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Original Investigation
Intermittent vs Continuous Proton Pump Inhibitor Therapy for High-Risk Bleeding Ulcers
A Systematic Review and Meta-analysis
Hamita Sachar, MD; Keta Vaidya, MD; Loren Laine, MD
IMPORTANCE Current guidelines recommend an intravenous bolus dose of a proton pump inhibitor (PPI) followed by continuous PPI infusion after endoscopic therapy in patients with high-risk bleeding ulcers. Substitution of intermittent PPI therapy, if similarly effective as bolus plus continuous-infusion PPI therapy, would decrease the PPI dose, costs, and resource use.
Supplemental content at jamainternalmedicine.com
OBJECTIVE To compare intermittent PPI therapy with the currently recommended bolus plus continuous-infusion PPI regimen for reduction of ulcer rebleeding.
DATA SOURCES Searches included MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases through December 2013; US and European gastroenterology meeting abstracts from 2009 to 2013; and bibliographies of systematic reviews.
STUDY SELECTION Randomized trials of patients with endoscopically treated high-risk bleeding ulcers (active bleeding, nonbleeding visible vessels, and adherent clots) comparing intermittent doses of PPIs and the currently recommended regimen (80-mg intravenous bolus dose of a PPI followed by an infusion of 8 mg/h for 72 hours).
DATA EXTRACTION AND SYNTHESIS Duplicate independent data extraction and risk-of-bias assessment were performed. Data were pooled using a fixed-effects model or a random effects model if statistical heterogeneity was present.
MAIN OUTCOMES AND MEASURES The primary outcome was rebleeding within 7 days; additional predefined outcomes included rebleeding within 3 and 30 days, need for urgent intervention, mortality, red blood cell transfusion, and length of hospital stay. The primary hypothesis, defined before initiation of the literature review, was that intermittent use of PPIs was noninferior to bolus plus continuous infusion of PPIs, with the noninferiority margin predefined as an absolute risk difference of 3%.
RESULTS The risk ratio of rebleeding within 7 days for intermittent vs bolus plus continuous infusion of PPIs was 0.72 (upper boundary of 1-sided 95% CI, 0.97) and the absolute risk difference was −2.64% (upper boundary of 1-sided 95% CI, −0.28%, which is well below the predefined noninferiority margin of 3%). Risk ratios for rebleeding within 30 days and 3 days, mortality, and urgent interventions were less than 1 and mean differences for blood transfusion and hospital length of stay were less than 0, indicating that no summary estimate showed an increased risk with intermittent therapy. The upper boundaries of 95% CIs for absolute risk differences were less than 1.50% for all predefined rebleeding outcomes.
CONCLUSIONS AND RELEVANCE Intermittent PPI therapy is comparable to the current guideline-recommended regimen of intravenous bolus plus a continuous infusion of PPIs in patients with endoscopically treated high-risk bleeding ulcers. Guidelines should be revised to recommend intermittent PPI therapy.
JAMA Intern Med. 2014;174(11):1755-1762. doi:10.1001/jamainternmed.2014.4056 Published online September 8, 2014.
Author Affiliations: Section of Digestive Diseases, Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut (Sachar, Vaidya, Laine); Section of Digestive Diseases, Department of Medicine, Veterans Affairs Connecticut Healthcare System, West Haven (Laine).
Corresponding Author: Loren Laine, MD, Section of Digestive Diseases, Department of Medicine, Yale School of Medicine, Yale University, PO Box 208019, New Haven, CT 06520
| Copyright 2014 American Medical Association. All rights reserved. |
Copyright 2014 American Medical Association. All rights reserved.
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lcers are the most common cause of upper gastroin- testinal bleeding.1 Current guidelines2,3 recommend that patients with bleeding ulcers who have high-risk
endoscopic findings (active bleeding, nonbleeding visible ves- sels, and adherent clots) receive an intravenous bolus dose fol- lowed bya continuous infusion ofa proton pump inhibitor (PPI) after endoscopic treatment. Specifically, an 80-mg intrave- nous bolus dose of a PPI followed by a continuous infusion at 8 mg/h for 72 hours is recommended.2
In vitro data suggest that an intragastric pH above 6 may be required to promote clot formation and stability.4,5 High- dose, continuous-infusion PPI therapy was consequently studied6 in an attempt to maintain an intragastric pH above
- Elimination half-lives of PPIs are short (approximately 1 hour). Thus, after clearance of a PPI administered as a bolus, whether intravenous or oral, new proton pumps may pro- duce It was therefore hypothesized7 that a constant in- fusion would be required to maintain an intragastric pH above 6, with a PPI present continuously to inhibit newly activated proton pumps. A meta-analysis7 of randomized trials com- pared high-dose continuous-infusion PPI therapy with pla- cebo or no therapy and showed a significant decrease in fur- ther bleeding, as well as surgery and mortality, among patients with high-risk bleeding ulcers after endoscopic therapy. How- ever, a meta-analysis7 of randomized trials of intermittent PPI
therapy vs placebo or no therapy also showed a significant re- duction in further bleeding in patients with high-risk bleed- ing ulcers after endoscopic therapy.
