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Effects of Preoperative Atorvastatin Treatment On Erectile Function After Radical Prostatectomy: Results From a Subgroup of ESTO1, a Randomized, Double-Blind, Placebo-Controlled Study
ORIGINAL RESEARCH & REVIEWS
Effects of Preoperative Atorvastatin Treatment On Erectile Function After Radical Prostatectomy: Results From a Subgroup of ESTO1, a Randomized, Double-Blind, Placebo-Controlled Study Aino Siltari, PhD,1 Jarno Riikonen, MD, PhD,2 Mikkel Fode, MD, PhD,3 and Teemu J. Murtola, MD1,2,4
ABSTRACT
Introduction: Erectile dysfunction is common after radical prostatectomy because of damage to the cavernous nerves. Thus, it is important to identify new ways to avoid this problem. For example, statins have shown positive effects on erectile function and may have anti-inflammatory effects that improve recovery after surgery. Aim: The aim of this exploratory analysis of a subgroup from ESTO1, a randomized, double-blind, placebocontrolled study, was to evaluate the preoperative use of atorvastatin on erectile function after radical prostatectomy. Method: Patients were randomized to either 80 mg atorvastatin or placebo daily before undergoing radical prostatectomy from study inclusion to the day of surgery. Altogether 118 men with prostate cancer and scheduled for radical prostatectomy were asked to fill out the 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire before surgery and at 3, 6, 9, and 12 months after surgery. Main Outcome Measurements: The study was exploratory, with the main outcome being the overall difference between IIEF-5 scores in the 2 groups at 12 months. Several hypotheses generating sub-analyses were conducted. Results: Overall, 85% filled out the IIEF-5 questionnaire before their operation and 85%, 81%, 78%, and 78% completed it at 3, 6, 9, and 12 months follow-up, respectively. 52% of men had information available at all time points. There were no statistically significant differences between the groups at baseline in either erectile function, comorbidities, or tumor characteristics. The median duration of use of atorvastatin and placebo before surgery was 27 and 25 days, respectively. Preoperative atorvastatin treatment had no statistically significant effect on erectile function after prostatectomy as compared with placebo, although IIEF-5 scores were higher at all time points in the statin arm. Furthermore, atorvastatin treatment compared with placebo improved IIEF-5 scores at 12 months after surgery when the cavernous nerves were at least partially intact bilaterally (P < .04, n ¼ 65); however, after full bilateral or unilateral nerve-sparing, the difference was not statistically significant. Clinical Implication: Short-term statin treatment did not improve recovery of erectile function after prostatectomy; however, further studies are needed before final conclusions. Strengths & Limitations: This was a randomized placebo-controlled study. Original ESTO1 study was designed to detect a difference in prostate cancer biomarkers. Conclusion: Short-term atorvastatin treatment before radical prostatectomy had no statistically significant effect on the recovery of erectile functions in a non-selected cohort of patients undergoing radical prostatectomy. Further studies will be needed to clarify the role of long-term atorvastatin use before and after prostatectomy. Siltari A, Riikonen J, Fode M, et al. Effects of Preoperative Atorvastatin Treatment On Erectile Function After Radical Prostatectomy: Results From a Subgroup of ESTO1, a Randomized, Double-Blind, PlaceboControlled Study. J Sex Med 2019;XX:XXXeXXX. Copyright 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Atorvastatin; Clinical Drug Study; Erectile Dysfunction; IIEF-5 Questionnaire; Radical Prostatectomy; Cavernous Nerves
Received April 24, 2019. Accepted July 3, 2019.
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Copyright ª 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jsxm.2019.07.001
Tampere University, Faculty of Medicine and Life Sciences, Tampere, Finland;
2
Tampere University Hospital, Department of Urology, Tampere, Finland;
Seinäjoki Central Hospital, Department of Surgery, Seinäjoki, Finland
3
Herlev and Gentofte Hospital, Department of Urology, Herlev, Denmark;
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INTRODUCTION
MATERIAL AND METHODS
Erectile dysfunction (ED) is common after radical prostatectomy because of damage to the cavernous nerves.1 Despite increasing experience with the procedure and the introduction of new surgical methods, the incidence of ED after radical prostatectomy has not declined in recent years.2 In addition, attempts at penile rehabilitation through treatment with erectogenic aids and neuromodulatory compounds after surgery have not achieved any clear benefits on long-term spontaneous erections.3e5 Therefore, there is an unmet clinical need for new methods of preserving post-prostatectomy erectile function.
Study Cohort
Statins decrease cholesterol levels by inhibiting the ratelimiting enzyme, HMG-CoA. Decreased cholesterol levels also affect the mevalonate pathway, which generates other sterols such as testosterone. Accordingly, statin treatment seems to slightly decrease testosterone levels in men.6 Thus, in theory, statins could increase ED by reducing testosterone levels. However, this does not seem to be the case, because, in practice, statins have actually been shown to improve erectile function.7 This is possibly due to increased nitric oxide generation and a subsequent improvement in endothelial function.8 Increased nitric oxide production in the vasculature9e11 may also enhance the effects of phosphodiesterase type 5 inhibitors, such as sildenafil. Finally, statins are known to possess anti-inflammatory properties12 and may reduce the neuronal inflammatory response and, thus, hasten recovery after nerve damage.13 Thus, statin therapy might be one feasible way to promote the recovery of the nerves responsible for erectile function after radical prostatectomy. A recent study investigated the effects of statins on neuronal damage in a microglia cell model.14 It was concluded that statin treatment seemed to attenuate the extent of the damage by inhibiting the nuclear factor-k B-pathway, which triggers the production of inflammatory cytokines. Nonetheless, the administration of a statin to improve erectile function after nerve-sparing radical prostatectomy has been investigated in only 1 clinical study.15 In that study, 50 men without hypercholesterolemia were randomized to receive either sildenafil on demand or 10 mg of atorvastatin daily plus sildenafil on demand for 90 days after surgery. Although not statistically significant, there was a tendency toward a better postoperative recovery of potency in the atorvastatin group (26.1% vs 55%, P ¼ .068). However, the study was hampered by a lack of blinding and uncertainty about the use of sildenafil in the 2 groups. Even more importantly, the postoperative dosing of atorvastatin meant that its putative anti-inflammatory effects in conjunction with surgery could not be evaluated, which may well have missed most of the theoretical benefits. In this subgroup study of the ESTO1 trial, a randomized placebo-controlled study, we investigated the effects of preoperative statin treatment on erectile function after radical prostatectomy in Finnish men.
This study presents the results of the planned exploratory subgroup analyses from the ESTO1-study population. Full information and results of the main endpoints of the ESTO1-study can be found in our previous publication.16 Briefly, the original study included 158 statin-naïve patients who were randomized to either 80 mg atorvastatin or placebo daily before undergoing radical prostatectomy from study inclusion to the day of surgery. From that population, 118 men were asked to complete the abridged, 5-item version of the International Index of Erectile Dysfunction (IIEF-5) questionnaire.17 Blinding was maintained throughout the trial. Clinical information of prostate cancer included details of the Gleason score from both biopsies and tumors, tumor T-stage, tumor volume, and the prostate-specific antigen value at the time of diagnosis. Data were supplemented with information of comorbidities at recruitment (categorized as yes or no), such as diabetes and hypertension, and some background information, such as smoking habits (categorized as current, previous, never). We also had information on nerve-sparing at prostatectomy (categorized as non-nerve sparing, partial/full on 1 side, at least partial on both sides, or full nerve-sparing on both sides) and prostate intrainflammation score, which was evaluated using histopathologic classification.18 Study protocol was approved by the Ethics Committee of the Pirkanmaa Hospital District (ETL R03230), and all subjects signed an informed consent form before enrollment into the study. The study was also registered by EudraCT (2011005438-20) and clinicaltrials.gov (NCT01821404) and was conducted by adhering to the principles of Good Clinical Practice and Declaration of Helsinki.
Information of Erectile Function The IIEF-5 questionnaire was collected at baseline and at 3, 6, 9, and 12 months after surgery. The severity of ED was divided into the following groups based on the IIEF-5 scores: score 1e7 severe, 8e11 moderate, 12e16 mild-moderate, 17e21 mild, and 22 no ED.
Statistical Analysis Non-parametric Mann-Whitney tests were used to compare IIEF-5 scores in the atorvastatin arm to placebo arm at different time points. Linear regression was used to test for trends in IIEF-5 scores over time after prostatectomy. Friedman test was used to evaluate statistical significance of differences in IIEF-5 trends between the study arms. Separate analyses for the subgroups of hypertensive and diabetic subjects, and based on the severity of baseline ED, smoking habits, duration of study drug use, and the degree of nerve-sparing at prostatectomy were conducted. Differences were assumed as statistically significant if P < .05.
