Journal of Clinical Pharmacy and Therapeutics, 2015
doi: 10.1111/jcpt.12277
Review Article
Meta-analysis of the effectiveness of esomeprazole in gastroesophageal reflux disease and Helicobacter pylori infection M. Teng* MHSc, A. L. Khoo* PhD, Y. J. Zhao* PhD, L. Lin* BSc (Pharm), B. P. Lim* BPharm, T. S. Wu† MHSM and Y. Y. Dan‡§ MBBS, PhD *Pharmacy and Therapeutics Office, Group Corporate Development, National Healthcare Group, †Department of Pharmacy, National University Hospital, ‡Department of Medicine, National University Hospital, and ‡§Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Received 1 December 2014, Accepted 24 March 2015
Keywords: esomeprazole, gastroesophageal reflux, Helicobacter pylori, meta-analysis, omeprazole, systematic review
ATPase, also known as proton pump) that transports acid from gastric parietal cells into the gastroesophageal lumen. They are indicated for the treatment of acid-related diseases such as gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD) and Helicobacter pylori (H. pylori) eradication in combination with antibiotics. PPIs are one of the most frequently prescribed classes of drug with worldwide sales totalling USD$265 billion in 2008.1 In fact, esomeprazole (Nexiumâ) was the top-selling single agent based on non-discounted price in the United States (USD$6 billion)2 and ranked 4th in the top 20 drug list by sales (USD$75 billion) in the global market in 2012.3 The new generation PPIs including esomeprazole, rabeprazole and dexlansoprazole are designed to have better bioavailability and clinical efficacy than early generation omeprazole.4 However, evidence comparing efficacy of these drugs with the older generation or between different dosing regimens has been inconsistent in relation to esophagitis healing, symptom resolution and H. pylori eradication. Furthermore, many of these trials were commissioned by pharmaceutical company and had compared doses of PPIs licensed by the United States Food and Drug Administration rather than pharmacologically equivalent doses that are used in the real world. Omeprazole, the first in PPI drug class, consists of a racemic compound of which only the S-enantiomer is active, whereas the R enantiomer is not. Esomeprazole contains only the purified Senantiomer and has been reported to have improved bioavailability of 68% compared with omeprazole (60%) at 20 mg, dose for dose.5,6 This translates into better and longer acid suppression and has been proposed to be the basis for enhanced clinical efficacy.7,8 Despite the advantage in bioavailability, comparative studies between esomeprazole and omeprazole have shown conflicting data with some meta-analyses presented a small although significant benefit in esophagitis healing,9 whereas other studies indicated no significant difference in efficacy.10,11 This obviously would have a big impact on cost difference where healthcare delivery system in every country is pressed to adopt new and innovative health technologies in an evidencebased manner, although ensuring that they can be managed within available resources. It also begs the question whether certain acidrelated disease groups would benefit specially from the advantage of esomeprazole and justify its high cost. The monthly prescription of esomeprazole (Nexiumâ) 20 mg/40 mg capsule costs USD $240, whereas that of generic omeprazole 20 mg costs USD $60, assuming the patient takes one pill daily.12 Therefore, we performed a systematic review and meta-analysis that included
SUMMARY What is known and objective: Proton pump inhibitors (PPIs) are one of the most widely used classes of drugs. However, the quantum clinical benefit of newer and more expensive PPIs over the older generation PPIs remains uncertain. This meta-analysis sought to assess the clinical and safety profiles of esomeprazole versus omeprazole at pharmacologically equivalent doses in healing gastroesophageal reflux disease (GERD), peptic ulcer disease and eradicating Helicobacter pylori (H. pylori) infection. Methods: PubMed and the Cochrane Library were searched for randomized controlled trials comparing esomeprazole with omeprazole at all doses up to February 2015. Trials were assessed by two reviewers for eligibility according to predefined study inclusion criteria. Meta-analysis was conducted using a random effects model, and heterogeneity in the estimated effects was investigated using meta-regression. Sensitivity analysis was performed to test the robustness of the findings. Results and Discussion: Fifteen trials were included and none of which compared esomeprazole with omeprazole in peptic ulcer disease. The included studies had not evaluated esomeprazole 20 mg versus omeprazole 40 mg. In GERD, esomeprazole 40 mg (relative risk (RR) = 107; 95% confidence interval (CI) 102 to 112) and 20 mg (RR=104; 95% CI 101 to 108) significantly improved esophagitis healing when compared with omeprazole 20 mg at week 8. The corresponding numbers needed to treat were 17 and 30, respectively. No significant difference was observed between esomeprazole 20 mg and omeprazole 20 mg at week 4. In H. pylori eradication, there was no difference in the treatment effects between esomeprazole 20 mg and omeprazole 20 mg (RR = 101;95% CI 096 to 105). Their safety profiles were comparable. What is new and conclusion: Esomeprazole demonstrated better esophagitis healing rate in patients with GERD than omeprazole at week 8. However, this clinical advantage diminished when both drugs were given at the same doses at week 4. Superiority of esomeprazole was not observed in the H. pylori eradication rates. WHAT IS KNOWN AND OBJECTIVE Proton pump inhibitors (PPIs) suppress gastric acid secretion by inhibiting hydrogen-potassium adenosine triphosphatase (H+K+ Correspondence: M. Teng, 3 Fusionopolis Link, #03-08 Nexus@onenorth, Singapore 138543. Tel.: +65 6496 6279; fax: +65 6496 6870; e-mail: [email protected]
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software, version 13.0 (StataCorp LP, College Station, TX, USA). Outcomes were summarized as relative risks (RR) with 95% confidence intervals (CI). We also calculated number needed to treat (NNT) from risk difference (absolute risk reduction). Statistical heterogeneity between trials was evaluated using chisquare test at a significance level of P < 01 and I2 statistic. The value of I2 statistic ranges from 0% to 100%, with 0% representing no observed heterogeneity and larger values indicating increasing heterogeneity. A value of I2 below 25% was chosen to represent low heterogeneity.14 When the P-value for the chi-square test was 25%, the heterogeneity would be considered important and meta-regression would be carried out to investigate the heterogeneity where possible. Sensitivity analysis or subgroup analysis was performed to test the robustness of the results and account for any differences in the study level characteristics such as ethnicity, antibiotic regimen and maintenance therapy in H. pylori eradication.
the most recent head-to-head trials to determine the efficacy and safety of esomeprazole compared with omeprazole at all doses. METHODS Search strategy A systematic search of PubMed and the Cochrane Library was conducted up to February 2015 to identify relevant trials. The Cochrane Collaboration’s sensitivity and precision-maximizing strategy13 using the following medical subject headings (MeSH), concepts and/or text words in various combinations was applied: gastroesophageal reflux, peptic ulcer, duodenal ulcer, gastric ulcer, Helicobacter pylori, omeprazole and esomeprazole (Appendix S1). We also searched for additional trials included in published systematic reviews and bibliographies of all relevant studies. Study selection and eligibility criteria
RESULTS
Two reviewers (MT and LL) screened abstracts according to predefined study inclusion criteria. Full text articles (published in English) were retrieved and reviewed if a decision on inclusion could not be made solely based on the abstract. Any disagreements were resolved by consensus between the two reviewers. We included head-to-head randomized controlled trials (RCTs) which compared oral esomeprazole with oral omeprazole, in any dose, in the management of GERD or peptic ulcer disease. The study participants were adults aged 18 years and above who had GERD, peptic ulcer disease or H. pylori infection. The outcomes of interest included resolution of GERD-related symptoms, esophagitis healing, peptic ulcer healing, H. pylori eradication, quality of life and adverse effects. Studies that involved specific patient groups (e.g. elderly), reported only intragastric acidity or pH measurement, and of which the PPIs were used as prophylaxis for NSAID-induced ulcers were excluded.
