COURAGE Trial Clinical Outcomes Utilizing Revascularization and Agressive Drug Evaluation

Transcrição

1 COURAGE Trial Clinical Outcomes Utilizing Revascularization and Agressive Drug Evaluation Ana Luisa B. Pena Marco Tulio R. R. Cunha Mariana Gondim P. Sprícigo Uberaba, 21 de Setembro de 2011

2 A Revista 1812 John Collins Warren (Boston) e James Jackson 1921 Massachusetts Medical Society Fator de Impacto: 53,48 em 2010 (o maior entre revistas médicas)* Nº de citações nos 2 últimos anos dos artigos do jornal dividido pelo nº de artigos publicados pelo NEJM nesses mesmos dois anos. É indexada (listada em bases de dados de consulta mundial reconhecidas)

3 A Revista 1812 John Collins Warren (Boston) e James Jackson 1921 Massachusetts Medical Society Fator de Impacto: 53,48 em 2010 (o maior entre revistas médicas) Nº de citações nos 2 últimos anos dos artigos do jornal dividido pelo nº de artigos publicados pelo NEJM nesses mesmos dois anos. É indexada (listada em bases de dados de consulta mundial reconhecidas)

4 A Revista 1812 John Collins Warren (Boston) e James Jackson 1921 Massachusetts Medical Society Fator de Impacto: 53,48 em 2010 (o maior entre revistas médicas) Nº de citações nos 2 últimos anos dos artigos do jornal dividido pelo nº de artigos publicados pelo NEJM nesses mesmos dois anos. É indexada (listada em bases de dados de consulta mundial reconhecidas)

5 COURAGE 25/03/ Sessão Científica Anual do American College of Cardiology 26/03/ New England Journal of Medicine (site) 27/03/2007 Capa do New York Times 12/04/2007 New England Journal of Medicine (revista - vol.356)

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7 COURAGE 25/03/ Sessão Científica Anual do American College of Cardiology New Orleans 26/03/ New England Journal of Medicine (site) 27/03/2007 Capa do New York Times 12/04/2007 New England Journal of Medicine (revista - vol.356)

8 COURAGE Autores: William E. Boden, M.D., Robert A. O'Rourke, M.D., Koon K. Teo, M.B., B.Ch., Ph.D., et al. Conflito de interesse: U.S. Departament of Veterans Affairs e Canadian Institutes of Health Research; Merck, Pfizer, Bristol-Meyers Squibb, Fujisawa, Kos Pharmaceuticals, Datascope, Astra-Zeneca, Key Pharmaceutical, Sanofi-Aventis, First Horizon, e GE Healthcare 515 citações

9 COURAGE Autores: William E. Boden, M.D., Robert A. O'Rourke, M.D., Koon K. Teo, M.B., B.Ch., Ph.D., et al. Conflito de interesse: U.S. Departament of Veterans Affairs e Canadian Institutes of Health Research; Merck, Pfizer, Bristol-Meyers Squibb, Fujisawa, Kos Pharmaceuticals, Datascope, Astra-Zeneca, Key Pharmaceutical, Sanofi-Aventis, First Horizon, e GE Healthcare 515 citações

10 Objetivo O Ensaio COURAGE(Clinical outcomes utilizing revascularization and agressive drug evaluation)- visou analisar se a intervenção coronariana percutânea (PIC)aliada ao tratamento médico ideal (tratamento médico intensivo, redução fatores de risco e intervenção no estilo de vida) reduzem o risco de morte e de infarto do miocardio não fatal em pacientes com doença arterial coronariana estável quando comparadas ao tratamento médico ideal isolado.

11 Desenho de estudo Um desenho de estudo é um plano do trabalho de investigação que inclui estratégias para encontrar a verdade, ao mesmo tempo que se tenta reduzir e minimizar o viés (erros sistemáticos que se cometem e podem ser evitados no planeamento do estudo), confundimento e acaso.

12 Desenho de estudo Estudo analítico experimental( ensaio randomizado)-hipótese->efeito 2287 pacientes evidência isquemia miocárdio e doença arterial coronariana significativa. 50 centros Can e EUA : 1149-> PIC+ tratamento médico ideal 1138-> tratamento médico ideal

13 Desenho de estudo Patrocínio e supervisão: Department os Veterans Affairs Cooperative Studies Program Institutos Canadenses de pesquisa em saúde Empresas farmacêuticas diversas *as empresas que forneceram suporte financeiro, produtos ou ambos não participaram do desenho, da análise ou interpretação do estudo.

