Antiplatelet therapy is now the standard treatment for patients who have percutaneous coronary intervention (PCI). After a balloon injury and the insertion of a stent, the inner layer of the blood vessel at that location becomes damaged. This leads to the activation of both the coagulation cascade and platelets (1, 2). After PCI, a key focus is on preventing blood clots in the newly widened arteries, which is where medications such as clopidogrel come into play. Clopidogrel is an antiplatelet drug, essential in post-PCI management. It works by inhibiting platelets in the blood from clumping together to form clots. This action is particularly important in patients who have had stents placed during PCI, as stents increase the risk of clot formation within the artery (3).

Clopidogrel, usually taken in combination with aspirin, significantly reduces the risk of stent thrombosis, a serious complication where a blood clot forms on the stent, potentially leading to major cardiovascular events (MACEs) (4). The duration of clopidogrel therapy can vary based on the type of stent used and the patient's overall risk profile. Recent advancements in drug-eluting stents have influenced the recommended length of clopidogrel therapy (5). Continuous monitoring and follow-up are essential to manage any side effects of clopidogrel, such as bleeding risk, and to adjust treatment plans as needed for the individual patient. The goal is to balance the prevention of clotting with the risk of excessive bleeding, optimizing patient outcomes post-PCI (6).

To alleviate these side effects, PPIs such as esomeprazole, lansoprazole, pantoprazole, omeprazole, and rabeprazole have been introduced. PPIs are a class of medications widely used to treat conditions caused by excessive stomach acid production. They work by irreversibly blocking the hydrogen/potassium ATPase enzyme system of the gastric parietal cells, effectively reducing gastric acid secretion. PPIs are primarily used to manage gastroesophageal reflux disease (GERD), peptic ulcers, and Zollinger–Ellison syndrome (7). They are also prescribed to prevent and treat gastric ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs) and to eradicate Helicobacter pylori infections in combination with antibiotics.

Combining PPIs with clopidogrel is beneficial for reducing the risk of GI bleeding in patients undergoing antiplatelet therapy. PPIs effectively decrease stomach acid, protecting the GI lining from damage, while clopidogrel prevents blood clots. The coadministration of antiplatelet agents and PPI is often a clinical choice for physical due to a decrease in the risk of GI bleeding (8). However, there are concerns about the potential interaction between clopidogrel and PPIs. The main concern is that both drugs use the same metabolic enzyme CYP2C19. PPIs might impede the conversion of clopidogrel into its active form through CYP2C19. This could result in lower blood levels of the active metabolite and possibly diminish clopidogrel's effectiveness in preventing platelet aggregation (9). It is noteworthy that different PPIs utilize different liver enzymes for metabolism. Due to the drug–drug interaction (DDI) concerns, the choice of PPI and clopidogrel should always be cautious. To figure out the effect of MACEs on coadministration in different PPIs with clopidogrel is important. Our study aims to determine which specific PPIs, when coadministered with clopidogrel, might have the lowest MACEs and GI bleeding risk.

We executed this study following the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) extension for network meta-analysis (PRISMA NMA) (10). The study has been registered on INPLASY under the registration number INPLASY2024-2-0009 (11). The approval from the ethical review board or securing informed consent from participants was unnecessary.

Our study results showed that the coadministration of esomeprazole, lansoprazole, pantoprazole, and omeprazole with clopidogrel significantly increased the risk of MACEs compared to using clopidogrel alone. However, when rabeprazole was coadministered with clopidogrel, there was no significant difference in MACEs compared to the placebo group. In the secondary analysis, the combination of esomeprazole, omeprazole, and pantoprazole with clopidogrel significantly reduced the risk of GI bleeding compared to clopidogrel alone. In contrast, the combinations of lansoprazole and rabeprazole with clopidogrel did not show a significant reduction in GI bleeding risk compared to the placebo group.

