Original Investigation | Urology

Assessment of Frailty and Association With Progression of Benign Prostatic

Hyperplasia Symptoms and Serious Adverse Events Among Men Using Drug Therapy
Scott R. Bauer, MD, ScM; Louise C. Walter, MD; Kristine E. Ensrud, MD; Anne M. Suskind, MD, MS; John C. Newman, MD, PhD; William A. Ricke, PhD; Teresa T. Liu, PhD;
Kevin T. McVary, MD; Kenneth Covinsky, MD

Abstract Key Points

Question Is frailty associated with
IMPORTANCE Benign prostatic hyperplasia (BPH) in older men can cause lower urinary tract
increased risk of progression of benign
symptoms (LUTS), which are increasingly managed with medications. Frailty may contribute to both
prostatic hyperplasia (BPH) symptoms
symptom progression and serious adverse events (SAEs), shifting the balance of benefits and harms
and serious adverse events among men
of drug therapy.
receiving drug therapy?

OBJECTIVE To assess the association between a deficit accumulation frailty index and clinical BPH Findings In a cohort study of 3047 men
progression or SAE. with moderate-to-severe lower urinary
tract symptoms due to suspected BPH,
DESIGN, SETTING, AND PARTICIPANTS This cohort study used data from the Medical Therapy of higher deficit accumulation frailty index
Prostatic Symptoms trial, which compared placebo, doxazosin, finasteride, and combination therapy was associated with a higher risk of
in men with moderate-to-severe LUTS, reduced urinary flow rate, and no prior BPH interventions, clinical BPH progression, particularly
hypotension, or elevated prostate-specific antigen. Enrollment was from 1995 to 1998, and follow-up among men receiving doxazosin with
was through 2001. Data were assessed in February 2021. finasteride, and serious adverse events.

Meaning These findings suggest that

EXPOSURES A frailty index (score range, 0-1) using 68 potential deficits collected at baseline was
frail men with lower urinary tract
used to categorized men as robust (score ⱕ0.1), prefrail (score 0.1 to <0.25), or frail (score ⱖ0.25).
symptoms due to suspected BPH are
more likely to have progression of
MAIN OUTCOMES AND MEASURES Primary outcomes were time to clinical BPH progression and
symptoms, despite drug therapy, as well
time to SAE, as defined in the parent trial. Adjusted hazard ratios (AHRs) were estimated using Cox
as serious adverse events.
proportional hazards regressions adjusted for demographic variables, treatment group, measures of
obstruction, and comorbidities.
+ Supplemental content
RESULTS Among 3047 men (mean [SD] age, 62.6 [7.3] years; range, 50-89 years) in this analysis, Author affiliations and article information are
745 (24%) were robust, 1824 (60%) were prefrail, and 478 (16%) were frail at baseline. Compared listed at the end of this article.

with robust men, frail men were older (age ⱖ75 years, 12 men [2%] vs 62 men [13%]), less likely to be
White (646 men [87%] vs 344 men [72%]), less likely to be married (599 men [80%] vs 342 men
[72%]), and less likely to have 16 years or more of education (471 men [63%] vs 150 men [31%]).
During mean (SD) follow-up of 4.0 (1.5) years, the incidence rate of clinical BPH progression was 2.2
events per 100 person-years among robust men, 2.9 events per 100 person-years among prefrail
men (AHR, 1.36; 95% CI, 1.02-1.83), and 4.0 events per 100 person-years among frail men (AHR, 1.82;
95% CI, 1.24-2.67; linear P = .005). Larger point estimates were seen among men who received
doxazosin or combination therapy, although the test for interaction between frailty index and
treatment group did not reach statistical significance (P for interaction = .06). Risk of SAE was higher
among prefrail and frail men (prefrail vs robust AHR, 1.81; 95% CI, 1.48-2.23; frail vs robust AHR, 2.86;
95% CI, 2.21-3.69; linear P < .001); this association was similar across treatment groups (P for
interaction = .76).

(continued)

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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Abstract (continued)

CONCLUSIONS AND RELEVANCE These findings suggest that frailty is independently associated
with greater risk of both clinical BPH progression and SAEs. Older frail men with BPH considering
initiation of drug therapy should be counseled regarding their higher risk of progression despite
combination therapy and their likelihood of experiencing SAEs regardless of treatment choice.

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Introduction
Bladder outlet obstruction due to benign prostatic hyperplasia (BPH), the histological process that
leads to an enlarged prostate, is a common cause of male lower urinary tract symptoms (LUTS).
Currently, one-third of men older than 75 years with newly diagnosed LUTS will receive BPH drug
therapy, twice the rate of younger men.1
Combination therapy with α-adrenergic-receptor antagonist (α-blocker) plus a 5α-reductase
inhibitor has been the standard drug therapy for BPH for over 2 decades since the landmark Medical
Therapy of Prostatic Symptoms (MTOPS) trial demonstrated lower rates of clinical BPH progression,
primarily symptom progression and acute urinary retention, compared with men receiving placebo.2
Drug therapy decreases the risk of clinical BPH progression by decreasing smooth-muscle tone in the
prostate and bladder neck (via α-blockers) and decreasing prostate volume (via 5α-reductase
inhibitors).3 However, LUTS among older men with and without BPH are extremely common and
heterogenous, with multifactorial causes,4,5 contributing to widespread and long-term use of BPH
medications.6-8 Medical BPH therapy is also associated with several important adverse drug events
that are particularly harmful for older men, including orthostatic hypotension, falls, depression,
dementia, and suicidal ideation.9-13 Still unknown is whether there are identifiable subsets of older
men (eg, those that are frail) for whom the risks of long-term drug therapy for BPH outweigh
benefits.
Frailty, as defined by the accumulation of health and functional problems (ie, deficit
accumulation frailty), is associated with morbidity and mortality because of a greater vulnerability to
stressors and is considered a marker of biological, rather than chronological, age.14,15 Although
associations between chronological age and male LUTS or BPH are well established,8,16-18 including
data from the MTOPs trial,19 frailty and other markers of biological age may represent more
important risk factors than chronological age alone.20-25 However, prior studies are limited by cross-
sectional design, lack of a clinical diagnosis or objective measures of benign prostatic obstruction
and frailty, BPH interventions that were neither randomized nor placebo controlled, and no formal
interaction testing.
This cohort study using data from the MTOPS trial evaluates the longitudinal association of a
deficit accumulation frailty index with risk of clinical BPH progression and serious adverse events
(SAEs), using standardized definitions for both. We hypothesized that greater frailty index assessed
at baseline would be independently associated with higher rates of both clinical BPH progression and
SAE and that both associations would be highest among men receiving combination therapy.

