Concurrent Use Of Clopidogrel Research Articles

Effects of treatment with clopidogrel with or without proton pump inhibitor omeprazole on the risk of ischemic stroke: a nationwide cohort study

Most proton pump inhibitors (PPIs) inhibit the bioactivation of clopidogrel to its active metabolite. There is controversy concerning whether PPIs alter the effectiveness of clopidogrel in reducing the risk of ischemic stroke (IS). We therefore aimed to examine the risk of IS associated with concomitant use of clopidogrel and omeprazole, a PPI commonly used in clinical settings. We conducted a retrospective cohort study using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohorts comprised 407 patients diagnosed with acute coronary syndrome (ACS) and with concomitant use of clopidogrel and omeprazole (the exposed cohort), 814 ACS patients with single use of clopidogrel (the comparison cohort), and 230 ACS patients with concurrent use of clopidogrel and pantoprazole (the reference cohort). The primary outcome was incident IS. The hazard ratios (HRs) and 95% confidence intervals (CIs) derived from the time-dependent Cox regression model were used to assess the association between concomitant use of clopidogrel and omeprazole and the risk of IS. The incidence rate of IS was significantly higher in the exposed cohort (81.67 per 1000 person-years) than in the comparison cohort (57.45 per 1000 person-years), resulting in an adjusted HR of 1.39 (95% CI 1.03–1.74). By contrast, there was no significant difference in the risk of IS between the exposed and reference cohorts (adjusted HR 1.11; 95% CI 0.81–1.52). The present study revealed that patients taking both clopidogrel and omeprazole was associated with an increased risk of IS.

Intermittent concurrent use of clopidogrel and proton pump inhibitors did not increase risk of adverse clinical outcomes in Chinese patients with coronary artery disease

BackgroundProton pump inhibitors (PPIs) are frequently prescribed to patients with coronary heart disease (CHD) under antiplatelet therapy to prevent gastrointestinal (GI) bleeding. However, its clinical impact is still under debate, especially in Asian population. This study was undertaken to explore the effects of concurrent use of clopidogrel and PPIs on the clinical outcomes in Chinese patients with CHD in secondary prevention.MethodsA single-center retrospective study was conducted in 638 patients with CHD on consecutive clopidogrel therapy for at least 1 year. After 18-month follow-up, adverse clinical events were collected. Cox regression was used to calculate hazard ratios (HR) and 95% confidence interval (CI) for the effect of PPI use on the outcomes. A total of 638 patients were recruited from 2014 to 2015 in this study, among whom 201 were sustained PPI users, 188 were intermittent PPI users and the remaining 249 were non-PPI users.ResultsCompared with sustained PPI users, intermittent use of PPIs was associated with a lower risk of stroke, major adverse cardiac events (MACE) and net adverse clinical event (NACE) (stroke: adjusted HR: 0.109, 95% CI 0.014–0.878, p = 0.037; MACE: adjusted HR: 0.293, 95% CI 0.119–0.722; p = 0.008; NACE: adjusted HR: 0.357, 95% CI 0.162–0.786, p = 0.011). Subgroup analysis further revealed the benefit of intermittent PPI use was significant in male CHD patients over 60 years old, with hypertension or chronic kidney disease, and undergoing percutaneous coronary intervention during hospitalization.ConclusionThe current findings suggest that the intermittent concurrent use of PPIs and clopidogrel is not associated with an increased risk of 18-month adverse clinical outcomes, and intermittent use of PPIs is associated with a lower rate of MACE and NACE.

Does concurrent use of clopidogrel and PPIs increase CV risk in patients with ACS?

No. Adding a proton pump inhibitor (PPI) in patients taking antiplatelet medications such as clopidogrel for acute coronary syndrome (ACS) doesn't increase the composite risk of cardiovascular (CV) events: CV death, myocardial infarction (MI), and cerebrovascular accident (CVA) (strength of recommendation: B, randomized, controlled trial [RCT] and prepon-derance of posthoc analyses of large RCTs).