An important issue in clinical practice is whether inter- mittent PPI therapy can be substituted for the currently rec- ommended bolus plus continuous-infusion PPI therapy. If intermittent PPI treatment achieves comparable clinical efficacy, it would be the preferred regimen given the decrease in cost and resources (eg, infusion pump, nursing and pharmacy personnel time, and requirement for moni- tored setting), the decrease in the PPI dose, and the greater ease of administration.
Although randomized trials comparing intermittent bo- luses with continuous infusion of PPIs have been performed, the absence of a significant difference in a trial cannot be in- terpreted as documenting that the 2 treatments are compa- rable. These trials were not designed or adequately powered to assess noninferiority of intermittent PPI therapy.
Meta-analyses of PPI therapy have been performed,7-11 but they have not addressed the clinically relevant question in this population: Is intermittent PPI therapy noninferior to the guide- line-recommended intravenous bolus plus continuous- infusion regimen? Prior meta-analyses have included patients without high-risk stigmata8-11 or patients with high-risk stig- mata who did not undergo endoscopic therapy8-11 and have com- pared high- vs low-dose PPIs rather than continuous vs inter- mittent administration.9,11 Furthermore, several randomized trials have been published since the literature searches of the prior meta-analyses were performed.
We therefore performed a systematic review and meta- analysis to assess the clinical efficacy of intermittent PPI regi- mens vs the standard bolus plus continuous-infusion regi- men after successful endoscopic therapy in patients with
bleeding ulcers. We hypothesized that the risk of recurrent bleeding with this regimen was noninferior to (ie, not unac- ceptably greater than) the risk with the currently recom- mended bolus plus continuous-infusion PPI therapy.
Methods
Data Sources and Searches
The search strategy, study inclusion and exclusion criteria, pri- mary and secondary outcomes, and analyses were defined a priori and are described below. The protocol was not regis- tered on an online registry site.
We searched 3 bibliographic databases—MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials—from inception (MEDLINE, 1946; EMBASE, 1974; and Cochrane Central Register of Controlled Trials, 1898) to De- cember 31, 2013, without language restriction. MEDLINE and EMBASE were searched using the Ovid interface. An exten- sive search strategy using a combination of subject headings and text words was constructed to find articles that relate to the treatment of upper gastrointestinal bleeding from ulcers with PPIs (eFigure 1 in the Supplement).
In addition, we searched for relevant abstracts from ma- jor gastroenterology scientific meetings (Digestive Disease Week, United European Gastroenterology Week, and Ameri- can College of Gastroenterology) from 2009 to 2013. Bibliog- raphies of prior systematic reviews were also evaluated.8-11
Two of us (H.S. and K.V.) independently reviewed titles and abstracts produced by the search. Studies deemed poten- tially relevant by either author were independently retrieved and reviewed in full by both authors to determine eligibility. Disagreements regarding the inclusion of a study were re- solved by discussion; if a consensus could not be reached, the senior author (L.L.) served as the final arbiter.
Study Selection
Study Design and Population
Only randomized clinical trials were included. Studies were in- cluded if patients presented with upper gastrointestinal bleed- ing; were found to have a gastric or duodenal ulcer with ac- tive bleeding, a nonbleeding visible vessel, or an adherent clot; and had received successful endoscopic hemostatic therapy, with randomization to intermittent or continuous PPI treat- ment, after endoscopic therapy. We excluded patients who had ulcers with flat spots and clean bases because such patients have a very low rate of clinically significant rebleeding, and current guidelines2 do not recommend endoscopic therapy or PPI infusion for these patients.
