Treatment of HF has evolved rapidly in recent years, with novel therapies and a fundamentally new treatment algorithm offering options for improved management of the disease across the full spectrum of ejection fraction.

Clinicians have historically struggled to treat symptom burden and improve quality of life in HF, particularly HF with preserved EF, for which drug trials initially failed to demonstrate the same benefits seen in HF with reduced EF. Moreover, HF with mildly reduced EF is a new phenotype with emerging but not yet fully subscribed evidence-based therapies.

“For years, we have been at a loss to understand how to best treat HFpEF,” Clyde W. Yancy, MD, MSc, MACC, FAHA, MACP, FHFSA, vice dean for diversity and inclusion, chief of cardiology, Magerstadt Professor and professor of medicine and medical social sciences at Northwestern University Feinberg School of Medicine and past president of the American Heart Association, told Cardiology Today. “In the past, our clinical trials yielded very little guidance, suggesting that we needed to go back and revisit our understanding of the phenotype, specifically HFpEF, but the same can be said for HF with mildly reduced EF. That exercise was for the good. It helped us understand there are multiple iterations of what qualifies as HFpEF. That allowed us to start thinking differently about how to approach the condition and reminded us that there are probably two uniquely important domains in the setting of HFpEF more so than other phenotypes: the likelihood of influencing mortality, and the importance of the concomitant comorbidities.”

Recent data from two landmark trials have upended the treatment paradigm for HFpEF. In 2021, the EMPEROR- Preserved trial demonstrated the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) improved clinical outcomes in HFpEF with or without diabetes, reducing the primary outcome of CV death or HF hospitalization by 21% compared with placebo. In August, data from DELIVER showed the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) similarly reduced risk for CV death and worsening HF compared with placebo in adults with HF with mildly reduced or preserved EF, with no attenuation of treatment benefit for patients with the highest EF.

“Importantly, DELIVER showed remarkable consistency, regardless of EF,” Scott D. Solomon, MD, professor of medicine at Harvard Medical School and senior physician at Brigham and Women’s Hospital and the principal investigator of the DELIVER trial, told Cardiology Today. “We saw the same benefit in patients with an EF over 60% as well as an EF under 60%. We also saw similar benefits in patients recently hospitalized with HF or enrolled in-hospital. We showed patients with HF with improved EF had a benefit that was at least as good as those patients with an EF consistently over 40%. We believe the results of DELIVER, which showed so much consistency, suggest the benefit of dapagliflozin was realized regardless of EF or care setting.”

Data from EMPEROR-Preserved and DELIVER, along with subsequent meta-analyses clearly demonstrate SGLT2 inhibitors as beneficial for the EF threshold of 40% or greater. Clinicians should now revisit the entirety of the HF treatment algorithm, Yancy said. Updated guidelines already reflect the use of SGLT2 inhibitors as the latest pillar of guideline-directed medical therapy (GDMT) in HFrEF, but the indication for use now extends throughout the full measure of left venticular EF.

“The strength of the aggregate studies, the subsequent meta-analyses of these studies, plus other data leave us with an incontrovertible truth: For the first time, we now have an evidence-based therapy that will reduce morbidity in the setting of HFpEF,” Yancy said.

“In 2022 and beyond, we end up with a triple-drug regimen for HFpEF — specifically [renin-angiotensin-aldosterone system] inhibition, plus a [mineralocorticoid receptor antagonist], plus the SGLT2 inhibitor. Just a few years ago, we were unable to articulate any such algorithm. This really does define what we think is a new era in the treatment of HFpEF.”

Treatment for the full spectrum of HF now has a stronger evidence base than ever, both for the spectrum of reduced EF and the spectrum of mildly reduced and preserved EF, Biykem Bozkurt, MD, PhD, The Mary and Gordon Cain Chair and Professor of Medicine and director of the Winters Center for Heart Failure Research at Baylor College of Medicine, past president of the Heart Failure Society of America and vice chair of the guideline writing committee, told Cardiology Today.

“Thus, clinicians should recognize the urgency of treating, because HF has mortality rates very similar to cancer,” Bozkurt said in an interview. “Like cancer, we would not delay initiation of lifesaving and disease-modifying therapies. Thus, in HF, the initiation and optimization of therapies should not be delayed.”

Individualized care key

Optimizing HF therapy is the best way to reduce disease morbidity and mortality and clinicians should consider personalizing and titrating guideline-directed medical therapy based on patient comorbidities, according to Alanna A. Morris, MD, MSc, FHFSA, FACC, FAHA, director of heart failure research at the Emory Cardiovascular Clinical Research Institute and associate professor of medicine in the division of cardiology at Emory University School of Medicine.

