Evidence Report/Technology Assessment

[Pages:770]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

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 epc@.

Carolyn M. Clancy, M.D. Director Agency for Healthcare Research and Quality

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

David C. Dale, M.D., F.A.C.P. President American College of Physicians

Beth A. Collins Sharp, Ph.D. Acting Director, EPC Program 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?, SCOPUSTM, 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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