Intervention
The study therapy was defined as PPIs administered in inter- mittent boluses. Because the degree of acid suppression re- quired to reduce rebleeding is not known, no restrictions were applied to the frequency of boluses (they could be once daily or more often), the doses of boluses, or the route of adminis- tration (oral vs intravenous). Because an oral bolus of a PPI pro- vides a pharmacodynamic effect comparable to that of the
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equivalent intravenous dose of a PPI,6 equal oral and intrave- nous doses would be postulated to have comparable efficacy.
Comparison
The control regimen was the standard PPI bolus plus continu- ous-infusion that has been documented to be effective in this population in a meta-analysis of randomized trials7 and is rec- ommended by current guidelines2: an 80-mg intravenous bo- lus followed by a continuous 8-mg/h intravenous infusion for 72 hours.
Outcomes
Studies reporting 1 or more of the following outcomes were eli- gible for inclusion: recurrent bleeding, mortality, need for ur- gent intervention (subsequent endoscopic therapy, surgery, or radiologic intervention), red blood cell transfusions, and length of hospitalization.
The primary outcome was defined as recurrent bleeding within 7 days as recommended by an international consensus conference12 on the methods used in trials for nonvariceal up- per gastrointestinal bleeding. Recurrent bleeding within 3 days (because this is the duration of treatment studied and recom- mended for continuous-infusion PPI therapy) and 30 days were assessed as secondary outcomes. Other predefined outcomes were mortality, need for surgery and radiologic intervention, need for urgent intervention, red blood cell transfusions, and length of hospitalization. Blood transfusion results reported in milliliters were converted to units (250 mL = 1 U of packed red blood cells). Studies that did not report the SD or allow calcu- lation of the SD (eg, SEs or CIs not provided13) for continuous outcomes were excluded for analysis of that outcome.
Data Extraction and Risk-of-Bias Assessment
A data extraction sheet was constructed to record informa- tion on study characteristics, patient characteristics, and pre- defined outcomes. Risk of bias was assessed using the Coch- rane Collaboration’s13 risk-of-bias tool and criteria for judging risk of bias. The domains assessed were random sequence gen- eration and allocation concealment (selection bias), blinding of study participants and personnel (performance bias), blind- ing of outcome assessment (detection bias), incomplete out- come data (attrition bias), selective reporting (reporting bias), and other bias.
Two of us (H.S. and K.V.) independently extracted data and assessed the risk of bias for each of the articles. Once this was done, the forms containing the assessments wereexchanged and reviewed for comparison. Any disagreements were again re- solved by discussion and consensus, withthe senior author (L.L.) serving as the final arbiter if consensus could not be reached. If studies had apparent contradictions that could not be resolved during data extraction (eg, bleeding definition varied within the same article) or did not report the results of their predefined out- comes sufficiently to allow inclusion in our meta-analyses (eg, SDs not given), the study’s authors were contacted.
Data Synthesis and Analysis
The dichotomous pooled outcomes were calculated as risk ra- tios (RRs) using the Mantel-Haenszel statistical method. For
the continuous pooled outcomes, mean difference was calcu- lated. Results for our primary analysis, which was a noninfe- riority analysis, are presented with the upper boundary of the 1-sided 95% CI. We chose 1-sided testing because we know of no physiologic, pharmacologic, or clinical basis on which to postulate that intermittent PPI therapy might be more effec- tive than high-dose bolus plus continuous-infusion PPI therapy. We calculated the absolute risk difference and upper bound- ary for the 1-sided 95% CI for proportional outcomes, such as rebleeding, by multiplying the incidence of the outcome in the control group by the relative risk increase (or reduction) with the intermittent regimen compared with the control regi- men.
The primary objective of the study was to demonstrate that the incidence of recurrent bleeding within 7 days of starting an intermittent PPI regimen is noninferior to the incidence of rebleeding with the standard bolus plus continuous-infusion PPI regimen. We defined the margin of noninferiority as an ab- solute risk difference of 3%. A prior meta-analysis7 reported an absolute risk difference of 8% in rebleeding with bolus plus continuous PPI infusion vs placebo or no treatment in the same population as analyzed in our systematic review. The margin of 3% represents 50% of the lower boundary of the 95% CI (ie, 6%) from that analysis.
