The latest science in heart failure
Four presenters build on the foundation of treatment and show advances in heart failure therapy.
The Late-Breaking Science presented during “Building on the Foundation of Treatment: Advances in Heart Failure Therapy” on Saturday, found:
- Positive cardiac, QoL and renal outcomes for empagliflozin in the largest HFpEF trial to date.
- SGLT2 inhibitors benefit both HFpEF and HFrEF.
- Empagliflozin is safe and effective in heart failure across the range of ejection fractions.
- Neutral overall trial but positive results for stem cell transplants on non-fatal myocardial infraction (MI), stroke and cardiac death.
Positive cardiac, QoL, renal outcomes for empagliflozin in the largest HFpEF trial to date
A prespecified analysis of the EMPEROR-Preserved trial data showed that the sodium-glucose cotransporter-2 inhibitor (SGLT2i) empagliflozin reduced the composite risk for cardiovascular death and hospitalization for heart failure (HF) in patients with heart failure with preserved ejection fraction defined as left ventricular ejection fraction (LVEF) ≥50%. This subanalysis is the first large-scale clinical trial to show benefit for patients with what researchers called “true HFpEF” defined by a LVEF of equal or greater than 50%, as opposed to mildly reduced LVEF of 41%-49%, or HFmrEF.
Empagliflozin also improved patients’ quality of life, increased the likelihood of being in a lower NYHA class after one year of treatment and slowed decline in renal function, reported Stefan D. Anker, MD, PhD, professor of tissue homeostasis in cardiology and metabolism at Charité Berlin in Germany.
EMPEROR-Preserved compared empagliflozin 10 mg against placebo in 5,988 patients with heart failure whose LVEF was greater than 40% who were receiving guideline-based treatment. Most patients in the trial, 4,005 (67%) patients, had a LVEF ≥50% and were evenly distributed between empagliflozin (2,002 patients) and placebo (2,003 patients). The mean age of patients with LVEF ≥50% was 73 years of age, 50% were female, their mean eGFR was 59 mL/min, 54% had atrial fibrillation (AF) at baseline, and 48% had diabetes. Patients with LVEF ≥50% were more likely to be older, female and have a higher body mass index compared to patients with mildly reduced LVEF of 41%-49%. Patients with LVEF ≥50% had a higher burden of hypertension, chronic kidney disease, AF and valvular heart disease, but were less likely to have a history of diabetes or myocardial infarction compared to those with an LVEF less than 50%. The median follow-up time was 26.2 months.
Empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure by 17% (p=0.0244) versus placebo in patients with LVEF ≥50%, driven primarily by a 22% reduction in initial hospitalization for heart failure (p=0.0128). In patients with LVEF ≥50%, empagliflozin also improved the mean Kansas City Cardiomyopathy Questionnaire Clinical Summary Score by 1.46 points (p=0.0006). Patients in the empagliflozin group also had a 34% greater likelihood of being in a lower NYHA class after 52 weeks of treatment and had less of a decline in renal function compared to placebo, slowing a reduction in eGFR by 1.24 mL/min/1.73 m2 per year (p<0.0001).
“EMPEROR-Preserved reinforces the importance of empagliflozin in the treatment of heart failure patients across the spectrum of ejection fraction,” Dr. Anker said. “Based on the results from the entire EMPEROR program, we believe that all individual patients with HFpEF should receive an SGLT2 inhibitor-like empagliflozin unless there is a specific contraindication present.”
CHIEF-HF suggests SGLT2 inhibitor class effect in HFpEF and HFrEF
Primary results from the Canagliflozin Impact on Health Status, Quality of Life and Functional Status in Heart Failure (CHIEF-HF) trial suggest a class effect on quality of life for patients with heart failure across the range of ejection fraction. The entire trial was performed using remote patient visits, underlining the broad safety profile of sodium-glucose co-transporter 2 inhibitors, SGLT2i, in patients with heart failure regardless of diabetes status.
CHIEF-HF was launched as a decentralized trial with no face-to-face visits March 2019, shortly before the nationwide COVID-19 lockdown. A total of 448 patients with heart failure were randomized to canagliflozin 100 mg (222 patients) or placebo (246 patients). The mean age was 63.4 years, 44.9% of patients were female and 14.5% were African American adults. Most patients, 59.6%, had HFpEF, and 27.9% had type 2 diabetes.
The primary outcome was change at 12 weeks using the self-administered Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS). The KCCQ-TSS was administered at the time of randomization and weeks 2, 4, 6 and 12. Data were collected remotely using a smartphone application, wearable accelerometers and health claims.
This may be the first major HF trial to focus on quality of life rather than physiologic outcomes or clinical events as the primary outcome, said John A. Spertus, MD, Lauer/Missouri Endowed Chair and professor of medicine at the University of Missouri-Kansas City and clinical director of outcomes research at Saint Luke’s Mid America Heart Institute. The recent EMPEROR-Preserved trial demonstrated clinical benefits for another SGLT2i, empagliflozin, in patients with HFpEF.
The baseline KCCQ-TSS was 57.4 in canagliflozin patients and 58.0 in placebo patients. Canagliflozin significantly improved KCCQ-TSS at 12 weeks versus placebo with a difference of 4.3 points (p=0.016). Separation between the two groups was clear at two weeks and was consistent across prespecified subgroups, including patients with HFpEF or HFrEF and those with or without type 2 diabetes.
There were no unexpected adverse events or new safety signals.
