ORIGINAL PAPER
Severe obstructive sleep apnoea syndrome and erectile dysfunction: a prospective randomised study to compare sildenafil vs. nasal continuous positive airway pressure A. L. Pastore,1,2 G. Palleschi,1,2 A. Ripoli,1 L. Silvestri,1 C. Maggioni,1 G. Pagliuca,3 F. M. Nobili Benedetti,3 A. Gallo,3 A. Zucchi,4 A. Maurizi,5 E. Costantini,4 A. Carbone1,2
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SUMMARY
What’s known
Background: A high incidence of erectile dysfunction (ED) among patients with obstructive sleep apnoea syndrome (OSAS) has been reported, with a strong correlation between obstructive sleep apnoea, ED, and quality of life (QOL), and it has been estimated that 10–60% of patients with OSAS suffer from ED. In this prospective randomised controlled trial, we investigated 82 men with ED consecutively who were referred to the outpatient clinic for sleep disorders and had severe OSAS (AHI> 30 events/h) without any other comorbidities as a possible cause of ED. The aim of this study was to evaluate and compare the efficacy of sildenafil vs. continuous positive airway pressure (CPAP) in men with ED and severe OSAS. Methods: Eighty-two patients were randomised to two main treatment groups: group 1 patients (n = 41) were treated with 100-mg sildenafil 1 h before sexual intercourse without CPAP, and group 2 patients (n = 41 men) were treated with only nasal CPAP during night time sleep. Both groups were evaluated with the same questionnaires (International Index of Erectile Function-EF domain; Sex Encounter Profile; Erectile Dysfunction Inventory Treatment Satisfaction) 12 weeks after treatment. Results: In patients receiving sildenafil treatment, 58.2% of those who attempted sexual intercourses were successful compared to 30.4% in the CPAP group. The mean number of successful attempts per week was significantly higher in the sildenafil group compared with the CPAP group (2.9 vs. 1.7, respectively; p < 0.0001). The mean IIEF-EF domain scores were significantly higher in the sildenafil group compared with the CPAP group (p < 0.0001). The overall satisfaction rate was 68% with sildenafil treatment and 29% with CPAP treatment. Conclusions: This study confirms that severe OSAS is strongly associated with erectile dysfunction. CPAP and sildenafil (100 mg) are safe and effective therapies for OSAS-related ED patients. In the present study sildenafil was more effective than CPAP in treating ED associated with OSAS, as indicated by a significantly higher rate of successful attempts at intercourse and higher IIEF-EF domain scores. Our study, to date, is the only that has investigated sildenafil in patients with severe OSAS.
Background Obstructive sleep apnoea syndrome (OSAS) is defined as a repetitive upper airway occlusion, which causes snoring, repetitive episodes of upper airway occlusion causing hypoxaemia; sleep fragmentation, and excessive daytime sleepiness (1). Recent studies have reported that the prevalence of OSAS is high and continually increasing, with evidence that up to 10% men > 40 years of age are affected, and it is ª 2014 John Wiley & Sons Ltd Int J Clin Pract doi: 10.1111/ijcp.12463
A high incidence of erectile dysfunction among patients with obstructive sleep apnoea syndrome has been reported. It has been estimated that 10–60% of patients with OSAS suffer from ED. Continuous Positive Airway Pressure provided either in mild or severe OSAS showed significant improvement in erectile function in men with OSAS and ED. Sildenafil in men with ED and OSAS resulted effective and provided superior patient satisfaction compared to CPAP.
What’s new Our study is, to date, the only prospective randomised protocol that has investigated PDE5i in patients with severe OSAS. In order to collect only subjects with severe OSAS as the main cause of ED, patients with the most frequently ED-related comorbidities (e.g. blood hypertension and diabetes) were excluded. Overall satisfaction with treatment was significantly higher among the patients and partners under sildenafil than that in the CPAP group.
believed that the prevalence of clinically diagnosed OSAS is underestimated (2,3). Furthermore, several studies have reported a high incidence of erectile dysfunction (ED) among patients with OSAS and have reported a strong correlation between OSAS, ED, and quality of life (QOL). It has been estimated that 10–60% of patients with OSAS also suffer from ED (4,5). The exact mechanism through which OSAS causes ED remains unclear. Many theories have been postu-
Department of Medico-Surgical Sciences and Biotechnologies, Urology Unit ICOT, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Latina, Italy 2 Uroresearch Association (nonprofit research), Latina, Italy 3 Department of Medico-Surgical Sciences and Biotechnologies, ENT Section, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Terracina, Italy 4 Department of Urology, University of Perugia, Perugia, Italy 5 Department of Urology, Molinette Central Hospital, Turin, Italy Correspondence to: Antonio Luigi Pastore, MD, PhD, Department of Medico-Surgical Sciences and Biotechnologies, Urology Unit, ICOT, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Via Franco Faggiana 1668, Latina 04100, Italy Tel.: + 39 3401 138 648 Fax: + 39 0773 651 3333 Email: [email protected]
Disclosures All authors certify that there are no conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g., employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending).
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Severe obstructive sleep aponea syndrome and erectile dysfunction
lated, with Margel et al. suggesting that the respiratory disturbance index was a predictive factor for ED in patients with severe OSAS (6). An early sign of sacral segment nerve involvement in causing ED has also been described by Fanfulla et al. in patients with OSAS (7). Alternatively, rapid-eye-movement (REM) sleep is often fragmented in patients with depression and OSAS, which in turn can lead to ED (8). Any disorder that alters the REM sleep pattern may also be implicated in producing an erectile dysfunction pattern. Other described factors present in patients with OSAS and ED include: an increased sympathetic tone, endothelial dysfunction and intermittent hypoxia. However, the exact underlying mechanisms have yet to be established. The effectiveness of shortterm and long-term continuous positive airway pressure (CPAP) treatment has shown to improve ED in OSAS patients (9,10). CPAP treatment involves the use of positive pressure to maintain a continuous level of positive airway pressure in a spontaneously breathing patient using a specific machine. Previous studies by Perimenis et al. (11,12) compared sildenafil, a selective phosphodiesterase 5 inhibitor (PDE5i), vs. CPAP for the treatment of ED in men with OSAS and found that both therapeutic methods were safe and effective, although sildenafil resulted in superior patient satisfaction. The same group conducted another study using the combination of sildenafil and CPAP and reported that the combination of treatments gave a greater efficacy than with PDE5i alone (12). In this prospective, randomised study, we investigated 82 men with ED who had been referred to the outpatient clinic for sleep disorders and had severe OSAS, without any other comorbidities that could represent a possible cause of ED. The aims of this study were to evaluate and compare the efficacy of sildenafil vs. CPAP in men with erectile dysfunction (ED) and severe OSAS and to evaluate and compare the rates of successful intercourse attempts, IIEF-EF scores and satisfaction with the treatment regimen for patients with ED treated with 100 mg sildenafil vs. nasal CPAP.
