Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing of Heart Failure Therapies - STRONG-HF

Contribution To Literature:

Highlighted text has been updated as of March 4, 2024.

The STRONG-HF trial showed that, among patients with admission for acute HF, an intensive treatment strategy of rapid up-titration of guideline-directed medication and close follow-up reduced the risk of 180-day all-cause death or HF readmission compared to usual care.


The goal of the trial was to compare a high-intensity intervention involving up-titration of heart failure (HF) treatments versus usual care among participants with admission for acute HF.

Study Design

The STRONG-HF trial was a multinational, open-label, randomized, parallel-group trial of participants admitted with acute HF not on full doses of HF guideline-directed medical therapy (GDMT). Patients were randomized in a 1:1 fashion to high-intensity up-titration (n = 542) or usual care (n = 536). Participants were stratified by left ventricular ejection fraction (LVEF) (≤40% vs. >40%).

High-intensity care involved up-titration of treatments to 100% of recommended doses within 2 weeks of discharge for beta-blockers, angiotensin-converting enzyme (ACE) inhibitors (or angiotensin-receptor blockers [ARBs] if the patient was intolerant to ACE inhibitors) or angiotensin receptor-neprilysin inhibitors, and mineralocorticoid receptor antagonists, and four scheduled outpatient visits over the 2 months after discharge with monitoring of clinical status, N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, and lab values.

The study was stopped early per Data and Safety Monitoring Board recommendation because of greater than expected between-group differences.

  • Total patients screened: 1,641
  • Total randomized participants: 1,078
  • Study terminated on September 23, 2022
  • Mean patient age: 63 years
  • Percentage female: 39%
  • Percentage Black: 21%

Inclusion criteria:

  • Age 18-85 years
  • Admission within 72 hours before screening for acute HF
  • Hemodynamically stable
  • NT-proBNP >2500 pg/mL and >10% decrease between screening and before randomization (but still >1500 pg/mL)
  • Without treatment of optimal doses of oral HF therapies within 2 days before hospital discharge

Exclusion criteria:

  • Intolerance to beta-blockers, ACE inhibitors, or ARBs

Other salient features/characteristics:

  • 29% with acute coronary syndrome
  • 29% with diabetes
  • 22% with New York Heart Association (NYHA) class IV HF 1 month before hospital admission
  • 15% with LVEF ≥50%
  • Baseline LVEF: 36%
  • Cardiac resynchronization therapy (CRT) at baseline: 1%

Principal Findings:

The primary outcome, first occurrence of all-cause death or HF readmission by day 180, for the high-intensity care group vs. usual care group, was: 15.2% vs. 23.3% (p = 0.0021).

The secondary outcome for high-intensity care group vs. usual care group:

  • All-cause death or HF readmission by day 90: 10.4% vs. 13.8% (p = 0.08)
  • All-cause death by day 180: 8.5% vs. 10.0% (p = 0.42)
  • Change in baseline to day 90 EQ-5D visual analogue scale: 0.88 vs. 0.90 (p < 0.0001)
  • HF readmission by day 180: 9.5% vs. 17.1% (p = 0.0011)
  • Adjusted mean change in systolic blood pressure by day 90: -3.7 vs. 1.6 mm Hg (p < 0.0001)
  • Adjusted mean change in body weight by day 90: -1.78 vs. -0.42 kg (p < 0.0001)
  • Adjusted ratio of geometric mean of NT-proBNP: 0.44 vs. 0.56 (p = 0.0003)

Effect of EF: 68% had LVEF ≤40%. By day 90, the proportion of patients randomized to high-intensity care who were uptitrated to full doses of all three drug classes was of 36.2% in the LVEF ≤40% group and of 36.9% in the LVEF >40% group, whereas this proportion was of 0.6% in the LVEF ≤40% group and of 0.0% in the LVEF >40% group for patients randomized to usual care (interaction p value = 0.97). Treatment benefit for the primary endpoint for the high-intensity group was stable for patients irrespective of baseline EF (p for interaction = 0.27). Both CV death (p for interaction = 0.03) and all-cause death (p = 0.02) at 180 days were better in the high-intensity treatment arm vs. usual care in the group with LVEF >40%. These differences were not observed after accounting for COVID-19 deaths. No treatment interactions for HF hospitalization were noted.

Role of NT-proBNP: Patients were stratified into tertiles of baseline NT-proBNP levels into those with <2159 ng/L, 2160-4165 ng/L, and ≥4165 ng/L plasma concentrations. Patients with higher NT-proBNP levels had worse outcomes but the benefit of high-intensity uptitration vs. usual care was preserved for the primary endpoint (p for interaction by NT-proBNP tertiles = 0.20). Assessment of the change from predischarge to 1 week post-discharge of NT-proBNP concentrations in the high-intensity care group showed a decrease (≥30%) in 30%, stable values (between <30% decrease and ≤10% increase) in 43%, and an increase (>10%) in 27%. Per protocol, patients with increased NT-proBNP received more diuretics and were uptitrated more slowly during the first weeks after discharge. However, by 6 months, they reached 70.4% optimal GDMT doses compared with 80.3% for those with NT-proBNP decrease. The primary endpoint at 60 and 90 days occurred in 8.3% and 11.1% of patients with increased NT-proBNP vs. 2.2% and 4.0% in those with decreased NT-proBNP (p = 0.039 and p = 0.045, respectively). However, no difference in outcome was found at 180 days (13.5% vs. 11 13.2%; p = 0.93).

