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Mc Causland FR, Lefkowitz MP, Claggett B, et al. Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure With Preserved Ejection Fraction. Circulation. 2020 Sep 29;142(13):1236-1245. doi: 10.1161/CIRCULATIONAHA.120.047643. Epub 2020 Aug 17. (Original study)
Abstract

BACKGROUND: In patients with heart failure, chronic kidney disease is common and associated with a higher risk of renal events than in patients without chronic kidney disease. We assessed the renal effects of angiotensin/neprilysin inhibition in patients who have heart failure with preserved ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction).

METHODS: In this randomized, double-blind, event-driven trial, we assigned 4822 patients who had heart failure with preserved ejection fraction to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein, we present the results of the prespecified renal composite outcome (time to first occurrence of either: =50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope.

RESULTS: At randomization, eGFR was 63±19 mL·min-1·1.73 m-2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio, 0.50 [95% CI, 0.33-0.77]; P=0.001). The treatment effect on the composite renal end point did not differ according to the baseline eGFR (<60 versus =60 mL·min-1·1.73 m-2 (P-interaction=0.92). The decline in eGFR was less for sacubitril/valsartan than for valsartan (-2.0 [95% CI, -2.2 to -1.9] versus -2.7 [95% CI, -2.8 to -2.5] mL·min-1·1.73 m-2 per year).

CONCLUSIONS: In patients with heart failure with preserved ejection fraction, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, in comparison with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Ratings
Discipline Area Score
Nephrology 7 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Internal Medicine 6 / 7
Cardiology 5 / 7
Comments from MORE raters

Family Medicine (FM)/General Practice (GP) rater

HFpEF is not studied as well as HFrEF, so it's refreshing to see a study focused on the condition. The study showed that an angiotensin receptor-neprilysin inhibitor improved the rate of decline of GFR. Although this study focuses on an important topic and suggests benefit, it remains to be seen whether this outcome connects to clinically relevant outcomes like need for medication dosing changes or dialysis.

General Internal Medicine-Primary Care(US) rater

This study has shed the light to another potential drug regimen than can slow the deterioration of kidney function with CKD patients with HFpEF. This is post hoc analysis of PARAGON HF study. However, one caveat is that they do not measure urine microalbuminuria as part of its outcomes.

Internal Medicine rater

This appears to show a small benefit in a small study. Nothing practice-changing.

Nephrology rater

This is useful because appropriate therapy for HFpEF has not been clear. However though the relative effect is significant, the absolute risk reduction is small (given the low rate of outcomes in the valsartan group).

Nephrology rater

Previous trials of nephrilysin inhibition have used slope of GFR. These results are aligned with those, in showing renal benefit, but allow us a more concrete grasp of the potential importance to patients. This is a secondary trial outcome in an RCT of HFpEF with eGFR>25: 50% decline in GFR, death from kidney causes or ESRD: 1.4% in sacubitril/valsartan and 2.7% in valsartan, NNT 76. Follow up time for these real outcomes is not given; instead modelled outcomes at full 4 year follow up are provided (only ~270 patients actually followed for 4 years): 2.1% vs 4.1% NNT 50. I don't see stratified analyses by baseline GFR, UACR, sex and age, though the discussion says that there was no interaction with GFR >60 v &lt;60. This is all useful new information.
Comments from EvidenceAlerts subscribers

Prof. Michal Nowicki (10/10/2020 3:54 AM)

The answer to the difference in renal effects between valsartan plus sacubitril versus valsartan alone are the data in Supplementary Table II. The combination has led to better control of blood pressure than valsartan alone, and this explains better renal outcome. This seems not to be due to any mysterious nephroprotective effect of neprilysin inhibitor but its mild blood pressure-lowering effect