Cardiovascular diseases (CVD) have become the leading causes of death worldwide. According to the 2013 Global Burden of Disease Study, approximately 17 million people died of CVD worldwide, accounting for approximately 31.5% of the total number of deaths [1]. Among the different types of CVDs, the mortality of coronary artery disease (CHD) was the highest [2, 3]. Therefore, it is important to prevent CHD.

The rupture or erosion of vulnerable plaques that induces platelet activation and aggregation are the key pathophysiological mechanisms, which contributes to the deaths of patients with CHD. Therefore, antiplatelet therapy is critical to reduce cardiovascular deaths in patients with CHD [4]. Clopidogrel combined with aspirin, called dual antiplatelet therapy (DAPT), is the basic treatment strategy for CHD, especially for acute coronary syndrome (ACS). DAPT can effectively prevent percutaneous coronary intervention (PCI) from in-stent thrombosis and reduce cardiovascular adverse events. Nevertheless, the risks of gastrointestinal (GI) and other bleeding events are significantly increased after treatment with DAPT. Thus, patients who accept DAPT, especially after PCI, often take proton pump inhibitors (PPIs) at the same time. Most PPIs such as omeprazole, esomeprazole and lansoprazole, are mainly metabolized by liver cytochrome (CYP) P450 isoenzyme CYP2C19, which also regulates clopidogrel metabolism. When combined with clopidogrel, PPIs may exert a competitive inhibitory effect, and thus affect the therapeutic effects of clopidogrel. Previous pharmacodynamic studies showed that the concurrent use of PPIs could reduce anti-platelet activities of clopidogrel [5‐8]. However, the results from clinical trials were inconsistent. Some large clinical studies such as ADAPT-DES, BASKET, and CAPRIE indicated that combined use was associated with an increased risk of cardiovascular adverse events [4, 9, 10]. However, the results from other large-scale prospective clinical studies such as COGENT, CREDO, PRINCIPLE-TIMI 44, PRODIGY, TRITON-TIMI 38 showed the opposite results, which indicated that the concurrent use of PPIs and clopidogrel did not increase the risk of net adverse clinical events (NACE) and even had benefits by reducing the risk of GI bleeding [7, 9, 11, 12]. Furthermore, clopidogrel was more frequently used in combination with PPIs in Asian countries than that in Western countries [13, 14]. However, researches on the clinical effect of the concurrent use on both cardiovascular adverse events and GI bleeding in the Asian population are very limited. Therefore, this study was aimed to investigate the effect of concurrent use of clopidogrel and PPIs on clinical outcomes (composite endpoint events such as cardiovascular events and GI bleeding) in Chinese patients with CHD.

The results of this study suggest that in patients with CHD taking clopidogrel, intermittent use of PPIs did not increase the risk of all-cause death, cardiovascular adverse events, and GI bleeding after 18-month follow-up. Instead, compared with the sustained PPI users, intermittent use of PPIs was associated with a reduced risk of NACE after 18 months, especially for male CHD patients with an age over 60 years old after PCI, with hypertension or CKD.

Clopidogrel, often combined with aspirin, is a gold standard treatment for CHD, especially for patients after PCI, to reduce the incidence of cardiovascular adverse events [18‐20]. However, since clopidogrel needs to be metabolized by the liver CYP450 enzyme system, combined use of the drug metabolized by this enzyme may exert inhibitory effect on clopidogrel [21]. One of the most concerned medications is PPIs, which are often used to prevent GI bleeding [22]. Previous pharmacodynamic studies have shown that the platelet inhibitory rate decreased when clopidogrel was combined with PPIs [23‐26]. Most observational studies found that patients under both clopidogrel and PPIs therapy had an increased risk of ischemic cardiovascular events [4, 9, 10, 27‐29]. In the BASKET study, the results of subgroup analysis showed that patients who took PPIs had a higher incidence of NACEs and MI after 3 years than those who did not [10]. The following CAPRIE study confirmed that patients with PPIs suffered a higher risk of ischemic cardiovascular events after one year than non-PPI users [9]. The results of the ADAPT-DES study further proved that the combination of PPIs was associated with increased platelet resistance, and that the incidence of NACE was significantly increased after 2 years [4]. These results indicated that PPIs were able to affect its antiplatelet activity of clopidogrel by disturbing its metabolism, and thereby led to an increased risk of cardiovascular adverse events. However, the results of randomized controlled trials (RCTs) and biased clinical studies were inconsistent [7, 11, 30, 31]. Results from PRINCIPLE-TIMI 44 and TRITON-TIMI 38 studies suggested that clopidogrel and PPIs use had no effects on the clinical adverse events, although the platelet activity induced by clopidogrel was affected by the concurrent use of PPIs [7]. The subsequent COGENT study included a multicenter randomized double-blind case–control study involving 5000 patients with ACS or stent implantation and randomly assigned to omeprazole based on DAPT. After 180 days of follow-up, studies confirmed that the incidence of total cardiovascular death, MI, target vessel revascularization and stroke was not significantly different in both groups when compared to placebo group [12]. Another recent RCT, the PRODIGY study, showed the similar results [11]. Studies in Asian populations have found that clopidogrel combined with PPIs was not associated with cardiovascular events (such as AMI, cardiovascular death, etc.) [32, 33]. The above series of clinical research conclusions were consistent with the results of this study. In this study, compared with patients without use of PPIs, intermittent or sustained use of PPIs did not significantly increase the occurrence of all-cause deaths and adverse clinical events. This further confirmed that although the combined use of PPIs might reduce the antiplatelet function caused by clopidogrel, it did not necessarily indicate an increased risk of clinical adverse events after combined use [34, 35]. Indeed, a recent clinical study involving more than 60,000 patients with gastroesophageal reflux disease suggested that patients taking PPIs were 1.2 times more likely to develop MI than non-PPI users, and their risk of cardiovascular death was twice higher than those who did not take it, but all these were independent of clopidogrel use [29]. The latest meta-analysis of this issue did not find a definitive answer either [34, 35]. Therefore, the clinical prognosis of CHD patients with combined use of clopidogrel and PPIs still requires further confirmation by the well-designed RCTs.

