Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC 89w4xqqQpKsWnHZhWtt3dQw S0066-782X2022005001216 S0066-782X2022000500894 abc.20210006 10.36660/abc.20210006 Artigo Original Desempenho Diagnóstico da Angiotomografia Computadorizada e da Avaliação Seriada de Troponina Cardíaca Sensível em Pacientes com Dor Torácica e Risco Intermediário para Eventos Cardiovasculares 0000-0002-3777-1947 Soeiro Alexandre de Matos 1 Biselli Bruno 1 Leal Tatiana C.A.T. 1 Bossa Aline Siqueira 1 César Maria Cristina 1 Jallad Sérgio 1 Goldstein Priscila Gherardi 1 Guimarães Patrícia Oliveira 1 Serrano Carlos Vicente Jr 1 Nomura Cesar Higa 1 Nakamura Débora 1 Rochitte Carlos Eduardo 1 Soares Paulo Rogério 1 Oliveira Múcio Tavares de Jr. 1 Instituto do Coração Faculdade de Medicina Universidade de São Paulo São Paulo SP Brasil Instituto do Coração (InCor) - Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP – Brasil Correspondência: Alexandre de Matos Soeiro • Instituto do Coração (InCor) - Faculdade de Medicina da Universidade de São Paulo - Av. Dr. Enéas de Carvalho Aguiar, 44. CEP 09541-001, São Paulo, SP – Brasil E-mail: alexandre.soeiro@bol.com.br

Contribuição dos autores

Concepção e desenho da pesquisa e Análise e interpretação dos dados: Soeiro AM; Obtenção de dados: Soeiro AM, Biselli B, Leal TCAT, Jallad S, Goldstein PG, Nomura CH, Nakamura D; Análise estatística: Soeiro AM, Bossa AS, Guimarães PO, César MC; Obtenção de financiamento: Soeiro AM, Nomura CH, Nakamura D, Rochitte CE; Redação do manuscrito: Soeiro AM, Bossa AS, Guimarães PO, Rochitte CE; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Serrano Jr CV, Soares PR, Oliveira Jr. MT.

Potencial conflito de interesse

Não há conflito com o presente artigo

 13 05 2022 05 2022 118 5 894 902 05 01 2021 30 05 2021 16 06 2021 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Resumo Fundamento

A angiotomografia coronária (ATC) tem sido usada para avaliação de dor torácica principalmente em pacientes de baixo risco, e poucos dados existem com pacientes em risco intermediário.

 Objetivo

Avaliar o desempenho de medidas seriadas de troponinas sensíveis e de ATC em pacientes de risco intermediário.

 Métodos

Um total de 100 pacientes com dor torácica, TIMI score 3 ou 4 e troponina negativa foram prospectivamente incluídos. Todos os pacientes foram submetidos à ATC, e aqueles com obstruções ≥ 50% foram encaminhados à cineangiocoronariografia. Pacientes com lesões < 50% recebiam alta hospitalar, receberam alta e foram contatados 30 dias depois por telefonema para avaliação dos desfechos clínicos. Os desfechos foram hospitalização, morte, e infarto agudo do miocárdio em 30 dias. A comparação entre os métodos foi realizada pelo teste de concordância kappa. O desempenho das medidas de troponina e da ATC na detecção de lesões coronárias significativas e desfechos clínicos foi calculado. Os resultados foram considerados estatisticamente significativos quando p <0,05.

 Resultados

Estenose coronária ≥ 50% na ATC foi encontrada em 38% dos pacientes e lesões coronárias significativas na angiografia coronária foram encontradas em 31 pacientes. Dois eventos clínicos foram observados. A análise de concordância Kappa mostrou baixa concordância entre as medidas de troponina e ATC na detecção de lesões coronárias significativas (kappa = 0,022, p = 0,78). O desempenho da ATC para detectar lesões coronárias significativas na angiografia coronária ou para prever eventos clínicos em 30 dias foi melhor que as medidas de troponina sensível (acurácia de 91% versus 60%).

 Conclusão

ATC teve melhor desempenho que as medidas seriadas de troponina na detecção de doença coronariana significativa em pacientes com dor torácica e risco intermediário para eventos cardiovasculares.

 Doenças Cardiovasculares Fatores de Risco Controle de Riscos Dor no Peito Tomografia Computadorizada por Imagem Raios X/métodos Troponina T Troponina I Angiotomografia Coronária/métodos Introdução

Dor torácica é uma das principais queixas nos serviços de emergências em todo o mundo. Grandes avanços foram feitos na prática clínica com o uso da angiotomografia coronária (ATC) e de troponina de alta sensibilidade no diagnóstico de síndrome coronária aguda (SCA).1 - 4

Os ensaios para detecção das troponinas T e I sensíveis e ultrassensíveis possuem limiares de detecção para lesão miocárdica 10 a 100 vezes menores que troponinas convencionais. Esses métodos têm melhor acurácia para o diagnóstico da SCA particularmente em pacientes com dor torácica de curta duração. A maioria dos estudos avaliando a acurácia de medidas repetidas de troponina em excluir SCA incluiu paciente com baixo risco de eventos cardiovasculares, como avaliado pelos escores de risco TIMI (trombólise no infarto do miocárdio), HEART e GRACE.5 , 6

A avaliação anatômica da árvore coronária usando ATC tem um papel importante na exclusão de SCA em pacientes com risco baixo a intermediário para doença arterial coronariana. Achados de ATC se correlacionaram bem com angiografia coronária invasiva em um estudo que incluiu 230 pacientes com dor torácica. Observaram-se alta sensibilidade e especificidade, e valores preditivos negativos quando as lesões eram maiores que 50% na ATC. No estudo ROMICAT-II, a estratégia com ATC foi tão segura como a estratégia convencional em termos de ocorrência de eventos cardiovasculares maiores em 28 dias. Assim, a ATC é um método não invasivo preciso para detecção de SCA em pacientes com dor torácica aguda. No entanto, sua validação foi feita principalmente em pacientes com perfis de baixo risco.7 O presente estudo teve como objetivo avaliar o desempenho da medida de troponina sensível e da ATC na detecção de lesões coronárias significativas na angiografia coronária e eventos clínicos em pacientes com dor torácica e risco intermediário para eventos cardiovasculares.

