Long-Term Effects of Proton Pump Inhibitors in Patients Undergoing Percutaneous Coronary Intervention in High-Risk Subgroups

Abstract

Background: Proton pump inhibitors (PPIs) reportedly reduce upper gastrointestinal bleeding (UGIB) in patients undergoing percutaneous coronary intervention (PCI). However, whether the benefits of PPIs differ in high-risk subgroups is unknown.

Methods and Results: Among 24,563 patients undergoing first PCI in the CREDO-Kyoto registry Cohort-2 and -3, we evaluated long-term effects of PPI for UGIB, defined as GUSTO moderate/severe bleeding, in several potential high-risk subgroups. In the study population, 45.6% of patients were prescribed PPIs. Over a median 5.6-year follow-up, PPIs were associated with lower adjusted risk of UGIB (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.50–0.80; P<0.001) and a non-significant but numerically lower risk of any gastrointestinal bleeding (HR 0.84; 95% CI 0.71–1.01; P=0.06). PPIs were not associated with a lower risk of GUSTO moderate/severe bleeding (HR 1.04; 95% CI 0.94–1.15; P=0.40) or a higher adjusted risk of myocardial infarction or ischemic stroke (HR 1.00; 95% CI 0.90–1.12; P=0.97), but were associated with higher adjusted mortality risk (HR 1.18; 95% CI 1.09–1.27; P<0.001). The effects of PPIs for UGIB, myocardial infarction or ischemic stroke, and all-cause death were consistent regardless of age, sex, acute coronary syndrome, high bleeding risk, oral anticoagulant use, and type of P2Y₁₂ inhibitor.

Conclusions: PPIs were associated with a lower risk of UGIB and a neutral risk of ischemic events regardless of high-risk subgroup.

Bleeding is a common complication in patients who undergo percutaneous coronary intervention (PCI), because antiplatelet therapy is mandatory to prevent ischemic events.^1,2 The most common bleeding in patients who undergo PCI is gastrointestinal bleeding.^1,2 Previous randomized controlled trials and meta-analysis have suggested that proton pump inhibitors (PPIs) reduced upper gastrointestinal bleeding (UGIB) without increasing cardiovascular events in patients with coronary artery disease (CAD) receiving dual antiplatelet therapy (DAPT).^3–5 In US guidelines, PPI therapy is a Class IIa recommendation for patients with CAD taking DAPT, whereas in European and Japanese guidelines PPIs are a Class I recommendation for patients with CAD taking DAPT at high risk of gastrointestinal bleeding.^6–8 The position paper of the National Association of Hospital Cardiologists and the Italian Association of Hospital Gastroenterologists and Endoscopists recommends PPI therapy in patients taking DAPT, or in patients on single antiplatelet therapy at high risk of gastrointestinal bleeding.⁹ However, it remains unclear whether there are some subgroups of patients undergoing PCI in which the benefits of PPI are particularly prominent for reducing UGIB. Therefore, the aim of the present study was to evaluate the effects of PPIs on bleeding and ischemic events, including several subgroup analyses in potentially high-risk populations, in patients who underwent PCI using a large Japanese observational database with long-term follow up.

Methods

Study Design

The CREDO-Kyoto PCI/CABG (Coronary Revascularization Demonstrating Outcome Study in Kyoto Percutaneous Coronary Intervention/Coronary Artery Bypass Grafting) registry Cohort-2 and Cohort-3 were physician-initiated, non-company-sponsored, multicenter registries enrolling consecutive patients who underwent first coronary revascularization with PCI or isolated coronary artery bypass grafting (CABG) without combined non-coronary surgery in the first-generation drug-eluting stent era (January 2005–December 2007) for Cohort-2 and in the new-generation drug-eluting stent era (January 2011–December 2013) for Cohort-3 (Supplementary Appendix).^10,11 The design and patient enrollment of the registries have been described previously.^10,11 Of the 30,257 patients enrolled in the registries (Cohort-2, n=15,330; Cohort-3, n=14,927), we excluded patients who refused to take part in the study (Cohort-2, n=99; Cohort-3, n=60), patients who underwent CABG (Cohort-2, n=2,173; Cohort-3, n=1,609), and patients who died in hospital death or experienced major bleeding (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) moderate or severe bleeding), and ischemic events (myocardial infarction [MI] or ischemic stroke; Cohort-2, n=836; Cohort-3, n=917); thus, the present study population consisted of 24,563 patients who underwent first PCI without in-hospital bleeding and ischemic events. We evaluated prescription for PPIs at the time of discharge from the index hospitalization for coronary revascularization. In the present study, we compared long-term clinical outcomes between patients with and without PPI therapy after the index hospitalization for coronary revascularization.

The present study was performed in accordance with the Declaration of Helsinki and was approved by the relevant ethics committees in all participating centers. Because of the retrospective enrollment of patients to the study, the requirement for written informed consent was waived; however, we excluded those patients who refused study participation when contacted for follow up. This strategy is concordant with the guidelines of the Japanese Ministry of Health, Labour, and Welfare.

