ORIGINAL ARTICLE
Transjugular Intrahepatic Portosystemic Shunt for Acute Variceal Bleeding A Meta-analysis Xingshun Qi, MD,*wz Jia Jia, MD,* Ming Bai, MD,* Xiaozhong Guo, MD,w Chunping Su, MLS,y Juan C. Garcı´a-Paga´n, MD,8 Guohong Han, MD,* and Daiming Fan, MD*
Background and Aims: Acute variceal bleeding is the most common lethal complication of liver cirrhosis. A meta-analysis was conducted to compare the outcomes of transjugular intrahepatic portosystemic shunt (TIPS) to those of medical/endoscopic therapy for acute variceal bleeding in cirrhotic patients. Methods: The PubMed, EMBASE, and Cochrane Library databases were searched for all relevant comparative studies. Odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI)were pooled for dichotomous and time-dependent variables, respectively. Subgroup analyses were performed according to the type of study design (randomized or nonrandomized studies), source of bleeding (esophageal or gastric varices), type of stent (covered or bare stent), and patient selection (high risk or unselected patients). Results: Six papers were eligible. TIPS was superior to medical/ endoscopic therapy in decreasing the incidence of treatment failure (OR = 0.22; 95% CI, 0.11-0.44), improving overall survival (HR = 0.55; 95% CI, 0.38-0.812), and decreasing the incidence of bleeding-related death (OR = 0.19; 95% CI, 0.06-0.59). Although TIPS did not significantly decrease the incidence of rebleeding (OR = 0.27; 95% CI, 0.06-1.29), it became significantly greater in Received for publication December 29, 2013; accepted July 15, 2014. From the *Xijing Hospital of Digestive Diseases, Fourth Military Medical University; yLibrary of Fourth Military Medical University, Xi’an; wDepartment of Gastroenterology, General Hospital of Shenyang Military Region; zDepartment of Gastroenterology, No. 463 Hospital of Chinese PLA, Shenyang, China; and 8Hepatic Hemodynamic Laboratory, Liver Unit, Institut de Malalties Digestives i Metaboliques, Hospital Clı´ nic, Institut d’Investigacions Biome`diques August Pi i Sunyer and Centro de Investigacio´n Biome´dica en Red de Enfermedades Hepa´ticas y Digestiva, Spain. X.Q., J.J., and M.B. contributed equally. This study was partially presented as a poster in GASTRO 2013 APDW (Asian Pacific Digestive Week 2013)/WCOG (World Congress of Gastroenterology) held in Shanghai, China, between 21 and 24 September 2013. X.Q. conceived and drafted the manuscript. X.Q., J.J., M.B., and C.S. performed the literature search and selection, data extraction, quality assessment, and/or statistical analyses; J.C.G.-P., G.H., and D.F. gave critical comments and revised the manuscript. All authors have made an intellectual contribution to the manuscript and approved the submission. J.C.G.-P. received speaker fees from GORE. The remaining authors declare that they have nothing to disclose. Reprints: Daiming Fan MD, PhD or Guohong Han MD, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, No. 17 Changle West Road, Xi’an, Shaanxi Province 710032, China (e-mails: [email protected] or guohhan@126. com). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www. jcge.com. Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
the subgroup meta-analyses of randomized studies (OR = 0.09; 95% CI, 0.03-0.32) than in those of nonrandomized studies (OR = 0.76; 95% CI, 0.40-1.45; subgroup difference, P = 0.003), and in the subgroup meta-analyses of studies including high-risk patients (OR = 0.06; 95% CI, 0.01-0.23) than in those including low-risk patients (OR = 0.83; 95% CI, 0.44-1.56; subgroup difference, P = 0.0007). In addition, TIPS did not significantly increase the incidence of posttreatment hepatic encephalopathy (OR = 1.37; 95% CI, 0.63-2.99). Conclusions: With the exception of the benefit of prevention from treatment failure, TIPS with covered stents might improve the overall survival of high-risk patients with acute variceal bleeding. Key Words: transjugular intrahepatic portosystemic shunt, acute variceal bleeding, liver cirrhosis, meta-analysis
