Highlights from the III International Symposium of Thrombosis and Anticoagulation (ISTA), October 14-16, 2010, Sao Paulo, Brazil

To discuss and share knowledge around advances in the care of patients with thrombotic disorders, the Third International Symposium of Thrombosis and Anticoagulation was held in So Paulo, Brazil, from October 14-16, 2010. This scientific program was developed by clinicians for clinicians, and was promoted by four major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, the Canadian VIGOUR Centre, and the Uppsala Clinical Research Center. Comprising 3 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

Highlights from the II international symposium of thrombosis and anticoagulation (ISTA), October 22-23, 2009, So Paulo, Brazil

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Streptokinase and Enoxaparin as an Alternative to Fibrin-Specific Lytic-Based Regimens An ExTRACT-TIMI 25 Analysis

Background: Enoxaparin was superior to unfractionated heparin (UFH), regardless of fibrinolytic agent in ST-elevation myocardial infarction (STEMI) patients receiving fibrinolytic therapy in ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment Thrombolysis in Myocardial Infarction 25) trial. Objective: This post hoc analysis compared outcomes with streptokinase plus enoxaparin to the standard regimen of fibrin-specific lytic (FSL) plus UFH and to the newer combination of FSL plus enoxaparin. Methods: In ExTRACT-TIMI 25, STEMI patients received either streptokinase or a FSL (alteplase, reteplase or tenecteplase) at the physician`s discretion and were randomized to enoxaparin or UFH, stratified by fibrinolytic type. Thirty-day outcomes were adjusted for baseline characteristics, region, in-hospital percutaneous coronary intervention (PCI) and a propensity score for the choice of lytic. Results: The primary trial endpoint of 30-day death/myocardial infarction (MI) occurred in fewer patients in the streptokinase-enoxaparin cohort (n = 2083) compared with FSL-UFH (n = 8141) [10.2% vs 12.0%, adjusted odds ratio [OR(adj)] 0.76; 95% CI 0.62, 0.93; p = 0.008]. Major bleeding was significantly increased with streptokinase-enoxaparin compared with FSL-UFH (ORadj 2.74; 95% CI 1.81; 4.14; p < 0.001) but intracranial haemorrhage (ICH) was similar (OR(adj) 0.90; 95% CI 0.40, 2.01; p = 0.79). Net clinical outcomes, defined as either death/MI/major bleeding or as death/MI/ICH tended to favour streptokinase-enoxaparin compared with FSL-UFH (OR(adj) 0.88; 95% CI 0.73, 1.06; p = 0.17; and OR(adj) 0.77; 95% CI 0.63, 0.93; p = 0.008, respectively). Patients receiving FSL-enoxaparin (n = 8142) and streptokinase-enoxaparin therapies experienced similar adjusted rates of the primary endpoint (OR(adj) 1.08; 95% CI 0.87, 1.32; p = 0.49) and net clinical outcomes. Conclusions: Our results suggest that fibrinolytic therapy with the combination of streptokinase and the potent anticoagulant agent enoxaparin resulted in similar adjusted outcomes compared with more costly regimens utilizing a FSL.

Statins withdrawal, vascular complications, rebound effect and similitude

Hahnemann considered the secondary action of medicines to be a law of nature and reviewed the conditions under which it occurs. It is closely related to the rebound effects observed with many modern drugs. I review the evidence of the rebound effect of statins that support the similitude principle. In view of their indications in primary and secondary prevention of cardiovascular diseases, statins are widely prescribed. Besides reducing cholesterol biosynthesis, they provide vasculoprotective effects (pleiotropic effects), including improvement of endothelial function, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory and thrombogenic responses, stabilisation of atherosclerotic plaques, and others. Recent studies suggest that suspension of statin treatment leads to a rebound imparing of vascular function, and increasing morbidity and mortality in patients with vascular diseases. Similarly to other classes of modern palliative drugs, this rebound effect is the same as a secondary action or vital reaction described by Samuel Hahnemann, and used in homeopathy in a therapeutic sense. Homeopathy (2010) 99, 255-262.

