Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC mkFbYM5pKfvpFXvPZCGZwfC S0066-782X2023000600303 00303 10.36660/abc.20220658 Artigo Original Manejo Invasivo versus Conservador de Pacientes com IAMSSST Com Idade ≥ 75 Anos 0000-0003-0473-6077 Hu Mengjin Concepção e desenho da pesquisa, Obtenção de dados, Análise e interpretação dos dados, Análise estatística e Redação do manuscrito 1 2 Li Xiaosong 1 Yang Yuejin Concepção e desenho da pesquisa, Obtenção de dados, Análise e interpretação dos dados, Análise estatística e Redação do manuscrito,Obtenção de financiamento e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante 1 Fuwai Hospital State Key Laboratory of Cardiovascular Disease Beijing China Fuwai Hospital State Key Laboratory of Cardiovascular Disease, Beijing – China Xuanwu Hospital Capital Medical University Beijing China Xuanwu Hospital, Capital Medical University, Beijing – China Correspondência: Yuejin Yang • Fuwai Hospital State Key Laboratory of Cardiovascular Disease – State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular D State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular D Beijing 100037 – China E-mail: yangyjfw@126.com

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 26 05 2023 2023 120 6 e20220658 14 09 2022 11 01 2023 08 03 2023 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 eficiência do manejo invasivo em pacientes mais velhos (≥75 anos) com infarto do miocárdio sem supradesnivelamento do segmento ST (IAMSSST) permanece ambígua.

 Objetivos

Avaliar a eficiência do tratamento invasivo em pacientes idosos com IAMSSST com base em metanálise e análise sequencial de estudo (TSA).

 Métodos

Ensaios clínicos randomizados relevantes (ECR) e estudos observacionais foram incluídos. Os resultados primários foram morte por todas as causas, infarto do miocárdio, acidente vascular cerebral e hemorragia grave. O odd ratio agrupado (OR) e o intervalo de confiança de 95% (IC) foram calculados. P<0,05 foi considerado estatisticamente significativo.

 Resultados

Cinco ECRs e 22 estudos observacionais com 1.017.374 pacientes foram incluídos.Com base nos resultados de ECR e TSA, o manejo invasivo foi associado a menores riscos de infarto do miocárdio (OR: 0,51; 95% IC: 0,40-0,65; I2=0%), eventos cardiovasculares adversos maiores (MACE; OR: 0,61; 95% IC: 0,49-0,77; I2=27,0%) e revascularização (OR: 0,29; 95% IC: 0,15-0,55; I2=5,3%) em comparação com o tratamento conservador. A combinação de resultados de ECRs e estudos observacionais com ajuste multivariável mostrou riscos consistentemente menores de morte por todas as causas (OR: 0,57; IC 95%: 0,50-0,64; I2 = 86,4%), infarto do miocárdio (OR: 0,63; IC 95%: 0,56 -0,71; I2=0%), acidente vascular cerebral (OR: 0,59; 95% IC: 0,51-0,69; I2=0%) e MACE (OR: 0,64; 95% IC: 0,54-0,76; I2=43,4%). O melhor prognóstico associado ao manejo invasivo também foi observado em cenários do mundo real. No entanto, para pacientes com idade ≥85 anos, o manejo invasivo pode aumentar o risco de sangramento maior (OR: 2,68; IC 95%: 1,12-6,42; I2=0%).

 Conclusões

O manejo invasivo foi associado a menores riscos de infarto do miocárdio, MACE e revascularização em pacientes idosos com IAMSSST,no entanto, pode aumentar o risco de sangramento maior em pacientes com idade ≥85 anos.

 Idoso Infarto do Miocárdio Intervenção Coronária Percutânea Manejo Invasivo CIFMS 2017YFC1700503 2016-I2M-1-009 Scientific and Technological Department of China 2011BAI11B02 Fontes de financiamento: O presente estudo foi financiado por National Key Research and Development Program of China (2017YFC1700503), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-009), and the Twelfth Five-Year Planning Project of the Scientific and Technological Department of China (2011BAI11B02). Introdução

A idade avançada é um preditor crucial para resultados adversos em pacientes com síndrome coronariana aguda (SCA), pois foram observados maiores riscos de mortalidade a curto e longo prazo em pacientes mais velhos em comparação com os mais jovens.1 As diretrizes atuais enfatizam o tratamento intervencionista intensivo e precoce em pacientes com SCA, particularmente aqueles com riscos mais elevados de eventos de curto prazo.2,3 Os pacientes idosos representam um subgrupo conhecido por estar em risco aumentado e podem se beneficiar da revascularização na mesma extensão que os pacientes mais jovens.4 No entanto, dados do banco de dados National Inpatient Sample nos EUA sugeriram que a taxa de angiografia coronária invasiva no infarto do miocárdio sem supradesnivelamento do segmento ST (IAMSSST) diminuiu com a idade, com apenas 38% dos pacientes com 81 anos ou mais recebem angiografia coronária invasiva, em comparação com 78% dos pacientes com 60 anos ou menos,5 o que pode ser explicado pelas preocupações sobre um risco potencial aumentado de complicações após procedimentos de revascularização.6

Devido ao rápido crescimento da população idosa, a Organização Mundial da Saúde prevê que as mortes causadas por doenças coronarianas aumentarão em 120-137% durante as próximas duas décadas.7 Como é a principal causa de morte globalmente,8 determinar uma estratégia eficiente para o tratamento de pacientes idosos com IAMSSST é essencial.No entanto, os pacientes idosos estão sub-representados em ensaios clínicos randomizados (ECR), pois a idade média dos pacientes inscritos é inferior a 75 anos nos ECRs. Portanto, a generalização e a tradução dos resultados do ECR para pacientes mais velhos são limitadas.Enquanto isso,o número de ECRs com foco no manejo invasivo em pacientes idosos (≥75 anos) com IAMSSST é limitado e pode ter pouca potência para os resultados de interesse. Consequentemente, o manejo de pacientes idosos com IAMSSST continua sendo uma questão complicada.

Na presente metanálise, nosso objetivo foi avaliar os eventos clínicos relacionados ao manejo invasivo em pacientes com IAMST com idade ≥ 75 anos com base em ECRs e análise sequencial de ensaios (TSA).9A TSA ajuda a determinar se um ECR pode ser encerrado precocemente quando um valor de p é suficientemente pequeno para mostrar o efeito antecipado ou a futilidade.10 Enquanto isso, estudos observacionais também foram incluídos para nos ajudar a entender os cenários do mundo real na prática clínica.

 Métodos Desenho e seleção do estudo

ECRs e estudos observacionais comparando invasivo (intervenção coronária percutânea [ICP]/enxerto de revascularização do miocárdio [CRM]) versus tratamento conservador em pacientes idosos (≥75 anos) com IAMSSST e relatando resultados clínicos foram considerados. Estudos com foco em pacientes com angina instável ou IAMCSST foram excluídos. Estudos relevantes foram pesquisados PubMed, Web of Science, Biblioteca Cochrane, ClinicalTrials.gov e Google Scholar usando as seguintes palavras-chave: idosos, septuagenários, octogenários, nonagenários, infarto do miocárdio, infarto do miocárdio sem supradesnivelamento do segmento ST, IAMSSST, invasivo, agressivo, intervenção coronária percutânea, ICP, cirurgia de revascularização miocárdica, CRM, angioplastia, seletiva, conservadora, terapia médica, terapia medicamentosa desde a publicação até 9 de maio de 2022. Dois investigadores revisaram independentemente os títulos, resumos e estudos para determinar se eles atendiam à inclusão critério. Esta metanálise foi realizada de acordo com a declaração Preferred Reporting Items for Systematic Review and Meta-Analysis,11 e foi registrada no International Prospective Register of Systematic Reviews (CRD42022301170).

 Resultados

Os desfechos primários foram morte por todas as causas, infarto do miocárdio (IM), acidente vascular cerebral e sangramento maior, de acordo com a definição de cada estudo individual. O desfecho secundário incluiu eventos cardiovasculares adversos maiores (MACE), morte cardíaca, revascularização e reinternação.

