Faculty Bibliography

This paper, developed from the proceedings of the 2007 Platelet Colloquium, considers emerging constructs in platelet biology, preclinical models of thrombosis, and their potential application to the development of platelet-directed pharmacotherapies. Discussed first is the developmental biology of platelets, including megakaryocyte maturation, and the role of apoptotic and growth factors and other proteins in thrombopoiesis. A brief overview of current methods and observations from platelet proteomic analyses is also presented, illustrating the complex interplay of genes, gene expression, protein expression, and protein modification in various atherothrombotic phenotypes. The factor Xa-platelet interface is used as a working model for discussion of anticoagulants as platelet antagonists, highlighting the importance of receptor expression, substrate binding kinetics, platelet subpopulations, and cofactors in thrombosis. Finally, we discuss the use of emerging technologies--such as intravital microscopy and ex vivo perfusion chambers--as translatable platforms for investigating the role of platelets and their pharmacologic inhibition in human health and disease.

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.

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.

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.

This paper provides a comprehensive up-to-date review of the medical and invasive management of patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), and ST-elevation myocardial infarction (STEMI), as supported by recent updates to the ACC/AHA Guidelines. The authors have summarized findings from key clinical trials published in recent years that contribute to clinician's understanding of how best to optimize therapy. The goals for the management of NSTE-ACS and STEMI are rapid and accurate risk stratification, appropriate and institution-specific triage to interventional versus medical strategies and optimal pharmacologic therapy - all of which provide for a smooth and seamless transition of care between the emergency department and the cardiology service. High-risk features or absolute treatment trigger criteria that support more aggressive medical therapy (i.e., addition of a small molecule gylcoprotein [GP] IIb/IIIa inhibitor to a core regimen of aspirin, enoxaparin or other anticoagulants, and in most cases, clopidogrel) and/or that would direct clinicians toward percutaneous interventional strategies as the preferred modality include, but are not limited to the presence of one or more of the following: 1) elevatedcardiac markers (troponin and/or CK-MB); 2) age older than 65 years; 3) presence of ST-T-wave changes; 4) TIMI Risk Score >/= 5; 5) clinical instability in the setting of suspected NSTE-ACS. Although additional refinements and changes in ACS management are still to come, evidence-based strategies suggest that prompt mechanical revascularization is associated with the best possible clinical outcomes, particularly for patients with high-risk features and in whom benefits of adjunctive, pharmacoinvasive antithrombotic therapies can be consolidated. Transfer for cardiac catheterization/percutaneous coronary intervention (PCI) is strongly recommended in patients who manifest high-risk features and/or aggressive treatment trigger criteria, so that this high-risk subgroup may receive definitive, interventional and/or cardiology-directed specialty care at appropriate sites of care. When available, interventional management is preferred in these patients. The importance of safe and effective anticoagulation in the spectrum of management strategies has been confirmed, and the evidence in support of enoxaparin and other antithrombotic agents has been reviewed. Dosing recommendations for enoxaparin use in the setting of PCI have been issued by the CATH Panel and have been summarized in this consensus report. Similar recommendations have been presented for the use of oral antiplatelet agents and GP IIb/IIIa antagonists. The addition of statins, angiotensin-converting enzyme (ACE) inhibitors and beta-blockers is also stressed as part of a comprehensive secondary cardioprotective strategy for patients with coronary heart disease.

Advances in the management of patients with acute coronary syndromes (ACS), specifically, the use of combined pharmacotherapy with antithrombotic and antiplatelet therapies and routine percutaneous coronary intervention (PCI), have greatly reduced rates of thrombotic outcomes and mortality in these patients. However, these same therapies also can increase the risk of bleeding and transfusion use, which are predictive of poor outcomes in patients with ACS. Accurate assessment of the risk-to-benefit ratio for any therapy depends on the use of clinically relevant, preferably standardized, definitions of endpoint events. Unfortunately, clinical trials of antithrombotic therapies have used various definitions for bleeding, most of which were originally developed for trials of fibrinolytic therapy in acute myocardial infarction (MI). These variations in bleeding definitions have complicated cross-study comparisons and assessments of drug class effects. Further, it is unclear whether these definitions remain clinically relevant in the era of routine PCI and aggressive antithrombotic therapy for ACS. Although an argument can be made for development of a standardized bleeding definition, a more prudent approach may be to develop standardized data elements, which can then be used to tailor bleeding definitions according to the goals of future clinical investigations.

Antithrombotic therapy and invasive risk stratification in selected high-risk patients have improved outcomes from non-ST-segment elevation acute coronary syndromes (NSTE-ACS), but carry a risk of bleeding and blood transfusion. Although the true incidence of bleeding depends on the population studied (i.e. clinical trial vs. registry), the definition used, and the use of invasive procedures, it is becoming clear that bleeding is associated with an increased risk for adverse outcomes including myocardial infarction and death. Blood transfusion itself may carry a risk for ischaemic outcomes that is independent of bleeding. Therefore, therapies that provide an adequate level of anticoagulation to reduce ischaemia while simultaneously minimizing the risk of bleeding and transfusion have the potential to improve outcomes among patients with NSTE-ACS. Anticoagulants studied in recent clinical trials that have focused on bleeding reduction include fondaparinux and bivalirudin. In this review, we discuss the clinical trial evidence for these agents, the association between bleeding and clinical outcomes, the biology of blood transfusion and potential mechanisms underlying its association with adverse outcomes, and propose strategies to deal with bleeding complications. Future directions for research and clinical practice are also discussed.

Evaluation of: Schachinger V, Erbs S, Elsasser A et al.: Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N. Engl. J. Med. 355, 1210-1221 (2006). The Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial, the largest randomized, placebo-controlled trial of stem cell therapy in acute myocardial infarction, studied the efficacy of the intracoronary delivery of bone marrow mononuclear cells (BMCs) versus placebo in patients with acute ST-segment elevation myocardial infarction following successful percutaneous coronary intervention. At 4 month follow-up, patients treated with BMCs had a significant improvement in left ventricular ejection fraction compared with placebo (+5.5 vs +3.0%, absolute difference +2.5%). In addition, treatment with BMCs was associated with a statistically significant reduction in adverse clinical events at 1 year follow-up. Despite these promising findings, other studies have shown mixed results and several unresolved clinical and physiological issues remain. Key findings from ongoing basic and clinical research will define the future role of stem cell therapy for acute myocardial infarction.

Anemia is common among patients with coronary artery disease (CAD) and portends a higher risk of short- and long-term mortality, major adverse cardiac events, and bleeding complications. Blood transfusion has long been the cornerstone of therapy for anemia; however, its benefit in patients with CAD is controversial and the appropriate threshold for transfusion has been widely debated. In this review, we summarize the studies evaluating the impact of anemia in patients with CAD undergoing percutaneous coronary intervention and address several issues regarding the use of transfusion in anemic patients. In addition, we discuss alternative options for the management of anemia, such as the use of erythropoietin, aqueous oxygen, and hemoglobin-based oxygen carriers.