Search results We identified 468 citations using the search strategy. Of these, we excluded 439 after examining the title and abstract including removal of duplicates. We retrieved and evaluated 29 articles in more detail, of which 14 articles were excluded, leaving 15 RCTs15–29 that were eligible for inclusion (Fig. 1). Study characteristics Of the 15 studies included, seven studies were related to GERD17,19,20,22,23,29,30 and eight on H. pylori infection.15,18,21,24–28 We did not identify any studies that directly compared esomeprazole and omeprazole in peptic ulcer disease. Six of the GERD studies were conducted in patients with endoscopically confirmed reflux esophagitis (RE),17,19,20,22,23,29 whereas the remaining one in patients with endoscopy-negative
Outcome assessment The outcome measures for efficacy were esophagitis healing rate and heartburn resolution rate in patients with GERD, and peptic ulcer healing rate and H. pylori eradication rate in patients with peptic ulcer disease. Outcomes derived from intention-to-treat (ITT) analyses were included. For safety, we analysed adverse effects associated with treatments.
Records identified through databases searching PubMed (n = 261)
Records identified through other sources (n = 2)
Cochrane (n = 205)
Data collection and risk of bias assessment
Records after duplicates removed (n = 333)
Data regarding study design, country, patient characteristics, dose and delivery of esomeprazole and omeprazole, duration of treatment, outcomes and funding source were extracted into evidence tables (Appendices S2 and S3). Risk of bias was assessed for each included study using the Cochrane Collaboration risk of bias tool13 based on six domains: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome and selective outcome reporting. Other potential source of bias such as sponsorship of the study was also taken into consideration. Judgement on the risk of bias was made for each domain and categorized as high, low or unclear.
Records screened (n = 333)
Full-text articles assessed for eligibility (n = 29)
Studies included (n = 15)
Data analysis We performed meta-analyses of outcomes as appropriate by combining trials based on a random effects model in Stata
Records excluded (n = 304)
Full-text articles excluded (n = 14) Reasons for articles exclusion included pharmacodynamic/ pharmacokinetic studies, studies that enrolled healthy subjects, and not in English
Fig. 1. Study flow diagram illustrating the study selection process.
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Effectiveness of esomeprazole reflux disease (ENRD).16 There were 6893 patients included in the GERD trials. The mean age of subjects ranged from 45 to 58 years old. Based on the Los Angeles (LA) classification system that categorized the severity of erosive esophagitis, the proportion of patients with grades A, B, C and D erosive esophagitis were 34%, 39%, 20% and 7%, respectively. Tables 1 and 2 summarized the characteristics and main results of these studies. There were eight studies15,18,21,24–28 comparing esomeprazole with omeprazole in combination with standard antibiotics for H. pylori treatment. A total of 2598 subjects were included. The mean age of patients ranged from 39 to 59 years old. Three studies15,18,24 compared esomeprazole 40 mg, whereas the other five21,25–28 evaluated esomeprazole 20 mg with omeprazole 20 mg twice daily. Table 3 summarized the characteristics and main results of these studies.
Table 2. Characteristics and main results of study evaluating endoscopy-negative reflux disease
Study
Treatment arms
N
Percentage of patients with heartburn resolution at week 4 (95% CI)
Armstrong 200416 (study A)
E 40 mg QD E 20 mg QD O 20 mg QD E 40 mg QD O 20 mg QD E 20 mg QD O 20 mg QD
425 423 434 347 346 336 334
567 605 581 703 679 619 596
Armstrong 200416 (study B) Armstrong 200416 (study C)
(52–62) (52–62) (53–63) (65–75) (63–73) (57–67) (54–65)
E, esomeprazole; O, omeprazole; QD, once daily.
Risk of bias assessment For the GERD trials, most of them clearly stated the method of randomization, concealment for allocation and blinding of participants. Six trials were funded by manufacturer. For the H. pylori trials, majority of them did not provide adequate information on the method used for generating the sequence of randomization, allocation concealment and blinding. Five trials were funded by manufacturer. The risk of bias plots can be found in online Appendices S4 and S5.
Esomeprazole versus omeprazole in GERD The primary outcomes of the studies evaluating RE were the proportion of patients who achieved endoscopically confirmed healing and the proportion who achieved complete resolution of GERD-related symptoms at week 8. Secondary outcomes included esophagitis healing and symptom relief at week 4. The primary endpoint of the study evaluating ENRD was the proportion of
Table 1. Characteristics and main results of studies evaluating endoscopically confirmed reflux esophagitis
LA grades of RE (%) (A, B, C, D)
N
Healing rate (week 4) by ITT n/N (%) | P value
Healing rate (week 8) by ITT n/N (%) | P value
16/25 64 | P > 005 10/22 455 550/656 838 | P > 005 572/654 875 | P < 005 529/650 814 508/587 865 | P > 005 484/588 823 1093/1216 899 | P < 005 978/1209 809 501/576 869 | P > 005 491/572 858 62/68 912 | P > 005 57/68 838
Study
Treatment arms
Chen 200517
E 40 mg QD
25
60, 28, 8, 4
Not reported
O 20 mg QD
23
48, 30, 9, 13
Not reported
E 20 mg QD
656
33, 42, 18, 7
E 40 mg QD
654
36, 39, 18, 7
O 20 mg QD
650
31, 41, 21, 7
E 20 mg QD
588
38, 35, 21, 6
436/656 665 | P > 005 465/654 711 | P < 005 399/650 614 Not reported
O 20 mg QD
588
36, 38, 17, 9
Not reported
E 40 mg QD
1216
35, 39, 21, 5
O 20 mg QD
1209
32, 41, 20, 7
E 40 mg QD
576
32, 35, 25, 8
O 20 mg QD
572
33, 37, 22, 8
E 40 mg QD
68
30, 38, 29, 3
955/1216 786 | P < 005 805/1209 666 393/576 682 | P > 005 379/572 663 Not reported
O 20 mg QD
68
30, 38, 29, 3
Not reported
Kahrilas 2000
19
Lightdale 200620
Richter 200122
Schmitt 200623
Zheng 200929
Heartburn resolution (week 4) n/N (%) | P value
Not reported Not reported 382/626 524 | P > 005 402/621 637 | P < 005 357/624 572 356/588a 605 | P > 005 355/587a 605 831/1216 683 | P < 005 702/1209 581 374/576 649 | P > 005 361/572 631 Not reported Not reported
E, esomeprazole; O, omeprazole; QD, once daily; LA, Los Angeles grading system; RE, reflux esophagitis; ITT, intention-to-treat. Heartburn resolution was measured at week 8.
a
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Table 3. Characteristics and main results of studies evaluating Helicobacter pylori infection
Study
Treatment arms
Antibiotics
Treatment duration
Anagnostopoulos 200415
E 40 mg QD
Amoxicillin 1 g BID Clarithromycin 500 mg BID
7 days
Amoxicillin 1 g BID Clarithromycin 500 mg BID
7 days
Metronidazole 400 mg BID Clarithromycin 500 mg BID
7 days
Amoxicillin 1 g BID Clarithromycin 500 mg BID
7 days
Amoxicillin 1 g BID Clarithromycin 500 mg BID
7 days + 3 weeks maintenancea
Amoxicillin 1 g BID Clarithromycin 500 mg BID
7 days + 3 weeks maintenancea
Amoxicillin 1 g BID Clarithromycin 500 mg BID
7 days
Metronidazole 500 mg BID Clarithromycin 500 mg BID
7 days + 3 weeks maintenancea
E 40 mg BID O 20 mg BID Choi 200718
E 40 mg BID O 20 mg BID
Miehlke 200321
E 20 mg BID O 20 mg BID
Sheu 200524
E 40 mg BID O 20 mg BID
Subei 200725
E 20 mg BID O 20 mg BID
Tulassay 200126
E 20 mg BID O 20 mg BID
Veldhuyzen 200027
E 20 mg BID O 20 mg BID
Veldhuyzen 200328
E 20 mg BID O 20 mg BID
Eradication rates by ITT n/N (%) | 95% CI
42/52 808 | 75–86 50/52 962 | 91–99 37/52 71 | 65–77 104/148 703 96/148 649 38/42 904 | 78–97 31/38 816 | 66–92 86/100 86 79/100 79 139/186 747 | 68–81 148/188 787 | 73–84 184/214 86 | 81–90 192/219 877 | 83– 92 137/189 897 | 85– 94 172/196 878 | 82– 92 144/190 758 137/189 725
E, esomeprazole; O, omeprazole; QD, once daily; BID, twice daily; ITT, intention-to-treat. a Omeprazole group continued with omeprazole 20 mg once daily, whereas esomeprazole group was on placebo.
