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Meta-Analysis of Efficacy and Safety of Proton Pump Inhibitors with Dual Antiplatelet Therapy for Coronary Artery Disease
Abstract
Background:
There is inconsistency in the literature regarding the clinical effects of proton pump inhibitors (PPI) when added to dual antiplatelet therapy (DAPT) in subjects with coronary artery disease (CAD). We performed meta-analysis stratified by study design to explore these differences.
Methods and results:
39 studies [4 randomized controlled trials (RCTs) and 35 observational studies) were selected using MEDLINE, EMBASE and CENTRAL (Inception-January 2018). In 221,204 patients (PPI = 77,731 patients, no PPI =143,473 patients), RCTs restricted analysis showed that PPI did not increase the risk of all-cause mortality (Risk Ratio (RR): 1.35, 95% Confidence Interval (CI), 0.56-3.23, P = 0.50, I2 = 0), cardiovascular mortality (RR: 0.94, 95% CI, 0.25-3.54, P = 0.92, I2 = 56), myocardial infarction (MI) (RR: 0.97, 95% CI, 0.62-1.51, P = 0.88, I2 = 0) or stroke (RR: 1.11, 95% CI, 0.25-5.04, P = 0.89, I2 = 26). However, PPI significantly reduced the risk of gastrointestinal (GI) bleeding (RR: 0.32, 95% CI, 0.20-0.52, P < 0.001, I2 = 0). Conversely, analysis of observational studies showed that PPI significantly increased the risk of all-cause mortality (RR: 1.25, 95% CI, 1.11-1.41, P < 0.001, I2 = 82), cardiovascular mortality (RR: 1.25, 95% CI, 1.03-1.52, P = 0.02, I2 = 71), MI (RR: 1.30, 95% CI, 1.16-1.47, P < 0.001, I2 = 82) and stroke (RR: 1.60, 95% CI, 1.43-1.78, P < 0.001, I2 = 0), without reducing GI bleeding (RR: 0.74, 95% CI, 0.45-1.22, P = 0.24, I2 = 79).
Conclusion:
Meta-analysis of RCTs endorsed the use of PPI with DAPT for reducing GI bleeding without worsening cardiovascular outcomes. These findings oppose the negative observational data regarding effects of PPI with DAPT.
... A meta-analysis published in 2017 demonstrated a significantly increased risk of stent thrombosis with the concomitant use of clopidogrel with proton pump inhibitors, although another published in 2019 did not demonstrate an increase in cardiovascular outcomes in patients using PPIs. and DAPT (Bundhun, Teeluck, Bhurtu, & Huang, 2017;Khan et al., 2019). A metaanalysis was recently published in which it was shown that the use of DAPT together with PPIs increases the risk of major adverse cardiovascular events (MACE) (HR =1.15 95% CI = 1.06-1.26, ...
... However, the clinical relevance of this interaction is still controversial with conflicting results in observational studies, clinical trials and meta-analyses (Bhatt et al., 2010;Bundhun et al., 2017;Cuisset et al., 2009;Drepper et al., 2009Drepper et al., ). al., 2012Khan et al., 2019;Luo et al., 2023;O'Donoghue et al., 2009;Tentzeris et al., 2010). ...
... Additional studies have corroborated the finding that PPIs reduce the risk of UGIB, GI ulcers, and erosions in patients on concurrent DAPT [36,[53][54][55][56]. Screening for risk factors of upper GI bleeding did not significantly reduce the incidence of UGIB in patients placed on DAPT and PPI [57]. ...
... There is evidence beyond COGENT data that PPI and DAPT co-therapy does not lead to an increase in MACCE. There are substantial data that demonstrate that patients treated with PCI and DAPT (clopidogrel and aspirin) have had similar all-cause death, MI, and cerebrovascular accident (CVA) among PPI and non-PPI users [27,[53][54][55][56][57][58][59][60]. A couple of studies in patients with CAD also concluded PPI and DAPT co-prescription did not lead to increased adverse risks [56,60]. ...
Dual-antiplatelet therapy (DAPT) prevents thrombotic complications associated with coronary artery disease, acute coronary syndrome, and stent thrombosis following the percutaneous coronary intervention or coronary artery bypass grafting. When initiating DAPT, the risk of thrombosis must be balanced with the increased risk of upper gastrointestinal bleed (UGIB). Proton-pump inhibitors (PPIs) are concurrently prescribed with DAPT to reduce bleeding risk.
In this review, we discuss the benefits and potential complications of DAPT/PPI co-prescription. The only large international randomized control trial (RCT), Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT), shows robust evidence that PPIs are a safe and effective method to reduce the risk of bleeding in patients on DAPT. However, more large-scale RCTs are needed to study potential long-term effects and draw a stronger conclusion on this topic.
... DDIs leading to decreased efficacy of antiplatelet drugs have raised concern because of the possibility of increased risk of thrombotic events, but some of the studies evaluating these DDIs did not have consistent results (132). A prime example of such DDI is an interaction of clopidogrel and PPIs for which even several meta-analyses have shown conflicting results (133)(134)(135). Meta-analyses of randomized controlled trials endorsed the use of PPI with DAPT for reducing gastrointestinal bleeding without worsening cardiovascular outcomes, while meta-analyses of observational studies showed that PPI significantly increased the risk of all-cause mortality, cardiovascular mortality, myocardial infarction and stroke without reducing gastrointestinal bleeding and this difference was attributed to differences in design and limitations of each study type (133)(134)(135). ...
... A prime example of such DDI is an interaction of clopidogrel and PPIs for which even several meta-analyses have shown conflicting results (133)(134)(135). Meta-analyses of randomized controlled trials endorsed the use of PPI with DAPT for reducing gastrointestinal bleeding without worsening cardiovascular outcomes, while meta-analyses of observational studies showed that PPI significantly increased the risk of all-cause mortality, cardiovascular mortality, myocardial infarction and stroke without reducing gastrointestinal bleeding and this difference was attributed to differences in design and limitations of each study type (133)(134)(135). The European Society of Cardiology (ESC) currently recommends PPI use in combination with DAPT in all coronary artery disease patients as a measure to minimize bleeding risk, but with a note that omeprazole and esomeprazole would appear to have the highest propensity for clinically relevant DDIs, while pantoprazole and rabeprazole have the lowest (136). ...
Drug-drug interaction (DDI) is defined as a clinically significant change in the exposure and/or response to a drug caused by co-administration of another drug which may result in a precipitation of an adverse event or alteration of its therapeutic effects. The aim of this systematic review was to provide an overview of DDIs that were actually observed or evaluated in acute coronary syndrome (ACS) patients with particular focus on DDIs with clinical relevance. Electronic searches of the literature were conducted in the following databases: MEDLINE, EBSCO, Scopus, Google Scholar and SCIndeks. A total of 117 articles were included in the review. This review showed that ACS patients can be exposed to a variety of DDIs with diverse outcomes which include decreased efficacy of antiplatelet drugs, thrombolytics or anticoagulants, increased risk of bleeding, rhabdomyolysis, hepatotoxicity, adverse effects on cardiovascular system (e.g. QT interval prolongation, arrhythmias, excessive bradycardia, severe hypotension), serotonin syndrome and drug-induced fever. Majority of the DDIs involved antiplatelet drugs (e.g. aspirin, clopidogrel and ticagrelor). Evidence of some of the reported DDIs is inconclusive as some of the studies have shown conflicting results. There is a need for additional post-marketing and population-based studies to evaluate the true effects of disease states and other factors on the clinical outcomes of DDIs. Clinicians should be attentive to the potential for DDIs and their associated harm in order to minimize or, if possible, avoid medication-related adverse events in ACS patients.
... ( Table 2) [16]. Other meta-analyses of mixed studies also show conflicting results indicating that PPI use significantly reduces the incidence of GI problems (bleeding, ulcers and GI erosions), as well as the incidence of post-PCI unstable angina, but there is no significant difference in MI, stroke, and CV mortality, albeit with a trend toward decreased all-cause mortality noted with PPIs [38,39]. Importantly, analyses of some observational or mixed studies show that PPIs may increase the risk of mortality and MACE, albeit with high heterogeneity noted in these studies for most harmful effects. ...
... In summary, some investigators maintain that there may be an increased risk of adverse CV events with PPI monotherapy according to their own analyses of pooled data from observational studies, but not from RCTs [16,31]. Furthermore, co-administration of PPIs with P2Y12 inhibitors has a protective effect on the GI events without worsening CV outcomes [38,39]. With regards to ischemic stroke, there does not seem to be a significant association between PPI use and ischemic stroke, after accounting for indications for PPI use, as prior reports of an increased risk of stroke may be due to residual confounding related to chronic conditions associated with PPI use [41]. ...
Proton pump inhibitors (PPIs) are among the most widely prescribed agents, either for treatment or prophylaxis of gastrointestinal (GI) disease, that are often administered for prolonged or chronic use. Patients with cardiovascular (CV) disease frequently receive PPIs for prophylaxis against GI bleeding due to common use of antithrombotic drugs. Over the last several years there is a growing number of reports associating chronic PPI use with a variety of serious CV and non-CV adverse effects. In this context, PPI use has been independently associated with an increased risk of CV morbidity (myocardial infarction, stroke, other CV events) and mortality. However, the critique remains that these data do not largely derive from randomized controlled trials. On the other hand, in certain conditions, the benefits of PPIs may outweigh the risks of adverse CV effects. As the indications for prolonged, particularly lifelong, prophylactic use of PPIs are not compelling and in the light of evidence of serious CV and other adverse effects, clinicians have to reconsider such long-term use of these drugs. Importantly, histamine 2 blockers have not been found to be associated with increased CV risk and thus may be an alternative therapeutic option in certain patients. These issues are amply discussed together with the potential mechanisms of these pleiotropic and off-target effects of PPIs, which are also depicted in an illustrative schema; data are also presented on differential effects of specific agents involved, alternative modes of therapy available, and relevant current guidelines on this issue.
... In a prospective cohort study consisting of 10,000 adults, it was found that PPI use was associated with a 20-50% higher risk of chronic kidney failure, and PPI was a risk factor for acute kidney injury (AKI) and chronic kidney disease (CKD). [13] Several studies also state that there is an increased risk of acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage renal disease (ESRD) in PPI users. [14] Therefore, researchers wanted to know the description of urea and creatinine in dyspepsia patients who took proton pump inhibitor drugs at the Indonesian Christian University Hospital. ...
Dyspepsia is a health problem often encountered by doctors in daily practice. Many people complain of symptoms of dyspepsia but do not seek help for treatment. Proton pump inhibitors are the drugs for the treatment of dyspepsia, such as omeprazol, lansoprazol, esomeprazol, rabeprazol, and pantoprazol. Some studies have explained that proton pump inhibitor drugs can interfere with kidney function due to acute interstitial nephritis due to the consumption of proton pump inhibitors, and this condition can end with chronic kidney disease that occurs due to undiagnosed acute interstitial nephritis. This study aimed to see how urea and creatinine levels in dyspepsia patients at Universitas Kristen Indonesia Hospital were taking proton pump inhibitors. This research is a descriptive research content analysis, hospital-based. Based on medical records at Universitas Kristen Indonesia Hospital in 2018, 80.3% high ureum levels and 19.7% normal ureum levels were found. In creatinine levels, it was found that men had more normal creatinine levels of 57.7% and high ureum levels of 42.3%, and women found more normal creatinine levels of 62.5% and high creatinine levels of 37.5%. Keywords: Dyspepsia, Proton Pump Inhibitor, Creatinine, Ureum
... On the other hand, TEG has been used to guide blood product use in various scenarios in patients with cirrhosis and impaired coagulation assessed using conventional methods (INR and platelet count)[61]. In randomized trials, TEG compared to conventional methods led to lower blood products use without an increase in bleeding complications in patients with bleeding varices and before invasive procedures [62,63]. Based on mentioned, TEG can theoretically be used to assess hemostatic pathways before administration of DAPT, with more freely DAPT usage in case of preserved hemostasis. ...