Methods Study design This prospective, randomised clinical study included 82 men who had been referred to the outpatient clinic for sleep disorders between January 2011 and February 2012. All men presented with ED and were proven to suffer from OSAS. The study was performed according to the WMA Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects (World Medical Association, The Declaration of Helsinki Principles, 2000).
Local ethical committee approval was obtained (ASL Lt/no.12985674/2012), and written informed consent was obtained from all patients. We included patients with severe OSAS, that is, those who had a apnoea/hypopnoea index (AHI) of more than 30 events/h, as evidenced by a full polysomnography performed no later than 6 months from the start of the treatment. Exclusion criteria included patients with ED treated with medication or intracavernous injections, blood hypertension (systolic blood pressure above 160 mmHg; diastolic blood pressure above 100 mmHg), use of nitrates, diabetes mellitus, vascular diseases (deep vein thrombosis, peripheral vascular disease, Raynaud’s disease, vasculitis syndromes), mild and moderate OSAS (AHI less than 30 events per hour), peripheral neuropathic disease, prostate cancer, pelvic trauma history, renal transplantation, aortic aneurysm, spinal cord injury, a body mass index (weight kg/height m2) greater than 30 kg/m2, endocrine disturbances, penile deformity, current alcohol or drug abuse, or medications that could affect erection such as beta blockers or H2 blockers. A total of 103 patients were screened for participation in the study, and of these, 82 were enrolled and randomised in two treatment groups. Twenty-five patients not included in the study were excluded for their mild grade of OSAS (9/25 patients), which was not in accordance with the selection study criteria, while the remaining patients were not included because of presence of concomitant comorbidities (seven had diabetes mellitus and a BMI > 30, seven had blood hypertension, and two were receiving treatment with b- blockers). Randomisation (after a stratified randomisation to control all the baseline covariates between the two study arms) was made using a computer table generation of random numbers. Group 1 (n = 41 men) was treated with 100 mg sildenafil 1 h before sexual intercourse without CPAP, and group 2 (n = 41 men) was treated with only nasal CPAP during night-time sleep. Both groups were evaluated with the same questionnaires after 3 months of treatment. All patients were investigated using the validated abridged version of the 15-item International Index of Erectile Function (IIEF-5 or Sexual Health Inventory for Men) questionnaire (13). Assessment of ED was performed by completion of the erectile function domain of the IIEF-5 questionnaire (questions 1–5 and 15) (Q1–Q5, Q15). These questions included the following information: Q1: the patient’s ability to achieve an erection; Q2: the frequency of erections that were hard enough for achieve penetration; Q3: the frequency of penetration; Q4: the frequency of maintained erection; Q5: ª 2014 John Wiley & Sons Ltd Int J Clin Pract
Severe obstructive sleep aponea syndrome and erectile dysfunction
the chance of maintaining an erection until completion; Q15: the self-confidence to achieve and maintain an erection. Each question was scored on a scale of 1–5, with 1 representing the worst score and 5 the best. The questionnaire was self-administered prior to commencing sildenafil or CPAP treatment and was repeated every 4 weeks with ongoing therapies. All patients were tested for a hormonal profile, which including levels of testosterone, prolactin, thyroid function, follicle-stimulating hormone, luteinizing hormone and sex hormone-binding globulin. Each enrolled patient was required to be in a stable relationship for at least 6 months and to engage in sexual intercourse once a week or more often. The patients were also instructed to record information regarding the success of the attempt at intercourse in a standardised event-log (SEP – Sexual Encounter Profile; SEP Q3 ‘did your erection last long enough for you to have a successful intercourse?’ [Yes/no] immediately after intercourse). Men were regularly assessed every 4 weeks and finally evaluated in detail at the end of treatment period where they completed an IIEF-EF domain form, and both the patient and his partner replied to the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) question 1: ‘Overall, how satisfied are you with this treatment?’ (14).
Statistical analysis Statistical analysis was performed using the statistical package SPSS⁄10.0 (SPSS, Chicago, IL), using a t-test student analysis. All p-values were two-tailed, and a result was considered statistically significant if it was less than 0.05 (p ≤ 0.05).
Polysomnography All patients were monitored for two consecutive nights for the OSAS diagnosis and for one additional night for therapeutic titration by polysomnography (Embla S7000 Polysomnograph; Embla, Broomfield, CO 80021, USA). Bedtime was based on each patient’s habits. At least seven hours of recording time per night were obtained. During recording, surface electrodes were placed on the patient to obtain an electroencephalogram (at positions C3/A2, C4/A1, O1/A2, and O2/A1); a bilateral electrooculogram; a chin, intercostal and bilateral anterior tibialis electromyogram; and an electrocardiogram. Respiration was monitored by measurement of the following: airflow measurement using a nasal cannula/pressure transducer system and a mouth thermocouple; chest and abdominal efforts were measured using uncalibrated respiratory plethysmographic belts; arterial oxygen saturation (SaO2) was measured with pulse-oximetry; snoring sounds were measured using a neck microphone; and body movements were measured with a ª 2014 John Wiley & Sons Ltd Int J Clin Pract
mercury gauge. Sleep stages and events were scored manually according to standard criteria (15). Apnoea was defined as the complete cessation of airflow for at least 10 s, and hypopnea as the reduction in airflow of at least 50% for ≥10 s or a reduction in breathing of less than 50% associated with a 3% desaturation of oxyhaemoglobin. The number of apnoea and hypopnea episodes per hour of sleep is called ‘apnea/hypopnea index’ (AHI). Patients with an AHI of more than 30 were designated as patients with severe OSAS and enrolled for the study (15).
