Concomitant Use Of Proton Pump Inhibitors Research Articles

Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial

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.

Relationship between cardiovascular outcomes and proton pump inhibitor use in patients receiving dual antiplatelet therapy after acute coronary syndrome

There is conflicting evidence regarding the potential interaction between clopidogrel and proton pump inhibitors (PPIs), with observational studies suggesting an increased risk of adverse cardiovascular (CV) outcomes and clinical trials suggesting there is no such risk. We conducted a retrospective cohort study to assess CV outcomes of 9753 patients taking dual antiplatelet therapy of aspirin plus clopidogrel with or without a PPI after hospitalization for acute coronary syndrome (ACS). Cox proportional hazards models were used to assess our primary endpoint of re-hospitalization for ACS in overall sample and a propensity score matching subsample. Among patients taking clopidogrel plus aspirin, concomitant use of PPI was not associated with the risk of re-hospitalization for ACS (adjusted hazard ratio [HR] 1.12 [95%CI 0.72-1.73]). The findings were consistent in the propensity score matching cohort (adjusted HR 0.82 [95%CI 0.43-1.54]). Compared with PPI nonusers, there is no significant association between each specific PPI users and the risk of re-hospitalization for ACS (adjusted HR; omeprazole 0.96 [95%CI 0.35-2.66], pantoprazole 1.05 [95%CI 0.38-2.92], rabeprazole 0.60 [95%CI 0.17-2.17], esomeprazole 0.31 [95%CI 0.10-0.99], and lansoprazole 0.82 [95%CI 0.32-2.07]). In conclusion, this population-based cohort study found that concomitant use of clopidogrel and PPI in patients who received dual antiplatelet therapy after ACS was not associated with risk of ACS re-hospitalization. Together, our study and findings of recently published clinical trials suggest that there was no apparent CV interaction between clopidogrel and PPI in patients who received dual antiplatelet therapy.

Clopidogrel pharmacogenetics: metabolism and drug interactions

The thienopyridine, clopidogrel bisulfate (clopidogrel), is the most widely prescribed antiplatelet therapy in the world. Clopidogrel, alone or in conjunction with aspirin as part of a dual antiplatelet therapy regimen, is the standard of care for reducing ischemic events in patients with acute coronary syndrome, recent myocardial infarction, recent stroke, or established peripheral artery disease. Initially approved for use in 1997, the label was updated by both the USA Food and Drug Administration and the European Medicines Agency in 2009 to include information regarding cytochrome P450 (CYP) genotype status and concomitant proton pump inhibitor use. Labeling warns of reduced effectiveness in those with impaired CYP2C19 function and to avoid concomitant clopidogrel use with drugs that are strong or moderate CYP2C19 inhibitors, such as omeprazole. The interpretation of this warning and the implementation in clinical practice is not without controversy. The following review provides a summary of the published evidence regarding CYP2C19 function, both genotype status and drug inhibition from concomitant proton pump inhibitors use, and response to clopidogrel.

Interactions Between Clopidogrel and Proton Pump Inhibitors: A Review of Evidence

Clopidogrel is a thienopyridine, which inhibits the platelet P2Y adenosine diphosphate (ADP) receptor termed P2Y(12). It is taken as a prodrug that requires biotransformation to an active metabolite by cytochrome P450 (CYP) isoenzymes. In addition, esterases shunt the majority of clopidogrel to an inactive pathway, whilst the remaining prodrug requires two separate CYP-dependent oxidative steps. PPIs might diminish the antiplatelet effects and the clinical effectiveness of clopidogrel possibly through inhibition of CYP2C19 and CYP3A4 isoenzymes. Treatment with clopidogrel and aspirin decreases recurrent cardiovascular events after an acute coronary syndrome. However, an inherent increment of major bleeding is also associated with antiplatelet therapy, as well as dyspepsia with aspirin. Also, major bleeding has been associated with high risk for ischemic events and mortality. For this reason, a proton pump inhibitor (PPI) is often co-prescribed to reduce the risk of gastrointestinal tract bleeding, but its concomitant use might reduce the inhibitory effect of clopidogrel on platelet aggregation. Nevertheless, doubts exist about the possible interaction of concomitant PPI use that may reduce the inhibitory effect of clopidogrel on platelet aggregation. Indeed, there is some controversy with regard to the true risk of cardiovascular adverse events arising from a potential drug-drug interaction between clopidogrel and PPI. In this article, we will review the current status and controversies in relation to a possible interaction between clopidogrel and PPIs.

