abcArquivos Brasileiros de CardiologiaArq. Bras. Cardiol.0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBCSão Paulo, SP, BrazilRLDfcRZhj8Bs3Ksn3MRs69J00012S0066-782X2005000300012S0066-782X(05)0840031210.1590/S0066-782X2005000300012Artigos OriginaisImplante de stent eluído com batimastat para o tratamento da doença arterial coronariana: resultados do estudo piloto brasileiroAraujoCristiana Marques deRandoGustavo Adolfo B.MauroMaria Fernanda Z.CristóvãoSalvador A. B.SanchezIsaac S. MoscosoSalmanAdnan AliOliveira NetoJoão B. deMangioneJosé ArmandoSão PauloHospital Beneficência Portuguesa de São PauloBrazil0320058432562602403200422012004This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
OBJETIVO: Os excelentes resultados obtidos com os stents eluídos com sirolimus (rapamicina) na prevenção da reestenose motivaram a avaliação de outras substâncias que também apresentassem esta propriedade. O batimastat é um bloqueador de alta eficácia da enzima metaloproteinase, com potencial para reduzir a degradação da matriz extracelular e inibir a migração das células musculares lisas, com conseqüente capacidade de controlar a reestenose coronariana. MÉTODOS: De outubro/2001 a abril/2002, foram selecionados prospectivamente, 34 pacientes com lesões "de novo", em artéria coronária nativa, >50% e < 100%, passíveis de tratamento com stents de 3 a 4 mm de diâmetro e de 18 mm de comprimento. O desfecho primário do estudo foi verificar a ocorrência de eventos cardiovasculares maiores (morte de origem cardíaca, infarto agudo do miocárdio e necessidade de revascularização do vaso alvo) aos 30 dias e aos 4 meses e o secundário avaliar a taxa de reestenose coronariana após 4 meses do implante e de trombose subaguda aos 30 dias. RESULTADOS: A taxa de sucesso do procedimento foi de 97,1%. O desfecho primário ocorreu em 2,9% e 27,2% dos pacientes aos 30 dias e aos 4 meses respectivamente. A taxa de reestenose binária ao estudo angiográfico foi de 39,3%. Não houve episódio de trombose subaguda. A análise comparativa entre os grupos que apresentaram ou não reestenose não mostrou diferenças significativas entre ambos, exceto na perda luminal tardia, maior no G-I. CONCLUSÃO: Os stents eluídos com batimastat apresentaram bom perfil de segurança, entretanto, não se mostraram efetivos no controle da reestenose coronariana.
Implante de stent eluído com batimastat para o tratamento da doença arterial coronariana. Resultados do estudo piloto brasileiro
Cristiana Marques de Araujo; Gustavo Adolfo B. Rando; Maria Fernanda Z. Mauro; Salvador A. B. Cristóvão; Isaac S. Moscoso Sanchez; Adnan Ali Salman; João B. de Oliveira Neto; José Armando Mangione
São Paulo, SP
Hospital Beneficência Portuguesa de São Paulo
Endereço para correspondência
RESUMO
OBJETIVO: Os excelentes resultados obtidos com os stents eluídos com sirolimus (rapamicina) na prevenção da reestenose motivaram a avaliação de outras substâncias que também apresentassem esta propriedade. O batimastat é um bloqueador de alta eficácia da enzima metaloproteinase, com potencial para reduzir a degradação da matriz extracelular e inibir a migração das células musculares lisas, com conseqüente capacidade de controlar a reestenose coronariana.
MÉTODOS: De outubro/2001 a abril/2002, foram selecionados prospectivamente, 34 pacientes com lesões "de novo", em artéria coronária nativa, >50% e < 100%, passíveis de tratamento com stents de 3 a 4 mm de diâmetro e de 18 mm de comprimento. O desfecho primário do estudo foi verificar a ocorrência de eventos cardiovasculares maiores (morte de origem cardíaca, infarto agudo do miocárdio e necessidade de revascularização do vaso alvo) aos 30 dias e aos 4 meses e o secundário avaliar a taxa de reestenose coronariana após 4 meses do implante e de trombose subaguda aos 30 dias.