Outcome Measures

The primary bleeding outcome measure was major UGIB, defined as GUSTO moderate or severe bleeding.¹² UGIB included overt bleeding of gastroduodenal origin confirmed by upper endoscopy or radiography, and overt UGIB of unknown origin (e.g., confirmed by melena). The primary ischemic outcome measure was a composite of MI or ischemic stroke. MI was adjudicated according to the Arterial Revascularization Therapies Study definition.¹³ Stroke was defined as stroke with neurological symptoms lasting >24 h. Secondary outcomes measures and their definitions are provided in the Supplementary Appendix. Persistent discontinuation of DAPT was defined as withdrawal of the P2Y₁₂ inhibitor or aspirin for at least 2 months.^10,11

Data Collection

Clinical, angiographic, and procedural data and medications were collected from hospital charts or hospital databases according to prespecified definitions by experienced clinical research coordinators belonging to an independent Clinical Research Organization (Research Institute for Production Development, Kyoto, Japan; Supplementary Appendix). Follow-up data were collected from hospital charts and/or obtained by contacting patients, their relatives, or referring physicians. All outcome measures were adjudicated by the Clinical Event Committee (Supplementary Appendix).

Statistical Analysis

Categorical variables are presented as numbers and percentages, and were compared using the Chi-squared test. Continuous variables are presented as the mean±SD or median with interquartile range (IQR). Continuous variables were compared using the t-test or Wilcoxon rank-sum test depending on their distribution. Cumulative incidences of outcome measures in patients with and without PPI therapy were estimated using the Kaplan-Meier method, and differences were assessed using the log-rank test. In addition, cumulative incidences were estimated according to the type of PPI among patients with PPI therapy, and differences were assessed using the log-rank test. The effects of PPI therapy relative to no PPI therapy for the outcome measures were estimated using Cox proportional hazard models, and are expressed as hazard ratios (HRs) with their 95% confidence intervals (CIs). Adjusted HRs were estimated by the multivariable Cox proportional hazard models adjusting for 37 clinically relevant factors listed in Table 1 in addition to participating center and “study” (i.e., CREDO-Kyoto Cohort-2 vs. Cohort-3), which were included as stratification variables. For gastrointestinal bleeding (bleeding site unknown) and definite stent thrombosis, we constructed a parsimonious model to avoid overfitting with use of 10 risk-adjusting variables (age ≥75 years, male sex, acute coronary syndrome, hypertension, prior MI, estimated glomerular filtration rate <30 mL/min/1.73 m² or hemodialysis, atrial fibrillation, hemoglobin <11.0 g/dL, platelet count <100×10⁹/L, malignancy) due to the small number of patients with events.

Table 1.

