BJUI. Irbesartan promotes erection recovery after nerve-sparing radical retropubic prostatectomy: a retrospective long-term analysis

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1 BJUI Irbesartan promotes erection recovery after nerve-sparing radical retropubic prostatectomy: a retrospective long-term analysis Robert L. Segal, Trinity J. Bivalacqua and Arthur L. Burnett Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA Accepted for publication 10 November 2011 Study Type Therapy (retrospective cohort) Level of Evidence 2b OBJECTIVE To evaluate retrospectively the potential benefit of administering irbesartan, an angiotensin-receptor blocker, to improve erectile function (EF) recovery after nerve-sparing radical retropubic prostatectomy (RRP). What s known on the subject? and What does the study add? Erectile dysfunction following radical prostatectomy (RP) is among the most common and dreaded adverse effects of the surgery. Multiple studies confirm the potential benefit of various drug classes to accelerate the return of erectile function (EF) after RP. There is pre-clinical evidence supporting the use of angiotensin-receptor blockers (ARBs) for this purpose, although this has not been studied in humans. The present study shows that there may be a benefit in the recovery of EF post-rrp in patients taking a daily dose of irbesartan, an ARB, following RRP. In addition, the use of irbesartan may curb the loss of stretched penile length which occurs postoperatively. Further study in the form of prospective, randomized, placebocontrolled clinical trials are necessary to confirm these findings. PATIENTS AND METHODS Before surgery potent patients who underwent nerve-sparing RRP between April and December 2009 elected to start daily oral irbesartan 300 mg on postoperative day 1 ( n = 17). A contemporaneously clinically matched cohort consisting of patients who declined irbesartan use served as the control group ( n = 12). Postoperative on demand use of erectile aids (phosphodiesterase type 5 [PDE5 ] inhibitors and intracavernous injections) was adopted. Potency was monitored by the administration of International Index of Erectile Function-5 (IIEF-5) questionnaires before surgery and at early (3 months) and long-term (12 and 24 months) postoperative intervals. Stretched penile length (SPL) was measured both immediately and 3 months after surgery. RESULTS EF status was no different between groups at baseline ( P > 0.05). While the IIEF-5 scores at 24 months after surgery were statistically similar between the two groups (control = 15.2 ± 2.0, irbesartan = 14.1 ± 3.1, P = 0.77), at 12 months the IIEF-5 scores of the irbesartan group were significantly higher than those of the control group (14 ± 2.6 vs. 7.2 ± 1.6, P < 0.05). The proportional loss of SPL after RRP was less in the irbesartan than in the control group at 3 months ( 0.9 ± 1.5% vs 5.6 ± 1.5, P < 0.05). CONCLUSION Regular irbesartan use after nervesparing RRP in patients with normal preoperative erectile function could improve EF recovery after surgery and mitigate early loss of SPL. KEYWORDS erectile dysfunction, irbesartan, penile rehabilitation, radical prostatectomy INTRODUCTION Prostate cancer is the most common cancer among men, representing over 25% of all new cancer diagnoses in the United States [1 ]. For clinically localized prostate cancer, the gold standard for therapy remains anatomical radical prostatectomy (RP). A major complication of this procedure is erectile dysfunction (ED), which can have a significant negative impact on quality of life [ 2 ]. This is the case despite an improved understanding of penile autonomic innervation and prostate anatomy [3 ], which has led to refinements in surgical technique [ 4 ], as well as the emergence of minimally invasive techniques for prostate removal, whose outcomes have rivalled that of the conventional open procedure in some series [5 ]. There are several purported mechanisms of ED after RP. Perhaps the most commonly attributed issue relates to cavernous nerve , doi: /j x x