Results Eighty-two patients were prospectively randomised to the 100 mg sildenafil (n = 41) or the CPAP (n = 41) treatment groups. Treatment groups were similar with regard to demographical characteristics (Table 1) and in severity of OSAS, with patient age ranging 38–59 years, and all had a body mass index of less than 30 kg/m2. Baseline mean scores for the erectile function domain of the IIEF were similar for patients randomised to sildenafil or CPAP (7.8 vs. 7.4, respectively; p = 0.5848). In the sildenafil group, 312/536 (58.2%) of attempted intercourses were successful compared with 156/512 (30.4%) in the CPAP group (Figure 1). The number of attempts reported by patients using sildenafil was slightly higher than patients using CPAP (mean: 13.0 vs. 12.4; p = 0.1995) and had a significant higher successful intercourse report (mean: 7.6 and 3.8; p < 0.0001). Moreover, the mean number of successful attempts per week was 2.9 in the sildenafil group, which was significantly higher than the 1.7 successful attempts per week in the CPAP group (p < 0.0001). The mean IIEF-EF domain scores were significantly increased in both groups compared with baseline (18.3 vs. 7.8, p < 0.0001 in the sildenafil group; and 11.7 vs. 7.4, p < 0.0001 in the CPAP group). When the mean IIEF-EF domain scores were compared, a significantly higher score was reported in sildenafil treatment group than the CPAP group (p < 0.0001). Overall, 12 of 41 men (29%) were satisfied with CPAP treatment for ED, whereas 28 of 41 men (68%) were satisfied with sildenafil. Satisfaction with treatment was significantly higher among the patients under sildenafil than that in the CPAP group (p = 0.0015). The corresponding partners’ reports confirmed these data satisfaction rates and were equal to those reported by the patients (29% with CPAP and 68% with sildenafil). Therapeutic satisfaction was clearly superior among partners of sildenafil-treated patients compared with partners of the CPAP group (p = 0.0006). The analytical assessment of the answers provided to EDITS Q1 from patients
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and their partners revealed that partners gave a different evaluation of treatment satisfaction. However, this difference was not statistically significant, and the satisfaction scores reported by patients and partners with sildenafil treatment were significantly higher than those in the CPAP group (Table 2).
Discussion In the literature, there is strong evidence suggesting a high incidence of ED among patients with OSAS (4,5). The most widely accepted theory is that OSAS -related ED is because of the coordination of hypoxic episodes, which are very common in cases with sleep apnoea and arousal-related hyperadrenergic reactions (7). This reduces circulating nitric oxide levels with a consequential increase in vasoconstriction and impairment of the vascular endothelial cells function, and this basic neurovascular event causes ED (16). Moreover, Goncalves et al. (17.) reported that a high percentage of patients with OSAS and ED have a low SaO2 (< 80%). In their study, severe ED was seen as the SaO2 percentage decreased. Taskin et al. reported a worsening of patient psychology as AHI increased (9). Thus, patients became depressive, which in turn resulted in ED. However, it was not clear whether ED was only because of psychological problems in the OSAS cases. Several studies have evaluated the efficacy of CPAP treatment on OSAS-associated ED (6,9,10,17). CPAP provided either in mild or severe OSAS cases has demonstrated a significant improvement in erectile function in men with OSAS and ED (10,17). Studies on long (12 week therapy) and short-term CPAP therapies have reported an erectile function improvement in OSAS-related ED (11,18). The effectiveness of CPAP is believed to be related to an increase in circulating nitric oxide levels resulting in an improvement in endothelial function (16). A study by Taskin et al. reported that CPAP treatment of patients with OSAS
and ED resulted in a gradual improvement in IIEF-5 scores, and the symptoms of ED diminished after treatment (9). Treatment of ED in patients with OSAS is still controversial and varies according to its main aetiology; however, the cause of OSAS-related ED remains unclear. Consequently, without defining the cause of ED, many drugs such as sildenafil have been used for treatment. Rozenblatt and colleagues, although could not clarify the mechanisms responsible, reported that treatment with 50-mg sildenafil interfered with the compensatory mechanisms in patients with OSAS, increasing the frequency and duration of respiratory desaturation events (19). Perimenis et al. reported the use of sildenafil with CPAP, showing that the efficacy of this combination was superior to sildenafil alone; however, approximately one-third of the patients studied remained dissatisfied even with this combination of treatments (12). In our study, we investigated only patients with severe OSASs and ED. Since our purpose was to study patients with ED secondary to severe OSAS only, a strict enrolment selection process was performed. To collect only subjects with severe OSAS as the main cause of ED, patients with the most frequently ED-related comorbidities (e.g. blood hypertension and diabetes) were excluded. CPAP therapy has been advised routinely in several reported case series. Patel et al. reported that patients treated with CPAP demonstrated significant improvement in the objective and subjective measures of sleepiness in patients with OSAS with ED (20). Whether this improvement was because of the CPAP effectiveness or because all patients had severe OSAS, it remains unclear. In the study by Perimenis et al., sildenafil increased CPAP effectiveness in patients with mild OSAS compared with CPAP alone (12). Our study is, to date, the only protocol that has investigated PDE5i in patients with severe OSAS. This study confirms that severe OSAS is strongly
Table 1 Baseline variables of enrolled population
Sildenafil group (n = 41)
Age (years) BMI (kg/m2) AHI (events/h) TST (min) Lowest SaO2(%) Mean SaO2(%) IIEF-EF domain score
47.4 25.5 46.9 456.6 85.6 92.8 7.8
9.8 4.1 14.5 34.9 8.2 3.2 1.2
CPAP group (n = 41)
48.6 25.8 47.3 457.1 85.9 91.9 7.4
8.5 3.8 14.9 35.6 8.6 2.9 1.4
p-value
ns ns ns ns ns ns ns
(p (p (p (p (p (p (p
= = = = = = =
0.5553) 0.732) 0.9023) 0.949) 0.872) 0.1858) 0.5848)
BMI, body mass index; AHI, apnoea/hypopnea index; TST, total sleep time; IIEF-EF, International Index of Erectile Function-Erectile Function.
