Diagnosis and Treatment of Erectile Dysfunction - Agency for

770 Pages·2009·9.7 MB·English

This report is based on research conducted by the University of Ottawa Evidence-based
Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality
(AHRQ), Rockville, MD (Contract No. 290-02-0021). The findings and conclusions in this
document are those of the author(s), who are responsible for its content, and do not
necessarily represent the views of AHRQ. No statement in this report should be construed as
an official position of AHRQ or of the U.S. Department of Health and Human Services.

The information in this report is intended to help clinicians, employers, policymakers, and
others make informed decisions about the provision of health care services. This report is
intended as a reference and not as a substitute for clinical judgment.

This report may be used, in whole or in part, as the basis for the development of clinical
practice guidelines and other quality enhancement tools, or as a basis for reimbursement and
coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of
such derivative products may not be stated or implied.
Evidence Report/Technology Assessment
Number 171

Diagnosis and Treatment of Erectile Dysfunction

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
540 Gaither Road
Rockville, MD 20850
www.ahrq.gov

Contract No. 290-02-0021

Prepared by:

University of Ottawa Evidence-based Practice Center, Ottawa, Canada

Investigators
Alexander Tsertsvadze, M.D., M.Sc.

Fatemeh Yazdi, M.Sc.

Howard A. Fink, M.D., Ph.D.

Roderick MacDonald, M.S.

Tim J.Wilt, M.D.

Karla Soares-Weiser, M.D., Ph.D.

Anthony J. Bella, M.D.

Dan Deforge, M.D.

Chantelle Garritty, M.Sc.(c)

Mohammed Ansari, M.D., M.Sc.

Margaret Sampson, M.L.I.S.

Raymond Daniel, B.A.

David Moher, Ph.D.

AHRQ Publication No. 08(09)-E016
May 2009
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This document is in the public domain and may be used and reprinted without permission except
those copyrighted materials noted for which further reproduction is prohibited without the
specific permission of copyright holders.

Suggested Citation:
Tsertsvadze A, Yazdi F, Fink HA, MacDonald R, Wilt TJ, Soares-Weiser K, Bella AJ, Deforge
D, Garritty C, Ansari M, Sampson M, Daniel R, Moher D. Diagnosis and Treatment of Erectile
Dysfunction. Evidence Report/Technology Assessment No.171 (Prepared by the University of
Ottawa Evidence-based Practice Centre (UO-EPC) under Contract No. 290-02-0021). AHRQ
Publication No. 08(09)-E016, Rockville, MD: Agency for Healthcare Research and Quality. May
2009.

No investigators have any affiliations or financial involvement (e.g. employment,
consultancies, honoraria, stock options, expert testimony, grants or patents received or
pending, or royalties) that conflict with material presented in this report.

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Preface

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based
Practice Centers (EPCs), sponsors the development of evidence reports and technology
assessments to assist public- and private-sector organizations in their efforts to improve the
quality of health care in the United States. The American College of Physicians requested and
provided funding for this report. The reports and assessments provide organizations with
comprehensive, science-based information on common, costly medical conditions and new
health care technologies. The EPCs systematically review the relevant scientific literature on
topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to
developing their reports and assessments.
To bring the broadest range of experts into the development of evidence reports and health
technology assessments, AHRQ encourages the EPCs to form partnerships and enter into
collaborations with other medical and research organizations. The EPCs work with these partner
organizations to ensure that the evidence reports and technology assessments they produce will
become building blocks for health care quality improvement projects throughout the Nation. The
reports undergo peer review prior to their release.
AHRQ expects that the EPC evidence reports and technology assessments will inform
individual health plans, providers, and purchasers as well as the health care system as a whole by
providing important information to help improve health care quality.
We welcome comments on this evidence report. They may be sent by mail to the Task Order
Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road,
Rockville, MD 20850, or by e-mail to [email protected].

Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H.
Director Director, Center for Outcomes and Evidence
Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality

David C. Dale, M.D., F.A.C.P. Beth A. Collins Sharp, Ph.D.
President Acting Director, EPC Program
American College of Physicians Agency for Healthcare Research and Quality

Steven Fox, M.D., M.P.H.
EPC Program Task Order Officer

Agency for Healthcare Research and Quality

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Acknowledgments

The authors would like to thank numerous individuals for their support of the present project.
Investigators thank Nathalie Lapierre, Gloria Baker, and Dorothey Ann Curran for their
assistance with screening articles and helping with data abstraction; David Mackie and Mary
Ocampo for helping with the evidence tables and appendices; and Tanya Horsley and Kasey
Parker, both of whom helped to coordinate the process. Investigators would also like to thank
Anne Marie Todkill, who assisted in the editing of the report.
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Structured Abstract

Objectives: To systematically review the evidence on efficacy and harms of pharmaceutical
treatments used in the management of male erectile dysfunction (ED); to explore the clinical
utility of routine hormonal blood tests (e.g. testosterone, prolactin) for identifying and treating
hormonal disorders and thereby affecting therapeutic outcomes for ED.

Data Sources: MEDLINE®, EMBASE, PsycINFO®, SCOPUS™, and Cochrane CENTRAL
were searched up to June 2007. Reference lists of relevant studies were also searched.

Review Methods: English language primary studies reporting effects of pharmaceutical
treatments used to treat men with ED were eligible for inclusion. The records were screened for
relevance, abstracted, and assessed for quality by two reviewers independently. The evidence
was summarized qualitatively and the results of randomized controlled trials (RCTs) were pooled
using meta-analyses. Subgroup and sensitivity analyses were also conducted.

Results: The evidence needed to ascertain the clinical utility of routine hormonal blood tests was
limited in terms of the amount and interpretability. Studies were heterogenous with wide
variations in the prevalence of hypogonadism or hyperprolactinemia in patients with ED. Overall
phosphodiesterase type 5 (PDE–5) inhibitors were superior to placebo in treating patients with
ED with clinically important and statistically significant between-group differences. Adverse
events however, were more frequent in PDE–5 inhibitor-treated patients. Few trials demonstrated
dose-response trends in the degree of efficacy or frequency of adverse events associated with
PDE–5 inhibitors. The clinical benefits conferred by use of PDE–5 inhibitors relative to placebo
were observed in patients with wide spectrum of comorbidities irrespective of the origin,
duration, or severity of ED. In head-to-head trials evaluating PDE–5 inhibitors, more patients
preferred tadalafil to sildenafil or vardenafil. Patients treated with intracavernosal or
subcutaneous injections experienced pain and priapism. The evidence for topical, intra-urethral,
and hormonal treatments for male ED was insufficient and inconclusive.

Conclusions: Evidence comparing cause-specific therapies (i.e. targeting underlying causes of
ED) to symptomatic treatments (e.g. PDE–5 inhibitors, injections, hormonal treatments) for
management of ED is lacking. Moreover, long-term effects of ED treatments have not been
adequately explored in RCTs. Studies using comparable study populations, diagnostic criteria,
and types of tests for hormonal disorders are needed to clarify the clinical utility of routine
hormonal blood tests in ED patients. There is also a need for trials comparing PDE–5 inhibitors
to other symptomatic treatments for ED (e.g. hormonal treatments, injections, topical
applications). This review outlined current gaps in knowledge that need to be addressed in future
research.

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Contents

Executive Summary........................................................................................................................ 1

Chapter 1. Introduction ................................................................................................................. 11

Objectives of the Systematic Review ........................................................................................... 11

Background................................................................................................................................... 11

Definition of Erectile Dysfunction............................................................................................ 11

Physiology of Erection.............................................................................................................. 11

Diagnosis of Erectile Dysfunction............................................................................................ 12

Epidemiology of Erectile Dysfunction ..................................................................................... 13

Classification of Erectile Dysfunction and Related Conditions ............................................... 13

Treatment of Erectile Dysfunction............................................................................................ 14

Utilization and Costs Related to Treatment of ED ................................................................... 14

Harms Observed in Clinical Trials ........................................................................................... 15

Measures of Efficacy in Erectile Dysfunction Therapy............................................................ 15

