Controversies still exist with the concomitant use of clopidogrel, one of the components of the Dual Anti-Platelet Therapy (DAPT) with Proton Pump Inhibitors (PPIs), especially omeprazole following Percutaneous Coronary Intervention (PCI). Even if the American College of Cardiology/Gastroenterology and the American Heart Association recommend prophylactic treatment with a PPI in those patients who require DAPT and those patients who are at high risk of gastrointestinal injury [1], recent studies have shown clopidogrel and PPIs to be metabolized by the same cytochrome P450 2C19 (CYP2C19) pathway [2].

Several studies showed no interaction between clopidogrel and PPIs. For example, Rassen et al. showed a slight increase in the rate of Myocardial Infarction (MI) and mortality in older patients discharged on clopidogrel and PPIs, but the authors were not able to conclude any interaction between PPIs and clopidogrel in terms of major clinical relevance [3]. Zairis et al. also showed no impact of omeprazole on the clinical efficacy of clopidogrel during the first year following PCI [4].

However, decrease in antiplatelet effects of clopidogrel with the concomitant use of PPIs has been observed. Patients had a higher level of platelet reactivity which resulted in an increased risk of adverse clinical outcomes [5]. For example, Gupta et al. concluded that the concomitant use of clopidogrel with PPIs following coronary stents implantation was associated with a significantly higher risk of major adverse cardiac events (MACEs) [6].

In 2012, Huang et al. conducted a meta-analysis based on the current idea, using old data (2009–2011) [7]. Results from their meta-analysis showed significantly increased risk of MACEs in patients with the concomitant use of clopidogrel and PPIs. Unfortunately, the high level of heterogeneity observed among the different subgroups analyzed was their major limitation.

Recently, many new studies were published based on the cardiovascular outcomes observed in patients treated with clopidogrel plus PPIs and clopidogrel alone following PCI. However, whether these controversies still exist in this new era is not clear. Therefore, we aim to show if the concomitant use of clopidogrel and PPIs is still associated with higher adverse outcomes following PCI using data obtained from recently published studies (2012 to 2016).

Controversies still exist with the concomitant use of clopidogrel and PPIs following coronary stenting, which remain to be solved in this new era. In this analysis, we aimed to compare the adverse clinical outcomes associated with the concomitant use of clopidogrel and PPIs versus clopidogrel alone following PCI using data obtained from recently published articles (2012–2016).

This current analysis showed that during a short term follow up period, mortality and revascularization were significantly lower in those patients who did not require treatment with PPIs. Moreover, during the long term follow up period, adverse cardiovascular outcomes such as MACEs, ST, MI and TVR significantly favored patients in the non-PPI group. However, result for the long-term mortality was similar manifested in both groups.

The previously published meta-analysis [7] which included 32 studies with publication date before the year 2012 (29 studies published in English and 3 studies published in Chinese), showed the concomitant use of PPI and clopidogrel to be associated with higher MACEs with OR: 1.27, 95% CI: 1.13–1.42 when a combination of data obtained from randomized trials and observational studies was used. However, pooling data only from randomized trials did not show any increase risk of MACEs with OR: 0.92, 95% CI: 0.53–1.58; P = 0.72, I² = 0%. When mortality was analyzed using a random effects model, a significant increase was observed with HR: 1.30, 95% CI: 0.91–1.86. But when a fixed effects model was used to analyze mortality, no significant increase was observed with clopidogrel plus PPI with OR: 0.92, 95% CI: 0.82–1.04.

Several reasons have been suggested for such a result. First of all, PPIs involve the same metabolic pathway (mainly CYP2C19 isoenzyme) with that of clopidogrel [10]. In other words, by occupying the same metabolic pathway as clopidogrel, PPIs are expected to reduce the antiplatelet effects of clopidogrel. Because PPIs can act as both, inhibitors and substrates of CYP2C19, patients treated with clopidogrel and PPIs are vulnerable to a reduced effectiveness of clopidogrel. This could in turn result in a higher platelet activity following PCI finally causing an increase in adverse clinical outcomes. Gilard et al. were the first ones to show the interaction of clopidogrel and PPIs [11]. Moreover, PPIs not only showed a high platelet reactivity but also showed an increased inflammatory state due to the rise in the level of interleukins-6 which in turn could increase the occurrence of ischemic events [12]. However, whether PPIs really have an effect on clopidogrel’s antiplatelet effect is still being debated.

