Association between high on-treatment platelet reactivity and occurrence of cerebral ischemic events in patients undergoing percutaneous coronary intervention.

INTRODUCTION: Percutaneous coronary angioplasty (PCI) has become a routine treatment in symptomatic patients with coronary artery disease. The use of new generation drug eluting stents (DES) and dual antiplatelet therapy has significantly improved treatment outcomes and increased patients' safety by reducing the risk of stent thrombosis. AIMS: The goal of this study was to assess whether high on treatment platelet reactivity (HTPR), despite clopidogrel treatment, measured with Multiplate Electrode Aggregometer (MEA) is associated with the risk of adverse ischemic cerebral events. METHODS: Symptomatic patients with coronary artery disease admitted for coronary angiography and angioplasty (PCI) were consecutively enrolled in this study. 249 consecutive patients underwent coronary artery stenting for stable angina (n=215) or non-ST-elevation acute coronary syndrome (n=34). Inhibition of platelet aggregation was assessed by MEA. Genetic polymorphism of CYP2C19 was tested by HRM Real-Time PCR method in 150 patients. RESULTS: Patients with HTPR were more frequently diagnosed with ischemic stroke (p=0.0351, OR=16.818, 95% CI [1.464-193.23]) and other ischemic cerebral events (stroke or TIA, p=0.0339, OR=6.5, 95% CI [1.36-31.07]). Cumulative assessment of all ischemic and hemorrhagic events showed no statistical significance. Cerebral ischemic event was the only adverse event that correlated with CYP2C19 (*2/*2) allele (p=0.0489, OR=10; 95% CI [1.39-71.80]). CONCLUSIONS: HTPR assessed by MEA, in patients treated with clopidogrel after coronary artery stenting was found to be an important risk factor of ischemic cerebral events. In concordance, the carriers of CYP2C19*2/*2 allele showed an increased rate of ischemic cerebral events.

Comparison of the antiplatelet effect of two clopidogrel bisulfate formulations: Plavix and generic-Egitromb.

Due to expansion of the pharmaceutical market it seems necessary to prove the efficacy of the generic drugs. The aim of this study is to compare the effects of two clopidogrel formulations: brand-name-Plavix and generic drug - Egitromb. This is a prospective, randomized study comparing two groups of patients treated with two clopidogrel: brand-name Plavix and generic drug- Egitromb. The 53 consecutive patients with stable coronary artery disease qualifying for coronary angiography and PCI were enrolled in this trial. They were randomized into two groups. In the group A (n = 28) patients received Egitromb 300 mg at admission followed by 8 days of 75 mg Egitromb daily. In the group B (n = 25) patients received Plavix 300 mg on the admission followed by 8 days of 75 mg Plavix maintenance therapy. Blood samples for multiple electrode aggregometry testing were drawn at baseline, 5 hours and 8 days after taking the loading dose. Median values of platelet aggregation inhibition did not differ between the Plavix and Egitromb groups when assessed at baseline: 239AU/min (IQR:329) vs. 209 (IQR:406; p = 0.894), 5 hours after loading: 183 AU/min (IQR:107) vs. 165 (IQR:171; p = 0.831) or at day 8: 174 AU/min (IQR:133) vs. 211 (IQR:133; p = 0.332. The study showed no difference in the therapeutic effect of two clopidogrel formulations (Egitromb and Plavix).

[Dual platelet inhibitors in intensive care units]. / Duale Plättchenhemmung in der Intensivmedizin.

BACKGROUND: The introduction of clopidogrel was a milestone in the development of modern antiplatelet therapy. However, the shortcomings in the pharmacokinetics of clopidogrel have led to the development of alternative substances. CURRENT CONCEPT: The two new drugs prasugrel and ticagrelor were included in the current guidelines for the treatment of patients with acute coronary syndrome. These potent platelet inhibitors, however, are associated with an increased rate of bleeding events, which is of particular importance in critically ill patients. However, the new platelet inhibitors are less effective in patients with cardiogenic shock or patients treated with therapeutic hypothermia. FUTURE: Recent studies underscore the assessment of the net clinical benefit in patient management. Since there is only a thin line between efficacy and safety in critically ill patients, future studies for risk stratification of antiplatelet therapy in terms of personalized medicine are mandatory.

