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Comparison of prophylactic effect of UGIB and effects on platelet function between PPIs and H2RAs combined with DAPT: systematic review and meta-analysis

Objective We compared prophylactic effects of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) on upper gastrointestinal bleeding (UGIB) associated with dual antiplatelet therapy (DAPT) and explored this influence on platelet function. Methods Randomized controlled trials and cohort studies comparing PPIs with H2RAs in adults receiving DAPT were collected from PubMed, EMBASE and Cochrane databases. Dichotomous data were pooled to obtain risk ratios (RRs) for UGIB, major adverse cardiovascular events (MACEs), poor responders to clopidogrel and rehospitalization, and continuous data were pooled to obtain mean differences (MDs) for P2Y12 reaction units (PRUs), with 95% confidence intervals (CIs). Results Twelve clinical trials (n=3,301) met the inclusion criteria. Compared to H2RAs, PPIs lessened UGIB (RR =0.16, 95% CI: 0.03–0.70), and there was no significant difference in the incidence of PRUs (MD =18.21 PRUs, 95% CI: −4.11–40.54), poor responders to clopidogrel (RR =1.21, 95% CI: 0.92–1.61), incidence of MACEs (RR =0.89, 95% CI: 0.45–1.75) or rehospitalization (RR =1.76, 95% CI: 0.79–3.92). Subgroup analysis confirmed fewer PRUs in the H2RAs group compared to the omeprazole group (2 studies, n=189, MD =31.80 PRUs, 95% CI: 11.65–51.96). However, poor responder data for clopidogrel and MACEs might be unreliable because few studies of this kind were included. Conclusion Limited evidence indicates that PPIs were better than H2RAs for prophylaxis of UGIB associated with DAPT and had no effect on platelet function. Further study is needed to confirm these observations.


Introduction
Dual antiplatelet therapy (DAPT; clopidogrel and aspirin) is commonly used for primary and secondary prevention of cardiovascular (CV) and cerebrovascular diseases. DAPT can reduce the risk of subsequent stroke for a year after the first event. 1 In a randomized controlled trial (RCT), DAPT was confirmed to reduce the risk of stroke by 32% compared to aspirin alone in patients with minor stroke or transient ischemic attacks. 2 As DAPT use increases, the incidence of DAPT-associated upper gastrointestinal (GI) injuries, including gastric mucosal erosions, peptic ulcers and bleeding, also rises. Morneau

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Yi et al GI bleeding (GIB), especially in patients with multiple risk factors. 3 Thus, GIB prophylaxis was suggested for patients receiving DAPT therapy.
In 2007, the American College of Cardiology recommended antiulcer drugs for patients with a history of GIB, and proton pump inhibitors (PPIs) effectively lowered the adjusted risk of aspirin-induced GIB by 28%. 4 Meanwhile, histamine-2 receptor antagonists (H 2 RAs) therapy can prevent ulcers for patients receiving low-dose aspirin. 5 Studies suggest that combination treatment with PPIs plus clopidogrel is associated with high platelet reactivity and more adverse events during long-term follow-up. 6,7 PPIs were also shown to reduce responsiveness to standard clopidogrel doses and increased CV events for patients with the cytochrome P450 (CYP) 2C19 loss-of-function allele. 8 Moreover, H 2 RAs may be as effective as PPIs plus DAPT for patients with no prior history of upper GI bleeding (UGIB). 9 Therefore, H 2 RAs might be a reasonable alternative to PPIs, as they do not affect CYP 2C19 genotypes. Therefore, we conducted a systematic review and meta-analysis to compare the efficacy and safety of PPIs compared with H 2 RAs for preventing UGIB associated with DAPT, and offered a foundation of evidence for clinical decision-making.