Lipid-lowering therapy following major cardiac events: progress and deficits

Objective: To assess hospital prescribing of lipid-lowering agents in a tertiary hospital, and examine continuation of, or changes to, such therapy in the 6-18 months following discharge. Design: Retrospective data extraction from the hospital records of patients admitted from October 1998 to April 1999. These patients and their general practitioners were then contacted to obtain information about ongoing management after discharge. Setting: Tertiary public hospital and community. Participants: 352 patients admitted to hospital with acute myocardial infarction or unstable angina, and their GPs. Main outcome measures: Percentage of eligible patients discharged on lipid-lowering therapy and percentage of patients continuing or starting such therapy 6-18 months after discharge. Results: 10% of inpatients with acute coronary syndromes did not have lipid-level estimations performed or arranged during admission. Documentation of lipid levels in discharge summaries was poor. Eighteen per cent of patients with a total serum cholesterol level greater than 5.5 mmol/L did not receive a discharge prescription for a cholesterol-lowering agent. Compliance with treatment on follow-up was 88% in the group discharged on treatment. However, at follow-up, 70% of patients discharged without therapy had not been commenced on lipid-lowering treatment by their GPs. Conclusions: Prescribing of lipid-lowering therapy for secondary prevention following acute coronary syndromes remains suboptimal. Commencing treatment in hospital is likely to result in continuing therapy in the community. Better communication of lipid-level results, treatment and treatment aims between hospitals and GPs might encourage optimal treatment practices.

Clinical trials with glycoprotein IIB/IIIA antagonists - No benefit without bleeding?

As the glycoprotein GPIIb/IIIa receptor is the final common pathway in platelet aggregation, antagonists of this receptor cause a profound inhibition of aggregation induced by any agonist. The short-term efficacy and safety of GPIIb/IIIa antagonists in patients undergoing coronary angioplasty was demonstrated with murine 7E3 Fab, but this antibody was immunogenic. Abciximab is a chimeric human-mouse monoclonal antibody that is less immunogenic. The first major trial with a GPIIb/IIIa antagonist was the EPIC trial with abciximab, which showed that abciximab reduced the ischemic complications of coronary balloon angioplasty and atherectomy in high-risk patients, but increased the risk of bleeding. Subsequent studies showed that using less concurrent heparin reduced bleeding. Abciximab also reduced the rate of revascularization. Further studies have shown that the benefits of abciximab extended to all patients undergoing angioplasty (EPILOG), including patients with unstable angina (CAPTURE) and acute myocardial infarction (RAPPORT). Clinical trials with eptifibatide and tirofiban have failed to demonstrate benefit, at the doses used, in angioplasty. Abciximab and eptifibatide, but not oral xemilofiban, improve the safety of the coronary stenting procedure. Shortterm intravenous treatment with lamifiban, eptifibatide or tirofiban is beneficial in acute coronary syndromes (unstable angina, non-Q wave myocardial infarction). Orally active GPIIb/IIIa antagonists are being developed for use in acute coronary syndromes and myocardial infarction. However, no benefit has been shown with lefradafiban in acute coronary syndromes and sibrafiban and orbofiban are harmful. Eptifibatide, lamifiban and abciximab improve coronary patency in myocardial infarction, and long-term trials of GPIIb/IIIa antagonists are being conducted in acute myocardial infarction. Abciximab can cause thrombocytopenia, and all the GPIIb/IIIa antagonists increase the incidence of bleeding, but there is no excess of intracranial hemorrhage. (C) 2001 Prous Science. All rights reserved.

Alteplase: descendancy in myocardial infarction, ascendancy in stroke

Tissue type plasminogen activator is available, through recombinant technology, for thrombolytic use as alteplase. Alteplase is relatively clot specific and should cause less bleeding side effects than the non-specific agents such as streptokinase. Alteplase has been used successfully in evolving myocardial infarction (MI) to reopen occluded coronary arteries. It is probably equally effective or superior to streptokinase in opening arteries and reducing mortality in Mi. Alteplase is most effective when given early in Mi and is probably ineffective when given 12 h after the onset of symptoms. The effectiveness of alteplase in Mi can be increased by front loading with a bolus of 15 mg, followed by an infusion of 50 mg over 30 min and 35 mg over 60 min. Percutaneous transluminal coronary angioplasty or stenting is associated with a greater patency and lower rates of serious bleeding, recurrent ischaemia and death than alteplase in MI and is likely to take over from alteplase as the standard Mi treatment. A reduced dose of alteplase to increase coronary artery patency prior to angioplasty may be useful in Mi. An exciting new indication for the use of alteplase is in stroke, where it has become the first beneficial intervention. Alteplase is used to reopen occluded cerebral vessels but is associated with an increased risk of intracerebral haemorrhage. Alteplase is beneficial if given within 3 h of the onset of stroke but not after this time period. Therefore, the next challenge is to increase the percentage of people being diagnosed and treated within this period. Clinical trials have not established a role for alteplase in the treatment of acute coronary syndromes or deep vein thrombosis. However, alteplase is useful in treating pulmonary thromboembolism and peripheral vascular disease.

