Ethan M. Balk, MD, MPH; Valerie N. Rofeberg, ScM; Gaelen P. Adam, MLIS; Hannah J. Kimmel, MPH; Thomas A. Trikalinos, MD, PhD; Peter C. Jeppson, MD
Disclaimer: The authors of this manuscript are responsible for its content. Statements in the article should not be construed as endorsement by PCORI, AHRQ, or the U.S. Department of Health and Human Services. AHRQ retains a license to display, reproduce, and distribute the data and the report from which this manuscript was derived under the terms of the agency's contract with the author.
Acknowledgment: The authors thank Aysegul Gozu, MD, MPH, their AHRQ Task Order Officer; Jennifer Croswell, MD, MPH, their PCORI Senior Program Officer; and Kimberly Bailey, MS, their PCORI Program Officer, for their contributions. They also thank and acknowledge the other research associates and staff who helped conduct this systematic review: Georgios Markozannes, MSc; Katherine Corsi, PharmD; Amanda Mogul, PharmD; Iman Saeed, ScM; Mengyang Di, PhD; Gowri Raman, MBBS, MS; Esther Avendano, MS; Andrew Zullo, PharmD, PhD; Jenni Quiroz, BS; and Anya Rader Wallack, PhD.
Financial Support: Under contract 290-20-1500002-I from AHRQ, U.S. Department of Health and Human Services, Rockville, Maryland.
Disclosures: All authors received a grant from AHRQ for the conduct of the study. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-3227.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement: Study protocol: Available from PROSPERO (www.crd.york.ac.uk/PROSPERO/; registration CRD42017069903). Statistical code: Available at www.brown.edu/public-health/cesh/resources/code-data-repository. Data set: Available at https://srdr.ahrq.gov/projects/1153.
Corresponding Author: Ethan Balk, MD, MPH, Brown University School of Public Health, Box G-S121-8, Providence, RI 02912; e-mail, email@example.com.
Current Author Addresses: Drs. Balk and Trikalinos, Ms. Rofeberg, Ms. Adam, and Ms. Kimmel: Brown University School of Public Health, Box G-S121-8, Providence, RI 02912.
Dr. Jeppson: Division of Urogynecology, Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, 2425 Camino de Salud, Albuquerque, NM 87106.
Author Contributions: Conception and design: E.M. Balk, T.A. Trikalinos, P.C. Jeppson.
Analysis and interpretation of the data: E.M. Balk, V.N. Rofeberg, G.P. Adam, H.J. Kimmel, P.C. Jeppson.
Drafting of the article: E.M. Balk, V.N. Rofeberg, G.P. Adam, H.J. Kimmel, P.C. Jeppson.
Critical revision for important intellectual content: E.M. Balk, T.A. Trikalinos, P.C. Jeppson.
Final approval of the article: E.M. Balk, V.N. Rofeberg, G.P. Adam, H.J. Kimmel, T.A. Trikalinos, P.C. Jeppson.
Statistical expertise: E.M. Balk, V.N. Rofeberg, H.J. Kimmel, T.A. Trikalinos.
Obtaining of funding: E.M. Balk, G.P. Adam, T.A. Trikalinos, P.C. Jeppson.
Administrative, technical, or logistic support: G.P. Adam, T.A. Trikalinos, P.C. Jeppson.
Collection and assembly of data: E.M. Balk, V.N. Rofeberg, G.P. Adam, H.J. Kimmel, P.C. Jeppson.
Urinary incontinence (UI), a common malady in women, most often is classified as stress, urgency, or mixed.
To compare the effectiveness of pharmacologic and nonpharmacologic interventions to improve or cure stress, urgency, or mixed UI in nonpregnant women.
MEDLINE, Cochrane Central Register of Controlled Trials (Wiley), Cochrane Database of Systematic Reviews (Wiley), EMBASE (Elsevier), CINAHL (EBSCO), and PsycINFO (American Psychological Association) from inception through 10 August 2018.
