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.¹