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improvement which is reported as statistically significant,
but which might actually be comparatively small, making
the clinical relevance potentially marginal. In addition, the
studies described generally take a pragmatic approach of
measuring all nocturnal voids, which is somewhat different
from the ICS definition, which focusses on patients who
‘‘wake at night to void.’’ Very little published evidence is
available to signify what implications this could have for
interpretation of results.
The review identified that antidiuretic therapy using
clinician-directed dose titration was more effective than
placebo in terms of reduced nocturnal voiding frequency and
duration of undisturbed sleep. Nocturia severity improve-
ment contributes to overall improvements in health-related
quality of life
[51]. The potential to worsen severity of the
abnormality means that hyponatremia is a contraindication
to antidiuretic therapy. Screening for hyponatremia must be
undertaken at baseline, after initiation or dose titration and
during treatment. The cumulative risk of hyponatremia over
time is not clear, although evidence suggests that sodium
imbalance may happen at any time during treatment. Three
out of nine desmopressin studies included in this systematic
review
[10–12]undertook dose titration with the active
treatment; this study design was to assign patients to the
dose with treatment response and also for safety consider-
ations. Clearly, a response selection phase will increase the
likelihood of a positive outcome in the RCT and the
associated effect sizes, since nonresponders will be excluded
before the full trial. Nonetheless, dose titration is a process
which can be undertaken in clinical practice in order to tailor
therapy to individual patients, both in terms of efficacy and
safety. Such a process adds to the burden on patients and
healthcare providers in increasing the number of clinical
contacts required.
Medications to treat LUTD in men (
a
-1 adrenergic
antagonists, 5-
a
reductase inhibitors, PDE-5 inhibitor, phy-
totherapy) were not significantly better than placebo in short-
term use. Data on OAB medications (antimuscarinics, beta-3
agonist) generally had a female-predominant population, and
were also not significantly better than placebo in short-term
use. It is an assumption that this would also apply in male-
only populations, but no studies specifically addressing the
impact of OAB medications on nocturia in men were
identified. Subcategorizing the ‘‘OAB-related’’ nocturia epi-
sodes appeared to yield benefit for antimuscarinic therapy in
one trial. Potential benefit was seen in long-term use in some
studies using
a
-1 adrenergic antagonists and 5-
a
reductase
inhibitors. Differences between therapies emerged in studies
where
a
-1 adrenergic antagonist was the comparator.
Benefits with combination therapies were not consistently
observed. Other medications (diuretics, agents to promote
sleep, NSAIDs), were sometimes reported as being associated
with response or quality of life improvement. Nonetheless,
additional research is needed to corroborate initial findings,
particularly for therapies like NSAIDs, where the mechanism
of action is uncertain.
The symptom of nocturia is an important one, since there
may a significant medical cause, potentially an opportunity to
screen for undiagnosed or suboptimally-managed disease,
perhaps reduced incidence of severe complication, and
potential economic benefits. Accordingly, clearly-relevant
causes of nocturia that can be treated by mechanism-specific
approaches, such as poorly controlled diabetes mellitus,
congestive heart failure, or sleep apnoea, require direct
intervention as the principal therapeutic priority. Since
nocturia is a symptom rather than a disease, causative
categories have been proposed
[6] ,and the diversity of the
affected population is manifest. The range of potentially
relevant contributors may well affect therapy outcome.
Despite this, research populations often include diverse
individuals, and may not undertake the full extent of
evaluation needed to categorize factors likely to affect therapy
response. However, the testing may limit the ability to deliver
a trial, and may be unfeasible in routine clinical practice. The
likelihood of developing a therapy that can be generalized
appears remote, so nocturia therapy choice needs to consider
the specific situation of individual patients. Accordingly, the
studies need to be considered for analysis of responders, as
well as the overall population response, since this may help
develop improved approaches to clinical assessment in the
future. Responder analysis is particularly interesting in
studies reporting modest reductions in nocturia, which might
be reported as statistically significant, but which are hard to
perceive as clinically significant. In such a setting, responder
analysismay help identifywhether a subgroup did get a larger
(clinically more useful) reduction in nocturia severity;
predictors of response to enable targeting of therapy to
individuals more likely to benefit would be a helpful advance.
Objective markers are scientifically preferable, but some
studies have used patient perception (such as the IPSS
Question 7), which is not uniformly consistent with
objective markers. Furthermore, reported effect sizes are
sometimes greater than perceived in clinical practice, so
findings of many studies merit independent corroboration
and follow up with real-life studies. Effect size is also likely
to be affected by baseline severity, and this should be
considered in the evaluation of trial outcomes. Finally, there
is very little information on long-term outcomes of drug
therapy for nocturia.
Author contributions:
Marcus J. Drake had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design:
Gravas, Drake, Sakalis, Karavitakis, Bach, Bosch,
Gacci, Gratzke, Herrman, Madersbacher, Mamoulakis, Tikkinen.
Acquisition of data:
Sakalis, Karavitakis, Bedretdinova.
Analysis and interpretation of data:
Sakalis, Karavitakis, Drake, Gravas.
Drafting of the manuscript:
Drake, Sakalis, Gravas.
Critical revision of the manuscript for important intellectual content:
Drake,
Gravas, Bach, Bosch, Gacci, Gratzke, Herrman, Madersbacher, Mamou-
lakis, Tikkinen.
Statistical analysis:
None.
Obtaining funding:
None.
Administrative, technical, or material support:
Bedretdinova.
Supervision:
Gravas, Drake.
Other:
None.
Financial disclosures:
Marcus J. Drake certifies that all conflicts of
interest, including specific financial interests and relationships and
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