Análise TSA

Na análise TSA, os ECRs são incluídos em ordem cronológica e a análise é realizada de forma repetitiva e cumulativa após a realização de novos ECRs. TSA também fornece um nível de significância ajustado para controlar os erros Tipo I e II.12 TSA ajuda a determinar se um ECR pode ser encerrado antecipadamente quando um valor p é suficientemente pequeno para mostrar o efeito antecipado ou futilidade.10 Quando a curva Z cumulativa cruza o limites de monitoramento sequencial de teste, indica que a análise é válida para benefício. A TSA foi conduzida pelo software TSA, versão 0.9 beta (Copenhagen Trial Unit, Copenhagen, Dinamarca).

 Análise estatística

Dados brutos e não ajustados de ECRs incluídos e estudos observacionais foram extraídos. O odd ratio agrupado (OR) e o intervalo de confiança de 95% (IC) foram calculados usando modelos de efeito aleatório (DerSimonian e Laird). Além disso, devido ao número limitado de ECRs, resultados combinados de ECRs e estudos observacionais com ajuste multivariável também foram calculados. A análise de subgrupo foi realizada de acordo com a idade dos pacientes (≥75, ≥80 e ≥85). A análise de meta-regressão foi realizada para explorar ainda mais a heterogeneidade dos efeitos do tratamento, estratificando por idade e percentual de revascularização. Além disso, uma análise de exclusão também foi realizada para avaliar se um único estudo influenciou os resultados agrupados. O viés de publicação foi avaliado por inspeção visual de gráficos de funil e Teste de Begg. A heterogeneidade entre os estudos foi avaliada usando a estatística12,13 com I2 <25%, 25%-75% e >75% considerados baixo, moderado e alto, respectivamente. P<0,05 foi considerado estatisticamente significativo. Todas as análises estatísticas foram realizadas usando Stata 16 SE (StataCorp, College Station, TX).

 Resultados Características iniciais dos estudos incluídos

Conforme mostrado na Figura 1, de 5.546 estudos potencialmente relevantes, cinco ECRs14-18e 22 estudos observacionais19-40preencheram os critérios de inclusão. Um total de 178.860 (17,6%) pacientes foram tratados de forma invasiva, enquanto 838.514 (82,4%) foram tratados de forma conservadora. As principais características dos estudos e pacientes incluídos são apresentadas na Tabela 1.

– Diagrama PRISMA para Inclusão no Estudo. IAMCSST: infarto do miocárdio com supradesnivelamento do segmento ST.

– Características iniciais dos estudos incluídos
Estudo, ano Design de estudo Número de pacientes Definição de MACE Anos de idade) Masc. (%) Hipertensão (%) Hiperlipidemia (%) Diabetes (%) FEVE (%) Insuficiência cardíaca Insuficiência renal (%) Acesso radial (%) Antagonista da GP IIb/IIIa (%) Tempo de acompanhamento
TÁTICAS–TIMI 14,18 2004 ECR, multicêntrico 139/139 Morte cardíaca, IM ou necessidade de revascularização coronária não planejada N / D N / D N / D N / D N / D N / D N / D N / D N / D N / D 6 meses
Registro ACOS19 2007 Prospectivo, multicêntrico, observacional 1005/931 Morte e IM 78,7/82,2 51,7/41,4 79,2/74,8 62,3/49,7 33,5/39,4 N / D N / D 4.5/9.2 N / D N / D 12 meses
GRACE, 20 2008 Prospectivo, multicêntrico, observacional 620/2390 Morte, IM e AVC 85 48 73 39 26 N / D 27 11 N / D 15 6 meses
LOURENÇO,21 2010 Prospectivo, de centro único, observacional 91/216 Morte, morte cardiovascular, infarto do miocárdio, readmissão por angina instável e ICP não programada 79,8/81,4 63,7/50,9 80,2/74,9 60,7/62,5 26,4/30,8 N / D 3,8/10,2 N / D N / D 39,6/30,1 18 meses
FIR,15 2012 ECR, multicêntrico 437/402 IM e infarto do miocárdio 76 63,5 39,0 15.7 14.8 N / D N / D N / D N / D N / D 5 anos
FAST-MI,22 2012 Prospectivo, multicêntrico, observacional 412/246 N / D N / D N / D N / D N / D N / D N / D N / D N / D N / D N / D 3 anos
Italian Elderly ACS,16 2012 ECR, multicêntrico, 154/159 Morte por todas as causas, IM, AVC, e repetir internação 81,8/81,8 49/51 92/85 44/50 38/41 49/48 10/8.9 N / D 71/78 17/6 1 ano
ACSIS,23 2013 Prospectivo, multicêntrico, observacional 192/158 N / D 83 54 81 N / D 36 N / D 29 N / D N / D 6 1 ano
PL-ACS,242013 Prospectivo, multicêntrico, observacional 3288/10419 N / D 82/83 47,5/37,2 78,6/71,0 36,3/32,6 30,9/30,5 N / D N / D N / D N / D 4,6/0,1 2 anos
Kolte,25 2013 Retrospectivo, multicêntrico, observacional 161640/ 806902 N / D 83,9/86,2 48.2/41 72/62,5 51,9/33,7 28.0/29.1 N / D 34,8/55 16,8/22,8 N / D N / D Hospitalização
MONICA/KORA MI,26 2016 Prospectivo, multicêntrico, observacional 360/286 N / D 78/80 55,8/46/5 90,6/85,0 47,8/33,6 40,0/50,0 N / D N / D 24,7/36,4 N / D 24,7/4,9 28 dias
Conti,27 2016 Prospectivo, de centro único, observacional 301/152 Morte e IM 80 52,8/34,2 91,7/90,8 53,5/38,8 41.2/42.1 N / D N / D N / D N / D N / D 1 ano
HUMIR,282016 Prospectivo, multicêntrico, observacional 654 N / D N / D N / D N / D N / D N / D N / D N / D N / D N / D N / D 1 ano
Estudo After Eighty, 17 2016 ECR, multicêntrico 229/228 IM, necessidade de revascularização urgente, AVC e morte 84,7/84,9 55/44 57/61 N / D 20/14 N / D N / D N / D 90 N / D 3 anos
AMI-OPTIMA,40 2018 Subanálise de ECR, multicêntrico 548/610 N / D 85,6 47,6 78,3 53.4 31.2 N / D N / D 25.3 N / D N / D no Hospital
Liu,29 2018 Retrospectivo, de centro único, observacional 319 N / D N / D N / D N / D N / D N / D N / D N / D N / D N / D N / D 32,3 meses
LONGEVO-SCA,30 2018 Prospectivo, multicêntrico, observacional 407/124 Morte cardíaca, IM ou necessidade de revascularização coronária não planejada 83,6/86,7 64,7/50,0 84.0/87.1 N / D 39,0/42,7 53,2/53,7 14,3/29,0 N / D 84,5 N / D 6 meses
SWEDE HEART, 31 2018 Prospectivo, multicêntrico, observacional 4158/9696 N / D 84/86 57/46 63/63 N / D N / D N / D N / D N / D N / D N / D 5 anos
Kvakkestad,32 2019 Prospectivo, centro único, observacional 1200/864 N / D 80,4/86,4 60,6/39,7 50,1/48,4 N / D 20,7/19,0 N / D N / D N / D N / D N / D 7 anos
CAMI,33 2019 Prospectivo, multicêntrico, observacional 551/1900 Morte por todas as causas, IM e AVC 80,37 54,6 65,8 6.0 25,0 53,41 10.8 N / D N / D 10.8 No Hospital
Sui,34 2019 Retrospectivo, de centro único, observacional 139/93 N / D 83,4/84,8 52,5/57,0 66,9/68,8 93,5/90,3 40,3/34,4 51,9/45,3 N / D 23,7/36,6 N / D N / D 4 anos
Gonçalves,35 2020 Retrospectivo, multicêntrico, observacional 237/87 N / D 87/87 54,0/60,9 86,4/90,7 58,8/59,5 29,6/43,7 52/49 N / D 14.1/9.4 64,5/80,7 N / D 1 ano
Hirlekar,182020 ECR, multicêntrico 93/93 IM, revascularização urgente, mortalidade por todas as causas, AVC e hospitalização recorrente 84/84 50,5/59,1 59,1/63,4 22,6/17,2 17,2/21,5 55/54 10,8/8,6 63,4/75,3 N / D N / D 1 ano
SENIOR-NSTEMI,36 2020 Prospectivo, multicêntrico, observacional 655/845 N / D 85,3/86,9 60/50 62/54 42/30 26/24 N / D 17/24 7/8 N / D N / D 4,8 anos
Nguyen,372020 Prospectivo, multicêntrico, observacional 42/78 Mortalidade por todas as causas, IM e AVC 84.1/85.2 59,5/44,9 97,6/85,9 N / D 21.4/23.1 N / D 21,4/48,7 N / D N / D N / D 3 meses
Phan,38 2020 Retrospectivo, de centro único, observacional 890/543 N / D 83,3/83,3 64,6/67,4 91.9/94.1 93,0/93,6 49,1/56,9 51/45 44,5/64,8 58,1/63,9 N / D N / D 2,6 anos
Kunniardy,39 2021 Retrospectivo, de centro único, observacional 99/953 N / D N / D N / D N / D N / D N / D N / D N / D N / D N / D N / D 1,3 anos

Todos os estudos adotaram 5% de significância estatística. Os dados foram relatados como manejo invasivo/conservador. CRM: cirurgia de revascularização miocárdica; MACE: eventos cardiovasculares adversos maiores; FEVE: fração de ejeção do ventrículo esquerdo; IM: infarto do miocárdio; ND: não disponível; ICP: intervenção coronária percutânea; ECR: ensaio controlado randomizado; AVC: acidente vascular cerebral.