14 Desenho de estudo O protocolo do estudo foi aprovado comitê de Direitos Humanos do centro coordenador e pelos conselhos de revisão das instituições locais de cada centro participante.

15 Critérios de inclusão Doença arterial coronariana estável Angina classe IV estabilizada com medicamentos Estenose de pelo menos 70% em no mínimo uma artéria coronariana epicárdica proximal e evidência real de isquemia do miocardio( mudanças substanciais na depressão segmento ST ou onda T invertida no ECG de repouso ou isquemia induzida por exercicio ou por estresse farmacologico por vasodilatadores.)

16 Critérios de inclusão Pelo menos uma estenose coronariana de no mínimo 80% e angina clássica sem teste provocativo.

17 Critérios de exclusão Angina classe IV persistente Teste de estresse positivo( depressão substancial do segmento ST ou resposta hipotensiva durante estágio 1 do protocolo de Bruce) Insuficiência cardíaca refratária Choque cardiogênico Fração de ejeção < 30% Revascularização últimos 6 meses Anatomia coronariana não adequada para PCI

18 Endpoints Um desfecho/endpoint de estudo clínico é um indicador medido em um participante, ou em uma amostra coletada do participante para avaliar a segurança, eficácia ou outro objetivo de um estudo clínico.

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20 Endpoints compostos Morte por qualquer causa e infarto de miocardio não fatal: 211 pctes PCI 202 pctes grupo terapia médica ideal(mtg) Eventos primários cumulativos 4.6 anos 19% PCI 18.5% MTG Para desfecho composto pré- especificado de morte, infarto de miocardio não fatal e derrame: 20% PCI 19.5% MTG

21 Endpoints simples Taxa de hospitalização por sd. Coronariana aguda: 12.4% PCI 11.8% MTG Infarto de miocardio 13.2% PCI 12.3% MTG

22 Morte 7.6% PCI 8.3% MTG Derrame 2.1% PCI 1.8% MTG Endpoints simples Revascularização (4.6 anos): 21.1% PCI 32.6% MTG

23 Endpoints simples Bypass artéria coronariana 77 pctes PCI 81 pctes MTG Redução angina 5 anos ( soft endpoint) 74% PCI 72% MTG

24 Pacientes elegíveis excluídos 3071 elegíveis 784 não consentiram 450 não aprovação médica 237 recusaram- se a dar permissão 97 motivos desconhecidos = 1568= 51,05%

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26 Os grupos Randomly Assigned: PCI and optimal medical therapy (PCI group) 1149; Optimal medical therapy alone (medical-therapy group) All patients received: antiplatelet therapy: aspirin (81 to 325 mg per day) or clopidogrel (75 mg per day, if aspirin intolerance); medical antiischemic: longacting metoprolol, amlodipine, and isosorbide mononitrate, alone or in combination, along with either lisinopril or losartan; aggressive therapy to LDL cholesterol levels (simvastatin alone or in combination with ezetimibe) target level = 60 to 85 mg/dl.

27 In PCI group: target-lesion revascularization was always attempted; complete revascularization was performed. Success after PCI as seen on angiography: normal coronary-artery flow; less than 50% stenosis in the luminal diameter after balloon angioplasty; less than 20% after coronary stent implantation. Clinical success was defined as angiographic success; absence of inhospital myocardial infarction; emergency CABG; death. OBS: Drug-eluting stents were not approved for clinical use until the final 6 months of the study.

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29 Resultados A total of 2168 patients (95%) had objective evidence of myocardial ischemia. Of the 1149 patients in the PCI group: 46 never underwent a procedure -> patient either declined treatment or had coronary anatomy unsuitable for PCI; 2%, the operator was unable to cross any lesions; 1006 received stent; In the stent group, 41% more than one stent. Drug-eluting stents were used in 31 patients; Stenosis in the luminal diameter was reduced from a mean (±SD) of 83±14% to 31±34% in the 244 lesions without stents and from 82±12% to 1.9±8% in the 1444 lesions treated with stents; After PCI = successful treatment as seen on angiography 93% lesions, and clinical success was achieved in 89% patients.