Use of an accelerated chest pain assessment protocol in patients at intermediate risk of adverse cardiac events

Objective: To determine the feasibility, safety and effectiveness of a structured clinical pathway for stratification and management of patients presenting with chest pain and classified as having intermediate risk of adverse cardiac outcomes in the subsequent six months. Design: Prospective clinical audit. Participants and setting: 630 consecutive patients who presented to the emergency department of a metropolitan tertiary care hospital between January 2000 and June 2001 with chest pain and intermediate-risk features. Intervention: Use of the Accelerated Chest Pain Assessment Protocol (ACPAP), as advocated by the Management of unstable angina guidelines - 2000 from the National Heart Foundation and the Cardiac Society of Australia and New Zealand. Main outcome measure: Adverse cardiac events during six-month follow-up. Results: 409 patients (65%) were reclassified as low risk and discharged at a mean of 14 hours after assessment in the chest pain unit. None had missed myocardial infarctions, while three (1%) had cardiac events at six months (all elective revascularisation procedures, with no readmissions with acute coronary syndromes). Another 110 patients (17%) were reclassified as high risk, and 21 (19%) of these had cardiac events (mainly revascularisations) by six months. Patients who were unable to exercise or had non-diagnostic exercise stress test results (equivocal risk) had an intermediate cardiac event rate (8%). Conclusions: This study validates use of ACPAP. The protocol eliminated missed myocardial infarction; allowed early, safe discharge of low-risk patients; and led to early identification and management of high-risk patients.

Estratégia Sistematicamente Invasiva nas Síndromes Coronárias Agudas sem Supradesnivelamento do Segmento ST: Será a Idade um Factor Limitante?

Introdução: A estratégia terapêutica sistematicamente invasiva das síndromes coronárias agudas (SCA) é actualmente aceite como segura e eficaz, sendo crescentes as evidências da sua superioridade em relação a uma atitude conservadora. O doente idoso, atendendo à sua maior susceptibilidade, é frequentemente excluído deste tipo de abordagem, o que poderá limitar os potenciais benefícios. Objectivo: Avaliar a influência da idade nas características e evolução clínica dos doentes com SCA tratados segundo uma estratégia invasiva, e se esta limita a sua adopção. Métodos: Estudaram-se retrospectivamente 203 doentes internados por SCA (não seleccionados e consecutivos), considerados de risco intermédio/elevado após estratificação e que efectuaram terapêutica com inibidores das glicoproteínas IIb/IIIa. Destes doentes 45 tinham idade 75 anos e constituíram o grupo intitulado de Idoso, os restantes constituíram o grupo Não Idoso. Foram analisadas e comparadas as características dos dois grupos, a terapêutica realizada e a evolução clínica que apresentaram. Resultados: A percentagem de mulheres no grupo idoso é bastante superior, embora a diferença não atinja significado estatístico. Das outras características estudadas as que apresentam diferenças significativas são a existência de história familiar de doença coronária e o tabagismo, que são menos frequentes entre os idosos. Houve uma tendência não significativa para cateterizar menos os idosos, sendo que os dois grupos são semelhantes em relação à terapêutica de revascularização adoptada. No total as complicações hemorrágicas foram mais frequentes no grupo Idoso, mas a diferença em relação às hemorragias significativas não teve valor estatístico. A mortalidade intra hospitalar foi maior nos idosos, mas diminuiu e não teve significado estatístico quando considerados apenas os doentes cateterizados. Conclusão: Nesta população os idosos tiveram um número maior de complicações hemorrágicas não significativas e a sua maior mortalidade não esteve associada à adopção de uma atitude invasiva. Desta forma sugere-se que a idade, por si só, não limita a adopção de uma estratégia sistematicamente invasiva.