 Resultados clínicos baseados em ECRs

Era óbvio que o manejo invasivo estava associado a menores riscos de infarto do miocárdio (OR: 0,51; IC 95%: 0,40-0,65; I2=0%; Figura 2B), sem influência significativa na morte por todas as causas (Figura 2A), AVC (acidente vascular cerebral) (Figura 2C) ou sangramento maior (Figura 2D). Para todas as causas de morte (Figura 3A), a curva Z cumulativa não ultrapassou os limites estatísticos convencionais, os limites de monitoramento sequencial do ensaio ou o tamanho de informação necessário ajustado à diversidade, indicando que não foi obtida informação suficiente. A curva Z cumulativa cruzou os limites de monitoramento sequencial do teste para benefício em IM (Figura 3B), indicando que informações suficientes foram obtidas. Para AVC (Figura 3C) e sangramento maior (Figura 3D), os resultados da TSA foram ignorados devido à pouca informação utilizada.

– Comparações de resultados primários com base em ensaios controlados randomizados. A) morte por todas as causas; B) infarto do miocárdio; C) acidente vascular cerebral; D) hemorragia grave.

– Resultados TSA para resultados primários. A) morte por todas as causas; B) infarto do miocárdio; C) acidente vascular cerebral; D) hemorragia grave. IM: infarto do miocárdio; TSA: análise sequencial do ensaio. A linha azul representa o Z-score cumulativo da metanálise. As linhas transversais vermelhas representam os limites estatísticos convencionais de p = 0,05. As linhas vermelhas inclinadas para dentro representam os limites de monitoramento sequencial de teste. As linhas vermelhas inclinadas para fora representam o limite de futilidade. As linhas verticais vermelhas representam o tamanho da informação necessária ajustada à diversidade.

Quanto aos desfechos secundários, o manejo invasivo foi associado a menores riscos de MACE (Material suplementar 1A) e revascularização (Material suplementar 1C) em comparação com o manejo conservador, sem diferenças significativas em morte cardíaca (Material suplementar 1B) ou readmissão (Material suplementar 1D). A curva Z cumulativa ultrapassou os limites de monitoramento sequencial do estudo para benefício em MACE (Material suplementar 2A) e revascularização (Material suplementar 2C). Em contraste, não foram obtidas informações suficientes para morte cardíaca (Material suplementar 2B) ou reinternação (Material suplementar 2D).

 Combinando resultados de ECRs e estudos observacionais com ajuste multivariável

Como os resultados da TSA revelaram que informações suficientes foram obtidas apenas para IM, MACE e revascularização, mas não para outros desfechos, os resultados de ECRs e estudos observacionais com ajuste multivariável também foram calculados para aumentar o tamanho da amostra e atenuar o viés o máximo possível. Os resultados indicaram que o manejo invasivo foi consistentemente associado a menores riscos de morte por todas as causas (OR: 0,57; IC 95%: 0,50-0,64; I2=86,4%; Figura 4A), IM (OR: 0,63; IC 95%: 0,56 -0,71; I2=0%; Figura 4B) e acidente vascular cerebral (OR: 0,59; IC 95%: 0,51-0,69; I2=0%; Figura 4C) em relação ao tratamento conservador, sem aumentar o risco de sangramento maior (Figura 4D). Além disso, o manejo invasivo pode reduzir o risco de MACE (Material suplementar 3A) sem influências significativas na morte cardíaca (Material suplementar 3B), revascularização (Material suplementar 3C) ou readmissão (Material suplementar 3D).

– Combinando resultados primários de Ensaios Randomizados Controlados Ensaios e Estudos Observacionais com Ajuste Multivariável. A) morte por todas as causas; B) infarto do miocárdio; C) acidente vascular cerebral; D) hemorragia grave.

O cenário do mundo real baseado em estudos observacionais

Os resultados de estudos observacionais revelaram que o manejo invasivo pode diminuir os riscos de morte por todas as causas (OR: 0,35; 95% IC: 0,28-0,44; I2=96,7%; Figura 5A) e acidente vascular cerebral (OR: 0,47; 95% IC: 0,36 -0,60; I2=26,0%; Figura 5C), sem repercussão em IM (Figura 5B) e sangramento maior (Figura 5D). Além disso, o manejo invasivo pode diminuir os riscos de MACE (OR: 0,41; IC 95%: 0,32-0,53; I2=64,2%; Material suplementar 4A) e morte cardíaca (OR: 0,32; IC 95%: 0,23-0,47; I2= 0%; Figura suplementar 4B).

– Comparações de Resultados Primários com Base em Estudos Observacionais do Mundo Real. A) morte por todas as causas; B) infarto do miocárdio; C) acidente vascular cerebral; D) hemorragia grave.

Viés de publicação, análises de sensibilidade, análises de meta-regressão e análises de subgrupo

As distribuições do gráfico de funil (Material suplementar 5) e os testes de Begg (Material suplementar 6) não revelaram nenhum viés de publicação para todos os resultados.Nas análises de sensibilidade de exclusão, os resultados permaneceram consistentes com a análise primária (Material suplementar 7). As análises de meta-regressão sobre a idade e a porcentagem de tratamento invasivo não revelaram efeitos nos resultados clínicos entre o tratamento invasivo e conservador (Tabela complementar 1). A análise de subgrupo de morte por todas as causas de acordo com a idade dos pacientes sugeriu que os benefícios em morte por todas as causas (Material suplementar 8A), IM (Material suplementar 8B) e acidente vascular cerebral (Material suplementar 8C) foram consistentes, exceto para pacientes mais velhos com mais de 85 anos, nos quais o manejo invasivo pode aumentar o risco de sangramento maior (OR: 2,68; IC 95%: 1,12-6,42; I2=0%; Material suplementar 8D) sem benefício nos demais parâmetros avaliados. Para desfechos secundários, o manejo invasivo foi associado a um menor risco de MACE (Material Suplementar 9A), independentemente da idade, com risco reduzido de morte cardíaca (Material Suplementar 9B) e revascularização (Material Suplementar 9C) em pacientes com mais de 80 anos.

 Discussão

Nesta metanálise e TSA, nossos achados podem ser resumidos da seguinte forma: (1) o manejo invasivo diminuiu os riscos de infarto do miocárdio, MACE e revascularização com evidências sólidas baseadas em resultados de ECRs e TSA; (2) nenhuma diferença significativa em morte por todas as causas, acidente vascular cerebral, sangramento maior, morte cardíaca e reinternação entre o tratamento invasivo e conservador em ECRs pode ser explicada pelo número limitado de pacientes incluídos de acordo com os resultados da TSA; (3) agrupar os resultados de ECRs e estudos observacionais com ajuste multivariado revelou que o manejo invasivo foi associado a riscos menores de morte por todas as causas, infarto do miocárdio, acidente vascular cerebral e MACE em relação ao manejo conservador; (4) O cenário do mundo real de estudos observacionais também sugeriu que o manejo invasivo pode diminuir os riscos de morte por todas as causas, acidente vascular cerebral, MACE e morte cardíaca; (5) para pacientes idosos com idade ≥85 anos, o manejo invasivo pode aumentar o risco de sangramento maior.