30 Primary Outcome Resultados A composite of death from any cause and nonfatal myocardial infarction occurred in 211 patients in the PCI group and 202 patients in the medicaltherapy group; The estimated 4.6-year cumulative primary event rates were 19.0T% in the PCI group and 18.5% in the medical-therapy group (unadjusted hazard ratiofor the PCI group, 1.05; 95% CI, 0.87 to 1.27; P = 0.62)

31 Secondary Outcomes Death, nonfatal myocardial infarction, and stroke, the event rate was 20.0% in the PCI group and 19.5% in the medical-therapy group (hazard ratio, 1.05; 95% CI, 0.87 to 1.27; P = 0.62); The rates of hospitalization for acute coronary syndromes were 12.4% in the PCI group and 11.8% in the medical-therapy group (hazard ratio, 1.07; 95% CI, 0.84 to 1.37; P = 0.56); Rates of myocardial infarction were 13.2% and 12.3%, respectively (hazard ratio, 1.13; 95% CI, 0.89 to 1.43; P = 0.33); For death alone, the rates were 7.6% and 8.3%, respectively (hazard ratio, 0.87; 95% CI, 0.65 to 1.16); For stroke alone, the rate was 2.1% in the PCI group and 1.8% in the medical-therapy group (hazard ratio, 1.56; 95% CI,0.80 to 3.04; P = 0.19); When the primary end point was calculated with the exclusion of periprocedural myocardial infarction, the event rates were 16.2% and 17.9% (hazard ratio, 0.90; 95% CI, 0.73 to 1.10; P = 0.29); 21.1% of patients in the PCI group had additional revascularization, as compared with 32.6% of those in the medical-therapy group (hazard ratio, 0.60; 95% CI, 0.51 to 0.71; P<0.001); The median time to subsequent revascularization was 10.0 months (interquartile range, 4.5 to 28.0) in the PCI group and 10.8 months (interquartile range, 3.2 to 30.7) in the medical-therapy group.

32 OBS: There was a statistically significant difference in the rates of freedom from angina throughout most of the follow-up period, in favor of the PCI group. At 5 years, 74% of patients in the PCI group and 72% of those in the medicaltherapy group were free of angina (P = 0.35).

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34 Subgrupos There was no significant interaction (P<0.01) between treatment effect and any predefined subgroup variable.

35 Há eficácia e segurança para utilização da medicação? Reinforce existing clinical practice guidelines, which state that PCI can be safely deferred in patients with stable coronary artery disease, even in those with extensive, multivessel involvement and inducible ischemia, provided that intensive, multifaceted medical therapy is instituted and maintained. PCI can be implemented safely in the majority of patients with stable coronary artery disease.

36 Discussão PCI added to optimal medical therapy did not reduce the primary end point of death and nonfatal myocardial infarction or reduce major cardiovascular events, as compared with optimal medical therapy alone (follow-up of 2.5 to 7.0 years). All secondary outcomes and individual components of the primary outcome showed no significant differences between the study groups, nor was there a significant interaction between treatment effect and any prespecified subgroup variable. Explanation: differences in atherosclerotic plaque morphology and vascular remodeling associated with acute coronary syndromes, as compared with stable coronary artery disease. Thus, unstable coronary lesions that lead to myocardial infarction are not necessarily severely stenotic, and severely stenotic lesions are not necessarily unstable.

37 Focal management of even severely stenotic coronary lesions with PCI in our study did not reduce the rate of death and myocardial infarction, presumably because the treated stenoses ere not likely to trigger an acute coronary event. Lower-than-projected event rate in the medical-therapy group = systemic therapy that reduced plaque vulnerability through aggressive intervention for multiple risk factors and evidence-based use of medication. These results are also concordant with a metaanalysis of all previous trials involving PCI versus medical management. In the aggregate, these studies, including COURAGE, include outcome data on more than 5000 patients and show that PCI has no effect in reducing major cardiovascular events.

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40 Limitations: The preponderance of male patients (85%); The lack of ethnic diversity (14% of the patients were nonwhite); Used bare-metal stents, since drug-eluting stents were not available until late during accrual; OBS: Approximately one third of these patients may subsequently require revascularization for symptom control or for subsequent development of an acute coronary syndrome.

41 Conclusão Although the addition of PCI to optimal medical therapy reduced the prevalence of angina, it did not reduce longterm rates of death, nonfatal myocardial infarction, and hospitalization for acute coronary syndromes.

