abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC São Paulo, SP, Brazil xYJknqpxkD5VT9txdbfF6pD 00002 S0066-782X2005000300002 S0066-782X(05)08400302 10.1590/S0066-782X2005000300002 Editorial Revascularização miocárdica em multiarteriais Abizaid Alexandre A. C. Siqueira Dimytri Alexandre Instituto Dante Pazzanese de Cardiologia 03 2005 84 3 202 205 This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. 19 08 2005

EDITORIAL

Revascularização miocárdica em multiarteriais

Alexandre A. C. Abizaid; Dimytri Alexandre Siqueira

São Paulo, SP

Instituto Dante Pazzanese de Cardiologia

Endereço para correspondência

Os objetivos no tratamento de pacientes com doença coronariana em múltiplos vasos incluem alívio dos sintomas de isquemia, redução na taxa de eventos cardíacos (infarto, arritmias) e preservação ou restauração da função ventricular esquerda, com conseqüente maior sobrevida a longo prazo. Com a publicação de importantes estudos na década de 70, que compararam a cirurgia de revascularização miocárdica com a terapia medicamentosa1-3, entendemos que tais objetivos eram melhor alcançados com a cirurgia, especialmente quando indicada a portadores de lesão de tronco de coronária esquerda, acometimento trivascular ou disfunção ventricular.

Grandes avanços na terapêutica clínica (estatinas, antiplaquetários potentes) e cirúrgica (maior emprego de enxertos arteriais, melhor proteção miocárdica, procedimentos sem circulação extracorpórea) ocorreram desde então, com comprovada melhoria no prognóstico desses pacientes. Nos últimos anos, a intervenção coronariana percutânea tornou-se a principal forma de revascularização miocárdica empregada no tratamento da doença coronariana. O incremento das técnicas e instrumentais permitiu que tal forma de revascularização, menos invasiva, pudesse ser oferecida à população de multivasculares, com segurança e eficácia semelhantes a revascularização cirúrgica em diversos estudos. Na presente edição, Silva e cols. apresentam os resultados de estudo randomizado unicêntrico4, realizado em nosso país, que avalia, a longo prazo, as vantagens das duas estratégias de revascularização sobre a evolução clínica desses pacientes.

As primeiras séries, publicadas na década de 90, compararam a cirurgia de revascularização miocárdica com angioplastia coronária por cateter-balão5-12. Esses estudos demonstraram, uniformemente, que as taxas de mortalidade e infarto não diferiam estatisticamente entre as duas formas de tratamento (fig.1); os pacientes submetidos à intervenção coronariana percutânea apresentavam, porém, maior necessidade de nova revascularização a longo prazo em razão da ocorrência de reestenose. Apesar de possuírem limitações no que se refere à seleção de pacientes (inclusão de univasculares, diferenças clínicas e angiográficas entre as populações), tais pesquisas comprovaram a segurança da angioplastia coronariana e reiteraram sua indicação a pacientes univasculares ou bivasculares com lesões menos complexas.

Inicialmente utilizados para o manejo de complicações da angioplastia (oclusões agudas, dissecções do vaso), o emprego de stents coronarianos tornou-se freqüente e recomendado, em razão de suas propriedades mecânicas de impedir o recolhimento elástico e o remodelamento negativo da parede vascular - fatores determinantes no processo de reestenose coronariana após angioplastia com balão. Ao reduzir a ocorrência de reestenose e de complicações agudas, os stents aproximaram ainda mais os resultados obtidos com a intervenção coronariana percutânea e a cirurgia.

Em meta-análise13 comparativa entre a intervenção coronariana percutânea com stents e cirurgia de revascularização miocárdica, composta por 2643 pacientes, abrangendo os estudos ARTS14, ERACI II15 e SOS16, observou-se que não havia diferença nas taxas de mortalidade e infarto não-fatal entre os dois grupos ao final de 1 ano. A necessidade de nova revascularização no grupo submetido a intervenção coronariana percutânea com stents foi de 15%, metade da incidência relatada com angioplastia por balão em multiarteriais. Os índices de nova revascularização continuavam, porém, significativamente maiores quando comparados à cirurgia de revascularização miocárdica, principalmente devido à reestenose intra-stent.