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Severe obstructive sleep aponea syndrome and erectile dysfunction
Table 2 Mean values or scores ( SD) reported in the two treatment groups
Sildenafil (n = 41)
No. of successful attempts No. of successful attempts per week IIEF-EF domain scores EDITS – Q 1 patient scores EDITS – Q 1 partner scores
7.6 2.9 18.3 3.5 3.4
1.6 0.8 4.9 1.6 1.3
CPAP (n = 41)
3.8 1.7 11.7 2.3 2.2
1.7 0.6 3.7 1.7 1.3
p-value
< 0.0001 < 0.0001 < 0.0001 0.0015 0.0006
IIEF-EF, International Index of Erectile Function-Erectile Function; EDITS-Q1, Erectile Dysfunction Inventory of treatment satisfactionquestion 1.
Attempted intercourses Total attemps Successeful attemps
600
400
even with this more effective treatment. These data suggest that there is still no specific treatment for ED-related OSAS and combination therapy (CPAP and sildenafil), as previously reported in the literature (12), does not appear to achieve significantly higher satisfaction rates. We conclude that a different therapeutic mode should be studied further.
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Conclusions 0
Sidenafil
CPAP
Figure 1 Profile of attempts for sexual intercourses in men with severe obstructed sleep apnoea syndrome and erectile dysfunction treated with Sildenafil or Continuous Positive Airway Pressure (CPAP).
associated with ED as previously reported by Margel et al. (4). In our study, we reported a high overall response rate to 100-mg sildenafil treatment compared with those reported in the previous studies in the literature (11,12,21). The encouraging results obtained in our study are correlated with the selection of enrolled patients, which provided strict exclusion criteria. The high response rate to sildenafil may be because of the exclusion of major diseases responsible for ED, such as hypertension, diabetes mellitus, peripheral vascular, neuropathic disease, prostate cancer, spinal cord injury, endocrine disturbances, current alcohol or drug abuse and medications, which could affect erectile function. The direct smooth muscle relaxation in the penile arteries and corpora cavernosa achieved by sildenafil may explain the higher effectiveness of this treatment compared with CPAP, and this efficacy may therefore explain the greater number of intercourse attempts, reflecting the patients strengthened self-confidence. Even though overall satisfaction with treatment was significantly higher among the patients under sildenafil than that in the CPAP group, approximately one-third (32%) of patients were not satisfied ª 2014 John Wiley & Sons Ltd Int J Clin Pract
This study represents the first trial that has investigated sildenafil in patients with ED related to severe OSAS only. CPAP and 100-mg sildenafil are both safe and effective therapies in the treatment of OSASrelated ED patients. In this study, sildenafil proved to be more effective in treating ED than CPAP as it resulted in a significantly higher rate of successful attempts of intercourse and higher IIEF-EF domain scores. Moreover, we reported a high overall response rate to sildenafil treatment compared with that reported in previous studies in the literature, possibly because of very strict exclusion criteria for patient enrolment that excluded all other aetiologies of ED.
Acknowledgements The patients and their partners are thanked for their willingness to participate.
Funding This study was not supported by any Foundation
Authors contributions ALP, GP, AC, EC and AG designed and ideated the study. FNB, GP, AG performed the polysomnography studies. AF, CM, LS collected all the study’s data. ALP, GP and GP drafted the manuscript. All the authors read and approved the final version of the manuscript.
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References 1 Malhotra A, White DP. Obstructive sleep apnoea. Lancet 2002; 360: 237–45. 2 Pagel JF. The burden of obstructive sleep apnea and associated excessive sleepiness. J Fam Pract 2008; 57(Suppl. 8): S3–8. 3 Kapur V, Strohl KP, Redline S, Iber C, O’Connor G, Nieto J. Underdiagnosis of sleep apnea syndrome in U.S. communities. Sleep Breath. 2002; 6: 49–54. 4 Margel D, Cohen M, Livne PM, Pillar G. Severe, but not mild, obstructive sleep apnea syndrome is associated with erectile dysfunction. Urology 2004; 63: 545–9. 5 Shin HW, Rha YC, Han DH et al. Erectile dysfunction and disease-specific quality of life in patients with obstructive sleep apnea. Int J Impot Res. 2008; 20: 549–53. 7 6 Margel D, Tal R, Livne PM, Pillar G. Predictors of erectile function improvement in obstructive sleep apnea patients with long-term CPAP treatment. Int J Impot Res 2005; 17: 186–90. 7 Fanfulla F, Malaguti S, Montagna T et al. Erectile dysfunction in men with obstructive sleep apnea: an early sign of nerve involvement. Sleep 2000; 23: 775–81. 8 Hirshkowitz M, Schmidt HM. Sleep-related erections: clinical perspectives and neural mechanisms. Sleep Med Rev 2005; 9: 311–29.