Subgroups were predefined and used to assess the influ- ence of specific factors on the results. Factors related to the intermittent PPI regimen were route of administration (oral vs intravenous), frequency (once-daily vs greater than once- daily dosing), total dose (≤240 mg vs >240 mg and ≤120 mg vs
>120 mg), and use of a higher-dose bolus at initiation of inter- mittent PPI therapy. In addition, the effect of dividing studies according to the risk of bias (lower risk [no high-risk domains and ≥5 low-risk domains] vs higher risk) was assessed, as was the effect of including abstracts in the analysis. Studies were also divided based on their geographic location (Asian vs non- Asian).
Our primary population for analysis was per protocol, as is commonly recommended for noninferiority analyses.12 How- ever, a sensitivity analysis for our primary analysis was planned using the intention-to-treat population. In addition, tradi- tional forest plots and pooled analyses with 2-sided 95% CIs for our predefined rebleeding outcomes were constructed using the intention-to-treat population. A post hoc sensitivity analy- sis using trial sequential meta-analysis was performed be- cause of relatively sparse rebleeding events. For studies that did not specifically conduct a per-protocol analysis, we selec- tively extracted and analyzed data on patients who had no pro- tocol violations. A protocol violation was considered to have occurred if a patient met the predefined exclusion criteria af- ter randomization (eg, gastric ulcer was malignant) or failed to follow-up within the period predefined for the assessment of the primary outcome (eg, 7 days).
Heterogeneity was assessed for the individual meta- analyses using the χ2 test and the I2 statistic. Significant hetero- geneity was defined as P < .10 using the χ2 test or I2 greater than 50%. A fixed-effects model was used when heterogeneity was not significant, and a random-effects model was used when statistical heterogeneity was present. Treatment-by-
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Figure 1. Flow Diagram
One of 3 arms in another study19 was excluded because no PPI
treatment was administered in that group. Two authors were
| 24 Studies assessed for eligibility |
| 2115 Records screened |
| 2091 Records excluded |
| 2115 Records after duplicates removed |
|
||||||||||||
contacted and provided clarification of contradictory statements20,25; a third author was contacted to provide SDs for transfusion and hospital length of stay outcomes,19 but these data were not obtained. Details of the included studies are displayed in Table 1,14-26 and the risk-of-bias assessment is shown in eFigure 2 in the Supplement.
| 13 Studies included in qualitative synthesis |
| 11 Studies excluded
5 Did not include only high-risk ulcers and/or did not give endoscopic therapy to all patients 3 Did not administer standard bolus plus continuous-infusion regimen 3 Not randomized or pseudorandomized |
| 13 Studies included in quantitative synthesis (meta-analysis) |
Search and selection process used for studies included in the systematic review.
subgroup interaction was assessed by calculating the hetero- geneity between subgroups using the χ2 test. Significant hetero- geneity was defined as P < .05. A funnel plot was created to assess for publication and other reporting biases; the funnel plot was examined visually for asymmetry, and an Egger test for asymmetry of a funnel plot was conducted. Analyses were done using RevMan, version 5.2, software (Nordic Cochrane Centre, The Cochrane Collaboration) and Trial Sequential Analysis software (Copenhagen Trial Unit).
Results
Search and Study Selection
We identified 2115 citations after removal of duplicates, in- cluding 2112 from our bibliographic database searches and 3 from other sources (Figure 1). Review of these titles and ab- stracts resulted in 21 full-text articles from the database searches being retrieved and assessed for eligibility. Eleven studies were excluded for reasons detailed in Figure 1, leav- ing 10 full-text articles from the database searches.14-23 In ad- dition, 1 relevant full-text article was identified from the ref- erence list of a systematic review24 and 2 meeting abstracts that met eligibility criteria were identified,25,26 resulting in a total of 13 studies for inclusion in the analysis.
No study was excluded from our review because of a con- tinuous-infusion dosage regimen that did not match our pre- defined criterion of an 80-mg bolus and 8-mg/h infusion. One of the 2 continuous-infusion arms in one study17 was ex- cluded from analysis because the regimen (40-mg bolus and 4-mg/h infusion) in this arm was half our predefined dosage.
Primary Outcome
Ten trials reported on recurrent bleeding within 7 days.14,16,17,20-26 Only 1 of the 10 studies26 reported a statisti- cally significant difference, which was in favor of the inter- mittent PPI bolus regimen. The RR of recurrent rebleeding within 7 days for intermittent vs continuous PPI administra- tion was 0.72 with a 1-sided 95% CI upper boundary of 0.97, without evidence of statistical heterogeneity. The upper bound- ary of the 1-sided 95% CI of the absolute risk difference was
−0.28% (Table 2), which was well below the predefined non- inferiority margin of 3%.
