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Professor of Medicine
Division of Cardiovascular Medicine
Department of Medicine
Section Chief, Advanced Heart Failure and Cardiac Transplant
University of Pennsylvania
Lee R. Goldberg, MD, MPH, FACC, has disclosed that he has received funds for research support from Respircardia and consulting fees from Abbott, Respircardia, and Viscardia.
For healthcare professionals who treat patients with heart failure, the 2021 American Heart Association Virtual Scientific Sessions (AHA 2021) offered a wealth of new data to put into our daily practice. Some major clinical trials broke new ground with familiar agents, whereas others offered validation of management approaches we have been following based on clinical experience. Here’s my take.
There has not been a successful clinical trial in patients with heart failure with preserved ejection fraction (HFpEF), certainly not in my career. But in perhaps the most exciting news from AHA 2021, we saw new results from the double-blind, randomized phase III EMPEROR‑Preserved trial showing a benefit of the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin in that patient population. Although the trial enrolled patients with HFpEF with left ventricular ejection fraction (LVEF) >40%, the investigators analyzed 4005 participants with “true” HFpEF, as defined by an ejection fraction ≥50%. In this group, empagliflozin therapy led to a reduced risk of first heart failure hospitalization or cardiovascular death vs placebo (HR: 0.83; 95% CI: 0.71-0.98; P = .0244). The difference was primarily driven by a reduction in first hospitalization for heart failure (HR: 0.78; 95% CI: 0.64-0.95; P = .013), as there was no significant difference in cardiovascular death, total heart failure hospitalization, or all-cause mortality.
Moreover, among 1983 participants with LVEF between 41% and 49%, empagliflozin significantly reduced the risk of first heart failure hospitalization or cardiovascular death (HR: 0.71; 95% CI: 0.57-0.88; P = .002) as well as the secondary endpoints of first heart failure hospitalization (HR: 0.58; 95% CI: 0.44-0.77; P <.001) and total heart failure hospitalizations (HR: 0.57; 95% CI: 0.42-0.79; P <.001).
These data significantly extend the reach of SGLT2 inhibitors from preventing hospitalizations in patients with heart failure with reduced ejection fraction, as we saw in the EMPEROR-Reduced trial, to improving outcomes in patients with HFpEF. In empagliflozin, we now have a first‑line drug for HFpEF, which changes clinical practice for this group of patients.
Previous data from the phase III PARAGON-HF trial suggested that patients with heart failure with LVEF between 45% and 57% benefit from sacubitril/valsartan. However, the trial did not meet its primary endpoint among all participants with LVEF >45%. Likewise, spironolactone has demonstrated some signal of improving heart failure in patients with HFpEF in the TOPCAT trial, albeit with controversial results over regional differences in outcomes. But with EMPEROR-Preserved, we have a legitimate, positive clinical trial that meets its prespecified endpoint for this population.
Empagliflozin in Hospitalized Patients
Expanding on new data with empagliflozin, at AHA 2021, we saw 2 studies assessing its efficacy in patients hospitalized with acute heart failure, which has been a little controversial. The first study, the EMPULSE trial, found that patients with acute heart failure who received empagliflozin 10 mg once daily had greater clinical benefit vs placebo, as defined by a hierarchical composite endpoint including time to all-cause death, time to first heart failure event, number of heart failure events, and 5-point or greater difference from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score (P = .0054). Among 530 patients enrolled, those who were randomized to receive empagliflozin (n = 265) had fewer serious adverse events and lower rates of acute renal failure vs placebo.
The second study was the EMPAG-HF trial, which investigated diuresis and renal function in 60 patients with acute decompensated heart failure (ADHF) receiving empagliflozin 25 mg once daily or placebo plus standard care, including loop diuretics. The trial met its primary endpoint, with patients in the empagliflozin group experiencing a 21% increase in cumulative urine output over 5 days compared with those receiving placebo (P = .003). Moreover, patients with ADHF receiving empagliflozin in the hospital had greater declines in NT-proBNP vs placebo, and the safety profile was similar to standard care.
Taken together, I would argue that these studies tell us that empagliflozin can benefit patients who are hospitalized with acute heart failure. This has been a controversial topic, at least at my institution. Our pharmacists and pharmacy leadership, whom we trust greatly, have been resistant to allowing us to start this medicine during an acute hospitalization because of the theoretical concern about certain adverse events of these drugs and potentially precipitating euglycemic ketoacidosis and some other metabolic challenges. And of interest, we have had this occur in a couple of cases, so we were very sensitized to their warnings. But these clinical trials are saying that we are probably being too conservative and that patients can benefit from starting empagliflozin in the hospital. In addition, there is a logistical ease of starting therapy in the hospital so the patient goes home with it.
For patients with heart failure who recover LVEF to normal limits, there was a long-standing question about whether they could safely withdraw from heart failure medications. Among physicians who specialize in heart failure, our clinical experience had informed us to continue their medications. However, there was no randomized data to support that conclusion and our colleagues in general cardiology, cardio‑oncology, and internal medicine were routinely discontinuing the medications.
The randomized, open-label, pilot TRED‑HF trial previously demonstrated that patients with dilated cardiomyopathy who recovered to normal LVEF and withdrew from their heart failure medications were significantly more likely to relapse within 6 months vs those who continued heart failure medications. This was an important clinical trial that validated the theory that even if patients recover LVEF, they should remain on angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and/or beta-blockers, which not all physicians were doing in practice.
At AHA 2021, we saw an interesting new analysis from TRED-HF, looking at imaging and biomarkers of relapse after medication withdrawal. They found that the earliest clinical indicator of relapse was an increase in heart rate, followed by increased blood pressure. Of note, in a detailed imaging analysis over time, they showed that patients who went on to relapse experienced structural remodeling of the left ventricle. Some of these changes preceded symptoms.
These new findings further enhance the importance of TRED-HF by both validating the initial trial results and characterizing important clinical indicators of relapse in this setting. I understand why some physicians and patients wish to discontinue their medications when they have recovered—particularly our cardio‑oncology patients who have endured taxing cancer treatments and want their life back. But TRED-HF illustrates that patients who have recovered from heart failure should remain on their medications to mitigate the risk of relapse.
Which new data from AHA 2021 will most affect your practice for patients with heart failure? Answer the polling question and join the conversation by posting a comment. For more detailed data from these and other studies, download Capsule Summaries and reuse the slides in your own noncommercial presentations.