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Platelet activation results in the release and upregulation of mediators responsible for immune cell activation and recruitment, suggesting that platelets play an active role in immunity. Animal models and retrospective data have demonstrated benefit of antiplatelet therapy on inflammatory mediator expression and clinical outcomes. This study sought to characterize effects of clopidogrel on the incidence and severity of community-acquired pneumonia (CAP). A retrospective cohort study was conducted of Kentucky Medicaid patients (2001-2005). The exposed cohort consisted of patients receiving at least six consecutive clopidogrel prescriptions; the non-exposed cohort was comprised of patients not prescribed clopidogrel. Primary endpoints included incidence of CAP and inpatient treatment. Secondary severity endpoints included mortality, intensive care unit admission, mechanical ventilation, sepsis, and acute respiratory distress syndrome/acute lung injury. CAP incidence was significantly greater in the exposed cohort (OR 3.39, 95% CI 3.27-3.51, p < 0.0001) that remained after adjustment (OR 1.48, 95% CI 1.41-1.55, p < 0.0001). Inpatient treatment was more common in the exposed cohort (OR 1.96, 95% CI 1.85-2.07, p < 0.0001), but no significant difference remained after adjustment. Trends favoring the exposed cohort were found for the secondary severity endpoints of mechanical ventilation (p = 0.07) and mortality (p = 0.10). Pooled analysis of published studies supports these findings. While clopidogrel use may be associated with increased CAP incidence, clopidogrel does not appear to increase--and may reduce--its severity among inpatients. Because this study was retrospective and could not quantify all variables (e.g., aspirin use), these findings should be explored prospectively.

Background: Proton pump inhibitors (PPIs) may interfere with the metabolic activation of clopidogrel via inhibition of cytochrome P450 2C19, but the clinical implications remain unclear., Methods and Results: 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)., Conclusions: 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.

Patients presenting for invasive cardiovascular procedures are frequently taking a variety of medications aimed to treat risk factors related to heart and vascular disease. During the procedure, antithrombotic, sedative, and analgesic medications are commonly needed, and after interventional procedures, new medications are often added for primary and secondary prevention of ischemic events. In addition to these prescribed medications, the use of over-the-counter drugs and supplements continues to rise. Most elderly patients, for example, are taking 5 or more prescribed medications and 1 or more supplements, and they often have some degree of renal insufficiency. This polypharmacy might result in drug-drug interactions that affect the balance of thrombotic and bleeding events during the procedure and during long-term treatment. Mixing of anticoagulants, for instance, might lead to periprocedural bleeding, and this is associated with an increase in long-term adverse events. Furthermore, the range of possible interactions with thienopyridine antiplatelets is of concern, because these drugs are essential to immediate and extended interventional success. The practical challenges in the field are great-some drug-drug interactions are likely present yet not well understood due to limited assays, whereas other interactions have well-described biological effects but seem to be more theoretical, because there is little to no clinical impact. Interventional providers need to be attentive to the potential for drug-drug interaction, the associated harm, and the appropriate action, if any, to minimize the potential for medication-related adverse events. This review will focus on drug-drug interactions that have the potential to affect procedural success, either through increases in immediate complications or compromising longer-term outcome., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Antiplatelet therapy is of paramount importance in the treatment and prevention of adverse cardiovascular events and stroke. Drug-drug interactions (DDIs) among antiplatelet therapies have been growing in both prevalence and clinical importance. Most DDIs with antiplatelet therapies are pharmacodynamic in nature. DDIs with thienopyridines and proton pump inhibitors have resulted in advisories from regulatory agencies although the full significance of this interaction is unknown. Other DDIs with thienopyridines may potentially exist with statins, calcium channel blockers, and warfarin but lack demonstratable evidence of harm. Aspirin may interact with a variety of medications, including non-steroidal anti-inflammatory agents and angiotensin inhibitors. DDIs requiring some level of intervention may also be present with dipyridamole and cilostazol. Overall, DDIs with antiplatelet drugs are biologically plausible and potentially clinically relevant. However, the full significance of these DDIs is largely unknown due to reliance on research of voluntary reports, registries, and claims databases to determine significance.

