Pre-endoscopy erythromycin versus metoclopramide for upper gastrointestinal bleeding: a systematic review and network meta-analysis
Article information
Abstract
Background/Aims:
Given the limited head-to-head trials comparing the outcomes of pre-endoscopy erythromycin and metoclopramide for upper gastrointestinal bleeding (UGIB), a network meta-analysis (NMA) and component NMA were conducted.
Methods:
A comprehensive review of the Medline, Embase, and Cochrane databases was conducted for randomized controlled trials comparing pre-endoscopy erythromycin or metoclopramide for UGIB with or without gastric lavage (GL) to placebo and/or GL. The primary outcome was the adequate visualization of the mucosa. The secondary outcomes were endoscopy visualization score, endoscopy duration, diagnosis established at initial endoscopy, second-look endoscopy, blood transfusions, mortality, and duration of hospitalization.
Results:
A total of 16 studies (1,447 patients) were included. No significant differences were observed between erythromycin and metoclopramide in all the outcomes, but erythromycin had significantly better outcomes than the control group in terms of endoscopic visualization score (standardized mean difference, 0.58; 95% confidence interval [CI], 0.26–0.91), adequate mucosal visualization (risk ratio, 1.55; 95% CI, 1.18–2.04), second-look endoscopy, transfusion requirements, and duration of hospitalization. Component network meta-analysis revealed that erythromycin, but not metoclopramide or GL, provided significantly better endoscopic visualization than the placebo.
Conclusions:
Erythromycin should be considered before UGIB endoscopy. The current data do not support the use of metoclopramide or GL.
INTRODUCTION
Upper gastrointestinal bleeding (UGIB) is one of the most common reasons for gastroenterology consultations and an indication for inpatient endoscopic evaluation. As a result, the economic impact of UGIB is huge, with an associated estimated cost of $7.6 billion per year.1 Consequently, any intervention that improves clinical outcomes can have a major impact.
Therapeutic options for the various causes of UGIB are widespread and continue to evolve. However, adequate mucosal visualization is paramount for identifying etiology and administering appropriate therapy. Prokinetic drugs such as erythromycin and metoclopramide have been studied as part of the pre-endoscopy management of UGIB to improve mucosal visualization during endoscopy.2,3 The rationale behind using these medications is to induce gastric contractions that propel the blood/clots downstream.4
Although randomized controlled trials (RCTs) have been conducted for erythromycin and metoclopramide for UGIB, only one small RCT compared these medications head-to-head, which was published as an abstract.5 Given the limited data for head-to-head comparison, we conducted a systematic review and network meta-analysis comparing pre-endoscopy erythromycin to metoclopramide. A component network meta-analysis (CNMA) was also conducted to study the contributions and the combined effects of various interventions included in the studies, as these studies included gastric lavage as part of their interventions.
METHODS
This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for systematic reviews, incorporating network meta-analyses for health care interventions (a PRISMA checklist is provided in Supplementary Material 1).6 The registration of the study was waived.
Search strategy, data extraction, and risk of bias assessment
A comprehensive search of Medline, Embase, and the Cochrane Library was performed with language restrictions. “Erythromycin,” “Metoclopramide,” “Upper Gastrointestinal Bleeding,” “Upper Gastrointestinal Hemorrhage,” “Gastrointestinal Bleeding,” and “Gastrointestinal Hemorrhage” were the search terms used in various combinations. Three authors (R.T.P., K.B., and S.C.) reviewed articles that met our inclusion criteria. Data on study-, participant-, disease-, and treatment-related characteristics were independently abstracted in a standardized format by the investigators, and discrepancies were resolved by consensus. The investigators rated the quality of the included trials using the Cochrane Risk of Bias Tool.7,8
Study selection
Studies included in this meta-analysis were RCTs that met the following inclusion criteria. (1) Patients: undergoing endoscopy for the management of upper gastrointestinal (GI) bleeding; (2) Intervention: intravenous (IV) erythromycin or metoclopramide; (3) Comparator: placebo, gastric lavage, or no control medication/gastric lavage; and (4) Outcome: any of the outcomes listed below. We excluded studies that used oral erythromycin or metoclopramide as interventions and those that did not report the outcomes of interest.