O artigo de Silva e cols.4 corrobora tais resultados: a sobrevida livre de eventos combinados em 5 anos, no estudo em questão (82% para o grupo cirúrgico e 55% para o grupo ATC, p=<0,001) é semelhante à relatada no estudo ARTS I, no mesmo período de seguimento (tab.I)17.

Vivemos hoje uma nova era no tratamento percutâneo da doença arterial coronariana. O emprego de stents eluídos com drogas antiproliferativas, carreadas e liberadas de forma controlada na parede vascular a partir de polímeros biocompatíveis, mostrou-se efetivo na redução da hiperplasia neo-intimal, principal determinante da ocorrência de reestenose intra-stent. Desde a primeira utilização clínica de stents recobertos com sirolimus, realizada em nosso meio18, vários estudos demonstraram a segurança e eficácia desta nova tecnologia para o tratamento de lesões coronarianas de novo19-22. Em meta-análise envolvendo 5.103 pacientes23, as taxas de reestenose angiográfica e eventos cardíacos adversos (predominantemente revascularização de lesão-alvo) foram significativamente menores nos pacientes tratados com sirolimus e paclitaxel, quando comparados a stents convencionais (8,9% vs 29,3% e 7,8% vs 16,4%, respectivamente).

Embora inicialmente aplicados a pacientes selecionados, com lesões únicas em vasos de maior calibre, os stents recobertos mostram-se eficazes também em situações mais adversas. No registro RESEARCH24, que incluiu indivíduos com lesões mais complexas (bifurcações, enxertos venosos, acometimento de tronco ou lesões longas que requeriam mais de um stent), a taxa de reestenose angiográfica evidenciada (7,9%) foi menor que a relatada com stents não-recobertos. A observação de que o tipo de reestenose intra-stent com stents eluídos é predominante focal é de grande importância clínica, pois permite nova abordagem percutânea com menor índice de recorrência25.

O impacto da utilização de stents eluídos com medicamentos em multiarteriais vem sendo investigado no estudo ARTS II17, que compara, através de análise pareada, a evolução de pacientes tratados com stents com sirolimus com a população incluída no ARTS I e submetida à cirurgia ou implante de stents não-recobertos. Resultados preliminares com seguimento de 6 meses revelam que, embora com maior percentagem de diabéticos, maior quantidade de lesões tratadas por paciente e utilização de stents mais longos em vasos mais finos (todos fatores preditores de reestenose), os indivíduos tratados com stents com sirolimus apresentam sobrevida livre de eventos maior que os pacientes avaliados no protocolo ARTS I (93,6% vs 91% no grupo cirúrgico e 80% no grupo intervenção coronariana percutânea). A ocorrência de morte, infarto e acidente vascular encefálico foi menor no grupo sirolimus (tab. II).

Pacientes portadores de diabetes mellitus e coronariopatia multivascular apresentam pior prognóstico a curto e longo prazo quando comparados a não-diabéticos, independentemente do tipo de revascularização miocárdica empregada. A reestenose é um dos principais fatores implicados no pior prognóstico dos diabéticos submetidos à intervenção coronariana percutânea. A presença de hiperplasia neo-intimal e o maior remodelamento negativo do vaso após angioplastia, bem como o aumento de agregação plaquetária e mecanismos reduzidos de fibrinólise explicam a maior propensão dos diabéticos em apresentar recorrência de obstrução coronária no sítio previamente tratado. Embora o emprego de stents tenha reduzido a incidência de reestenose, a maioria dos estudos comparativos com a cirurgia apontam para maiores taxas de nova revascularização mesmo quando utilizamos estes dispositivos26. No estudo ARTS I, ao final do seguimento de 1 ano, os diabéticos tratados com intervenção coronariana percutânea apresentaram maior necessidade de nova revascularização quando comparados aos diabéticos submetidos à cirurgia (22,3% vs 3,1%, p<0,001)27, ressaltando a influência da hiperplasia neointimal exagerada neste subgrupo como determinante de reestenose intra-stent.

Os beneficios alcançados com a utilização de stents eluídos com medicamentos são estendidos aos diabéticos, que apresentam menor incidência de reestenose angiográfica e revascularização da lesão-alvo se tratados com stents com sirolimus, quando comparados a stents não-recobertos. Os resultados de uma subanálise do estudo SIRIUS28, que trata especificamente dos diabéticos, demonstram que a revascularização da lesão-alvo é significativamente menor quando emprega-se stents eluídos com sirolimus (22,3% vs 6,9%, p<0,001). Quando confrontados com os resultados do estudo ARTS, percebe-se que a ocorrência de eventos cardiovasculares é significativamente menor no grupo com sirolimus (fig. 2).