of esomeprazole versus omeprazole became less pronounced as the proportion of patients with LA grades C and D increased. Therefore, the statistical heterogeneity could be attributed to the different distribution of patients with specified baseline disease severity according to LA grades across the included studies. This relationship was, however, not statistically significant (P = 0053 at week 8 and P = 0216 at week 4). A subgroup analysis by ethnicity showed that esomeprazole 40 mg was not statistically better than omeprazole 20 mg at week 8 (RR=111; 95% CI 095 to 130) among the participants in eastern Asia.17,29
patients with complete resolution of heartburn as defined by no heartburn episodes during the previous seven consecutive days. In all of these studies, symptom relief was assessed subjectively by investigator or patients. Esophagitis healing rates. We meta-analysed the esophagitis healing rates at week 4 and week 8. The RRs for esomeprazole 40 mg and 20 mg compared with omeprazole 20 mg at week 8 were 107 (95% CI 102 to 112) and 104 (95% CI 101 to 108), respectively (Fig. 2). The calculated risk differences were 6% and 33%, which corresponded to NNT of 17 and 30, respectively. At week 4, the RR of esomeprazole 40 mg versus omeprazole 20 mg was 113 (95% CI 104 to 122) and the corresponding NNT was 12. There was no significant difference between esomeprazole 20 mg versus omeprazole 20 mg (based on one study) (Fig. 3). The results were robust to sensitivity analysis by excluding the study29 with high risk of performance and detection bias. Heterogeneity was observed in the analyses of esomeprazole 40 mg at week 8 (I2 = 64%, P = 0025) and week 4 (I2 = 75%, P = 0018). The meta-regression analysis revealed that the efficacy
Heartburn resolution rates. Three of the RE studies19,22,23 reported the proportion of patients with heartburn resolution at week 4. The heartburn resolution rate ranged from 64% to 68% for patients on esomeprazole 40 mg and 57% to 63% for those on omeprazole 20 mg. Meta-analysis for the rate of heartburn resolution was not performed given that the definition of this endpoint differed among the studies. Only one study evaluating ENRD16 was included. In this study, esomeprazole 40 mg and 20 mg were compared with omeprazole
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Author
Year
RR 95% CI
% Weight
Esomeprazole 40 mg
Chen
2005
1·41 (0·82, 2·43) 0·36
Kahrilas
2000
1·07 (1·03, 1·13) 18·28
Richter
2001
1·11 (1·07, 1·15) 22·37
Schmitt
2006
1·01 (0·97, 1·06) 18·55
Zheng
2009
1·09 (0·96, 1·24) 5·40
Subtotal (I-squared = 64·1%, P = 0·025)
1·07 (1·02, 1·12) 64·96
. Esomeprazole 20 mg
2000
1·03 (0·98, 1·08) 17·44
Lightdale 2006
1·05 (1·00, 1·10) 17·60
Subtotal (I-squared = 0·0%, P = 0·569)
1·04 (1·01, 1·08) 35·04
Kahrilas
.
Fig. 2. Forest plot demonstrating the relative risk (RR) with 95% confidence interval (CI) of esophagitis healing rates of esomeprazole 40 mg and 20 mg compared with omeprazole 20 mg once daily at week 8.
Overall (I-squared = 57·1%, P = 0·030)
1·06 (1·03, 1·10) 100·00
·8
1
1·2
Omeprazole better
Author
1·5
Esomeprazole better
Year
RR (95% CI)
% Weight
Esomeprazole 40 mg
KahrilasPJ
2000
1·16 (1·07, 1·25) 23·69
Richter JE
2001
1·18 (1·12, 1·24) 30·29
Schmitt C
2006
1·03 (0·95, 1·12) 23·11
Subtotal (I-squared = 75·2%, P = 0·018)
1·13 (1·04, 1·22) 77·09
. Esomeprazole 20 mg
Kahrilas PJ
2000
1·08 (1·00, 1·17) 22·91
Subtotal (I-squared = NA .%, P = NA .)
1·08 (1·00, 1·17) 22·91
.
Fig. 3. Forest plot demonstrating the relative risk (RR) with 95% confidence interval (CI) of esophagitis healing rates of esomeprazole 40 mg and 20 mg compared with omeprazole 20 mg once daily at week 4.
Overall (I-squared = 68·0%, P = 0·025)
1·12 (1·05, 1·19) 100·00
·5
1 Omeprazole better
1·5 Esomeprazole better
H. pylori eradication rates. The eradication rate associated with esomeprazole (regardless of dose) ranged from 70% to 96%, whereas that for omeprazole ranged from 65% to 88%. The RRs for esomeprazole 40 mg and 20 mg compared with omeprazole 20 mg twice daily were 116 (95% CI 101 to 132) and 101 (95% CI 096 to 105), respectively (Fig. 4). Heterogeneity was observed in the analysis of esomeprazole 40 mg dose (I2 = 53%, P = 012). However, meta-regression analysis could not be performed due to insufficient number of studies. The results were robust to analysis taking into account the different antimicrobial agents (amoxicillin versus metronidazole). The results of subgroup analysis based on studies21,28 that included 3-week omeprazole maintenance therapy and ethnicity were as follows: esomeprazole 20 mg was superior to omeprazole
20 mg once daily for 4 weeks in symptomatic patients with ENRD. There was no significant difference in the proportion of patients who achieved heartburn resolution among the groups. Esomeprazole versus omeprazole in H. pylori The treatments in all the eight included studies15,18,21,24–28 were the standard 7-day triple-therapy regimen with the co-administered antibiotics being either amoxicillin and clarithromycin or metronidazole and clarithromycin. In three studies,25,26,28 omeprazole was continued for another 3 weeks as maintenance monotherapy versus placebo in esomeprazole treatment arm. The primary endpoint of these studies was the H. pylori eradication rate at 4–8 weeks as assessed by histology and urea breath test.
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Author
RR 95% CI
Year
% Weight
Esomeprazole 40 mg Anagnostopoulos 2004
1·35 (1·13, 1·62) 7·47
Choi
2007
1·08 (0·92, 1·27) 9·02
Sheu
2005
1·09 (0·96, 1·24) 11·67
Subtotal (I-squared = 53·2%, P = 0·118)
1·16 (1·01, 1·32) 28·16
. Esomeprazole 20 mg Miehlke
2003
1·11 (0·93, 1·33) 7·54
Subei
2007
0·95 (0·85, 1·06) 13·50
Tulassay
2000
0·98 (0·91, 1·06) 18·80
Veldhuyzen
2000
1·02 (0·95, 1·10) 19·33
Veldhuyzen
2003
1·05 (0·93, 1·18) 12·67
Subtotal (I-squared = 0·0%, P = 0·521)
1·01 (0·96, 1·05) 71·84
. Overall (I-squared = 50·8%, P = 0·047)
1·05 (0·99, 1·11) 100·00
·8 Omeprazole better
1
1·2
1·5
Esomeprazole better
Fig. 4. Forest plot demonstrating the relative risk (RR) with 95% confidence interval (CI) of H. pylori eradication rates of esomeprazole 40 mg and 20 mg compared with omeprazole 20 mg twice daily.