(J Clin Gastroenterol 2015;49:495–505)
A
cute variceal bleeding remains the leading lethal complication of liver cirrhosis with a 6-week mortality of 20%.1 Despite advances in the prevention and treatment of variceal bleeding leading to improved outcomes after acute variceal bleeding,2 the treatment failure and mortality rates have remained high in patients with a hepatic venous pressure gradient (HVPG) of Z20 mm Hg or with poor liver function.3 The previous American Association for the Study of Liver Diseases (AASLD) practice guideline recommended that a combination of medical and endoscopic treatment should be the first-line choice of therapy for the management of acute variceal bleeding, and transjugular intrahepatic portosystemic shunt (TIPS) should be considered as a rescue therapy if esophageal variceal bleeding cannot be controlled by the combination of medical and endoscopic therapy.4 This recommendation was primarily attributed to the potential drawbacks of TIPS: (1) TIPS cannot improve overall survival; and (2) TIPS can increase the incidence of posttreatment hepatic encephalopathy.5 However, a randomized controlled trial showed that the use of early TIPS could lead to a survival benefit for patients at a high risk for treatment failure (ie, an HVPGZ20 mm Hg).6 Recently, another randomized controlled trial also demonstrated that the incidence of failure to control bleeding or of rebleeding and the rate of mortality were significantly lower in “high-risk” cirrhotic patients (ie, Child-Pugh class C or Child-Pugh class B with active bleeding at endoscopy despite intravenous vasoactive drug treatment) who received early TIPS with polytetrafluoroethylene-covered stents than in those receiving medical/endoscopic therapy.7 More recently, this positive result
Volume 49, Number 6, July 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.jcge.com |
495
J Clin Gastroenterol
Qi et al
was confirmed by a surveillance study.8 Generally, these important findings have substantially challenged the previous AASLD practice guideline recommendations. Accordingly, the Baveno V consensus has recommended that early TIPS within 72 hours (ideally r24 h) should be considered in patients at a high risk for treatment failure (ie, Child-Pugh class C 50% was considered to indicate substantial heterogeneity) and the w2 test (P < 0.10 was considered to represent significant heterogeneity).17 Sensitivity analyses were performed by the sequential omission of every individual study, to explore the cause of heterogeneity among the studies. Funnel plots were
Copyright
r
2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 49, Number 6, July 2015
not used to assess publication bias due to the relatively small number of studies included in our meta-analysis. The Egger bias test was conducted to evaluate the presence of publication bias for all of the pooled values with 95% CIs (P < 0.10 was considered to represent significant publication bias). All of the analyses were conducted using the Review Manager statistical software version 5.1 (The Nordic Cochrane Center, The Cochrane Collaboration, 2011, Copenhagen, Denmark) or StatsDirect statistical software version 2.7.8 (StatsDirect Ltd, Sale, Cheshire, UK).
RESULTS Study Selection The search strategy yielded a total of 561 articles. Among these articles, 6 met the eligibility criteria (Fig. 1), including 3 randomized controlled trials6,7,18 and 3 nonrandomized studies.8,19,20 These studies included 388 cirrhotic patients with acute variceal bleeding, of whom 195 and 193 were assigned to the TIPS and medical/endoscopic groups, respectively.