Baseline Characteristics

	PPI (n=12,018)	No PPI (n=14,298)	P value
Type of PPI
Omeprazole	1,151 (10.3)	0 (0)	–
Lansoprazole	6,404 (57.2)	0 (0)	–
Rabeprazole	2,434 (21.7)	0 (0)	–
Esomeprazole	1,243 (11.1)	0 (0)	–
Clinical characteristics at index PCI
Age (years)	69.5±11.3	68.3±11.1	<0.001
Age ≥75 yearsA	4,305 (35.8)	4,448 (31.1)	<0.001
Male sexA	8,599 (71.6)	10,459 (73.2)	0.004
BMI (kg/m2)	23.6±3.6	23.9±3.6	<0.001
BMI <25.0 kg/m2 A	8,288 (69.0)	9,568 (66.9)	<0.001
Acute coronary syndromeA	5,924 (49.3)	5,195 (36.3)	<0.001
Acute MI	5,522 (45.9)	4,515 (31.6)	<0.001
Unstable angina	402 (3.3)	680 (4.8)
HypertensionA	9,883 (82.2)	11,721 (82.0)	0.59
DiabetesA	4,493 (37.4)	5,447 (38.1)	0.24
On insulin therapy	1,002 (8.3)	1,082 (7.6)	0.02
Current smokingA	3,513 (29.2)	4,308 (30.1)	0.11
Heart failureA	3,005 (25.0)	2,724 (19.1)	<0.001
LVEF (%)	57.9±13.1	59.1±13.0	<0.001
LVEF ≤40%	1,122 (10.8)	1,151 (9.6)	0.003
Mitral regurgitation grade ≥3/4	704 (6.3)	710 (5.2)	<0.001
Prior MIA	1,358 (11.3)	1,472 (10.3)	0.01
Prior strokeA	1,434 (11.9)	1,649 (11.5)	0.32
Peripheral vascular diseaseA	1,007 (8.4)	1,166 (8.2)	0.51
eGFR <30 mL/min/1.73 m2 or HD	1,198 (10.0)	989 (6.9)	<0.001
eGFR <30 mL/min/1.73 m2, without HDA	625 (5.2)	488 (3.4)	<0.001
HDA	573 (4.8)	501 (3.5)
Atrial fibrillationA	1,200 (10.0)	1,200 (8.4)	<0.001
Hemoglobin <11.0 g/dLA	1,670 (13.9)	1,475 (10.3)	<0.001
Platelet count <100×109/LA	236 (2.0)	221 (1.5)	0.01
COPDA	482 (4.0)	510 (3.6)	0.06
Liver cirrhosisA	293 (2.4)	377 (2.6)	0.31
MalignancyA	1,393 (11.6)	1,469 (10.3)	0.001
History of gastrointestinal bleedingB	308 (3.8)	101 (2.4)	<0.001
ARC-HBR	5,972 (49.7)	6,005 (42.0)	<0.001
Procedural characteristics of index PCI
No. target lesions	1.5±0.8	1.4±0.8	<0.001
Target of proximal LADA	7,187 (59.8)	8,281 (57.9)	0.002
Target of unprotected LMCAA	521 (4.3)	548 (3.8)	0.04
Target of chronic total occlusionA	1,194 (9.9)	1,657 (11.6)	<0.001
Target of bifurcationA	4,595 (38.2)	4,851 (33.9)	<0.001
Bifurcation with 2 stentsA	511 (4.3)	627 (4.4)	0.60
Total no. stents	1.9±1.4	1.8±1.3	0.10
Total stent length (mm)	41.4±32.6	39.7±30.2	<0.001
Total stent length >28 mmA	5,739 (50.0)	6,458 (48.2)	0.01
Minimum stent size (mm)	2.9±0.5	2.9±0.5	0.004
Minimum stent size <3.0 mmA	5,717 (49.8)	6,298 (47.0)	<0.001
DES use	8,504 (74.1)	8,618 (64.3)	<0.001
New-generation DES use	6,726 (58.6)	3,457 (25.8)	<0.001
IVUS or OCT useA	7,754 (64.5)	7,486 (52.4)	<0.001
Radial approach	4,411 (36.8)	4,685 (32.9)	<0.001
Staged PCIA	2,612 (21.7)	2,755 (19.3)	<0.001
Medication at discharge
P2Y12 inhibitorA	11,824 (98.4)	13,904 (97.2)	<0.001
Ticlopidine	2,779 (24.8)	8,321 (62.3)	<0.001
Clopidogrel	8,187 (73.1)	4,717 (35.3)	<0.001
Unknown	75 (0.7)	67 (0.5)	0.08
AspirinA	11,948 (99.4)	14,028 (98.1)	<0.001
CilostazolA	945 (7.9)	1,924 (13.5)	<0.001
StatinsA	8,781 (73.1)	8,181 (57.2)	<0.001
High-intensity statins	188 (1.6)	207 (1.4)	0.44
β-blockersA	4,763 (39.6)	4,415 (30.9)	<0.001
ACEi/ARBA	7,925 (65.9)	8,218 (57.5)	<0.001
Calcium channel blockersA	4,459 (37.1)	6,008 (42.0)	<0.001
Oral anticoagulantsA	1,348 (11.2)	1,129 (7.9)	<0.001
Warfarin	1,210 (10.1)	1,086 (7.6)	<0.001
DOAC	139 (1.2)	44 (0.3)	<0.001
Histamine H2 receptor blockersA	99 (0.8)	4,955 (34.7)	<0.001
Study
Cohort-2	3,370 (28.0)	9,688 (67.8)	<0.001
Cohort-3	8,648 (72.0)	4,610 (32.2)

Continuous variables are expressed as the mean±SD. Categorical variables are expressed as number (percentage). Values were missing for LVEF in 3,505 patients, for mitral regurgitation in 1,366 patients, and for the radial approach in 90 patients. ^ARisk-adjusting variables selected for the Cox proportional hazard models. ^BHistory of gastrointestinal bleeding was only collected in the CREDO-Kyoto registry Cohort-3. ACE-i, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; ARC-HBR, Academic Research Consortium for High Bleeding Risk; BMI, body mass index; COPD, chronic obstructive pulmonary disease; DES, drug-eluting stent; DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate; HBR, high bleeding risk; HD, hemodialysis; IVUS, intravascular ultrasound; LAD, left anterior descending coronary artery; LMCA, left main coronary artery; LVEF, left ventricular ejection fraction; MI, myocardial infarction; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; PPI, proton pump inhibitor.

We also conducted several subgroup analyses stratified by advanced age (≥75 years), sex, acute coronary syndrome, high bleeding risk (HBR) as defined by the Academic Research Consortium for High Bleeding Risk (ARC-HBR), the use of oral anticoagulants, the type of P2Y₁₂ inhibitor (ticlopidine or clopidogrel), and the study (CREDO-Kyoto registry Cohort-2 or Cohort-3). As a sensitivity analysis, we constructed Cox proportional hazard models for the primary bleeding and ischemic outcome measures with DAPT discontinuation as a time-updated covariate together with the same risk-adjusting variables as in the main analysis, because the duration of DAPT may be associated with bleeding and ischemic events. We also calculated the cumulative incidence and HRs of the primary bleeding and ischemic outcome measures accounting for the competing risk of all-cause death as a sensitivity analysis. Furthermore, we conducted the main analysis using propensity score matching as another sensitivity analysis. The detailed method of propensity score matching is described in the Supplementary Appendix.