Outcomes & definitions
The primary outcome was the adequate visualization of the mucosa. The secondary outcomes were the endoscopic visualization score, endoscopy duration, diagnosis established at the initial endoscopy, second-look endoscopy, number of blood transfusions, mortality, duration of hospitalization, and adverse events due to the drugs. The scoring of the endoscopy visualization varied between studies. While the majority of the studies utilized the scoring system proposed by Frossard et al.,2 other scoring systems were also used. As per Frossard et al.’s scoring system, the visibility of the gastric fundus, body, antrum, and bulb were scored on a scale of 0–2 (0, <25% of mucosal visibility; 1, 25% to 75% mucosal visibility; 2, >75% mucosal visibility) and added to a maximal score of 8.2 A score of 6 or greater was considered as an adequate visualization of the mucosa. Habashi et al.5 categorized patients into those in whom the entire mucosa was visualized versus not. Carbonell et al.9 defined adequate visualization as the absence of clots that could not be suctioned out. Rudzki et al.10 assigned a global score of 0–2 (0, insufficient; 1, sufficient; 2, good). Altraif et al.11 considered a score of 15 or greater (maximum score, 16) as an empty stomach by scoring the esophagus and the gastric fundus, body, and antrum on a scale of 0–4 (0, <25% of mucosal visibility; 1, 25% to 75% mucosal visibility; 2, 50% to 75% mucosal visibility; 3, 75% to 95% mucosal visibility; 4, >95% mucosal visibility). Coffin et al.12 scored the mucosal visibility of the esophagus, stomach, and duodenum on a cumulative score of 0–3 (0, insufficient preparation; 1, poor preparation; 2, good preparation; 3, excellent preparation). Promsorn13 scored mucosal visibility of the gastric body, fundus, pylorus, and antrum, but the scale was not specified.
Data analysis
Frequentist NMA and CNMA were conducted using the ‘netmeta’ package in R ver. 2021.09.1+372 (R Foundation for Statistical Computing).14,15 CNMA helps to understand the contributions of multiple interventions in the study arm.15 Network graphs were used to visualize the network geometry. Sensitivity analysis was conducted with full-text articles and studies that utilized the endoscopic visualization score proposed by Frossard et al.,2 after excluding studies with a high risk of bias. Heterogeneity was assessed using the I2 test. An I2 value of >50% was considered to indicate substantial heterogeneity. Transitivity was assessed based on inconsistencies between direct and indirect comparisons. Publication bias was assessed using funnel plots and Egger’s test. The standardized mean difference (SMD) and risk ratio (RR) were used as measures of association for continuous and categorical variables, respectively. Ninety-five percent confidence intervals (95% CIs) were calculated for all the outcomes.
RESULTS
Study characteristics
A total of 16 RCTs (1,447 patients) were included in the study.2,3,5,9-13,16-23 The PRISMA flow diagram in Figure 1 illustrates the study selection process.24 Individual study characteristics are listed in Table 1.2,3,5,9-13,16-23 Ten RCTs (seven full-text, three abstracts) compared erythromycin to the control group,2,9-12,16-20 whereas five RCTs (two full-text, three abstracts) evaluated metoclopramide in the control group.3,13,21-23 One RCT (abstract) compared erythromycin to metoclopramide.5 The control group was placebo in five RCTs,2,11,13,22,23 gastric lavage plus placebo in four RCTs,3,5,9,18 and gastric lavage alone in five RCTs.12,16,17,19,20 Two studies did not have any intervention or placebo in the control arm.10,21 The mean age of the patients was 61.12±15.24 years and 70.38% of them were males. The most common etiologies of bleeding were ulcers (43.39%) and varices (34.73%) (Supplementary Table 1).
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram for the study.
Individual study characteristics
Heterogeneity, inconsistency, and risk of bias
Substantial heterogeneity was noted in the endoscopy visualization score, adequate mucosal visualization, endoscopy duration, number of blood transfusions, and duration of hospitalization (Supplementary Table 2). Inconsistency could not be assessed for any of the outcomes as there were no closed loops. Risk of bias analysis revealed a high risk of bias in at least two studies for adequate mucosal visualization, endoscopic visualization score, and endoscopy duration (Supplementary Figs. 3–5), and a low risk of bias for the rest of the outcomes (Supplementary Figs. 6–10). Publication bias assessment was deferred, as none of the interventions included more than ten studies.