A funnel plot is presented in Figure 2. Visual inspection shows no suggestion of publication bias favoring intermit- tent therapy. The Egger test indicated no statistically signifi- cant reporting bias (P = .49). No significant interaction effect was seen in any of the predefined subgroup analyses of the pri- mary outcome (eTable in the Supplement).
The sensitivity analysis of the primary outcome in the in- tention-to-treat population showed results that were similar to the primary per-protocol analysis for recurrent bleeding within 7 days: RR, 0.74; 1-sided 95% CI upper boundary, 1.00; and up- per boundary of the 1-sided 95% CI of absolute risk difference, 0%, which is well below the noninferiority margin of 3%. A for- est plot of the individual studies and pooled analysis with 2-sided 95% CIs for rebleeding within 7 days in the intention- to-treat population is shown in Figure 3.14,16,17,20-26 The results of this standard meta-analysis (RR, 0.74; 95% CI, 0.52-1.06) and the post hoc sensitivity analysis using trial sequential analysis (RR, 0.74; 95% CI, 0.51-1.07) were virtually identical.
Additional Outcomes
Nine trials14,16,17,20-24,26 reported recurrent bleeding at 3 days. One26 of the 9 studies showed a significant difference in favor of the intermittent regimen. Noninferiority for intermittent vs bolus plus continuous-infusion PPI therapy was also seen for rebleeding at 3 days: RR, 0.73; 1-sided 95% CI upper bound- ary, 1.02; and upper boundary of the 1-sided 95% CI of the ab- solute risk difference, 0.17% (Table 2). Thirteen trials re- ported recurrent bleeding within 30 days. Two of the 13 studies reported a significant difference (1 in favor of the bolus plus continuous-infusion PPI regimen15 and the other in favor of the intermittent PPI regimen26), and again noninferiority was
demonstrated for intermittent administration of PPIs: RR, 0.89; 1-sided 95% CI upper boundary, 1.17; and upper boundary of the 1-sided 95% CI of the absolute risk difference, 1.49% (Table 2). Similar findings were seen for mortality, surgery/ radiologic intervention, urgent intervention, red blood cell transfusions, and hospital length of stay (Table 2). All RRs were less than 1 and mean differences were less than 0, indicating
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Table 1. Characteristics of Studies Included in the Meta-analysis
|
Source |
PPI |
Dose, Route, and Frequency of Intermittent PPI | Cumulative Dose of Intermittent PPI, mg |
Type of Study |
Stigmata of Recent Hemorrhage |
Endoscopic Therapy |
| Andriulli et al,14 | Omeprazole | 40 mg/d IV | 120 | Superiority | Spurting, 50; oozing, | Epinephrine; |
| 2008 | (n = 330); | 155; NBVV, 166; clot, | epinephrine with | |||
| pantoprazole | 103 | bipolar/argon plasma | ||||
| (n = 144) | coagulation; | |||||
| epinephrine with clips | ||||||
| Chan et al,15 | Omeprazole | 40 mg/d IV | 120 | Equivalence | Spurting, 8; oozing, | Epinephrine; |
| 2011 | 46; NBVV, 39; clot, | epinephrine | ||||
| 29 | with heater probe; | |||||
| epinephrine with | ||||||
| clips | ||||||
| Chen et al,16 | Omeprazole | 40 mg/d IV | 120 | Superiority | Spurting,12; oozing, | Epinephrine with |
| 2012 | 71; NBVV, 117; clot, | heater probe | ||||
| 0 | ||||||
| Choi et al,17 | Pantoprazole | 40 mg/d IV | 120 | Superiority for pH | Spurting, NS; oozing, | Epinephrine with |
| 2009 | difference | NS; NBVV, NS; clot, | argon plasma | |||
| NS | coagulation with or | |||||
| without clips | ||||||
| Hsu et al,18 | Pantoprazole | Bolus: 80 mg IV | 560 | Superiority | Spurting,12; oozing, | Epinephrine with |
| 2010 | once, then 40 mg IV | 40; NBVV, 52; clot, | bipolar; bipolar | |||
| every 6 h | 16 | |||||