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Atorvastatin and Erectile Function
Table 1. Population characteristics
Table 1. Continued
Trial arm Atorvastatin (n ¼ 60)
Trial arm Placebo (n ¼ 58)
Age, median (IQR) 64 (58.5e68) 64 (58e69) 27 (17e33) 25 (17e36) Preoperative statin use, median days (IQR) 100 (82e102) 97 (89e102) Compliance (used study drugs from the goal), median (IQR) (%) Compliance (IIEF-5 questionnaire available), n (%) Baseline 51 (85) 49 (84) 3 months after 51 (85) 49 (84) operation 6 months after 48 (80) 47 (81) operation 51 (85) 41 (71) 9 months after operation 12 months after 46 (77) 46 (79) operation BMI (kg/m2), median 26.5 (24.1e29.3) 26.4 (24.7e28.9) (IQR) Smoking Current regular (%) 10 (16) 6 (10) Current irregular (%) 2 (3) 1 (2) Previous smoker (%) 1 (3) 0 (0) Never smoked (%) 46 (75) 51 (86) Comorbidities Hypertension (%) 24 (39) 21 (36) Diabetes mellitus (%) 6 (10) 7 (12) Gleason score from biopsy 6 (%) 25 (41) 23 (39) 7 (%) 27 (44) 28 (48) 8e10 (%) 9 (15) 8 (14) Clinical T-stage T1 (%) (not specified) 1 (2) T1a (%) 1 (2) T1b (%) 1 (2) T1c (%) 36 (59) 36 (61) T2 (%) (not 8 (13) 7 (12) specified) T2a (%) 3 (5) 2 (3) T2b (%) 1 (2) 2 (3) T2c (%) 8 (13) 8 (14) T3 (%) 3 (5) 2 (3) Preoperative PSA value <5 ng/mL (%) 6 (10) 4 (7) 5e10 ng/mL (%) 27 (44) 23 (39) >10 ng/mL (%) 7 (11) 12 (20) (continued)
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Atorvastatin (n ¼ 60) High-grade PCa (T-stage T2c or more) (%) Prostate volume, median (IQR) (mL) Intra-prostate inflammation score* 9 (%) 9> (%) Testosterone levels† Preoperative, median (IQR) (nmol/L) Postoperative, median (IQR) (nmol/L) Nerve-sparing Bilateral, n (%) Unilateral, n (%) Partial, n (%) None, n (%)
11 (18)
Placebo (n ¼ 58) 10 (17)
34 (29.5-47.5)
34 (25-45)
23 (38) 36 (60)
23 (40) 33 (57)
14.5 (11.1-19) 13.4 (11.2-17.5)
20 17 14 9
(33) (28) (23) (15)
14.6 (13-20.2) 16 (11.6-23.2)
17 14 22 4
(29) (24) (38) (7)
BMI ¼ body mass index; IIEF-5 ¼ 5-item version of the International Index of Erectile Function; IQR ¼ interquartile range; PCa ¼ prostate cancer; PSA ¼ prostate-specific antigen. A randomized placebo-controlled study on preoperative statin treatment on erectile function after radical prostatectomy. *Scores were created based on international consensus criteria.18 † Data were available in only part of the study population; normal limit values in Finland 10e38 nmol/L.
To determine the detectable between-group difference in IIEF-5 scores in the study, a power analysis was performed based on the size of our study population and the observed IIEF-5 SD (5.7). This showed that, with 46 subjects in each arm, the median difference between the groups would need to be 3.6 points or more to achieve a power of 80% with the a ¼ 0.05. Accordingly, this difference should be considered the primary end point of the study. All statistical tests were done using IBM SPSS statistics (version 24; Chicago, IL, USA).
RESULTS Population Characteristics There were no differences in population characteristics between the study arms (Table 1). The median age of the study subjects was 64 years old, and the median body mass index was 26.5 in the statin group and 26.4 in the placebo group. Most of the study participants were non-smokers (82%). In both arms, about every third participant had hypertension, and about 1 in 10 had diabetes. The median duration of preoperative study drug use was 27 days in the statin arm and 25 days in the placebo arm. Median compliance with the drug
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use was 97e100%, and compliance in filling out of the IIEF-5 questionnaire varied from 71e85% (Table 1). Full data in the form of IIEF-5 questionnaire at all time points was available in 61 men (52%), and 77 patients (65%) filled out the questionnaire at baseline and 12 months after the surgery. Only 15% in the atorvastatin arm and 7% in the placebo arm had undergone non-nerve-sparing surgery, whereas full nervesparing was performed in 33% and 29% of patients, respectively. All others had at least partial nerve-sparing at prostatectomy (Table 1). Furthermore, intra-prostate inflammation scores were similar between the study arms (Table 1).
Effects of Preoperative Use Of Atorvastatin On Erectile Functions After Prostatectomy At baseline, 43% of men in the statin arm and 45% in the placebo arm had normal erectile function (IIEF-5 score of 22 or more) (Table 2). The proportion declined 3 months after surgery to 4% in the statin arm and 2% in placebo arm; at 12 months from surgery, the proportions recovered to 9% in the statin arm and 4% in the placebo arm (Table 2). Only 8% and 4% from statin and placebo arms, respectively, had severe ED (IIEF-5 score 7 or less) at the baseline. 3 months after surgery, the prevalence of severe ED was 78% in the statin and 90% in the placebo groups; at 12 months after surgery, the values were still high, that is, 65% in the statin arm and 78% in the placebo arms (Table 2). There were no significant differences in IIEF-5 scores between the study arms at any time point after prostatectomy or at the baseline (Table 3). Figure 1 illustrates the distribution of IIEF-5 scores at different time points in both arms. P values for the Friedman test, which take into account all time points, were .098 for atorvastatin arm and .513 for the placebo arm. Furthermore, regression coefficients did not statistically differ between the 2
arms (P ¼ .174). When taking into account the severity of ED (Table 3), no differences were evident between the study arms for ED of any grade. Noteworthy, IIEF-5 scores were higher in the statin arm compared with the placebo arm at 12 months after surgery in almost all analyses; however, the difference was not statistically significant. Taking into account baseline diabetes, hypertension, smoking, or duration of atorvastatin use did not modify the result (Table 4). The median difference in IIEF-5 scores between the arms 12 months after surgery was 1.6. When nerve sparing at prostatectomy was taken into account, atorvastatin treatment compared with placebo seemed to improve IIEF-5 scores at 12 months after surgery, when the nerves were at least partially intact bilaterally (P < .04) (Table 5). The trend was similar at other time points after surgery (Table 5). However, in patients in the statin arm with full bilateral or unilateral nerve-sparing surgery displayed no statistically significant beneficial effect in their IIEF-5 scores (Table 5). When the analysis was limited to men who had normal erectile function (IEEF-5 score more than 21) at the baseline and had full nerve-sparing at surgery, no significant difference was evident in postoperative erectile function between the arms (9.7 ± 2.2 vs 11.1 ± 2.3 atorvastatin vs placebo for 12 months after surgery). However, when subjects with nervesparing surgery and high intra-prostate inflammation were analyzed, atorvastatin use improved IIEF-5 scores (P ¼ .023) (Table 5).