 Métodos Pacientes

O delineamento do estudo está apresentado na Figura 1 . Nós incluímos prospectivamente um total de 100 pacientes com dor torácica na admissão no serviço de emergência do Instituto do Coração (InCor) da Faculdade de Medicina da Universidade de São Paulo, Brasil. Foram incluídos pacientes com idade entre 40 e 75 anos, apresentando dor torácica com duração de pelo menos duas horas antes da chegada ao serviço, com um risco TIMI de 3 ou 4. Além disso, para a inclusão no estudo, um novo (ou provavelmente novo) desvio de ST de no mínimo 0,5 mV e/ou inversão de onda T de pelo menos 0,2 mV não deviam estar presentes no eletrocardiograma, e a primeira medida da troponina sensível deveria ser < percentil 99. Os critérios de exclusão foram gestantes, pacientes com instabilidade hemodinâmica, creatinina sérica > 1,5 mg/dL, intolerância a betabloqueadores, alergia a contraste com iodo, asma, trauma torácico nos últimos 30 dias, índice de massa corporal > 40 Kg/m2, história de revascularização (bypass) da artéria coronária, e lesão da artéria coronária ≥ 50%. O estudo foi aprovado pelo comitê de ética para estudos envolvendo seres humanos de nossa instituição, e todos os participantes assinaram o termo de consentimento. Não há conflito de interesse de nenhum autor.

– Delineamento e fluxograma do estudo; CABG: coronary artery bypass grafting (revascularização com enxerto de bypass da artéria coronária).

Troponina sensível

As amostras de sangue foram colhidas para a determinação de troponina I sensível em dois momentos: na admissão e três horas depois. Os investigadores desconheciam (cegos) essa segunda medida até o final do estudo. A determinação quantitativa de troponina I foi obtida por um imunoensaio tipo sanduíche realizado em três estágios, que utiliza a tecnologia de quimioluminescência direta e quantidades constantes de dois anticorpos monoclonais. Um reagente foi adicionado para detectar as ligações não específicas. Foi usado um kit comercial ADVIA Centaur® TnI-Ultra (Siemens Healthcare Diagnostics, Tarrytown, NY, EUA) em um equipamento automático do mesmo fabricante.

 Angiotomografia coronária

Após a inclusão no estudo, todos os pacientes foram submetidos à ATC. As imagens da ATC foram adquitidas usando um tomógrafo de 320 detectores (Aquilion ONE, Canon Medical Systems, Japão) e um protocolo padrão de escaneamento. Para atingir uma frequência cardíaca menor que 65 bpm durante a aquisição, os pacientes receberam metoprolol via oral (50-100 mg).

 Desfechos do estudo

Dois subgrupos foram estudados: a) pacientes com estenose coronária ≥ 50%; na ATC e que se submeteram à angiografia coronária, e b) pacientes cuja ATC não mostrou nenhuma lesão ou apresentou lesões < 50%, que receberam alta e foram contatados 30 dias depois por telefonema para avaliação dos desfechos clínicos. Lesões coronárias ≥ 70% na angiografia coronária foram consideradas significativas. Desfechos clínicos de interesse foram internação hospitalar, morte, e infarto do miocárdio.

 Análise estatística

Os dados foram analisados usando o programa SAS Statview 5.0. Análise descritiva das características basais foi realizada usando médias e desvios padrões quando se assumiu distribuição normal dos dados, e medianas e intervalos interquartis foram usados para dados sem distribuição normal. O teste de Kolmogorov-Smirnov foi usado para avaliar a normalidade da distribuição das variáveis contínuas. Comparações do tempo entre a chegada do paciente até a segunda medida de troponina e o tempo entre a chegada até ATC foram feitas pelo teste t não pareado.

Comparação entre os métodos diagnósticos foi realizada pelo teste de concordância Kappa. Nós comparamos a concordância entre as medidas de troponina e lesões coronárias significativas detectadas na angiografia coronária ou desfechos clínicos. Os resultados foram considerados estatisticamente significativos quando p<0,05. Calculamos a sensibilidade, a especificidade, valores preditivos positivos, valores preditivos negativos e acurácia da troponina sensível na detecção de lesões coronárias significativas no subgrupo que se submeteu à angiografia coronária (n=38). O desempenho foi calculado usando como resultado positivo uma concentração de troponina acima do percentil 99 na segunda medida, e a porcentagem de variação do método em relação à primeira medida, identificando-se o melhor ponto de corte pela curva ROC. Foi realizada uma análise complementar calculando-se a área sob a curva ROC e o escore de corte do aumento (%) nos níveis de troponina e lesões coronárias significativas detectadas por angiografia coronária e eventos clínicos ou somente por angiografia coronária.

Com base em um erro alfa de 0,05 e usando um poder de 0,8 para desfechos primários, nós calculamos que o número de indivíduos necessários para este estudo seria de 71 ou mais de acordo com estudos prévios, considerando a incidência de lesões coronárias com estenose ≥ 50% em risco intermediário (TIMI), uso de ATC em cerca de 24% dos pacientes,8 e diagnóstico de SCA pelo uso de troponina sensível em 11,4% dos pacientes submetidos a protocolos de dor torácica.6 Esses dados foram usados para avaliar a hipótese de uma diferença no desempenho entre esses métodos.

