Intervenções Farmacológicas para pessoas com Estenose Assintomática de Carótidas: uma revisão sistemática e metanálise Cochrane
Data
2023-06-22
Autores
Clezar, Caroline Nicacio Bessa 
Orientadores
Flumignan, Ronald Luiz Gomes
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: A estenose carotídea é causada pela aterosclerose e é mais frequente em pacientes homens com mais de 70 anos e com fatores de risco como diabetes, hipertensão, dislipidemia e tabagismo. Como essa lesão pode se desenvolver de modo assintomático, o primeiro sintoma pode ser um acidente vascular cerebral fatal ou incapacitante, um problema de saúde pública mundial. Objetivos: Avaliar os efeitos das intervenções farmacológicas no tratamento de pessoas com estenose carotídea assintomática, no intuito de prevenir comprometimento neurológico, acidente vascular cerebral, incapacidade, morte e outras complicações. Métodos: Pesquisamos os registros de ensaios clínicos do Cochrane Stroke Group, dos bancos de dados CENTRAL, MEDLINE, Embase, LILACS e IBECS, bem como ClinicalTrials.gov, Organização Mundial de Saúde e Clinical Trials Registry Platform desde seus inícios até 9 de agosto de 2022. Também verificamos as referências listadas em quaisquer revisões sistemáticas relevantes identificadas e contatados especialistas na área para referências adicionais aos ensaios. Incluímos todos os ensaios clínicos randomizados (ECRs), independentemente do status de publicação e linguagem comparando uma intervenção farmacológica com placebo, nenhum tratamento ou outra intervenção farmacológica para estenose carotídea assintomática. Usamos os procedimentos metodológicos padrão da Cochrane: dois revisores extraíram independentemente os dados e avaliaram o risco de viés dos estudos e um terceiro revisor resolveu as divergências. Avaliamos a certeza dos principais resultados usando o GRADE. Resultados: Incluímos 34 RCTs (11.571 participantes). O período médio de acompanhamento foi de 2,5 anos. Realizamos a análise de sensibilidade comparando efeito fixo versus efeito aleatório para o desfecho 'AVC maior ipsilateral ou incapacitante' em duas comparações: 'Agente hipolipemiante versus placebo ou nenhum tratamento' e 'Uma classe de agente anti-hipertensivo em comparação com outra classe de agente anti-hipertensivo'. Nenhum estudo avaliou o comprometimento neurológico e a qualidade de vida. Quando comparados ao placebo, o agente antiplaquetário (1 estudo; 372 participantes) pode resultar em nenhuma diferença no AVC ipsilateral maior ou incapacitante (taxa de risco (RR) 1,08, intervalo de confiança de 95% (CI) 0,47-2,47; P = 0,86), na mortalidade relacionada ao AVC (RR 1,40, IC 95% 0,54-3,59; P=0,49), na progressão da estenose carotídea (RR 1,16, IC 95% 0,79-1,71; P=0,44) e nos eventos adversos (RR 0,82, IC 95% 0,42 -1,62; P=0,57), com evidência de baixa certeza. O efeito do agente antiplaquetário no sangramento maior é muito incerto (RR 0,98, IC 95% 0,06-15,53; P=0,99; evidência de certeza muito baixa). Agentes hipolipemiantes podem resultar em nenhuma diferença em AVC maior ipsilateral ou incapacitante (RR 0,36, IC 95% 0,09-1,53; P=0,13; 5 estudos; 2235 participantes) e as análises de sensibilidade de efeito fixo mudaram substancialmente a estimativa do efeito (RR 0,39 , IC 95% 0,18-0,87), mortalidade relacionada ao AVC (RR 0,25, IC 95% 0,03-2,29; P=0,82; 2 estudos, 1366 participantes) e eventos adversos (RR 0,76, IC 95% 0,53-1,10; P =0,04; 7 estudos; 3726 participantes) quando comparado