Faculty Bibliography

BACKGROUND:Factor Xa and factor IIa (thrombin) play roles in thrombotic complications after percutaneous coronary intervention. M118 is a novel low-molecular-weight heparin that has been rationally designed to capture the desired attributes of unfractionated heparin (UFH) and low-molecular-weight heparin: Potent activity against factor Xa and IIa, predictable pharmacokinetics after both intravenous and subcutaneous administration, ability to be monitored by use of point-of-care coagulation assays, and reversibility with protamine sulfate. We performed a phase 2 randomized trial to evaluate the safety and feasibility of M118 in the setting of elective percutaneous coronary intervention. METHODS AND RESULTS/RESULTS:Overall, 503 patients undergoing elective percutaneous coronary intervention at 43 centers in the United States and Canada were randomized in an open-label fashion to 1 of 4 arms: UFH 70 U/kg, M118 50 IU/kg IV, M118 75 IU/kg IV, or M118 100 IU/kg IV. The primary outcome was the composite of death, myocardial infarction, repeat revascularization, stroke, thrombocytopenia, catheter thrombus, bailout use of glycoprotein IIb/IIIa inhibitor, or any bleeding through 30 days. The primary end point occurred in 31.1% of patients randomized to UFH and in 22.7%, 28.3%, and 30.1% of patients randomized to M118 50, 75, and 100 IU/kg, respectively. The primary analysis comparing the rates of the primary end points between the pooled M118 groups versus UFH demonstrated that M118 was noninferior to UFH at preventing percutaneous coronary intervention-related complications (28.4% pooled M118 arms versus 31.1% UFH). The adverse event profiles of M118 and UFH were comparable. CONCLUSIONS:This phase 2 randomized trial demonstrates that M118 is well tolerated and feasible to use as an anticoagulant in patients undergoing elective percutaneous coronary intervention and forms the basis for further investigation of this agent in ischemic heart disease. CLINICAL TRIAL REGISTRATION/BACKGROUND:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00543400.

BACKGROUND:Previous data on bleeding after percutaneous coronary intervention (PCI) have been obtained primarily from randomized trials that focused on in-hospital bleeding. The incidence of late bleeding after PCI, its independent predictors, and its prognostic importance in clinical practice has not been fully addressed. METHODS AND RESULTS/RESULTS:We evaluated 22 798 patients aged >65 years who underwent PCI from December 1, 2003, to March 31, 2007, in Ontario, Canada. Cox proportional hazard models were used to determine factors associated with late bleeding, which was defined as hospitalization for bleeding after discharge from the index PCI, and to estimate risk of death or myocardial infarction associated with late bleeding. We found that 2.5% of patients were hospitalized for bleeding in the year after PCI, with 56% of bleeding episodes due to gastrointestinal bleed. The most significant predictor of late bleeding was warfarin use after PCI (hazard ratio [HR], 3.12). Other significant predictors included age (HR, 1.41 per 10 years), male sex (HR, 1.24), cancer (HR, 1.80), previous bleeding (HR, 2.42), chronic kidney disease (HR, 1.93), and nonsteroidal antiinflammatory drug use (HR, 1.73). After adjusting for baseline covariates, hospitalization for a bleeding episode was associated with a significantly increased 1-year hazard of death or myocardial infarction (HR, 2.39; 95% CI, 1.93 to 2.97) and death (HR, 3.38; 95% CI, 2.60 to 4.40). CONCLUSIONS:Hospitalization for late bleeding after PCI is associated with substantially increased risk of death and myocardial infarction. The use of triple therapy (i.e., aspirin, thienopyridine, and warfarin) is associated with the highest risk of late bleeding.

AIMS/OBJECTIVE:To correlate inhibition of platelet aggregation (IPA) with bleeding events assessed by TIMI, GUSTO, and BleedScore scales in a large cohort of patients with coronary artery disease (CAD) and ischaemic stroke (IS) treated with chronic low-dose aspirin plus clopidogrel. Data from recent trials and registries suggest a link between increased risk of bleeding and cardiovascular mortality. However, the potential association of bleeding risk and IPA is not established. It may play a critical role for the safety of more aggressive platelet inhibition or/and individual tailoring of antiplatelet strategies. METHODS AND RESULTS/RESULTS:Secondary post hoc analyses of 5 microM ADP-induced IPA and bleeding complications assessed by TIMI, GUSTO, and BleedScore scales in a combined data set consisting of patients with documented CAD (n = 246) and previous IS (n = 117). Demographic characteristics differ substantially depending on the underlying vascular disease; however, IPA and bleeding risks were similar between CAD and IS. All three bleeding scales adequately captured serious haemorrhagic events, where the TIMI scale was the most exclusive, whereas BleedScore was the most inclusive. Over half of all patients experienced superficial event(s), most commonly occurring during two to three distinct bleeding episodes. There was no correlation between IPA and duration of antiplatelet therapy. Inhibition of platelet aggregation >50% strongly correlates with minor (r(2) = 0.58, P < 0.001; c-statistic = 0.92), but not severe (r(2) = 0.11, P = 0.038; c-statistic = 0.57), bleeding events. CONCLUSION/CONCLUSIONS:Chronic oral combination antiplatelet regimens are associated with a very high (56.5-60.7%) prevalence of superficial bleeding episodes, which are grossly underestimated in trials and registries. The role of such frequent mild complications for the overall benefit of antiplatelet therapy is entirely unknown, as is their effect on compliance. Although IPA is well suited for defining the risk of minor complications, prediction of more severe bleeding events may be challenging.

