Proton pump inhibitors for gastrointestinal bleeding prevention after percutaneous coronary intervention: Comparing evidence in dual antiplatelet therapy

Abstract

BACKGROUND

Dual antiplatelet therapy (DAPT), combining aspirin with a P2Y12 inhibitor, is the standard of care following percutaneous coronary intervention (PCI), but it significantly increases the risk of gastrointestinal (GI) bleed. Proton pump inhibitors (PPIs) are commonly co-prescribed to mitigate this risk, though concerns about potential drug interactions, particularly with clopidogrel, have led to clinical uncertainty.

AIM

To evaluate the impact of PPI co-therapy on GI bleed, major bleed, upper and lower GI bleed, and all-cause mortality in patients receiving DAPT after PCI.

METHODS

A systematic literature search of PubMed, Cochrane Library, and Google Scholar was conducted through March 2025. Eligible studies included randomized controlled trials (RCTs) and observational studies reporting outcomes in adult patients receiving DAPT with or without PPI use. Primary outcomes included GI bleed, major bleed, upper and lower GI bleed, and all-cause mortality. A random-effects model was used to estimate pooled relative risks (RRs) with 95% confidence intervals (CIs).

RESULTS

Fourteen studies (6 RCTs and 8 observational studies) involving 106954 patients (101567 in observational studies; 5387 in RCTs) were included. RCTs found that PPI use was associated with a significantly reduced risk of overall GI bleed (RR = 0.39; 95%CI: 0.21-0.74; P = 0.004), with this effect being most prominent in omeprazole subgroup (RR = 0.45; 95%CI: 0.21-0.96; P = 0.04). Moreover, PPI use significantly lowered the risk of upper GI bleed in RCTs (RR = 0.50; 95%CI: 0.28-0.89; P = 0.02). In observational studies, the PPI group was associated with an increased risk of lower GI bleed (RR = 1.65; 95%CI: 1.31-2.06; P < 0.0001) and a decreased major bleed events (RR = 0.59; 95%CI: 0.48-0.72; P < 0.00001), these effects were not studied in RCTs. Observational studies failed to show any significant effect on all-cause mortality, total GI bleed, or upper GI bleed.

CONCLUSION

PPI co-therapy significantly reduces risk of overall GI bleed in DAPT-treated patients post-PCI. However, a modest increase in hypothesis-generated lower GI bleed found only in observational studies underscores the need for further studies to explore this association.

Key Words: Dual antiplatelet therapy; Percutaneous coronary intervention; Proton pump inhibitors; Gastrointestinal bleeding; All-cause mortality

Core Tip: Proton pump inhibitor (PPI) co-therapy remains an effective strategy for preventing upper gastrointestinal (GI) bleeding in patients receiving dual antiplatelet therapy after percutaneous coronary intervention. This systematic review and meta-analysis separately evaluated randomized trials and observational studies, demonstrating consistent protection against upper GI bleeding while highlighting differences in effect estimates across study designs. Observational findings regarding lower GI bleeding, major bleeding, and all-cause mortality should be interpreted cautiously because of lower certainty and potential confounding. These findings support current guideline recommendations for PPI use while emphasizing the need for further high-quality studies to clarify long-term safety and comparative efficacy among individual PPIs.

INTRODUCTION

Dual antiplatelet therapy (DAPT), combining aspirin with a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor), has become the cornerstone of management of acute coronary syndrome (ACS) especially those requiring percutaneous coronary intervention (PCI). Their role is furthermore defined in patients receiving drug-eluting stents. DAPT by inhibiting platelet activation and aggregation, significantly reduces the incidence of stent thrombosis and recurrent ischemic events. This benefit is pronounced during the early post-procedural period when thrombotic risk is highest. Current guidelines recommend 12 months of DAPT following PCI as a default strategy for all ACS patients, not at increased risk of bleed. While several strategies including shorter durations of 3 months to 6 months, ticagrelor monotherapy after 1 months of DAPT (for patients on aspirin and ticagrelor), or addition of a proton pump inhibitors (PPIs), can be employed for patients with increased risk of gastrointestinal (GI) bleed[1-4].

