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Early initiation of sacubitril/valsartan associated with better outcomes in heart failure

12 Mar 2020
In patients with heart failure with reduced ejection fraction (HFrEF) hospitalized for acute decompensated HF (ADHF) who have achieved haemodynamic stability, early in-hospital initiation of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan is associated with a significant reduction in HF rehospitalization or cardiovascular (CV) death compared with delayed initiation of sacubitril/valsartan after 8 weeks of enalapril treatment, a secondary analysis of the PIONEER-HF trial has shown. 

Reduction in HF rehospitalization or CV death

In the PIONEER-HF trial, patients with HFrEF hospitalized for ADHF were randomized, after haemodynamic stabilization, to receive sacubitril/valsartan (target dose, 97/103 mg BID; n=440) or enalapril (target dose, 10 mg BID; n=441) for 8 weeks. [N Engl J Med 2019;380:539-548] Following the 8-week randomized trial period, 832 patients (94 percent; 417 in the sacubitril/valsartan arm, 415 in the enalapril arm) received another 4 weeks of open-label treatment with sacubitril/valsartan at the same target dose. [JAMA Cardiol 2019, doi: 10.1001/jamacardio.2019.4665]

Results of a secondary analysis, reported after the 4-week open-label extension phase, showed a 31 percent relative reduction in incidence of HF rehospitalization or CV death over the entire 12 weeks of follow-up among patients who were started on sacubitril/valsartan earlier during HF hospitalization, compared with those who were started on enalapril in the hospital and switched to sacubitril/valsartan 8 weeks later (ie, post-hospitalization) (13.0 percent vs 18.1 percent; hazard ratio [HR], 0.69; 95 percent confidence interval [CI], 0.49 to 0.97; p=0.03). [JAMA Cardiol 2019, doi: 10.1001/jamacardio.2019.4665]

“The benefits of in-hospital initiation of sacubitril/valsartan on CV events were observed early after hospital discharge at 8 weeks and remained substantial at 12 weeks,” the investigators noted.

In an earlier exploratory analysis of HF rehospitalization or CV death in the randomized cohort (n=881), a 42 percent relative risk reduction was seen at 8 weeks, after clinical events committee (CEC) adjudication, in patients randomized to receive sacubitril/valsartan vs enalapril (9.2 percent vs 15.2 percent; HR, 0.58; 95 percent CI, 0.39 to 0.87; p=0.007). A 42 percent relative risk reduction was also seen at 8 weeks in the prespecified serious clinical event composite endpoint of all-cause death, HF rehospitalization, left ventricular assist device (LVAD) implantation, or listing for cardiac transplantation in the sacubitril/valsartan vs enalapril group (9.8 percent vs 16.3 percent; HR, 0.58; 95 percent CI, 0.40 to 0.85; p=0.005). [Circulation 2019;139:2285-2288  

Further reductions in NT-proBNP after switching to ARNI

The primary endpoint of the PIONEER-HF trial was time averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. Among 881 patients in the randomized cohort, the ratio of the geometric mean of values obtained at weeks 4 and 8 to the baseline value was 0.53 in the sacubitril/valsartan group vs 0.75 in the enalapril group, with a 46.7 percent vs 25.3 percent reduction in NT-proBNP (ratio of change with sacubitril/valsartan vs enalapril, 0.71; 95 percent CI, 0.63 to 0.81; p<0.001). [N Engl J Med 2019;380:539-548]

At the beginning of the open-label extension phase, median NT-proBNP level was 1,218 pg/mL among patients from the sacubitril/valsartan group and 1,630 pg/nL in those from the enalapril group. After 4 weeks of open-label sacubitril/valsartan treatment, patients who switched from enalapril to sacubitril/valsartan had a further 37.4 percent reduction in NT-proBNP level, while those who continued to take sacubitril/valsartan had a further 17.2 percent reduction (p<0.001 for changes between two groups). At 12 weeks, NT-proBNP levels were similar between those who switched to and those who continued to take sacubitril/valsartan (981 pg/mL and 1,009 pg/mL, respectively). [JAMA Cardiol 2019, doi: 10.1001/jamacardio.2019.4665]

“The data from PIONEER-HF, along with those from the PARADIGM-HF and TRANSITION studies, demonstrate that sacubitril/valsartan treatment is associated with a rapid decrease in NT-proBNP levels regardless of whether the treatment is initiated in the hospital when patients are congested, prior to discharge from the hospital, soon after discharge, or as stable outpatients,” the investigators noted. [J Am Coll Cardiol 2016;68:2425-2436; Circulation 2018;138(Suppl):A15567]

NT-proBNP decreases linked to reverse cardiac remodelling

“Reductions in NT-proBNP levels in patients with HFrEF treated with sacubitril/valsartan are associated with future improvements in cardiac structure and function,” noted the PIONEER-HF investigators, who were referring to results of the PROVE-HF study.

