Erectile dysfunction (ED) is defined as the inability to attain or maintain penile erection sufficient for successful sexual intercourse. ED carries a notable influence on quality of life, with significant implications for family and social relationships. Because atherosclerosis of penile arteries represents one of the most frequent causes of ED, patients presenting with it should always be investigated for potential coexistent coronary or peripheral disease. Up to 75% of patients with ED have a stenosis of the iliac-pudendal-penile arteries, supplying perfusion of the male genital organ. Recently the potential treatment of this pathological condition by percutaneous approaches has emerged in different single-center studies and randomized clinical trials. The ZEN trial, by the group of Mass General Hospital in Boston, was the first of these studies; it was designed as a prospective, multicentre, single-arm trial that sought to evaluate the safety and feasibility of zotarolimus-eluting stent implantation in focal atherosclerotic lesions of the internal pudendal arteries (IPA) among men with ED and a suboptimal response to phosphodiesterase-5 inhibitors.
Between the 89 patients included in the trial and undergoing pelvic vessel angiography, 60 (67%) had critical stenosis of the internal pudendal artery but only 33.7% (n = 30) had appropriate anatomical features suitable for endovascular approach. Target lesions were most prevalent in the distal IPA (24 lesions, 53.3%), followed by six lesions in the ostial IPA (13.3%), five proximal IPA lesions (11.1%), and four lesions in the mid-IPA (8.9%), with an average length of the segment affected by atheromatous disease of 17.6 ± 99 mm; 45 lesions were treated with stents with a 100% procedural success and without complications at 30 days (primary endpoint). The percentage of pre-procedural angiographically significant stenosis was 63.3%, reduced to 23.3% after the procedure (acute gain 1:13 ± 0:54), and it returned to 41.4% at six months (late loss 0:56 ± 0:57), with a restenosis incidence of 34.4% (n = 11). A non-significant increase in the peak systolic velocity Doppler of the penile arteries at six months (from 14.4 ± 10.7 to 22.5 ± 23.7 cm/s) was documented. Despite the moderate rate of flow increase and the significant incidence of restenosis, in the intention-to-treat analysis, the primary efficacy endpoint (improvement of erectile function pre- vs. post-procedural evaluated with all IIEF-5 Rating ≥4 in 50% of subjects) at three and six months was achieved in 59.3% of patients (95% confidence interval 38.8-77.6). In the PERFECT-2 study, a single-arm, single-center trial by Taiwan colleagues Dr. Wann et al., enrolled between December 2012 and January 2014, 22 patients suffering from ED and 34 isolated pudendal artery stenosis were treated with balloon angioplasty. Twenty out of 22 patients were treated with balloons of 1.5 mm. The mean lesion length was 11.1±9.0 mm (mean reference vessel diameter 1.7±0.4 mm). The primary endpoint was angiographic restenosis at 12-month CT angiography with a clinical endpoint of a ≥5 IIEF-5 score at follow-up compared with baseline. Late loss in this study was 0.32 ± 0.60 and a binary restenosis occurred in 14 of the 34 treated lesions (41%). At one year, sustained clinical success was achieved in 11 of 22 patients. However, it has to be emphasized that many patients had more than one lesion and the incidence of restenosis per patient was 59%.
The same authors have presented in 2015 a prospective randomized study (the PERFECT-3) in which they enrolled 52 patients treated with a drug-eluting balloon (n = 20), DES (n = 12) or POBA (n = 20) and who had focal artery stenosis of the internal pudendal artery. The primary endpoint was the rate of binary restenosis in the segment treated assessed on angiography or CT control, while the secondary endpoint was the percentage of stenosis at eight months associated with clinical success (defined as a variation of the IIEF score -5 > 4 between pre- and post-process or normalization of the same ≥22 to six months). It is important to note that in this study, enrolment in the DES group was prematurely discontinued for a high restenosis rate; this result together with that of the ZEN trial suggests that this type of treatment is not effective in this district. This notion is probably to be referred to as a different tissue response of the penile vessels implant of a metallic stent or to the size of the vessels treated significantly lower than those of the coronary district (which in itself involves a higher rate of restenosis). Conversely, the use of drug-coated balloons may be favorable as documented with a clinical success of 85% in patients with vascular ED linked to an internal pudendal artery stenosis.
