Rapid up-titration of GDMT therapy helps reduce mortality risk and readmissions in acute HF patients

19 Jan 2023

In the American Heart Association (AHA) Scientific Sessions 2022, Dr. Alexandre Mebazaa from Université Paris Cité, France, presented his group’s study on up-titration of guideline-directed medical therapy (GDMT) in patients with acute heart failure (HF).1 

In general, acute HF leads to over 10 million hospitalizations per year, amounting to over US$100 billion in health costs.1 International guidelines on acute HF management recommend a close follow-up within 1-4 weeks post-discharge after an acute HF episode, but the level of evidence for this was low.1 Hence, the STRONG-HF study was conducted to address these unmet needs.1 This randomized, multinational, open-label, parallel-group study examined the efficacy and safety of rapid up-titration of GDMT oral HF drugs in hospitalized patients being treated for acute HF with close follow-up.1 

STRONG-HF screened 1,641 patients aged 18-85 years hospitalized for acute HF who were ready to be discharged with no or suboptimal dose of HF therapies and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) >1,500pg/mL from 87 hospitals in 14 countries, beginning May 10, 2018.1 A total of 1,078 eligible patients were randomly assigned 1:1 to receive either high-intensity care (HIC, n=542) or usual care (UC, n=536).1 The UC arm consisted of the standard local therapy regimen, while the HIC care arm patients received half of the optimal dose of HF therapy before discharge.1 This HF therapy consisted of renin-angiotensin system inhibitor (RASi), β-blocker (BB), and mineralocorticoid receptor antagonist (MRA).1 These patients were required for a safety visit after a week of post-discharge, during which clinical status, laboratory results, NT-proBNP concentrations, potassium, creatinine, and hemoglobin were evaluated.1 The most crucial visit in the HIC care arm was at week 2 because at this time point, based on the clinical tests, medications were up-titrated to full optimal dose of prescribed HF medicines.1 The safety visit was then repeated at week 3 and week 6, while the dosage was maintained at full optimal dose throughout this period.1 At 90 days, patients from both the study arms were required for a follow-up.1 The primary endpoint was HF readmission or all-cause mortality assessed at 180 days.1 The study was terminated on September 23, 2022 (n=1,069) by the Data and Safety Monitoring Board (DSMB) for a larger-than-expected difference in the primary endpoint, also because it was unethical to keep patients in UC.1 

The baseline characteristics were similar in both arms.1 Of note, in both arms, the left ventricular ejection fraction (LVEF) was ≤40% in two-thirds of patients and >40% in one-third of patients.1 At day 90, almost 50% of the patients in the HIC group had received a full optimal dose of RASi, BB, and that over 80% of the patients had received a full optimal dose of MRA, and this was much higher than that was seen in the UC arm.1 When half to full optimal dose was taken into consideration, all 3 drugs were given to over 80% of patients in the HIC arm at day 90, and this was maintained at day 180.1 Improvement in hemodynamics was seen in the HIC arm at day 90; heart rate (adjusted treatment effect=-5.8; 95% CI: -7.3 to -4.3; p<0.0001) and systolic blood pressure (adjusted treatment effect=-5.4; 95% CI: -7.2 to -3.5; p<0.0001) had significantly gone down.1 All the measured parameters of congestion, including body weight, respiratory rate, peripheral edema, jugular venous pressure, the New York Heart Association (NYHA) functional classification, and NT-proBNP, were improved in the HIC arm.1 The primary endpoint, i.e., readmission for HF or all-cause death at 180-day, was also significantly lower in the HIC care arm compared with the UC arm (risk difference=8.1%; 95% CI: 2.9-13.2; p=0.0021).1 The secondary endpoint which measured the quality of life (QoL) was also significantly improved in the HIC arm compared with the UC arm (treatment effect=3.5; 95% CI: 1.7-5.2; p=0.0001).1 Besides, the all-cause mortality at 180 days was lower in the HIC group, but this difference was not significant (risk difference=1.6%; 95% CI: -2.3 to 5.4; p=0.42).1 However, when deaths from Coronavirus disease 2019 (COVID-19) were excluded, there was a significant decrease in 180-day readmission for HF or all-cause mortality in the HIC arm compared with the UC arm (risk difference=8.9%; 95% CI: 3.9-14.0; p=0.0005).1 

The primary endpoint was also compared in various subgroups categorized by age (≤65 years vs. >65 years), LVEF (≤40% vs. >40%), baseline systolic blood pressure (≤median vs. >median), baseline NT-proBNP (≤median vs. >median), region (non-Europe vs. Europe), race (Caucasian/white vs. non-white), sex (male vs. female), and baseline estimated glomerular filtration rate (eGFR) (≤median vs. >median).1 All these analyses favored the HIC arm. Of note, there was no difference in the primary endpoint between patients with high vs. low LVEF.1 Also, the effect was higher in patients with a high baseline NT-proBNP compared with patients in which NT-proBNP was less than the median.1 As to safety, there was a higher number of adverse events (AEs) seen in the HIC arm, possibly due to a higher number of visits to the hospitals by this group of patients for safety check-ups.1 Besides, serious and fatal serious AEs in both groups were comparable.1

The rapid titration of HF treatments to full optimal dose under close monitoring, which includes comprehensive clinical examinations and NT-proBNP, is safe and helps reduce the risk of HF readmission or all-cause mortality, as well as enhances patients' QoL.1 But still, there is an urgent need to educate healthcare providers to implement this approach in routine clinical practice.

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