The prevalence of coronary artery disease (CAD) increases in patients with end-stage liver disease, with part of them receiving the percutaneous coronary intervention (PCI) as a treatment option. Dual antiplatelet therapy (DAPT), a standard of care after PCI, could result in catastrophic consequences in this population. Before PCI and the start of DAPT, it is recommended to assess patient bleeding risk. Based on novel findings, liver cirrhosis does not necessarily lead to a significant increase in bleeding complications. Furthermore, conventional methods, such as the international normalized ratio, might not be appropriate in assessing individual bleeding risk. The highest bleeding risk among cirrhotic patients has a subgroup with severe thrombocytopenia (< 50 × 109/L) and elevated portal pressure. Therefore, every effort should be made to maintain thrombocyte count above > 50 × 109/L and prevent variceal bleeding. There is no solid evidence for DAPT in patients with cirrhosis. However, randomized trials investigating short (one month) DAPT duration after PCI with new drug-eluting stents (DES) in a high bleeding risk patient population can be implemented in patients with cirrhosis. Based on retrospective studies (with older stents and protocols), PCI and DAPT appear to be safe but with a higher risk of bleeding complications with longer DAPT usage. Finally, novel methods in assessing CAD severity should be performed to avoid unnecessary PCI and potential risks associated with DAPT. When indicated, PCI should be performed over radial artery using contemporary DES. Complementary medical therapy, such as proton pump inhibitors and beta-blockers, should be prescribed for lower bleeding risk patients. Novel approaches, such as thromboelastography and “preventive” upper endoscopies in PCI circumstances, warn clinical confirmation.
... As elderly patients with a history of bleeding or MI had a higher risk of BARC ≥2 type bleeding, it is therefore important to tailor the DAPT regimen for patients (≥75 years) undergoing PCI. The usage of PPI was supposed to have a protective role to reduce the gastrointestinal bleeding risk in CAD patients who received antiplatelet treatment (Khan et al., 2019); however, no association was found between the use of PPI and the reduction of BARC ≥2 type bleeding events in elderly patients in our study. The reasons may be due to the irregular usage of PPIs in the clinics and the limited number of patients enrolled in our study. ...
Purpose: To determine the incidence and risk factors of bleeding events as well as assess the performance of the PRECISE-DAPT score in elderly patients (≥75 years) who underwent percutaneous coronary intervention (PCI) and one-year dual antiplatelet therapy (DAPT).
Methods: A total of 940 patients (≥75 years) who received PCI and one-year DAPT were retrospectively enrolled into the study. The multivariable logistic regression analysis was conducted to identify risk factors of antiplatelet-related bleeding complications. The receiver operating characteristic (ROC) curve analysis and the Delong test were performed to obtain the optimized PRECISE-DAPT score.
Results: It was observed that 89 (9.47%) patients suffered bleeding complications, while 37 (3.94%) of them had the Bleeding Academic Research Consortium (BARC, type ≥2) bleeding events. We stratified the PRECISE-DAPT score in tertiles (T1: ≤23; T2:24 to 32; T3: ≥33) and found that BARC ≥ 2 type bleeding occurred more frequently in T3 than in T1 and T2 (8.25 vs. 1.46% vs. 2.40%, p <0.05). The ROC curve analysis revealed that the PRECISE-DAPT score cutoff for BARC ≥2 type bleeding prediction was 33. In comparison with the current recommended cutoff score of 25 (AUC: 0.608, based on ROC analysis), the Delong test indicated significantly improved ability for predicting BARC ≥ 2 type bleeding events using the proposed cutoff value of 33, AUC of 0.676 ( p = 0.03), and Brier Score of 0.04. The multivariable logistic regression analysis demonstrated that the PRECISE-DAPT score ≥ 33 [OR: 3.772; 95% CI (1.229, 11.578); p = 0.02] was associated with BARC ≥ 2 type bleeding event, along with a history of hemorrhagic stroke [OR: 6.806; 95% CI (1.465, 31.613); p = 0.014], peptic ulcer [OR: 3.871; 95% CI (1.378, 10.871); p = 0.01], and/or myocardial infarction [MI, OR: 3.081; 95% CI (1.140, 8.326); p = 0.027].
Conclusion: A higher PRECISE-DAPT score of 33 might be a more reasonable cutoff value for predicting BARC ≥2 type bleeding risk in CAD patients (≥75 years). In addition, the history of hemorrhagic stroke, peptic ulcer, and myocardial infarction were identified as the risk factors of BARC ≥2 type bleeding events.
... 92,93 A more recent meta-analysis, however, has shown that the use of PPIs and dual antiplatelet therapy improves outcomes of GI bleeding, without compromising cardiovascular outcomes and that further randomized trials are required in this area. 94 There are numerous alternatives to PPIs that have been trialed with various degrees of success. Histamine-2 receptor antagonists (H 2 RAs), such as ranitidine, nizatidine, famotidine, and cimetidine, although historically the first-line therapy, are less effective than PPIs in symptom control and esophageal healing and are often used as the step-down therapy or as an adjunct to PPIs. ...
Gastroesophageal reflux disease (GERD) is a common clinical condition for which our understanding has evolved over the past decades. It is now considered a cluster of phenotypes with numerous anatomical and physiological abnormalities contributing to its pathophysiology. As such, it is important to first understand the underlying mechanism of the disease process for each patient before embarking on therapeutic interventions. The aim of our paper is to highlight the mechanisms contributing to GERD and review investigations and interpretation of these results. Finally, the paper reviews the available treatment modalities for this condition, ranging from medical intervention, endoscopic options through to surgery and its various techniques.
Background:
Researchers and decision-makers often use evidence from randomised controlled trials (RCTs) to determine the efficacy or effectiveness of a treatment or intervention. Studies with observational designs are often used to measure the effectiveness of an intervention in 'real world' scenarios. Numerous study designs and their modifications (including both randomised and observational designs) are used for comparative effectiveness research in an attempt to give an unbiased estimate of whether one treatment is more effective or safer than another for a particular population. An up-to-date systematic analysis is needed to identify differences in effect estimates from RCTs and observational studies. This updated review summarises the results of methodological reviews that compared the effect estimates of observational studies with RCTs from evidence syntheses that addressed the same health research question.
Objectives:
To assess and compare synthesised effect estimates by study type, contrasting RCTs with observational studies. To explore factors that might explain differences in synthesised effect estimates from RCTs versus observational studies (e.g. heterogeneity, type of observational study design, type of intervention, and use of propensity score adjustment). To identify gaps in the existing research comparing effect estimates across different study types.
Search methods:
We searched MEDLINE, the Cochrane Database of Systematic Reviews, Web of Science databases, and Epistemonikos to May 2022. We checked references, conducted citation searches, and contacted review authors to identify additional reviews.
Selection criteria:
We included systematic methodological reviews that compared quantitative effect estimates measuring the efficacy or effectiveness of interventions tested in RCTs versus in observational studies. The included reviews compared RCTs to observational studies (including retrospective and prospective cohort, case-control and cross-sectional designs). Reviews were not eligible if they compared RCTs with studies that had used some form of concurrent allocation.
Data collection and analysis:
Using results from observational studies as the reference group, we examined the relative summary effect estimates (risk ratios (RRs), odds ratios (ORs), hazard ratios (HRs), mean differences (MDs), and standardised mean differences (SMDs)) to evaluate whether there was a relatively larger or smaller effect in the ratio of odds ratios (ROR) or ratio of risk ratios (RRR), ratio of hazard ratios (RHR), and difference in (standardised) mean differences (D(S)MD). If an included review did not provide an estimate comparing results from RCTs with observational studies, we generated one by pooling the estimates for observational studies and RCTs, respectively. Across all reviews, we synthesised these ratios to produce a pooled ratio of ratios comparing effect estimates from RCTs with those from observational studies. In overviews of reviews, we estimated the ROR or RRR for each overview using observational studies as the reference category. We appraised the risk of bias in the included reviews (using nine criteria in total). To receive an overall low risk of bias rating, an included review needed: explicit criteria for study selection, a complete sample of studies, and to have controlled for study methodological differences and study heterogeneity. We assessed reviews/overviews not meeting these four criteria as having an overall high risk of bias. We assessed the certainty of the evidence, consisting of multiple evidence syntheses, with the GRADE approach.
Main results:
We included 39 systematic reviews and eight overviews of reviews, for a total of 47. Thirty-four of these contributed data to our primary analysis. Based on the available data, we found that the reviews/overviews included 2869 RCTs involving 3,882,115 participants, and 3924 observational studies with 19,499,970 participants. We rated 11 reviews/overviews as having an overall low risk of bias, and 36 as having an unclear or high risk of bias. Our main concerns with the included reviews/overviews were that some did not assess the quality of their included studies, and some failed to account appropriately for differences between study designs - for example, they conducted aggregate analyses of all observational studies rather than separate analyses of cohort and case-control studies. When pooling RORs and RRRs, the ratio of ratios indicated no difference or a very small difference between the effect estimates from RCTs versus from observational studies (ratio of ratios 1.08, 95% confidence interval (CI) 1.01 to 1.15). We rated the certainty of the evidence as low. Twenty-three of 34 reviews reported effect estimates of RCTs and observational studies that were on average in agreement. In a number of subgroup analyses, small differences in the effect estimates were detected: - pharmaceutical interventions only (ratio of ratios 1.12, 95% CI 1.04 to 1.21); - RCTs and observational studies with substantial or high heterogeneity; that is, I2 ≥ 50% (ratio of ratios 1.11, 95% CI 1.04 to 1.18); - no use (ratio of ratios 1.07, 95% CI 1.03 to 1.11) or unclear use (ratio of ratios 1.13, 95% CI 1.03 to 1.25) of propensity score adjustment in observational studies; and - observational studies without further specification of the study design (ratio of ratios 1.06, 95% CI 0.96 to 1.18). We detected no clear difference in other subgroup analyses.
Authors' conclusions:
We found no difference or a very small difference between effect estimates from RCTs and observational studies. These findings are largely consistent with findings from recently published research. Factors other than study design need to be considered when exploring reasons for a lack of agreement between results of RCTs and observational studies, such as differences in the population, intervention, comparator, and outcomes investigated in the respective studies. Our results underscore that it is important for review authors to consider not only study design, but the level of heterogeneity in meta-analyses of RCTs or observational studies. A better understanding is needed of how these factors might yield estimates reflective of true effectiveness.
