Sex differences in the efficacy and safety of sacubitril/valsartan in patients with heart failure - systematic review and individual patient data meta-analysis

Sex differences in the efficacy and safety of sacubitril/valsartan in patients with heart failure - systematic review and individual patient data meta-analysis

Background: Heart failure (HF) poses a global burden for patients, families and healthcare systems. Over 10 years ago Sacubitril/ valsartan as a new treatment was approved in the United States of America and Europe. Despite causes (e.g. gestational diabetes) and symptoms (e.g. extreme fatigue) of heart failure differ between men and women, the trials of Sacubitril/ Valsartan included, in majority, men as study participants. We aim to analyze data from several clinical trials to see if Sacubitril/ Valsartan is as effective and safe for women as it is for men. The results will help us understand what men and women need individually for an effective treatment with sacubitril/valsartan. Purpose: We want to find out whether there are any differences in how well sacubitril/valsartan works for men and women with heart failure. We will look at the results of the treatment for both sexes separately.Methods: To overview the existing literature, we conducted a preliminary systematic review including adult patients with heart failure, treated with sacubitril/ valsartan in a randomized controlled design to identify relevant trials and publications. After screening and data extraction, we identified a lack of reporting of sex-specific results in the current literature, which led to the exclusion of 186 publications. Based on the lack of sex-specific stratification in published reports, we planned an individual patient data analysis and requested individual patient data for the included trials. An individual patient-data analysis enables us to close the gap between reporting and available study results / information. While a traditional meta-analysis statistically summarizes the aggregated results of published literature an individual patient data analysis uses the individual study data from each participant. This approach allows us, to analyze detailed questions in terms of unpublished study outcomes or subgroups (e.g. men vs. women). This will help us answer any remaining questions about detailed or unpublished sex-specific effects and safety in the use of sacubitril/ valsartan. This is a public health problem because we don't know if sacubitril/valsartan has the same effect on men and women, or if it causes the same problems for both sexes. So, we want to look at how well sacubitril/valsartan works and how safe it is for both men and women with heart failure. As set out in the PROSPERO registration process for the review (CRD420251138114), we defined Quality of Life as the main way to measure how well the treatment worked, and treatment discontinuations due to adverse events as the main way to measure safety. Secondary outcomes include common heart failure outcomes: death (cardiovascular, all-cause), hospitalization, (cardiovascular, all-cause), NT-Pro BNP, a highly sensitive marker for diagnosing, excluding and monitoring heart failure and The New York Heart Association (NYHA) Functional Classification to classify the severity of heart failure. Some of the other secondary safety outcomes we are looking at include low blood pressure, kidney problems, stopping treatment, swelling, high creatinine levels and high potassium levels. We will look at whether there are any differences between men and women in these outcomes.

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