Temporal trends in use of antisecretory agents among patients administered clopidogrel‐based dual antiplatelet therapy after percutaneous coronary intervention

Antisecretory drugs are commonly prescribed with clopidogrel‐based dual antiplatelet therapy (DAPT) to prevent gastrointestinal bleeding in high‐risk patients after percutaneous coronary intervention (PCI). However, omeprazole and esomeprazole (inhibiting proton pump inhibitors [PPIs]) may increase cardiovascular event rates on co‐administration with clopidogrel.

• This study examines the use of antisecretory drugs in patients receiving clopidogrel-based dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI).
• Inhibiting PPIs, which can interfere with clopidogrel and increase cardiovascular risks, were used increasingly despite FDA warnings.

Plain Language Summary
Patients undergoing percutaneous coronary intervention (PCI) often receive a treatment combining clopidogrel and aspirin, known as dual antiplatelet therapy (DAPT), to prevent blood clots.
To protect against stomach bleeding caused by this treatment, doctors also prescribe antisecretory agents.Our study examined the prescription trends of these medications in South Korea from 2009 to 2020.We observed an increase in the use of proton pump inhibitors (PPIs) and a decrease in H2 receptor antagonists (H2RAs).Notably, the usage of certain PPIs that can reduce clopidogrel's effectiveness and increase heart risks-known as inhibiting PPIs-also rose significantly, from 4.2% in 2009 to 30.7% in 2020.This trend continued even after FDA warnings about the potential dangers of combining these PPIs with clopidogrel.Our findings highlight a preference for PPIs despite their cardiovascular risks, underscoring the need for more cautious prescribing and better awareness among healthcare providers about these drug interactions to ensure patient safety.

| INTRODUCTION
Dual antiplatelet therapy (DAPT), with an oral P2Y 12 inhibitor and aspirin, is the cornerstone treatment for patients undergoing percutaneous coronary intervention (PCI). 1 Antiplatelet therapy reduces recurrent major adverse cardiovascular events by inhibiting platelet activation and aggregation. 2Compared to mono-antiplatelet therapy, DAPT imparts more intense platelet inhibition and subsequent incremental reduction in thrombotic events after PCI. 2 However, concomitantly, they increase the risk of gastrointestinal (GI) bleeding. 3erefore, American College of Cardiology and the American Heart Association (ACC/AHA) guidelines recommend proton pump inhibitors (PPIs) for gastric protection in patients receiving DAPT, if the patients are at a high risk of GI bleeding (such as a history of GI hemorrhage/ulcer, chronic use of corticosteroids/non-steroidal antiinflammatory drugs, anticoagulant therapy, or two or more of the following: age ≥65 years, dyspepsia, gastro-esophageal reflux disease (GERD), Helicobacter pylori infection, or chronic alcohol consumption). 4ong P2Y 12 inhibitors, clopidogrel is widely known for drugdrug interactions with some PPIs.6][7][8] Inhibiting clopidogrel's metabolization reduces the active metabolite concentration and increases cardiovascular events after PCI. 9 Therefore, in 2009, the United States Food and Drug Administration (FDA) warned against the concomitant use of clopidogrel and inhibiting PPIs (particularly omeprazole). 10They recommended other drugs, such as alternate PPIs or H2 receptor antagonists (H2RAs) as antisecretory agents for patients prescribed clopidogrel. 10Prior studies examined trends in clopidogrel and PPI use after the FDA warning and reported significant changes in prescriptions, [11][12][13] which changed the landscape for antisecretory agents.In 2019, some ranitidine products containing N-nitroso-dimethylamine as an impurity, which can increase the risk of cancer, were withdrawn from the market. 14reover, in 2019, a new potassium competitive acid blocker (P-CAB), tegoprazan, was approved by the Ministry of Food and Drug Safety and was subsequently used as an antisecretory agent.
In this study, we aimed to evaluate trends in the use of antisecretory agents among patients administered clopidogrel-based DAPT and investigate the status of using clopidogrel and inhibiting PPIs concomitantly.Approximately 97% of South Korea's population is enrolled in the NHI, while 3% are in the MedAid plan, a type of health insurance that offers low-income families access to affordable medical treatment, and 0.5% of the population are in the PVI plan.Drug codes (Supplementary Table 1) were used to extract information regarding antisecretory agents and antiplatelet therapy.

| Study population
First, we selected patients who underwent PCI between January and November each year using procedure codes (Supplementary Table 1).
If the patient received PCI more than once during the study period, only the first PCI episode was considered.Two weeks after PCI is defined as the window period, 15 and the first outpatient records from the same medical institution where PCI was performed within the window period were investigated.If this outpatient prescription included both clopidogrel and aspirin, it was classified as clopidogrelbased DAPT.If there were two or more types of P2Y 12 inhibitors, the drug with the longest duration of administration was selected.
The DAPT period was defined as the duration of taking clopidogrel and aspirin concurrently.Patients who benefited from the PVI were excluded.Only outpatient prescriptions were primarily included in our study, and long-term hospitalized patients were excluded because they mainly received inpatient services.Patient comorbidities were extracted from 40 tables within HIRA-NIS. 16These data predominantly represent previously diagnosed disorders.However, certain disorders, particularly acute conditions, may occur during hospitalization.