according to baseline disease severity (LA grades).20,23 In these two studies, greater between-treatment differences in favour of esomeprazole were observed in patients with moderate to severe esophagitis (LA grades C and D) at baseline than patients with mild esophagitis (LA grades A and B). When used in combination with antibiotics for H. pylori eradication, a statistically significant difference was observed between esomeprazole 40 mg and omeprazole 20 mg, but this analysis was associated with significant heterogeneity and a lower bound CI approaching 10. There was no significant difference in efficacy between esomeprazole 20 mg and omeprazole 20 mg. Given that esomeprazole is the active isomer, it is expected that esomeprazole would achieve more potent antisecretory activity than omeprazole on milligram basis and result in better efficacy. However, our analysis showed that the efficacy of esomeprazole and omeprazole did not differ significantly in achieving H. pylori eradication when combined with antimicrobial agents (amoxicillin and clarithromycin or clarithromycin and metronidazole) as a standard triple therapy. This was likely due to the fact that the extent of bacterial susceptibility to antimicrobial agents contributes to the H. pylori eradication and that the necessary level of acid inhibition for H. pylori eradication within a standard triple therapy could be achieved with either omeprazole or esomeprazole. It was noteworthy that omeprazole 20 mg was inferior to esomeprazole 20 mg in the absence of omeprazole maintenance therapy. Nonetheless, these results were derived from the meta-analysis of only two studies. The rate of adverse effects was generally greater in studies on GERD than H. pylori eradication, which implied that the treatment duration correlated to incidence of adverse effects. Treatment with esomeprazole was associated with higher rates of adverse effects such as abdominal pain and headache than omeprazole. However, the difference did not reach statistical significance. Overall, both drugs demonstrated similar safety profiles. Our study distinguished itself from previous reviews by including most recent comparative trials of esomeprazole and omeprazole. Majority of the previous systematic reviews compar-
20 mg when there was no omeprazole maintenance therapy (RR=110; 95% CI 101 to 120), and the treatment difference between esomeprazole 40 mg and omeprazole 20 mg was insignificant among participants from the Eastern Asia (RR=109; 95% CI 098 to 120). Safety The data on adverse effects in all the included studies comprising 9200 patients were pooled. The safety profiles of esomeprazole and omeprazole were generally similar. The pooled estimates of the treatment-associated adverse effects for esomeprazole versus omeprazole were abdominal pain (32% vs 29%), diarrhoea (31% vs 30%), flatulence (32% vs 38%) and headache (66% vs 56%). Meta-analyses of these adverse effects did not reveal any statistically significant differences between esomeprazole and omeprazole. DISCUSSION Our meta-analyses demonstrated that esomeprazole 40 mg and 20 mg were statistically more effective than omeprazole 20 mg once daily for esophagitis healing at 8 weeks in patients with GERD. However, the difference was marginal, with the lower bound of CI approaching 10. The corresponding NNT17,30 was also not promising. According to a Cochrane systematic review31 that compared PPIs with H2-receptor antagonists and placebo in the treatment of esophagitis, PPI was associated with a NNT of three and two, respectively. Esomeprazole 20 mg did not significantly improve the esophagitis healing at week 4. This suggested that esomeprazole would have limited clinical advantage over omeprazole if the duration of PPI therapy was 4 weeks. Analysis of healing rates relative to the baseline disease severity was not conducted due to inadequate number of studies. Two of the included studies reported the treatment difference between esomeprazole and omeprazole in patients with GERD stratified
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Effectiveness of esomeprazole
ing PPIs in the management of GERD were supported by industry.9,32,33 These studies evaluated the effects of esomeprazole 40 mg versus other PPIs and reported that esomeprazole was superior in healing esophagitis. In addition, the treatment difference between esomeprazole at 20 mg and other PPIs was not investigated. In our study, a rigorous and systematic search strategy was applied, which provides more robust results. To provide a realistic comparison given that esomeprazole is the active enantiomer of omeprazole, which is akin to omeprazole at double dose, we analysed the effectiveness of esomeprazole versus omeprazole on pharmacologically comparable doses. As with any systematic review and meta-analysis, the results of our study relied on the number and quality of the included trials. The risk of publication bias having an effect on our results could not be ruled out given that only English articles and studies with fully published results were considered for inclusion. The limited number of studies and reported outcomes did not made provision to generate more insights into the relative efficacy of esomeprazole and omeprazole in other aspects. For instance, we were unable to analyse the treatment difference between esomeprazole and omeprazole in patients with GERD relative to their baseline disease severity and cytochrome P450 2C19 (CYP2C19) genotype. In H. pylori eradication, studies have reported that treatment failure could be caused by insufficient gastric acid inhibition as a result of CYP2C19 genotype apart from bacterial susceptibility to antimicrobial agents.34 As esomeprazole is the active enantiomer of omeprazole, it would be more rational to compare omeprazole 40 mg with esomeprazole 20 mg. However, there were no available clinical studies that compared omeprazole 40 mg with esomeprazole. A potential research area would be to compare the effectiveness of omeprazole 40 mg with esomeprazole in treating GERD.
WHAT IS NEW AND CONCLUSION Esomeprazole provided a statistically significant but marginal degree of improvement in esophagitis healing when compared with omeprazole. However, this clinical advantage in patients with GERD diminished when the treatment duration was within 4 weeks. There was no difference in the H. pylori eradication rates when esomeprazole and omeprazole were given at the same doses. Based on our analysis, it is prudent to consider other factors such as the cost of therapy, severity of esophagitis, bacterial susceptibility to antimicrobial agents and variation in CYP2C19 genotype when prescribing these agents to patients with GERD or H. pylori infection. CONFLICT OF INTERESTS No conflict of interests have been declared. SOURCE OF FUNDING None. SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Appendix S1. Search strategy. Appendix S2. Studies evaluating gastroesophageal reflux disease. Appendix S3. Studies evaluating Helicobacter pylori infection. Appendix S4. Risk of bias assessment for studies evaluating gastroesophageal reflux disease. Appendix S5. Risk of bias assessment for studies evaluating Helicobacter pylori infection.
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12. Choosing a PPI to treat heartburn, acid reflux and GERD. Consumer Reports 2013. Available at: https://www.consumerre ports.org/health/resources/pdf/best-buydrugs/Heartburn_2pager09.pdf. (accessed 1 March 2014). 13. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available at: www.cochrane-handbook.org. (accessed 1 March 2014) 14. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. BMJ, 2003;327:4. 15. Anagnostopoulos GK, Tsiakos S, Margantinis G, Kostopoulos P, Arvanitidis D. Esomeprazole versus omeprazole for the eradication of Helicobacter pylori infection: results of a randomized controlled study. J Clin Gastroenterol, 2004;38:503–506. 16. Armstrong D, Talley NJ, Lauritsen K et al. The role of acid suppression in patients with endoscopy-negative reflux disease: the effect of treatment with esomeprazole or
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17.