Clinical implications of drug-drug interactions with P2Y12 receptor inhibitors.

Polypharmacy in patients undergoing coronary artery stenting or in those presenting with an acute coronary syndrome is common. Nevertheless, the risk of drug-drug interactions in patients treated simultaneously with P2Y12 receptor inhibitors is less well considered in routine clinical practice. Whereas the irreversible P2Y12 receptor inhibitors clopidogrel and prasugrel are prodrugs requiring cytochrome P450 (CYP) enzymes for metabolic activation, such activation is not necessary for the direct-acting reversible P2Y12 receptor inhibitor ticagrelor. Several drugs frequently used in cardiology have been shown to interact with the metabolism of P2Y12 receptor inhibitors in pharmacodynamic studies. Whereas several drug-drug interactions have been described for clopidogrel and ticagrelor, prasugrel seems to have a low potential for drug-drug interactions. The clinical implications of these interactions have raised concern. In general, concomitant administration of P2Y12 receptor antagonists and strong inhibitors or inducers of CYP3A/CYP2C19 should be performed with caution in patients treated with clopidogrel/ticagrelor. Under most circumstances, clinicians have the option of prescribing alternative drugs with less risk of drug-drug interactions when used concomitantly with P2Y12 receptor inhibitors.

Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study.

BACKGROUND: Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies. OBJECTIVES: To compare different assays for prediction of events during long-term follow-up. METHODS: In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator-stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA-100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12-month follow-up. RESULTS: Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c-index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA-100 (c-index < 0.70; P > 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c-index < 0.56; P > 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra-metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status. CONCLUSIONS: Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping.

Low-molecular-weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis.

BACKGROUND: The aim of the current study was to perform two separate meta-analyses of available studies comparing low-molecular-weight heparins (LMWHs) vs. unfractionated heparin (UFH) in ST-elevation myocardial infarction (STEMI) patients treated (i) with primary percutaneous coronary intervention (pPCI) or (ii) with PCI after thrombolysis. METHODS: All-cause mortality was the pre-specified primary endpoint and major bleeding complications were recorded as the secondary endpoints. Relative risk (RR) with a 95% confidence interval (CI) and absolute risk reduction (ARR) were chosen as the effect measure. RESULTS: Ten studies comprising 16,286 patients were included. The median follow-up was 2 months for the primary endpoint. Among LMWHs, enoxaparin was the compound most frequently used. In the pPCI group, LMWHs were associated with a reduction in mortality [RR (95% CI) = 0.51 (0.41-0.64), P < 0.001, ARR = 3%] and major bleeding [RR (95% CI) = 0.68 (0.49-0.94), P = 0.02, ARR = 2.0%] as compared with UFH. Conversely, no clear evidence of benefits with LWMHs was observed in the PCI group after thrombolysis. Meta-regression showed that patients with a higher baseline risk had greater benefits from LMWHs (r = 0.72, P = 0.02). CONCLUSIONS: LMWHs were associated with greater efficacy and safety than UFH in STEMI patients treated with pPCI, with a significant relationship between risk profile and clinical benefits. Based on this meta-analysis, LMWHs may be considered as a preferred anticoagulant among STEMI patients undergoing pPCI.

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.

Tacrolimus-eluting carbon-coated stents versus sirolimus-eluting stents for prevention of symptom-driven clinical end points.