Clopidogrel, commonly combined with aspirin, has been a standard treatment post-PCI. Prior research has indicated that clopidogrel, when used as a post-PCI medication, is effective in preventing cardiovascular (CV) events, death, or thrombosis. However, the use of dual antiplatelet therapy or prolonged antiplatelet treatment significantly increases the risk of GI bleeding (36–38). To address this, PPIs have been recommended as a co-treatment with clopidogrel to reduce GI bleeding risk (39). However, it is widely known that clopidogrel and PPIs are both metabolized by the same liver enzyme, resulting in a significant DDI. Clopidogrel is a prodrug that initially needs to be metabolized by liver enzymes CYP1A2, CYP2C19, and CYP2B6 to form the intermediate compound 2-oxo-clopidogrel. In the second metabolic phase, 2-oxo-clopidogrel is further processed by enzymes CYP3A4/5, CYP2C9, CYP2C19, and CYP2B6 to become its active form, inhibiting platelet aggregation (40). The CYP2C19 plays a critical role in both phases of forming the active compound of clopidogrel, and then PPIs inhibit the CYP2C19 enzyme. Unlike clopidogrel, prasugrel requires only one hepatic CYP450-dependent metabolism step to convert to its active metabolite, involving CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Therefore, its anti-aggregation effect is less likely to be affected by CYP2C19 inhibitors. Ticagrelor binds to the ADP receptor at a different site than ADP, acting as an allosteric antagonist. It inhibits ADP-induced P2Y12 receptor signaling non-competitively and does not require metabolic activation to produce its active metabolite (41). A previous in vivo RCT study also demonstrated that for patients with AMI undergoing primary PCI, omeprazole reduced the incidence of gastrointestinal bleeding without diminishing ticagrelor's antiplatelet aggregation effect or increasing the risk of MACEs (42).

The extent of interaction between specific PPIs and clopidogrel remains a topic of debate (43). Our study aims to use network meta-analysis to identify the specific PPI least associated with MACEs and also had GI bleeding prevention.

PPIs are mainly metabolized by CYP2C19 and can inhibit this enzyme. The degree and duration of CYP2C19 inhibition vary among individual PPIs (44). Studies have shown distinct mechanisms among different PPIs. Lansoprazole and pantoprazole, being direct-acting inhibitors, can directly inhibit CYP2C19 and have a short elimination half-life, possibly having a less significant impact on clinical MACE risk. However, lansoprazole has been shown to strongly inhibit CYP2C19 in vitro, leading to controversy in findings. Omeprazole and esomeprazole irreversibly inhibit CYP2C19 at low concentrations through NADPH coenzyme assistance, known as metabolism-dependent inhibitors (MDIs) (45). Both of them were thought to be strong CYP2C19 inhibitors to interfere with clopidogrel’s turn to active form. Rabeprazole, which is believed to be metabolized not only through CYP enzyme-mediated pathways but also via non-enzymatic routes, is considered to have a lesser impact on clopidogrel (46). Ilaprazole, a new PPI, is believed to have a limited effect on the pharmacodynamics of clopidogrel, suggesting it may not be clinically relevant according to in vitro studies (47). Our study observed that only the combination of rabeprazole and clopidogrel did not significantly increase the risk of MACEs compared to placebo. In contrast, omeprazole, esomeprazole, pantoprazole, and lansoprazole all showed a significant increase in MACE risk. Notably, the combination of lansoprazole and clopidogrel was associated with the highest increase in MACE risk.

In recent years, attention has turned to how genetic differences can influence drug metabolism. Clopidogrel is a notable example, with its metabolism varying across races. Studies have revealed significant racial differences in clopidogrel metabolism. Genetic mutations, such as the single nucleotide variations in CYP2C19*2 and CYP2C19*3 compared to the CYP2C19*1, result in poor metabolism of clopidogrel due to reduced enzyme activity (48). Asian populations (12%–100%) more frequently exhibit these poor metabolizers (PM) of CYP2C19 genotypes compared to Caucasians and Africans (3%–5%) (49). Patients with these mutations have significantly reduced clopidogrel antiplatelet efficacy and a higher risk of CV events than those with normal genotypes (50). Interestingly, while there have been studies on CYP2C19 variations across races, there is a few of research on the pharmacokinetics and pharmacodynamics of clopidogrel–PPI co-metabolism across different racial groups and the effect of different CYP2C19 genotype impacted (51, 52). Recent meta-analyses found no significantly increased MACEs in groups without CYP2C19 variant alleles when any PPI was coadministrated with clopidogrel. In contrast, those with CYP2C19 variant alleles showed a significant increase in MACEs (53). To summarize, while some studies recommend PPIs with clopidogrel, especially for high bleeding risk populations, this may be controversial for Asian populations with a higher prevalence of variant alleles, potentially leading to more frequent MACEs.