Degree of GDMT achieved and outcomes: The authors assessed the percentage of the optimal doses of 3 classes of HF medications achieved (renin-angiotensin system inhibitors, beta-blockers, and mineralocorticoid receptor antagonists) in the high-intensity care arm. Patients were classified into 3 dose categories: low (<50%), medium (50% to <90%), and high (≥90%). At 2 weeks, 7.6% achieved low doses, 49.3% achieved medium doses, and 43.1% achieved high doses. Patients with lower blood pressure and more congestion were less likely to be up-titrated to optimal GDMT doses at week 2. As a continuous time-dependent covariate, an increase of 10% in the average percentage optimal dose was associated with a reduction in 180-day HF readmission or all-cause death (primary endpoint: adjusted hazard ratio [aHR], 0.89; 95% confidence interval [CI], 0.81-0.98; p = 0.01) and a decrease in 180-day all-cause mortality (aHR, 0.84; 95% CI, 0.73-0.95; p = 0.007). Quality of life at 90 days, measured by the EQ-5D visual analog scale, demonstrated a borderline statistically significant improvement in patients treated with higher doses of GDMT (mean difference, 0.10; 95% CI, −4.88 to 5.07; and 3.13; 95% CI, −1.98 to 8.24 points in the medium- and high-dose groups relative to the low-dose group, respectively; p = 0.07). Adverse events occurred less frequently in patients in the high-intensity care arm who were prescribed higher GDMT doses at week 2.


The results of this trial show that, among patients with hospitalization for acute decompensated HF, rapid up-titration of HF treatments in a high-intensity care model was safe and associated with a reduced risk of death or being readmitted for HF at 180 days, irrespective of baseline EF or baseline NT-proBNP. In the high-intensity care arm, patients achieving a higher percentage of the optimal dose had a greater improvement compared with those achieving lower doses. The trial did not show reductions in all-cause death at 180 days, but this study was likely underpowered to detect such a difference. Improvements in quality of life, blood pressure, and body weight were also noted. Serious adverse events were similar. The reductions in readmission and improvements in quality of life are of value in the HF population given the substantial burden of disease and the morbidity associated with hospital stays. With the advent of newer classes of HF GDMT, there is a push to treatment with optimal doses of GDMT. However, this is poorly accomplished in real-life clinical settings, and the evidence supporting rapid initiation of GDMT was mostly observational. STRONG-HF provides important, rigorous trial evidence showing that high-intensity care of participants with HF to rapidly up-titrate and treat HF.

STRONG-HF was initiated prior to approval of SGLT2 inhibitors for treatment of HF, and this medication class was mostly not used in this trial. However, the findings from this trial will likely also be applicable to early initiation of SGLT2 inhibitors, whose use has been associated with further reductions in HF hospitalization. Finally, it is interesting that the trial also included a subset of participants with HF with preserved EF (HFpEF), where the evidence for medical therapy is much less robust than for patients with HF with reduced EF (HFrEF). Despite this, the benefit appeared preserved irrespective of baseline EF.


Cotter G, Deniau B, Davison B, et al. Optimization of Evidence-Based Heart Failure Medications After an Acute Heart Failure Admission: A Secondary Analysis of the STRONG-HF Randomized Clinical Trial. JAMA Cardiol 2024;9:114-24.

Editorial: Allen LA, Thompson JS, Stehlik J. STRONG-HF Evidence for Proactive, Patient-Centered Prescribing. JAMA Cardiol 2024;9:103-4.

Pagnesi M, Metra M, Cohen-Solal A, et al. Uptitrating Treatment After Heart Failure Hospitalization Across the Spectrum of Left Ventricular Ejection Fraction. J Am Coll Cardiol 2023;81:2131-44.

Editorial Comment: Fonarow GC, Greene SJ. Rapid and Intensive Guideline-Directed Medical Therapy for Heart Failure: Strong Impact Across Ejection Fraction Spectrum. J Am Coll Cardiol 2023;81:2145-8.

Adamo M, Pagnesi M, Mebazaa A, et al. NT-proBNP and High-Intensity Care for Acute Heart Failure: The STRONG-HF Trial. Eur Heart J 2023;44:2947-62.

Editorial: Bayes-Genis A, Pascual-Figal D. Making STRONGer the Transition Phase: Personalized GDMT Through NT-proBNP Monitoring. Eur Heart J 2023;44:2963-5.

Mebazaa A, Davison B, Chioncel O, et al. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomized, trial. Lancet 2022;400:1938-52.

Editorial Comment: Cox ZL, Lindenfeld J. STRONG start for implementation of guideline-directed medical therapies. Lancet 2022;400:1901-3.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Heart Failure, Natriuretic Peptide, Brain

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