RESULTADOS: A taxa de sucesso do procedimento foi de 97,1%. O desfecho primário ocorreu em 2,9% e 27,2% dos pacientes aos 30 dias e aos 4 meses respectivamente. A taxa de reestenose binária ao estudo angiográfico foi de 39,3%. Não houve episódio de trombose subaguda. A análise comparativa entre os grupos que apresentaram ou não reestenose não mostrou diferenças significativas entre ambos, exceto na perda luminal tardia, maior no G-I.
CONCLUSÃO: Os stents eluídos com batimastat apresentaram bom perfil de segurança, entretanto, não se mostraram efetivos no controle da reestenose coronariana.
Os stents coronarianos demonstraram superioridade em relação ao cateter balão, por proporcionarem maior segurança ao procedimento, maior ganho luminal imediato e um menor índice de reestenose1,2. Apesar destes benefícios, a incidência de reestenose coronariana ainda é elevada, podendo ser > 30% em determinados grupos de pacientes3-6.
Os mecanismos envolvidos no seu surgimento são: o remodelamento negativo do vaso, a formação local de trombo, a proliferação neointimal e a produção excessiva de matriz extracelular7-9.
Demonstrou-se que uma alteração no metabolismo do colágeno pode estar envolvida no processo da reestenose10. A enzima metaloproteinase (MP) que possui a capacidade de degradar o colágeno e outras proteínas, como a elastina e os proteoglicanos11, facilitando a migração das células musculares lisas, apresenta atividade aumentada após a injúria com cateter balão12-14. Por este motivo, o batimastat (BB94), um inibidor não específico desta enzima, apresenta-se potencialmente útil no controle da reestenose coronariana.
Neste estudo avaliamos os resultados clínicos e angiográficos de um stent coronariano eluído com batimastat no tratamento da doença arterial coronariana.
Métodos
O stent utilizado neste estudo é composto de aço inoxidável e revestido com polímero de fosforilcolina (PC), do sistema BiodivYsio Drug Delivery (DD) PC-Stent da Biocompatibles, submerso em solução contendo batimastat, na dose de 2,0 mg por mm de stent. O revestimento de PC tem a capacidade de absorver cerca de 30 mg da droga, dose esta que se mostrou efetiva em estudos com modelos animais. Estudos in vitro estimaram um período de liberação do batimastat de 24 dias (T100%) e in vivo um período de liberação de 28 dias (T99%). Não há evidência de eventos sistêmicos com a utilização do stent revestido com batimastat em seguimento de 6 meses de ratos e coelhos que receberam a droga via intraperitoneal e foram submetidos a angioplastia com balão.
O protocolo do estudo foi aprovado pelo Comitê de Ética em Pesquisa e todos os pacientes assinaram o termo de consentimento informado.
Foram selecionados, prospectivamente, para o estudo pacientes maiores de 18 anos, com diagnóstico de angina estável, instável ou isquemia silenciosa documentada, portadores de lesões "de novo" < 18 mm de comprimento, em artéria coronária nativa, com estenose > 50% e < 100% em vasos de 3 a 4 mm de diâmetro. A fração de ejeção ventricular esquerda deveria ser > 30%.
Os critérios de exclusão foram: expectativa de vida < 9 meses, necessidade de intervenção cirúrgica de grande porte nos 6 meses do desenvolvimento do estudo, infarto agudo do miocárdio nos últimos 30 dias, valores de creatinina sérica > 2,0 mg/dl, dosagem de plaquetas < 100.000 células/mm3, diabéticos dependentes ou não de insulina, lesões reestenóticas, lesões em pontes de safena ou aorto-ostiais, contra-indicações para a utilização das medicações preconizadas e finalmente, pacientes que participaram de outro estudo de investigação com drogas ou dispositivos nos últimos 30 dias.
Os pacientes foram medicados com ácido acetilsalicílico 200 mg e clopidogrel 75 mg ou ticlopidina 250 mg 2 vezes ao dia, iniciados 3 dias antes do procedimento. A aspirina foi mantida indefinidamente e o clopidogrel ou a ticlopidina durante 3 meses.
A avaliação laboratorial inicial incluiu dosagem de hemoglobina, hematócrito, leucócitos, sódio, potássio, uréia, creatinina, TGO, TGP, CKMB. O ECG com 12 derivações foi realizado 24h antes e a cada 8h após o procedimento.