2 IRBESARTAN AND ERECTION RECOVERY AFTER RADICAL PROSTATECTOMY TABLE 1 Characteristics of patients in the subject groups Variable (mean ± SEM) Age, years 58.4 ± ± Serum PSA level, ng/dl 5.25 ± ± Comorbidity [n/n (%)] [n/n (%)] CAD (Coronary Artery Disease) 1/17 (6%) 0 Hypertension 7/17 (41%) 3/12 (25%) Diabetes mellitus 1/17 (6%) 4/12 (33%) Smoking 2/17 (12%) 0 Hyperlipidaemia 10/17 (59%) 7/12 (58%) injury, which occurs in spite of a careful nerve-sparing approach. Most evidently, this denervation impedes the neuromuscular transmission needed for functional erections. Furthermore, this leads to corporal smooth muscle atrophy and fibrosis [6 ]. As a result, failure to achieve regular cavernosal cycling between the flaccid and erect states could contribute to further cavernosal smooth muscle structural damage [7 ], characterized histologically by degeneration of nerve terminals, deterioration of corporeal smooth muscle, and infiltration of cavernosal tissue with collagen [8 ]. Angiotensin-receptor blockers (ARBs) have long been part of the treatment armamentarium for hypertension. Recent evidence, however, has implicated angiotensin II, as well as the activity of the angiotensin receptor (AT1), in vascular oxidative stress and inflammatory processes which contribute to endothelial dysfunction [9 11 ]. ARBs have further shown benefit in preserving erectile function (EF) after cavernous nerve injury in rats. Canguven et al. [12 ] demonstrated that low- and high-dose losartan preserved EF after bilateral cavernous nerve crush injury compared with controls. In addition, losartan administration attenuated the up-regulated expression of fibronectin, psmad2 and thrombospondin, activators of TGF- β, which is known to induce vascular fibrosis [13 16 ]. These findings reinforce the notion that cavernous nerve injury (a good simulation in an animal model of the injury that occurs after radical retropubic prostatectomy [RRP ] ) results in heightened vascular fibrosis which contributes to diminished EF. The aim of the present study is, based on these basic scientific findings, to assess the potential benefit of irbesartan administration to patients who have undergone RRP in improving EF recovery. PATIENTS AND METHODS TABLE 2 Comorbidities of patients Patients were enrolled among those scheduled to undergo bilateral nerve-sparing radical retropubic prostatectomy by a single surgeon (A.L.B.) for clinically localized prostate cancer between April and December The patients opting for irbesartan treatment were started on a dose of 300 mg orally once daily, commencing on the first postoperative day. Patients were counselled as to the off-label use of this medication for the purpose of penile rehabilitation (defined as medical treatment at the time of or after RRP to improve the restoration of natural penile mechanics which results in spontaneous erectile function) [17 ], as well as the adverse effects of the medication, such as orthostatic hypotension, metabolic changes (including hyperkalaemia) and dizziness. The present study was approved by the Institutional Review Board of the Johns Hopkins Hospital. Clinical outcomes were based on a preoperative abbreviated International Index of Erectile Function (IIEF-5) questionnaire [ 18 ] score of 22 or greater out of a possible 25 who acknowledged having a sexual partner. Patients were excluded if they had used a phosphodiesterase type 5 (PDE5) inhibitor for treating ED before surgery or if a penile deformity such as Peyronie s disease was present. Postoperative use of erectile aids (PDE5 inhibitors or intracavernous injections) was permitted on an on demand basis, and the extent of the use of these aids was not recorded. Data were accrued by retrospective compilation of responses from IIEF-5 questionnaires which were completed at early (3 months) and long-term (12 and 24 months) postoperative intervals. This assessment was performed by routinely retrieving completed questionnaires in the clinic or by mail. Endpoints included total IIEF-5 questionnaire scores, as well as specific scores on Question 4 of the IIEF-5, which refers to the ability to maintain erections for completion of sexual intercourse, whereby a score of 4 or 5 represents clinically meaningful erectile function. Results are reported with or without erectile aid use. Stretched penile length (SPL) was recorded both immediately and at 3 months after surgery by measuring the dorsal aspect of the penis from the penopubic junction to the corona of the glans penis (in units of cm). The comparison group consisted of potent patients consecutively undergoing bilateral nerve-sparing RRP during the same time period who declined irbesartan therapy. Patients in this control group were subsequently managed in a similar fashion to the irbesartan-treated patients. Statistical analysis was performed using the unpaired t -test with ANOVA post-hoc analysis. Results are reported as means ± standard error, with P < 0.05 considered to indicate statistical significance. RESULTS The final analysis consisted of all irbesartantreated patients ( n = 17; treatment group) and patients who were not treated with irbesartan ( n = 12; control group). Patients in the two groups demonstrated no significant differences with respect to age, comorbidities and preoperative and postoperative variables ( Tables 1 and 2 ). Additionally, proportions of patients with Gleason scores < 7, 7 and 8 10 were not