Materials and methods search strategy and inclusion criteria
We searched PubMed (January 1966 to August 2016), EMBASE (January 1974 to August 2016) and the Cochrane Collaboration's Central Register of Controlled Trials (CENTRAL) (2016 Issue 8) to identify clinical trials comparing the efficacy of PPIs to H 2 RAs for patients treated with DAPT consisting of aspirin and clopidogrel. The following search terms were used: aspirin, acetylsalicylic, clopidogrel, proton pump inhibitors, PPIs, esomeprazole, pantoprazole, omeprazole, rabeprazole, lansoprazole, histamine receptor blocker, H 2 receptor antagonists, H 2 blocker, H 2 RA, cimetidine, ranitidine, famotidine, roxatidine, nizatidine and lafutidine. Reference lists of original articles and reviews were manually searched for additional relevant studies. Experts in this field of study were consulted.
For this review, inclusion criteria included 1) RCTs (parallel or crossover design) and cohort studies; 2) patients treated with aspirin and clopidogrel; 3) PPIs versus H 2 RAs; 4) primary outcome of UGIB; secondary outcomes were P2Y 12 reaction units (PRUs), number of poor responders to clopidogrel, major adverse CV events (MACEs) and rehospitalization frequency. All manuscripts were in English. UGIB referred to hematemesis, melena or a hemoglobin decrease of .2 g/dL, with or without endoscopy. Poor clopidogrel responder was defined by a PRU value .240 or a PRU% 20% or a platelet reactivity index .50%. MACEs referred to death from CV causes, spontaneous myocardial infarction, unstable angina, stent thrombosis, target vessel revascularization, nontarget vessel revascularization and ischemic stroke. The systematic review with meta-analysis was registered on PROSPERO (No CRD42015030158).
study selection and quality assessment Two authors (ZMY and TTQ) independently selected potentially eligible studies from the literature according to title and abstracts. Then, full-text versions were screened for potentially eligible studies to determine eligibility based on inclusion criteria.
Two authors (ZMY and TTQ) independently assessed the risk of bias in included studies. The methodological quality of eligible RCTs was evaluated with the Cochrane risk of bias assessment tool, 10 in which critical quality assessments are made separately for different domains including method of randomization, concealment of allocation, blinding, incomplete outcome data, selective reporting and other biases. Considering that the observational studies were more vulnerable to the potential selection bias than RCTs, the methodological quality of eligible cohort studies was evaluated with the Newcastle-Ottawa scale. 11 Three domains including selection, comparability and outcome were assessed. All disagreements about study selection and quality assessment were resolved through discussion.

Data extraction and synthesis
Data extraction was performed by each author (ZMY and TTQ) according to a predesigned review form, and study characteristics (author, publication year and type of study), participant characteristics (inclusion criteria, sample size, age and sex), intervention information (dosage, administration route and duration) and outcome measures (primary and secondary outcomes) were collected. All disagreements were resolved through discussion.
Meta-analyses were performed with RevMan 5.3. Dichotomous and continuous outcomes were expressed with random effect model as the risk ratio (RR) with 95% confidence interval (CI) and mean difference (MD) with 95% CI, respectively. Statistical heterogeneity was assessed with the Mantel-Haenszel chi-square test and quantified using an I 2 test (P-value of heterogeneity was 0.10). Subgroup analyses among different PPIs were conducted to explore sources of clinical heterogeneity in data regarding PRUs. According to the guidance in Chapter 16 of Cochrane Handbook for Systematic Reviews of Interventions, when carryover or period effects were not serious for crossover studies, all measurements were analyzed as if the trials were parallel-group trials. 12 Sensitivity analysis was conducted by changing the random-effects methods to fixed-effects methods to pool the trials.