 Resultados População do estudo

Foram incluídos 100 pacientes consecutivos com dor torácica aguda e escores de risco TIMI de 3 ou 4. Características clínicas dos pacientes estão apresentadas na Tabela 1 . A inclusão e o acompanhamento dos pacientes foram realizados entre abril de 2016 e março de 2019 quando o tamanho amostral estimado previamente foi alcançado. A idade média dos pacientes foi 62,9 ± 10,5 anos e 58% eram do sexo feminino. A maioria da população (81%) do estudo tinha um risco TIMI de 3. Variações de 20% na troponina sensível foram observadas em 29 pacientes. Estenose coronária ≥ 50% na ATC foi observada em 38% dos pacientes (≥ 70% em 25 pacientes). Todos esses foram submetidos à angiografia coronária. Lesões coronárias significativas na angiografia coronária foram observadas em 31 pacientes.

– Características basais dos pacientes do estudo (n=100)
Características demográficas
Idade (anos) 62,9 (± 10,5)
Sexo masculino 42 (42%)
Comorbididades/fatores de risco
Hipertensão 87 (87%)
Diabetes 49 (49%)
Dislipidemia 79 (79%)
AVC /AIT prévio 5 (5%)
IAM prévio 18 (18%)
ICP prévia 16 (16%)
Tabagismo (atual ou prévio) 52 (52%)
História familiar de DAC 44 (44%)
Apresentação clínica
Pressão arterial sistólica (mmHg) 144,9 (± 23,7)
Frequência cardíaca (bpm) 71,9 (± 13,0)
Escore de risco TIMI de 3 81 (81%)
Escore de risco TIMI de 4 19 (19%)
Resultados laboratoriais
Hemoglobina (g/dL) 13,8 (± 1,5)
Creatinina (mg/dL) 0,92 (± 0,3)

AVC: acidente vascular cerebral; AIT: ataque isquêmico transitório, IAM: infarto agudo do miocárdio; DAC: doença arterial coronariana; ICP: intervenção coronária percutânea; TIMI: trombólise no infarto do miocárdio.

Eventos clínicos

Todos os pacientes estavam vivos no dia 30. Entre os pacientes que receberam alta sem angiografia coronária, foram observadas duas novas internações em 30 dias. Não houve ocorrência de morte ou infarto do miocárdio durante o acompanhamento.

 Análise de concordância na população geral Concordância entre troponina sensível e achados na ATC

Esta análise incluiu todos os pacientes do estudo (n=100). O teste de concordância kappa revelou uma leve concordância entre a segunda medida de troponina positiva e ATC na detecção de lesões coronárias significativas (kappa = 0,022; p = 0,78). O tempo decorrido entre a chegada do paciente e a segunda medida de troponina foi 312,08 ± 82,39 minutos versus 256,70 ± 83,91 minutos entre a chegada do paciente e a ATC (p < 0,0001). O tempo médio entre a ATC até a alta foi 6837,10 ± 8068,17 minutos, e todos os pacientes foram submetidos à angiografia coronária nas primeiras 24 horas de admissão. Cinco pacientes mostram um resultado positivo de troponina na segunda medida, mas receberam alta do hospital uma vez que não apresentaram lesões significativas na ATC.

 Concordância entre variações na troponina sensível e presença de lesões coronárias significativas na angiografia coronária ou ocorrência de eventos clínicos

Usando a presença de lesões coronárias significativas na angiografia coronária ou a ocorrência de eventos clínicos em 30 dias como o padrão ouro, o teste de concordância de kappa com a segunda medida de troponina positiva mostrou uma leve concordância (kappa = 0,002, p=0,979). O melhor ponto de corte para a variação de troponina do momento basal até a segunda medida quanto à presença de lesões coronárias significativas na angiografia coronária ou ocorrência de eventos clínicos em 30 dias foi de 20%. A área sob a curva ROC para a variação de 20% na troponina sensível foi 0,508 (IC95% 0,386 – 0,629) ( Figura 2 ).

– Curva ROC para a variação de 20% na troponina sensível e detecção de (A) lesões significativas na angiografia coronária ou ocorrência de eventos e (B) lesões significativas somente por angiografia coronária. AUC: área sob a curva; IC: intervalo de confiança.

Desempenho das medidas de troponina sensível ou lesões coronárias ≥ 50% na ATC na detecção de lesões coronárias importantes na angiografia coronária ou ocorrência de eventos clínicos

A sensibilidade, a especificidade, valor preditivo positivo, valor preditivo negativo, e acurácia: a) da segunda medida de troponina positiva; b) de variações de 20% nos níveis de troponina; e c) de lesões coronárias ≥ 50% na ATC para detecção de lesões ≥70% na angiografia coronária ou para predição de eventos clínicos em 30 dias estão apresentados na Tabela 2 . O desempenho geral da ATC para detectar os desfechos compostos foi melhor que o as concentrações de troponina.

– Desempenho da segunda medida de troponina positiva, variação de troponina de 20%, e lesões coronárias ≥ 50% na angiotomografia coronariana na detecção de lesões ≥ 70% na angiografia coronária ou na predição de eventos clínicos em 30 dias
Sensibilidade Especificidade Valor preditivo positivo Valor preditivo negativo Acurácia
Segundo resultado positivo de troponina 12,1% 88,1%% 33,3% 67,0% 63,0%
Variação na troponina ≥ 20% 33,3% 73,1% 37,9% 69,0% 60,0%
Lesões coronárias ≥ 50% na ATC 93,9% 89,6% 81,6% 96,8% 91,0%

ATC: angiotomografia computadorizada.