3 SEGAL ET AL. statistically different between groups (data not shown; P = 0.64). In the treatment group, two patients reported discontinuing irbesartan as a result of the development of epistaxis and muscle cramping of the back and legs, respectively. It was otherwise well tolerated by the other patients. The mean preoperative IIEF-5 scores for the treatment and control groups were 23.4 ± 0.52 and 22 ± 0.69, respectively ( P > 0.05, Table 3 ). At 3 and 24 months after surgery, there were no significant differences in mean IIEF-5 scores between the two groups, but at 12 months after surgery, the mean IIEF-5 score in the irbesartan group was statistically significantly higher (14 ± 2.6 vs 7.2 ± 1.6, P < 0.05). It is acknowledged that scores for both groups at all time points fall within the range of ED as designated by the scoring system of the IIEF instrument [18 ]. At 24 months, there was no significant difference between groups with respect to scores on Question 4 of the IIEF-5 (data not shown). The mean SPL measured immediately after surgery while still in the operating room was statistically shorter in the irbesartan group ( Table 4 ) than in the control group. Whereas absolute SPL measurements at 3 months were not different from the postoperative lengths, when the proportional loss of SPL was considered, the irbesartan-treated group showed a statistically significantly reduced SPL loss compared with the control group ( 0.9 ± 1.5% vs 5.6 ± 1.5%, respectively, P < 0.05). DISCUSSION The results of this long-term analysis suggest that daily administration of irbesartan after nerve-sparing RRP offers potential benefit to improve EF recovery. Specifically, the EF recovery at 1 year after surgery was greater in the irbesartantreated group than in the control group. This result, in combination with the similarity of EF recovery between the groups at the other studied postoperative time points, suggests that irbesartan could function to accelerate EF recovery relatively early on, with a gradual stabilization of EF recovery beyond 1 year after surgery. Another benefit of irbesartan as reflected in these results is a curbing of SPL loss at 3 group (mean ± SEM) months in the treatment group. While the clinical importance of these relatively small proportional changes remains to be ascertained, there is a well-documented effect of RP on diminishing SPL after surgery [19 21 ]. It is possible that the potential antifibrotic effect of ARBs and the resultant outcome on SPL would be more evident in RP operations where the nerve-sparing effort was not as meticulous, where a greater neuropathic insult is expected. Indeed, Gontero et al. [22 ] found, first, that the loss of penile length was most evident early after surgery, and, secondly, that nerve-sparing status was an independent predictor of penile size after surgery on multivariate analysis. As such, early administration of ARB, as in this analysis, could be what is necessary to obviate corporal fibrosis and loss of penile length. The use of ARBs in treating organic ED has some justification in the literature. Multiple studies have shown improvements in endothelial function as well as EF after the administration of various ARBs (candesartan, irbesartan, losartan and telmisartan) to rodents with different features of the metabolic syndrome [23 26 ]. This has been translated to humans, as therapy with irebesartan for 6 months has been shown to ameliorate EF in patients with the metabolic syndrome, as shown by a significant improvement in the IIEF score (three to four points), as well as significant increases in orgasmic function and intercourse satisfaction, and a significant decrease in IIEF-5 score Preoperative 23.4 ± ± months 7.9 ± ± months 14 ± ± months 14.1 ± ± TABLE 4 SPL immediately and 3 months after surgery group (mean ± SEM) TABLE 3 IIEF-5 scores before surgery and at 3, 12 and 24 months after surgery SPL, cm Immediately after surgery ± ± months after surgery ± ± the overall prevalence of ED [27 ]. The mechanism of this improvement is thought to be related to the reduction of vascular inflammation induced by the ARB, which in turn improves endothelial function [28 ]. Furthermore, these improvements appear to be independent of blood pressure reduction. The rationale for ARB use in treating ED related to cavernous nerve injury after nerve-sparing RRP is based on the study by Canguven et al. [12 ], which showed preserved EF after bilateral cavernous nerve crush injury in