Network meta-analysis
The geometry of the network graph was the same across the outcomes, except for second-look endoscopy. The network graph for adequate mucosal visualization demonstrated in Supplementary Figure 1 served as the template for the rest of the network graphs, except for second-look endoscopy (Supplementary Fig. 2), with the number of studies being the only change. Erythromycin ranked the highest, followed by metoclopramide, for all interventions (Table 2).
Ranking of interventions for all outcomes
1) Endoscopic visualization outcomes
The rates of adequate mucosal visualization did not differ significantly between erythromycin and metoclopramide (RR, 1.32; 95% CI, 0.79–2.19; eight studies, 721 patients) (Fig. 2).2,5,9-11,17,19,23 Erythromycin was associated with significantly higher rate of adequate visualization compared to the control group (RR, 1.55; 95% CI, 1.18–2.04).
Forest plot for adequate mucosal visualization. RR, risk ratio; CI, confidence interval.
A composite endoscopic mucosal visualization score was assessed in ten studies (1,215 patients).2,3,9,11-13,17,19,20,23 These scores were not significantly different between erythromycin and metoclopramide (SMD, 0.26; 95% CI, –0.30 to 0.83), but erythromycin had a significantly better visualization score compared to the control group (SMD, 0.58; 95% CI, 0.26–0.91) (Fig. 3).
Forest plot for endoscopic visualization score. SMD, standardized mean difference; CI, confidence interval.
No significant difference was observed in the duration of endoscopy between erythromycin and metoclopramide (SMD, –0.55; 95% CI, –1.37 to 0.27; nine studies, 1,056 patients) (Table 3).2,3,9,11,13,17-19,23 Erythromycin was associated with a significantly lower endoscopy duration than the control group (SMD, –0.52; 95% CI, –1.02 to –0.03).
League table for endoscopy duration
2) Clinical efficacy outcomes
No significant differences were observed between erythromycin and metoclopramide in terms of establishing a diagnosis at initial endoscopy (RR, 1.00; 95% CI, 0.92–1.09; seven studies, 861 patients),2,3,9,16,17,19,23 second-look endoscopy rate (RR, 0.71; 95% CI, 0.40–1.28; 13 studies, 1,309 patients),2,3,5,9-13,17,18,21-23 number blood transfusions (SMD, –0.56; 95% CI, –1.30 to 0.19; nine studies, 897 patients),2,9,11-13,17-19,23 mortality rate (RR, 0.83; 95% CI, 0.25–2.76; seven studies, 796 patients),3,11,12,17,18,21,23 and duration of hospitalization (SMD, –0.38; 95% CI, –0.89 to 0.13; eight studies, 677 patients) (Supplementary Tables 3–7).2,9,11-13,18,22,23
Compared to the control group, erythromycin group had a significantly lower rate of second-look endoscopy (RR, 0.61; 95% CI, 0.44–0.84) (Supplementary Table 4), transfusion requirements (SMD, –0.43; 95% CI, –0.79 to –0.06) (Supplementary Table 5), and duration of hospitalization (SMD, –0.43; 95% CI, –0.75 to –0.11) (Supplementary Table 7). There were no significant differences in these outcomes between the metoclopramide and control groups (Supplementary Tables 4, 5, 7).
Analysis of adverse events due to the drug could not be performed because no adverse events were reported in any of the studies except one.