In a subsequent trial, the PERFECT-4 study, Wang et al. randomized 44 ED patients undergoing angioplasty for penile arteries with a renovascular disease (RVD) ≥1.5 mm to plain balloon angioplasty versus additional anti-restenotic treatment with cisplatin, etoposide and bleomycin (PEB). The RVD was 1.8 mm in the plain angioplasty group and 1.9 mm in the group treated with drug-coated balloons (DCB). At eight months, binary in-segment restenosis by computed tomographic angiography (CTA) was 40% in the plain angioplasty group vs 48% in the DCB group. Given that there were no significant differences in restenosis rates comparing conventional angioplasty with DCB, elastic recoil may be the most important mechanism of failure subsequent to angioplasty of these small-caliber arteries. To prevent elastic recoil, drug-eluting stents (DES) are recommended over bare-metal stents.
In this setting, a recent study by Diehm et al. evaluated the incidence of elastic recoil in patients presenting with erectile dysfunction (ED) undergoing endovascular revascularization of the pudendal or penile arteries. They analyzed 21 ED patients (mean age 58.3±9.3 years) undergoing minimally invasive revascularization of 31 arteries. ED lesions included the pudendal arteries (n=27) and the penile artery (n=4). The mean lesion length was 20.6±13.9 mm. Early recoil was defined as manual lymphatic drainage (MLD) reduction >10%. Elastic recoil with >10% lumen compromise was treated with drug-coated balloons, while severe elastic recoil (>30%) required DES. Elastic recoil was observed in all 31 lesions and resulted in a mean lumen compromise of 21.2%. Severe (>30%) recoil was observed in 14 arteries, which underwent DES therapy. There were no differences in the restenosis rate or clinical outcomes of lesions treated with DCB angioplasty compared to the patients treated with a stent, even though the follow-up was very short.
A review and systematic metanalysis about the safety and efficacy of endovascular therapy in the treatment of arterial insufficiency have been published. The arterial insufficiency cohort contained 162 patients most commonly treated via stenting of the internal pudendal artery (40.1%; n=65). The study found an overall clinical success rate of 63.2% in AI patients. Complications occurred in 4.9% of patients (n=8), with four considered to be mild and four considered to be severe. The authors concluded that endovascular therapy for medically refractory ED is safe and may provide a treatment alternative to more invasive surgical management, even though conclusions are limited by the heterogeneity of clinical success definitions among the included studies.
Our personal experience is in agreement with these results. We evaluated 112 patients with ED in whom a positive dynamic doppler after prostaglandin injections was positive in 64 (57%). Those patients were then submitted to selective pudendal angiography that demonstrated a critical stenosis of the proximal internal pudendal artery in 36 (44%) and in the distal internal pudendal artery in 46 (56%). Paclitaxel eluting balloon (PEB) was utilized in all lesions with a procedural success of 96%. An IIEF-5 score greater than 22 was observed in 81% of patients at eight months follow-up with a clinical success in 89% defined as delta IIEF ≥ 4. More recently, sirolimus-eluting balloon (SEB) was also utilized by our group for the treatment of pudendal and dorsalis penis arteries in 41 patients with a good success rate in the mid-term FU as demonstrated by a six-month clinical success rate (Delta IEF-5 basal vs. FU) greater than 72%.
We believe that mechanical revascularization of the pudendal district by drug-eluting balloon and/or stent is "ready for the prime time” and should be tested in large randomized clinical studies to demonstrate the efficacy in restoring normal erectile function in patients affected by vasculogenic erectile dysfunction.
Written by: Giuseppe Sangiorgi, MD, Professor of Cardiovascular Pathology, School of Specialization in Pathological Anatomy, University of Tor Vergata, Contract Professor for the Peripheral Interventional Course, Chair of Vascular Surgery, University of Sassari, Rome, Italy, and Nichola Diehm, MD, MBA, Medical Director, Vascular Institute Central Switzerland, Attending Physician, Hirslanden Clinic Aarau and Brugg Medical Center, Aarau, Switzerland
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