Bleeding events are associated with an increase in markers of inflammation in acute coronary syndromes: an ACUITY trial substudy.

Bleeding events have been associated with adverse early and late outcomes in virtually all clinical settings. The mechanism behind this observation remains poorly understood. We sought to determine if the reason might be the provocation of an inflammatory response by bleeding events. In a formal substudy of the ACUITY trial, plasma samples of a range of biomarkers were collected at baseline, discharge, 30 days, and 1 year from 192 patients with acute coronary syndromes (ACS) and were analyzed in a central core laboratory. Temporal changes in biomarker levels were assessed in patients who experienced in-hospital hemorrhagic events, recurrent ischemic events, or neither. Sixteen patients were excluded from the study (7 with incomplete samples, 5 undergoing coronary artery bypass grafting (CABG) during index hospitalization; 1 had both bleeding and ischemic events). Median high sensitivity C-reactive protein (hs-CRP) levels (mg/l) increased significantly more from admission to discharge among the 9 patients who experienced an in-hospital major bleed compared to either the 9 patients who had a recurrent ischemic event (+6.0 vs. +0.70, P = 0.04) or the 151 patients who had no event (+6.0 vs. +0.60, P = 0.003). Compared to patients with no in-hospital events, median interleukin-6 (IL-6) levels (pg/ml) increased from admission to hospital discharge non-significantly in those with a bleeding event (+0.92 vs. +2.46, P = 0.55) and in those who experienced an in-hospital recurrent ischemic event (+0.92 vs. +3.60, P = 0.09). These data suggest that major bleeding is associated with development of a pro-inflammatory state. If confirmed, this mechanism may in part explain the poor prognosis of patients experiencing an acute hemorrhagic event.

Variable platelet responsiveness to aspirin and clopidogrel: role of platelet function and genetic polymorphism testing.

Dual antiplatelet therapy with aspirin and clopidogrel is the standard treatment for patients with an acute coronary syndrome or percutaneous coronary intervention. However, at standard doses, many patients still experience an adverse cardiovascular event. Numerous studies have demonstrated that a laboratory assessment of platelet resistance to an antiplatelet medication is associated with adverse outcomes. The gold standard in assessing platelet function is light transmittance aggregometry. However, because of the time necessary to complete the test, the need for skilled technicians, and the associated costs, newer point-of-care tests have been developed to assess rapidly an individual's platelet responsiveness. Although numerous studies demonstrate an association with adverse outcomes and platelet resistance, currently no clinical trial results demonstrate a treatment strategy to mitigate the adverse outcomes associated with platelet resistance. Studies currently underway are evaluating treatment options for a laboratory assessment of platelet resistance, such as increasing the clopidogrel maintenance dose. Until such results are available, routine testing of platelet resistance to aspirin or clopidogrel should be used only in a research setting.

Stent parameters predict major adverse clinical events and the response to platelet glycoprotein IIb/IIIa blockade: findings of the ESPRIT trial.

BACKGROUND: Only limited data describe relationships between stent parameters (length and diameter), adverse events after percutaneous coronary intervention, and effects of platelet glycoprotein IIb/IIIa blockade by stent parameters. METHODS AND RESULTS: In this post hoc analysis of the 1983 patients receiving a stent in the Enhanced Suppression of the Platelet Glycoprotein IIb/IIIa Receptor with Integrilin Therapy randomized percutaneous coronary intervention trial of eptifibatide versus placebo, rates of the major adverse cardiac event (MACE) end point (death, myocardial infarction, urgent target-vessel revascularization, or thrombotic bailout) at 48 hours and 1 year were correlated with stent parameters and then analyzed by randomization to eptifibatide versus placebo. In the placebo group, MACE increased with number of stents implanted, total stent length (by quartiles of <15, 15 to <18, 18 to <30, and >or=30 mm), and total stented vessel area (by quartiles of area <141, 141 to <188, 188 to <292, and >or=292 mm(2)). By stent parameters, MACE at 48 hours was reduced in the eptifibatide group at stent lengths of 18 to <30 mm (odds ratio [OR], 0.55; 95% CI, 0.32 to 0.94; P=0.030) and >or=30 mm (OR, 0.43; 95% CI, 0.25 to 0.75; P=0.003), stent diameters of >2.5 to <3.5 mm (OR, 0.56; 95% CI, 0.39 to 0.82; P=0.002), and with 2 stents implanted (OR, 0.39; 95% CI, 0.22 to 0.69; P=0.001). In the placebo group, near-linear relationships were observed between both increasing stent length and increasing stented vessel area and MACE at 48 hours and 1 year (all, P<0.001); these gradients were flattened in the eptifibatide group (P=0.005 for stent length). CONCLUSIONS: Stent parameters predict MACE after percutaneous coronary intervention. Glycoprotein IIb/IIIa blockade mitigates much of the hazard of increasing procedural complexity.

Drug-eluting stents and antiplatelet resistance.

Resistance to the antiplatelet effects of both aspirin and clopidogrel is common and is associated with poorer clinical outcomes in patients receiving antiplatelet therapy. Available data indicate that hyporesponsiveness to clopidogrel is overcome in some patients by increasing the loading dose from 300 mg to 600 mg, with the higher loading dose being associated with reduced risk for adverse cardiovascular outcomes. Recent studies in patients undergoing coronary stent implantation indicate that antiplatelet resistance is associated with increased risk of stent thrombosis. A study in 804 patients receiving drug-eluting stents showed that nonresponse (defined as >70% aggregation at 10 micromol/L adenosine diphosphate) after a clopidogrel 600-mg loading dose was associated with a significantly increased risk of stent thrombosis (8.6% vs 2.3% for nonresponders vs responders, respectively) and cardiovascular death at 6 months. Another study in 380 patients showed that high posttreatment platelet reactivity (top tertile of values) on a rapid assay was associated with significantly greater out-of-hospital 6-month rates of stent thrombosis (4.0% vs 0.4% for high posttreatment reactivity group vs low posttreatment reactivity group, respectively), cardiovascular death, and nonfatal myocardial infarction. Further studies are needed to provide standardized definitions of antiplatelet resistance to better correlate resistance with clinical outcomes in patients receiving stents and to identify treatment alternatives in patients with resistance.

Timing and correlates of very early major adverse clinical events following percutaneous coronary intervention.

We attempted to determine the incidence, timing and correlates of very early (< 24 hours) major adverse clinical events in patients undergoing contemporary percutaneous coronary intervention (PCI). Early discharge following PCI may offer significant advantages to patient and practitioner, but the timing of, and risk factors for, very early (< 24 hours) major adverse clinical events following PCI are not well characterized. A retrospective analysis of the CREDO trial was performed. A total of 1,815 patients underwent a PCI procedure and 139 patients (7.7%) experienced a major adverse clinical event (death, myocardial infarction or urgent target vessel revascularization) within the first 28 days. The majority of these events (111 patients) occurred within the first 24 hours, with the greatest risk of an event within the first 6 hours. Multivariable predictors of very early events were age, AHA lesion grade, history of peripheral vascular disease, preprocedural TIMI flow grade and no. of vessels with stenosis > 50%. These data show a very low and constant risk of adverse events 6 hours following PCI.