Effects of Diabetes, Hypertension, and Smoking on Erectile Function At baseline, diabetic subjects’ median IIEF-5 scores were lower in comparison to their non-diabetic counterparts (15.9 ± 2 vs 19.7 ± 0.6; P ¼ .056). Hypertensive and non-hypertensive participants did not differ at the baseline, but unexpectedly, at 3 months after
Table 2. Amount of participants in different groups of erectile dysfunction based on the IIEF-5 scores Baseline IIEF-5 score 7 or less (severe erectile dysfunction) Statin, n (%) Placebo, n (%) IIEF-5 score 8e11 (moderate erectile dysfunction) Statin, n (%) Placebo, n (%) IIEF-5 score 12e16 (mild-moderate erectile dysfunction) Statin, n (%) Placebo, n (%) IIEF-5 score 17e21 (mild erectile dysfunction) Statin, n (%) Placebo, n (%) IIEF-5 score 22 (normal erectile function) Statin, n (%) Placebo, n (%)
3 months
6 months
9 months
12 months
4 (8) 2 (4)
40 (78) 44 (90)
33 (69) 37 (79)
33 (65) 36 (88)
30 (65) 36 (78)
4 (8) 3 (6)
2 (4) 2 (4)
4 (8) 3 (6)
6 (12) 1 (2)
3 (7) 3 (7)
6 (12) 7 (14)
4 (8) 2 (4)
5 (10) 4 (9)
3 (6) 5 (12)
6 (13) 2 (4)
15 (29) 15 (31)
3 (6) 2 (4)
5 (10) 3 (6)
3 (6) 2 (5)
3 (7) 3 (7)
22 (43) 22 (45)
2 (4) 1 (2)
1 (2)
3 (6) 0
4 (9) 2 (4)
0
IIEF-5 ¼ 5-item version of the International Index of Erectile Function. J Sex Med 2019;-:1e9
Atorvastatin and Erectile Function
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Table 3. Effects of statin treatment on erectile functions measured using IIEF-5 questionnaire 3, 6, 9, and 12 months after radical prostatectomy in Finnish men Baseline Baseline IIEF-5 score All cases Statin Control >7 Statin Control >11 Statin Control >16 Statin Control >21 Statin Control
3 months
6 months
9 months
12 months
N IIEF-5 score P N IIEF-5 score P N IIEF-5 score P N IIEF-5 score P N IIEF-5 score P value (mean ± SEM) value value (mean ± SEM) value value (mean ± SEM) value value (mean ± SEM) value value (mean ± SEM) value .78 51 49
18.8 ± 0.9 19.6 ± 0.7
47 47
20 ± 0.7 20.1 ± 0.6
43 44
20.9 ± 0.6 20.8 ± 0.5
37 37
22 ± 0.4 22 ± 0.4
22 22
24 ± 0.2 23.6 ± 0.3
.63 51 49
7.7 ± 0.7 6.6 ± 0.6
41 38
8 ± 0.9 7 ± 0.7
39 36
8.2 ± 0.9 7.1 ± 0.8
33 30
8.8 ± 1 7.4 ± 0.6
20 17
8.3 ± 1.4 7.1 ± 1.1
.93
.96 48 47
8.2 ± 0.8 7.1 ± 0.5
36 38
7.7 ± 0.8 7.2 ± 0.6
34 35
7.5 ± 0.8 7.4 ± 0.6
28 29
8.1 ± 0.9 7.1 ± 0.7
16 19
8.3 ± 1.3 7.4 ± 0.9
.71
.77
39 33
7.4 ± 0.7 7.3 ± 0.7
36 30
7.6 ± 0.8 7.5 ± 0.8
31 25
8 ± 0.9 7.3 ± 0.7
18 16
8.8 ± 1.4 7.9 ± 1
9.3 ± 0.9 7.7 ± 0.8
35 37
8.2 ± 0.9 7.9 ± 0.9
33 34
7.9 ± 0.8 8.2 ± 0.9
28 30
8.5 ± 1 8.1 ± 1
16 17
9 ± 1.5 8.4 ± 1.5
.55
.74
.97
.61
.18 46 46
.77
.34
.41
.29
8.2 ± 0.8 7.2 ± 0.6
.49
.7
.84
.55 51 41
.84
.75
.94
.49
.86
.61
IIEF-5 ¼ 5-item version of the International Index of Erectile Function; SEM ¼ standard error of the mean.
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theoretical considerations to indicate that statins could be of value in conjunction with radical prostatectomies. In this study, we were unable to find evidence that preoperative statins can achieve overall significant improvements of postoperative erectile function. According to the power analysis, our sample size was sufficient to demonstrate an IIEF-5 score difference 3.6. Therefore, we cannot rule out smaller IIEF-5 differences. Notably, the median IIEF-5 score at 12 months was 1.6 points better in the atorvastatin arm compared with the placebo arm, suggesting a benefit by statin use that is too small to detect in this sample size. Therefore, larger studies are needed to confirm our findings. Figure 1. Distribution of IIEF-5 values at baseline and after prostatectomy in the atorvastatin arm and the placebo arm. P ¼ .513 in the placebo arm and P ¼ .098 in the atorvastatin arm. P ¼ .174 for regression comparison between the arms. Collums from left: baseline, 3, 6, 9, and 12 months' time points, respectively; IIEF-5 ¼ 5-item version of the International Index of Erectile Function. surgery, the hypertensive patients had higher IIEF-5 scores than their non-hypertensive counterparts (7.9 ± 0.8 vs 6.7 ± 0.6; P ¼ .015). Smokers and non-smokers had similar IIEF-5 scores at the baseline; however, at 3 months after surgery, non-smokers had a better recovery in their IIEF-5 scores (5.1 ± 0.1 vs. 7.5 ± 0.6, P ¼ .01). Similar trends with smoking were also seen at other time points, although differences were not statistically significant (5.4 ± 0.3 vs 8.0 ± 0.5 for 6 months, 6.2 ± 0.6 vs 8.1 ± 0.6 for 9 months, and 5.8 ± 0.4 vs 9.0 ± 0.7 for 12 months after the operation).
DISCUSSION ED is one of the main side effects encountered after radical prostatectomy; thus, it is important to devise new ways to avoid this problem. This study is the first that has evaluated the preoperative use of atorvastatin on erectile function after radical prostatectomy in a randomized setting. According to some publications10,19-21 but not all clinical studies,22,23 statin treatment may improve ED in men in general. In these studies, the daily doses of the statin have varied from 10 mg to 80 mg and the duration of the treatment from 6 weeks to 6 months. Some of the studies investigated the effects of statin treatment on erectile function among sildenafil nonresponders.10,19,21,24 In all of these studies, patients had ED, but none that was due to cavernous nerve damage after radical prostatectomy. Rather, the main pathophysiology has been cardiovascular disease, although in only 2 studies was either hypercholesterolemia specifically described19or endothelial dysfunction22 applied as an inclusion criterion. Thus, the patients in our study are not directly comparable to those in the above-mentioned publications. However, as described, there are
In the subgroup of patients with at least partially spared nerves bilaterally, the atorvastatin group did show better IIEF-5 scores at 12 months after surgery. Considering the size of the subgroup and the exploratory nature of our analyses, this cannot be taken as evidence of an actual effect. Nonetheless, it does indicate that an anti-inflammatory effect of statins may be of specific benefit in partially intact nerves. This seems intuitive because statins cannot be expected to restore the function of resected nerves, and, thus, further studies in this subgroup are justified. Furthermore, it is not known how long statins need to be administered to exhibit a significant anti-inflammatory response. In our study, the statin treatment was short term, that is, the median duration of use was 27 days. It may be that, to achieve anti-inflammatory response, which would protect nerves during surgery and improve the subsequent recovery, longer-term statin use may be needed. This hypothesis is supported by the finding that intraprostatic inflammation was quantified in our study population and found to be similar in both study arms.16 In a cell model involving microglial cells, statin use protected cells from nerve damage by decreasing the inflammatory response.14 However, we did not measure the inflammatory status of nervous tissue in this study; thus, the putative antiinflammatory effect of statin treatment on cavernous nerves will need to be confirmed. In addition, additional benefits of statin use could become evident by extending the dosing into the post-operative period, a hypothesis that could be evaluated in further clinical studies. Meanwhile, the statin dose in our study (80 mg daily) was high when compared with the average defined daily dose (20 mg daily) as listed by the World Health Organization25 for treatment of hypercholesterolemia or atherosclerosis, diseases for which they are usually prescribed. Thus, it is unclear whether average doses of statin could impact on the recovery of erectile function after prostatectomy. Diabetes is a known risk factor for ED in men.26 This can be seen also in our study: baseline IIEF-5 scores were lower among diabetic subjects than in non-diabetics. A similar phenomenon was not seen among smokers and non-smokers or between hypertensive and normotensive subjects at baseline. However, our study did not point to any specific benefits in these subgroups. Hypertensive subjects had higher IIEF-5 scores at 3 months from
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Table 4. Effects of statin treatment on erectile function Baseline
3 months
12 months
IIEF-5 score P IIEF-5 score IIEF-5 score n-value (mean ± SEM) value n-value (mean ± SEM) P value n-value (mean ± SEM) P value Diabetic Statin 6 Control 6 Non-diabetic Statin 45 Control 42 Hypertensive Statin 21 Control 17 Non-hypertensive Statin 29 Control 31 Smokers Statin 12 Control 4 Non-smokers Statin 37 Control 44 Preoperative statin use 28 days Statin 22 Control 20 Preoperative statin use 27 days Statin 29 Control 28 Intra-prostate inflammation score >9 Statin 18 Control 19
.63
1
14.2 ± 3.5 17.7 ± 2
5 6
6.2 ± 0.8 5.8 ± 0.5
45 44
7.9 ± 0.8 6.7 ± 0.6
22 18
9.2 ± 1.3 6.2 ± 0.7
28 31
8.9 ± 1.2 6.8 ± 0.8
10 6
5 ± 0.1 5.2 ± 0.2
39 43
8.4 ± 0.9 6.8 ± 0.7
.73 19.4 ± 0.8 20 ± 0.8
7.1 ± 1.1 7.5 ± 1.2
.39
9.7 ± 1.4 7.2 ± 0.8
7 5
6.1 ± 0.7 5.4 ± 0.4
37 41
10.2 ± 1.1 8 ± 0.8
.29
.53
.2
.43 19 21
10.2 ± 1.6 7.5 ± 1.1
.25 28 33
8.1 ± 1 6.2 ± 0.6
.92 18.6 ± 1.6 19.9 ± 1.1
26 27
.44
.52 23 16
18.1 ± 1.1 19.5 ± 1
9 ± 1.3 8.4 ± 1.4
.41
.56 19.7 ± 1.3 10 ± 1
19 19
.1
.64
.35 18.2 ± 1.1 19.9 ± 0.8
9.6 ± 1 7.5 ± 0.8
.55
.32 20.1 ± 1.6 17.8 ± 3
42 40 .19
.54 18.6 ± 1.3 20.4 ± 0.9
6.3 ± 0.8 9±2
.6
.77 18.8 ± 1.1 18.4 ± 1.3
.32 4 6
.27 27 25
8.8 ± 1.1 7.9 ± 1.1
.52 19 18
8.2 ± 1.4 7.6 ± 1.4
.19 15 17
10.2 ± 1.9 6.8 ± 1
IIEF-5 ¼ 5-item version of the International Index of Erectile Function; SEM ¼ standard error of the mean. Participants stratified by comorbidities, by smoking, or by preoperative duration of study drug use or by intra-prostate inflammation score.