Carotid Endarterectomy and Concurrent Clopidogrel Use: National Practice Patterns in the United States

Patients with diagnoses of high-grade carotid stenosis are often placed on antiplatelet therapy and undergo carotid endarterectomy (CEA) during their hospital stay. There is intersurgeon variability in offering CEA to patients specifically on the potent antiplatelet agent clopidogrel. Utilizing the Premier database, data from adults with principal discharge diagnosis of stroke, transient ischemic attack (TIA), or carotid artery stenosis or occlusion without stroke/TIA (CAS) who had a CEA during the same hospital stay in 2014 were analyzed. Recent clopidogrel or aspirin use was defined as within 3 days before CEA. Univariate and multivariate analyses were used to examine the association of age, race, gender, symptomatic versus asymptomatic carotid stenosis, academic versus non-academic center, and regions of the United States with recent antiplatelet use before CEA. There were 15,381 patients (median age, 71 years, interquartile range 65-78; 42% females) with stroke, TIA, or CAS who had a CEA during the same hospital stay in 2014 within the Premier databse. Of these, 2570 patients (16.7%) received clopidogrel, 4992 (32.5%) received aspirin but no clopidogrel, and 7819 (50.8%) received no clopidogrel/aspirin immediately before CEA. Younger patient age, treatment at a non-academic center, symptomatic carotid stenosis, and being in the Northeast or South were associated higher odds of being on clopidogrel therapy prior to CEA. Across the United States, 1 in 6 patients was on clopidogrel therapy prior to undergoing a CEA. Patients with symptomatic carotid stenosis were most likely to be on clopidogrel therapy prior to their CEA. Future systematic analysis of differences in outcomes and safety events are needed.

Abstract WP147: Carotid Endarterectomy and Concurrent Clopidogrel Use: U.S. National Practice Patterns

Background: Patients diagnosed with high-grade carotid stenosis often receive a carotid endarterectomy (CEA) during their hospital stay and most receive antiplatelet medication. There is inter-surgeon variability in performing CEA in patients receiving clopidogrel due to its potent antiplatelet effect. Methods: Utilizing the PREMIER database (a representative sample of 15% of US hospital discharges with procedure codes and medications); adults with principal discharge diagnosis coded as stroke, transient ischemic attack (TIA) or carotid artery stenosis or occlusion without stroke/TIA(CAS) (ICD-9: 434, 435, 433.10, and 433.11 respectively), who had a CEA (ICD-9 38.12) during the same hospital stay, in 2014 were analyzed. Clopidogrel use was defined as receiving any dose within the 3 days prior to the CEA. Univariate and multivariable analyses; T-test, Chi-square and multiple logistic regression, were used to examine the association of age, race, gender, principal diagnosis of stroke/TIA vs. CAO, academic vs non-academic center, and region of the US, with CEA following clopidogrel use. Results: There were 15,381 patients with stroke, TIA, or CAS who had a CEA during the same hospital stay in 2014. Patients were median age 71 years, (IQR 65-78), 86% were Caucasians, 4% Black, and 10% other race; 42% were female. 2570 patients (17 %) received a dose of clopidogrel within 3 days prior to their procedures. In univariate analysis, male sex, having a stroke/TIA vs CAS, not being at a teaching hospital, being in the Northeast or South were associated with CEA after clopidogrel. Results for the multivariable analysis are presented in the Table. Conclusions: Our study found that across the US, about 1 in 6 patients who undergo CEA have clopidogrel in their system. Younger age, having a stroke/TIA vs CAS, non-teaching hospitals, and areas other than the West are found to convey higher odds of CEA while on clopidogrel. Future analysis of differences in outcomes and safety events are needed.