3) Sensitivity analyses
All sensitivity analyses were performed using 250 mg IV and metoclopramide 10 mg IV doses. Studies were excluded if the doses were not clearly mentioned. In addition, sensitivity analyses were performed using full-text articles, studies with a high risk of bias, as well as studies using only full-text articles without a high risk of bias, wherever appropriate. For endoscopic visualization outcomes, a sensitivity analysis was also performed in studies that used the endoscopic visualization scale proposed by Frossard et al.2
Erythromycin 250 mg IV had a significantly better rate of adequate mucosal visualization, endoscopic visualization score, and endoscopy duration than the control group in almost all sensitivity analyses (Supplementary Tables 8–10).2,3,9,11-13,17,19,20,23 No significant differences were observed between these groups when using the Frossard et al. scale to determine adequate mucosal visualization (Supplementary Table 8) or when using data from full-text articles for endoscopy duration (Supplementary Table 10). Erythromycin 250 mg IV had a significantly better endoscopic visualization score compared to metoclopramide (MD, 0.61; 95% CI, 0.07–1.15) after excluding studies with high risk of bias (Supplementary Table 9). None of the other sensitivity analyses showed significantly better outcomes with erythromycin than with metoclopramide (Supplementary Tables 8–11).2,3,9,11-13,17,19,20,23
Sensitivity analyses for obtaining a diagnosis on initial endoscopy and mortality did not show any significant differences from those of the initial analysis (Supplementary Table 11). Sensitivity analysis of full-text articles did not show any significant differences between the erythromycin and control groups for second-look endoscopy, blood transfusions, and duration of hospitalization, which favored erythromycin in the initial analysis (Supplementary Table 11).
4) Component network meta-analysis
CNMA was performed using studies with erythromycin 250 mg IV and metoclopramide 10 mg IV doses. Only erythromycin was associated with significantly higher rates of adequate mucosal visualization and better endoscopic visualization scores (Supplementary Figs. 11, 12). However, this did not translate into significantly better clinical outcomes (Supplementary Figs. 13–16). Metoclopramide and the addition of gastric lavage to erythromycin/metoclopramide did not lead to significantly better outcomes than placebo (Supplementary Figs. 11–16).
DISCUSSION
This NMA revealed key findings regarding the efficacy of erythromycin and metoclopramide in the treatment of UGIB. Erythromycin was superior to metoclopramide in terms of all endoscopic and clinical outcomes. The erythromycin group was found to have significantly better outcomes than the control group for most outcomes; however, the outcomes of the metoclopramide group were not significantly different from those of the control group. CNMA demonstrated significant endoscopic procedural benefits with erythromycin. However, no such benefits were observed with metoclopramide, gastric lavage, or their combination.
Erythromycin exerts its prokinetic effect through motilin receptor agonism in the gastroduodenal smooth muscles.25 On the other hand, metoclopramide increases motility by increasing acetylcholine release through its actions on dopamine-2, 5-hydroxytryptamine-4, and muscarinic receptors.26 Although both medications have prokinetic activity, the evidence for them in UGIB is not uniform. The American College of Gastroenterology guidelines for upper GI bleeding suggest administering erythromycin pre-endoscopy, but did not recommend metoclopramide due to limited data.4 Since then, two RCTs with some favorable outcomes with metoclopramide have been published, which have been included in our NMA.3,23
The findings of our NMA are consistent with those of previous meta-analyses of RCTs that demonstrated the superior efficacy of erythromycin compared with the control group.27,28 In our NMA, although no significant difference was observed in outcomes between metoclopramide and erythromycin, metoclopramide also did not demonstrate any significant benefit over the control group in terms of endoscopic or clinical outcomes. A recent observational study using a large number of patients from a research database also demonstrated no benefit of receiving metoclopramide versus no treatment.29 In addition, the study also demonstrated significantly lower rates of repeat endoscopy with erythromycin than with metoclopramide. This is also supported by studies with critically ill patients that demonstrated the superiority of erythromycin over metoclopramide in enhancing gastric motility.30,31
Some studies included in our NMA investigated the effects of gastric lavage as part of the management. Therefore, a CNMA was performed, which revealed that gastric lavage did not have any significant effect on outcomes. The CNMA also demonstrated that erythromycin, but not metoclopramide, was associated with significantly better outcomes than placebo. However, better endoscopic outcomes do not necessarily translate into better clinical outcomes.