All P values are 2-tailed and P<0.05 was considered statistically significant. All analyses were performed using R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Baseline Characteristics

PPIs were prescribed at discharge to 45.6% of patients (Figure 1). There was a wide variation in the prescription rate of PPIs across the participating centers (11.9–70.0%; Supplementary Table 1). The most common PPI was lansoprazole (57.2%), and the second most common was rabeprazole (Table 1). The prescription rate of PPIs was much higher for patients in CREDO-Kyoto registry Cohort-3 (2011–2013) than Cohort-2 (2005–2007; 65.7% vs. 25.3%, respectively; P<0.001).

Figure 1.

Study flowchart. CABG, coronary artery bypass grafting; CREDO-Kyoto, Coronary Revascularization Demonstrating Outcome study in Kyoto; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; PCI, percutaneous coronary intervention; PPI, proton pump inhibitor.

Patients prescribed PPIs were older, more often women, and more often presented as acute coronary syndrome than those without PPI prescriptions (Table 1). Patients prescribed PPIs more often had comorbidities such as diabetes requiring insulin therapy, heart failure, left ventricular systolic dysfunction, mitral regurgitation, prior MI, chronic kidney disease, atrial fibrillation, anemia, thrombocytopenia, malignancy, and a history of gastrointestinal bleeding than those without PPI prescriptions. The prevalence of ARC-HBR-defined HBR was higher among patients with than without PPI prescriptions (49.7% vs. 42.0%, respectively; P<0.001). Patients with PPI prescriptions more often had complex coronary artery disease, as indicated by the higher number of target lesions, lesions in the left main coronary artery, and lesions in the bifurcation, and a longer total stent length than patients without PPI prescriptions (Table 1). The prevalence of target of chronic total occlusion lesions was lower in patients with than without PPI prescriptions. In terms of medications at discharge, the prescription rates of statins, β-blockers, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and oral anticoagulants were higher for patients with than without PPI prescriptions, whereas prescription rates of cilostazol, calcium channel blockers, and histamine H₂ receptor blockers were lower among patients with PPI prescriptions (Table 1).

DAPT Discontinuation

In patients with PPI prescriptions, the cumulative incidence of persistent discontinuation of DAPT was approximately 37% at 1 year, 64% at 3 years, and 75% at 5 years, compared with approximately 45% at 1 year, 62% at 3 years, and 71% at 5 years for patients without PPI prescriptions (log-rank P=0.08; Supplementary Figure). The duration of DAPT in patients with persistent discontinuation of DAPT was longer in patients with than without PPI prescriptions (median 363 [IQR 103–744] vs. 184 [IQR 33–604] days, respectively; P<0.001). In terms of the type of single antiplatelet therapy after stopping DAPT among patients who discontinued DAPT, of patients with PPI prescriptions, 86.2% of patients took aspirin and 13.8% of patients took P2Y₁₂ inhibitors, compared with 89.5% and 10.5%, respectively, of patients without PPI prescriptions (P<0.001).

Clinical Outcomes

The median follow-up duration was 5.6 years (IQR 4.8–6.5 years), and complete 1-, 3-, and 5-year clinical follow-up information was obtained for 98.1%, 95.6%, and 75.5% of patients, respectively. Complete 1-, 3-, and 5-year clinical follow-up rates did not differ between patients with (97.8%, 95.0%, and 75.7%, respectively) and without (98.5%, 96.2%, and 75.4%, respectively) PPI prescriptions.

The cumulative 5-year incidence of UGIB did not differ between patients with and without PPI prescriptions (1.7% vs. 1.9%, respectively; log-rank P=0.17; Figure 2A). However, after adjusting for confounders, the risk of UGIB was lower for patients with than without PPI prescriptions (adjusted HR 0.64; 95% CI 0.50–0.80; P<0.001; Table 2). There was no significant difference between patients with and without PPI prescriptions in the adjusted risk of gastrointestinal bleeding, lower gastrointestinal bleeding, and GUSTO moderate or severe bleeding (Table 2).

Figure 2.

Kaplan-Meier curves for (A) upper gastrointestinal bleeding, (B) myocardial infarction or ischemic stroke, and (C) all-cause death in patients with and without treatment with a proton pump inhibitor (PPI). Cumulative incidence was estimated by the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by the univariate Cox proportional hazard model.

Table 2.