Na sala de hemodinâmica, após a colocação do introdutor arterial, foi administrada heparina com o objetivo de manter o TCA entre 250 a 300 s. Injetou-se nitroglicerina intracoronária na dose de 50 a 200 mg, realizando-se a filmagem de 2 projeções ortogonais onde a lesão a ser tratada era melhor visibilizada.
A implantação do stent foi realizada após pré-dilatação da lesão com cateter balão. Foram utilizados stents de 11, 15, e 18 mm de comprimento e de 3.0, 3.5, 4.0 mm de diâmetro. Procurou-se manter uma relação balão/artéria de 1:1.
Os parâmetros hemodinâmicos, analisados pelos próprios investigadores com angiografia digital quantitativa, realizada em aparelhagem Phillips H 5000, pré e pós-implante de stents foram: diâmetro luminal mínimo, diâmetro de referência, porcentual de estenose e perda luminal tardia. O sucesso do procedimento foi definido como uma lesão residual < 10% e obtenção de fluxo coronariano normal (TIMI III).
Após o procedimento a retirada do introdutor era realizada quando o TCA encontrava-se < 180 s. Dosagens de CKMB foram efetuadas a cada 8h. Não foi utilizado inibidor da GP IIbIIIa.
A avaliação dos pacientes após 1 e 4 meses incluía: anamnese, exame físico, realização de ECG, hemograma e dosagem de Na+, K+, uréia, creatinina, TGO e TGP.
A angiografia coronariana de controle foi realizada em média 4±1 meses após o implante do stent. Considerou-se como reestenose a porcentagem de obstrução > 50% da luz do vaso.
O desfecho primário do estudo foi verificar a ocorrência de eventos cardíacos maiores (morte de origem cardíaca, infarto agudo do miocárdio e necessidade de revascularização do vaso alvo) após 30 dias e 4 meses. Infarto agudo do miocárdio foi definido como "Q" quando ocorreu aumento dos níveis de CKMB > 2,5 vezes do seu valor normal e aparecimento de novas ondas Q em pelo menos 2 derivações contíguas ao eletrocardiograma e "não Q" quando somente a elevação enzimática foi observada.
Os desfechos secundários incluíram reestenose binária aos 4 meses (estenose > 50% do diâmetro luminal) e incidência de trombose subaguda do stent ao final de 30 dias.
As variáveis contínuas foram expressas como média e desvio padrão e analisadas pelo teste T de Student. As variáveis categóricas foram apresentadas em porcentagem e comparadas utilizando-se o teste exato de Fischer. Considerou-se significativo um valor de p < 0,05.
Resultados
No período de outubro de 2001 a abril de 2002, 34 pacientes foram submetidos a implante de stent eluído com batimastat. As características clínicas básicas encontram-se na tabela I.
O sucesso do procedimento foi obtido em 33 (97,1%) pacientes. Em um paciente não se conseguiu a progressão do stent devido à acentuada tortuosidade coronariana. Neste paciente o stent não foi implantado na lesão e, conseqüentemente, foi excluído do estudo.
Um (2,9%) paciente apresentou infarto agudo do miocárdio não Q na fase hospitalar. O desfecho primário aos 4 meses dos pacientes elegíveis foi de 27,2%, devido exclusivamente à necessidade de revascularização do vaso alvo. Os eventos cardíacos adversos maiores estão na tabela II.
Nenhum paciente apresentou trombose subaguda do stent aos 30 dias, como também não foi verificada trombose após 4 meses. A reestenose binária aos 4 meses foi observada em 13 dos 33 pacientes elegíveis (39,3%).
Devido ao elevado índice de reestenose encontrado, dividimos os pacientes em 2 grupos: o dos que apresentaram reestenose (G-I) e dos que não reestenosaram (G-II), para que se pudesse identificar um possível fator determinante da mesma. Entretanto a análise comparativa não demonstrou diferenças quanto as principais variáveis clínicas e angiográficas associadas ao processo de reestenose, entre os grupos G-I e G-II (tab. III).