com placebo ou nenhum tratamento (evidência de baixa certeza). É incerto se um agente hipolipemiante mais um agente anti-hipertensivo (1 estudo; 225 participantes) previne AVC maior ipsilateral ou incapacitante (RR 0,64, IC 95% 0,27-1,50; P=0,30) ou aumenta eventos adversos (RR 20,09, 95 %CI 1,19-338,84; P=0,04) quando comparado a um agente anti-hipertensivo (evidência de certeza muito baixa). É incerto se uma classe de agente hipolipemiante tem alguma diferença de efeito no AVC maior ou incapacitante ipsilateral (RR 2,96, IC 95% 0,12-72,24; P=0,50; 1 estudo, 332 participantes) e eventos adversos (RR 0,92, 95% CI 0,30-2,86; P=0,89; 2 estudos; 497 participantes) quando comparado a outra classe de agente hipolipemiante (evidência de certeza muito baixa). Duas classes de agentes hipolipemiantes (1 estudo, 683 participantes) podem resultar em nenhuma diferença no AVC maior ou incapacitante ipsilateral (RR 3,04, IC 95% 0,12-74,46; P = 0,49) e eventos adversos (RR 1,25, IC 95% 0,61-2,56; P=0,54) quando comparado a uma classe de agente hipolipemiante (evidência de baixa certeza). Uma dose mais alta de um agente hipolipemiante pode não resultar em diferença no AVC maior ou incapacitante ipsilateral (RR 0,33, IC 95% 0,01-7,72; P=0,49; 1 estudo, 40 participantes; evidência de baixa certeza) e seu efeito sobre eventos adversos é incerto (RR 1,57, IC 95% 0,66-3,71; P=0,31; 1 estudo, 278 participantes; evidência de certeza muito baixa) quando comparado a uma dose baixa da mesma classe de agente hipolipemiante. Quando comparado ao placebo, o efeito de um agente anticoagulante (1 estudo, 919 participantes) em sangramento maior é muito incerto (RR 1,19, IC 95% 0,97-1,46; P=0,10; evidência de certeza muito baixa). No entanto, um agente anticoagulante pode reduzir os eventos adversos (RR 0,89, IC 95% 0,81-0,99; P=0,04; evidência de baixa certeza). Os agentes anti-hipertensivos podem resultar em nenhuma diferença no AVC maior ipsilateral ou incapacitante (RR 0,14, IC 95% 0,02-1,16; P=0,07; 1 estudo, 793 participantes) e mortalidade relacionada ao AVC (RR 0,57, IC 95% 0,17-1,94; P=0,37; 1 estudo, 793 participantes). No entanto, eles podem prevenir a progressão da estenose carotídea quando comparados ao placebo (RR 0,45, IC 95% 0,23-0,91; P=0,02; 1 estudo, 129 participantes; evidência de baixa certeza). Uma classe de agente anti-hipertensivo mais um agente hipolipemiante pode resultar em pouca ou nenhuma diferença no AVC maior ipsilateral ou incapacitante quando comparada a outra classe de agente anti-hipertensivo mais um agente hipolipemiante (RR 0,34, IC 95% 0,01-8,23; P =0,51; 1 estudo, 254 participantes; evidência de baixa certeza). Uma classe de agente anti-hipertensivo pode resultar em pouca ou nenhuma diferença no AVC maior ou incapacitante ipsilateral (RR 0,99, IC 95% 0,34-2,87; P=0,17; 2 estudos, 2.918 participantes) e as análises de sensibilidade de efeito fixo não alteraram o efeito estimado substancialmente (RR 0,88, IC 95% 0,43-1,79). Também pode resultar em pouca ou nenhuma diferença em eventos adversos (RR 1,00, IC 95% 0,82-1,21; P=0,97; 4 estudos, 3239 participantes) quando comparado a outra classe de agente anti-hipertensivo (evidência de baixa certeza). Conclusões: Embora não haja evidência de alta certeza para apoiar a intervenção farmacológica, anticoagulantes podem ter menos eventos adversos que o uso de placebo e anti hipertensivos podem reduzir a probabilidade de progressão da estenose de carótida quando comparado ao placebo.