| Hung et al,19 | Pantoprazole | Bolus: 80 mg IV | 320 | Superiority of PPI | Spurting, 11; oozing, | Epinephrine; |
| 2007 | once, then 40 mg IV | infusion to no | 52; NBVV, 26; clot, | epinephrine with | ||
| every 12 h | treatment | 13 | heater probe | |||
| Jang et al,24 | Pantoprazole | 40 mg PO every 12 h | 400 | Uncertain | Spurting,2; oozing, 4; | Epinephrine; argon |
| 2006 | NBVV, 13; clot, 0 | plasma coagulation; | ||||
| clips | ||||||
| Javid et al,20 | Omeprazole (n = 36); | Bolus: 80 mg PO | 320, | Noninferiority for pH | Spurting, 17; oozing, | Epinephrine with |
| 2009 | pantoprazole | once, then 40 mg PO | 520, | difference | 20; NBVV, 53; clot, 0 | heater probe |
| (n = 35); | every 12 h; bolus: | 320 | ||||
| rabeprazole (n = 35) | 80 mg PO once, then | |||||
| 80 mg PO every | ||||||
| 12 h; bolus: 80 mg | ||||||
| PO once, then 40 mg | ||||||
| PO every 12 h | ||||||
| Kim et al,21 | Rabeprazole | 20 mg PO every 12 h | 120 | Noninferiority | Spurting, 10; oozing, | Epinephrine; |
| 2012 | 29; NBVV, 44; clot, | epinephrine with | ||||
| 23 | monopolar; | |||||
| epinephrine with | ||||||
| clips; epinephrine | ||||||
| with monopolar | ||||||
| and clips | ||||||
| Sung et al,25 | Esomeprazole | 40 mg PO every 12 h | 240 | Superiority | Spurting, NS; oozing, | NS |
| 2012 | NS; NBVV, NS; clot, | |||||
| NS | ||||||
| Ucbilek et al,26 | Pantoprazole | Bolus: 80 mg IV | 320 | Uncertain | Spurting, NS; oozing, | Epinephrine with |
| 2013 | once, then 40 mg IV | NS; NBVV, NS; clot, | sclerotherapy | |||
| every 12 h | NS | |||||
| Yamada et al,22 | Pantoprazole | Bolus: 80 mg IV | 240 | Superiority | Spurting, 13; oozing, | Epinephrine; |
| 2012 | once, then 40 mg IV | 3; NBVV, 6; clot, 5 | epinephrine with | |||
| every 12 h | bipolar; epinephrine | |||||
| with clips | ||||||
| Yüksel et al,23 | Pantoprazole | 40 mg IV every 12 h | 240 | Uncertain | Spurting, 7; oozing, | Epinephrine with |
| 2008 | 60; NBVV, 30; clot, 0 | heater probe |
Abbreviations: IV, intravenous; NBVV, nonbleeding visible vessel; NS, not stated; PO, orally; PPI, proton pump inhibitor.
that no summary estimate showed an increased risk with in- termittent therapy. Forest plots of individual studies and meta- analysis with 2-sided 95% CIs for rebleeding within 3 and 30 days in the intention-to-treat population are shown in eFig- ure 3 and eFigure 4 in the Supplement.
Discussion
Our systematic review and meta-analysis in patients with bleeding ulcers and high-risk endoscopic findings establish that intermittent PPI therapy is noninferior to the currently rec- ommended regimen of intravenous bolus plus continuous in-
fusion of an intravenous PPI for 3 days. The upper boundary of the 95% CI for the absolute risk difference between inter- mittent and continuous PPI therapy was −0.28% for our pri- mary outcome of rebleeding within 7 days, indicating that there is no increase in recurrent bleeding with intermittent vs con- tinuous PPI therapy.
The upper boundaries of the 95% CI for the absolute risk differences for secondary outcomes of rebleeding within 3 days (0.17%) and 30 days (1.49%) also were well below our pre- defined noninferiority margin of 3%. We believe that these very small potential differences would be widely accepted by cli- nicians as indicative of noninferiority. Furthermore, the treat- ment effects were consistent across a variety of predefined sub-
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Table 2. Meta-analysis of Intermittent PPI vs Bolus With Continuous-Infusion PPIa
Figure 2. Funnel Plot of Rebleeding Within 7 Days From Individual Studies in the Meta-analysis
0
0.5
1.0
1.5
2.0
Abbreviations: PPI, proton pump inhibitor; RI, radiologic intervention.
