The present meta-analysis of A1Bs in the treatment of BPH and its related symptoms is, to our knowledge, the most complete of its kind to date. The results demonstrate that the use of A1Bs in BPH treatment confers an added risk of vascular-related adverse events compared with placebo. The exception to this finding was that tamsulosin, although associated with a trend toward greater odds of experiencing a vascular-related adverse event, was not statistically significantly different from placebo.
The occurrence of vasodilatory side effects among patients using A1Bs for the treatment of BPH/LUTS may be related to the specific selectivity profile for α-adrenergic receptor subtypes of each individual agent (8
). Of the three known α-adrenergic receptors –α1A
is predominant in the prostate, while the α1B
subtype is localised in the peripheral vasculature, and the α1D
-receptor subtype is expressed in the bladder and spinal cord (6
). Terazosin and doxazosin are long-acting, non-subtype-selective A1Bs, both of which were initially developed and marketed as antihypertensive agents. This non-selectivity and propensity to induce vascular-related effects has been demonstrated, in that both drugs, when used at therapeutic levels, are associated with an increased risk for hypotension and dizziness (9
). Indeed, the results of this meta-analysis reflect the heightened odds for experiencing both of these side effects, as well as increased risk for vascular-related side effects overall, with terazosin and doxazosin treatment. Doxazosin GITS is a controlled release formulation of doxazosin that reduces the peak-to-trough ratio minimising the need for titration (40
). Nevertheless, the odds of experiencing a vascular event are similar to those of non-subtype-selective A1Bs. Alfuzosin is also non-subtype-selective. This may account for the observed increase in the odds for an adverse vascular event with alfuzosin treatment (7
). Tamsulosin is much more selective at α1A
receptors than at α1B
). Tamsulosin’s low risk of vasodilatory effects, as observed in the results of this meta-analysis, is likely the result of its subtype receptor selectivity. It is most likely because of these pharmacological differences of agents that statistical heterogeneity among trials could not be ruled out for any agent for the primary end-point. Upon subgroup analyses of trials of individual agents, however, statistical heterogeneity was not present for any agent except doxazosin.
While the safety aspect of this meta-analysis is limited to vascular-related adverse events because of their potentially life-threatening effects, it should be noted that A1Bs are associated with other kinds of adverse events, including those related to sexual function. This adverse event may be a significant differentiating factor that physicians use to determine which A1B treatment is optimal, particularly for younger sexually active men with BPH. Tamsulosin and terazosin are both associated with low but statistically significant increases in risk for abnormal ejaculation compared with placebo (11
). Most studies of alfuzosin have observed no significant increase in risk of ejaculation disorder, although one comparative study of tamsulosin and alfuzosin found no significant difference between the two agents for risk of abnormal ejaculation (47
In terms of treatment efficacy for BPH/LUTS, this meta-analysis found no differences in improving Qmax
and AUA-SI/IPSS symptom scores among the different A1Bs compared with placebo. These results are consistent with earlier meta-analyses produced by the AUA Practice Guidelines Committee as well as by Djavan and Marberger (2
). Taking this into consideration, the preference between A1Bs for the treatment of BPH/LUTS will be necessarily contingent, at least in part, upon the differing side effect profiles. This is particularly the case for vascular-related side effects, as BPH/LUTS disproportionately affects elderly patients who may be more susceptible than younger patients to such adverse events. Kaplan and Neutel underscored this point in a recent publication, in which they recommended that clinicians keep themselves knowledgeable about the latest clinical evidence for differential risk of vasodilatory side effects between the available A1Bs (51
). They noted that the use of an A1B with the lowest risk of vascular-related adverse events is advisable for symptomatic older patients in order to ensure safe and effective BPH/LUTS treatment and to improve patient outcomes (51
A common limitation in undertaking meta-analyses is the issue of publication bias, in which clinical trials with statistically significant results are published and those with undesirable results frequently are not (52
). In conducting the present meta-analysis, an attempt was made to avoid publication bias by seeking out and including clinical trial data that have not been previously published in peer-reviewed journals (e.g. data from the FDA web site). Accordingly, publication bias was not present through visual inspection of the funnel plot or through Egger’s weighted regression. Lastly, this meta-analysis could not rule out heterogeneity through Cochrane’s Q
-statistic. However, upon further assessment with subgroup analyses of trials of individual agents, statistical heterogeneity was not present for any agent except doxazosin.