Conclusion: Concomitant use of PPIs and clopidogrel has been proved not to be associated with elevated cardiovascular risks according to RCTs. Based on our results, no restrictions should be applied whenever PPIs and clopidogrel are administered simultaneously. The literature consists of contradictory findings on the concomitant usage of clopidogrel and proton pump inhibitors PPIs. A combination of antiplatelet drugs is used for the treatment of acute coronary syndrome i. It is well-documented that dual antiplatelet therapy is followed by possible side-effects, such as higher risk for gastrointestinal GI bleeding increasing both mortality and ischaemic complications Nikolsky et al.
In vitro findings suggested that PPIs reduce the antiplatelet effect of clopidogrel Gilard et al. A higher risk for CV outcomes was found in several studies, systematic reviews and meta-analyses in patients with clopidogrel on PPI therapy. Generally, whenever observational studies were included, a positive association was described. On the other hand, whenever propensity-matched groups were compared the difference between the groups disappeared Rassen et al.
Therefore, it is clear that a precise investigation is crucial to understanding the potential CV risk of co-administration of clopidogrel and PPIs. Two independent investigators AD and ERB separately screened the titles and abstracts for eligible studies published from inception to 30 December The flowchart for this process is shown in Figure 1.
Figure 1. Flowchart for study selection and inclusion. Studies published in English were selected. Duplicates were eliminated from the analysis manually. Numeric and texted data were extracted from the eligible articles as follows: author, publication year, study type, study endpoints, number of patients in the study, in PPI and in non-PPI treatment groups, and number of patients who received clopidogrel. We also collected the specified generic name of the PPI and patient number if indicated.
The Newcastle—Ottawa quality assessment scale Wells et al. We used the Cochrane risk of bias tool Higgins et al. Between-study heterogeneity was tested with the I 2 statistic, where I 2 is the proportion of total variation attributable to between-study variability.
Fixed or random effects models were used for comparison between the two groups clopidogrel alone or clopidogrel plus PPI , based on the degree of heterogeneity, or based on methodological factors such as difference between study designs or applied PPIs, not homogeneous patient population etc.
We estimated publication bias through a visual inspection of funnel plots Figures 5A—C. The statistical analysis was performed by a trained biostatistician TL.
Two hundred and thirty-six articles were identified in the preliminary search. One hundred and ninety-three studies were excluded Figure 1. Seventy-six publications 25 full texts, 10 abstracts, and 41 articles from previous meta-analyses were assessed for eligibility and qualitative synthesis. Forty-seven of them were excluded due to insufficient data on study groups and another two for statistical reasons the event rate was zero. A total of 27 studies Rassen et al.
The researchers and committee involved in the selection 5 investigators were in total agreement on all the inclusions and exclusions. Seventeen of them were observational studies, 16 were cohorts Rassen et al.
The method and the study selection are shown in Figure 1. All the studies included were published between and The characteristics of the studies involved in the meta-analysis are summarized in Table 1 according to the major outcome groups, and in Supplementary Tables 1A—D. The number of patients involved was , A total of 63, received PPI plus clopidogrel treatment ranging from 18 to 6, , and 99, ranging from 20 to 17, were in the clopidogrel alone group.
Risk of MACE was determined from data from , patients, MI risk was assessed on the basis of data from 82, patients, and risk of CV death was evaluated based on data from 53, patients.
The PPIs used in the studies were esomeprazole, omeprazole, pantoprazole, rabeprazole, and lansoprazole, but in this meta-analysis as a subgroup analysis we only drew conclusions on the results for omeprazole, esomeprazole, and pantoprazole due to the low number of studies separating data for different PPIs.
Twenty-three studies O'Donoghue et al. Figure 2. Forrest plots representing the estimated risk of overall major adverse cardiac events A and in case of taking specific proton pump inhibitors B CI, confidence interval; PPI, proton pump inhibitor; RCT, randomized controlled trials. In case of patients on omeprazole among the 6 publications included Bhatt et al.
In the case of esomeprazole 4 publications, Hsu et al. In the pantoprazole group, we only found two eligible publications Simon et al. The results of analyzing the adjusted events for the overall outcome and for different PPIs are presented as Supplementary Material. Data on CV death was reported in 10 studies Rassen et al. Analysis of the adjusted events for CV death can be found in the Supplementary Material.