Por muito tempo, o tratamento de pacientes idosos com IAMSSST tem sido uma questão desafiadora e complicada, pois esses pacientes mais velhos têm maior probabilidade do que seus colegas mais jovens de apresentar sintomas atípicos, como ausência de dor torácica na SCA.41 Além disso, a idade avançada per se é considerada um fator de risco independente para morbidade e mortalidade precoces após a apresentação de IAMSSST.42 Além disso, o pior desfecho associado a pacientes idosos é influenciado não apenas por doença arterial coronariana extensa, mas também por doenças mais complexascomorbidades,43 como doença de calcificação coronariana multiarterial complexa, anatomia vascular tortuosa, função ventricular prejudicada, perfil de maior risco e comorbidade substancial.44 Todas as razões acima contribuíram para a incerteza sobre a relação risco-benefício do manejo invasivo.

Dados do mundo real mostraram que pacientes mais velhos com IAMSSST acompanhados de múltiplas comorbidades eram menos propensos a receber tratamento invasivo, possivelmente devido a uma relação risco-benefício desfavorável percebida. Nossa metanálise mostra que pacientes que não receberam manejo invasivo eram mais propensos a ter insuficiência cardíaca ou insuficiência renal. Talvez a preocupação com a nefropatia induzida por contraste os tenha impedido de receber manejo invasivo. No estudo After Eighty,17 457 pacientes com IAMSSST com idade ≥80 anos foram designados aleatoriamente para uma estratégia invasiva (n=229) ou uma estratégia conservadora (n=228). Durante um acompanhamento médio de 1,53 anos, o desfecho primário definido como um composto de infarto do miocárdio, necessidade de revascularização urgente, acidente vascular cerebral e morte ocorreu com menos frequência no grupo invasivo em comparação com o grupo conservador (40,6% vs. 61,4%; risco ratio [HR]: 0,53; IC 95%: 0,41–0,69; p=0,0001), devido principalmente aos riscos reduzidos de IM (HR: 0,52; IC 95%: 0,35–0,76; p=0,0010) e revascularização urgente (HR: 0,19; IC 95%: 0,07–0,52; p=0,0010). Na metanálise realizada por Abusnina et al., eles compararam a eficiência de uma estratégia invasiva em pacientes com IAMSSST com mais de 80 anos. Um total de três ECRs e 893 pacientes foram incluídos.45 Em comparação com a estratégia conservadora,de acordo com nossos resultados de TSA, os resultados não significativos em morte por todas as causas, acidente vascular cerebral e sangramento maior entre o manejo invasivo e conservador em ECRs podem ser explicados pelo número limitado de pacientes incluídos e pela falta de poder para os resultados de interesse. Portanto, mais estudos são necessários para validar o efeito de umestratégia invasiva em pacientes com IAMSSST. Além disso, considerando o número limitado de ECRs, os resultados agrupados de ECRs e estudos observacionais com ajuste multivariado também foram conduzidos como análises complementares. A inclusão dos últimos estudos relevantes pode tornar os resultados mais convincentes. Além disso, os critérios de inclusão e exclusão foram rígidos nos ECRs, o que pode limitar a generalidade dos resultados à prática do mundo real; portanto, a análise de subgrupo baseada apenas em estudos observacionais também foi realizada. Todas as análises acima indicaram consistentemente que a estratégia invasiva foi superior ao tratamento conservador. No entanto, um risco aumentado de sangramento maior foi observado em pacientes com idade ≥85 anos, o que sugere cautela ao considerar o tratamento invasivo em pacientes muito idosos.46

Na prática do mundo real, aproximadamente metade dos pacientes com IAMSSST com estenose significativa não foi submetida a ICP.19 As razões podem ser explicadas por doença de pequenos vasos inelegível para tratamento invasivo, doença arterial coronariana grave (por exemplo, multiarterial/tronco principal esquerdo) combinada com grave doença periférica e doença arterial coronariana grave após CRM inelegível para refazer cirurgia e ICP. No estudo conduzido por Phan et al.,38 foram relatados os dois motivos mais comuns para o manejo conservador: 1. baixa candidatura ao manejo invasivo devido à fragilidade, anatomia coronária abaixo do ideal, comorbidades médicas ou outros motivos a critério do médico ( 38,9%); 2. doença arterial coronariana obstrutiva significativa com alta relação risco-benefício, o que favorece uma tentativa de terapia médica primeiro (36,3%).

Os dados de nossa metanálise revelaram uma associação positiva entre uma estratégia invasiva e melhores resultados, mas o benefício de uma estratégia invasiva pode ser diluído pelo peso da idade, com risco aumentado de sangramento maior em pacientes com idade ≥85 anos. Devido ao número limitado de ECRs, estudos mais extensos e ECRs são obrigatórios para esclarecer o papel do manejo invasivo em pacientes idosos com IAMSSST. O estudo SENIOR-RITA (NCT03052036) foi desenvolvido para determinar se uma estratégia invasiva reduz a morte cardiovascular ou infarto do miocárdio em pacientes com IAMSSST com idade ≥75 anos quando comparada com uma estratégia de tratamento conservador. No entanto, estima-se que o ensaio seja concluído até 2029.

Limitação

Algumas limitações devem ser reconhecidas em nossa metanálise. Primeiro, o manejo invasivo foi realizado de forma mista ICP e/ou CRM. No entanto, análises de subgrupos com base em ECRs recentes demonstraram resultados comparáveis após ICP ou CRM em pacientes idosos, sendo a ICP preferida para pacientes frágeis com maiores riscos de eventos periprocedimentos, enquanto

a CRM é melhor para alcançar a revascularização completa.47,48 Em segundo lugar, MACE é comumente usados em nossos estudos incluídos, mas seus componentes e combinações diferem. Portanto, MACE foi considerado como um desfecho secundário em vez de primário em nossa metanálise.

 Conclusão

Entre os pacientes mais velhos (≥75 anos) com IAMSSST, o manejo invasivo pode diminuir os riscos de IM, MACE e revascularização com evidências sólidas baseadas em resultados de ECRs e TSA. A combinação de resultados de ECRs e estudos observacionais com ajuste multivariável indicou consistentemente que o manejo invasivo foi melhor para melhorar o prognóstico. No entanto, para pacientes muito idosos com idade ≥85 anos, o manejo invasivo pode aumentar o risco de sangramento maior, o que deve chamar nossa atenção.

 Agradecimentos

Este trabalho foi apoiado pelo National Key Research and Development Program of China (2017YFC1700503), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-009) e o Twelfth Five-Year Planning Project of the Scientific and Technological Department of China (2011BAI11B02).

