Atherothrombotic disorders: new insights from hematology.
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Biomedical subjects
Publications and source records attributed to Richard C Becker.
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BACKGROUND: Heparin-induced thrombocytopenia (HIT) is estimated to occur in 1-5% of all patients receiving heparin, and 25-50% of such cases develop heparin-induced thrombocytopenia with thrombosis (HITT) A conservative estimate based only on cardiovascular patients suggests that in the United States approximately 100,000 patients develop thrombocytopenia, and 25-50,000 develop HITT annually. Both HIT and HITT are associated with high morbidity and mortality and represent substantial worldwide public health concerns. REGISTRY DESIGN: The objective of the Complication After Thrombocytopenia Caused by Heparin (CATCH) Registry is to identify the incidence of HIT and/or HITT in patients treated with systemic heparin (unfractionated or low molecular weight heparin) in contemporary practice. Additional objectives include to: (1) provide a comprehensive database of patients with suspected HIT or HITT, (2) monitor and define clinical events, including thrombocytopenia, thrombosis, and mortality among patients treated with prolonged (> 96 hours) heparin, (3) describe the incidence and outcomes of HIT and HITT in patients who are treated with heparin and who develop thrombocytopenia in the Coronary Care Unit setting, and (4) document and characterize current diagnostic and therapeutic strategies of suspected HIT. The unblinded registry will record approximately 5,000 patients at 60-80 US hospitals with either prolonged systemic heparin administration or thrombocytopenia and those with suspected HIT or HITT. Enrollment began in the first quarter 2003 and was completed at the end of 2004. IMPLICATIONS: The registry will provide valuable insights to the incidence and consequences of HIT and HITT that will enable improvements in diagnosis and treatment.
Atrial fibrillation, an increasingly common arrhythmia whose prevalence will reach epidemic proportions over the next two decades, is characterized by atrial/atrial appendage inflammation, fibrosis, remodeling, and endocardial thrombosis. Biomarkers measured within the peripheral circulation reflect these pathobiologic events with evidence of heightened thrombin generation and activity, platelet activity, fibrin formation, endocardial injury, inflammatory mediator release, and reduced fibrinolytic potential Unfortunately, the correlation between traditional biomarkers and clinical events is weak at best, as is their ability to predict successful treatment (prevention of cardioembolism) with antithrombotic agents. Future efforts devoted to the investigation of cellular biomarkers will likely provide greater practical yield and insights concerning the development, diagnosis, prognosis, and management of atrial fibrillation.
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The evolution of anticoagulant therapy for the prevention and treatment of thrombotic disorders has progressed at a relatively modest pace considering the scope of the problem and our current understanding of platelet biology, coagulation proteases, and vascular science as they apply to protective haemostasis and pathologic thrombosis. Recent observations, dedicated to cellular-based models of coagulation, provide fundamental constructs, mechanistic clarity, and potentially unparalleled opportunity for accelerating the development and wide-scale clinical use of safe, effective, regulatable and patient-specific therapies. The following review introduces a novel domain of anticoagulant therapy referred to as aptamers (derived from the Latin aptus - to fit), considering their history, development, and potential application in patient care arenas.
The totality of data--the vascular biology and dinical trial data available to date--support the following conclusions: if COX-2 inhibitors are to be used, they should be considered as 2nd- or 3rd-line agents. They should be used for brief periods of time among patients who are at low risk for cardiovascular events. It is worth pointing out that COX-2 inhibitors were designed initially for use in patients at risk for bleeding ulcers, to minimize gastrointestinal toxicity. Large healthcare databases show, however, that the largest growth of COX-2-inhibitor use has occurred among individuals at low risk for GI side effects. COX-2 inhibitors increase the risk for cardiovascular events. The risk differs, to some degree, across agents, and does appear to be dose related. The relationship between cardiovascular risk and duration of therapy is an important question that requires further consideration. Early risk, from the perspective of pathobiology, may differ from long-term risk. The mechanism of cardiovascular risk is multifactorial and relates to sites of COX-2 synthesis, expression within the vasculature, and related local consequences of an imbalance between thromboxane A2 and prostacyclin. Considered collectively, increased platelet aggregation, hypertension, endothelial cell dysfunction, impaired angiogenesis, and destabilization of the atherosclerotic plaque matrix are important contributors to the "prothrombotic environment." Randomized clinical trials are required to better understand the hazards among individuals at low and high risk for cardiovascular events.
