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Therapeutic Effects of HF Medical Therapies on Kidney Outcomes
Quick Takes
- The event rates of standardized composite kidney endpoints in clinical studies were largely influenced by different eGFR thresholds used to define a sustained and meaningful decline in kidney function.
- Furthermore, when applying stringent endpoint definitions, steroidal MRAs, ARNI, and SGLT2 inhibitors had either neutral or beneficial effects on kidney outcomes.
- These data underscore the importance of carefully considering the definition of the composite kidney outcomes when interpreting studies, as well as evaluation of enriched HF patient populations for kidney risk.
Study Questions:
What are the effects of steroidal mineralocorticoid receptor antagonists (MRAs), the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, and sodium-glucose cotransporter-2 (SGLT2) inhibitors on composite kidney endpoints using uniform definitions in six contemporary heart failure (HF) trials?
Methods:
The investigators included individual participant-level data from trials of steroidal MRAs (EMPHASIS-HF, TOPCAT Americas), ARNI (PARADIGM-HF, PARAGON-HF), and SGLT2 inhibitors (DAPA-HF, DELIVER). The standardized composite kidney endpoint was defined as a sustained decline (a reduction in estimated glomerular filtration rate [eGFR] confirmed by a subsequent measurement ≥30 days later) in eGFR by 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. The effect of the investigational therapy versus placebo or an active comparator on the composite kidney endpoint, and on end-stage kidney disease alone, was evaluated separately for each trial with Cox proportional-hazards models.
Results:
Among 28,690 participants across the six trials (median age 69 years [interquartile range, 62-76]; 9,656 [33.7%] women), the proportion experiencing the composite kidney endpoint with a more stringent definition of a sustained decline in kidney function (eGFR threshold of 57%) ranged from 0.3% to 3.3%. The proportion of patients experiencing this endpoint with a less stringent definition (eGFR threshold of 40%) ranged from 1.0% and 10.0%. The steroidal MRAs doubled the risk of the composite kidney endpoint when applying the least stringent definition compared with placebo, but these effects were less apparent and no longer significant with application of more stringent definitions. ARNI appeared to consistently reduce the occurrence of the composite kidney endpoints irrespective of specific eGFR threshold applied. The potential benefits of SGLT2 inhibitors on the composite kidney endpoints appeared more apparent when defined by more stringent eGFR thresholds, although none of these effects individually were statistically significant.
Conclusions:
The authors report that applying standardized stringent kidney endpoint definitions, steroidal MRAs, ARNI, and SGLT2 inhibitors have either neutral or beneficial effects on kidney outcomes in HF.
Perspective:
This study examined standardized kidney endpoints with three therapeutic classes in patients with HF with reserved ejection fraction (EF) and HF with mid-range EF/HF with preserved EF and report that the event rates of standardized composite kidney endpoints were largely influenced by different eGFR thresholds used to define a sustained and meaningful decline in kidney function, with substantially higher event rates observed with less stringent definitions. Furthermore, when applying stringent endpoint definitions, steroidal MRAs, ARNI, and SGLT2 inhibitors had either neutral or beneficial effects on kidney outcomes. On the other hand, applying less stringent endpoint definitions substantially increased event rates but included acute declines in GFR that might not ultimately reflect long-term kidney effects. These data underscore the importance of carefully considering the definition of the composite kidney outcomes when interpreting studies, as well as evaluation of enriched HF patient populations for kidney risk.
Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Prevention
Keywords: Glomerular Filtration Rate, Heart Failure, Kidney Diseases, Novel Agents
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