While DAPT improves cardiovascular outcomes, it substantially increases the risk of bleed, particularly GI bleed and intracranial hemorrhage[4]. Aspirin, in addition to its antiplatelet effect, contributes to mucosal injury by reducing protective prostaglandins, further elevating GI bleed risk[5]. This has prompted a shift toward individualized DAPT durations, especially in high-bleed-risk populations[6]. Recent trials, including SMART-DATE, STOPDAPT-2, and TWILIGHT, have shown that shortening DAPT to 1-3 months followed by monotherapy can reduce bleed complications without increasing the risk of major adverse cardiovascular events (MACE)[6-11].

To further minimize GI bleed, PPIs are often co-prescribed with DAPT. However, early concerns were raised about potential drug interaction, particularly with clopidogrel, due to competition for the cytochrome P450 2C19 metabolic pathway. Observational data, including findings from the PARIS registry, suggested a potential increase in MACE among patients using PPIs with DAPT and reported no significant reduction in bleed[12]. In contrast, more recent randomized trials and meta-analyses have not supported these concerns, showing no significant differences in cardiovascular outcomes and confirming the protective effect of PPIs against GI bleed[13,14].

Despite growing evidence, clinical uncertainty remains due to variability in study designs, populations, and outcome measures. As a result, the role of PPIs in patients on DAPT after PCI remains an area of ongoing debate. Therefore, this meta-analysis aims to provide a comprehensive assessment of the impact of PPI co-therapy on cardiovascular and bleed outcomes in patients receiving DAPT following PCI. By synthesizing current evidence, it seeks to clarify the safety and utility of PPIs in this setting and help inform clinical decision-making.

MATERIALS AND METHODS

Study design and objectives

This systematic review and meta-analysis was reported in accordance with preferred reporting items for systematic reviews and meta-analyses statement (Figure 1)[15]. The objective was to investigate the association between PPI use and the risk of GI bleed and cardiovascular outcomes in patients with ACS receiving DAPT following PCI. The analysis integrated data from both randomized controlled trials (RCTs) and observational studies comparing outcomes in PPI group vs non-users in this clinical context. The protocol for this meta-analysis was registered and published with PROSPERO (No. CRD42024605760).

Figure 1 Preferred reporting items for systematic reviews and meta-analyses flow diagram representing breakdown of screened and included studies. ¹Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). ²If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

Literature search and data sources

A structured search strategy was applied across PubMed, the Cochrane Library, and Google Scholar to identify studies published up to March 2025. The search combined MeSH terms and keywords to formulate a search string: “(Dual antiplatelet therapy OR DAPT OR clopidogrel OR ticagrelor) AND (proton pump inhibitor OR PPI OR pantoprazole OR omeprazole) AND (percutaneous coronary intervention OR drug-eluting stent OR PCI) AND (GI bleed OR GI bleed OR major bleed)”. Only clinical studies comparing patients on DAPT with and without PPI were included. Clinical trials.gov was searched to screen for ongoing studies using the following words: Dual antiplatelet therapy, DAPT, clopidogrel, ticagrelor, proton pump inhibitors, PPI, pantoprazole, omeprazole, percutaneous coronary intervention, drug eluding stents, PCI, GI bleed, GI bleed and major bleed.

Eligibility criteria and study selection

Only clinical studies (including both RCTs and observational studies) comparing patients on DAPT with and without PPI were included. Eligible studies enrolled adult patients (aged 18 years or older) with ACS who were treated with DAPT after PCI and reported clinical outcomes stratified by PPI use. These outcomes included primary outcomes- total GI bleed events, and secondary outcomes- upper GI bleeds, lower GI bleeds, major GI bleed events, and all-cause mortality. Studies were excluded if they lacked a comparator group, did not differentiate outcomes by PPI exposure, involved non-human subjects, or were not published in English. Title and abstract screening were conducted independently by two reviewers (Khattak R and Sohail R), followed by full-text assessment. Any disagreements were resolved through discussion or with input from a third reviewer (Khan Z).

Data collection and quality evaluation

Study characteristics and relevant outcome data were extracted using a predefined data collection form, formulated by the authors. Extracted variables included study design, population demographics, type and dose of PPI, DAPT regimen, duration of follow-up, and reported endpoint.

Risk of bias

The risk of bias was evaluated using the risk of bias tool (ROB-2) for RCTs and risk of bias in non-randomized studies of interventions (ROBINS-I) for observational studies[16-18]. Discrepancies in bias assessment were discussed among the authors until consensus was achieved.