Clinical Outcomes

	No. patients with event (cumulative 5-year incidence; %)		Crude HR (95% CI)	P value	Adjusted HR (95% CI)	P value
	PPI (n=11,202)	No PPI (n=13,361)
Primary bleeding outcome measure: UGIB	184 (1.7)	257 (1.9)	0.88 (0.72–1.06)	0.17	0.64 (0.50–0.80)	<0.001
Gastrointestinal bleeding	363 (3.4)	406 (3.0)	1.10 (0.95–1.26)	0.21	0.84 (0.71–1.01)	0.06
Lower gastrointestinal bleeding	159 (1.5)	114 (0.8)	1.71 (1.35–2.18)	<0.001	1.32 (0.97–1.79)	0.08
Gastrointestinal bleeding (bleeding site unknown)A	20 (0.2)	35 (0.3)	0.70 (0.40–1.21)	0.21	0.58 (0.33–1.02)	0.06
GUSTO moderate or severe bleeding	1,226 (11.0)	1,238 (8.8)	1.22 (1.13–1.32)	<0.001	1.04 (0.94–1.15)	0.40
GUSTO severe bleeding	565 (5.1)	544 (3.9)	1.26 (1.12–1.42)	<0.001	0.97 (0.84–1.13)	0.72
Primary ischemic outcome measure: MI or ischemic stroke	935 (8.0)	1,099 (7.7)	1.04 (0.95–1.14)	0.36	1.00 (0.90–1.12)	0.97
MI	486 (4.1)	525 (3.7)	1.13 (1.00–1.28)	0.046	1.06 (0.90–1.24)	0.49
Ischemic stroke	481 (4.2)	602 (4.2)	0.98 (0.87–1.10)	0.72	0.96 (0.82–1.12)	0.58
All-cause death	2,006 (16.0)	2,008 (12.9)	1.23 (1.15–1.31)	<0.001	1.18 (1.09–1.27)	<0.001
Cardiovascular death	928 (7.8)	904 (6.0)	1.26 (1.15–1.38)	<0.001	1.17 (1.04–1.31)	0.01
Non-cardiovascular death	1,078 (8.9)	1,104 (7.4)	1.20 (1.11–1.31)	<0.001	1.18 (1.06–1.32)	0.003
Definite stent thrombosisA	83 (0.7)	125 (0.9)	0.81 (0.61–1.06)	0.13	0.75 (0.57–0.99)	0.04
Any coronary revascularization	3,176 (29.0)	4,339 (32.6)	0.86 (0.82–0.90)	<0.001	1.05 (0.99–1.11)	0.14

The number of patients with an event was counted throughout the entire follow-up period. The cumulative 5-year incidence was estimated by the Kaplan-Meier method. HRs and 95% CIs were estimated throughout the entire follow-up period by Cox proportional hazard models. ^AIn the multivariable analysis, we used a parsimonious model adjusting for 10 variables (age ≥75 years, male sex, acute coronary syndrome, hypertension, prior MI, eGFR <30 mL/min/1.73 m² or HD, atrial fibrillation, hemoglobin <11.0 g/dL, platelet count <100×10⁹/L, malignancy) due to the small number of patients with events. CI, confidence interval; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; HR, hazard ratio; UGIB, upper gastrointestinal bleeding. Other abbreviations as in Table 1.

The cumulative 5-year incidence of MI or ischemic stroke did not differ between patients with and without PPI prescriptions (8.0% vs. 7.7%, respectively; log-rank P=0.36; Figure 2B). After adjusting for confounders, there was no significant difference in the risk of MI or ischemic stroke in patients with PPI prescriptions relative to those without PPI prescriptions (adjusted HR 1.00; 95% CI 0.90–1.12; P=0.97; Table 2). The adjusted risk of patients with PPI prescriptions relative to those without PPI prescriptions was lower for definite stent thrombosis, but not significantly different for any coronary revascularization (Table 2).

The cumulative 5-year incidence of all-cause death was higher among patients with than without PPI prescriptions (16.0% vs. 12.9%, respectively; log-rank P<0.001; Figure 2C). After adjusting for confounders, the higher risk of all-cause death for patients with PPI prescriptions relative to those without remained significant (HR 1.18; 95% CI 1.09–1.27; P<0.001; Table 2). The higher risk of patients with PPI prescriptions relative to those without was significant for both cardiovascular death and non-cardiovascular death (Table 2).

In the subgroup analyses, the risks of the group with PPI prescriptions relative to the group without PPI prescriptions were consistent with those in the entire study population for UGIB, MI or ischemic stroke, and all-cause death regardless of age, sex, acute coronary syndrome, ARC-HBR, oral anticoagulant use, the type of P2Y₁₂ inhibitors, and the study (Table 3). There were no significant treatment-by-subgroup interactions for UGIB, MI or ischemic stroke, and all-cause death (Table 3).

Table 3.