losartan-treated rats. Their work further revealed that the mechanism could be related to the attenuated expression of fibronectin, psmad2 and thrombospondin, which are activators of TGF- β. Inhibiting the effects of TGF- β by ARB administration has been shown to be of benefit in other disorders, such as Marfan s syndrome, wherein aortic-root dilation is significantly slowed [29 ]. While the results reported here are promising, this work represents a proof of principle study, and more research in the field is necessary. Our conclusion was reached by retrospectively comparing postoperative erection outcomes of a well-matched group of patients undergoing surgery who did not use the therapy. This was an unblinded analysis with a few patients, for whom data accrual was difficult due to the substantial proportion of the patients who did not complete the mailed follow-up questionnaires. The patients in the therapy group, furthermore, were not only

4 IRBESARTAN AND ERECTION RECOVERY AFTER RADICAL PROSTATECTOMY aware that they were receiving active treatment, but also volunteered to be included in the study, which could reflect a selection bias for patients who were more motivated for good sexual outcomes after surgery. As such, the results of the present study are by no means conclusive. Further prospective, blinded, placebocontrolled studies are necessary to better elucidate the role of ARBs in treating post-rrp ED, as well as penile rehabilitation [17 ]. Based on the purported mechanism of benefit of ARBs as aforementioned, this could truly be considered a rehabilitative effort, as the results of the present study suggest that an underlying cause of post-rrp ED is being addressed and reversed by ARB administration. Nevertheless, several questions remain. The dose employed in this analysis, 300 mg daily, is the maximum dose of irbesartan recommended. Could a lower dose be effective? Could other ARBs show a similar effect, as has been shown in organic ED models in animals? This retrospective analysis, showing that patients treated after nerve-sparing RRP with daily high-dose irbesartan recovered EF more significantly than did untreated patients at 1 year after surgery, suggests the possible efficacy of the drug to be used to promote erection recovery in this circumstance. The potential utility of this drug for this purpose is supported by preclinical data showing a potential antifibrotic mechanism of cavernous neuroprotection of ARBs. This evaluation appears to be the first demonstration of a pharmacological approach to condition or remodel the cavernosal tissue to ensure EF clinically after RP. Further study is needed to confirm this potential benefit. CONFLICT OF INTEREST None declared. REFERENCES 1 Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, CA Cancer J Clin ; 60 : Litwin MS, Flanders SC, Pasta DJ, Stoddard ML, Lubeck DP, Henning JM. 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5 SEGAL ET AL. 23 Tobili JE, Stella I, Mazza ON, Ferder L, Inserra F. Candesartan cilexil protects cavernous tissue in spontaneously hypertensive rats. Int J Impot Res 2004 ; 16 : Baumh ä kel M, Custodis F, Schlimmer N, Laufs U, B ö hm M. Improvement of endothelial function of the corpus cavernosum in apolipoprotein E knockout mice treated with irbesartan. J Pharmacol Exp Ther 2008 ; 327 : Yang R, Yang B, Wen Y et al. Losartan, an angiotensin type I receptor, restores erectile function by downregulation of cavernous renin-angiotensin system in streptozocin-induced diabetic rats. J Sex Med 2009 ; 6 : Schlimmer N, Kratz M, B ö hm M, Baumh ä kel M. Telmisartan, ramipril and their combination improve endothelial function in different tissues in a murine model of cholesterol-induced atherosclerosis. Br J Pharm 2011 ; 163 : Baumh ä kel M, Schlimmer N. Böhm M on behalf of the DO-IT investigators. Effect of irbesartan on erectile function in patients with hypertension and metabolic syndrome. Int J Impot Res 2008 ; 20 : Sola S, Mir MQ, Cheema FA et al. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation 2005 ; 111 : Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC III. Angiotensin II blockade and aortic-root dilation in Marfan s syndrome. NEJM 2008 ; 358 : Correspondence: Arthur L. Burnett, Department of Urology, Johns Hopkins Hospital, 600 North Wolfe Street, Marburg 407, Baltimore, MD 21287, USA. aburnet1@jhmi.edu Abbreviations : ARBs, angiotensin-receptor blockers ; ED, erectile dysfunction ; EF, erectile function ; RRP, radical retropubic prostatectomy ; IIEF-5, International Index of Erectile Function-5 ; PDE5, phosphodiesterase type 5 ; RP, radical prostatectomy ; SPL, Stretched penile length