By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: Early intensive up-titration of guideline-recommended therapy in patients admitted for heart failure reduced 180-day readmission and all-cause mortality rates at the cost of more adverse events (but not serious or fatal ones).
SOURCE: 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;400:1938-1952.
Early post-discharge time after a hospital admission for acute heart failure (HF) can be a high-risk period. Closer follow-up, with faster up-titration of guideline-recommended medications, is advised. However, there are a paucity of data supporting this recommendation. The authors of the STRONG-HF study assessed the safety and efficacy of rapid up-titration of medications before discharge from an acute HF admission and during the early post-discharge weeks vs. usual care.
Mebazaa et al assessed the safety by history, physical exam for signs of congestion, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Guideline-recommended HF therapy included beta-blockers, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB; if the patient was intolerant to ACEI or angiotensin receptor-neprilysin inhibitors [ARNI]), and mineralocorticoid receptor antagonists (MRA). Patients were eligible for inclusion if they had been admitted to a hospital within 72 hours before screening for acute HF, were hemodynamically stable, recorded elevated NT-proBNP levels (higher than 2,500 pg/mL), and had not been treated with optimal doses of recommended therapies. Left ventricular ejection fraction (EF) was not an inclusion criterion, and only patients known to be intolerant to high doses of recommended therapies were excluded.
Enrolled patients were randomly assigned to usual care or the intensification of treatment. The latter group received at least half-recommended doses of the recommended medications within two days before discharge. Then, researchers evaluated these patients at one, two, three, and six weeks after discharge, and moved to maximally tolerated doses of the recommended medications and diuretics as needed. Mebazaa et al followed patients in both groups for 90 days and conducted phone interviews at 180 days. The primary efficacy endpoint was HF readmission or all-cause death at 180 days. Secondary endpoints included quality of life. The primary safety endpoint was adverse events up to 90 days.
The final study population was 1,078 patients (mean age was 63 years, 39% were women, 77% were white, and 21% were Black). The authors recruited these patients between 2018 and 2022 from 87 hospitals in 14 countries. As expected, the high-intensity group was more likely to receive full doses of recommended therapies at 90 days compared with the usual care group: ACEI/ARB/ARNI (55% vs. 2%), beta-blockers (49% vs. 4%), and MRA (84% vs. 46%). This was accomplished with a mean of 4.8 visits in the high-intensity group vs. one visit in the usual care group.
The primary endpoint at 180 days occurred in 15% of the high-intensity group and 23% of the usual care group (relative risk, 0.66; 95% CI, 0.50-0.86; P = 0.002). NT-proBNP levels were lower in the intensive group (1,537 patients) vs. the usual care group (1,730 patients; P = 0.003), along with quality of life scores (average = 3.5 points higher; P < 0.0001). Adverse events after 90 days were more common in the intensive group compared to the usual care group (41% vs. 29%): hypotension (5% vs. < 1%), hyperkalemia (3% vs. none), and worse renal function (3% vs. < 1%). However, serious adverse events (16% vs. 17%) and fatal events (5% vs. 6%) were similar between the groups. Also, at 90 days, blood pressure, pulse, New York Heart Association (NYHA) class, and weight measurements all were lower in the intensive group.
After approximately 1,000 patients had reached the 90-day follow-up visit, the Data Safety and Monitoring Board stopped the trial because of the larger-than-expected reduction in the primary endpoint in the high-intensity care group. The authors concluded intensive up-titration of guideline-recommended HF therapy, starting in the hospital followed by close follow-up after discharge, reduced the risk of HF readmission and all-cause mortality at 180 days.
COMMENTARY
This well-conducted study confirms what most of us taking care of HF patients know — namely, that rapidly putting patients on recommended doses of medications is beneficial, but requires a follow-up visit intensity that many health systems cannot manage. In the STRONG-HF study, it was an average of five days vs. one day with usual care. Notably, the United States was not one of the countries involved in STRONG-HF. Why is the visit intensity needed in this digital age? Because of the adverse effects of the recommended medications. Clinicians cannot check potassium, creatinine, or BNP levels on a virtual visit, and it is difficult to assess congestion accurately on Zoom. Also, not every patient can take their own blood pressure and pulse. There were considerably more adverse events in the intensive treatment arm, but this could be explained partly by the higher number of visits. The usual care group could have experienced unmeasured adverse events. Also, serious and fatal adverse events, which likely would be reported equally in the usual care group, were not different between the two strategies.
There were some interesting findings in the STRONG-HF study. There was no EF requirement for entry, and 15% of the study population recorded EF > 50%. However, the benefits of intensive therapy were the same in the preserved EF group. Also, MRA was the most prescribed medication in the study. The reason for this is unclear, especially since all but the ARNI are generic drugs.
There were limitations to the study. Few patients received SGLT2 inhibitors or iron therapy, since these therapies are relatively new and often expensive. Since the study ended early, there is insufficient power to examine secondary endpoints. For example, of the components of the primary endpoint, only HF rehospitalization was significantly different; all-cause mortality was not. Also, the study was open label, so the assessment of quality of life, NYHA class, and other subjective events may be biased by patients knowing their group assignment. In addition, the authors did not assess the circumstances of HF readmissions. Despite these limitations, the STRONG-HF study confirms more intensive medication titration and closer early follow-up of patients admitted for HF is warranted. Now, we just have to figure out how to garner the resources to accomplish it in the United States.
Early intensive up-titration of guideline-recommended therapy in patients admitted for heart failure reduced 180-day readmission and all-cause mortality rates at the cost of more adverse events (but not serious or fatal ones).
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