Análise de concordância em pacientes que se submeteram à angiografia coronária Concordância entre variações nas medidas de troponina e presença de lesões coronárias significativas na angiografia coronária

Esta análise incluiu somente os pacientes que se submeteram à angiografia coronária (n=38). Usando a presença de lesões coronárias significativas na angiografia coronária como padrão ouro, o teste de concordância kappa, com um resultado de troponina positivo na segunda medida, mostrou concordância leve (kappa = 0,006; p=0,922). O melhor ponto de corte para a variação de troponina quanto à presença de lesões coronárias significativas na angiografia coronária foi 20%. A área sob a curva ROC para a variação de 20% na troponina sensível foi 0,465 (IC95% 0,230 – 0,701) ( Figura 2 ).

 Desempenho das medidas de troponina sensível na detecção de lesões coronárias significativas na angiografia coronária

A sensibilidade, a especificidade, valor preditivo positivo, valor preditivo negativo, e acurácia: a) da segunda medida de troponina positiva; e b) de variações de 20% nos níveis de troponina na detecção de lesões ≥70% na angiografia coronária estão apresentados na Tabela 3 . Lesões coronárias importantes foram detectadas por angiografia coronária em 81,6% dos pacientes com lesões ≥ 50% na ATC. Essa proporção foi maior em comparação à troponina positiva na segunda medida ou suas variações. Elevada especificidade foi encontrada para resultado de troponina positivo na segunda medida, e variações de troponina de 20% - 85,7% e 71,4%, respectivamente.

– Desempenho do resultado positivo de troponina na segunda medida e da variação de troponina de 20% na detecção de lesões ≥ 70% na angiografia coronária
Sensibilidade Especificidade Valor preditivo positivo Valor preditivo negativo Acurácia
Segundo resultado positivo de troponina 12,9% 85,7%% 80% 18,2% 26,3%
Variação na troponina ≥ 20% 32,3% 71,4% 83,3% 19,2% 39,5%

Discussão

Nosso estudo apresenta o desempenho de medidas de troponina sensível ou da ATC na detecção de lesões coronárias significativas na angiografia coronária e/ou de eventos clínicos em pacientes com dor torácica e risco intermediário para eventos cardiovasculares. As medidas de troponina sensível mostraram fraca concordância com a detecção de lesões coronárias significativas na ATC o uma angiografia coronária, e com a ocorrência de eventos clínicos. A ATC foi superior à medida de troponina seriada, com melhor sensibilidade e valor preditivo negativo na detecção de doença arterial coronariana. Na prática clínica, os pacientes com dor torácica aguda normalmente recebem alta hospitalar de acordo com protolocos de dor torácica baseados somente na medida seriada de troponina. Nossos achados sugerem que pacientes em risco intermediário sem alterações isquêmicas no eletrocardiograma deveriam ser estratificados na admissão por ATC. Enfatizamos o fato de que a avaliação de eventos clínicos é secundária nesse contexto devido ao tamanho amostral e, assim, a concordância com o diagnóstico de doença coronariana foi nosso principal achado.

Não é incomum que pacientes com dor torácica sejam liberados das salas de emergências após avaliação inicial, e desenvolvam eventos isquêmicos nas horas seguintes. Esses indivíduos não recebem tratamento adequado em tempo apropriado,3 , 9 e estima-se que um em cada oito pacientes com angina instável sofre um infarto agudo do miocárdio (IAM) nas duas semanas seguintes. A mortalidade em pacientes com IAM admitidos ou erroneamente liberados dos departamentos de emergência varia entre 6% e 25%,3 o que leva a ações judiciais relacionadas a mal práticas.4 A incidência de eventos adversos em pacientes com escore de risco TIMI de 3 e 4 pode ser de até 11,1%.10 , 11 No entanto, estudos sobre estratégias diagnósticas para avaliação de dor torácica nessa população específica são escassos e derivam principalmente de análises secundárias.

Em 2006, Morris et al.,8 conduziram um estudo incluindo 1000 pacientes consecutivos com dor torácica aguda para investigar se o uso do escore de risco TIMI ajuda a predizer eventos combinados em 30 dias nessa população. A AUC foi 0,79 (IC 95%: 0,75 – 0,84), que mostrou uma boa aplicabilidade do escore. Desde então, estudos sugerem que pacientes com escore intermediário (3 e 4) deveriam ter os níveis de troponina medidos e submetidos a um teste isquêmico provocativo sempre que possível.8 , 12 Nossos resultados também sugerem que é uma melhor avaliação da presença de doença coronariana por meio de teste não invasivo além das medidas de troponina nessa população.

A realização de duas medidas seriadas de troponina sensível com intervalos curtos de tempo é uma boa abordagem para excluir SCAs em pacientes em baixo risco, o que permite a implementação de protocolos de avaliação rápida de dor torácica.5 , 6 , 13 , 14 - 31 Um estudo com pacientes com suspeita de SCA mostrou que um aumento de 20% nos níveis de troponina ultrassensível foi associado com maior probabilidade de SCA, com uma área sob a curva ROC de 0,785. Outros estudos relataram que variações na troponina T ultrassensível ao longo de algumas horas mostraram valores preditivos negativos mais altos.32 Contudo, vale mencionar que a população incluída na maioria dos estudos que mostraram uma acurácia muito alta da troponina ultrassensível era de baixo risco. Em nosso estudo, o valor preditivo negativo de uma variação de 20% na troponina sensível foi de 69%, um índice abaixo do apontado na literatura, o que pode ser justificado pela inclusão de pacientes em risco intermediário.