Methods
Participants
The MTOPS study design has been previously described.2,26 Participants provided written informed
consent, and institutional review boards at each participating center approved the study. Our local
institutional review board deemed this study to be not human participants research because we only
had access to deidentified data. This analysis follows the Strengthening the Reporting of
Observational Studies in Epidemiology (STROBE) reporting guidelines for observational studies.27

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 JAMA Network Open | Urology Frailty and Progression of BPH Symptoms and Serious Adverse Events Among Men Using Drug Therapy

Men aged 50 years and older were recruited from December 1995 to March 1998 and were
enrolled if they reported moderate-to-severe LUTS (American Urological Association Symptom Index
[AUASI] score, 8-30), demonstrated a reduced urinary flow rate (maximum of 4-15 mL/s), and denied
a history of surgical treatment or recent drug therapy for BPH, hypotension (defined as supine blood
pressure below 90/70 mm Hg), or elevated prostate-specific antigen (>10 ng/mL [to convert to
micrograms per liter, multiply by 1]). Men taking anticholinergic medications for any reason except
glaucoma were also excluded. The eligible participants were randomized to receive placebo,
doxazosin monotherapy, finasteride monotherapy, or combination therapy with both agents, and
were followed for a mean (SD) of 4.0 (1.5) years. Follow-up time was calculated from date of
randomization until the first event of clinical BPH progression, SAE, invasive therapy related to BPH
(252 participants underwent transurethral prostatectomy, transurethral incision of the prostate, laser
therapy, stenting, open prostatectomy, or transurethral microwave therapy), prostate cancer (167
participants), bladder cancer (12 participants), or death (127 participants).

Clinical BPH Progression

Clinical BPH progression was defined as a composite end point including the occurrence of any of the
following: LUTS progression (increase from baseline of at least 4 points in the AUASI), acute urinary
retention (inability to urinate, requiring catheterization in the absence of an obvious cause other than
BPH, such as anesthesia), urinary incontinence, recurrent urinary tract infection or urosepsis, or an
increase in serum creatinine attributable to BPH of at least 1.5 mg/dL (to convert to micromoles per
liter, multiply by 88.4) and to a value at least 50% above baseline.2 The AUASI and other composite
end points were assessed every 3 months. All composite outcomes were adjudicated by clinical
review committee.2

Serious Adverse Events

SAEs were defined as fatal or life-threatening, permanently disabling, requiring or prolonging
inpatient hospitalization, a congenital anomaly or cancer, an overdose, or any medical event that
jeopardized the patient on the basis of appropriate medical judgment and may have required medical
or surgical intervention to prevent an adverse outcome. Adverse events caused by doxazosin and/or
finasteride, but also other causes occurring at a similar rate among participants randomized to
placebo, were assessed every 3 months and adjudicated by a data and safety monitoring board.

Frailty Index
We followed a standardized approach to creating a frailty index based on deficit accumulation using
data collected at baseline.28 We started with deficits from the Systolic Blood Pressure Intervention
Trial frailty index29 and added deficits from another frailty index based on abnormal laboratory
values.30 Finally, we included additional self-reported conditions, functional status, and symptoms
associated with increasing age, with multifactorial causes, and associated with negative health
outcomes. The final frailty index included 68 items (eTable 1 in the Supplement), each weighted
equally, and was calculated as the sum of the score for each item (range, 0-1) divided by total number
of nonmissing items. All participants had more than 30 nonmissing items and were included in the
primary analysis. The frailty index categorized participants as robust (score ⱕ0.1), prefrail (score 0.1
to <0.25), or frail (score ⱖ0.25).31 To confirm that the frailty index was associated with known
constructs as expected among MTOPS participants, we determined that higher frailty index scores
were associated with both older age and mortality (data not shown).

Other Covariates
Demographic characteristics, including race and ethnicity, marital status, and education, were
assessed at baseline. Race and ethnicity were self-identified by the participants and were assessed in
this study because both deficit accumulation frailty and risk of BPH progression vary according to
these demographic factors. Objective measures of benign prostatic obstruction, including maximum

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urinary flow rate (with a voided volume of ⱖ125 mL), serum prostate-specific antigen level, postvoid
residual, and prostate volume (ellipsoid volume of total prostate gland assessed by transrectal
ultrasonography32) were assessed at baseline by technicians trained and monitored by the MTOPS
Biostatistical Coordinating Center.

Statistical Analysis
For this post hoc analysis, the primary independent variable was deficit accumulation frailty index,
and the 2 primary dependent variables were clinical BPH progression and SAE. LUTS progression and
acute urinary retention, the most common composite events, were considered secondary outcomes.
We first compared distributions of established LUTS and BPH risk factors across categories of frailty
status using analysis of variance and 2-sided χ2 tests, as appropriate. We then generated cumulative
incidence curves for each dependent variable stratified by frailty status and tested for differences
between the curves using log-rank tests. To test the hypothesis that greater frailty index at baseline
is independently associated with a greater risk of clinical BPH progression, we used adjusted Cox
proportional hazards regression models because of the fixed follow-up period. We used the same
approach to test the hypothesis that greater frailty index score at baseline is independently
associated with SAE.
To adjust for confounders, we sequentially added groups of covariates to multivariable models.
First, we adjusted for chronological age at enrollment. We further adjusted for treatment group plus
objective markers of benign prostatic obstruction (prostate volume, postvoid residual, and maximum
flow rate). In the fully adjusted model, we adjusted for age, treatment group, markers of benign
prostatic obstruction, demographic variables (race and ethnicity, marital status, and education), body
mass index (calculated as weight in kilograms divided by height in meters squared), and
comorbidities (heart disease, hypertension, diabetes, pulmonary disease, neurological disease, and
gastrointestinal disease). We assessed for modification of the main associations by including a cross-
product term of frailty index (continuous) by treatment group (any drug vs placebo). We also
conducted a sensitivity analysis excluding men with any missing frailty index items.
P < .05 was considered statistically significant in all analyses, which were performed using Stata
statistical software version 15.1 (StataCorp). Data were assessed in February 2021.

Results
Among 3047 men in the analytic cohort (mean [SD] age, 62.6 [7.3] years; range, 50-89 years), 745
(24%) were robust, 1824 (60%) were prefrail, and 478 (16%) were frail at baseline (Table 1).
Compared with robust men, frail men were older (age ⱖ75 years, 12 men [2%] vs 62 men [13%]), less
likely to be White (646 men [87%] vs 344 men [72%]), less likely to be married (599 men [80%] vs
342 men [72%]), and were less likely to have 16 years or more of education (471 men [63%] vs 150
men [31%]). In terms of BPH disease severity at baseline, frail participants had higher AUASI scores,
including both voiding and storage subscores, higher maximum flow rate, and lower postvoid
residuals compared with robust participants, but prostate volume and serum prostate-specific
antigen level were similar across frailty categories (Table 1). Components of the frailty index also
varied as expected by frailty status; frail men had higher body mass index and systolic blood pressure,
worse renal function, worse physical and mental health, took more medications, and had a greater
burden of comorbidities compared with robust men.
Figure 1 displays cumulative incidence curves for clinical BPH progression (351 events), LUTS
progression (274 events [78% of men]), and acute urinary retention (41 events [12% of men]),
stratified by frailty status. In addition, 31 men (9%) developed urinary incontinence, less than 1%
developed recurrent infections or urosepsis (5 men), and 0 had an increase in serum creatinine
attributable to BPH. Table 2 reports the association of frailty with clinical BPH progression as well as
separate associations with the 2 most common event types, LUTS progression and acute urinary
retention. The incidence rates of clinical BPH progression were 2.2 events per 100 person-years

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Table 1. Baseline Characteristics of Study Population, by Frailty Status

Participants, No. (%) (N = 3047)

