abcArquivos Brasileiros de CardiologiaArq. Bras. Cardiol.0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBCSão Paulo, SP, BrazilM3NWBh9rbvH7DpmCZ75m4PM00006S0066-782X2004001300006S0066-782X(04)0830010610.1590/S0066-782X2004001300006Artigos OriginaisBraquiterapia intracoronariana. Tratamento da reestenose intra-stent com o sistema Beta-Cath: experiência inicial na América LatinaMuñozJuan SimonFeresFaustoAbizaidAlexandre C.MattosLuiz A.StaicoRodolfoCentemeroMarinellaTanajuraLuiz F.PintoIbraimSousaAmanda G.M.R.SousaJ. EduardoSão PauloSão PauloInstituto Dante Pazzanese de CardiologiaBrazil07200483157620607200316042003This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
OBJETIVO: Avaliar a segurança e eficácia da braquiterapia intracoronariana usando o sistema Beta-CathTM na prevenção da recorrência de restenose intra-stent (RIS), por meio da análise dos resultados clínicos, angiográficos e pelo ultra-som intracoronariano (USIC). MÉTODO: Foram submetidos à angioplastia com cateter-balão, seguida de beta-radiação intracoronariana com o sistema Beta-CathTM (90Sr/Y) 30 pacientes com RIS em artérias coronárias nativas e, posteriormente, avaliados. RESULTADOS: Incluíram-se lesões reestenóticas complexas (77% do tipo difuso-proliferativo) com extensão elevada (18,66±4,15 mm). O sucesso da braquiterapia foi de 100%. A dose média utilizada foi de 20,7±2,3 Gy, liberada em um período médio de 3,8±2,1 min. No seguimento tardio, o diâmetro luminal mínimo (DLM) intra-stent diminuiu discretamente (1,98±0,30mm para 1,84±0,39 aos 6 meses, p=0,13), com uma perda tardia de 0,14±0,18 mm. O DLM intra-segmentar foi significativamente menor do que o intra-stent (1,55±0,40mm vs.1,84±0,39mm, p=0,008), associando-se à perda tardia (0,40±0,29mm vs. 0,14±0,18mm; p=0,0001). No USIC, observou-se discreto incremento do tecido neointimal em 6,8±14,3 mm³ aos 6 meses (p=0,19) e a percentagem de obstrução volumétrica aumentou em 4,7±7,5%. A reestenose binária e a revascularização do vaso-alvo recorreram em 17% dos casos; houve 1 caso (3%) de oclusão tardia, associada a infarto do miocárdio. A sobrevida livre de eventos foi de 80%. CONCLUSÃO: O manejo da reestenose intra-stent com a beta-radiação intracoronariana mostrou-se procedimento seguro e eficaz, com alta taxa de sucesso imediato, representando uma opção terapêutica para a inibição da hiperplasia neointimal.
Braquiterapia intracoronariana. Tratamento da reestenose intra-stent com o sistema Beta-Cath. experiência inicial na América Latina
Juan Simon Muñoz; Fausto Feres; Alexandre C. Abizaid; Luiz A. Mattos; Rodolfo Staico; Marinella Centemero; Luiz F. Tanajura; Ibraim Pinto; Amanda G.M.R. Sousa; J. Eduardo Sousa
Instituto Dante Pazzanese de Cardiologia
São Paulo, SP
Endereço para correspondência
RESUMO
OBJETIVO: Avaliar a segurança e eficácia da braquiterapia intracoronariana usando o sistema Beta-CathTM na prevenção da recorrência de restenose intra-stent (RIS), por meio da análise dos resultados clínicos, angiográficos e pelo ultra-som intracoronariano (USIC).
MÉTODO: Foram submetidos à angioplastia com cateter-balão, seguida de beta-radiação intracoronariana com o sistema Beta-CathTM (90Sr/Y) 30 pacientes com RIS em artérias coronárias nativas e, posteriormente, avaliados.
RESULTADOS: Incluíram-se lesões reestenóticas complexas (77% do tipo difuso-proliferativo) com extensão elevada (18,66±4,15 mm). O sucesso da braquiterapia foi de 100%. A dose média utilizada foi de 20,7±2,3 Gy, liberada em um período médio de 3,8±2,1 min. No seguimento tardio, o diâmetro luminal mínimo (DLM) intra-stent diminuiu discretamente (1,98±0,30mm para 1,84±0,39 aos 6 meses, p=0,13), com uma perda tardia de 0,14±0,18 mm. O DLM intra-segmentar foi significativamente menor do que o intra-stent (1,55±0,40mm vs.1,84±0,39mm, p=0,008), associando-se à perda tardia (0,40±0,29mm vs. 0,14±0,18mm; p=0,0001). No USIC, observou-se discreto incremento do tecido neointimal em 6,8±14,3 mm3 aos 6 meses (p=0,19) e a percentagem de obstrução volumétrica aumentou em 4,7±7,5%. A reestenose binária e a revascularização do vaso-alvo recorreram em 17% dos casos; houve 1 caso (3%) de oclusão tardia, associada a infarto do miocárdio. A sobrevida livre de eventos foi de 80%.
CONCLUSÃO: O manejo da reestenose intra-stent com a beta-radiação intracoronariana mostrou-se procedimento seguro e eficaz, com alta taxa de sucesso imediato, representando uma opção terapêutica para a inibição da hiperplasia neointimal.
Palavra-chave: reestenose intra-stent, braquiterapia, sistema Beta-CathTM
Embora o implante de stent coronariano tenha-se tornado o procedimento percutâneo predominante de revascularização miocárdica nas últimas décadas, a presença de reestenose persiste como sua maior limitação e sua resolução constitui um dos maiores desafios da cardiologia intervencionista contemporânea 1. A recorrência de estenose após implante de stent coronariano varia entre 7 a 37% dos casos, dependendo das características clínicas do paciente, morfológicas da lesão e técnicas do procedimento2-4. A reestenose intra-stent é causada, principalmente, pela proliferação do tecido neo-intimal distribuído de forma focal ou difusa4,5. A incidência de eventos cardíacos maiores, em especial revascularização do vaso alvo, após tratamento convencional da reestenose intra-stent é elevada (30%-80%), independentemente da técnica e do instrumental utilizado6-9.