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Sui YG Teng SY Qian J Wu Y Dou KF Tang YD et al A Retrospective Study of an Invasive versus Conservative Strategy in Patients Aged ≥80 Years with Acute ST-Segment Elevation Myocardial Infarction J Int Med Res 2019 47 9 4431 4441 10.1177/0300060519860969 35. Gonçalves FF, Guimarães JP, Borges SC, Mateus PS, Moreira JI. Impact of Coronary Angioplasty in Elderly Patients with Non-ST-Segment Elevation Myocardial Infarction. J Geriatr Cardiol. 2020;17(8):449-454. doi: 10.11909/j.issn.1671-5411.2020.08.001. Gonçalves FF Guimarães JP Borges SC Mateus PS Moreira JI Impact of Coronary Angioplasty in Elderly Patients with Non-ST-Segment Elevation Myocardial Infarction J Geriatr Cardiol 2020 17 8 449 454 10.11909/j.issn.1671-5411.2020.08.001. 36. Kaura A, Sterne JAC, Trickey A, Abbott S, Mulla A, Glampson B, et al. Invasive versus Non-Invasive Management of Older Patients with Non-ST Elevation Myocardial Infarction (SENIOR-NSTEMI): A Cohort Study Based on Routine Clinical Data. Lancet. 2020;396(10251):623-34. doi: 10.1016/S0140-6736(20)30930-2. Kaura A Sterne JAC Trickey A Abbott S Mulla A Glampson B et al Invasive versus Non-Invasive Management of Older Patients with Non-ST Elevation Myocardial Infarction (SENIOR-NSTEMI): A Cohort Study Based on Routine Clinical Data Lancet 2020 396 10251 623 634 10.1016/S0140-6736(20)30930-2 37. Nguyen TV, Bui KX, Tran KD, Le D, Nguyen TN. Non-ST Elevation Acute Coronary Syndrome in Patients Aged 80 Years or Older in Vietnam: An Observational Study. PLoS One. 2020;15(6):e0233272. doi: 10.1371/journal.pone.0233272. Nguyen TV Bui KX Tran KD Le D Nguyen TN Non-ST Elevation Acute Coronary Syndrome in Patients Aged 80 Years or Older in Vietnam: An Observational Study PLoS One 2020 15 6 e0233272 10.1371/journal.pone.0233272 38. Phan DQ, Rostomian AH, Schweis F, Chung J, Lin B, Zadegan R, et al. Revascularization versus Medical Therapy in Patients Aged 80 Years and Older with Acute Myocardial Infarction. J Am Geriatr Soc. 2020;68(11):2525-33. doi: 10.1111/jgs.16747. Phan DQ Rostomian AH Schweis F Chung J Lin B Zadegan R et al Revascularization versus Medical Therapy in Patients Aged 80 Years and Older with Acute Myocardial Infarction J Am Geriatr Soc 2020 68 11 2525 2533 10.1111/jgs.16747 39. Kunniardy P, Koshy AN, Meehan G, Murphy AC, Ramchand J, Clark DJ, et al. Invasive versus Conservative Management in Patients Aged ≥85 Years Presenting with Non-ST-Elevation Myocardial Infarction. Intern Med J. 2022;52(7):1167-73. doi: 10.1111/imj.15258. Kunniardy P Koshy AN Meehan G Murphy AC Ramchand J Clark DJ et al Invasive versus Conservative Management in Patients Aged ≥85 Years Presenting with Non-ST-Elevation Myocardial Infarction Intern Med J 2022 52 7 1167 1173 10.1111/imj.15258 40. Couture EL, Farand P, Nguyen M, Allard C, Wells GA, Mansour S, et al. Impact of an Invasive Strategy in the Elderly Hospitalized with Acute Coronary Syndrome with Emphasis on the Nonagenarians. Catheter Cardiovasc Interv. 2018;92(7):E441-E448. doi: 10.1002/ccd.27877. Couture EL Farand P Nguyen M Allard C Wells GA Mansour S et al Impact of an Invasive Strategy in the Elderly Hospitalized with Acute Coronary Syndrome with Emphasis on the Nonagenarians Catheter Cardiovasc Interv 2018 92 7 E441 E448 10.1002/ccd.27877 41. Brieger D, Eagle KA, Goodman SG, Steg PG, Budaj A, White K, et al. Acute Coronary Syndromes without Chest Pain, an Underdiagnosed and Undertreated High-Risk Group: Insights from the Global Registry of Acute Coronary Events. Chest 2004;126(2):461-9. doi: 10.1378/chest.126.2.461. Brieger D Eagle KA Goodman SG Steg PG Budaj A White K et al Acute Coronary Syndromes without Chest Pain, an Underdiagnosed and Undertreated High-Risk Group: Insights from the Global Registry of Acute Coronary Events Chest 2004 126 2 461 469 10.1378/chest.126.2.461 42. Lee PY, Alexander KP, Hammill BG, Pasquali SK, Peterson ED. Representation of Elderly Persons and Women in Published Randomized Trials of Acute Coronary Syndromes. JAMA. 2001;286(6):708-13. doi: 10.1001/jama.286.6.708. Lee PY Alexander KP Hammill BG Pasquali SK Peterson ED Representation of Elderly Persons and Women in Published Randomized Trials of Acute Coronary Syndromes JAMA 2001 286 6 708 713 10.1001/jama.286.6.708 43. Hasdai D, Holmes DR Jr, Criger DA, Topol EJ, Califf RM, Harrington RA. Age and Outcome after Acute Coronary Syndromes without Persistent ST-Segment Elevation. Am Heart J. 2000;139(5):858-66. doi: 10.1016/s0002-8703(00)90018-8. Hasdai D Holmes DR Jr Criger DA Topol EJ Califf RM Harrington RA Age and Outcome after Acute Coronary Syndromes without Persistent ST-Segment Elevation Am Heart J 2000 139 5 858 866 10.1016/s0002-8703(00)90018-8 44. Behan M, Dixon G, Haworth P, Blows L, Hildick-Smith D, Holmberg S, et al. PCI in Octogenarians--Our Centre ‘Real World’ Experience. Age Ageing. 2009;38(4):469-73. doi: 10.1093/ageing/afp055. Behan M Dixon G Haworth P Blows L Hildick-Smith D Holmberg S et al PCI in Octogenarians--Our Centre ‘Real World’ Experience Age Ageing 2009 38 4 469 473 10.1093/ageing/afp055 45. Abusnina W, Alam M, Dahal K. Meta-Analysis Comparing Outcomes of Invasive versus Conservative Strategy in Octogenarians with Non-ST Segment Elevation Acute Myocardial Infarction. Am J Cardiol. 2021;160:130-2. doi: 10.1016/j.amjcard.2021.08.039. Abusnina W Alam M Dahal K Meta-Analysis Comparing Outcomes of Invasive versus Conservative Strategy in Octogenarians with Non-ST Segment Elevation Acute Myocardial Infarction Am J Cardiol 2021 160 130 132 10.1016/j.amjcard.2021.08.039 46. Tegn N, Eek C, Abdelnoor M, Aaberge L, Endresen K, Skårdal R, et al. Patients Aged 80 Years or Older with Non-ST-Elevation Myocardial Infarction or Unstable Angina Pectoris Randomised to an Invasive versus Conservative Strategy: Angiographic and Procedural Results from the After Eighty Study. Open Heart. 2020;7(2):e001256. doi: 10.1136/openhrt-2020-001256. Tegn N Eek C Abdelnoor M Aaberge L Endresen K Skårdal R et al Patients Aged 80 Years or Older with Non-ST-Elevation Myocardial Infarction or Unstable Angina Pectoris Randomised to an Invasive versus Conservative Strategy: Angiographic and Procedural Results from the After Eighty Study Open Heart 2020 7 2 e001256 10.1136/openhrt-2020-001256 47. Merten GJ, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ, et al. Prevention of Contrast-Induced Nephropathy with Sodium Bicarbonate: A Randomized Controlled Trial. JAMA. 2004;291(19):2328-34. doi: 10.1001/jama.291.19.2328. Merten GJ Burgess WP Gray LV Holleman JH Roush TS Kowalchuk GJ et al Prevention of Contrast-Induced Nephropathy with Sodium Bicarbonate: A Randomized Controlled Trial JAMA 2004 291 19 2328 2334 10.1001/jama.291.19.2328 48. Giacoppo D, Gargiulo G, Buccheri S, Aruta P, Byrne RA, Cassese S, et al. Preventive Strategies for Contrast-Induced Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Procedures: Evidence from a Hierarchical Bayesian Network Meta-Analysis of 124 Trials and 28 240 Patients. Circ Cardiovasc Interv. 2017;10(5):e004383. doi: 10.1161/CIRCINTERVENTIONS.116.004383. Giacoppo D Gargiulo G Buccheri S Aruta P Byrne RA Cassese S et al Preventive Strategies for Contrast-Induced Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Procedures: Evidence from a Hierarchical Bayesian Network Meta-Analysis of 124 Trials and 28 240 Patients Circ Cardiovasc Interv 2017 10 5 e004383 10.1161/CIRCINTERVENTIONS.116.004383

Fontes de financiamento: O presente estudo foi financiado por National Key Research and Development Program of China (2017YFC1700503), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-009), and the Twelfth Five-Year Planning Project of the Scientific and Technological Department of China (2011BAI11B02).

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 Original Article Invasive Versus Conservative Management of NSTEMI Patients Aged ≥ 75 Years 0000-0003-0473-6077 Hu Mengjin Conception and design of the research, Acquisition of data, Analysis and interpretation of the data, Statistical analysis and Writing of the manuscript 1 2 Li Xiaosong 1 Yang Yuejin Conception and design of the research, Acquisition of data, Analysis and interpretation of the data, Statistical analysis and Writing of the manuscript, Obtaining financing and Critical revision of the manuscript for important intellectual content 1 China Fuwai Hospital State Key Laboratory of Cardiovascular Disease, Beijing – China China Xuanwu Hospital, Capital Medical University, Beijing – China Mailing Address: Yuejin Yang • Fuwai Hospital State Key Laboratory of Cardiovascular Disease – State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular D State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular D Beijing 100037 – China E-mail: yangyjfw@126.com

Potential conflict of interest

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

 Abstract Background

The efficiency of invasive management in older patients (≥75 years) with non-ST-segment elevation myocardial infarction (NSTEMI) remains ambiguous.