Os resultados da angiografia digital quantitativa, incluindo a perda luminal tardia (PLT), definida como a diferença entre o diâmetro luminal mínimo (DLM) imediatamente após o implante do stent e o DLM aos 4 meses, estão listados na tabela IV. Demonstrou-se diferença significativa apenas na PLT, maior no G-I.
Discussão
Apesar da utilização dos stents, a reestenose coronariana tem sido o fator limitante do sucesso da revascularização coronariana percutânea a longo prazo1,2.
Alguns dispositivos tais como a braquiterapia15, a aterectomia rotacional, direcional e o laser16-18, foram utilizados no controle da reestenose, apresentando no entanto, resultados limitados.
A reestenose após o implante do stent ocorre como resultado da proliferação e migração de células musculares lisas (CML) para a luz do vaso e da excessiva produção da matriz extracelular19-22. As metaloproteinases (MP) enzimas envolvidas na migração das CML, pertencentes ao grupo das proteinases, podem ser subdivididas em 3 classes: colagenases, estromelisinas e gelatinases. Estas enzimas possuem a capacidade de degradar os componentes da matriz extracelular, incluindo o colágeno e a membrana de glicoproteínas, facilitando desta forma a migração de células musculares lisas23.
O batimastat é um peptídeo mimético de baixo peso molecular, contendo um grupo hidroxamato responsável pela quelação do átomo de zinco no sítio ativo das metaloproteinases e assim inibindo a ação desta enzima, sendo inicialmente utilizado como uma droga oncológica24.
Estudos em animais demonstraram que o batimastat foi efetivo na prevenção do remodelamento negativo arterial e na prevenção da perda luminal tardia após angioplastia com cateter balão25-27.
Neste estudo, a utilização dos stents eluídos com batimastat mostrou-se segura, não ocorrendo trombose do stent, nem qualquer efeito deletério detectável da droga. Entretanto, não se observou controle da reestenose angiográfica (39,3%) e da necessidade de nova revascularização (27,2%) aos 4 meses. A análise dos subgrupos de pacientes com e sem reestenose não demonstrou diferenças significativas na comparação de suas variáveis clínicas e angiográficas.
Nossos resultados estão de acordo com o estudo prospectivo, não randomizado, multicêntrico europeu, (Brillant I - batimastat anti-restenosis trial utilizing the Biodivysio local drug delivery PC stent), ainda não publicado, que selecionou 173 portadores de lesões "de novo" em artérias coronárias nativas. Ao final de 30 dias após o implante foram verificados 2 (1,2%) casos de infarto agudo do miocárdio não Q relacionados com o procedimento, e o controle angiográfico aos 6 meses mostrou taxa de reestenose binária de 25%.
Estudos randomizados recentes28-32, com o emprego de stents eluídos com sirolimus (rapamicina) e paclitaxel, que apresentam mecanismo de ação distinto do batimastat, mostraram resultados extremamente favoráveis, com diminuição significativa da taxa de reestenose e da necessidade da revascularização da lesão alvo. A análise angiográfica e, através de ultra-som intracoronariano de um desses estudos, demonstrou supressão sustentada da proliferação neointimal 1 ano após o implante33. Esses achados demonstram que os stents eluídos com medicamentos são uma forma segura e efetiva de tratamento e com o potencial de mudar a terapia de doença coronariana no futuro.
Outras drogas estão sendo investigadas tais como: estradiol34,35, tacrolimus36, everolimus37, com bons resultados iniciais e poderão brevemente estar disponíveis para utilização na prática diária, aumentando as opções de tratamento e contribuindo para diminuir o custo do procedimento.
Em conclusão, os resultados deste estudo demonstraram que os stents eluídos com batimastat nesta dose e com a cinética de liberação empregada não se mostrou eficiente para inibir a reestenose coronariana, mostrando inclusive taxas maiores do que as encontradas no estudo SOPHOS38, em que o stent BiodivYsio foi utilizado sem a eluição do medicamento.