surgery, which was not seen at other time points. This may also be a random finding and will need to be confirmed in the future. Unfortunately, we did not have access to the blood pressure levels of the subjects, nor did we have information on which specific antihypertensive medications had been prescribed for the patients, meaning that no specific hypothesis can be constructed in this regard. Our study has some important strengths. First, it is a randomized, placebo-controlled double-blind study; thus, influence of background confounding factors was controlled in the study design. Compliance with the study intervention was documented to be high: 100% in the statin group and 97% in the placebo group. In addition, the compliance rate for completing the IIEF-5 questionnaire was high: 85% at baseline and 78% at 12 months after surgery. 65% of men filled out the
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IIEF-5 questionnaire both at baseline and at the 12-month time point. As a limitation, erectile function was not the primary endpoint for the trial, which was designed to detect a difference in prostate cancer biomarkers. This means that there was considerable variation in baseline erectile function and nervesparing. In addition, our study may be affected by a type 2 error, and especially in the subgroup analysis, the statistical power is low. Also, we only evaluated erectile function. Overall sexual function is impacted also by other aspects of sexuality, such as confidence and orgasmic function. Future studies should preferably use more sophisticated surveys measuring other aspects of sexuality to obtain a more comprehensive view on statins’ effects on sexuality preservation after radical prostatectomy.
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Table 5. Effects of statin treatment on erectile functions. Participants stratified by nerve-sparing after prostatectomy Baseline
3 months
12 months
IIEF-5 score P IIEF-5 score P IIEF-5 score P n-value (mean ± SEM) value n-value (mean ± SEM) value n-value (mean ± SEM) value Intact nerves both side Statin Control At least partial nerves on both side Statin Control At least partial nerves on 1 side Statin Control No intact nerves after surgery Statin Control At least partial nerves on both side and intra-prostate inflammation score >9 Statin Control
.74 18 15
20.1 ± 1.1 20.8 ± 1
34 37
20.4 ± 0.8 19.5 ± 0.9
9 10
19.9 ± 1.9 19.9 ± 1.4
8 2
10.8 ± 1.9 18.5 ± 3.5
.13 17 17
9.5 ± 1.4 6.9 ± 1.2
34 35
8.9 ± 1 6.8 ± 0.7
10 10
5.2 ± 0.1 6.5 ± 1.2
7 4
5 5.3 ± 0.3
.49
31 34
10.8 ± 1.2 8.2 ± 1
.04
.48
.18
.67 8 9
5.5 ± 0.2 6.7 ± 1.1
7 3
7.1 ± 2.1 5.3 ± 0.3
.53
.61
20.7 ± 1.6 20.4 ± 1.2
10.4 ± 1.7 9.9 ± 1.8
.17
.66
11 14
.45 16 16
.83
.29
11 12
10.4 ± 2.1 8.8 ± 2
.023
9 12
13.6 ± 3 7.3 ± 1.4
IIEF-5 ¼ 5-item version of the International Index of Erectile Function; SEM ¼ standard error of the mean.
CONCLUSION
STATEMENT OF AUTHORSHIP
Overall, we conclude that short-term atorvastatin treatment before radical prostatectomy conferred no significant benefit on the recovery of the erectile function in this unselected group of men. However, because the IIEF-5 scores were consistently higher, but not statistically significantly, in the statin arm, there may be effects in specific subgroups. Our results will need confirmation from larger trials, with postoperative erectile function as a main outcome, and the effects of extended postoperative statin use will need to be evaluated in other clinical studies.
Category 1
Corresponding Author: Aino Siltari, Tampere University, Faculty of Medicine and Health Technology, Arvo Ylpön katu 34, 33520 Tampere, Finland. Tel: þ358 29 412 5347; Fax: þ358 191 25364; E-mail: aino.siltari@helsinki.fi Conflicts of Interest: Dr. Siltari reports no conflicts of interest; Dr. Riikonen receives reimbursements for travel and conferences from Swanmedica, Astellas, and Ferring and trial participation from Astellas, Pfizer, Bayer, Orion, and Myovant; Dr. Fode receives consultant fees from Ferring Pharmacuticals and advisory board representative consultation fees and lecture fees for Astellas Pharma; Prof. Murtola receives consultation fees from Astellas, Ferring and Janssen and lecture fees from Astellas and Janssen. Funding: Funded by Expert Responsibility Area of the Pirkanmaa Hospital District (grant number 9X032) and Cancer Society of Finland (grant number 25024194).
(a) Conception and Design Mikkel Fode; Teemu J. Murtola (b) Acquisition of Data Jarno Riikonen; Teemu J. Murtola (c) Analysis and Interpretation of Data Aino Siltari; Teemu J. Murtola Category 2 (a) Drafting the Article Aino Siltari; Teemu J. Murtola (b) Revising It for Intellectual Content Jarno Riikonen; Mikkel Fode Category 3 (a) Final Approval of the Completed Article Aino Siltari; Jarno Riikonen; Mikkel Fode; Teemu J. Murtola
REFERENCES 1. Burnett AL, Aus G, Canby-Hagino ED, et al. Erectile function outcome reporting after clinically localized prostate cancer treatment. J Urol 2007;178:597-601. 2. Schauer I, Keller E, Muller A, et al. Have rates of erectile dysfunction improved within the past 17 years after radical prostatectomy? A systematic analysis of the control arms of prospective randomized trials on penile rehabilitation. Andrology 2015;3:661-665. 3. Fode M, Ohl DA, Ralph D, et al. Penile rehabilitation after radical prostatectomy: What the evidence really says. BJU Int 2013;112.
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4. Montorsi F, Brock G, Stolzenburg JU, et al. Effects of tadalafil treatment on erectile function recovery following bilateral nerve-sparing radical prostatectomy: A randomised placebocontrolled study (REACTT). Eur Urol 2014;65:587-596.
16. Murtola TJ, Syvälä H, Tolonen T, et al. Atorvastatin versus placebo for prostate cancer before radical prostatectomy—A randomized, double-blind, placebo-controlled clinical trial. Eur Urol 2018;74:697-701.
5. Mulhall JP, Klein EA, Slawin K, et al. A randomized, doubleblind, placebo-controlled trial to assess the utility of tacrolimus (FK506) for the prevention of erectile dysfunction following bilateral nerve-sparing radical prostatectomy. J Sex Med 2018;15:1293-1299.
17. Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11:319-326.
6. Schooling CM, Au Yeung SL, et al. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med 2013;11:57.
18. Nickel JC, True LD, Krieger JN, et al. Consensus development of a histopathological classification system for chronic prostatic inflammation. BJU Int 2001;87:797-805.
7. Kostis JB, Dobrzynski JM. The effect of statins on erectile dysfunction: A meta-analysis of randomized trials. J Sex Med 2014;11:1626-1635. 8. Gelosa P, Cimino M, Pignieri A, et al. The role of HMG-CoA reductase inhibition in endothelial dysfunction and inflammation. Vasc Health Risk Manag 2007;3:567-577. 9. Castro MM, Rizzi E, Rascado RR, et al. Atorvastatin enhances sildenafil-induced vasodilation through nitric oxide-mediated mechanisms. Eur J Pharmacol 2004;498:189-194. 10. El-Sisi AA, Hegazy SK, Salem KA, et al. Atorvastatin improves erectile dysfunction in patients initially irresponsive to Sildenafil by the activation of endothelial nitric oxide synthase. Int J Impot Res 2013;25:143-148. 11. Baspınar O, Bayram F, Korkmaz S, et al. The effects of statin treatment on adrenal and sexual function and nitric oxide levels in hypercholesterolemic male patients treated with a statin. J Clin Lipidol 2016;10:1452-1461. 12. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005;45:89-118. 13. Bimbova K, Bacova M, Kisucka A, et al. A single dose of atorvastatin applied acutely after spinal cord injury suppresses inflammation, apoptosis, and promotes axon outgrowth, which might be essential for favorable functional outcome. Int J Mol Sci 2018;19(4).
