Editorial by Ian Eardley on pp. 123–124 of this issue
Effect of Tadalafil on Male Lower Urinary Tract Symptoms: An Integrated Analysis of Storage and Voiding International Prostate Symptom Subscores from Four Randomised Controlled Trials☆
The international prostate symptom score (IPSS) evaluates lower urinary tract symptoms (LUTS) in men with suspected benign prostatic hyperplasia (BPH); the total score does not differentiate between storage and voiding and is unevenly weighted (four questions [57%] on voiding, three questions [43%] on storage).
Objective
To evaluate the relative contributions of storage and voiding IPSS subscores to total IPSS at baseline and in response to treatment with tadalafil.
Design, setting, and participants
Integrated analysis of data from four placebo-controlled, 12-wk studies of tadalafil (5 mg once daily) in 1499 men with LUTS/BPH.
Outcome measurements and statistical analysis
Relationships between total IPSS and the storage and voiding subscores were assessed using graphical exploration and linear regression modelling. Linear modelling was performed for the baseline and endpoint and for changes in subscores. The optimal storage subscore to total IPSS (S:T) ratio for IPSS improvement was identified using nonparametric regression and gradient-descent optimisation.
Results and limitations
The contribution of storage and voiding subscores at baseline and endpoint was 38.8% and 61.2%, and 39.2% and 60.7%, respectively. This intuitive 40:60 storage-to-voiding ratio was similar at baseline and endpoint by treatment group and for changes in subscores, but spanned the entire range for individuals. Changes in total IPSS were greatest for a storage subscore percentage contribution to total IPSS of 42.7%. There was no statistical association between S:T ratio (≥40% vs <40%) at baseline and response to tadalafil. The main limitation was the use of unvalidated storage and voiding IPSS subscores.
Conclusions
A constant S:T ratio of 4:10 was observed at baseline and endpoint. The greatest effect on total IPSS was noted for an S:T percentage contribution of 42.7%. Tadalafil efficacy was unaffected by the level of storage dysfunction at baseline.
Patient summary
This analysis shows that for men with BPH, improvements during treatment with tadalafil apply to both storage and voiding symptoms at a constant ratio. The extent of storage dysfunction before treatment did not affect the response to treatment.
Introduction
In men with lower urinary tract symptoms (LUTS) who are thought to have benign prostatic hyperplasia (BPH), symptoms are commonly of a mixed nature. Storage symptoms interfere more with quality of life (QoL) than voiding symptoms do [1], [2] and exhibit tighter correlations with QoL across all treatment modalities [3]. Storage symptoms also contribute to a greater reduction in disease-specific QoL associated with male LUTS [4]. The unpredictability of storage symptoms and their interference with activities of daily living are often a key reason for patient consultation [5].
Treatments for LUTS/BPH traditionally target the prostate, despite the important role of the bladder in the pathogenesis of the most bothersome LUTS [6]. Storage symptoms often persist after medical therapy of LUTS/BPH [7], [8], [9] or surgical treatment of bladder outlet obstruction [10].
Despite its limitations, the International Prostate Symptom Score (IPSS) is internationally recognised as a validated 1-mo recall assessment of LUTS/BPH [11], [12]. The IPSS is based on the answers to seven questions about urinary symptoms and one question concerning QoL. Each question on urinary symptoms allows the patient to choose one of six answers indicating increasing severity of the particular symptom. The answers are assigned points from 0 to 5. The total score can therefore range from 0 to 35 (1–7, mild; 8–19, moderate; 20–35, severe). A potential criticism of the IPSS is that it fails to emphasise the differential bothersomeness of storage compared with voiding symptoms. Furthermore, only one of the two typical post-micturition symptoms (feelings of incomplete bladder emptying) is assessed by the IPSS and is categorised as a voiding symptom. Despite these limitations, a reduction of ≥25% in total IPSS from baseline to endpoint has been suggested as a threshold for therapeutic response [13], whereas a change in total IPSS of ≥3 points has been suggested as the threshold at which a patient becomes aware of potential therapeutic efficacy [11].