The European Medicines Agency (EMEA) recently issued a public statement on a possible interaction between clopidogrel and proton pump inhibitors (PPIs) and recommended that the product information for all medicines containing clopidogrel be amended to discourage concomitant use of PPIs unless absolutely necessary. This follows a prior alert issued by the United States Food and Drug Administration (FDA) earlier this year, stating that PPIs might interfere with the effectiveness of clopidogrel and that clinicians should reevaluate starting or continuing treatment with a PPI in patients taking clopidogrel. However, several experts have voiced their concern that the clopidogrel-PPI interaction has been given undue importance, given that all clinical studies suggesting this problem are observational. In this review, we critically analyze the available data and make practical suggestions for the clinician regarding appropriate use of PPIs in patients receiving clopidogrel. Based on currently available evidence, we suggest that the decision to prescribe a PPI to a patient on clopidogrel must be made on an individual patient basis balancing the gastrointestinal risk with the possible thrombotic risk and that PPIs should only be used for truly appropriate indications.

Background: Variable platelet response to clopidogrel has been widely observed. Studies have shown that the mean aggregation response to clopidogrel can be changed by a higher maintenance dose. However, these studies have not focused on individual changes., Objectives: This study examined the platelet function effects of increasing the maintenance clopidogrel dose from 75 to 150 mg/day with a focus on inter-individual response., Patients/methods: Twenty patients with known coronary artery disease receiving 75 mg/day clopidogrel were recruited and given 150 mg/day clopidogrel for 30 days, then returned to 75 mg/day for an additional 30 days. Platelet function was assessed through light-transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay at baseline, 30 days, and 60 days., Results: Mean platelet inhibition was significantly improved with the increased maintenance dose when measured by the VerifyNow P2Y12 assay (P2Y12 reaction units: 191+/-15 vs. 158+/-17, P=0.013), but not when measured by LTA (LTA-adenosine diphosphate 5: 40+/-3 vs. 36+/-3, P = 0.11; LTA-adenosine diphosphate 20: 50+/-3 vs. 47+/-3, P = 0.23). However, only 50% of individual patients experienced improved platelet inhibition, as measured by the VerifyNow P2Y12 assay, when treated with the increased maintenance dose. Furthermore, poor baseline platelet response did not predict improved responsiveness at the increased dose., Conclusion: Despite changing the population's mean antiplatelet response, an increased maintenance dose of clopidogrel did not improve antiplatelet response in a substantial number of patients; nor did baseline platelet function predict response to a higher maintenance dose.

Background: Aspirin therapy is a cornerstone in the prevention of atherothrombotic events, but recurrent vascular events are estimated to occur in 8-18% of patients taking aspirin for secondary prevention after 2 years. Estimates of biologic aspirin resistance vary from 5% to 60%, depending on the assay used. However, the relationship between biologic measurements of aspirin resistance and adverse clinical events remains unclear., Objective: To determine whether patients with documented myocardial infarction (MI) while on aspirin therapy (cases) were more likely to be aspirin resistant than were patients with coronary artery disease (CAD) who had no history of MI (controls) and to assess clinical predictors of aspirin resistance in patients with stable CAD., Methods: This case-control study examined aspirin responses using the VerifyNow Aspirin Assay system in 50 cases and 50 controls who had taken a dose of aspirin within 48 hours of presentation to the clinic visit. Odds ratios were estimated to determine the association between aspirin resistance and MI. Independent predictors of aspirin resistance were determined using univariate and multivariate analyses., Results: An increase in the prevalence of aspirin resistance among cases (16% vs 12% in controls) was not observed (OR 1.40; 95% CI 0.45 to 4.37; p = 0.566). In the overall CAD population, female sex was independently associated with aspirin resistance (OR 4.01; 95% CI 1.15 to 13.92; p = 0.029)., Conclusions: Additional large studies are required to understand whether biologically defined aspirin resistance is associated with increased risk for cardiovascular events, with special attention paid to sex differences.

Despite aggressive antiplatelet therapy in the setting of PCI, the incidence of acute stent thrombosis remains approximately 0.5-2%. We report a patient with simultaneous thrombosis of two drug-eluting coronary artery stents, suggesting a systemic thrombotic state. Evaluation by optical platelet aggregometry revealed clopidogrel resistance, which was overcome at a higher drug dose. We aim to highlight the potential utility of platelet function analysis to guide therapy for patients in whom inadequate antiplatelet therapy may have catastrophic clinical outcomes.