 Objectives

To assess the efficiency of invasive management in older patients with NSTEMI based on meta-analysis and trial sequential analysis (TSA).

 Methods

Relevant randomized controlled trials (RCT) and observational studies were included. The primary outcomes were all-cause death, myocardial infarction, stroke, and major bleeding. Pooled odd ratio (OR) and 95% confidence interval (CI) were calculated. P <0.05 was considered statistically significant.

 Results

Five RCTs and 22 observational studies with 1017374 patients were included. Based on RCT and TSA results, invasive management was associated with lower risks of myocardial infarction (OR: 0.51; 95% CI: 0.40-0.65; I2=0%), major adverse cardiovascular events (MACE; OR: 0.61; 95% CI: 0.49-0.77; I2=27.0%), and revascularization (OR: 0.29; 95% CI: 0.15-0.55; I2=5.3%) compared with conservative management. Pooling results from RCTs and observational studies with multivariable adjustment showed consistently lower risks of all-cause death (OR: 0.57; 95% CI: 0.50-0.64; I2=86.4%), myocardial infarction (OR: 0.63; 95% CI: 0.56-0.71; I2=0%), stroke (OR: 0.59; 95% CI: 0.51-0.69; I2=0%), and MACE (OR: 0.64; 95% CI: 0.54-0.76; I2=43.4%). The better prognosis associated with invasive management was also observed in real-world scenarios. However, for patients aged ≥85 years, invasive management may increase the risk of major bleeding (OR: 2.68; 95% CI: 1.12-6.42; I2=0%).

 Conclusions

Invasive management was associated with lower risks of myocardial infarction, MACE, and revascularization in older patients with NSTEMI, yet it may increase the risk of major bleeding in patients aged ≥85 years.

 Aged Myocardial Infarction Percutaneous Coronary Intervention Conservative Treatment Introduction

Older age is a crucial predictor for adverse outcomes in patients with acute coronary syndrome (ACS), as higher risks of short- and long-term mortality were observed in older patients compared to younger counterparts.1 Current guidelines emphasize intensive and early interventional treatment in ACS patients, particularly those with higher risks of short-term events.2,3 Elderly patients represent a subgroup known to be at increased risk, and they may benefit from revascularization to the same extent as younger patients.4 However, data from the National Inpatient Sample database in the USA suggested that the rate of invasive coronary angiography in non-ST-segment elevation myocardial infarction (NSTEMI) declined with age, with only 38% of patients who are aged 81 years or older receiving invasive coronary angiography, as compared with 78% of patients who are aged 60 years or younger,5 which may be explained by the worries about a potential increased risk of complications following revascularization procedures.6

Because of the rapid growth of the elderly population, the World Health Organization predicts that the deaths caused by coronary heart disease will increase by 120-137% during the next two decades.7 As the leading cause of death globally,8 determining an efficient strategy for treating elderly patients with NSTEMI is essential. However, elderly patients are underrepresented in randomized controlled trials (RCT), as the average age of enrolled patients is younger than 75 years in RCTs. Therefore, the generalizability and translation of RCT results to older patients are limited. Meanwhile, the number of RCTs focusing on invasive management in older patients (≥75 years) with NSTEMI is limited and may be underpowered for the outcomes of interest. Consequently, the management of elderly patients with NSTEMI remains a tricky issue.

In the present meta-analysis, we aimed to assess the clinical events related to invasive management in NSTEMI patients aged ≥ 75 years based on RCTs and trial sequential analysis (TSA).9 TSA helps determine whether an RCT could be terminated early when a p value is sufficiently small to show the anticipated effect or futility.10 Meanwhile, observational studies were also included to help us understand real-world scenarios in clinical practice.

 Methods Study design and selection

RCTs and observational studies comparing invasive (percutaneous coronary intervention [PCI]/coronary artery bypass grafting [CABG]) versus conservative management in older patients (≥75 years) with NSTEMI and reporting clinical outcomes were considered. Studies focusing on patients with unstable angina or STEMI were excluded. Relevant studies were searched through PubMed, Web of Science, the Cochrane Library, ClinicalTrials.gov, and Google Scholar using the following keywords: elderly, older, septuagenarians, octogenarians, nonagenarians, myocardial infarction, non-ST-segment elevation myocardial infarction, NSTEMI, invasive, aggressive, percutaneous coronary intervention, PCI, coronary artery bypass grafting, CABG, angioplasty, selective, conservative, medical therapy, drug therapy from publication to May 9th, 2022. Two investigators independently reviewed the titles, abstracts, and studies to determine whether they met the inclusion criteria. This meta-analysis was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement,11 and it has been registered in the International Prospective Register of Systematic Reviews (CRD42022301170).

 Outcomes

The primary outcomes were all-cause death, myocardial infarction (MI), stroke, and major bleeding, according to the definition of per individual study. The secondary outcome included major adverse cardiovascular events (MACE), cardiac death, revascularization, and re-admission.

 TSA analysis

In TSA analysis, RCTs are included in chronological order, and analysis is performed repetitively and cumulatively after new RCTs are conducted. TSA also provides an adjusted significance level for controlling Type I and II errors.12 TSA helps determine whether an RCT could be terminated early when a p value is sufficiently small to show the anticipated effect or futility.10When the cumulative Z-curve crosses the trial sequential monitoring boundaries, it indicates the analysis is valid for benefit. TSA was conducted by TSA software, version 0.9 beta (Copenhagen Trial Unit, Copenhagen, Denmark).

 Statistical analysis

Raw, unadjusted data from included RCTs and observational studies were extracted. The pooled odd ratio (OR) and 95% confidence interval (CI) were calculated by using random-effect (DerSimonian and Laird) models. Moreover, due to the limited number of RCTs, pooling results from RCTs and observational studies with multivariable adjustment were also calculated. Subgroup analysis was performed according to patients’ age (≥75, ≥80, and ≥85). Meta-regression analysis was performed to explore the heterogeneity of treatment effects further, stratifying by age and percentage of revascularization. Moreover, a leave-one-out analysis was also conducted to assess whether a single study influenced the pooled results. Publication bias was evaluated by visual inspection of funnel plots and Begg’s test. Heterogeneity across studies was assessed using the I2 statistic,12,13 with I2 <25%, 25%-75%, and >75% considered low, moderate, and high, respectively. P <0.05 was considered statistically significant. All statistical analyses were performed using Stata 16 SE (StataCorp, College Station, TX).

 Results Baseline characteristics of included studies

As shown in Figure 1, of 5546 potentially relevant studies, five RCTs14-18 and 22 observational studies19-40 met the inclusion criteria. A total of 178860 (17.6%) patients were managed invasively, whereas 838514 (82.4%) were managed conservatively. The major characteristics of the included studies and patients are shown in Table 1.

– PRISMA Diagram for Study Inclusion. STEMI: ST-segment elevation myocardial infarction.