Endereço para correspondência
Dr. José Armando Mangione
Rua Comendador Elias Jafet, 415
São Paulo - SP - Cep 05653-000
E-mail:
uci@uol.com.br
Recebido em 22/01/2004 - Aceito em 24/03/2004
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OBJECTIVE: The excellent results obtained with sirolimus (rapamicin)-eluting stents for preventing restenosis have motivated the evaluation of other substances with that property. Batimastat is a highly effective metalloproteinase enzyme blocker, with the potential to reduce the degradation of extracellular matrix and to inhibit the migration of smooth muscle cells, with the consequent capacity to control coronary restenosis. METHODS: From October 2001 to April 2002, 34 patients were prospectively selected with de novo lesions in a native coronary artery >50% and < 100%, which could be treated with stents of 3 to 4 mm in diameter and 18 mm in length. The primary outcome of the study was to assess the occurrence of major cardiovascular events (death of cardiac origin, acute myocardial infarction, and the need for revascularizing the target vessel) by the 30th day and fourth month; the secondary outcome of the study was to assess the rate of coronary restenosis 4 months after implantation and subacute thrombosis by the 30th day. RESULTS: The success rate of the procedure was 97.1%. The primary outcome occurred in 2.9% and 27.2% of the patients by the 30th day and fourth month, respectively. The binary restenosis rate on angiography was 39.3%. No episode of subacute thrombosis occurred. The comparative analysis between groups with and without restenosis showed no significant difference between both, except for late luminal loss, which was greater in G-I. CONCLUSION: Batimastat-eluting stents had a good safety profile; however, they were not effective in controlling coronary restenosis.
restenosiscoronary stentcoronary angioplasty
ORIGINAL ARTICLE
Batimastat-eluting stent implantation for the treatment of coronary artery disease. Results of the Brazilian pilot study
Cristiana Marques de Araujo; Gustavo Adolfo B. Rando; Maria Fernanda Z. Mauro; Salvador A. B. Cristóvão; Isaac S. Moscoso Sanchez; Adnan Ali Salman; João B. de Oliveira Neto; José Armando Mangione
São Paulo, SP - Brazil
Hospital Beneficência Portuguesa de São Paulo
Correspondence
ABSTRACT
OBJECTIVE: The excellent results obtained with sirolimus (rapamicin)-eluting stents for preventing restenosis have motivated the evaluation of other substances with that property. Batimastat is a highly effective metalloproteinase enzyme blocker, with the potential to reduce the degradation of extracellular matrix and to inhibit the migration of smooth muscle cells, with the consequent capacity to control coronary restenosis.
METHODS: From October 2001 to April 2002, 34 patients were prospectively selected with de novo lesions in a native coronary artery >50% and < 100%, which could be treated with stents of 3 to 4 mm in diameter and 18 mm in length. The primary outcome of the study was to assess the occurrence of major cardiovascular events (death of cardiac origin, acute myocardial infarction, and the need for revascularizing the target vessel) by the 30th day and fourth month; the secondary outcome of the study was to assess the rate of coronary restenosis 4 months after implantation and subacute thrombosis by the 30th day.
RESULTS: The success rate of the procedure was 97.1%. The primary outcome occurred in 2.9% and 27.2% of the patients by the 30th day and fourth month, respectively. The binary restenosis rate on angiography was 39.3%. No episode of subacute thrombosis occurred. The comparative analysis between groups with and without restenosis showed no significant difference between both, except for late luminal loss, which was greater in G-I.
CONCLUSION: Batimastat-eluting stents had a good safety profile; however, they were not effective in controlling coronary restenosis.
Coronary stents have proved to be better than balloon catheters, because they provide greater safety to the procedure, greater immediate luminal gain, and a smaller rate of restenosis 1,2. Despite these benefits, the incidence of coronary restenosis remains elevated, being > 30% in certain groups of patients 3-6.
The mechanisms involved in the appearance of restenosis are as follows: negative remodeling of the vessel, local formation of thrombus, neointimal proliferation, and excessive production of extracellular matrix 7-9.
An alteration in collagen metabolism has been shown to be probably involved in the restenosis process 10. The metalloproteinase enzyme (MP), which has the capacity to degrade collagen and other proteins, such as elastin and proteoglycans 11, facilitating the migration of smooth muscle cells, has an increased activity after injury with a balloon catheter 12-14. Thus, batimastat (BB94), a nonspecific inhibitor of that enzyme, is potentially useful in controlling coronary restenosis.
This study assessed the clinical and angiographic results of batimastat-eluting coronary stents in the treatment of coronary artery disease.
