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Having multiple non-cardiac comorbidities does not limit optimization of HF therapies


This summary is based on the publication of Chioncel O et al. - Non-cardiac comorbidities and intensive up-titration of oral treatment in patients recently hospitalized for heart failure: Insights from the STRONG-HF trial. Eur J Heart Fail. 2023 Sep 20. doi: 10.1002/ejhf.3039.

Introduction and methods


Observational studies have demonstrated that in patients with acute HF (AHF), non-cardiac comorbidities are common and are associated with increased mortality and morbidity risks [1,2]. The STRONG-HF (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-ProBNP Testing, of Heart Failure Therapies) trial recently showed that high-intensity care (HIC) improved quality of life and reduced the risk of 180-day all-cause mortality or HF rehospitalization compared with usual care [3].

Aim of the study

In a STRONG-HF analysis, the authors assessed the potential interaction between non-cardiac comorbidities and the feasibility, efficacy, and safety of HIC versus usual care in patients hospitalized for AHF.


The STRONG-HF trial was an international, multicenter, open-label RCT in which 1078 patients with a recent hospital admission for AHF, high NT-proBNP level at screening (>2500 pg/mL), and >10% decrease in NT-proBNP level between screening and randomization (with NT-proBNP >1500 pg/mL before discharge) were enrolled. Within 2 days before the anticipated discharge date, participants were randomized to a HIC strategy, consisting of early uptitration of oral HF medications and close follow-up with multiple early ambulatory visits, or usual care.

Patients in the HIC group had follow-up visits at 1, 2, 3, and 6 weeks after randomization. In this group, oral doses of beta-blocker, ACEi/ARB/ARNI, and MRA were rapidly uptitrated to full optimal doses at week 2, guided by NT-proBNP, serum potassium, and eGFR levels, and systolic blood pressure. Usual care was provided according to local practice.

At baseline, the following 8 non-cardiac comorbidities were reported: anemia, diabetes, renal dysfunction, severe liver disease, COPD/asthma, stroke/TIA, psychiatric/neurological disorders, and malignancies.


The primary endpoint was a composite outcome of first HF rehospitalization or all-cause mortality at 180 days. Secondary endpoints included all-cause mortality at 180 days and the change in quality of life as assessed by the EuroQol-5D (EQ-5D) visual analogue scale (VAS) score from baseline to 90 days. To evaluate safety, the incidence of adverse events and serious adverse events at 90 days was assessed.

Main results

Non-cardiac comorbidities and oral HF therapy uptitration

  • The prevalence of 0, 1, 2 and ≥3 non-cardiac comorbidities was 24.3%, 39.8%, 24.5% and 11.4%, respectively. The most common non-cardiac comorbidity was renal dysfunction (52.0%), followed by diabetes (29.1%), anemia (27.2%), and history of stroke/TIA (9.2%).
  • In the HIC group, similar proportions of patients achieved full doses of guideline-directed medical therapies (GDMTs) at 90 and 180 days, irrespective of their number of non-cardiac comorbidities.

Clinical outcomes

  • In the HIC group, the primary endpoint occurred in 10.0%, 16.6%, 13.6% and 26.2% of the patients with 0, 1, 2 and ≥3 non-cardiac comorbidities, respectively, compared with 19.1%, 25.4%, 23.3% and 26.2% of those in the usual-care group (P for interaction in unadjusted model=0.80; P for interaction in adjusted model=0.95).
  • There was also no significant interaction between the treatment effect and non-cardiac comorbidity number for 180-day all-cause mortality (P for interaction in adjusted model=0.79) and change in EQ-5D VAS score (P for interaction in adjusted model=0.99 ).
  • In addition, the treatment benefit of HIC over usual care on the primary endpoint did not differ significantly by any individual comorbidity (all P for interaction>0.05).


  • The most common adverse events were cardiac related (99 in the HIC group vs. 96 in the usual-care group). There was no significant interaction between the incidence of any adverse event and non-cardiac comorbidity number (P for interaction=0.28).
  • The incidence rate of serious adverse events increased with the number of non-cardiac comorbidities, but with no significant interaction by non-cardiac comorbidity number (P for interaction=0.11).


In patients recently hospitalized for AHF, the number of non-cardiac comorbidities did not limit rapid uptitration of GDMTs coupled with high-intensity follow-up, nor influence the beneficial effects of HIC on 180-day HF rehospitalization or all-cause mortality compared with usual care. Patients with multiple non-cardiac comorbidities had more serious adverse events, but the risk–benefit ratio favored the HIC strategy even in this subgroup.

“Although physicians managing HF patients cite comorbidity burden as a ‘reason’ for not applying standard therapies,” the results of this STRONG-HF analysis could counteract this belief, according to the authors.


1. Chioncel O, Benson L, Crespo-Leiro MG, Anker SD, Coats AJS, Filippatos G, et al. Comprehensive characterization of non-cardiac comorbidities in acute heart failure – An analysis of ESC-HFA EORP Heart Failure Long-Term Registry. Eur J Prev Cardiol 2023;30:1346–1358.

2. Bhatt AS, Ambrosy AP, Dunning A, DeVore AD, Butler J, Reed S, et al. The burden of non-cardiac comorbidities and association with clinical outcomes in an acute heart failure trial – Insights from ASCEND-HF. Eur J Heart Fail 2020;22:1022–1031.

3. Mebazaa A, Davison B, Chioncel O, Cohen-Solal A, Diaz R, Filippatos G, et al. Safety, tolerability and efficacy of uptitration of guideline-directed medical therapies for acute heart failure (STRONG-HF): A multinational, open-label, randomised, trial. Lancet 2022;400:1938–1952.

Find this article online at Eur J Heart Fail.

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Schedule28 May 2024