As evidências de maior mortalidade a longo prazo nos diabéticos submetidos à angioplastia coronariana provém de 2 estudos (CABRI6 e BARI7), conduzidos ainda na era pré-stents. Em subanálise (não pré-especificada) do estudo BARI29, os pacientes diabéticos multivasculares submetidos à cirurgia de revascularização miocárdica apresentaram, após 5 anos, mortalidade geral menor que aqueles submetidos à angioplastia com balão (19,4% x 34,5%, p=0,0024). Este benefício da cirurgia sobre a angioplastia foi restrito aos diabéticos revascularizados com implante de artéria torácica interna para a descendente anterior, sendo a evolução dos que receberam exclusivamente enxertos venosos semelhante aos tratados por angioplastia. Tal observação não foi corroborada por grandes registros (inclusive o próprio registro do BARI) e outras séries mais contemporâneas. No estudo ARTS30, quando se analisa o subgrupo dos diabéticos (208 pacientes), a mortalidade após 3 anos de acompanhamento foi de 7,1% no grupo submetido a angioplastia e 4,2% no grupo cirúrgico (p=NS).

Na era dos stents eluídos com medicamentos, não há dúvidas de que melhor evolução clínica será experimentada pelos pacientes multiarteriais submetidos à intervenção percutânea, em função de revascularização mais duradoura. Contudo, importantes questões ainda devem ser analisadas antes da generalização de resultados para a prática clínica.

A maioria dos estudos em multivasculares determinaram como critério de inclusão a necessidade de se obter revascularização miocárdica completa tanto por intervenção coronariana percutânea como por cirurgia de revascularização miocárdica. Indivíduos com anatomia coronariana mais extensa e complexa, disfunção ventricular esquerda e já revascularizados previamente por intervenções percutâneas foram sistematicamente excluídos. Da mesma forma, portadores de síndromes coronarianas agudas, insuficiência renal, doença cerebrovascular constituíram minoria da população. Portanto, a população analisada foi constituída por pacientes multivasculares com perfil clínico e angiográfico de menor severidade. A melhor estratégia de revascularização em pacientes mais graves ainda não é definida.

O estudo SINTAX17 pretende randomizar 1.500 portadores de doença de tronco da coronária esquerda ou acometimento multivascular para intervenção percutânea com implante de stents eluídos com paclitaxel e cirurgia de revascularização. A inclusão de indivíduos com perfil clínico mais grave (presença de disfunção ventricular, insuficiência renal e acidente vascular encefálico prévio), bem como portadores de lesões complexas (oclusões crônicas, por exemplo) aproximará a população estudada daquela do mundo real.

Embora não uniforme, a observação de maior mortalidade a longo prazo nos diabéticos submetidos à angioplastia coronariana ainda é motivo de debate. O estudo FREEDOM17, multicêntrico e randomizado, pretende avaliar a evolução de 2.400 diabéticos submetidos à cirurgia de revascularização miocárdica (com ou sem circulação extracorpórea) e intervenção coronariana com uso de stents com sirolimus e paclitaxel. Com seguimento clínico de 3 anos, a comparação de ocorrência de desfechos primários (morte, infarto e acidente vascular encefálico) fornecerá informações relevantes para o manejo deste subgrupo de pacientes.

Na abordagem de pacientes com doença coronária multivascular, os limites definidores da estratégia a ser empregada têm se tornado menos rigorosos. A apresentação clínica, extensão e severidade da doença coronária, a presença de disfunção ventricular esquerda e comorbidades continuam a influenciar a escolha do tratamento inicial. Na era dos stents eluídos com medicamentos, vislumbra-se que a indicação de intervenção coronariana percutânea será ampliada, uma vez que reestenose não será a principal limitação. Neste contexto, a redução de eventos cardíacos (morte, infarto) se estabelece como o objetivo primário a ser alcançado. Além de tratamento medicamentoso eficaz, o desenvolvimento e aprimoramento de métodos para a identificação de indivíduos e lesões coronarianas vulneráveis e a avaliação da terapêutica recomendada (inclusive abordagem de lesões propensas à instabilização com stents recobertos) serão requeridos.