search results and study characteristics
Studies identified are depicted in Figure 1 along with strategies for including relevant papers. Among studies that retrieved full text for inspection, 20 studies were excluded, and the details were as following: 4 had no comparisons between PPIs and H 2 RAs, 4 were duplications, patients did not meet inclusion criteria in 3 studies, 2 were case series, 1 presented no separate data on the PPIs and H 2 RAs, 1 studied prescription rates of PPIs and H 2 RAs, 1 was a review, 1 was a commentary, 1 was an animal experiment, 1 was a case-control study and 1 was a Chinese article with English abstract (Figure 1). Table 1 depicts study characteristics, and bias risk data are shown in Tables 2 and 3. A total of 12 studies containing 3,301 patients (2,068 in the PPIs group, 1,233 in H 2 RAs group) were included in the analysis. [13][14][15][16][17][18][19][20][21][22][23][24] The risk of bias for all included RCTs is high except the low risk of bias for Furtado et al 14 and moderate risk of bias for Ng et al. 16 For cohort studies, the risk of bias for Cappelletti Galante et al, 21 Ng et al 23

incidence of UgiB
Three RCTs 16,18,20 reported the incidence of UGIB, and Figure 2 depicts the lack of heterogeneity between included trials and the pooled RR, confirming that PPIs   Moceri et al reported a decreased mean PRU% for those treated with esomeprazole compared to those treated with no drug (P0.0001), but no statistical difference was found in the ranitidine group (P=0.97). 15 Three RCTs 15,18,20 reported of poor responders to clopidogrel (75 mg). The washout period in the study by Moceri et al 15 was 48 h, and blood samples were collected at the end of each phase. This washout period was sufficient to eliminate the effect of clopidogrel for poor responders and data were assessed as if this was a parallel-group trial. Heterogeneity of included trials was insignificant (see Figure 4 for data), and there were no statistically significant differences among numbers of poor responders to clopidogrel between the PPIs and H 2 RAs groups ( Figure 4).
Parri et al reported that pantoprazole plus DAPT significantly increased ADP-MA compared with ranitidine at 5 and 30 days' follow-ups (P=0.01 and P=0.03, respectively), indicating that pantoprazole interfered with antiplatelet effects of clopidogrel. 17    The patients of proton pump inhibitor group had significantly higher proportion of anemia (P=0.019) and previous coronary artery bypass graft (P=0.048). d some of the clinical follow-up data were collected through telephone calls.
Abbreviation: nOs, newcastle-Ottawa scale. and reported that rabeprazole plus DAPT did not attenuate antiplatelet function compared with famotidine combined with DAPT. 19

Cardiovascular events
Two RCTs reported the incidence of MACEs 16,20 and there was no heterogeneity between the trials (P=0.44, I 2 =0%) as well as no difference in the incidence of MACEs between PPIs and H 2 RAs therapy (RR =0.89, 95% CI 0.45-1.75). Yew et al published a retrospective cohort study in Singapore that included post-PCI patients who received either omeprazole or a H 2 RAs and DAPT and they confirmed that significantly more CV complications occurred in the omeprazole group (P=0.042). 24  22 Heterogeneity of included trials was substantial and there were no statistically significant differences among incidence of rehospitalization between the PPIs and H 2 RAs groups ( Figure 5).

sensitivity analysis and publication bias
All pooled results were not affected by the different methods used. Due to a limited number of included studies for each outcome, we could not assess the risk of publication bias.