Cardiovascular disease (CVD) is a class of disorders of the heart and blood vessels and the leading cause of death worldwide. Yet, treatment of CVDs is the major challenge in medicine because they are mostly multifactorial and multi-mechanism conditions that require simultaneous targeting on multitargets to produce optimal results. Even monogenic CVDs are influenced by multiple cellular regulators and environmental factors. Because of these traits of CVDs, it has recently come to a common consensus that combination therapies overall produce superior outcomes for many types of CVDs compared to monotherapy. In this chapter, we will introduce the polypharmacology strategy, particularly free-dose drug combination (CDT), fixed-dose single-pill drug combination (FDC), and multitarget drug, for the treatment of some most common CVDs including hypertension, hyperlipidemia, coronary artery disease (CAD), heart failure (HF), cardiac arrhythmias, and stroke. At present, while CDT and FDC have been utilized in nearly all major type of CVDs, the application of MTD is primarily restricted to hypertension and arrhythmias.KeywordsCardiovascular polypharmacologyHypertensionCoronary artery disease (CAD)Heart failure (HF)Cardiac arrhythmias
Background
There have been ongoing efforts to understand when and how data from observational studies can be applied to clinical and regulatory decision making. The objective of this review was to assess the comparability of relative treatment effects of pharmaceuticals from observational studies and randomized controlled trials (RCTs).
Methods
We searched PubMed and Embase for systematic literature reviews published between January 1, 1990, and January 31, 2020, that reported relative treatment effects of pharmaceuticals from both observational studies and RCTs. We extracted pooled relative effect estimates from observational studies and RCTs for each outcome, intervention-comparator, or indication assessed in the reviews. We calculated the ratio of the relative effect estimate from observational studies over that from RCTs, along with the corresponding 95% confidence interval (CI) for each pair of pooled RCT and observational study estimates, and we evaluated the consistency in relative treatment effects.
Results
Thirty systematic reviews across 7 therapeutic areas were identified from the literature. We analyzed 74 pairs of pooled relative effect estimates from RCTs and observational studies from 29 reviews. There was no statistically significant difference (based on the 95% CI) in relative effect estimates between RCTs and observational studies in 79.7% of pairs. There was an extreme difference (ratio < 0.7 or > 1.43) in 43.2% of pairs, and, in 17.6% of pairs, there was a significant difference and the estimates pointed in opposite directions.
Conclusions
Overall, our review shows that while there is no significant difference in the relative risk ratios between the majority of RCTs and observational studies compared, there is significant variation in about 20% of comparisons. The source of this variation should be the subject of further inquiry to elucidate how much of the variation is due to differences in patient populations versus biased estimates arising from issues with study design or analytical/statistical methods.
Gastroesophageal reflux disease (GERD) continues to be among the most common diseases seen by gastroenterologists, surgeons, and primary care physicians. Our understanding of the varied presentations of GERD, enhancements in diagnostic testing, and approach to patient management have evolved. During this time, scrutiny of proton pump inhibitors (PPIs) has increased considerably. Although PPIs remain the medical treatment of choice for GERD, multiple publications have raised questions about adverse events, raising doubts about the safety of long-term use and increasing concern about overprescribing of PPIs. New data regarding the potential for surgical and endoscopic interventions have emerged. In this new document, we provide updated, evidence-based recommendations and practical guidance for the evaluation and management of GERD, including pharmacologic, lifestyle, surgical, and endoscopic management. The Grading of Recommendations, Assessment, Development, and Evaluation system was used to evaluate the evidence and the strength of recommendations. Key concepts and suggestions that as of this writing do not have sufficient evidence to grade are also provided.
Proton pump inhibitors (PPIs) are popular and widely used “gastroprotectives”. More than 10% of our population is treated. In addition to classical indications such as gastroduodenal peptic disease or gastroesophageal reflux disease, they are indicated for the reduction of hemorrhagic complications in the digestive tract during antithrombotic treatment. The effect of PPIs on reducing upper gastrointestinal bleeding in antithrombotic treatment (rivaroxaban, acetylsalicylic acid or a combination) was called into question by a recently published randomised mega-study - COMPASS pantoprazole. Treatment of PPIs is accompanied by a number of significant drug interactions, in particular a severe reduction in the bioactivation of clopidogrel and a reduction in the absorption of acetylsalicylic acid or dabigatran. As a result, the effect of these antithrombotics is reduced. A number of observational studies - in the indication of PPIs in the treatment of gastroduodenal or gastrooesophageal disease or when used in the treatment of PPIs in antithrombotic treatment - found a greater incidence of major vascular events and an increase in mortality. So are PPIs effective in protecting gastrointestinal bleeding and are they safe?
Background
Controversies were previously observed with the concomitant use of clopidogrel and Proton Pump Inhibitors (PPIs), especially omeprazole, following coronary angioplasty. Even though several studies showed no interaction between clopidogrel and PPIs, questions have been raised about the decrease in antiplatelet effects of clopidogrel with PPIs. A previously published meta-analysis showed concomitant use of clopidogrel and PPIs to be associated with higher adverse cardiovascular outcomes. However, data which were used were extracted from studies published before the year 2012. 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 Percutaneous Coronary Intervention (PCI) using data obtained from recently published studies (2012 to 2016).
Methods
Electronic databases were searched for recent publications (2012–2016) comparing (clopidogrel plus PPIs) versus clopidogrel alone following PCI. Adverse cardiovascular outcomes were considered as the clinical endpoints. Odds Ratios (OR) with 95% Confidence Intervals (CI) were used as the statistical parameters and the pooled analyses were performed with RevMan 5.3 software.
Results
Eleven studies with a total number of 84,729 patients (29,235 patients from the PPIs group versus 55,494 patients from the non-PPIs group) were included. Results of this analysis showed that short term mortality and Target Vessel Revascularization (TVR) significantly favored the non-PPIs group with OR: 1.55; 95% CI: 1.43–1.68, P < 0.00001 and OR: 1.26; 95% CI: 1.06–1.49, P = 0.009 respectively. Long-term Major Adverse Cardiac Events (MACEs), Myocardial Infarction (MI), Stent Thrombosis (ST) and TVR significantly favored patients who did not use PPIs with OR: 1.37; 95% CI: 1.23–1.53, P < 0.00001, OR: 1.41; 95% CI: 1.26–1.57, P < 0.00001 and OR: 1.38; 95% CI: 1.13–1.70, P = 0.002 and OR: 1.28; 95% CI: 1.01–1.61, P = 0.04 respectively. However, the result for long term mortality was not statistically significant.
Conclusion
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.
Objectives:
In 2009, the FDA issued a warning that omeprazole-a proton pump inhibitor (PPI)-reduces the antithrombotic effect of clopidogrel by almost half when taken concomitantly. This study aims to analyze the impact of the FDA Safety Communications on prescribing clopidogrel together with PPIs.
Methods:
This retrospective study identified clopidogrel users from the Truven Health Analytics MarketScan Databases (01/2006-12/2012). Rates of clopidogrel-PPI combination therapy were estimated in 6-month intervals for patients with ≥1 clopidogrel prescription fill, then were analyzed pre- and post-safety communication (11/17/2009). Analyses were also conducted by grouping PPIs into CYP2C19 inhibitors (omeprazole and esomeprazole) and CYP2C19 non-inhibitors (pantoprazole, lansoprazole, dexlansoprazole, and rabeprazole).
Results:
Overall, 483,074 patients met the selection criteria; of these, 157,248 used a clopidogrel-PPI combination. On average, 30.5% of patients in the pre- and 19.9% in the post-communication period used a clopidogrel-PPI combination therapy. Among clopidogrel users, the probability of using clopidogrel-PPI combinations fell by over 40% in the post-communication period (OR = 0.57; p<0.001); the proportion of patients using esomeprazole fell from 12.9% to 5.3%, and the proportion using omeprazole fell from 10.1% to 6.3%. Among combination therapy users, the probability of patients using a combination with a CYP2C19 inhibitor decreased by 53% (OR = 0.47; p<0.001); however, 31.5% of patients were still prescribed a clopidogrel-PPI combination therapy. Trends were similar for all and newly treated patients, regardless of clopidogrel indication and physician specialty.
Conclusions:
The FDA Safety Communication resulted in a reduction in the number of patients undergoing combination therapy; however approximately one-third of patients still used combination therapy post-communication.
Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.
Background
Observational studies evaluating the possible interaction between proton pump inhibitors (PPIs) and clopidogrel have shown mixed results. We conducted a systematic review comparing the safety of individual PPIs in patients with coronary artery disease taking clopidogrel.
Methods and Results
Studies performed from January 1995 to December 2013 were screened for inclusion. Data were extracted, and study quality was graded for 34 potential studies. For those studies in which follow‐up period, outcomes, and multivariable adjustment were comparable, meta‐analysis was performed.
The adjusted odds or hazard ratios for the composite of cardiovascular or all‐cause death, myocardial infarction, and stroke at 1 year were reported in 6 observational studies with data on individual PPIs. Random‐effects meta‐analyses of the 6 studies revealed an increased risk for adverse cardiovascular events for those taking pantoprazole (hazard ratio 1.38; 95% CI 1.12–1.70), lansoprazole (hazard ratio 1.29; 95% CI 1.09–1.52), or esomeprazole (hazard ratio 1.27; 95% CI 1.02–1.58) compared with patients on no PPI. This association was not significant for omeprazole (hazard ratio 1.16; 95% CI 0.93–1.44). Sensitivity analyses for the coronary artery disease population (acute coronary syndrome versus mixed) and exclusion of a single study due to heterogeneity of reported results did not have significant influence on the effect estimates for any PPIs.
Conclusions
Several frequently used PPIs previously thought to be safe for concomitant use with clopidogrel were associated with greater risk of adverse cardiovascular events. Although the data are observational, they highlight the need for randomized controlled trials to evaluate the safety of concomitant PPI and clopidogrel use in patients with coronary artery disease.
Objective:
To investigate whether there is an increased risk of cardiac events in diabetic patients with a combined therapy of clopidogrel (CLO) and proton pump inhibitors (PPIs) after drug-eluting stent (DES) deployment.
Methods:
By using National Health Insurance Research Database, all patients who received CLO with or without PPI therapy within 90 days after undergoing DES (limus-eluting or paclitaxel-eluting stents) deployment were enrolled. Endpoints were acute coronary syndrome (ACS) and readmission for revascularization (percutaneous coronary intervention or coronary artery bypass graft surgery) after 3, 6, and 12 months.
Results:
A total of 6,603 diabetic patients received LESs (5,933 in the CLO subgroup and 670 in the CLO plus PPIs subgroup), and 3,202 patients received PESs (2,923 in the CLO subgroup and 279 in the CLO plus PPIs subgroup). The patients who received CLO plus PPIs were at higher risk of ACS than those receiving CLO within 1 year after DES deployment (LESs: 6-month hazard ratio [HR] = 1.63, and 1-year HR = 1.37; PESs: 3-month HR = 1.72). Patients with a history of ACS who received CLO plus PPIs were at higher risk of ACS after LES implantation (HR = 1.55) than those in the CLO group.
Conclusion:
In "real-world" diabetic patients with LES deployment, the combination of PPIs and CLO is associated with higher rates of ACS after 6 months and 1 year. Even after correction for confounding factors, concomitant PPI use remained an independent predictor of cardiac events, emphasizing the clinical importance of this drug-drug interaction.
Dual antiplatelet therapy is the standard of care after coronary stent placement but increases the bleeding risk. The effects of proton pump inhibitors (PPIs) on clopidogrel metabolism have been described, but the clinical significance is not yet definitive. We aimed to do an updated meta-analysis comparing outcomes in patients receiving clopidogrel with and without PPIs.
