxazosin and combination therapy groups (but not the finasteride group) were statistically significant compared with improvement in the BII for placebo at 4 years. The effect size was small, with no significant differences between drug groups at 4 years. However, significant improvements in longitudinal changes in both BII and I-PSS-QoL scores were observed in men assigned to the drug groups compared to placebo. It is noteworthy that the amount of improvement of QoL in all treatment groups we observed, including placebo, has previously been shown to be clinically significant.20
192
DRUG THERAPY FOR BENIGN PROSTATIC HYPERPLASIA AND QUALITY OF LIFE
A
year 1
year 2
year 3
MOS-SF-36 Mental Component Summary
B
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baseline
year 4
year 1
year 2
year 3
year 4
601 631 626 664
585 621 605 647
484 526 506 535
2.00
0.00
0.00
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Finasteride vs. doxazosin: p=0.005 Finasteride vs. combinaon: p<0.001 -2.00
-4.00 Placebo Doxazosin Finasteride Combinaon
698 712 723 739
626 641 648 661
PLACEBO
601 631 626 664
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585 621 605 647
Placebo Doxazosin Finasteride Combinaon
484 526 506 535
FINASTERIDE
698 712 723 739
626 641 648 661
PLACEBO
COMBINATION
DOXAZOSIN
FINASTERIDE
COMBINATION
Figure 1. Mean change from baseline in quality of life measures over time in MOS-SF-36 Physical Component Summary and MOS-SF-36 Mental Component Summary. Wei-Lachin test of stochastic ordering was used to determine p values for all followup visit measurements.
patients with BPH and in epidemiological studies of LUTS.21–24 Both the BII and the I-PSS-QoL have been used as secondary outcomes in a number of clinical trials of drug therapy for BPH.7,11,25,26 As expected, we found both of these measures to be more sensitive to change than the MOS-SF-36 because both were developed to capture domains of QoL directly related to LUTS. Previous studies have reported significant improvements of the BII as a result of treatment with finasteride compared with placebo in shortterm (12 months) clinical trials,25,26 and during 4 years in a clinical trial of dutasteride, tamsulosin and combination therapy.11 The strengths of our study were the large sample size, long duration of followup, use of general and disease specific measures of QoL, analysis by intent to treat, a comparison (placebo) group, high rates of followup (assessment of QoL), and evaluation of 2 drugs
Despite the finding of a significant benefit of each drug on clinical progression of BPH in the MTOPS Study (an increase in AUA-SI score was the most common component of this composite outcome),5 we did not observe a comparable improvement in QoL as assessed by the PCS and the MCS when drug groups were compared with placebo. The absence of improvement of the MOS-SF-36 summary scores following drug treatment despite improvement of the AUA-SI suggests that this instrument likely does not capture the urological aspects of QoL of men with LUTS. Alternatively, the absence of significant improvement in overall QoL in drug treatment groups compared with placebo determined by the MOS-SF-36 may be a result of the adverse effects of the drugs, including dizziness, postural hypotension, asthenia, erectile dysfunction, decreased libido, abnormal ejaculation, among others. Previously, the MOS-SF-36 has been used as an outcome measure for invasive but not drug therapy in BII
A
I-PSS-QoL
B
0.00
0.00 PLACEBO
DOXAZOSIN
FINASTERIDE
COMBINATION
PLACEBO
DOXAZOSIN
FINASTERIDE
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Doxazosin vs. placebo: p<0.001 Finasteride vs. placebo: p=0.005 Combinaon vs. placebo: p<0.001 -1.00
-1.00
Doxazosin vs. placebo, finasteride vs. placebo, combinaon vs. placebo, finasteride vs. combinaon, finasteride vs. doxazosin: p<0.001 -2.00 Placebo Doxazosin Finasteride Combinaon
698 712 723 739
633 645 653 670
616 640 636 670
591 626 614 653
516 565 539 571
-2.00 Placebo Doxazosin Finasteride Combinaon
698 712 723 739
633 646 654 670
615 640 637 670
592 625 614 653
517 565 539 571
Figure 2. Mean change from baseline in quality of life measures over time in BII and I-PSS-QoL. Wei-Lachin test of stochastic ordering was used to determine p values for all followup visit measurements.
DRUG THERAPY FOR BENIGN PROSTATIC HYPERPLASIA AND QUALITY OF LIFE
commonly used (singly or combined) to treat BPH. We recognize that the generalizability of our findings may be limited because most of the men we studied were white and many were relatively well educated.
CONCLUSIONS QoL in men with BPH, as measured by disease specific QoL instruments, the BII and the I-PSSQoL, improved in men assigned to finasteride alone,
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doxazosin alone, and combination therapy compared with those assigned to placebo. No significant change in QoL was observed when a general measure, the MOS-SF-36, was used. QoL improved significantly during 4 years in men assigned to the doxazosin and combination therapy groups compared with those assigned to finasteride only when assessed with the I-PSS-QoL. QoL in men with BPH should be assessed with instruments specific to that disease.
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