19. Dadkhah F, Safarinejad MR, Asgari MA, et al. Atorvastatin improves the response to sildenafil in hypercholesterolemic men with erectile dysfunction not initially responsive to sildenafil. Int J Impot Res 2010;22:51-60. 20. Herrmann HC, Levine LA, Macaluso J Jr, et al. Can atorvastatin improve the response to sildenafil in men with erectile dysfunction not initially responsive to sildenafil? Hypothesis and pilot trial results. J Sex Med 2006;3:303-308. 21. Gokce M_I, Gülpınar Ö, Öztürk E, et al. Effect of atorvastatin on erectile functions in comparison with regular tadalafil use. A prospective single-blind study. Int Urol Nephrol 2012; 44:683-687. 22. Mastalir ET, Carvalhal GF, Portal VL. The effect of simvastatin in penile erection: A randomized, double-blind, placebocontrolled clinical trial (Simvastatin treatment for erectile dysfunction-STED TRIAL). Int J Impot Res 2011;23:242-248. 23. Trivedi D, Kirby M, Wellsted DM, et al. Can simvastatin improve erectile function and health-related quality of life in men aged 40 years with erectile dysfunction? Results of the Erectile Dysfunction and Statins Trial [ISRCTN66772971]. BJU Int 2013;111:324-333. 24. Bank AJ, Kelly AS, Kaiser DR, et al. The effects of quinapril and atorvastatin on the responsiveness to sildenafil in men with erectile dysfunction. Vasc Med 2006;11:251-257.
14. Lu D, Shen L, Mai H, et al. HMG-CoA reductase inhibitors attenuate neuronal damage by suppressing oxygen glucose deprivation-induced activated microglial cells. Neural Plast 2019:7675496.
25. World Health Organization (WHO). ATC/DDD index 2016. Available at: http://www.whocc.no/atc_ddd_index/. Accessed April 1, 2019.
15. Hong SK, Han BK, Jeong SJ, et al. Effect of statin therapy on early return of potency after nerve sparing radical retropubic prostatectomy. J Urol 2007;178:613-616.
26. Maiorino MI, Bellastella G, Esposito K. Diabetes and sexual dysfunction: Current perspectives. Diabetes Metab Syndr Obes 2014;7:95-105.
J Sex Med 2019;-:1e9
Effects of Preoperative Atorvastatin Treatment On Erectile Function After Radical Prostatectomy: Results From a Subgroup of ESTO1, a Randomized, Double-Blind, Placebo-Controlled Study Aino Siltari, PhD,1 Jarno Riikonen, MD, PhD,2 Mikkel Fode, MD, PhD,3 and Teemu J. Murtola, MD1,2,4
ABSTRACT
Introduction: Erectile dysfunction is common after radical prostatectomy because of damage to the cavernous nerves. Thus, it is important to identify new ways to avoid this problem. For example, statins have shown positive effects on erectile function and may have anti-inflammatory effects that improve recovery after surgery. Aim: The aim of this exploratory analysis of a subgroup from ESTO1, a randomized, double-blind, placebocontrolled study, was to evaluate the preoperative use of atorvastatin on erectile function after radical prostatectomy. Method: Patients were randomized to either 80 mg atorvastatin or placebo daily before undergoing radical prostatectomy from study inclusion to the day of surgery. Altogether 118 men with prostate cancer and scheduled for radical prostatectomy were asked to fill out the 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire before surgery and at 3, 6, 9, and 12 months after surgery. Main Outcome Measurements: The study was exploratory, with the main outcome being the overall difference between IIEF-5 scores in the 2 groups at 12 months. Several hypotheses generating sub-analyses were conducted. Results: Overall, 85% filled out the IIEF-5 questionnaire before their operation and 85%, 81%, 78%, and 78% completed it at 3, 6, 9, and 12 months follow-up, respectively. 52% of men had information available at all time points. There were no statistically significant differences between the groups at baseline in either erectile function, comorbidities, or tumor characteristics. The median duration of use of atorvastatin and placebo before surgery was 27 and 25 days, respectively. Preoperative atorvastatin treatment had no statistically significant effect on erectile function after prostatectomy as compared with placebo, although IIEF-5 scores were higher at all time points in the statin arm. Furthermore, atorvastatin treatment compared with placebo improved IIEF-5 scores at 12 months after surgery when the cavernous nerves were at least partially intact bilaterally (P < .04, n ¼ 65); however, after full bilateral or unilateral nerve-sparing, the difference was not statistically significant. Clinical Implication: Short-term statin treatment did not improve recovery of erectile function after prostatectomy; however, further studies are needed before final conclusions. Strengths & Limitations: This was a randomized placebo-controlled study. Original ESTO1 study was designed to detect a difference in prostate cancer biomarkers. Conclusion: Short-term atorvastatin treatment before radical prostatectomy had no statistically significant effect on the recovery of erectile functions in a non-selected cohort of patients undergoing radical prostatectomy. Further studies will be needed to clarify the role of long-term atorvastatin use before and after prostatectomy. Siltari A, Riikonen J, Fode M, et al. Effects of Preoperative Atorvastatin Treatment On Erectile Function After Radical Prostatectomy: Results From a Subgroup of ESTO1, a Randomized, Double-Blind, PlaceboControlled Study. J Sex Med 2019;XX:XXXeXXX. Copyright 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Atorvastatin; Clinical Drug Study; Erectile Dysfunction; IIEF-5 Questionnaire; Radical Prostatectomy; Cavernous Nerves
Received April 24, 2019. Accepted July 3, 2019.
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Copyright ª 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jsxm.2019.07.001
Tampere University, Faculty of Medicine and Life Sciences, Tampere, Finland;
2
Tampere University Hospital, Department of Urology, Tampere, Finland;
Seinäjoki Central Hospital, Department of Surgery, Seinäjoki, Finland
3
Herlev and Gentofte Hospital, Department of Urology, Herlev, Denmark;
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INTRODUCTION
MATERIAL AND METHODS
Erectile dysfunction (ED) is common after radical prostatectomy because of damage to the cavernous nerves.1 Despite increasing experience with the procedure and the introduction of new surgical methods, the incidence of ED after radical prostatectomy has not declined in recent years.2 In addition, attempts at penile rehabilitation through treatment with erectogenic aids and neuromodulatory compounds after surgery have not achieved any clear benefits on long-term spontaneous erections.3e5 Therefore, there is an unmet clinical need for new methods of preserving post-prostatectomy erectile function.
Study Cohort
Statins decrease cholesterol levels by inhibiting the ratelimiting enzyme, HMG-CoA. Decreased cholesterol levels also affect the mevalonate pathway, which generates other sterols such as testosterone. Accordingly, statin treatment seems to slightly decrease testosterone levels in men.6 Thus, in theory, statins could increase ED by reducing testosterone levels. However, this does not seem to be the case, because, in practice, statins have actually been shown to improve erectile function.7 This is possibly due to increased nitric oxide generation and a subsequent improvement in endothelial function.8 Increased nitric oxide production in the vasculature9e11 may also enhance the effects of phosphodiesterase type 5 inhibitors, such as sildenafil. Finally, statins are known to possess anti-inflammatory properties12 and may reduce the neuronal inflammatory response and, thus, hasten recovery after nerve damage.13 Thus, statin therapy might be one feasible way to promote the recovery of the nerves responsible for erectile function after radical prostatectomy. A recent study investigated the effects of statins on neuronal damage in a microglia cell model.14 It was concluded that statin treatment seemed to attenuate the extent of the damage by inhibiting the nuclear factor-k B-pathway, which triggers the production of inflammatory cytokines. Nonetheless, the administration of a statin to improve erectile function after nerve-sparing radical prostatectomy has been investigated in only 1 clinical study.15 In that study, 50 men without hypercholesterolemia were randomized to receive either sildenafil on demand or 10 mg of atorvastatin daily plus sildenafil on demand for 90 days after surgery. Although not statistically significant, there was a tendency toward a better postoperative recovery of potency in the atorvastatin group (26.1% vs 55%, P ¼ .068). However, the study was hampered by a lack of blinding and uncertainty about the use of sildenafil in the 2 groups. Even more importantly, the postoperative dosing of atorvastatin meant that its putative anti-inflammatory effects in conjunction with surgery could not be evaluated, which may well have missed most of the theoretical benefits. In this subgroup study of the ESTO1 trial, a randomized placebo-controlled study, we investigated the effects of preoperative statin treatment on erectile function after radical prostatectomy in Finnish men.