| Outcome
Recurrent bleeding Within 7 d Within 30 d Within 3 d Mortality Surgery/RI Urgent interventions Length of hospital stay, d Blood transfusion, U |
| No. of
No. of Studies Patients |
| (95% CI, Upper Boundary)
Risk Ratio Absolute Risk Difference, % |
| 1014,16,17,20-26
1314-26 914,16,17,20-24,26 1114-16,18-24,26 1214-24,26 914-20,22,23 814-16,18,21-23,26 914-16,18,21-24,26 |
| 1346
1691 1146 1453 1491 1283 1204 1242 |
| 0.72 (0.97)
0.89 (1.17) 0.73 (1.02) 0.64 (1.21) 0.87 (1.49) 0.95 (1.27) −0.26 (0.09)b −0.22 (−0.02)b |
| −2.64 (−0.28)
−0.97 (1.49) −2.36 (0.17) −0.74 (0.43) −0.30 (1.12) −0.45 (2.43) |
a Statistical heterogeneity was not noted in any analysis.
b Data represent the mean difference.
for intermittent (oral 80-mg bolus and 40-80 mg every 12 hours) and continuous infusion of PPIs in one study,20 not significantly different for intermittent (intravenous 80-mg bolus and 40 mg every 12 hours) vs continuous PPI infusion in another study (49% vs 59%),19 and significantly lower with intermittent (intravenous 40-mg bolus every 24 hours) vs continuous infusion in a third trial (39% vs 71%)17; the generalizability of these studies, all performed in Asia, to patients in Western countries is uncertain. An alternative explanation for the similar efficacy of intermittent PPI administration is that an intragastric pH above 4 to 5 may suffice to prevent clot lysis.5,27
Our ability to determine the most appropriate intermit- tent PPI regimen is limited by the variation in intermittent PPI
regimens used in the studies included in our systematic re-
0.01
0.1
1.0
Risk Ratio
10.0
100.0
view. A variety of dosing schedules and total doses were used,
different PPIs were given, and both oral and intravenous routes
SE indicates standard error.
group analyses and for the predefined sensitivity analysis of the primary outcome, as well as across other predefined clini- cal outcomes, such as red cell transfusion, hospital stay, need for urgent intervention, and mortality.
The primary objective of our meta-analysis was to assess noninferiority of intermittent PPI therapy vs bolus plus con- tinuous-infusion PPI therapy. The finding that the upper boundary of the 1-sided 95% CI of RR was less than 1.0 in the primary analysis might be taken by some to suggest that in- termittent PPI therapy is perhaps marginally superior to the bolus plus continuous PPI infusion therapy. However, this is not a correct interpretation of our findings and is not sup- ported by the results of the standard analysis used to assess for superiority, which was determination of RR with 2-sided 95% CIs in the intention-to-treat population (RR, 0.74; 95% CI, 0.52-1.06).
Our review does not allow us to determine the reason that the efficacy of intermittent administration of a PPI is similar to a continuous infusion in patients with bleeding ulcers. One possible explanation is that high-dose intermittent PPI therapy achieves an intragastric pH similar to that attained with continuous infusion of PPIs, falling in the range of 6 to
- Among the studies in our systematic review that assessed intragastric pH, the proportion of time that the pH was greater than 6 was virtually identical at approximately 100%
of administration were used. Increasing the frequency of ad- ministration or the dose of PPIs increases their antisecretory effect,6 although our subgroup analyses did not document that more frequent or higher doses improved the treatment ef- fect. Furthermore, oral administration provides an antisecre- tory effect comparable to that of equivalent doses of intrave- nous PPIs.6 Subgroup analysis did not reveal significant heterogeneity between the results for oral and intravenous in- termittent PPI therapy, although the 95% CI for the intermit- tent oral PPI vs continuous-infusion PPI comparison was wide. Given the pharmacodynamic profile of PPIs, we would favor intermittent, high-dose PPIs given at least twice daily, using oral PPIs in patients able to tolerate oral medications. Never- theless, oral PPI therapy should be studied for noninferiority to intravenous PPI therapy to provide direct evidence sup- porting the use of the oral dosage form.