No estudo ROMICAT, o uso de ATC além do escore de risco TIMI aumentou a acurácia para predição de eventos.33 O estudo ROMICAT-II incluiu 1000 pacientes com dor torácica e primeiro resultado negativo de troponina, que foram randomizados para serem submetidos à ATC ou seguir o protocolo usual de dor torácica.34 Durante os dois anos de acompanhamento incluindo 333 pacientes, observou-se que a ATC apresentou poder preditivo elevado, com uma área sob a curva de 0,61 para eventos cardiovasculares combinados. Quando associada ao escore TIMI, a AUC alcançou 0,84. Nesse estudo, somente 5,4% dos pacientes apresentaram um escore TIMI entre 3 e 4.35 , 36 Nós acreditamos que nossos achados contribuem para esses resultados, uma vez que, em pacientes em risco intermediário, a ATC teve um desempenho melhor que as medidas seriadas de troponina sensível.

Em comparação aos protocolos de dor torácica tradicionais, a ATC não altera desfechos tais como morte ou IAM, embora reduza o período de internação e o número de internações desnecessárias.5 , 7 , 37 - 56 Litt et al.,7 mostraram que o uso de ATC, em comparação ao protocolo tradicional de avaliação de dor torácica, apresentou um excelente perfil de segurança em pacientes de baixo risco, pois não houve morte ou IAM em 30 dias. Ainda, a ATC possibilitou um maior número de altas hospitalares (49,6% vs. 22,7%) e menor permanência hospitalar (18 horas vs. 24,8 horas, p < 0,001). A concordância entre a ATC e os achados do cateterismo cardíaco também parece ser alta.44 , 45 No estudo ROMICAT-II, o tempo de internação foi 7,6 horas menor no grupo ATC em comparação ao grupo de cuidado usual. Em nosso estudo, nós observamos que o intervalo de tempo entre a chegada do paciente e a ATC foi aproximadamente uma hora menor que o intervalo entre a chegada do paciente e o resultado da segunda medida de troponina.

Algumas limitações devem ser consideradas na interpretação de nossos resultados. Este foi um estudo unicêntrico, com um tamanho amostral relativamente pequeno, e o número de eventos clínicos foi baixo. Assim, estudos maiores devem ser realizados para validar nossos achados. Pacientes com risco intermediário foram raramente representados em estudos anteriores investigando estratégias de avaliação de dor torácica. Nossos resultados sugerem que a ATC tem um papel importante na exclusão de SCAs nessa população, e acreditamos que esses achados contribuam para a literatura existente.

 Conclusões

A ATC apresentou melhor desempenho que as medidas de troponina sensível na detecção de doença coronariana importante em pacientes com dor torácica e risco intermediário para eventos cardiovasculares.

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Registro

NCT02772991 – CONECTTIN trial

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Fontes de financiamento:O presente estudo foi parcialmente financiado por Siemens Healthcare Diagnósticos e Canon Medical Systems.

 Original Article Diagnostic Performance of Coronary Tomography Angiography and Serial Measurements of Sensitive Cardiac Troponin in Patients With Chest Pain and Intermediate Risk for Cardiovascular Events 0000-0002-3777-1947 Soeiro Alexandre de Matos 1 Biselli Bruno 1 Leal Tatiana C.A.T. 1 Bossa Aline Siqueira 1 César Maria Cristina 1 Jallad Sérgio 1 Goldstein Priscila Gherardi 1 Guimarães Patrícia Oliveira 1 Serrano Carlos Vicente Jr 1 Nomura Cesar Higa 1 Nakamura Débora 1 Rochitte Carlos Eduardo 1 Soares Paulo Rogério 1 Oliveira Múcio Tavares de Jr. 1 Brazil Instituto do Coração (InCor) - Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP – Brazil Mailing Address: Alexandre de Matos Soeiro • Instituto do Coração (InCor) - Faculdade de Medicina da Universidade de São Paulo - Av. Dr. Enéas de Carvalho Aguiar, 44. Postal Code 09541-001, São Paulo, SP Brazil E-mail: alexandre.soeiro@bol.com.br

Author Contributions

Conception and design of the research and Analysis and interpretation of the data: Soeiro AM; Acquisition of data: Soeiro AM, Biselli B, Leal TCAT, Jallad S, Goldstein PG, Nomura CH, Nakamura D; Statistical analysis: Soeiro AM, Bossa AS, Guimarães PO, César MC; Obtaining financing: Soeiro AM, Nomura CH, Nakamura D, Rochitte CE; Writing of the manuscript: Soeiro AM, Bossa AS, Guimarães PO, Rochitte CE; Critical revision of the manuscript for intellectual content: Serrano Jr CV, Soares PR, Oliveira Jr. MT.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 Abstract Background

Coronary tomography angiography (CTA) has been mainly used for chest pain evaluation in low-risk patients, and few data exist regarding patients at intermediate risk.

 Objective

To evaluate the performance of serial measures of sensitive troponin and CTA in intermediate-risk patients.

 Methods

A total of 100 patients with chest pain, TIMI risk scores of 3 or 4, and negative troponin were prospectively included. All patients underwent CTA and those with coronary stenosis ≥ 50% were referred to invasive coronary angiography. Patients with coronary lesions <50% were discharged and contacted 30 days later by a telephone call to assess clinical outcomes. Outcomes were hospitalization, death, and myocardial infarction at 30 days. The comparison between methods was performed by Kappa agreement test. The performance of troponin measures and CTA for detecting significant coronary lesions and clinical outcomes was calculated. Results were considered statistically significant when p < 0.05.

 Results

Coronary stenosis ≥ 50% on CTA was found in 38% of patients and significant coronary lesions on coronary angiography were found in 31 patients. Two clinical events were observed. Kappa agreement analysis showed low agreement between troponin measures and CTA in the detection of significant coronary lesions (kappa = 0.022, p = 0.78). The performance of CTA for detecting significant coronary lesions on coronary angiography or for predicting clinical events at 30 days was better than sensitive troponin measures (accuracy of 91% versus 60%).

 Conclusion

CTA performed better than sensitive troponin measures in the detection of significant coronary disease in patients with chest pain and intermediate risk for cardiovascular events.