This study presents the results of the planned exploratory subgroup analyses from the ESTO1-study population. Full information and results of the main endpoints of the ESTO1-study can be found in our previous publication.16 Briefly, the original study included 158 statin-naïve patients who were randomized to either 80 mg atorvastatin or placebo daily before undergoing radical prostatectomy from study inclusion to the day of surgery. From that population, 118 men were asked to complete the abridged, 5-item version of the International Index of Erectile Dysfunction (IIEF-5) questionnaire.17 Blinding was maintained throughout the trial. Clinical information of prostate cancer included details of the Gleason score from both biopsies and tumors, tumor T-stage, tumor volume, and the prostate-specific antigen value at the time of diagnosis. Data were supplemented with information of comorbidities at recruitment (categorized as yes or no), such as diabetes and hypertension, and some background information, such as smoking habits (categorized as current, previous, never). We also had information on nerve-sparing at prostatectomy (categorized as non-nerve sparing, partial/full on 1 side, at least partial on both sides, or full nerve-sparing on both sides) and prostate intrainflammation score, which was evaluated using histopathologic classification.18 Study protocol was approved by the Ethics Committee of the Pirkanmaa Hospital District (ETL R03230), and all subjects signed an informed consent form before enrollment into the study. The study was also registered by EudraCT (2011005438-20) and clinicaltrials.gov (NCT01821404) and was conducted by adhering to the principles of Good Clinical Practice and Declaration of Helsinki.
Information of Erectile Function The IIEF-5 questionnaire was collected at baseline and at 3, 6, 9, and 12 months after surgery. The severity of ED was divided into the following groups based on the IIEF-5 scores: score 1e7 severe, 8e11 moderate, 12e16 mild-moderate, 17e21 mild, and 22 no ED.
Statistical Analysis Non-parametric Mann-Whitney tests were used to compare IIEF-5 scores in the atorvastatin arm to placebo arm at different time points. Linear regression was used to test for trends in IIEF-5 scores over time after prostatectomy. Friedman test was used to evaluate statistical significance of differences in IIEF-5 trends between the study arms. Separate analyses for the subgroups of hypertensive and diabetic subjects, and based on the severity of baseline ED, smoking habits, duration of study drug use, and the degree of nerve-sparing at prostatectomy were conducted. Differences were assumed as statistically significant if P < .05.
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Atorvastatin and Erectile Function
Table 1. Population characteristics
Table 1. Continued
Trial arm Atorvastatin (n ¼ 60)
Trial arm Placebo (n ¼ 58)
Age, median (IQR) 64 (58.5e68) 64 (58e69) 27 (17e33) 25 (17e36) Preoperative statin use, median days (IQR) 100 (82e102) 97 (89e102) Compliance (used study drugs from the goal), median (IQR) (%) Compliance (IIEF-5 questionnaire available), n (%) Baseline 51 (85) 49 (84) 3 months after 51 (85) 49 (84) operation 6 months after 48 (80) 47 (81) operation 51 (85) 41 (71) 9 months after operation 12 months after 46 (77) 46 (79) operation BMI (kg/m2), median 26.5 (24.1e29.3) 26.4 (24.7e28.9) (IQR) Smoking Current regular (%) 10 (16) 6 (10) Current irregular (%) 2 (3) 1 (2) Previous smoker (%) 1 (3) 0 (0) Never smoked (%) 46 (75) 51 (86) Comorbidities Hypertension (%) 24 (39) 21 (36) Diabetes mellitus (%) 6 (10) 7 (12) Gleason score from biopsy 6 (%) 25 (41) 23 (39) 7 (%) 27 (44) 28 (48) 8e10 (%) 9 (15) 8 (14) Clinical T-stage T1 (%) (not specified) 1 (2) T1a (%) 1 (2) T1b (%) 1 (2) T1c (%) 36 (59) 36 (61) T2 (%) (not 8 (13) 7 (12) specified) T2a (%) 3 (5) 2 (3) T2b (%) 1 (2) 2 (3) T2c (%) 8 (13) 8 (14) T3 (%) 3 (5) 2 (3) Preoperative PSA value <5 ng/mL (%) 6 (10) 4 (7) 5e10 ng/mL (%) 27 (44) 23 (39) >10 ng/mL (%) 7 (11) 12 (20) (continued)
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Atorvastatin (n ¼ 60) High-grade PCa (T-stage T2c or more) (%) Prostate volume, median (IQR) (mL) Intra-prostate inflammation score* 9 (%) 9> (%) Testosterone levels† Preoperative, median (IQR) (nmol/L) Postoperative, median (IQR) (nmol/L) Nerve-sparing Bilateral, n (%) Unilateral, n (%) Partial, n (%) None, n (%)
11 (18)
Placebo (n ¼ 58) 10 (17)
34 (29.5-47.5)
34 (25-45)
23 (38) 36 (60)
23 (40) 33 (57)
14.5 (11.1-19) 13.4 (11.2-17.5)
20 17 14 9
(33) (28) (23) (15)
14.6 (13-20.2) 16 (11.6-23.2)
17 14 22 4
(29) (24) (38) (7)
BMI ¼ body mass index; IIEF-5 ¼ 5-item version of the International Index of Erectile Function; IQR ¼ interquartile range; PCa ¼ prostate cancer; PSA ¼ prostate-specific antigen. A randomized placebo-controlled study on preoperative statin treatment on erectile function after radical prostatectomy. *Scores were created based on international consensus criteria.18 † Data were available in only part of the study population; normal limit values in Finland 10e38 nmol/L.
To determine the detectable between-group difference in IIEF-5 scores in the study, a power analysis was performed based on the size of our study population and the observed IIEF-5 SD (5.7). This showed that, with 46 subjects in each arm, the median difference between the groups would need to be 3.6 points or more to achieve a power of 80% with the a ¼ 0.05. Accordingly, this difference should be considered the primary end point of the study. All statistical tests were done using IBM SPSS statistics (version 24; Chicago, IL, USA).
RESULTS Population Characteristics There were no differences in population characteristics between the study arms (Table 1). The median age of the study subjects was 64 years old, and the median body mass index was 26.5 in the statin group and 26.4 in the placebo group. Most of the study participants were non-smokers (82%). In both arms, about every third participant had hypertension, and about 1 in 10 had diabetes. The median duration of preoperative study drug use was 27 days in the statin arm and 25 days in the placebo arm. Median compliance with the drug
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use was 97e100%, and compliance in filling out of the IIEF-5 questionnaire varied from 71e85% (Table 1). Full data in the form of IIEF-5 questionnaire at all time points was available in 61 men (52%), and 77 patients (65%) filled out the questionnaire at baseline and 12 months after the surgery. Only 15% in the atorvastatin arm and 7% in the placebo arm had undergone non-nerve-sparing surgery, whereas full nervesparing was performed in 33% and 29% of patients, respectively. All others had at least partial nerve-sparing at prostatectomy (Table 1). Furthermore, intra-prostate inflammation scores were similar between the study arms (Table 1).
Effects of Preoperative Use Of Atorvastatin On Erectile Functions After Prostatectomy At baseline, 43% of men in the statin arm and 45% in the placebo arm had normal erectile function (IIEF-5 score of 22 or more) (Table 2). The proportion declined 3 months after surgery to 4% in the statin arm and 2% in placebo arm; at 12 months from surgery, the proportions recovered to 9% in the statin arm and 4% in the placebo arm (Table 2). Only 8% and 4% from statin and placebo arms, respectively, had severe ED (IIEF-5 score 7 or less) at the baseline. 3 months after surgery, the prevalence of severe ED was 78% in the statin and 90% in the placebo groups; at 12 months after surgery, the values were still high, that is, 65% in the statin arm and 78% in the placebo arms (Table 2). There were no significant differences in IIEF-5 scores between the study arms at any time point after prostatectomy or at the baseline (Table 3). Figure 1 illustrates the distribution of IIEF-5 scores at different time points in both arms. P values for the Friedman test, which take into account all time points, were .098 for atorvastatin arm and .513 for the placebo arm. Furthermore, regression coefficients did not statistically differ between the 2
arms (P ¼ .174). When taking into account the severity of ED (Table 3), no differences were evident between the study arms for ED of any grade. Noteworthy, IIEF-5 scores were higher in the statin arm compared with the placebo arm at 12 months after surgery in almost all analyses; however, the difference was not statistically significant. Taking into account baseline diabetes, hypertension, smoking, or duration of atorvastatin use did not modify the result (Table 4). The median difference in IIEF-5 scores between the arms 12 months after surgery was 1.6. When nerve sparing at prostatectomy was taken into account, atorvastatin treatment compared with placebo seemed to improve IIEF-5 scores at 12 months after surgery, when the nerves were at least partially intact bilaterally (P < .04) (Table 5). The trend was similar at other time points after surgery (Table 5). However, in patients in the statin arm with full bilateral or unilateral nerve-sparing surgery displayed no statistically significant beneficial effect in their IIEF-5 scores (Table 5). When the analysis was limited to men who had normal erectile function (IEEF-5 score more than 21) at the baseline and had full nerve-sparing at surgery, no significant difference was evident in postoperative erectile function between the arms (9.7 ± 2.2 vs 11.1 ± 2.3 atorvastatin vs placebo for 12 months after surgery). However, when subjects with nervesparing surgery and high intra-prostate inflammation were analyzed, atorvastatin use improved IIEF-5 scores (P ¼ .023) (Table 5).