9 Taskin U, Yigit O, Acioglu E, Aricigil M, Toktas G, Guzelhan Y. Erectile dysfunction in severe sleep apnea patients and response to CPAP. Int J Impot Res 2010 Mar; 22: 134–9. 10 Karkoulias K, Perimenis P, Charokopos N et al. Does CPAP therapy improve erectile dysfunction in patients with obstructive sleep apnea syndrome? Clin Ter 2007; 158: 515–8. 11 Perimenis P, Karkoulias K, Markou S et al. Erectile dysfunction in men with obstructive sleep apnea syndrome: a randomized study of the efficacy of sildenafil and continuous positive airway pressure. Int J Impot Res 2004; 16: 256–60. 12 Perimenis P, Konstantinopoulos A, Karkoulias K, Markou S, Perimeni P, Spyropoulos K. Sildenafil combined with continuous positive airway pressure for treatment of erectile dysfunction in men with obstructive sleep apnea. Int Urol Nephrol 2007; 39: 547–52. 13 Rosen RC, Riley A, Wagner G et al. The International Index of Erectile Dysfunction (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: 822–30. 14 Althof SE, Corty EW, Levine SB et al. EDITS: development of questionnaires for evaluating satisfaction with treatment for erectile dysfunction. Urology 1999; 53: 793–9. 15 American Academy of Sleep Medicine Task force. Sleep related breathing disorders in adults: recommendations for syndrome definition and measure-
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ments techniques in clinical research. Sleep 1999; 22: 667–89. Ip MS, Lam B, Chan LY et al. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care 2000; 162: 2166–71. Goncalves MA, Guilleminault C, Ramos E, Palha A, Paiva T. Erectile dysfunction, obstructive sleep apnea syndrome and nasal CPAP treatment. Sleep Med 2005; 6: 333–9. Karacan I, Karatas M. Erectile dysfunction in sleep apnea and response to CPAP. J Sex Marital Ther 1995; 21: 239–47. Roizenblatt S, Guilleminault C, Poyars D, Cintra F, Kauati A, Tufik S. A double blind, placebo controlled, crossover study of sildenafil in obstructive sleep apnea. Arch Intern Med 2006; 166: 1763–7. Patel SR, White DP, Malhotra A, Stanchina ML, Ayas NT. Continuous positive airway pressure therapy for treating sleepiness in a diverse population with obstructive sleep apnea: results of a metaanalysis. Arch Intern Med 2003; 163: 565–71. Li X, Dong Z, Wan Y, Wang Z. Sildenafil versus continuous positive airway pressure for erectile dysfunction in men with obstructive sleep apnea: a meta-analysis. Aging Male 2010; 13: 82–6.
Paper received January 2014, accepted April 2014
ª 2014 John Wiley & Sons Ltd Int J Clin Pract
Severe obstructive sleep apnoea syndrome and erectile dysfunction: a prospective randomised study to compare sildenafil vs. nasal continuous positive airway pressure A. L. Pastore,1,2 G. Palleschi,1,2 A. Ripoli,1 L. Silvestri,1 C. Maggioni,1 G. Pagliuca,3 F. M. Nobili Benedetti,3 A. Gallo,3 A. Zucchi,4 A. Maurizi,5 E. Costantini,4 A. Carbone1,2
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SUMMARY
What’s known
Background: A high incidence of erectile dysfunction (ED) among patients with obstructive sleep apnoea syndrome (OSAS) has been reported, with a strong correlation between obstructive sleep apnoea, ED, and quality of life (QOL), and it has been estimated that 10–60% of patients with OSAS suffer from ED. In this prospective randomised controlled trial, we investigated 82 men with ED consecutively who were referred to the outpatient clinic for sleep disorders and had severe OSAS (AHI> 30 events/h) without any other comorbidities as a possible cause of ED. The aim of this study was to evaluate and compare the efficacy of sildenafil vs. continuous positive airway pressure (CPAP) in men with ED and severe OSAS. Methods: Eighty-two patients were randomised to two main treatment groups: group 1 patients (n = 41) were treated with 100-mg sildenafil 1 h before sexual intercourse without CPAP, and group 2 patients (n = 41 men) were treated with only nasal CPAP during night time sleep. Both groups were evaluated with the same questionnaires (International Index of Erectile Function-EF domain; Sex Encounter Profile; Erectile Dysfunction Inventory Treatment Satisfaction) 12 weeks after treatment. Results: In patients receiving sildenafil treatment, 58.2% of those who attempted sexual intercourses were successful compared to 30.4% in the CPAP group. The mean number of successful attempts per week was significantly higher in the sildenafil group compared with the CPAP group (2.9 vs. 1.7, respectively; p < 0.0001). The mean IIEF-EF domain scores were significantly higher in the sildenafil group compared with the CPAP group (p < 0.0001). The overall satisfaction rate was 68% with sildenafil treatment and 29% with CPAP treatment. Conclusions: This study confirms that severe OSAS is strongly associated with erectile dysfunction. CPAP and sildenafil (100 mg) are safe and effective therapies for OSAS-related ED patients. In the present study sildenafil was more effective than CPAP in treating ED associated with OSAS, as indicated by a significantly higher rate of successful attempts at intercourse and higher IIEF-EF domain scores. Our study, to date, is the only that has investigated sildenafil in patients with severe OSAS.
Background Obstructive sleep apnoea syndrome (OSAS) is defined as a repetitive upper airway occlusion, which causes snoring, repetitive episodes of upper airway occlusion causing hypoxaemia; sleep fragmentation, and excessive daytime sleepiness (1). Recent studies have reported that the prevalence of OSAS is high and continually increasing, with evidence that up to 10% men > 40 years of age are affected, and it is ª 2014 John Wiley & Sons Ltd Int J Clin Pract doi: 10.1111/ijcp.12463
A high incidence of erectile dysfunction among patients with obstructive sleep apnoea syndrome has been reported. It has been estimated that 10–60% of patients with OSAS suffer from ED. Continuous Positive Airway Pressure provided either in mild or severe OSAS showed significant improvement in erectile function in men with OSAS and ED. Sildenafil in men with ED and OSAS resulted effective and provided superior patient satisfaction compared to CPAP.