We systematically searched PubMed, Scopus and the Cochrane Central Register of Controlled Trials for randomised controlled trials (RCTs) and controlled observational studies in patients taking clopidogrel stratified by concomitant PPI use. Heterogeneity was examined with the Cochran Q test and I(2) statistics; p values inferior to 0.10 and I(2) >25% were considered significant for heterogeneity.
We included 39 studies with a total of 214 851 patients, of whom 73 731 (34.3%) received the combination of clopidogrel and a PPI. In pooled analysis, all-cause mortality, myocardial infarction, stent thrombosis and cerebrovascular accidents were more common in patients receiving both drugs. However, among 23 552 patients from eight RCTs and propensity-matched studies, there were no significant differences in mortality or ischaemic events between groups. The use of PPIs in patients taking clopidogrel was associated with a significant reduction in the risk of gastrointestinal bleeding.
The results of our meta-analysis suggest that PPIs are a marker of increased cardiovascular risk in patients taking clopidogrel, rather than a direct cause of worse outcomes. The pharmacodynamic interaction between PPIs and clopidogrel most likely has no clinical significance. Furthermore, PPIs have the potential to decrease gastrointestinal bleeding in clopidogrel users.
Some clinical studies have demonstrated that the proton pump inhibitor (PPI) could decrease clopidogrel platelet response and increase major adverse cardiovascular events (MACE) in white or black subjects. However, that remains to be determined in Chinese patients. In this study, we sought to determine whether there could be an increased risk for developing MACE after concomitant use of dual antiplatelet therapy (DAT) and a PPI in Chinese patients treated with percutaneous coronary intervention (PCI) and stenting.
This study was a 5-year, single-center, retrospective cohort analysis of eligible patients (n = 6188) who received DAT and a PPI concomitantly (defined as PPI users) before discharge and/or 12-month follow-up after discharge as compared with those who received DAT alone (also defined as non-PPI users, n = 1465). The incidence of recurrent MACE, such as myocardial infarction (MI), definite stent thromboses (ST), or cardiovascular death, was compared between the PPI users and non-users.
PPI users had a significantly higher incidence of the MACE than non-users (13.9% vs. 10.6%; adjusted HR: 1.33; 95% CI: 1.12 - 1.57, P = 0.007). Stratified analysis revealed that concurrent use of DAT and a PPI was associated with a significantly increased risk for developing ST compared with DAT alone (1% vs. 0.4%; adjusted HR: 2.66, 95% CI: 1.16 - 5.87, P = 0.012). However, there were no significant differences in the risk of MI, cardiovascular death and other adverse events, regardless of combination of clopidogrel and a PPI.
The study further suggests that concomitant use of DAT and a PPI may be associated with an increased risk for developing MACE, in particular definite ST, in Chinese PCI patients after discharge as compared with use of DAT alone.
Proton pump inhibitors (PPIs) may interfere with the metabolic activation of clopidogrel via inhibition of cytochrome P450 2C19, but the clinical implications remain unclear.
The impact of PPI use on the 1-year primary end point (ischemic stroke, myocardial infarction [MI], or vascular death) in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial and the 28-day (all-cause death, MI, or urgent target vessel revascularization) and 1-year (all-cause death, MI, or stroke) primary end points in the Clopidogrel for Reduction of Events During Observation (CREDO) trial were examined. Clopidogrel appeared to elevate risk for the primary end point in CAPRIE among PPI users (estimated hazard ratio [EHR] 2.66, 95% CI 0.94 to 7.50) while lowering it for non-PPI users (EHR 0.90, 95% CI 0.83 to 0.99, interaction P=0.047). Moreover, PPI use was associated with worse outcomes in patients receiving clopidogrel (EHR 2.39, 95% CI 1.74 to 3.28) but not aspirin (EHR 1.04, 95% CI 0.70 to 1.57, interaction P=0.001). Clopidogrel did not significantly alter risk for the 1-year primary end point in CREDO among PPI users (EHR 0.82, 95% CI 0.48 to 1.40) while lowering it for non-PPI users (EHR 0.71, 95% CI 0.52 to 0.98, interaction P=0.682). Also, PPI use was associated with worse outcomes in both patients receiving clopidogrel (EHR 1.67, 95% CI 1.06 to 2.64) and those receiving placebo (EHR 1.56, 95% CI 1.06 to 2.30, interaction P=0.811).
In CREDO, the efficacy of clopidogrel was not significantly affected by PPI use. However, in CAPRIE, clopidogrel was beneficial to non-PPI users while apparently harmful to PPI users. Whether this negative interaction is clinically important for patients receiving clopidogrel without aspirin needs further study.
This study aimed to assess if proton pump inhibitors (PPIs) may reduce the effectiveness of clopidogrel, than H2 antagonist (anti-H2) in order to determine rehospitalization for acute coronary syndrome (re-ACS), target vessel revascularization (TVR) and cardiac death. This case-control study included 176 patients with ACS undergoing angioplasty (PCI) with drug-eluting stent implantation. The population was divided into two groups: PPI group (n = 121) consisting of patients receiving at discharge dual antiplatelet therapy (DAT) plus PPI and anti-H2 group (n = 55), consisting of patients receiving at discharge DAT + H2 receptor antagonist (H2RA). In a followup of 36 months the prevalence of ACS event (P = 0.014), TVR (P = 0.031) was higher in the PPI group than in the anti-H2 group; instead there was no statistically significant difference between groups for death. The variables independently associated with ACS were the diabetes, omeprazole, and esomeprazole; instead the variables independently associated with TVR were only omeprazole. Our data shows that the use of omeprazole and esomeprazole, with clopidogrel, is associated with increased risk of adverse outcomes after PCI with drug-eluting stent implantation.
To measure the association between use of proton pump inhibitors and a range of harmful outcomes in patients using clopidogrel and aspirin.
Observational cohort study and self controlled case series.
United Kingdom General Practice Research Database with linked data from the Myocardial Ischaemia National Audit Project (MINAP) and the Office for National Statistics (the cardiovascular disease research using linked bespoke studies and electronic records (CALIBER) collaboration)
24,471 patients receiving clopidogrel and aspirin.
The primary outcome was death or incident myocardial infarction. Secondary outcomes were death, incident myocardial infarction, vascular death, and non-vascular death. Comparisons were made between proton pump inhibitor use and non-use.
Of the 24,471 patients prescribed clopidogrel and aspirin, 12,439 (50%) were also prescribed a proton pump inhibitor at some time during the study. Death or incident myocardial infarction occurred in 1419 (11%) patients while they were receiving a proton pump inhibitor compared with 1341 (8%) who were not receiving a proton pump inhibitor. In multivariate analysis, the hazard ratio for the association between proton pump inhibitor use and death or incident myocardial infarction was 1.37 (95% confidence interval 1.27 to 1.48). Comparable results were seen for secondary outcomes and with other 2C19 inhibitors and with non-2C19 inhibitors. With the self controlled case series design to remove the effect of differences between people, there was no association between proton pump inhibitor use and myocardial infarction, with a rate ratio of 0.75 (0.55 to 1.01). Similarly, with the self controlled case series there was no association with myocardial infarction for other 2C19 inhibitors/non-inhibitors.
The lack of a specific association and the discrepancy between findings of the analyses between and within people suggests that the interaction between proton pump inhibitors and clopidogrel is clinically unimportant.
Many meta-analyses contain only a small number of studies, which makes it difficult to estimate the extent of between-study heterogeneity. Bayesian meta-analysis allows incorporation of external evidence on heterogeneity, and offers advantages over conventional random-effects meta-analysis. To assist in this, we provide empirical evidence on the likely extent of heterogeneity in particular areas of health care.
Our analyses included 14 886 meta-analyses from the Cochrane Database of Systematic Reviews. We classified each meta-analysis according to the type of outcome, type of intervention comparison and medical specialty. By modelling the study data from all meta-analyses simultaneously, using the log odds ratio scale, we investigated the impact of meta-analysis characteristics on the underlying between-study heterogeneity variance. Predictive distributions were obtained for the heterogeneity expected in future meta-analyses.
Between-study heterogeneity variances for meta-analyses in which the outcome was all-cause mortality were found to be on average 17% (95% CI 10-26) of variances for other outcomes. In meta-analyses comparing two active pharmacological interventions, heterogeneity was on average 75% (95% CI 58-95) of variances for non-pharmacological interventions. Meta-analysis size was found to have only a small effect on heterogeneity. Predictive distributions are presented for nine different settings, defined by type of outcome and type of intervention comparison. For example, for a planned meta-analysis comparing a pharmacological intervention against placebo or control with a subjectively measured outcome, the predictive distribution for heterogeneity is a log-normal (-2.13, 1.58(2)) distribution, which has a median value of 0.12. In an example of meta-analysis of six studies, incorporating external evidence led to a smaller heterogeneity estimate and a narrower confidence interval for the combined intervention effect.
Meta-analysis characteristics were strongly associated with the degree of between-study heterogeneity, and predictive distributions for heterogeneity differed substantially across settings. The informative priors provided will be very beneficial in future meta-analyses including few studies.
Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30
The aim of the study was to evaluate the effect of the concomitant treatment with proton-pump inhibitors (PPIs) and clopidogrel on the incidence of stent thrombosis, acute coronary syndrome (ACS) and death in patients who underwent percutaneous coronary intervention (PCI) and stent implantation. In total, 1,210 patients under dual antiplatelet therapy, who underwent PCI and stent implantation, were included in a prospective registry from January 2003 until December 2006. The patients were divided retrospectively into those with or without long-term PPI treatment (for the duration of dual antiplatelet therapy). All-cause mortality, cardiovascular death, re-hospitalisation for re-ACS, stent thrombosis, as well as the combined endpoint all-cause death, re-ACS or stent thrombosis were evaluated over a mean follow-up period of 7.8 (± 3.63) months (range 1-12 months). Propensity score analysis was performed to reduce potential selection bias and exhibited no significant difference between the two study groups with respect to all-cause mortality, cardiovascular death, re-ACS, stent thrombosis and the combined endpoint. In pre-specified subgroup analyses performed in patients presenting with ACS and referred for acute PCI or for stable patients referred for elective PCI, receiving drug-eluting stents or bare metal stents, in diabetics or non-diabetics, in males or females, and in patients older than 75 years or ≤75 years of age use of PPIs had no significant impact on clinical outcome. Our data suggest that a combined use of clopidogrel as part of dual antiplatelet therapy (DAPT) after coronary stenting and PPIs does not significantly influence the clinical outcome.
Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel.
We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing.
We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole.
Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).
Controversy remains on whether the dual use of clopidogrel and proton-pump inhibitors (PPIs) affects clinical efficacy of clopidogrel.
To examine the risk for adverse cardiovascular outcomes related to concomitant use of PPIs and clopidogrel compared with that of PPIs alone in adults hospitalized for myocardial infarction.
A nationwide cohort study based on linked administrative registry data.
All hospitals in Denmark.
All patients discharged after first-time myocardial infarction from 2000 to 2006.
The primary outcome was a composite of rehospitalization for myocardial infarction or stroke or cardiovascular death. Patients were examined at several assembly time points, including 7, 14, 21, and 30 days after myocardial infarction. Follow-up was 1 year.