 Cardiovascular Diseases Risk Factors Risk Management Chest Pain Tomography, X-Ray Computed/methods Troponin T Troponin I Angiotomography Coronary/methods Introduction

Chest pain is one of the most common complaints in emergency rooms worldwide. Great advances in clinical practice have been achieved with the use of coronary tomography angiography (CTA) and high-sensitivity troponin in the diagnosis of acute coronary syndrome (ACS).1 - 4

Sensitive and high-sensitivity troponin T and I assays have detection thresholds for myocardial injury 10 to 100 times lower than conventional troponins. These assays have better accuracy for the diagnosis of ACS, particularly in patients with short-term chest pain. Most studies evaluating the accuracy of repeated troponin measures in ruling out ACS included patients with low risk for cardiovascular events as assessed by the TIMI (thrombolysis in myocardial infarction), HEART or GRACE risk scores.5 , 6

The anatomic evaluation of the coronary tree using CTA has a special role in the exclusion of ACS in patients at low-to-intermediate risk for coronary artery disease. CTA findings correlated well with invasive coronary angiography in a study that included 230 patients with chest pain. High sensitivity and specificity, and negative predictive values were seen when lesions greater than 50% were found in CTA. In the ROMICAT-II trial, the CTA strategy was as safe as the usual care strategy with respect to major cardiovascular events at 28 days. Therefore, CTA is an accurate non-invasive method for detecting ACS in patients with acute chest pain. However, its validation was mainly done in patients with low-risk profiles.7 The present study aims to evaluate the performance of sensitive troponin assays and CTA in the detection of significant coronary lesions on coronary angiography and clinical events in patients with chest pain and intermediate risk for cardiovascular events.

 Methods Study Patients

The study design is presented in Figure 1 . We prospectively included a total of 100 patients presenting with chest pain at the Emergency Department of the Heart Institute, InCor, University of Sao Paulo Medical School, Sao Paulo, Brazil. To be included, patients had to be aged between 40 and 75 years old, present with chest pain for at least two hours before arrival and have a TIMI risk score of 3 or 4. Additionally, a new or probable new deviation of ST of at least 0.5 mV and/or T wave inversion of at least 0.2 mV should not be present on the electrocardiogram, and their first measure of sensitive troponin should be < 99 percentile for trial inclusion. Exclusion criteria comprised: pregnancy, hemodynamic instability, serum creatinine > 1.5 mg/dL, intolerance to beta-blockers, allergy to iodine contrast, asthma, thoracic trauma in the previous 30 days, body mass index > 40 kg/m2, previous coronary artery bypass graft surgery, and known coronary lesion > 50%. Our Institutional Review Board for human subject studies approved this study, and all participants provided written informed consent prior to enrolment. There is no conflict of interest of any author.

– Study design and flowchart; CABG: coronary artery bypass grafting.

Sensitive troponin assay

Blood samples were drawn for sensitive troponin I measurement at two time points: at presentation and three hours later. The investigators were blinded to the second measurement until the end of the study period. Quantitative determination of troponin I was made by a sandwich-type immunoassay performed in three stages that uses direct chemiluminescence technology and constant quantities of two monoclonal antibodies. A reagent was added for detection of non-specific bindings. The commercial kit ADVIA Centaur®TnI-Ultra (Siemens Healthcare Diagnostics, Tarrytown, NY, USA) was used for this in an automated equipment of the same brand. The 99th percentile value was 0.04 ng/ml. Sensitive troponin assays was donated by Siemens Healthcare Diagnostics.

 Coronary tomography angiography

After trial inclusion, all patients underwent CTA. CTA images were acquired using a 320 detector-row scanner (Aquilion ONE, Canon Medical Systems, Japan) and a standard scanning protocol. To reach a heart rate lower than 65 bpm during acquisition, patients received oral metoprolol (50-100 mg).

 Study outcomes

Two subgroups were studied: a) patients who underwent coronary angiography when CTA showed coronary stenosis ≥ 50%; and b) patients whose CTA showed no lesions or lesions < 50% and were discharged and contacted 30 days later by a telephone call to assess clinical outcomes. Coronary lesions > 70% at coronary angiography were considered significant. Clinical outcomes of interest were hospitalization, death and myocardial infarction.

 Statistical analysis

Data were analyzed with the SAS Statview 5.0 software. Descriptive analysis of baseline characteristics was performed using means and standard deviations when a normal distribution of data was assumed, and median and interquartile intervals were used in non-normal distribution. The Kolmogorov-Smirnov test was used to assess the normality of distribution of continuous variables. Comparison of the time from patient arrival to the second troponin test versus time from patient arrival to CTA was made using the unpaired T-test.

The comparison between diagnostic methods was performed through Kappa agreement analysis. We compared the agreement between troponin measures and significant coronary lesions on coronary angiography or clinical outcomes. The results were considered statistically significant when p < 0.05. We calculated the sensitivity, specificity, positive predictive values, negative predictive values and accuracy of sensitive troponin or CTA in the detection of significant coronary lesions in coronary angiography or clinical events in the whole population (N=100). We also calculated the performance of troponin measures in the detection of significant coronary lesions in the subpopulation who underwent coronary angiography (N=38). Performance was calculated using as positivity a second troponin result above the 99th percentile and the percentage variation of the method in relation to the first measurement, identifying the best cutoff point by the ROC curve. Complementary analysis was made by calculating the area under the ROC curve and the cut-off score of troponin percentage increase and significant coronary lesions determined by coronary angiography and clinical events or by coronary angiography alone.

