Pivotal Trials in Heart Failure in 2024—Putting Evidence into Clinical Practice!

Abstract

The intricate interplay of physiological, psychological, and social factors presents considerable challenges in addressing heart failure. It is imperative to comprehend the epidemiology and pathophysiology, identify predictors and their influence on clinical outcomes, and effectively utilize the diagnostic tools. Such evidence is vital for formulating innovative therapeutic strategies to decelerate the growing heart failure epidemic. As of 2024, the field of heart failure has witnessed significant advancements in therapies applicable to both heart failure with preserved and reduced ejection fraction. Recent studies in this domain yielded valuable insights into the latest developments in cardiovascular medicine, which possess the potential to revolutionize treatment strategies. These advancements advocate for a more integrated approach to patient care and aim to enhance overall clinical outcomes. Below is a concise overview of key studies showcased at scientific meetings over the past year, which promise to improve heart failure management.

Heart failure (HF) is considered a “growing epidemic,” according to recent evidence. ¹ The Global Burden of Disease Study reported that in 2019, 57 million individuals had HF. ² Over the last decade, the number of HF-related hospitalizations has nearly doubled, with approximately half of the patients needing to be hospitalized within 6 months following discharge. ³ Age significantly influences survival rates after an HF diagnosis. In the UK, for instance, the 5-year survival rates range from 80% for individuals aged 45 to 64 to around 20% for octogenarians. ⁴ Notably, HF is associated with a 2.4-fold more significant loss of time alive compared to the age- and sex-matched general population over 10 years. ⁵

The multifaceted nature of physiological, psychological, social, and healthcare factors makes addressing HF challenging. Understanding the epidemiology and pathophysiology, recognizing predictors and their impact on outcomes, and utilizing diagnostic modalities are crucial in devising new therapeutic approaches to combat this epidemic. Recent advancements have led to the development of various new drugs, devices, and diagnostic care strategies. We summarize several key recent trials that have the potential to guide and improve our management of patients with HF beyond the “four pillars.”

RELIEVE HF Trial: Atrial Shunt Therapy for Heart Failure

HF is characterized by increased left atrial pressure and pulmonary venous congestion in both preserved (HFpEF) and reduced ejection fraction (HFrEF) subgroups. The left atrial pressure rises with exercise and fluid overload and may be challenging to regulate pharmacologically. An interatrial shunt (IAS) may provide an autoregulatory mechanism to decrease the left atrial pressure and improve symptoms and prognosis of HF.

In pilot studies, Ventura IAS (V-wave Ltd.) reduced filling pressures, improved cardiac structure and function, and provided symptomatic relief and functional improvement in patients with HFrEF and HFpEF.

Device description: The device has an hourglass shape with ePTFE encapsulation, making it non-thrombogenic. It features a 5.1-mm central opening that enables a 1 L/min blood flow from the left to the right atrium, with an effective Qp:Qs ratio of around 1.2:1. The novel hourglass design is engineered to create a venturi tube-like effect from the high-pressure atrium to the low-pressure atrium. The device is implanted in the fossa ovalis via a transvenous route.

The RELIEVE-HF trial was a multicenter, randomized, double-blind, placebo-controlled study of the V-Wave Ventura® Interatrial Shunt in symptomatic patients with advanced HF, regardless of left ventricular ejection fraction (LVEF). ⁶

This trial included 508 patients with either ischemic or non-ischemic cardiomyopathy, with reduced (≤40%) or preserved (>40%) LVEF and documented HF for at least 6 months. These patients had NYHA class II, III, or ambulatory IV HF and had experienced HF hospitalization within the prior 12 months. They were receiving optimized guideline-directed medical therapy (GDMT) for drugs and devices with a class I indication.

Around 40% of the participants had HFrEF, and 60% had HFpEF. The majority of the patients were older than 70 years and belonged to a high-risk population, with over 80% having stage 3a and above chronic kidney disease (CKD), more than 95% having NYHA class III symptoms, markedly reduced 6MWD, low Kansas City Cardiomyopathy Questionnaire (KCCQ) score, and high natriuretic peptide levels. Almost a quarter of the patients already had cardiac resynchronization therapy (CRT) and an implantable cardioverter defibrillator (ICD).

The device was successfully implanted in all 250 patients. There were no device-related or procedure-related major adverse cardiovascular or neurological events (MACNE), such as all-cause death, stroke, systemic embolism, and the need for cardiac or endovascular surgical repair during the first 30 days and through 2-year follow-up.