Robust Prefrail Frail
(FI score (FI score (FI score
Characteristic ≤0.1) 0.1-0.25) ≥0.25) P valuea
Sample size 745 (24) 1824 (60) 478 (16)
Demographic variables
Age, y
50 to <55 153 (21) 277 (15) 47 (10)
55 to <60 184 (25) 374 (21) 87 (18)
60 to <65 197 (26) 436 (24) 106 (22)
<.001
65 to <70 131 (18) 379 (21) 108 (23)
70 to <75 68 (9) 244 (13) 68 (14)
≥75 12 (2) 114 (6) 62 (13)
Race or ethnicity
Black 46 (6) 164 (9) 60 (13)
Hispanic 41 (6) 115 (6) 67 (14)
<.001
White 646 (87) 1519 (83) 344 (72)
b
Other 12 (2) 26 (1) 7 (2)
Married 599 (80) 1396 (77) 342 (72) .002
Education, y
<12 29 (4) 139 (8) 91 (19)
12 to <16 245 (33) 806 (44) 237 (50) <.001
≥16 471 (63) 879 (48) 150 (31)
Markers of health status, mean (SD)
Body mass indexc 26.4 (3) 27.9 (4) 29.1 (5) <.001
Systolic blood pressure, mm Hg 128 (14) 136 (17) 141 (18) <.001
Estimated glomerular filtration rate, 79 (13) 77 (15) 76 (17) <.001
mL/min/1.73 m2
MOS SF-36 Physical Component Score 56 (3) 51 (6) 38 (9) <.001
MOS SF-36 Mental Component Score 56 (4) 53 (8) 46 (12) <.001
Medications, No.
Mean (SD) 1.3 (2) 2.1 (2) 3.1 (2)
<.001
Median (IQR) 1 (0-2) 2 (0-3) 3 (1-4)
Self-reported comorbidities
Heart disease 57 (8) 366 (20) 170 (36) <.001
Hypertension 81 (11) 541 (30) 249 (52) <.001
Diabetes 13 (2) 149 (8) 98 (21) <.001
Pulmonary disease 29 (4) 220 (12) 87 (18) <.001
Neurological disease 14 (2) 109 (6) 29 (6) <.001
Gastrointestinal disease 92 (12) 559 (31) 155 (32) <.001
Cancer 4 (1) 76 (4) 43 (9) <.001
Benign prostatic hyperplasia disease severity, Abbreviations: FI, frailty index; MOS SF-36, Medical
mean (SD) Outcome Study Short Form (36-item).
American Urological Association Symptom Index SI conversion factor: To convert prostate-specific
Total score 16.2 (6.0) 16.9 (6.0) 18.2 (6.0) <.001 antigen to micrograms per liter, multiply by 1.
Voiding subscore 7.1 (3.0) 7.6 (3.0) 8.2 (3.0) <.001 a
Calculated using analysis of variance or Kruskal-Wallis
Storage subscore 9.1 (4.0) 9.3 (4.0) 10.0 (4.0) <.001 test for continuous variables and Pearson χ2 test for
Prostate volume, mLd 35 (20) 37 (20) 37 (21) .15 categorical or binary variables.
b
Maximum urinary flow rate, mL/s 10.3 (3.0) 10.5 (3.0) 10.7 (3.0) .02 Other refers to Alaska Native, American Indian,
Asian, or Pacific Islander.
Postvoid residual, mL
c
Body mass index is calculated as weight in kilograms
Mean (SD) 65 (79) 72 (86) 60 (78) .009
divided by height in meters squared.
Median (IQR) 39 (12-86) 42 (13-100) 33 (11-81) .01
d
Prostate volume was measured by transrectal
Serum prostate-specific antigen, ng/mL 2.3 (2.0) 2.4 (2.0) 2.4 (2.0) .61
ultrasonography.

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(LUTS progression, 1.8 events per 100 person-years; acute urinary retention, 0.2 event per 100
person-years) among robust men, 2.9 events per 100 person-years (LUTS progression, 2.2 events per
100 person-years; acute urinary retention, 0.3 event per 100 person-years) among prefrail men, and
4.0 events per 100 person-years (LUTS progression, 3.2 events per 100 person-years; acute urinary
retention, 0.4 event per 100 person-years) among frail men. Compared with robust men, the risk of
clinical BPH progression was 36% and 82% higher among prefrail and frail men, respectively (prefrail
vs robust adjusted hazard ratio [AHR], 1.36; 95% CI, 1.02-1.83; frail vs robust AHR, 1.82; 95% CI,
1.24-2.67; linear P = .005). Compared with robust men, the risk of LUTS progression was 29% and
79% higher among prefrail and frail men, respectively (prefrail vs robust AHR, 1.29; 95% CI,
0.93-1.78; frail vs robust AHR, 1.79; 95% CI, 1.16-2.75; linear P = .02). Among participants who
experienced LUTS progression, the mean (SD) increase in AUASI voiding subscore from baseline was
4.9 (2.8) among robust men and 4.1 (2.5) among frail men, whereas the mean (SD) increase in AUASI
storage subscore from baseline was 2.5 (2.3) among robust men and 2.9 (1.9) among frail men
(eTable 2 in the Supplement). In sensitivity analyses restricted to men with 0 missing frailty index
items, higher frailty index scores remained associated with greater risk of both clinical BPH and LUTS

Figure 1. Cumulative Incidence Curves for Clinical Benign Prostatic Hyperplasia (BPH) Progression, Lower Urinary Tract Symptoms Progression, and Acute Urinary
Retention, by Frailty Status
A Clinical benign prostatic hyperplasia progression B Lower urinary tract symptoms progression
25 25
Log-rank P =.002 Log-rank P =.01
20 20
Cumulative incidence, %

Cumulative incidence, %
Frail
Prefrail
15 15
Robust

10 10

5 5

0 0
0 1 2 3 4 5 0 1 2 3 4 5
Follow-up, y Follow-up, y
No. at risk No. at risk
Frail 475 456 435 409 398 381 363 347 255 180 93 26 Frail 472 453 430 407 396 380 364 354 263 192 101 27
Prefrail 1816 1751 1684 1625 1581 1529 1490 1438 1136 826 480 146 Prefrail 1813 1747 1679 1628 1589 1547 1509 1465 1160 847 495 152
Robust 744 716 695 678 662 648 637 626 511 377 224 94 Robust 744 717 696 679 666 654 641 629 515 381 229 96

C Acute urinary retention

5
Log-rank P =.23
4
Cumulative incidence, %

0
0 1 2 3 4 5
Follow-up, y
No. at risk
Frail 475 466 454 445 435 426 411 393 292 214 113 34
Prefrail 1816 1781 1742 1707 1683 1649 1622 1580 1250 918 538 165
Robust 744 726 715 707 699 688 681 673 552 413 252 106

Clinical BPH progression is defined according to the original trial as the occurrence of any cause of acute retention other than BPH, such as anesthesia), urinary tract infection or
of the following: lower urinary tract symptom progression (an increase from baseline of urosepsis, incontinence, or an increase in the serum creatinine level, attributable to BPH,
at least 4 points in the American Urological Association symptom index), acute urinary of at least 1.5 mg/dL (to convert to micromoles per liter, multiply by 88.4) and to a value
retention (the inability to urinate requiring catheterization in the absence of an obvious at least 50% above baseline values.