Referências

1. European Coronary Surgery Study Group. Long-term results of prospective randomized study of coronary artery bypass surgery in stable angina pectoris. Lancet 1982;2: 1173-80.

2. Alderman EL, Bourassa MG, Cohen LS, et al. Ten-year follow-up of survival and myocardial infarction in the randomized Coronary Artery Surgery Study. Circulation 1990;82: 1629-46.

3. Detre KM, Takaro T, Hultgren H, et al. Long-term mortality and morbidity results of the Veterans Administration randomized trial of coronary artery bypass surgery. Circulation 1985;72(supl 5): 84.

4. Silva PRD, Hueb WA, César LAM, Oliveira SA, Ramires JAF. Estudo comparativo dos resultados da intervenção cirúrgica e da angioplastia na revascularização do miocárdio em portadores de comprometimento multiarterial equivalente. Arq Bras Cardiol 2005;84: 214-21.

5. RITA Trial Participants. Coronary angioplasty vs coronary artery bypass surgery: the Randomized Intervention Treatment of Angina (RITA) trial. Lancet 1993;343: 573-80.

6. CABRI Trial Participants. First-year results of CABRI (Coronary Angioplasty vs. Bypass Revascularization Investigation). Lancet 1995;346: 1179-84.

7. The Bypass Angioplasty Revascularization (BARI) Investigators. Comparision of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335: 217-25.

8. Rodriguez A, Boullon F, Perez-Balino N, et al. Argentine randomized trial of percutaneous transluminal coronary angioplasty vs coronary artery bypass surgery in multivessel dissease (ERACI): in-hospital results and 1-year follow-up,. J Am Coll Cardiol 1993;22: 1060-7.

9. Hamm CW, Reimers J, Ischinger T, et al. for the German Angioplasty Bypass Surgery Investigation. A randomized study of coronary angioplasty compared with bypass surgery in patients with symptomatic multivessel coronary disease. N Engl J Med 1994;331: 1037-43.

10. King SB, Lembo NJ, Weintraub WS, et al. A randomized trial comparing coronary angioplasty with coronary bypass surgery. N Engl J Med 1994;331: 1044-50.

11. BARI investigators. Influence of diabetics on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease. Circulation 1997;96: 1761-9.

12. King SB, Kosinski AS, Guyton RA, et al. Eight-year mortality in the Emory Angioplasty vs Surgery Trial (EAST). J Am Coll Cardiol 2000;35: 1116 -21.

13. Hoffman SN, TenBrook JA, Wolf WP, et al. A meta-analysis of randomized controlled trials comparing coronary bypass graft with percutaneous transluminal coronary angioplasty: one to eight-year outcomes. J Am Coll Cardiol. 2003;41: 1293-304.

14. Serruys PW, Unger F, Sousa JE, et al. Comparison of coronary artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 2001;344: 1117-24.

15. Rodriguez A, Bernardi V, Navia J, et al. Argentine randomized study: coronary angioplasty with stenting vs coronary bypass surgery in patients with multiple-vessel disease (ERACI-II): 30 day and one-year follow-up results. J Am Coll Cardiol 2001;37: 51-8.

16. SoS Investigators. Coronary artery bypass vs percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a randomized controlled trial. Lancet 2002;360: 965-70.

17. Disponível na internet: http. www. theheart.org e tctmd.com.

18. Sousa JE, Costa MA, Abizaid A, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional ultrasound study. Circulation 2001; 103: 192-95.

19. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparision of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346: 1773-80.

20. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents vs standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349: 1315-23.

21. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350: 221-31.

22. Park SJ, Shin WH, Ho DS, et al. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med. 2003;348: 1537-45.

23. Babapulle MN, Joseph L, Belisle P, et al. A hierarchical bayesian meta-analysis of randomized clinical trials of drug-eluting stents. Lancet 2004;364: 557-8.

24. Lemos PA, Hoye A, Goedhart D, et al. Clinical, angiographic and procedural predictors of angiographic restenosis after sirolimus-eluting stent implantation on complex patients. Circulation 2004;109: 1366-70.

25. Lemos PA, Saia F, Lighart JM, et al. Coronary restenosis after sirolimus-eluting stent implantation: morphological description and mechanistic analysis from a consecutive series of cases. Circulation 2003;108: 257-60.

