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McDonagh MS, Carson S, Thakurta S. Drug Class Review: Proton Pump Inhibitors: Final Report Update 5 [Internet]. Portland (OR): Oregon Health & Science University; 2009 May.

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Drug Class Review: Proton Pump Inhibitors: Final Report Update 5 [Internet].

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Summary

Table 17 summarizes the evidence for this report.

Table 1

Summary table

Key QuestionStrength of evidenceConclusion
Key Question 1. Gastroesophageal reflux disease, short-term efficacy
Erosive gastroesophageal reflux disease: SymptomsGoodIn 16 head-to-head trials, the only difference between proton pump inhibitors on the outcome of complete symptom relief at 4 weeks was in the comparison of esomeprazole 40 mg with omeprazole 20 mg; the pooled risk difference in 3 trials was 8% (95% CI 3 to 13), with a number needed to treat of 13.
Time to relief of heartburn was similar for all proton pump inhibitors in head-to-head trials, but the methods used to measure and report this outcome varied in the 14 studies.
Erosive gastroesophageal reflux disease: Esophagitis healingGoodGood evidence shows no difference between omeprazole, lansoprazole, pantoprazole, and rabeprazole for healing of esophagitis. Thirteen head- to-head trials found these 4 proton pump inhibitors to be equally effective in healing at 4 and 8 weeks. Pooled analysis of 4- and 8-week healing rates from 4 trials of esomeprazole 40 mg compared to omeprazole 20 mg indicate esomeprazole to be superior; risk difference 7% (95% CI 1 to 12) and a number needed to treat of 14 and 5% (95% CI 1 to 9), number needed to treat = 20, respectively.
Three trials compared esomeprazole 40 mg with lansoprazole 30 mg. The pooled difference in healing rate was significantly greater with esomeprazole at 4 and 8 weeks, risk differences 5% (95% CI 2 to 7) and 3% (95% CI 1 to 5), respectively.
Four trials compared esomeprazole 40 mg and pantoprazole 40 mg. Pooled difference in healing rate was significantly greater with esomeprazole at 4 weeks, but not at 8 weeks, risk differences 5% (95% CI 2 to 8) and 1% (95% CI –3 to 5).
Healing in moderate to severe erosive esophagitisFairEsomeprazole 40 mg was more effective at healing esophagitis at 4 and 8 weeks than omeprazole 20 mg and lansoprazole 30 mg. The pooled risk difference in 3 studies comparing omeprazole 20 mg with esomeprazole 40 mg was 16% at 4 weeks and 13% at 8 weeks (number needed to treat = 6 at 4 weeks, 8 at 8 weeks).The pooled risk difference in 2 studies comparing lansoprazole 30 mg with esomeprazole 40 mg was 8% at 4 weeks and 9% at 8 weeks (number needed to treat = 13 at 4 weeks, 11 at 8 weeks). Evidence is mixed on differences between esomeprazole 40 mg and pantoprazole 40 mg. At 4 weeks, esomeprazole 40 mg had a higher healing rate \than pantoprazole 40 mg - pooled risk difference (2 studies), 14% (95% CI 7 to 20). At 8 weeks, no difference was found in a single small study.
Lansoprazole 30 mg (2 studies) and esomeprazole 20 mg (1 study) were no different to omeprazole 20 mg at 4 or 8 weeks.
Erosive gastroesophageal reflux disease: Prevention of relapseGoodFor maintenance of healed esophagitis, there is good evidence that no difference exists between omeprazole, lansoprazole, and rabeprazole. The longest study (over 5 years) compared omeprazole with rabeprazole. No difference was found between esomeprazole 20 mg and pantoprazole 20 mg in combined symptomatic and endoscopic remission rates after 6 months.
Esomeprazole 20 mg was found to have lower relapse rates than pantoprazole 20 mg in 2 6-month studies.
Non-erosive or empirically- treated gastroesophageal reflux disease: SymptomsFairThree head-to-head trials in patients with endoscopy-negative gastroesophageal reflux disease found no difference between esomeprazole 20 mg and omeprazole 20 mg, pantoprazole 20 mg, and rabeprazole 10 mg. These studies used different outcome measures.
Limited indirect evidence from placebo- and active- controlled trials suggests similar efficacy for heartburn resolution and complete symptom relief for the 5 proton pump inhibitors.
Non-erosive or empirically- treated gastroesophageal reflux disease: Prevention of relapseFair to PoorIn a 6-month head-to-head trial of on-demand esomeprazole compared with daily lansoprazole 15 mg, more patients discontinued lansoprazole.. On-demand rabeprazole 10 mg, on-demand esomeprazole 20 mg, and daily omeprazole 10 mg were more effective than placebo in prevention of relapse of symptoms over 6 months in patients with endoscopy negative gastroesophageal reflux disease.
Gastroesophageal reflux disease: Evidence in ChildrenPoorThere are no direct comparisons of proton pump inhibitors for reflux esophagitis in children. A fair quality placebo-controlled trial in infants did not find omeprazole to be superior to placebo.
Key Questions 2, 3, 4. Peptic ulcer, Helicobacter pylori eradication
Duodenal UlcerFairAll newer proton pump inhibitors have been compared to omeprazole. The evidence from 10 head to head trials suggests no difference between the proton pump inhibitors in healing rates or symptom relief.
Gastric UlcerFairThree head-to-head studies were found, comparing rabeprazole to omeprazole. No significant differences in healing rate was found. Minor improvements in symptom relief were found with a higher dose of rabeprazole (20 mg) compared to omeprazole 20 mg, but not with a lower dose (rabeprazole 10 mg). There are no other direct comparisons.