Based on an alpha error of 0.05 and using a power of 0.8 for primary outcomes, the number of individuals needed for this study was at least 71 according to previous studies, considering the incidence of coronary lesions with stenosis greater than or equal to 50% in patients at intermediate risk (TIMI risk), use of CTA in around 24% of patients,8 and diagnosis of ACS by the use of sensitive troponin in 11.4% of patients undergoing chest pain protocols.6 These data were used to evaluate the hypothesis of an existing difference in performance between these methods.

 Results Study population

A total of 100 patients with acute chest pain and TIMI risk scores of 3 or 4 were consecutively included. Clinical characteristics are presented in Table 1 . Inclusion and follow-up of patients were performed between April 2016 and March 2019 when the previously estimated sample size was reached. Overall, mean age was 62.9 ± 10.5 years and 58% were female. Most of the study population (81%) had a TIMI risk score of 3. Sensitive troponin variations of 20% were observed in 29 patients. Coronary stenosis ≥ 50% on CTA was found in 38% of patients (≥ 70% in 25 patients), and all of them underwent coronary angiography. Significant coronary lesions at coronary angiography were found in 31 patients.

– Baseline characteristics of study patients (n=100)
Demographic characteristics
Age (years) 62.9 (± 10.5)
Male sex 42 (42%)
Comorbidities/risk factors
Hypertension 87 (87%)
Diabetes 49 (49%)
Dyslipidemia 79 (79%)
Previous stroke/TIA 5 (5%)
Previous acute MI 18 (18%)
Previous PCI 16 (16%)
Smoking (current or previous) 52 (52%)
Family history of CAD 44 (44%)
Clinical presentation
Systolic blood pressure (mmHg) 144.9 (± 23.7)
Heart rate (bpm) 71.9 (± 13.0)
TIMI risk 3 81 (81%)
TIMI risk 4 19 (19%)
Laboratory results
Hemoglobin (g/dL) 13.8 (± 1.5)
Creatinine (mg/dL) 0.92 (± 0.3)

CAD: coronary artery disease; MI: myocardial infarction; PCI: percutaneous coronary intervention; SD: standard deviation; TIA: transient ischemic attack; TIMI: thrombolysis in myocardial infarction.

Clinical Events

All patients were alive at 30 days. In patients discharged without coronary angiography, two new hospitalizations were observed at 30 days. There were no observed deaths or myocardial infarctions in the follow-up.

 Agreement analysis in the overall population Agreement between sensitive troponin and CTA findings

This analysis included all patients of the study (N=100). The kappa agreement test showed a slight agreement between the second measure of positive troponin and CTA in the detection of significant coronary lesions (kappa = 0.022, p = 0.78). The time between patient arrival and the result of the second troponin was 312.08 ± 82.39 minutes versus 256.70 ± 83.91 minutes between patient arrival and CTA (p < 0.0001). The mean time between CTA to discharge was 6,837.10 ± 8,068.17 minutes, and all patients were submitted to coronary angiography in the first 24 hours of admission. Five patients showed a positive troponin result in the second measurement but were discharged as they did not present significant lesions on CTA.

 Agreement between sensitive troponin variations and the presence of significant coronary lesions at coronary angiography or the occurrence of clinical events

Using the presence of significant coronary lesions at coronary angiography or the occurrence of clinical events at 30 days as the gold standard, the Kappa agreement test with a positive troponin result in the second measurement showed a slight agreement (kappa = 0.002, p = 0.979). The best cut-off for troponin variation from baseline to the second measure regarding the presence of significant coronary lesions on coronary angiography or the occurrence of clinical events at 30 days was 20%. The area under the ROC curve for the 20% variation in sensitive troponin was 0.508 (CI 95%: 0.386 – 0.629) ( Figure 2 ).

– ROC curve for 20% variation in sensitive troponin and detection of (A) significant coronary lesions at coronary angiography and the occurrence of clinical events and (B) significant coronary lesions at coronary angiography only. AUC: area under curve; CI: confidence interval

Performance of sensitive troponin measures or coronary lesions ≥ 50% on CTA in the detection of significant coronary lesions on coronary angiography or the occurrence of clinical events

The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of a) a positive troponin result in the second measure; b) troponin variations of 20%; and c) coronary lesions ≥ 50% on CTA for detection of lesions ≥ 70% on coronary angiography or for prediction of clinical events at 30 days are presented in Table 2 . The overall performance of CTA for detecting the composed outcome was better than troponin measures.

– Performance of the second measure of positive troponin, troponin variation of 20%, and coronary lesions ≥ 50% at computed tomography angiography in detecting lesions ≥ 70% at coronary angiography or to predict clinical events at 30 days
Sensitivity Specificity Positive predictive value Negative predictive value Accuracy
Second positive troponin result 12.1% 88.1%% 33.3% 67.0% 63.0%
Troponin variation ≥ 20% 33.3% 73.1% 37.9% 69.0% 60.0%
Coronary lesions ≥ 50% at CTA 93.9% 89.6% 81.6% 96.8% 91.0%

CTA: computed tomography angiography.

Agreement analysis in patients who underwent coronary angiography Agreement between sensitive troponin variations and the presence of significant coronary lesions on coronary angiography

This analysis included only patients who underwent coronary angiography (N=38). Using the presence of significant coronary lesions on coronary angiography as the gold standard, the Kappa agreement test with a positive troponin result in the second measure showed slight agreement (kappa = 0.006, p = 0.922). The best cut-off for troponin variation regarding the presence of significant coronary lesions on coronary angiography was 20%. Area under ROC curve for the 20% variation in sensitive troponin was 0.465 (CI 95%: 0.230 – 0.701) ( Figure 2 ).

 Performance of sensitive troponin measures in the detection of significant coronary lesions on coronary angiography

The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of a) a positive troponin result in the second measure, and b) troponin variations of 20% in the detection of lesions ≥ 70% at coronary angiography are presented in Table 3 .z Significant coronary lesions were detected by coronary angiography in 81.6% of patients with lesions ≥ 50% on CTA. This proportion was higher than the one for positive troponin in the second measure or its variations. High specificities were found for a positive troponin result in the second measure and troponin variations of 20% - 85.7% and 71.4%, respectively.