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progression (eTable 3 in the Supplement). Frailty index was not significantly associated with acute
urinary retention in any models, although acute urinary retention was a rare event in all
treatment groups.
Figure 2 displays the cumulative incidence curve for SAE, stratified by frailty status, and Table 2
reports the association of frailty with SAE (857 events). The incidence rate of SAEs was 4.0 events
per 100 person-years among robust men, 6.8 events per 100 person-years among prefrail men, and
10.1 events per 100 person-years among frail men. Compared with robust men, the risk of SAE was
almost 2 and 3 times higher among prefrail and frail men, respectively (prefrail vs robust AHR, 1.81;
95% CI, 1.48-2.23; frail vs robust AHR, 2.86; 95% CI, 2.21-3.69; linear P < .001). In sensitivity analyses
restricted to men with 0 missing frailty index items, higher frailty index scores remained associated
with greater risk of SAE (eTable 3 in the Supplement). There was no modification of the association
between frailty and SAE by treatment group (P for interaction = .76) (eTable 4 in the Supplement).
Table 3 reports the association of frailty with clinical BPH progression stratified by treatment
group. Although the test for interaction between frailty index and treatment group did not reach the
a priori threshold of statistical significance (P for interaction between frailty index and treatment
group = .06), the association of frailty with clinical BPH progression appeared to vary according to

Table 2. Association of Frailty With Clinical BPH Progression, LUTS Progression, Acute Urinary Retention, and Serious Adverse Events in MTOPS

Frailty status
Robust Prefrail Frail
Varirable (FI score ≤0.1) (FI score 0.1-0.25) (FI score ≥0.25) Per 1 SD of FI Linear P value
Clinical BPH progressiona
Incidence rate, events/100 person-years (95% CI) 2.2 (1.7-2.7) 2.9 (2.5-3.3) 4.0 (3.2-5.1) NA NA
Unadjusted HR (95% CI)b 1 [Reference] 1.33 (1.01-1.74) 1.83 (1.31-2.55) 1.18 (1.07-1.30) .001
Partially adjusted HR (95% CI)c 1 [Reference] 1.30 (0.99-1.72) 1.73 (1.23-2.43) 1.16 (1.05-1.29) .004
Fully adjusted HR (95% CI)d 1 [Reference] 1.36 (1.02-1.83) 1.82 (1.24-2.67) 1.18 (1.05-1.33) .005
LUTS progression
Incidence rate, events/100 person-years (95% CI) 1.8 (1.4-2.3) 2.2 (1.9-2.6) 3.2 (2.4-4.1) NA NA
b
Unadjusted HR (95% CI) 1 [Reference] 1.22 (0.90-1.65) 1.73 (1.20-2.51) 1.17 (1.05-1.30) .006
Partially adjusted HR (95% CI)c 1 [Reference] 1.22 (0.89-1.66) 1.67 (1.14-2.44) 1.15 (1.03-1.29) .01
Fully adjusted HR (95% CI)d 1 [Reference] 1.29 (0.93-1.78) 1.79 (1.16-2.75) 1.17 (1.02-1.33) .02
Acute urinary retention
Incidence rate, events/100 person-years (95% CI) 0.2 (0.1-0.4) 0.3 (0.2-0.5) 0.4 (0.2-0.8) NA NA
Unadjusted HR (95% CI)b 1 [Reference] 1.97 (0.81-4.78) 2.35 (0.81-6.81) 1.16 (0.87-1.55) .33
Partially adjusted HR (95% CI)c 1 [Reference] 1.87 (0.75-4.62) 2.05 (0.68-6.21) 1.13 (0.84-1.54) .42
Fully adjusted HR (95% CI)d 1 [Reference] 1.80 (0.70-4.62) 1.90 (0.56-6.39) 1.10 (0.77-1.56) .60
e
Serious adverse events
Incidence rate, events/100 person-years (95% CI) 4.0 (3.3-4.7) 6.8 (6.3-7.4) 10.1 (8.8-11.6) NA NA
Unadjusted HR (95% CI)b 1 [Reference] 2.00 (1.65-2.42) 3.39 (2.71-4.24) 1.42 (1.34-1.50) <.001
Partially adjusted HR (95% CI)c 1 [Reference] 1.93 (1.59-2.34) 3.15 (2.50-3.95) 1.39 (1.31-1.47) <.001
Fully adjusted HR (95% CI)d 1 [Reference] 1.81 (1.48-2.23) 2.86 (2.21-3.69) 1.37 (1.27-1.47) <.001
c
Abbreviations: BPH, benign prostatic hyperplasia; FI, frailty index; HR, hazard ratio; Adjusted for age, treatment group, prostate volume, postvoid residual, and maximum
LUTS, lower urinary tract symptoms; NA, not applicable. urinary flow rate.
a d
Clinical BPH progression was defined according to the original trial as the occurrence Further adjusted for race and ethnicity, marital status, education, body mass index, and
of any of the following: LUTS progression (an increase from baseline of at least 4 points history of heart disease, hypertension, diabetes, pulmonary disease, neurological
in the American Urological Association Symptom Index), acute urinary retention (the disease, and gastrointestinal disease. For the acute urinary retention model, no men
inability to urinate requiring catheterization in the absence of an obvious cause of acute with diabetes had an event so that covariate was removed and both race and ethnicity
retention other than BPH, such as anesthesia), urinary tract infection or urosepsis, and education covariates were collapsed because of small cell sizes.
incontinence, or an increase in the serum creatinine level, attributable to benign e
Serious adverse events were defined according to the original trial as fatal or life-
prostatic hyperplasia, of at least 1.5 mg/dL (to convert to micromoles per liter, multiply threatening, permanently disabling, requiring or prolonging inpatient hospitalization, a
by 88.4) and to a value at least 50% above baseline values. congenital anomaly or cancer, an overdose, or medical events that jeopardize the
b
HR and 95% CI were calculated using proportional hazards model. Linear P value was patient and may require medical or surgical intervention to prevent a serious
calculated using FI as continuous variable. adverse event.

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treatment group. Frailty was not associated with risk of clinical BPH progression among men
randomized to placebo or finasteride monotherapy. However, among men randomized to doxazosin
monotherapy, the AHR for clinical BPH progression was 2.64 (95% CI, 1.16-6.00) for frail vs robust
men. In the combination therapy group, the AHR for clinical BPH progression was 2.46 (95% CI,
0.86-7.01) for frail vs robust men. The eFigure in the Supplement displays the cumulative incidence
curve for clinical BPH progression stratified by frailty status and treatment group.

Figure 2. Cumulative Incidence Curve for Serious Adverse Events,

by Frailty Status.
100
Log-rank P <.001
80
Cumulative incidence, %

Frail
60 Prefrail
Robust

40

20

0
0 1 2 3 4 5
Follow-up, y
No. at risk
Frail 475 464 449 436 425 417 403 390 291 219 116 34
Prefrail 1816 1779 1734 1701 1680 1654 1629 1590 1259 927 546 167
Robust 744 725 714 706 699 688 681 674 554 413 251 104

Serious adverse events were defined according to the original trial as fatal or
life-threatening, permanently disabling, requiring or prolonging inpatient
hospitalization, a congenital anomaly or cancer, an overdose, or medical events
that jeopardize the patient and may require medical or surgical intervention to
prevent a serious adverse event.