| Statistical analyses
Univariate statistics were used to describe the general features of patients and medical institutions.For categorical variables, the data were illustrated as counts and percentages.The p-value was determined using chi-squared tests for categorical variables.Demographic characteristics included individual factors (age and sex), social factors (insurance coverage), and health factors (hypertension, chronic heart failure, diabetes, dyslipidemia, arrhythmia, liver disease, peripheral vascular disease, cerebrovascular disease, chronic pulmonary disease, malignancy, rheumatic disease, peptic ulcer, GERD, dyspepsia, or GI bleeding).We grouped the study population by age: ≤54, 55-59, 60-64, 65-69, 70-74, and ≥75 years.

Antisecretory agent use was investigated in patients undergoing
clopidogrel-based DAPT.When an antisecretory agent was prescribed at least for one day during the window period, it was regarded as concurrent use.Among antisecretory agents, we focused on all PPIs, particularly inhibiting PPIs.We also determined antisecretory agent use in patients receiving other DAPT therapies, including ticagrelor, prasugrel, and ticlopidine.We aimed to compare and contrast the use of antisecretory agents in two patient groups.
To ascertain the annual trend of drug utilization, we used the Cochran-Armitage trend test.
Data were analyzed using R Statistical Software (version 3.5.1;R Foundation for Statistical computing, Vienna, Austria) with statistical significance set at a p-level of <0.05.

| Characteristics of study population
The number of patients undergoing PCI during the study period was 74 426.Among them, 35 277 patients had outpatient follow-up visits within the window period; among these, we identified 23 134 patients receiving clopidogrel and aspirin (Figure 1).The age group accounting for the majority of the study population was the group aged ≤54 years (20.8%),followed by the group aged ≥75 years (19.5%).There were more male patients than female patients (69.4% vs. 30.6%) in the study (Table 1).

| Use of antisecretory agents
Among the 23 134 patients, 53.2% (n = 12 306) were prescribed one or more antisecretory drugs.H2RAs were the most preferred antisecretory agents during the study period, which accounted for 57.8% (n = 7114) of the antisecretory drugs used.PPI accounted for 55.5% (n = 6828), and P-CAB accounted for 1.3% (n = 166).Among the clopidogrel-based DAPT users, 2025 patients used inhibiting PPI (8.8%), accounting for 16.5% of the antisecretory users (Table 1) and 29.7% of the PPI users.First, the preference for PPIs over H2RAs may stem from a growing body of evidence supporting the superior efficacy of PPIs in managing GERD and erosive/non-erosive reflux disease. 17Previous studies have demonstrated that PPIs are more effective in providing gastroprotection, potentially making them a preferred choice for clinicians. 18,19Moreover, the recall of ranitidine, a commonly used H2RA, may have further contributed to the decline in H2RA use. 14r findings demonstrated a proportional rise in inhibiting PPI prescriptions alongside an overall increase in PPI utilization, surging from 4.2% to 30.7% (Table 1).Furthermore, when analyzing the broader population of all DAPT users, inhibiting PPIs accounted for 29.7% of antisecretory drugs in 2020, with varying percentages across different types of DAPT, including 30.7% in clopidogrel-based DAPT, 23.1% in prasugrel-based DAPT, and 27.7% in ticagrelor-based DAPT (Supplementary Table 3).This trend suggests that clinicians may select PPIs without adequately considering their differences in terms of interactions with P2Y 12 inhibitors.This observed trend contrasts with prior studies reporting a decline in the use of inhibiting PPI after the FDA's 2009 safety communication. 11,12,20For instance, one study reported a 50% reduction   Concurrent administration of inhibiting PPIs and clopidogrel is generally advised against it can impair clopidogrel activation, leading to reduced antiplatelet activity. 9Although several studies suggest a potential association between their combined use and increased adverse cardiovascular outcomes, including myocardial infarction, the existing literature presents conflicting findings.One meta-analysis, which retrospectively analyzed randomized controlled trials (RCTs)