A braquiterapia é um tratamento promisor para redução de nova reestenose intra-stent, fundamentando-se no potencial de inibição que a radiação exerce sobre a proliferação das células musculares lisas, principal constituinte do tecido neo-intimal10. Atua por meio de um isótopo ativo, liberado para bloquear a fase mitótica do ciclo celular, causando uma dupla ruptura da cadeia do DNA da célula muscular lisa11,12.
Em estudos prévios, a angioplastia com cateter balão, seguida de radiação gama intracoronariana com irídio-1929,13,14 ou radiação beta-intracoronariana com estrôncio/ytrio 90 (Sr90/Y90)15 relatou redução da recorrência clínica e angiográfica nas recidivas difusas.
Nosso objetivo foi avaliar a segurança e viabilidade da braquiterapia intracoronariana após angioplastia com cateter balão, usando o sistema Beta-CathTM (Novoste Corp., Norcross, Georgia), bem como analisar os resultados clínicos, angiográficos e do ultra-som intracoronariano imediatamente após a intervenção e aos 180 dias do seguimento tardio.
Método
De agosto/2001 a setembro/2002 foram incluídos 30 pacientes com reestenose intra-stent, com antecedentes de implante de stent em artérias coronárias nativas, apresentando sintomas de angina ou isquemia silenciosa. Os critérios angiográficos de inclusão foram: estenose de > 50% no local da lesão intra-stent, diâmetro de referência entre 2,5mm e 4,0mm, extensão da lesão <25 mm e sucesso angiográfico (estenose residual <50%) imediatamente após angioplastia com balão. Excluíram-se os pacientes com disfunção ventricular esquerda importante (fração de ejeção <30%), infarto agudo do miocardio recente (<72h), evidência de trombos pela angiografia, presença de múltiplas lesões no vaso alvo e radioterapia torácica prévia. Durante o processo de inclusão, aqueles que não preencheram o criterio angiográfico de sucesso, não receberam tratamento intracoronariano com radiação beta, porém não foram excluídos do registro. Todos os pacientes foram previamente informados das características do procedimento e assinaram o termo de consentimento antes da inclusão.
Todos receberam ácido acetilsalicílico (325mg/dia) na véspera do procedimento. Administrou-se heparina intravenosa (100 UI/Kg) antes da intervenção, para manter o tempo de coagulação ativado > 300s. O regime terapêutico pós-intervenção consistiu de ácido acetilsalicílico e tienopiridínicos (ticlopidina:500mg/dia ou clopidogrel:75mg/dia) por no mínimo 4 meses.
Antes da intervenção, documentamos, angiograficamente (> 2 projeções), a extensão e a gravidade da lesão, assim como o diâmetro luminal nos segmentos de referência proximal e distal.
O sistema Beta-Cath™ disponível no nosso serviço (Novoste Corp., Norcross, Georgia) consiste de uma serie de 16 sementes cilíndricas independentes e radiopacas, que contém emissor beta puro estrôncio/ytrio 90 (90Sr/ 90Y), limitados por 2 marcadores de ouro radiopacos, separados por 40mm, constituindo a extensão da fonte. O perfil do cateter é de 5 French e o sistema da fonte não é centralizado. A liberação da dose ocorre a 2mm da fonte e é adaptada ao diâmetro do vaso15.
Após a angioplastia com cateter-balão, realizamos ultra-som intracoronariano com administração intracoronariana prévia de dinitrato de isosorbida (0,2 mg). Em seguida, avançamos o cateter liberador da fonte (beta-railTM) pré-montado sobre o fio-guia, colocado de forma "chis-distante", desde o centro do segmento que recebeu injúria até 7mm além de suas bordas, pela visão angiográfica dos marcadores da fonte (40mm). Após a retirada do fio-guia, a fonte é transportada hidraulicamente até a porção distal do cateter liberador e seu posicionamento sempre documentado angiograficamente. Imediatamente após o término do tempo de radiação calculado pelo oncologista (tab. I), a fonte é retirada e o cateter liberador (beta-railTM) removido. Repetimos a avaliação angiográfica nas mesmas projeções ortogonais e o ultra-som intracoronariano, finalizando assim a intervenção.
O sucesso angiográfico foi definido como a presença de estenose residual < 50%, sem intercorrência técnica durante o processo de radiação. O sucesso da braquiterapia foi caracterizado pela liberação completa (>90%) da dose de radiação estabelecida. O sucesso clínico foi definido como a ausência de eventos cardíacos maiores (óbito, infarto agudo do miocárdio, documentado por critérios eletrocardiográficos e enzimáticos [CK-MB > 10-13 U/L ou >5% da CK atividade e/ou elevação de troponina T-I] e revascularização do vaso alvo) durante a hospitalização. Definiu-se sucesso do procedimento após braquiterapia como a associação dos três anteriores.
A análise pela angiografia coronariana quantitativa foi realizada pelo método off-line usando o sistema QCA-CMSâ versão 5.1 (MEDIS - Medical Imaging Sistems Inc. - AJ Leiden, The Netherlands), no laboratório de dados e análises hemodinâmicas de nossa Instituição. Todas as angiografias foram realizadas após administração prévia de nitrato intracoronariano, calculando-se o diâmetro luminal mínimo, a percentagem de estenose (%DS) e o diâmetro de referência. O ganho luminal agudo foi determinado como o diâmetro luminal mínimo após o tratamento – diâmetro luminal mínimo inicial e a perda tardia foi calculada como o diâmetro luminal mínimo após tratamento – diâmetro luminal mínimo tardio. Angiograficamente, a definição de aneurisma se baseou na presença de diâmetro luminal no segmento tratado 25% maior do que o diâmetro da luz nos segmentos de referência adjacentes 16.