Statistical analysis

Meta-analytic pooling was performed using a random-effects model to address potential heterogeneity among included studies. Risk estimates were presented as relative risks (RRs) with 95% confidence intervals (CIs). The I² statistic was used to quantify heterogeneity, with a threshold of > 50% indicating considerable heterogeneity[19]. Due to increased heterogeneity, subgroup analysis based on type of PPI was performed. Due to the limited number of included studies, funnel plot analysis for publication bias and meta-regression could not be performed. Statistical significance was defined as P < 0.05.

Certainty of evidence assessment

For evaluation of the certainty of the evidence, the grading of recommendations, assessment, development, and evaluation (GRADE) approach was used, and the quality of evidence of the pooled estimates was judged as high, moderate, low, or very low according to the GRADE Working Group[20,21].

Ethical statement

Since this study used only data from previously published literature, ethical approval and informed consent were not applicable.

RESULTS

This meta-analysis included a total of 106954 patients from 14 studies (6 RCTs and 8 observational studies) evaluating the effect of PPI co-therapy in patients receiving DAPT following PCI. Among these, 5387 patients were included in RCTs (PPI group: 2233 and non-PPI group: 3154) and 101567 were in observational studies (PPI group: 50074 and non-PPI group: 52493).

Baseline characteristics and risk of bias

Studies were divided into RCTs and observational studies for separate analysis. RCTs were conducted between years 2008 to 2020, with most of them centered in China. Although majority of the studies only used aspirin and clopidogrel combination, 1 study used ticagrelor instead of clopidogrel while 2 studies included patients of either of the two P2Y12 inhibitors, without subgroup analysis (Table 1).

Table 1 Baseline characteristics of included randomized controlled trials.

Ref.	Year	Country	Total patients (n)	PPI group (n)	Non-PPI group (n)	PPI used	DAPT agents used	Duration of study
Wei et al[25]	2016	China	207	123	84	Pantoprazole 40 mg	Aspirin and clopidogrel	6 months
Vaduganathan et al[24]	2016	Spain and United States	2676	870	1806	Omeprazole 20 mg	Aspirin and clopidogrel	110 days
Jensen et al[23]	2017	Denmark	2009	997	1012	Pantoprazole 40 mg	Aspirin and clopidogrel or ticagrelor	1 year
Zhang et al[27]	2020	China	86	43	43	Omeprazole	Aspirin and ticagrelor	6 months
Ren et al[26]	2011	China	172	86	86	Omeprazole	Aspirin and clopidogrel	30 days
Gao et al[22]	2008	China	237	114	123	Omeprazole	Aspirin and clopidogrel or ticagrelor	14 days

PPI: Proton pump inhibitor; DAPT: Dual antiplatelet therapy.

On the contrary, most of the observational studies included Korean population and were conducted between 2011 to 2025. Similarly, aspirin and clopidogrel was the combination used in most of the studies except for two (using both clopidogrel and ticagrelor groups) (Table 2). Funnel and traffic plots were also generated individually for the two types of studies (Figures 2 and 3).

Figure 2 Risk of bias assessment for randomized controlled trials. A: Summary plot; B: Risk-of-bias traffic plot.

Figure 3 Risk of bias assessment for observational studies. A: Summary Plot; B: Traffic plot.

Table 2 Baseline characteristics of included observational retrospective studies.

Ref.	Year	Country	Total patients (n)	PPI group (n)	Non-PPI group (n)	PPI used	DAPT agents used	Duration of study
Kang et al[31]	2025	Korea	71120	35560	35560	Non-selective PPI	PCI and DAPT	1 year
Kim et al[32]	2024	Korea	2266	1133	1133	Non-selective PPI	Aspirin and clopidogrel	15 years
Yamamoto et al[34]	2024	Japan	24563	11202	13361	Non-selective PPI	Aspirin plus clopidogrel or ticagrelor	3 years
Rossini et al[33]	2011	Italy	1328	1158	170	Omeprazole/pantoprazole/Lansoprazole	Aspirin and clopidogrel	12 months
Yasu et al[35]	2010	Japan	302	103	199	Rabeprazole	Aspirin and clopidogrel	395 days
Aihara et al[29]	2012	Japan	1000	500	500	Non-selective PPI	Aspirin and clopidogrel	1 year
Chitose et al[28]	2012	Japan	1270	331	939	Non-selective PPI	Aspirin and clopidogrel or ticagrelor	18 months
Häuptle et al[30]	2012	Switzerland	718	87	631	Non-selective PPI	Aspirin and clopidogrel	12 months

PPI: Proton pump inhibitor; DAPT: Dual antiplatelet therapy; PCI: Percutaneous coronary intervention.