What’s new Our study is, to date, the only prospective randomised protocol that has investigated PDE5i in patients with severe OSAS. In order to collect only subjects with severe OSAS as the main cause of ED, patients with the most frequently ED-related comorbidities (e.g. blood hypertension and diabetes) were excluded. Overall satisfaction with treatment was significantly higher among the patients and partners under sildenafil than that in the CPAP group.
believed that the prevalence of clinically diagnosed OSAS is underestimated (2,3). Furthermore, several studies have reported a high incidence of erectile dysfunction (ED) among patients with OSAS and have reported a strong correlation between OSAS, ED, and quality of life (QOL). It has been estimated that 10–60% of patients with OSAS also suffer from ED (4,5). The exact mechanism through which OSAS causes ED remains unclear. Many theories have been postu-
Department of Medico-Surgical Sciences and Biotechnologies, Urology Unit ICOT, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Latina, Italy 2 Uroresearch Association (nonprofit research), Latina, Italy 3 Department of Medico-Surgical Sciences and Biotechnologies, ENT Section, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Terracina, Italy 4 Department of Urology, University of Perugia, Perugia, Italy 5 Department of Urology, Molinette Central Hospital, Turin, Italy Correspondence to: Antonio Luigi Pastore, MD, PhD, Department of Medico-Surgical Sciences and Biotechnologies, Urology Unit, ICOT, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Via Franco Faggiana 1668, Latina 04100, Italy Tel.: + 39 3401 138 648 Fax: + 39 0773 651 3333 Email: [email protected]
Disclosures All authors certify that there are no conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g., employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending).
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Severe obstructive sleep aponea syndrome and erectile dysfunction
lated, with Margel et al. suggesting that the respiratory disturbance index was a predictive factor for ED in patients with severe OSAS (6). An early sign of sacral segment nerve involvement in causing ED has also been described by Fanfulla et al. in patients with OSAS (7). Alternatively, rapid-eye-movement (REM) sleep is often fragmented in patients with depression and OSAS, which in turn can lead to ED (8). Any disorder that alters the REM sleep pattern may also be implicated in producing an erectile dysfunction pattern. Other described factors present in patients with OSAS and ED include: an increased sympathetic tone, endothelial dysfunction and intermittent hypoxia. However, the exact underlying mechanisms have yet to be established. The effectiveness of shortterm and long-term continuous positive airway pressure (CPAP) treatment has shown to improve ED in OSAS patients (9,10). CPAP treatment involves the use of positive pressure to maintain a continuous level of positive airway pressure in a spontaneously breathing patient using a specific machine. Previous studies by Perimenis et al. (11,12) compared sildenafil, a selective phosphodiesterase 5 inhibitor (PDE5i), vs. CPAP for the treatment of ED in men with OSAS and found that both therapeutic methods were safe and effective, although sildenafil resulted in superior patient satisfaction. The same group conducted another study using the combination of sildenafil and CPAP and reported that the combination of treatments gave a greater efficacy than with PDE5i alone (12). In this prospective, randomised study, we investigated 82 men with ED who had been referred to the outpatient clinic for sleep disorders and had severe OSAS, without any other comorbidities that could represent a possible cause of ED. The aims of this study were to evaluate and compare the efficacy of sildenafil vs. CPAP in men with erectile dysfunction (ED) and severe OSAS and to evaluate and compare the rates of successful intercourse attempts, IIEF-EF scores and satisfaction with the treatment regimen for patients with ED treated with 100 mg sildenafil vs. nasal CPAP.
Methods Study design This prospective, randomised clinical study included 82 men who had been referred to the outpatient clinic for sleep disorders between January 2011 and February 2012. All men presented with ED and were proven to suffer from OSAS. The study was performed according to the WMA Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects (World Medical Association, The Declaration of Helsinki Principles, 2000).
Local ethical committee approval was obtained (ASL Lt/no.12985674/2012), and written informed consent was obtained from all patients. We included patients with severe OSAS, that is, those who had a apnoea/hypopnoea index (AHI) of more than 30 events/h, as evidenced by a full polysomnography performed no later than 6 months from the start of the treatment. Exclusion criteria included patients with ED treated with medication or intracavernous injections, blood hypertension (systolic blood pressure above 160 mmHg; diastolic blood pressure above 100 mmHg), use of nitrates, diabetes mellitus, vascular diseases (deep vein thrombosis, peripheral vascular disease, Raynaud’s disease, vasculitis syndromes), mild and moderate OSAS (AHI less than 30 events per hour), peripheral neuropathic disease, prostate cancer, pelvic trauma history, renal transplantation, aortic aneurysm, spinal cord injury, a body mass index (weight kg/height m2) greater than 30 kg/m2, endocrine disturbances, penile deformity, current alcohol or drug abuse, or medications that could affect erection such as beta blockers or H2 blockers. A total of 103 patients were screened for participation in the study, and of these, 82 were enrolled and randomised in two treatment groups. Twenty-five patients not included in the study were excluded for their mild grade of OSAS (9/25 patients), which was not in accordance with the selection study criteria, while the remaining patients were not included because of presence of concomitant comorbidities (seven had diabetes mellitus and a BMI > 30, seven had blood hypertension, and two were receiving treatment with b- blockers). Randomisation (after a stratified randomisation to control all the baseline covariates between the two study arms) was made using a computer table generation of random numbers. Group 1 (n = 41 men) was treated with 100 mg sildenafil 1 h before sexual intercourse without CPAP, and group 2 (n = 41 men) was treated with only nasal CPAP during night-time sleep. Both groups were evaluated with the same questionnaires after 3 months of treatment. All patients were investigated using the validated abridged version of the 15-item International Index of Erectile Function (IIEF-5 or Sexual Health Inventory for Men) questionnaire (13). Assessment of ED was performed by completion of the erectile function domain of the IIEF-5 questionnaire (questions 1–5 and 15) (Q1–Q5, Q15). These questions included the following information: Q1: the patient’s ability to achieve an erection; Q2: the frequency of erections that were hard enough for achieve penetration; Q3: the frequency of penetration; Q4: the frequency of maintained erection; Q5: ª 2014 John Wiley & Sons Ltd Int J Clin Pract
Severe obstructive sleep aponea syndrome and erectile dysfunction
the chance of maintaining an erection until completion; Q15: the self-confidence to achieve and maintain an erection. Each question was scored on a scale of 1–5, with 1 representing the worst score and 5 the best. The questionnaire was self-administered prior to commencing sildenafil or CPAP treatment and was repeated every 4 weeks with ongoing therapies. All patients were tested for a hormonal profile, which including levels of testosterone, prolactin, thyroid function, follicle-stimulating hormone, luteinizing hormone and sex hormone-binding globulin. Each enrolled patient was required to be in a stable relationship for at least 6 months and to engage in sexual intercourse once a week or more often. The patients were also instructed to record information regarding the success of the attempt at intercourse in a standardised event-log (SEP – Sexual Encounter Profile; SEP Q3 ‘did your erection last long enough for you to have a successful intercourse?’ [Yes/no] immediately after intercourse). Men were regularly assessed every 4 weeks and finally evaluated in detail at the end of treatment period where they completed an IIEF-EF domain form, and both the patient and his partner replied to the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) question 1: ‘Overall, how satisfied are you with this treatment?’ (14).