Ainda em relação ao diâmetro luminal mínimo, aferiram-se: 1) diâmetro luminal mínimo intra-stent: compreendido pelo segmento alvo - margem distal e proximal da lesão alvo; 2) diâmetro luminal mínimo intra-segmentar: compreendido pelo segmento que recebeu injúria, localizado entre as marcas proximal e distal do balão. Outros parâmetros avaliados foram o segmento irradiado, limitado pelas marcas proximal e distal do cateter de radiação e o segmento do vaso, limitado por duas referências anatômicas (ramos) nos quais incluíram-se o segmento alvo, segmento que recebeu injúria e o segmento irradiado. A aplicação desta classificação tem sido comumente utilizada em outros estudos clínicos17 (fig. 1).
O ultra-som intracoronariano foi realizado rotineiramente antes da intervenção, após a angioplastia com cateter balão, pós-braquiterapia e no seguimento tardío. Os estudos foram realizados pelo sistema CVIS (Boston Scientific Corp., Maple Grove, MN) incorporando um transdutor de 30 MHz com uma rotação de 1800rpm. Para obter a sequência de imagens, o transdutor de ultra-som foi tracionado por um equipamento automático à velocidade de 0,5mm/s. A reconstrução tridimensional da imagem foi processada por meio de um sistema computarizado (IndecSystems, Mountain View, CA).
As análises volumétricas foram calculadas a partir da fórmula de Simpson: Volume=S Área total do vaso, indentificada pela membrana elástica externa, stent, placa (membrana elástica externa – stent), hiperplasia neo-intimal (HNI) e lúmen. Para avaliar as mudanças volumétricas de cada elemento do vaso, aos 6 meses, o valor para cada medida foi calculado em delta (Dvolume), resultando da diferença entre os valores volumétricos obtidos no seguimento tardio e após intervenção. Da mesma forma, calculou-se a percentagem de obstrução volumétrica (%Obstrução= [volume HNI/volume stent] x 100), para os 3 períodos de avaliação (pré, pós-intervenção e aos 6 meses)17-18. Ao ultra-som intracoronariano, a formação de aneurisma foi definido como a presença de área luminal máxima no local tratado 50% maior do que a área luminal no segmento de referencia normal16.
A posição incompleta do stent foi definido como 1 ou mais hastes do stent claramente separadas da parede do vaso, com evidência ultra-sonográfica de fluxo sangüíneo atrás da haste19,20.
Aferiu-se a ocorrência de falha do vaso alvo –FVA- (óbito, infarto agudo do miocárdio, reestenose pelo critério binario [lesão >50%] e revascularização do vaso alvo) e a percentagem de obstrução volumétrica aos 180 dias após a braquiterapia.
A análise estatística foi realizada utilizando o programa SPSS versão 8.0.0 (SPSS Inc, Chicago, Illinois, USA). As variáveis continuas foram expressas como médias e desvio padrão, enquanto as categóricas foram apresentadas como freqüências absolutas e percentagens. As variáveis categóricas foram comparadas pelo teste do qui-quadrado com correção de continuidade ou pelo teste exato de Fisher, quando apropriado. A comparação entre as variáveis continuas foi feita por meio do teste t de "Student"com correção do test de Welch, quando necessário; medidas que não apresentassem distribuição normal foram analisadas pelo teste não-paramétrico de Mann-Whiteney. O nível de significância foi de p <0,05. As correlações entre as mudanças das varíaveis continuas foram realizadas pelo teste de correlação de Pearson.
Resultados
As características clínicas e angiográficas dos 30 pacientes incluídos encontram-se na tabela II. Dez (33%) pacientes apresentavam diabetes mellitus, 44% apresentavam angina estável, 4(13%) já tinham mais de uma intervenção para o tratamento de reestenose intra-stent e o tempo medio transcorrido desde a última intervenção foi de 7,3±2,3 meses. Predominaram as lesões complexas: 60% foram difusas, 17% proliferativas, 17% focais e 6% sob a forma de oclusão 3.
A angioplastia com cateter balão foi realizada em todas as lesões intra-stent. Em um dos procedimentos realizou-se aterectomia rotacional antes da dilatação com balão. No nosso estudo, não houve nenhum caso de estenose residual > 50% imediatamente após do procedimento. Observou-se uma dissecção tipo A (não fluxo-limitante), que não necessitou tratamento adicional. Em relação à braquiterapia, a aplicação foi realizada em 100% dos pacientes, sem apresentar alterações eletrocardiográficas sugestivas de isquemia miocárdica durante o procedimento. Foi utilizada a fonte de 40mm de extensão, com uma dosagem média de 20,7±2,3 Gy, aplicada em 3,8±2,1min.
A extensão do segmento alvo e o segmento que recebeu injúria foram de 18,6±4,1mm e 23,3±3,8mm, respectivamente. O diâmetro luminal mínimo intra-stent e o intra-segmentar aumentaram significativamente após intervenção (ambos p<0,0001), resultando em ganhos luminais agudos de 0,91±0,41mm e 0,85±0,40mm, respectivamente (tab. III). Aos 6 meses, o seguimento angiográfico foi realizado na totalidade dos casos. O diâmetro luminal mínimo intra-stent diminuiu de forma não significante (1,98±0,30mm para 1,84±0,39mm aos 6 meses; p=0,13), associando-se com uma perda tardia de 0,14±0,18mm. O diâmetro luminal mínimo intra-segmentar foi significativamente menor que o intra-stent aos 6 meses do tratamento (1,55±0,40mm versus 1,84±0,39mm, p=0,008), associando-se com maior perda tardia intra-segmentar (0,40±0,29mm versus 0,14±0,18mm; p=0,0001). Observaram-se cinco casos com reestenose angiográfica (17%) no seguimento tardio. Um paciente apresentou reestenose na extremidade distal do stent, outro, 2 lesões reestenóticas (intra-stent e em sua extremidade distal) e um terceiro apresentou reestenose no corpo da endoprótese. Dois casos apresentaram lesões estenóticas na extremidade proximal do segmento irradiado.