GI bleed

Subgroup analysis by study design demonstrated that this protective effect was seen in RCTs, where PPI use was associated with a 63% reduction in GI bleed (RR = 0.39; 95%CI: 0.21-0.74; P = 0.004; I² = 46%)[22-27]. In contrast, observational studies showed a non-significant trend toward benefit with PPI group (RR = 0.00; 95%CI: -0.01 to 0.00; P = 0.27; I² = 73%), suggesting some heterogeneity in outcomes in the setting of observational studies related heterogeneity (Figure 4)[28-35].

Figure 4 Forest plot representing comparison of bleed risk among study and non-proton pump inhibitor groups. A: Randomized controlled trials (RCTs); B: RCTs and omeprazole; C: RCTs and pantoprazole; D: Observational studies only. PPI: Proton pump inhibitor; CI: Confidence interval.

RCT population was further divided into subgroups on the basis of type of PPI used. Omeprazole-only group showed significant protective effect against GI bleed with an RR of 0.45 (95%CI: 0.21-0.96; P = 0.04; I² = 34%)[22,24,26,27] (Figure 4). Pantoprazole group failed to show any significant protective benefit against GI bleed (RR = 0.28; 95%CI: 0.05-1.55; P = 0.15; I² = 77%) (Figure 4)[23,25]. The high heterogeneity in the pantoprazole group can be explained by diverse patient population and limited number of included studies.

Upper GI bleed

PPI use was significantly protective against upper GI bleed in RCTs, with a pooled RR of 0.50 (95%CI: 0.28-0.89; P = 0.02; I² = 0%)[22-24] (Figure 5). However, observational studies failed to show any association between PPI use and upper GI bleed (RR = 0.89; 95%CI: 0.16-5.02; P = 0.90; I² = 65%) (Figure 5)[30,35]. High risk of confounding in observational study design explains the significant heterogeneity. When RCT population was subdivided by the type of PPI use, omeprazole only population retained the protective benefit (RR = 0.42; 95%CI: 0.19-0.91; P = 0.03, I² = 0%)[22,24] (Figure 5).

Figure 5 Forest plot representing comparison of upper gastrointestinal bleed risk among study and non-proton pump inhibitor groups. A: Randomized controlled trials (RCTs); B: RCTs and omeprazole only; C: Observational studies. PPI: Proton pump inhibitor; CI: Confidence interval.

Observational studies only outcomes

Conversely, PPI use was associated with an increased risk of lower GI bleed in observational studies, with a pooled RR of 1.65 (95%CI: 1.31-2.06; P < 0.0001; I² = 0%). As the effect was only seen in observational studies with no supporting evidence from RCTs, results cannot be generalized (Figure 6A)[30,34,35]. Across the included observational studies, PPI group was significantly associated with a reduced risk of major bleed events. The pooled RR for major bleed was 0.59 (95%CI: 0.48-0.72; P < 0.00001; I² = 0%) (Figure 6B)[31,35]. There was no significant difference in all-cause mortality between patients (in observational studies) receiving PPI and those who did not (RR = 1.10; 95%CI: 0.75-1.63; P = 0.62; I² = 0%) (Figure 6C)[29,32,33].

Figure 6 Forest plot representing comparison of among study and non-proton pump inhibitor groups in observational studies. A: Lower gastrointestinal (GI) bleed; B: Major GI bleed; C: All-cause mortality. PPI: Proton pump inhibitor; CI: Confidence interval.

Certainty of evidence

GRADE analysis was performed on all the outcomes to determine the certainty of evidence (Table 3).

Table 3 Certainty of evidence assessment using grading of recommendations, assessment, development, and evaluation.