Subgroup Analysis

	No. patients with event/no. patients (cumulative 5-year incidence; %)		Crude HR (95% CI)	P value	Adjusted HR (95% CI)	P value	Pinteraction
	PPI (n=11,202)	No PPI (n=13,361)
Primary bleeding outcome measure: UGIB
Age
≥75 years	91/3,854 (2.6)	96/3,978 (2.6)	1.01 (0.76–1.35)	0.94	0.67 (0.47–0.96)	0.03	0.11
<75 years	93/7,348 (1.3)	161/9,383 (1.6)	0.75 (0.58–0.97)	0.03	0.61 (0.45–0.84)	0.002
Sex
Male	131/8,141 (1.7)	200/9,869 (2.0)	0.81 (0.65–1.01)	0.06	0.59 (0.45–0.77)	<0.001	0.27
Female	53/3,061 (1.8)	57/3,492 (1.5)	1.10 (0.76–1.60)	0.62	0.76 (0.47–1.24)	0.27
Acute coronary syndrome
Yes	80/5,345 (1.5)	74/4,479 (1.7)	0.92 (0.67–1.26)	0.61	0.66 (0.43–1.01)	0.054	0.69
No	104/5,857 (1.9)	183/8,882 (2.0)	0.89 (0.70–1.13)	0.33	0.66 (0.50–0.88)	0.01
ARC-HBR
Yes	132/5,369 (2.6)	159/5,367 (3.2)	0.86 (0.68–1.08)	0.19	0.67 (0.50–0.88)	0.01	0.56
No	52/5,833 (0.9)	98/7,994 (1.1)	0.73 (0.52–1.02)	0.07	0.59 (0.39–0.90)	0.01
Oral anticoagulants useA
Yes	32/1,234 (2.7)	36/1,067 (3.8)	0.79 (0.49–1.27)	0.34	0.76 (0.47–1.22)	0.26	0.80
No	152/9,968 (1.6)	221/12,294 (1.7)	0.87 (0.71–1.07)	0.18	0.80 (0.64–0.98)	0.03
P2Y12 inhibitor
Ticlopidine	39/2,779 (1.5)	135/8,321 (1.5)	0.92 (0.65–1.32)	0.66	0.68 (0.46–1.01)	0.06	0.48
Clopidogrel	141/8,187 (1.8)	117/4,717 (2.5)	0.71 (0.55–0.90)	0.01	0.63 (0.47–0.86)	0.003
Study
Cohort-2	42/3,089 (1.4)	140/9,133 (1.5)	0.96 (0.68–1.35)	0.81	0.72 (0.49–1.05)	0.09	0.19
Cohort-3	142/8,113 (1.8)	117/4,228 (2.8)	0.65 (0.51–0.83)	<0.001	0.62 (0.46–0.83)	0.001
Primary ischemic outcome measure: MI or ischemic stroke
Age
≥75 years	376/3,854 (10.1)	424/3,978 (10.8)	0.94 (0.82–1.09)	0.42	0.99 (0.83–1.19)	0.93	0.16
<75 years	559/7,348 (6.9)	675/9,383 (6.5)	1.07 (0.96–1.20)	0.22	1.00 (0.86–1.15)	0.95
Sex
Male	688/8,141 (8.0)	835/9,869 (7.8)	1.02 (0.92–1.13)	0.70	1.00 (0.87–1.13)	0.94	0.70
Female	247/3,061 (7.8)	264/3,492 (7.4)	1.11 (0.93–1.32)	0.25	1.01 (0.80–1.26)	0.95
Acute coronary syndrome
Yes	444/5,345 (7.8)	368/4,479 (8.0)	1.03 (0.90–1.19)	0.64	1.04 (0.86–1.27)	0.68	0.50
No	491/5,857 (8.1)	731/8,882 (7.6)	1.05 (0.93–1.17)	0.43	0.99 (0.86–1.14)	0.87
ARC-HBR
Yes	585/5,369 (11.5)	598/5,367 (11.0)	1.01 (0.90–1.14)	0.83	1.03 (0.89–1.19)	0.69	0.81
No	350/5,833 (5.1)	501/7,994 (5.7)	0.96 (0.83–1.10)	0.51	0.95 (0.80–1.14)	0.60
Oral anticoagulant use
Yes	132/1,234 (11.1)	106/1,067 (9.5)	1.11 (0.86–1.44)	0.41	0.99 (0.69–1.40)	0.94	0.99
No	803/9,968 (7.6)	993/12,294 (7.6)	1.02 (0.93–1.12)	0.66	0.99 (0.88–1.12)	0.92
P2Y12 inhibitor
Ticlopidine	254/2,779 (9.3)	689/8,321 (7.8)	1.20 (1.04–1.38)	0.01	1.11 (0.94–1.31)	0.24	0.54
Clopidogrel	662/8,187 (7.5)	387/4,717 (7.6)	1.04 (0.92–1.18)	0.54	0.95 (0.81–1.11)	0.49
Study
Cohort-2	251/3,089 (8.8)	729/9,133 (7.6)	1.12 (0.97–1.30)	0.11	1.09 (0.92–1.28)	0.32	0.98
Cohort-3	684/8,113 (7.7)	370/4,228 (7.9)	1.04 (0.92–1.18)	0.55	0.93 (0.80–1.09)	0.38
All-cause death
Age
≥75 years	1,190/3,854 (28.6)	1,146/3,978 (25.1)	1.12 (1.03–1.21)	0.01	1.14 (1.02–1.26)	0.02	0.20
<75 years	816/7,348 (9.6)	862/9,383 (7.8)	1.23 (1.12–1.35)	<0.001	1.27 (1.12–1.43)	<0.001
Sex
Male	1,411/8,141 (15.4)	1,493/9,869 (13.1)	1.18 (1.09–1.26)	<0.001	1.16 (1.06–1.28)	0.002	0.53
Female	595/3,061 (17.7)	515/3,492 (12.4)	1.37 (1.22–1.55)	<0.001	1.24 (1.06–1.44)	0.01
Acute coronary syndrome
Yes	880/5,345 (14.8)	661/4,479 (12.9)	1.14 (1.03–1.27)	0.01	1.17 (1.02–1.35)	0.03	0.98
No	1,126/5,857 (17.1)	1,347/8,882 (12.9)	1.31 (1.21–1.42)	<0.001	1.18 (1.07–1.30)	0.001
ARC-HBR
Yes	1,575/5,369 (27.2)	1,449/5,367 (23.8)	1.13 (1.06–1.22)	0.001	1.20 (1.09–1.31)	<0.001	0.86
No	431/5,833 (6.0)	559/7,994 (5.7)	1.06 (0.93–1.20)	0.40	1.11 (0.94–1.31)	0.22
Oral anticoagulant use
Yes	300/1,234 (22.3)	248/1,067 (20.0)	1.07 (0.91–1.27)	0.40	1.16 (0.92–1.47)	0.20	0.95
No	1,706/9,968 (15.3)	1,760/12,294 (12.3)	1.23 (1.15–1.31)	<0.001	1.18 (1.08–1.28)	<0.001
P2Y12 inhibitors
Ticlopidine	556/2,779 (18.7)	1,196/8,321 (12.7)	1.52 (1.37–1.68)	<0.001	1.27 (1.13–1.42)	<0.001	0.07
Clopidogrel	1,401/8,187 (15.1)	757/4,717 (13.1)	1.13 (1.04–1.24)	0.01	1.10 (0.98–1.23)	0.10
Study
Cohort-2	597/3,089 (18.8)	1,291/9,133 (12.8)	1.54 (1.39–1.69)	<0.001	1.24 (1.11–1.39)	<0.001	0.12
Cohort-3	1,409/8,113 (15.0)	717/4,228 (13.2)	1.12 (1.02–1.22)	0.02	1.12 (0.996–1.25)	0.06