Background:Carotid artery stenosis is narrowing of the carotid arteries. Asymptomatic carotid stenosis is when this narrowing occurs in people without a history or symptoms of this disease, and it is caused by atherosclerosis, i.e. the build-up of fats, cholesterol, and other substances in and on the artery walls. Atherosclerosis is more likely to occur in people with several risk factors, such as diabetes, hypertension, hyperlipidaemia, and smoking. As this damage can develop without symptoms, the first symptom can be a fatal or disabling stroke, known as ischaemic stroke. Carotid stenosis leading to ischaemic stroke is most common in men older than 70 years. Ischaemic stroke is a worldwide public health problem. Objectives: To assess the effects of pharmacological interventions for the treatment of asymptomatic carotid stenosis in preventing neurological impairment, ipsilateral major or disabling stroke, death, major bleeding, and other outcomes. Methods We searched the Cochrane Stroke Group trials register, CENTRAL, MEDLINE, Embase, LILACS and IBECS databases, as well as ClinicalTrials.gov, World Health Organization International, and Clinical Trials Registry Platform from their inception to 9 August 2022. We also checked the reference lists of any relevant systematic reviews identified and contacted specialists in the field for additional references to trials. We included all randomised controlled trials (RCTs), irrespective of publication status, and language comparing one pharmacological intervention with placebo, no treatment, or another pharmacological intervention for asymptomatic carotid stenosis. We used standard Cochrane methodological procedures. Two review authors independently extracted the data and assessed the risk of bias of the trials. A third reviewer solved disagreements. We assessed the certainty of key outcomes using GRADE. Results: We included 34 RCTs (11,571 participants). The mean follow-up period was on average 2.5 years. We performed the sensitivity analysis comparing fixed-effect versus random-effect for the 'ipsilateral major or disabling stroke' outcome in two comparisons: 'Lipid-lowering agent versus placebo or no treatment' and 'One class of antihypertensive agent compared to another class of antihypertensive agent'. Any study assessed neurological impairment and quality of life.When compared to placebo, antiplatelet agents (1 study; 372 participants) may result in no difference in ipsilateral major or disabling stroke (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.47-2.47; P=0.86), stroke-related mortality (RR 1.40, 95%CI 0.54-3.59; P=0.49), progression of carotid stenosis (RR 1.16, 95%CI 0.79-1.71; P=0.44), and adverse events (RR 0.82, 95%CI 0.42-1.62; P=0.57), with low-certainty evidence. The effect of antiplatelet agents on major bleeding is very uncertain (RR 0.98, 95%CI 0.06-15.53; P=0.99; very low-certainty evidence). Lipid-lowering agents may result in no difference in ipsilateral major or disabling stroke (RR 0.36, 95%CI 0.09-1.53; P=0.13; 5 studies; 2235 participants) and fixed-effect sensitivity analyses changed the effect estimate substantially (RR 0.39, 95%CI 0.18-0.87), stroke-related mortality (RR 0.25, 95%CI 0.03-2.29; P=0.82; 2 studies, 1366 participants), and adverse events (RR 0.76, 95%CI 0.53-1.10; P=0.04; 7 studies; 3726 participants) when compared to placebo or no treatment (low-certainty evidence). It is uncertain whether a lipid-lowering agent plus an antihypertensive agent (1 study; 225 participants) prevent ipsilateral major or disabling stroke (RR 0.64, 95%CI 0.27-1.50; P=0.30) or increase adverse events (RR 20.09, 95%CI 1.19-338.84; P=0.04) when compared to an antihypertensive agent (very low-certainty evidence). It is uncertain whether one class of lipid-lowering agent has any difference of effect in ipsilateral major or disabling stroke (RR 2.96, 95%CI 0.12-72.24; P=0.50; 1 study, 332 participants) and adverse events (RR 0.92, 95%CI 0.30-2.86; P=0.89; 2 studies; 497 participants) when compared to another class of lipid-lowering agent (very low-certainty evidence). Two classes of lipid-lowering agent (1 study, 683 participants) may result in no difference in ipsilateral major or disabling stroke (RR 3.04, 95%CI 0.12-74.46; P=0.49) and adverse events (RR 1.25, 95%CI 0.61-2.56; P=0.54) when compared to one class of lipid-lowering agent (low-certainty evidence). A higher dose of a lipid-lowering agent may result in no difference in ipsilateral major or disabling stroke (RR 0.33, 95%CI 