Certainty assessment							Number of patients		Effect		Certainty	Importance
Number of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	GI bleed-RCTs only	Placebo	Relative (95%CI)	Absolute (95%CI)
GI bleed-RCTs only
6	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	30/2564 (1.2%)	100/4093 (2.4%)	RR 0.37 (0.20-0.68)	15 fewer per 1000 (from 20 fewer to 8 fewer)	High	Critical
GI bleed-RCTs and omeprazole only
4	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	17/1113 (1.5%)	53/2058 (2.6%)	RR 0.45 (0.21-0.96)	14 fewer per 1000 (from 20 fewer to 1 fewer)	High	Critical
GI bleed- RCTs and pantoprazole
2	Randomized trials	Not serious	Not serious	Not serious	Serious3	None	12/1120 (1.1%)	30/1096 (2.7%)	RR 0.28 (0.05-1.55)	20 fewer per 1000 (from 26 fewer to 15 more)	Moderate1,2	Critical
GI bleed-observational only
8	Non-randomized studies	Serious1	Not serious	Not serious	Serious2	All plausible residual confounding would suggest spurious effect, while no effect was observed	737/49743 (1.5%)	965/51554 (1.9%)	RR 0.00 (-0.01 to 0.00)	5 fewer per 1000 (from 10 fewer to 1 more)	Very low1,2	Important
Upper GI bleed-RCTs only
3	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	16/1981 (0.8%)	37/2941 (1.3%)	RR 0.50 (0.28-0.89)	6 fewer per 1000 (from 9 fewer to 1 fewer)	High	Critical
2	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	8/984 (0.8%)	24/1929 (1.2%)	RR 0.42 (0.19-0.91)	7 fewer per 1000 (from 10 fewer to 1 fewer)	High	Critical
Upper GI bleed-observational studies only
2	Non-randomized studies	Serious1	Not serious	Not serious	Serious2	All plausible residual confounding would suggest spurious effect, while no effect was observed	17/190 (8.9%)	77/830 (9.3%)	RR 0.89 (0.16-5.02)	10 fewer per 1000 (from 78 fewer to 373 more)	Very low1,2	Critical
Lower GI bleed-observational studies only
3	Non-randomized studies	Serious1	Not serious	Not serious	Serious2	All plausible residual confounding would suggest spurious effect, while no effect was observed	170/11392 (1.5%)	146/14191 (1.0%)	RR 1.65 (1.31-2.06)	7 more per 1000 (from 3 more to 11 more)	Moderate1,2	Critical
Major bleed
2	Non-randomized studies	Serious1	Not serious	Not serious	Not serious	All plausible residual confounding would suggest spurious effect, while no effect was observed	141/35663 (0.4%)	240/35759 (0.7%)	RR 0.59 (0.48-0.73)	3 fewer per 1000 (from 3 fewer to 2 fewer)	Low1	Critical
All-cause mortality-observational studies only
3	Non-randomized studies	Serious1	Not serious	Not serious	Serious2	All plausible residual confounding would suggest spurious effect, while no effect was observed	70/2791 (2.5%)	43/1803 (2.4%)	RR 1.10 (0.75-1.63)	2 more per 1000 (from 6 fewer to 15 more)	Very low1,2	Important

¹Observational studies are prone to confounding, selection bias, and misclassification even if adjusted.

²95% confidence interval crosses the line of no effect (1.0), suggesting uncertainty.

³Wide confidence interval, almost crossing the line of non-effect.

CI: Confidence interval; RR: Relative risk; RCT: Randomized controlled trial; GI: Gastrointestinal.

DISCUSSION

Mechanism of interaction

This meta-analysis reinforces the protective role of PPIs among patients receiving DAPT following PCI. PPIs mitigate GI bleed primarily through profound acid suppression achieved by irreversible inhibition of the gastric hydrogen potassium adenosine triphosphatase[36]. This effect enhances mucosal healing, stabilizes hemostatic clots, and reduces acid-mediated mucosal injury[37,38]. Because aspirin and P2Y12 inhibitors impair prostaglandin-mediated mucosal defense and platelet aggregation, PPIs restore epithelial protection and reduce the risk of erosions and ulceration. These mechanisms collectively explain the substantial reduction in upper GI bleed observed across RCTs[39,40].