Statistical analysis Statistical analysis was performed using the statistical package SPSS⁄10.0 (SPSS, Chicago, IL), using a t-test student analysis. All p-values were two-tailed, and a result was considered statistically significant if it was less than 0.05 (p ≤ 0.05).
Polysomnography All patients were monitored for two consecutive nights for the OSAS diagnosis and for one additional night for therapeutic titration by polysomnography (Embla S7000 Polysomnograph; Embla, Broomfield, CO 80021, USA). Bedtime was based on each patient’s habits. At least seven hours of recording time per night were obtained. During recording, surface electrodes were placed on the patient to obtain an electroencephalogram (at positions C3/A2, C4/A1, O1/A2, and O2/A1); a bilateral electrooculogram; a chin, intercostal and bilateral anterior tibialis electromyogram; and an electrocardiogram. Respiration was monitored by measurement of the following: airflow measurement using a nasal cannula/pressure transducer system and a mouth thermocouple; chest and abdominal efforts were measured using uncalibrated respiratory plethysmographic belts; arterial oxygen saturation (SaO2) was measured with pulse-oximetry; snoring sounds were measured using a neck microphone; and body movements were measured with a ª 2014 John Wiley & Sons Ltd Int J Clin Pract
mercury gauge. Sleep stages and events were scored manually according to standard criteria (15). Apnoea was defined as the complete cessation of airflow for at least 10 s, and hypopnea as the reduction in airflow of at least 50% for ≥10 s or a reduction in breathing of less than 50% associated with a 3% desaturation of oxyhaemoglobin. The number of apnoea and hypopnea episodes per hour of sleep is called ‘apnea/hypopnea index’ (AHI). Patients with an AHI of more than 30 were designated as patients with severe OSAS and enrolled for the study (15).
Results Eighty-two patients were prospectively randomised to the 100 mg sildenafil (n = 41) or the CPAP (n = 41) treatment groups. Treatment groups were similar with regard to demographical characteristics (Table 1) and in severity of OSAS, with patient age ranging 38–59 years, and all had a body mass index of less than 30 kg/m2. Baseline mean scores for the erectile function domain of the IIEF were similar for patients randomised to sildenafil or CPAP (7.8 vs. 7.4, respectively; p = 0.5848). In the sildenafil group, 312/536 (58.2%) of attempted intercourses were successful compared with 156/512 (30.4%) in the CPAP group (Figure 1). The number of attempts reported by patients using sildenafil was slightly higher than patients using CPAP (mean: 13.0 vs. 12.4; p = 0.1995) and had a significant higher successful intercourse report (mean: 7.6 and 3.8; p < 0.0001). Moreover, the mean number of successful attempts per week was 2.9 in the sildenafil group, which was significantly higher than the 1.7 successful attempts per week in the CPAP group (p < 0.0001). The mean IIEF-EF domain scores were significantly increased in both groups compared with baseline (18.3 vs. 7.8, p < 0.0001 in the sildenafil group; and 11.7 vs. 7.4, p < 0.0001 in the CPAP group). When the mean IIEF-EF domain scores were compared, a significantly higher score was reported in sildenafil treatment group than the CPAP group (p < 0.0001). Overall, 12 of 41 men (29%) were satisfied with CPAP treatment for ED, whereas 28 of 41 men (68%) were satisfied with sildenafil. Satisfaction with treatment was significantly higher among the patients under sildenafil than that in the CPAP group (p = 0.0015). The corresponding partners’ reports confirmed these data satisfaction rates and were equal to those reported by the patients (29% with CPAP and 68% with sildenafil). Therapeutic satisfaction was clearly superior among partners of sildenafil-treated patients compared with partners of the CPAP group (p = 0.0006). The analytical assessment of the answers provided to EDITS Q1 from patients
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and their partners revealed that partners gave a different evaluation of treatment satisfaction. However, this difference was not statistically significant, and the satisfaction scores reported by patients and partners with sildenafil treatment were significantly higher than those in the CPAP group (Table 2).