0.01-7.72; P=0.49; 1 study, 40 participants; low-certainty evidence), and its effect on adverse events is uncertain (RR 1.57, 95%CI 0.66-3.71; P=0.31; 1 study, 278 participants; very low-certainty evidence) when compared to a low dose of the same class of lipid-lowering agent. When compared to placebo, the effect of an anticoagulant agent (1 study, 919 participants) on major bleeding is very uncertain (RR 1.19, 95%CI 0.97-1.46; P=0.10; very low-certainty evidence). However, an anticoagulant agent may reduce adverse events (RR 0.89, 95%CI 0.81-0.99; P=0.04; low-certainty evidence). Antihypertensive agents may result in no difference in ipsilateral major or disabling stroke (RR 0.14, 95%CI 0.02-1.16; P=0.07; 1 study, 793 participants) and stroke-related mortality (RR 0.57, 95%CI 0.17-1.94; P=0.37; 1 study, 793 participants). However, they may prevent the progression of carotid stenosis when compared to placebo (RR 0.45, 95%CI 0.23-0.91; P=0.02; 1 study, 129 participants; low-certainty evidence). One class of antihypertensive agent plus a lipid-lowering agent may result in little to no difference in ipsilateral major or disabling stroke when compared to another class of antihypertensive agent plus a lipid-lowering agent (RR 0.34, 95%CI 0.01-8.23; P=0.51; 1 study, 254 participants; low-certainty evidence). One class of antihypertensive agent may result in little to no difference in ipsilateral major or disabling stroke (RR 0.99, 95%CI 0.34-2.87; P=0.17; 2 studies, 2918 participants) and fixed-effect sensitivity analyses did not change the effect estimate substantially (RR 0.88, 95%CI 0.43-1.79). It also may result in little to no difference in adverse events (RR 1.00, 95%CI 0.82-1.21; P=0.97; 4 studies, 3239 participants) when compared to another class of antihypertensive agent (low-certainty evidence). Conclusions: Although there is no high-certainty evidence to support pharmacological intervention, anticoagulants may have fewer adverse events than the use of placebo and antihypertensives may reduce the progression of carotid stenosis when compared to placebo.
Background:Carotid artery stenosis is narrowing of the carotid arteries. Asymptomatic carotid stenosis is when this narrowing occurs in people without a history or symptoms of this disease, and it is caused by atherosclerosis, i.e. the build-up of fats, cholesterol, and other substances in and on the artery walls. Atherosclerosis is more likely to occur in people with several risk factors, such as diabetes, hypertension, hyperlipidaemia, and smoking. As this damage can develop without symptoms, the first symptom can be a fatal or disabling stroke, known as ischaemic stroke. Carotid stenosis leading to ischaemic stroke is most common in men older than 70 years. Ischaemic stroke is a worldwide public health problem. Objectives: To assess the effects of pharmacological interventions for the treatment of asymptomatic carotid stenosis in preventing neurological impairment, ipsilateral major or disabling stroke, death, major bleeding, and other outcomes. Methods We searched the Cochrane Stroke Group trials register, CENTRAL, MEDLINE, Embase, LILACS and IBECS databases, as well as ClinicalTrials.gov, World Health Organization International, and Clinical Trials Registry Platform from their inception to 9 August 2022. We also checked the reference lists of any relevant systematic reviews identified and contacted specialists in the field for additional references to trials. We included all randomised controlled trials (RCTs), irrespective of publication status, and language comparing one pharmacological intervention with placebo, no treatment, or another pharmacological intervention for asymptomatic carotid stenosis. We used standard Cochrane methodological procedures. Two review authors independently extracted the data and assessed the risk of bias of the trials. A third reviewer solved disagreements. We assessed the certainty of key outcomes using GRADE. Results: We included 34 RCTs (11,571 participants). The mean follow-up period was on average 2.5 years. We performed the sensitivity analysis comparing fixed-effect versus random-effect for the 'ipsilateral major or disabling stroke' outcome in two comparisons: 'Lipid-lowering agent versus placebo or no treatment' and 'One class of antihypertensive agent compared to another class of antihypertensive agent'. Any study assessed neurological impairment and quality of life.When compared to placebo, antiplatelet agents (1 study; 372 participants) may result in no