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© The Canadian Journal of Urology™; 18(Supplement 1); April 2011
with men who received placebo.
23
In another trial,
finasteride was less effective than alpha blockers
in reducing LUTS and achieved virtually the same
response as the placebo arm.
30
A long term trial
with dutasteride in symptomatic men with prostate
volumes of at least 30 cc showed that it reduced
symptoms in these patients at least as much or even
more effectively than tamsulosin.
31
Combination therapy
Based on the fact that alpha blockers and 5-ARIs have
different mechanisms of action, long term effects,
and efficacies (reduction of progression of BPH), two
large recent clinical trials were designed to compare
long term outcomes achieved by using combination
therapy (an alpha blocker and a 5-ARI) compared to
monotherapy (an alpha blocker a 5-ARI or placebo).
Earlier trials that compared combination therapy
with finasteride plus an alpha blocker versus placebo
concluded that this combination therapy was no better
than placebo in treating symptoms of BPH. However,
the reasons postulated for failure were that the trial
durations may have been too short (12 months) and
the inclusion criteria may have included prostates that
were too small to see any benefit from the shrinking
effect seen with 5-ARIs.
22,30,32
Taking the weaknesses of these earlier trials
into account, two large, “longer term” (4-or 5-year)
trials of combination therapy were performed and
the results were recently reported. These trials --
Medical Therapy of Prostate Symptoms (MTOPS) and
Combination of Avodart and Tamsulosin (CombAT)
-- investigated the effects of delivering long term
combination therapy to treat BPH. The goal was to
determine if “signs of progression” of BPH -- such
as deterioration of IPSS score, development of acute
urinary retention, or the need for surgery -- were
reduced in the combination-therapy arm versus
the monotherapy arms (in CombAT) or versus the
monotherapy arms or placebo (in MTOPS).
In MTOPS, patients were randomized to one of
the four treatment arms: an alpha blocker (doxazosin)
alone or a 5-ARI (finasteride) alone or combination
therapy (finasteride plus doxazosin) or placebo. In
CombAT), patients were randomized to an alpha
blocker (tamsulosin) alone or a 5-ARI (dutasteride)
alone or to combination therapy with (dutasteride
plus tamsulosin).
13,33
In MTOPS, to be included in the study, patients
had to be at least age 50, have no clinical signs of
prostate cancer, and have an IPSS score of at least 8.
There was no minimum requirement for prostate size.
In CombAT, the inclusion criteria were the same as
17
previously determined and accepted characteristics to
predict thosemen at higher risk for progression of BPH
symptoms -- age 50 and older, prostate volume greater
than 30 cc, and moderate IPPS (
≥
12). As a result, the
members of the ethical review boards excluded the
placebo arm in CombAT, since they felt that in this
at-risk population, the risk of disease progression after
4 years was too high to justify withholding treatment.
The primary endpoint in MTOPS was a composite
endpoint of clinical progression of BPH (ie, renal
failure, recurrent urinary tract infections, urinary
retention, etc.) at 4 years. At 1 year the rate of clinical
progression of BPH was not significantly improved
in the combination arm versus the placebo or
monotherapy arms. However, at 4 years the rate of
clinical progression of their BPH symptoms and signs
was significantly lower in the combination therapy
arm versus the other arms.
The pr imary endpoints of CombAT were
improvement in IPSS at 2 years and reduction in risk
of AUR or surgery at 4 years.
31,33
In CombAT, up to 3months, the slopes of the curves
of “symptom response” over time were identical
for tamsulosin and for combination therapy. As
early as 15 months, however, patients treated with
the 5-ARI dutasteride achieved a better
symptom
response
compared to patients treated with the alpha
blocker tamsulosin -- which was the first time that
a trial showed that patients with BPH achieved a
better symptom response with a 5-ARI than with an
alpha blocker. At 4 years, symptom improvement
for patients in the combination arm was statistically
superior to that of patients in either monotherapy arm.
(There was no placebo arm).
Both trials also looked at the incidence of acute
urinary retention, which, if not reversible, results
in the need for surgery on the prostate. In MTOPS,
McConnell et al reported a 67% risk reduction in acute
urinary retention or the need for surgery at 4 years
in the combination arm
compared to placebo.
The risk
reduction for same endpoints in the CombAT trial
was virtually identical -- 66%. However, the 66%
improvement in this trial was combination therapy
compared to the active treatment tamsulosin, not
versus placebo as shown in the MTOPS trial.
In CombAT, 6% of participants in the combination
arm versus 4% of participants in either monotherapy
arm withdrew from the study due to severe adverse
effects. The difference in withdrawal rates was not
statistically significant.
Another very significant difference between alpha
blockers and 5-ARIs is that there is an expectation of a
50%drop in PSAlevels after a patient has been taking a
Benign prostatic hyperplasia and lower urinary tract symptoms: evidence and approaches for best casemanagement