– Baseline characteristics of included studies
Study, year Study design Number of patients Definition of MACE Age (years) Male (%) Hypertension (%) Hyperlipidemia (%) Diabetes (%) LVEF (%) Heart failure Renal failure (%) Radial access (%) GP IIb/IIIa antagonist (%) Follow-up time
TACTICS–TIMI 14,18 2004 RCT, multicenter 139/139 cardiac death, MI or need for unplanned coronary revascularisation NA NA NA NA NA NA NA NA NA NA 6 months
ACOS Registry,19 2007 prospective, multicenter, observational 1005/931 death and MI 78.7/82.2 51.7/41.4 79.2/74.8 62.3/49.7 33.5/39.4 NA NA 4.5/9.2 NA NA 12 months
GRACE,20 2008 prospective, multicenter, observational 620/2390 death, MI, and stroke 85 48 73 39 26 NA 27 11 NA 15 6 months
LOURENÇO,21 2010 prospective, single-center, observational 91/216 death, cardiovascular death, MI, re-admission for unstable angina, and unscheduled PCI 79.8/81.4 63.7/50.9 80.2/74.9 60.7/62.5 26.4/30.8 NA 3.8/10.2 NA NA 39.6/30.1 18 months
FIR,15 2012 RCT, multicenter 437/402 cardiovascular death and MI 76 63.5 39.0 15.7 14.8 NA NA NA NA NA 5 years
FAST-MI,22 2012 prospective, multicenter, observational 412/246 NA NA NA NA NA NA NA NA NA NA NA 3 years
Italian Elderly ACS,16 2012 RCT, multicenter, 154/159 all-cause mortality, MI, stroke, and repeat hospital stay 81.8/81.8 49/51 92/85 44/50 38/41 49/48 10/8.9 NA 71/78 17/6 1 year
ACSIS,23 2013 prospective, multicenter, observational 192/158 NA 83 54 81 NA 36 NA 29 NA NA 6 1 year
PL-ACS,24 2013 prospective, multicenter, observational 3288/10419 NA 82/83 47.5/37.2 78.6/71.0 36.3/32.6 30.9/30.5 NA NA NA NA 4.6/0.1 2 years
Kolte,25 2013 retrospective, multicenter, observational 161640/ 806902 NA 83.9/86.2 48.2/41 72/62.5 51.9/33.7 28.0/29.1 NA 34.8/55 16.8/22.8 NA NA in-hospital
MONICA/KORA MI,26 2016 prospective, multicenter, observational 360/286 NA 78/80 55.8/46/5 90.6/85.0 47.8/33.6 40.0/50.0 NA NA 24.7/36.4 NA 24.7/4.9 28 days
Conti,27 2016 prospective, single-center, observational 301/152 death and MI 80 52.8/34.2 91.7/90.8 53.5/38.8 41.2/42.1 NA NA NA NA NA 1 year
HUMIR,28 2016 prospective, multicenter, observational 654 NA NA NA NA NA NA NA NA NA NA NA 1 year
After Eighty study,17 2016 RCT, multicenter 229/228 MI, need for urgent revascularisation, stroke, and death 84.7/84.9 55/44 57/61 NA 20/14 NA NA NA 90 NA 3 years
AMI-OPTIMA,40 2018 sub-analysis of RCT, multicenter 548/610 NA 85.6 47.6 78.3 53.4 31.2 NA NA 25.3 NA NA in-hospital
Liu,29 2018 retrospective, single-center, observational 319 NA NA NA NA NA NA NA NA NA NA NA 32,3 months
LONGEVO-SCA,30 2018 prospective, multicenter, observational 407/124 cardiac death, MI, or need for unplanned coronary revascularization 83.6/86.7 64.7/50.0 84.0/87.1 NA 39.0/42.7 53.2/53.7 14.3/29.0 NA 84.5 NA 6 months
SWEDEHEART,31 2018 prospective, multicenter, observational 4158/9696 NA 84/86 57/46 63/63 NA NA NA NA NA NA NA 5 years
Kvakkestad,32 2019 prospective, single center, observational 1200/864 NA 80.4/86.4 60.6/39.7 50.1/48.4 NA 20.7/19.0 NA NA NA NA NA 7 years
CAMI,33 2019 prospective, multicenter, observational 551/1900 all-cause death, MI, and stroke 80.37 54.6 65.8 6.0 25.0 53.41 10.8 NA NA 10.8 in-hospital
Sui,34 2019 retrospective, single-center, observational 139/93 NA 83.4/84.8 52.5/57.0 66.9/68.8 93.5/90.3 40.3/34.4 51.9/45.3 NA 23.7/36.6 NA NA 4 years
Gonçalves,352020 retrospective, multicenter, observational 237/87 NA 87/87 54.0/60.9 86.4/90.7 58.8/59.5 29.6/43.7 52/49 NA 14.1/9.4 64.5/80.7 NA 1 year
Hirlekar,18 2020 RCT, multicenter 93/93 MI, urgent revascularization, all-cause mortality, stroke, and recurrent hospitalization 84/84 50.5/59.1 59.1/63.4 22.6/17.2 17.2/21.5 55/54 10.8/8.6 63.4/75.3 NA NA 1 year
SENIOR-NSTEMI,36 2020 prospective, multicenter, observational 655/845 NA 85.3/86.9 60/50 62/54 42/30 26/24 NA 17/24 7/8 NA NA 4,8 years
Nguyen,37 2020 prospective, multicenter, observational 42/78 all-cause mortality, MI, stroke 84.1/85.2 59.5/44.9 97.6/85.9 NA 21.4/23.1 NA 21.4/48.7 NA NA NA 3 months
Phan,38 2020 retrospective, single-center, observational 890/543 NA 83.3/83.3 64.6/67.4 91.9/94.1 93.0/93.6 49.1/56.9 51/45 44.5/64.8 58.1/63.9 NA NA 2,6 years
Kunniardy,39 2021 retrospective, single- center, observational 99/953 NA NA NA NA NA NA NA NA NA NA NA 1,3 years

All studies adopted 5% of statistical significance.Data were reported as invasive/conservative management.CABG: coronary artery bypass grafting; MACE: major adverse cardiovascular events; LVEF: left ventricular ejection fraction; MI: myocardial infarction; NA: not avaliable; PCI: percutaneous coronary intervention; RCT: randomized controlled trial.

 Clinical outcomes based on RCTs

It was obvious that invasive management was associated with lower risks of MI (OR: 0.51; 95% CI: 0.40-0.65; I2=0%; Figure 2B), without significant influences on all-cause death (Figure 2A), stroke (Figure 2C) or major bleeding (Figure 2D). For all-cause death (Figure 3A), the cumulative Z-curve did not cross the conventional statistical boundaries, the trial sequential monitoring boundaries, or the diversity-adjusted required information size, indicating that sufficient information was not obtained. The cumulative Z-curve crossed the trial sequential monitoring boundaries for benefit in MI (Figure 3B), indicating sufficient information was obtained. For stroke (Figure 3C) and major bleeding (Figure 3D), TSA results were ignored due to too little information used.

– Comparisons of Primary Outcomes Based on Randomized Controlled Trials. A) all-cause death; B) myocardial infarction; C) stroke; D) major bleeding.

– TSA Results for Primary Outcomes. A) all-cause death; B) myocardial infarction; C) stroke; D) major bleeding. TSA: trial sequential analysis. The blue line represents the cumulative Z-score of the meta-analysis. The red transverse lines represent the conventional statistical boundaries of p = 0.05. The red inward-sloping lines represent the trial sequential monitoring boundaries. The red outward sloping lines represent the futility boundary. The red vertical lines represent the diversity-adjusted required information size.

As to secondary outcomes, invasive management was associated with lower risks of MACE (Supplementary material 1A) and revascularization (Supplementary material 1C) compared with conservative management, without significant differences in cardiac death (Supplementary material 1B) or re-admission (Supplementary material 1D). Cumulative Z-curve crossed the trial sequential monitoring boundaries for benefit in MACE (Supplementary material 2A) and revascularization (Supplementary material 2C). In contrast, sufficient information was not obtained for cardiac death (Supplementary material 2B) or re-admission (Supplementary material 2D).

 Pooling results from RCTs and observational studies with multivariable adjustment

As TSA results revealed that sufficient information was only obtained for MI, MACE, and revascularization but not for other outcomes, results from RCTs and observational studies with multivariable adjustment were also calculated to enlarge sample size and mitigate bias as much as possible. The results indicated that invasive management was consistently associated with lower risks of all-cause death (OR: 0.57; 95% CI: 0.50-0.64; I2=86.4%; Figure 4A), MI (OR: 0.63; 95% CI: 0.56-0.71; I2=0%; Figure 4B), and stroke (OR: 0.59; 95% CI: 0.51-0.69; I2=0%; Figure 4C) relative to conservative management, without increasing the risk of major bleeding (Figure 4D). Additionally, invasive management could reduce the risk of MACE (Supplementary material 3A) without significant influences on cardiac death (Supplementary material 3B), revascularization (Supplementary material 3C), or re-admission (Supplementary material 3D).

– Pooling Primary Outcomes from Randomized Controlled Trials and Observational Studies with Multivariable Adjustment. A) all-cause death; B) myocardial infarction; C) stroke; D) major bleeding.