26. Abizaid A, Kornowsky R, Mintz GS, et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol 1998;32: 584-9.

27. Abizaid A, Costa MA, Centemero M, et al. Clinical and economic impact of diabetes mellitus on percutaneous and surgical treatment of multivessel coronary artery disease patients: insights from the Arterial Revascularization Therapy Study (ARTS) trial. Circulation 2001;104: 533-8.

28. Moussa I, Leon MB, Baim DS, et al. Impact of sirolimus-eluting stents on outcome in diabetic patients. Circulation 2004;109: 2273-8.

29. Detre K, Guo P, Holubkov R, et al. Coronary revascularization in diabetic patients: a comparison of the randomized and observational components of the Bypass Angioplasty Revascularization Investigation (BARI). Circulation 1999;99: 633-40.

30. Legrand VMG, Serruys PW, Unger F, et al. Three-year outcome after coronary stenting vs bypass surgery for the treatment of multivessel disease. Circulation 2004; 109: 1114-20.

Endereço para correspondência

Alexandre A. C. Abizaid

Rua Dom Paulo Pedrosa, 673/72B

05687-001 - São Paulo - SP

E-mail:

abizaid@cardiol.br e

aabizaid@uol.com.br

Enviado para publicação em 10/12/2004

Aceito em 10/12/2004

Editorial Myocardial revascularization in patients with multivessel disease

EDITORIAL

Myocardial revascularization in patients with multivessel disease

Alexandre A. C. Abizaid; Dimytri Alexandre Siqueira

São Paulo, SP - Brazil

Instituto Dante Pazzanese de Cardiologia - São Paulo - SP

Correspondence

The treatment of patients with multivessel disease aims at relieving the symptoms of ischemia, reducing the rate of cardiac events (infarction, arrhythmias), and preserving or restoring left ventricular function, resulting in a greater long-term survival. Important studies carried out during the 1970s comparing coronary artery bypass graft with the medicamentous therapy 1-3 led us to believe that such objectives were better achieved with surgery, especially when indicated to patients with a lesion in the left main coronary artery, three-vessel disease or ventricular dysfunction.

Great advances in clinical (statins, potent antiplatelet agents) and surgical (greater use of arterial grafts, better myocardial protection, procedures without extracorporeal circulation) therapy have occurred, resulting in an undeniable improvement in the prognosis of those patients. In recent years, percutaneous transluminal coronary angioplasty has become the most common form of myocardial revascularization used for the treatment of coronary artery disease. The improvement in the techniques and instruments allowed such less invasive form of revascularization to be offered to patients with multivessel disease with safety and efficacy similar to those of surgical revascularization reported in several studies. Silva et al 4 have reported the results of a randomized study carried out in a single center in our country, assessing the long-term advantages of both strategies of revascularization regarding the clinical evolution of patients with multivessel coronary disease.

The first case series, published in the 1990s, compared coronary artery bypass surgery with balloon-catheter coronary angioplasty 5-12. Those studies showed in a uniform way that the mortality and infarction rates did not statistically differ between the 2 forms of treatment (fig.1); patients undergoing the percutaneous coronary intervention, however, more often required a new revascularization in the long run, due to the occurrence of restenosis. Although those studies had limitations regarding the selection of patients (inclusion of patients with one-vessel disease, clinical and angiographic differences between the populations), they confirmed the safety of coronary angioplasty and its indication to patients with one- or two-vessel disease and less complex lesions.

Initially used for managing complications of angioplasty (acute occlusions, vessel dissections), the implantation of coronary stents has become frequent and has been recommended due to their mechanical properties of preventing elastic recoil and negative remodeling of the vascular wall, which are determinant factors in the process of coronary restenosis after balloon angioplasty. By reducing the occurrence of restenosis and acute complications, stent implantation produced results even closer to those obtained with surgery.

A meta-analysis 13 comparing coronary artery bypass graft with percutaneous transluminal coronary angioplasty involving 2,643 patients and comprising the ARTS 14, ERACI II 15, and SOS 16 studies showed no difference in the mortality and non-fatal infarction rates between the 2 groups at the end of one year. The need for a new revascularization in the group undergoing percutaneous transluminal coronary angioplasty with stents was 15%, half of the incidence reported for balloon angioplasty in patients with multivessel disease. The indices of new revascularization, however, continued significantly greater than those of coronary artery bypass graft, mainly due to intra-stent restenosis.

