Decline in glomerular filtration rate as an endpoint in heart failure clinical trials: challenges and solutions

Chronic kidney disease (CKD) and cardiovascular disease are tightly interconnected, with common mechanisms that underlie the development and progression of both diseases, recently articulated into the framework of the cardiovascular-kidney-metabolic syndrome. CKD and heart failure commonly coexist in the same individual, with increasing evidence for common therapies in both disease states. It is valuable for patients, clinicians, and regulatory agencies to understand how to best assess CKD progression in patients with heart failure for evaluation of individual patients and as part of an endpoint for outcome trials. Given the relatively short duration of most heart failure outcome trials, early measures of CKD progression prior to the occurrence of clinical events of kidney replacement therapy would be desirable. Such surrogate measures include slowing of the decline in glomerular filtration rate (GFR) decline either computed as annualized mean change in GFR (GFR slope) or time to substantial declines in GFR by specified threshold percentages (40% or 50% GFR decline). Regulatory agencies accept these endpoints for full drug approval which has enabled progress in design and conduct of trials for CKD progression. Application of these endpoints in heart failure outcome trials has the potential for similar progress. However, an immediate reduction in GFR is common following initiation of several of the guideline directed therapy for heart failure. Understanding how to best interpret an immediate GFR reduction vs long term kidney benefit is critical to optimal assessment of endpoint in an outcome trial and in the use of these medications for management of patients with heart failure. Here, the intersection of heart failure and CKD is described, how GFR and its change over time are assessed in both individual patients and in interventional trials, the evidence supporting use of GFR changes as endpoints in CKD progression trials, and the challenges and possible solutions for the use of GFR as endpoint in heart failure outcome trials and for care of individual patients, guided by case studies to inform the discussion.