Clopidogrel is a crucial drug used for patients post-PCI treatment. While clopidogrel reduces the risk of MACEs, it carries the potential side effect of GI bleeding, with patients at high risk of GI bleeding requiring careful consideration as guideline recommendations (9). Long-term use of antiplatelet agents can notably increase the risk of GI bleeding, particularly with dual antiplatelet therapy. In patients with a history of prior GI bleeding, Helicobacter pylori infection, or concurrent use of other drugs such as antiplatelets, anticoagulants, corticosteroids, or NSAIDs, the risk of GI bleeding may be further heightened. For these populations, combining PPIs with antiplatelet agents could be a strategy to mitigate GI bleeding risk (9). In our analysis of secondary outcomes, it was observed that lansoprazole and rabeprazole, when coadministered with clopidogrel, did not significantly enhance GI bleeding prevention compared to the group receiving clopidogrel alone. On the other hand, omeprazole, esomeprazole, and pantoprazole demonstrated a significant reduction in GI bleeding incidents compared to the placebo group. The esomeprazole combined with clopidogrel could reduce the most GI bleeding risk.

Another factor we should though about is the influence of the PPI dosage. Although our study and previous studies had shown that omeprazole and esomeprazole coadministrated with clopidogrel increased MACEs, studies by Yano et al. (omeprazole 10 mg) and Ng et al. (esomeprazole 20 mg) suggested that lower doses of PPIs might not increase the risk of MACEs while still providing bleeding protection. In our study, although the combination of esomeprazole or omeprazole with clopidogrel appeared to increase the risk of MACEs, both PPIs significantly reduced GI bleeding. Future research should aim to determine whether lower doses of omeprazole and esomeprazole can effectively prevent GI bleeding without increasing the risk of MACEs.

Our study has some limitations. Firstly, our primary objective was to assess the risk of MACEs, but there was variability in the definition of MACEs across the studies we analyzed. While most included myocardial infarction (MI), stroke, and/or cardiovascular death, some also considered other conditions (such as thrombosis). Secondly, the duration of follow-up in our studies varied widely, ranging from a minimum of one month to several years. Different follow-up durations post-PCI can indicate varying levels of MACE risk. Additional limitations included as follows: (1) The included studies varied in patient characteristics, such as a history of previous GI bleeding, Helicobacter pylori infection, and so on, which could increase bleeding risk when using clopidogrel. (2) The absence of data on the CYP2C19 genotypes. There is a need for further randomized, high-quality studies in this area.

In our network meta-analysis, we discovered that the combination of lansoprazole, pantoprazole, esomeprazole, and omeprazole with clopidogrel might increase the risk of major adverse cardiac events (MACEs). However, coadministration of rabeprazole with clopidogrel did not appear to significantly impact MACE risk. We also noted that using omeprazole, esomeprazole, and pantoprazole concurrently with clopidogrel could significantly reduce the risk of gastrointestinal (GI) bleeding compared to using clopidogrel alone. However, using rabeprazole and lansoprazole did not reduce GI bleeding risk in post-PCI patients. Lansoprazole combined with clopidogrel significantly increased MACEs and without GI bleeding protection function in post-PCI patients. Our study was the first network meta-analysis study to figure out the best regiment when concurrent clopidogrel with individual PPI. However, further randomized and high-quality studies are necessary to substantiate this conclusion.