O ultra-som intracoronariano foi realizado em 87% (26/30) dos pacientes imediatamente após intervenção e aos 180 dias do seguimento tardio. Aos seis meses, o volume do tecido neointimal aumentou discretamente (DHNI=+6,75±14,3mm3; p=0,19), associando-se com uma redução não significativa do volume da luz intra-stent (Dlumen= -10,38±15,7mm3; p=0,18) (tab. IV). Houve um aumento quantitativo tanto do volume do vaso como da placa aos 6 meses, porém sem atingir significância estatística. O percentual de obstrução volumétrica foi reduzido de 61,1±8,1% para 26,8±7,2% após a intervenção (p<0,0001), elevando-se para 30,5±8,0%, aos 6 meses de seguimento clínico (D%Obstrução= +4,7±7,5%; p=0,09). Não foram observados aneurismas nem aposição incompleta tardia dos stents.
Aos 6 meses, o volume do vaso apresentou uma correlação positiva com as mudanças no volume da placa (r=0,963, p=0,01).
Não houve eventos cardíacos maiores durante o período de hospitalização (48,8±6,2h), nem foram registrados casos de trombose subaguda. Dos 30 casos analisados no seguimento clínico tardio houve 1 (3%) caso de trombose tardia (aos 46 dias após intervenção), que cursou com infarto agudo do miocárdio sem onda Q, e 5 casos de revascularização do vaso alvo (17%), dos quais 60% (3/5 casos) foram realizados por via percutânea. Em total o percentual de falha do vaso alvo foi de 20% nesta série, determinando uma sobrevida livre de eventos de 80% aos 6 meses de evolução clínica (tab. V).
Discussão
Em nosso estudo, a utilização da braquiterapia intracoronariana com o sistema Beta-Cath sugere ser um procedimento técnicamente seguro e viável, apresentando-se com resultados favoráveis no manejo da reestenose intra-stent21,22 aos seis meses seguimento clínico (fig. 2).
As reestenoses difusas e proliferativas, que representaram 77% dos nossos casos, são as de pior prognóstico após manejo percutâneo. No estudo de Mehran e cols.3, esses casos apresentaram nova recidiva em 50-80% dos casos após a angioplastia com cateter balão, contrastando com nossos resultados, onde a taxa de recidiva 6 meses após a braquiterapia foi de 17%, sugerindo a superioridade da braquiterapia sobre o tratamento convencional com balão e confirmando os resultados de investigações prévias 21-23.
A dosagem de radiação pré-estabelecida foi liberada totalmente em todas as lesões. Todos os pacientes receberam terapia antiplaquetária (ácido acetilsalicílico indefinidamente) e tienopiridínicos por um tempo mínimo de 4 meses; não ocorreram eventos cardíacos maiores durante o primeiro mês. Observou-se uma (3%) oclusão trombótica tardia, manifestada como infarto agudo do miocárdio sem onda Q, percentagem inferior do que a dos estudos WRIST, Long-WRIST, SVG-WRIST, GAMMA-1 e BETA-WRIST (9,1% aos 5 meses após o procedimento)24 e semelhante à dos estudos WRIST-PLUS25 e INHIBIT26. Apenas, uma dissecção (não fluxo-limitante) foi documentada no final do procedimento, sem requerer tratamento adicional, embora, tardiamente, ela tenha-se associado com uma das reestenoses observadas (extremidade distal do stent). O impacto no prognóstico das dissecções não fluxo-limitantes em pacientes que realizam braquiterapia ainda é desconhecido. Em duas séries de 16 pacientes cada uma, a presença de dissecção aguda após angioplastia com balão e beta-radiação persistiu em aproximadamente 50% dos pacientes aos 6 meses de seguimento clínico27,28, não apresentando associação na recorrência da angina ou com qualquer evento clínico em particular28.
Em relação aos eventos clínicos aqui documentados, nossos resultados foram similares aos encontrados em estudos prévios que utilizaram a beta-radiação intracoronariana, nos quais a incidência de eventos cardíacos maiores situou-se entre 18% e 33%: START(18%)29, INHIBIT(22%)26 e BETA-WRIST(33%)30. De forma análoga, a taxa de reestenose nesses estudos variou entre 15% e 29%22,26,30.
Quando é comparada a perda tardia entre os segmentos definidos angiograficamente, evidenciou-se que o diâmetro luminal mínimo intra-segmentar apresentou uma redução estatísticamente maior que o diâmetro luminal mínimo intra-stent, em decorrência da lesão causada pelo balão nos segmentos adjacentes ao stent. Esse fenômeno, descrito como "perda geográfica", observado em 13% dos nossos casos, é caracterizado principalmente por uma radiação inadequada no segmento que recebeu injúria31. Teoricamente, esta condição ocorre quando danificam-se as extremidades do segmento irradiado, nos quais, por definição, a dose emitida é muito baixa. Em uma análise restrospectiva31 de 50 pacientes consecutivos tratados com radiação beta após angioplastia com cateter balão ou stent, a incidência deste fenômeno foi de 32%.
A análise volumétrica pelo ultra-som intracoronariano mostrou que o crescimento do tecido neointimal foi discreto aos 6 meses do seguimento clínico, resultado semelhante ao de outros estudos32. Quanto ao crescimento do vaso (+21,4±27,8 mm3), observado aos 180 dias de tratamento, sugere que a radiação beta intracoronariana induziu um remodelamento positivo da pared arterial, caracterizado por um processo "acomodativo" da placa (correlação no aumento do Dmembrana elástica externa vs. Dplaca, r=0,963, p<0,01), preservando o volume da luz intra-stent. Dados experimentais têm sugerido que a radiação tem um efeito no remodelamento do vaso devido à modificação da resposta celular na camada adventícia33,34. O remodelamento positivo, acomodando o crescimento neo-intimal após 6 meses, tem sido demonstrado pelas análises ultrassonográficas35, considerando-se que outros estudos não relataram mudanças da área total do vaso ou da placa atrás do stent27.
Comparada com a radiação gama, a radiação beta apresenta menor profundidade de penetração, minimizando a exposição de radiação para pacientes e operadores e, conseqüentemente, menor requerimento de rádio-protecção. Porém, a queda rápida da dose de radiação beta dentro dos 2-5mm de profundidade está associada a uma liberação de dose menos homogênea32. Além disto, o "efeito de escudo" produzido pelas hastes do stent estaria associado a uma atenuação da dose de radiação através das suas hastes, maior do que 15%36. Quando foram comparados os resultados pelo ultra-som intracoronariano em dois grandes estudos13,15, observou-se que a radiação beta apresentou maior beneficio que a gama na prevenção da hiperplasia neo-intimal no interior do stent37,38.