The number of patients with an event was counted throughout the entire follow-up period. The cumulative 5-year incidence was estimated by the Kaplan-Meier method. HRs and 95% CIs were estimated throughout the entire follow-up period by Cox proportional hazard models. ^AIn the multivariable analysis, we used a parsimonious model adjusting for 10 variables (age ≥75 years, male sex, acute coronary syndrome, hypertension, prior MI, eGFR <30 mL/min/1.73 m² or HD, atrial fibrillation, hemoglobin <11.0 g/dL, platelet count <100×10⁹/L, malignancy) due to the small number of patients with events. Abbreviations as in Tables 1,2.

The cumulative incidences of UGIB and MI or ischemic stroke were not different regardless of the type of PPI, whereas the cumulative incidence of all-cause death was higher among patients prescribed omeprazole and lansoprazole than in those prescribed rabeprazole and esomeprazole (Supplementary Table 2). The results of the sensitivity analyses incorporating DAPT discontinuation during follow-up were fully consistent with those of the main analyses (Supplementary Table 3). In the sensitivity analyses accounting for the competing risk of all-cause death, the cumulative 5-year incidence of UGIB was 1.6% and 1.8% in patients with and without PPI prescriptions, respectively, whereas that of MI or ischemic stroke was 7.5% and 7.3% in patients with and without PPI prescriptions, respectively (Supplementary Table 4). The results are fully consistent with those of the main analyses (Supplementary Table 4). After propensity score matching in the sensitivity analyses, the clinical characteristics of patients with and without PPI prescriptions were much more comparable than those in the entire study population (Supplementary Table 5). The results of analyses after propensity score matching were consistent with those of the main analyses (Supplementary Table 6).

Discussion

The main findings of this real-world study evaluating PPI and long-term outcomes in patients undergoing PCI were that: (1) PPI use, compared with no PPI use, was associated with a lower risk of UGIB; (2) PPI use, compared with no PPI use, was not associated with a higher risk of ischemic events, but was associated with a higher risk of all-cause death; and (3) the effects of PPIs for UGIB, ischemic events, and all-cause death were consistent across the high-risk subgroups evaluated in this study.

Gastrointestinal bleeding is a common complication in patients undergoing PCI, because they need to take DAPT with a P2Y₁₂ inhibitor and aspirin, which induces gastric mucosal injury.^1,2 A randomized controlled trial demonstrated that PPIs reduced the rate of gastrointestinal bleeding in patients who had ulcer complications after low-dose aspirin and Helicobacter pylori infection.³ More recently, the COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) trial demonstrated that PPIs reduced the rate of UGIB in patients with CAD receiving aspirin and clopidogrel.⁴ Consistent with these randomized controlled trials, in the present study the use of PPIs was associated with a lower risk of UGIB in patients undergoing PCI. The US, European, and Japanese guidelines and a position paper recommend PPIs for patients at high risk of gastrointestinal bleeding, such as those with a history of gastrointestinal bleeding, anticoagulant therapy use, chronic non-steroidal anti-inflammatory drug or corticosteroid use, advanced age, dyspepsia, gastroesophageal reflux disease, H. pylori infection, or chronic alcohol use.^6–9 However, data are scarce in the guidelines and position paper regarding the effects of PPIs in these high-risk groups, and it remains unclear whether there are some patient subgroups in which the benefits of PPIs are particularly prominent in terms of reducing UGIB in patients undergoing PCI. Therefore, we performed subgroup analyses in this study based on several potential high-risk factors, and found that PPIs conferred a lower risk of UGIB consistently, regardless of advanced age, female sex, acute coronary syndrome, ARC-HBR, and the use of oral anticoagulants.