However, the primary effectiveness endpoint was not met, as there was no significant difference between the groups for a hierarchical composite ranking of death from any cause, need for heart transplant or left ventricular (LV) assist device, HF hospitalizations, worsening of outpatient HF events, and change in the quality of life. The risk of all cardiovascular events was similar in both groups. It is worth noting that a marked improvement in quality of life (KCCQ score) across all groups was seen, suggesting a placebo effect.

There were significant differences in outcomes between patients with reduced and preserved ejection fraction. Patients with reduced ejection fraction experienced a 45% reduction in cardiovascular events over the 2-year follow-up ( p  < 0.0001), a significant reduction in HF hospitalizations ( p  = 0.01), a borderline reduction in the need for heart transplant or LV assist device implantation ( p  = 0.05), and a trend toward a 37% reduction in mortality.

On the other hand, patients with preserved ejection fraction had a 68% increase in cardiovascular outcomes ( p  < 0.0001), a doubling of HF hospitalizations ( p  = 0.008), and a three-fold increase in mortality ( p  = 0.004).

The likely reason for this difference is related to the distinct hemodynamics in the two HF subgroups. In HFrEF, the left ventricle is compliant, pulmonary pressures are not very high, and the right heart can accommodate the increased blood flow through the shunt. In contrast, in patients with preserved ejection fraction, the ventricles are less compliant (stiff), resulting in increased pressure in the right side of the heart and higher pulmonary pressures, leading to decreased cardiac output. Interestingly, the quality-of-life outcome measure was similar in both groups of HF patients.

Several studies have previously examined using a device to reduce left atrial pressure in HF patients. The REDUCE LAP-HF I trial, a phase II clinical trial, showed that the active treatment led to a more significant reduction in exercise pulmonary capillary wedge pressure than a sham procedure. ⁷ In the phase III clinical trial, REDUCE LAP-HF II, a low-risk patient group with preserved ejection fraction and exercise-induced increase in pulmonary pressures, was studied. It did not show any benefits of using the interatrial shunt in reducing cardiovascular death, non-fatal ischemic stroke, HF events, or improving quality of life. The HF events rate was higher in the patients who received the device compared to those who had the sham procedure, suggesting a negative impact of the interatrial shunt device. ⁸

The study's findings underscore the need to consider tailored treatment approaches based on the distinct characteristics of HF subgroups, thereby enhancing the overall effectiveness of interventions.

EMPACT MI: SGLT2i in Post-MI Heart Failure

Up to 30% of patients presenting with acute myocardial infarction (AMI) remain at risk of developing HF over the first year. ⁹ The outlook is abysmal for those patients who experience congestion or LV dysfunction as a result of the AMI. ¹⁰

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have consistently been proven to lower the risk of HF in patients at high risk of developing HF (e.g., those with type 2 diabetes and high cardiovascular risk or CKD) as well as in those who already have HF, regardless of their LVEF. ¹¹

The EMPACT-MI trial was conducted to assess the effectiveness and safety of empagliflozin in patients following an AMI event. The trial was a large-scale international study conducted in 22 countries at 451 sites. It was a randomized, double-blind, phase III, placebo-controlled superiority trial. ¹²

Patients 18 years of age or older who were hospitalized with an AMI, either ST-segment elevation myocardial infarction (STEMI) or non-STEMI, within 14 days of admission were included in the trial. These patients were randomized, regardless of whether they had type 2 diabetes. Before randomization, the patients had to have evidence of newly developed HF with LVEF below 45% or show signs or symptoms of congestion requiring treatment.

Patients also needed to have at least one risk factor, such as being 65 years or older, having newly developed LVEF below 35%, a history of MI, atrial fibrillation, type 2 diabetes, CKD, elevated biomarkers or uric acid levels, elevated pulmonary artery systolic pressure, triple vessel coronary artery disease, peripheral artery disease, or no revascularization strategy for their index MI.

A total of 6,522 patients were randomized and followed up for an average of 17.9 months. In a 1:1 ratio, patients were randomized to receive a placebo or 10 mg of empagliflozin daily in addition to standard care.

About 57% of patients had signs and symptoms of congestion, 78% had LVEF below 45%, 75% were men, 50% were aged 65 or older, 32% had type 2 diabetes, 74% had STEMI, 31% had triple vessel disease, and 70% had two or more HF risk factors.

For their index MI, 89% of patients received revascularization at discharge, 82 to 85% were prescribed RAS inhibitors and beta blockers, and 48% were given a mineralocorticoid receptor antagonist.

The study found that empagliflozin significantly reduced the risks of first HF hospitalization and the total number of HF hospitalizations compared with a placebo. The drug also reduced the risks of HF hospitalization or death due to HF, adverse events requiring HF hospitalization, and fatal outcomes. These benefits were consistent across different patient groups, such as age, sex, and concurrent medication use.

