NZHTA REPORT August 2004 Volume 7 Number 4
Evidence based review of medicines for sexual dysfunction in men:
A report commissioned by the New Zealand Accident Compensation Corporation (ACC)
Claire Stewart and Sarah Hogan
New Zealand Health Technology Assessment
Department of Public Health and General Practice Christchurch School of Medicine Christchurch, NZ.
Division of Health Sciences, University of Otago NEW ZEALAND HEALTH TECHNOLOGY ASSESSMENT (NZHTA)
Department of Public Health and General Practice Christchurch School of Medicine, Christchurch, New Zealand
Evidence based review of medicines for sexual dysfunction in men:
A report commissioned by the New Zealand Accident Compensation Corporation (ACC)
Claire Stewart and Sarah Hogan
NZHTA REPORT August 2004 Volume 7 Number 4
This report should be referenced as follows:
Stewart, C. & Hogan, S. Evidence based review of medicines for sexual dysfunction in men: a report commissioned by the New Zealand Accident Compensation Corporation (ACC). NZHTA Report 2004 ; 7(4) .
2004 New Zealand Health Technology Assessment (NZHTA) ISBN 1-877235-66-0 ISSN 1174-5142
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CONTRIBUTION BY AUTHORS
This report was prepared by Dr Claire Stewart (Contract Researcher) who conducted the critical appraisals and prepared the report project. Ms Sarah Hogan (NZHTA Health Economist) was responsible for the health economics component.
ACKNOWLEDGEMENTS
Dr Ray Kirk (NZHTA Director) provided comment on various drafts and coordinated the overall project. Ms Margaret Paterson (NZHTA Information Specialist) developed and undertook the search strategy, and coordinated retrieval of documents and referencing. Mrs Ally Reid (NZHTA Administrative Secretary) provided document formatting.
The Canterbury Medical Library assisted with the retrieval of articles.
NZHTA is a Research Unit of the University of Otago funded under contract to the Ministry of Health.
DISCLAIMER
New Zealand Health Technology Assessment (NZHTA) takes great care to ensure the information supplied within the project timeframe is accurate, but neither NZHTA, the University of Otago, nor the contributors involved can accept responsibility for any errors or omissions. The reader should always consult the original database from which each abstract is derived along with the original articles before making decisions based on a document or abstract. All responsibility for action based on any information in this report rests with the reader. NZHTA and the University of Otago accept no liability for any loss of whatever kind, or damage, arising from reliance in whole or part, by any person, corporate or natural, on the contents of this report. This document is not intended as personal health advice. People seeking individual medical advice are referred to their physician. The views expressed in this report are those of NZHTA and do not necessarily represent those of the University of Otago or the New Zealand Ministry of Health.
This study was funded and supported by the Accident Compensation Corporation (ACC), Wellington, New Zealand. The views and conclusions contained in this report are those of NZHTA and may not reflect the position of ACC.
COPYRIGHT
Copyright © to Accident Compensation Corporation 2004. All rights reserved. No part of this report may be reproduced or distributed by any person without prior written permission and/or licence from the Accident Compensation Corporation. http://www.acc.co.nz/
CONTACT DETAILS
New Zealand Health Technology Assessment (NZHTA) Department of Public Health and General Practice Christchurch School of Medicine and Health Sciences PO Box 4345 Christchurch New Zealand Tel: +64 3 364 3696 Fax: +64 3 364 3697
Email: [email protected] Web Site: http://nzhta.chmeds.ac.nz/
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC ii
TABLE OF CONTENTS
CONTRIBUTION BY AUTHORS ...... i ACKNOWLEDGEMENTS ...... i DISCLAIMER ...... i COPYRIGHT ...... i CONTACT DETAILS ...... i TABLE OF CONTENTS ...... ii LIST OF TABLES ...... iv EXECUTIVE SUMMARY ...... v Background...... v Search strategy ...... v Selection criteria...... v Main results...... v Conclusions ...... vi 1. BACKGROUND AND RESEARCH OBJECTIVES 1
1.1 RESEARCH OBJECTIVES ...... 1 2. HEALTH TECHNOLOGY 3
2.1 DEFINITION ...... 3 2.2 PHYSIOLOGY OF ERECTILE FUNCTION ...... 3 2.3 AETIOLOGY OF ERECTILE DYSFUNCTION ...... 3 2.4 PREVALENCE OF ERECTILE DYSFUNCTION ...... 3 2.5 TREATMENT OF ERECTILE DYSFUNCTION ...... 4 2.6 ISSUES IN EFFICACY AND SAFETY STUDIES ...... 5 3. METHODS 7
3.1 CRITERIA FOR SELECTING STUDIES ...... 7 3.1.1 Inclusion criteria...... 7 3.1.2 Exclusion criteria ...... 7 3.2 SEARCH STRATEGY AND INFORMATION SOURCES ...... 7 Bibliographic databases...... 8 Review databases ...... 8 3.3 METHODS OF REVIEW ...... 8 3.3.1 Levels of evidence...... 8 3.3.2 Validity criteria ...... 9 3.4 DESCRIPTION OF STUDIES...... 10 4. RESULTS 11
4.1 INTRACAVERNOUS INJECTIONS ...... 11 4.1.1 Papaverine ...... 12 4.1.2 Alprostadil (PGE1)...... 12 4.1.3 Intracavernous alprostadil and men with SCI...... 14 4.1.4 Combinations of vasoactive agents ...... 14 4.1.5 Comparative studies between different intracavernous injections ...... 14 4.1.6 Comparison between intracavernous injection and other ED treatments...... 14 4.1.7 Treatment of priapism ...... 15 ® 4.2 INTRAURETHRAL ALPROSTADIL (MUSE ) ...... 15 4.2.1 Comparative studies: Intracavernous versus intraurethral alprostadil ...... 16 4.3 ORAL MEDICATIONS ...... 16 4.3.1 Sildenafil...... 17 4.3.2 Vardenafil...... 20 4.3.3 Tadalafil ...... 21 4.3.4 Comparison between oral medicines...... 21 4.3.5 Apomorphine...... 22 4.3.6 Comparison between apomorphine and sildenafil ...... 23
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4.4 OTHER PREFERENCE STUDIES BETWEEN MEDICINES...... 23 4.5 OTHER ERECTILE DYSFUNCTION TREATMENTS ...... 23 4.6 SUMMARY OF EFFICACY AND SAFETY RESULTS ...... 24 5. ECONOMIC ASSESSMENT 25
5.1 COST DRIVERS ...... 25 5.1.1 Population ageing...... 25 5.1.2 Advertising and consumer awareness...... 25 5.1.3 Shift in the treatment of choice...... 25 5.1.4 Dosage ...... 26 5.1.5 Frequency of use of treatment...... 26 5.2 COSTS ...... 27 5.2.1 Direct costs ...... 27 5.2.2 Indirect costs...... 28 5.3 COST -EFFECTIVENESS ...... 29 5.3.1 Cost-effectiveness of oral medicines ...... 29 5.3.2 Cost-effectiveness of papaverine and sildenafil ...... 29 5.3.3 Cost-effectiveness of papaverine and alprostadil...... 30 5.3.4 Alprostadil...... 30 5.3.5 Sildenafil versus alprostadil...... 30 5.4 SUMMARY OF COST -EFFECTIVENESS COMPARISONS ...... 30 5.5 COST PER QALY GAINED THROUGH THE USE OF SILDENAFIL ...... 31 5.6 CONCLUSION OF ECONOMIC ASSESSMENT ...... 32 6. CONCLUSIONS AND RECOMMENDATIONS 33
APPENDIX 1: EVIDENCE TABLES 35
APPENDIX 2: CRITICAL APPRAISAL CHECKLISTS 61
RANDOMISED AND NON -RANDOMISED CONTROLLED TRIALS ...... 61 Assessment of Internal Validity ...... 61 ASSESSMENT OF EXTERNAL VALIDITY (GENERALISABILITY )...... 62 CASE SERIES ...... 62 Internal validity...... 62 External validity ...... 62 STUDIES REPORTING COMPLICATIONS /ADVERSE EFFECTS ...... 63 Assessment of Internal Validity ...... 63 Assessment of External Validity ...... 63 SYSTEMATIC REVIEWS ...... 63 ECONOMIC STUDIES ...... 64 Assessment of Internal Validity ...... 64 Assessment of External Validity ...... 64 APPENDIX 3: SEARCH STRATEGIES 65 Medline strategy...... 65 Medline (extra economics search)...... 66 Embase strategy ...... 67 Psychinfo...... 68 Cinahl strategy ...... 68 Searches from other sources ...... 69 REFERENCES 71
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LIST OF TABLES
Table 1. Designations of levels of evidence ...... 8 Table 2. Validity criteria according to study design...... 9 Table 3. Validity criteria...... 9 Table 4. Comparison of adverse events by vasoactive agents ...... 12 Table 5. Most frequently reported adverse events from sildenafil RCTs (n=5198) ...... 19 Table 6. Most commonly reported adverse events after 3 years of open label sildenafil treatment ....19 Table 7. Discontinuations by year during 3 years of open-label sildenafil treatment, number (%).....19 Table 8. Cost of medicines ...... 28 Table 9. Range of costs for oral medicines...... 29
Evidence Table 1a. Alprostadil intracavernous injection ...... 36 Evidence Table 1b. Alprostadil intracavernous injection ...... 38 Evidence Table 2. Comparison intracavernosal injection and vacuum constriction device...... 39 Evidence Table 3a. MUSE – Alprostadil Intraurethral...... 41 Evidence Table 3b. MUSE – Alprostadil Intraurethral...... 42 Evidence Table 3c. MUSE – Alprostadil Intraurethral...... 44 Evidence Table 4a. Comparative study between intracavernous injection alprostadil and intraurethral alprostadil...... 46 Evidence Table 4b. Comparative study between intracavernous injection alprostadil and intraurethral alprostadil...... 47 Evidence Table 5. Meta-analysis: Sildenafil...... 49 Evidence Table 5a. Systematic review: Sildenafil use in men with SCI ...... 51 Evidence Table 6a. Vardenafil...... 53 Evidence Table 6b. Vardenafil...... 55 Evidence Table 7a. Tadalafil...... 56 Evidence Table 7b. Tadalafil...... 57 Evidence Table 8. Comparative preference study between sildenafil and tadalafil...... 59 Evidence Table 9. Apomorphine ...... 60
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EXECUTIVE SUMMARY
Background As the costs of, and demand for, sexual dysfunction medicines grow and new products enter the market, ACC needs to determine the relative effectiveness and cost-effectiveness of the products available in order to establish a consistent policy on which medicines to fund. The review evaluated the relative effectiveness, safety and cost-effectiveness of medicines for the treatment of male claimants with erectile dysfunction due to accident or injury.
Search strategy The literature search was limited to major relevant bibliographic and review databases and clinical trials websites. In addition to this, a number of guideline sites, government webpages, and evidence- based sources were also searched. A range of subject headings and keyword searches were used to search the indexed databases. The search was not restricted by date, but was restricted to English language. In addition to this, a methodology filter was used to identify systematic reviews, randomised controlled trials, and economics studies.
Selection criteria The review included English-language reports of randomised controlled trials of at least four weeks duration, in adults of mixed aetiology with symptoms related to male erectile dysfunction, with 50 or more cases at enrolment and that measured clinically relevant outcomes. Studies were included where one identified product was compared against another one in the list, one product was compared against another sexual dysfunction medicine not on the list (if this situation arose), and/or placebo. Given the small number of studies that considered populations similar to ACC claimants, all English-language studies found for this group were reviewed. For assessment of adverse effects, observational cohort studies where available were also included.
Main results Few studies with populations similar to ACC claimants were located. Sildenafil was the only medicine for which good quality studies were available for some of this group and that was for men with spinal cord injury. On the basis of the efficacy, safety and cost-effectiveness evidence available, the oral medicine sildenafil is the preferred treatment for men whose erectile dysfunction is due to accident or injury. While studies to date on the newer medicines vardenafil and tadalafil demonstrate good efficacy and safety profiles, and there are some indications for preference for tadalafil with its extended period of effectiveness, longer-term efficacy and safety data is not yet available. Many of the trials with these medicines also excluded men with spinal cord injury, the group most similar to ACC claimants located in the literature. There were, however, two comparative studies (one with SCI men) published after the completion of the review that indicated some preference for tadalafil with its longer responsiveness post dosing. There is evidence for the efficacy of intracavernous injection therapy (alprostadil, papaverine or combinations of vasoactive agents) for those who continue with its use in the treatment of erectile dysfunction, although the evidence is generally at a lower level and from poorer quality studies than that found for sildenafil, vardenafil or tadalafil. There are high drop-out rates from intracavernosal injection programmes however, and higher rates of serious adverse events (particularly for papaverine monotherapy), including prolonged erection, for this method of treatment. Comparative studies have demonstrated greater efficacy for intracavernosal alprostadil than for intraurethral alprostadil (MUSE ®). While some evidence for the efficacy of apomorphine SL has been demonstrated, it is considered to be less effective than the PDE5 inhibitors sildenafil, vardenafil and tadalafil and its efficacy has not been demonstrated with men with erectile dysfunction due to spinal cord injury.
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Conclusions On the basis of the studies reviewed, oral medication with PDE5 inhibitors appear to be the first line treatment for ACC claimants whose erectile dysfunction is due to accident or injury. Sildenafil, as the oldest and most researched to date of these medicines, is the preferred treatment on the basis of its efficacy, safety and cost-effectiveness. Results from comparative studies between sildenafil, vardenafil and tadalafil and investigation of vardenafil and tadalafil use with men with spinal cord injury should continue to be monitored with regard to purchasing decisions as new evidence emerges. Intracavernosal injection of alprostadil (monotherapy or in a combination treatment) may be considered as a second line treatment when sildenafil or other PDE5 are contraindicated or there is non-response to those treatments.
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 1
1. Background and Research Objectives
ACC funds the rehabilitation of claimants' social function. It therefore funds drug treatments for male claimants with sexual dysfunction caused by damage due to accident or injury (ACC does not fund drug treatments for claimants whose sexual dysfunction is due to psychological causes such as depression). As the costs of, and demand for, sexual dysfunction medicines grow and new products enter the market, ACC needs to determine the relative effectiveness and cost-effectiveness of the products available in order to establish a consistent policy on which medicines to fund.
1.1 RESEARCH OBJECTIVES
1. What is the relative effectiveness and cost-effectiveness of specified drugs (see below) for the treatment of male claimants with sexual dysfunction due to accident or injury? 2. How do the specified drugs compare in terms of: Safety Contraindications Patient acceptability?
3. What are the circumstances in which the various drug treatments should be used? Examples might include cases where one or more of the drugs prove ineffective for a particular claimant, or where a claimant is unable to take one or more of the drugs due to contraindications.
Products to be investigated (source: May 2003 New Ethicals Catalogue): Caverject ® (alprostadil) injection Cialis ® (tadalafil) tablets Levitra ® (vardenafil hydrocholoride trihydrate) tablets Muse ® (alprostadil) injection Uprima SL ® (apomorphine) tablets, sublingual Viagra ® (sildenafil) tablets Papaverine injection, currently the only drug funded by PHARMAC Aramine (metaraminol), used as an antidote to injections
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2. Health Technology
2.1 DEFINITION
In reviewing male sexual dysfunction medicines, consideration is given to the efficacy, safety and cost- effectiveness of treatments for erectile dysfunction (ED). ED is a more precise and now preferred term for impotence (Montague et al. 1996). ED is defined as the inability to attain or maintain a penile erection sufficient for satisfactory intercourse (Anonymous 1993).
2.2 PHYSIOLOGY OF ERECTILE FUNCTION
Physiologically, erectile response is a vascular event initiated in its most common form, by neuronal action which integrates psychological stimuli, such as sexual perception and desires, and controls sympathetic and parasympathetic innervation of the penis. Once initiated, a sexually stimulated erection is maintained by a complex interplay between vascular and neurologic events, in which sensory stimulation from the penis are especially important. Smooth muscle relaxation, arterial dilation and venous compression must occur simultaneously to create an erection (Montague et al. 1996).
2.3 AETIOLOGY OF ERECTILE DYSFUNCTION
Numerous factors can disrupt the normal physiologic mechanisms involved in an erection (Fazio and Brock 2004). Until the 1970s, ED was commonly attributed to psychogenic causes, or physiologically, to abnormalities in testosterone metabolism (Montague et al. 1996). Now it is understood that most ED has an organic cause, especially in older men (Fazio and Brock 2004) and although testosterone deficiency may affect libido, it does not necessarily affect the ability to have erections (Montague et al. 1996).
Organic causes of ED may be vascular (atherosclerosis, ischemic heart disease, peripheral vascular disease, cavernosal disorders), neurologic (cerebral diseases, spinal cord injury, spinal disease, peripheral neuropathy), hormonal (hypogonadism, hyper or hypothyrodism, Cushing’s syndrome, Addisons disease) or other diseases (diabetes mellitus, renal failure, hyperlipidemia, hypertension, chronic obstructive pulmonary disease) (Dinsmore 2004; Guay et al. 2003). ED may also be caused by medications such as antihypertensives, antidepressants, antiandrogens and lifestyle factors such as smoking, alcohol abuse and narcotics use (Fazio and Brock 2004). The dysfunction may be a consequence of a combination of factors or be of mixed etiologic organic and psychologic origin. Determining whether psychologic factors are the main problem or a minor accompaniment to organic problems can be difficult (Guay et al. 2003).
2.4 PREVALENCE OF ERECTILE DYSFUNCTION
The prevalence of ED increases with age and co-morbid conditions such as diabetes, heart disease, hypotension, neurologic and psychiatric conditions, smoking and some surgical therapies (Fazio and Brock 2004). The Massachusetts Male Aging Survey between 1987 and 1989 found 52% of men aged 40-70 reported some degree of sexual dysfunction (Dinsmore 2004). By the age of 70, only 32% of men portrayed themselves as free of ED (Seftel et al. 2004). Men with ED have been found to have a lower overall quality of life, suffer anxiety, lose self-esteem and have less confidence (Wilt et al. 1999). The impact of male sexual dysfunction affects not only the patient, but can also affect his relationship with his partner.
The incidence of erectile dysfunction after spinal cord injury (SCI) has been reported as approximately 75% (Burns et al., 2001). The effect of SCI on sexual response depends on the degree of injury and location on spinal cord (Benevento and Sipski 2002; Derry et al. 2002). While many men with SCI are able to have some type of erectile function, they report that the quality of their erections is often
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 4 insufficient for sexual intercourse. Other generalisations suggest greater recovery in men with incomplete versus complete lesions, upper versus lower motor neuron lesions and higher versus lower cord level lesions. The level of severity of injury can also affect the relative incidence of reflexogenic and psychogenic erection.
2.5 TREATMENT OF ERECTILE DYSFUNCTION
Distinguishing between ED and other sexual dysfunctions (e.g., premature ejaculation or loss of libido) is the first step in diagnosis. Once established, examination is undertaken to detect the severity of ED (Fazio & Brock, 2004). In treating men with cardiovascular complications, the cardiovascular risk of sexual activity needs to be considered. If cardiac risk is in doubt, an exercise test should be done. If no significant ischemia, arrhythmias or fall in systolic blood pressure occurs then there is not thought to be risk during normal sexual activity (UK Medicines Information Pharmacists Group 2003).
A number of non-pharmacological treatments for ED are available that target smooth muscle in the penis (Burns et al. 2001; Dinsmore 2004). The most invasive of these are surgical interventions. Penile prothesis implantation is divided into two general types: non-hydraulic (commonly referred to as semi-rigid rod prothesis) and hydraulic (often referred to as inflatable protheses) (Montague et al. 1996). Venous surgery aims to correct corporovenous occlusive dysfunction and generally involves resection and/or ligation of penile veins. Arterial surgery aims to correct arterial insufficiency of the corpora cavernosa (Montague et al. 1996). Vacuum erection devices, known as vacuum constriction devices (VCD) are non-surgical, non-pharmacological ED treatment methods. VCDs create negative pressure, which increases blood flow into the corpus cavernosa, inducing an erection. The erection is maintained by a constricting band at the base of the penis which traps blood by preventing venous outflow and usually produces rigidity sufficient for penetration.
The first pharmacological treatments that were widely used were those involving the intracavernosal injection of vasoactive agents directly into the corpora cavernosa to promote blood flow into the penis resulting in erection (Burns et al. 2001). The onset of intracavernosal therapy began with the work of Virag in 1982 concerning the erectile inducing properties of papaverine (Porst et al. 2000; Shokeir et al. 1999). As a result of adverse effects (priapism and penile fibrosis), papaverine monotherapy for ED is currently mainly used in combination therapy with other agents (Porst et al. 2000). Alprostadil is the generic name for the synthetic form of prostaglandin E1 (PGE1). Alprostadil used alone in intracavernous injection therapy was approved by US FDA in 1995 for the treatment of erectile dysfunction. Alprostadil for intracavernosal injection is marketed as Caverject ® (sterile powder) by Pharmacia and as Viridal Duo ® by Schwarz. Parallel to the development of monotherapy with papaverine and alprostadil, intracavernosal injections using combinations of vasoactive agents (papaverine/phentolamine, papaverine/phentolamine/prostaglandin E1) have also been introduced.
A method (MUSE ®) of intraurethral administration of alprostadil was developed to obtain the benefits of alprostadil in treating ED but avoid the problems of delivery by injection. The transurethral application of alprostadil by means of MUSE ® (Medicated Urethral System for Erection) was US FDA approved for treatment of erectile dysfunction in November 1996.
Oral therapy with phosphodiesterase type 5 inhibitors (PDE5) has emerged as the first line treatment for male sexual dysfunction in a way that has transformed both the manner in which public views male sexual dysfunction and health care providers deliver care (Fazio and Brock 2004). Sildenafil (Viagra ®), marketed by Pfizer, was the first PDE5 inhibitor on the market and was US FDA approved for use in treatment of erectile dysfunction in March 1998. Tadalafil (Cialis ®), marketed by Lilly was launched in February 2003 and vardenafil (Levitra ®), marketed by Bayer, in March 2003. Both have recently received US FDA approval for the treatment of male erectile dysfunction (Seftel et al. 2004).
Apomorphine (Uprima SL ®) has a different mechanism of action than the PDE5 inhibitors. It is taken sublingually and is a centrally acting agent. Apomorphine was launched in 2001 and is marketed by Abbott.