The article by Silva et al 4 corroborated those results: the combined-event-free survival in 5 years reported in the study in question (82% for the surgical group, and 55% for the PTCA group, P < 0.001) was similar to that reported in the ARTS I study for the same follow-up period (tab. I) 17.

We face a new era in the percutaneous treatment of coronary artery disease. The use of stents coated with antiproliferative drugs, carried and released in a controlled way in the vascular wall from biocompatible polymers proved effective in reducing neointimal hyperplasia, which is the major determinant of the occurrence of intra-stent restenosis. Since the first clinical use of sirolimus-eluting stents here in Brazil 18, several studies have shown the safety and efficacy of that new technology for the treatment of de novo coronary lesions 19-22. In a meta-analysis involving 5,103 patients 23, the angiographic restenosis rate and the adverse cardiac event rate (mainly revascularization of the target lesion) were significantly lower in patients treated with sirolimus- and paclitaxel-eluting stents as compared with those in patients treated with conventional stents (8.9% vs 29.3% and 7.8% vs 16.4%, respectively).

Although initially applied to selected patients with single lesions in larger-caliber vessels, the drug-eluting stents proved to be effective also in more adverse situations. In the RESEARCH study24, including individuals with more complex lesions (bifurcations, venous grafts, impairment of the left main coronary artery, or long lesions requiring more than one stent), the evidenced angiographic restenosis rate (7.9%) was smaller than that reported for conventional stents. The observation that the type of intra-stent restenosis with drug-eluting stents is predominantly focal is of great clinical importance, because it allows the taking of a new percutaneous approach with a lower recurrence rate 25.

The impact of the use of drug-eluting stents in patients with multivessel disease has been investigated in the ARTS II study 17, which compares, by use of paired analysis, the evolution of patients treated with sirolimus-eluting stents with that of the population in the ARTS I study, which had undergone surgery or implantation of conventional stents. Preliminary results referring to a 6-month follow-up have revealed that, although with a greater percentage of diabetic patients, greater quantity of treated lesions per patient, and use of longer stents in narrower vessels (all predictive factors of restenosis), the individuals treated with sirolimus-stents had a longer event-free survival than that of the patients assessed in the ARTS I protocol (93.6% vs 91% in the surgical group and 80% in the percutaneous coronary artery intervention group). The occurrence of death, infarction, and stroke was smaller in the sirolimus group (tab. II).

Patients with diabetes mellitus and multivessel coronary disease have a poorer prognosis in the short and long run as compared with that of nondiabetic patients, independently of the type of myocardial revascularization used. Restenosis is one of the major factors implicated in the worst prognosis of diabetic patients undergoing percutaneous coronary intervention. The presence of neointimal hyperplasia and the greater negative remodeling of the vessel after angioplasty, in addition to the increase in platelet aggregation and the reduction in the mechanisms of fibrinolysis explain the greater tendency of diabetic patients towards recurring coronary artery obstruction in the previously treated site. Although the use of stents has reduced the incidence of restenosis, most studies comparing the results of the use of stents with those of surgery point to greater rates of new revascularization even when those devices are used 26. In the ARTS I study, at the end of the first year of follow-up, the diabetic patients treated with percutaneous coronary angioplasty more often required a new revascularization when compared with the diabetic patients undergoing surgery (22.3% vs 3.1%; P < 0.001) 27. That stresses the influence of the excessive neointimal hyperplasia in that subgroup as a determinant factor of intra-stent restenosis.

The benefits obtained with the use of drug-eluting stents may be extended to diabetic patients, who have a lower incidence of angiographic restenosis and revascularization of the target lesion when treated with sirolimus-eluting stents as compared with those receiving conventional stents. The results of a subanalysis of the SIRIUS study 28, which specifically assessed diabetic patients, have shown that revascularization of the target lesion is significantly lower when sirolimus-eluting stents are used (22.3% vs 6.9%; P<0.001). When these results are compared with those of the ARTS study, the occurrence of cardiovascular events is significantly lower in the sirolimus group (fig. 2).