84 randomized trials that evaluated 14 categories of interventions and reported categorical cure or improvement outcomes.
1 researcher extracted study characteristics, results, and study-level risk of bias, with verification by another independent researcher. The research team collaborated to assess strength of evidence (SoE) across studies.
84 studies reported cure or improvement outcomes (32 in stress UI, 16 in urgency UI, 4 in mixed UI, and 32 in any or unspecified UI type). The most commonly evaluated active intervention types included behavioral therapies, anticholinergics, and neuromodulation. Network meta-analysis showed that all interventions, except hormones and periurethral bulking agents (variable SoE), were more effective than no treatment in achieving at least 1 favorable UI outcome. Among treatments used specifically for stress UI, behavioral therapy was more effective than either α-agonists or hormones in achieving cure or improvement (moderate SoE); α-agonists were more effective than hormones in achieving improvement (moderate SoE); and neuromodulation was more effective than no treatment for cure, improvement, and satisfaction (high SoE). Among treatments used specifically for urgency UI, behavioral therapy was statistically significantly more effective than anticholinergics in achieving cure or improvement (high SoE), both neuromodulation and onabotulinum toxin A (BTX) were more effective than no treatment (high SoE), and BTX may have been more effective than neuromodulation in achieving cure (low SoE).
Scarce direct (head-to-head trial) evidence and population heterogeneity based on UI type, UI severity, and history of prior treatment.
Most nonpharmacologic and pharmacologic interventions are more likely than no treatment to improve UI outcomes. Behavioral therapy, alone or in combination with other interventions, is generally more effective than pharmacologic therapies alone in treating both stress and urgency UI.
Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42017069903)
Table 1. Categories of Interventions Evaluated by Eligible Studies
Evidence search and selection.
AE = adverse event; NRCS = nonrandomized comparative study; QoL = quality of life; UI = urinary incontinence.
* MEDLINE, Cochrane Central Register of Controlled Trials (Wiley), Cochrane Database of Systematic Reviews (Wiley), EMBASE (Elsevier), CINAHL (EBSCO), and PsycINFO (American Psychological Association).
† ClinicalTrials.gov and U.S. Food and Drug Administration.
Risk of bias for studies with urinary incontinence outcomes.
Evidence graph of all trials evaluating cure.
The graph comprises nodes depicting different intervention categories and edges showing links between nodes. An edge exists when the interventions represented by the nodes it connects have been compared head to head in at least 1 trial. The numbers of trials comparing each pair of intervention categories are indicated by the numbers along the edges (and the width of the edges). A = α-agonist; B = onabotulinum toxin A; C = anticholinergic; H = hormones; N = neuromodulation; P = sham/placebo/no treatment; T = behavioral therapy; U = periurethral bulking; V = intravesical pressure release.
Evidence graph of all trials evaluating improvement.
Table 2. Cure in Stress UI: Comparative Effectiveness From Analyses of All Studies and of Studies Specific to Women With Stress UI*
Table 3. Improvement in Stress UI: Comparative Effectiveness From Analyses of All Studies and of Studies Specific to Women With Stress UI*
Table 4. Cure in Urgency UI: Comparative Effectiveness From Analyses of All Studies and of Studies Specific to Women With Urgency UI*
Table 5. Improvement in Urgency UI: Comparative Effectiveness From Analyses of All Studies and of Studies Specific to Women With Urgency UI*
Table 6. Summary of Comparative Effectiveness and Comparisons Versus Placebo for Cure, Improvement, and Adverse Events
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In this video, Peter C. Jeppson, MD, offers additional insight into the article, "Pharmacologic and Nonpharmacologic Treatments for Urinary Incontinence in Women: A Systematic Review and Network Meta-analysis of Clinical Outcomes."