Safety of clopidogrel and proton pump inhibitors in patients undergoing drug-eluting stent implantation

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.

Proton pump inhibitors and the risk of overanticoagulation during acenocoumarol maintenance treatment

In the Netherlands, several reports have described a potentiation of acenocoumarol-induced anticoagulation by co-medication of omeprazole or esomeprazole and competitive inhibition of CYP2C19 has been suggested as a possible mechanism for this interaction. We conducted an observational cohort study to investigate the effects of various proton pump inhibitors (PPIs) on acenocoumarol effectiveness. All 2755 subjects from the Rotterdam Study who received acenocoumarol maintenance treatment between April 1st, 1991 and September 9th, 2009 were followed for events of an international normalized ratio (INR)≥6, until death, end of treatment, or end of the study period. The Andersen-Gill extension of the Cox proportional hazards model was used to calculate risks for repeated events of overanticoagulation in relation to concomitant PPI use. The risk for overanticoagulation was most pronounced for esomeprazole (HR 1·99, 95% CI 1·55-2·55) and lansoprazole (HR 1·49, 95% CI 1·05-2·10). There was also a lower and non-significant risk increase for the other PPIs. We did not detect a modification of these results by CYP2C19*2 genotype. Caution should be paid to co-medication with esomeprazole and lansoprazole during acenocoumarol treatment and possibly also with other PPIs.

Vertebral fracture efficacy during risedronate therapy in patients using proton pump inhibitors

Recent evidence suggests that proton pump inhibitor (PPI) use may affect fracture risk, an important issue for patients being concurrently treated for osteoporosis. The results of our post hoc analysis showed that, regardless of PPI concomitant use, risedronate significantly reduced the risk of new vertebral fractures compared with placebo. Recent evidence suggests that PPI use may affect fracture risk, an important issue for patients being concurrently treated for osteoporosis. Moreover, data suggest that concomitant use of PPIs may wane the anti-fracture effect of bisphosphonates. We explored the relationship between concomitant use of PPIs and incident vertebral fractures among patients treated with risedronate or placebo. Bone mineral density (BMD) and upper gastrointestinal (UGI) adverse events (AEs) were also assessed. This study is a post hoc analysis of a subset of patients participating in three prospective, randomized, placebo-controlled clinical trials, with durations of up to 3 years, which evaluated the efficacy of risedronate in reducing fracture risk: Vertebral Efficacy with Risedronate Trial-MultiNational (VERT-MN); Vertebral Efficacy with Risedronate Trial-North America (VERT-NA); and the risedronate Hip Intervention Program (HIP). Total enrollment included 2,729 risedronate and 2,725 placebo patients. Concomitant acid-suppressing drugs were used by 8.8% of the total population (n = 482). Regardless of PPI concomitant use, risedronate significantly reduced the risk of new vertebral fractures compared with placebo (risk reduction: PPI users 57%, p = 0.009; PPI non-users 38%, p < 0.001). BMD increased with risedronate, independent of PPI use. PPI users were at a 2.5-fold greater risk of experiencing at least one UGI AE compared with non-users. Risedronate significantly reduced the risk of new vertebral fractures compared with placebo, regardless of PPI concomitant use.

Impact of concomitant use of proton-pump inhibitors and thienopyridine derivatives on the antiplatelet effects

