Should combination therapy be standard for benign prostatic hyperplasia?

John M Fitzpatrick  About the author

The treatment of benign prostatic hyperplasia (BPH) that causes lower urinary tract symptoms has advanced enormously since the days when it was a simple choice between no treatment with reassurance, and transurethral resection of the prostate (TURP). Improvements in treatment arose from our recognition that one of the commonest urologic conditions affecting men required other therapeutic options that fitted somewhere between these two extremes. This, in turn, led to a huge amount of laboratory and clinical research that increased our understanding of BPH, and the number of pharmacologic and technological treatments available. As a result, there has been a dramatic decrease in the number of patients treated by TURP, and an equally dramatic increase in the number of patients treated by pharmacologic manipulation. Drug treatment of BPH was initially viewed with suspicion by urologists, but has gradually achieved widespread acceptance, with excellent consequences for patients.

Pharmacologic treatment of BPH is based on two concepts: first, that -adrenergic blockade reduces smooth-muscle tone in the prostate and bladder neck; and second, that 5--reductase inhibition causes atrophy of prostate epithelium. Studies showed that, as monotherapy, both classes of drugs produced improvements in patients' symptoms and quality of life. Although their effects were not in any way comparable to the symptomatic improvements afforded by TURP, they tipped the balance irrevocably in favor of nonsurgical treatments for BPH.^{1, 2, 3, 4}

Urologists had further questions, however. Could these -blockers or 5--reductase inhibitors prevent the long-term complications of BPH—such as acute urinary retention, recurrent urinary tract infection, or obstructive nephropathy and chronic renal failure—and could they prevent or delay the requirement for TURP? Also, would a combination of these drugs result in greater symptomatic relief and an improvement in peak urinary flow (Q_max)?

The first question has largely been answered by a 4-year trial with finasteride. This study showed that BPH is a progressive condition that can lead to a worsening of symptoms, acute urinary retention and a need for surgery. Treatment with finasteride alone produced a 50% reduction in the relative risk of patients with symptomatic BPH developing these problems.⁵

Two studies have attempted to answer the second question. The Veterans' Affairs Cooperative Studies Benign Prostatic Hyperplasia Study compared four groups of patients with symptomatic BPH, treated with terazosin, finasteride, a combination of both, or placebo.⁶ The Prospective European Doxazosin and Combination Therapy Trial compared four groups of patients with symptomatic BPH treated with doxazosin, finasteride, a combination of both, or placebo.⁷ Both trials had similar results: there was no additional benefit in taking a combination of finasteride and the -blocker in question compared with taking the -blocker alone. These trials were considered decisive by many, and the option of combination therapy was put aside. Both studies, however, were only of moderate duration (12 months in both cases), and have been criticized for their short duration, and the fact that only changes in symptom score and Q_max were used to define success or failure of treatment. Some felt that the effect of combination therapy on the longer term consequences of the disease should be assessed.

This was the rationale for the Medical Therapy of Prostatic Symptoms (MTOPS) study. Rather than concentrate on the effect of combination therapy on longitudinal changes, the aim of this trial was to find out whether doxazosin or finasteride, either alone or in combination, could delay or prevent the clinical progression of BPH, its longer term complications, and the requirement for surgery, compared with placebo. The study enrolled 3,047 men, which provided 81% power to detect a 33% reduction in the incidence of disease progression in an active-therapy group, allowing for a 5% loss to follow-up per year.⁸ Clinical disease progression was defined as the occurrence of any of the following: a 4-point increase from baseline in the American Urological Association symptom score, acute urinary retention, urinary tract infection, urosepsis, incontinence or a 1.5 mg/dl increase in serum creatinine level or to a value 50% above baseline. At 1 year there was little difference between the doxazosin and combination groups, but over the following 3 years combination therapy was significantly better than any other therapy at preventing progression. The number of patients that needed to be treated to prevent one instance of overall clinical progression was 8.4 for the combination group, 13.7 for the doxazosin group and 15.0 for finasteride group. In a preplanned subgroup analysis of patients with larger prostates, the number needed to treat was halved in the combination group. When individual progression events were looked at, an interesting observation could be made regarding the cumulative incidence of acute urinary retention. Combination therapy reduced the relative risk of developing retention by 81%. Finasteride delayed the time to acute urinary retention, and reduced the rate and relative risk of retention, whereas doxazosin only delayed its onset. The risk of invasive therapy was reduced by 64% in the finasteride group and by 67% in the combination group. Doxazosin alone did not reduce the cumulative risk. The number of patients that needed to be treated to prevent one patient from undergoing invasive therapy was 25.9 for the combination group, 60.1 for the doxazosin group and 29.0 for the finasteride group. Again, the number needed to treat was initially halved among patients with larger glands. Serum PSA was an accurate marker for prostate size.

Before reaching a conclusion on the use of combination therapy for BPH, one other piece of evidence should be presented. The Symptom Management After Reducing Therapy (SMART-1) trial examined the combination of dutasteride and tamsulosin, followed by withdrawal of tamsulosin in symptomatic men.⁹ This trial enrolled a smaller group of patients and was not placebo-controlled. Patients were randomized to dutasteride and tamsulosin for 36 weeks, or to both for 24 weeks followed by dutasteride plus placebo for a further 12 weeks. Consistent with earlier trials, the combination produced a rapid improvement in symptoms. After tamsulosin withdrawal, the condition of patients with mild or moderate symptoms did not deteriorate, but the condition of patients with severe symptoms did.

Having reviewed the evidence, should we recommend a combination of an -blocker and 5--reductase inhibitor as standard therapy for BPH? On the basis of a single large placebo-controlled trial⁸ the answer has to be yes, but, in my opinion, it should not be recommended for every case. The trial referred specifically to a combination of doxazosin and finasteride; in order to accept that any combination of -blocker and 5--reductase inhibitor can be used, proof of a class effect is required. One can draw one's own conclusions from the fact that many pharmaceutical companies are trying to disprove this class effect.¹⁰ Candidates for combination treatment are patients with severe symptoms and larger prostates, for whom withdrawal of the -blocker at 6 months is not an option. Serum PSA can be used as a surrogate marker for prostate size. If the patient is worried about the risk of invasive therapy, and does not have severe symptoms, either finasteride or a combination of finasteride plus an -blocker can be used. A combination is significantly more effective than either agent alone in reducing the relative risk of disease progression, which was a more frequent event in the MTOPS trial than the development of acute urinary retention or the requirement for invasive therapy. In my opinion, combination therapy is here to stay, and has its own niche in the treatment of symptomatic BPH.

Competing interests

The author declared no competing interests.

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