ORIGINAL RESEARCH-PHARMACOTHERAPY FOR EDED: Efficacy and Safety of Daily Tadalafil in Men with Erectile Dysfunction Previously Unresponsive to On‐demand Tadalafil
Introduction
Community‐based epidemiological studies suggest that erectile dysfunction (ED) is a common disorder in men, affecting up to 52% of men between the ages of 40 and 70 years, and is associated with reduced quality of life [1, 2].
It is now recognized that vascular disease of the penile arteries is the most common cause of ED, accounting for up to 80% of these cases [3, 4]. The nitric oxide–cyclic guanosine‐3′5′‐monophosphate (NO‐cGMP) system is important in producing the arterial dilation and venous occlusion necessary to attain and sustain an erection. Abnormalities of this vasodilator system because of endothelial dysfunction are present in atherosclerosis and play an important role in the pathophysiology of ED [5, 6, 7]. Kaiser et al. reported that patients with ED and no significant cardiac risk factors or other clinical cardiovascular diseases have a peripheral vascular abnormality in the NO‐cGMP pathway, suggesting that ED may be the first clinical manifestation of cardiovascular disease [8].
Phosphodiesterase type 5 inhibitor drugs (PDE‐5), which inhibit the breakdown of cGMP producing vasodilation and improve endothelial cell function, are very effective in treating ED [9]. Tadalafil is a potent selective inhibitor of PDE‐5, which is rapidly absorbed with a tmax of 2 hours and a terminal half‐life of 17.5 hours. Multicenter international placebo‐controlled clinical trials have demonstrated that patients receiving 20 mg tadalafil experienced a significant mean improvement in the International Index of Erectile Function (IIEF) erectile function (EF) domain score, successful completion of 75% of intercourse attempts, and an 81% reported rate of improved erections [10]. The extended half‐life of tadalafil offers patients a prolonged period of responsiveness with the successful completion of 59.2% of intercourse attempts at 36 hours after tadalafil dosing [11].
The efficacy of PDE‐5 inhibitor drugs appears related to the extent and severity of ED, with significantly reduced efficacy demonstrated in patients with diabetic ED, severe vasculogenic ED, and post‐radical prostatectomy ED. Several authors have reported their experience with salvage treatment for PDE‐5 inhibitor nonresponders using patient reeducation to ensure correct drug usage and optimize response, testosterone replacement in men with androgen deficiency, high dose sildenafil, intracavernous injection therapy, and combination therapy with sildenafil and intracavernous injection therapy or intraurethral alprostadil [12, 13, 14, 15, 16, 17].
There have been several anecdotal reports that administration of PDE‐5 inhibitors on consecutive days is associated with an improved erectile response. A study was designed to assess the efficacy and tolerability of flexible dose daily tadalafil in patients unresponsive to on‐demand tadalafil.
Section snippets
Study Design
This study was conducted at the Australian Centre for Sexual Health. The study was an open‐label flexible dose evaluation of the efficacy and safety of daily tadalafil in men who had previously failed to respond to on‐demand 20 mg tadalafil and comprised 3 phases: (i) an initial 4‐week on‐demand 20 mg tadalafil phase; (ii) a 4‐week treatment‐free period; and (iii) a 12‐week daily tadalafil treatment period (Figure 1).
Inclusion Criteria
Eligible patients were men 18 years of age or older in a stable heterosexual
Patient Population and Demographics
One hundred and twelve men with a mean age of 63.0 (range 21–79) were enrolled. The aetiology of ED was psychogenic in 5 patients (4.5%), organic in 92 patients (82.1%), and mixed psychogenic/organic in 15 patients (13.4%). The mean duration of ED from first symptom was 26.6 months. Fifty‐two men (46.4%) had diabetes mellitus; 63 (56.3%) had hypertension; 70 (61.6%) had hyperlipidemia, and 48 (42.9%) smoked cigarettes (Table 1). Sildenafil had previously been used by 104 men (92.9%), 96 of
Discussion
PDE‐5 inhibitor drugs have reduced efficacy in patients with diabetic ED, comorbid hypertension, severe vasculogenic ED, and post‐radical prostatectomy ED. Saenz de Tejada et al. reported that diabetic patients receiving daily 20 mg tadalafil had a mean IIEF EF domain score of 18.9 compared with 23.9 in unselected men with ED [18]. Intercourse was successfully completed by diabetic men treated with 20 mg tadalafil on only 57% of attempts (Sexual Encounter Profile question 3) compared with 75%
Conclusions
Treatment with daily tadalafil significantly improved all treatment outcomes in men previously unresponsive to on‐demand tadalafil. Sexual intercourse was successfully completed on 58% of attempts. Daily tadalafil was well tolerated and had a similar side‐effect profile to on‐demand tadalafil.
Conflict of Interest. Dr. McMahon is a paid consultant and/or investigator and/or member of speakers panel for Pfizer, Bayer, GlaxoSmithKline, Eli Lilly, Icos Corp., American Medical Systems, and Johnson &
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