Antithrombotic Therapy Recommendations in the European Society of Cardiology Guidelines: How Robust Are the Randomized Controlled Trials Underpinning Them?

Luísa Prada,Fausto J Pinto,João Costa,Joaquim J Ferreira,Daniel Caldeira,Cláudio David,Catarina M Dos Santos

doi:10.1055/s-0041-1725043

Abstract

Introduction Criticisms have been raised against the sole use of p -value in interpreting results from randomized controlled trials (RCTs). Additional tools have been suggested, like the fragility index (FI), a measure of a trial's robustness/fragility, and derivative measures. The FI is the minimum number of patients who would have to be converted from nonevents to events, in the group with the least events, for a result to lose statistical significance. Objective This study aimed to evaluate RCT supporting European Society of Cardiology (ESC) guidelines regarding antithrombotics, using the FI and FI-related measures. Methods FI, fragility quotient (FQ), and FI minus LTF lost to follow-up (FI − LTF) were calculated for the RCT underpinning recommendations regarding antithrombotic therapy from the updated ESC guidelines. LTF was compared with FI. Results were calculated for the total group of studies, as per guideline and as per recommendation type. Results Overall, 61 studies were included. The median FI was 24.5 (interquartile range [IQR]: 9.0–60.0) and median FQ was 0.0035 (IQR: 0.0019–0.0056). Median FI − LTF was 2.0 (IQR: 0.0–38.0). Twenty (32.8%) of the studies had one primary or main safety outcome with LTF exceeding FI. Peripheral arterial disease guideline and chronic coronary syndrome guideline had the lowest (2.5; IQR: 1.8–3.3) and the highest (48.5; IQR: 23.8–73.0) FI, respectively. Conclusion The median FI suggests robustness of clinical trials evaluating antithrombotic drugs cited in the guidelines, but about one-third of them had LTF larger than FI. This emphasizes the need for assessing trials' robustness when constructing guidelines.

Highlights

Criticisms have been raised against the sole use of p-value in interpreting results from randomized controlled trials (RCTs)
The median fragility index (FI) suggests robustness of clinical trials evaluating antithrombotic drugs cited in the guidelines, but about one-third of them had lost to follow-up (LTF) larger than FI
We propose to assess the robustness of the outcomes of RCT underpinning the recommendations regarding antithrombotic therapy in the most recent versions of the European Society of Cardiology (ESC) guidelines[9] through the FI and related measurements

Summary

Introduction

Criticisms have been raised against the sole use of p-value in interpreting results from randomized controlled trials (RCTs). The FI is the minimum number of patients who would have to be converted from nonevents to events, in the group with the least events, for a result to lose statistical significance. Introduced in 1990 by Feinstein[4] and brought back in 2014 by Walsh et al,[5] it is a tool for assessing a trial’s robustness It can be defined as the minimum number of patients who would have to be converted from nonevents to events, in the group with the least events, for the results to lose their statistical significance. The lower it is, the less robust or more fragile a study is considered.[5–7]. If study A has a sample size of 100 and study B of 1,000, FQ for study A is 0.1 whereas FQ for study B is 0.01

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Discussion

Conclusion