Por fim, é importante ressaltar que a participação latino-americana no desenvolvimento desta inovadora opção terapéutica no manejo das lesões estenóticas, tem sido determinante. A primeira experiência clínica registrada com radiação em arterias coronárias humanas foi realizada por Condado e cols., na Venezuela39, que introduziram uma guia de192 iridio no interior de um cateter não centralizado na luz do vaso, por meio de um dispositivo de liberação manual, demonstrando assím, que a administração de radiação no interior da arteria coronária era factível e segura, embora com elevadas taxas de restenose observada nesta experiência inicial.
Este estudo consistiu de uma serie inicial e consecutiva de casos de reestenose intra-stent tratados no nosso serviço, com evolução clínica tardia limitada a 6 meses. Devido ao número relativamente pequeno de pacientes avaliados e pelo desenho do estudo (não aleatorizado, sem grupo controle, excluindo-se casos de maior complexidade), os resultados aqui documentados não devem ser extrapolados para a totalidade dos casos que cursam com esta afecção.
Apesar dos eventos clínicos observados no seguimento tardio não diferirem com os dos grandes estudos randomizados, não se pode afirmar que são clinicamente equivalentes, pois o tamanho da nossa amostra inviabiliza esta conclusão. Independentemente das observações já citadas, este registro permitiu-nos uma experiência clínica inicial satisfatória com o uso desta técnica. Os pacientes do estudo permanecem em evolução clínica, e novos casos são incorporados progressivamente.
Concluindo, o presente estudo sugere que a braquiterapia intracoronariana usando o sistema Beta-CathTM após angioplastia com cateter balão representa uma opção terapêutica segura e eficaz para pacientes com reestenose intra-stent. Desta forma, em casos com as características clínicas e angiográficas semelhantes às deste estudo, a braquiterapia intracoronariana pode ser considerada parte do arsenal terapêutico de escolha no tratamento desta afecção. Estes resultados iniciais somam-se aos de estudos clínicos randomizados previamente realizados, atestando a segurança, factibilidade e pertinência do método.
Endereço para correspondência
Juan Simon Muñoz
Av. Dante Pazzanese, 500
São Paulo – SP Cep 04012-909
E-mail:
jsmuro@hotmail.com
Recebido para Publicação 16/4/03
Aceito 6/7/03
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OBJECTIVE: To assess the safety and efficacy of intracoronary brachytherapy using the Beta-Cath systemTM for preventing recurrence of in-stent restenosis (ISR), by analyzing clinical, angiographic, and intracoronary ultrasound (ICUS) results. METHODS: This study assessed 30 patients with ISR in native coronary arteries who underwent balloon catheter angioplasty followed by intracoronary beta radiation with the Beta-Cath systemTM (90Sr/Y). RESULTS: The study comprised complex, extensive (18.66±4.15 mm) restenotic lesions, 77% of which were of the diffuse-proliferative type. Brachytherapy was successful in 100% of the cases. The mean radiation dose used was 20.7±2.3 Gy, released for a mean period of 3.8±2.1 minutes. On late follow-up, the in-stent minimum luminal diameter (MLD) slightly decreased (from 1.98±0.30 mm to 1.84±0.39 mm at 6 months; P=0.13), with a late loss of 0.14±0.18 mm. The intrasegmentary MLD was significantly smaller than the in-stent diameter (1.55±0.40 mm vs 1.84±0.39 mm; P=0.008), and was associated with a more significant late loss (0.40±0.29 mm vs 0.14±0.18 mm; P=0.0001). On ICUS, a mild increase of 6.8±14.3 mm³ in the neointimal tissue was observed at 6 months (P=0.19), and the percentage of volumetric obstruction increased by 4.7±7.5%. Binary restenosis and revascularization of the target vessel recurred in 17% of the cases; late occlusion associated with myocardial infarction occurred in 1 case (3%). Event-free survival was 80%. CONCLUSION: The management of in-stent restenosis with intracoronary beta radiation proved to be a safe and effective procedure, with a high rate of immediate success, representing a therapeutic option for inhibiting neointimal hyperplasia.
in-stent restenosisbrachytherapyBeta-Cath system
ORIGINAL ARTICLE
Intracoronary brachytherapy. Treatment of in-stent restenosis with the Beta-Cath system. Initial experience in Latin America
Juan Simon Muñoz; Fausto Feres; Alexandre C. Abizaid; Luiz A. Mattos; Rodolfo Staico; Marinella Centemero; Luiz F. Tanajura; Ibraim Pinto; Amanda G.M.R. Sousa; J. Eduardo Sousa
Instituto Dante Pazzanese de Cardiologia
São Paulo, SP - Brazil
Correspondence
OBJECTIVE: To assess the safety and efficacy of intracoronary brachytherapy using the Beta-Cath systemTM for preventing recurrence of in-stent restenosis (ISR), by analyzing clinical, angiographic, and intracoronary ultrasound (ICUS) results.
METHODS: This study assessed 30 patients with ISR in native coronary arteries who underwent balloon catheter angioplasty followed by intracoronary beta radiation with the Beta-Cath systemTM (90Sr/Y).
RESULTS: The study comprised complex, extensive (18.66±4.15 mm) restenotic lesions, 77% of which were of the diffuse-proliferative type. Brachytherapy was successful in 100% of the cases. The mean radiation dose used was 20.7±2.3 Gy, released for a mean period of 3.8±2.1 minutes. On late follow-up, the in-stent minimum luminal diameter (MLD) slightly decreased (from 1.98±0.30 mm to 1.84±0.39 mm at 6 months; P=0.13), with a late loss of 0.14±0.18 mm. The intrasegmentary MLD was significantly smaller than the in-stent diameter (1.55±0.40 mm vs 1.84±0.39 mm; P=0.008), and was associated with a more significant late loss (0.40±0.29 mm vs 0.14±0.18 mm; P=0.0001). On ICUS, a mild increase of 6.8±14.3 mm3 in the neointimal tissue was observed at 6 months (P=0.19), and the percentage of volumetric obstruction increased by 4.7±7.5%. Binary restenosis and revascularization of the target vessel recurred in 17% of the cases; late occlusion associated with myocardial infarction occurred in 1 case (3%). Event-free survival was 80%.