Effects of Diabetes, Hypertension, and Smoking on Erectile Function At baseline, diabetic subjects’ median IIEF-5 scores were lower in comparison to their non-diabetic counterparts (15.9 ± 2 vs 19.7 ± 0.6; P ¼ .056). Hypertensive and non-hypertensive participants did not differ at the baseline, but unexpectedly, at 3 months after
Table 2. Amount of participants in different groups of erectile dysfunction based on the IIEF-5 scores Baseline IIEF-5 score 7 or less (severe erectile dysfunction) Statin, n (%) Placebo, n (%) IIEF-5 score 8e11 (moderate erectile dysfunction) Statin, n (%) Placebo, n (%) IIEF-5 score 12e16 (mild-moderate erectile dysfunction) Statin, n (%) Placebo, n (%) IIEF-5 score 17e21 (mild erectile dysfunction) Statin, n (%) Placebo, n (%) IIEF-5 score 22 (normal erectile function) Statin, n (%) Placebo, n (%)
3 months
6 months
9 months
12 months
4 (8) 2 (4)
40 (78) 44 (90)
33 (69) 37 (79)
33 (65) 36 (88)
30 (65) 36 (78)
4 (8) 3 (6)
2 (4) 2 (4)
4 (8) 3 (6)
6 (12) 1 (2)
3 (7) 3 (7)
6 (12) 7 (14)
4 (8) 2 (4)
5 (10) 4 (9)
3 (6) 5 (12)
6 (13) 2 (4)
15 (29) 15 (31)
3 (6) 2 (4)
5 (10) 3 (6)
3 (6) 2 (5)
3 (7) 3 (7)
22 (43) 22 (45)
2 (4) 1 (2)
1 (2)
3 (6) 0
4 (9) 2 (4)
0
IIEF-5 ¼ 5-item version of the International Index of Erectile Function. J Sex Med 2019;-:1e9
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Table 3. Effects of statin treatment on erectile functions measured using IIEF-5 questionnaire 3, 6, 9, and 12 months after radical prostatectomy in Finnish men Baseline Baseline IIEF-5 score All cases Statin Control >7 Statin Control >11 Statin Control >16 Statin Control >21 Statin Control
3 months
6 months
9 months
12 months
N IIEF-5 score P N IIEF-5 score P N IIEF-5 score P N IIEF-5 score P N IIEF-5 score P value (mean ± SEM) value value (mean ± SEM) value value (mean ± SEM) value value (mean ± SEM) value value (mean ± SEM) value .78 51 49
18.8 ± 0.9 19.6 ± 0.7
47 47
20 ± 0.7 20.1 ± 0.6
43 44
20.9 ± 0.6 20.8 ± 0.5
37 37
22 ± 0.4 22 ± 0.4
22 22
24 ± 0.2 23.6 ± 0.3
.63 51 49
7.7 ± 0.7 6.6 ± 0.6
41 38
8 ± 0.9 7 ± 0.7
39 36
8.2 ± 0.9 7.1 ± 0.8
33 30
8.8 ± 1 7.4 ± 0.6
20 17
8.3 ± 1.4 7.1 ± 1.1
.93
.96 48 47
8.2 ± 0.8 7.1 ± 0.5
36 38
7.7 ± 0.8 7.2 ± 0.6
34 35
7.5 ± 0.8 7.4 ± 0.6
28 29
8.1 ± 0.9 7.1 ± 0.7
16 19
8.3 ± 1.3 7.4 ± 0.9
.71
.77
39 33
7.4 ± 0.7 7.3 ± 0.7
36 30
7.6 ± 0.8 7.5 ± 0.8
31 25
8 ± 0.9 7.3 ± 0.7
18 16
8.8 ± 1.4 7.9 ± 1
9.3 ± 0.9 7.7 ± 0.8
35 37
8.2 ± 0.9 7.9 ± 0.9
33 34
7.9 ± 0.8 8.2 ± 0.9
28 30
8.5 ± 1 8.1 ± 1
16 17
9 ± 1.5 8.4 ± 1.5
.55
.74
.97
.61
.18 46 46
.77
.34
.41
.29
8.2 ± 0.8 7.2 ± 0.6
.49
.7
.84
.55 51 41
.84
.75
.94
.49
.86
.61
IIEF-5 ¼ 5-item version of the International Index of Erectile Function; SEM ¼ standard error of the mean.
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theoretical considerations to indicate that statins could be of value in conjunction with radical prostatectomies. In this study, we were unable to find evidence that preoperative statins can achieve overall significant improvements of postoperative erectile function. According to the power analysis, our sample size was sufficient to demonstrate an IIEF-5 score difference 3.6. Therefore, we cannot rule out smaller IIEF-5 differences. Notably, the median IIEF-5 score at 12 months was 1.6 points better in the atorvastatin arm compared with the placebo arm, suggesting a benefit by statin use that is too small to detect in this sample size. Therefore, larger studies are needed to confirm our findings. Figure 1. Distribution of IIEF-5 values at baseline and after prostatectomy in the atorvastatin arm and the placebo arm. P ¼ .513 in the placebo arm and P ¼ .098 in the atorvastatin arm. P ¼ .174 for regression comparison between the arms. Collums from left: baseline, 3, 6, 9, and 12 months' time points, respectively; IIEF-5 ¼ 5-item version of the International Index of Erectile Function. surgery, the hypertensive patients had higher IIEF-5 scores than their non-hypertensive counterparts (7.9 ± 0.8 vs 6.7 ± 0.6; P ¼ .015). Smokers and non-smokers had similar IIEF-5 scores at the baseline; however, at 3 months after surgery, non-smokers had a better recovery in their IIEF-5 scores (5.1 ± 0.1 vs. 7.5 ± 0.6, P ¼ .01). Similar trends with smoking were also seen at other time points, although differences were not statistically significant (5.4 ± 0.3 vs 8.0 ± 0.5 for 6 months, 6.2 ± 0.6 vs 8.1 ± 0.6 for 9 months, and 5.8 ± 0.4 vs 9.0 ± 0.7 for 12 months after the operation).