Although empagliflozin did not reduce the primary combined endpoint of HF hospitalization or all-cause death, it did lower the time to first HF hospitalization and the total number of HF hospitalizations. This suggests that empagliflozin may play a role in preventing HF after AMI.

With these EMPACT-MI results, it can be postulated that empagliflozin can treat patients after acute MI who are at risk for HF by reducing the burden of developing HF. Empagliflozin reduced the risk of time to first hospitalization for HF by 23% and the total number of hospitalizations for HF by 33%, supporting its potential role in treating patients at risk for HF after AMI. The study also highlighted empagliflozin's consistent benefits in reducing HF-related adverse events.

The DAPA MI trial ¹³ examined the effects of dapagliflozin on patients who had experienced a recent heart attack (within 10 days). It did not show the same decrease in HF or cardiovascular events, but it did improve cardiometabolic outcomes at 1 year compared to a placebo. In the recent EMMY trial, empagliflozin resulted in a significant reduction in NT-proBNP over 26 weeks for patients with recent AMI and a notable improvement in echocardiographic parameters. ¹⁴ Table 1 highlights the differences between the EMPACT-MI and the DAPA-MI trials.

Table 1. Comparison of DAPA-MI and EMPACT-MI trials.

	DAPA-MI ( n  = 4,017 across 103 sites in the UK and Sweden)	EMPACT-MI ( n  = 6,522 across 451 sites in 22 countries)
Presentation	STEMI: 72% NSTEMI: 28% Within 7–10 days	STEMI: 74% NSTEMI: 26% Within 14 days
Age	63 years	64 years
Diabetes mellitus	Patients with diabetes were excluded	32% of the participants had a history of type 2 diabetes
LVEF	• 7% had an LVEF <30% • 67% had an LVEF between 30 and 49% • 21% had an LVEF ≥50%	• 26% had an LVEF <35% • 53% had an LVEF between 35 and <45% • 21% having an LVEF ≥45%
Comorbidities (Patients in EMPACT-MI shared a considerably higher burden of cardiometabolic comorbidities at baseline)	Hypertension: 37% Prior acute MI: 9% eGFR: 84 mL/min/1.73 m 2	Hypertension: 69% Prior acute MI: 13% eGFR: 76 mL/min/1.73 m 2
Revascularization	94% of the DAPA-MI participants with STEMI and 77% of those with NSTEMI underwent revascularization via percutaneous coronary intervention	88.8% underwent percutaneous coronary intervention and 0.5% coronary artery bypass graft before being randomized
Conclusion	Significant wins for dapagliflozin in cardiometabolic outcomes ( p  < 0.001). The composite of time to cardiovascular death/hospitalization for heart failure in dapagliflozin vs. placebo group (HR, 0.95; 95% CI, 0.64 to 1.40).	No significant difference in primary endpoint (hospitalization for heart failure (HF) or death from any cause) between empagliflozin and placebo ( p  = 0.21). Empagliflozin significantly reduced the risk of time to first hospitalization for HF by 23% and the total number of hospitalizations for HF by 33%.

Abbreviations: LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTEMI, non-STEMI; STEMI, ST-segment elevation myocardial infarction.

Overall, the study demonstrated that empagliflozin's benefits extend to patient populations with acute MI, with or without diabetes, and its safety is consistent with the findings of previous trials.

STEP-HFpEF DM Trial: Heart Failure Benefit Beyond Weight Loss

Excess adiposity plays a significant role in the development and progression of HF with preserved ejection fraction (HFpEF) and type 2 diabetes. Type 2 diabetes is highly prevalent among patients with HFpEF. It is associated with adverse hemodynamic and clinical features. In previous studies involving patients with HFpEF and obesity but without type 2 diabetes, it was observed that treatment with semaglutide led to more significant reductions in HF-related symptoms and physical limitations, along with more significant weight loss and improvements in exercise function compared to those receiving a placebo. ^{15 16 17} Fig. 1 highlights the mechanisms of benefit of semaglutide in obesity-related HFpEF.

Fig. 1.

Pathogenesis of diabetic cardiomyopathy and potential role of aldose reductase inhibitors. ROS, Reactive Oxygen Species.

STEP-HFpEF DM is a double-blind, randomized, placebo-controlled trial conducted at 108 sites across 16 countries. ¹⁸ Eligible participants were individuals aged 18 years or older who had documented HF, an LVEF of at least 45%, a body mass index (BMI) of at least 30, and at least one of the following findings: elevated LV filling pressures, elevated natriuretic peptide levels along with echocardiographic abnormalities, or hospitalization for HF within the 12 months before screening alongside echocardiographic abnormalities or ongoing treatment with diuretics. Participants were also required to have received a diagnosis of type 2 diabetes at least 90 days before screening and to have a glycated hemoglobin level of no more than 10%.