Upper vs lower GI bleed effects

PPIs exert their strongest protective effects in the upper GI tract, where acid suppression directly prevents mucosal injury and promotes healing of aspirin and clopidogrel-related erosions[31,41]. This benefit is consistently demonstrated in RCTs and endoscopic studies. Conversely, emerging data suggest a possible association between PPI use and an increased risk of lower GI bleed[27,29]. Proposed mechanisms include alterations in intestinal microbiota, small intestinal bacterial overgrowth, and reduced mucosal immune defense caused by chronic hypochlorhydria. However, this finding is based exclusively on observational studies, which are prone to detection bias and unmeasured confounding[42]. Accordingly, the evidence supporting this association is of lower certainty and should be interpreted cautiously. Additional prospective studies are needed before a causal relationship can be established. Importantly, these findings should not detract from the well-established benefits of PPIs in preventing upper GI bleed in patients receiving DAPT after PCI[43].

Discussion of observational outcomes

Several outcomes, including lower GI bleed, major bleed, and all-cause mortality, were evaluated exclusively in observational studies. While these analyses provide valuable real-world insights, they are inherently susceptible to residual confounding, confounding by indication, and selection bias. Consequently, the certainty of evidence for these outcomes is lower than that supporting the reduction in upper GI bleed demonstrated in RCTs. These findings should therefore be interpreted cautiously and considered hypothesis-generating rather than definitive evidence of treatment effect. Future prospective studies and randomized trials are needed to better define the impact of PPI group on these outcomes.

Discrepancy between RCTs and observational studies

A key observation in this analysis is the stronger and more consistent gastroprotective effect seen in RCTs compared with observational studies. This discrepancy likely arises from differences in study design, population characteristics, and control of confounders. RCTs employ randomization and standardized protocols, ensuring balanced baseline risk and adherence, thereby providing a more accurate estimate of therapeutic efficacy. In contrast, observational studies often include patients at inherently higher bleed risk, as PPIs are more likely to be prescribed to older individuals and those with multiple comorbidities or prior GI disease. This confounding by indication may attenuate the apparent protective effect of PPIs despite statistical adjustment.

Additional differences in medication adherence, follow-up duration, and outcome reporting likely contribute to the heterogeneity observed across observational studies. Furthermore, outcomes such as lower GI bleed, major bleed, and all-cause mortality were evaluated exclusively in observational studies, limiting the certainty of these findings. Consequently, these results should be viewed as hypothesis-generating rather than definitive evidence and interpreted within the context of their observational design.

Moreover, an important consideration when interpreting these findings is the geographic distribution of the included studies. Most RCTs were conducted in China, while the observational studies predominantly originated from Korea. Although the mechanisms underlying PPI-mediated acid suppression are unlikely to differ substantially across populations, variations in genetic polymorphisms affecting PPI metabolism (particularly CYP2C19), Helicobacter pylori prevalence, dietary habits, baseline GI bleeding risk, and antiplatelet prescribing practices may influence both efficacy and safety outcomes. Consequently, caution should be exercised when generalizing these results to more diverse populations, particularly those from Western countries. Additional multinational randomized and real-world studies are needed to validate the consistency of these findings across different ethnic and geographic populations.

Finally, while subgroup analyses suggested a statistically significant reduction in upper GI bleed among studies evaluating omeprazole, the absence of statistical significance in the pantoprazole subgroup should not be interpreted as evidence of inferior efficacy. The limited number of studies and wide CIs reduce the precision of these estimates, and the available data are insufficient to conclude that one PPI is superior to another.

Subgroup analysis: Omeprazole vs pantoprazole

Concerns about PPIs diminishing clopidogrel efficacy via CYP2C19 inhibition have not been substantiated by randomized evidence[44,45]. While early observational data suggested higher cardiovascular risk, this likely reflected confounding, as higher-risk patients were preferentially prescribed PPIs. Large RCTs and pharmacodynamic studies consistently show no increase in ischemic events or mortality, and newer P2Y12 inhibitors not reliant on CYP2C19 further mitigate this theoretical interaction[41,46].

