The clinical relevance of the interaction between clopidogrel and proton pump inhibitors (PPIs) has been discussed in several guidelines. The 2010 American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) expert consensus document on the concomitant use of PPI and thienopyridines states that clinical studies that assessed the degree to which different PPIs interact with CYP2C19 (the enzyme responsible for the interaction between PPIs and clopidogrel) have yielded inconsistent results. However, a clinically relevant interaction may exist, particularly in specific subgroups, such as poor metabolizers of clopidogrel. The 2011 American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACCF/AHA/SCAI) guidelines for percutaneous coronary intervention (PCI) as well as the 2012 ACCF/AHA guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction mentioned the potential drug interaction between clopidogrel and omeprazole. Given the conflicting data supporting the importance of this interaction, the panels do not prohibit use of PPIs in appropriate clinical settings. However, the risk-to-benefit ratio of administering PPI with concurrent clopidogrel should be evaluated. [1], [2], [3]
On the other hand, the 2014 guidelines from the American Heart Association/American Stroke Association (AHA/ASA) on the prevention of stroke in patients with stroke and transient ischemic attack referred to a population study that proposed PPIs alone may increase the risk of cardiovascular events. Thus, the authors recommend considering histamine-2 receptor antagonists (H2RAs) when the administration of antacid is required in a patient taking clopidogrel. It was also suggested that if a PPI is desired, pantoprazole may be preferable to omeprazole because of reduced effects at the CYP2C19 cytochrome site. [4], [5]
A 2021 meta-analysis evaluated the influence of individual PPIs on adverse cardiovascular events in patients receiving dual antiplatelet therapy with clopidogrel following percutaneous coronary intervention (PCI; 28 studies; N= 131,412 patients). The pooled meta-analysis revealed that the concomitant use of clopidogrel with any PPI was associated with an increased risk of major adverse cardiovascular endpoints (MACE; relative risk [RR] 1.30; 95% confidence interval [CI] 1.15 to 1.48; p<0.001). The risk of myocardial infarction (MI) was also higher in the PPI group (RR 1.43; 95% CI 1.25 to 1.64; p <0.001). It should be noted that there was significant heterogeneity between studies for MACE and MI outcomes, limiting these findings. Inconsistent findings were obtained to analyze the specific effects of individual PPIs. Random-effects meta-analyses with individual PPIs demonstrated an increased risk of MACE in those taking pantoprazole (RR 1.31; 95% CI 1.07 to 1.61, p= 0.01) or lansoprazole (RR 1.35; 95% CI 1.19 to 1.54, p <.0001) compared with patients not on PPIs, but not for omeprazole, esomeprazole or rabeprazole. Random-effects meta-analysis of adjusted events for MACE from non-randomized controlled trials showed an increased risk of MACE for all PPIs except rabeprazole (hazard ratio [HR] 1.32; 95% CI 0.69 to 2.53; p= 0.40) and esomeprazole (HR 1.17; 95% CI 0.93 to 1.47; p= 0.19). The risk of gastrointestinal bleeding was lower when only half-dose PPI was used compared with H2RAs (RR 0.25; 95% CI 0.08 to 0.73; p= 0.01). Based on these findings, it was suggested that the concomitant use of clopidogrel with PPI in post-PCI patients is associated with an increased risk of MACE and MI. While the results of rabeprazole were not robust due to the small number of evaluated clinical trials for this agent, it was the only PPI that did not demonstrate an increased risk of MACE. [6]
A recent meta-analysis evaluated the cardiovascular risk of combined PPI/clopidogrel therapy. Co-therapy was found to heighten the risk of all-cause death (odds ratio [OR] 1.50, 95% CI 1.23 to 1.82, p <0.001). However, co-therapy did not increase the risk of MACEs, MI, stroke, target vessel revascularization (TVR), or cardiovascular disease (CVD). After performing a sensitivity analysis (heterogeneity of 0), the co-prescription of PPIs and clopidogrel was at increased risk of MACEs (p <0.001), CVD (p= 0.008), and TVR (p <0.001) but remained statistically non-significant for risk of MI (p= 0.11). Based on these results, there appears to be inconsistent evidence regarding the effects of combined PPI/clopidogrel therapy. [7]
Another 2021 meta-analysis evaluating the safety and efficacy of PPI in patients with coronary artery disease receiving dual antiplatelet therapy (DAPT) included data from 6 randomized controlled trials (RCTs; n= 6,930) and 16 observational studies (n= 183,546). Pooled analysis of RCTs found PPI users did not experience increased incidences of MACEs (risk ratio [RR] 0.89; 95% CI 0.75 to 1.05]), MI (RR 0.93; 95% CI 0.76 to 1.15), and all-cause mortality (RR 0.79; 95% CI 0.50 to 1.23) compared to the non-users. On the other hand, findings from observational studies demonstrated use of lansoprazole (RR 1.24; 95% CI 1.07 to 1.45, I2= 9%) and pantoprazole (RR 1.30; 95% CI 1.04 to 1.61], I2= 77%) led to significantly increased risk of MACEs with concomitant clopidogrel, but not omeprazole, esomeprazole, and rabeprazole. Given the lack of data for the incidence of MI and all-cause mortality in observational studies, a subgroup analysis of each PPI was not performed. As considerable heterogeneity was noticed across observational studies, results should be interpreted with caution. Additionally, actual adherence to PPI regimens in observational studies remained uncertain as the exposure to PPIs was mainly retrieved from prescription and pharmacy dispensing record databases. [8]
Another 2021 meta-analysis evaluated the efficacy and safety of PPI/clopidogrel concomitant therapy in patients undergoing PCI. A total of three randomized controlled trials and 4 cohort studies were included for analysis (N= 9,932). There was found to be a significantly lower risk of gastrointestinal bleeding events in the PPI group compared to the no PPI group (OR 3.06, 95% CI 1.89 to 4.95, p <0.00001). There was, however, no difference in MACEs between the PPI group and non-PPI group (OR 1.05, 95% CI 0.91 to 1.21, p= 0.50). Due to strict inclusion/exclusion criteria, relatively few studies were included for analysis, which may limit the impact of the results. [9]
Similarly, a 2016 meta-analysis also evaluated the effect of concomitant clopidogrel/PPI therapy on adverse cardiovascular outcomes in patients receiving PCI. A total of 12 cohort studies comprising 50,277 PCI patients were included for analysis. Concomitant therapy following PCI results in a significant increase in composite MACE (HR 1.28, 95% CI 1.24 to 1.32), MI (HR 1.51, 95% CI 1.40 to 1.62), and stroke (HR 1.46, 95% CI 1.15 to 1.86). Differences in all-cause death, cardiovascular death, and stent thrombosis were not statistically significant between concomitant therapy and clopidogrel monotherapy. Notably, the inconsistent definition of MACE outcomes may have affected the findings. [10]
A 2012 pharmacodynamic study found lansoprazole and esomeprazole to be the most potent CYP2C19 inhibitors, followed by dexlansoprazole and omeprazole. Rabeprazole and pantoprazole were observed to be the weakest inhibitors of CYP2C19. After taking plasma levels (static and dynamic), protein binding, and metabolism-dependent inhibition into consideration, it is suggested that esomeprazole and omeprazole are more likely to lead to clinically relevant inhibition of CYP2C19. [11]