Study Description All of the included studies were published in peerreviewed journals between 1997 and 2013, and 4 and 2
TIPS for Acute Variceal Bleeding
studies were single-center and multicenter studies, respectively (Table 1). The target population was cirrhotic patients with acute variceal bleeding, in whom the source of bleeding was esophageal varices in 3 studies,7,8,18 gastric varices in 1 study,19 and mixed esophageal and/or gastric varices in 2 studies.6,20 In addition, only “high-risk” patients were enrolled in 3 studies. High risk was defined as patients with HVPGZ20 mm Hg in 1 study6 or patients with a Child-Pugh score of 10 to 13 or a Child-Pugh score of 7 to 9 with active bleeding on diagnostic endoscopy in 2 studies.7,8 The interventional modality in the experimental groups was TIPS in all of the studies. The type of TIPS stent was bare in 2 studies,18,19 unknown in 2 studies,6,20 and covered in 2 studies.7,8 The interventional modality in the control groups was medical therapy and endoscopic sclerotherapy in 1 study,18 medical therapy and N-butyl-2cyanoacrylate (histoacryl) glue injections in 2 studies,19,20 and medical and/or endoscopic therapy in 3 studies.6–8 The detailed eligibility criteria of all of the included studies are described in Supplementary Table 1 (Supplemental Digital Content 1, http://links.lww.com/JCG/ A152). Most of the baseline characteristics were comparable between the 2 groups (Table 2). Notably, compared with the control group, the TIPS group had a significantly higher
FIGURE 1. Flowchart of study inclusion. TIPS indicates transjugular intrahepatic portosystemic shunt.
Copyright
r
2014 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.jcge.com |
497
J Clin Gastroenterol
Qi et al
Volume 49, Number 6, July 2015
TABLE 1. Characteristics of Every Study Included in the Meta-analysis
References
Region or Country
Design
Cello et al18 Single-center RCT
Experimental Groups
Participants
California, Massive or USA submassive acute gastrointestinal tract hemorrhage from large esophageal varices
Noh et al20 Retrospective Gwangju, comparative Korea analysis
Acute esophagogastric variceal bleedings
TIPS
Some or more expandable metal mesh stents (Wallstent; Schneider Inc., Minneapolis, MN) Wallstents (Pfizer, Bulach, Switzerland) or Memotherm (Angiomed, Karlsruhe, Germany) stents Unknown
Monescillo Single-center RCT et al6
Madrid, Spain
Acute variceal bleeding with a HVPGZ20 mmHg (esophageal or gastric varices)
TIPS
Unknown
Mahadeva et al19
TIPS
TIPS Stent
Retrospective Leeds, UK Acute bleeding gastric comparative varices analysis
TIPS
Garcı´ aPaga´n et al7
9 European centers RCT
Europe
Acute esophageal variceal bleeding (Child-Pugh score of 10-13, or ChildPugh score of 7-9 but with active bleeding at diagnostic endoscopy)
TIPS
e-PTFEcovered stents (Viatorr TIPS endoprosthesis; Gore)
Garcı´ aPaga´n et al8
9 European Europe centers retrospective comparative analysis
Acute esophageal variceal bleeding (Child-Pugh score of 10-13, or ChildPugh score of 7-9 but with active bleeding at diagnostic endoscopy)
TIPS
e-PTFEcovered stents (Viatorr TIPS endoprosthesis; Gore)
Control Groups
No. Period of Patients Enrollment
Repeated endoscopic sclerotherapy
49
1991.111995.12
Endoscopic Nbutyl-2cyanoacrylate (histoacryl) glue injections
43
1995.11999.12 (TIPS); 2000.12001.10 (control)
Endoscopic Nbutyl-2cyanoacrylate injections b-blockers, and/or endoscopic band ligation, TIPS as a rescue therapy Vasoactive drugs, nonselective b-blockers plus endoscopic band ligation, TIPS as a rescue therapy Vasoactive drugs, nonselective b-blockers plus endoscopic band ligation, TIPS as a rescue therapy
106
1995.42002.6
52
1997.62000.11
63
2004.52007.3
75
2007.32011.1
HVPG indicates hepatic venous pressure gradient; RCT, randomized controlled trial; TIPS, transjugular intrahepatic portosystemic shunt.