BACKGROUND: There is increasing interest in the non-lipid-lowering effects of statins and their effect on outcomes in patients with acute coronary syndrome. It has been suggested that withdrawal of statin therapy during an acute coronary syndrome may attenuate any benefits of pretreatment, thereby providing indirect evidence of the importance of their non-lipid-lowering effects. METHODS: This observational study compared the demographic and clinical characteristics and hospital outcomes in patients with non-ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction 4. Comparison groups consisted of patients previously receiving statins who also received statins within 24 hours of hospital admission (n = 9,001), patients previously using statins in whom therapy was discontinued (n = 4,870), and patients who did not receive statins at any time before or during hospitalization (n = 54,635). RESULTS: Of 13,871 patients receiving statins before hospital admission, 35.1% had treatment withdrawn during the first 24 hours of hospitalization. These patients had increased hospital morbidity and mortality rates relative to patients in whom therapy was continued, with higher rates of heart failure, ventricular arrhythmias, shock, and death. In multivariate analyses, these patients were at statistically significant increased risk of hospital death compared with those continuing statin therapy and at similar risk compared with those not receiving statins before or during hospitalization. CONCLUSIONS: Withdrawal of statin therapy in the first 24 hours of hospitalization for non-ST-segment elevation myocardial infarction is associated with worse hospital outcomes. In the absence of data from randomized clinical trials, our findings suggest that statin therapy should be continued during hospitalization for myocardial infarction unless strongly contraindicated.
CONTEXT: Enoxaparin has demonstrated advantages over unfractionated heparin in low- to moderate-risk patients with non-ST-segment elevation acute coronary syndromes (ACS) treated with a conservative strategy. OBJECTIVES: To compare the outcomes of patients treated with enoxaparin vs unfractionated heparin and to define the role of enoxaparin in patients with non-ST-segment elevation ACS at high risk for ischemic cardiac complications managed with an early invasive approach. DESIGN, SETTING, AND PARTICIPANTS: The Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial was a prospective, randomized, open-label, multicenter, international trial conducted between August 2001 and December 2003. A total of 10 027 high-risk patients with non-ST-segment elevation ACS to be treated with an intended early invasive strategy were recruited. INTERVENTIONS: Subcutaneous enoxaparin (n = 4993) or intravenous unfractionated heparin (n = 4985) was to be administered immediately after enrollment and continued until the patient required no further anticoagulation, as judged by the treating physician. MAIN OUTCOME MEASURES: The primary efficacy outcome was the composite clinical end point of all-cause death or nonfatal myocardial infarction during the first 30 days after randomization. The primary safety outcome was major bleeding or stroke. RESULTS: The primary end point occurred in 14.0% (696/4993) of patients assigned to enoxaparin and 14.5% (722/4985) of patients assigned to unfractionated heparin (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.86-1.06). No differences in ischemic events during percutaneous coronary intervention (PCI) were observed between enoxaparin and unfractionated heparin groups, respectively, including similar rates of abrupt closure (31/2321 [1.3%] vs 40/2364 [1.7%]), threatened abrupt closure (25/2321 [1.1%] vs 24/2363 [1.0%]), unsuccessful PCI (81/2281 [3.6%] vs 79/2328 [3.4%]), or emergency coronary artery bypass graft surgery (6/2323 [0.3%] vs 8/2363 [0.3%]). More bleeding was observed with enoxaparin, with a statistically significant increase in TIMI (Thrombolysis in Myocardial Infarction) major bleeding (9.1% vs 7.6%, P =.008) but nonsignificant excess in GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Arteries) severe bleeding (2.7% vs 2.2%, P =.08) and transfusions (17.0% vs 16.0%, P =.16). CONCLUSIONS: Enoxaparin was not superior to unfractionated heparin but was noninferior for the treatment of high-risk patients with non-ST-segment elevation ACS. Enoxaparin is a safe and effective alternative to unfractionated heparin and the advantages of convenience should be balanced with the modest excess of major bleeding.