Similar to the results of this current analysis, many other previously published studies showed that adverse clinical outcomes were significantly increased in the PPIs group. Gupta et al. concluded that the concomitant use of clopidogrel with PPIs was associated with an increased risk of MACEs following PCI [6]. In addition, Ho et al. showed increased risk of adverse outcomes with clopidogrel plus PPIs [13].

However, even if many studies supported these current results, several other studies showed results which were completely different. For example, Rassen et al. showed that although a slight increase in hospitalization due to MI and death was observed in older patients who were prescribed PPIs and clopidogrel together, there was not enough evidence to conclude any major interaction between these 2 drugs [3]. In the analysis from the Guthrie Health Off-Label Stent (GHOST) Investigators, the authors also concluded that the use of PPIs with DAPT was not associated with any increase in MACEs following PCI [14]. However, their study had a follow up period of only 6 months. Zairis et al. also showed no impact of omeprazole on the clinical efficacy of clopidogrel during the first year following successful PCI [4]. However, the authors concluded that further highly powered studies should be conducted to confirm whether or not, omeprazole has any effect on the antiplatelet mechanism of clopidogrel. In addition, the COGENT study also did not observe any apparent interaction between clopidogrel and omeprazole, but however, the authors strictly mentioned that their results did not rule out clinically meaningful differences in adverse cardiovascular outcomes due to the use of PPIs [15].

Nevertheless, among all the PPIs, omeprazole is considered to have a higher effect on the mechanism of clopidogrel. Other studies did not show any notable inter-reaction among non-omeprazole PPIs and clopidogrel. For example, when pantoprazole was used along with clopidogrel, no increase in adverse events was observed and therefore pantoprazole has been recommended compared to omeprazole in patients treated with clopidogrel. In addition, in a sub-analysis of the randomized PRODIGY trial, it was reported that the concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel, was not associated with adverse clinical outcomes. However, it should also be noted that only less than 1.5% of the patients used omeprazole while more than 90% of the patients in that particular trial used lansoprazole, suggesting that this type of PPIs might be safer to use with clopidogrel [16].

Since the adverse clinical events associated with non-omeprazole PPIs and clopidogrel have still not clearly been studied, further research is recommended with these individual PPIs (esomeprazole, rabeprazole, lansoprazole, and pantoprazole). In addition, bleeding events especially gastrointestinal bleeding associated with the concomitant use of clopidogrel with these individual PPIs should also be carefully studied.

A moderate level of heterogeneity was observed among certain subgroups analyzing the cardiovascular outcomes. Only English publications were considered, and articles written in other languages were ignored, therefore, a language bias might most probably be present. Moreover, data obtained from conference abstracts and other unpublished studies were not included. However, since most of the data used in this analysis were obtained from observational studies, it could be one of the reasons contributing to the moderate risk of bias observed. In addition, a high level of heterogeneity could also have been due to the fact that different types of patients were included (chronic stable angina, STEMI, NSTEMI) and the type of stent following PCI was also not taken into consideration; patients implanted with DES and BMS were combined and analyzed.

Novelty in this study is the fact that a lower level of heterogeneity was present among several subgroups compared to the previously published meta-analysis. Moreover, different from other studies which mainly report either short term, mid-term or long term outcomes, this analysis has compared the long term and short term adverse clinical outcomes in patients with and without the concomitant use of clopidogrel and PPIs. In addition, this analysis included data obtained from newly published research articles.

The combined use of clopidogrel with PPIs is still associated with significantly higher adverse cardiovascular events such as MACEs, ST and MI following PCI supporting results of the previously published meta-analysis. However, long-term mortality is not statistically significant warranting further analysis with randomized patients.