Globally, cardiovascular disorders are the main reason for mortality and disability, with coronary artery disease (CAD) being among the highest prevalent cardiovascular disorders, which may typically lead to acute myocardial infarction (AMI) and, ultimately, heart failure (HF) [1, 2]. Nowadays, with the unprecedented development of coronary revascularization, in particular, percutaneous coronary intervention (PCI), the prognosis of CAD patients, has been greatly improved [3]. Conventional dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is a base for the treatment of antithrombosis following AMI and PCI; the recommended period of treatment is at least 12 months—the duration put forth in the 2019 recommendations from The European Society of Cardiology (ESC) [4]. Nevertheless, antithrombotic treatment not only decreases the incidence of ischemic incidents, but also elevates the probability of bleeding events, especially the incidence of gastrointestinal bleeding [5].

In the above-mentioned 2019 ESC guidelines, proton pump inhibitors (PPIs) are the first choice category recommendation when it comes to reducing gastrointestinal hemorrhage risk in patients medicated with DAPT and could be a successful therapy in terms of enhancing the safety and prognosis [4]. However, clopidogrel and PPIs share the same cytochrome enzyme cytochrome P450 2C19 (CYP2C19), and the drug-drug interactions have drawn widespread clinical attention [6]. It has been proven that PPIs can significantly decrease the inhibitory effect on the platelets of clopidogrel in vitro [7], which may result in thrombotic events such as myocardial infarction and revascularization.

In clinical trials, the results are conflicting and even contradictory in well-conducted observational research besides randomized controlled trials (RCTs) concerning the influence of PPIs on cardiovascular outcomes [8]. Some included observational trials lack data on PPI doses and may ascertain exposure [8, 9]. Thus, to provide more reasonable evidence for clinical practice, only RCTs were eligible for inclusion here. Moreover, a systematic review was carried out to compare the cardiovascular and gastrointestinal events between DAPT and DAPT + PPI in acute coronary syndrome (ACS) patients or patients with coronary stent (PCI patients), and to estimate, for the first time, the sample size needed to produce reliable results via trial sequential analysis (TSA).

This study detected eight RCTs with 5441 patients medicated with DAPT + PPI and 5448 patients medicated with DAPT only or DAPT + placebo. The results demonstrate that DAPT + PPI probably has no significant impact on cardiovascular outcomes such as MACEs in patients with coronary intervention, while a specific decrease was displayed in gastrointestinal events, such as gastrointestinal ulcers and gastrointestinal bleeding (including upper gastrointestinal bleeding). To the best of our knowledge, this is the first study to conduct a TSA, and the results provided firm evidence regarding the benefit of cardiovascular and gastrointestinal outcomes associated with DAPT + PPI.

DAPT in ACS patients subjected to coronary stent implantation for at least 6 to 12 months is the IA recommendation [26, 27], but it must be noted that gastrointestinal bleeding can be caused by DAPT. PPIs are indicated for patients who suffer from a higher-than-average probability of gastrointestinal hemorrhage to decrease gastrointestinal outcomes [26, 27]. The metabolism of clopidogrel may be affected by PPIs, as they share the same metabolizing enzymes: CYP2C19. Gilard et al. [7] first observed that the PPI treatment might diminish the biological action of clopidogrel in vitro and then revealed that omeprazole can significantly decrease the action of clopidogrel on inhibiting platelet P2Y12 in an RCT [28]. Concerns were raised, as the low bioactivities of clopidogrel might result in ischemic events. Subsequent experiments [29, 30, 31] revealed that pantoprazole, esomeprazole, and rabeprazole do not influence the antiplatelet effect of clopidogrel, thus suggesting that they are more suitable for the combination of DAPT. However, in real-world studies, researchers found that the cutoff of clinically significant poor response to clopidogrel is fairly higher than that commonly achieved by PPI treatment [32]. The cardiovascular outcomes among the two groups are insignificant. This result has been confirmed by our study and previous studies [9, 19, 21].

Ticagrelor, a novel, oral, direct-acting P2Y12 inhibitor, does not need to be metabolized via CYP2C19, thus meaning that its inhibitory effects are not impacted by PPIs [33]. The PLATO trial first illustrated that, compared to clopidogrel, ticagrelor could significantly reduce the rate of MACEs (9.8% vs. 11.7%, p 0.001) with no rise in the total frequency of severe hemorrhage (11.6% vs. 11.2%, p = 0.43) [34]. However, the incidence rate of gastrointestinal bleeding was significantly increased (1.3% vs. 1.0%, p = 0.048) [35]. The GLOBAL LEADERS trial also demonstrated that the combination of PPI and ticagrelor monotherapy might be safe. Nevertheless, the utilization of PPIs was not randomized, and the unknown confounding factors should be considered [36]. In our study, only one included RCT with 86 patients compared the combination of PPI with aspirin and ticagrelor. They found a non-significant variation in MACEs incidence rate, while the incidence rate of gastrointestinal bleeding significantly declined [25]. For patients with high bleeding risk, de-escalation from ticagrelor to clopidogrel is common [37]. There is still an absence of adequate proof regarding the combination of PPI with aspirin and ticagrelor, and more studies are needed in the future [38].