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The World Health Organisation introduced management guidelines for the treatment of ED with a stepped-care health delivery model (Lyseng-Williamson and Wagstaff 2002). Using a disease management algorithm, after confirming the diagnosis of ED and altering any modifiable risk factors or cause (e.g. drugs, lifestyle, psychosocial factors, hormones, sexual technique), oral agents (PDE5 inhibitors) are the first line therapy unless contraindicated, then second line is intracavernosal therapy or vacuum devices and surgical implants are viewed as third line options.
2.6 ISSUES IN EFFICACY AND SAFETY STUDIES
An ideal treatment for ED should have many or all of the following features: free of toxicity and side effects, effective regardless of aetiology, severity or duration of ED, or age of patient, be non-invasive, be easy to use and useful “on demand” and be affordable (Wilt et al. 1999).
Mulhall (2003) identifies a number of key issues in the investigation of efficacy and safety of male sexual dysfunction medicines. The incidence of neurological, hormonal and vascular co-morbidities in study participants must be considered. As discussed, the general erectile dysfunction population typically has significant incidence of co-morbidities such as diabetes, hypertension, hyperlipidemia, history of cigarette smoking and coronary artery disease and this must be reflected in studies of mixed aetiology of ED groups. Patient age at time of enrolment is also an important issue. Enrolling trial populations with mean ages less than 50 years may result in overestimation of efficacy as well as potential underestimation of hemodynamic effects and adverse events (Mulhall, 2003, p.354). It has been estimated that two thirds of men with erectile dysfunction have moderate to severe erectile dysfunction, therefore studies that enrol predominately men with mild erectile dysfunction, in all likelihood, are not representative of men with erectile dysfunction.
The goal of treatment is usually satisfactory resumption of sexual relations, the first step toward which is restoration of the ability to achieve an erection hard enough for sexual relations. There is debate regarding which end points are the most clinically meaningful and, indeed, who should define these end points. The only modality to use objective data is penile tumescence, typically measured by a rigidity assessment system such as RigiScan. There are, however, weaknesses in this technology and a lack of consensus on normative criteria and the value of rigidity assessment. It is also not a measure that is usable outside of the clinic office and does not measure clinically meaningful outcomes.
The efficacy of medicines in improving erectile functioning is typically assessed using one or more of three types of self-report measures: self-administered questionnaires, diaries/event logs and/or interviews (Mulhall 2003). The most commonly used method for assessing treatment effects (and sometimes erectile dysfunction baseline severity as well) in more recent studies has been to use the International Index of Erectile Dysfunction Questionnaire (IIEF). The IIEF is a 15-question validated inventory that includes five domains: erectile function, libido, orgasmic function, sexual satisfaction and overall satisfaction. The erectile functioning domain, and in particular questions three (ability of patient to obtain an erection of sufficient rigidity to achieve penetration) and four (ability of patient to maintain erection), are the most frequently cited end points to treatment when the IIEF is used. Most trials use a global assessment question, which asks the patient whether the medication has improved his erections, although this has limited clinical application as men may have improved erectile rigidity but remain unable to achieve vaginal penetration (Mulhall 2003).
Many trials include the use of an event log, which is completed after each administration of the trial drug. More recently, the Sexual Encounter Profile (SEP), which is used by the patient and partner, has become the gold standard event log (Mulhall 2003). Partner ratings are also being increasingly used but tend to be found only in more recent studies. The inclusion of quality of life and patient satisfaction measures may permit a more expansive view of treatment effects. However, until recently there has not been an ED population specific instrument (Mulhall 2003). Two instruments are being developed but to date neither has been used widely in ED medicine trials.
Two main methods, symptom checklists and structured interviews are used to assess safety and adverse events (Mulhall 2003). More recent studies have presented adverse events per patient and per administration. Adverse events are typically reported as mild, moderate or severe and are defined by the investigator as being possibly, probably or definitely related to the investigational agent.
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The paucity of direct head to head comparative studies has been commented on in a number of reviews of ED treatments (Fink et al. 2002; Mulhall 2003; Wilt et al. 1999). Indirect comparisons have been made by comparing results of individual trials of different medicines. Caution must be exercised, however, when trying to compare efficacy findings and adverse event profiles between trials assessing different agents, as treatment exposure, methods of evaluating outcomes and the means of reporting adverse events are typically different (Mulhall 2003; Wilt et al. 1999).
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3. Methods
3.1 CRITERIA FOR SELECTING STUDIES
Studies were selected to be reviewed on the basis of the following inclusion/exclusion criteria.
3.1.1 Inclusion criteria For assessment of efficacy and safety, the review included English-language reports of randomised controlled trials of at least four weeks duration, in adult men of mixed aetiology with symptoms related to erectile dysfunction, with 50 or more cases at enrolment and that measured clinically relevant outcomes. Studies were included where one identified product was compared against another on the list, one product was compared against another sexual dysfunction medicine not on the list (if this situation arose), and/or placebo.
Given the small number of studies that considered populations similar to ACC claimants, all English- language studies found for this group were reviewed. The lower level of evidence and poorer study quality was noted where it occurred for these studies.
For assessment of adverse effects and adverse event rates, observational cohort studies were included as well as randomised controlled trials. Such studies often include broader populations, carry out observations over a longer time period, utilise higher quality methodological techniques for assessing adverse events, or examine larger sample sizes than are seen in randomised control trials.
3.1.2 Exclusion criteria Studies were excluded if they were non-published work, studies which reported no clinical results, non- English language articles (due to time constraints), non-systematic (narrative) reviews, letters, editorials, expert opinion/viewpoint articles, comments, overviews, articles published in abstract form only, conference proceedings or studies on animal subjects, studies which duplicated or preceded a subsequent study addressing the same question from the same institution(s) or were reports based on expert opinion only. Studies were excluded if there were less than 50 cases reported overall at enrolment. The exception to this was where there were few studies in areas of particular interest such as where subjects were similar to ACC claimants – e.g., spinal cord injury. In these cases, the lower quality of the studies was noted. Studies were also excluded where only a specific population group (for example cardiovascular disease, diabetes, erectile dysfunction secondary to depression) were studied as opposed to a general mixed aetiology population.
3.2 SEARCH STRATEGY AND INFORMATION SOURCES
Search strategy A comprehensive literature search of major relevant bibliographic and review databases was undertaken together with additional searches for clinical trials, guidelines, government publications, and other evidence-based materials. A range of subject headings and keyword searches was used to search indexed databases (see Appendix 3). The search was not restricted by date, but was restricted to English language articles. In addition, a methodology filter was used to identify systematic reviews, randomised controlled trials, and economic studies.
This comprehensive strategy identified 1,247 potentially relevant journal references. After screening the abstracts of these references, 179 full text articles were retrieved for analysis. Relevant health technology assessment resources were also examined.
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The following databases were searched using the search strategy outlined in Appendix 3.
Bibliographic databases
Medline Cinahl Embase Web of Science Current Contents Psychinfo Toxnet BIOSIS International Pharmaceutical Abstracts Cochrane Controlled Trials Register
Review databases
Cochrane Database of Systematic Reviews Database of Abstracts of Reviews of Effectiveness Health Technology Assessment Database NHS Economic Evaluation Database
3.3 METHODS OF REVIEW
Studies were rated for the level of evidence they provided (strength of the evidence, size of the effect and relevance of the evidence) and validity criteria applied to assess the quality of evidence. Outcomes assessed were functional outcomes (successful sexual intercourse), quality of life, and adverse effects, including drug interactions.
3.3.1 Levels of evidence Levels of evidence for studies reviewed were assessed and classified using the dimensions of evidence defined by the NHMRC (2000) to determine the designation of the level of evidence provided.
Table 1. Designations of levels of evidence*
Level of Study design evidence I Evidence obtained from a systematic review of all relevant randomised controlled trials II Evidence obtained from at least one properly-designed randomised controlled trial III-1 Evidence obtained from well-designed pseudorandomised controlled trials (alternate allocation or some other method) III-2 Evidence obtained from comparative studies (including systematic reviews of such studies) with concurrent controls and allocation not randomised, cohort studies, case-control studies, or interrupted time series with a control group III-3 Evidence obtained from comparative studies with historical control, two or more single arm studies, or interrupted time series without a parallel control group IV Evidence obtained from case series, either post-test or pre-test/post-test
*Modified from NHMRC (2000). How to use the evidence: assessment and application of scientific evidence . Canberra: National Health and Medical Research Council.
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3.3.2 Validity criteria Evaluation of the validity of evidence from the various study designs was made using the UK NHS Centre for Reviews and Dissemination validity criteria listed in Table 2.
Table 2. Validity criteria according to study design*
Study design
RCT Randomised method Allocation concealment Blinding of patients, investigators and outcome assessors Proportion lost to follow-up Intention to treat analysis Cohort Prospective/ retrospective Comparable groups at inception Identification and adjustment for confounding factors Blind outcome assessment Sufficient duration of follow-up Proportion lost to follow-up Case-control Explicit definition of cases Adequate details of selection of controls Comparable groups with respect to confounding factors Interventions and other exposures assessed in same way for cases and controls Appropriate statistical analysis Case series Explicit description of patients Explicit inclusion/exclusion criteria All study subjects included Explicit description of techniques
*Modified from Khan K.S, ter Riet, G, Glanville, J, Sowden, A.J. & Kleijnen, J. (2001). Undertaking systematic reviews of research on effectiveness: CRD’s guidance for those carrying out or commissioning reviews. CRD Report No. 4 2 nd edition.
Critical appraisal of the identified literature will be performed against these checklists that use qualitative criteria designed to assess whether the research study was performed in a valid, reliable and rigorous way to minimise bias. The checklists for randomised and non-randomised control trials, case series, observational studies of adverse events and cost-effectiveness studies are presented in Appendix 2.
Controlled trials that have a fatal flaw in one or more categories were rated poor quality; trials which met all criteria, were rated good quality; the remainder were rated fair quality. A “poor quality” trial is likely not to be valid – i.e., the results are at least as likely to reflect flaws in the study design as the true difference between the sexual dysfunction medicine and comparator. Observational studies of adverse events were rated as good quality for adverse event assessment if they adequately met six or more of the seven predefined criteria, fair if they met three to five criteria, and poor if they met two or fewer criteria.
For systematic reviews, specific criteria were used to assess whether the review asked a focused question, if the eligibility criteria for included trials were explicit, what search strategy was used, how the validity of included trials was assessed and whether results of included trials were similar. A summary of these criteria is presented in Table 3 below.
Table 3. Validity criteria
Appraisal of secondary studies Is there a focused research question?
Are inclusion and exclusion criteria for selected studies stated?
Is there an explicit and comprehensive search strategy?
Are the included trials appraised for validity?
Are results consistent from study to study?
Summary of main results Strengths and limitations
Adapted from Evidence-based medicine toolkit. Available from: http://www.med.ualberta.ca/ebm/ebm.htm
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Economic assessment The purpose of the economic assessment of treatment of male sexual dysfunction is to establish the cost and cost-effectiveness of different treatment options for men with sexual dysfunction as a result of accident or injury. A review of the literature on the cost and cost-effectiveness of male sexual dysfunction and its various treatments was conducted and incorporated evidence from efficacy and safety studies.
3.4 DESCRIPTION OF STUDIES
Older studies, which included most of the studies evaluating intracavernous injections, tended to be of lower quality and drew on lower levels of evidence. More recent studies, which were mainly of oral medicines, particularly sildenafil, were more likely to use higher levels of evidence (randomised, double-blind controlled trials) and meet more of the quality criteria. Few studies, however, gave details as to how groups were randomised and many were sponsored by drug companies. Sildenafil was the only medicine for which meta-analyses of trials were found. As would be expected given the relatively recent development of oral medication treatments, studies of long-term efficacy and safety of these medicines are limited. There are some studies of sildenafil emerging that include data from three to four years of follow-up (Padma-Nathan et al. 2002). Most of the long-term follow-up information that is available, however, refers to intracavernous injections.
There is a paucity of direct head to head comparisons of efficacy and safety between different ED medicines. There are some inherent difficulties in being able to blind participants to treatment received when the method of administration is different – e.g., oral medication compared with intracavernous injection, intracavernous injection compared with intraurethral administration or when there are different dosing instructions. Four comparative studies were located that met the criteria to be included in evidence tables. Two compared alprostadil administered either by intracavernosal injection or intraurethrally, one compared intracavernosal injection (trimix combination) with vacuum constriction devices and one was a preference study between sildenafil and tadalafil. These studies were all direct head to head comparisons between active medicines or treatments and did not include placebo comparison. No comparative ED medicine studies with men with SCI were found.
Typically, comparisons between medicines have been made by comparing individual medicine trial outcomes with other individual medicine trial outcomes. Different trials are not however directly comparable as different population groups are involved and different outcome measures used. There are some studies where men have switched from one ED medicine to another (e.g., from intracavernous injection to sildenafil). Given the small number of direct comparative studies, these case series studies are discussed in the review although they provide only low levels of evidence regarding treatment comparability.
A limited number of studies were located that investigated efficacy and safety of the listed sexual dysfunction medicines with populations similar to ACC claimants. Of those studies found all were with men with ED as a result of SCI and typically had small numbers of participants. There were no studies located that specifically looked at the treatment of ED as a result of other neurological injury or accidents. Some studies of ED medicines with general populations of mixed aetiology may have included men with SCI or other ED as a result of other neurological injury or accident but usually aetiology was not specified beyond organic/psychogenic or by delineating organic into neurological or vascular aetiology. It was not possible therefore to draw any conclusions from study participants in mixed aetiology trials who might be similar to ACC claimants.
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4. Results
In the following sections, individual medicines are reviewed by the mode of delivery of the medicine: intracavernous injection, intraurethral application and oral medications. For each medicine efficacy, safety, contraindications and patient acceptability from studies with mixed aetiology ED are reviewed. Where located, studies with men with SCI are included in the section on the relevant individual medicine.
4.1 INTRACAVERNOUS INJECTIONS
Before the advent of oral medications intracavernous injections of vasoactive agents had become the treatment of choice for erectile dysfunction either as monotherapy (papaverine, alprostadil) or in combinations of vasoactive agents (papaverine/phentolamine, papaverine/phentolamine/alprostadil). Intracavernous injection is still considered as a second line treatment for ED if first time patients do not respond to, or have contraindications for sildenafil (Montorsi et al. 2002). Contraindications for use of intracavernous injections are disorders that predispose to prolonged erections, such as sickle cell anaemia, multiple myeloma or leukemia.
Although there has been some renewed interest in intracavernosal injections through the raised profile of ED treatment as a result of the success of sildenafil, most studies of efficacy and safety of intracavernosal injections were conducted pre 1998 (late 1980s to mid 1990s for most). The studies tend to offer lower levels of evidence and be of a lower quality; however, because the medicines have been available for longer there is long-term follow-up information available.
Studies, albeit based on lower levels of evidence or poorer study quality (Montague et al. 1996), have reported that the injection of vasoactive drugs is an effective treatment for erectile dysfunction (Porst et al. 2000). Irrespective of which vasoactive drug is administered, however, all published studies with self-injection of cavernous bodies reveal relatively high drop-out rates, often up to 40-50% in long- term follow-up (Fazio and Brock 2004; Shokeir et al. 1999). These high drop-out rates are considered to be a function of a number of factors. Ineffectiveness is the most frequently cited reason for early discontinuation of intracavernosal injection and also throughout injection programmes (Gupta et al. 1997; Purvis et al. 1999). The two most important complications are prolonged erections (usually encountered in the dose titration phase) and the development of fibrotic nodules within the corpora cavernosa which may led to penile curvature (Montorsi et al. 2002). Penile scarring or nodules become more prevalent as reasons for discontinuation after the first six months (Gupta et al. 1997). Other adverse reactions include hypotension, tachycardia and liver dysfunction. High attrition rates may also result from an aversion to self-injection or injections, penile pain from injections and the inconvenience of maintaining a supply of medicines that require refrigeration (Gupta et al. 1997; Porst 1996; Purvis et al. 1999). A retrospective study of 1,089 patients enrolled in an ED treatment programme from 1988 to 1996 did not identify any risk factor for ED or associated conditions as a risk factor for attrition (Gupta et al. 1997), although another survey of intracavernous injection users found dissatisfaction to be higher in younger age groups of users (Purvis et al. 1999). Those who continue with intracavernous use, however, report high rates of efficacy and satisfaction (Gupta et al. 1997; Porst 1996; Purvis et al. 1999). It is suggested that adverse events are minimised in those who use the correct technique for needle insertion (in terms of needle related injuries) and that those who experience success in terms of outcome are more likely to use the method long-term.
A greater incidence of priapism as a result of intracavernous injection of vasoactive agents among young spinal cord-injured patients than general populations has been reported (Broderick 1996). It has been suggested those patients at particular risk of priapism with ICI therapy are younger men with better baseline erectile function or those with psychogenic or neurogenic cause (Earle et al. 2003).
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4.1.1 Papaverine Papaverine belongs to the family of non-selective phosphodiesterase inhibitors and is a smooth muscle relaxant that increases arterial inflow and venous outflow resistance which acts directly on the muscle itself to promote erection (Yarkony et al. 1995). After intracavernosal application, maximum plasma levels are reached within 10 to 30 minutes and the half-life is approximately one to two hours. It is recommended that papaverine not be used more than twice a week (Cada et al. 1996). Another contraindication other than those already noted for intracavernous injection, was the presence of complete atrioventricular heart block.
There was limited good quality data on papaverine monotherapy (Wilt et al. 1999) and no studies were found that met the criteria for inclusion in evidence tables. This is most likely a consequence of discontinuation of papaverine monotherapy in most industrialised countries due to the side effects of priapism and penile fibrosis (Porst et al. 2000). Due to its low costs self-injection monotherapy still continues in many developing countries. Even the papaverine product information states the intracorporeal injection of papaverine hydrochloride for the treatment of impotence by injection is contraindicated as persistent priapism requiring medical and surgical intervention has been reported.
An analysis of 19 publications that included 2,181 patients administered papaverine demonstrated an in office (assessing penile rigidity of erection only) success rate of 61% (Porst 1996). At home (assessing ability to achieve an erection hard enough for sexual relations), efficacy rates between 27% and 78% have been reported (Montorsi et al. 2002) and patient satisfaction with treatment of over 65% (Wilt et al. 1999). Drop-out rates from papaverine use as high as 64% have been reported (Wilt et al. 1999). Adverse events have been: priapisms in 3-19% which mostly occurred in the titration phase, fibrotic alterations in 5-30% with an average of 5.7% in retrospective studies (Wilt et al. 1999). In long-term self-injection trials, papaverine produced liver enzyme elevations in 1.6% of patients which was evidence of hepatotoxic potential. Higher rates of priapism, fibrosis and elevated liver enzymes have been reported with papaverine use than other vasoactive agents injected intracavernously (see Table 4).
Table 4. Comparison of adverse events by vasoactive agents
Drug No. of patients Priapism (%) Fibrosis (%) Pain (%) Liver enzymes (No. of elevated publications)
Papaverine 1527 (15) 7.1 5.7 4 1.6
Papaverine/ 2263 (22) 7.8 12.4 11.6 5.4 Phentolamine
PGE1 (Alprostadil) 2745 (10) 0.36 0.8 7.2 0
Porst (2000, p. S93)
Two studies on papaverine use with men with SCI were found (Chancellor et al. 1994; Yarkony et al. 1995). Both were in office studies only, with limited periods of administration and either poor or no reporting of clinically meaningful outcomes. Both demonstrated efficacy for papaverine. While one study (Yarkony et al. 1995) concluded that low dose papaverine is a safe and effective means of restoring erections in spinal cord injured men, the conclusions were limited by the small number of participants and the reporting only of in-office testing results and not at-home-use outcomes.
4.1.2 Alprostadil (PGE1) Alprostadil is the generic synthetic name for prostaglandin E1 (PGE1). Alprostadil is an andogenous substance that has a strong relaxing effect on the smooth muscle of the corpus cavernosum and the helicine and cavernous arteries, both processes that are critical in the erectile mechanism. Alprostadil induces erection by relaxation of penile trabecular smooth muscle and dilation of cavernosal arteries. This augments arterial inflow of blood, expanding the corporal sinusoids and impeding venous outflow, thereby producing penile rigidity (Montorsi et al., 2002; Porst et al., 2000). Erection occurs within five to 20 minutes of administration. The dosage used may need to be titrated to limit duration of effect to less than one hour. Alprostadil (sterile powder) is marketed as Caverject ® and alprostadil (alfadex) as Viradil or Edex. Contraindications are those for intracavernous use, that is where there is a
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 13 predisposition to prolonged erections, not for use with other agents used in the treatment of ED, with penile implants or when sexual activity is medically inadvisable. Product information lists 15 possible drug interactions with alprostadil including with ACE inhibitors, alpha blockers, beta blockers, diuretics and nitrates, all of which may enhance hypotensive effects.
Alprostadil has become the global leader in intracavernosal pharmacotherapy (Porst et al. 2000). Alprostadil (PGE1) monotherapy has been proposed as the preferred vasoactive drug treatment in self- injection therapy as it achieves high efficacy with lower side effect for priapisms and fibrotic alterations (Porst, 1996). Alprostadil is also the most widely used component in multi drug vasoactive mixtures (Montorsi et al. 2002). There are few published studies that specifically evaluate Caverject® (alprostadil) (Cada et al. 1996). The majority use extemporaneously prepared alprostadil or extemporaneously prepared combinations of alprostadil with other agents.
Trials have shown alprostadil to be significantly superior to placebo although these have tended to be either office-based or with limited or no comparison with placebo for home outcomes (Linet and Ogrinc 1996; Porst et al. 1998). Two open label at home studies of alprostadil (Evidence Tables 1a and 1b) have documented success rates between 70-74% for intracavernosal alprostadil either as Caverject ® (Linet and Ogrinc 1996) or Edex/Viridal (Porst et al. 1998). The at-home trials were undertaken only with those for whom an adequate dose was established in office testing – e.g., in the Linet & Orging trial, an adequate dose established for 606 out of 683 men tested.
Similar to self-injection trials with all vasoactive drugs, the drop-out rates in alprostadil studies have been relatively high, 55% after 18 months continuation in Caverject ® and 54% after 24 months in Viridal trial. After four year follow-up, 33% continued with therapy with Viridal and 22% with regular therapy with Caverject ® (Porst et al. 2000). For those who continue with alprostadil, however, satisfaction rates with treatment of nearly 90% have been reported (Porst 1996).