“The guidelines for treatment of HF with mildly reduced ejection fraction and HFpEF are quite new, and may still be surprising to some clinicians,” Morris told Cardiology Today. “For many years, most of the therapies for HF have been targeted at patients with HFrEF; however, it is important to treat all patients with HF, because they are all at high risk for adverse outcomes. It is critical that clinicians understand the treatment guidelines across the spectrum of EF categories.”

Solomon said clinicians should understand that “EF still matters,” even as new data suggest the SGLT2 inhibitors are beneficial for all HF phenotypes.

“Not all therapies are as clearly beneficial across the full range of EF as SGLT2 inhibitors,” Solomon said. “When we think about how we might use drugs like sacubitril/valsartan (Entresto, Novartis), there we do see attenuation of benefit in the highest EF ranges, so it would be important to know what EF is when using that drug. The same is true for beta-blockers, for which there is no evidence for their use in HF in patients with an EF over 40% unless they are required for other purposes, such as atrial fibrillation, ischemic heart disease or hypertension.”

Solomon said clinicians must also use an EF threshold when considering device therapies, such as an implantable cardioverter defibrillator or cardiac resynchronization therapy.

“EF is not going away, but with respect to the use of SGLT2 inhibitors in HF, we do not need to know what an EF is, so long as we believe the patient truly has HF,” Solomon said.

Guideline-directed therapy use low

Today, the proportion of patients with HF who are receiving GDMT remains low, and strategies to improve the use of these therapies are urgently needed, Morris said.

“Sometimes in the advanced HF clinic, all I do for patients is put them on an [mineralocorticoid receptor antagonist], adjust the diuretic therapy and [the patient] thinks I am a savior,” Morris said. “When, in fact, many of these patients never need to go through transplant or [left ventricular assist device]. It is just simple tweaks to their basic medical therapy, and they feel so much better when you decongest them and give them therapies that will help them.”

An updated, joint guideline from the American College of Cardiology, AHA and Heart Failure Society of America published in April redefined HF stages to focus on prevention of HF and recommends HF treatment with novel therapies, including SGLT2 inhibitors and angiotensin receptor/neprilysin inhibitors (ARNIs), Morris said. The new guideline is the first full revision since 2013.

The guideline now emphasizes a four-drug regimen for adults with HFrEF, including SGLT2 inhibitors, along with beta-blockers, mineralocorticoid receptor antagonists (MRAs) and renin-angiotensin-aldosterone inhibition with ARNIs (preferred), ACE inhibitors or angiotensin receptor blockers.

“Treatment for the spectrum of HFrEF should be done in a stepwise manner, initiate quadruple therapy, optimize quadruple therapy, and then consider add-on therapies, such as devices and additional medications,” Bozkurt said.

The guidelines also include recommendations for patients with HF with mildly reduced EF, Morris said; a class 2A recommendation for SGLT2 inhibitors and a class 2B recommendation for ARNIs, angiotensin receptor blockers or ACE inhibitors, and MRAs and beta-blockers.

There are also new recommendations for patients with HFpEF, which also includes a class 2A recommendation for SGLT2 inhibitors and class 2B recommendations for MRAs, ARNIs and angiotensin receptor blockers, she said.

Patients who have improved their LVEF in response to medical therapy for HFrEF where the EF is greater than 40% should continue their HFrEF treatment, Morris said.

“Do not stop their therapy,” Morris said. “We have seen many of these patients come in [with] cardiogenic shock because a clinician or patient decided to stop their therapy because they thought they were cured, because their EF is 55%. We now have randomized data to show that if you withdraw therapy for patients who normalize their EF and their natriuretic peptides, almost 50% of those patients will have a recurrence of HF within 6 months.

“We need to tell patients that their HF is in remission, not cured, keep them on therapy and explain why that is so important,” Morris said.

Titrating therapy: ‘We want to do this rapidly’

GDMT for HF should be initiated and titrated rapidly, with clinicians conducting serial reassessment and optimizing dosing, adherence and patient education to address the goals of care, Morris said.

Clinicians should consider specific patient scenarios, such as NYHA class, race and comorbidities, and implement additional GDMT and device therapy as needed, all while reassessing symptoms, labs, health status and LVEF. Ideally, medical therapy should be titrated and optimized every 1 to 2 weeks, Morris said.

“We do not want to uptitrate the doses to those used in randomized trials at the expense of having patients on all four drugs,” Morris said. “At the beginning, you put them on a low-dose beta-blocker; a low-dose SGLT2 inhibitor, and then you bring them back in 1 to 2 weeks and start the MRA, and then you bring them back in 2 weeks and you start the ARNI. Then, you can uptitrate to the doses based on the patient’s BP and other factors. This is a great place where telemedicine can be useful. We want to do this rapidly.”

Data from STRONG-HF, presented at the 2022 AHA Scientific Sessions and simultaneously published in The Lancet, demonstrated that an intensive treatment strategy of rapid uptitration of appropriate medications and close follow-up reduced death and readmission at 180 days compared with usual care in adults hospitalized for acute HF.