BACKGROUND: Clinical trials of antithrombotic agents for the treatment of ACS routinely assess bleeding as a safety endpoint, but variation in bleeding definitions makes comparison of the relative safety of these agents difficult. METHODS: The ABC Multidisciplinary Working Group, an informal working group comprising clinical researchers and representatives from the US Food and Drug Administration, the National Institutes of Health, and the pharmaceutical industry, sought to develop a consensus approach to measuring the incidence and severity of bleeding complications during clinical trials of acute coronary syndromes (ACS). A meeting of the ABC was convened in April 2008 in Washington, DC, with the goal of developing a consensus approach to measuring the incidence and severity of hemorrhagic complications during clinical trials of ACS. Relevant literature on bleeding was reviewed through a series of short lectures and intensive group discussion. RESULTS: Using existing evidence on bleeding and outcomes as well as clinical judgment, criteria for the assessment of bleeding were developed through expert consensus. This consensus statement divides bleeding-related data elements into three categories: essential, recommended, and optional. CONCLUSIONS: The ABC Group recommendations for collection and reporting of bleeding complications provide a framework for consistency in the collection of information on hemorrhagic complications in trials of ACS. Widespread adoption of the statement recommendations will facilitate understanding of the mechanisms of adverse outcomes after bleeding and comparisons of the relative safety of antithrombotic agents, as well as the interpretation of safety results from future studies.

BACKGROUND:Currently recommended anticoagulant agents used in the setting of percutaneous coronary intervention (PCI) inhibit, with varying degrees of intensity, 2 critical targets (factor Xa and/or IIa) of the coagulation cascade, yet they carry significant limitations. M118-a novel, rationally engineered heparin-provides consistent anti-Xa and anti-IIa activity with a constant anti-Xa:anti-IIa ratio over time. M118 also combines the desired anticoagulant effects of unfractionated heparin with the beneficial attributes of low-molecular-weight heparin, and may represent the next generation of heparin therapy in patients diagnosed with acute coronary syndrome. STUDY DESIGN/METHODS:The EMINENCE trial is a prospective, randomized, open-label, multicenter phase 2 study that will evaluate the safety and feasibility of M118 as an anticoagulant versus unfractionated heparin in subjects with stable coronary artery disease undergoing PCI. The primary end point of the study will be the combined incidence of clinical events defined as the composite of 30-day death, myocardial infarction, repeat revascularization, catheter thrombus, stroke, thrombocytopenia, bailout use of glycoprotein IIb/IIIa inhibitors, and major or minor bleeding. CONCLUSION/CONCLUSIONS:The EMINENCE trial will assess the safety and feasibility of M118 as an anticoagulant in the setting of PCI and will provide important information to determine the appropriate therapeutic range of activated clotting time for M118 and the appropriate dose or doses to be explored in a phase 3 clinical trial.

BACKGROUND:Interest in the biology of endogenous progenitor cells (EPCs) continues to grow as evidence of their role in vascular repair mounts. EPC enumeration requires specialized laboratory techniques and is performed immediately after sample acquisition, limiting the clinical contexts in which EPC enumeration can be performed and the ability to increase sample sizes through multi-center participation. METHODS:We compared the numbers of EPCs enumerated in samples processed immediately after acquisition (n = 36) with EPCs enumerated in specimens stored for 24 hours or after cryopreservation of mononuclear cells (MNC) using two EPC identification strategies: cell surface marker expression (CD133/CD34) and aldehyde dehydrogenase activity (ALDH(br) cells). RESULTS:EPCs assessed in fresh samples correlated with EPCs enumerated after whole blood storage (r = 0.699 for CD133(+)CD34(+) cells, r = 0.880 for ALDH(br) cells, P < 0.005 and P < 0.0001, respectively) or mononuclear cryopreservation (r = 0.590 for CD133(+)CD34(+) cells, r = 0.894 for ALDH(br) cells, P < 0.0001 for each); however, correlation based on assessment of ALDH(br) cells was higher (P < 0.0003 for comparison of correlation coefficients). Initial results from a multi-site clinical trial suggest that EPC enumeration after mononuclear cell cryopreservation is feasible. CONCLUSION/CONCLUSIONS:EPC analysis based on ALDH activity is reproducible, even after extended whole blood storage or MNC cryopreservation.