Effects of heart failure therapies on standardised kidney outcomes
Chronic kidney disease (CKD) is common in people with heart failure (HF) and increases in prevalence as HF progresses. This may complicate treatment, and people with HF with CKD have worse outcomes than those without.
Trials of new pharmacological therapies for HF have found potentially favourable effects on kidney function. As eGFR slope is not well validated as a measure of kidney function decline in HF populations, composite endpoints of more clinically relevant kidney outcomes have been constructed for key trials.
There has, however, been no standardisation between these trials, making it difficult to compare and interpret results. Butt and colleagues, therefore, examined the effects of three therapeutic classes – steroidal mineralocorticoid receptor antagonists (MRAs), the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan and sodium–glucose cotransporter 2 inhibitors (SGLT2is) – on composite kidney endpoints using uniform definitions.
Individual participant-level data were included from six outcomes trials in HF: two trials of MRAs (EMPHASIS-HF and TOPCAT Americas), two of ARNI (PARADIGM-HF and PARAGON-HF) and two of SGLT2is (DAPA-HF and DELIVER). The standardised composite endpoint was defined as a sustained decline in eGFR of 40%, 50% or 57%; end-stage kidney disease; or renal death. eGFR was recalculated in a standardized manner using the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation.
Across the six trials, 28,690 participants (median age, 69 years; 9656 [33.7%] women) were included in the analysis. When applying a more stringent definition of a sustained decline in kidney function (eGFR threshold of 57%) the proportion experiencing the composite kidney endpoint ranged from 0.3% to 3.3%. The proportion experiencing this endpoint with a less stringent definition (eGFR threshold of 40%) ranged from 1.0% to 10.0%.
In both trials, the steroidal MRAs doubled the risk of the composite kidney endpoint when applying the least stringent definition compared with placebo. These effects were less apparent and no longer significant with the application of more stringent definitions.
Neprilysin inhibition with ARNI appeared consistently to reduce the occurrence of the composite kidney endpoint, compared with enalapril and valsartan, irrespective of the specific eGFR threshold applied. The reduction was only statistically significant with the least stringent definition.
In both SGLT2i trials, the potential benefits on the composite kidney endpoint were more apparent when defined by more stringent eGFR thresholds compared with placebo. None of these effects individually were statistically significant.
When applying stringent endpoint definitions, the three therapeutic classes had either neutral or beneficial effects on composite kidney outcomes in HF. Applying less stringent definitions increased events rates, but included acute declines in eGFR that might not ultimately reflect long-term kidney effects.
The authors suggest that the choice of kidney endpoint definitions in HF trials should consider the characteristics of the investigational drug and the population of interest.
The full article can be read here.
