STRONG-HF Analysis: More Rapid Uptitration of Heart Failure Therapies Confers Greater Benefit


Post hoc analysis of STRONG-HF trial underscores benefits of higher guideline-directed medical therapy doses in acute heart failure, showing lower rates of death or readmission at 6 months with more rapid uptitration.

Alexandre Mebazaa, MD, PhD | Credit:

Alexandre Mebazaa, MD, PhD

A post hoc secondary analysis of the landmark STRONG-HF trial further underlines the safety and efficacy of rapid, uptitration of guideline-directed medical therapy among patients hospitalized for acute heart failure.

Results of the analysis, which assessed results according to the percentage of optimal doses achieved in the high-intensity uptitration arm of the trial, suggest patients able to tolerate greater doses of guideline-directed medical therapy had lesser rates of death or readmission at 6 months, which investigators purport underlines the importance of optimizing guideline-directed medical therapy early in the treatment course of heart failure.1

“This post hoc secondary analysis from the STRONG-HF study demonstrated that higher achieved doses of [heart failure] [guideline-directed medical therapy] medications were associated with better outcomes and greater improvement of quality of life, with the best results seen in patients treated with an average dose of 90% or more of maximally recommended doses,” wrote investigators.1 “Therefore, when patients can tolerate higher doses of [guideline-directed medical therapy], all efforts should be made to rapidly uptitrate patients with [acute heart failure] to optimal doses of the 3 and (likely) 4 pillars of [heart failure] medications”

Originally presented at the American heart Association 2022 annual scientific sessions by Alexandre Mebazaa, MD, PhD, chairman of the department of anesthesia and critical care at the University of Paris, the STRONG-HF trial brought forth definitive evidence confirming the suspected benefit of early, rapid uptitration of guideline-directed medical therapy in hospitalized patients with heart failure. A multinational, open-label, randomized, parallel-group trial of participants admitted with acute heart failure not on full doses of guideline-directed medical therapy, STRONG-HF randomized 1078 patients in a 1:1 ratio to high-intensity uptitration or usual care, with stratification by left ventricular ejection fraction.2

Results of the study demonstrated randomization to the high-intensity uptitration arm was associated with a reduction in the risk of the first occurrence of 180-day all-cause death or heart failure readmission relative to usual care (adjusted risk difference, 8.1%; [95% Confidence interval [CI], 2.9-13.2]; P=.0021; risk ratio, 0.66; [95% CI, 0.50-0.86]). Further analysis of the trial revealed the apparent benefits of high-intensity up-titration were conferred irrespective of baseline ejection fraction or NT-proBNP.2,3

In the current study, investigators sought to assess the association between the degree of optimal doses of guideline-directed medical therapy achieved by patients in the high-intensity care arm and clinical outcomes. A post hoc secondary analysis, the study determined the mean percentage of the diseases RAASi, β-blockers, and MRAs, with patients classified into 3 categories based on whether they achieved low (<50%), medium (50% to <90%), or high (90%) doses at 2 weeks.1

The 515-patient cohort included in the study had a mean age of 62.7 (Standard deviation [SD], 13.4) years and 60.4% were male. At 2 weeks, 7.6% achieved low doses, 49.3% achieved medium doses, and 43.1% achieved high doses of guideline-directed medical therapy.1

When assessed as a continuous time-dependent covariate, results indicated an increase of 10% in the average percentage optimal dose was associated with a reduction in 180-day heart failure readmission or all-cause death (adjusted hazard ratio [aHR], 0.89; 95% CI, 0.81-0.98; P=.01) as well as a reduction in 180-day all-cause mortality (aHR, 0.84; 95% CI, 0.73-0.95; P=.007).1

Further analysis suggested those achieving medium (mean difference, 0.10; 95% CI, -4.88 to 5.07) and high doses (mean difference, 3.13; 95% CI, -1.98 to 8.24) of guideline-directed medical therapy experienced greater improvements in quality of life at 90 days than those in the low-dose group (P=.07). Investigators also highlighted adverse event rates at day 90 demonstrated such events occurred less frequently among those receiving higher doses of guideline-directed medical therapy at week 2.1

In an editorial, Larry Allen, MD, MHS, of the University of Colorado School of Medicine, Jocelyn Thompson, MA, University of Colorado School of Medicine, and Josef Stehlik, MD, MPH, of the University of Utah School of Medicine, underscored the importance of these findings given the backdrop of an increasing burden of heart failure on public health systems. The trio urged clinicians to consider the limitations of the secondary analysis, but highlighted the inherent dangers of clinical inertia for patients hospitalized with heart failure.4

“Clinical inertia is real, and it represents a lost opportunity. Patient intolerance of maximal [guideline-directed medical therapy] is real, too, and must be addressed to minimize the harms and burdens of therapy and maintain patient buy-in. This takes time, clinician commitment, and patient engagement,” wrote the trio.4 “The current study confirms that for every 10% increase in [guideline-directed medical therapy] dosing, we can expect 10% relative reduction of readmission or all-cause death in patients. Let us get to work.”


  1. Cotter G, Deniau B, Davison B, et al. Optimization of Evidence-Based Heart Failure Medications After an Acute Heart Failure Admission. JAMA Cardiology. Published online December 27, 2023. doi: 10.1001/jamacardio.2023.4553
  2. 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, randomised, trial. Lancet. 2022;400(10367):1938-1952. doi:10.1016/S0140-6736(22)02076-1
  3. American College of Cardiology. Safety, tolerability and efficacy of rapid optimization, helped by NT-probnp testing, of heart failure therapies. American College of Cardiology. May 30, 2023. Accessed December 21, 2023.
  4. Allen LA, Thompson JS, Stehlik J. STRONG-HF Evidence for Proactive, Patient-Centered Prescribing. JAMA Cardiology. Published online December 27, 2023. doi: 10.1001/jamacardio.2023.4565.
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