Subgroup analysis revealed that the gastroprotective benefit of PPIs was primarily driven by omeprazole-based regimens, with pantoprazole demonstrating a less pronounced or statistically nonsignificant effect. This difference may reflect pharmacokinetic and pharmacodynamic variability rather than true clinical divergence. Off note this impact of both omeprazole and pantoprazole was based on small number of trials, limiting the generalizability of outcomes. Omeprazole achieves more consistent intragastric potential of hydrogen elevation, while pantoprazole’s weaker inhibition of CYP2C19 may reduce theoretical drug-drug interactions but provide less potent acid suppression. In light of smaller number of studies in the pantoprazole group and wide CI, the current data seems insufficient and should be interpreted with caution as this lack of evidence seems insufficient to support definitive conclusion. Nevertheless, head-to-head comparisons are limited, and the apparent superiority of omeprazole should be interpreted cautiously pending further direct comparative trial.

Stratification by dosage and duration

The existing evidence do not stratify PPI based on their dosage or total duration of treatment, therefore subgroup analysis on this basis was not possible. Furthermore, due to limited number of papers in each group (less than 10) meta-regression and funnel-plots were not possible.

Clinical implications

The protective effect of PPIs against upper GI bleed in patients receiving DAPT after PCI has been established in previous randomized trials and earlier meta-analyses. However, important uncertainties remain regarding the consistency of this benefit across different study designs, the comparative findings from randomized vs observational evidence, and the potential effects on lower GI bleed and other clinically relevant outcomes.

The present meta-analysis addresses these gaps by integrating both RCTs and observational studies while analyzing them separately to preserve methodological validity. This approach allows direct comparison of efficacy estimates across study designs, provides a comprehensive assessment of both upper and lower GI bleed outcomes, and incorporates recently published evidence unavailable to prior reviews. Additionally, the subgroup analyses by PPI type and the formal assessment of evidence certainty using ROB-2, ROBINS-I, and GRADE provide a more nuanced interpretation of the available literature. Collectively, these findings strengthen the evidence supporting PPI co-therapy for prevention of upper GI bleed while emphasizing the lower certainty surrounding observational outcomes and the need for further high-quality research.

Alignment with existing literature and guidelines

The findings of this analysis align with prior evidence and are consistent with current international recommendations. Both the European Society of Cardiology and the American College of Cardiology/American Heart Association endorse PPI use for patients at elevated GI bleed risk receiving DAPT as a class 1A recommendation, a recommendation echoed by the American College of Gastroenterology[1,4,5,47-50]. Moreover, the analysis from RCTs have not shown significant difference in ischemic events in omeprazole users[51]. The apparent discordance between RCTs and observational findings likely reflects real-world prescribing behaviors and incomplete implementation of guideline-directed gastroprotection. Taken together, these data reaffirm that PPIs remain an effective and safe strategy to reduce bleed complications without compromising cardiovascular efficacy when used judiciously and tailored to patient[52].

Limitations

This meta-analysis has some limitations that should be considered when interpreting the findings. First, notable heterogeneity was observed among included studies with respect to design, sample size, population characteristics, follow-up duration, and outcome definitions. Although random-effects modeling was applied to mitigate variability, residual heterogeneity may still influence the pooled estimates. Second, several important outcomes, including lower GI bleed, major bleed, and all-cause mortality, were reported exclusively in observational studies, which are inherently susceptible to confounding, selection bias, and inconsistent endpoint reporting. Third, stratified analyses by specific PPI type, dosage, or adherence were limited, which may have affected subgroup comparisons between omeprazole and pantoprazole. Fourth, publication bias and incomplete adjustment for concomitant medications, such as anticoagulants and nonsteroidal anti-inflammatory drugs, may have further influenced outcomes. Finally, given the limited number of eligible studies per outcome, meta-regression analysis was not feasible, precluding a detailed exploration of sources of heterogeneity or effect modifiers. Despite these limitations, this study provides valuable pooled evidence supporting the gastroprotective benefit and cardiovascular safety of PPIs in patients receiving DAPT, while underscoring the need for large prospective trials to confirm these associations.

CONCLUSION

In conclusion, PPI co-therapy significantly reduces GI bleed risk among patients receiving DAPT after PCI, without compromising cardiovascular safety. The protective effect appears most pronounced in the upper GI tract, particularly with omeprazole-based regimens. Although observational data suggest potential increases in lower GI bleed and variability across studies, these findings remain exploratory given inherent design limitations. Overall, PPIs represent an effective and safe adjunctive strategy for bleed prevention in high-risk patients on DAPT. Future large-scale randomized trials are warranted to confirm real-world observations, clarify the impact of specific PPI agents, and further define optimal gastroprotective strategies in this population.