Methods
The stents used in this study were composed of stainless steel and coated with a phosphorylcholine polymer (PC) of the BiodivYsio Drug Delivery (DD) PC-Stent system of Biocompatibles, immersed in a solution containing batimastat at the dosage of 2.0 mg per mm of stent. The PC's coating has the capacity to absorb approximately 30 mg of the drug, a dose that proved effective in studies with animal models. In vitro studies have estimated the period of batimastat release at 24 days (T100%), while in vivo studies have estimated it at 28 days (T99%). The use of batimastat-eluting stents showed no evidence of systemic events in a 6-month follow-up in rats and rabbits receiving the drug intraperitoneally and undergoing balloon angioplasty.
The study protocol was approved by the committee on ethics in research, and all patients signed a written informed consent.
This study prospectively selected patients older than 18 years diagnosed with stable or unstable angina or documented silent ischemia, who had de novo lesions < 18 mm in length in a native coronary artery, and stenosis > 50% and < 100% in vessels whose diameters ranged from 3 to 4 mm. The left ventricular ejection fraction should be > 30%.
The exclusion criteria were as follows: life expectancy < 9 months; need for great surgical intervention during the 6 months studied; acute myocardial infarction within the preceding 30 days; serum creatinine values > 2.0 mg/dL; platelet count < 100,000 cells/mm3; insulin-dependent or noninsulin-dependent diabetic patients; restenotic lesions; lesions in saphenous or aorto-ostial bypass grafts; contraindications for the use of recommended medications; and, finally, patients who had participated in another investigational study with drugs or devices in the preceding 30 days.
The patients were medicated with 200 mg of acetylsalicylic acid and 75 mg of clopidogrel or 250 mg ticlopidine twice a day, initiated 3 days before the procedure. Aspirin was indefinitely maintained, and clopidogrel or ticlopidine was maintained for 3 months.
Initial laboratory assessment included the following measurements: hemoglobin, hematocrit, leukocytes, sodium, potassium, urea, creatinine, GOT, GPT, CK-MB. The 12-lead ECG was performed 24 hours before and every 8 hours after the procedure.
In the hemodynamic laboratory, after placement of the arterial introducer, heparin was administered aiming at maintaining ACT between 250 and 300 seconds. Nitroglycerin was injected intracoronarily at the dosage of 50 to 200 mg, and 2 orthogonal projections where the lesion to be treated was better visualized were filmed.
Stents were implanted after lesion predilation with a balloon catheter. Eleven-, 15-, and 18-mm-long and 3.0-, 3.5-, and 4.0-mm-diameter stents were used. We tried to maintain a balloon/artery ratio of 1:1.
The hemodynamic parameters analyzed by the investigators with digital quantitative angiography performed in a Phillips H 5000 device before and after stent implantation were as follows: minimum luminal diameter, reference diameter, percentage of stenosis, and late luminal loss. Success of the procedure was defined as a residual lesion < 10% and normal coronary flow obtainment (TIMI III).
After the procedure, the introducer was withdrawn when ACT was < 180 seconds. CK-MB measurements were taken every 8 hours. GP IIbIIIa inhibitor was not used.
Assessment of patients after 1 and 4 months included: anamnesis, physical examination, ECG, hemogram, and serum measurements of Na+, K+, urea, creatinine, GOT, and GPT.
Control coronary angiography was performed, on average, 4±1 months after stent implantation. Restenosis was considered a vessel lumen obstruction > 50%.
The primary outcome of the study was to assess the occurrence of major cardiac events (death of cardiac origin, acute myocardial infarction, and the need for revascularization of the target vessel) by the 30th day and the fourth month. Acute myocardial infarction was defined as "Q" when CKMB levels increased more than 2.5 times its normal value, and new Q waves appeared in at least 2 contiguous leads on an electrocardiogram. The acute myocardial infarction was defined as "non Q" when only the enzymatic elevation was observed.
The secondary outcomes included binary restenosis by the fourth month (stenosis > 50% of the luminal diameter) and incidence of subacute thrombosis of the stent by the 30th day.
The continuous variables were expressed as mean and standard deviation and analyzed by using the Student t test. The categorical variables were expressed as percentages and compared by using the Fisher exact test. The significance level of P<0.05 was adopted.