– Performance of the second positive troponin result or troponin variation of 20% in detecting lesions ≥ 70% on coronary angiography
Sensitivity Specificity Positive predictive value Negative predictive value Accuracy
Second measure of positive troponin 12.9% 85.7%% 80% 18.2% 26.3%
Troponin variation ≥ 20% 32.3% 71.4% 83.3% 19.2% 39.5%

Discussion

Our study presents the performance of sensitive troponin measures or CTA in the detection of significant coronary lesions on coronary angiography and/or clinical events in patients with chest pain and intermediate risk for cardiovascular events. Sensitive troponin measures agreed poorly with the detection of significant coronary lesions on CTA or coronary angiography and with the occurrence of clinical events. CTA was superior to the measure of serial troponin, with better sensitivity and negative predictive value in the detection of coronary artery disease. In clinical practice, patients with acute chest pain are often discharged from the hospital according to chest pain protocols based only on the serial measurement of troponins. Our findings suggest that intermediate risk patients without ischemic alterations on the electrocardiogram should preferably be stratified at admission by CTA. This strategy may reduce the chance of erroneous hospital discharge in these situations. We emphasize the fact that the assessment of clinical events becomes secondary in this context due to the sample size, and hence the agreement with the diagnosis of coronary heart disease was the most relevant finding.

It is not uncommon that patients with chest pain are released from emergency rooms after initial evaluation and develop ischemic events in the following hours. These individuals do not receive an adequate treatment at the appropriate time.3 , 9 It is estimated that one in eight patients with unstable angina will suffer an acute myocardial infarction (AMI) in the next two weeks. Mortality in patients with AMI admitted or mistakenly released from the emergence departments ranges from 6% to 25%,3 which leads to lawsuits related to medical malpractice.4 The incidence of adverse outcomes in patients with TIMI risk score of 3 and 4 can reach up to 11.1%.10 , 11 However, studies exploring diagnostic strategies for chest pain evaluation in this specific population are scarce and come mostly from secondary analyses.

In 2006, Morris et al.8 conducted a study including 1,000 consecutive patients with acute chest pain to explore whether the use of TIMI risk score could help predict combined events at 30 days in this population. The AUC was 0.79 (CI 95%: 0.75 - 0.84), which showed a good applicability of the score. Since then, studies have suggested that patients with intermediate scores (3 and 4) should have troponin measured and a provocative ischemic test performed, when possible.8 , 12 Our findings also suggest that it is important to better evaluate the presence of coronary heart disease in this population using a non-invasive test in addition to troponin measures.

Using two serial measurements of sensitive troponin with short time intervals is a good approach to rule out acute coronary syndromes in low-risk patients, which allows the implementation of rapid chest pain assessment protocols.5 , 6 , 13 , 14 - 31 A study on patients with suspected ACS showed that a 20% increase in high-sensitivity troponin levels were associated with greater probability of ACS, with an area under the ROC curve of 0.785. Other studies observed that variations in high-sensitivity troponin T over a few hours also had high negative predictive values.32 However, it is worth noting that the population included in most studies that showed a very high accuracy of ultrasensitive troponin had a low risk. The negative predictive value of a 20% variation in sensitive troponin in our study was 69%, an index below what the literature has shown, which may be justified by the inclusion of patients at intermediate risk.

In ROMICAT study, the use of CTA in addition to the TIMI risk score increased the accuracy for event prediction.33 The ROMICAT-II study included 1000 patients with chest pain and first negative troponin result, who were randomized to perform CTA or follow the usual chest pain protocol.34 During the 2-year follow-up including 333 patients, it was observed that CTA had high predictive power with an AUC of 0.61 for combined cardiovascular events. When associated with the TIMI score, the AUC reached 0.84. In this study, only 5.4% of patients had TIMI risk between 3 and 4.35 , 36 We believe our findings add to these results as we showed that, in intermediate risk patients, CTA performed better than serial measures of sensitive troponin.

When compared to traditional chest pain protocols, CTA does not alter outcomes such as death or AMI, however it reduces length of hospital stay and the number of unnecessary hospital admissions.5 , 7 , 37 - 56 Litt et al.7 showed that the use of CTA, compared with the traditional chest pain evaluation protocol, had an excellent safety profile in low-risk patients, as no death or AMI occurred at 30 days. Additionally, CTA promoted a higher number of hospital discharges (49.6% vs. 22.7%) and shorter hospital stay (18 hours vs. 24.8 hours, p < 0.001). The agreement between CTA and cardiac catheterization findings also seems to be strong.44 , 45 In ROMICAT-II, hospital stay was 7.6 hours shorter in the CTA group compared to the usual care group. In our study, we also observed that the time interval between patient arrival and CTA was approximately one hour shorter than the time between patient arrival and the result of the second troponin.

Our results should be interpreted in light of some limitations. This was a single center study, with a relatively small sample size, and the number of clinical events was low. Therefore, larger studies should be performed to validate our findings. Intermediate risk patients were rarely represented in previous studies investigating strategies for chest pain evaluation. We believe our findings add to the existing literature and suggest that CTA may have an important role in ruling out acute coronary syndromes in this population.

 Conclusions

CTA performed better than sensitive troponin measures in the detection of significant coronary disease in patients with chest pain and intermediate risk for cardiovascular events.

Registration

NCT02772991 – CONECTTIN trial

Study Association

This study is not associated with any thesis or dissertation work.

Sources of Funding: This study was partially funded by Siemens Healthcare Diagnósticos and Canon Medical Systems.