BACKGROUND: Coating of stents has been shown to minimize the interactions between platelets, stent surface and vascular response following stent implantation. The aim of our study was to compare the tacrolimus-eluting carbon-coated JANUS(®) stent with sirolimus-eluting CYPHER(®) stent for the prevention of symptom-driven clinical end points in a real world clinical setting. METHODS: This prospective registry with a follow-up period of 24 months was conducted in 90 consecutive patients undergoing coronary artery stenting receiving CYPHER(®) (n = 48) or JANUS(®) (n = 42) stents. The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction and target vessel revascularisation, and the secondary end point was clinically driven in-stent restenosis. RESULTS: The primary combined endpoint occurred in 38% of patients (n = 16) in the JANUS(®) group compared to 10% (n = 5) in the CYPHER(®) group. The relative risk increase of the composite end point was therefore 63% higher in patients receiving JANUS(®) stents compared to the CYPHER(®) stents (crude HR = 1.63, 95% CI = 1.17-2.28, p = 0.004; adjusted HR = 1.79, CI = 1.26-2.55, p = 0.001). Interestingly, 75% of events in the JANUS(®) group occurred during the first 6 months after stent implantation. Similarly, the rate of clinically driven in-stent restenosis was higher in patients receiving JANUS(®) stent (n = 10, 2%) compared to the CYPHER(®) stent (n = 2, 4%). Concordantly, the relative risk for clinically driven in-stent restenosis was 81% higher in the JANUS(®) group compared to the CYPHER(®) group (crude HR = 1.81, 95% CI = 1.08-3.02, p = 0.02; adjusted HR = 2.24, CI = 1.26-3.96, p = 0.006). CONCLUSION: The use of tacrolimus-eluting carbon coated JANUS(®) stent was associated with worse clinical outcome compared to the sirolimus-eluting CYPHER(®) stent in clinical routine use.

Multiple electrode aggregometry predicts stent thrombosis better than the vasodilator-stimulated phosphoprotein phosphorylation assay.

BACKGROUND AND AIM: The prognostic value of the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and multiple electrode aggregometry (MEA) for thrombotic adverse events has been shown in independent studies. As no direct comparison between the two methods has been made so far, we investigated which laboratory approach has a better predictive value for stent thrombosis. METHODS: The VASP phosphorylation assay and MEA were performed in 416 patients with coronary artery disease undergoing percutaneous coronary intervention. The rate of stent thrombosis was recorded during a 6-month follow-up. RESULTS: Definite stent thrombosis occurred in three patients (0.7%) and probable stent thrombosis in four (1%). Receiver operating characteristic (ROC) analysis demonstrated that MEA distinguishes between patients with or without subsequent stent thrombosis better than the VASP phosphorylation assay: the area under the ROC curve was higher for MEA (0.92; P=0.012) than for the VASP phosphorylation assay (0.60; P=0.55). At equal levels of sensitivity (100%), the specificity was greater for MEA than for the VASP phosphorylation assay (86% vs. 37%). Stent thrombosis occurred in 9% of patients with platelet hyperreactivity in MEA, who were simultaneously clopidogrel non-responders in the VASP phosphorylation assay. Interestingly, clopidogrel non-responders in the VASP phosphorylation assay without platelet hyperreactivity in MEA did not suffer from stent thrombosis. CONCLUSIONS: Platelet hyperreactivity in MEA might be a better risk predictor for stent thrombosis than the assessment of the specific clopidogrel effect with the VASP phosphorylation assay.

Strain differences in toxic effects of long-lasting isoflurane anaesthesia between Wistar rats and Sprague Dawley rats.

We investigated if long-lasting (5 h) anaesthesia with isoflurane has different pharmacological effects in two different rat strains: Wistar and Sprague Dawley. The mean blood pressure was 34% higher in Sprague Dawley rats as compared to the Wistar rats (p = 0.04). In Wistar rats, the pH value decreased to 7.1, lactate increased by 53%, creatinine increased 2.7-fold, alanine amino transferase and aspartate amino transferase increased more than 4-fold and lactate dehydrogenase increased 9-fold (p < 0.05). There were no changes in laboratory parameters in Sprague Dawley rats. This indicates that the Wistar rats were more sensitive to a 5 h anaesthesia with isoflurane after a premedication with ketamin/xylazine in the described study design.