| Temporal trend of antisecretory agents
and observational studies focusing on patients with PCI, concluded that concomitant clopidogrel-PPI therapy is linked to an increased risk of major adverse cardiovascular events (MACEs). 21Another metaanalysis reported an elevated risk of MACEs in ACS patients receiving a combination of clopidogrel and specific PPIs (omeprazole, lansoprazole, esomeprazole, and pantoprazole), but this association was observed predominantly in CYP2C19 rapid metabolisers. 22However, the COGENT trial, a large RCT, indicated that the concurrent use of omeprazole and clopidogrel does not significantly impact cardiovascular events compared to clopidogrel alone. 23ternational guidelines vary in their recommendations for the doubled (from 34.7% to 69.0%) (Table 1).This increase can be attrib-  25 Finally, the increase in antisecretory drug use may be related to doctors' concerns regarding the increased risk of GI bleeding in PCI-treated patients, particularly in East Asia, during antithrombotic therapy. 26,27ere are a few limitations in our study that warrant discussion.
First, the dataset's initial purpose was not for research; instead, it was to handle insurance benefits.Second, in the prevalence measurement of clopidogrel use with PPI, we were unable to verify the patient's contraindications, drug allergies, and the patient's exact clinical laboratory data.Finally, while most comorbidities reflect previously diagnosed disorders, it's possible that certain acute disorders, such as GI bleeding, might have developed during hospitalization.
Despite these limitations, this study is meaningful.Few studies have examined the trend in clopidogrel and antisecretory agent use.
However, we examined that many prescriptions did not consider the interaction of clopidogrel and inhibiting PPIs.Furthermore, due to the higher prevalence of the CYP2C19 loss-of-function allele in Koreans, there is an elevated risk of CV event during clopidogrel treatment compared to other races. 28In light of this, the coprescription of inhibiting PPIs and clopidogrel becomes particularly crucial in this population.
Thus, implementing continuous notifications to assist clinicians in considering drug interactions and supplementing the drug utilization review system with information on clopidogrel and inhibiting PPIs could address the issue of decreased drug efficacy due to these drug interactions.

| CONCLUSIONS
Our study indicates a growing use of inhibiting PPIs with clopidogrel in patients undergoing PCI in Korea, raising concerns about increased cardiovascular risks.Despite FDA warnings and limited evidence of its safety, the prevalence of inhibiting PPIs continues to increase.This underscores the need for cautious prescription practices and better awareness among clinicians, particularly when considering genetic factors, such as the CYP2C19 loss-of-function allele that is prevalent in Koreans.
We used the Health Insurance Review & Assessment Service National Inpatient Sample (HIRA-NIS) data from 2009 to 2020, which randomly selected 10%-13% of the inpatients in Korea and extracted their medical records.The International Classification of Diseases, Tenth Revision codes, were used to identify diagnostic information for patient encounters.The HIRA datasets include medical practices and prescription data in the Korean National Health Insurance (NHI) Service.There are the following three types of health insurance plans in Korea: NHI, Medical Aid (MedAid), and Patriots & Veterans Insurance (PVI).

Table 1 and
Figure 2 show the temporal trend of antisecretory agent use.From 2009 to 2020, the H2RA users decreased steadily.H2RA users accounted for 82.5% (n = 477) of the antisecretory drug users in 2009, but accounted for 25.3% (n = 306) in 2020 (Cochran-Armitage trend test; p < 0.001).In contrast, PPI use more than tripled from 2009 to 2020 (23.7%-82.0%,p < 0.001).Inhibiting PPI use increased 25%-points from 2009 to 2020 (4.2%-30.7%,p < 0.001).P-CABs were rarely used before 2019, but in 2020, they accounted for 7.8% (n = 95) of the total antisecretory agent usage.4| DISCUSSIONOur study revealed a trend in the co-prescription of clopidogrel and inhibiting PPIs among patients undergoing PCI in South Korea.Despite FDA safety warnings regarding potential interactions, we observed a substantial increase in the number of prescriptions for inhibiting PPIs.These drugs constituted 30.7% of all antisecretory agent usage among clopidogrel-based DAPT users in 2020.During the study period, the utilization of H2RA significantly declined from 82.5% to 25.3%, whereas PPI use surged from 23.7% to 82.0%.This shift in the prescription patterns may have been influenced by several factors.
Inhibiting PPIs, omeprazole, esomeprazole; Non-inhibiting PPIs, dexlansoprazole, ilaprazole, lansoprazole, pantoprazole, S-pantoprazole, rabeprazole; The sum of the percentages may exceed 100.Abbreviations: ASA, aspirin; CHF, congestive heart failure; GERD, gastroesophageal reflux disease; H2RAs, H2 receptor antagonist; P-CABs, potassium competitive acid blockers; PPIs, proton pump inhibitor; PUD, peptic ulcer disease.a Fisher's exact test. in esomeprazole use with clopidogrel (42.3%-26.8% of PPI users) after the FDA safety communication,12 and another found that the prevalence of inhibiting PPI use along with clopidogrel declined to 0.8% by the end of 2016.11 use of PPIs in patients receiving DAPT.The 2018 European Society of Cardiology (ESC) guidelines recommend PPIs for all individuals on DAPT, whereas the American College of Cardiology Foundation/ American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) guidelines advise PPI use primarily for high-risk patients with DAPT. 24Our study, which revealed a high prevalence of inhibiting PPI use, highlighted a tendency among clinicians to favor the clinical benefits of PPIs, despite the lack of substantial evidence supporting their risk profile.Our study also identified an overall increase in antisecretory drug use in patients receiving clopidogrel-based DAPT during the study period.From 2009 to 2020, the use of antisecretory drugs nearly F I G U R E 2 Antisecretory drug use from 2009 to 2020.H2RA, H2 receptor antagonist; P-CAB, potassium competitive acid blocker; PPI, proton pump inhibitor; Inhibiting PPI, omeprazole and esomeprazole; The sum of percentages may exceed 100%.