Faculty Bibliography

Bleeding complications after percutaneous coronary interventions (PCI) are a significant clinical problem associated with worse patient outcomes, including mortality. A number of studies have demonstrated that the majority of bleeding complications in patients undergoing PCI are related to access-site bleeding. Employing the transradial artery approach to PCI markedly reduces these bleeding rates. The reductions in bleeding and transfusions from employing the transradial approach may be associated with improved survival in PCI patients. Despite these data, the prevalence of transradial PCI remains low and its adoption by operators has been slow to increase. Growing data to support the superior clinical outcomes with radial artery PCI, coupled with improved awareness of this data, may lead to increases in its adoption and improved clinical outcomes and mortality after PCI.

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:Bleeding in patients undergoing percutaneous coronary intervention (PCI) is associated with increased morbidity, mortality, length of hospitalization, and cost. We identified baseline clinical characteristics associated with bleeding complications after PCI and developed a simplified, clinically useful algorithm to predict patient risk. METHODS AND RESULTS/RESULTS:Data were analyzed from 302 152 PCI procedures performed at 440 US centers participating in the National Cardiovascular Data Registry. As defined by the National Cardiovascular Data Registry, bleeding required transfusion, prolonged hospital stay, and/or a drop in hemoglobin >3.0 g/dL from any location, including percutaneous entry site, retroperitoneal, gastrointestinal, genitourinary, and other/unknown location. Bleeding complications occurred in 2.4% of patients. From the best-fitting model consisting of 15 clinical elements associated with post-PCI bleeding in a random 80% training cohort, we developed a parsimonious risk algorithm. Predictors of bleeding included age, gender, previous heart failure, glomerular filtration rate, peripheral vascular disease, no previous PCI, New York Heart Association/Canadian Cardiovascular Society Functional Classification class IV heart failure, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, and cardiogenic shock. The parsimonious model was validated in the remaining 20% of the population (c-statistic, 0.72) and in clinically relevant subgroups of patients. This simplified model was used to derive a clinical risk algorithm, with larger numbers corresponding with greater risk. In 3 categories, bleeding rates were greater in patients with higher estimates (<or=7, 0.7%; 8 to 17, 1.8%; >or=18, 5.1%). CONCLUSIONS:This report identifies baseline clinical factors associated with bleeding and proposes a clinically useful algorithm to estimate bleeding risk. This model is potentially actionable in altering therapeutic decision making and improving outcomes in patients undergoing PCI.

BACKGROUND: Treatments for non-ST-segment-elevation myocardial infarction (NSTEMI) reduce ischemic events but increase bleeding. Baseline prediction of bleeding risk can complement ischemic risk prediction for optimization of NSTEMI care; however, existing models are not well suited for this purpose. METHODS AND RESULTS: We developed (n=71 277) and validated (n=17 857) a model that identifies 8 independent baseline predictors of in-hospital major bleeding among community-treated NSTEMI patients enrolled in the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) Quality Improvement Initiative. Model performance was tested by c statistics in the derivation and validation cohorts and according to postadmission treatment (ie, invasive and antithrombotic therapy). The CRUSADE bleeding score (range 1 to 100 points) was created by assignment of weighted integers that corresponded to the coefficient of each variable. The rate of major bleeding increased by bleeding risk score quintiles: 3.1% for those at very low risk (score < or = 20); 5.5% for those at low risk (score 21-30); 8.6% for those at moderate risk (score 31-40); 11.9% for those at high risk (score 41-50); and 19.5% for those at very high risk (score >50; P(trend) <0.001). The c statistics for the major bleeding model (derivation=0.72 and validation=0.71) and risk score (derivation=0.71 and validation=0.70) were similar. The c statistics for the model among treatment subgroups were as follows: > or = 2 antithrombotics=0.72; <2 antithrombotics=0.73; invasive approach=0.73; conservative approach=0.68. CONCLUSIONS: The CRUSADE bleeding score quantifies risk for in-hospital major bleeding across all postadmission treatments, which enhances baseline risk assessment for NSTEMI care.

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.

OBJECTIVES: We sought to examine angiographic and clinical outcomes with sirolimus-eluting stents (SES) in total coronary occlusion (TCO) revascularization. BACKGROUND: Despite evaluation of drug-eluting stents beyond approved indications, few studies have evaluated their clinical benefit in TCO revascularization. METHODS: Among 15 centers in North America, 200 consecutive TCO patients (78.8% >6 weeks TCO age) were enrolled for treatment with SES. The primary end point was 6-month angiographic binary restenosis within the treated segment. RESULTS: Patient characteristics included: diabetes, 24.5%; prior infarction, 33.5%; and stent length, 45.9 mm median (quartile 1, 30.2 mm; quartile 2, 62.1 mm). A total of 199 patients (99.5%) were treated with SES, and procedural success was 98.0%. The 6-month binary restenosis rates were 9.5% in-stent, 12.4% in-segment, and 22.6% in-"working length" representing the entire treatment segment. Rates of 1-year target lesion revascularization, myocardial infarction, and target vessel failure were 9.8%, 1.0%, and 10.9%, respectively. Stent thrombosis occurred in 2 patients (1.0%). Using logistic regression modeling with propensity score adjustment, the absolute reduction in binary restenosis with SES compared with a historical bare-metal stent control was 37.7% (95% confidence interval [CI]: 27.2% to 48.3%, p < 0.001; odds ratio: 0.17, 95% CI: 0.09 to 0.30, p < 0.0001). Among 32 patients (16%) identified with stent fracture, target lesion revascularization was more common than patients without fracture (25.0% vs. 6.7%, p = 0.005). CONCLUSIONS: Despite greater lesion complexity than prior TCO trials, percutaneous revascularization with SES appears safe and results in substantial reductions in angiographic restenosis and failed patency and a low rate of repeat revascularization. These findings support the use of SES in TCO revascularization. (The ACROSS/TOSCA Trial; NCT00378612).