Non-Warfarin Oral Anticoagulants in Heparin-Induced Thrombocytopenia

Introduction: Heparin-Induced Thrombocytopenia (HIT) is an antibody-mediated reaction where exposure to heparin products (unfractionated and, less commonly, low molecular weight heparins) leads to a paradoxical prothrombotic state. Current treatment guidelines recommend immediate cessation of all heparin products and initiation of a non-heparin anticoagulant. This is typically accomplished with argatroban and then transitioning to a vitamin K antagonist once platelets have recovered. An attractive alternative is the use of the non-warfarin oral anticoagulants (NOACs) in the treatment of HIT, namely the direct Xa inhibitors apixaban and rivaroxaban which have already proven safe and effective for the treatment of venous thromboembolism.Methods: We designed a retrospective analysis of all patients at the University of Virginia with a positive serotonin release assay (for a definitive diagnosis of HIT) that were treated with either apixaban or rivaroxaban since September 2011. Results from heparin induced platelet antibody testing were also recorded. Patients were reviewed for recurrent thrombi, severe bleeding or other complications that led to changes in their management.Results: Eleven patients were identified based on the inclusion criteria. All patients had a positive serotonin release assay despite 4/11 (36%) testing negative for heparin induced platelet antibody. All patients received intravenous argatroban or bivalirudin at the time of diagnosis and were transitioned to an oral anticoagulant at time of hospital discharge. 9/11 (81%) were treated with apixaban and 2/11 (19%) were treated with rivaroxaban. Zero patients developed recurrent thrombi (summarized in Table 1). One patient in each group developed major bleeding leading to discontinuation of anticoagulation. Of these, both had additional risk factors for bleeding prior to initiation of anticoagulation (one with concurrent clopidogrel use after coronary artery bypass grafting and prior bleeding from gastric varices; the other with previously diagnosed metastatic squamous cell lung cancer). Of the remaining 9 patients, safe and effective anticoagulation with a NOAC was noted for up to18 months without adverse effects.Conclusion: Apixaban and rivaroxaban, along with all forms of anticoagulation, should be used with caution in patients with risk factors for severe bleeding. These medications, however, showed to be a safe and effective first line outpatient regimen for patients with HIT. Further prospective studies are needed before their use should be accepted as standard of care.Table 1Patients with Heparin-Induced Thrombocytopenia Treated with Non-Warfarin Oral AnticoagulantPatientHeparin Induced Platelet Antibody (%)Serotonin Release Assay (%)AnticoagulantLength of Therapy (in months)Bleeding ComplicationsThrombotic ComplicationsCurrent Plan1-+ (93)Apixaban8NoNoContinue2+ (110)+ (100)Apixaban2*NoNoContinue3+ (81)+ (53)Apixaban13NoNoContinue4-+ (91)Apixaban9NoNoContinue5+ (108)+ (100)Apixaban16NoNoContinue6-+ (92)Apixaban6NoNoContinue7+ (126)+ (100)Apixaban2†GastrointestinalNoOff since bleed8-+ (30)Rivaroxaban1‡HemoptysisNoOff since bleed9+ (107)+ ( 77)Apixaban10NoNoContinue10+ (89)+ (44)Apixaban6NoNoContinue11+ (106)+ (67)Rivaroxaban18NoNoContinue*No evidence of thrombosis at diagnosis, only thrombocytopenia†severe bleeding from known gastric varices; also on clopidogrel for CAD‡moderate hemoptysis secondary to known squamous cell lung cancer DisclosuresOff Label Use: Apixaban and rivaroxaban use in patients with heparin-induced thrombocytopenia.

In-hospital bleeding in the era of newer P2Y12 inhibitors in real-life patients with acute coronary syndrome: results from the GReek AntiPlatElet (GRAPE) registry