A high-intensity care intervention included the introduction of half-doses of GDMT at discharge, a safety visit at 1 week, a safety visit at 2 weeks — in which full doses of GDMT were initiated if safe — a safety visit at 3 weeks and a safety visit at 6 weeks. The study was stopped in September, well short of the planned enrollment of 1,800 patients, because of greater-than-expected differences between the groups in the primary endpoint, making it unethical to keep patients in the usual care group.

In a down-weighted adjusted Kaplan-Meier estimate, at 180 days, the primary endpoint of all-cause death or readmission for HF occurred in 15.2% of the high-intensity group and 23.3% of the usual care group (adjusted risk difference, 8.1 percentage points; 95% CI, 2.9-13.2; P = .0021; RR = 0.66; 95% CI, 0.5-0.86).

“Medical therapy for HF across the range of EF has evolved dramatically, yet we know implementation is sorely lacking,” Anu Lala, MD, associate professor of medicine (cardiology) and of population health science and policy at the Icahn School of Medicine at Mount Sinai, told Cardiology Today. “The population [of STRONG-HF] was more diverse than other studies at least with respect to race and gender, and two-thirds had EF less than or equal to 40%.

“The study adds undeniable evidence showing us the time is now to implement the therapies discovered to benefit our patients,” Lala said. “This means improving equitable access to care and creating workflows to allow for the close and frequent follow-up needed following hospital discharge for HF.”

Implementation science: ‘We have to go further’

Yancy said knowledge gaps remain regarding the best ways to initiate and titrate HF therapies, particularly in different patient populations.

“Remarkably, we know what to do, but we are still wrestling with exactly how to do it,” Yancy said. “Is there a sequence? If there is a sequence, what is the timing? Is there a titration schedule? If there is a titration schedule, what are the dosing increments? What are the risks at each step in the titration scheme? The point being, as far as we have come, we have to go further.”

Bozkurt said clinicians should be aware that new models of care coordination — including the transition from the hospital to outpatient care — can entail individualization and modernization of approaches.

“We can use telehealth,” Bozkurt said. “We can use multidisciplinary teams with clinicians and advanced practitioners. We can implement uptitration without having to bring the patient to a face-to-face visit. We realize our systems are challenged with capacity issues. Multidisciplinary care delivery across teams, in a virtual manner or hub and spoke manner, have been successful.”

Additionally, Bozkurt said, hospitalized patients “create a unique opportunity” to optimize HF therapies before discharge.

“Evidence from studies such as EMPULSE or SOLOIST demonstrate the efficacy and safety of initiating these therapies before discharge,” Bozkurt said. “In the guidelines, we have class 1 recommendations for initiation of GDMT once a patient is stabilized in the hospital setting and that GDMT not be arbitrarily withheld or discontinued, especially in the setting of transient rises in creatinine or an asymptomatic drop in BP. We are alerting clinicians not to withhold therapy, but to optimize therapy.”

Emphasizing HF prevention

The guideline updates include a new focus on preventing HF in people who are showing early signs of “pre-heart failure,” with an emphasis on optimizing BP and adherence to a healthy lifestyle. The societies also revised the ACC/AHA stages of HF — from stage A to stage D — to emphasize development and progression of the disease, with advanced stages indicating more serious disease and reduced survival rate.

Stage A, defined as “at risk but without symptoms,” includes people with hypertension, diabetes, metabolic syndrome and obesity, or exposure to medications or treatments that may damage the heart or hereditary risk factors. The new guidance puts a sizable portion of the U.S. population at risk for HF; approximately 121.5 million people in the U.S. have hypertension, 100 million have obesity and 28 million have diabetes. The guideline recommends clinicians consider SGLT2 inhibitors for people with type 2 diabetes and either established CVD or high CV risk.

“We could not have a cogent discussion about HF prevention even 10 years ago. Now, we know what does work,” Yancy said. “We know exquisite BP control in at-risk people reduces the likelihood of HF. We know that for people with type 2 diabetes, when treated with an SGLT2 inhibitor, there is a significant reduction in developing HF. We know that the Southern diet, as a defined eating pattern, is strongly associated with the development of HF. We know something as straightforward as following what was known as the AHA’s Life’s Simple 7, now Life’s Essential 8, reduces HF incidence. We now have an enhanced understanding of the possibility of preventing this condition, which, from my judgement is a much better approach therapeutically than treating symptomatic HF downstream.”

Additionally, Solomon said, there is still a need for good basic science to better understand the mechanisms of drugs like SGLT2 inhibitors and why they work in HF.

“The most important thing to remember is that even with the benefits seen in the DELIVER and EMPEROR trials, there is still a huge amount of residual risk,” Solomon said. “These patients, even in the SGLT2 inhibitor arms of these trials, who were well treated in many cases with other agents, still have a fairly high event rate. That means we have a long way to go before we cure HF.”