Discussion
This review compared the effectiveness and safety of PPIs to H 2 RAs for patients receiving DAPT, as assessed in RCTs and cohort studies. Limited evidence suggested that compared to H 2 RAs, PPIs decreased UGIB, and no differences were found in PRUs, poor responders to clopidogrel, or incidences of MACEs and rehospitalization. Among the PPIs, subgroup analyses suggested that omeprazole may increase PRUs. A meta-analysis including ten RCTs by Mo et al showed that PPIs reduced LDA-associated UGIB. 25 Another metaanalysis of 39 studies by Cardoso et al indicated that PPIs decreased the risk of UGIB for patients taking clopidogrel and these data agreed with our results. 26 Only two trials were included in comparisons between PPIs and H 2 RAs by Mo et al, 25 and no comparisons of this nature were made by 374 Yi et al Cardoso et al. 26 Regarding CV events, Yasuda et al reported significantly more coronary stenotic lesions after treatment with PPIs compared with H 2 RAs, 27 whereas the CALIBER study confirmed that both PPIs and ranitidine were associated with higher incidence of death or myocardial infarctions. 28 A meta-analysis of RCTs and observational studies by Melloni et al had conflicting results regarding PPIs 29 and CV outcomes, and a systematic review by Focks et al challenged the validity of conclusions about PPI-clopidogrel interactions on platelet function and MACEs based on quantitative analyses of predominantly nonrandomized data. 30 A recent published RCT by Gargiulo et al also indicated that DAPT concomitant with PPIs did not increase death for myocardial infarction or cerebrovascular accident. 31 We found no difference in the incidence of MACEs and between PPIs and H 2 RAs. This suggested that the safety profile of PPIs were comparable with H 2 RAs. However, the small number of included studies might compromise the validity of this conclusion. Patients with increased upper GI risk are more likely to receive PPIs and patients with increased CV risk are more likely to receive DAPT instead of aspirin or clopidogrel alone, and DAPT treatment is more likely to be paired with PPIs due to increased UGIB risk compared to aspirin or clopidogrel alone. Therefore, in cohort studies, imbalances in baseline characteristics and prescription bias may affect observed outcomes; patient prognostic factors at the RCT baseline may differ from a cohort study. Here, we noted conflicting results between RCTs and cohort studies for ADP-MA and MACEs and these results may be biased due to inherent difference in study characteristics (study designs, study population and different treatment durations from 7 days to 35 months). DAPT length may influence the bleeding risk; the PRODIGY study suggested an increase in bleeding risk without benefit from ischemic adverse events, 32 while benefit overcame the risk for some subgrousps at higher risk. 33 Thus, more studies are needed to draw firm conclusions.
Our report is the first of its kind to directly compare PPIs with H 2 RAs for prophylaxis and safety when used with DAPT and we included RCTs and cohort studies. A recent meta-analysis to compare the effects of concomitant use of PPIs and DAPT concluded that observational studies and RCTs have conflicting outcomes regarding PPIs on CV outcomes when coadministered with DAPT. 27 Thus, the results of both RCTs and cohort studies can decrease potential reporting bias. Subgroup analyses of four different types of PPIs to explore the potential effect differences indicate that omeprazole modified CYP 2C19 metabolism and reduced antiplatelet effects, 34 and this was consistent with our results.
Since 2009, the US FDA recommended against concomitant use of clopidogrel and omeprazole and suggested, instead, the use of a weak CYP 2C19 inhibitor, pantoprazole. 35 However, in our study, two reports (one RCT and one cohort study) indicate that pantoprazole may have antiplatelet effects; so, we compared "poor responders to clopidogrel", which was a more direct indicator of antiplatelet activity compared to PRUs.
Our study has some limitations. First, our topic has few reports in the literature and so clinical guidelines are similarly scarce 36 or unjustified based on current evidence. 37,38 Thus, high-quality research is required to assess clinical practices and support guideline recommendations. Second, in this systematic review, we could not combine RCTs with observational studies due to lack of matching propensity scores or reporting adjusted RRs. Although 12 studies were included in the review, only 8 RCTs were included in our meta-analysis. Additionally, aggregate sample sizes of all included studies were small and this decreased precision of estimates. Subgroup analysis based on individual CYP 2C19 genotypes and Heliobacter pylori status could not be performed because few studies reported these data. Furthermore, only English-language studies were included and conference abstracts were not manually searched, although important conference abstracts were included in databases searched and included in our review.

Conclusion
The available evidence suggests that PPIs outperformed H 2 RAs for prophylaxis of UGIB associated with DAPT, and no differences in platelet function were observed. Likely, differences in antiplatelet activity are caused by omeprazole, but larger randomized controlled studies are required to compare PPIs with H 2 RAs for preventing UGIB during DAPT treatment.

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