Alain Braillon MD PhD
University hospital Amiens, France
March 20, 2019
“Systematic review” and “network meta-analysis”: the Emperor’s new clothes
“If you torture the data enough, nature will always confess.” Ronald H. Coase
The use of the terms “systematic review” and “network meta-analysis” for the article about pharmacologic and non-pharmacologic treatments for urinary incontinence in women deserves comment.(1) The first combination of these terms appeared in a title in 2007 and its success (148 appearances in 2017, 223 in 2018; according to PubMed searches) may convey a hijacking for marketing purpose.
First, why systematic reviews are so rarely systematic? A treatment has two sides, benefit and harm, the latter being overlooked here,(1) as most usually. Among treatments reviewed, duloxetine deserved specific insights: Nine references were provided but none about safety.(1) Duloxetine has no advantages vs others antidepressants but only specific harms: a) life-threatening liver injury;(2) b) severe skin reactions including Stevens-Johnson Syndrome.(http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm255064.htm) c) hyponatremia, ranking first among antidepressants for this.(3) Why is duloxetine classified among alpha agonist,(1) it is a serotonin and norepinephrine reuptake inhibitor,(4) accordingly harms also include suicidality and violent behaviour. Duloxetine is in the yearly list of “drugs to avoid” (drugs on the market that are more harmful than beneficial) from the independent drug bulletin Prescrire International.(5) Finally, patients with stress incontinence are usually old, as a result coexistence of other somatic diseases is frequent with poly-medication, a major safety issue.
Second, could “network meta-analysis” be a wolf in sheep clothing? No magic bullet can overcome poor data from flawed controlled trials deliberately using a placebo instead of adequate comparators as required by the Helsinki’s declaration. Whose interests are served by the European Medicines Agency which granted a marketing authorization for stress urinary incontinence to duloxetine? Neither assessment of efficacy vs an adequate comparator nor concern for safety despite red flags. Wisely, the Food and Drug Agency does not list this indication. Why this European exception? Exceptions in medicine rarely benefit to the patients!
Could the tsunami of “systematic review/network meta-analysis” be an indicator of the shipwreck of clinical research? Only searching for the Holy Grail could be harder than for two robust and well-designed trials on the same topic. E.g., since 1971 tens of trials, all at high risk of bias, have been performed about glucocortico-steroids in patients alcoholic hepatitis. Trials results have been most conflicting as conclusions of serial systematic reviews, the most recent in 2017. Systematic review/network meta-analysis has not invalidated Mellin’s warning in 1957: “garbage in, garbage out”.
1 Balk EM, Rofeberg VN, Adam GP, et al. Pharmacologic and nonpharmacologic treatments for urinary incontinence in women. Ann Intern Med 2019. Online 19 March 2019. Doi: 10.7326/M18-3227.
2 Wernicke J, Pangallo B, Wang F et al. Hepatic effects of duloxetine-I: non-clinical and clinical trial data. Curr Drug Saf 2008;3:132-42.
3 Revol R, Rault C, Polard E, Bellet F, Guy C. [Hyponatremia associated with SSRI/NRSI: Descriptive and comparative epidemiological study of the incidence rates of the notified cases from the data of the French National Pharmacovigilance Database and the French National Health Insurance]. Encephale 2018;44:291-296.
4 Thor KB, Katofiasc MA. Effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of lower urinary tract function in the chloralose-anesthetized female cat. J Pharmacol Exp Ther 1995;274:1014-24.
5 Prescrire Int. Towards better patient care: drugs to avoid in 2018. Prescrire Int 2016;27:107-1. Available at http://english.prescrire.org/Docu/DownloadDocu/PDFs/DrugsToAvoid_2016update.pdf Accessed 19 March 2019
Balk EM, Rofeberg VN, Adam GP, Kimmel HJ, Trikalinos TA, Jeppson PC. Pharmacologic and Nonpharmacologic Treatments for Urinary Incontinence in Women: A Systematic Review and Network Meta-analysis of Clinical Outcomes. Ann Intern Med. [Epub ahead of print 19 March 2019]170:465–479. doi: 10.7326/M18-3227
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Published: Ann Intern Med. 2019;170(7):465-479.
Published at www.annals.org on 19 March 2019
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