Some studies have reported better response rates for psychogenic and neurogenic etiologies for erectile dysfunction than for those with vasculogenic aetiology (Linet and Ogrinc 1996). In particular, diabetic patients with predominantly neurogenic dysfunction, had better responses to alprostadil than diabetic men with vascular or mixed neurologic/vascular etiologies. Studies have also suggested that men with psychogenic or neurogenic aetiology may be more prone to longer erections and lower doses should initially be used (Cada et al. 1996).
Compared with results from studies with injections of other vasoactive agents, trials with alprostadil show it as less likely to cause priapism or fibrosis but more likely to cause pain to users (Linet and Ogrinc 1996; Porst 1996; Porst et al. 1998; Wilt et al. 1999). Penile pain is the most commonly reported adverse event for alprostadil self-injection with reported occurrence rates between 8-52% (Linet and Ogrinc 1996; Porst 1996; Porst et al. 1998). With long-term follow-up and individual dose adjustment, pain rates decreased to 1-11% (Porst et al. 1998). Priapisms are almost exclusively observed in the titration phase and varied between 0.25 and 1% (Porst et al. 1998). The lower incidence of priapism is supported by a Western Australian audit (Earle et al. 2003) of intracavernous- injection-therapy-induced priapism from 1985-2000 which showed that the incidence of priapism fell from 1989 when PGE1 became the drug of choice for intracavernous injection therapy for erectile dysfunction. In the two major trials with both alprostadil preparations, penile fibrotic alterations were encountered in 7.5-11.7% of patients during the course of four to five year follow-up (Porst et al. 1998). The majority of fibrotic alterations were small nodules which did not interfere with erectile function or vaginal penetration, and between 33% and 47% of these penile fibroses healed spontaneously suggesting that the incidence of persistent penile fibroses in patients on long-term injection therapy is 5-7%. These rates are higher than those reported in Table 4 which was compiled from a 1996 review (Porst 1996), and included studies of shorter duration of alprostadil use.
A retrospective review (Gupta et al. 1997) of 1,089 patients enroled in an ED program from 1988 to 1996 undertaken to compare characteristics of active patients and those who discontinued intracavernous injection therapy, found the overall attrition rate for all vasoactive agents was 37.6% and among alprostadil users was lower at 27.5%. Higher satisfaction with treatment rates were reported in this study with alprostadil than with papaverine plus phentolamine or papaverine plus alprostadil.
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4.1.3 Intracavernous alprostadil and men with SCI Only one study was located that evaluated intracavernosal alprostadil in men with SCI (Tang et al. 1995). The study was with 15 spinal cord injured patients with erectile dysfunction and found intracavernous injection of prostaglandin E1 significantly improved the erectile condition. All the participants achieved functional erection adequate for coitus after treatment except one patient who was found to have venogenic impotence. No systemic side effect or any other complication was noted except that pain at the injection site was documented in two patients with incomplete lesions. The study was limited by small numbers and the lack of detail in reporting results.
4.1.4 Combinations of vasoactive agents In efforts to capitalise on the specific pharmaco-relaxing properties of individual intracavernous agents, reduce the pain associated with PGE1, reduce corporal fibrosis and heptic dysfunction associated with papaverine, and minimise cost and volume of injections, clinical investigators have turned to combination therapy with vasoactive agents (Broderick 1996). Combinations of vasoactive agents developed have been either in bimixes (papaverine/phentolamine) or trimixes (papaverine/ phentolamine/PGE1).
Papaverine/phentolamine is marketed in Europe as Androskat. Home use efficacy ratings of Androskat as high as 90% have been reported (Montorsi et al. 2002). Global efficacy rates for various combinations have been evaluated as 68.5% (Porst 1996). Adverse events are similar to those found with papaverine monotherapy, priapism 6-15% and fibrosis in an average of 12% treated (see Table 4). Long-term results of a self-injection programme (Valdevenito and Melman 1994) with a papaverine/phentolamine/PGE1 mix demonstrated the trimix solution was effective in 84.4% (254/301) men with a wide variety of etiologies, including vascular insufficiency, diabetes mellitus, neurogenic and psychogenic ED. Most men with intact vasculature (neurogenic and psychogenic) achieved a better response and tended to use lower dose medication compared to vasculogenic and diabetic patients. Rates of priapism and scar formation were 4.7% and 5.9% respectively.
4.1.5 Comparative studies between different intracavernous injections No studies making direct head to head comparisons of different intracavernous injections were found. Reported data have been extrapolated from individual medicine trials of monotherapy or combination therapy to make comparisons (Porst 1996) as discussed in previous sections. Another method of comparison has been to progressively trial different agents as in a comparative evaluation (Baniel et al. 2000) which started with simpler and less costly drugs and advanced to more complex combinations. A high in-office positive response rate of (97.6%) was achieved when all combinations were totalled with 57.2% achieving successful sexual intercourse on follow-up. Four intracavernous injection protocols were used: 1. papaverine plus phentolamine; 2. prostaglandin E(1); 3. papaverine, phentolamine, and prostaglandin E(1); and 4. atropine sulfate, papaverine, phentolamine, and prostaglandin E(1). Patients for whom the basic protocol failed were successively switched to the more advanced protocols until a positive response was achieved. A positive response was achieved by 415 (66.4%) of the 625 patients given protocol 1; 75 (36%) of the remaining 210 patients given protocol 2; 98 (72.6%) of the 135 patients given protocol 3; and 22 (59.5%) of 37 patients given protocol 4. All four protocols failed in only 15 patients (2. 4%). At the three-year follow-up visit (n = 610), 349 had achieved coitus, 65 (10.6%) without an injection and 202 (33.1%) with an injection. Eighty-two patients sometimes performed coitus without an injection. Sixty-three patients (10.3%) abandoned the programme because of marital or health problems; 198 asked to be switched to sildenafil during the follow-up period, and 120 returned to the programme.
4.1.6 Comparison between intracavernous injection and other ED treatments One study (Soderdahl et al. 1997) was located that compared intracavernosal injection (trimix: papaverine/phentolamine/PGE1) with vacuum constriction devices in a randomised crossover study with 50 men with ED (see Evidence Table 2). Forty-four men completed the trial. Both methods produced higher scores on erectile functioning than before treatment. Participant ratings on satisfaction with treatment favoured intracavernous injection therapy and more men continued with injection therapy than with vacuum devices at the conclusion of the study.
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4.1.7 Treatment of priapism Priapism is a prolonged erection (typically defined as an erection lasting longer than four to six hours). Severely prolonged erections are associated with development of irreversible problems with erectile function (Mulhall and Honig 1996). One of the possible causes of priapism is intracavernous injections and today it is the most common cause of the disorder (Melman and Serels 2000). Priapism is divided into low flow (ischemic) and high flow (non-ischemic). Low flow priapism which is the more common form and can be caused by hematologic disease states, oral medications, intracavernous injection therapy, metastatic disease and neurologic causes.
The literature relating to the management of priapism is small and is comprised of mostly case reports and small case series rather than controlled trials (Montague et al. 2003). As a consequence, the relative efficacy and safety of different treatments, including the listed product metaraminol (Aramine), is difficult to determine.
Guidelines on the treatment of priapism recommend a stepwise approach beginning with intracavernous injection of an alpha-adrenergic sympathomimetic agent, with or without evacuation of old blood, and followed where necessary by a surgical shunting procedure (Montague et al. 2003). The listed medicine metaraminol (Aramine) is an alpha-adrenergic sympathomimetic agent used in the treatment of priapism. Other sympathomimetic drugs used in the treatment of priapism are epinephrine, norepinephrine, phenylephrine and ephedrine. There are no published direct efficacy comparisons of these agents. Summary data (Montague et al. 2003) showed that for all patients with ischemic priapism resolution occurred in 81% treated with epinephrine, 70% with metaraminol, 43% with norepinephrine, and 65% with phenylephrine. Recommendations of a panel of experts from the Urologic Association of America are that for low blood flow (ischemic) priapism, an intracavernous injection of a sympathomimetic agent phenylephrine be used because this agent minimises the risk of cardiovascular side effects that can occur with other sympathomimetic medications (Montague et al. 2003). The use of metaraminol has been essentially abandoned due to a reported death from its use (Melman and Serels 2000).
4.2 INTRAURETHRAL ALPROSTADIL (MUSE ®)
Concerns about the difficulties caused by using a needle to self-inject alprostadil and injuries caused by needle use led to the development of an alternative method of administration of alprostadil. The MUSE® system involves the placement of a medicated pellet in the tip of a hollow plastic applicator that is then inserted into the urethra. The onset of effect is within five to 10 minutes after administration and the duration of effect is approximately 30 to 60 minutes. In addition to the general contraindications for alprostadil where engaging in sexual activity is inadvisable for medical reasons, the use of intraurethral alprostadil is contraindicated in cases of urethral stricture, severe hypospadia, severe curvature, balanitis and urethritis.
Three randomised double-blind controlled trials (see Evidence Tables 3a, 3b and 3c) evaluating MUSE ® with men with a mixed aetiology of erectile dysfunction were located, two of which were parallel design (Padma-Nathan et al. 1997; Williams et al. 1998) and one a crossover design (Hellstrom et al. 1996). In studies of intraurethral alprostadil (MUSE ®), the active agent produced a large and significant improvement in erectile dysfunction when compared with placebo (Hellstrom et al. 1996; Padma-Nathan et al. 1997; Williams et al. 1998). The reported efficacy (successful sexual intercourse) of intraurethral alprostadil therapy is variable, with response rates from two large scale at home studies over three months of 65% to 69% (Padma-Nathan et al. 1997; Williams et al. 1998). These success rates, however, are from an enriched enrollment group of men who responded to MUSE ® in office pre- testing. In this pre-testing, 34% (Padma-Nathan et al. 1997) and 36% (Williams et al. 1998) of men did not achieve a response to MUSE ® sufficient to continue with the at home trial. The rates of successful intercourse (65-69%) achieved in the studies also indicate that erections following administration of MUSE ® in office are not perfectly predictive of successful intercourse at home following use of MUSE ®.
Similar results were found in two open label trials. In one (Khan et al. 2002), only 35% of the 100 patients (aged 46-73 years) with ED of mixed aetiology were initially successfully treated with MUSE ® and all but two required a 1,000 µg dose. After six months, only 43% of these initially successfully
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 16 treated patients continued to use MUSE ®; of these, 33% only found it effective on every third occasion, or worse. MUSE ® was therefore only effective about a third of the time in only about a third of men who were treated for ED. The remaining 57% of the initially successfully treated patients stopped taking MUSE ® because it was no longer effective or it caused side effects (such as urethral bleeding and/or irritation). In the other study (Mulhall et al. 2001), only 34% of men achieved in office success with MUSE ® and for those who used MUSE ® at home, the overall consistency rate of successful sexual intercourse was 51%. After 9 months, only 31% were still using MUSE ®. In a retrospective study, the sole characteristic found to be associated with a positive outcome in the use of MUSE ® was the ability to achieve a partial erection prior to treatment (Engel and McVary 1998), while another retrospective study (Guay et al. 2000) indicated that men over 50 with ED of organic aetiology had better response than others to intraurethral alprostadil.
The most commonly reported side effect is local penile pain caused by drug-mediated sensitisation of nerve fibres. A review of adverse events for MUSE ® (Wilt et al. 1999) reported that penile pain occurred in 32.7% with MUSE ® administration compared with 3.3% with placebo and urethral pain was 12.1% with MUSE ® compared with 4.1% with placebo. Partner adverse events such as vaginal itching or burning were more likely in MUSE ® than placebo. Systemic adverse events are uncommon. In a study comparing efficacy and safety at different doses reported that no serious dose-related systemic effects were seen (Ekman et al. 2000).
Studies of MUSE ® with populations of mixed aetiology have included men with organic and psychogenic etiologies, but not stipulated whether this included men with SCI. Some studies (Hellstrom et al. 1996; Padma-Nathan et al. 1997) excluded men with an indewelling catheter and Padma-Nathan et al. (1999) excluded men with paraplegia or quadriplegia. In a study (Bodner et al. 1999) with 15 patients with SCI in-office testing to evaluate the effectiveness of intraurethral alprostadil in treating SCI associated erectile dysfunction, it was reported that MUSE ® appears to be somewhat effective in creating erections. However, these were less rigid erections than those obtained with intracavernosal therapy and provided less overall satisfaction (reported from previous intracavernosal use not direct comparison). All patients were at least one year after injury, and all had previously used intracavernosal injections successfully (Schramek's grade 5 erection). The authors concluded that MUSE ® should always be used in the patient with SCI after placement of a constriction ring to prevent hypotension. The three patients with grade 4 erections tried the MUSE ® at home. All three patients were dissatisfied with the quality of the erection, did not continue to use MUSE ® and returned to intracavernosal injection therapy.
4.2.1 Comparative studies: Intracavernous versus intraurethral alprostadil Three studies were located that directly compared the efficacy and safety of intracavernosal alprostadil with that of intraurethral alprostadil (MUSE ®). Of these two (see Evidence Tables 4a and 4b) were in home comparisons, one was a crossover study (Shabsigh et al. 2000) and the other a parallel design (Shokeir et al. 1999). The third involved in office administrations only (Porst 1997). The results were similar in all studies in demonstrating greater efficacy for intracavernosal alprostadil than for intraurethral delivery of alprostadil. There were higher drop-out rates in home studies for intracavernosal administration and MUSE ® was rated as easier to use. In both in home studies, the incidence of pain for intracavernous injections was greater than with intraurethral administrations. Intraurethral administrations produced more site reaction adverse events (urethral bleeding) in comparison to injection but these events occurred at a much lower rate than the incidence of pain.
4.3 ORAL MEDICATIONS
Phosphodiesterase type 5 (PDE5) inhibition is the basis of the oral therapy medicines sildenafil, vardenafil and tadalafil. PDE5 inhibitors influence local regulatory mechanisms, potentiating the smooth muscle relaxing effects of nitric oxide (NO) on resistance arteries and trabecular smooth muscle within the corpus cavernosum to promote erection (Brock 2002). All PDE5 inhibitors are contraindicated in men who use or may need to use nitrates or in whom vasodilation or sexual activity are inadvisable. Manufacturer’s instructions also contraindicate the use of these drugs where there is hypotension, recent stroke, unstable angina and myocardial infarction.
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4.3.1 Sildenafil Viagra ® (sildenafil) was the first PDE5 inhibitor on the market. Sidenafil rarely produces erections in the absence of sexual stimulation and does not enhance libido or normal erectile function (Dinsmore 2004). The recommended dose for most patients is 50mg, taken about one hour before sexual intercourse. Sildenafil is rapidly absorbed with peak plasma concentrations occurring within one hour and the terminal half-life is approximately four hours. It is recommended patients do not use more than one dose a day. Meal intake, especially of fatty foods, decreases the rate and extent of absorption. In addition to the general contraindications for PDE5 inhibitors, the use of sildenafil is also contraindicated with hereditary degenerative retinal disorders.
Sildenafil has been the subject of the most studies of any of the male sexual dysfunction medicines reviewed. Three systematic review/meta-analyses were located. Only the most recent review (Fink et al., 2002 - 37 placebo controlled trials) is presented in Evidence Table 5a as the review contains most of the studies used in the earlier reviews (Moore, 2001 - 10 randomised controlled clinical trials undertaken by Pfizer; Burls et al., 2001 - 21 trials) as well as additional studies.
All clinical studies of sildenafil show it has significant benefits over placebo on the primary and secondary outcome measures used. The use of sildenafil improved ability to achieve an erection in 50 to 84% of patients (Burls et al. 2001; Fink et al. 2002; Moore et al. 2002). The number needed to treat (NNT) for one man to have improved erections was reported as between 1.7 (Moore et al. 2002) and 2 (Burls et al. 2001) at the 95% confidence level. The more conservative NNT of 2 is probably a better reflection of populations presenting for treatment as it was not based solely on clinical trials. The mean percentage of participants’ sexual intercourse attempts that were successful with sildenafil was 57% compared with placebo 21% (Fink et al. 2002). Excluding sexual intercourse attempts that failed for reasons other than an insufficiently hard or long lasting erection, 66% of attempts were successful in the sildenafil group versus 25% for placebo. The NNT for one man to achieve 60% successful attempts at intercourse was 2.7 (Moore et al. 2002). Many trial participants had some baseline erectile function and it is probable that in clinical practice, where the erectile function tends to be more impaired, the number needed to treat may be higher (Burls et al. 2001). Weighted mean end of treatment scores IIEF questions three and four (as discussed in section 2.6, p.5) were significantly greater for sildenafil than placebo. Improvements in efficacy of sildenafil use were corroborated in the optional partner questionnaires completed seven of the 21 trials reviewed (Burls et al. 2001). Detailed analysis was not possible due to limited data but from 20% of partners who completed questionnaires, 94% reported improvements in their partner’s ability to successfully have sexual intercourse with sildenafil use.
The dose of sildenafil used in the trials reviewed typically ranged from 25-100mg. In data from parallel design trials with fixed dosing, efficacy of sildenafil appeared slightly greater at higher doses for some efficacy measures (Fink et al., 2002). The mean percentage per participant of successful intercourse attempts appeared greater at 50 or 100mg compared with that at 25mg but no different between the two higher doses. However, the percentage of men who reported at least one successful sexual intercourse attempt in the four weeks preceding the end of treatment assessment appeared the same with each sildenafil dose. Improvement in erections was reported more frequently with each increase in treatment dose (Fink et al., 2002, p.1353).
In four trials that measured quality of life, statistically significant but small treatment effects were found for sildenafil (Burls et al. 2001). These were improvements in areas such as satisfaction with sexual life, sexual relations with partners and general mental health such as well-being, self-control and satisfaction with relationships (Giuliano et al. 2001).
Response rates varied with different etiologies. Seftel et al. (2004) suggest that the use of sildenafil following radical retropubic prostatectomy, or with patients who have undergone non-nerve sparing procedures is poor in comparison to those who have undergone nerve-sparing procedures or radiotherapy. Sildenafil has been reported effective and well tolerated in men with diabetes, in those with cardiovascular disease, including those taking beta blockers, angiotensin-converting enzyme inhibitors, or calcium channel blockers and in those where the cause of erectile dysfunction is psychogenic.
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Several studies have documented the efficacy of sildenafil in the SCI population (Burns et al. 2001). A systematic review (Derry et al. 2002) (see Evidence Table 5b) found six studies, two randomised controlled trials and four prospective case series that assessed the efficacy and safety of sildenafil in the treatment of erectile dysfunction in men with SCI. A meta-analysis was not possible on the studies, but the review concluded that the existing evidence suggested that sildenafil is an effective and well tolerated treatment for erectile dysfunction in men with SCI (see Table 5a for doses used). Although erectile response rates were generally higher (74-100%) in patients with incomplete grades (B, C and D) versus patients with complete (A) lesions, the authors noted that large percent of patients with complete lesions also benefited significantly from sildenafil treatment with erectile response rates up to 74%.
The advantages of sildenafil use included the option of discrete use, far less invasiveness than surgery or injection, and ease of administration in men whose motor function may have been compromised by SCI.
It has been suggested that men with ED caused by SCI responded to sildenafil better than those with ED of vasculogenic origin (Schmid et al. 2000). The authors argue that men with SCI are typically younger with no organic damage to cavernosal tissue and that they have intact erectile function before their injury. This claim was analysed in the systematic review of sildenafil use in men with SCI (Derry et al. 2002) where some support was found for higher response rates to sildenafil for the treatment of ED in SCI men than for those with diabetes and slightly higher response rates than those with hypotension based on comparisons of extracted response rates from other studies. There was no difference found between SCI and vascular aetiology groups, however, on IIEF questions three and four. It has also been suggested that the mean effectiveness of sildenafil in treating ED in men with SCI with LMN in which reflexive erection is partial or absent is about 50% (Del Popolo, Marzi, Mondaini & Lombardi, 2004).
Safety Most reported sildenafil associated adverse events were vasodilatory effects – e.g., headache, flushing, nasal congestion, with gastrointestinal (dyspepsia) and visual (abnormal colour vision) effects reported less frequently (Burls et al. 2001; Fink et al. 2002; Moore et al. 2002; Padma-Nathan et al. 2002). Frequencies of most of these events tended to rise with increasing sildenafil doses. There have been no reports of priapism.
In an analysis of clinical trial results (Moore et al. 2002), treatment-related adverse events occurred in 30% of men on dose optimised sildenafil compared with 11% on placebo; the number needed to harm (NNH) was 5.4 (4.3 to 7.3). All cause discontinuations were less frequent with sildenafil (10%) than with placebo (20%). Sildenafil dose optimisation gave efficacy equivalent to the highest fixed doses, and adverse events equivalent to the lowest fixed doses.
In an evaluation of adverse events in men exposed to sildenafil for up to four and a half years in both clinical trials and independent post-marketing studies (Padma-Nathan et al. 2002), it was concluded that these studies have established an excellent overall safety profile for sildenafil. A summary of findings from randomised controlled trials is presented in Table 5 and from open label studies in Table 6. Reasons for discontinuation from open label studies are outlined in Table 7.
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Table 5. Most frequently reported adverse events from RCT (n=5198)
Placebo Sildenafil (%) (%) All causality Headache 5.6 19.0 Facial flushing 2.0 14.2 Dyspepsia 1.6 8.7 Dizziness 1.9 3.1 Rhinitis 1.5 5.1 Abnormal vision 0.7 5.9 Treatment related Headache 3.3 14.6 Facial flushing 1.9 14.1 Dyspepsia 0.7 6.2 Dizziness 1.1 2.2 Rhinitis 0.2 2.6 Abnormal vision 0.3 5.2 Discontinuations because of treatment related events 2.3 2.0
Adapted from Padma-Nathan et al., 2002, p.70
Table 6. Most commonly reported adverse events after 3 years of open label sildenafil treatment Adverse event Treatment Not treatment related related n (%) n (%) Coronary artery disease 0 (0.0) 19 (2.0) Prostrate disorder 0 (0.0) 12 (1.3) Dyspepsia 9 (0.9) 2 (0.2) Carcinoma 0 (0.0) 9 (0.9) Headache 9 (0.9) 0 (0.0) Myocardial infarction 0 (0.0) 8 (0.8) Abnormal vision 4 (0.4) 0 (0.0) Facial flushing 4 (0.4) 0 (0.0) Rhinitis 3 (0.3) 0 (0.0) Congestive heart failure 0 (0.0) 2 (0.2) Adapted from Padma-Nathan et al., 2002, p.72
Table 7. Discontinuations by year during 3 years of open-label sildenafil treatment, number (%)
Year 1 Year 2 Year 3 Total Treatment related Insufficient response 23 (2.4) 17 (1.7) 16 (1.6) 56 (5.7) Adverse event 5 (0.5) 3 (0.3) 2 (2.0) 10 (1.0) Total 28 (2.9) 20 (2.0) 18 (1.8) 66 (6.7)
Not treatment related • Adverse event 30 (3.1) 14 (1.4) 13 (1.3) 57 (5.8) • Lost to follow-up 21 (2.1) 17 (1.7) 18 (1.8) 56 (5.7) • Study violation 14 (1.4) 9 (0.9) 5 (0.5) 28 (2.9) • Withdrawn consent 17 (1.7) 16 (1.6) 16 (1.6) 49 (5.0) • Death 1 (0.1) 3 (0.3) 2 (0.2) 6 (0.6) • Other 29 (3.0) 11 (1.1) 12 (1.2) 52 (5.3) • Total 112 (11.5) 70 (7.2) 66 (6.7) 248 (25.3) • Grand total 140 (14.3) 90 (9.2) 84 (8.6) 314 (32.1) Padma-Nathan et al., 2002, p.72
In light of the mechanisms of action of PDE5 inhibitors and as a consequence of early post-marketing reports of deaths by sildenafil users, particular attention has been paid to the cardiovascular safety of sildenafil. Limits on the type of data that can be obtained from post marketing reports make it difficult to determine whether the deaths recorded were related to sildenafil, sexual activity, patient’s underlying disease or a combination of factors (Fink et al. 2002).