DISCUSSION ED is one of the main side effects encountered after radical prostatectomy; thus, it is important to devise new ways to avoid this problem. This study is the first that has evaluated the preoperative use of atorvastatin on erectile function after radical prostatectomy in a randomized setting. According to some publications10,19-21 but not all clinical studies,22,23 statin treatment may improve ED in men in general. In these studies, the daily doses of the statin have varied from 10 mg to 80 mg and the duration of the treatment from 6 weeks to 6 months. Some of the studies investigated the effects of statin treatment on erectile function among sildenafil nonresponders.10,19,21,24 In all of these studies, patients had ED, but none that was due to cavernous nerve damage after radical prostatectomy. Rather, the main pathophysiology has been cardiovascular disease, although in only 2 studies was either hypercholesterolemia specifically described19or endothelial dysfunction22 applied as an inclusion criterion. Thus, the patients in our study are not directly comparable to those in the above-mentioned publications. However, as described, there are
In the subgroup of patients with at least partially spared nerves bilaterally, the atorvastatin group did show better IIEF-5 scores at 12 months after surgery. Considering the size of the subgroup and the exploratory nature of our analyses, this cannot be taken as evidence of an actual effect. Nonetheless, it does indicate that an anti-inflammatory effect of statins may be of specific benefit in partially intact nerves. This seems intuitive because statins cannot be expected to restore the function of resected nerves, and, thus, further studies in this subgroup are justified. Furthermore, it is not known how long statins need to be administered to exhibit a significant anti-inflammatory response. In our study, the statin treatment was short term, that is, the median duration of use was 27 days. It may be that, to achieve anti-inflammatory response, which would protect nerves during surgery and improve the subsequent recovery, longer-term statin use may be needed. This hypothesis is supported by the finding that intraprostatic inflammation was quantified in our study population and found to be similar in both study arms.16 In a cell model involving microglial cells, statin use protected cells from nerve damage by decreasing the inflammatory response.14 However, we did not measure the inflammatory status of nervous tissue in this study; thus, the putative antiinflammatory effect of statin treatment on cavernous nerves will need to be confirmed. In addition, additional benefits of statin use could become evident by extending the dosing into the post-operative period, a hypothesis that could be evaluated in further clinical studies. Meanwhile, the statin dose in our study (80 mg daily) was high when compared with the average defined daily dose (20 mg daily) as listed by the World Health Organization25 for treatment of hypercholesterolemia or atherosclerosis, diseases for which they are usually prescribed. Thus, it is unclear whether average doses of statin could impact on the recovery of erectile function after prostatectomy. Diabetes is a known risk factor for ED in men.26 This can be seen also in our study: baseline IIEF-5 scores were lower among diabetic subjects than in non-diabetics. A similar phenomenon was not seen among smokers and non-smokers or between hypertensive and normotensive subjects at baseline. However, our study did not point to any specific benefits in these subgroups. Hypertensive subjects had higher IIEF-5 scores at 3 months from
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7
Atorvastatin and Erectile Function
Table 4. Effects of statin treatment on erectile function Baseline
3 months
12 months
IIEF-5 score P IIEF-5 score IIEF-5 score n-value (mean ± SEM) value n-value (mean ± SEM) P value n-value (mean ± SEM) P value Diabetic Statin 6 Control 6 Non-diabetic Statin 45 Control 42 Hypertensive Statin 21 Control 17 Non-hypertensive Statin 29 Control 31 Smokers Statin 12 Control 4 Non-smokers Statin 37 Control 44 Preoperative statin use 28 days Statin 22 Control 20 Preoperative statin use 27 days Statin 29 Control 28 Intra-prostate inflammation score >9 Statin 18 Control 19
.63
1
14.2 ± 3.5 17.7 ± 2
5 6
6.2 ± 0.8 5.8 ± 0.5
45 44
7.9 ± 0.8 6.7 ± 0.6
22 18
9.2 ± 1.3 6.2 ± 0.7
28 31
8.9 ± 1.2 6.8 ± 0.8
10 6
5 ± 0.1 5.2 ± 0.2
39 43
8.4 ± 0.9 6.8 ± 0.7
.73 19.4 ± 0.8 20 ± 0.8
7.1 ± 1.1 7.5 ± 1.2
.39
9.7 ± 1.4 7.2 ± 0.8
7 5
6.1 ± 0.7 5.4 ± 0.4
37 41
10.2 ± 1.1 8 ± 0.8
.29
.53
.2
.43 19 21
10.2 ± 1.6 7.5 ± 1.1
.25 28 33
8.1 ± 1 6.2 ± 0.6
.92 18.6 ± 1.6 19.9 ± 1.1
26 27
.44
.52 23 16
18.1 ± 1.1 19.5 ± 1
9 ± 1.3 8.4 ± 1.4
.41
.56 19.7 ± 1.3 10 ± 1
19 19
.1
.64
.35 18.2 ± 1.1 19.9 ± 0.8
9.6 ± 1 7.5 ± 0.8
.55
.32 20.1 ± 1.6 17.8 ± 3
42 40 .19
.54 18.6 ± 1.3 20.4 ± 0.9
6.3 ± 0.8 9±2
.6
.77 18.8 ± 1.1 18.4 ± 1.3
.32 4 6
.27 27 25
8.8 ± 1.1 7.9 ± 1.1
.52 19 18
8.2 ± 1.4 7.6 ± 1.4
.19 15 17
10.2 ± 1.9 6.8 ± 1
IIEF-5 ¼ 5-item version of the International Index of Erectile Function; SEM ¼ standard error of the mean. Participants stratified by comorbidities, by smoking, or by preoperative duration of study drug use or by intra-prostate inflammation score.
surgery, which was not seen at other time points. This may also be a random finding and will need to be confirmed in the future. Unfortunately, we did not have access to the blood pressure levels of the subjects, nor did we have information on which specific antihypertensive medications had been prescribed for the patients, meaning that no specific hypothesis can be constructed in this regard. Our study has some important strengths. First, it is a randomized, placebo-controlled double-blind study; thus, influence of background confounding factors was controlled in the study design. Compliance with the study intervention was documented to be high: 100% in the statin group and 97% in the placebo group. In addition, the compliance rate for completing the IIEF-5 questionnaire was high: 85% at baseline and 78% at 12 months after surgery. 65% of men filled out the
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IIEF-5 questionnaire both at baseline and at the 12-month time point. As a limitation, erectile function was not the primary endpoint for the trial, which was designed to detect a difference in prostate cancer biomarkers. This means that there was considerable variation in baseline erectile function and nervesparing. In addition, our study may be affected by a type 2 error, and especially in the subgroup analysis, the statistical power is low. Also, we only evaluated erectile function. Overall sexual function is impacted also by other aspects of sexuality, such as confidence and orgasmic function. Future studies should preferably use more sophisticated surveys measuring other aspects of sexuality to obtain a more comprehensive view on statins’ effects on sexuality preservation after radical prostatectomy.
8
Siltari et al
Table 5. Effects of statin treatment on erectile functions. Participants stratified by nerve-sparing after prostatectomy Baseline
3 months
12 months
IIEF-5 score P IIEF-5 score P IIEF-5 score P n-value (mean ± SEM) value n-value (mean ± SEM) value n-value (mean ± SEM) value Intact nerves both side Statin Control At least partial nerves on both side Statin Control At least partial nerves on 1 side Statin Control No intact nerves after surgery Statin Control At least partial nerves on both side and intra-prostate inflammation score >9 Statin Control
.74 18 15
20.1 ± 1.1 20.8 ± 1
34 37
20.4 ± 0.8 19.5 ± 0.9
9 10
19.9 ± 1.9 19.9 ± 1.4
8 2
10.8 ± 1.9 18.5 ± 3.5
.13 17 17
9.5 ± 1.4 6.9 ± 1.2
34 35
8.9 ± 1 6.8 ± 0.7
10 10
5.2 ± 0.1 6.5 ± 1.2
7 4
5 5.3 ± 0.3
.49
31 34
10.8 ± 1.2 8.2 ± 1
.04
.48
.18
.67 8 9
5.5 ± 0.2 6.7 ± 1.1
7 3
7.1 ± 2.1 5.3 ± 0.3
.53
.61
20.7 ± 1.6 20.4 ± 1.2
10.4 ± 1.7 9.9 ± 1.8
.17
.66
11 14
.45 16 16
.83
.29
11 12
10.4 ± 2.1 8.8 ± 2
.023
9 12
13.6 ± 3 7.3 ± 1.4
IIEF-5 ¼ 5-item version of the International Index of Erectile Function; SEM ¼ standard error of the mean.
CONCLUSION
STATEMENT OF AUTHORSHIP
Overall, we conclude that short-term atorvastatin treatment before radical prostatectomy conferred no significant benefit on the recovery of the erectile function in this unselected group of men. However, because the IIEF-5 scores were consistently higher, but not statistically significantly, in the statin arm, there may be effects in specific subgroups. Our results will need confirmation from larger trials, with postoperative erectile function as a main outcome, and the effects of extended postoperative statin use will need to be evaluated in other clinical studies.
Category 1
Corresponding Author: Aino Siltari, Tampere University, Faculty of Medicine and Health Technology, Arvo Ylpön katu 34, 33520 Tampere, Finland. Tel: þ358 29 412 5347; Fax: þ358 191 25364; E-mail: aino.siltari@helsinki.fi Conflicts of Interest: Dr. Siltari reports no conflicts of interest; Dr. Riikonen receives reimbursements for travel and conferences from Swanmedica, Astellas, and Ferring and trial participation from Astellas, Pfizer, Bayer, Orion, and Myovant; Dr. Fode receives consultant fees from Ferring Pharmacuticals and advisory board representative consultation fees and lecture fees for Astellas Pharma; Prof. Murtola receives consultation fees from Astellas, Ferring and Janssen and lecture fees from Astellas and Janssen. Funding: Funded by Expert Responsibility Area of the Pirkanmaa Hospital District (grant number 9X032) and Cancer Society of Finland (grant number 25024194).
(a) Conception and Design Mikkel Fode; Teemu J. Murtola (b) Acquisition of Data Jarno Riikonen; Teemu J. Murtola (c) Analysis and Interpretation of Data Aino Siltari; Teemu J. Murtola Category 2 (a) Drafting the Article Aino Siltari; Teemu J. Murtola (b) Revising It for Intellectual Content Jarno Riikonen; Mikkel Fode Category 3 (a) Final Approval of the Completed Article Aino Siltari; Jarno Riikonen; Mikkel Fode; Teemu J. Murtola
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