42 The New York Times Published: March 27, 2007 The use of stents has boomed in the United States in the last 10 years. Angioplasty with stenting generally costs $25,000 and up. The latest drug-coated stents cost $2,200 apiece. Stents generate nearly $3 billion a year in sales in the United States for Boston Scientific and Johnson & Johnson, the two companies that dominate the market. Dr. David E. Kandzari, chief medical officer of the Cordis Cardiology business at Johnson & Johnson, said that modern drugs slowed the progression of coronary artery disease, but that stenting was superior at relieving symptoms, so both should be available. His counterpart at Boston Scientific, Dr. Donald S. Baim, said what was apparently the loss of the symptom relief advantage of stents over time in the study might have occurred because the trial ended in 2004, just as the drugcoated stents were introduced. Just 3 percent of the patients received them. Nearly one-third of the group that started on drug treatment ended up receiving stents or having bypass surgery because their symptoms worsened. He said most of them would have been free of angina symptoms after five years because of stents but would have still been counted in the drug group.

43 Guidelines from the American Heart Association and the American College of Cardiology have since 2002 called for using angioplasty and stenting or bypass surgery only after extensive efforts to treat such patients symptoms with drugs. But cardiologists say patients and doctors increasingly ignore the guidelines, choosing the quicker and initially reliable relief of stenting. There will be a lot of analysis and dissection of the study, said Dr. Boden of the University at Buffalo. But that doesn t necessarily mean we will do far fewer angioplasties. Examples of how the results might be questioned emerged even before the data. Dr. Kandzari of Cordis noted that the nearly 2,300 patients in the trial were largely from veterans hospitals in the United States and Canada. Those patients receive many medicines free and are more likely to take them as prescribed. The trial was supported financially by eight major drug companies in addition to the United States and Canadian governments.

44 Cartas ao editor Thomas P. Wharton, Jr., M.D. Exeter Hospital, Exeter approximately 85% of all PCI procedures are undertaken electively. (according to Feldman et al: 31%) of the 31% of patients who underwent elective procedures, many probably had criteria that would have excluded them from the COURAGE trial: class IV angina, a markedly positive exercise test, refractory heart failure, poor ventricular function, or recent revascularization. it must be recognized that they reflect the findings in only a small minority of patients with coronary disease, mostly with mild symptoms, one third of whom ultimately required revascularization within a median of 10 months.

45 Cartas para o editor Atman P. Shah, M.D. David M. Shavelle, M.D. William J. French, M.D. Harbor UCLA Medical Center, Torrance issues of patient-selection bias and PCI methodology weaken these conclusions. First, the authors excluded more than 90% of the patients who were evaluated, suggesting a highly selected study population. Of those patients, 6554 about three times the reported study size were excluded for logistic reasons, with no further explanation. Among the patients who underwent PCI, 14.5% of the lesions were treated with coronary angioplasty without placement of a stent, a procedure that is subject to rates of revascularization and periprocedural myocardial infarction that are higher than those among patients receiving stents. Trials involving the use of drug-eluting stents, are warranted.

46 Cartas para o editor Stefano De Servi, M.D. Azienda Ospedaliera Ospedale Civile di Legnano, Italy Although two thirds of patients in the COURAGE trial had multivessel disease, 59% received only one stent when treated with PCI, suggesting that revascularization was incomplete in most cases. In a recent report on data from the New York State PCI Registry, incomplete revascularization was recognized as a powerful independent predictor of mortality and need for subsequent revascularization.

47 COURAGE X Prática Clínica (Among) more than 460,000 patients, the percentage who received optimal medical therapy with an antiplatelet agent, a beta-blocker, and a statin before PCI actually increased slightly from 43.5% to 44.7% after COURAGE was reported. Although the change was statistically significant, had marginal clinical significance, the authors noted. Collectively, these findings suggest a limited effect of an expensive, highly publicized clinical trial on routine clinical practice. Journal of the American Medical Association, May 11, 2011

48 Referências Optimal Medical Therapy with or without PCI for Stable Coronary Disease. Disponível em: t. Acesso em: 18 de set. de The COURAGE Trial: PCI is not superior to medical therapy in patients with stable coronary disease. Disponível em: Acesso em: 18 de set. de The COURAGE Trial Aftermath No Change in Practice. Disponível em: Acesso em: 18 de set. de The Truth and Consequences of the COURAGE Trial. Disponível em: Acesso em: 18 de set. de In Trial, Drugs Equal Benefits of Artery Stents. Disponível em: nted=all. Acesso em: 18 de set. de 2011.