Abstract Introduction Despite the well-documented efficacy of phosphodiesterase type 5 inhibitors (PDE5i), up to 30–40% of men with erectile dysfunction (ED) show suboptimal response to monotherapy with a single PDE5i, mainly due to pharmacokinetic variability, endothelial dysfunction, or receptor desensitization. Tadalafil, with its long half-life (~17.5 hours), ensures sustained cavernosal cGMP elevation, while vardenafil provides a rapid onset of action and higher PDE5 selectivity. Combining these two agents at low, alternating doses may provide a synergistic pharmacodynamic effect through continuous cGMP availability and improved smooth muscle responsiveness. Objective To evaluate the efficacy, safety, and patient satisfaction of sequential or combined tadalafil–vardenafil therapy in men with ED non-responsive to single PDE5i treatment. Methods A prospective pilot study included 62 men (mean age 48.1 ± 7.6 years) previously unresponsive to ≥8 attempts of either tadalafil or vardenafil monotherapy. Patients received tadalafil 5 mg daily combined with vardenafil 10 mg on-demand before intercourse, for 12 weeks. Clinical evaluation included baseline and follow-up assessments at 4 and 12 weeks using the IIEF-5 questionnaire, Erection Hardness Score (EHS), and a patient satisfaction scale. Adverse events, blood pressure, and tolerability were monitored throughout treatment. Results Combination therapy yielded a significant improvement in erectile function: mean IIEF-5 increased from 11.2 ± 2.8 at baseline to 18.9 ± 3.6 after 12 weeks (p 0.001), while EHS improved from 2.1 ± 0.5 to 3.4 ± 0.6 (p 0.01). Clinical response (IIEF-5 gain ≥5 points) was achieved in 74% of patients, including 68% of those with moderate ED and 45% with severe ED. Patient satisfaction reached 84%, and 78% reported restored sexual spontaneity due to tadalafil’s steady-state effect. Adverse events were mild and transient: headache (9.7%), facial flushing (8%), nasal congestion (5%), and dyspepsia (3%). No treatment discontinuations occurred due to adverse effects. Conclusions The combination of daily tadalafil with on-demand vardenafil is a feasible and well-tolerated therapeutic strategy for men with erectile dysfunction unresponsive to single PDE5i therapy. The dual pharmacologic profile-steady-state endothelial priming by tadalafil and acute PDE5 inhibition by vardenafil-enhances penile vascular responsiveness and patient confidence. These findings suggest that flexible or sequential PDE5i therapy could represent a promising personalized approach in refractory erectile dysfunction. Controlled randomized trials are warranted to confirm the synergistic benefit and establish standardized protocols for combined PDE5i use. Disclosure No
Arian et al. (Mon,) studied this question.