Although there has been an intense debate whether concomitant use of proton-pump inhibitors (PPIs) attenuates the antiplatelet effects of thienopyridine derivatives, the drug-drug interaction remains unclear in Japanese patients with coronary artery disease. Platelet function test was performed in 461 patients who were scheduled for or had undergone stent implantation, treated with 100mg/day of aspirin and a thienopyridine (200mg/day of ticlopidine or 75 mg/day of clopidogrel) for at least 14 days. Adenosine diphosphate-induced platelet aggregation was evaluated with screen filtration pressure method, and the upper quartile of high platelet reactivity was defined as high on-treatment platelet reactivity (HPR). PPI use was at physician's discretion. Patients taking a thienopyridine plus a PPI (n=166) were older and had a higher incidence of acute coronary syndromes on admission compared with patients taking a thienopyridine without a PPI (n=295). The rate of HPR was higher in patients taking a thienopyridine plus a PPI than in patients taking a thienopyridine without a PPI (31% vs 21%, p=0.01). On multivariate logistic regression analysis, independent predictors of HPR were concomitant PPI use [odds ratio (OR): 1.66, 95% confidence interval (CI): 1.03-2.68], diabetes mellitus (OR: 1.76, CI: 1.11-2.81), and calcium channel blockers use (OR: 1.93, CI: 1.18-3.18). However, there was no significant difference in the rate of extremely high platelet reactivity [58 patients (12.5%) with PATI<4.0 μM] between patients treated with a thienopyridine plus a PPI and those without a PPI (14% vs 11%, NS). HPR was frequently observed in Japanese patients treated with thienopyridines plus PPIs compared to those without PPIs. Further prospective studies are needed to estimate the risk of adverse cardiovascular events associated with concomitant use of PPIs and thienopyridines.

Experts OK Antiplatelets and PPIs for Heart Patients With GI Bleeding Risks

AFTER 2 YEARS OF CONFUSION AND anxiety from conflicting research results, physicians have new guidance in determining which patients with cardiovascular disease who take antiplatelet therapy will reap the most benefit from also taking a proton pump inhibitor (PPI) to reduce the risk of gastrointestinal (GI) bleeding. In mid-November, the American College of Cardiology Foundation, the American College of Gastroenterology, and the American Heart Association released a consensus document that gives a green light to the concomitant use of antiplatelet drugs and PPIs in patients who are at high risk for upper GI bleeding (http://tinyurl.com /289g85d). “The key messages we want to get through to physicians and patients is that physicians should not prescribe [PPIs] routinely, but they should weigh the individual risks and benefits for each patient,” said Neena Abraham, MD, chair of the writing committee that produced the document and a gastroenterologist at the Michael E. DeBakey VA Medical Center in Houston. “Our consensus group really tried to . . . highlight the group in which the proton pump inhibitors would have the most bang for the buck,” she added. The document recommends concomitant antiplatelet and PPI medications for patients with a history of prior upper GI bleeding, which is the strongest risk factor linked with GI bleeding while taking antiplatelet agents. Additional factors that increase the risk of GI bleeding with antiplatelets are advanced age; current use of anticoagulants, steroids, or nonsteroidal anti-inflammatory drugs including aspirin; and infection with Helicobacter pylori, which is known to increase the risk of ulcers. The use of PPIs is appropriate in patients who take antiplatelet drugs and have multiple risk factors, according to the document.

Concomitant Use of Proton Pump Inhibitors and Clopidogrel in Patients With Coronary, Cerebrovascular, or Peripheral Artery Disease in the Factores de Riesgo y ENfermedad Arterial (FRENA) Registry

Among patients receiving clopidogrel for coronary artery disease, concomitant therapy with proton pump inhibitors (PPIs) has been associated with an increased risk for recurrent coronary events. Factores de Riesgo y ENfermedad Arterial (FRENA) is an ongoing, multicenter, observational registry of consecutive outpatients with coronary artery disease, cerebrovascular disease, or peripheral artery disease. We retrospectively examined the influence of concomitant use of PPIs on outcome in patients receiving clopidogrel. As of March 2009, 1222 patients were using clopidogrel: 595 had coronary artery disease, 329 cerebrovascular disease, and 298 had peripheral artery disease. Of these, 519 (42%) were concomitantly using PPIs. Over a mean follow-up of 15 months, 131 patients (11%) had 139 subsequent ischemic events: myocardial infarction 44, ischemic stroke 40, and critical limb ischemia 55. Seventeen of them (13%) died within 15 days of the subsequent event. PPI users had a higher incidence of myocardial infarction (rate ratio, 2.5; 95% confidence interval [CI], 1.3-4.8), ischemic stroke (rate ratio, 1.9; 95% CI, 1.03-3.7), and a nonsignificantly higher rate of critical limb ischemia (rate ratio, 1.6; 95% CI, 0.95-2.8) than nonusers. On multivariate analysis, concomitant use of clopidogrel and PPIs was independently associated with an increased risk for subsequent ischemic events both in the whole series of patients (hazard ratio, 1.8; 95% CI, 1.1-2.7) and in those with cerebrovascular disease or peripheral artery disease (hazard ratio, 1.5; 95% CI, 1.01-2.4). In patients with established arterial disease, concomitant use of PPIs and clopidogrel was associated with a nearly doubling of the incidence of subsequent myocardial infarction or ischemic stroke. This higher incidence persisted after multivariate adjustment.