It should be noted that although PPIs are used to reduce gastrointestinal outcomes such as gastrointestinal ulcers and upper gastrointestinal bleeding in high-risk patients [39], lower gastrointestinal complications might arise due to PPI use [40]. The first three months is the high-risk period for both upper and lower gastrointestinal hemorrhage in PCI patients undergoing DAPT, and the incidence of lower gastrointestinal hemorrhage is higher than that of upper gastrointestinal bleeding [41]. According to researchers, short-term (six months) DAPT followed by P2Y12 inhibitor monotherapy can lower the incidence of severe hemorrhage after PCI without elevating the risk of AMI [42]. In addition, the OPTION trial depicted that indobufen + clopidogrel DAPT, compared to aspirin + clopidogrel DAPT, significantly decreased gastrointestinal bleeding, thus meaning that the former may be a safer choice in the future [43]. Nevertheless, the OPT-PEACE study demonstrated that almost every patient who received single antiplatelet therapy (SAPT) or DAPT experienced a gastrointestinal injury; however, hemorrhage was uncommon [44]. SAPT and DAPT cause injuries in the upper and lower digestive tract. Washio et al. [45] indicated that PPIs raised the probability of short-term nonsteroidal anti-inflammatory drug-induced minor intestinal damage, possibly due to the altered luminal environment caused by the substantial inhibition of stomach acid secretion [45, 46]. The small-intestinal mucosal damage may be exacerbated by the altered microbiota [47].

There are, as yet, no effective preventive measures for lower gastrointestinal bleeding. During the use of DAPT, attention should be paid to monitoring patients’ symptoms, their fecal occult blood test results, and their blood routine. Therefore, although PPIs effectively reduce upper gastrointestinal complications, lower gastrointestinal complications might rise due to PPI use [40]. Taking these confounding factors into consideration, the true effect of PPIs on the whole DAPT-related gastrointestinal bleeding needs to be further verified with more RCTs [40]. Future studies can distinguish between lower and upper gastrointestinal bleeding via magnetically controlled capsule endoscopy and other new technologies.

The strengths of our research include a pre-registered process, a TSA for estimating sample size, and a GRADE assessment of the certainty of evidence. Nevertheless, it has certain drawbacks. First, the insufficient granularity regarding the types of DAPT (i.e., ticagrelor), the types of patients (i.e., patients at high risk of experiencing thrombosis and hemorrhage), and the types of PPIs (i.e., lansoprazole, esomeprazole, and rabeprazole) may affect risk adjustment. What is more, the incorporated investigations were heterogenous in some results regarding the various definitions of MACEs, gastrointestinal events, and gastrointestinal bleeding. Fortunately, the clinical heterogeneity was not reflected in statistically significant discrepancy among any of the desired results. Despite our efforts to restrict the analysis to studies that involved patients taking aspirin and clopidogrel or ticagrelor, one study [24] also enrolled patients who took prasugrel. However, even if included, these patients accounted for only 0.02% of the sample and would thus not be likely to critically affect the results. Though the TSA showed that the meta-analysis pool had sufficient studies (RIS = 6874) to reach 80% study power, we think more large-scale RCTs with other types of PPIs are still needed in the future to explore its effects on lower gastrointestinal bleeding.

In patients with coronary intervention, compared to DAPT, DAPT + PPI can significantly reduce gastrointestinal outcomes without affecting cardiovascular outcomes. DAPT + PPI has a significant protective effect on gastrointestinal ulcers and upper gastrointestinal bleeding, while to determine its protective impact on lower gastrointestinal bleeding, further large-scale studies are required.

All data generated or analyzed during this study are included in this published article.

All authors have contributed to the development of the research question and study design. SCL, MM, YHC and JZ developed the literature search. SCL, MM, YHC, JZ and JL performed the study selection. SCL, MM, YHC, JL, SLJ and YQW analysed the data. SCL, MM, YHC, JZ, JL, SLJ, YQW, HH and YH interpret the results and wrote the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

We would like to express our gratitude to all the peer reviewers for their opinions and suggestions.

This work was supported by the Applied and fundamental study of Sichuan Province (No. 2017JY0026), the Fellowship of China Postdoctoral Science Foundation (No. 2020M683325), the Post-Doctor Research Project, West China Hospital, Sichuan University (No. 2020HXBH048), the Innovative scientific research project of medical youth in Sichuan Province (No. Q20061), and the Key Research and the Development Programs of Sichuan Province (No. 2022YFS0357).

The authors declare no conflict of interest.