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A review of the safety of sildenafil (Padma-Nathan et al. 2002) that considered both randomised controlled trials (RCT) and open label studies concluded that there were no risks to cardiovascular safety with sildenafil when dosed according to prescribing information and current treatment guidelines. In 18 placebo controlled trials, the incidence of cardiovascular adverse events, aside from facial flushing, was 3.0% for sildenafil users and 3.5% for placebo. Overall, nearly 80% of cardiovascular adverse events were classified as mild, 16% moderate and 6% severe. In three years of open investigation, 3.6% of men discontinued because of adverse events involving cardiovascular systems. None of these were assessed by investigators as being related to sildenafil use. Sildenafil was not found to cause an increase in myocardial infarction (MI) or other serious cardiovascular events in a number of reviews (Mittleman et al. 2003; Padma-Nathan et al. 2002; Tran and Howes 2003).
Although sildenafil is a potent and selective inhibitor of PDE5, it also has an approximate 10-fold lower affinity for PDE6, which is present in high concentrations in the retinal photoreceptors (Padma- Nathan et al. 2002). Given that PDE6 is a key enzyme in the phototransduction cascade, the overall safety of sildenafil in the visual system has been extensively evaluated. While some visual adverse reactions have been reported these have typically been mild and overall incidence of abnormal vision low at about 2% (Padma-Nathan et al. 2002).
The existing evidence indicates that sildenafil use is not associated with significant structural or functional alterations to the visual system (Padma-Nathan et al. 2002). Sildenafil use is, however, contraindicated in men who have hereditary degenerative retinal disorders.
The incidence and types of adverse events experienced by men with SCI were similar to those published in other populations: headache, facial flushing, nasal congestion, dyspepsia and visual disturbance (Derry et al. 2002). Less than 6% of men with SCI discontinued sildenafil use during studies as a consequence of adverse events (Derry et al. 2002). In a randomised, double-blind, placebo- controlled, crossover study with 23 participants with SCI investigating cardiovascular responses to sildenafil there were no significant adverse events or outcomes reported (Ethans et al. 2003). Sildenafil did, however, induce significant hypotension in people with cervical-level injuries and, to a lesser extend in people with thoracic-level injuries. Sildenafil can cause dizziness in both populations. Autonomic dysreflexia (AD) is a concern in those with lesions above T6. In those studies that considered AD, none of the adverse events reported were considered to be related to AD (Derry et al. 2002).
4.3.2 Vardenafil On the basis of its pharmacokinetic profile, Levitra ® (vardenafil) is similar to sildenafil (Seftel et al. 2004). The recommended dose is 10mg and is taken as needed approximately 25-60 minutes before sexual activity. Similar to sildenafil, vardenafil is rapidly absorbed with a half-life of approximately four hours and the rate and extent of absorption is affected by meal intake. In addition to the general contraindications for PDE5 inhibitors, as with sildenafil, the use of vardenafil is also contraindicated in those with hereditary degenerative retinal disorders.
Two randomised double-blind, placebo controlled trials are presented in Evidence Tables 6a and 6b (Hellstrom et al. 2003; Porst et al. 2001). Both excluded men with ED after SCI and also excluded non- responders to sildenafil.
Trials with vardenafil have demonstrated significantly improved erectile function in comparison to placebo (Hellstrom et al. 2003; Porst et al. 2001). Overall, among active treatment patients, more than 70% of intercourse attempts were successful compared with 40% with placebo. Depending on dose (see Table 6b), success rates ranged between 65 and 85% for active treatment with vardenafil. In analysis of subgroups, it was reported that vardenafil improved erectile function regardless of the general aetiology, baseline severity of erectile dysfunction, or patient age (Porst et al. 2003). Improvements in erectile function and other key IIEF domains were consistently seen throughout the study. These findings are limited to subgroups of aetiology of ED included in the trials and excluded men with SCI.
The most common adverse effects of vardenafil reported have been headache, cutaneous flushing, dyspepsia and rhinitis in the mild to moderate range (Hellstrom et al. 2002; Hellstrom et al. 2003). Vardenafil has also been associated with minor visual disturbances, mainly transient increases in
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 21 brightness and haziness. The rates of the most common adverse events (headache, flushing, and dyspepsia) were either constant or declined over time; they were generally mild to moderate and transient in nature (Porst et al. 2003). No cases of priapism were reported.
A recent double-blind randomised study (Auerbach et al. 2004), that is currently only available in abstract form, reported that vardenafil produced clinically significant gains over placebo in erectile functioning domain scores in men who were non responders to sildenafil. It has been suggested that vardenafil may be the most effective of the three oral PDE5 inhibitors with respect to diabetes as judged by global assessment questions and most effective in the treatment of ageing men (Seftel et al. 2004). However, in the absence of published direct head to head trials, these are speculative suggestions only at this stage.
4.3.3 Tadalafil In both chemical structure and its PDE subtype selectivity profile, Cialis ® (tadalafil) differs markedly from sildenafil and vardenafil (Brock 2002). Tadalafil exhibits a prolonged plasma residence and window of therapeutic response with a half life of approximately 17.5 hours which means efficacy may persist up to 24 or even 36 hours post-dose. The recommended dose is 10mg taken 30 minutes to 12 hours prior to anticipated sexual activity. The pharmacokinetics of tadalafil are also not clinically significantly influenced by extrinsic factors, such as food or alcohol intake, or intrinsic factors, such as diabetes or renal or hepatic impairment (Dinsmore, 2004). The foregoing advantages, particularly the reduced need to plan sexual activity around time of either dosing or meal/alcohol consumption, have led suggestions that these factors may translate in clinical practice to enhanced convenience and acceptability of tadalafil to men with erectile dysfunction and/or their partners. In addition to the general contraindications for PDE5 inhibitors, the use of tadalafil is also contraindicated with moderate heart failure, uncontrolled arrhythmias and uncontrolled hypertension.
Two studies of tadalafil are presented in Evidence Tables 7a and 7b. One is a randomised, placebo controlled trial (Brock 2002) and the other an open label extension (Montorsi et al. 2004) from the same study. The studies were with men with mixed aetiology of ED. They excluded men with ED with a recent history (previous six months) of SCI but it is not clear from the description of participants whether or not any men with ED and a longer history of SCI were included.
Tadalafil significantly enhanced erectile functioning in men with histories of mild to severe erectile dysfunction ascribed to various causes in comparison to placebo (Brock 2002). A dose of 20mg tadalafil improved ability to achieve an erection in 81% of men with erectile dysfunction, showed similar efficacy in older and younger patients, and had consistent levels of efficacy in patients with mild (86%), moderate (83%) and severe (72%) erectile dysfunction. The number of successful intercourse attempts were 61% at 10mg dose and 75% at 20mg.
Adverse events associated with tadalafil were the same as those usually associated with PDE5 inhibitors including headache, flushing, dyspepsia, rhinitis, myalgia and back pain (Brock 2002; Montorsi et al. 2004). All were generally rated as mild to moderate and typically lessened with continued treatment. The incidence of adverse events was similar in younger and older patients, men with or without diabetes or hypertension, and irrespective of concomitant antihypertensives (Montorsi et al. 2004). Of note, a less frequent side effect specific to tadalafil is myalgia. No cases of priapism have been reported.
4.3.4 Comparison between oral medicines The only comparative study between PDE5 inhibitors is in Evidence Table 8 and compares preference for sildenafil versus tadalafil (Von Keitz et al. 2004). At the completion of the trial, 73% of participants chose tadalafil for extension and 27% sildenafil. From those in the dosing preference arm, the majority preferred tadalafil dosing instructions. The study did not thoroughly assess patient reasons for preference. Higher doses of tadalafil (20mg) were used in the study than recommended dose (10mg) and the numbers who were able to be on the higher 100mg dose of sildenafil in the study were restricted to 35%.
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A recent independent open label study (Porst et al. 2004) with 222 men with ED, currently available in abstract form only, investigated reasons for preferences between the three PDE5 inhibitors. Participants were exposed in arbitrary sequence to all three PDE5 inhibitors, after each sequence completed IIEF and a preference module. At the end of the trial preference, rates were: tadalafil 44% (97/222), vardenafil 32% (71/222), sildenafil 14% (31/222) and no preference 10% (23/222). Among the diabetic men in the trial preference, rates were vardenafil 35% (17/49), tadalafil 27% (13/49), sildenafil 14% (7/49) and no preference (no response at all) 24% (12/49). Of those who preferred tadalafil, 96% (93/97) cited duration of action as the main reason for their preference, of those who preferred vardenafil, 61% (43/71) cited onset of action as the main reason and of those who preferred sildenafil, 77% (24/31) cited efficacy as the main reason. Headache was the most common side effect: sildenafil 23%, vardenafil 17%, tadalafil 13%, but no analysis was reported in the abstract in order to determine whether the differences were significant.
4.3.5 Apomorphine Apomorphine (Uprima SL ®) has a different method of action than that of the PDE5 inhibitors. Apomorphine is a centrally acting agent and its pro-erectile effects appear to be induced by agonistic action to dopamine D1/D2 receptors within the hypothalamus (Brock 2002; Strebel et al. 2004). Sublingual apomorphine is a rapidly acting oral treatment whose half-life is two to three hours. The initial dose recommended is 2mg taken approximately 20 minutes before sexual activity. Subsequent doses may be increased to 3mg if necessary, with a minimum of eight hours between doses. Absorption across the sublingual mucosa is efficient and unaltered by food intake. Desired central dopaminergic effects are reportedly achieved at low doses. Contraindications listed for apomorphine are recent myocardial infarction, severe unstable angina, severe heart failure or hypotension and conditions where sexual activity is medically inadvisable. Product information lists potential harmful interactions between apomorphine and nebivolol or nicorandil and sildenafil.
One clinical trial of apomorphine is presented in Evidence Table 9 (Dula et al. 2000). The trial is part of a series conducted by the Apomorphine Study Group. The trials are with men with ED of mixed aetiology but exclude men with SCI. In clinical trials, apomorphine has been found to be effective in patients with ED of various etiologies and levels of severity, albeit with substantially less efficiency than reported with any of the PDE5 inhibitors (Dula et al. 2000; Heaton 2001). Among men who received apomorphine 2 or 4 mg, 42% and 51% of attempts, respectively, led to successful intercourse compared with 31% for placebo giving an implied NNT for apomorphine of about six. In 54.4% of attempts at 4mg (versus 33.8% placebo, P < 0.001), erections suitable for intercourse were documented. A majority of the attempts at intercourse (50.6%, P < 0.001) were successful at 4mg, a doubling of baseline rates (Heaton 2001). The percentage of attempts resulting in erections firm enough for intercourse was greatest in patients with mild or moderate ED; 89% of these patients who received at least eight doses of apomorphine SL 3mg achieved adequate erections during treatment (Stief et al. 2002).
Observed adverse events from apomorphine administration included nausea, yawning, dizziness, headache and somnolence. Most adverse events were rated as mild, transient and self-limiting and did not significantly affect compliance (Dula et al. 2000). Mild nausea was the most common but infrequent side effect and the rare occurrence of syncope was the most significant (Heaton 2001). There were no deaths, myocardial infarctions or cerebrovascular accidents attributed to the study drug and no reports of priapism.
An investigation of sublingual apomorphine as a treatment for erectile dysfunction in 22 patients with spinal cord injury concluded that the overall success rate was low for efficacy of apomorphine in improving erectile function in patients with SCI, irrespective of lesion type or number of attempts (Strebel et al. 2004). Seven patients had some response and reported that the drug helped them to obtain an erection, but only two reported erections sufficient for intercourse and would agree to continue apomorphine SL as their standard treatment; all the others reported being disappointed. Nine patients reported side effects. Adverse events were not clearly reported in the study but they appeared to be nausea, headache, increased tiredness, circulation problems, vertigo and blurred vision. There were no significant correlations for electrophysiological or urodynamic findings and treatment success. Of the 22 patients, 20 preferred the sublingual administration rather than the normal administration but only two rated apomorphine as more effective than previous ED treatments used (the authors did not state what these treatments were). On the basis of current evidence, the overall low rates of response
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 23 either for primary or secondary treatment suggest that apomorphine will have limited applicability in patients with SCI.
4.3.6 Comparison between apomorphine and sildenafil Perimenis et al., (2004) in a comparative, crossover study of the efficacy and safety of sildenafil and apomorphine in 43 men with evidence of arteriogenic erectile dysfunction found a greater overall success rate with sildenafil (63.7%) compared to apomorphine (32.1%). Incidence of adverse events was higher for men on 3mg apomorphine (nausea, headache, dizziness, syncope, two discontinued due to adverse events) than with sildenafil 100mg (mild headaches, dyspepsia, none discontinued due to adverse events). Satisfaction with treatment was reported by 77% of men with sildenafil, 14% for apomorphine and 21% were not satisfied with either drug. The significance of the findings is limited by the small number of participants.
4.4 OTHER PREFERENCE STUDIES BETWEEN MEDICINES
There were no direct comparative studies between oral medicines and different modes of delivery of vasoactive agents such as intracavernous injection. There were, however, a number of case series that investigated preference for medicines where men have received one type – e.g., intracavernous injections and then changed to another medicine, usually an oral medication. Given the paucity of direct head to head comparative studies findings from these studies have been included to give further information about preferences for different types of medicines. These studies are, however, of a lower quality and provide lower levels of evidence.
In three studies, previously successful intracavernous injection users (alprostadil monotherapy or in bimix or trimix combination) were asked to try sildenafil. Of those who switched, success rates of successful change to sildenafil were 75% (Hatzichristou et al. 2000), 69% (Giuliano et al. 2000), 2000) and 78% (Buvat et al. 2002). In a study that compared sildenafil use with previous intracavernous injection of alprostadil (Guiliano et al. 2000), success was reported as higher with injection than sildenafil (90% versus 79%, p<0.001). Data from the event log indicated a mean of 3.6 successful attempts at intercourse per four attempts monthly for alprostadil versus 10.9 per 13.7 attempts for sildenafil (p<0.001). Mean scores on questions three and four IIEF were similar after treatment with alprostadil and sildenafil. Mean satisfaction scores (Erectile Dysfunction Index) however, were higher after sildenafil use than with alprostadil, 73.8% and 63.9% respectively (p<0.001). In one study (Hatzichristou et al. 2000) of those who responded to sildenafil, after one month of treatment 71 (61.2%) preferred to continue with sildenafil, 31 (26.7%) returned to intracavernous injection and 14 (12.1%) used each drug alternatively. Three months later 74/116 responders (63.8%) preferred oral treatment and 38 (32.8%) chose intracavernous injection, while four (3.4%) continued to use each treatment alternatively. This study excluded men with known neurological disease such as paraplegia or multiple sclerosis.
In a reversal of the previous studies a programme of progressive intracavernous injections (increasingly complex combinations of vasoactive agents; papaverine, phentolamine, prostaglandin E1 and atropine sulphate) was trialled in men with ED with cardiovascular disease for whom sildenafil was not an option (Israilov et al. 2002). A total success rate of 94% for intracavernosal injection of vasoactive agents was reported.
4.5 OTHER ERECTILE DYSFUNCTION TREATMENTS
Yohimine (YOH) is a derivative of the African yohimbe and has been available as a treatment to enhance erectile functioning for several decades (Guay et al. 2003). The mechanism by which YOH operates is not fully understood but it is a potent selective alpha-2 androreceptor antagonist with weaker alpha-1 antagonist activity (Tam et al., 2001). Relatively few well-designed studies investigating the efficacy and safety of YOH have been completed (Guay et al. 2003; Tam et al. 2001). From those that have been undertaken, however, it appears that YOH as a monotherapy has only modest efficacy in treating men with ED (Tam et al. 2001). The evidence is even weaker in men whose ED is of organic aetiology (Guay et al. 2003). Reported major side effects are uncommon and minor adverse events include headaches, dizziness, insomnia and anxiety (Guay et al. 2003).
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Vacuum constriction devices (VCD) were described earlier in the report and the results of a study comparing intracavernosal injection and VCD (Soderdahl et al. 1997) discussed and presented in Evidence Table 2. Constriction sufficient to maintain rigidity may be safely maintained for 30 minutes. Differences from a normal erection include decreased penile skin temperature, cyanosis, distension of penile veins and increased penile circumference (Montague et al. 1996). Reported outcomes show relatively high probability estimates for a return to intercourse and for patient and partner satisfaction with VCD use (Montague et al. 1996). Pain and a degree of discomfort have been reported as side effects, although severe pain occurs infrequently and drop-out as a result of pain is uncommon. Older men with long standing relationships tend to accept VCD as a form of therapy more than younger men who may not have a steady partner (Guay et al. 2003).
4.6 SUMMARY OF EFFICACY AND SAFETY RESULTS
In summary, from available evidence from studies of efficacy, acceptability and safety for men with sexual dysfunction similar to ACC claimants (based largely on SCI populations and general studies mixed aetiology) the strongest evidence for efficacy and safety is for oral medications and in particular sildenafil. While there is good evidence for vardenafil and tadalafil and some indications for a preference for tadalafil with its longer half-life, for mixed aetiology ED this comes mainly from trials which have excluded men with SCI.
Of note is a study published after the completion of the literature search for the review in which sildenafil and tadalafil were compared in a randomised, blinded, crossover clinical trial in the treatment of 30 SCI men with ED (Del Popolo et al., 2004). Tadalafil use allowed 19 of the 28 men (67.9%) who completed the trial to achieve successful intercourse at the 24 hour post dosing period compared to 5/28 men (17.9%) on sildenafil (P<0.01). There were no significant differences between the two medications up to 12 hours post dosing. Tadalafil use also rated more highly than sildenafil on the quality of life measures of improved overall sex life satisfaction and sexual relations with partner. The authors suggested that the advantages of tadalafil in extending the duration of responsiveness may explain some of the positive participant responses to quality of life measures. They also caution that there needs to be more data in order to more fully evaluate tadalafil, particularly its long-term use and use in high risk groups.
Other advantages for the oral medications include the option of discrete use, far less invasiveness than injection, and ease of administration in men whose motor function may have been compromised by neurological injury.
High efficacy rates from intracavernous injections for those who continue with intracavernosal therapy are reported, although the evidence is from poorer quality studies than those for oral medications. There are high drop-out rates from these injection treatment programmes that limit the effectiveness of intracavernous injections as treatment option and unacceptable side effects of prolonged erections or penile fibrosis for some. If intracavernosal injections are used then there must be access to treatment of priapism should this occur. There is limited evidence for the effectiveness of intraurthral aprostadil (MUSE ®) or apomorphine SL in men with SCI.
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5. Economic assessment
A limited number of studies were located that investigated cost-effectiveness of the listed sexual dysfunction medicines. There were few direct comparisons of the cost-effectiveness of the listed medicines except for a small number which compared sildenafil with papaverine injection. None of the studies provided information on the New Zealand context. Nevertheless, several articles provided information which was useful to the economic analysis for this review, both as background or contextual information and also as specific data on the medicines being considered.
5.1 COST DRIVERS
Concern about the rising cost of treating male sexual dysfunction is the motivation for many of the studies of cost and cost-effectiveness. However, rather than taking rising costs as inevitable, health systems must note that several factors which influence cost trends can be clearly identified and this may lead to more realistic expectations of future costs. The major factors which have driven and may continue to drive the cost of treating male sexual dysfunction are:
population ageing advertising and consumer awareness a shift in the treatment of choice dosage frequency of use of treatment.
5.1.1 Population ageing It is noted throughout the literature that population ageing is the main driver of rising costs overall. Most males with erectile dysfunction are older and as this age group grows in number and grows as a proportion of the total population, it is expected that the total cost of treating erectile dysfunction will rise unless the cost per patient decreases significantly. This effect, however, may be a major driver of the demand for treatment for erectile dysfunction within the general population but not necessarily within certain subgroups: of most interest to this review, population ageing is not likely to affect the number of men presenting with erectile dysfunction as a result of injury or accident.
5.1.2 Advertising and consumer awareness To a lesser extent, the increase in direct-to-consumer advertising of treatment for erectile dysfunction, particularly since the introduction of effective oral medicines, is thought to have contributed to increasing the number of men presenting with erectile dysfunction. In addition to raising awareness about treatment availability, advertising creates the impression that the condition is quite common and helps to remove the embarrassment associated with the condition. Advertising of the currently available medicines, however, is likely to have had its effect already as it seems highly unlikely that many men would not be aware of the availability of treatment for erectile dysfunction at this point in time. Furthermore, it is questionable whether men whose erectile dysfunction is a consequence, even an expected consequence, of an identified medical condition would be as responsive to advertising as other men.
5.1.3 Shift in the treatment of choice In part, the large amount of advertising of treatment for erectile dysfunction in recent years is due to the availability of oral medicines which are considered to be more acceptable to patients than injection, prosthesis or vacuum devices. This acceptability appears to have led to a shift in the preferred treatment: Wilson et al. (2002) found that although the number of men presenting with erectile dysfunction and total cost to the British National Health Service of treating this condition increased
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 26 significantly from 1997 to 2000, the cost per patient fell by approximately 25% (Wilson et al. 2002). The decrease in cost per patient is attributed to the increasing use of sildenafil as a substitute for intracavernosal injections, prosthesis surgery, and vacuum devices and the corresponding shifting of cost from specialist to GP services. It is questionable, however, how long this shift will have an impact on costs: oral medicines have been available for several years now and awareness of this is generally high. Furthermore, there will be some point at which there will be no patients who may shift from an existing treatment to oral medicines either because of contraindications, effectiveness issues, or cost. As a result, this cost driver is likely to be temporary.