Table 3. Association of Frailty With Clinical Benign Prostatic Hyperplasia Progression, Stratified by Treatment Groupa

Frailty status
Robust Prefrail Frail
Treatment group (FI score ≤0.1) (FI score 0.1-0.25) (FI score ≥0.25) Per 1 SD of FI Linear P value
Placebo
Incidence rate, events/100 person-years (95% CI) 3.7 (2.6-5.3) 4.8 (3.8-5.9) 5.3 (3.5-8.2) NA NA
Fully adjusted HR (95% CI)b 1 [Reference] 1.40 (0.88-2.23) 1.57 (0.80-3.08) 1.05 (0.85-1.30) .65
Finasteride
Incidence rate, events/100 person-years (95% CI) 2.5 (1.6-3.9) 2.8 (2.2-3.7) 4.0 (2.6-6.3) NA NA
b
Fully adjusted HR (95% CI) 1 [Reference] 1.12 (0.64-1.97) 1.46 (0.70-3.05) 1.20 (0.95-1.51) .13
Doxazosin
Incidence rate, events/100 person-years (95% CI) 1.7 (1.0-2.9) 2.9 (2.2-3.7) 4.2 (2.7-6.6) NA NA
Fully adjusted HR (95% CI)b 1 [Reference] 1.87 (0.98-3.57) 2.64 (1.16-6.00) 1.24 (0.98-1.58) .08
Combination therapy (finasteride plus doxazosin)
Incidence rate, events/100 person-years (95% CI) 0.8 (0.4-1.8) 1.4 (1.0-2.1) 2.8 (1.6-4.9) NA NA
Fully adjusted HR (95% CI)b 1 [Reference] 1.40 (0.59-3.35) 2.46 (0.86-7.01) 1.43 (1.07-1.91) .02

Abbreviations: FI, frailty index; HR, hazard ratio.
a
Clinical benign prostatic hyperplasia progression was defined according to the original
b
trial as the occurrence of any of the following: lower urinary tract symptoms
progression (an increase from baseline of at least 4 points in the American Urological
Association Symptom Index), acute urinary retention (the inability to urinate requiring
catheterization in the absence of an obvious cause of acute retention other than
benign prostatic hyperplasia, such as anesthesia), urinary tract infection or urosepsis,
incontinence, or an increase in the serum creatinine level, attributable to benign
prostatic hyperplasia, of at least 1.5 mg/dL (to convert to micromoles per liter, multiply
by 88.4) and to a value at least 50% above baseline values.
HR and 95% CI were calculated using proportional hazards model adjusted for age,
treatment group, prostate volume, postvoid residual, maximum urinary flow rate, race
and ethnicity (collapsed to White vs all other races), marital status, education, body
mass index, and history of heart disease, hypertension, diabetes, pulmonary disease,
neurological disease, and gastrointestinal disease. Linear P value was calculated using
FI as the continuous variable.

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Discussion
In this cohort study using data from a placebo-controlled randomized clinical trial, frail and prefrail
men with LUTS due to suspected BPH were more likely to develop clinical BPH progression, primarily
manifesting as increased LUTS severity, compared with robust men. This association was highest in
the combination therapy (doxazosin plus finasteride) and doxazosin monotherapy groups. Frailty
was similarly associated with greater risk of SAE, whether receiving placebo or drug therapy for BPH.
These results suggest that among men with symptoms and objective measures suggestive of
obstruction due to BPH, frailty is independently associated with worsening LUTS despite
combination therapy. Frailty may, therefore, represent a novel mechanism of LUTS progression and
medical BPH therapy failure. Although frail men receiving any drug had a higher risk of SAE compared
with robust men, this risk was not significantly higher than among frail men randomized to placebo.
A growing body of evidence suggests that frail older men are more likely to report severe LUTS,
overall as well as specific subtypes, compared with robust older men. Our team previously evaluated
the association between phenotypic frailty (the presence of at least 3 of the components of
weakness, slowness, weight loss, fatigue, and low physical activity15) and LUTS severity among 5979
community-dwelling older men enrolled in the Osteoporotic Fractures in Men Study.33 In that study,
we found that the prevalence of moderate and severe LUTS was 46% and 13%, respectively, among
frail men compared with 37% and 5% among robust men (moderate LUTS adjusted odds ratio, 1.4;
95% CI, 1.1-1.7; severe LUTS adjusted odds ratio, 2.5; 95%, 1.8-3.6).33 These associations were
independent of age, comorbidities, multimorbidity, or LUTS treatments and persisted among men
without urinary incontinence. A similar association was observed in a smaller study34 of older Korean
men, where the prevalence of phenotypic frailty was 43% among men with severe LUTS, 16% among
men with moderate LUTS, and 7% among men with no or mild LUTS. Phenotypic frailty and a higher
deficit accumulation frailty index were both cross-sectionally associated with LUTS severity among
older men and women in Japan.23 Positive associations have also been reported between measures
of frailty and LUTS subtypes, such as overactive bladder,35 as well as physiological abnormalities that
can cause LUTS, such detrusor overactivity36 and nocturnal polyuria.24 We previously demonstrated
that compared with older men seeking treatment for other urologic conditions, older men with
overactive bladder, mixed overactive bladder and BPH, and BPH were 2.6, 1.8, and 1.7 times,
respectively, more likely to have slow Timed-Up-And-Go-Test times, an easily measurable surrogate
for frailty.21 Our longitudinal analysis builds on this prior literature by reporting a positive association
of deficit accumulation frailty index with a higher risk of clinical BPH progression and LUTS
progression among men rigorously assessed for inclusion in a BPH trial and monitored carefully for
progression events.
On the basis of current clinical guidelines, patients for whom maximal medical BPH therapy with
combination therapy fails should be considered for more aggressive surgical interventions targeting
the same mechanism of prostatic obstruction.37 However, our findings suggest that this algorithmic
approach with sequential escalation of BPH interventions may frequently fail because the true cause
of LUTS is rarely known and current surrogates of benign prostatic obstruction are neither sensitive
nor specific. Accordingly, we believe that men who experience LUTS progression despite maximal
medical BPH therapy could be experiencing progression due to mechanisms related to advanced
biological age, manifesting as frailty, rather than prostatic obstruction. There is a critical need for
diagnostic tests capable of distinguishing LUTS due to BPH and bladder outlet obstruction vs frailty
and other systemic causes. The role of frailty as an indicator of surgical outcomes for BPH should also
be evaluated.
The weight of prior literature and our results suggest that frailty is a systemic marker of
biological age that potentially mediates the well-established association between chronological age
and LUTS or BPH. Importantly, frailty and other systemic markers of increased biological age are
currently not targeted by any existing male LUTS interventions4,38 and, thus, may represent a
promising novel therapeutic target, particularly in men for whom maximal medical BPH therapy has