CONCLUSION: The management of in-stent restenosis with intracoronary beta radiation proved to be a safe and effective procedure, with a high rate of immediate success, representing a therapeutic option for inhibiting neointimal hyperplasia.
Key words: in-stent restenosis, brachytherapy, Beta-Cath system
Although implantation of coronary stents has become the most common percutaneous procedure for myocardial revascularization in recent decades, the presence of restenosis remains the major limitation of the procedure, and its solution is one of the greatest challenges in current interventional cardiology 1. Recurrence of stenosis after coronary stent implantation ranges from 7 to 37% of the cases, depending on the clinical characteristics of the patient, the morphological characteristics of the lesion, and the techniques of the procedure 2-4. In-stent restenosis is mainly caused by focal or diffuse proliferation of the neointimal tissue 4,5. The incidence of major cardiac events, especially revascularization of the target vessel, after conventional treatment of in-stent restenosis is high (30%-80%), independently of the technique and instrumentation used 6-9.
Brachytherapy is a promising treatment for the reduction of new in-stent restenosis, based on the potential of inhibition exerted by radiation on the proliferation of smooth muscle cells, which are the major constituents of neointimal tissue 10. It acts through an active isotope, released to block the mitotic phase of the cell cycle, causing a double rupture in the DNA strand of the smooth muscle cell 11,12.
Previous studies on balloon catheter angioplasty followed by intracoronary gamma-radiation treatment with iridium-192 9,13,14 or intracoronary beta radiation with strontium/yttrium 90 (Sr90/Y90) 15 reported a reduction in clinical and angiographic diffuse recurrences.
Our objective was to assess the safety and feasibility of intracoronary brachytherapy after balloon catheter angioplasty using the Beta-Cath systemTM (Novoste Corp., Norcross, Georgia, USA), as well as to analyze the clinical, angiographic, and intracoronary ultrasonographic results immediately after the intervention and at 180 days of late follow-up.
Methods
From August 2001 to September 2002, 30 patients with in-stent restenosis, antecedents of stent implantation in native coronary arteries, and symptoms of angina or silent ischemia were included in the study. The angiographic criteria of inclusion were as follows: stenosis > 50% at the site of the in-stent lesion; reference diameter between 2.5 mm and 4.0 mm; extension of the lesion < 25 mm; and angiographic success (residual stenosis < 50%) immediately after balloon angioplasty. Patients with the following characteristics were excluded from the study: significant left ventricular dysfunction (ejection fraction < 30%); recent acute myocardial infarction (< 72h); evidence of thrombi on angiography; presence of multiple lesions in the target vessel; and previous thoracic radiotherapy. During the process of inclusion, those who did not meet the angiographic criterion of success did not receive intracoronary treatment with beta radiation, but were not excluded from the records. All patients were previously informed about the characteristics of the procedure and signed a written informed consent prior to inclusion.
All patients received acetylsalicylic acid (325 mg/day) one day before the procedure. Intravenous heparin (100 UI/kg) was administered before the intervention to keep the activated coagulation time > 300 seconds. The therapeutic regimen after the intervention consisted of acetylsalicylic acid and thienopyridinic derivatives (ticlopidine: 500 mg/day or clopidogrel: 75 mg/day) for at least 4 months.
Prior to intervention, the extension and severity of the lesion, and the luminal diameter in the proximal and distal segments of reference were documented on angiography (> 2 projections).
The Beta-Cath systemTM available at our facility (Novoste Corp., Norcross, Georgia, USA) consists of a series of 16 independent, radiopaque, cylindrical seeds containing a pure beta strontium/yttrium 90 (90Sr/90Y) emitter, limited by 2 radiopaque gold markers positioned 40 mm apart, constituting the extension of the source. The catheter's profile is 5 French and the source system is not centralized. The release of the dose occurs 2 mm from the source, being adapted to the diameter of the vessel 15.
After balloon catheter angioplasty, intracoronary ultrasound with previous intracoronary administration of isosorbide dinitrate (0.2 mg) was performed. Then, the beta-railTM delivery catheter premounted on a guidewire was advanced and placed equidistantly from the center of the injured segment, with proximal and distal margins of at least 7 mm, through the angiographic vision of the markers of the source (40 mm). After removing the guidewire, the source was hydraulically transported to the distal portion of the delivery catheter, and its position was always angiographically documented. Immediately after finishing the radiation time calculated by the oncologist (tab. I), the source was withdrawn and the beta-railTM delivery catheter was removed. Angiographic assessment in the same orthogonal projections and intracoronary ultrasound were repeated, thus finishing the intervention.
Angiographic success was defined as the presence of residual stenosis < 50%, with no technical intercurrence during the radiation process. The success of brachytherapy was characterized by the complete delivery (> 90%) of the established radiation dose. Clinical success was defined as absence of major cardiac events [death, acute myocardial infarction documented according to electrocardiographic and enzymatic criteria (CK-MB > 10-13 U/L or > 5% of the CK activity, or elevation in troponin T-I, or both), and revascularization of the target vessel] during hospitalization. Success of the procedure after brachytherapy was defined as the association of the preceding 3 successes.
Analysis through quantitative coronary angiography was performed with the off-line method using the QCA-CMS systemâ version 5.1 (MEDIS - Medical Imaging Systems Inc. - AJ Leiden, The Netherlands) in the hemodynamic data and analyses laboratory of our institution. All angiographies were performed after previous intracoronary administration of nitrate, calculating the minimum luminal diameter, the percentage of stenosis (%DS), and the reference diameter. The acute luminal gain was determined by the subtraction of the initial minimum luminal diameter from the minimum luminal diameter after treatment, and the late loss was calculated by the subtraction of the late minimum luminal diameter from the minimum luminal diameter after treatment. Angiographically, the definition of aneurysm was based on a 25% increase in the luminal diameter of the segment treated compared with the luminal diameter of the adjacent segments of reference 16.