Figure 3. Forrest plot representing the estimated risk of cardiovascular death. Fourteen of the twenty-seven studies contained eligible data on MI, with data for 82, patients for evaluation Rassen et al. We only found two eligible articles Bhatt et al. We present the result for the analysis of adjusted MI events in the Supplementary Material. Figure 4. Forrest plots representing the estimated risk of overall myocardial infarction A and in case of applying omeprazole as proton pump inhibitor B CI, confidence interval; PPI, proton pump inhibitor; RCT, randomized controlled trials.
Risk of bias was assessed in 17 non-RCT studies Rassen et al. The risk of bias within the 27 studies included in this meta-analysis is summarized in the Supplementary Figures 7A,B. Funnel plots were constructed for each outcome and showed symmetry on visual inspection, suggesting that publication bias was not large and was unlikely to alter conclusions Figures 5A—C.
Figure 5. Funnel plots for studies in major adverse cardiac event A , in cardiovascular death B and in myocardial infarction C groups. A possible interaction between clopidogrel and PPIs came to the fore after an observational study had been performed in , which found clopidogrel activity on platelets was diminished in patients receiving PPI treatment Gilard et al. Later, this potential interaction was tested in the randomized controlled OCLA Omeprazole CLopidogrel Aspirin study, where omeprazole significantly decreased the effect of clopidogrel on in vitro platelet activation Gilard et al.
The active metabolite then binds irreversibly to platelet adenosine diphosphate receptor P2Y12 Hulot et al. This is associated with the dephosphorylation of the intraplatelet vasodilator-stimulated phosphoprotein.
Vasodilator-stimulated phosphoprotein phosphorylation provides an index to evaluate platelet reactivity to clopidogrel Ward and Kearns, The findings on mechanisms underlying clopidogrel resistance are contradictory; these mechanisms may relate to heterogeneity in clopidogrel metabolism.
CYP2C19 activity can have a profound effect on the conversion of clopidogrel to its active metabolite Hulot et al. Rabeprazole uses these enzymes the least, being mostly converted to its thioether analog non-enzymatically. Lansoprazole was the most potent inhibitor of CYP2C19 enzyme in vitro , followed by omeprazole and esomeprazole.
It has been suggested that rabeprazole has significantly less drug-drug interactions than other PPIs, and the main reason is claimed to be its non-enzyme catalyzed degradation, but the results of Li et al suggest that omeprazole and rabeprazole have similar affinity to CYP3A4 Li et al. The potential interaction mechanism lies in the fact that both clopidogrel and PPIs, in varying degrees, are metabolized by the same cytochrome P enzyme CYP2C PPIs have the potential to competitively inhibit the metabolism of clopidogrel to its active metabolite, which leads to reduced circulating concentrations of the active compound Disney et al.
The data on the interactions between clopidogrel and PPIs remain unclear despite the numerous in vitro and in vivo studies on the subject. The in vitro studies have shown that the effectiveness of clopidogrel decreases with simultaneous use of clopidogrel and PPIs Gilard et al.
Several possible causative factors may lie behind this phenomenon. One of them is the connected bio-transformational route of clopidogrel and PPIs, or the possible differences in genetic polymorphism of these enzymes Hulot et al. There are several studies, mostly observational ones, whose findings are consistent with these in vitro results, showing an elevated risk for CV side-effects in patients on combined clopidogrel and PPI treatment Pezalla et al.
However, it should be noted that prophylactic PPIs are more likely prescribed to patients with a higher risk for CV events Disney et al. There is considerable disagreement between the various clinical studies that show no increased risk of CV outcomes O'Donoghue et al. In several cases, the authors used multivariable adjustments for covariates to standardize because the effect of possible factors such as age, co-morbidities, and co-medication could modify the outcomes Rassen et al.
In a well-designed case-control study, a current PPI plus clopidogrel group result was compared to the results for patients on current clopidogrel plus past PPI therapy. The association between PPI therapy and the recurrence of MI has disappeared suggesting that the appearance of recurrent MI is a result of a residual confounding Valkhoff et al. Patients with acute coronary syndrome and prior upper GI bleeding are at substantial CV risk, so dual antiplatelet therapy with concomitant use of a PPI may provide the optimal balance of risk and benefit.
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