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omeprazole. Aliment Pharmacol Ther, 2004;20:413–421. Chen CY, Lu CL, Luo JC, Chang FY, Lee SD, Lai YL. Esomeprazole tablet vs omeprazole capsule in treating erosive esophagitis. World J Gastroenterol, 2005;11:3112–3117. Choi HS, Park DI, Hwang SJ et al. Doubledose, new-generation proton pump inhibitors do not improve Helicobacter pylori eradication rate. Helicobacter, 2007;12:638– 642. Kahrilas PJ, Falk GW, Johnson DA et al. Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial. The Esomeprazole Study Investigators. Aliment Pharmacol Ther, 2000;14:1249–1258. Lightdale CJ, Schmitt C, Hwang C, Hamelin B. A multicenter, randomized, double-blind, 8-week comparative trial of low-dose esomeprazole (20 mg) and standard-dose omeprazole (20 mg) in patients with erosive esophagitis. Dig Dis Sci, 2006;51:852–857. Miehlke S, Schneider-Brachert W, Bastlein E et al. Esomeprazole-based one-week triple therapy with clarithromycin and metronidazole is effective in eradicating Helicobacter pylori in the absence of antimicrobial resistance. Aliment Pharmacol Ther, 2003;18:799–804. Richter JE, Kahrilas PJ, Johanson J et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized
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controlled trial. Am J Gastroenterol, 2001;96:656–665. Schmitt C, Lightdale CJ, Hwang C, Hamelin B. A multicenter, randomized, double-blind, 8-week comparative trial of standard doses of esomeprazole (40 mg) and omeprazole (20 mg) for the treatment of erosive esophagitis. Dig Dis Sci, 2006;51:844–850. Sheu BS, Kao AW, Cheng HC, Hunag SF, Chen TW, Lu CC, Wu JJ. Esomeprazole 40 mg twice daily in triple therapy and the efficacy of Helicobacter pylori eradication related to CYP2C19 metabolism. Aliment Pharmacol Ther, 2005;21:283–288. Subei IM, Cardona HJ, Bachelet E, Useche E, Arigbabu A, Hammour AA, Miller T. One week of esomeprazole triple therapy vs 1 week of omeprazole triple therapy plus 3 weeks of omeprazole for duodenal ulcer healding in Helicobacter pylori-positive patients. Dig Dis Sci, 2007;52:1505–1512. Tulassay Z, Kryszewski A, Dite P et al. One week of treatment with esomeprazole-based triple therapy eradicates Helicobacter pylori and heals patients with duodenal ulcer disease. Eur J Gastro Hepatol, 2001;13:1457– 1465. Veldhuyzen Van Zanten S, Lauritsen K, Delchier JC et al. One-week triple therapy with esomeprazole provides effective eradication of Helicobacter pylori in duodenal ulcer disease. Aliment Pharmacol Ther, 2000;14:1605–1611. Veldhuyzen Van Zanten S, Machado S, Lee J One-week triple therapy with esomepraz-
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Journal of Clinical Pharmacy and Therapeutics, 2015 8
doi: 10.1111/jcpt.12277
Review Article
Meta-analysis of the effectiveness of esomeprazole in gastroesophageal reflux disease and Helicobacter pylori infection M. Teng* MHSc, A. L. Khoo* PhD, Y. J. Zhao* PhD, L. Lin* BSc (Pharm), B. P. Lim* BPharm, T. S. Wu† MHSM and Y. Y. Dan‡§ MBBS, PhD *Pharmacy and Therapeutics Office, Group Corporate Development, National Healthcare Group, †Department of Pharmacy, National University Hospital, ‡Department of Medicine, National University Hospital, and ‡§Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Received 1 December 2014, Accepted 24 March 2015
Keywords: esomeprazole, gastroesophageal reflux, Helicobacter pylori, meta-analysis, omeprazole, systematic review
ATPase, also known as proton pump) that transports acid from gastric parietal cells into the gastroesophageal lumen. They are indicated for the treatment of acid-related diseases such as gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD) and Helicobacter pylori (H. pylori) eradication in combination with antibiotics. PPIs are one of the most frequently prescribed classes of drug with worldwide sales totalling USD$265 billion in 2008.1 In fact, esomeprazole (Nexiumâ) was the top-selling single agent based on non-discounted price in the United States (USD$6 billion)2 and ranked 4th in the top 20 drug list by sales (USD$75 billion) in the global market in 2012.3 The new generation PPIs including esomeprazole, rabeprazole and dexlansoprazole are designed to have better bioavailability and clinical efficacy than early generation omeprazole.4 However, evidence comparing efficacy of these drugs with the older generation or between different dosing regimens has been inconsistent in relation to esophagitis healing, symptom resolution and H. pylori eradication. Furthermore, many of these trials were commissioned by pharmaceutical company and had compared doses of PPIs licensed by the United States Food and Drug Administration rather than pharmacologically equivalent doses that are used in the real world. Omeprazole, the first in PPI drug class, consists of a racemic compound of which only the S-enantiomer is active, whereas the R enantiomer is not. Esomeprazole contains only the purified Senantiomer and has been reported to have improved bioavailability of 68% compared with omeprazole (60%) at 20 mg, dose for dose.5,6 This translates into better and longer acid suppression and has been proposed to be the basis for enhanced clinical efficacy.7,8 Despite the advantage in bioavailability, comparative studies between esomeprazole and omeprazole have shown conflicting data with some meta-analyses presented a small although significant benefit in esophagitis healing,9 whereas other studies indicated no significant difference in efficacy.10,11 This obviously would have a big impact on cost difference where healthcare delivery system in every country is pressed to adopt new and innovative health technologies in an evidencebased manner, although ensuring that they can be managed within available resources. It also begs the question whether certain acidrelated disease groups would benefit specially from the advantage of esomeprazole and justify its high cost. The monthly prescription of esomeprazole (Nexiumâ) 20 mg/40 mg capsule costs USD $240, whereas that of generic omeprazole 20 mg costs USD $60, assuming the patient takes one pill daily.12 Therefore, we performed a systematic review and meta-analysis that included
SUMMARY What is known and objective: Proton pump inhibitors (PPIs) are one of the most widely used classes of drugs. However, the quantum clinical benefit of newer and more expensive PPIs over the older generation PPIs remains uncertain. This meta-analysis sought to assess the clinical and safety profiles of esomeprazole versus omeprazole at pharmacologically equivalent doses in healing gastroesophageal reflux disease (GERD), peptic ulcer disease and eradicating Helicobacter pylori (H. pylori) infection. Methods: PubMed and the Cochrane Library were searched for randomized controlled trials comparing esomeprazole with omeprazole at all doses up to February 2015. Trials were assessed by two reviewers for eligibility according to predefined study inclusion criteria. Meta-analysis was conducted using a random effects model, and heterogeneity in the estimated effects was investigated using meta-regression. Sensitivity analysis was performed to test the robustness of the findings. Results and Discussion: Fifteen trials were included and none of which compared esomeprazole with omeprazole in peptic ulcer disease. The included studies had not evaluated esomeprazole 20 mg versus omeprazole 40 mg. In GERD, esomeprazole 40 mg (relative risk (RR) = 107; 95% confidence interval (CI) 102 to 112) and 20 mg (RR=104; 95% CI 101 to 108) significantly improved esophagitis healing when compared with omeprazole 20 mg at week 8. The corresponding numbers needed to treat were 17 and 30, respectively. No significant difference was observed between esomeprazole 20 mg and omeprazole 20 mg at week 4. In H. pylori eradication, there was no difference in the treatment effects between esomeprazole 20 mg and omeprazole 20 mg (RR = 101;95% CI 096 to 105). Their safety profiles were comparable. What is new and conclusion: Esomeprazole demonstrated better esophagitis healing rate in patients with GERD than omeprazole at week 8. However, this clinical advantage diminished when both drugs were given at the same doses at week 4. Superiority of esomeprazole was not observed in the H. pylori eradication rates. WHAT IS KNOWN AND OBJECTIVE Proton pump inhibitors (PPIs) suppress gastric acid secretion by inhibiting hydrogen-potassium adenosine triphosphatase (H+K+ Correspondence: M. Teng, 3 Fusionopolis Link, #03-08 Nexus@onenorth, Singapore 138543. Tel.: +65 6496 6279; fax: +65 6496 6870; e-mail: [email protected]
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software, version 13.0 (StataCorp LP, College Station, TX, USA). Outcomes were summarized as relative risks (RR) with 95% confidence intervals (CI). We also calculated number needed to treat (NNT) from risk difference (absolute risk reduction). Statistical heterogeneity between trials was evaluated using chisquare test at a significance level of P < 01 and I2 statistic. The value of I2 statistic ranges from 0% to 100%, with 0% representing no observed heterogeneity and larger values indicating increasing heterogeneity. A value of I2 below 25% was chosen to represent low heterogeneity.14 When the P-value for the chi-square test was 25%, the heterogeneity would be considered important and meta-regression would be carried out to investigate the heterogeneity where possible. Sensitivity analysis or subgroup analysis was performed to test the robustness of the results and account for any differences in the study level characteristics such as ethnicity, antibiotic regimen and maintenance therapy in H. pylori eradication.
the most recent head-to-head trials to determine the efficacy and safety of esomeprazole compared with omeprazole at all doses. METHODS Search strategy A systematic search of PubMed and the Cochrane Library was conducted up to February 2015 to identify relevant trials. The Cochrane Collaboration’s sensitivity and precision-maximizing strategy13 using the following medical subject headings (MeSH), concepts and/or text words in various combinations was applied: gastroesophageal reflux, peptic ulcer, duodenal ulcer, gastric ulcer, Helicobacter pylori, omeprazole and esomeprazole (Appendix S1). We also searched for additional trials included in published systematic reviews and bibliographies of all relevant studies. Study selection and eligibility criteria
RESULTS
Two reviewers (MT and LL) screened abstracts according to predefined study inclusion criteria. Full text articles (published in English) were retrieved and reviewed if a decision on inclusion could not be made solely based on the abstract. Any disagreements were resolved by consensus between the two reviewers. We included head-to-head randomized controlled trials (RCTs) which compared oral esomeprazole with oral omeprazole, in any dose, in the management of GERD or peptic ulcer disease. The study participants were adults aged 18 years and above who had GERD, peptic ulcer disease or H. pylori infection. The outcomes of interest included resolution of GERD-related symptoms, esophagitis healing, peptic ulcer healing, H. pylori eradication, quality of life and adverse effects. Studies that involved specific patient groups (e.g. elderly), reported only intragastric acidity or pH measurement, and of which the PPIs were used as prophylaxis for NSAID-induced ulcers were excluded.
Search results We identified 468 citations using the search strategy. Of these, we excluded 439 after examining the title and abstract including removal of duplicates. We retrieved and evaluated 29 articles in more detail, of which 14 articles were excluded, leaving 15 RCTs15–29 that were eligible for inclusion (Fig. 1). Study characteristics Of the 15 studies included, seven studies were related to GERD17,19,20,22,23,29,30 and eight on H. pylori infection.15,18,21,24–28 We did not identify any studies that directly compared esomeprazole and omeprazole in peptic ulcer disease. Six of the GERD studies were conducted in patients with endoscopically confirmed reflux esophagitis (RE),17,19,20,22,23,29 whereas the remaining one in patients with endoscopy-negative
Outcome assessment The outcome measures for efficacy were esophagitis healing rate and heartburn resolution rate in patients with GERD, and peptic ulcer healing rate and H. pylori eradication rate in patients with peptic ulcer disease. Outcomes derived from intention-to-treat (ITT) analyses were included. For safety, we analysed adverse effects associated with treatments.
Records identified through databases searching PubMed (n = 261)
Records identified through other sources (n = 2)
Cochrane (n = 205)
Data collection and risk of bias assessment
Records after duplicates removed (n = 333)
Data regarding study design, country, patient characteristics, dose and delivery of esomeprazole and omeprazole, duration of treatment, outcomes and funding source were extracted into evidence tables (Appendices S2 and S3). Risk of bias was assessed for each included study using the Cochrane Collaboration risk of bias tool13 based on six domains: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome and selective outcome reporting. Other potential source of bias such as sponsorship of the study was also taken into consideration. Judgement on the risk of bias was made for each domain and categorized as high, low or unclear.
Records screened (n = 333)
Full-text articles assessed for eligibility (n = 29)
Studies included (n = 15)
Data analysis We performed meta-analyses of outcomes as appropriate by combining trials based on a random effects model in Stata
Records excluded (n = 304)
Full-text articles excluded (n = 14) Reasons for articles exclusion included pharmacodynamic/ pharmacokinetic studies, studies that enrolled healthy subjects, and not in English
Fig. 1. Study flow diagram illustrating the study selection process.
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Effectiveness of esomeprazole reflux disease (ENRD).16 There were 6893 patients included in the GERD trials. The mean age of subjects ranged from 45 to 58 years old. Based on the Los Angeles (LA) classification system that categorized the severity of erosive esophagitis, the proportion of patients with grades A, B, C and D erosive esophagitis were 34%, 39%, 20% and 7%, respectively. Tables 1 and 2 summarized the characteristics and main results of these studies. There were eight studies15,18,21,24–28 comparing esomeprazole with omeprazole in combination with standard antibiotics for H. pylori treatment. A total of 2598 subjects were included. The mean age of patients ranged from 39 to 59 years old. Three studies15,18,24 compared esomeprazole 40 mg, whereas the other five21,25–28 evaluated esomeprazole 20 mg with omeprazole 20 mg twice daily. Table 3 summarized the characteristics and main results of these studies.
Table 2. Characteristics and main results of study evaluating endoscopy-negative reflux disease
Study
Treatment arms
N
Percentage of patients with heartburn resolution at week 4 (95% CI)
Armstrong 200416 (study A)
E 40 mg QD E 20 mg QD O 20 mg QD E 40 mg QD O 20 mg QD E 20 mg QD O 20 mg QD
425 423 434 347 346 336 334
567 605 581 703 679 619 596
Armstrong 200416 (study B) Armstrong 200416 (study C)
(52–62) (52–62) (53–63) (65–75) (63–73) (57–67) (54–65)
E, esomeprazole; O, omeprazole; QD, once daily.
Risk of bias assessment For the GERD trials, most of them clearly stated the method of randomization, concealment for allocation and blinding of participants. Six trials were funded by manufacturer. For the H. pylori trials, majority of them did not provide adequate information on the method used for generating the sequence of randomization, allocation concealment and blinding. Five trials were funded by manufacturer. The risk of bias plots can be found in online Appendices S4 and S5.
Esomeprazole versus omeprazole in GERD The primary outcomes of the studies evaluating RE were the proportion of patients who achieved endoscopically confirmed healing and the proportion who achieved complete resolution of GERD-related symptoms at week 8. Secondary outcomes included esophagitis healing and symptom relief at week 4. The primary endpoint of the study evaluating ENRD was the proportion of
Table 1. Characteristics and main results of studies evaluating endoscopically confirmed reflux esophagitis
LA grades of RE (%) (A, B, C, D)
N
Healing rate (week 4) by ITT n/N (%) | P value
Healing rate (week 8) by ITT n/N (%) | P value
16/25 64 | P > 005 10/22 455 550/656 838 | P > 005 572/654 875 | P < 005 529/650 814 508/587 865 | P > 005 484/588 823 1093/1216 899 | P < 005 978/1209 809 501/576 869 | P > 005 491/572 858 62/68 912 | P > 005 57/68 838
Study
Treatment arms
Chen 200517
E 40 mg QD
25
60, 28, 8, 4
Not reported
O 20 mg QD
23
48, 30, 9, 13
Not reported
E 20 mg QD
656
33, 42, 18, 7
E 40 mg QD
654
36, 39, 18, 7
O 20 mg QD
650
31, 41, 21, 7
E 20 mg QD
588
38, 35, 21, 6
436/656 665 | P > 005 465/654 711 | P < 005 399/650 614 Not reported
O 20 mg QD
588
36, 38, 17, 9
Not reported
E 40 mg QD
1216
35, 39, 21, 5
O 20 mg QD
1209
32, 41, 20, 7
E 40 mg QD
576
32, 35, 25, 8
O 20 mg QD
572
33, 37, 22, 8
E 40 mg QD
68
30, 38, 29, 3
955/1216 786 | P < 005 805/1209 666 393/576 682 | P > 005 379/572 663 Not reported
O 20 mg QD
68
30, 38, 29, 3
Not reported
Kahrilas 2000
19
Lightdale 200620
Richter 200122
Schmitt 200623
Zheng 200929
Heartburn resolution (week 4) n/N (%) | P value
Not reported Not reported 382/626 524 | P > 005 402/621 637 | P < 005 357/624 572 356/588a 605 | P > 005 355/587a 605 831/1216 683 | P < 005 702/1209 581 374/576 649 | P > 005 361/572 631 Not reported Not reported
E, esomeprazole; O, omeprazole; QD, once daily; LA, Los Angeles grading system; RE, reflux esophagitis; ITT, intention-to-treat. Heartburn resolution was measured at week 8.
a
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Table 3. Characteristics and main results of studies evaluating Helicobacter pylori infection
Study
Treatment arms
Antibiotics
Treatment duration
Anagnostopoulos 200415
E 40 mg QD
Amoxicillin 1 g BID Clarithromycin 500 mg BID
7 days
Amoxicillin 1 g BID Clarithromycin 500 mg BID
7 days
Metronidazole 400 mg BID Clarithromycin 500 mg BID
7 days
Amoxicillin 1 g BID Clarithromycin 500 mg BID
7 days
Amoxicillin 1 g BID Clarithromycin 500 mg BID
7 days + 3 weeks maintenancea
Amoxicillin 1 g BID Clarithromycin 500 mg BID
7 days + 3 weeks maintenancea
Amoxicillin 1 g BID Clarithromycin 500 mg BID
7 days
Metronidazole 500 mg BID Clarithromycin 500 mg BID
7 days + 3 weeks maintenancea
E 40 mg BID O 20 mg BID Choi 200718
E 40 mg BID O 20 mg BID
Miehlke 200321
E 20 mg BID O 20 mg BID
Sheu 200524
E 40 mg BID O 20 mg BID
Subei 200725
E 20 mg BID O 20 mg BID
Tulassay 200126
E 20 mg BID O 20 mg BID
Veldhuyzen 200027
E 20 mg BID O 20 mg BID
Veldhuyzen 200328
E 20 mg BID O 20 mg BID
Eradication rates by ITT n/N (%) | 95% CI
42/52 808 | 75–86 50/52 962 | 91–99 37/52 71 | 65–77 104/148 703 96/148 649 38/42 904 | 78–97 31/38 816 | 66–92 86/100 86 79/100 79 139/186 747 | 68–81 148/188 787 | 73–84 184/214 86 | 81–90 192/219 877 | 83– 92 137/189 897 | 85– 94 172/196 878 | 82– 92 144/190 758 137/189 725
E, esomeprazole; O, omeprazole; QD, once daily; BID, twice daily; ITT, intention-to-treat. a Omeprazole group continued with omeprazole 20 mg once daily, whereas esomeprazole group was on placebo.
of esomeprazole versus omeprazole became less pronounced as the proportion of patients with LA grades C and D increased. Therefore, the statistical heterogeneity could be attributed to the different distribution of patients with specified baseline disease severity according to LA grades across the included studies. This relationship was, however, not statistically significant (P = 0053 at week 8 and P = 0216 at week 4). A subgroup analysis by ethnicity showed that esomeprazole 40 mg was not statistically better than omeprazole 20 mg at week 8 (RR=111; 95% CI 095 to 130) among the participants in eastern Asia.17,29
patients with complete resolution of heartburn as defined by no heartburn episodes during the previous seven consecutive days. In all of these studies, symptom relief was assessed subjectively by investigator or patients. Esophagitis healing rates. We meta-analysed the esophagitis healing rates at week 4 and week 8. The RRs for esomeprazole 40 mg and 20 mg compared with omeprazole 20 mg at week 8 were 107 (95% CI 102 to 112) and 104 (95% CI 101 to 108), respectively (Fig. 2). The calculated risk differences were 6% and 33%, which corresponded to NNT of 17 and 30, respectively. At week 4, the RR of esomeprazole 40 mg versus omeprazole 20 mg was 113 (95% CI 104 to 122) and the corresponding NNT was 12. There was no significant difference between esomeprazole 20 mg versus omeprazole 20 mg (based on one study) (Fig. 3). The results were robust to sensitivity analysis by excluding the study29 with high risk of performance and detection bias. Heterogeneity was observed in the analyses of esomeprazole 40 mg at week 8 (I2 = 64%, P = 0025) and week 4 (I2 = 75%, P = 0018). The meta-regression analysis revealed that the efficacy
Heartburn resolution rates. Three of the RE studies19,22,23 reported the proportion of patients with heartburn resolution at week 4. The heartburn resolution rate ranged from 64% to 68% for patients on esomeprazole 40 mg and 57% to 63% for those on omeprazole 20 mg. Meta-analysis for the rate of heartburn resolution was not performed given that the definition of this endpoint differed among the studies. Only one study evaluating ENRD16 was included. In this study, esomeprazole 40 mg and 20 mg were compared with omeprazole
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Author
Year
RR 95% CI
% Weight
Esomeprazole 40 mg
Chen
2005
1·41 (0·82, 2·43) 0·36
Kahrilas
2000
1·07 (1·03, 1·13) 18·28
Richter
2001
1·11 (1·07, 1·15) 22·37
Schmitt
2006
1·01 (0·97, 1·06) 18·55
Zheng
2009
1·09 (0·96, 1·24) 5·40
Subtotal (I-squared = 64·1%, P = 0·025)
1·07 (1·02, 1·12) 64·96
. Esomeprazole 20 mg
2000
1·03 (0·98, 1·08) 17·44
Lightdale 2006
1·05 (1·00, 1·10) 17·60
Subtotal (I-squared = 0·0%, P = 0·569)
1·04 (1·01, 1·08) 35·04
Kahrilas
.
Fig. 2. Forest plot demonstrating the relative risk (RR) with 95% confidence interval (CI) of esophagitis healing rates of esomeprazole 40 mg and 20 mg compared with omeprazole 20 mg once daily at week 8.
Overall (I-squared = 57·1%, P = 0·030)
1·06 (1·03, 1·10) 100·00
·8
1
1·2
Omeprazole better
Author
1·5
Esomeprazole better
Year
RR (95% CI)
% Weight
Esomeprazole 40 mg
KahrilasPJ
2000
1·16 (1·07, 1·25) 23·69
Richter JE
2001
1·18 (1·12, 1·24) 30·29
Schmitt C
2006
1·03 (0·95, 1·12) 23·11
Subtotal (I-squared = 75·2%, P = 0·018)
1·13 (1·04, 1·22) 77·09
. Esomeprazole 20 mg
Kahrilas PJ
2000
1·08 (1·00, 1·17) 22·91
Subtotal (I-squared = NA .%, P = NA .)
1·08 (1·00, 1·17) 22·91
.
Fig. 3. Forest plot demonstrating the relative risk (RR) with 95% confidence interval (CI) of esophagitis healing rates of esomeprazole 40 mg and 20 mg compared with omeprazole 20 mg once daily at week 4.
Overall (I-squared = 68·0%, P = 0·025)
1·12 (1·05, 1·19) 100·00
·5
1 Omeprazole better
1·5 Esomeprazole better
H. pylori eradication rates. The eradication rate associated with esomeprazole (regardless of dose) ranged from 70% to 96%, whereas that for omeprazole ranged from 65% to 88%. The RRs for esomeprazole 40 mg and 20 mg compared with omeprazole 20 mg twice daily were 116 (95% CI 101 to 132) and 101 (95% CI 096 to 105), respectively (Fig. 4). Heterogeneity was observed in the analysis of esomeprazole 40 mg dose (I2 = 53%, P = 012). However, meta-regression analysis could not be performed due to insufficient number of studies. The results were robust to analysis taking into account the different antimicrobial agents (amoxicillin versus metronidazole). The results of subgroup analysis based on studies21,28 that included 3-week omeprazole maintenance therapy and ethnicity were as follows: esomeprazole 20 mg was superior to omeprazole
20 mg once daily for 4 weeks in symptomatic patients with ENRD. There was no significant difference in the proportion of patients who achieved heartburn resolution among the groups. Esomeprazole versus omeprazole in H. pylori The treatments in all the eight included studies15,18,21,24–28 were the standard 7-day triple-therapy regimen with the co-administered antibiotics being either amoxicillin and clarithromycin or metronidazole and clarithromycin. In three studies,25,26,28 omeprazole was continued for another 3 weeks as maintenance monotherapy versus placebo in esomeprazole treatment arm. The primary endpoint of these studies was the H. pylori eradication rate at 4–8 weeks as assessed by histology and urea breath test.