Still in regard to the minimum luminal diameter, the following parameters were assessed: 1) in-stent minimum luminal diameter, comprising the target segment and the distal and proximal margins of the lesion; 2) intrasegmentary minimum luminal diameter, comprising the injured segment located between the proximal and distal marks of the balloon. Other parameters assessed were the irradiated segment limited by the proximal and distal marks of the radiation catheter, and the segment of the vessel limited by 2 anatomic references (branches), in which the target segment, the injured segment, and the irradiated segment were included. This classification has been frequently used in other clinical studies 17 (fig. 1).
Intracoronary ultrasound was routinely performed before the intervention after balloon catheter angioplasty, after brachytherapy, and in late follow-up. The studies were performed with the CVIS system (Boston Scientific Corp., Maple Grove, MN, USA) incorporating a 30-MHz transducer with a rotation of 1800 rpm. For obtaining the sequence of images, the transducer of the ultrasound was pulled by an automated device at a velocity of 0.5 mm/s. The 3-dimensional reconstruction of the image was processed with a computed system (IndecSystems, Mountain View, CA, USA).
The volumetric analyses were calculated based on the formula of Simpson: Volume =S total area of the vessel, identified by the external elastic membrane, stent, plaque (external elastic membrane – stent), neointimal hyperplasia (NIH), and lumen. To assess the volumetric changes in each element of the vessel at 6 months, the value of each measure was calculated as delta (Dvolume), resulting from the difference between the volumetric values obtained in late follow-up and after the intervention. Similarly, the percentage of volumetric obstruction was calculated [% of obstruction = (NIH volume/stent volume) x 100] for the 3 periods assessed (pre-, postintervention, and at 6 months) 17,18. On intracoronary ultrasound, aneurysm formation was defined as a 50% increase in the maximum luminal area in the place treated compared with the luminal area in the normal segment of reference16.
Incomplete position of the stent was defined as the presence of 1 or more rods of the stent clearly separated from the wall of the vessel, with evident blood flow behind the rod on ultrasonography 19,20.
The occurrence of a defect in the target vessel (DTV) [death, acute myocardial infarction, restenosis according to the binary criterion (lesion > 50%), and revascularization of the target vessel] and the percentage of volumetric obstruction 180 days after brachytherapy were assessed.
The statistical analysis was performed using SPSS software, version 8.0 (SPSS Inc, Chicago, Illinois, USA). The continuous variables were expressed as means and standard deviation, while the categorical variables were presented as absolute frequencies and percentages. The categorical variables were compared using the chi-square test with continuity correction, or the Fisher exact test, when appropriate. The continuous variables were compared using the Student t test with correction using the Welch test, when necessary. Measures without a normal distribution were analyzed using the nonparametric Mann-Whitney test. The significance level adopted was P < 0.05. The correlations between the changes in continuous variables were performed with the Pearson correlation test.
Results
The clinical and angiographic characteristics of the 30 patients studied are shown in table II. Ten (33%) patients had diabetes mellitus, 44% had stable angina, 4 (13%) had already undergone more than 1 intervention for the treatment of in-stent restenosis, and the mean time since the last intervention was 7.3±2.3 months. Complex lesions predominated as follows: 60% were diffuse, 17% were proliferative, 17% were focal, and 6% were occlusions 3.
Balloon catheter angioplasty was performed in all in-stent lesions. In 1 of the procedures, rotational atherectomy was performed prior to balloon dilation. In our study, no case of residual stenosis > 50% was observed immediately after the procedure. One type A dissection (nonflow-limiting) was evidenced, but required no additional treatment. In regard to brachytherapy, it was used in 100% of the patients, with no electrocardiographic alterations suggestive of myocardial ischemia during the procedure. A 40-mm extension source was used, with a mean radiation dose of 20.7±2.3 Gy applied for 3.8±2.1 minutes.
The extensions of the target segment and the injured segment were 18.6±4.1 mm and 23.3±3.8 mm, respectively. The in-stent minimum luminal diameter and the intrasegmentary diameter significantly increased after the intervention (both P < 0.0001), resulting in acute luminal gains of 0.91±0.41 mm and 0.85±0.40 mm, respectively (tab. III). At 6 months, angiographic follow-up was performed in all cases. The in-stent minimum luminal diameter decreased nonsignificantly (1.98±0.30 mm to 1.84±0.39 mm at 6 months; P = 0.13), associated with a late loss of 0.14±0.18 mm. The intrasegmentary minimum luminal diameter was significantly smaller than the in-stent diameter at 6 months of treatment (1.55±0.40 mm versus 1.84±0.39 mm; P=0.008), associated with a greater late intrasegmentary loss (0.40±0.29 mm versus 0.14±0.18 mm; P=0.0001). Five cases of angiographic restenosis (17%) were observed in late follow-up. One patient had restenosis in the distal extremity of the stent; another had 2 restenotic lesions (in-stent and in its distal extremity); another third patient had restenosis in the body of the endoprosthesis. Two cases had stenotic lesions in the proximal extremity of the irradiated segment.
Intracoronary ultrasound was performed in 87% (26/30) of the patients immediately after the intervention and at 180 days of late follow-up. At 6 months, the neointimal tissue volume increased slightly (DNIH = +6.75±14.3 mm3; P = 0.19), and a nonsignificant reduction in the volume of the in-stent lumen was observed (Dlumen = -10.38±15.7 mm3; P = 0.18) (tab. IV). A quantitative increase both in the volume of the vessel and in the plaque was observed at 6 months, without reaching statistical significance. The percentage of volumetric obstruction was reduced from 61.1±8.1% to 26.8±7.2% after the intervention (P < 0.0001), but increased to 30.5±8.0% with 6 months of clinical follow-up (D% obstruction = +4.7±7.5%; P = 0.09). Neither aneurysms, nor late incomplete apposition of the stents was observed.
At 6 months, the volume of the vessel showed a positive correlation with the changes in the volume of plaque (r = 0.963; P = 0.01).
