Title: Composite primary endpoints for randomised controlled trials of invasive and surgical procedures
Funder: The Academy of Medical Sciences

Abstract: Background: Randomised controlled trials (RCTs) of surgery face challenges in the selection of an appropriate primary endpoint, significant costs, and recruitment difficulties. The use of a composite primary endpoint can mitigate these hindrances through reduction of requisite sample size and duration of study, whilst representing the broader effects of an intervention. Inappropriate usage of composite endpoints carries the risk of censoring outcomes and misleading trial results. No dedicated assessment of the use of composite endpoints in surgical RCTs has been conducted to date, and guidance in general is scant. Aim: To improve methods for developing and reporting composite primary endpoints in surgical trials, focussing on chronic limb threatening ischaemia (CLTI) as an exemplar case study. Methods: A systematic review will be conducted to understand the strengths and deficiencies associated with the use of composite endpoints in surgical RCTs, and develop guidance in this domain. Component outcomes of relevance to a composite endpoint for CLTI intervention will be identified from registered RCTs and semi-structured interviews with participants (approximately 30 patients and clinicians). Outcomes will be ranked for inclusion in 30-day and 1-year composite endpoints through nominal group consensus with patients, stakeholders, statisticians and methodologists, taking into account lessons learned from the preceding systematic review. Appropriate statistical methods will be used to analyse the proposed composite outcomes. Subsequent validity and feasibility testing will permit refinement of the composites and honing of guidance that will be relevant to surgeons in general in this field.

Lay abstract: Research studies that compare two surgical treatments are hard to design and undertake. One reason is because it is difficult to select the best endpoint to measure the benefits/harms of the procedures being evaluated. One solution to this problem is to use a measure that combines several different types of endpoints. This is called a ‘composite endpoint’. As the composite endpoint involves several endpoints being measured at once, fewer patients are needed in the research study. This means the study can be completed more efficiently. However, there is little guidance about how a composite endpoint should be created and used, particularly in studies of surgery. Chronic limb threatening ischaemia (CLTI) is a condition in which diseased blood vessels reduce the blood supply to the leg. Patients with CLTI are at high risk of death, leg amputation, disability and reduced quality of life. A national survey revealed CLTI to be the most important area needing research in blood vessel disease. However, these studies are particularly challenging to recruit patients to. Using a well-developed composite endpoint may improve the quality of research studies in CLTI. We aim to develop guidance for developing composite endpoints for studies of surgical procedures, using CLTI as a case study. We will use a range of research methods and work with patients, surgeons and experts in designing research studies. During our work, we will also develop and test composite endpoints for research studies in CLTI.

Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE