Eight mixed comparisons and 7 indirect comparisons in heartburn relief were generated in NMA (contribution matrix in Supplementary Figure 3, http://links.lww.com/MD/B886). Figure 7 graphically described the summary effects for the heartburn relief. Favourable and statistical significant results were observed for esomeprazole 40 mg compared with omeprazole 20 mg (OR = 1.29, 95% CI: 1.07–1.56) and lansoprazole 30 mg (OR = 1.29, 95% CI: 1.03–1.62). Generally, none of the rest treatment comparisons in the NMA controlling for heartburn relief produced any statistically meaningful difference.
Twelve mixed comparisons and 16 indirect comparisons in acceptability were generated in NMA (contribution matrix in Supplementary Figure 4, http://links.lww.com/MD/B886). The summary effects for the acceptability outcome are shown in Fig. 8. Only dexlansoprazole 60 mg had more statistically discontinuations than did omeprazole 20 mg, pantoprazole 40 mg, and lansoprazole 30 mg. For analysis of the rest comparisons, no significant estimates were yielded for any agents on acceptability. Furthermore, we progressed network meta-analysis for withdrawals due to adverse events between each intervention (Supplementary Figure 5, http://links.lww.com/MD/B886). Compared with omeprazole 20 mg, pantoprazole 40 mg, lansoprazole 30 mg, and rabeprazole 20 mg, dexlansoprazole 60 mg exhibited the significantly increased withdrawal rates because of adverse events by 2 to 3-folds. There was little variation in withdraw rates and no significant differences among other treatments founded no change in direction.
Considering the integrity of the data on all interventions, we only performed the clustering analysis for the endoscopic healing rates at 8 weeks and the acceptability (Fig. 9). The cluster ranking plot shows 4 separate clusters. Esomeprazole 40 mg, pantoprazole 40 mg, esomeprazole 20 mg, and lansoprazole 30 mg formed a cluster of “the most effective and reasonable compliance” agents in the upper right corner. Omeprazole 20 mg and rabeprazole 20 mg represented the “low effective and withdrawal rate” cluster. Moreover, placebo was the ineffective and low compliance agent in the most left position. Dexlansoprazole 60 mg formed a single cluster of “the moderate effective but the poorest compliance” agent in the bottom right corner.
Despite the current nationally trusted guidelines about GERD pointed out, there were no major differences in efficacy among different PPIs (not included dexlansoprazole), based on the results of the old traditional pairwise meta-analysis in 2006.[7,22] Then, we made a further network meta-analysis to access the effectiveness and acceptability of FDA-licensed PPIs for the prevention of mucosal erosions and heartburn symptom in EE patients.
Simultaneous ranking of PPI interventions on 2 primary outcomes revealed that a single most effective and safest intervention does not exist. In terms of the effectiveness for prevention of mucosal breaks of the oesophagus at 8 weeks, esomeprazole 40 mg outperformed other PPIs. On the basis of the limited data of dexlansoprazole 60 mg, esomeprazole 40 mg seemed to produce a highest probability for the mucosal healing at 4 weeks (98%). The greater efficacy could be interpreted by its property of acid control. Esomeprazole 40 mg produced significantly longer time of intragastric acid suppression maintaining PH >4 compared with the stand-dose pantoprazole, lansoprazole, rabeprazole, and omeprazole,[52,53] and longer than the low-dose esomeprazole  in GERD patients. But dexlansoprazole 60 mg provided higher intragastric PH and significant difference in the time of acid control than esomeprazole 40 mg in healthy subjects. It may be that the drug efficacy in clinical practice was affected by many confounding factors.
Dexlansoprazole, a right-handed(R)-isomer of lansoprazole and a novel dual delayed-release formulation, is the newest addition to the PPI class, which has been approved for GERD by FDA since 2009. Similar to 1 recent indirect meta-analysis, this NMA estimated no difference between esomeprazole and dexlansoprazole in healing rates at 8 weeks. Furthermore, we found that there were no significant differences between dexlansoprazole with each of PPIs in clinical settings, although the new formulation drug was released twice daily at several-hour interval with the longer time of intragastric acid suppression.[53,55] The finding could be probably interpreted that the number of the included studies tended to be small.
For the secondary outcome, esomeprazole 40 mg seemed to be the highest probability for heartburn relief (86.9%) and no significant results were seen among almost all interventions. Our NMA summarized that rabeprazole 20 mg and omeprazole 20 mg were not found statistically different, which was in contrast with 1 earlier review that showed that rabeprazole 20 mg had higher symptom relief rates than omeprazole 20 mg. Only 1 trial was included in our study to evaluate the difference for these 2 interventions with the identical estimated time and explicit endpoint. Nevertheless, a single RCT reported that rabeprazole 20 mg was significantly superior to omeprazole 20 mg (32.2% of patients compared with 18.9%, P = .001) for complete heartburn relief after 1 week of therapy.
In terms of the measure of acceptability, we directly investigated the discontinuation rather than the side effects or toxic effects, which showed that dexlansoprazole 60 mg was a “better efficacy but highest drop-out rate” treatment in the all PPIs because of both all causes and adverse events. The percentage of patients with adverse events leading to discontinuation was 2.3% in dexlansoprazole 60 mg therapy group, a higher incidence than shown in other groups. In summary, dexlansoprazole 60 mg demonstrated the better efficacy in increasing the mucosal healing, but were accompanied with the potential risks of the adverse events. More relative head-to-head comparisons will be needed. All agents included in the review did not differ from placebo with regard to all-caused discontinuations. Generally, the most common adverse reactions reported in short term of PPI treatment included diarrhea, nausea, vomiting, abdominal pain, headache, upper respiratory tract infections, flatulence, and constipation, be regarded as relative safety medications.
Overall, no significant correlation was synthesized in almost all analyses comparing the healing rates, heartburn relief rates, and discontinuation rates between omeprazole 20 mg, pantoprazole 40 mg, lansoprazole 30 mg, rabeprazole 20 mg, and esomeprazole 20 mg, which was similar to the traditional meta-analyses.[57–60]
The previous pairwise meta-analyses always compared 1 agent at both the upper dose and lower dose of its therapeutic range as a group with another agent within the same study.[22,24] In this NMA, we only considered studies randomizing patients to the standard- and low-dose PPIs and provided a formal rank order for each outcome. Meanwhile, the primary results in this NMA are also presented by simultaneous clustered ranking outcome. There are several limitations in this NMA. First, disease severity at baseline is thought to be a source of between-study heterogeneity, as the endoscopic healing effect sizes decreased with increasing severity. Only 7 RCTs reported the healing rates at 4 weeks for a high grade of oesophagitis: omeprazole 20 mg (4 RCTs, 383 cases), pantoprazole 40 mg (3 RCTs, 447 cases), lansoprazole 30 mg (3 RCTs, 711 cases), esomeprazole 40 mg (4 RCTs, 1074 cases). Ten RCTs reported the healing rates at 8 weeks for a high grade of oesophagitis: omeprazole 20 mg (4 RCTs, 505 cases), pantoprazole 40 mg (2 RCTs, 411 cases), lansoprazole 30 mg (5 RCTs, 1130 cases), esomeprazole 20 mg (1 RCT, 158 cases), esomeprazole 40 mg (5 RCTs, 1129 cases), dexlansoprazole 60 mg (2 RCTs, 373 cases). It is difficult to extract the quantitative data of the severe erosive reflux disease to make a sensitive analysis. The second limitation is the measurement of outcome; compared with the primary endpoint based on endoscopy examination, the secondary endpoint based on the diary or investigator-assessment was more subjective to cause the uncertainty of heartburn relief rates. In addition, it should be caution to interpret the relationship among all PPI interventions for preventing the relapse in a longer period of time, as all trials just invariably reported the short-term data of 4 to 8 weeks.
This comprehensive NMA showed that the standard-dose esomeprazole had substantial advantages compared with other licensed PPIs in mucosal erosion healing and heartburn relief. After clustering analysis of the 2 primary outcomes, esomeprazole 40 mg, pantoprazole 40 mg, esomeprazole 20 mg, and lansoprazole 30 mg showed more benefits in effectiveness and acceptability than other interventions.
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