transfusion requirement in 1 study,18 a significantly lower hemoglobin concentration in 1 study,19 a significantly worse Child-Pugh score in 1 study,18 a significantly higher proportion of hepatic encephalopathy in 1 study,7 and a significantly higher bilirubin level in 1 study.6
blinding method was impractical due to the nature of interventional modalities. Two nonrandomized studies were scored 5 points according to the Newcastle Ottawa scale, and they were considered to be of high quality (Supplementary Table 3, Supplemental Digital Content 3, http:// links.lww.com/JCG/A154).8,20
Study Quality All of the randomized studies were scored
Transjugular Intrahepatic Portosystemic Shunt for Acute Variceal Bleeding A Meta-analysis Xingshun Qi, MD,*wz Jia Jia, MD,* Ming Bai, MD,* Xiaozhong Guo, MD,w Chunping Su, MLS,y Juan C. Garcı´a-Paga´n, MD,8 Guohong Han, MD,* and Daiming Fan, MD*
Background and Aims: Acute variceal bleeding is the most common lethal complication of liver cirrhosis. A meta-analysis was conducted to compare the outcomes of transjugular intrahepatic portosystemic shunt (TIPS) to those of medical/endoscopic therapy for acute variceal bleeding in cirrhotic patients. Methods: The PubMed, EMBASE, and Cochrane Library databases were searched for all relevant comparative studies. Odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI)were pooled for dichotomous and time-dependent variables, respectively. Subgroup analyses were performed according to the type of study design (randomized or nonrandomized studies), source of bleeding (esophageal or gastric varices), type of stent (covered or bare stent), and patient selection (high risk or unselected patients). Results: Six papers were eligible. TIPS was superior to medical/ endoscopic therapy in decreasing the incidence of treatment failure (OR = 0.22; 95% CI, 0.11-0.44), improving overall survival (HR = 0.55; 95% CI, 0.38-0.812), and decreasing the incidence of bleeding-related death (OR = 0.19; 95% CI, 0.06-0.59). Although TIPS did not significantly decrease the incidence of rebleeding (OR = 0.27; 95% CI, 0.06-1.29), it became significantly greater in Received for publication December 29, 2013; accepted July 15, 2014. From the *Xijing Hospital of Digestive Diseases, Fourth Military Medical University; yLibrary of Fourth Military Medical University, Xi’an; wDepartment of Gastroenterology, General Hospital of Shenyang Military Region; zDepartment of Gastroenterology, No. 463 Hospital of Chinese PLA, Shenyang, China; and 8Hepatic Hemodynamic Laboratory, Liver Unit, Institut de Malalties Digestives i Metaboliques, Hospital Clı´ nic, Institut d’Investigacions Biome`diques August Pi i Sunyer and Centro de Investigacio´n Biome´dica en Red de Enfermedades Hepa´ticas y Digestiva, Spain. X.Q., J.J., and M.B. contributed equally. This study was partially presented as a poster in GASTRO 2013 APDW (Asian Pacific Digestive Week 2013)/WCOG (World Congress of Gastroenterology) held in Shanghai, China, between 21 and 24 September 2013. X.Q. conceived and drafted the manuscript. X.Q., J.J., M.B., and C.S. performed the literature search and selection, data extraction, quality assessment, and/or statistical analyses; J.C.G.-P., G.H., and D.F. gave critical comments and revised the manuscript. All authors have made an intellectual contribution to the manuscript and approved the submission. J.C.G.-P. received speaker fees from GORE. The remaining authors declare that they have nothing to disclose. Reprints: Daiming Fan MD, PhD or Guohong Han MD, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, No. 17 Changle West Road, Xi’an, Shaanxi Province 710032, China (e-mails: [email protected] or guohhan@126. com). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www. jcge.com. Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