Of 56 406 included patients, 9137 (16.2%) were re-hospitalized for myocardial infarction or stroke or experienced cardiovascular death. Of the 24 702 patients (43.8%) who received clopidogrel, 6753 (27.3%) received concomitant PPIs. The hazard ratio for cardiovascular death or rehospitalization for myocardial infarction or stroke for concomitant use of a PPI and clopidogrel among the cohort assembled at day 30 after discharge was 1.29 (95% CI, 1.17 to 1.42). The corresponding ratio for use of a PPI in patients who did not receive clopidogrel was 1.29 (CI, 1.21 to 1.37). No statistically significant interaction occurred between a PPI and clopidogrel (P = 0.72).
Unmeasured and residual confounding, time-varying measurement errors of exposure, and biases from survival effects were possible.
Proton-pump inhibitors seem to be associated with increased risk for adverse cardiovascular outcomes after discharge, regardless of clopidogrel use for myocardial infarction. Dual PPI and clopidogrel use was not associated with any additional risk for adverse cardiovascular events over that observed for patients prescribed a PPI alone.
Proton-pump inhibitors (PPIs) and clopidogrel are frequently coprescribed, although the benefits and harms of their concurrent use are unclear.
To examine the association between concurrent use of PPIs and clopidogrel and the risks for hospitalizations for gastroduodenal bleeding and serious cardiovascular disease.
Retrospective cohort study using automated data to identify patients who received clopidogrel between 1999 through 2005 after hospitalization for coronary heart disease.
Tennessee Medicaid program.
20,596 patients (including 7593 concurrent users of clopidogrel and PPIs) hospitalized for myocardial infarction, coronary artery revascularization, or unstable angina pectoris.
Baseline and follow-up drug use was assessed from automated records of dispensed prescriptions. Primary outcomes were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease (fatal or nonfatal myocardial infarction or sudden cardiac death, stroke, or other cardiovascular death).
Pantoprazole and omeprazole accounted for 62% and 9% of concurrent PPI use, respectively. Adjusted incidence of hospitalization for gastroduodenal bleeding in concurrent PPI users was 50% lower than that in nonusers (hazard ratio, 0.50 [95% CI, 0.39 to 0.65]). For patients at highest risk for bleeding, PPI use was associated with an absolute reduction of 28.5 (CI, 11.7 to 36.9) hospitalizations for gastroduodenal bleeding per 1000 person-years. The hazard ratio associated with concurrent PPI use for risk for serious cardiovascular disease was 0.99 (CI, 0.82 to 1.19) for the entire cohort and 1.01 (CI, 0.76 to 1.34) for the subgroup of patients who had percutaneous coronary interventions with stenting during the qualifying hospitalization.
Unmeasured confounding and misclassification of exposure (no information on adherence or over-the-counter use of drugs) and end points (not confirmed by medical record review) were possible. Because many patients entered the cohort from hospitals with relatively few cohort members, the analysis relied on the assumption that after adjustment for observed covariates, PPI users from one such hospital could be compared with nonusers from a different hospital.
In patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of hospitalizations for gastroduodenal bleeding. The corresponding point estimate for serious cardiovascular disease was not increased; however, the 95% CI included a clinically important increased risk.
Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute.
Background Proton pump inhibitors (PPIs) are frequently prescribed in combination with clopidogrel, but conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use and clinical outcomes for patients treated with percutaneous coronary intervention (PCI) and dual-antiplatelet therapy (DAPT) with clopidogrel plus aspirin. Methods and results In the PRODIGY trial, 1,970 patients were randomized to 6- or 24-month DAPT at 30 days from index procedure. Among them, 738 patients (37.5%) received PPI (mainly lansoprazole; 90.1%) at the time of randomization. Proton pump inhibitor users were older, were most likely to be woman, had a lower creatinine clearance, presented more frequently with acute coronary syndrome, and had a higher CRUSADE bleeding score. After adjustment, the primary efficacy end point (composite of all-cause death, myocardial infarction, and cerebrovascular accident) was similar between no PPI and PPI users (9.2% vs 11.5%, adjusted hazard ratio [HR] 1.051, 95% CI 0.788-1.400, P = .736). Bleeding rates did not differ between the 2 groups (Bleeding Academic Research Consortium type 2, 3, or 5: adjusted HR 0.996, 95% CI 0.672-1.474, P = .980). Net clinical adverse events were also similar in no PPI and PPI patients (12.9% vs 14.9%, adjusted HR 0.99, 95% CI 0.772-1.268, P = .93). Results remained consistent at sensitivity analysis when focusing on the 548 patients who remained on PPI for the whole study duration. Conclusions The current findings suggest that the concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel is not associated with adverse clinical outcome.
Certain proton pump inhibitors (PPIs) interfere with clopidogrel metabolism, potentially attenuating P2Y12 receptor inhibition. Previous observational and randomized trials report conflicting results regarding the clinical significance of this pharmacological interaction. We examined the interaction between concomitant administration of PPI and clopidogrel on platelet reactivity and clinical outcomes in the large-scale, prospective Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents study. Methods and Results-On-treatment P2Y12 platelet reactivity testing was performed using the VerifyNow assay after clopidogrel loading and successful drug-eluting stent implantation at 11 sites in the United States and Germany. PPIs were prescribed at the discretion of treating physicians; patients were followed for 2 years. High platelet reactivity was defined as P2Y12 reactivity units >208. Of 8582 enrolled patients, 2697 (31.4%) were taking a PPI at the time of coronary intervention. After adjustment for differences in baseline characteristics, PPI use was independently associated with high platelet reactivity (odds ratio, 1.38: 95% confidence interval, 1.25-1.52, P=0.0001). A total of 2162 (25.2%) patients were prescribed a PPI at hospital discharge. In a propensity-adjusted multivariable analysis, discharge PPI use was independently associated with increased risk for postdischarge major adverse cardiac events (cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization) at 2-year follow-up (hazard ratio, 1.21; 95% confidence interval, 1.04-1.42, P=0.02). Conclusions-In patients treated with clopidogrel after successful drug-eluting stents implantation, the concomitant administration of PPI was associated with high platelet reactivity and a greater rate of adverse outcomes during long-term follow-up. Additional studies are warranted to determine the risk-benefit ratio of PPIs in patients with drug-eluting stents treated with clopidogrel. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966.
Discordant results have been reported on the effects of concomitant use of proton pump inhibitors (PPIs) and dual antiplatelet therapy (DAPT) for cardiovascular outcomes. We conducted a systematic review comparing the effectiveness and safety of concomitant use of PPIs and DAPT in the postdischarge treatment of unstable angina/non-ST-segment-elevation myocardial infarction patients.
We searched for clinical studies in MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, from 1995 to 2012. Reviewers screened and extracted data, assessed applicability and quality, and graded the strength of evidence. We performed meta-analyses of direct comparisons when outcomes and follow-up periods were comparable. Thirty-five studies were eligible. Five (4 randomized controlled trials and 1 observational) assessed the effect of omeprazole when added to DAPT; the other 30 (observational) assessed the effect of PPIs as a class when compared with no PPIs. Random-effects meta-analyses of the studies assessing PPIs as a class consistently reported higher event rates in patients receiving PPIs for various clinical outcomes at 1 year (composite ischemic end points, all-cause mortality, nonfatal MI, stroke, revascularization, and stent thrombosis). However, the results from randomized controlled trials evaluating omeprazole compared with placebo showed no difference in ischemic outcomes, despite a reduction in upper gastrointestinal bleeding with omeprazole.
Large, well-conducted observational studies of PPIs and randomized controlled trials of omeprazole seem to provide conflicting results for the effect of PPIs on cardiovascular outcomes when coadministered with DAPT. Prospective trials that directly compare pharmacodynamic parameters and clinical events among specific PPI agents in patients with unstable angina/non-ST-segment-elevation myocardial infarction treated with DAPT are warranted.
© 2015 American Heart Association, Inc.
Background:
Current medical therapies for patients who have an acute coronary syndrome (ACS) focus on the coagulation cascade and platelet inhibition. These, coupled with early use of cardiac catheterization and revascularization, have decreased morbidity and mortality rates in patients who have acute ischemic heart disease with risk of bleeding.
Objective:
The study aimed to determine the incidence of gastrointestinal bleeding after percutaneous coronary intervention (PCI). The effect of proton-pump inhibitor (PPI) treatment was also analyzed.
Methods:
This case-control study evaluated gastrointestinal bleeding within a year of PCI for stable angina and acute coronary syndromes at Nanjing First Hospital between 2008 and 2011. Cases were identified and outcomes assessed using linkage analysis of data from cardiology and gastroenterology department databases. Analysis of the case and control groups for both risk and protective factors was performed using independent two-sample Student's t-test with Fisher's exact P value and logistic regression.
Results:
The incidence of gastrointestinal bleeding following PCI was 1.3% (35/2680 patients). The risk factors for gastrointestinal bleeding were advanced age, female gender, smoking, drinking, previous peptic ulcer and previous gastrointestinal bleeding. PPI use after PCI (P=0.000) was accompanied by a lower risk of gastrointestinal bleeding, with only a few cases of gastrointestinal bleeding events reported.
Conclusion:
The incidence of gastrointestinal bleeding associated with the combination of aspirin and clopidogrel therapy was estimated to be 1.3%. Advanced age, being female, smokers, drinkers, previous peptic ulcer and previous gastrointestinal bleeding were significant independent risk factors. PPI for the prevention and treatment of gastrointestinal bleeding induced by the combination of aspirin and clopidogrel in patients after PCI was safe and effective.
To examine the effect of the drug interaction between clopidogrel and proton pump inhibitors (PPIs) on the risk of an adverse cardiovascular event.
Population-based, retrospective cohort study.
IMS LifeLink Health Plan administrative claims database.
A total of 10,101 patients aged 18 years or older with a diagnosis of acute coronary syndrome (ACS) made during a hospitalization or emergency department visit between 2001 and 2008 and who had their first clopidogrel prescription within 90 days after their ACS diagnosis were included in the study. Patients were stratified according to concurrent use (clopidogrel plus PPI group) or no use (clopidogrel alone group) of the following PPIs: esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole.
Data were collected on baseline patient demographic and clinical characteristics. Patients were followed from their first clopidogrel prescription until they experienced an adverse cardiovascular event, defined as inpatient hospitalization or emergency department visits for myocardial infarction, percutaneous coronary intervention, or intermediate coronary syndrome; were disenrolled; discontinued clopidogrel; or reached the end of the study period. Using a propensity scoring method, the clopidogrel plus PPI group was matched in a 1:1 ratio with the clopidogrel alone group. Exposure to overlapping clopidogrel-PPI prescriptions was modeled as a time-dependent covariate. The Cox hazards regression model was used to estimate the risk of an adverse cardiovascular event in the clopidogrel plus PPI group versus the clopidogrel alone group. Propensity score matching resulted in 2674 patient pairs. In the propensity score-matched sample, the mean age was 61.30 years, with a mean follow-up of 268 days, and 70.04% were male. Concurrent use of clopidogrel with a PPI was associated with a significantly increased risk of a cardiovascular adverse event (hazard ratio 1.438, 95% confidence interval 1.237-1.671) compared with clopidogrel alone.
Concurrent use of clopidogrel plus a PPI was associated with a significant increase in risk of an adverse cardiovascular event in patients with ACS. Large randomized studies are needed to confirm this finding. Until then, clinicians should prescribe the concurrent use of these two drugs cautiously.