Adverse events due to erythromycin and metoclopramide were almost non-existent in the included RCTs. However, erythromycin should be avoided in patients with QT interval prolongation on the electrocardiogram. Additionally, there is a theoretical risk of inducing antibiotic resistance to macrolides. However, metoclopramide is associated with extrapyramidal side effects within 24 to 48 hours of treatment initiation and should be avoided in patients already receiving medications associated with extrapyramidal side effects.26
Our NMA has several strengths. To our knowledge, this is the first NMA to compare erythromycin with metoclopramide for the treatment of UGIB. Extensive sensitivity analyses were performed using various exclusion criteria. CNMA was also conducted to understand the effects of gastric lavage, which has never been performed in prior meta-analyses evaluating the efficacy of erythromycin and the effects of gastric lavage as a co-intervention with erythromycin in some trials. Our NMA has some limitations. Some studies did not specify the dosage of the medications used, with most studies being published in the abstract form. In addition, the endoscopic visualization scoring varied between the studies. However, an SMD was used to mitigate this variability. In addition, extensive sensitivity analyses were conducted using various criteria, such as full-text articles only, studies utilizing the scoring system presented by Frossard et al.,2 and those that specified medication dosing. The timing of endoscopy from the time of admission and the diagnosis of UGIB differed among studies.
In conclusion, erythromycin can be administered before endoscopy for UGIB. The current data do not support the use of metoclopramide or gastric lavage. Head-to-head and larger RCTs are required to assess the relative efficacies of erythromycin and metoclopramide.
Supplementary Material
Supplementary Material 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist for reporting a network meta-analysis.
Supplementary Table 1. Etiology of upper gastrointestinal bleeding.
Supplementary Table 2. Heterogeneity and inconsistency for the outcomes.
Supplementary Table 3. League table for diagnosis established at initial endoscopy.
Supplementary Table 4. League table for need for second-look endoscopy.
Supplementary Table 5. League table for number of blood transfusions.
Supplementary Table 6. League table for mortality.
Supplementary Table 7. League table for duration of hospitalization.
Supplementary Table 8. Sensitivity analysis for adequate mucosal visualization.
Supplementary Table 9. Sensitivity analysis for endoscopic visualization score.
Supplementary Table 10. Sensitivity analysis for endoscopy duration.
Supplementary Table 11. Sensitivity analysis with full-text articles.
Supplementary Fig. 1. Network graph for adequate mucosal visualization.
Supplementary Fig. 2. Network graph for need for second-look endoscopy.
Supplementary Fig. 3. Risk of bias analysis for adequate mucosal visualization.
Supplementary Fig. 4. Risk of bias analysis for endoscopic visualization score.
Supplementary Fig. 5. Risk of bias analysis for endoscopy duration.
Supplementary Fig. 6. Risk of bias analysis for diagnosis of bleeding lesion on initial endoscopy.
Supplementary Fig. 7. Risk of bias analysis for need for a second-look endoscopy.
Supplementary Fig. 8. Risk of bias analysis for need for blood transfusions.
Supplementary Fig. 9. Risk of bias analysis for need for mortality.
Supplementary Fig. 10. Risk of bias analysis for duration of hospitalization.
Supplementary Fig. 11. Forest plot of network meta-analysis and component network meta-analysis for adequate visualization of mucosa.
Supplementary Fig. 12. Forest plot of network meta-analysis and component network meta-analysis for endoscopic visualization score.
Supplementary Fig. 13. Forest plot of network meta-analysis and component network meta-analysis for endoscopy duration.
Supplementary Fig. 14. Forest plot of network meta-analysis and component network meta-analysis for diagnosis established at initial endoscopy.
Supplementary Fig. 15. Forest plot of network meta-analysis and component network meta-analysis for second-look endoscopy.
Supplementary Fig. 16. Forest plot of network meta-analysis and component network meta-analysis for number of blood transfusions.
Supplementary materials related to this article can be found online at https://doi.org/10.5946/ce.2024.351.
Notes
Ethical Statements
Not applicable.
Conflicts of Interest
The authors have no potential conflicts of interest.
Funding
None.
Author Contributions
Conceptualization: BPM; Data curation: RTP, KB, SC; Formal analysis: RTP; Investigation: RTP, KB, SC; Methodology: RTP, BPM; Project administration: RTP, BPM; Software: RTP; Visualization: RTP; Resources: all authors; Validation: RTP, BPM; Writing–original draft: RTP, BPM; Writing–reviewing & editing: all authors.