A total of 616 HFpEF patients (median age 69 years; 44% women) were randomized to receive once-weekly semaglutide, starting at the lowest dose (0.25 mg for the first 4 weeks) and escalating to the maintenance dose of 2.4 mg by week 16, or a placebo. The median BMI of the participants was 36.9, with 64% having a BMI of 35 or higher, and the median duration of diabetes was 8 years. Alongside diuretics, renin-angiotensin system blockers, and beta-blockers, approximately one-third of patients were also on mineralocorticoid receptor antagonists and sodium-glucose cotransporter 2 inhibitors.

At 52 weeks, the mean change in the Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score (KCCQ-CSS) was 13.7 points in the semaglutide group compared to 6.4 points in the placebo group. The percentage change in body weight was 9.8% in the semaglutide group and 3.4% in the placebo group ( P  < 0.001 for both comparisons). The results of the 6-minute walk test showed an improvement of 12.7 meters in the semaglutide group and a decrease of 1.6 meters in the placebo group ( P  = 0.008). An analysis of the hierarchical composite endpoint indicated a greater stratified win ratio for semaglutide compared to placebo (1.58; 95% CI 1.29–1.94). These findings were consistent across most key components of the hierarchical composite endpoint, driven by a 15-point difference in the KCCQ-CSS. C-reactive protein (CRP) levels were 42% lower in the semaglutide group at 52 weeks, whereas the placebo group experienced a 12.8% reduction ( P  < 0.001). For NT-proBNP, the semaglutide group saw a 23.2% change, in contrast to a 4.6% change from the baseline for the placebo group. Hospitalizations or urgent HF-related visits occurred in 18 patients in the placebo group compared to 7 patients in the semaglutide group (HR 0.40; 95% CI 0.15–0.92).

Serious adverse events and adverse events of special interest, including hypoglycemia and diabetic retinopathy, occurred in 17.7% of semaglutide users versus 28.8% of those receiving placebo ( P  = 0.002). Treatment discontinuation due to any serious adverse event was recorded at rates of 10.6% in the semaglutide group and 8.2% in the placebo group. Notably, 6.5% of discontinuations in the GLP-1 group were due to gastrointestinal adverse events, which are common with these agents.

The results of the STEP-HFpEF DM trial enhance the earlier findings of the STEP-HFpEF trial in several ways. First, they confirm semaglutide provides clinical benefits and a favorable safety profile for individuals with HF with preserved ejection fraction (HFpEF) and type 2 diabetes. Second, even though patients with type 2 diabetes experienced about 40% less weight loss with semaglutide than those without diabetes, the benefits in HF suggest that mechanisms beyond weight loss, such as improved decongestion and insulin resistance, may be at play. Third, the trial shows consistent positive effects of semaglutide on HF outcomes in patients with and without SGLT2 inhibitors, the standard HFpEF treatment.

For patients with obesity-related HF with preserved ejection fraction, semaglutide is an effective and well-tolerated treatment option. In this patient population, obesity is not merely a comorbidity, it is likely a primary cause of both the development and progression of HF. Therefore, addressing obesity should be a key focus of intervention.

IMPROVE-HCM: Bridging the Gap in Non-Obstructive HCM Management

While obstructive hypertrophic cardiomyopathy (HCM) has seen medical advancements and invasive therapies that reduce LV outflow tract obstruction and improve morbidity, the options for managing non-obstructive HCM (nHCM) are limited to beta-blockers and calcium channel blockers, which have significant side effects. Nearly 40% of patients with nHCM experience HF symptoms that significantly impact their quality of life. ^{19 20 21 22} Currently, there are no approved therapies targeting the underlying disease mechanism for HF.

In HCM, there is a heightened need for energy production substrate, leading to an energy-deficient state exacerbated by microvascular ischemia due to myocardial hypertrophy. ²³ This negatively affects the physiological process of myocardial relaxation, which is highly energy-dependent, resulting in an inability to increase stroke volume during exercise and reduced functional capacity. Compromised energetics represent a vital defect and a potential therapeutic target. Mitotropes, which influence myocardial energetics, have emerged as a possible solution. Ninerafaxstat is a novel cardiac mitotrope designed to restore myocardial energy balance. ²⁴ It enhances the efficiency of ATP generation for cardiac function through partial inhibition of mitochondrial fatty acid oxidation, mainly by competing directly with 3-KAT, the final enzyme in the mitochondrial long-chain fatty acid beta-oxidation pathway, thus shifting cardiac metabolism toward glucose.