Definitions of bleeding must be considered when evaluating results of clinical trials. Assessments of bleeding impact based on clinical criteria may be more relevant to patient outcomes than those based on simple laboratory measures like an isolated change in hemoglobin, that do not appear to affect patient care. The risk of excessive bleeding in patients who receive antiplatelet and antithrombotic therapy is related to a combination of patient characteristics (older age, female sex, impaired renal function), and delivery factors (excessive dosing, stacking of anticoagulants). Investigators should justify components of bleeding endpoints as being clinically meaningful, sufficiently frequent in the study population, and affected by the intervention.

The purpose of this study was to determine international patterns of blood transfusion in patients with acute coronary syndrome (ACS). Previous studies showed geographic heterogeneity in some aspects of ACS care. Data for variability in the use of blood transfusion in ACS management are limited. Pooled data from 3 international randomized trials of patients with non-ST-segment elevation ACS (n = 23,906) were analyzed to determine the association between non-United States (US) location and blood transfusion after stratifying by the use of invasive procedures. The analysis adjusted for differences in patient characteristics and was repeated using a 2-stage mixed-model approach and in patients who underwent in-hospital coronary artery bypass grafting. Compared with US patients, both unadjusted and adjusted hazards for blood transfusion were significantly lower in non-US patients who did not undergo invasive procedures (unadjusted hazard ratio [HR] 0.23, 95% confidence interval [CI] 0.17 to 0.33; adjusted HR 0.20, 95% CI 0.14 to 0.28). This was also true in non-US patients who underwent invasive procedures (unadjusted HR 0.34, 95% CI 0.27 to 0.44; adjusted HR 0.31, 95% CI 0.23 to 0.42). Results were similar in both validation analyses. In conclusion, there was substantial international variation in blood transfusion use in patients with ACS. These results, along with the controversy regarding the appropriate use of transfusion in patients with coronary heart disease, emphasize the need for understanding the role of blood transfusion in the management of patients with ACS and factors that influence transfusion decisions.

BACKGROUND:Bleeding and blood transfusion are associated with increased morbidity and mortality among patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS); however, the economic consequences of these complications are not well defined. We sought to determine the relationship between bleeding, blood transfusion, and measures of costs among patients with non-ST-segment elevation ACS. METHODS:We analyzed data from the economic substudy of the GUSTO IIb trial (n = 1235) to determine the relationship between bleeding; transfusion; and hospital costs, physician costs, total costs, and length of stay. Linear regression models were developed to determine the cost implications of each bleeding and transfusion event. RESULTS:Of the patients in the economic substudy of GUSTO IIb, 36.8% (n = 455) experienced a bleeding event. As bleeding severity increased, there was a stepwise increase in length of stay (no bleeding 5.4 days, mild bleeding 6.9 days, moderate bleeding 15.0 days, severe bleeding 16.4 days; P < .01) and unadjusted total costs (no bleeding $14,282, mild $21,674, moderate $45,798, severe $66,564; P < .01). After adjustment for baseline differences among patients, each moderate or severe bleeding event increased costs by $3770 and each transfusion event increased costs by $2080. Further modeling demonstrated that the increase in costs was driven by increases in length of stay. CONCLUSIONS:Bleeding and transfusion are associated with increased resource use among patients with NSTE ACS. These data suggest that strategies that reduce both ischemia and the risk for bleeding have the potential to produce important reductions in the costs of care for patients with NSTE ACS.

AIMS/OBJECTIVE:Non-invasive risk stratification of low- and intermediate-risk non-ST-elevation acute coronary syndromes (NSTE ACS) patients has been recommended, but limited data exist about the variation in clinical practice of stress testing in these patients and the impact of such testing on their outcomes. METHODS AND RESULTS/RESULTS:Patients with NSTE ACS enrolled in the GUSTO IIb (Global Use of Strategies To Open occluded coronary arteries in acute coronary syndromes-IIb) trial (n = 8011) were analysed to evaluate patterns of stress testing in US and non-US patients and to further evaluate the clinical characteristics, procedure use, and outcomes of patients who underwent stress testing compared with those who did not. Stress testing was performed in 1878 (24%) patients. Compared with patients not undergoing stress testing, those undergoing stress testing had low-risk characteristics and significantly lower death (0.6% vs. 4.8%), and death or myocardial infarction (MI, 3.9% vs. 11%) rates at 30 days. Stress testing was performed as often after as before coronary angiography. Importantly, stress testing was helpful in stratifying patients into low (equivocal or negative test) or high (positive test) risk groups (30 day death 3.1% vs. 5%). Stress testing was performed more often in non-US than US patients, and US patients were 3.5 times more likely to undergo imaging as part of stress testing. However, the risks of 30-day death or MI; 6-month death, MI or revascularization; and 1-year death did not differ between US and non-US patients. CONCLUSION/CONCLUSIONS:Stress testing is commonly performed in low-risk NSTE ACS patients and provides modest additional prognostic information in this cohort. Significant geographical variation exists in the use of stress testing. Therefore, in the current practice environment where cardiac catheterization is often the first diagnostic modality used in patients with NSTE ACS, the role of non-invasive testing both before and after invasive procedure is in need of further study.