Higher achieved doses of GDMT associated with better clinical outcomes after acute HF

In a post-hoc analysis of STRONG-HF, higher doses of guideline-directed medical therapies (GDMTs) 2 weeks after discharge were associated with lower risk of 180-day HF readmission or all-cause mortality in patients who had been hospitalized for acute HF.

This summary is based on the publication of 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 Feb 1;9(2):114-124. doi: 10.1001/jamacardio.2023.4553

Introduction and methods

Background

After hospital admission for acute HF (AHF), rapid uptitration of guideline-directed medical therapy (GDMT), combined with close follow-up, reduced the risk of 180-day HF readmission or all-cause mortality, improved quality of life, and was safe compared with usual care, as recently shown by the STRONG-HF (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by N-Terminal Pro-Brain Natriuretic Peptide Testing of Heart Failure Therapies) trial [1]. However, not all patients in this trial were prescribed 100% of the GDMT doses 2 weeks after discharge, despite recommendations to do so.

Aim of the study

In a post-hoc secondary analysis of the STRONG-HF trial, the authors assessed the association between the level of uptitration of GDMT medications achieved with a high-intensity care (HIC) strategy and the clinical outcomes.

Methods

The STRONG-HF trial was an international, multicenter, open-label, parallel-group RCT conducted from May 2018 to September 2022 in which 1078 patients admitted to the hospital for AHF were randomized ≤2 days before the anticipated discharge to an HIC strategy or usual care. The HIC strategy comprised early uptitration of oral HF medications: beta-blockers (BBs), RAASis, and MRAs (SGLT2 inhibitors were not yet approved during most of the trial). Study eligibility criteria included NT-proBNP >1500 pg/mL at randomization; and prescription of either (1) ≤50% of the optimal RAASi dose, no BB, and ≤50% of the optimal MRA dose or (2) no RAASi, ≤50% of the optimal BB dose, and ≤50% of the optimal MRA dose.

Follow-up visits were scheduled at 1, 2, 3, and 6 weeks, with a subsequent study visit at 90 days. BB, RAASi, and MRA medications were uptitrated to 50% of the optimal doses at randomization and to full (100%) optimal doses at 2 weeks as long as there were indications that uptitration was safe. The study protocol recommended doses of the medications in the 3 classes to be uptitrated together. The Data and Safety Monitoring Board terminated the trial early because of greater than expected between-group differences.

In this post-hoc secondary analysis, 515 patients assigned to the HIC strategy were included.

Outcomes

The study’s primary endpoint was a composite outcome of first HF readmission or all-cause mortality at 180 days. Secondary endpoints were the change in quality of life as assessed with the EQ-5D visual analog scale (EQ-VAS) score from baseline to 90 days, all-cause mortality at 180 days, and a composite outcome of first HF readmission or all-cause mortality at 90 days.

Main results

• At 2 weeks, 39 of the 515 patients (7.6%) were prescribed, on average, <50% of the optimal GDMT doses (low dose), 254 patients (49.3%) received 50%–89% of the optimal doses (medium dose), and 222 patients (43.1%) had achieved ≥90% of the optimal doses (high dose).
• Patients with lower systolic blood pressure and more congestion at baseline were less likely to receive optimal GDMT doses at 2 weeks.
• When the GDMT dose was analyzed as a continuous time-dependent covariate, each 10% increase in the average percentage optimal dose was associated with a reduction in the risk of the primary endpoint (i.e., 180-day HF readmission or all-cause mortality) (adjusted HR: 0.89; 95%CI: 0.81–0.98; P=0.01) and a risk reduction in 180-day all-cause mortality (adjusted HR: 0.84; 95%CI: 0.73–0.95; P=0.007).
• Compared with the low-dose group, there were no significant improvements in quality of life in the other 2 groups after covariate adjustment: The change in EQ-VAS score from baseline to 90 days was 0.10 points (95%CI: −4.88 to 5.07) higher in the medium-dose group and 3.13 points (95%CI: −1.98 to 8.24) higher in the high-dose group compared with the low-dose group (P=0.07).
• In a multivariable model, a higher average percentage optimal dose at 2 weeks was associated with higher systolic blood pressure at baseline, lower NYHA class 1 month before and at randomization, history of diabetes, history of HF, nonischemic HF etiology, lower urea level, lack of edema at prerandomization, and jugular venous pressure <6 cm at prerandomization.
• The frequency of adverse events from 2 weeks to 90 days was 21 of the 39 patients (53.8%) in the low-dose group, 98 of 254 (38.6%) in the medium-dose group, and 51 of 222 (23.0%) in the high-dose group (P<0.001). Cardiac disorders were most frequently observed.

Conclusion

This post-hoc secondary analysis of the STRONG-HF trial among hospitalized AHF patients who were randomly assigned to the HIC strategy showed higher doses of GDMT medications achieved 2 weeks after discharge were associated with a lower risk of HF readmission or all-cause mortality at 180 days. In addition, patients prescribed higher GDMT doses experienced fewer adverse events. The results suggested that patients with a less stable clinical status before discharge were less likely to receive optimal GDMT doses at 2 weeks.

Based on their study results, the authors believe that “when patients can tolerate higher doses of GDMT, all efforts should be made to rapidly uptitrate patients with AHF to optimal doses of the 3 and (likely) 4 pillars of HF medications, including RAASis, BBs, MRAs and SGLT2 [inhibitors].”

Find this article online at JAMA Cardiol.

Reference

1. 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