The IMPROVE-HCM trial was a phase 2, multicenter, randomized, placebo-controlled, double-blind study. It aimed to assess the safety, tolerability, and potential effectiveness of ninerafaxstat in patients with symptomatic nHCM and evidence of exercise limitation. ²⁵ During a 4-week screening period, eligible patients were randomly assigned to receive ninerafaxstat or a placebo. Before and after the 12-week treatment, the patients underwent assessment using the KCCQ, cardiopulmonary exercise testing (CPET), echocardiography, biomarkers, and clinical evaluations.

Eligible patients were adult men and women aged 18 to 80, diagnosed with nHCM, with peak oxygen consumption (pVo2) ≤80% predicted for age and sex, end-diastolic LV wall thickness ≥15 mm (or ≥13 mm), and a family history of HCM (or positive for a pathogenic sarcomere gene mutation) and absence of resting and exercise-provocable LV outflow tract obstruction. Patients were required to have an LVEF ≥50% at baseline and to be able to perform an upright treadmill CPET with a peak respiratory exchange ratio ≥1.05.

Ninerafaxstat, 200 mg modified-release tablets, was administered orally twice a day. The primary endpoint was to assess the incidence and severity of treatment-emergent adverse events (TEAEs), comparing ninerafaxstat and placebo. Secondary objectives included evaluating the drug's effects on exercise capacity, heart function, symptoms, patient-reported health status, and biomarkers. Exploratory objectives involved further assessment of exercise responses and biomarkers.

The study included participants with an average age of 57, predominantly women (55%) and White ethnicity (83.6%). About 59% of the participants were in NYHA class II, and 35% were in NYHA class III. At baseline, the exercise capacity with peak VO2 was 19.2 mL/kg/minute, 60.5% of the predicted capacity, indicating significant exercise limitation.

At the 12-week mark, 11.8% of patients in the ninerafaxstat group experienced TEAEs, such as diverticulitis, pyelonephritis, CABG, and COVID-19 pneumonia. This was compared to 6.1% of patients in the placebo group, who experienced TEAEs, including septic shock and acute hypoxic events. One or more TEAEs were experienced by 70.6% of patients in the ninerafaxstat group and 60.6% of patients the placebo group. No significant differences were observed between the groups regarding changes in ejection fraction, blood pressure, or heart rate.

In addition, patients in the ninerafaxstat group showed significantly improved ventilatory efficiency (VE/VCO2 slope) compared to those in the placebo group, with a between-group least square (LS) mean difference of −2.1 ( p  = 0.006). However, there was no significant difference in peak VO2 ( p  = 0.9). Although there was a directional but not significant improvement in KCCQ-CCS ( p  = 0.2), a post hoc analysis revealed a significant improvement with the novel agent versus placebo among 35 patients with a baseline KCCQ-CSS score of ≤80 ( p  = 0.04). By week 12, treatment with ninerafaxstat was associated with a non-significant 39% decrease in serum NT-proBNP levels ( p  = 0.80). Additionally, the left atrial dimension, a surrogate marker of diastolic function, showed a positive impact, with a mean decrease of 0.9 mm ( P  = 0.01).

The study suggests that improving cardiac energy metabolism can positively affect LV filling, which is energy-dependent. The phase 2 study found that treatment with ninerafaxstat was safe and well tolerated. It also showed potential for improving cardiac energetics in non-obstructive HCM patients, indicating the need for a more significant phase 3 study.

ARISE-HF Trial: Treating Early-Stage Heart Failure in Diabetes

HF is a major cardiovascular complication among individuals with diabetes mellitus (DM). Patients with DM have a two times higher risk for HF development, ²⁶ which is further indicated by a decrease in exercise capacity. DM itself may result in heart muscle disease, known as diabetic cardiomyopathy (DbCM). ²⁷ It is estimated that 20% of patients with DM may have DbCM. Consequently, DbCM represents an independent target for HF prevention if recognized and treated.

Pathogenesis of DbCM and Hyperactivation of Polyol Pathway ²⁸

Normal Krebs Cycle

The Krebs cycle is an aerobic biological process that begins with the breakdown of acetyl-CoA to produce the reduced coenzymes (NADH2 and FADH2) and CO ₂ . Oxaloacetate (OAA), which comes from the carboxylation of pyruvate, is the first substance involved in the Krebs cycle. OAA combines with acetyl-CoA to create citric acid. Therefore, sugar is the source of OAA. In diabetic patients with lower levels of sugar and pyruvate in their cells, the amount of OAA is reduced; thus, the Krebs cycle activity is reduced.

Polyol Pathway

Under hyperglycemic conditions, the polyol pathway reduces glucose to sorbitol, which is then converted to fructose. This process leads to tissue injury and fibrosis. Aldose reductase is the first step in the polyol pathway, and inhibiting this enzyme has been suggested as a potential treatment for DbCM. Fig. 1 highlights the pathogenesis of DbCM and potential role of aldose reductase inhibitors.