One factor related to the shift which may drive costs increasingly as the number of options increases is the process of selecting a treatment regime. Initially, patients being treated for sexual dysfunction may choose one of several options presented to them by their physician. Typically the treatment that is most acceptable to the patient in terms of cost and other factors (although not necessarily effectiveness as different patients experience success with different treatment) will be chosen in the first instance. Over a trial period, the patient’s dosage may be adjusted to generate a successful outcome or to reduce the occurrence of unpleasant side effects. Over this period, therefore, costs are likely to fluctuate. After the successful treatment option has been identified and an appropriate dosage has been determined costs will remain fairly constant unless frequency of use varies. Switching treatment regime after a certain period of time may imply a longer total trial period and, because a trial period may imply higher costs than the longer term average costs due to increased number of medical consultations as well as dosage adjustment, switching treatment regimes may itself be a costly option. The more options there are for treating erectile dysfunction, the more switching is likely to take place, resulting in patients spending longer periods in a phase of adjusting dosages. For this reason, it may be more cost-effective to have patients start on a treatment regime that they are most likely to remain with over the longer term rather than trying a lower cost option which may have a higher rate of attrition.
5.1.4 Dosage In addition to dosage adjustments over the short term after beginning treatment for sexual dysfunction, further adjustments can be made to dosage if required, either to reduce the occurrence of side-effects or to improve effectiveness. Most of the medicines are available in different strengths, which could result in costs varying significantly from what may have been expected. It is possible that the availability of medicines which are associated with a reduced rate of side effects would increase the willingness of patients to request higher doses and the willingness of physicians to prescribe them.
5.1.5 Frequency of use of treatment Frequency of use of treatment for sexual dysfunction has the potential to become a major cost driver as the shift from intracavernosal injections to oral medicines continues. Stolk et al. (2000) point out that the use of intracavernosal injections is recommended to be limited to once a week (New Zealand guidelines suggest a maximum of twice per week) but the recommended limit on the use of sildenafil is once per day (Stolk et al. 2000). Consequently, and in the absence of imposed limits, the choice of treatment for male sexual dysfunction may affect total costs beyond simply the difference in unit costs. In most studies of cost-effectiveness, values for cost per QALY gained are calculated assuming once a week usage of sildenafil. Doubling the frequency of use of sildenafil to twice a week, for example, would double the cost per QALY gained and, therefore, significantly affect cost-effectiveness.
The measurement of the benefit of treating male sexual dysfunction may be problematic for estimating cost-effectiveness at different frequencies of use: as net cost increases, net benefit would also have to increase to maintain the same cost-effectiveness ratio. Because net benefit is typically simply stated as the difference between utility for life potent and utility for life impotent, it would have to be demonstrated that utility of life impotent is lower for men who would use the treatment more frequently. Although this may seem to be a reasonable hypothesis, the quality of data may not permit this effect to be demonstrated.
Many health systems, HMOs and private health insurers which subsidise treatment of erectile dysfunction have introduced some element of rationing the supply of subsidised treatment in order to control costs when usage of a treatment is not medically rationed. Frequency of use, and therefore rationing, can have a significant effect on the cost per QALY gained (this effect is illustrated in detail
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 27 in section 5.5). Currently, ACC typically funds a maximum of four sexual dysfunction treatments per month per claimant.
Treatment rationing can effectively take two forms:
the non-medically-rationed treatment can receive a lower subsidy than the medically rationed treatment the non-medically-rationed treatment can receive a full subsidy but a limit is placed on how many times in a given period a subsidised prescription may be filled. This method is a more effective means of controlling costs as it imposes a firm upper limit on expenditures by the health system or insurer.
5.2 COSTS
In order to determine the cost of treatment of erectile dysfunction in New Zealand it is necessary to consider both direct and indirect costs and also to consider who is responsible for these costs as even without ACC involvement there are at least three major parties financing treatment of erectile dysfunction: the public health system, patients and their families, and private health insurance. For simplicity, costs are categorised as direct and indirect.
5.2.1 Direct costs Direct costs are medical costs which concern the purchase and use of the specific treatment. These would include the costs of health sector resources used and drug costs. The costs of any tests required to establish that the patient has a sexual dysfunction, which are also direct costs, are not included in this review as the analysis is done from the point of patients having been diagnosed. This review considered:
drug/treatment costs medical resource use (cost of physician time).
The direct costs which are currently incurred by the New Zealand health system include only the portion of drug cost which is subsidised and the portion of medical resource use which is subsidised. Papaverine injection is currently the only treatment for erectile dysfunction which is subsidised by Pharmac. Because papaverine is fully subsidised, its direct cost to the health system is the supplier price.
Some treatment options will imply greater costs to the New Zealand health system than others. Most notably, those treatments which involve injection often require specialist care rather than GP care. These would, therefore, probably imply greater direct costs in terms of medical resource use for these treatments.
The direct costs to the patient are all out-of-pocket expenses faced by patients in obtaining treatment. These include the cost to the patient of the medicines and also any charge faced by the patient for the medical consultation.
In order to identify the cost of medicines, an internet-based search on the cost of the treatment options was conducted and this resulted in a range of costs as well as subsidy information. Sources included Pharmac, the Male Clinic, the Australian Schedule of Pharmaceutical Benefits, and various web-based pharmacies including chemist.co.nz , scriptexpress.co.nz , and pharmacyweb.co.nz . The range of costs for each product is narrow, suggesting that although there may be some variability depending on supplier, the supply of these products is reasonably competitive in New Zealand. Costs are also reasonably similar across many of the different treatment options. These costs are presented in Table 8.
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Table 8. Cost of Medicines
Product Format/Cost Cost per use (range) Caverject ® (alprostadil) injection 10mcg: $24.00 $24.00 20mcg: $35.00 $35.00 Alprostadil (intraurethral) 10mcg: $24.00 $24.00 Papaverine injection 5 injections: $88.31 $17.66 ($73.31 subsidy) $3.00 (current cost to patient) Cialis ® (tadalafil) 4 x 10mg tabs: $73 - $80 $18.25 - $20.00 4 x 20mg tabs: $85 - $88.15 $21.25 - $22.04 Levitra ® (vardenafil hydrochloride 4 x 5mg tabs: $64.80 $16.20 trihydrate) 4 x 10mg tabs: $82 - $82.50 $20.50 - $20.63 4 x 20mg tabs: $89 - $91.40 $22.25 - $22.85 Uprima SL ® (apomorphine) 4 x 2/3mg tabs: $76 - $84 $19.00 - $21.00 Viagra ® (sildenafil) 4 x 25 mg tabs: $66.50 - $68 $16.63 - $17.00 4 x 50 mg tabs: $82 - $84 $20.50 - $21.00 4 x 100 mg tabs: $83 - $91.95 $20.75 - $22.99 Aramine/metaraminol 5 injections: $30.68 ($15.68 subsidy) $15.00 (treatment of priapism) Estimating the cost of medical resource use is problematic as it is unknown which patients have specialist care and which have GP care. Furthermore, the cost of consultations varies considerably across physicians. Over the long-term, however, the cost of medical consultations is likely to be small in relation to the cost of the treatment.
5.2.2 Indirect costs Indirect costs are medical costs which concern any related side effect or treatment that occurs as a result of the specific therapy as well as the associated use of medical resources (e.g., antidote to injections or treatment of fibrosis as well as physician time) and the cost of time, which may be experienced as lost wages. This review considered:
the medical resource cost of side effects the treatment cost of side effects the cost of medical consultations with GPs or specialists in order to adjust dosage or change treatment option the opportunity cost of time spent seeking treatment.
Most treatment for erectile dysfunction results in mild to moderate side effects or adverse events. Typically these do not require medical treatment and any follow-up care a patient receives to adjust dosage is likely to apply equally across treatment options. Again, however, certain treatments are likely to result in higher costs: Priapism and other more serious side effects, which are most common in patients using treatments which are injected, require urgent care and may often result in specialist care. The cost of metaraminol (Aramine) would be considered an indirect cost to the use of any treatment for which priapism is a risk but because it is heavily subsidised in New Zealand, it has a low cost to the patient. As noted earlier in this review, however, its use has been abandoned due to a reported death (Melman and Serels 2000). Alternative treatments of priapism may be more costly and in some cases surgery is required. Furthermore, less effective or more unpleasant treatments are likely to result in more switching of treatment options.
The costs associated with medical consultations and treatment of side effects cannot be estimated due to a lack of data. However, side effects which require treatment are sufficiently rare that the expected cost would be small and it is useful to note that side effects requiring treatment are typically associated with intracavernous injection, principally of papaverine.
The opportunity cost of time varies from patient to patient. This review, however, considered that on average there would be more time spent in consultations if treatment is less effective, has side effects, or is unpleasant.
The indirect costs to other sectors include any lost or gained productivity or requirements on other sectors related to the specific treatment. This review considered the potential for lost productivity as a result of workers being ill or temporarily absent from work. This is most likely to be associated with
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 29 injected treatments as these are more likely to result in serious side effects, but the rarity of these events, combined with the possibility that many of the men considered in this review may not participate in the labour force, makes lost productivity negligible.
5.3 COST-EFFECTIVENESS
Ideally, the effectiveness of all the treatment options would be stated in clinical reviews according to a common set of criteria in order to enable a meaningful formal evaluation of cost-effectiveness where the cost-effectiveness ratio of each treatment option could be compared and ranked reliably. Unfortunately, however, evidence on the effectiveness of many treatment options is scarce and where evidence exists, different trial design, criteria and definitions have been used. As a result, a formal cost-effectiveness analysis cannot be conducted on the entire range of treatment options. It is possible, nevertheless, to obtain useful information from the available data and to make comparisons over selected options. 5.3.1 Cost-effectiveness of oral medicines In the evaluation of effectiveness of the various treatments for erectile dysfunction, it was concluded that sildenafil would be a first line treatment due to its high effectiveness and low rate of adverse events. Based on the cost data presented in Table 8, the cost of sildenafil is expected to be from $16.63 to $22.99 per use. Although the clinical evidence does not allow a formal economic evaluation of the cost-effectiveness of each treatment option, it is possible to compare the costs of the treatments in light of the overall evidence of effectiveness in such a way that meaningful conclusions can be drawn. Given the cost of sildenafil and its rank as the treatment of choice for erectile dysfunction if only effectiveness and safety are considered, for another treatment to be preferred in terms of cost- effectiveness it would have to be significantly less costly. However, the other oral medicines – vardenafil, tadalafil, and apomorphine are associated with a cost that is in same range as the cost of sildenafil, as shown in Table 9 below.
Table 9. Range of costs for oral medicines
Treatment Minimum cost per use Maximum cost per use Average cost per use Sildenafil 16.63 22.99 19.81 Vardenafil 16.20 22.85 19.53 Tadalafil 18.25 22.04 20.15 Apomorphine 19.00 21.00 20.00 Minimum and maximum cost per use are determined by the unit prices of different dosages as well as the range across suppliers.
As shown in Table 9, not only do these treatments all have a cost per use within a fairly narrow range, the average cost per use is approximately $20.00 across all the treatment options. Given that vardenafil, tadalafil and apomorphine are in the same cost per use range as sildenafil, and given that their effectiveness has been shown to be inferior, it is clear that sildenafil is a more cost-effective treatment of erectile dysfunction than any of the above-mentioned alternatives. Any other costs associated with these medicines are not likely to vary significantly across the options. It follows, therefore, that amongst these options sildenafil would be a first line treatment and that vardenafil and tadalafil (to a lesser extent apomorphine, due to its significantly inferior effectiveness) would be considered where there are contraindications to using sildenafil. It is possible that, in some cases, tadalafil could be more cost-effective than assumed here, due to its longer life, which allows for a longer dosing interval and, hence, fewer doses over a given period.
5.3.2 Cost-effectiveness of papaverine and sildenafil There is some literature which makes a direct comparison of papaverine-phentolamine with sildenafil and the results are remarkably consistent. The literature suggests that amongst the most commonly prescribed treatments, sildenafil is generally found to be the most cost-effective. The most comprehensive cost-effectiveness analysis (Stolk et al. 2000) found that sildenafil compares favourably with papaverine-phentolamine injection. These results, however, are based on the assumption that frequency of use is the same for sildenafil as for papaverine-phentolamine, an assumption which could prove unreasonable in the absence of rationing.
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Wilson et al. (2002) found that although the number of men presenting with erectile dysfunction and total cost to the British National Health Service of treating this condition increased significantly from 1997 to 2000, the cost per patient fell by approximately 25%. The decrease in cost per patient is attributed to the increasing use of sildenafil as a substitute for intracavernosal injections, prosthesis surgery, and vacuum devices and the corresponding shifting of cost from specialist to GP services. This result suggests that the higher cost of medical resources associated with the use of intracavernous injection may be more significant than the different in treatment cost.
These results, however, depend on who pays the cost of the treatment. In New Zealand, patients face a very small cost for sildenafil as papaverine is heavily subsidised. From the point of view of the patient, therefore, papaverine could be as cost-effective as sildenafil although there is considerable uncertainty surrounding the medical consultation costs (which could involve specialist care) and indirect costs (mainly associated with treatment of side effects) associated with papaverine.
From the point of view of the New Zealand health system, and therefore taxpayers in general, which takes into account the true cost of papaverine, it is unlikely that papaverine could be as cost-effective as sildenafil.
5.3.3 Cost-effectiveness of papaverine and alprostadil The direct cost to the patient per use of papaverine injection is small and the medical consultation costs would be the same as for intracavernous alprostadil. Due to the subsidy on papaverine, from the point of view of the patient the only major costs associated with the use of papaverine injection are those related to medical consultations and the treatment of side effects (provided the treatment of side effects does not involve metaraminol as the latter is also heavily subsidised). To the New Zealand health system, however, papaverine is significantly more costly but still significantly less costly than alprostadil. Even though alprostadil is less likely to result in serious side effects, it is unlikely that it could be more cost-effective than papaverine. This conclusion is also supported by the limited evidence offered by the literature: Stolk et al. (2000) suggest that the reason sildenafil is most often compared with papaverine/papaverine-phentolamine than with alprostadil is that alprostadil is known to be more costly and is not significantly more effective. The results presented in the effectiveness and safety section, however, regarding the increased risk of priapism associated with the use of papaverine may make it less attractive to patients than other treatment options.
5.3.4 Alprostadil The cost per use of intracavernosal alprostadil is the same as intraurethral alprostadil. It is clear, therefore, that intracavernosal alprostadil is more cost-effective as intraurethral alprostadil has been shown to be less effective (Porst 1997; Shabsigh et al. 2000; Shokeir et al. 1999).
5.3.5 Sildenafil versus alprostadil The effectiveness of intracavernosal alprostadil is not significantly different from the effectiveness of sildenafil but its cost per use is higher. Only a frequency of use of sildenafil exceeding twice per week (which can be controlled by rationing), therefore, could result in a more favourable cost-effectiveness ratio for alprostadil. This conclusion is supported by the findings, above, that papaverine injection is likely to be more cost-effective than alprostadil and that sildenafil is more cost-effective than papaverine injection. It was also noted in the effectiveness section that in patients who have tried both alprostadil injections and sildenafil, the majority preferred sildenafil.
5.4 SUMMARY OF COST-EFFECTIVENESS COMPARISONS
The conclusions which can be drawn from the available cost-effectiveness evidence do not suggest a significantly different ranking than that recommended by the effectiveness section of this review. Sildenafil is likely to be the most cost-effective treatment for erectile dysfunction, with vardenafil and tadalafil being options resulting in somewhat lower cost-effectiveness on average. However, due to the potential for cost-effectiveness to deteriorate with frequency of use, rationing of oral medicines may be advisable (the following section elaborates on rationing of sildenafil and suggests that more than twice
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 31 per week usage would result in an unfavourable cost-effectiveness ratio). From the point of view of a public health system, papaverine injection is not as cost-effective as sildenafil but it is likely to be more cost-effective than alprostadil. Intracavernous alprostadil is more cost-effective than intraurethral alprostadil. Apomorphine would likely be among the least cost-effective options due mainly to its low effectiveness and a cost that is consistent with the cost of one of the most effective treatments (sildenafil).
5.5 COST PER QALY GAINED THROUGH THE USE OF SILDENAFIL
The conclusion on cost-effectiveness is strengthened by the significant amount of literature regarding the overall cost-effectiveness of sildenafil.
Stolk et al. (2000): the incremental cost-utility ratio for introduction of sildenafil was under $12,000 per additional QALY in the first year and improving thereafter. Suggested acceptable thresholds of cost-utility range from $25,000 to $75,000. Many interventions with less favourable cost-utility ratios are currently funded by public health systems. Using time-trade-off in a sample of 169 people from the general population mean utility gain attributable to sildenafil was found to be 0.11 (mean utility went from 0.807 at baseline to 0.915 at the end of treatment with sildenafil and from 0.819 to 0.821 for men receiving a placebo). Treatment with sildenafil is, therefore, determined to be cost-effective. The authors also calculated the incremental cost per incremental QALY gained, which determines whether the additional benefit of sildenafil over papaverine-phentolamine also falls within the threshold for cost-effectiveness. The result of the calculation was that the incremental cost per incremental QALY gained would be approximately $10,066 suggesting that the increased benefit of sildenafil over papaverine-phentolamine is derived at a reasonable cost. This calculation was based on a once per week use of either treatment and, more importantly, cost data from the Netherlands where papaverine- phentolamine costs approximately 20% less per dose than sildenafil. In New Zealand, papaverine costs only 10 to 15% less than sildenafil
Smith et al. (2000) investigated the cost-effectiveness of sildenafil in terms of QALYs gained compared with no treatment. This analysis included direct medical costs and indirect costs of obtaining care and, in the consideration of third party payer, also considered only direct costs. The cost per QALY gained for sildenafil treatment compared with no therapy was US$11,290 from the societal perspective and US$11,230 from a third party payer perspective. This study was biased against sildenafil, in that it assumed higher rates of morbidity and mortality than what is reported and also assumed a loss of treatment effect over time, an effect which had not yet been established.
Kwok (1999) calculated that the utility of life with impotence would have to be equal to or less than 0.98 compared with quality of life without impotence for Viagra ® (sildenafil) to meet conventional criterion for cost-effectiveness (i.e., less than U.S.$50,000 per QALY gained) (Kwok and Kim 1999). These estimates were based on assumptions that Viagra ® is used twice a week and costs U.S.$10 per pill. Corresponding utilities for once or three times a week are 0.99 and 0.97 respectively. For context, the utility associated with hypertension alone is estimated to be 0.94, based on the reported utilities of people with and without hypertension 0.98 is the estimated utility of people with allergies or hiatal hernia.
Using the New Zealand cost data and the utility gain attributable to the use of sildenafil from Stolk et al. (2000), it is possible to estimate the cost per QALY gained through the use of sildenafil in the New Zealand context (it is unlikely that utilities related to erectile dysfunction would be different in New Zealand so only costs will affect results). Cost per QALY gained is calculated as the difference between the cost of treatment with sildenafil and the cost of no treatment divided by the difference in utility offered by sildenafil. 1
1 Strictly speaking this is the calculation of cost-utility but in the context of treatment of erectile dysfunction, cost-utility is the same as cost per QALY gained because the adjustment for remaining life years applies equally to the cost (numerator) and to the utility difference (denominator). Consequently, the question of remaining life years does not need to be addressed as the number cancels out in the calculation.
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Using an assumption of once per week use of sildenafil, the direct annual cost of the treatment is approximately $1,040. Based on an improvement in utility of 0.11 (Stolk et al. 2000), the result is a cost per QALY gained of $9,455. If sildenafil is used twice per week, the cost-utility increases to $18,909. These calculations do not include the cost of medical consultations, although this cost would likely be small relative to the annual cost of sildenafil.
It should be noted, however, that the literature focuses on medical costs of erectile dysfunction in men who are not affected by spinal cord injury. Costs may be different for spinal cord injury patients. In addition, utilities may be different for spinal cord injury patients.
5.6 CONCLUSION OF ECONOMIC ASSESSMENT
The data on effectiveness and cost of treatment of erectile dysfunction did not allow for a formal economic evaluation of the different treatment options. However, based on the available cost data and the general conclusion of the effectiveness section, meaningful comparisons could nevertheless be made in order to provide some sense of relative cost-effectiveness of the treatment options.
The overall conclusion of the economic review of treatment of erectile dysfunction is that, given its high effectiveness and relatively low cost, sildenafil is likely to be the most cost-effective treatment of erectile dysfunction amongst the options considered when considered from the point of view of a public health system.
There is, however, an important qualifier to this result: In the absence of rationing any subsidy on sildenafil, sildenafil could be a significantly less cost-effective treatment option than intracavernosal injections (studies of patients not affected by spinal cord injury suggest twice per week rationing would ensure favourable cost-effectiveness). Estimates of cost per QALY gained suggest that the cost- effectiveness of sildenafil is within the acceptable range and that the increased benefits of sildenafil relative to papaverine/papaverine-phentolamine are at a reasonable additional cost.
Papaverine/papaverine-phentolamine injection is likely to be more cost-effective than alprostadil injection although the increased risk of priapism is not factored into cost-effectiveness calculations.
In the absence of rationing on oral medicines, the shifting of demand from intracavernosal injections to oral medicines is the only factor expected to continue to increase demand for treatment of erectile dysfunction.
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6. Conclusions and recommendations
Few studies with populations similar to ACC claimants were located. Sildenafil was the only medicine for which there were good quality studies available for some of this group, men with spinal cord injury. On the basis of the efficacy, safety and cost-effectiveness evidence available sildenafil is the preferred treatment for men whose erectile dysfunction is due to accident or injury. While studies to date on the newer medicines vardenafil and tadalafil demonstrate good efficacy and safety profiles and comparable costs, and there are some indications for preference for tadalafil (including a comparative study with men with SCI published after completion of the review) with its extended period of effectiveness, longer term efficacy and safety data is not yet available and most trials with these two medicines appear to have excluded men with spinal cord injury.