PROVE-HF was a prospective, 12-month, single-group, open-label study that evaluated the correlation between changes in NT-proBNP concentrations and long-term changes in measures of cardiac remodelling among patients with HFrEF (n=794) treated with sacubitril/valsartan. Among 654 patients who completed the study, median NT-proBNP concentration decreased from 816 pg/mL at baseline to 455 pg/mL at 12 months. The reduction in NT-proBNP concentration was weakly, yet significantly, correlated with changes in left ventricular ejection fraction (LEVF; r=–0.381; p<0.001), LV end-diastolic volume index (LVEDVI; r=0.320; p<0.001), LV end-systolic volume index (LVESVI; r=0.405; p<0.001), left atrial volume index (LAVI; r=0.263; p<0.001), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e’; r=0.269; p<0.001) at 12 months. [JAMA 2019, doi: 10.1001/jama.2019.12821]

“At 12 months, LVEF increased from 28.2 percent to 37.8 percent, while LVEDVI decreased from 86.93 mL/m2 to 74.15 mL/m2 and LVESVI decreased from 61.68 mL/mto 45.46 mL/m2 [all p<0.001]. LAVI and E/e’ ratio also decreased significantly,” the PROVE-HF investigators noted. “The observed reverse cardiac remodelling may provide a mechanistic explanation for the effects of sacubitril/valsartan in patients with HFrEF.”

Safety of starting ARNI in hospital or post-discharge

In the open-label extension phase of PIONEER-HF, rates of safety events were similar between patients who continued to take sacubitril/valsartan and those who switched from enalapril to sacubitril/valsartan. Worsening renal function, hyperkalaemia, and symptomatic hypotension occurred in 8.6 percent vs 9.6 percent (relative risk [RR], 0.89; 95 percent CI, 0.58 to 1.37), 2.4 percent vs 4.1 percent (RR, 0.59; 95 percent CI, 0.27 to 1.26), and 3.4 percent vs 4.6 percent (RR, 0.73; 95 percent CI, 0.37 to 1.44) of patients, respectively. No angioedema was reported in either group. [JAMA Cardiol 2019, doi: 10.1001/jamacardio.2019.4665]

Rates of these safety events were also similar between the sacubitril/valsartan and enalapril groups during the 8-week randomized trial period (worsening renal function: 13.6 percent vs 14.7 percent; RR, 0.93; 95 percent CI, 0.67 to 1.28) (hyperkalaemia: 11.6 percent vs 9.3 percent; RR, 1.25; 95 percent CI, 0.84 to 1.84) (symptomatic hypotension: 15.0 percent vs 12.7 percent; RR, 1.18; 95 percent CI, 0.85 to 1.64) (angioedema: 0.2 percent vs 1.4 percent; RR, 0.17; 95 percent CI, 0.02 to 1.38). [N Engl J Med 2019;380:539-548]

Embracing ARNI as new frontier in HF

“HF guidelines recommend initiation of evidence-based medications before hospital discharge,” the PIONEER-HF investigators noted. [Circulation 2013;128:e240-e327] “The current [secondary] analysis extends these recommendations by demonstrating that in-hospital initiation of sacubitril/valsartan leads to an early improvement in post-discharge outcomes that may be lost by delaying the initiation of sacubitril/valsartan in the outpatient setting.”

“The parent study of the secondary analysis was not powered to clinical endpoints, but rather reduction in biomarkers only … However, the sacubitril/valsartan story remains consistent. The effect size of further reductions in clinical events (HR, 0.69; 95 percent CI, 0.49 to 0.97) that occurred within 4 weeks (weeks 8–12) during this open-label extension is convincing and validates previous findings seen in multiple studies,” wrote Dr Jane E. Wilcox of Northwestern University Feinberg School of Medicine, Chicago, Illinois, US, in an editorial accompanying the PIONEER-HF secondary analysis report. [JAMA Cardiol 2019, doi: 10.1001/jamacardio.2019.4822]

“The clinical benefit of sacubitril/valsartan has now been described across all spectrums of reduced ejection fraction, regardless of HF aetiology (non-ischaemic vs ischaemic), or the presence of background medical therapy for HF among stable outpatients with New York Heart Association functional class II to III HF, and now among inpatients with ADHF who have achieved haemodynamic stability,” she added.

Given these findings, Wilcox suggested that it is time to embrace ARNI therapy as the new frontier in HF. “The optimal time to implement sacubitril/valsartan for hospitalized patients with HF is now. Early implementation of sacubitril/valsartan in clinical practice has the potential to reduce the overall burden of HF,” she commented.

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