The real-world scenario based on observational studies

Results from observational studies revealed that invasive management might decrease the risks of all-cause death (OR: 0.35; 95% CI: 0.28-0.44; I2=96.7%; Figure 5A) and stroke (OR: 0.47; 95% CI: 0.36-0.60; I2=26.0%; Figure 5C), without impact on MI (Figure 5B) and major bleeding (Figure 5D). Additionally, invasive management may decrease the risks of MACE (OR: 0.41; 95% CI: 0.32-0.53; I2=64.2%; Supplementary material 4A) and cardiac death (OR: 0.32; 95% CI: 0.23-0.47; I2=0%; Supplementary material 4B).

– Comparisons of Primary Outcomes Based on Real-World Observational Studies. A) all-cause death; B) myocardial infarction; C) stroke; D) major bleeding.

Publication bias, sensitivity analyses, meta-regression analyses, and subgroup analyses

Funnel-plot distributions (Supplementary material 5) and Begg’s tests (Supplementary material 6) revealed no publication bias for all outcomes. In leave-one-out sensitivity analyses, the results remained consistent with the primary analysis (Supplementary material 7). Meta-regression analyses on age and the percentage of invasive management revealed no effects on clinical outcomes between invasive and conservative management (Supplementary Table 1). Subgroup analysis of all-cause death according to patients’ age suggested that the benefits in all-cause death (Supplementary material 8A), MI (Supplementary material 8B), and stroke (Supplementary material 8C) were consistent except for older patients aged more than 85 years, in whom the invasive management may increase the risk of major bleeding (OR: 2.68; 95% CI: 1.12-6.42; I2=0%; Supplementary material 8D) with no benefits in other parameters evaluated. For secondary outcomes, invasive management was associated with a lower risk of MACE (Supplementary material 9A) regardless of age, with reduced risk of cardiac death (Supplementary material 9B) and revascularization (Supplementary material 9C) in patients aged more than 80 years.

 Discussion

In this meta-analysis and TSA, our findings can be summarized as follows: (1) invasive management decreased the risks of MI, MACE, and revascularization with firm evidence based on RCTs and TSA results; (2) no significant differences in all-cause death, stroke, major bleeding, cardiac death, and re-admission between invasive and conservative management in RCTs may be explained by the limited number of included patients according to TSA results; (3) pooling results from RCTs and observational studies with multivariable adjustment revealed that invasive management was associated with lower risks of all-cause death, MI, stroke, and MACE relative to conservative management; (4) real-world scenario from observational studies also suggested that invasive management may decrease the risks of all-cause death, stroke, MACE, and cardiac death; (5) for older patients aged ≥85 years, invasive management may increase the risk of major bleeding.

For a long time, treating elderly patients with NSTEMI has been a challenging and tricky issue as these older patients are more likely than their younger counterparts to present atypical symptoms, such as an absence of chest pain in ACS.41 Further, older age per se is considered an independent risk factor for early morbidity and mortality following the presentation of NSTEMI.42 Additionally, the poorer outcome associated with elderly patients is influenced not only by extensive coronary artery disease but also by more complex comorbidities,43 such as complex multivessel coronary calcification disease, tortuous vascular anatomy, impaired ventricular function, higher risk profile, and substantial comorbidity.44 All of the reasons above have contributed to the uncertainty about the risk-benefit ratio of invasive management.

Real-world data showed that older patients with NSTEMI accompanied by multiple comorbidities were less likely to receive invasive management, possibly due to a perceived unfavorable risk-benefit ratio. Our meta-analysis shows that patients who did not receive invasive management were more likely to have heart failure or renal failure. Maybe the worries about contrast-induced nephropathy hindered them from receiving invasive management. In the After Eighty study,17 457 NSTEMI patients aged ≥80 years were randomly assigned to an invasive strategy (n=229) or a conservative strategy (n=228). During a median follow-up of 1.53 years, the primary outcome defined as a composite of MI, need for urgent revascularization, stroke, and death occurred less frequently in the invasive group compared with the conservative group (40.6% vs. 61.4%; hazard ratio [HR]: 0.53; 95% CI: 0.41–0.69; p=0.0001), which was mainly due to the reduced risks of MI (HR: 0.52; 95% CI: 0.35–0.76; p=0.0010) and urgent revascularization (HR: 0.19; 95% CI: 0.07–0.52; p=0.0010). In the meta-analysis conducted by Abusnina et al., they compared the efficiency of an invasive strategy in NSTEMI patients aged more than 80 years. A total of three RCTs and 893 patients were included. Compared with the conservative strategy, the invasive strategy was associated with reduced risks of MI (relative risk [RR]: 0.58; 95% CI: 0.44-0.77; p=0.0002) and revascularization (RR: 0.24; 95% CI: 0.13-0.46; p<0.0001), without differences in all-cause mortality (RR: 0.89; 95% CI: 0.68-1.16; p=0.40), major bleeding (RR: 1.56; 95% CI: 0.60-4.05; p=0.36), or stroke (RR: 0.78; 95% CI: 0.39-1.956; p=0.48).45 However, according to our TSA results, the nonsignificant results in all-cause death, stroke, and major bleeding between invasive and conservative management in RCTs may be explained by the limited number of included patients and underpowered for the outcomes of interest. Therefore, further studies are needed to validate the effect of an invasive strategy on patients with NSTEMI. Moreover, considering the limited number of RCTs, pooling results from RCTs and observational studies with multivariable adjustment were also conducted as supplementary analyses. The inclusion of the latest relevant studies may make the results more convincing. Additionally, the inclusion and exclusion criteria were strict in RCTs, which may limit the generality of the results to real-world practice; therefore, subgroup analysis just based on observational studies was also performed. All of the analyses above consistently indicated that the invasive strategy was superior to the conservative management. However, an increased risk of major bleeding was observed in patients aged ≥85 years, which suggested that caution should be paid when considering invasive management in very old patients.46

In real-world practice, approximately half of the NSTEMI patients with significant stenosis did not undergo PCI.19 The reasons could be explained by small vessel disease ineligible for invasive management, severe coronary artery disease (e.g., multivessel/left main) combined with severe peripheral disease and severe coronary artery disease after CABG ineligible for redo surgery and PCI. In the study conducted by Phan et al.,38 the two most common reasons for conservative management were reported: 1. poor candidacy for invasive management due to frailty, suboptimal coronary anatomy, medical comorbidities, or other reasons at the discretion of the physician (38.9%); 2. significant obstructive coronary artery disease with high risk-benefit ratio, which favors a trial of medical therapy first (36.3%).

Data from our meta-analysis revealed a positive association between an invasive strategy and better outcomes, yet the benefit of an invasive strategy might be diluted by the weight of age, with an increased risk of major bleeding in patients aged ≥85 years. Due to the limited number of RCTs, more extensive studies and RCTs are mandatory to clarify the role of invasive management in older patients with NSTEMI. The SENIOR-RITA trial (NCT03052036) is designed to determine whether an invasive strategy reduces cardiovascular death or MI in NSTEMI patients aged ≥75 years when compared with a conservative management strategy. However, the trial is estimated to be completed by 2029.

Limitation

Some limitations should be acknowledged in our meta-analysis. First, invasive management was performed in mixed PCI and/or CABG manners. However, subgroup analyses based on recent RCTs demonstrated comparable outcomes after PCI or CABG in older patients, with PCI being preferred for frail patients with higher risks of periprocedural events, while CABG is better at achieving complete revascularization.47,48 Second, MACE is commonly used in our included studies, but their components and combinations differ. Therefore, MACE was regarded as a secondary outcome instead of a primary one in our meta-analysis.

 Conclusion

Among older patients (≥75 years) with NSTEMI, invasive management could decrease the risks of MI, MACE, and revascularization with firm evidence based on RCTs and TSA results. Pooling results from RCTs and observational studies with multivariable adjustment consistently indicated that invasive management was better in improving prognosis. However, for very older patients aged ≥85 years, invasive management may increase the risk of major bleeding, which should raise our attention.

 Acknowledgements

This work was supported by the National Key Research and Development Program of China (2017YFC1700503), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-009), and the Twelfth Five-Year Planning Project of the Scientific and Technological Department of China (2011BAI11B02).

Sources of funding: This study was partially funded by National Key Research and Development Program of China (2017YFC1700503), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-009), and the Twelfth Five-Year Planning Project of the Scientific and Technological Department of China (2011BAI11B02).

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