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Recent hospitalizations for HF may identify HFpEF at higher risk that may benefit from ARNI
Literature - Vaduganathan M, Claggett BL, Desai AS et al., - J Am Coll Cardiol. 2019.

Introduction and methods

The period shortly after hospitalization for heart failure (HF) is a high-risk window for recurrent clinical events, including rehospitalization or death [1,2]. The angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan was found to be safe when initiated during hospitalization for HF with reduced ejection fraction (HFrEF) and it led to short-term reductions in natriuretic peptides (NP) [3] and clinical events [4], when compared with enalapril.

Limited therapeutic progress is seen for patients with preserved ejection fraction (HFpEF). Recently, modest reductions in the risk of total HF hospitalizations (HFH) and CV death was seen upon treatment with sacubitril/valsartan compared with valsartan monotherapy in ambulatory patients with HFpEF in the PARAGON-HF trial (HR: 0.87, 95%CI: 0.75-1.005, P=0.058)[5]. Clinical trials in HFpEF are challenged by the disease heterogeneity and confounding of HF diagnosis by comorbid medical illness. In PARAGON-HF, patients could be screened during hospitalization for HFpEF (but not during an episode of acute decompensated HF). Recent hospitalization may identify patients with congestion, who are at higher risk of disease progression. Their phenotype may be more modifiable.

This posthoc analysis of PARAGON-HF evaluated whether the risk of clinical events and response to sacubitril/valsartan varies in relation to whether their HFH was closer in time or not or to the burden (number of visits) of HFH in the prior year. PARAGON-HF included patients ≥50 years of age with chronic HF, LVEF ≥45% within the 6 months prior to screening, NYHA class II-IV symptoms, elevated NP levels evidence of structural heart disease and use of diuretics for at least 30 days. Median follow-up was 35 months (IQR: 30-41), in which 1083 first primary endpoints (HFH and CV death) occurred and 1903 total primary endpoints.

Main results

  • 622 (13%) Patients were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31-90 days, 435 (9%) within 91-180 days, 694 (14%) after 180 days, and 2490 (52%) were never previously hospitalized.
  • Risk of total HFH and CV death was inversely and non-linearly associated with timing from prior HFH (P<0.001 for overall trend, P=0.03 for non-linearity), with shorter times from prior HFH being associated with higher risk of recurrent primary events, independent of covariates.
  • 658 Patients discontinued therapy due to a serious adverse event. Rate did not vary by timing of prior HFH.
  • Those screened during or shortly after hospitalization showed the greatest treatment effect of sacubitril/valsartan. A numerical gradient was seen across categories from recent HFH to longer ago or never hospitalized (rate ratio: 0.73, 95%CI: 0.53-0.99) to no HFH: RR: 1.00, 95%CI: 0.80-1.24, P-interaction: 0.15).
  • Absolute risk reduction showed a significant trend (P-interaction=0.050), with primary event rates being 26.7, 24.2, 20.7, 15.7 and 7.9 per 100 PY in the respective timing categories with valsartan monotherapy, and 6.4%, 4.6%, 3.4%, -0.2% and -0.02% with sacubitril/valsartan.
  • When looking at the burden of HFH, those with 2 or more HFH in the last 12 months showed a higher rate of either first or total primary composite endpoints compared with those with fewer HFH. A gradient (P-int for relative effects: 0.12) of effect of the ARNI in reducing total primary events was seen, with RR:0.63 (95%CI: 0.41-0.97) for those with ≥2 HFH, to RR: 1.00 (95%CI: 0.80-1.24) in those without prior hospitalization.


This post-hoc analysis shows that HFpEF patients who have recently been hospitalized, and particularly those with multiple recent HFHs, have a 2 – 3-fold higher risk of rehospitalization and CV death. A gradient was seen in relative treatment effects with sacubitril/valsartan with declining treatment effect if the hospitalization was more remote in time. Timing of prior HFH did not affect the rate of patients who discontinued drug due to adverse events.


1. Vaduganathan M, Bonow RO, Gheorghiade M. Thirty-day readmissions: the clock is ticking. JAMA 2013;309:345-6.

2. Desai AS, Claggett BL, Packer M et al. Influence of Sacubitril/Valsartan (LCZ696) on 30-Day Readmission After Heart Failure Hospitalization. J Am Coll Cardiol 2016;68:241-248.

3. Velazquez EJ, Morrow DA, DeVore AD et al. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med 2019;380:539-548.

4. Morrow DA, Velazquez EJ, DeVore AD et al. Clinical Outcomes in Patients With Acute Decompensated Heart Failure Randomly Assigned to Sacubitril/Valsartan or Enalapril in the PIONEER-HF Trial. Circulation 2019;139:2285-2288.

5. Solomon SD, McMurray JJV, Anand IS et al. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med 2019.

Find this article online at J Am Coll Cardiol.

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