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Long-term BPH treatment

Study
Results
Clinical outcomes
Adverse events
Comment
Pulling it together
Step-down treatment
Results
Who to treat?
And finally

Bandolier has several times examined treatments for benign prostatic hyperplasia (BPH), and this Bandolier Internet site has a whole section devoted to systematic reviews and trials conducted in this area. Even so, it is terrific when a new study comes along that extends our thinking. That is particularly the case when such a study [1] fulfils the criteria of high quality, to minimise bias, of validity, to maximise the utility of the results, and size, to be large enough to avoid errors of chance. The Medical Therapy of Prostatic Symptoms (MTOPS) study examined whether therapy with an alpha-blocker (doxazosin) or 5-alpha-reductase inhibitor (finasteride), or combination of both was the better choice.

Study

Men 50 years old or older who had American Urological Association scores of 8 to 30 (moderate or severe, Bandolier 11) and a maximum urinary flow rate of between 4 and 15 mL/second were recruited. Excluded were men with prior medical or surgical interventions, with low blood pressure, or with a PSA value of more than 10 ng/mL.

Men were randomised to receive placebo, doxazosin (beginning with 1 mg a day and rising to 4 to 8 mg daily), finasteride 5 mg a day, or a combination of both doxazosin and finasteride. All treatments were identical. A number of outcomes were examined, including increased symptom score of four points or more over baseline, acute urinary retention, renal insufficiency, urinary tract infection, urinary incontinence, and invasive therapy for BPH (transurethral prostatectomy or incision, laser therapy, stenting, or microwave therapy, or open prostatectomy.

The primary outcome was overall clinical progression (symptom increase, retention, renal insufficiency, recurrent urinary tract infection or incontinence).

Results

Groups were well matched at baseline. Mens' average age was 62 years, most (81%) were white, with a mean symptom score of 16 points, prostate volume of 31 mL, PSA of 1.6 ng/mL, and maximum urinary flow rate of 10.7 mL/second. The overall follow up was 4.5 years in 3,047 men.

At four years, the primary outcome of any clinical BPH progression occurred in 17% of men treated with placebo (Table 1). Lower rates were found with doxazosin (10%) and finasteride (10%), and an even lower rate (5.3%) with combination therapy. The number needed to treat with combination therapy for four years compared with placebo to prevent progression was 9 (95% confidence interval 7 to 12). Pre-planned subgroup analysis for the 20% of men with a baseline PSA of more than 4 ng/mL had NNTs of 5 for finasteride and combination therapy. Pre-planned subgroup analysis for the 30% of men with prostate volume of more than 40 mL was 7 for both subgroups.


Table 1: Main outcomes of MTOPS at four years


Placebo
Doxazosin
Finasteride
Combination
Number of patients
737
756
768
786
Outcome
Percent
Percent
NNT
(95% CI)
Percent
NNT
(95% CI)
Percent
NNT
(95% CI)
Any clinical BPH progression
17
9.7
15 (10 to 27)
10
16 (10 to 34)
5.3
9 (7 to 12)
Symptom score increase ≥4 points
13
7.3
17 (11 to 35)
8.5
21 (13 to 64)
4.6
12 (9 to 17)
Acute retention
2.4
1.2
NS
0.8
60 (34 to 260)
0.5
52 (32 to 140)
Invasive BPH therapy
5.0
3.4
NS
1.8
31 (20 to 74)
1.5
27 (19 to 59)

The major reason for progression was men having at least a four-point increase in symptom score. Median symptom scores (Figure 1) and maximum urinary flow rates (Figure 2) improved with treatment, especially combination therapy.


Figure 1: Median symptom improvement after four years of treatment















Figure 2: Median urinary flow rate improvement after four years of treatment
















Clinical outcomes

Important clinical outcomes of acute urinary retention and invasive therapy for BPH were also reduced with combination treatment. With placebo 2.4% of men had acute urinary retention and 5.0% invasive therapy over four years. For every 52 (32 to 140) men treated with combination therapy for four years, one was spared acute urinary retention (Table 1).