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 JAMA Network Open | Urology Frailty and Progression of BPH Symptoms and Serious Adverse Events Among Men Using Drug Therapy

failed. Consistent with this hypothesis, we observed evidence of a possible interaction between
frailty status and treatment where frailty was most associated with clinical BPH progression among
men receiving either combination therapy or doxazosin monotherapy. Frailty interventions often
include physical activity, nutrition, multicomponent interventions, or individually tailored geriatric
care models.39-43 Other interventions are designed to improve specific components of the frailty
phenotype, such as resistance training to increase or maintain muscle mass among older adults,44,45
or to target frailty by interfering with upstream mechanisms of biological aging.46-48 Although
targeting frailty may represent a novel approach to preventing or treating LUTS in older men, most
frailty intervention studies have not measured LUTS severity, so it remains unknown whether
preventing or reversing frailty will prevent LUTS progression.
To our knowledge, our analysis is the first to report a positive association between frailty based
on deficit accumulation and SAE among men with LUTS due to suspected BPH. This is consistent
with a large body of literature demonstrating substantial associations between frailty indices and
morbidity, mortality, and adverse drug events.28,30,49,50 Contrary to our initial hypothesis, treatment
group did not appear to modify the association between frailty and SAE (or vice versa). Therefore,
the greater risk of SAE among frail men likely reflects the greater risk of morbidity and mortality
among frail men in general, rather than the effect of any BPH drugs. Frail older men considering long-
term medical BPH therapy should be counseled on their higher risk of SAE, albeit not specifically due
to doxazosin or finasteride, and LUTS progression despite combination therapy. Current behavioral
or surgical interventions with shorter time to benefit may be preferable for those who prefer to
prioritize current quality of life and minimize polypharmacy.

Strengths and Limitations

Strengths of this analysis included large sample size, adjudicated cases of clinical BPH progression,
and SAE in the setting of a rigorously conducted clinical trial, repeated measurements using a
reference standard LUTS questionnaire, and randomly assigned medical BPH therapies and placebo.
This analysis also has important limitations. First, men were not randomized to their frailty status;
therefore, unmeasured confounding is possible. However, we suspect that confounding by
unmeasured factors, such as nutritional status or socioeconomic status, would be explained by
demographic or clinical variables that we adjusted for in our multivariable model. Second, the MTOPS
trial was conducted more than 2 decades ago, and doxazosin is an older generation α-blocker less
commonly used than newer generation formulations, such as tamsulosin and alfuzosin.51 However,
evidence from pooled analyses of randomized clinical trials suggests that older and newer generation
α-blockers have similar efficacy, whereas newer generation α-blockers generally have fewer adverse
effects.52 Clinical guidelines for LUTS due to suspected BPH have also remained unchanged since the
MTOPS trial was published; combination therapy with any generation of α-blocker plus a
5α-reductase inhibitor is still first-line treatment for preventing clinical BPH progression.3,53 We do
not have reason to expect that the association between frailty and clinical BPH progression or SAE
has changed since the data were collected, although it is possible that the reporting of LUTS and a
small subset of subjective frailty index items has changed over time as a result of evolving
socioecological norms. Third, men enrolled in MTOPS were predominantly younger than 70 years,
healthy enough to enroll in a BPH trial, and White; therefore, generalizability is unknown for an older,
more ill, or more racially diverse population of men with LUTS due to suspected BPH. Fourth,
although we believed that it was important to formally test for interactions between frailty and
treatment group, our power was limited to detect statistically significant yet clinically meaningful
interactions. Fifth, we were only able to assess deficit accumulation frailty.

Conclusions
In conclusion, a discussion of both potential benefits and harms via shared decision-making is
needed before initiating medical BPH therapy in this population of older frail men. In particular, such

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 JAMA Network Open | Urology Frailty and Progression of BPH Symptoms and Serious Adverse Events Among Men Using Drug Therapy

patients should be counseled regarding their higher risk of LUTS progression despite combination
therapy and their likelihood of experiencing SAE regardless of treatment choice. Frailty-related
mechanisms of LUTS progression should be investigated, and LUTS should be assessed in future
frailty intervention trials. Ultimately, interventions targeting frailty may represent a novel approach
to preventing LUTS progression in older men.

ARTICLE INFORMATION
Accepted for Publication: September 17, 2021.
Published: November 24, 2021. doi:10.1001/jamanetworkopen.2021.34427
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Bauer SR
et al. JAMA Network Open.
Corresponding Author: Scott R. Bauer, MD, ScM, Division of General Internal Medicine, Department of Medicine,
University of California, 4150 Clement St, Bldg 2, Rm 135, San Francisco, CA 94121 (scott.bauer@ucsf.edu).
Author Affiliations: Division of General Internal Medicine, Department of Medicine, University of California, San
Francisco (Bauer); Department of Urology, University of California, San Francisco (Bauer, Suskind); San Francisco
Veterans Affairs Medical Center, San Francisco, California (Bauer, Walter, Covinsky); Division of Geriatrics,
Department of Medicine, University of California, San Francisco (Walter, Newman, Covinsky); Department of
Medicine and Division of Epidemiology and Community Health, University of Minnesota, Minneapolis (Ensrud);
Center for Care Delivery and Outcomes Research, Veterans Affairs Health Care System, Minneapolis, Minnesota
(Ensrud); Buck Institute for Research on Aging, Novato, California (Newman); George M. O’Brien Center of
Research Excellence, Department of Urology, University of Wisconsin School of Medicine and Public Health,
Madison (Ricke, Liu); Department of Urology and Center for Male Health, Stritch School of Medicine and Loyola
University Medical Center, Maywood, Illinois (McVary).
Author Contributions: Dr Bauer had full access to all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Concept and design: Bauer, Ensrud, Suskind, Newman, Ricke, McVary, Covinsky.
Acquisition, analysis, or interpretation of data: Bauer, Walter, Ensrud, Ricke, Liu, McVary, Covinsky.
Drafting of the manuscript: Bauer, Ricke, McVary.
Critical revision of the manuscript for important intellectual content: Bauer, Walter, Ensrud, Suskind, Newman, Liu,
McVary, Covinsky.
Statistical analysis: Bauer, McVary.
Obtained funding: Bauer, Covinsky.
Administrative, technical, or material support: Ricke, McVary, Covinsky.
Supervision: Suskind, Newman, McVary.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by grants from the National Institute of Diabetes, Digestive, and
Kidney Disorders (grant 1K12DK111028 to Dr Bauer, the National Institute on Aging (grant 1R03AG067937 to Dr
Bauer) and the UCSF Claude D. Pepper Older Americans Independence Center funded by National Institute on
Aging (grant P30 AG044281 to Dr Covinsky).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.
Disclaimer: The Medical Therapy of Prostatic Symptoms (MTOPS) study was conducted by the MTOPS
Investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The
data from the MTOPS study reported here were supplied by the NIDDK Central Repository. This manuscript was
not prepared in collaboration with Investigators of the MTOPS study (except Dr Kevin T. McVary) and does not
necessarily reflect the opinions or views of the MTOPS study, the NIDDK Central Repository, or the NIDDK.