Neither major cardiac events, nor cases of subacute thrombosis, occurred during the hospitalization period (48.8±6.2 h). Of the 30 cases analyzed on late clinical follow-up, 1 (3%) had late thrombosis (46 days after intervention), which evolved with non-Q-wave acute myocardial infarction, and 5 had revascularization of the target vessel (17%), of which 60% (3/5 cases) were performed through a percutaneous route. The total percentage of defect in the target vessel in this series was 20%, resulting in an event-free survival of 80% at 6 months of clinical evolution (tab. V).
Discussion
In our study, the use of intracoronary brachytherapy with the Beta-Cath system suggests that it is a technically safe and feasible procedure, with favorable results in the management of in-stent restenosis 21,22 at 6 months of clinical follow-up (fig. 2).
Diffuse and proliferative restenoses, which represented 77% of our cases, have the worst prognosis after percutaneous management. In the study by Mehran et al 3, those cases had a new relapse in 50-80% of the cases after balloon catheter angioplasty, in contrast with our results, in which the relapse rate 6 months after brachytherapy was 17%. This suggests that brachytherapy is better than the conventional treatment with the balloon, confirming the results of previous investigations 21-23.
The pre-established radiation dose was totally delivered in all lesions. All patients received antiplatelet therapy (acetylsalicylic acid indefinitely) and thienopyridinic derivatives for at least 4 months; no major cardiac events occurred during the first month. One (3%) late thrombotic occlusion was observed, manifested as non-Q-wave acute myocardial infarction, a percentage lower than that reported in the WRIST, Long-WRIST, SVG-WRIST, GAMMA-1, and BETA-WRIST studies (9.1%, 5 months after the procedure) 24 and similar to that reported in the WRIST-PLUS 26 and INHIBIT studies 26. Only 1 nonflow-limiting dissection was documented at the end of the procedure; although it did not require additional treatment, it later was associated with 1 of the restenoses observed (distal extremity of the stent). The impact of nonflow-limiting dissections on the prognosis of patients undergoing brachytherapy is still unknown. In 2 series of 16 patients each, the presence of acute dissection after balloon angioplasty and beta radiation persisted in approximately 50% of the patients after 6 months of clinical follow-up 27,28, and it showed no association with the recurrence of angina or any other clinical event in particular 28.
In regard to the clinical events here documented, our results were similar to those found in previous studies using intracoronary beta radiation, in which the incidence of major cardiac events ranged from 18% to 33% as follows: START (18%) 29, INHIBIT (22%) 26, and BETA-WRIST (33%) 30. Similarly, the restenosis rate in these studies ranged from 15% to 29% 22,26,30.
Comparing the late loss in the segments angiographically defined, the intrasegmentary minimum luminal diameter showed a statistically greater reduction than the in-stent minimum luminal diameter, due to the lesion caused by the balloon in the segments adjacent to the stent. This phenomenon, reported as "geographical loss," observed in 13% of new cases, is mainly characterized by inadequate radiation in the injured segment 31. Theoretically, this condition occurs when the extremities of the irradiated segment are damaged, in which, by definition, the dose emitted is very low. In a retrospective analysis 31 of 50 consecutive patients treated with beta radiation after balloon catheter angioplasty or stent, the incidence of that phenomenon was 32%.
The volumetric analysis on intracoronary ultrasound showed that the growth of neointimal tissue was mild after 6 months of clinical follow-up, a result similar to that of other studies 32. The growth of the vessel (+21.4±27.8 mm3) observed after 180 days of treatment suggests that intracoronary beta radiation induced a positive remodeling of the arterial wall, characterized by an "accommodative" process of the plaque (correlation of the increase in the D external elastic membrane vs D plaque, r=0.963, P < 0.01), preserving the volume of the in-stent lumen. Experimental data have suggested that radiation has an effect on the remodeling of the vessel, due to the change in cell response in the adventitia layer 33,34. Positive remodeling, accommodating the neointimal growth after 6 months, has been shown on ultrasonographic analyses 35, considering that other studies did not report changes in the total area of the vessel or of the plaque behind the stent 27.
Compared with gamma radiation, beta radiation has a smaller depth of penetration, minimizing the exposure to radiation for patients and operators, requiring, therefore, less radioprotection. However, the rapid decrease in the dose of beta radiation within 2-5mm of depth is associated with a less homogeneous release of the dose 32. In addition, the "shield effect" produced by the rods of the stent could be associated with an attenuation in the radiation dose through its rods greater than 15% 36. Comparing the results on intracoronary ultrasound in 2 large studies 13,15, beta radiation showed a greater benefit than gamma radiation did in preventing neointimal hyperplasia inside the stent 37,38.
Finally, it is worth emphasizing that the Latin-American participation in the development of this innovative therapeutic option in managing stenotic lesions has been paramount. The first clinical experience with radiation in human coronary arteries was reported by Condado et al 39 in Venezuela. Those authors introduced an iridium 192 guide inside a catheter, which was not centralized in the lumen of a vessel, using a manually deployed device. They, therefore, showed that the administration of radiation inside the coronary artery was feasible and safe, although followed by high restenosis rates in that initial experience.
Our study consisted of an initial series of consecutive cases of in-stent restenosis treated at our facility, with a late clinical follow-up limited to 6 months. Due to the relatively reduced number of patients assessed and to the design of the study (nonrandomized, with no control group, and with the exclusion of more complex cases), the results here reported should not be extrapolated to all cases of this affliction.
Although the clinical events observed in the late follow-up of our patients did not differ from those reported in the large randomized studies, one cannot say they are clinically equivalent, because our sample size does not allow this conclusion. Independently of the already cited observations, this study provided a satisfactory initial clinical experience with the use of this technique. The patients studied continue to be followed up, and new cases have been progressively incorporated.
In conclusion, the present study suggests that intracoronary brachytherapy with the Beta-Cath systemTM after balloon catheter angioplasty is a safe and efficient therapeutic option for patients with in-stent restenosis. Therefore, in cases with clinical and angiographic characteristics similar to those in this study, intracoronary brachytherapy may be considered part of the therapeutic arsenal in the treatment of this affliction. These initial results add to those of previous randomized clinical studies, confirming the safety, feasibility, and pertinence of the method.