the subgroup meta-analyses of randomized studies (OR = 0.09; 95% CI, 0.03-0.32) than in those of nonrandomized studies (OR = 0.76; 95% CI, 0.40-1.45; subgroup difference, P = 0.003), and in the subgroup meta-analyses of studies including high-risk patients (OR = 0.06; 95% CI, 0.01-0.23) than in those including low-risk patients (OR = 0.83; 95% CI, 0.44-1.56; subgroup difference, P = 0.0007). In addition, TIPS did not significantly increase the incidence of posttreatment hepatic encephalopathy (OR = 1.37; 95% CI, 0.63-2.99). Conclusions: With the exception of the benefit of prevention from treatment failure, TIPS with covered stents might improve the overall survival of high-risk patients with acute variceal bleeding. Key Words: transjugular intrahepatic portosystemic shunt, acute variceal bleeding, liver cirrhosis, meta-analysis
(J Clin Gastroenterol 2015;49:495–505)
A
cute variceal bleeding remains the leading lethal complication of liver cirrhosis with a 6-week mortality of 20%.1 Despite advances in the prevention and treatment of variceal bleeding leading to improved outcomes after acute variceal bleeding,2 the treatment failure and mortality rates have remained high in patients with a hepatic venous pressure gradient (HVPG) of Z20 mm Hg or with poor liver function.3 The previous American Association for the Study of Liver Diseases (AASLD) practice guideline recommended that a combination of medical and endoscopic treatment should be the first-line choice of therapy for the management of acute variceal bleeding, and transjugular intrahepatic portosystemic shunt (TIPS) should be considered as a rescue therapy if esophageal variceal bleeding cannot be controlled by the combination of medical and endoscopic therapy.4 This recommendation was primarily attributed to the potential drawbacks of TIPS: (1) TIPS cannot improve overall survival; and (2) TIPS can increase the incidence of posttreatment hepatic encephalopathy.5 However, a randomized controlled trial showed that the use of early TIPS could lead to a survival benefit for patients at a high risk for treatment failure (ie, an HVPGZ20 mm Hg).6 Recently, another randomized controlled trial also demonstrated that the incidence of failure to control bleeding or of rebleeding and the rate of mortality were significantly lower in “high-risk” cirrhotic patients (ie, Child-Pugh class C or Child-Pugh class B with active bleeding at endoscopy despite intravenous vasoactive drug treatment) who received early TIPS with polytetrafluoroethylene-covered stents than in those receiving medical/endoscopic therapy.7 More recently, this positive result
Volume 49, Number 6, July 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.jcge.com |
495
J Clin Gastroenterol
Qi et al
was confirmed by a surveillance study.8 Generally, these important findings have substantially challenged the previous AASLD practice guideline recommendations. Accordingly, the Baveno V consensus has recommended that early TIPS within 72 hours (ideally r24 h) should be considered in patients at a high risk for treatment failure (ie, Child-Pugh class C 50% was considered to indicate substantial heterogeneity) and the w2 test (P < 0.10 was considered to represent significant heterogeneity).17 Sensitivity analyses were performed by the sequential omission of every individual study, to explore the cause of heterogeneity among the studies. Funnel plots were
Copyright
r
2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 49, Number 6, July 2015
not used to assess publication bias due to the relatively small number of studies included in our meta-analysis. The Egger bias test was conducted to evaluate the presence of publication bias for all of the pooled values with 95% CIs (P < 0.10 was considered to represent significant publication bias). All of the analyses were conducted using the Review Manager statistical software version 5.1 (The Nordic Cochrane Center, The Cochrane Collaboration, 2011, Copenhagen, Denmark) or StatsDirect statistical software version 2.7.8 (StatsDirect Ltd, Sale, Cheshire, UK).
RESULTS Study Selection The search strategy yielded a total of 561 articles. Among these articles, 6 met the eligibility criteria (Fig. 1), including 3 randomized controlled trials6,7,18 and 3 nonrandomized studies.8,19,20 These studies included 388 cirrhotic patients with acute variceal bleeding, of whom 195 and 193 were assigned to the TIPS and medical/endoscopic groups, respectively.