For every 27 (19 to 59) men treated with combination therapy for four years, one was spared invasive BPH treatment, mostly transurethral or open prostatectomy (Table 1). Similar results were found with finasteride alone, but results for these outcomes with doxazosin were not significantly better than placebo. The NNT for sparing invasive therapy with the combination treatment was reduced (improved) to 23 and 16 respectively for men with PSA values of more than 4 ng/mL or prostate volumes of 40 mL or more at baseline.

Adverse events

Table 2 shows adverse events. Dizziness, postural hypotension and asthenia occurred more frequently when doxazosin was used. Erectile dysfunction, decreased libido and abnormal ejaculation occurred more frequently when finasteride was used. Dizziness and erectile dysfunction, for instance, would have affected about one man in 50 more with combination therapy than placebo. Discontinuation rates for any reason were 27% with doxazosin, 24% with finasteride, and 18% (both drugs) with combination therapy. The most common reason for discontinuation was adverse events.


Table 2: Main adverse events (% of men) in MTOPS over four years. Bold and shaded areas indicate significant increase over placebo


Adverse event
Placebo
Doxazosin
Finasteride
Combination
Dizziness
2.3
4.4
2.3
5.4
Postural hypotension
2.3
4.0
2.6
4.3
Asthenia
2.1
4.1
1.6
4.2
Peripheral oedema
0.7
0.9
0.7
1.3
Dyspnoea
0.6
0.9
0.6
1.2
Erectile dysfunction
3.3
3.6
4.5
5.1
Decreased libido
1.4
1.6
2.4
2.5
Abnormal ejaculation
0.8
1.1
1.8
3.1


Comment

What we have here is a trial that adds substantially to our knowledge of medical treatment of BPH. It was designed to minimise bias. It was valid because it reported sensible and important outcomes, and was of long duration. Medical treatment of BPH is likely to be life long, so a few months of data is not helpful. And it was large enough to minimise random errors occurring by the whim of chance.

Perhaps the best systematic review of the alpha-blocker terazosin at doses of 2.5 to 10 mg daily [2] examined 10 randomised, double blind studies in over 3,000 men, but over from eight weeks to one year only. Mean improvements in symptom score (30-70%) and maximum flow rate (2-3 mL/second) were about the same as found for doxazosin over four years in MTOPS. The overall all-cause discontinuation rate with terazosin at 27% was the same as found with doxazosin in MTOPS, and with adverse events of dizziness, asthenia and postural hypotension.

The most recent systematic review of finasteride (5 mg daily) [3] had similar results to those from MTOPS. It had data on almost 15,000 men from 19 placebo-controlled studies over three months to four years. Over 18 months to four years the systematic review reported a similar improvement in symptom score (by about 5-6 points) and maximum urinary flow rate (by about 2 mL/second). All-cause discontinuations were also similar, from 13% at one year to 34% at four years.

NNTs compared to placebo at four years to prevent acute retention or BPH-related surgery were 26 and 18, respectively. While somewhat lower (better) than for MTOPS (Table 1), patients included in the systematic review had higher rates of retention and surgery with placebo (Table 3), though the four-year data came from a single large trial [4]. Table 3 also shows two-year data from the systematic review, again with consistent results. MTOPS recruited men who had relatively small prostates (average 31 mL), so the lower rates of acute retention and invasive therapy are consistent with older studies in the systematic review that mainly recruited men with larger prostates.


Table 3: Acute retention and invasive therapy for BPH in two four-year randomised trials (MTOPS, PLESS) at four years, and a meta-analysis at two years


Outcome
Placebo
%
Finasteride
%
Relative risk
(95% CI)
NNT
(95%CI)
MTOPS - 4 years
Acute retention
2.4
0.8
0.3 (0.2 to 0.5)
60 (34 to 260)
Invasive BPH therapy
5.0
1.8
0.4 (0.2 to 0.7)
31 (20 to 74)
PLESS - 4 years
Acute retention
6.5
2.8
0.4 (0.3 to 0.6)
26 (19 to 44)
Invasive BPH therapy
10.0
4.5
0.5 (0.3 to 0.6)
18 (14 to 27)
Meta-analysis - 2 years
Acute retention
3.7
1.7
0.5 (0.3 to 0.7)
48 (31 to 112)
Invasive BPH therapy
8.1
4.8
0.6 (0.5 to 0.8
31 (20-61)


Pulling it together

So what does all this mean to men with symptoms of prostatic hyperplasia? Alpha-blockers and finasteride are both effective in reducing symptom scores and improving maximum urinary flow rate. In addition, finasteride but not alpha-blockers reduce the chance of acute retention or surgical intervention for BPH. Both come at a price of some (different) adverse events. Combination therapy is even better, but at a higher cost in adverse events, and acquisition costs. Whether the additional benefit of combination therapy over finasteride is worth the extra cost, offset by lower operation rates, is probably moot.