Another potential limitation of our analysis relates to the variability in endoscopic therapies used across studies and of- ten within studies. Differing endoscopic therapies may have achieved different results for the primary outcome of rebleed- ing and therefore theoretically could confound the results. However, where reported, the proportion of patients who re- ceived the same endoscopic therapy was comparable in both study arms of the individual studies, and results for compari- sons of rebleeding rates for intermittent vs continuous PPI regi- mens in patients receiving the same endoscopic therapy were similar to the results in the full population. In addition, we were
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Figure 3. Forest Plot of Studies Comparing Intermittent With Bolus Plus Continuous-Infusion Proton Pump Inhibitors in Patients With High-Risk Bleeding Ulcers
| Intermittent Bolus, No. |
| Continuous Infusion, No. |
| Source Events Total Events Total
Andriulli et al,14 2008 19 239 28 243 Chen et al,16 2012 6 101 7 100 Choi et al,17 2009 3 21 1 19 Jang et al,24 2006 0 19 2 19 Javid et al,20 2009 4 53 4 53 Kim et al,21 2012 2 54 1 52 Sung et al,25 2012 3 105 2 95 Ucbilek et al,26 2013 3 37 10 36 Yamada et al,22 2012 4 13 5 15 Yüksel et al,23 2008 3 49 4 50 Total (95% CI) 47 691 64 682 |
| Risk Ratio (M–H, Fixed, 95% CI)
0.69 (0.40-1.20) 0.85 (0.30-2.44) 2.71 (0.31-23.93) 0.20 (0.01-3.91) 1.00 (0.26-3.79) 1.93 (0.18-20.60) 1.36 (0.23-7.95) 0.29 (0.09-0.97) 0.92 (0.31-2.73) 0.77 (0.18-3.24) 0.74 (0.52-1.06) |
| Favors Favors Bolus Infusion |
| Heterogeneity: χ2 = 5.96 (P = .74) I 2 = 0%
9 Test for overall effect: z = 1.65 (P = .10) |
Weight,
%
43.2
11.0
1.6
3.9
6.2
1.6
3.3
15.8
7.2
6.2
100.0
0.01
0.1
1.0
10 100
Risk Ratio (M–H, Fixed, 95% CI)
The outcome examined was rebleeding within 7 days in the intention-to-treat population. M-H indicates Mantel-Haenszel.
unable to assess whether the results might vary based on risk factors, such as the stigmata of hemorrhage (eg, active bleed- ing vs adherent clot).
Studies in this systematic review were of variable qual- ity, and many had potential risks of bias related to allocation concealment and blinding. As is common in many reviews, the included studies frequently failed to provide the detail re- quired to be considered low risk for allocation concealment by Cochrane methods,13 and 12 of the 13 studies were consid- ered to have unclear risk of bias in this domain. Perhaps more important, 8 of the 13 studies were not blinded. However, sub- group analysis showed no evidence of significant heteroge- neity related to risk of bias, with no suggestion of lower effi- cacy for intermittent therapy in higher-quality studies (eTable in the Supplement).
Although a methodologically sound randomized clini- cal trial would be preferred to definitively test our hypoth- esis, given the relatively low rate of recurrent bleeding in patients receiving endoscopic therapy and continuous-
infusion PPI therapy, such a study would be very large and likely impractical to undertake. For example, assuming that the risk of rebleeding within 7 days with the continuous PPI infusion is 9.4% (based on our pooled data), a sample size of 2342 patients would be required to be 80% certain that the intermittent regimen is not worse than the infusion regimen by 3%.
Conclusions
Intermittent PPI regimens are comparable to continuous PPI infusion regimens in patients with bleeding ulcers and high- risk endoscopic findings. Given the greater ease of use and lower cost and resource utilization, intermittent PPI therapy should be the regimen of choice after endoscopic therapy in such patients. Current national and international guidelines2,3 should be revised to incorporate this new information and rec- ommend intermittent PPI therapy.
ARTICLE INFORMATION
Accepted for Publication: June 28, 2014.
Author Contributions: Drs Sachar and Laine had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Sachar, Laine. Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Sachar, Laine. Critical revision of the manuscript for important intellectual content: Sachar, Vaidya.
Statistical analysis: All authors. Administrative, technical, or material support: Laine.
Study supervision: Laine.
Published Online: September 8, 2014. doi:10.1001/jamainternmed.2014.4056.
Conflict of Interest Disclosures: Dr Laine reported serving on the data safety monitoring board for a study of a nongastrointestinal investigational drug made by Eisai, which is a manufacturer of PPIs. No other disclosures are reported.
Funding/Support: The study was funded by grant T32 DK007017 from the National Institutes of Health (Dr Sachar).
Role of the Sponsor: The National Institutes of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Previous Presentation: This study was presented as an abstract at Digestive Disease Week; May 4, 2014; Chicago, Illinois.
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