Study Description All of the included studies were published in peerreviewed journals between 1997 and 2013, and 4 and 2
TIPS for Acute Variceal Bleeding
studies were single-center and multicenter studies, respectively (Table 1). The target population was cirrhotic patients with acute variceal bleeding, in whom the source of bleeding was esophageal varices in 3 studies,7,8,18 gastric varices in 1 study,19 and mixed esophageal and/or gastric varices in 2 studies.6,20 In addition, only “high-risk” patients were enrolled in 3 studies. High risk was defined as patients with HVPGZ20 mm Hg in 1 study6 or patients with a Child-Pugh score of 10 to 13 or a Child-Pugh score of 7 to 9 with active bleeding on diagnostic endoscopy in 2 studies.7,8 The interventional modality in the experimental groups was TIPS in all of the studies. The type of TIPS stent was bare in 2 studies,18,19 unknown in 2 studies,6,20 and covered in 2 studies.7,8 The interventional modality in the control groups was medical therapy and endoscopic sclerotherapy in 1 study,18 medical therapy and N-butyl-2cyanoacrylate (histoacryl) glue injections in 2 studies,19,20 and medical and/or endoscopic therapy in 3 studies.6–8 The detailed eligibility criteria of all of the included studies are described in Supplementary Table 1 (Supplemental Digital Content 1, http://links.lww.com/JCG/ A152). Most of the baseline characteristics were comparable between the 2 groups (Table 2). Notably, compared with the control group, the TIPS group had a significantly higher
FIGURE 1. Flowchart of study inclusion. TIPS indicates transjugular intrahepatic portosystemic shunt.
Copyright
r
2014 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.jcge.com |
497
J Clin Gastroenterol
Qi et al
Volume 49, Number 6, July 2015
TABLE 1. Characteristics of Every Study Included in the Meta-analysis
References
Region or Country
Design
Cello et al18 Single-center RCT
Experimental Groups
Participants
California, Massive or USA submassive acute gastrointestinal tract hemorrhage from large esophageal varices
Noh et al20 Retrospective Gwangju, comparative Korea analysis
Acute esophagogastric variceal bleedings
TIPS
Some or more expandable metal mesh stents (Wallstent; Schneider Inc., Minneapolis, MN) Wallstents (Pfizer, Bulach, Switzerland) or Memotherm (Angiomed, Karlsruhe, Germany) stents Unknown
Monescillo Single-center RCT et al6
Madrid, Spain
Acute variceal bleeding with a HVPGZ20 mmHg (esophageal or gastric varices)
TIPS
Unknown
Mahadeva et al19
TIPS
TIPS Stent
Retrospective Leeds, UK Acute bleeding gastric comparative varices analysis
TIPS
Garcı´ aPaga´n et al7
9 European centers RCT
Europe
Acute esophageal variceal bleeding (Child-Pugh score of 10-13, or ChildPugh score of 7-9 but with active bleeding at diagnostic endoscopy)
TIPS
e-PTFEcovered stents (Viatorr TIPS endoprosthesis; Gore)
Garcı´ aPaga´n et al8
9 European Europe centers retrospective comparative analysis
Acute esophageal variceal bleeding (Child-Pugh score of 10-13, or ChildPugh score of 7-9 but with active bleeding at diagnostic endoscopy)
TIPS
e-PTFEcovered stents (Viatorr TIPS endoprosthesis; Gore)
Control Groups
No. Period of Patients Enrollment
Repeated endoscopic sclerotherapy
49
1991.111995.12
Endoscopic Nbutyl-2cyanoacrylate (histoacryl) glue injections
43
1995.11999.12 (TIPS); 2000.12001.10 (control)
Endoscopic Nbutyl-2cyanoacrylate injections b-blockers, and/or endoscopic band ligation, TIPS as a rescue therapy Vasoactive drugs, nonselective b-blockers plus endoscopic band ligation, TIPS as a rescue therapy Vasoactive drugs, nonselective b-blockers plus endoscopic band ligation, TIPS as a rescue therapy
106
1995.42002.6
52
1997.62000.11
63
2004.52007.3
75
2007.32011.1
HVPG indicates hepatic venous pressure gradient; RCT, randomized controlled trial; TIPS, transjugular intrahepatic portosystemic shunt.
transfusion requirement in 1 study,18 a significantly lower hemoglobin concentration in 1 study,19 a significantly worse Child-Pugh score in 1 study,18 a significantly higher proportion of hepatic encephalopathy in 1 study,7 and a significantly higher bilirubin level in 1 study.6
blinding method was impractical due to the nature of interventional modalities. Two nonrandomized studies were scored 5 points according to the Newcastle Ottawa scale, and they were considered to be of high quality (Supplementary Table 3, Supplemental Digital Content 3, http:// links.lww.com/JCG/A154).8,20
Study Quality All of the randomized studies were scored