Previous studies suggested that PPIs may reduce the antiplatelet effect of clopidogrel, which is mediated P2Y₁₂ receptors, primarily by inhibiting hepatic cytochrome P450 2C19 (CYP2C19).^14,15 In addition, several observational studies have reported that the use of PPIs could lead to an increase in ischemic events in patients with CAD.^16–19 However, there were no apparent signs of an increased risk of ischemic events with the use of PPIs in randomized controlled trials or a meta-analysis.^4,5 Nevertheless, the number of patients included in the meta-analysis of randomized trials (6,930 patients) was not large enough to detect a modest increase in ischemic events.⁵ Moreover, the duration of the follow-up in the randomized trials was relatively short (1 month–1 year),⁵ although long-term use of PPIs was a common clinical practice when used in combination with aspirin or DAPT.^20,21 Consistent with the data from previous randomized controlled trials, we found that PPI use was not associated with a higher adjusted risk of ischemic events regardless of the type of P2Y₁₂ inhibitor (ticlopidine or clopidogrel) in Japanese patients, who have been reported to have high prevalence of CYP2C19 loss-of-function alleles, over a median 5.6-year follow-up period.²² Conversely, PPI use was associated with a higher adjusted mortality risk without an increased risk of ischemic events in the present study. Several observational studies also raised concerns that PPI use may increase several non-cardiovascular adverse events, including pneumonia, fracture, Clostridium difficile infection, enteric infection, or dementia.^23–26 However, in the randomized COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial evaluating pantoprazole vs. placebo in patients receiving aspirin or rivaroxaban, PPI use did not increase adverse events such as all-cause death, cardiovascular events, pneumonia, fracture, C. difficile infection, or dementia, although the rate of enteric infection was higher among patients with pantoprazole than in the placebo group over the 3-year follow-up.²⁷ When considering the results of the COMPASS trial, the higher adjusted mortality risk of PPIs in the present study may be due to residual confounding. Further studies are warranted to demonstrate the benefit and risk of the long-term use of PPI.

Study Limitations

This study has several important limitations. First, and most importantly, the present study was not a randomized controlled trial. Although we performed multivariable analyses and several sensitivity analyses including propensity score matching, selection bias and residual confounding may be inevitable. The higher mortality risk of PPI sin this study may represent residual confounding, because there were no associations between PPI and mortality in the previous large randomized controlled trial with a 3-year follow-up. In fact, we did not collect data on several important factors, such as history of peptic disease, dyspepsia or gastroesophageal reflux disease, H. pylori infection, chronic alcohol use, frailty, or cognitive dysfunction, which could be residual confounders in the present study. Second, we did not collect data on the follow-up information and non-compliance with PPIs. Therefore, we could not evaluate the effect of discontinuation of PPIs in this study. Third, the clinical practice and medication use patterns in this study may be different from those in contemporary clinical practice. The duration of DAPT after PCI was relatively long, and the prescription rate of direct oral anticoagulants was low. These differences may be related to the incidence of gastrointestinal bleeding and the effects of PPI. Fourth, this study was conducted in Japan, and it is unknown whether the results may be extrapolated to other countries.

Conclusions

In conclusion, in a real-world population of patients undergoing PCI, PPI use was associated with a lower risk of UGIB and a neutral risk of ischemic events regardless of the high-risk subgroups.

Acknowledgments

The authors appreciate the support and collaboration of the coinvestigators participating in the CREDO-Kyoto PCI/CABG Registry Cohort-2 and Cohort-3. The authors are indebted to the clinical research coordinators for data collection.

Sources of Funding

This study was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan), and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan (Tokyo, Japan).

Disclosures

T.M. reports lecturer fees from Bayer, Daiichi Sankyo, Japan Lifeline, Kyocera, Mitsubishi Tanabe, Novartis, and Toray; manuscript fees from Bristol-Myers Squibb and Kowa; and serving on advisory boards for Asahi Kasei, Boston Scientific, Bristol-Myers Squibb, and Sanofi. H. Shiomi reports personal fees from Abbott Vascular, Boston Scientific, and Daiichi Sankyo. Y.F. reports honoraria from Ono Pharmaceutical, Novartis, Daiichi Sankyo, Bayer, Otsuka Pharmaceutical, Kowa, Takeda, Sumitomo Dainippon Pharma, Pfizer, Bristol-Myers Squibb, and Sanofi. T.K. reports personal fees from Abbott Vascular, Abiomed, Astellas, Astellas Amgen Biopharma, AstraZeneca, Bayer, Boston Scientific, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Edwards Lifescience, Eisai, Daiichi Sankyo, Interscience, Japan Society for the Promotion of Science, Kowa, Kowa Pharmaceutical, Lifescience, Medical Review, MSD, MSD Life Science Foundation, Mitsubishi Tanabe Pharma, Novartis Pharma, Ono Pharmaceutical, OrbusNeich, Otsuka Pharmaceutical, Pharmaceuticals and Medical Devices Agency, Philips, Public Health Research Foundation, Sanofi, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Terumo, Toray, and Tsumura. The remaining authors have nothing to disclose.

IRB Information

The present study was approved by the Kyoto University Graduate School and Faculty of Medicine, Ethics Committee (Reference no. E2400).

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0371

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