The evidence of greater mortality in the long run in diabetic patients undergoing coronary angioplasty is found in 2 studies (CABRI 6 and BARI 7), which were carried out in the pre-stent era. In a non pre-specified subanalysis of the BARI study 29, the diabetic patients with multivessel disease who underwent coronary artery bypass grafting showed, after 5 years, a lower overall mortality than those who underwent balloon angioplasty (19.4% x 34.5%; P = 0.0024). This benefit of surgery over angioplasty was restricted to diabetic patients revascularized with implantation of the internal thoracic artery to the anterior descending artery, and the evolution of those who received exclusively venous grafts was similar to that of those treated with angioplasty. Such observation has not been corroborated by the large registers (including the BARI study) and other more contemporary case series. In the ARTS study 30, when the subgroup of diabetic patients is considered (208 patients), the mortality rate after 3 years of follow-up is 7.1% in the group undergoing angioplasty and 4.2% in the surgical group (P=NS).

In the era of drug-eluting stents, a better clinical evolution will certainly be experienced by the patients with multivessel disease undergoing percutaneous intervention, due to longer-lasting revascularization. However, important questions should still be analyzed before extending the results to clinical practice.

The inclusion criteria in most studies of patients with multivessel disease was the need for obtaining complete myocardial revascularization both for percutaneous coronary intervention and coronary artery bypass graft. Individuals with more extensive and complex coronary anatomy and left ventricular dysfunction, who had already undergone previous revascularization through percutaneous intervention, were systematically excluded. Similarly, patients with acute coronary syndromes, renal failure, and cerebrovascular disease were the minority of the population studied, which, therefore, comprised patients with multivessel disease with a less severe clinical and angiographic profile. The best strategy of revascularization in more critically ill patients has not yet been defined.

The SINTAX study 17 aims at randomizing 1,500 patients with left main coronary artery or multivessel disease for percutaneous intervention with implantation of paclitaxel-eluting stents and coronary artery bypass graft. By including individuals with a more severe clinical profile (presence of ventricular dysfunction, renal failure, and previous stroke), as well as patients with complex lesions, such as chronic occlusions, the population studied will near that of the real world.

Although nonuniform, the observation of greater mortality in the long run in diabetic patients undergoing coronary angioplasty is still controversial. The FREEDOM study 17, multicentric and randomized, aims at assessing the evolution of 2,400 diabetic patients undergoing coronary artery bypass graft (with or without extracorporeal circulation) and coronary intervention with the use of sirolimus- and paclitaxel-eluting stents. With a clinical 3-year follow-up, the comparison of the occurrence of primary outcomes (death, infarction, and stroke) will provide relevant information for the management of that subgroup of patients.

When approaching patients with multivessel coronary disease, the limits defining the strategy to be used have become less strict. The clinical presentation, extension, and severity of the coronary artery disease, and the presence of left ventricular dysfunction and comorbidities continue to influence the choice of the initial treatment. In the era of drug-eluting stents, indication for percutaneous transluminal coronary angioplasty will be widened, because restenosis will not be the major limitation. In such context, the reduction in cardiac events (death, infarction) is established as the primary objective to be achieved. In addition to the medicamentous treatment, the development and refinement of methods to identify vulnerable individuals and coronary artery lesions, and the evaluation of the therapy recommended (including the approach of lesions prone to instability with drug-eluting stents) will be required.

References

1. European Coronary Surgery Study Group. Long-term results of prospective randomized study of coronary artery bypass surgery in stable angina pectoris. Lancet 1982;2: 1173-80.

2. Alderman EL, Bourassa MG, Cohen LS et al. Ten-year follow-up of survival and myocardial infarction in the randomized Coronary Artery Surgery Study. Circulation 1990;82: 1629-46.

3. Detre KM, Takaro T, Hultgren H et al. Long-term mortality and morbidity results of the Veterans Administration randomized trial of coronary artery bypass surgery. Circulation 1985;72(supl 5): 84.

4. Silva PRD et al. Estudo comparativo dos resultados da intervenção cirúrgica e da angioplastia na revascularização do miocárdio em portadores de comprometimento multiarterial equivalente. Arq Bras de Cardiologia 2005.

5. RITA Trial Participants. Coronary angioplasty vs coronary artery bypass surgery: the Randomized Intervention Treatment of Angina (RITA) trial. Lancet 1993;343: 573-80.

6. CABRI Trial Participants. First-year results of CABRI (Coronary Angioplasty vs. Bypass Revascularization Investigation). Lancet 1995;346: 1179-84.

7. The Bypass Angioplasty Revascularization (BARI) Investigators. Comparision of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335: 217-25.