Aldose reductase inhibitors (ARIs) were previously developed to treat microvascular complications. Most first-generation ARIs were not very effective and caused many side effects.

AT-001, a highly potent, selective, and well-tolerated ARI, is promising in treating DbCM. ²⁹

The ARISE-HF study aimed to test whether treating people with DbCM and reduced exercise capacity who are at high risk of HF with an ARI could slow the progression of DbCM, which is reflected in the stabilization of peak VO2. ³⁰

The ARISE-HF study was a phase III randomized, double-blind, placebo-controlled clinical trial conducted at 62 global sites. It involved 675 patients with DbCM or stage B HF who were at high risk of progressing to overt HF.

To be eligible, patients had to be at least 40 years old, have type 2 diabetes, DbCM, and a peak oxygen consumption (VO2) value of less than 75% of the predicted average value based on their age and gender, with at least one of the following: Global longitudinal strain (GLS) <16%, increased LV mass index, LA volume index >34 mL/m ² , E/E' >13, RVSP >35 mmHg, NT-proBNP >50 ng/L, hs-cTnT >6 ng/L. Patients with known or suspected stage C HF, on loop diuretics, obesity (BMI >45 kg/m ² ), prior Acute Coronary Syndrome (ACS), or severe Coronary artery disease (CAD) were excluded.

Patients were randomized into three groups: 1,500 mg AT-001, 1,000 mg AT-001, and placebo, with 181 patients per treatment group. AT-001 was administered twice daily. Approximately 50% of the patients were female, with an average age of 68 years and a long history of T2DM with a mean HbA1c of 6.98%. However, these numbers may not be representative of actual patients with DbCM. Only about 25% of patients had high-risk NT-proBNP or hs-cTnT levels. Also, the mean baseline KCCQ scores were well-preserved.

During the study, placebo-group patients showed a mean decline in CPET performance (peak VO2) of −0.31 mL/kg/min over 15 months. The high-dose AT-001 group demonstrated stable condition with a mean change of −0.01 mL/kg/min in peak VO2. The difference between groups (0.30 mL/kg/min) did not reach statistical significance ( p  = 0.210) despite favoring active treatment. Notably, the effect was dose-dependent, with the low dose demonstrating an intermediate effect between the high dose and placebo.

The ARISE-HF study assessed the impact of adding AT-001 to standard diabetes treatments. A subgroup of participants (around 62%) not receiving SGLT2 or GLP-1 therapies showed that high-dose AT-001 stabilizes CPET performance over 15 months, whereas the placebo group experienced a decline. In this subgroup, the placebo group had a higher percentage of patients (46%) with a significant worsening in cardiac functional capacity (6% or more) compared to the high-dose AT-001 treated group (32.7%) ( p  = 0.035). There were no significant differences between the groups in NT-proBNP levels, KCCQ domains, or Physical Activity Scale for the Elderly (PASE) changes.

AT-001 was well tolerated, and there were insignificant differences in serious adverse events between the AT-001 treated and placebo groups. Renal or hepatic dysfunction was not observed.

The study has significant implications for the treatment of DbCM. Currently, there are no approved therapies for DbCM, and there is a high unmet need for a treatment that can prevent the worsening of the condition and progression to symptomatic HF. The stabilization of cardiac functional capacity observed in this study is a promising finding, as declining functional capacity is a marker of progression to overt HF. These findings provide valuable insights and potential directions for future research and treatment strategies.

FINEARTS-HF Trial: Addressing the Enormous Unmet Need in HFpEF

Mineralocorticoid receptor antagonists (MRAs) are critical in managing HF with reduced ejection fraction, as both European and American guidelines classify their use as class I interventions. ^{31 32} Clinical trials have demonstrated significant reductions in overall mortality, cardiovascular-related mortality, and HF hospitalizations with MRA therapy. However, their efficacy in patients with mildly reduced or preserved ejection fraction must be more clearly defined. Despite the role of alternative therapies like SGLT2 inhibitors in this population, there is still a notable gap in effective treatment options. Finerenone, a nonsteroidal MRA, has exhibited promise in treating patients with CKD and HF in the context of diabetes, warranting further exploration in a broader HF cohort. ^{33 34}