Results
From October 2001 to April 2002, 34 patients underwent batimastat-eluting stent implantation. Their basic clinical characteristics are shown in table I.
The procedure was successful in 33 (97.1%) patients. In one patient, progression of the stent was not possible due to marked tortuosity of the coronary artery. As the stent could not be implanted in the lesion, the patient was excluded from the study.
One (2.9%) patient had non-Q acute myocardial infarction in the in-hospital phase. Primary outcome of eligible patients on the fourth month was 27.2%, due exclusively to the need for revascularization of the target vessel. The major adverse cardiac events are shown in table II.
Subacute thrombosis of the stent was observed neither by the 30th day, nor after 4 months. Binary restenosis by the fourth month was observed in 13 of the 33 (39.3%) eligible patients.
Because of the high restenosis rate found, and in an attempt to identify a possible determining factor, the patients were divided into 2 groups as follows: G-I, patients with restenosis; and G-II, patients with no restenosis. However, the comparative analysis showed no differences between both groups regarding the major clinical and angiographic variables associated with the restenosis process (tab. III).
The results of digital quantitative angiography, including late luminal loss (LLL), defined as the difference between the minimum luminal diameter (MLD) immediately after stent implantation and MLD in the fourth month, are listed in table IV. Significant differences were observed only in the LLL, which were greater in G-I.
Discussion
Despite the use of stents, coronary restenosis has been the limiting factor of the percutaneous coronary revascularization success in the long run 1,2.
Some techniques, such as brachytherapy 15, rotational and directional atherectomy, and excimer laser 16-18, have been used to control restenosis, but with limited results.
Restenosis after stent implantation occurs as a result of the proliferation and migration of smooth muscle cells (SMC) to the vascular lumen and the excessive production of extracellular matrix19-22. The metalloproteinase (MP) enzymes involved in migration of the SMC and that belong to the group of proteinases may be subdivided into 3 classes: collagenoses, stromelysines, and gelatinases. Those enzymes can degrade the components of the extracellular matrix, including collagen, and the glycoprotein membrane, therefore, facilitating the migration of smooth muscle cells 23.
Batimastat is a low-molecular-weight mimetic peptide containing a hydroxamate group responsible by chelation of the zinc atom in the active site of the metalloproteinases, therefore inhibiting the action of that enzyme. It was initially used as an oncologic drug 24.
Studies with animals have shown that batimastat was effective in preventing both negative arterial remodeling and late luminal loss after balloon catheter angioplasty 25-27.
In this study, the use of batimastat-eluting stents proved to be safe; neither thrombosis of the stent, nor any detectable deleterious effect of the drug was observed. However, control neither of angiographic restenosis (38.2%), nor of the need for new revascularization (27.2%), was observed in the fourth month. Analysis of the subgroups of patients with and without restenosis showed no significant differences when comparing the clinical and angiographic variables.
Our results are in accordance with those of the unpublished European prospective nonrandomized multicentric study, Brillant I (batimastat anti-restenosis trial utilizing the BiodivYsio local drug delivery PC stent), which selected 173 patients with de novo lesions in native coronary arteries. Thirty days after implantation, 2 (1.2%) patients had non-Q acute myocardial infarction related to the procedure, and the 6-month angiographic control showed a binary restenosis rate of 25%.
Recent randomized studies 28-32 using sirolimus (rapamicin)- and paclitaxel-eluting stents, whose action mechanism differs from that of batimastat, had extremely favorable results, with a significant decrease in the restenosis rate and in the need for revascularization of the target lesion. The angiographic analysis and intracoronary ultrasound in one of those studies showed sustained suppression of neointimal proliferation one year after implantation33. Those findings have shown that drug-eluting stents are a safe and effective form of treatment, with the potential to change coronary artery disease therapy in the future.
Other drugs, such as stradiol34,35, tacrolimus36, and everolimus37, have been investigated with good initial results, and they may soon be available for daily use, enlarging the treatment options and contributing to reduce the cost of the procedure.
In conclusion, our results showed that batimastat-eluting stents, at the recommended dosage and with the release kinetic used, were not effective in inhibiting coronary restenosis; it even showed greater rates than those reported in the SOPHOS study 38, in which the BiodivYsio stent was used without drug elution.