Recent clinical studies reported the drug interaction between proton-pump inhibitors (PPI) and clopidogrel, which remains controversial. The aim of this study was to determine whether the concurrent use of PPI with clopidogrel or ticlopidine is associated with increased risk for adverse cardiovascular outcomes in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). In this retrospective cohort study, we assessed the cardiovascular outcomes associated with the concurrent use of PPI and clopidogrel or ticlopidine in the well-characterized 1286 patients with CAD undergoing PCI in the University of Tokyo Hospital. In the Japanese patients with CAD undergoing PCI, the concurrent use of PPI was significantly associated with increased risk for major adverse cardiovascular events in the ticlopidine users (hazard ratio 2.63; 95 % confidence interval 1.65-4.18; P < 0.001), but not in the clopidogrel users. In the clopidogrel users as well as the ticlopidine users, PPI use did not affect the occurrence of target lesion revascularization, but significantly increased the risk for new lesion formation in the coronary arteries, which required subsequent revascularization. The adverse cardiovascular effects of the concurrent use of PPI and ticlopidine were identified in the patients with CAD undergoing PCI. Also, new lesion formation in the coronary arteries was shown to be increased when PPI was coprescribed for the thienopyridine users.
We investigated the effect of individualised proton pump inhibitors (PPI) prescription on upper gastrointestinal adverse events in a cohort of patients who received combination antiplatelet therapy (aspirin and clopidogrel) after percutaneous coronary intervention (PCI).
Upper gastrointestinal risk factors and other parameters were extracted from a dedicated electronic database. Patients were contacted with a standardised questionnaire. A structured phone interview was performed in all patients with upper gastrointestinal adverse events.
A cohort of 718 patients on combination therapy yielded 87 (12.1%) patients with prophylactic PPI treatment. Upper gastrointestinal adverse events occurred in 18.4% patients with and in 11.1% patients without prophylactic PPI (OR 1.80, P = 0.054). Co-treatment with corticosteroids was the main identifiable risk factor for upper gastrointestinal adverse events (adjusted OR 5.45, P = 0.014).
Individualised prescription of PPI-prophylaxis after PCI in patients on combined antiplatelet therapy based on risk assessment for upper gastrointestinal bleeding seems to represent an effective measure to minimise upper gastrointestinal adverse events after PCI.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Conflicting results have been reported regarding the increased risk of adverse outcomes in the concomitant use of clopidogrel and proton pump inhibitors (PPIs) compared with the use of clopidogrel alone.
WHAT THIS STUDY ADDS
• Our study indicated no statistically significant increase in the risk of rehospitalization for acute coronary syndrome due to concurrent use of clopidogrel and PPIs in an Asian population with higher prevalence of CYP2C19 intermediate and poor metabolizers. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for acute coronary syndrome.
AIMS Our study aimed to examine the impact of concomitant use of proton pump inhibitors (PPIs) with clopidogrel on the cardiovascular outcomes of patients with acute coronary syndrome (ACS). Furthermore, we sought to quantify the effects of five individual PPIs when used concomitantly with clopidogrel.
METHODS We conducted a retrospective cohort study of patients who were newly hospitalized for ACS between 1 January 2006 and 31 December 2007 retrieved from the Taiwan National Health Insurance Research Database (NHIRD) and who were prescribed clopidogrel (n= 37 099) during the follow-up period. A propensity score technique was used to establish a matched cohort in 1:1 ratio (n= 5173 for each group). The primary clinical outcome was rehospitalization for ACS, while secondary outcomes were rehospitalization for percutaneous transluminal coronary angioplasty (PTCA) with stent, PTCA without stent and revascularization (PTCA or coronary artery bypass graft surgery) after the discharge date for the index ACS event.
RESULTS The adjusted hazard ratio of rehospitalization for ACS was 1.052 (95% confidence interval, 0.971–1.139; P= 0.214) in the propensity score matched cohort. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for ACS (adjusted hazard ratio, 1.226; 95% confidence interval, 1.066–1.410; P= 0.004). Concomitant use of esomeprazole, pantoprazole, rabeprazole and lansoprazole did not increase the risk.
CONCLUSIONS Our study indicated no statistically significant increase in the risk of rehospitalization for ACS due to concurrent use of clopidogrel and PPIs overall. Among individual PPIs, only omeprazole was found to be statistically significantly associated with increased risk of rehospitalization for ACS.
The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear.
We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (n=6539) compared with those not on a PPI (n=12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04-1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07-1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79-1.23; ticagrelor, HR, 0.89; 95% CI, 0.73-1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12-1.49; ticagrelor, HR, 1.30; 95% CI, 1.14-1.49).
The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events.
http://www.clinicaltrials.gov. Unique identifier: NCT00391872.
Objectives:
The aim of this study was to evaluate whether combination therapy of clopidogrel and proton pump inhibitors (PPIs) causes higher numbers of cardiovascular events than clopidogrel alone in Japanese patients.
Background:
PPIs are often prescribed in combination with clopidogrel following coronary stenting. PPIs are reported to diminish the effect of clopidogrel because both are metabolized by CYP2C19. However, no reports address the effects of PPIs on cardiovascular events following coronary stenting in the Japanese population.
Methods:
A total of 1,887 patients treated with clopidogrel following coronary stenting were enrolled in the Ibaraki Cardiac Assessment Study (ICAS) registry. All subjects were classified into two groups according to treatment without (n = 819) or with (n = 1,068) PPI. Propensity score analysis matched 1:1 according to treatment without PPI (n = 500) or with PPI (n = 500). Primary endpoint was the composite of all-cause death or myocardial infarction.
Results:
No significant difference was observed in the primary endpoint between the group without PPI and the group with PPI (4.6% vs. 4.6%, P = 0.77). In contrast, a significant difference was found between the group without PPI and with PPI in regard to the incidence of gastrointestinal bleeding at the end of the follow-up period and the specific PPI prescribed (2.4% vs. 0.8%, adjusted HR = 0.30, 95% Confidence interval 0.08-0.87, P = 0.026) after propensity score matching.
Conclusions:
No significant association between PPI use and primary endpoint was observed in the Japanese population, whereas PPI use resulted in a significant reduction in the rate of gastrointestinal bleeding.
The aim of this study was to examine the effect of proton-pump inhibitor (PPI) on clinical outcomes in Japanese patients who undergo coronary stent implantation.
A total of 1,270 patients (males 915, 69 years) were enrolled and dual antiplatelet therapy of aspirin and a thienopyridine derivative was prescribed (clopidogrel 630, ticlopidine 640). Patients were divided into 2 groups treated with or without PPI. PPI was administered in 331 cases (26%), and non-PPI in 939 (74%). There were no significant differences in cardiovascular death (PPI vs. non-PPI: 5 vs. 11 cases), nonfatal myocardial infarction (3 vs. 5), and stroke (3 vs. 16) between PPI and non-PPI groups, but the ratio of gastrointestinal events had a higher tendency in non-PPI group compared with PPI group (1 vs. 17, P=0.08). In subgroup analysis of patients taking clopidogrel, or patients with acute coronary syndrome, there was no significant difference in the ratio of cardiovascular events (7 vs. 16, 6 vs. 17, NS). The non-PPI group had a tendency of an increased risk of gastrointestinal events compared with the PPI group (0 vs. 9, P=0.06; 1 vs. 7, P=0.14).
In contrast to the negative drug interaction of PPI reported elsewhere, in the present study the intake of PPI was not associated with an increased risk for adverse clinical outcomes in patients treated with stents.
Little is known about the efficacy of proton pump inhibitors compared with H(2) receptor antagonists in preventing adverse upper gastrointestinal complications in patients with acute coronary syndrome (ACS) or ST elevation myocardial infarction (STEMI) receiving aspirin, clopidogrel, and enoxaparin or thrombolytics. The objective of this study was to compare the efficacies of esomeprazole and famotidine in preventing gastrointestinal complications.
A double-blind, randomized, controlled trial was performed in patients receiving a combination of aspirin, clopidogrel, and either enoxaparin or thrombolytics. Patients received either esomeprazole (20 mg nocte) or famotidine (40 mg nocte) orally for 4-52 weeks, depending on the duration of dual antiplatelet therapy. The primary end point was upper gastrointestinal bleeding (GIB), perforation, or obstruction from ulcer/erosion (http://www.clinicaltrials.gov NCT00683111).
In all, 311 patients were recruited, with 163 and 148 patients in the esomeprazole and famotidine groups, respectively. Mean (s.d.) follow-up was 19.2 (17.6) and 17.6 (18.0) weeks, respectively. One (0.6%) patient in the esomeprazole group and 9 (6.1%) in the famotidine group reached the primary end point (log-rank test, P=0.0052, hazard ratio=0.095, 95% confidence interval: 0.005-0.504); all had upper GIB.
In patients with ACS or STEMI, esomeprazole is superior to famotidine in preventing upper gastrointestinal complications related to aspirin, clopidogrel, and enoxaparin or thrombolytics.
To investigate whether there is an increased risk of cardiac events with a combined therapy of clopidogrel and proton pump inhibitors (PPIs) after percutaneous coronary intervention (PCI).
In the BAsel Stent Kosten Effektivitäts Trial (BASKET), all patients undergoing PCI received 6 months of clopidogrel and were analysed for the use of PPI therapy. Endpoints were major adverse cardiac events (MACE), myocardial infarction (MI), death and target vessel revascularization (TVR) after 36 months.
Of 801 patients with available discharge medication data, 109 (14%) received PPIs. Patients who received PPIs were older (66.5 ± 10.5 vs. 63.3 ± 11.3 years, P = 0.006), more likely to be woman (80% vs. 69%, P = 0.009) and have a history of diabetes (29.6% vs. 17.3%, P = 0.002) or gastrointestinal ulcer disease (8.3% vs. 3.3%, P = 0.015) and more often received nonsteroidal anti-inflammatory drugs (7.3% vs. 2.2%, P = 0.003) and corticosteroids (11% vs. 3.6%, P = 0.001) but not aspirin (91.7% vs. 97%, P = 0.008) compared with those who did not receive PPIs. Patients who received PPI therapy had higher rates of MACE (30.3% vs. 20.8%, P = 0.027) and MI (14.7% vs. 7.4%, P = 0.01) but similar rates of death (9.2% vs. 7.4%, P = 0.51) and TVR (20.2% vs. 15.3%, P = 0.2) compared with those who did not. By multivariate analysis, diabetes (hazard ratio 1.83, 95% confidence interval 1.07-3.15) and PPI use (hazard ratio 1.88, 95% confidence interval 1.05-3.37) were the only independent risk factors for MI.
In a real-world PCI population, the combination of PPIs and clopidogrel was associated with a doubling of MI rates after 3 years. Even after correction for confounding factors, concomitant PPI use remained an independent predictor of outcome emphasizing the clinical importance of this drug-drug interaction.
Omeprazole, usually used in the antiplatelet therapy during percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS), has been reported to increase ischemic events in retrospective studies. However, other clinical trials gave paradoxical results. The aim of this study was to assess the effects of omeprazole on clopidogrel efficacy and clinical events.
All patients (n = 172) received aspirin (loading dose 300 mg and maintenance dose 100 mg/d) and clopidogrel (loading dose 600 mg and maintenance dose 75 mg/d) during the therapy. They were randomized to receive omeprazole (20 mg/d) or placebo for 30 days. Residual platelet activities in the adenosine 5'-diphosphate (ADP) pathway were detected on the fifth day after PCI with thrombelastography (TEG)-mapping. The clinical events were recorded after one month.