Knowledge Gaps and Uncertainties.......................................................................................... 15

Chapter 2. Methods....................................................................................................................... 17

Key Questions Addressed in This Report..................................................................................... 17

Analytic Framework ..................................................................................................................... 18

Search Strategy ......................................................................................................................... 19

Study Eligibility Criteria and Selection Process....................................................................... 19

Data Abstraction ....................................................................................................................... 20

Assessment of Study and Reporting Quality ............................................................................ 22

Synthesis of Evidence............................................................................................................... 22

Chapter 3. Results ......................................................................................................................... 25

Question 1. What is the Clinical Utility of Routine Blood Tests

(Testosterone/Prolactin/Luteinizing Hormone/Follicle-stimulating Hormone) in Identifying and

Affecting Therapeutic Outcomes for Treatable Causes of Erectile Dysfunction (ED)? ............. 25

Prevalence of Hormonal Abnormalities in ED Patients ............................................................... 25

The Efficacy of Hormonal Therapy in Treating Erectile Dysfunction in Patients with Hormonal

Abnormalities................................................................................................................................ 28

Questions 2-3. What is the Evidence of the Relative Clinical Benefits and Harms of

Pharmaceutical Treatments (e.g. Oral Medications) for Men Diagnosed With Erectile

Dysfunction?................................................................................................................................. 30

Oral Treatments — Phosphodiesterase Type 5 (PDE–5) Inhibitors - Sildenafil.......................... 30

Oral Treatments — Phosphodiesterase Type 5 (PDE–5) Inhibitors – Vardenafil........................ 44

Oral Treatments — Phosphodiesterase Type 5 (PDE–5) Inhibitors – Tadalafil .......................... 54

Sublingual Treatments - Apomorphine......................................................................................... 67

Injection Treatments - Intracavernosal Injection .......................................................................... 74

Injection Treatments - Subcutaneous Injections........................................................................... 82

Intra-urethral Suppositories .......................................................................................................... 84

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Topical Treatments ....................................................................................................................... 88

Hormonal Treatments ................................................................................................................... 91

Other Treatments (Off Label) ..................................................................................................... 100

Question 3a. What are the Harms of Pharmaceutical Treatments for Male Patients With ED?. 103

Oral Medications: PDE–5 Inhibitors .......................................................................................... 103

Injection Treatments ................................................................................................................... 103

Chapter 4. Discussion ................................................................................................................. 105

Strength of the Evidence............................................................................................................. 105

Question 1: What is the Clinical Utility of Routine Blood Tests—Testosterone, Prolactin,

Luteinizing Hormone, Follicle-stimulating Hormone—in Identifying and Affecting Therapeutic

Outcomes for Treatable Causes of ED?...................................................................................... 107

Questions 2–3: What Are the Benefits and Harms of Pharmaceutical Treatments for ED? ..... 109

Question 2a-b: Do Specific Patient Characteristics (e.g. Origin, Severity, or Duration of ED,

and Comorbid Conditions) Affect Prognosis or Treatment Success for ED patients?............... 117

Questions 3a: Specific Harms of Pharmaceutical Treatments in Male Patients with ED .......... 118

Methodological and Logistic Limitations of the Systematic Review......................................... 119

Future Research Recommendations............................................................................................ 120

