In this study, we found 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 doubled (from 34.7–69.0%) (Table 1). This increase can be attributed to the following two phenomena. First, the number of elderly patients above 65 years of age administered clopidogrel-based DAPT increased. Older patients accounted for 44.8% (n = 747) of the patients undergoing clopidogrel-based DAPT in 2009, which increased to 54.2% (n = 950) in 2020 (Supplementary Table 2). Thus, an almost 10% increase was observed, and the increasing trend was statistically significant (p < 0.001). Second, the number of patients with GERD also increased from 4.6% (n = 77) in 2009 to 38.3% (n = 671) in 2020 (p < 0.001). A previous study found a similar increasing trend in patients with GERD who received PPIs from 2012 to 2016 [16].
We further observed a steady increase in PPI prescriptions. Despite the FDA recommendation in 2009 and tegoprazan introduction in 2019, the rate of PPI uses increased to 82.0% (n = 993) of the antisecretory agent usage in 2020. This accounted for 56.6% of the clopidogrel-based DAPT users. PPI has been demonstrated to be superior to H2RA in the treatment of GERD and erosive/non-erosive reflux disease [17]. Ranitidine, a commonly used H2RA, was also withdrawn in 2019 due to NMDA [14]. Therefore, in 2019, H2RA accounted for 40.7% (n = 494) of the antisecretory drugs, which declined to 25.3% in 2020. As the usage of H2RA decreased, it was replaced with PPI and P-CAB.
The FDA warnings substantially altered the antisecretory prescriptions in patients using clopidogrel [11, 12, 18]. Prescriptions of inhibiting PPI in patients using clopidogrel decreased substantially after 2009 [11, 12]. One study found a reduction of 50% in patients using esomeprazole with clopidogrel (42.3–26.8% of PPI users) after the FDA safety communication [12]. Another study found that the prevalence of using inhibiting PPIs with clopidogrel declined to 0.8% at the end of 2016 [11]. In contrast, our results were different from those of previous studies.
The inhibiting PPI prescriptions increased proportionally with an increase in PPI prescriptions. Inhibiting PPIs should be avoided in patients administered clopidogrel since the concurrent use of both drugs can lead to harmful clinical outcomes [19]. Omeprazole and esomeprazole increase the risk of major adverse cardiovascular events in patients administered clopidogrel (odds ratio (OR): 1.40 vs 1.59; confidence interval (CI): 1.15–1.70 vs 1.29–1.95; respectively) [19]. However, inhibiting PPIs accounted for one-third of the PPI use in clopidogrel users. In addition, the proportion of inhibiting PPI use in patients administered clopidogrel-based DAPT. Compared to the proportion of patients administered PPIs with clopidogrel in 2009, those in 2020 increased by approximately seven-fold (4.2% vs 30.7%). It is presumed that healthcare providers did not recognize potential pharmacodynamic/pharmacokinetic drug interactions between clopidogrel and the inhibiting PPIs. According to our analysis, inhibiting PPIs accounted for 17.1% of PPI in other DAPT users, 19.1% in prasugrel-based DAPT users, and 20.0% in ticagrelor-based DAPT users (Supplementary Table 3). This indicates that clinicians select PPIs without recognizing their differences in terms of drug interactions with P2Y12 inhibitors.
The systemic limitation is also a problem., A drug utilization review (DUR) system in South Korea monitors the prescription of drugs in real-time. In 2010, this system was nationally adopted to reduce adverse drug events [20]. This system can detect drug-drug interactions and contraindications. However, co-prescription of clopidogrel and inhibiting PPIs is not registered as a contraindicated drug pair in the current DUR system. Therefore, clinicians are not notified when they simultaneously prescribe these two drugs.
In 2019, tegoprazan was approved by the Ministry of Food and Drug Safety to be used as an antisecretory agent. Our study showed that, in 2020, 5.4% of the clopidogrel-based DAPT users and 5.6% of all types of DAPT users used P-CAB; P-CAB’s applicability in therapy is not yet established. Clopidogrel is an important medication for patients who underwent PCI; hence, drugs influencing clopidogrel’s activity should be avoided.
There 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.
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.
Thus, clinician negligence and loopholes in the DUR system contribute to the continued prescribing of clopidogrel and inhibiting PPIs.