© 2015 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2015 5
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Effectiveness of esomeprazole
Author
RR 95% CI
Year
% Weight
Esomeprazole 40 mg Anagnostopoulos 2004
1·35 (1·13, 1·62) 7·47
Choi
2007
1·08 (0·92, 1·27) 9·02
Sheu
2005
1·09 (0·96, 1·24) 11·67
Subtotal (I-squared = 53·2%, P = 0·118)
1·16 (1·01, 1·32) 28·16
. Esomeprazole 20 mg Miehlke
2003
1·11 (0·93, 1·33) 7·54
Subei
2007
0·95 (0·85, 1·06) 13·50
Tulassay
2000
0·98 (0·91, 1·06) 18·80
Veldhuyzen
2000
1·02 (0·95, 1·10) 19·33
Veldhuyzen
2003
1·05 (0·93, 1·18) 12·67
Subtotal (I-squared = 0·0%, P = 0·521)
1·01 (0·96, 1·05) 71·84
. Overall (I-squared = 50·8%, P = 0·047)
1·05 (0·99, 1·11) 100·00
·8 Omeprazole better
1
1·2
1·5
Esomeprazole better
Fig. 4. Forest plot demonstrating the relative risk (RR) with 95% confidence interval (CI) of H. pylori eradication rates of esomeprazole 40 mg and 20 mg compared with omeprazole 20 mg twice daily.
according to baseline disease severity (LA grades).20,23 In these two studies, greater between-treatment differences in favour of esomeprazole were observed in patients with moderate to severe esophagitis (LA grades C and D) at baseline than patients with mild esophagitis (LA grades A and B). When used in combination with antibiotics for H. pylori eradication, a statistically significant difference was observed between esomeprazole 40 mg and omeprazole 20 mg, but this analysis was associated with significant heterogeneity and a lower bound CI approaching 10. There was no significant difference in efficacy between esomeprazole 20 mg and omeprazole 20 mg. Given that esomeprazole is the active isomer, it is expected that esomeprazole would achieve more potent antisecretory activity than omeprazole on milligram basis and result in better efficacy. However, our analysis showed that the efficacy of esomeprazole and omeprazole did not differ significantly in achieving H. pylori eradication when combined with antimicrobial agents (amoxicillin and clarithromycin or clarithromycin and metronidazole) as a standard triple therapy. This was likely due to the fact that the extent of bacterial susceptibility to antimicrobial agents contributes to the H. pylori eradication and that the necessary level of acid inhibition for H. pylori eradication within a standard triple therapy could be achieved with either omeprazole or esomeprazole. It was noteworthy that omeprazole 20 mg was inferior to esomeprazole 20 mg in the absence of omeprazole maintenance therapy. Nonetheless, these results were derived from the meta-analysis of only two studies. The rate of adverse effects was generally greater in studies on GERD than H. pylori eradication, which implied that the treatment duration correlated to incidence of adverse effects. Treatment with esomeprazole was associated with higher rates of adverse effects such as abdominal pain and headache than omeprazole. However, the difference did not reach statistical significance. Overall, both drugs demonstrated similar safety profiles. Our study distinguished itself from previous reviews by including most recent comparative trials of esomeprazole and omeprazole. Majority of the previous systematic reviews compar-
20 mg when there was no omeprazole maintenance therapy (RR=110; 95% CI 101 to 120), and the treatment difference between esomeprazole 40 mg and omeprazole 20 mg was insignificant among participants from the Eastern Asia (RR=109; 95% CI 098 to 120). Safety The data on adverse effects in all the included studies comprising 9200 patients were pooled. The safety profiles of esomeprazole and omeprazole were generally similar. The pooled estimates of the treatment-associated adverse effects for esomeprazole versus omeprazole were abdominal pain (32% vs 29%), diarrhoea (31% vs 30%), flatulence (32% vs 38%) and headache (66% vs 56%). Meta-analyses of these adverse effects did not reveal any statistically significant differences between esomeprazole and omeprazole. DISCUSSION Our meta-analyses demonstrated that esomeprazole 40 mg and 20 mg were statistically more effective than omeprazole 20 mg once daily for esophagitis healing at 8 weeks in patients with GERD. However, the difference was marginal, with the lower bound of CI approaching 10. The corresponding NNT17,30 was also not promising. According to a Cochrane systematic review31 that compared PPIs with H2-receptor antagonists and placebo in the treatment of esophagitis, PPI was associated with a NNT of three and two, respectively. Esomeprazole 20 mg did not significantly improve the esophagitis healing at week 4. This suggested that esomeprazole would have limited clinical advantage over omeprazole if the duration of PPI therapy was 4 weeks. Analysis of healing rates relative to the baseline disease severity was not conducted due to inadequate number of studies. Two of the included studies reported the treatment difference between esomeprazole and omeprazole in patients with GERD stratified
© 2015 John Wiley & Sons Ltd
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Effectiveness of esomeprazole
ing PPIs in the management of GERD were supported by industry.9,32,33 These studies evaluated the effects of esomeprazole 40 mg versus other PPIs and reported that esomeprazole was superior in healing esophagitis. In addition, the treatment difference between esomeprazole at 20 mg and other PPIs was not investigated. In our study, a rigorous and systematic search strategy was applied, which provides more robust results. To provide a realistic comparison given that esomeprazole is the active enantiomer of omeprazole, which is akin to omeprazole at double dose, we analysed the effectiveness of esomeprazole versus omeprazole on pharmacologically comparable doses. As with any systematic review and meta-analysis, the results of our study relied on the number and quality of the included trials. The risk of publication bias having an effect on our results could not be ruled out given that only English articles and studies with fully published results were considered for inclusion. The limited number of studies and reported outcomes did not made provision to generate more insights into the relative efficacy of esomeprazole and omeprazole in other aspects. For instance, we were unable to analyse the treatment difference between esomeprazole and omeprazole in patients with GERD relative to their baseline disease severity and cytochrome P450 2C19 (CYP2C19) genotype. In H. pylori eradication, studies have reported that treatment failure could be caused by insufficient gastric acid inhibition as a result of CYP2C19 genotype apart from bacterial susceptibility to antimicrobial agents.34 As esomeprazole is the active enantiomer of omeprazole, it would be more rational to compare omeprazole 40 mg with esomeprazole 20 mg. However, there were no available clinical studies that compared omeprazole 40 mg with esomeprazole. A potential research area would be to compare the effectiveness of omeprazole 40 mg with esomeprazole in treating GERD.
WHAT IS NEW AND CONCLUSION Esomeprazole provided a statistically significant but marginal degree of improvement in esophagitis healing when compared with omeprazole. However, this clinical advantage in patients with GERD diminished when the treatment duration was within 4 weeks. There was no difference in the H. pylori eradication rates when esomeprazole and omeprazole were given at the same doses. Based on our analysis, it is prudent to consider other factors such as the cost of therapy, severity of esophagitis, bacterial susceptibility to antimicrobial agents and variation in CYP2C19 genotype when prescribing these agents to patients with GERD or H. pylori infection. CONFLICT OF INTERESTS No conflict of interests have been declared. SOURCE OF FUNDING None. SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Appendix S1. Search strategy. Appendix S2. Studies evaluating gastroesophageal reflux disease. Appendix S3. Studies evaluating Helicobacter pylori infection. Appendix S4. Risk of bias assessment for studies evaluating gastroesophageal reflux disease. Appendix S5. Risk of bias assessment for studies evaluating Helicobacter pylori infection.
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