There are lower levels of evidence for the efficacy of intracavernous injection therapy (alprostadil, papaverine or combinations of vasoactive agents) for those who continue with its use in the treatment of erectile dysfunction. There are high drop-out rates from intracavernosal injection programmes, however, and higher rates of serious adverse events, including prolonged erection, for this method of treatment than for oral medications. While papaverine is cheap (and the only medicine currently funded by Pharmac), its use as a monotherapy for erectile dysfunction had been discontinued in many countries due to its higher rates of adverse side effects. Comparative studies have demonstrated greater efficacy for intracavernosal alprostadil than for intraurethral alprostadil (MUSE ®). While some evidence for the efficacy of apomorphine SL has been demonstrated, it is considered to be less effective than the PDE5 inhibitors sildenafil, vardenafil and tadalafil and its efficacy has not been demonstrated with men with erectile dysfunction due to spinal cord injury.
On the basis of the studies reviewed, oral medication with PDE5 inhibitors appear to be the first line treatment for ACC claimants whose erectile dysfunction is due to accident or injury. Sildenafil, as the oldest and most researched to date of these medicines, is the preferred treatment on the basis of its efficacy, safety and cost-effectiveness. Given the promise shown for vardenafil and tadalafil in mixed aetiology ED trials, results from comparative studies between sildenafil, vardenafil and tadalafil and investigation of vardenafil and tadalafil use with men with spinal cord injury should continue to be monitored with regard to purchasing decisions as further evidence for efficacy, preference and safety emerges. Tadalafil, in particular, with its longer half life appears to warrant consideration. Intracavernosal injection of alprostadil (monotherapy or in a combination treatment) may be considered as a second line treatment when sildenafil is contraindicated or where there is a non-response to this treatment. While alprostadil is a more expensive option than papaverine, given papaverine’s higher rate of adverse events and discontinuation of use in the treatment of ED in most industralised countries, alprostadil is favoured.
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 34
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 35
Appendix 1: Evidence Tables
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 36
Evidence Table 1a. Alprostadil intracavernous injection
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Linet et al. Study design Participants Efficacy and safety Dose response, no man In men with ED, (1996) Parallel-design, double Dose response 296 men, Men trained to self-inject responded to placebo intracavernosal injection of blind, dose response; men age 54 yrs. Dose before beg. 6 month trial. Dose related clinical P<0.001 alprostadil is an effective single-blind dose finding 201, mean age 54. Recorded in diaries freq. of response therapy with tolerable side escalation; open label, Efficacy and safety (open drug use, evaluations of Median effective dose (ug). Psychogenic 3.0 effects. flexible dose study label phase). 683 given erection (full, partial, none) Neurogenic 4.0 efficacy and safety. trial dose. and intercourse after each Efficacy and safety Vasculogenic 5.0 No long-term comparison Complete description injection. Sexual activity rated 606 adequate dose with placebo. Non- for open label phase Open label group ED by men and partners as determined, 577 began completers from open only in table. aetiology– 57% satisfactory or unsatisfactory. treatment at home, 471 label study 31%. Rate of vasculogenic, 13% Optional for partners rating (69%) completed 6 month drop-out lower than that Objective neurogenic, 10% satisfaction. study. reported elsewhere Investigate efficacy psychogenic, 20% mixed possibly because of close and safety of Age 20-75 (mean 56). Monthly clinic visits open- Dose titration monitoring of participants alprostadil formulated ended questions to elicit Mean dose at end of study and free drug supply. for intracavernosal Inclusion criteria information adverse medical 20.7ug c.f. 17.7ug at start. Side effects similar to those treatment in three ED > 4 months, stable events. Satisfactory sexual activity reported in other studies separate multi- sexual relationship, intact after alprostadil injection 11,924/13,762 (87%) using different formulations institutional sacral arc. Partner rating of satisfactory of alprostadil. prospective studies in sexual activity. 8496/9892 (86%). men with ED of Exclusion criteria Study sponsored by vasculogenic, penile deformity, history of Adverse events Upjohn. neurogenic, priapism, sickle cell, recent Penile pain reported by 50% psychogenic and major illness, uncontrolled of men receiving trial dose Level 111-1 mixed causes. diabetes or hypotension, (683). Pain occurred after major psychiatric disorder, 1873 of 16,575 injections Rating fair Study location HIV, heavy smoker. (11%), 6% withdrew from USA. study because of pain. Prolonged erection 35 men Duration (5%) of whom 3 Dose response and discontinued treatment. dose-finding in office administration/limited administration.
Efficacy and safety Home study, 6 months.
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 37
Evidence Table 1a. Alprostadil intracavernous injection (continued)
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Linet et al. Priapism occurred in 5 men (1996) (1%). Penile fibrosis detected in 15 men (2%). Systemic (Continued) adverse events occurred in 39 men (6%), most affected urogenital system (e.g., testicular pain and swelling; scrotal pain and edema; decreased or increased urinary frequency; hematuria: pelvic pain. 9 men (1%) reported side effects potentially related to hypotension.
Reasons for withdrawal adverse reactions, most often penile pain (64), lack of efficacy (56), loss to follow-up (27), dislike of self- injection (19), violation of protocol (14), difficulty scheduling visits (10), problems with partner (8), no need for drug (5), difficulty with injection technique (4), intercurrent illness (3), lack of sex drive (1), death (1 unrelated to study).
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 38
Evidence Table 1b. Alprostadil intracavernous injection
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Porst et al. Study design Participants In office titration Completers/drop-outs by Long running trial (1998) Open label. 162 men Men trained to self-inject. year of enrolment demonstrates that Mean age 54 Follow-up visits every 2 months First year (after 1 year of Completers 116 (71.6%) alprostadil (Alfadex) Objective (range 22-70) during first 3 years, quarterly therapy three centres with Drop-outs 46 (28.4%) represents a safe and Assess long-term during fourth year. 23 patients closed). effective treatment for ED efficacy and safety of Mean duration Second year) Completers 74 (45.7%) of both psychogenic and Alprostadil-Alfadex ED 4 years (1-37 years) At each visit diary recording all Drop-outs 88 (54.3%) organic origin. (EDEX/VIRIDAL). injections and side effects Third year Completers 63 (38.9%) Inclusion criteria examined and penile check Drop-outs 99 (61.1%) Decrease for all adverse Study location ED longer than I year, up conducted. Fourth year Completers 54 (33.3%) events across course of Multicentre, Germany, proven organic aetiology Drop-outs 108 (66.7%) study. France, Netherlands, or exceptionally After every 12 months Reasons for discontinuation: Denmark. psychogenic aetiology if intracavernous injection test closure centre 23; personal Total drop-out 66.7% over psychosexual counselling using same dosage as used at reasons, 19; patient lost, 11; four years. Duration for at least 6 months had home, combined with adverse events, 13; partner 4 years. failed. dopper/duplex sonography problems, 12; return High satisfaction rates carried out, also routine lab spontaneous erections, 11; among completers. Exclusion criteria check up and lack of efficacy, 4, protocol Not stated. electrocardiogram. Both violation, 4; other reasons, 5. Level – IV patient and spouse assessed tolerability and efficacy on Primary efficacy variable 1st year 90.7% Rating - Fair questionnaire. Ability of patients to achieve 2nd year 93.8% erection sufficient for sexual 3rd year 94.3% intercourse. 4th year 96.3% Total 93.1% 54 completers’ satisfaction rates more than 98% at completion of study.
Adverse events Prolonged erections >6 hrs 2 (1.2%) Pain 47 (29%) Hematoma 54 (33.3%) False injections 34 (21%) Fibrotic changes. 19 (11.7%)
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 39
Evidence Table 2. Comparison intracavernosal injection and vacuum constriction device
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Soderdahl et al. Study design Participants Exposure Outcomes Both the vacuum device (1997) Prospective 50 men First group of 27 men given 44/50 completed study and and injections are randomised, crossover Mean age 62.3, age range demonstration of vacuum were included in statistical effective treatment trial. 38-84, mean duration ED device then used method 15 analysis. 4 patients withdrew modalities for impotence 40 mths (range 38-84). times. Second group of 23 (2 due to illness, I moved and are associated with Objective given demonstration of ICI and 1 had priapism after first good long-term success. To determine if there is Inclusion criteria therapy, returned after a week injection) and 2 lost to a significant difference Previously untreated to demonstrate proficiency follow-up. Overall, there was a trend between organic impotence, stable then used method 15 times. (not significant) favouring intracavernosal sexual relationship. Erectile quality scores injection therapy over injection (papaverine/ Comparison Patient EVD 4.3 vacuum device which was phentolamine /PGE-1 Exclusion criteria After 15 uses, each group ICI 5.1 most significant in younger mix) and external Low testosterone levels if completed questionnaire Partner EVD 4.3 patients, those with short vacuum devices when elected hormonal detailing efficacy, satisfaction ICI 5.3 duration of impotence, compared directly for treatment, if psychogenic and side effects, repeated Trend favouring ICI over EVD and those impotent satisfaction, ED and testing with NPT after 15 uses of crossover but did not reach secondary to radical effectiveness and side showed normal nocturnal method. After using both significance. prostectomy. effects. erection patterns, if failed methods participants and to achieve satisfactory partners completed Both methods produced P<0.001 Advantages ICI quick and Study location(s) erection after using either questionnaire. higher scores than before easy with practice, USA, in home vacuum device or treatment. involved no ‘mess’ and treatment. injection-dose titration, if Patients contacted by phone provided a more ‘natural stated preferred one at 18-24 months and asked if Patient ratings of satisfaction EVD 5.4, ICI 6.5 P<0.05 erection’. Disadvantages Duration method to the other prior they had successfully used (Scale 1-10) invasive, occasionally Followed for 18-24 to study. either method in past month. Partner’s ratings of EVD 5.1, ICI 6.5 P<0.05 produced prolonged months. satisfaction erections, pain at injection (Scale 1-10) site, need for refrigeration no impact on final of solution, ‘thought of the preference from order in needle’. which treatments used Patient preferences at end ICI 25, EVD 12, both 6, none 4 Advantages EVD reliable, of treatment period non-invasive, quick and Contacted 18-24 months ICI – 17 ICI, 3EVD, 3 protheses, easy with practice, after study choice of 1 neither, 1 lost to FU; EVD suitable for travel. treatment by choice of 7EVD, 1 both, 2 neither, 2 lost treatment at end of study to FU; Both 2ICI, 2EVD, 1 return of normal erection, 1 lost to Adverse events FU; neither 1 prothesis Not reported except one withdrew following priapism after first injection.
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 40
Evidence Table 2. Comparison intracavernosal injection and vacuum constriction device (continued)
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Soderdahl et al. Disadvantages bulky, (1997) messy, time consuming, applying tension ring (Continued) sometimes difficult, often led to penile temperature changes (cooler at tip) and ‘hinging’ at base.
Some partners felt the device detracted from ‘the romance’.
No baseline erectile functioning described. Long follow-up but conclusions limited by small numbers completing study.
Level III-1
Rating Fair
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Evidence Table 3a. MUSE ® – Alprostadil Intraurethral
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Hellstrom et al. Study design Participants Exposure Outcomes Study provides short-term (1996) Multicentre, N=68 Self-administration of one dose Reported from 65 men. data that MUSE ® can randomised double- 26.8-76.4 years of placebo and four doses of EAS response of 4 or 5 125ug 19.7% restore erections and blind, crossover, Mean 58.6 transurethral alprostadil (125, (erection sufficient for 250ug 30.3% sexual intercourse in many placebo-controlled. ED> 41 months 250, 500 & 1000 ug) intercourse) reported by 500ug 26.7% men with organic ED. Aetiology – vascular (32), administered in random 49.2% on at least one dose. 1000ug 31.7% Local urogenital pain was Objective surgery/trauma (18), sequence. the most commonly Assess safety and diabetes (10), other (8). Each alprostadil dose reported adverse event efficacy of alprostadil Comparison significantly better than P<0.001 associated with MUSE ®. administered Inclusion criteria Active doses with placebo on placebo (score of 4 or Generally rated as mild to intraurethrally at home Unable to achieve ability to have sexual better 4.8%) moderate. for treatment of ED. spontaneous erection intercourse after each dose, Reported sexual intercourse Overall 63.6% 125ug 39.4% sufficient for intercourse in erectile response on 1-5 on at least one dose. 250ug 33.3% Enriched enrolment, only Study location(s) previous three months, in Erection Assessment Scale 500ug 40.0% those who successfully USA. stable monogamous (EAS), penile length and 1000ug 50.0% completed clinic relationship. circumference, penile Placebo 12.5% evaluation. Only one Duration response on 0-100 visual P <0.01 administration at each 2-4 weeks, at home Exclusion criteria analogue scale (VAS). Each Response rate was similar dose and placebo use. History of urethral end point assessed across etiologies No information on constricture; auria; immediately prior to and at 7, Inverse relationship between P <0.001 withdrawals. indewelling urethral 15, 20, 40 and 60 minutes after overall comfort ratings and catheter; prior penile drug administration. “Ease of alprostadil dose. Part funded by VIVUS Ltd. surgery; sickle cell disease; administration” and overall unstable angina or recent comfort 0-100 VAS. Adverse events Level 111-1 myocardial infarction; Penile pain or discomfort poorly controlled diabetes most frequently reported Fair to poor or congestive heart failure, ranged 9.1% (125 ug) to recent use of another 18.3% (1000 ug). Penile pain investigational agent. not associated with placebo administration Dizziness (1).
One episode prolonged erection and 2 of sustained erection (by same patient).
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Evidence Table 3b. MUSE ® – Alprostadil Intraurethral
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Padma-Nathan Study design Participants Exposure Outcomes Transurethral administration et al. (1997) Randomised double- Total 996 – Alprostadil 485, Self-administration of either Of 996 men who had of alprostadil was well blind, placebo- mean age 62 (38-84). selected dose alprostadil or treatment at home, 961 tolerated and effectively controlled. Placebo 511, mean age 61 placebo. reported results of at least restored capacity for (30-83). one administration and 873 erections and sexual Objective Comparison (87.7%) completed entire 3 intercourse in a substantial Evaluate system by Duration ED - Alprostadil After each administration, both month treatment period. proportion of men with which alprostadil is mean 48 months (3-528) man and partner, enter in chronic erectile delivered Placebo mean 49 months diary penile response, Sexual intercourse reported Alprostadil 299/461 dysfunction. intraurethrally at home (3-360). Aetiology occurrence of sexual at least once by 299/461 on 64.9% for treatment of ED. Alprostadil vascular intercourse, whether orgasm alprostadil, compared with Placebo 93/500 Enriched enrollment, only (28.9%), diabetes (19.2%), reached, overall level of 93/500 men in placebo (18.6%) those who had EAS Study location(s) surgery or trauma (31.1%), comfort with use of (18.6%). P<0.001 response of 4 or 5 to clinic USA. other (21.3%). Placebo medication, any adverse test dose and tolerated vascular (28.4 %), diabetes events noted. Among men in alprostadil alprostadil offered at Duration (18.8%), surgery or trauma group who reported having home trial. 996/1511 3 months at home. (31.8%), other (20.6%). sexual intercourse at least (65.9%) of men evaluated once, 7/10 administrations at clinic responded to Inclusion criteria were followed by alprostadil. Successful in clinic testing, intercourse (66.4% stable monogamous administrations in first month, Some of research team relationship, unable to 69% in second & 73.5% in employed by Vivus Ltd. achieve spontaneous third). erection sufficient for P<0.001 Level III-1 intercourse in previous Intraurethral alprostadil three months. effective regardless of Rating - Fair cause of ED or age of Exclusion criteria subject. History of urethral constricture; indwelling Alprostadil more effective P <0.001 urethral catheter; prior than placebo at each dose penile surgery; sickle cell studied. disease; unstable angina or recent myocardial infarction; poorly controlled diabetes or congestive heart failure, paraplegia or quadriplegia.
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Evidence Table 3b. MUSE ® – Alprostadil Intraurethral (continued)
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Padma-Nathan Among men who did not et al. (1997) complete study, 27 did not comply with study protocol, (Continued) 26 withdrew for personal reasons, 23 lost to follow-up, 15 withdrew because of adverse effects, 13 because treatment not efficacious, 3 had unrelated illnesses, and 16 withdrew for other reasons.
Adverse events Penile pain reported after 10% of alprostadil administrations by 32.7% of men.
At least one episode of minor urethral trauma reported by 5.1% Dizziness reported by 1.9%
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Evidence Table 3c. MUSE ® – Alprostadil Intraurethral
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Williams at al. Study design Participants Exposure Outcomes Success rate high in light of (1998) Parallel, randomised, Total 159. Alprostadil 78, Randomly assigned in a 249 men entered outpatient severity of study group. As double-blind, placebo mean age 57.3 (25-78). blinded manner to either most dosing phase. 159/249 (64%) study restricted to men controlled. Placebo 81, mean age comfortable, effective dose of achieved EAS score of 4 or 5 with complete organic ED, 57.3 (26-77). alprostadil or placebo for at (an erection sufficient for efficacy in men with mild Objective home administration. Men and intercourse or a full or moderate ED could be Examine safety and Duration ED - Alprostadil their partners agreed to erection). 140/159 reported expected to be higher. efficacy of mean 59.6 months (3-644). attempt intercourse at least 4 their responses to at least Effective in a broad range transurethral alprostadil Placebo mean 63.3 times. one dose and were of patients. for treatment of ED. months (4-417). included in analysis of Comparison efficacy. 159 men were Homogeneity of response Study location(s) Aetiology - Alprostadil Active doses with placebo on randomised to alprostadil or across subgroups. Most England, France, vascular (33), diabetes ability to have sexual placebo for home found method of therapy Germany, Ireland, the (18), surgery or trauma intercourse after each dose, treatment and were to be associated with Netherlands. (24), other (24). Placebo erectile response on 1-5 included in the analysis of minimal or no discomfort. vascular (41), diabetes Erection Assessment Scale, safety. Treatment well tolerated. Duration (15), surgery or trauma level of discomfort associated 3 months at home. (21), other (24). with treatment and any A total of 117 (74%) Enriched enrollment adverse reactions for patient completed 3 months of 26% did not complete. Inclusion criteria or partner. treatment. Intent to treat Successful in clinic testing, efficacy 44%. Four authors funded by stable monogamous Vivus Ltd. relationship, unable to Efficacy achieve spontaneous Intercourse during three MUSE ® 46/67 Level III-1 erection sufficient for months reported at least (69%) intercourse in previous once. Placebo 8/73 Rating - Fair three months. (11%) P<0.001 Exclusion criteria Not stated.
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Evidence Table 3c. MUSE ® – Alprostadil Intraurethral (continued)
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Williams at al. Patients administered 763 (1998) doses of transurethral alprostadil and reported (Continued) intercourse after 51% (390/763) administrations.
Responsive patients, those who reported intercourse at least once, were successful after 61% (390/763) administrations; with 56%, 67% and 65% success following administrations in first, second and third months.
Adverse events With active medication, drug-related urogenital pain reported by 11 (14%), minor urethral bleeding by 1 (1.3%) and dizziness by 2 (2.6%).
Of the 42 men who discontinued treatment, 12 lost to follow-up, 10 left for ‘other’ reasons, 5 did not comply, 5 requested discontinuation, 4 discontinued due to adverse reactions, 3 were improperly enrolled and 3 reported lack of efficacy.
Of these 42, 25 were on alprostadil and 17 were on placebo.
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Evidence Table 4a. Comparative study between intracavernous injection alprostadil and intraurethral alprostadil
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Shokier et al. Study design Participants Exposure Outcomes Although MUSE ® is less (1999) Prospective parallel N=60, Group 1 Self-administration of either Intercourse at home at least Grp 1 26 (87%) effective than randomised study. (intracavernosal) =30 selected dose intracavernosal once. Grp 2 16 (53%) intracavernosal PGE1, it is Group 2 intraurethral=30 or intrurethral alprostadil. P<0.05 more attractive and Objective Mean age Group1-55, Doses administered Grp 1 242 accepted well by most Compare Group2-56. Comparison Grp 2 360 patients as an easy intracavernosal After each home Intercourse reported after Grp1 206(85%) method of treatment with alprostadil with Aetiology Group1 vascular administration recorded in dose administered. Grp2 198 (55%) minimal or no discomfort. intraurethral alprostadil (9), diabetes (15), surgery/ diary EAS score, whether or not P<0.05 in the at home trauma (3), other organic sexual intercourse occurred Completed 3 month trial. Grp1 10 Small numbers in each treatment of ED. (3). Group2 vascular (6), and any adverse reactions; Grp2 25 treatment. diabetes (18), surgery/ comfort and ease of Home treatment assessed Grp1 12 (40%) Study location(s) trauma (3), other organic administration. as easy. Grp2 27 (90%) High drop-out rates from Saudi Arabia. (3). Intracavernosal alprostadil Adverse events Grp1 14 (47%) compared with Duration Mean ED duration (mths) Urogential pain. Grp2 2 (7%) intraurethral. 3 months. Group1 36, Group2 38. P<0.05 Discontinued because of Grp1 9 (30%) Level III-1 Inclusion criteria pain. Grp2 none Over 18, ED primarily Rating - Fair organic, unable to Group 2 urethral blood achieve spontaneous spotting, 1 (3%) and dizziness erection sufficient for due to hypotension (2 (7%). intercourse in previous three months. All patients Drop-out rates including those with poor Intracavernosal 67% response to outpatient Intraurethral 17% dosing were included in at P<0.05 home treatment.
Exclusion criteria Not stated.