The primary objective of this trial was to evaluate the efficacy of finerenone in reducing the composite endpoint of worsening HF events. These events were defined as unplanned hospitalizations or urgent care visits related to HF, as well as cardiovascular mortality, in patients with mildly reduced to preserved ejection fraction (EF). This was a double-blind, randomized, international, event-driven trial conducted in 37 countries. Finerenone was administered at a dose of either 20 or 40 mg daily, stratified by renal function. Eligible participants were required to be at least 40 years old and to present with symptomatic HF classified as NYHA classes II to IV, with an LVEF of 40% or higher, elevated NT-proBNP levels, and a minimum of 30 days of diuretic therapy prior to randomization. Additionally, all participants were required to have evidence of structural heart disease and to be on standard HF treatment regimens. Exclusion criteria included severe CKD (glomerular filtration rate [GFR] of less than 25 mL/min), serum potassium levels exceeding 5 mmol/L at any point during the study, and recent use of mineralocorticoid receptor antagonists. ³⁵

Finerenone demonstrated a significant reduction in the composite endpoint of HF events, encompassing initial and recurrent hospitalizations and cardiovascular (CV) mortality, relative to placebo. The event rate for the finerenone cohort was 14.9 per 100 patient-years, contrasted with 17.7 per 100 patient-years for the placebo group, resulting in a 16% relative risk reduction for the primary outcome (rate ratio: 0.84; p  = 0.007). Although there was a numerical decrement in all-cause mortality within the finerenone group (16.4% vs. 17.4% with placebo), this difference did not reach statistical significance. Additionally, finerenone was associated with a modest enhancement in quality of life, as reflected by an improvement in KCCQ scores compared to placebo. Although the trial did not reveal significant effects on renal outcomes, such as the progression of CKD, there were indications of potential benefits in specific subgroups, particularly those with comorbid kidney disease and diabetes. Notably, finerenone did not demonstrate a reduction in the risk of secondary kidney disease in patients deemed at low risk for progression. However, it did confer a protective effect on those with kidney disease and diabetes. The study also reported no significant impact on cardiovascular mortality, consistent with challenges observed in prior investigations in this patient population. It is worth noting that only a minority of participants received SGLT2 inhibitors, agents known to confer benefits for patients with HF with mid-range or preserved ejection fraction (HFmrEF/HFpEF). Further research is warranted to evaluate the potential synergistic effects of finerenone in conjunction with SGLT2 inhibitors. Lastly, the treatment with finerenone was associated with a higher incidence of hyperkalemia (14.3% vs. 6.9% in placebo) and hypotension, which are critical considerations in clinical practice, particularly for patients with CKD. Fig. 2 depicts the spectrum of clinical studies with finerenone in HF.

Fig. 2.

Summary of Major clinical studies of the novel non-steroidal MRA - Finerenone in HF. The green boxes indicate studies that have been completed while the orange boxes indicate which are ongoing/recruiting. *Acute HF or Recently discharged with HF. **Combination with SGLT-2 inhibitor. -Primary Outcome is CV death/HHF. ^# Primary outcome is CV death/HHF.

SUMMIT Trial: A Massive Success in Managing HFpEF in Obese Patients

Obesity is a significant contributor to the expansion of visceral fat, which subsequently leads to a series of biological transformations that alter the synthesis of adipocytokines. These adipocytokines are responsible for secreting various molecules with anti-natriuretic and pro-inflammatory properties. The anti-natriuretic molecules promote sodium retention in the body, increasing plasma volume and potential fluid overload. Concurrently, the pro-inflammatory molecules lead to myocardial injury and fibrosis. This cascade of biological changes is recognized as one of the underlying mechanisms contributing to HF with preserved ejection fraction. Understanding this relationship between obesity, visceral fat, and cardiac health is essential for developing effective prevention and treatment strategies.

Clinical trials involving semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, have demonstrated favorable outcomes in patients with HF and preserved ejection fraction (HFpEF) coupled with obesity. ^{15 18} These conclusions were derived from exploratory analyses with a relatively brief median follow-up duration of 52 weeks. To provide further insights, researchers conducting the SUMMIT trial investigated the cardiovascular outcomes of tirzepatide. This agonist targets glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors over an extended period in patients with HFpEF and obesity. ³⁶ The trial's objective was to compare the safety and efficacy of tirzepatide among patients with HF with preserved ejection fraction (HFpEF) and obesity.

A total of 731 patients diagnosed with HFpEF and obesity were randomized to receive either tirzepatide or a placebo. Specifically, 364 participants (including 200 women) received tirzepatide, while 367 patients (including 193 women) were administered the placebo. These individuals were recruited from 129 medical centers across nine countries and received weekly subcutaneous injections of tirzepatide, with doses reaching up to 15 mg for a median duration of 2 years. All participants presented with HFpEF, defined by an LVEF of 50% or higher and a BMI exceeding 30 kg/m ² . They also exhibited significant health-related limitations, as indicated by the KCCQ-CSS and the 6-minute walk test. Furthermore, nearly 50% of participants had experienced hospitalization or had utilized urgent care services for exacerbations of HF within the 12 months preceding the study.