4. Impact of CYP2C19 Polymorphism and Proton Pump Inhibitors on Clinical Outcomes during Dual Antiplatelet Therapy

Clopidogrel is a prodrug that has to be converted to an active metabolite. CYP2C19 genotype is a key factor impacting the response to clopidogrel and the drug interaction between proton pump inhibitors (PPIs) and clopidogrel. The prevalence of CYP2C19 loss-of-function alleles is much higher in East Asians including Japanese, than in people in Western countries. The American College of Cardiology Foundation (ACCF), American College of Gastroenterology (ACG) and American Heart Association (AHA) recommended in a 2010 conference that it is acceptable to use PPI with thienopyridines such as clopidogrel in patients at high risk of upper gastrointestinal bleeding. Several studies have indicated that concomitant use of clopidogrel and PPI is associated with reduced antiplatelet efficacy of clopidogrel, and increased adverse clinical outcomes after stent implantation in patients with acute coronary syndrome. However, several reports show that concomitant use of PPI and clopidogrel after stent implantation is not associated with an increased risk of cardiovascular events. We investigated whether CYP2C19 polymorphism or concomitant use of PPI and clopidogrel is associated with on-treatment platelet reactivity and clinical outcomes following stent implantation in patients with coronary artery disease. Our results indicated that the presence of CYP2C19 loss-of-function allele, but not the use of a PPI, was associated with an increased risk of cardiovascular outcomes. In conclusion, the use of a PPI should not be hesitated in patients with a high risk of gastrointestinal bleeding or ulcer.

Consensus Document: Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting

The optimal regimen of the anticoagulant and antiplatelet therapies in patients with atrial fibrillation who have had a coronary stent is unclear. It is well recognised that "triple therapy" with aspirin, clopidogrel, and warfarin is associated with an increased risk of bleeding. National guidelines have not made specific recommendations given the lack of adequate data. In choosing the best antithrombotic options for a patient, consideration needs to be given to the risks of stroke, stent thrombosis and major bleeding. This document describes these risks, provides specific recommendations concerning vascular access, stent choice, concomitant use of proton-pump inhibitors and the use and duration of triple therapy following stent placement based upon the risk assessment.

Clinical Outcomes Associated with Concomitant Use of Dual Anti-platelet Therapy and Proton Pump Inhibitors After Percutaneous Coronary Intervention

Abstract: Long term dual anti-platelet therapy (DAT) can lead to increase gastrointestinal haemorrhage (GIH). The addition of proton pump inhibitor (PPI) after percutaneous coronary intervention (PCI) may be protective against GIH. Long term clinical outcomes associated with concomitant use of DAT and PPI are limited with conflicting results. Aims: To determine the long term clinical outcome of patients treated with PPI and DAT following PCI (elective or acute) at a single tertiary centre. Methods: A total of 362 consecutive patients referred to our institution between January 2006 and December 2007 were included. Patients were divided retrospectively into those with or without planned long-term PPI treatment. Baseline characteristics, H. pylori status, concomitant use of IIbIIIa inhibitor or anticoagulation, PCI results and major adverse events during hospitalisation and 36-month follow up were analysed. Results: Mean age (S.D.) of patients was 65(±9.5) years and 71% of them were male. Proton pump inhibitor were used in 30.1% (109) of patients. Patients not on PPI are associated with significant cardiovascular events (13.3% vs. 8.3% p = 0.03). Non-PPI patients have increase GIH risks (3.6% vs. 1.7%); however this result was not statistically significant (p = 0.54). Patients positive for H. pylori were more likely to be on DAT and PPI and have a previous history of GIH. Conclusion: Our data suggest that a combined use of DAT and PPI does not significantly influence the long term clinical outcome in patients after PCI and stent implantation.

Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis.

To investigate whether proton pump inhibitors (PPIs) negatively affect clinical outcome in patients treated with clopidogrel. Systematic review and meta-analysis. Outcomes evaluated were combined major adverse cardiac events (MACE), myocardial infarction (MI), stent thrombosis, death and gastrointestinal bleeding. Studies included were randomized trials or post-hoc analyzes of randomized trials and observational studies reporting adjusted effect estimates. Twenty five studies met the selection criteria and included 159 138 patients. Administration of PPIs together with clopidogrel corresponded to a 29% increased risk of combined major cardiovascular events [risk ratio (RR) = 1.29, 95% confidence intervals (CI) = 1.15-1.45] and a 31% increased risk of MI (RR = 1.31, 95%CI = 1.12-1.53). In contrast, PPI use did not negatively influence the mortality (RR = 1.04, 95%CI = 0.93-1.16), whereas the risk of developing a gastrointestinal bleed under PPI treatment decreased by 50% (RR = 0.50, 95% CI = 0.37-0.69). The presence of significant heterogeneity might indicate that the evidence is biased, confounded or inconsistent. The sensitivity analysis, however, yielded that the direction of the effect remained unchanged irrespective of the publication type, study quality, study size or risk of developing an event. Two studies indicate that PPIs have a negative effect irrespective of clopidogrel exposure. In conclusion, concomitant PPI use might be associated with an increased risk of cardiovascular events but does not influence the risk of death. Prospective randomized trials are required to investigate whether a cause-and-effect relationship truly exists and to explore whether different PPIs worsen clinical outcome in clopidogrel treated patients as the PPI-clopidogrel drug-drug interaction does not seem to be a class effect.

Controversy of proton pump inhibitor and clopidogrel interaction: A review

A proton pump inhibitor (PPI) is often co-prescribed with clopidogrel to reduce the gastrointestinal risk of bleeding ulcers in patients following acute coronary syndrome or a stent implant. However, the safety issue of such practice has been scrutinized after some studies reporting an increased incidence of cardiovascular events and mortality, although there have also been contrary research reports. This has lead to a warning statement from the US Food and Drug Administration cautioning the concomitant use of PPI and clopidogrel. This review examines the evidence of PPI as gastroprotective agent, histamine H(2) antagonists as an alternative therapy, the influence of PPI on the antiplatelet effect of clopidogrel, and the controversies of various studies.

ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use

This expert consensus document was developed by the American College of Cardiology Foundation (ACCF), the American College of Gastroenterology (ACG), and the American Heart Association (AHA). Expert consensus documents inform practitioners, payers, and other interested parties of the opinion of ACCF and document cosponsors concerning evolving areas of clinical practice or medical technologies. Expert consensus documents cover topics for which the evidence base, experience with technology, or clinical practice is not considered sufficiently well developed to be evaluated by the formal ACCF/AHA Practice Guidelines process. Often, the topic is the subject of considerable ongoing investigation. Thus, the reader should view the expert consensus document as the best attempt of the ACCF and document cosponsors to inform clinical practice in areas where rigorous evidence may not yet be available. To avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the writing committee, all members of the writing committee, as well as peer reviewers of the document, are asked to disclose all current healthcare-related relationships and those existing 12 months before initiation of the writing effort. The ACCF Task Force on Clinical Expert Consensus Documents (CECD) reviews these disclosures to determine which companies make products (on market or in development) that pertain to the document under development. Based on this information, a writing committee is formed to include a majority of members with no relevant relationships with industry (RWI), led by a chair with no relevant RWI. Authors with relevant RWI are not permitted to draft or vote on text or recommendations pertaining to their RWI. RWI are reviewed on all conference calls and updated as changes occur. Author and peer reviewer RWI pertinent to this document are disclosed in Appendixes 1 and 2, respectively. Additionally, to ensure complete transparency, …