Purpose: Data on in-hospital bleeding events with the concurrent use of clopidogrel, prasugrel and ticagrelor in real-life practice are lacking. Methods: In the context of GReek AntiPlatelet rEgistry (GRAPE), a prospective, observational, multicenter cohort study conducted in in 8 PCI-capable hospitals in Greece, we investigated in-hospital bleeding events (Bleeding Academic Research Consortium -BARC classification) in ACS patients undergoing percutaneous coronary intervention (PCI). Results: Between January and December 2012, 1280 patients were included in analysis (82.8% men, 22.7% diabetics, 53.5% admitted with ST elevation myocardial infarction (STEMI), with a mean age of 61.8±12.4 years). Overall, in-hospital bleeding BARC type 1, 2 3a and 3b occurred in 54 (4.2%), 31 (2.4%), 21 (1.6%) and 5 (0.4%) patients respectively. No fatal bleeding event occurred. In the subgroup of patients who were initially treated either with clopidogrel (N=478), prasugrel (N=92) or ticagrelor (N=228) without switching thereafter, multivariate analysis (backward logistic regression) revealed age≥75 years and recent/recurrent gastrointestinal (GI) bleeding as predictive factors of in-hospital bleeding BARC of any type (OR=2.14, 1.21-3.80 95% CIs, p=0.009 and OR=6.48, 1.13-37.2 95% CIs, p=0.04 respectively). In 215 propensity-matched pairs of patients, rate of in-hospital bleeding BARC of any type did not differ significantly between clopidogrel vs prasugrel or ticagrelor -treated patients (3.7% vs 7.9%, p=0.098). Conclusions: In a real-world PCI-treated ACS population, older age and previous GI bleeding are associated with an increased risk of low to moderate severity in-hospital bleeding events. A trend towards more bleeding with the newer agents is apparent.

IN-HOSPITAL BLEEDING EVENTS WITH THE USE OF NEWER P2Y12 INHIBITORS IN REAL-LIFE PATIENTS WITH ACS: RESULTS FROM THE GREEK ANTIPLATELET (GRAPE) REGISTRY

Few comparative data exist on in-hospital bleeding events with the concurrent use of clopidogrel, prasugrel and ticagrelor in real-life patients with ACS undergoing percutaneous coronary intervention (PCI). We performed detailed recording of bleeding events (Bleeding Academic Research Consortium -

Cardiovascular outcomes associated with concomitant use of clopidogrel and proton pump inhibitors in patients with acute coronary syndrome in Taiwan

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. 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. 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. 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. 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.

Effect of the Clopidogrel–Proton Pump Inhibitor Drug Interaction on Adverse Cardiovascular Events in Patients with Acute Coronary Syndrome

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.

Adverse cardiovascular outcomes associated with concurrent use of clopidogrel or ticlopidine and proton-pump inhibitors in patients undergoing percutaneous coronary intervention

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.

Outcomes With Concurrent Use of Clopidogrel and Proton-Pump Inhibitors

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.

In light of recent study data,* the Irish Medicines Board has issued interim advice on concurrent use of clopidogrel and proton pump inhibitors

In light of recent study data,* the Irish Medicines Board has issued interim advice on concurrent use of clopidogrel and proton pump inhibitors

Effect of oral antiplatelet agents on major bleeding in users of coumarins

Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. In order to elucidate the bleeding risk of users of antiplatelet drugs among users of coumarins, we assessed the odds ratio of major bleeding associated with use of antiplatelet drugs in users of the coumarins acenocoumarol and phenprocoumon. We used data from a Dutch record linkage system, including pharmacy and linked hospitalization records for approximately two million subjects, to conduct a nested case control study in a cohort of new users of coumarins. Cases were patients who were hospitalized with a primary diagnosis of major bleeding while taking coumarin and were matched with up to four control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CI). We identified 1848 case patients who were matched to 5818 controls. Users of clopidogrel or aspirin showed a significantly increased risk of hospitalization because of major bleeding (OR 2.9, 95% CI 1.2-6.9 and OR 1.6, 95% CI 1.3-1.9, respectively), whereas users of dipyridamole and combinations of antiplatelet drugs showed a strong trend (OR 1.5, 95% CI 1.0-2.3 and OR 1.8, 95 % CI 1.0-3.3, respectively). In all cases, the risks were greater for upper gastrointestinal bleedings than for other bleedings. In conclusion, the use of any antiplatelet drug increases the risk of hospitalization for major bleeding among users of coumarins. Concurrent use of clopidogrel or dipyridamole and coumarins is probably not safer than concurrent use of aspirin and coumarins.

Concurrent use of clopidogrel (Plavix) and atorvastatin (Lipitor) is contraindicated.

Concurrent use of clopidogrel (Plavix) and atorvastatin (Lipitor) is contraindicated.

Concurrent use of clopidogrel (Plavix) and atorvasatin (Lipitor) is contraindicated.

Concurrent use of clopidogrel (Plavix) and atorvasatin (Lipitor) is contraindicated.