According to the five levels of platelet activities, the frequency distributions of the inhibition rates were significantly different (P = 0.0062). However, no significant change was seen in the distribution among the highest or the lowest inhibiting levels (> 95% and < 30% inhibition rate). And there were no significant differences (P > 0.05) in events incidence, while gastro-intestinal bleeding decreased in co-administration of omeprazole.
Omeprazole significantly blunts clopidogrel efficacy while not exacerbates ischemic events in ACS undergoing PCI. Omeprazole even can decrease gastro-intestinal bleeding in those patients.
The concomitant use of proton pump inhibitors (PPIs) with clopidogrel is suspected to be associated with an adverse impact on clinical outcomes in patients with coronary artery disease. We sought to evaluate whether the use of PPIs with clopidogrel was associated with worse clinical outcomes after percutaneous coronary intervention (PCI) compared with the use of clopidogrel alone.
We studied 2651 consecutive patients discharged alive after coronary stenting for stable or unstable coronary artery disease between 2001 and 2007. All patients received aspirin indefinitely and a thienopyridine for 1 to 12 months. Patients were categorized into 2 groups: those taking a PPI [PPI (+), n=751] and those not taking a PPI [PPI (-), n=1900] at discharge. The primary end points were the 6-month incidence of major adverse cardiovascular events (MACE) (composite of death, myocardial infarction, target vessel revascularization, and stent thrombosis) and net adverse clinical events (NACE) (composite of MACE and thrombolysis in myocardial infarction major or minor bleeding), which were evaluated using propensity-adjusted Cox regression analysis. In addition, propensity-matched analysis was performed in 685 pairs of patients. The PPI (+) group was older and had more comorbid conditions than the PPI (-) group. In propensity-adjusted as well as propensity-matched analyses, the use of PPIs was not associated with an increased risk of MACE or NACE.
The use of PPIs with dual antiplatelet therapy was not associated with any adverse influence on MACE or NACE after PCI.
A pharmacodynamic interaction between clopidogrel and proton pump inhibitors (PPIs) has been suggested, leading to reduced clopidogrel-induced platelet inhibitory effects. However, data from clinical studies are conflicting. The aim of this study was to evaluate the safety of long-term clopidogrel and PPI therapy.
A total of 1328 consecutive patients (age 63±11 years; 81% male) undergoing drug-eluting stent implantation and 1-year follow-up were included. All patients were treated with a standard aspirin and clopidogrel treatment regimen for 12 months. The concomitant PPI therapy for the same duration was at the discretion of the clinical cardiologist. PPI therapy included lansoprazole (30 mg/day), pantoprazole (20 mg/day), or omeprazole (20 mg/day). At 1-year follow-up, major adverse cardiac events (MACE), defined as death, myocardial infarction (MI), acute coronary syndrome leading to hospitalization and nonfatal stroke, were recorded. All cause death, any stent thrombosis (ST), and bleeding (Thrombolysis in MI major and minor) were also assessed.
Lansoprazole, pantoprazole, and omeprazole were administered to 855, 178, and 125 patients, whereas 170 were not prescribed any PPI therapy. Among patients treated with PPIs, those on pantoprazole had more often prior MI, multivessel coronary artery disease, and chronic kidney disease, whereas earlier peptic ulcer was more frequent among patients treated with omeprazole. The incidence of 1-year MACE was not statistically different between patients in the PPI and no-PPI groups (7.5 vs. 5.0%; P=0.26). Similarly, 1-year rates of all cause death, ST, and Thrombolysis in MI major and minor bleedings did not significantly differ. After statistical adjustment for potential confounders, the concomitant use of clopidogrel and PPIs was not associated with the risk of 1-year MACE [odds ratio (OR) 1.54, P=0.38], death (OR: 0.97, P=0.961), and ST (OR: 1.01, P=0.998). No differences across the three PPI types were found.
The association of clopidogrel and PPIs after drug-eluting stent implantation, prescribed on clinical judgement, seems safe.
Clopidogrel is an antiplatelet agent converted to its active metabolite by cytochrome P-450 isoenzymes. Numerous drugs are known to inhibit P-450 isoenzymes, including proton pump inhibitors (PPIs), which are often associated with aspirin and clopidogrel to prevent adverse gastrointestinal effects. In vitro studies first showed that PPIs reduced the antiplatelet effect of clopidogrel, while recent clinical studies have raised concerns that the addition of a PPI to clopidogrel in acute coronary syndrome (ACS) patients could actually increase the risk of recurrent cardiovascular events.
The aim of this study was to evaluate whether the prescription of a PPI conferred a worse prognosis in patients discharged with aspirin and clopidogrel treatment after ACS.
A total of 876 patients admitted with ACS and discharged with aspirin and clopidogrel, with a planned duration of at least six months, from January 2004 to March 2008, were reviewed. Patients were classified in two groups according to whether or not a PPI was prescribed at discharge. The PPIs considered were those mainly metabolized by cytochrome P-450 2C19. We excluded patients with insufficient information available on either prescription or clinical records that could allow clearly confirm or exclude exposure to a PPI. Primary end points were six-month all-cause mortality and the composite of death, myocardial infarction and unstable angina at six months.
Of the 802 patients considered for further analysis, 274 (34.2%) individuals were medicated with a PPI in addition to dual antiplatelet therapy. Patients taking PPIs were older, more often had renal insufficiency and less often had a history of coronary revascularization and smoking. They more often presented with Killip class >I and lower hemoglobin concentration on admission. There were no significant differences between the two groups in terms of medical treatment (during hospital stay and at discharge) or invasive procedures. By multivariate analysis, independent and positive predictors of PPI prescription were older age and lower hemoglobin concentration on admission. Patients taking PPIs had a slightly higher prevalence of six-month mortality (6.5% vs. 3.9%) and of the composite end point (12.9% vs. 9.2%), although without statistical significance. By multivariate analysis including potential confounding variables, the prescription of a PPI on top of aspirin and clopidogrel was still n ot associated with a worse prognosis.
In the present study, PPI precription in addition to aspirin and clopidogrel after ACS was not associated with a worse six-month prognosis.
Clopidogrel requires metabolic activation by cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs.
The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naïve patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08; P=0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively.
PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles.
Objectives:
We sought to compare the 1-year risk of re-hospitalization for acute coronary syndrome (ACS) between patients taking clopidogrel with proton pump inhibitors (PPIs) vs. clopidogrel without PPIs.
Materials and methods:
We conducted a retrospective cohort study among 3896 patients with ACS, at low risk for gastrointestinal bleeding, discharged from all hospitals of the Emilia-Romagna region of Italy during the period January-August 2008. Patients' consumption of clopidogrel and PPIs at hospital discharge and follow-up was based on pharmacy refill data. Of these 3896 patients, 90% (n = 3519) were prescribed PPIs at hospital discharge and/or at some time during follow-up.
Results:
At 1-year follow-up, hospitalization for ACS occurred in 15% of patients taking clopidogrel with PPIs vs. 3.4% of those taking clopidogrel without PPIs (P < 0.001). No difference in terms of all-cause mortality could be detected between the two groups. At multivariate regression analysis with PPI use as a time-varying covariate, periods of use of clopidogrel with PPIs were associated, at 1-year follow-up, with a significantly higher risk of hospitalization for ACS (hazard ratio 1.29, P = 0.025). Notably, this event occurred mostly in patients who underwent revascularization during the index hospitalization (n = 3045, hazard ratio 1.52, P = 0.004). No significant effect of PPI prescription could be observed in terms of 1-year all-cause mortality and revascularization.
Conclusion:
This study suggests the hypothesis that a concomitant use of clopidogrel and PPIs in patients with ACS, at low risk for gastrointestinal bleeding, having mostly undergone coronary revascularization, is associated with an approximately 30% higher risk of nonfatal hospitalization for ACS.
The aim of the present study was to analyze the effect of drug exposure patterns of clopidogrel and proton pump inhibitors (PPIs) on the clinical outcomes after percutaneous coronary intervention (PCI). Previous analyses predominantly included discharge medications and did not explore the effect of the drug exposure patterns. We analyzed all-cause death, nonfatal myocardial infarction, repeat revascularization, and major adverse cardiovascular events (MACE) in a cohort of 23,200 post-PCI patients (January 2003 to December 2008) using a multivariate adjusted Cox model and propensity-matched case-control analysis. The adjusted hazard ratio for MACE on PPI according to the exposure patterns of clopidogrel after PCI for 6 years was 1.24 (95% confidence interval [CI] 1.11 to 1.38) and 1.12 (95% CI 1.03 to 1.22) for "continuous" (consistent clopidogrel with or without PPIs) and "switched" (clopidogrel with or without varying PPIs) respectively. However, the propensity score adjusted odds ratios for MACE on PPI use was 0.97 (95% CI 0.65 to 1.44) for "continuous" and 1.04 (95% CI 0.87 to 1.25) for "switched." Moreover, in the first year after PCI, the use of "rescue" (≤30 days before MACE) nitroglycerin was greater in the patients taking clopidogrel and PPIs than in those taking clopidogrel alone, as was the overall use of rescue PPIs (p <0.001). In conclusion, PPI use in clopidogrel-treated post-PCI patients was not associated with an increased risk of MACE after controlling for the confounding effect of PPI use with propensity matching. A potential for the misdiagnosis of angina symptoms and rescue use of nitroglycerin and PPIs in post-PCI patients exists, a finding that might have confounded previous observational analyses.
After coronary stent implantation, dual-antiplatelet therapy (DAT), such as aspirin and clopidogrel, is essential to prevent stent thrombosis. Proton-pump inhibitors (PPIs) may be used to prevent gastrointestinal (GI) bleeding during DAT, but there is no evidence for the efficacy of PPIs in this setting. Because both clopidogrel and PPIs are metabolized by cytochrome P450 (CYP) 2C19, there is a possibility that, through drug interaction, PPIs diminish the antiplatelet effect of clopidogrel. In this retrospective cohort study, we evaluated the efficacy and safety of rabeprazole in patients receiving DAT of clopidogrel and aspirin after drug-eluting stent implantation. In 199 patients treated with DAT alone (control group) and 103 patients treated with rabeprazole plus DAT (rabeprazole group), we examined the incidences of GI bleeding and major adverse cardiac events (MACE) including stent thrombosis. The incidence of GI bleeding was not significantly different between the groups (hazard ratio 0.47 [95% confidence interval 0.15-1.42], P=0.18; P=0.17 in log-rank test), although no patient with severe bleeding was observed in the rabeprazole group. The use of rabeprazole did not increase the incidence of MACE (hazard ratio 1.28 [95% confidence interval 0.54-3.00], P=0.56; P=0.56 in log-rank test). One patient who developed subacute stent thrombosis under DAT was genetically proven to be a CYP2C19 poor metabolizer. The effect of rabeprazole to prevent GI bleeding is limited in patients receiving DAT. It remains to be confirmed whether these results may depend on CYP2C19 polymorphisms or a class of PPIs.
Dual antiplatelet therapy (aspirin plus clopidogrel) is recommended in patients undergoing percutaneous coronary intervention (PCI). Treatment with proton pump inhibitors (PPIs) decreases bleeding rate. Alarming reports have been made that PPIs may decrease the antiplatelet activity of clopidogrel. We sought to determine whether levels of interleukin-6 (IL-6) and transforming growth factor-β1 (TGF-β1) might help distinguish individuals at risk for adverse events.