8. Rodriguez A, Boullon F, Perez-Balino N et al. Argentine randomized trial of percutaneous transluminal coronary angioplasty vs coronary artery bypass surgery in multivessel dissease (ERACI): in-hospital results and 1-year follow-up. J Am Coll Cardiol 1993;22: 1060-7.

9. Hamm CW, Reimers J, Ischinger T et al. for the German Angioplasty Bypass Surgery Investigation. A randomized study of coronary angioplasty compared with bypass surgery in patients with symptomatic multivessel coronary disease. N Engl J Med 1994;331: 1037-43.

10. King SB, Lembo NJ, Weintraub WS et al. A randomized trial comparing coronary angioplasty with coronary bypass surgery. N Engl J Med 1994;331: 1044-50.

11. BARI investigators. Influence of diabetics on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease. Circulation 1997;96: 1761-9.

12. King SB, Kosinski AS, Guyton RA et al. Eight-year mortality in the Emory Angioplasty vs Surgery Trial (EAST). J Am Coll Cardiol 2000;35: 1116 -21.

13. Hoffman SN, TenBrook JA, Wolf WP et al. A meta-analysis of randomized controlled trials comparing coronary bypass graft with percutaneous transluminal coronary angioplasty: one to eight-year outcomes. J Am Coll Cardiol. 2003;41: 1293-304.

14. Serruys PW, Unger F, Sousa JE et al. Comparison of coronary artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 2001;344: 1117-24.

15. Rodriguez A, Bernardi V, Navia J et al. Argentine randomized study: coronary angioplasty with stenting vs coronary bypass surgery in patients with multiple-vessel disease (ERACI-II): 30 day and one-year follow-up results. J Am Coll Cardiol 2001;37: 51-8.

16. SoS Investigators. Coronary artery bypass vs percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a randomized controlled trial. Lancet 2002;360: 965-70.

17. Disponível na internet: http.www.theheart.org e tctmd.com.

18. Sousa JE, Costa MA, Abizaid A et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional ultrasound study. Circulation 2001; 103: 192-95.

19. Morice MC, Serruys PW, Sousa JE et al. A randomized comparision of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346: 1773-80.

20. Moses JW, Leon MB, Popma JJ et al. Sirolimus-eluting stents vs standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349: 1315-23.

21. Stone GW, Ellis SG, Cox DA et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350: 221-31.

22. Park SJ, Shin WH, Ho DS et al. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med. 2003;348: 1537-45.

23. Babapulle MN, Joseph L, Belisle P et al. A hierarchical bayesian meta-analysis of randomized clinical trials of drug-eluting stents. Lancet 2004;364: 557-8.

24. Lemos PA, Hoye A, Goedhart D et al. Clinical, angiographic and procedural predictors of angiographic restenosis after sirolimus-eluting stent implantation on complex patients. Circulation 2004;109: 1366-70.

25. Lemos PA, Saia F, Lighart JM et al. Coronary restenosis after sirolimus-eluting stent implantation: morphological description and mechanistic analysis from a consecutive series of cases. Circulation 2003;108: 257-60.

26. Abizaid A, Kornowsky R, Mintz GS et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol 1998;32: 584-9.

27. Abizaid A, Costa MA, Centemero M et al. Clinical and economic impact of diabetes mellitus on percutaneous and surgical treatment of multivessel coronary artery disease patients: insights from the Arterial Revascularization Therapy Study (ARTS) trial. Circulation 2001;104: 533-8.

28. Moussa I, Leon MB, Baim DS et al. Impact of sirolimus-eluting stents on outcome in diabetic patients. Circulation 2004;109: 2273-8.

29. Detre K, Guo P, Holubkov R et al. Coronary revascularization in diabetic patients: a comparison of the randomized and observational components of the Bypass Angioplasty Revascularization Investigation (BARI). Circulation 1999;99: 633-40.

30. Legrand VMG, Serruys PW, Unger F et al. Three-year outcome after coronary stenting vs bypass surgery for the treatment of multivessel disease. Circulation 2004; 109: 1114-20.

Alexandre A. C. Abizaid

Rua Dom Paulo Pedrosa, 673/72B

Cep 05687-001 - São Paulo, SP, Brazil

E-mail:

abizaid@cardiol.br and

aabizaid@uol.com.br

Received for publication: 12/10/2004

Accepted for publication: 12/10/2004

English version by Stela Maris Costalonga

22. Park SJ, Shin WH, Ho DS, et al. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med. 2003;348: 1537-45.