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Safety and tolerability of sacubitril-valsartan : a systematic review and meta-analysis
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Introdução
O Sacubitril-valsartan é um fármaco recente que já tem um papel importante na gestão da insuficiência cardíaca. Deste modo, realizámos uma revisão sistemática e meta-análise de ensaios clínicos randomizados (ECR) para sintetizar a evidência disponível referente à segurança e tolerabilidade do sacubitril-valsartan.
Métodos
Fizemos uma pesquisa procurando ECRs com doentes sob terapêutica com sacubitril-valsartan para qualquer patologia médica, comparando com a terapêutica standard ou placebo, nas bases de dados CENTRAL, Embase, MEDLINE e registos de ensaios clínicos (outubro/2019). Os dados foram rastreados, extraídos e avaliados por dois revisores independentes. Agrupámos os resultados usando o modelo de efeitos aleatórios e aplicando o risco relativo (RR) com um intervalo de confiança de 95% (IC95%). Os outcomes foram acontecimentos adversos graves (AAG), descontinuação devido a acontecimentos adversos, acontecimentos adversos (AA) e cinco acontecimentos de interesse (angioedema; tosse; hipercaliemia; hipotensão; lesão renal aguda [LRA]). Seguimos as guidelines PRISMA e avaliámos a confiança na evidência usando as normas GRADE.
Resultados
Incluímos vinte ECRs, representando 22510 participantes. O risco de AAG não foi significativamente reduzido com o sacubitril-valsartan (RR=0.94, IC95% 0.86-1.01; I2=32%; certeza moderada), tal como o risco de AA (RR=1.00, IC95% 0.97-1.03; I2=41%; certeza baixa). Contudo, a descontinuação devido a AAs apresenta uma redução de risco de 9% (IC95% 0.84-0.99; I2=0%; certeza elevada). Por outro lado, o risco de hipotensão foi significativamente aumentado (RR=1.46 IC95% 1.28-1.65; I2=18%; certeza moderada). Não existiram diferenças significativas, relativamente ao risco de angioedema, tosse, hipercaliemia e LRA. Considerando as análises de subgrupos, o sacubitril-valsartan apresentou uma redução do risco de AAG (RR=0.91, IC95% 0.87-0.95; I2=0%) comparando com IECA. Além disso, existiu um risco reduzido de descontinuação devido AAs (RR=0.92, IC95% 0.84-1.00; I2=0%), para um período superior a doze meses. Não foram encontradas diferenças significativas noutros outcomes primários. Conclusões
O Sacubitril-Valsartan demonstrou ser pelo menos tão seguro e tolerável como qualquer outro controlo. Este apresentou um menor risco de descontinuação, com uma redução significativa durante períodos extensos, como um risco diminuído de eventos adversos sérios, quando comparado com IECA. Contudo, apresentou risco aumentado de hipotensão. Relativamente aos outros eventos adversos de interesse, não se observaram diferenças significativas no risco associado.
Background Sacubitril-valsartan is a recent drug which has already a major role in the management of heart failure. Therefore, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to summarize the available evidence regarding the safety and tolerability of sacubitril-valsartan. Methods We searched for RCTs enrolling patients receiving sacubitril-valsartan for any medical condition, compared with standard therapy or placebo, in CENTRAL, EMBASE, MEDLINE, and trial registries (October/2019). Data was screened, extracted, and assessed by two independent reviewers. We pooled results using a random-effects model and applied Risk Ratios (RR) with 95% confidence intervals (95%CI). Outcomes were serious adverse events (SAE), discontinuation due to adverse events, adverse events (AE), and five events of interest (angioedema; cough; hyperkalemia; hypotension; acute kidney injury [AKI]). We followed the PRISMA guidelines and appraised confidence in the evidence using the GRADE norms. Results We included twenty RCTs, enrolling 22510 participants. The risk of SAE was not significantly reduced with sacubitril-valsartan (RR=0.94, 95%CI 0.86-1.01; I2=32%; moderate certainty), as well as the risk of AE (RR=1.00, 95%CI 0.97-1.03; I2=41%; low certainty). However, discontinuation due to AEs presented a 9% risk reduction (95%CI 0.84-0.99; I2=0%; high certainty). Conversely, the risk of hypotension was significantly increased (RR=1.46 95%CI 1.28-1.65; I2=18%; moderate certainty). There were non-significant differences, concerning the risk of angioedema, cough, hyperkalemia and AKI. Regarding subgroup analyses, sacubitril-valsartan reported a reduced risk of SAE (RR=0.91, 95%CI 0.87-0.95; I2=0%) compared to ACEi. Furthermore, there was a reduced risk of discontinuation due to AEs (RR=0.92, 95%CI 0.84-1.00; I2=0%), for a longer than twelve months period. We found non-significant differences in other primary outcomes. Conclusions Sacubitril-Valsartan was at least as safe and tolerable as any other control. It presented a decreased risk of discontinuation, with a significant reduction during extended periods, as well as a diminished risk of serious adverse events, when compared to ACEi. However, it was in greater risk of hypotension. Concerning the other adverse events of interest, there were non-significant differences of associated risk.
Background Sacubitril-valsartan is a recent drug which has already a major role in the management of heart failure. Therefore, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to summarize the available evidence regarding the safety and tolerability of sacubitril-valsartan. Methods We searched for RCTs enrolling patients receiving sacubitril-valsartan for any medical condition, compared with standard therapy or placebo, in CENTRAL, EMBASE, MEDLINE, and trial registries (October/2019). Data was screened, extracted, and assessed by two independent reviewers. We pooled results using a random-effects model and applied Risk Ratios (RR) with 95% confidence intervals (95%CI). Outcomes were serious adverse events (SAE), discontinuation due to adverse events, adverse events (AE), and five events of interest (angioedema; cough; hyperkalemia; hypotension; acute kidney injury [AKI]). We followed the PRISMA guidelines and appraised confidence in the evidence using the GRADE norms. Results We included twenty RCTs, enrolling 22510 participants. The risk of SAE was not significantly reduced with sacubitril-valsartan (RR=0.94, 95%CI 0.86-1.01; I2=32%; moderate certainty), as well as the risk of AE (RR=1.00, 95%CI 0.97-1.03; I2=41%; low certainty). However, discontinuation due to AEs presented a 9% risk reduction (95%CI 0.84-0.99; I2=0%; high certainty). Conversely, the risk of hypotension was significantly increased (RR=1.46 95%CI 1.28-1.65; I2=18%; moderate certainty). There were non-significant differences, concerning the risk of angioedema, cough, hyperkalemia and AKI. Regarding subgroup analyses, sacubitril-valsartan reported a reduced risk of SAE (RR=0.91, 95%CI 0.87-0.95; I2=0%) compared to ACEi. Furthermore, there was a reduced risk of discontinuation due to AEs (RR=0.92, 95%CI 0.84-1.00; I2=0%), for a longer than twelve months period. We found non-significant differences in other primary outcomes. Conclusions Sacubitril-Valsartan was at least as safe and tolerable as any other control. It presented a decreased risk of discontinuation, with a significant reduction during extended periods, as well as a diminished risk of serious adverse events, when compared to ACEi. However, it was in greater risk of hypotension. Concerning the other adverse events of interest, there were non-significant differences of associated risk.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2020
Palavras-chave
Sacubitril-valsartan Segurança Revisão sistemática Meta-análise Acontecimentos adversos