Tables
Table 1: Population Characteristics of Studies Measuring Hypogonadism in Men with Erectile
Dysfunction…………………………………………………………………………………..…121
Table 2: Prevalence of Hypogonadism in Men With Erectile Dysfunction (Serum Total
Testosterone………………………………………………………………………………….....125
Table 3: Prevalence of Hypogonadism in Men With Erectile Dysfunction (Serum Free or
Calculated Testosteron…………………………………………………………………………128
Table 4: Prevalence of Hypogonadism in Men With Erectile Dysfunction (Serum Bioavailable
Testosterone…………………………………………………………………………………….129
Table 5: Population Characteristics of Studies Measuring Hyperprolactinemia in Men with
Erectile Dysfunction……………………………………………………………………………129
Table 6: Prevalence of Hyperprolactinemia in Men With Erectile Dysfunction (Serum Prolactin
Levels…………………………………………………………………………………………...131
Table 7: Prevalence of Hyperprolactinemia in Men With and Without Erectile Dysfunction
(Serum Prolactin Levels)………………………………………………………………………133
Table 8: Population Characteristics of Studies Measuring Serum LH/FSH Levels in Men With
Erectile Dysfunction……………………………………………………………………………133
Table 9: Prevalence of Primary or Secondary Hypogonadism in Men With Erectile Dysfunction
(Total Serum Levels of LH and FSH) ………………………………………………………….135
Table 10: Serious Adverse Events in Sidenafil vs. Placebo (Data From RCTs) ………………137
Table 11: Efficacy Results of Tadalafil by ED Severity Groups……………………………….139
Table 12: Intracavernosal Injection: Sexual Intercourse Success………………………………140
Table 13: Intracavernosal Injection: Improvement in Erections ………………………………140
Table 14: Intracavernosal Injection: Patients With Adverse Events……………………………145
Table 15: Subcutaneous Injection: Improvement in Erections…………………………………150
Table 16: Subcutaneous Injection: Patients With Adverse Events……………………………...151
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Table 17: Intra-urethral Treatment: Sexual Intercourse………………………………………...152

Table 18: Intra-urethral Treatment: Improvement in Erections ……………………………….154

Table 19: Intra-urethral Treatment: Patients With Adverse Events…………………………….155

Table 20: Alprostadil (Topical Cream) vs. Placebo: Sexual Encounter Profile (SEP)…………158

Table 21: Topical Treatment: Improvement in Erections ……………………………………..158

Table 22: Topical Treatment: Patients With Adverse Events

..........................................................................................…………………………………...160

Table 23: Testosterone: Improvement in Sexual Intercourse Outcomes...........................……..162

Table 24: Testosterone (T) Combined With PDE–5 inhibitors: Improvement in Sexual

Intercourse Outcomes…………………………………………………………………………..164

Table 25: Testosterone Treatment: Improvement in Erections…………………………………166

Table 26: Testosterone Treatment: Patients With Adverse Events ……………………...……171

Table 27: Miscellaneous Treatments: Efficacy and Adverse Events…………………………...175

Table 28: Nonarteritic Anterior Ischemic Optic Neuropathy (NAION)………………………..177

Table 29: Penile Fibrosis in Studies of Intracavernosal Injection (Non-randomized)………….179

Figures
Figure 1. Analytic Framework for the Diagnosis and Treatment of Erectile Dysfunction....... …18

Figure 2. Modified QUOROM Flow Chart .............................................................................. …22

Figure 3. The Mean IIEF “EF Domain” Score ......................................................................... ..182

Figure 4. The Mean IIEF–Q3 Score ......................................................................................... ..182

Figure 5. The Mean IIEF–Q4 Score ......................................................................................... ..182

Figure 6. Improved Erection (GEQ–Q1) .................................................................................. ..183

Figure 7. Any Adverse Events (All Causes)............................................................................. ..183

Figure 8. Any Treatment-related Adverse Events .................................................................... ..183

Figure 9. Headache (All Causes) .............................................................................................. ..184

Figure 10. Flushing (All Causes)................................................................................................184

Figure 11. Visual Disturbances................................................................................................. ..185

Figure 12. Improved Erection (GEQ–Q1): Type I and II Diabetes Patients Combined........... ..185

Figure 13. Improved Erection (GEQ–Q1): Type II Diabetes Patients Only............................. ..186

Figure 14. The Mean IIEF–Q3 Score: Type I and II Diabetes Patients Combined....................186

Figure 15. The Mean IIEF–Q4 Score: Type I and II Diabetes Patients Combined....................186

Figure 16. Any Treatment-related Adverse Event: Type I and II Diabetes Patients Combined 187

Figure 17. Any Treatment-related Adverse Events:Type II Diabetes Oatients Only.................187

Figure 18. Successful Intercourse Attempts: Patients With Major Depressive Disorder in