Impacto da Combinação de Terapêutica Farmacológica na Mortalidade em Doentes com Síndrome Coronária Aguda

INTRODUCTION: Conventional risk stratification after acute myocardial infarction is usually based on the extent of myocardial damage and its clinical consequences. However, nowadays, more aggressive therapeutic strategies are used, both pharmacological and invasive, with the aim of changing the course of the disease. OBJECTIVES: To evaluate whether the number of drugs administered can influence survival of these patients, based on recent clinical trials that demonstrated the benefit of each drug for survival after acute coronary events. METHODS: This was a retrospective analysis of 368 consecutive patients admitted to our ICU during 2002 for acute coronary syndrome. A score from 1 to 4 was attributed to each patient according to the number of secondary prevention drugs administered--antiplatelets, beta blockers, angiotensin-converting enzyme inhibitors and statins--independently of the type of association. We evaluated mortality at 30-day follow-up. RESULTS: Mean age was 65 +/- 13 years, 68% were male, and 43% had ST-segment elevation acute myocardial infarction. Thirty-day mortality for score 1 to 4 was 36.8%, 15.6%, 7.8% and 2.5% respectively (p < 0.001). The use of only one or two drugs resulted in a significant increase in the risk of death at 30 days (OR 4.10, 95% CI 1.69-9.93, p = 0.002), when corrected for other variables. There was a 77% risk reduction associated with the use of three or four vs. one or two drugs. The other independent predictors of death were diabetes, Killip class on admission and renal insufficiency. CONCLUSIONS: The use of a greater number of secondary prevention drugs in patients with acute coronary syndromes was associated with improved survival. A score of 4 was a powerful predictor of mortality at 30-day follow-up

Aderência às Recomendações para o Tratamento das Síndromes Coronárias Agudas: Evolução ao Longo do Tempo

Introdução: O tratamento das Síndromes Coronárias Agudas (SCA) sofreu várias alterações muito rápidas nos últimos anos, traduzido nas múltiplas propostas de recomendações pelo ACC/AHA/ESC, baseados na evidência clínica. Avaliamos a implementação destas recomendações, comparando uma população de doentes de 2002, com uma população de 2005. Métodos: Estudo retrospectivo de 368 doentes admitidos em 2002 e 420 doentes admitidos em 2005 por SCA (com e sem elevação do segmento ST). Analisaram-se características clínicas e estratégias de tratamento. Resultados: Não se verificaram diferenças em termos de idade, sexo masculino, factores de risco para doença coronária ou história prévia de revascularização miocárdica. Verificou-se uma redução de doentes com antecedentes de enfarte do miocárdico e insuficiência renal e aumento da apresentação como enfarte com elevação do segmento ST. O tratamento com clopidogrel (6% versus 87%), bloqueador-beta(54% versus 79%), inibidores da enzima de conversão da angiotensina (72% versus 84%) e estatinas (78% versus 91%) aumentou (para todos p<0,001). Por outro lado, verificou-se um pequeno decréscimo na utilização de ácido acetilsalicílico (98% versus 95%, p=0,039) (com maior utilização de clopidogrel) e a ticlopidina deixou de ser utilizada (46% versus 0%, p<0,001). Os antagonistas dos receptores da glicoproteína IIb/IIIa não se alteraram significativamente (66% versus 67%, p=NS). Aumentaram as intervenções coronárias percutâneas (53% versus 67%, p<0,001). Não se verificou diferença em termos de mortalidade hospitalar (8,2% versus 6,4%) e aos 30 dias (9,0% versus. 8,6%), com redução ao 1ºano de seguimento (17,1% versus 11,7%, p=0,039). As estatinas e os bloqueadores beta são preditores independentes de mortalidade, com efeito de protecção. Conclusões: Entre 2002 e 2005, o tratamento das SCA melhorou significativamente de acordo com as recomendações existentes, traduzindo-se numa melhoria da mortalidade ao 1º ano de seguimento.