Platelet Activity Associated with Concomitant Use of Clopidogrel and Proton Pump Inhibitors in Children with Cardiovascular Disease

In adults with acute coronary syndrome, decreased platelet inhibition associated with concomitant use of clopidogrel and proton pump inhibitors (PPI) has been reported. To evaluate platelet activity associated with PPI + clopidogrel vs. clopidogrel alone in children enrolled in the Platelet Inhibition in Children On cLOpidogrel (PICOLO) trial of clopidogrel in children with a cardiac condition at risk for arterial thrombosis. Patients 0-24 m randomized to active therapy in the PICOLO trial were included in the present analysis. Platelet aggregation inhibition at baseline and steady state were evaluated in patients taking clopidogrel + PPI vs. clopidogrel only in the overall cohort and sub-group of clopidogrel responders. A total of 49 patients were included (44 clopidogrel only, five clopidogrel + PPI); median age 38 days (interquartile range [IQR] 17-157 days). The majority of patients in each group had undergone systemic-to-pulmonary artery shunt. Compared with the clopidogrel group, patients in the clopidogrel + PPI group had a trend toward lower percent inhibition of maximum extent of platelet aggregation overall (median 6%, IQR 0-44% vs. 49%, IQR 19-63%, P= 0.09), and a significant reduction in the clopidogrel responders sub-group (median 25%, IQR 3-45% vs. 53%, IQR 38-65%, P= 0.04). There was no difference in percent inhibition of rate of platelet aggregation. Concomitant use of PPI + clopidogrel may be associated with decreased platelet inhibition in children with cardiac disease. Further study in a larger population and assessment of associated clinical outcomes is warranted.

Dilemma zwischen Magenschutz und Kardioprotektion

Long-term low-dose aspirin intake leads to a 2 - 4-fold risk of risk for upper gastrointestinal bleeding. The additional intake of clopidogrel further increases the risk of upper GI bleeding (OR 7.4). Because of the potential interaction between proton pump inhibitors (PPI) and clopidogrel that compromises the efficacy of clopidogrel on platelet aggregation, there has been a warning in the product information by health authorities in the US and in Europe who discourage the concomitant use of PPI and clopidogrel. In the present study we performed a selected review of the published literature on the indications for gastric protection with PPI in patients on mono- or dual antiplatelet therapy focussing on the possible interaction between clopidogrel and PPI. In ex vivo analyses of platelet function, a reduced efficacy of clopidogrel was observed in patients on comedication with omeprazole. This was not the case with the comedication of other PPIs. To date, clear evidence is missing to state that comedication with PPI reduces the efficacy of clopidogrel IN VIVO. If both Clopidogrel and PPI need to be prescribed, a split dosage regimen of PPI in the morning and clopidogrel in the evening can be recommended. The short half-life of both medications explains the rationale of this recommendation.

Risk of recurrent myocardial infarction with the concomitant use of clopidogrel and proton pump inhibitors

The association between myocardial infarction (MI) and co-administration of proton pump inhibitors (PPIs) and clopidogrel remains controversial. To quantify the association between concomitant use of PPIs and clopidogrel and occurrence of recurrent MI. We conducted a case-control study within a cohort of acute MI patients in PHARMO Record Linkage System (1999-2008). The cases were patients readmitted for MI. PPI exposure was categorized as current (3-1 days before MI), past (30-3 days before MI), or no use (>30 days before MI). We used conditional logistic regression analyses. Among 23 655 patients hospitalized following MI, we identified 1247 patients readmitted for MI. Among clopidogrel users, current PPI use was associated with an increased risk of recurrent MI (OR: 1.62, 95% CI: 1.15-2.27) when compared with no PPI use, but not when compared with past PPI use (OR: 0.95, 95% CI: 0.38-2.41). Among clopidogrel non-users, current PPI use was associated with an increased risk of recurrent MI (OR: 1.38, 95% CI: 1.18-1.61) when compared with no PPI use. The apparent association between recurrent MI and use of PPIs with clopidogrel depends on the design, and is affected by confounding by indication. The association is not present when (un)measured confounding is addressed by design.

Proton-Pump Inhibitors Are Associated With Increased Cardiovascular Risk Independent of Clopidogrel Use

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.