difference in ipsilateral major or disabling stroke (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.47-2.47; P=0.86), stroke-related mortality (RR 1.40, 95%CI 0.54-3.59; P=0.49), progression of carotid stenosis (RR 1.16, 95%CI 0.79-1.71; P=0.44), and adverse events (RR 0.82, 95%CI 0.42-1.62; P=0.57), with low-certainty evidence. The effect of antiplatelet agents on major bleeding is very uncertain (RR 0.98, 95%CI 0.06-15.53; P=0.99; very low-certainty evidence). Lipid-lowering agents may result in no difference in ipsilateral major or disabling stroke (RR 0.36, 95%CI 0.09-1.53; P=0.13; 5 studies; 2235 participants) and fixed-effect sensitivity analyses changed the effect estimate substantially (RR 0.39, 95%CI 0.18-0.87), stroke-related mortality (RR 0.25, 95%CI 0.03-2.29; P=0.82; 2 studies, 1366 participants), and adverse events (RR 0.76, 95%CI 0.53-1.10; P=0.04; 7 studies; 3726 participants) when compared to placebo or no treatment (low-certainty evidence). It is uncertain whether a lipid-lowering agent plus an antihypertensive agent (1 study; 225 participants) prevent ipsilateral major or disabling stroke (RR 0.64, 95%CI 0.27-1.50; P=0.30) or increase adverse events (RR 20.09, 95%CI 1.19-338.84; P=0.04) when compared to an antihypertensive agent (very low-certainty evidence). It is uncertain whether one class of lipid-lowering agent has any difference of effect in ipsilateral major or disabling stroke (RR 2.96, 95%CI 0.12-72.24; P=0.50; 1 study, 332 participants) and adverse events (RR 0.92, 95%CI 0.30-2.86; P=0.89; 2 studies; 497 participants) when compared to another class of lipid-lowering agent (very low-certainty evidence). Two classes of lipid-lowering agent (1 study, 683 participants) may result in no difference in ipsilateral major or disabling stroke (RR 3.04, 95%CI 0.12-74.46; P=0.49) and adverse events (RR 1.25, 95%CI 0.61-2.56; P=0.54) when compared to one class of lipid-lowering agent (low-certainty evidence). A higher dose of a lipid-lowering agent may result in no difference in ipsilateral major or disabling stroke (RR 0.33, 95%CI 0.01-7.72; P=0.49; 1 study, 40 participants; low-certainty evidence), and its effect on adverse events is uncertain (RR 1.57, 95%CI 0.66-3.71; P=0.31; 1 study, 278 participants; very low-certainty evidence) when compared to a low dose of the same class of lipid-lowering agent. When compared to placebo, the effect of an anticoagulant agent (1 study, 919 participants) on major bleeding is very uncertain (RR 1.19, 95%CI 0.97-1.46; P=0.10; very low-certainty evidence). However, an anticoagulant agent may reduce adverse events (RR 0.89, 95%CI 0.81-0.99; P=0.04; low-certainty evidence). Antihypertensive agents may result in no difference in ipsilateral major or disabling stroke (RR 0.14, 95%CI 0.02-1.16; P=0.07; 1 study, 793 participants) and stroke-related mortality (RR 0.57, 95%CI 0.17-1.94; P=0.37; 1 study, 793 participants). However, they may prevent the progression of carotid stenosis when compared to placebo (RR 0.45, 95%CI 0.23-0.91; P=0.02; 1 study, 129 participants; low-certainty evidence). One class of antihypertensive agent plus a lipid-lowering agent may result in little to no difference in ipsilateral major or disabling stroke when compared to another class of antihypertensive agent plus a lipid-lowering agent (RR 0.34, 95%CI 0.01-8.23; P=0.51; 1 study, 254 participants; low-certainty evidence). One class of antihypertensive agent may result in little to no difference in ipsilateral major or disabling stroke (RR 0.99, 95%CI 0.34-2.87; P=0.17; 2 studies, 2918 participants) and fixed-effect sensitivity analyses did not change the effect estimate substantially (RR 0.88, 95%CI 0.43-1.79). It also may result in little to no difference in adverse events (RR 1.00, 95%CI 0.82-1.21; P=0.97; 4 studies, 3239 participants) when compared to another class of antihypertensive agent (low-certainty evidence). Conclusions: Although there is no high-certainty evidence to support pharmacological intervention, anticoagulants may have fewer adverse events than the use of placebo and antihypertensives may reduce the progression of carotid stenosis when compared to placebo.
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Citação
CLEZAR,Caroline Nicacio Bessa. Intervenções Farmacológicas para pessoas com Estenose Assintomática de Carótidas: uma revisão sistemática e metanálise Cochrane. 2023. 313 f. Tese (Doutorado em Saúde Baseada em Evidências) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP). São Paulo, 2023.