Attempts have been made to determine the diagnostic value of assessing IPSS subscores [14], [15]. Lee et al. [14] investigated the importance of improvements in storage dysfunction in Korean men with moderate to severe LUTS/BPH after combination therapy with an alpha-blocker and a 5-alpha reductase inhibitor, stratifying patients by severity of storage symptoms. However, the relative contribution of the subscore to total IPSS was not assessed. Liao et al. [15] assessed the contribution of voiding and storage subscores to total IPSS, using the voiding-to-storage subscore ratio to differentiate between voiding failure (ratio >1) and storage failure (ratio ≤1), but did not take into consideration the relative maximum contributions that voiding and storage subscores make to total IPSS (approx. 40% and 60%, respectively). The limitation of using unvalidated individual subscores has previously been highlighted [16].
Tadalafil is a long-acting phosphodiesterase type 5 (PDE5) inhibitor approved by the US Food and Drug Administration for treatment of erectile dysfunction (ED), signs and symptoms of BPH/ED, symptoms of BPH, and pulmonary arterial hypertension (classified as World Health Organization group 1) to improve exercise ability [17]. The efficacy and safety of once-daily tadalafil in men with LUTS/BPH have been demonstrated in four pivotal, global, randomised, placebo-controlled clinical trials [18], [19], [20], [21]. This analysis was performed to gain a better understanding of the relative effects of tadalafil on urinary storage versus voiding symptoms.
Using these four studies, we conducted an integrated analysis of baseline and outcome data for tadalafil in LUTS/BPH to assess the relative contributions of storage and voiding IPSS subscores to total IPSS at baseline and the impact of these contributions on the response to treatment in terms of total IPSS at endpoint. The varying contributions of the subscores to the total score are not often taken into consideration when making management decisions for men with LUTS, yet a preponderance of one pattern of disease (even in men with the same total IPSS) can impact the bothersomeness of disease at baseline, as well as response to therapy.
Section snippets
Patients and methods
This integrated post hoc analysis used pooled data from four randomised, double-blind, placebo-controlled, 12-wk studies of once-daily tadalafil in men with LUTS/BPH [18], [19], [20], [21] with similar inclusion and exclusion criteria. Participants were aged ≥45 yr with a history of LUTS secondary to BPH for >6 mo, IPSS ≥13, and a peak urinary flow rate of 4–15 ml/s. In all studies, a 4-wk washout of other LUTS/BPH medication preceded a 4-wk placebo lead-in period before the baseline visit. At
Results
Of 1499 men with LUTS thought to be secondary to BPH, 752 were randomised to tadalafil and 747 to placebo [18], [19], [20], [21].
Relationships between storage and voiding subscores and total IPSS at baseline and endpoint, and the change from baseline to endpoint, are presented in Figure 1. Linear regression modelling suggested that the percentage contribution of the storage subscore to total IPSS was 38.8% (95% CI 37.2–40.5%) at baseline and 39.2% (95% CI 38.1–40.4%) at endpoint. The voiding
Discussion
The mechanism of action of the long-acting PDE5 inhibitor tadalafil in the treatment of men with LUTS secondary to BPH is believed to be associated with stimulation of increased activity of the nitric oxide/cGMP/protein kinase G pathway via inhibition of PDE5 isoenzymes in different tissues of the lower urinary tract. It is postulated that this results in (1) smooth muscle relaxation in the bladder, urethra, prostate, and supporting vasculature, (2) increased blood perfusion to the pelvic area,
Conclusions
In this analysis, the efficacy of tadalafil from baseline to study end at 12 wk did not differ between men with high and low degrees of storage dysfunction at baseline (as indicated by S:T ≥40% or <40%, respectively). Improvements in total IPSS were driven by an average 40% contribution from the storage subscore, a result in accordance with previous studies on alpha-antagonist therapy. These findings lend support to the view that contemporary pharmacotherapy for LUTS—at the therapeutic doses
Content validity of the Benign Prostatic Hyperplasia Impact Index (BII); a measure of how urinary trouble and problems associated with BPH may impact the patient
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Role of voiding and storage symptoms for the quality of life before and after treatment in men with voiding dysfunction
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Symptom-specific quality of life in patients with benign prostatic hyperplasia