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 47
Evidence Table 4b. Comparative study between intracavernous injection alprostadil and intraurethral alprostadil
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Shabsigh et al. Study design Participants Exposure Outcomes Intracavenous injection (2000) Crossover, open label, N=111 Receive either EDEX or MUSE ® Analysed on intent to treat therapy more efficacious, randomised study. Age range 30-79, mean during first treatment period, basis 95 men who had both better tolerated and 59.2 crossing over to opposite in office titration. 68 preferred by patients and Objective Aetiology of ED not stated. therapy for second treatment completed at home phase. their partners. Compare efficacy, period. Two phases in each At home treatment EDEX safety and patient Inclusion criteria treatment period: in office 315 administrations, MUSE ® Small numbers completed preference of ED at least 6 months, in dose titration 1-14 days and as 313. Mean number study but study enhanced intracavernosal stable heterosexual home treatment 21 days. administrations either drug by crossover design. alprostadil (EDEX) with relationship. 4.6, ACTIS used with 33% intraurethral alprostadil Comparison MUSE ® administrations Study funded by Schwarz (MUSE ®). Exclusion criteria Completed IIEF at baseline At least one erection EDEX 63 (92.6%) Pharma, two authors paid Previously received and at end of each treatment sufficient for intercourse. MUSE ® 42 (61.8%) consultants to the sponsor. Study location(s) intracavernosal or phase. At end of second P<0.0001 USA, home-based intrurethral treatment, treatment period, patient and At least 75% successful EDEX 51 (75%) Level II treatment. chemotherapy or other partner preferences assessed MUSE ® 25 (36.8%) medications that might using Product Assessment P<0.0001 Fair to good – difficult to Duration promote excess bleeding Survey. Safety monitored by Erectile function (Q1-5, 15) EDEX 25.3 conceal medication used 3+ months. or bruising after drug adverse event recording and MUSE ® 17.3 given different administration, physical and urologic P<0.0001 administration method. monoamine oxidase examination at intervals during Intercourse satisfaction (Q6- EDEX 10.7 inhibitors up to 2 weeks study. 8) MUSE ® 7.9 prior, concomitant P<0.0001 medication for ED or Patient and partner alpha-adrenergic receptor satisfaction ratings blocking agents, ED due to significantly higher with EDEX urologic abnormality, than MUSE ®. At end of study systolic BP< 100 mm Hg. both patients and partners indicated greater preference for EDEX (69%, 63%) than MUSE ® (16%, 10%). 42 chose to continue with EDEX compared with 12 who choose MUSE ®.
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Evidence Table 4b. Comparative study between intracavernous injection alprostadil and intraurethral alprostadil (continued)
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Shabsigh et al. Adverse events (at home) (1999) Patients with at least one EDEX 52.9% AE. MUSE ® 57.4% (Continued) Administrations resulting in EDEX 17.5% AE MUSE ® 18.2%
Application site reaction EDEX 1.5% MUSE ® 10.3% Other penile pain EDEX 33.8% MUSE ® 25 Local bleeding EDEX 1.5% MUSE ® 2.9% Prolonged erection EDEX only
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 49
Evidence Table 5. Meta-analysis: Sildenafil
Authors Focused Inclusion/ Explicit and Included trials Results Summary of main results Conclusions, strengths research exclusion comprehensive appraised for validity consistent study and limitations question criteria stated? research strategy to study? Level of evidence Fink et al. To determine Trials were eligible Studies identified by For each trial, two Overall yes, with 27 placebo-controlled trials involving Meta-analysis found (2002) the efficacy if included men searching MEDLINE, reviewers independently some differences 6,659 men met selection criteria. Most sildenafil use significantly and safety of with erectile HealthSTAR, Current assessed eligibility. between frequent trial design involved parallel improves erectile function sildenafil citrate dysfunction, Contents and Differences in eligibility subgroups and treatment design and flexible PRN and is well tolerated in in the treatment compared Cochrane library (1995 resolved by discussion. dose levels. dosing (n=14). Mean age 55 years, men with ED. of male erectile sildenafil with to 2000); bibliographies mean ED duration 4.8 years. dysfunction. control, were of relevant studies and Independent review, not randomised. review articles; urology Use of sildenafil produced a larger and drug company sponsored. journals and statistically significant improvement in Also, were of at conference erectile function compared with Results cannot be least 7 days proceeding abstracts, placebo. extrapolated to subgroups duration and FDA website; of men excluded from assessed clinically contacting Mean percentage of participants’ most evaluated trials with relevant manufacturer of sexual intercourse attempts that were the probable exception of outcomes (e.g., sildenafil. successful, sildenafil 57%, placebo 21% men with ED secondary to success of sexual (WMD, 33.7; 95% CI, 29.2-38.2). 83% of SCI for whom there are intercourse men sildenafil group reported at least data from trials that attempt, one successful intercourse attempt enrolled only those participant global compared with 45% of those receiving individuals. assessment of placebo (RBI, 1.8; 95% CI, 1.7-1.9). 78% treatment). sildenafil group reported that None of the trials lasted treatment ‘improved’ their erections longer than 26 weeks so compared with 25% placebo group long-term efficacy and (WMD, 39.4%; 95% CI, 35.6-43.2). safety data from randomised controlled Excluding sexual intercourse attempts trials not available. that failed for reasons other than an insufficiently hard or long lasting Only two published trials erection, 66% successful attempts in detailed an adequate sildenafil, 25% placebo (WMD, 39.4; method of random (95% CI, 35.6-43.2). allocation and concealment of treatment. WMD-weighted mean difference, RBI-weighted relative benefit increases, RRI-weighted relative risk assessment.
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 50
Evidence Table 5. Meta-analysis: Sildenafil (continued)
Authors Focused Inclusion/ Explicit and Included trials Results Summary of main results Conclusions, strengths research exclusion comprehensive appraised for validity consistent study and limitations question criteria stated? research strategy to study? Level of evidence Fink et al. Weighted mean end of treatment (2002) scores IIEF Q3 (n=3291), 3.8 sildenafil group, 2.3 placebo (WMD, 1.4; 95% CI, (Continued) 1.3-1.5), Q4 3.6 sildenafil vs 2.1 placebo (WMD, 1.5; 95% CI, 1.4-1.6).
Treatment response varied between patient subgroups but in all instances improved erectile function. Sildenafil may be slightly more efficacious at higher doses (50 vs 25mg).
Adverse events Men randomised to sildenafil less likely than those allocated to placebo to drop-out (7 vs 14%; RRI, 0.6; 95% CI, 0.7- 2.3) and no more likely to drop-out due to adverse event (1.3% vs 1.2%). 28% sildenafil group reported at least one adverse event compared with 36% in placebo.
Most commonly reported AEs for sildenafil: headache (11% vs 4% placebo), flushing (12% vs 2%), dyspepsia (5% vs 1%), visual disturbances (3% vs 0.8%); all differences were statistically significant. Adverse events more frequent at higher doses, most AEs mild or moderate in severity. WMD-weighted mean difference, RBI-weighted relative benefit increases, RRI-weighted relative risk assessment.
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Evidence Table 5a. Systematic review: Sildenafil use in men with SCI
Authors Focused Inclusion/ Explicit and Included trials Results Summary of main results Conclusions, strengths research exclusion comprehensive appraised for validity consistent study and limitations question criteria stated? research strategy to study? Level of evidence Derry et al. Review of All studies found Not stated. Not stated. Yes Two randomised controlled trials and 4 Author’s conclusions (2002) evidence for the on sildenafil use in prospective case series. Sample sizes Existing evidence suggests efficacy and SCI to date ranged from 13 to >170 men sildenafil effective and well safety of (2002). Inclusion criteria 4 studies included tolerated treatment for ED sildenafil patients with cervical lesions for in men with SCI. RCT that treatment in participants, 3 studies included demonstrated the smallest men with SCI. patients with sacral lesions, 1 did not improvement and where provide data on SCI level. 4/6 studies some of gains did not SCI severity classified according to reach statistical American Spinal Injury Association significance may be due (ASIA) Impairment Scale, in ¾ slightly to a number of factors – more than half had grade A small sample size, use of (complete) lesions. Mean age 37 fixed 50mg dose, short (range 19-68). Mean duration ED 9 study (4 weeks). years (range 6-11 years). Although erectile response Dose rates were generally higher In 1 RCT dose fixed at 50mg taken daily (74-100%) in patients with for 28 days, in the other RCT dosing incomplete grades (B, C & flexible and study drug could be D) versus patients with adjusted to 100 or 25 mg during 12 complete (A) lesions, a week treatment period. Dose in case large % of patients with series flexible ranged 25-100mg, complete lesions also treatment ranged from 3 months to 2 benefited significantly from years. sildenafil treatment with erectile response rates up Global efficacy (sildenafil improved to 74%. Incidences and erections) in 2 RCT 75% &76% “yes” types of AEs experienced compared with 7% & 4% placebo (P < similar to those published in 0.004, P<0.001 respectively). other populations. Proportions of patients with improved erections after sildenafil treatment higher in 4 case studies c.f. RCTs ranging from 88-94%. In the 2 RCTs intercourse success rate 30% for patients who received a fixed 50mg dose and 55% those who received a flexible (25-100mg) dosing regime.
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E Evidence Table 5a. Systematic review: Sildenafil use in men with SCI (continued)
Authors Focused Inclusion/ Explicit and Included trials Results Summary of main results Conclusions, strengths research exclusion comprehensive appraised for validity consistent study and limitations question criteria stated? research strategy to study? Level of evidence Derry et al. Corresponding rates for patients who (2002) received placebo 15% and 0%. Difference between groups statistically (Continued) significant in latter (P<0.001). In the one case series that examined this variable intercourse success rate was higher at 72%. Erectile function on IIEF questions 4 studies found statistically significant differences in mean scores.
Adverse events Among patients treated with sildenafil incidence of AEs from all causes ranged from 10-42%. In 2 RCT incidence all AEs patients treated with placebo ranged 6-31%. Incidence of treatment related AEs ranged from 6% (placebo) to 31% (sildenafil). In 3 of the case series 50%, 10% & 24% reported AEs (one study did not provide data). Most commonly reported AEs associated with sildenafil: headache (<18%), facial flushing (<10%), nasal congestion (<6%), dyspepsia (<4%) and visual disturbances (<4%).
Less than 6% of all patients discontinued treatment because of AEs. One study reported a subgroup of patients who were observed for >18 months who experienced no adverse side effects. Because 4/6 studies included patients with SCI lesions above T6, autonomic dysreflexia (AD) was a concern and incidence monitored. One study reported AEs were probably not AD related, 2 reported none of the patients reported dysreflexia symptoms, AD not mentioned in other 3 studies.
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Evidence Table 6a. Vardenafil
Authors Study design Participants inclusion/ Exposure/ Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Hellstrom et al. Study design Participants Exposure Outcomes Sustained improvement in (2003) Phase III, multi-centre, N=805, 197 randomised to Phase 1 4-week baseline when 1311 men screened, 805 erectile function over 26 randomised, double- placebo, 205 to vardenafil no ED treatment permitted; continued. During 26 week week period. Temporal blind, placebo- 5mg, 206 to vardenafil Phase 2 randomisation (by treatment 37% patients reduction in adverse controlled, 4-arm, 10mg, 197 to vardenafil random code) to 26 weeks discontinued, 54% of events. parallel group. 20mg. treatment with vardenafil or discontinuations were placebo; Phase 3 1 week placebo patients, 20% due Mean erectile functioning Objective Age range 57-78 years follow-up evaluation to to insufficient therapeutic scores at baseline Examine the influence Mean duration ED 2.3 monitor for adverse events. effect. consistent with moderate of time on key efficacy years. ED. parameters and safety Comparison Among vardenafil of vardenafil. Organic aetiology most Time course of IIEF-EF domain discontinuations 31% High number did not common diagnosis. scores at 4, 8, 12, 18 & 26 discontinued, 13% continue from initial Study location(s) weeks of treatment, time insufficient therapeutic screening. USA. Inclusion criteria course of Sexual Encounter effect in 5mg group, 10% Age >18, ED>6 months, Profile diary questions 2 (“Were (20) lost to follow-up. Funded by Bayer Corp. Duration patients with diabetes you able to insert your penis in Evaluation, 8% (15) adverse 26 weeks. included if glycosylated your partner’s vagina?”) and 3 events in 20mg group Level of evidence – II hemoglobin <12%. (“Did your erection last long IIEF domain score, enough for you to have regardless of dose, Quality rating Good Exclusion criteria successful intercourse?”) and vardenafil significantly P<0.0017 Anatomic penile time course of treatment- superior to placebo at each abnormalities, hypoactive emergent adverse events. time point. sexual desire, history of radical prostatectomy, Overall per patient success myocardial infarction or rates on ability to penetrate P=0.007 stroke in preceding six partner improved months, unstable angina significantly compared with pectoris, SCI, no response placebo. At 10mg & 20mg to previous sildenafil improved significantly at all treatment. time points versus placebo, 5mg statistically significant only at weeks 4 & 8.
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Evidence Table 6a. Vardenafil (continued)
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Hellstrom et al. Per patient success in (2003) maintaining erection until successful completion of (Continued) intercourse improved significantly for all men in 10mg & 20mg versus placebo.
Week 12 success rates Placebo 51.7% 5mg 65.5% 10mg 75% 20mg 80.5% Week 26 success rates Placebo 27.6% 5mg 64.9% 10mg 79.8% 20mg 85.2% Adverse events Most frequently observed in first four weeks and decreased over time. Headache, flushing, dyspepsia higher in those receiving vardenafil than placebo. With the exception of headache, incidence of adverse events increased with increasing dose. 8% (15 ) discontinued because of adverse events, all in 20mg.
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Evidence Table 6b. Vardenafil
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Porst et al. Study design Participants Exposure Outcomes Vardenafil treatment (2001) Phase IIb, multi-centre, 601 randomised, 11 did not Four week run in period during 590 evaluated for safety resulted in high efficacy randomised, double- take medication leaving which attempted intercourse population. Out of 590, 10 and low adverse event blind, placebo- 590 men, 152 in placebo, at least four times, then did not have an efficacy profile in a population with controlled, parallel 147 -5mg, 141 - 10mg, 150 - randomised into placebo evaluation at either baseline mixed etiologies. group. 20mg. tablets or vardenafil 5mg, or post-baseline leaving 580, 10mg or 20mg tablets. To be out of these 580, 74 Vardenafil safe and well Mean age for each group taken on demand but not exhibited a variety of tolerated. Efficacious in Objective approx. 52yrs more than once a day. Over protocol violations, leaving treating a population with Evaluate safety and Mean duration ED 12 week treatment. 506 in the valid for efficacy mild to severe ED efficacy vardenafil in approached 3yrs. population, placebo (124), 25% plus in all groups first at home use. Comparison 5mg (128), 10mg (123), psychogenic aetiology Inclusion criteria Primary outcome variables Q3 20mg (131). and would expect higher Study location(s) Required to be in stable and 4 IIEF. In addition various response rates than for USA, Belgium, France, heterosexual relationship, domains IIEF calculated. Efficacy organic aetiology ED. Germany, Poland, ED duration of at least six Patients answered Fugl-Meyer Q3 & Q4 score increase P<0.001 South Africa. months. Quality of Life Questionnaire vardenafil groups and Global Assessment compared to placebo Level of evidence – II Duration Exclusion criteria Question “Has the treatment IIEF all 3 doses vardenafil 12 weeks. Diabetes mellitus, SCI, you have been taking over the significant improvements in Rating Fair to good radical prostatectomy, past 4 weeks improved your domain score from baseline P<0.001 significant coronary heart erections?”. Diary kept by and significantly greater disease, history of hepatitis patients with details of their changes than placebo B and/or C, hypogonodal sexual encounters. GAQ all vardenafil groups testosterone levels (300 greater than placebo. P<0.001 ng/dl), thyroid stimulating Patients asked to record any hormone levels (<0, adverse events during course Rates of successful Placebo 23.7/39.5 28mU/l), non-response to of trial and followed for further intercourse 5mg 28.9/71.1 sildenafil. seven days after trial %baseline/%treatment. 10mg 26.1/70.9 completion to monitor for 20mg24.2/74.6 No other ED treatments serious adverse effects. permitted currently. Adverse events Androgens, antiandrogens, Headache 7-15% anticoagulants (except Flushing 10-11% low-dose asprin), Dyspepsia 1-7% cimetidine, ketoconazole, Rhinitis 3-7% rifampicin not allowed. In 12 patients AEs led to premature discontinuation, placebo (2), 5mg (7), 10mg (2), 20mg (1).
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Evidence Table 7a. Tadalafil
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Brock et al. Study design Participants Exposure Outcomes Treatment with tadalafil, (2002) Randomised, double- N=1,112 Following screening patients 995 (89%) completed particularly doses of 10 blind, placebo- Mean age 59 years, range who made at least 4 attempts treatment. 20 (less than 2%) and 20mg, significantly controlled, parallel 22-82 at sexual intercourse during a 4 discontinued because of improved erectile function groups. 90% had ED for > 1 year week treatment free run-in protocol violations. in a broad spectrum of 41% mild ED, 23% period were randomly patients with ED. Objective moderate, 36% severe allocated to 12 weeks Efficacy Evaluate efficacy and 61% organic aetiology, 31% treatment with placebo (308), Treatment with tadalafil Study supported by Lilly safety of tadalafil for mixed, 9% psychogenic. tadalafil at doses 2.5mg (74), significantly enhanced ICOS LLC, all authors either ED. Hypotension present in 30% 5mg (151), 10mg (321) or 20mg erectile function (versus financial interest or other of men, diabetes in 21% (258). placebo) across all three relationship with Lilly-ICOS, Study location(s) primary efficacy outcome P<0.001 Eli Lilly or ICOS Corporation. Not stated clearly but Inclusion criteria Comparison variables. authors from USA, 18 years or older, minimum For effects of tadalafil on Percentage of successful Placebo 32% Level of evidence II Canada, Australia, 3 month history mild to erectile function IIEF, Sexual intercourse attempts. 2.5mg 36% P<0.05 Taiwan severe ED, steady female Encounter Profile (SEP) and 5mg 42% P<0.001 Rating Fair partner. Global Assessment Question 10mg 61%P<0.001 Duration (GAQ). 20mg 75%P<0.001 12 weeks. Exclusion criteria Mean IIEF score change Placebo 0.6 Failure to achieve erection Vital signs assessed at each from baseline to endpoint 2.5mg 3.2 P<0.05 after radical visit (4 weekly) and patients 5mg 4.6 P<0.001 prostatectomy or pelvic followed for possible treatment 10mg 6.5 P<0.001 surgery, penile deformities related adverse events. 20mg 7.9 P<0.001 or penile implants, recent SEP Q3 analysed by intervals history of stroke or spinal 73-80% of intercourse cord trauma, attempts between 30 cardiovascular diseases, minutes and 36 hours post- clinically significant renal or dose resulted in successful hepatic insufficiency, completion in 20mg group. treatment with nitrates, Efficacy of tadalafil similar antiandrogens or cancer for patients. chemotherapy. Adverse events Most common AEs Headache 114 (14%) Dyspepsia 81 (10%) Back pain 50 (6%) Rhinitis 12 (4%) Myalgia 6 (2%) Flushing 6 (2%) Rate of discontinuation due to adverse events in tadalafil group 2.1% compared with 1.3% placebo
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Evidence Table 7b. Tadalafil
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Conclusions, comments level of Objective exclusion adverse events) evidence, quality rating Study location(s) Duration Montorsi et al. Study design Participants Exposure Outcomes Tadalafil safe and well tolerated. Most (2004) Multi-label extension trial. 1173 enrolled, 727 (62%) prior Initial washout period 493 (42%) completed 24 patients received dose of 20mg and most trial with tadalafil, 335 (28.6%) followed by initial 10mg dose months open label treatment. of the remainder 10mg. Objective placebo or 111 (9.5%) sildenafil taken as needed before 234 (19.9%) discontinued after Assess the long-term safety and Mean age 57 years, range 23.4- intercourse at maximum 18 months treatment due to a Patients had all participated in prior 8- tolerability of tadalafil for patients 82.8. frequency of once daily. At sponsor decision to reduce week or 12 week randomised, double- with ED. subsequent visits, doses could duration of study. Of the blind, placebo-controlled tadalafil 74.8% on medication for be increased by one dose remaining 446 patients, there studies. Study location(s) concomitant conditions level (e.g. from 10 to 20mg or were 4 deaths, 40 lost to Canada, Belgium, Italy, Germany, Inclusion Participated in prior 5 to 10 mg). follow-up, 402 Aetiology of participants not stated, only Spain, the Netherlands, Argentina, tadalafil studies, did not discontinuations. co-morbidities Mexico. discontinue and wished to Comparison continue ED treatment. 18 years Patients seen one month For 402 discontinuations, 173 Funded by ICOS LLC Duration or older, minimum 3 month after study entry and at three due to patient-perceived 24 months. history mild to severe ED, stable month intervals beginning at lack of efficacy, 94 personal Level of evidence III-1 heterosexual relationship. month 3. Safety analysis conflict or other patient included evaluation of decision, 74 adverse events, Rating Fair to Good Exclusion criteria adverse events, vital signs, 42 protocol and entry criteria Any of the following in the six serum chemistry, violations, 19 investigator or months prior to screening: haematology, EEGs, urinalysis. sponsor decisions. myocardial infarction, cardiac intervention, unstable angina Treatment emergent adverse Adverse events pectoris, angina pectoris during events were defined as any 71% patients had 1 or more intercourse, congestive heart untoward medical adverse events. Treatment- failure, sustained tachycardia, occurrences that either first emergent events reported by cardioverter-defibrillator, poorly appeared or worsened in a 2% or more of patients: controlled BP, significant patient receiving tadalafil. headache 185 (15.8%), hepatobiliary disease, dyspepsia 139 (11.8%), supraventricular arrhythmia, Serious adverse events were nasopharyngitis 134 (11.4%), recent history renal insufficiency, defined as adverse events back pain 96 (8.2%), influenza stroke or other CNS injury, drug, that resulted in one of 52 (4.4%), hypertension 48 alcohol or substance abuse. following outcomes: death, (4.1%), flushing 42 (3.6%), treatment with nitrates, initial or prolonged nasal congestion 42 (3.6%), antiandrogens or cancer hospitalization, life- arthralgia 41 (3.5%), cough 38 chemotherapy. threatening experience, (3.2%), influenza –like illness 37 severe or permanent (3.2%), myalgia 34 (2.9%), disability, cancer or bronchitis 32 (2.7%), diarrhea congenital anomaly. 30 (2.6%), dizziness 28 (2.4%), upper abdominal pain 27 (2.3%), nausea 25 (2.1%), limb pain 23 (2%).
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Evidence Table 7b. Tadalafil (continued)
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Conclusions, comments level of Objective exclusion adverse events) evidence, quality rating Study location(s) Duration Montorsi et al. Four deaths (3 cardiac (2004) deaths, 1 suicide) occurred during 24 month trial, none of (Continued) which assessed as treatment related. No clinically significant laboratory or EEG findings.
Serious events were experienced by 101 (8.6%) patients, of these 35 withdrew from treatment (3% total enrolled). No consistent pattern of serious events casually related to tadalafil emerged during study.
74 (6.3%) discontinued prior to completion, 36 (3.1%) due to AEs that were investigator assessed as possibly related to tadalafil. For any single event discontinuation rate less than 1% (headache 0.8%, dyspepsia 0.6%, myocardial infarction 0.6%, back pain, 0.4%, cerebrovascular accident 0.4%, angina pectoris 0.3%). Occular events that may have been related to PDE inhibition uncommon and generally mild or moderate.