The possibility is raised of starting with combination therapy, and then removing either finasteride or alpha-blocker. There is one randomised trial that has looked at part of this equation, step-down from combination therapy to finasteride alone [5].

Step-down treatment

The study [5] examined whether men with BPH could be started on dual alpha-blocker and reductase inhibitor treatment, and then have the alpha-blocker withdrawn. Men with clinical BPH, prostates of 40 mL or larger, AUA symptom score of 20 or more, and PSA or less than 4 ng/mL were enrolled. They were given an initial treatment regimen of 5 mg finasteride and 2 mg doxazosin daily, with the doxazosin dose titrated up to 4 or 8 mg. One month later their symptoms were reassessed, and those with a reduction in symptom score and who tolerated the medicines continued in the study.

These were randomised into dosage groups of 2, 4 and 8 mg doxazosin daily, together with 5 mg finasteride daily. They were also randomly assigned to discontinue doxazosin at 3, 6, 9 or 12 months. Patients were evaluated every three months until discontinuation, and then one month after discontinuation of the doxazosin.

The final evaluation consisted of symptom scoring and the question “Would you like to restart the doxazosin?”. Successful discontinuation was defined by both the absence of any increase in symptom score following discontinuation and a negative response to the question.

Results

The average age of the men was 66 years, and their average prostate size was 54 mL. The rates of successful discontinuation of doxazosin rose from about 20% after 3 months, to about 80% or more at nine and 12 months (Figure 3).


Figure 3: Successful discontinuation of alpha-blocker doxazosin (2, 4 or 8 mg) in combination with finasteride after different periods of use




















Finasteride is effective over the longer term, and continues to reduce the size of the prostate over at least four years. Alpha-blockers have effects on maximum flow rates almost immediately, but there is no subsequent improvement with longer-term use. Combination therapy seems sensible, but is expensive. This study indicates that for most men the alpha-blocker can be discontinued after nine to 12 months.

Who to treat?

Wise old heads often say that treatment efficacy should not be the prime target of evidence-based thinking, but rather finding out whom to treat with what. Not what to use but who to treat. MTOPS helps here, to some extent. Both for clinical progression and for invasive therapy, lower (better) NNTs were found in men with PSA above 4 ng/mL and with prostate volumes larger than 40 mL.

Prostate volume may be measured in secondary care, but that is unlikely in primary care. Men who do not have enlarged prostates but have a PSA above 4 ng/mL and more severe symptoms might be prime targets for treatment with combination therapy.

And finally

It is rare that we are able to compare both systematic reviews of treatments and subsequent large randomised trials, where the criteria of quality, validity, and size are all met in both. We have that for alpha-blockers [2] and for finasteride [3]. They produce essentially the same results. MTOPS [1], independent and principally supported by the NIH, produced results essentially the same as those from systematic reviews of trials supported principally by manufacturers for both alpha-blockers and finasteride. In addition, the prediction of the systematic review of finasteride, that finasteride works well in men with smaller prostates, was vindicated by MTOPS. Good news all round.

References:

  1. JD McConnell et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. New England Journal of Medicine 2003 349: 2387-2398.
  2. TJ Wilt et al. Terazosin for treating symptomatic benign prostatic obstruction: a systematic review of efficacy and adverse effects. BJU International 2002 89: 214-225.
  3. JE Edwards, RA Moore. Finasteride in the treatment of clinical benign prostatic hyperplasia: a systematic review of randomised trials. BMC Urology 2002 2: 14 ( http://www.biomedcentral.com/1471-2490/2/14).
  4. JD McConnell et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. New England Journal of Medicine 1998 338: 557-563.
  5. KC Baldwin et al. Discontinuation of alpha-blockade after initial treatment with finasteride and doxazosin in men with lower urinary tract symptoms and clinical evidence of benign prostatic hyperplasia. Urology 2001 58: 203-209.

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