“This is the first heart failure trial to show that these benefits occur within two weeks of initiating therapy,” Dr. Spertus said. “CHIEF-HF shows a remarkable benefit of this class of agents in the outcomes that patients care more about: their symptoms, function and quality of life. And it’s powerful that we were able to detect this benefit in a very small trial. I would have a very low threshold for using SGLT2i agents. They don’t alter potassium or renal function. They help patients live longer and feel better and may improve the risk of other adverse events.”
Empagliflozin is safe, effective in patients hospitalized with acute heart failure across a range of ejection fraction
The first major randomized trial of empagliflozin in patients hospitalized for acute heart failure (AHF) showed similar safety and efficacy results as other trials of SGLT2 inhibitors regardless of ejection fraction and diabetes status. The EMPULSE trial randomized 530 patents hospitalized with de novo acute heart failure or decompensated chronic heart failure to empagliflozin or placebo after initial stabilization.
“The story is amazing about SGLT2 inhibitors, starting off with patients with diabetes showing hospitalization for heart failure being reduced,” said Adriaan Voors, MD, PhD, professor of cardiology at the University Medical Centre in Groningen, The Netherlands. “EMPEROR-Reduced and DAPA-HF were clearly positive, then SOLOIST in more acute forms of heart failure and EMPEROR-Preserved in chronic heart failure with preserved ejection fraction. The missing link is patients with acute heart failure irrespective of their diabetes and heart failure status; our population in EMPULSE and our results were very similar to those other trials.”
The mean age of patients in EMPULSE was 70, 33.8% were female, 33.0% had de novo AHF, 45.4% had diabetes, their mean baseline left ventricular ejection fraction was 35.1% and 31.9% had a LVEF >40%. The primary outcome was clinical benefit at 90 days, a composite of time to all-cause death, the total number of heart failure related events (hospitalization and urgent/unplanned outpatient heart failure visit), time to first heart failure event and a 5-point or greater increase in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS).
Patients who received empagliflozin were 36% more likely to show clinical benefit versus placebo (HR 1.36, p=0.0054). Dr. Voors emphasized the empagliflozin benefit was consistent across all composites of the primary outcome: all-cause mortality (4.2% with empagliflozin versus 8.3% with placebo); heart failure events (10.6% versus 14.7%); and KCCQ-TSS mean change from baseline (36.9 versus 31.6). Fewer patients taking empagliflozin experienced serious adverse events (32.3% versus 43.6%), and acute renal failure was seen in 7.7% of empagliflozin patients versus 12.1% of placebo patients. There were no reports of ketoacidosis.
“This is a very efficient, very beneficial drug for our patients with heart failure,” Dr. Voors said, “and it’s not tremendously expensive in Europe. There has been hesitation to start SGLT2 inhibitors when patients are hospitalized, but now we know it is safe and effective to start treatment as soon as they are stable. These are acutely sick people with a very high risk of readmission soon after discharge. We now have a drug that can reduce readmissions, reduce death and improve quality of life within 90 days. It is obvious from all these studies that SGLT2 inhibitors are beneficial with benign side effect profiles. I hope uptake will increase.”
Allogeneic mesenchymal precursor cells reduce cardiac mortality in heart failure trial
The largest trial of cell therapy in heart failure to date found that allogeneic mesenchymal precursor cells, or MPCs, can reduce non-fatal myocardial infarction or non-fatal stroke in patients with NYHA class II or III heart failure with reduced ejection fraction, (HFrEF), as well as cardiac death in patients with NYHA class II heart failure and inflammation as measured by elevated baseline levels of high-sensitivity C-reactive protein, hsCRP, levels.
DREAM-HF was a double-blind, sham-controlled, phase 3 trial conducted across 51 centers in the United States and Canada. A total of 537 HFrEF patients were randomly assigned to receive either a single transendocardial injection procedure of 150 million MPCs (261 patients) or a sham scripted procedure without cell injections (276 patients). The MPCs used in the trial were expanded from MPC donations from young, healthy volunteers, said Emerson Perin, MD, PhD, medical director of the Texas Heart Institute. MPCs were injected into damaged, but viable, cardiac tissue via catheter under fluoroscopic guidance and a real-time, three-dimensional visualization of each patient’s heart.
All patients in the trial had high-risk chronic NYHA class II or III HFrEF treated with guideline directed medical therapy (GDMT) and revascularization therapies. The primary endpoint was recurrent decompensated heart failure events. Other outcomes evaluated included measures of non-fatal MI, non-fatal stroke and cardiac death. All patients were assessed at baseline for systemic inflammation using hsCRP, a common blood biomarker of inflammation.
MPCs decreased the risk of the composite of CV death, nonfatal MI or nonfatal stroke by 33% (HR=0.667, p=0.021) across all patients in the treatment group and by 45% (HR=0.551, p=0.012) in a prespecified subgroup of 301 patients with hsCRP ≥ 2 mg/L, levels indicating high systemic inflammation. MPC treatment also reduced the risk of time to cardiac death by 80% in patients with NYHA class II heart failure with hsCRP ≥ 2 mg/L (HR=0.204, p=0.005) but not in class III patients with high inflammation levels. However, there was no effect of MPC treatment on recurrent decompensated heart failure events, the trial’s primary endpoint.
“MPCs can reduce inflammation in large vessels throughout the body, thus decreasing plaque rupture, which causes stroke and heart attack,” Dr. Perin said, “and the cells also work at the level of the microvasculature to protect ischemic heart muscle against apoptosis and scar tissue formation, thus improving cardiac function. We believe one of the mechanisms of MPCs is the transformation of the inflammatory environment; these cells induce pro-inflammatory M1 macrophages to become M2 macrophages, which are primarily anti-inflammatory and pro-healing. Future trials may focus on the targeted use of MPCs in patients with NYHA class II high-risk chronic HFrEF with biomarker evidence of inflammation.”