‘Dips’ in eGFR after sacubitril/valsartan transition should not stall HF therapy
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Key takeaways:
- Declines in estimated glomerular filtration rate after transition to sacubitril/valsartan for HF are mild and temporary.
- Clinicians should not stall or discontinue therapy due to “dips” in renal function.
Declines in renal function observed during transition from a renin-angiotensin system inhibitor to sacubitril/valsartan for HF are variable but usually small and partially recoverable for most patients, researchers reported.
Although renal impairment is an important adverse prognostic indicator in people with HF, many therapies used in HF management, such as renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists and SGLT2 inhibitors may result in early declines in estimated glomerular filtration rate (eGFR), Scott D. Solomon, MD, professor of medicine at Harvard Medical School and senior physician at Brigham and Women’s Hospital, and colleagues wrote in the Journal of the American College of Cardiology. The declines in eGFR are thought to reflect intraglomerular hemodynamic alterations and mechanisms of tubuloglomerular feedback, and not intrinsic kidney injury, they wrote.
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“Moreover, although some of these drugs have demonstrated renal protective effects, renal dysfunction remains a common clinical concern and may prompt premature discontinuation of the drug,” the researchers wrote. “Understanding the heterogeneity in response to declines in renal function early after starting HF therapies is therefore important.”
Assessing renal function
Solomon and colleagues evaluated the association between the occurrence of moderate eGFR decline (>15%) after initial exposure to sacubitril/valsartan (Entresto, Novartis) and subsequent CV outcomes and its treatment benefits, using data from the PARADIGM-HF and PARAGON-HF studies. Study participants received enalapril 10 mg twice daily and then sacubitril/valsartan 97 mg/103 mg twice daily (in PARADIGM-HF) or valsartan 80 mg twice daily and then sacubitril/valsartan 49 mg/51 mg twice daily (in PARAGON-HF).
Among randomly assigned participants, 11% in PARADIGM-HF and 10% in PARAGON-HF experienced an eGFR decline of at least 15% during the sacubitril/valsartan run-in period. For these participants, eGFR partially recovered by week 16 after randomization regardless of sacubitril/valsartan continuation or a switch to a renin-angiotensin system inhibitor.
For both trials, eGFR decline was not consistently associated with clinical outcomes. Treatment benefits of sacubitril/valsartan vs. a renin-angiotensin system inhibitor on primary outcomes were similar irrespective of an eGFR decline in PARADIGM-HF (HR = 0.69; 95% CI, 0.53-0.9) vs. no eGFR decline (HR = 0.8; 95% CI, 0.73-0.88; P for interaction = .32). Results were similar in analyses of the PARAGON-HF trial, with outcomes similar among participants who experienced an eGFR decline (RR = 0.84; 95% CI, 0.52-1.36) or no eGFR decline (RR = 0.87; 95% CI, 0.75-1.02; P for interaction = .92).
The treatment effect of sacubitril/valsartan did not vary across a range of eGFR declines, according to the researchers.
“The occurrence of eGFR decline on transition from treatment with a renin-angiotensin system inhibitor to sacubitril/valsartan is highly variable, usually mild, and partially recoverable in most patients,” the researchers wrote. “Moderate eGFR declines with transition to sacubitril/valsartan do not appear to portend adverse prognostic significance consistently. Moreover, the treatment benefits of sacubitril/valsartan vs. renin-angiotensin system inhibitor remains apparent across a range of acute early eGFR declines. Taken together, early treatment-related eGFR changes with sacubitril/valsartan should not deter its continuation or stall uptitration.”
Managing short-term ‘pain’ of eGFR dip
In a related editorial, Steven G. Coca, DO, MS, a professor medicine and associate chair of clinical and translational research in the department of medicine at Icahn School of Medicine at Mount Sinai, wrote that therapies that reduce risk for major CV outcomes can be associated with early eGFR decline, with a greater magnitude of the eGFR decline (or “dip”) seen when combining such therapies.
“This is the clinical tension; drug therapies that can improve outcomes over the long-term often come with some short-term ‘pain’ as manifested by the initial rise in serum creatinine/dip in eGFR,” Coca wrote.
Coca wrote that the eGFR dips after starting drugs with a CV benefit are analogous to a renal stress test that denotes overall higher baseline risk, meaning continuation of therapy, and no discontinuation or de-escalation, is key.
“Moderate declines in eGFR do not signify intolerability to the therapy,” Coca wrote. “In order to improve the health of patients with HF, our collective goal as treating clinicians should be to rid our propensity to react to these modest changes in eGFR and rather accept them as the expected physiologic effect.”
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