REFERENCES
1. Welliver C, Feinstein L, Ward JB, et al; Urologic Diseases in America Project. Trends in lower urinary tract
symptoms associated with benign prostatic hyperplasia, 2004 to 2013: the Urologic Diseases in America Project.
J Urol. 2020;203(1):171-178. doi:10.1097/JU.0000000000000499

JAMA Network Open. 2021;4(11):e2134427. doi:10.1001/jamanetworkopen.2021.34427 (Reprinted) November 24, 2021 11/14

Downloaded From: https://jamanetwork.com/ by Nguyen Tuan on 05/02/2022

 JAMA Network Open | Urology Frailty and Progression of BPH Symptoms and Serious Adverse Events Among Men Using Drug Therapy

2. McConnell JD, Roehrborn CG, Bautista OM, et al; Medical Therapy of Prostatic Symptoms (MTOPS) Research
Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of
benign prostatic hyperplasia. N Engl J Med. 2003;349(25):2387-2398. doi:10.1056/NEJMoa030656
3. Abrams P, Chapple C, Khoury S, Roehrborn C, de la Rosette J; International Consultation on New Developments
in Prostate Cancer and Prostate Diseases. Evaluation and treatment of lower urinary tract symptoms in older men.
J Urol. 2013;189(1)(suppl):S93-S101. doi:10.1016/j.juro.2012.11.021
4. Lepor H. Pathophysiology of lower urinary tract symptoms in the aging male population. Rev Urol. 2005;7(7)
(suppl):S3-S11.
5. Clement KD, Burden H, Warren K, Lapitan MC, Omar MI, Drake MJ. Invasive urodynamic studies for the
management of lower urinary tract symptoms (LUTS) in men with voiding dysfunction. Cochrane Database Syst
Rev. 2015;(4):CD011179. doi:10.1002/14651858.CD011179.pub2
6. Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL. Trends in prescription drug use among adults in the
United States from 1999-2012. JAMA. 2015;314(17):1818-1831. doi:10.1001/jama.2015.13766
7. Erickson BA, Lu X, Vaughan-Sarrazin M, Kreder KJ, Breyer BN, Cram P. Initial treatment of men with newly
diagnosed lower urinary tract dysfunction in the Veterans Health Administration. Urology. 2014;83(2):304-309.
doi:10.1016/j.urology.2013.09.042
8. Wei JT, Calhoun E, Jacobsen SJ. Urologic Diseases in America Project: benign prostatic hyperplasia. J Urol.
2008;179(5)(suppl):S75-S80. doi:10.1016/j.juro.2008.03.141
9. Oelke M, Becher K, Castro-Diaz D, et al. Appropriateness of oral drugs for long-term treatment of lower urinary
tract symptoms in older persons: results of a systematic literature review and international consensus validation
process (LUTS-FORTA 2014). Age Ageing. 2015;44(5):745-755. doi:10.1093/ageing/afv077
10. Welk B, McArthur E, Fraser LA, et al. The risk of fall and fracture with the initiation of a prostate-selective α
antagonist: a population based cohort study. BMJ. 2015;351:h5398. doi:10.1136/bmj.h5398
11. Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J. Anticholinergic drug exposure and the risk
of dementia: a nested case-control study. JAMA Intern Med. 2019;179(8):1084-1093. doi:10.1001/jamainternmed.
2019.0677
12. Sarkar RR, Parsons JK, Bryant AK, et al. Association of treatment with 5α-reductase inhibitors with time to
diagnosis and mortality in prostate cancer. JAMA Intern Med. 2019;179(6):812-819. doi:10.1001/jamainternmed.
2019.0280
13. Duan Y, Grady JJ, Albertsen PC, Helen Wu Z. Tamsulosin and the risk of dementia in older men with benign
prostatic hyperplasia. Pharmacoepidemiol Drug Saf. 2018;27(3):340-348. doi:10.1002/pds.4361
14. Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as a proxy measure of aging.
ScientificWorldJournal. 2001;1:323-336. doi:10.1100/tsw.2001.58
15. Walston J, Bandeen-Roche K, Buta B, et al. Moving frailty toward clinical practice: NIA Intramural Frailty Science
Symposium Summary. J Am Geriatr Soc. 2019;67(8):1559-1564. doi:10.1111/jgs.15928
16. Platz EA, Joshu CE, Mondul AM, Peskoe SB, Willett WC, Giovannucci E. Incidence and progression of lower
urinary tract symptoms in a large prospective cohort of United States men. J Urol. 2012;188(2):496-501. doi:10.
1016/j.juro.2012.03.125
17. Jacobsen SJ, Girman CJ, Lieber MM. Natural history of benign prostatic hyperplasia. Urology. 2001;58
(6)(suppl 1):5-16. doi:10.1016/S0090-4295(01)01298-5
18. Wei JT, Schottenfeld D, Cooper K, et al. The natural history of lower urinary tract symptoms in black American
men: relationships with aging, prostate size, flow rate and bothersomeness. J Urol. 2001;165(5):1521-1525. doi:
10.1016/S0022-5347(05)66341-0
19. Crawford ED, Wilson SS, McConnell JD, et al; MTOPS RESEARCH Group. Baseline factors as predictors of
clinical progression of benign prostatic hyperplasia in men treated with placebo. J Urol. 2006;175(4):1422-1426.
doi:10.1016/S0022-5347(05)00708-1
20. Bauer SR, Grimes B, Suskind AM, Cawthon PM, Cummings S, Huang AJ. Urinary incontinence and nocturia in
older men: associations with body mass, composition, and strength in the Health ABC Study. J Urol. 2019;202(5):
1015-1021. doi:10.1097/JU.0000000000000378
21. Bauer SR, Jin C, Kamal P, Suskind AM. Association between lower urinary tract symptoms and frailty in older
men presenting for urologic care. Urology. 2021;148:230-234. doi:10.1016/j.urology.2020.09.041
22. Bauer SR, Scherzer R, Suskind AM, et al; Osteoporotic Fractures in Men (MrOS) Research Group.
Co-occurrence of lower urinary tract symptoms and frailty among community-dwelling older men. J Am Geriatr
Soc. 2020;68(12):2805-2813. doi:10.1111/jgs.16766

JAMA Network Open. 2021;4(11):e2134427. doi:10.1001/jamanetworkopen.2021.34427 (Reprinted) November 24, 2021 12/14

Downloaded From: https://jamanetwork.com/ by Nguyen Tuan on 05/02/2022

 JAMA Network Open | Urology Frailty and Progression of BPH Symptoms and Serious Adverse Events Among Men Using Drug Therapy