Nonsteroidal anti-inflammatory drug-induced ulcerPoorNo head-to-head studies. In trials of omeprazole and lansoprazole compared with ranitidine, no difference in healing rates or symptom resolution rates were apparent.
Prevention of nonsteroidal anti- inflammatory drug induced ulcerPoorDirect comparison of pantoprazole 20 mg, 40 mg and omeprazole 20 mg daily did not indicate statistically significant differences in rates of therapeutic or endoscopic failure at 6 months in a group of patients taking nonsteroidal anti-inflammatory drugs regularly for arthritic conditions.
There are no other direct comparisons.
Eradication of Helicobacter pyloriFairFive fair quality systematic reviews and 29 more recent trials indicate that eradication rates among the proton pump inhibitors do not differ significantly. Pooled analysis of eradication rates stratified by number of days of treatment and dose comparison did not find statistically significant differences in eradication rate among the proton pump inhibitors. Differences between the antibiotic regimens, participants and study designs limit the strength of this evidence.
In children, evidence is extremely limited, with only 2 trials of lansoprazole versus placebo. Neither trial found the addition of lansoprazole to result in higher eradication rates than antibiotic therapy alone.
Key Question 5. Dosing strategies for maintenance therapy in gastroesophageal reflux disease
Standard dose compared with low-dose proton pump inhibitorGoodBased on 11 studies, time in remission was longer for higher doses compared with lower doses for omeprazole and rabeprazole, but the same for higher and lower doses of lansoprazole. Evidence on esomeprazole was inconclusive.
Rates of endoscopically verified remission at study end were greater with the higher dose of rabeprazole compared with the lower dose, but no different between dose strategies for omeprazole and lansoprazole. Rates of relapse of symptoms were generally higher with lower doses of omeprazole, lansoprazole, and rabeprazole.
Standard dose compared with intermittent or on-demand proton pump inhibitorFairIn 3 studies of patients with healed erosive esophagitis, a regimen of daily proton pump inhibitor was superior in preventing relapse of esophagitis or recurrence of symptoms compared with 3 days a week or on-demand regimens at 6 months.
In 3 studies of patients with nonerosive esophagitis, assessments of symptom severity or relapse of symptoms was not different between daily and on- demand regimens. Patient satisfaction and quality of life ratings at study end were also not different, although the mean change in quality of life score from baseline was better with daily therapy. In 2 studies of patients presenting with symptoms of gastroesophageal reflux disease, but without endoscopic assessment, evidence is mixed.
Proton pump inhibitor compared with H2 receptor antagonistFairDaily proton pump inhibitor therapy was found superior to daily H2 antagonist therapy (rantidine 300 mg daily) in preventing relapse of erosive esophagitis, or symptoms of gastroesophageal reflux disease in 4 studies.
In children, at 3 months omeprazole 0.7 mg/kg daily was not different to ranitidine 10 mg/kg daily or placebo.
Key Question 6. Adverse events
Long-term studiesComparative evidence = PoorThree comparative trials. Evidence from single-drug follow-up studies indicates no differences between the proton pump inhibitors. A pharmacovigilance study found increased risk of adverse events related to specific PPIs – study limitations indicate a need for further study.
Noncomparative evidence indicates a potential for increased risk of colorectal cancer (1 study), clostridium difficile diarrhea (2 studies), and fracture (4 studies). Mixed evidence was found on the risk of community acquired pneumonia with proton pump inhibitor use.
Short-term studiesFairEvidence from short-term head-to-head comparison trials does not indicate a difference in the rate of overall adverse events, serious adverse events or the rate of dropouts due to adverse events. These studies are very short-term and include highly selected patient populations; evidence may not be generalizable to patients with co-morbidities and longer-term treatment.
Key Question 7. Subpopulations
Fair2 studies found no difference in adverse effects in subgroups of age, gender, and racial groups A single open-label study of 320 patients with mean age of 77 years with erosive esophagitis found that that pantoprazole 40 mg and rabeprazole 20 mg were superior to omeprazole 20 mg in healing rate at 8 weeks, no difference compared to lansoprazole 30 mg. Pantoprazole and rabeprazole were superior to both omeprazole and lansoprazole in symptom relief at 8 weeks. These results differ to those found in younger populations and need confirmation. Based on a cohort study of more than 8000 patients, use of a proton pump inhibitor concomitant with clopidogrel following acute coronary syndrome can increase the risk of death or rehospitalization for acute coronary syndrome with adjusted odds ratio of 1.25 (95% CI 1.11 to 1.41).
Similarly, use of a proton pump inhibitor concomitant with clopidogrel following acute myocardial infarction can increase the risk of readmission for recurrent myocardial infarction within 90 days with adjusted odds ratio 1.27 (95% CI 1.03 to 1.57) based on a smaller nested case-control study of 734 cases and 2057 controls. Analysis of the subgroup taking pantoprazole indicated no increased risk, while analysis of the other proton pump inhibitors (as a group) indicated a similar increase in risk.
No other comparative evidence in subgroups.
Copyright © 2009, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK47261

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