Adjudicated deaths attributed to cardiovascular causes or incidents of worsening HF were observed in 36 patients (9.9%) within the tirzepatide group, compared to 56 patients (15.3%) in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.41 to 0.95; P  = 0.026). Incidents of worsening HF occurred in 29 patients (8.0%) in the tirzepatide cohort and 52 patients (14.2%) in the placebo cohort (hazard ratio, 0.54; 95% CI, 0.34 to 0.85). Furthermore, adjudicated deaths resulting from cardiovascular causes were recorded in 8 patients (2.2%) in the tirzepatide group, as opposed to 5 patients (1.4%) in the placebo group (hazard ratio, 1.58; 95% CI, 0.52 to 4.83).

In other findings, the KCCQ-CSS and 6MWD demonstrated significant improvement among patients in the tirzepatide group compared to those in the placebo group after 52 weeks. Moreover, patients administered tirzepatide experienced a substantial reduction in body weight, averaging 11.6% (with a CI of −12.9% to −10.4%).

A secondary analysis of the SUMMIT trial investigated the impact of tirzepatide on cardiac structure and function in a cohort of 106 patients from the principal SUMMIT study. This cohort underwent imaging assessments to evaluate LV mass and epicardial adipose tissue at baseline and 52 weeks post-treatment. Findings indicated that tirzepatide reduced LV mass by 11 g and decreased paracardiac adipose tissue by 45 mL compared to the placebo group. Both the groups experienced reductions in epicardial adipose tissue. Researchers concluded that the observed decrease in heart size may contribute to the reduction in HF events reported in the main SUMMIT trial.

One limitation of this clinical trial is that only approximately 17% of participants received SGLT2 inhibitors at baseline. It remains uncertain whether the observed improvement was primarily attributable to weight loss, which implies that other weight management interventions may also present potential benefits, or if the effects were independent of this factor. Notably, the reduction in hs-CRP, a marker of inflammation associated with tirzepatide, may indicate a possible mechanism underlying its therapeutic advantages.

Conclusion

Advancements in HF treatments are promising, especially for HF with preserved ejection fraction (HFpEF), post-myocardial infarction HF, and HCM. GLP-1 receptor agonists, effective for weight loss, are showing positive results for HF in the STEP HFpEF trial. The SUMMIT trial found that tirzepatide significantly reduced cardiovascular mortality and worsening HF events in obese patients with HFpEF. Research continues on aldose reductase inhibitors for DbCM and SGLT2 inhibitors for those at risk of HF after myocardial infarction. The FINEARTS-HF trial indicated that finerenone reduced the risk of worsening HF and cardiovascular mortality in patients with HFmrEF or HFpEF. A phase 2 study of ninerafaxstat (IMPROVE HCM) showed it was safe and may improve cardiac energetics in non-obstructive HCM patients. The RELIEVE-HF trial demonstrated that while the Ventura interatrial shunt (V-Wave) is safe, it did not improve prognosis or symptoms in HF patients and could potentially harm those with HFpEF.

Future Perspectives on Heart Failure Treatment

Future perspectives on managing HF emphasize enhancing early detection, personalizing treatments, and achieving improved long-term outcomes through a technology-augmented multidisciplinary approach. The integration of precision medicine and genomics is pivotal for creating new therapeutic agents alongside conventional therapies. CRISPR Gene Editing (MAGNITUDE TRIAL, NCT03748641) has demonstrated promising outcomes in lowering TTR protein levels and boosting cardiac function. Researchers are investigating stem cell therapy to repair damaged cardiac tissue in individuals with dilated cardiomyopathy. Presently, numerous phase 3 clinical trials are ongoing worldwide to evaluate innovative pharmacological treatments, device-based interventions, and regenerative strategies aimed at improving outcomes across different types of HF.

Trial name	Population	Intervention	Objective
COMET-HF NCT06736574	HFrEF	Omecamtiv Mecarbil	Reduce CV death and HF events
CardiAMP HF II NCT02438306	Ischemic HFrEF	Bone marrow cell therapy	Stimulate cardiac repair
CORCINCH-HF NCT04331769	Symptomatic HFrEF	AccuCinch(R) Restoration System	Improve LV function
ALT-FLOW II NCT05686317	HFpEF	APTURE Shunt System	Reduce left atrial pressure
LEADR LBBAP NCT04863664	CRT candidates	LBBAP	Compare to biventricular pacing
Eplontersen Trial NCT04136184	ATTR-CM	Eplontersen	Reduce TTR levels, improve function