Thirty-eight patients on aspirin and clopidogrel were enrolled and divided into two groups: group 1 [patients receiving omeprazole (n = 18)] and group 2 [patients not receiving omeprazole (n = 20)]. Patients underwent PCI and were scheduled for twelve-month clinical follow-up. The major, adverse cardiac and cerebrovascular events (MACCE) include death, re-hospitalization for acute coronary syndromes, and stroke.
Median concentrations of IL-6 were higher in group 1 at 4.7 pg/mL, in comparison with group 2, 1.65 pg/mL (p = 0.003). Median concentrations of TGF-β1 were similar in both groups (p = 0.5). Patients in group 1 had a significantly higher leukocyte count [103/mm3] (median 7.5 vs 6.5; p = 0.04). There were no deaths during follow-up. The incidence of myocardial infarction was higher in group 1 (33.4% vs 5.0%; p = 0.03). MACCE at twelve months were more frequent in group 1 (55.6% vs 20.0%; p = 0.02). The cut-off value to predict MACCEs for IL-6 was > 3.6 pg/mL (sensitivity 64%, specificity 88%, positive predictive value 75%, negative predictive value 81%).
We show here that concomitant omeprazole use is associated with an increased inflammatory reaction. Drug interactions may reduce the anti-inflammatory effect of clopidogrel. This mechanism maybe responsible for an increased risk of non-fatal, cardiovascular events, following stent placement.
Clopidogrel is a prodrug that is converted via the hepatic cytochrome P450 system into its active thiol metabolite. Evidence is accumulating that proton pump inhibitors (PPIs) inhibit this enzymatic pathway and may therefore attenuate the antiplatelet effect of clopidogrel. The objective of this study was to investigate whether patients on clopidogrel therapy after drug-eluting stent (DES) placement who also receive a PPI are at higher risk of stent thrombosis (ST). This is a retrospective analysis of patients who received dual antiplatelet treatment including clopidogrel after DES placement. Outcomes were compared according to PPI therapy. The primary endpoint was the incidence of definite ST at 30 days. Secondary endpoints were death, combined death or ST and myocardial infarction (MI). The study population included 3,338 patients and 698 patients (20.9%) received PPIs. Patients receiving a PPI had a higher risk profile at baseline. Multivariate analysis showed that PPI treatment was not independently associated with the occurrence of ST [adjusted HR 1.8 (95% CI: 0.7-4.7), p=0.23] or MI [adjusted HR 1.3 (0.8-2.3), p=0.11]. PPI treatment was significantly associated with death [adjusted HR 2.2 (1.1-4.3), p=0.02] and death or ST [adjusted HR 3.3(1.7-6.7), p=0.02]. Concomitant treatment with a PPI in patients receiving dual antiplatelet treatment after coronary stenting is not an independent predictor of ST. The higher mortality is probably due to confounding as patients on PPIs had a higher risk profile at baseline.
To investigate the potential impact of proton pump inhibitors (PPIs) on the effectiveness of clopidogrel in preventing recurrent ischemic events after percutaneous coronary intervention (PCI) with stent placement.
Population-based, retrospective cohort study.
National medical and pharmacy benefit claims database comprising approximately 19 million members.
A total of 16,690 patients who had undergone PCI with stent placement and who were highly adherent to clopidogrel therapy alone (9862 patients) or to clopidogrel with a PPI (6828 patients) between October 1, 2005, and September 30, 2006.
The primary end point was the occurrence of a major adverse cardiovascular event during the 12 months after stent placement. These events were defined as hospitalization for a cerebrovascular event (stroke or transient ischemic attack), an acute coronary syndrome (myocardial infarction or unstable angina), coronary revascularization (PCI or coronary artery bypass graft), or cardiovascular death. A composite event rate was compared between patients who received clopidogrel alone and those who received concomitant clopidogrel-PPI therapy. Baseline differences in covariates were adjusted by using Cox proportional hazards models. In the 9862 patients receiving clopidogrel alone, 1766 (17.9%) experienced a major adverse cardiovascular event compared with 1710 patients (25.0%) who received concomitant clopidogrel-PPI therapy (adjusted hazard ratio 1.51, 95% confidence interval 1.39-1.64, p<0.0001). Similar associations of increased risk were observed for each PPI studied (omeprazole, esomeprazole, pantoprazole, and lansoprazole).
Concomitant use of a PPI and clopidogrel compared with clopidogrel alone was associated with a higher rate of major adverse cardiovascular events within 1 year after coronary stent placement.
The purpose of this study was to determine the readmission rate for acute myocardial infarction (AMI) in patients discharged on clopidogrel and a proton-pump inhibitor (PPI) versus patients discharged on clopidogrel alone after experiencing an AMI and undergoing stent placement. Clopidogrel is a prodrug that requires metabolism in the liver by the cytochrome P450 system (CYP450), in particular cytochrome P450 2C19 (CYP2C19).(1) Recent studies have suggested that medications metabolized by CYP450, such as PPIs, influence the effect of clopidogrel on platelet function(2,3) with an increased risk of cardiovascular events.(4,5) PPIs are often administered with clopidogrel due to the increased bleeding risk of dual antiplatelet therapy, a strategy endorsed by existing consensus guidelines.(6)
Treatment with a PPI in combination with clopidogrel would increase the risk of readmission for an AMI after stent placement for AMI.
We collected data on all patients discharged on clopidogrel after stent placement for an AMI between January 2003 and January 2008. Patients were followed for 1 year after their index hospitalization for readmission for an AMI. Rates of readmission were determined for those discharged on clopidogrel alone versus those discharged on clopidogrel and a PPI.
Patients discharged on clopidogrel and a PPI had higher rates of readmission for AMI within 1 year of stent implantation for AMI.
Patients discharged on clopidogrel and a PPI, including esomeprazole and pantoprazole, seem to be at an increased risk of recurrent AMI within 1 year after stent placement for an AMI.
Recent evidence has shown that clopidogrel and proton pump inhibitors (PPIs) are metabolized by the same pathway and that patients taking both drugs have greater levels of platelet reactivity and more adverse outcomes than patients taking only clopidogrel. We sought to examine the effect of a PPI at discharge from the hospital after percutaneous coronary intervention with drug-eluting stents on the incidence of major adverse cardiac events (MACE) at 1 year. We compared 502 patients who were not prescribed a PPI at discharge and 318 patients who were prescribed a PPI. All patients were taking clopidogrel. We followed patients for 1 year with regard to MACE, including death, Q-wave myocardial infarction, target vessel revascularization, and stent thrombosis. We performed multivariate Cox regression to adjust for confounding variables, including compliance with clopidogrel, to assess the effect of a PPI at discharge on the 1-year outcomes. The baseline characteristics of patients discharged with a PPI were similar to those of patients discharged without a PPI. Univariate survival analysis of the outcomes showed a greater rate of MACE (13.8% vs 8.0%, p = 0.008) and overall mortality (4.7% vs 1.8%, p = 0.02) in the PPI group. After multivariate analysis, the adjusted MACE hazard ratio for PPI at discharge was 1.8 (95% confidence interval 1.1 to 2.7, p = 0.01). In conclusion, in patients undergoing percutaneous coronary intervention with drug-eluting stents and receiving clopidogrel, the prescription of a PPI at discharge was associated with a greater rate of MACE at 1 year.
Because clopidogrel is converted to its active metabolite by P450 isoenzymes, which are also involved in the metabolism of omeprazole, there is concern regarding whether the action of clopidogrel would be reduced in patients also taking omeprazole.
To evaluate the impact of omeprazole administration on the effectiveness of clopidogrel drug therapy during the first year following successful coronary stenting (CS).
A total of 588 consecutive patients who underwent successful CS for stable or unstable coronary artery disease were studied. Patients were classified into those who were treated (group A, n=340) or not treated (group B, n=248) with omeprazole for seven or more consecutive days during the entire observation period. The composite of cardiac death or rehospitalization for nonfatal myocardial infarction during the first year was the prespecified primary study end point.
Baseline characteristics, and dual clopidogrel and acetylsalicylic acid drug therapy were well balanced between the study groups. By one year, the primary end point was reached by 58 (9.9%) patients, including 20 (3.4%) who died due to cardiac reasons and 38 (6.5%) who were rehospitalized because of a nonfatal myocardial infarction. Patients in groups A and B, respectively, were at similar risk of the primary composite end point (10% versus 9.7%, hazard ratio 1.1 [95% CI 0.6 to 1.8]; P=0.89).
According to the results of the present study, treatment with omeprazole had no impact on the clinical efficacy of clopidogrel drug therapy during the first year after successful CS.
Recent studies have suggested that proton pump inhibitors (PPIs) attenuate the benefits of clopidogrel. The clinical relevance of this interaction in patients who have undergone percutaneous coronary intervention (PCI) is unknown. We hypothesized that post-PCI patients discharged on clopidogrel will have higher cardiovascular events if concomitant PPI therapy is used.
To determine whether post-PCI patients discharged on clopidogrel will have higher cardiovascular events if concomitant PPI therapy is used.
We reviewed the medical records of all the patients discharged on clopidogrel who underwent PCI from January 2003 to August 2004. The primary outcome studied was a major adverse cardiovascular event (MACE), which was defined as a composite of death, myocardial infarction, and target vessel failure.
Of the 315 post-PCI patients who were discharged on clopidogrel, 72 were discharged on PPI. During a mean follow-up period of 50 months, patients discharged on concomitant clopidogrel-PPI therapy had a MACE rate of 56% (vs. 38% in the clopidogrel alone group) (P = 0.025) and had 95% excess risk of MACE.
Concomitant use of clopidogrel and PPI in post-PCI patients is associated with a higher risk of MACE. This suggests that PPIs may attenuate clopidogrel's beneficial antiplatelet effect, which is crucial after PCI. Prospective randomized studies are warranted to provide definitive evidence for this interaction.
Proton-pump inhibitors (PPIs) are often prescribed in combination with thienopyridines. Conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use, measures of platelet function, and clinical outcomes for patients treated with clopidogrel or prasugrel.
In the PRINCIPLE-TIMI 44 trial, the primary outcome was inhibition of platelet aggregation at 6 h assessed by light-transmission aggregometry. In the TRITON-TIMI 38 trial, the primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. In both studies, PPI use was at physician's discretion. We used a multivariable Cox model with propensity score to assess the association of PPI use with clinical outcomes.
In the PRINCIPLE-TIMI 44 trial, 201 patients undergoing elective percutaneous coronary intervention were randomly assigned to prasugrel (n=102) or high-dose clopidogrel (n=99). Mean inhibition of platelet aggregation was significantly lower for patients on a PPI than for those not on a PPI at 6 h after a 600 mg clopidogrel loading dose (23.2+/-19.5% vs 35.2+/-20.9%, p=0.02), whereas a more modest difference was seen with and without a PPI after a 60 mg loading dose of prasugrel (69.6+/-13.5% vs 76.7+/-12.4%, p=0.054). In the TRITON-TIMI 38 trial, 13,608 patients with an acute coronary syndrome were randomly assigned to prasugrel (n=6813) or clopidogrel (n=6795). In this study, 33% (n=4529) of patients were on a PPI at randomisation. No association existed between PPI use and risk of the primary endpoint for patients treated with clopidogrel (adjusted hazard ratio [HR] 0.94, 95% CI 0.80-1.11) or prasugrel (1.00, 0.84-1.20).
The current findings do not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel.
Daiichi Sankyo Company Limited and Eli Lilly and Company sponsored the trials. This analysis had no funding.