23. Soma O, Hatakeyama S, Imai A, et al. Relationship between frailty and lower urinary tract symptoms among
community-dwelling adults. Low Urin Tract Symptoms. 2020;12(2):128-136. doi:10.1111/luts.12292
24. Monaghan TF, Wagg AS, Bliwise DL, et al. Association between nocturia and frailty among elderly males in a
veterans administration population. Aging Clin Exp Res. 2020;32(10):1993-2000. doi:10.1007/s40520-019-
01416-y
25. Suskind AM. Frailty and lower urinary tract symptoms. Curr Urol Rep. 2017;18(9):67. doi:10.1007/s11934-017-
0720-9
26. Bautista OM, Kusek JW, Nyberg LM, et al. Study design of the Medical Therapy of Prostatic Symptoms
(MTOPS) trial. Control Clin Trials. 2003;24(2):224-243. doi:10.1016/S0197-2456(02)00263-5
27. Vandenbroucke JP, von Elm E, Altman DG, et al; STROBE Initiative. Strengthening the Reporting of
Observational Studies in Epidemiology (STROBE): explanation and elaboration. Ann Intern Med. 2007;147(8):
W163-W194. doi:10.7326/0003-4819-147-8-200710160-00010-w1
28. Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci. 2007;
62(7):722-727. doi:10.1093/gerona/62.7.722
29. Pajewski NM, Williamson JD, Applegate WB, et al; SPRINT Study Research Group. Characterizing frailty status
in the systolic blood pressure intervention trial. J Gerontol A Biol Sci Med Sci. 2016;71(5):649-655. doi:10.1093/
gerona/glv228
30. Blodgett JM, Theou O, Howlett SE, Rockwood K. A frailty index from common clinical and laboratory tests
predicts increased risk of death across the life course. Geroscience. 2017;39(4):447-455. doi:10.1007/s11357-017-
9993-7
31. Rockwood K, Andrew M, Mitnitski A. A comparison of two approaches to measuring frailty in elderly people.
J Gerontol A Biol Sci Med Sci. 2007;62(7):738-743. doi:10.1093/gerona/62.7.738
32. Roehrborn CG, Girman CJ, Rhodes T, et al. Correlation between prostate size estimated by digital rectal
examination and measured by transrectal ultrasound. Urology. 1997;49(4):548-557. doi:10.1016/S0090-4295
(97)00031-9
33. Bauer SR, Scherzer R, Covinsky KE, Marshall LM. Occurrence of lower urinary tract symptoms and frailty
among community-dwelling older men. J Am Geriatr Soc. 2020;68(12):2805-2813. doi:10.1111/jgs.16766
34. Jang IY, Lee CK, Jung HW, et al. Urologic symptoms and burden of frailty and geriatric conditions in older men:
the Aging Study of PyeongChang Rural Area. Clin Interv Aging. 2018;13:297-304. doi:10.2147/CIA.S158717
35. Omae K, Yamamoto Y, Kurita N, et al. Gait speed and overactive bladder in the healthy community-dwelling
super elderly: the Sukagawa Study. Neurourol Urodyn. 2019;38(8):2324-2332. doi:10.1002/nau.24148
36. Song S, Jin C, Kamal P, Suskind AM. The association between frailty and detrusor overactivity in older adults.
Neurourol Urodyn. 2020;39(5):1584-1591. doi:10.1002/nau.24414
37. Foster HE, Barry MJ, Dahm P, et al. Surgical management of lower urinary tract symptoms attributed to benign
prostatic hyperplasia: AUA Guideline. J Urol. 2018;200(3):612-619. doi:10.1016/j.juro.2018.05.048
38. Bechis SK, Otsetov AG, Ge R, Olumi AF. Personalized medicine for the management of benign prostatic
hyperplasia. J Urol. 2014;192(1):16-23. doi:10.1016/j.juro.2014.01.114
39. Walston J, Buta B, Xue QL. Frailty screening and interventions: considerations for clinical practice. Clin Geriatr
Med. 2018;34(1):25-38. doi:10.1016/j.cger.2017.09.004
40. Hazuda HP, Pan Q, Florez H, et al. Association of intensive lifestyle and metformin interventions with frailty in
the Diabetes Prevention Program Outcomes Study. J Gerontol A Biol Sci Med Sci. 2021;76(5):929-936. doi:10.
1093/gerona/glaa295
41. Travers J, Romero-Ortuno R, Bailey J, Cooney MT. Delaying and reversing frailty: a systematic review of primary
care interventions. Br J Gen Pract. 2019;69(678):e61-e69. doi:10.3399/bjgp18X700241
42. Puts MTE, Toubasi S, Andrew MK, et al. Interventions to prevent or reduce the level of frailty in community-
dwelling older adults: a scoping review of the literature and international policies. Age Ageing. 2017;46(3):
383-392. doi:10.1093/ageing/afw247
43. Manal B, Suzana S, Singh DK. Nutrition and frailty: a review of clinical intervention studies. J Frailty Aging.
2015;4(2):100-106. doi:10.14283/jfa.2015.49
44. Fiatarone MA, Marks EC, Ryan ND, Meredith CN, Lipsitz LA, Evans WJ. High-intensity strength training in
nonagenarians: effects on skeletal muscle. JAMA. 1990;263(22):3029-3034. doi:10.1001/jama.1990.
03440220053029
45. Villareal DT, Aguirre L, Gurney AB, et al. Aerobic or resistance exercise, or both, in dieting obese older adults.
N Engl J Med. 2017;376(20):1943-1955. doi:10.1056/NEJMoa1616338

JAMA Network Open. 2021;4(11):e2134427. doi:10.1001/jamanetworkopen.2021.34427 (Reprinted) November 24, 2021 13/14

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46. Justice J, Miller JD, Newman JC, et al. Frameworks for proof-of-concept clinical trials of interventions that
target fundamental aging processes. J Gerontol A Biol Sci Med Sci. 2016;71(11):1415-1423. doi:10.1093/gerona/
glw126
47. Newman JC, Milman S, Hashmi SK, et al. Strategies and challenges in clinical trials targeting human aging.
J Gerontol A Biol Sci Med Sci. 2016;71(11):1424-1434. doi:10.1093/gerona/glw149
48. Tchkonia T, Kirkland JL. Aging, cell senescence, and chronic disease: emerging therapeutic strategies. JAMA.
2018;320(13):1319-1320. doi:10.1001/jama.2018.12440
49. Cullinan S, O’Mahony D, O’Sullivan D, Byrne S. Use of a frailty index to identify potentially inappropriate
prescribing and adverse drug reaction risks in older patients. Age Ageing. 2016;45(1):115-120. doi:10.1093/ageing/
afv166
50. Romskaug R, Skovlund E, Straand J, et al. Effect of clinical geriatric assessments and collaborative medication
reviews by geriatrician and family physician for improving health-related quality of life in home-dwelling older
patients receiving polypharmacy: a cluster randomized clinical trial. JAMA Intern Med. 2020;180(2):181-189. doi:
10.1001/jamainternmed.2019.5096
51. Wei JT, Miner MM, Steers WD, et al; BPH Registry Steering Committee. Benign prostatic hyperplasia evaluation
and management by urologists and primary care physicians: practice patterns from the observational BPH registry.
J Urol. 2011;186(3):971-976. doi:10.1016/j.juro.2011.04.081
52. Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists in
patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol. 1999;36(1):1-13.
doi:10.1159/000019919
53. Gratzke C, Bachmann A, Descazeaud A, et al. EAU guidelines on the assessment of non-neurogenic male lower
urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2015;67(6):1099-1109. doi:10.1016/j.
eururo.2014.12.038

SUPPLEMENT.
eTable 1. Items and Scoring Scheme for the MTOPS Frailty Index
eTable 2. Mean Change in AUA Symptom Index Among Men With Lower Urinary Tract Symptom Progression,
Overall and by Frailty Status
eTable 3. Association of Frailty With Clinical Benign Prostatic Hyperplasia (BPH) Progression, Lower Urinary Tract
Symptoms (LUTS) Progression, Acute Urinary Retention, and Serious Adverse Events Among Men With 0 Missing
Frailty Index Items
eTable 4. Cumulative Incidence Rate of Serious Adverse Events, by Treatment Arm and Frailty Status
eFigure. Cumulative Incidence Curves for Clinical Benign Prostatic Hyperplasia (BPH) Progression, by Frailty Status
and Treatment Arm

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