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Evidence Table 8. Comparative preference study between sildenafil and tadalafil
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Von keitz et al. Study design Participants Exposure Outcomes In doses utilised in study, (2004) Randomised, double- 299 screened 265 eligible Drug preference either 181 (83%) in drug 73% of men preferred blind , crossover study to enrol. sildenafil 50mg or tadalafil preference study and 36 tadalafil with dosing consisting of four 20mg. Dosing instruction (78%) in dosing instruction instructions for treatment of treatment arms. 219 allocated to drug preference tadalafil therapy study chose to continue their ED over sildenafil with preference study tadalafil with either tadalafil or double-blind treatment in sildenafil dosing Objective (treatment arm 1, 105; sildenafil dosing instructions. extension period. 2 patients, instructions. During tadalafil Assess patient treatment arm 2, 114), 46 1 each sildenafil and therapy, 67% of men preference for ED to dosing instruction After 12 weeks patients tadalafil discontinued due preferred tadalafil dosing treatment between preference study crossed over. Following to perceived lack of instructions over sildenafil either sildenafil or (treatment arm 3, 24, crossover treatment period efficacy. Drug preference 132(73%) tadalafil dosing instructions. tadalafil, each treatment arm 4, 22) patients chose preferred choice for extension. 49(27%) sildenafil administered with their Mean age 52.5, age range double-blind treatment with P<0.001 Strengthened by crossover respective dosing 21-65, ED<1yr (6%), >1yr instructions to receive in 12 Preference held in all age arm. instructions, and to (94%), moderate to severe week extension. categories, across sites and evaluate preference ED (82%), organic or mixed existence of comorbidities, Limits to study 35% for either sildenafil or aetiology (93%). Comparison order of treatments or limitation on titration to tadalafil dosing Primary outcome patient titration did not affect sildenafil 100mg. Used instructions during Inclusion criteria preference for ED treatment as preference 20mg tadalafil, however tadalafil therapy. 18-65, in sexual relationship assessed by blinded patient Dosing instruction 24(67%) tadalafil with tadalafil 10mg recommended with female partner, at choice between either preference for extension. instructions dose. Study location(s) least 3 month history of ED, sildenafil or tadalafil to receive 12(33%) tadalafil with Germany, Spain, USA, non-responsive to previous during extension, Secondary sildenafil instructions P=0.046 Study did not thoroughly in home treatment. sildenafil treatment. outcomes included Adverse events assess reasons for patient preference for either sildenafil Treatment emergent events preference. Duration Exclusion criteria or tadalafil dosing instructions experienced by 2% or more 12 weeks plus 12 weeks Rapid ejaculation, ED due during tadalafil therapy and patients in drug preference 6/9 authors employed by crossover plus 12 week to untreated endocrine time between dosing and study Eli Lilly Co. extension offered?=. disorder, history of pelvic sexual attempt. BP and Headache Tadalafil 26(11.9%) surgery without evidence incidence of AEs recorded at Sildenafil 17(17.8%) Level of evidence II of preserved erectile every clinic visit. Dyspepsia Tadalafil 14(6.4%) function, stroke or SCI in Sildenafil 10(4.6%) Rating Fair to Good preceding 6 mths, HIV, Back pain Tadalafil 9(4.1%) current treatment with Sildenafil 4(1.8%) nitrates, myocardial Myalgia Tadalafil 9(4.1%) infarction or coronary Sildenafil 1(0.5%) revascularisation in Flushing Tadalafil 6(2.7%) preceding 90 days, Sildenafil 8(3.7%) unstable angina, retinitis Nasal congestion Tadalafil 6(2.7%) pigmentosa. Sildenafil 10(4.6%) Influenza like illness Tadalafil 3(1.4%) Sildenafil 7(3.2%)
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Evidence Table 9. Apomorphine
Authors Study design Participants inclusion/ Exposure/Comparison Outcomes (Include Effect size and precision Conclusions, comments Objective exclusion adverse events) level of evidence, Study location(s) quality rating Duration Dula et al. Study design Participants Exposure Outcomes Apomorphine SL is an (2000) Parallel, randomised, N=549. Age range 21-73 Randomly assigned to one of 44 completed 8 week effective and safe double-blind, placebo Duration ED 4.8 years four groups: dose optimization treatment period. treatment for ED, with 2 & 4 controlled. ED severe (35%), moderate apomorphine dose adjusted Mean percentage of Active treatment groups 47- mg providing the most (37%), mild (28%). 46% had weekly for 4 weeks as attempts resulting in 53 acceptable therapeutic Objective one or more of appropriate, then held stable erections firm enough for Placebo 35 index. Assess efficacy and hypertension (29%), for 4 weeks; two fixed dose intercourse. P<0.002 safety of several doses diabetes (6%), benign groups either 5 or 6 mg for 8 Incidence of nausea and of apomorphine SL in a prostatic hperplasia (16%), weeks; 8 week placebo group. Percentage of attempts Active treatment groups 45- other side effects dose optimisation coronary artery disease resulting in successful 51 diminished substantially schedule compared (12%). Comparison intercourse. Placebo 33 from first to second four with placebo. Percent of attempts resulting in week period. Inclusion criteria an erection firm enough for Patients in all apomorphine Study location(s) Stable heterosexual intercourse, percentage of groups had significantly Supported in part by grant USA. relationship at least 6 attempts resulting in an greater improvements in P<0.01 from TAP Holdings Inc. months, failed to achieve erection firm enough as rated erectile function compared Study part of Duration and maintain erections by partner, percentages of with placebo on IIEF Apormorphine study 8 weeks. firm enough for satisfactory attempts resulting in successful Partner satisfaction from P<0.05 group. intercourse in at least 50% intercourse, time between baseline to final visit greater attempts previous three drug administration and in all apomorphine groups Doses of 5 and 6mg higher months, evidence of erection. Information compared with placebo. than the recommended 2 intrinsic ability to have collected from home-use or 3mg dose. erection. questionnaires IIEF and BSFI Adverse events Dose optimization group 30%, completed by both parties Most common was nausea. 5mg 38%, 6mg 49%, placebo Level of evidence – II Exclusion criteria 98 % nausea events mild or 3%. Multiple sclerosis, SCI, Adverse events moderate. Rating Fair Parkinson’s disease, NS. hypogonadism, Other AEs, headache, hyperprolactinemia, dizziness, sweating, yawning, uncontrolled diabetes, somnolence. Seven cases of hypertension, radical syncope in apomorphine prostatectomy, major groups. Adverse event penile deformity, penile discontinuations prothesis, drug treatment ED previous 3 months, drug Reason for premature or alcohol abuse, AIDS, termination HIV, major psychiatric Adverse event, partial or disorder, history of cancer, complete lack of efficacy, partner breast feeding or non-compliant or lost to pregnant. follow-up, patient or partner request.
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Appendix 2: Critical Appraisal checklists
RANDOMISED AND NON-RANDOMISED CONTROLLED TRIALS
Assessment of Internal Validity
1. Was the assignment to the treatment groups really random? Adequate approaches to sequence generation: - computer-generated random numbers - random numbers tables.
Inferior approaches to sequence generation:
- use of alternation, case record numbers, birth dates or weekdays.
Not reported.
2. Was the treatment allocation concealed? Adequate approaches to concealment of randomization: - centralised or pharmacy-controlled randomisation - serially-numbered identical containers - on-site computer based system with a randomization sequence that is not readable until allocation - other approaches sequence to clinicians and patients.
Inferior approaches to concealment of randomization: - use of alternation, case record numbers, birth dates or weekdays - open random numbers lists - serially numbered envelopes (even sealed opaque envelopes can be subject to manipulation).
Not reported.
3. Were the groups similar at baseline in terms of prognostic factors?
4. Were the eligibility criteria specified?
5. Were outcome assessors blinded to the treatment allocation?
6. Was the care provider blinded?
7. Was the patient kept unaware of the treatment received?
8. Did the article include an intention-to-treat analysis, or provide the data needed to calculate it – i.e., number assigned to each group, number of subjects who finished in each group, and their results?
9. Did the study maintain comparable groups?
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10. Did the article report attrition, crossovers, adherence, and contamination?
11. Is there important differential loss to follow-up or overall high loss to follow-up? (Give numbers in each group).
ASSESSMENT OF EXTERNAL VALIDITY (GENERALISABILITY)
1. How similar is the population to the population to whom the intervention would be applied?
2. How many patients were recruited?
3. What were the exclusion criteria for recruitment? (Give numbers excluded at each step).
4. What was the funding source and role of funder in the study?
5. Did the control group receive the standard of care?
6. What was the length of follow-up? (Give numbers at each stage of attrition).
CASE SERIES
Internal validity
1. Was the study conducted prospectively?
2. Was the method of selection of cases identified and appropriate
3. Was the duration and completeness of follow-up reported and was it adequate?
4. Was the compliance/adherence to treatment measured and reported on?
5. Was the level of compliance likely to cause important bias?
External validity
1. Were descriptions of settings and locations of source population, eligible populations and sampling frame strategy sufficient to determine generalisability?
2. What percentage of eligibles participated?
3. What were the reasons for non-participation?
4. Were study exposures (i.e., interventions) feasible and affordable in usual practice?
5. Were all important outcomes considered?
6. Was it possible to determine the balance of benefits and harms of study exposure (i.e., interventions)?
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STUDIES REPORTING COMPLICATIONS/ADVERSE EFFECTS
Assessment of Internal Validity
1. Was the selection of patients for inclusion non-biased? (Was any group of patients systematically excluded?)
2. Is there important differential loss to follow-up or overall high loss to follow-up? (Give numbers in each group).
3. Were the events investigated specified and defined?
4. Was there a clear description of the techniques used to identify the events?
5. Was there non-biased and accurate ascertainment of events (independent ascertainer; validation of ascertainment technique)?
6. Were potential confounding variables and risk factors identified and examined using acceptable statistical techniques?
7. Did the duration of follow-up correlate to reasonable timing for investigated events? (Does it meet the stated threshold?)
Assessment of External Validity
1. Was the description of the population adequate?
2. How similar is the population to the population to whom the intervention would be applied?
3. How many patients were recruited?
4. What were the exclusion criteria for recruitment? (Give numbers excluded at each step).
5. What was the funding source and role of funder in the study?
SYSTEMATIC REVIEWS
1. Is there a clear review question and inclusion/exclusion criteria reported relating to the primary studies?
2. Is there evidence of a substantial effort to search for all relevant research?
3. Is the validity of included studies adequately assessed?
4. Is sufficient detail of the individual studies presented?
5. Are the primary studies summarized appropriately?
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ECONOMIC STUDIES
Assessment of Internal Validity
Framing
1. Was a well-defined question posed in answerable form? 2. Was a comprehensive description of the competing alternatives given? 3. Are the interventions and populations compared appropriate? 4. Is the study conducted from the societal perspective? 5. Is the time horizon clinically appropriate and relevant to the study question?
Effects
1. Are all important drivers of effectiveness included? 2. Are key harms included? 3. Is the best available evidence used to estimate effectiveness? 4. Are long-term outcomes used? 5. Do effect measures capture preferences or utilities?
Costs
1. Are costs and outcomes measured accurately? 2. Are costs and outcomes valued credibly? 3. Are costs and outcomes adjusted for differential timing? 4. Are all appropriate downstream medical costs included? 5. Are charges converted to costs appropriately? 6. Are the best available data used to estimate costs? (like first question) 7. Are all important and relevant costs and outcomes for each alternative identified?
Results
1. Are incremental cost-effectiveness ratios presented? 2. Are appropriate sensitivity analyses performed? 3. How far do study results include all issues of concern to users?
Assessment of External Validity
1. Are the results generalisable to the setting of interest in the review?
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Appendix 3: Search strategies
Medline strategy
1 Sex Disorders/ (3598) 2 impotence/ (8441) 3 impotence, vasculogenic/ (478) 4 Penile Erection/ (3621) 5 Libido/ (2778) 6 Ejaculation/ (3771) 7 coitus/ (4369) 8 orgasm/ (1179) 9 Infertility, Male/ (11875) 10 exp Fertility Agents, Male/ (11169) 11 ((erect$ or sex$ or ejaculat$) adj3 (dysfunct$ or function$ or disorder$)).mp. (14697) 12 genitalia, male/ (4422) 13 or/1-12 (56657) 14 caverject.mp. (11) 15 Alprostadil/ (5504) 16 cialis.mp. (15) 17 Phosphodiesterase Inhibitors/ (6668) 18 tadalafil.mp. (52) 19 levitra.mp. (8) 20 Imidazoles/ (24358) 21 muse.mp. (109) 22 Alprostadil/ (5504) 23 (pge1$ or prostaglandin e1$).mp. (8308) 24 Apomorphine/ (7410) 25 (apomorphine or uprima).mp. (9299) 26 Piperazines/ (17585) 27 (viagra or sildenafil).mp. (1662) 28 PAPAVERINE/ (4811) 29 papaverine.mp. (6174) 30 Metaraminol/ (783) 31 aramine.mp. (34) 32 or/14-31 (71763) 33 13 and 32 (2936) 34 randomized controlled trials/ (32035) 35 randomized controlled trial.pt. (188086) 36 random allocation/ (50531) 37 double blind method/ (77825) 38 single blind method/ (8032) 39 clinical trial.pt. (380807) 40 exp clinical trials/ (153620) 41 (clinic$ adj trial$).tw. (77346) 42 ((singl$ or doubl$ or treb$ or tripl$) adj (blind$ or mask$)).tw. (74436) 43 placebos/ (22956) 44 placebo$.tw. (83635) 45 randomly allocated.tw. (7616) 46 (allocated adj2 random).tw. (604) 47 meta-analysis/ (5341) 48 (metaanaly$ or meta analy$).tw. (11124) 49 meta analysis.pt. (9015) 50 exp review, literature/ (1986) 51 (systematic adj (review$ or overview$)).tw. (5426) 52 or/34-51 (550514)
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 66
53 33 and 52 (618) 54 comment.pt. (248544) 55 letter.pt. (503488) 56 editorial.pt. (160791) 57 animal/ (3601604) 58 human/ (8443364) 59 57 not (57 and 58) (2775049) 60 or/54-56,59 (3443804) 61 53 not 60 (595)
Medline (extra economics search)
1 Sex Disorders/ (3598) 2 impotence/ (8441) 3 impotence, vasculogenic/ (478) 4 Penile Erection/ (3621) 5 Libido/ (2778) 6 Ejaculation/ (3771) 7 coitus/ (4369) 8 orgasm/ (1179) 9 Infertility, Male/ (11875) 10 exp Fertility Agents, Male/ (11169) 11 ((erect$ or sex$ or ejaculat$) adj3 (dysfunct$ or function$ or disorder$)).mp. (14697) 12 genitalia, male/ (4422) 13 or/1-12 (56657) 14 caverject.mp. (11) 15 Alprostadil/ (5504) 16 cialis.mp. (15) 17 Phosphodiesterase Inhibitors/ (6668) 18 tadalafil.mp. (52) 19 levitra.mp. (8) 20 Imidazoles/ (24358) 21 muse.mp. (109) 22 Alprostadil/ (5504) 23 (pge1$ or prostaglandin e1$).mp. (8308) 24 Apomorphine/ (7410) 25 (apomorphine or uprima).mp. (9299) 26 Piperazines/ (17585) 27 (viagra or sildenafil).mp. (1662) 28 PAPAVERINE/ (4811) 29 papaverine.mp. (6174) 30 Metaraminol/ (783) 31 aramine.mp. (34) 32 or/14-31 (71763) 33 13 and 32 (2936) 34 economics/ (23792) 35 "costs and cost analysis"/ (32237) 36 cost allocation/ (1659) 37 cost-benefit analysis/ (32883) 38 cost control/ (15753) 39 cost savings/ (4744) 40 cost of illness/ (5924) 41 cost sharing/ (917) 42 health care costs/ (11435) 43 direct service costs/ (663) 44 drug costs/ (5879) 45 hospital costs/ (4263) 46 health expenditures/ (7945) 47 economics, pharmaceutical/ (1333)
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 67
48 ((low or high) adj cost$).mp. (10494) 49 (health?care adj cost$).mp. (835) 50 (fiscal or funding or financial or finance).tw. (31036) 51 (cost adj (estimate$ or variable$)).mp. (792) 52 (unit adj cost$).mp. (562) 53 (economic$ or pharmacoeconomic$ or price$ or pricing).tw. (67030) 54 or/34-53 (208271) 55 33 and 54 (52)
Embase strategy
1 Sexual Dysfunction/ (4556) 2 anorgasmia/ (196) 3 libido disorder/ (524) 4 Orgasm Disorder/ (75) 5 male sexual dysfunction/ (785) 6 Ejaculation Disorder/ (276) 7 potency disorder/ (20) 8 premature ejaculation/ (358) 9 impotence/ (5329) 10 erectile dysfunction/ (3329) 11 exp Male Infertility/ (9497) 12 exp male genital system/ (47495) 13 ((erect$ or sex$ or ejaculat$) adj3 (dysfunct$ or function$ or disorder$ or abnormalit$ or problem$ or insufficiency or disabilit$ or disturb$)).mp. (14788) 14 or/1-13 (72834) 15 Prostaglandin E1/ (5927) 16 (alprostadil or caverject).mp. (578) 17 Tadalafil/ (200) 18 (tadalafil or cialis).mp. (242) 19 Vardenafil/ (261) 20 (levitra or vardenafil).mp. (271) 21 muse.tw. (175) 22 apomorphine/ (5529) 23 (uprima sl or apomorphine).mp. (5966) 24 Sildenafil/ (2936) 25 (sildenafil or viagra).mp. (2995) 26 PAPAVERINE/ (4110) 27 papaverine.mp. (4485) 28 Metaraminol/ (399) 29 (aramine or metaraminol).mp. (428) 30 or/15-29 (18360) 31 14 and 30 (3805) 32 exp meta analysis/ (18191) 33 (metaanaly$ or meta analy$).tw. (10007) 34 (systematic$ adj (review$ or overview$)).mp. (5055) 35 randomized controlled trials/ (84438) 36 clinical trial/ (293803) 37 randomization/ (10351) 38 single blind procedure/ (4700) 39 double blind procedure/ (47129) 40 crossover procedure/ (14871) 41 placebo/ (43964) 42 randomi?ed controlled trial$.tw. (13282) 43 (clinic$ adj trial$).tw. (63165) 44 ((singl$ or doubl$ or tripl$ or trebl$) adj (blind$ or mask$)).tw. (55239) 45 placebo$.tw. (65410) 46 (random$ adj allocat$).tw. (6552) 47 prospective study/ (37210)
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 68
48 or/32-47 (417167) 49 31 and 48 (988) 50 case study/ (1631) 51 case report.tw. (65559) 52 abstract report/ or editorial/ or letter/ (406240) 53 or/50-52 (472219) 54 49 not 53 (939) 55 animal/ (7032) 56 exp animal experiment/ (639986) 57 55 or 56 (643872) 58 human/ (3798981) 59 57 not (57 and 58) (598290) 60 54 not 59 (936)
Psychinfo
1 caverject.mp. (0) 2 alprostadil.mp. (18) 3 cialis.mp. (1) 4 tadalafil.mp. (3) 5 exp Cyclic Adenosine Monophosphate/ (332) 6 (levitra or vardenafil).mp. (1) 7 alprostadil.mp. (18) 8 uprima.mp. (0) 9 apomorphine.mp. (2402) 10 exp APOMORPHINE/ (1590) 11 viagra.mp. (58) 12 sildenafil.mp. (102) 13 papaverine/ (34) 14 aramine.mp. (1) 15 metaraminol.mp. (18) 16 or/1-15 (2918) 17 "erection (penis)"/ or impotence/ (1096) 18 exp Sexual Function Disturbances/ (3474) 19 libido/ or inhibited sexual desire/ or sex drive/ (722) 20 sexual satisfaction/ or sexual arousal/ (1537) 21 ((erect$ or sex$ or ejaculat$ or penile or penis) adj (dysfunct$ or function$ or disorder$ or abnormal$ or problem$ or insufficiency or disabilit$ or disturb$)).mp. (5678) 22 exp male genitalia/ (897) 23 or/17-22 (9226) 24 16 and 23 (167) 25 male.af. (386554) 26 human males/ (12775) 27 or/25-26 (386699) 28 24 and 27 (137) 29 limit 28 to english language (134) 30 limit 29 to ("0700 editorials" or "0810 case study" or 1200 letter) (134)
Cinahl strategy
1 exp Sexual Dysfunction, Male/ (1274) 2 ejaculation/ or orgasm/ or penile erection/ (251) 3 ((erect$ or sex$ or ejaculat$) adj3 (dysfunct$ or function$ or disorder$ or abnormalit$ or problem$ or insufficiency or disabilit$ or disturb$)).tw. (1839) 4 Infertility/ (1139) 5 or/1-4 (3655) 6 caverject.mp. (2)
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 69
7 exp Prostaglandins/ (715) 8 cialis.mp. (3) 9 tadalafil.mp. (6) 10 levitra.mp. (4) 11 vardenafil.mp. (8) 12 muse.mp. (17) 13 alprostadil.mp. (15) 14 Apomorphine/ or uprima.mp. (20) 15 viagra.mp. or Sildenafil/ (316) 16 papaverine.mp. or PAPAVERINE/ (29) 17 aramine.mp. (1) 18 metaraminol.mp. (2) 19 or/6-18 (1076) 20 5 and 19 (277) 21 Meta Analysis/ (4411) 22 (meta analy$ or metaanaly$).tw. (2275) 23 (systematic$ adj (review$ or overview$)).mp. (5174) 24 "literature review"/ or "systematic review"/ (3121) 25 exp Clinical Trials/ (26082) 26 clinical trial.pt. (10557) 27 (clinic$ adj trial$).tw. (6010) 28 randomi?ed controlled trial$.tw. (5036) 29 ((singl$ or doubl$ or tripl$ or trebl$) adj (blind$ or mask$)).tw. (3491) 30 Placebos/ (2350) 31 placebo$.tw. (5372) 32 (random$ adj allocat$).tw. (752) 33 or/21-32 (35236) 34 20 and 33 (47)
Searches from other sources In databases and all other sources without controlled vocabulary combinations of the index terms and additional keywords from the above strategies were used in the search. Searching was completed in May 2004.
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 70
EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC 71
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EVIDENCE BASED REVIEW OF MEDICINES FOR SEXUAL DYSFUNCTION IN MEN : A REPORT COMMISSIONED BY THE NEW ZEALAND ACC