Remission………………………………………………………………………………………..187

Figure 19. Improved Erection (GEQ–Q1): Patients With Major Depressive Disorder in

Remission.................................................................................................................................. ..187

Figure 20. The Mean IIEF–Q3 Score: Patients With Major Depressive Disorder in Remission.188

Figure 21. The Mean IIEF–Q4 Score: Patients With Major Depressive Disorder in Remission 188

Figure 22 The Mean IIEF–Q3 Score: Patients With Hypertension on Antihypertensive Drugs 188

Figure 23. The Mean IIEF–Q4 Score: Patients With Hypertension on Antihypertensive Drugs

………………………................................................................................................... …189

Figure 24. Improved Erection (GEQ–Q1): Patients With Hypertension on Antihypertensive

Drugs……………..................................................................................................................... ..189

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Figure 25. Successful Intercourse Attempts: Patients With Hypertension on Antihypertensive

Drugs………………………………………………………………………………………….....189

Figure 26. Any Adverse event (All causes): Patients With Hypertension on Antihypertensive

Drugs………………………………………………………………………………………….....190

Figure 27. Headache (Treatment-related): Patients With Hypertension on Antihypertensive

Drugs…..................................................................................................................................... ..190

Figure 28. Dyspepsia (Treatment-related): Patients With Hypertension on Antihypertensive

Drugs…..................................................................................................................................... ..190

Figure 29. Flushing (Treatment-related): Patients With Hypertension on Antihypertensive

Drugs…..................................................................................................................................... ..190

Figure 30. Improved Erection (GEQ–Q1) ................................................................................ ..191

Figure 31. Headache (All Causes) ............................................................................................ ..191

Figure 32. Flushing (All Causes)................................................................................................191

Figure 33. Visual Disturbances (All Causes)............................................................................ ..191

Figure 34. Improved Erection (GEQ–Q1) ................................................................................ ..192

Figure 35. Headache (All Cause).............................................................................................. ..192

Figure 36. Flushing (All Cause)................................................................................................ ..192

Figure 37. Visual Disturbances (All Cause) ............................................................................. ..193

Figure 38. The Mean IIEF “EF Domain” Score ....................................................................... ..193

Figure 39. Successful Intercourse Attempts (SEP–Q2)..............................................................193

Figure 40. Successful Intercourse Attempts (SEP–Q3)..............................................................194

Figure 41. Improved Erection (GAQ–Q1)................................................................................ ..194

Figure 42. Improved Erection Without Carson 2004 (GAQ–Q1) ............................................ ..194

Figure 43. IIEF-EF ≥ 26 at Follow up (Weeks 10–12)............................................................. ..195

Figure 44. Any Adverse Events (All Causes).............................................................................195

Figure 45. Withdrawals due to Adverse Events........................................................................ ..195

Figure 46. Serious Adverse Events........................................................................................... ..196

Figure 47. Headache (All Cause).............................................................................................. ..196

Figure 48. Flushing (All Cause)................................................................................................ ..196

Figure 49. Dyspepsia (All Cause)............................................................................................. ..197

Figure 50. Serious Adverse Events: Patients With Diabetes .................................................... ..197

Figure 51. Withdrawals due to Adverse Events: Patients With Diabetes................................. ..197

Figure 52. The Mean IIEF “EF Domain” Score (at Week 12–104) ......................................... ..198

Figure 53. Improved Erection (GAQ–Q1) (at Week 12)............................................................198

Figure 54. Any Adverse Events (all Cause).............................................................................. ..198

Figure 55. Serious Adverse Events........................................................................................... ..199

Figure 56. Withdrawals due to Adverse Events........................................................................ ..199

Figure 57. Headache (All Cause).............................................................................................. ..199

Figure 58. Flushing (All Cause)................................................................................................ ..200

Figure 59. Dyspepsia (All Cause)............................................................................................. ..200

Figure 60. Absolute Mean Change in IIEF–EF Score .............................................................. ..200

Figure 61. Mean Per-patient Percent Absolute Change From Baseline in SEP–Q2 ................ ..201

Figure 62. Improved Erection (GAQ–Q1)................................................................................ ..201

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