The purpose of using PPIs is mainly to prevent or reduce the occurrence of GI bleeding. Although relatively few studies focused on the benefit of clopidogrel combined with PPIs on GI bleeding, the risk of GI bleeding was found to be reduced after combined with PPIs [11, 12, 31, 36]. In the COGENT study, although there was no significant difference in the overall incidence of cardiovascular adverse events, the risk of GI bleeding was lower in the omeprazole group than in the placebo after 180 days. However, this study was terminated early and the follow-up time was short. Therefore, the risk of GI bleeding after long-term treatment could not be evaluated in this study [12, 31]. The PRODIGY study found that the occurrences of BARC bleeding standard type 2, 3, and 5 bleeding events at 6 months and 24 months were not statistically different between groups with or without PPIs use. However, no comparison among various bleeding events such as GI bleeding events was conducted in that study [11]. This study focused on the observation of GI bleeding in patients with CHD taking clopidogrel combined with PPIs. There was no significant difference in GI bleeding incidence. However, among the sustained PPI users, 45 people suffered gastrointestinal ulcer disease, and the incidence of GI bleeding was 4.4% after 18 months; among the non-PPI users, 20 people suffered stomach intestinal ulcer disease, the incidence of GI bleeding was up to 10% after 18 months. It seemed that the occurrence of GI bleeding in the non-PPI users was higher than that in the sustained PPI users. Due to the small number of events, it could not be confirmed by multivariate analysis. However, this result was consistent with the research published earlier by the Chitose T. team in Japan, which suggested that the group without the PPIs use showed a tendency of increasing GI bleeding [36]. Therefore, use of PPIs was unlikely to increase the risk of clinical adverse events but may exert benefit on GI bleeding prevention.

How to prescribe PPIs to the CHD patients in clinical practice is another important issue. Till now, only few studies have explored the impact of various frequencies of PPIs use on clinical prognosis. Such as the PRODIGY study, the study defined those who took PPIs at the 30-day follow-up as the PPIs use group. Patients who took less than 30-day PPIs and those who discontinued PPIs were excluded [11]. Other studies, such as ADAPT-DES and BASKET, regarded patients discharged with PPIs as the PPI group, but did not consider the changes of PPIs dosage or the frequency of concurrent use after discharge [4, 10]. In the clinical practice, most patients may accept PPIs treatment when they suffer digestive discomfort. Therefore, to identify the optimal PPI regimens in CHD patients to achieve beneficial clinical impacts is of great importance. Based on the duration of PPI use during the follow-up period, PPI users were divided into the sustained and intermittent PPI users groups. No significant difference was found on the individual clinical adverse events of the two PPI-user groups. Surprisingly, the intermittent PPI user group had a significantly lower incidence of NACE than the sustained PPI users, of which the main benefit may be due to a reduction in stroke. Further subgroup analysis suggested that male CHD patients with an age over 60 old years, after PCI treatment, with hypertension or CKD, might benefit more from intermittent use of PPIs. Therefore, for certain populations, intermittent use may be related to a reduction in NACE. In fact, this was in line with the recommendations of the latest US ACC/AHA guidelines. The guideline considered that PPIs may be used appropriately for people at high risk, such as the elderly, who were at high risk for GI bleeding [19, 20]. In addition, for PCI patients, who were necessary to take DAPT continuously for at least 1 year, it was particularly critical to prevent complications such as GI bleeding that forced to discontinue DAPT. The present study indicated that the appropriate and intermittent concurrent use of PPI with clopidogrel may be available for patients after PCI. Nevertheless, because of the low incidence of GI bleeding and other bleeding events in this study, it was impossible to further analyze whether the benefit of NACE came from the reduction of GI bleeding or was affected by the imbalanced baseline. However, multivariate analysis adjusted for possible confounders reduced the impact of baseline imbalances to a certain extent. According to previous large-scale clinical studies such as the PRODIGY study, the incidence of NACE in the sustained user and the non-PPI user group in this study was comparable, also between 10.0 and 15.0%, while the intermittent user group was significantly reduced, which indicated that the results of this study had considerable credibility [11].

There were several limitations in this study. Firstly, this study was a single-center retrospective study. Population included is heterogeneous, considering patients in single and dual antiplatelet therapy. The included sample size was relatively small. Thus, the inherent bias would inevitably occur. Secondly, the small number of clinical adverse events might have a certain impact on the research results. Thirdly, the occurrence of clinical events and the consumption of drugs were obtained by telephone or outpatient follow-up, which might inevitably lead to reporting bias. However, the majority of baseline data, medication treatments, and some clinical adverse events were collected or confirmed in the hospital medical system that would minimize the reporting bias. Fourthly, there are only 65 NACEs in this study, while the multivariable model used 11 covariates, which may have a high risk of overfitting. Thus, we should be cautious when interpreting the current findings.

In summary, the intermittent combination of clopidogrel and PPI did not increase the risk of all-cause death and cardiovascular adverse events in patients with CHD. Intermittent use of PPIs is associated with a lower rate of MACE and NACE. Although there was no statistically significant difference in the incidence of GI bleeding among the three groups, there was a tendency of decreased incidence of GI bleeding with the use of PPIs. However, larger RCTs are needed to further confirm the conclusions of this study.