Position Statement on Bioresorbable Vascular Scaffolds in Portugal

BACKGROUND: Bioresorbable vascular scaffolds (BVS) were recently approved for percutaneous coronary intervention in Europe. The aim of this position statement is to review the information and studies on available BVS, to stimulate discussion on their use and to propose guidelines for this treatment option in Portugal. METHODS AND RESULTS: A working group was set up to reach a consensus based on current evidence, discussion of clinical case models and individual experience. The evidence suggests that currently available BVS can produce physiological and clinical improvements in selected patients. There are encouraging data on their durability and long-term safety. Initial indications were grouped into three categories: (a) consensual and appropriate - young patients, diabetic patients, left anterior descending artery, long lesions, diffuse disease, and hybrid strategy; (b) less consensual but possible - small collateral branches, stabilized acute coronary syndromes; and (c) inappropriate - left main disease, tortuosity, severe calcification. CONCLUSION: BVS are a viable treatment option based on the encouraging evidence of their applicability and physiological and clinical results. They should be used in appropriate indications and will require technical adaptations. Outcome monitoring and evaluation is essential to avoid inappropriate use. It is recommended that medical societies produce clinical guidelines based on high-quality registries as soon as possible.

Myocardial Ischaemia National Audit Project (MINAP)

The Myocardial Infarction Audit Project (MINAP) began in late 1998 when a broadly based steering group developed a dataset for acute myocardial infarction (AMI). This allowed clinicians to examine the management of myocardial infarction within their hospitals against targets specified by the National Service Framework for Coronary Heart Disease (NSF). The audit project produces annual reports "How the NHS manages heart attacks" to show the performance of hospitals, ambulance services and cardiac networks in England and Wales against national standards and targets for the care of heart attack patients. MINAP has recently changed its name from the Myocardial Infarction National Audit Project to the Myocardial Ischaemia National Audit Project to reflect the importance of all acute coronary syndromes.

Dramatic effect of early clopidogrel administration in reducing mortality and MACE rates in ACS patients. Data from the Swiss registry AMIS-Plus.

BACKGROUND: Patients who have acute coronary syndromes with or without ST-segment elevation have high rates of major vascular events. We evaluated the efficacy of early clopidogrel administration (300 mg) (<24 hours) when given with aspirin in such patients. METHODS: We included 30,243 patients who had an acute coronary syndrome with or without ST segment elevation. Data on early clopidogrel administration were available for 24,463 (81%). Some 15,525 (51%) of the total cohort were administrated clopidogrel within 24h of admission. RESULTS: In-hospital death occurred in 2.9% of the patients in the early clopidogrel group treated with primary PCI and in 11.4% of the patients in the other group without primary percutaneous coronary intervention (PCI) and no early clopidogrel. The unadjusted clopidogrel odds ratio (OR) for mortality was 0.31 (95% confidence interval 0.27-0.34; p <0.001). Incidence of major adverse cardiac death (MACE) was 4.1% in the early clopidogrel group treated with 1°PCI and 13.5% in the other group without primary PCI and no early clopidogrel (OR 0.35, confidence interval 0.32-0.39, p <0.001). Early clopidogrel administration and PCI were the only treatment lowering mortality as shown by mutlivariate analysis. CONCLUSIONS: The early administration of the anti-platelet agent clopidogrel in patients with acute coronary syndromes with or without ST-segment elevation has a beneficial effect on mortality and major adverse cardiac events. The lower mortality rate and incidence of MACE emerged with a combination of primary PCI and early clopidogrel administration.

79-OR: Measurement of β-tryptase in postmortem serum in cardiac death

Mast cells are well known for their role in hypersensitivity reactions. However, there is increasing evidence that they might also participate in both developing and weakening atherosclerotic plaques, potentially causing plaque instability. Some clinical studies have therefore postulated the existence of relationships between blood β-tryptase levels and acute coronary syndromes. In this study, we investigated postmortem serum β-tryptase levels in a series of 90 autopsy cases with various degrees of coronary atherosclerosisthat had undergone medico-legal investigations. β-tryptase concentrations in these cases were compared to levels observed in 6 fatal anaphylaxis cases following contrast material administration. Postmortem serum β-tryptase concentrations in the anaphylactic deaths ranged from 146 to 979 ng/ml. In 9 out of 90 cases of cardiac deaths, β-tryptase levels were higher than clinical reference values of 11.4 ng/ml and ranged from 21 to 65 ng/ml. These results indicate that increased postmortem serum β-tryptase levels can be observed, though not systematically, in cardiac deaths with varying degrees of coronary atherosclerosis disease, thereby suggesting that mast cell activation in this disease cannot be ascertained by postmortem serum β-tryptase measurements.