Discussion In the literature, there is strong evidence suggesting a high incidence of ED among patients with OSAS (4,5). The most widely accepted theory is that OSAS -related ED is because of the coordination of hypoxic episodes, which are very common in cases with sleep apnoea and arousal-related hyperadrenergic reactions (7). This reduces circulating nitric oxide levels with a consequential increase in vasoconstriction and impairment of the vascular endothelial cells function, and this basic neurovascular event causes ED (16). Moreover, Goncalves et al. (17.) reported that a high percentage of patients with OSAS and ED have a low SaO2 (< 80%). In their study, severe ED was seen as the SaO2 percentage decreased. Taskin et al. reported a worsening of patient psychology as AHI increased (9). Thus, patients became depressive, which in turn resulted in ED. However, it was not clear whether ED was only because of psychological problems in the OSAS cases. Several studies have evaluated the efficacy of CPAP treatment on OSAS-associated ED (6,9,10,17). CPAP provided either in mild or severe OSAS cases has demonstrated a significant improvement in erectile function in men with OSAS and ED (10,17). Studies on long (12 week therapy) and short-term CPAP therapies have reported an erectile function improvement in OSAS-related ED (11,18). The effectiveness of CPAP is believed to be related to an increase in circulating nitric oxide levels resulting in an improvement in endothelial function (16). A study by Taskin et al. reported that CPAP treatment of patients with OSAS
and ED resulted in a gradual improvement in IIEF-5 scores, and the symptoms of ED diminished after treatment (9). Treatment of ED in patients with OSAS is still controversial and varies according to its main aetiology; however, the cause of OSAS-related ED remains unclear. Consequently, without defining the cause of ED, many drugs such as sildenafil have been used for treatment. Rozenblatt and colleagues, although could not clarify the mechanisms responsible, reported that treatment with 50-mg sildenafil interfered with the compensatory mechanisms in patients with OSAS, increasing the frequency and duration of respiratory desaturation events (19). Perimenis et al. reported the use of sildenafil with CPAP, showing that the efficacy of this combination was superior to sildenafil alone; however, approximately one-third of the patients studied remained dissatisfied even with this combination of treatments (12). In our study, we investigated only patients with severe OSASs and ED. Since our purpose was to study patients with ED secondary to severe OSAS only, a strict enrolment selection process was performed. To collect only subjects with severe OSAS as the main cause of ED, patients with the most frequently ED-related comorbidities (e.g. blood hypertension and diabetes) were excluded. CPAP therapy has been advised routinely in several reported case series. Patel et al. reported that patients treated with CPAP demonstrated significant improvement in the objective and subjective measures of sleepiness in patients with OSAS with ED (20). Whether this improvement was because of the CPAP effectiveness or because all patients had severe OSAS, it remains unclear. In the study by Perimenis et al., sildenafil increased CPAP effectiveness in patients with mild OSAS compared with CPAP alone (12). Our study is, to date, the only protocol that has investigated PDE5i in patients with severe OSAS. This study confirms that severe OSAS is strongly
Table 1 Baseline variables of enrolled population
Sildenafil group (n = 41)
Age (years) BMI (kg/m2) AHI (events/h) TST (min) Lowest SaO2(%) Mean SaO2(%) IIEF-EF domain score
47.4 25.5 46.9 456.6 85.6 92.8 7.8
9.8 4.1 14.5 34.9 8.2 3.2 1.2
CPAP group (n = 41)
48.6 25.8 47.3 457.1 85.9 91.9 7.4
8.5 3.8 14.9 35.6 8.6 2.9 1.4
p-value
ns ns ns ns ns ns ns
(p (p (p (p (p (p (p
= = = = = = =
0.5553) 0.732) 0.9023) 0.949) 0.872) 0.1858) 0.5848)
BMI, body mass index; AHI, apnoea/hypopnea index; TST, total sleep time; IIEF-EF, International Index of Erectile Function-Erectile Function.
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Severe obstructive sleep aponea syndrome and erectile dysfunction
Table 2 Mean values or scores ( SD) reported in the two treatment groups
Sildenafil (n = 41)
No. of successful attempts No. of successful attempts per week IIEF-EF domain scores EDITS – Q 1 patient scores EDITS – Q 1 partner scores
7.6 2.9 18.3 3.5 3.4
1.6 0.8 4.9 1.6 1.3
CPAP (n = 41)
3.8 1.7 11.7 2.3 2.2
1.7 0.6 3.7 1.7 1.3
p-value
< 0.0001 < 0.0001 < 0.0001 0.0015 0.0006
IIEF-EF, International Index of Erectile Function-Erectile Function; EDITS-Q1, Erectile Dysfunction Inventory of treatment satisfactionquestion 1.
Attempted intercourses Total attemps Successeful attemps
600
400
even with this more effective treatment. These data suggest that there is still no specific treatment for ED-related OSAS and combination therapy (CPAP and sildenafil), as previously reported in the literature (12), does not appear to achieve significantly higher satisfaction rates. We conclude that a different therapeutic mode should be studied further.
200
Conclusions 0
Sidenafil
CPAP
Figure 1 Profile of attempts for sexual intercourses in men with severe obstructed sleep apnoea syndrome and erectile dysfunction treated with Sildenafil or Continuous Positive Airway Pressure (CPAP).
associated with ED as previously reported by Margel et al. (4). In our study, we reported a high overall response rate to 100-mg sildenafil treatment compared with those reported in the previous studies in the literature (11,12,21). The encouraging results obtained in our study are correlated with the selection of enrolled patients, which provided strict exclusion criteria. The high response rate to sildenafil may be because of the exclusion of major diseases responsible for ED, such as hypertension, diabetes mellitus, peripheral vascular, neuropathic disease, prostate cancer, spinal cord injury, endocrine disturbances, current alcohol or drug abuse and medications, which could affect erectile function. The direct smooth muscle relaxation in the penile arteries and corpora cavernosa achieved by sildenafil may explain the higher effectiveness of this treatment compared with CPAP, and this efficacy may therefore explain the greater number of intercourse attempts, reflecting the patients strengthened self-confidence. Even though overall satisfaction with treatment was significantly higher among the patients under sildenafil than that in the CPAP group, approximately one-third (32%) of patients were not satisfied ª 2014 John Wiley & Sons Ltd Int J Clin Pract
This study represents the first trial that has investigated sildenafil in patients with ED related to severe OSAS only. CPAP and 100-mg sildenafil are both safe and effective therapies in the treatment of OSASrelated ED patients. In this study, sildenafil proved to be more effective in treating ED than CPAP as it resulted in a significantly higher rate of successful attempts of intercourse and higher IIEF-EF domain scores. Moreover, we reported a high overall response rate to sildenafil treatment compared with that reported in previous studies in the literature, possibly because of very strict exclusion criteria for patient enrolment that excluded all other aetiologies of ED.
Acknowledgements The patients and their partners are thanked for their willingness to participate.
Funding This study was not supported by any Foundation
Authors contributions ALP, GP, AC, EC and AG designed and ideated the study. FNB, GP, AG performed the polysomnography studies. AF, CM, LS collected all the study’s data. ALP, GP and GP drafted the manuscript. All the authors read and approved the final version of the manuscript.
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Paper received January 2014, accepted April 2014
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