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Even as New HFpEF Drugs Transform Care, Penn Team Pushes Further


Following 2022's revision of heart failure guidelines, clinicians treating a form of the condition with relatively normal pumping volumes have new reasons for optimism.

Prescribing medical therapy for heart failure with preserved ejection fraction (HFpEF) no longer means choosing from limited options with questionable efficacy. Instead, the guidelines feature two notable additions, backed by stronger evidence and recommendations: sodium-glucose cotransporter-2 (SGLT2) inhibitors and, to a lesser extent, an angiotensin receptor-neprilysin inhibitor (ARNi).

Drugs from both groups are now specifically approved for HFpEF, following clinical trials that showed the potential for improved prognosis and quality of life.

"For the first time, we have several medical therapies that have gained traction in terms of the evidence," says Stuart Prenner, MD, a cardiologist who treats and investigates HFpEF at the Hospital of the University of Pennsylvania. "Like all forms of heart failure, HFpEF is progressive, so we can potentially institute treatments that delay it from advancing."

Given that promise, Prenner and other members of the Penn Heart Failure Program see a "bright future" for HFpEF care — albeit one with continuing challenges.

Identifying the condition remains difficult, frequently requiring specialized equipment practices may not own and an extensive consideration of other possible diagnoses.

Compared to other forms of heart failure, high mortality persists because patients are also older and often have demanding comorbidities. And the prevalence of HFpEF — already more than half of heart failure cases — is projected to grow as the population ages. The continued rise in metabolic conditions is likely to further increase HFpEF incidence as well.

In response, the Penn team is investigating more effective ways to treat HFpEF and related comorbidities affecting outcomes, particularly obesity and hypertension. Team members are also partnering with community physicians to provide support for their patients, including thorough comprehensive evaluations.

"We finally have specific medications shown to improve quality of life and outcomes, so making the diagnosis is more important than ever," says Lee Goldberg, MD, section chief of Advanced Heart Failure and Cardiac Transplant at Penn Medicine.

Recognizing the Signs of Heart Failure with Preserved Ejection Fraction

To meet the initial criteria for HFpEF, patients should have heart failure symptoms, such as volume overload, fatigue or unexplained dyspnea. Physicians should rule out other causes for shortness of breath such as chronic obstructive pulmonary disease, pulmonary hypertension or valvular heart disease.

Patients should also have a left ventricular ejection fraction (LVEF) above 50 percent, with no previous history of falling below that mark. (While treatments overlap, disease with LVEF below 50 percent — heart failure with mildly reduced ejection fraction — requires its own approach.)

Other clues include age over 60 and HFpEF risk factors such as hypertension, renal dysfunction, diabetes, obesity and metabolic syndrome. Physicians should also watch for atrial fibrillation, a common comorbidity. Many of these considerations influence a scoring system the Penn team recommends called H2FPEF, backed by evidence and available online.

Anyone with a mid- to high-range score likely needs further evaluation. A detailed assessment — and often, specialized testing — is required to ensure diagnoses are not missed. For example, while measuring B-type natriuretic peptide (BNP) can provide some insight, one-third of patients have normal BNP levels. A comprehensive approach can also rule out less-common conditions that mimic HFpEF but require different treatment.

"Diagnosing HFpEF requires a high index of suspicion," Prenner says. "It's also important to have an open mind to what the differential might be."

Using Echocardiogram to Start HFpEF Diagnosis

In addition to gauging LVEF, cardiac echo can measure flow velocity at the mitral valve and estimate pulmonary artery systolic pressure, two elements of risk scoring. Echo can also point to pulmonary hypertension when left atrial enlargement is present and rule out severe valvular heart disease, both potential causes of symptoms.

Echo also has limitations for HFpEF, however. While many patients will show classic significant left ventricular hypertrophy or diastolic stiffness, others will not. That realization has moved the field away from the term "diastolic heart failure" and toward a broader view of the condition as HFpEF.

"We were missing the diagnosis," Prenner says. "We would do echoes, and unless patients had a lot of diastolic dysfunction, we would not feel comfortable with the label."

Turning to Right Heart Catheterization, Cardiac MRI and PYP Scans

Given the constraints with echo, using right heart catheterization (RHC) to measure filling pressures remains the gold standard for diagnosing HFpEF. Here, too, clinicians can run into challenges.

While a resting RHC can confirm pulmonary hypertension, it often misses HFpEF, especially when patients present early. At least 50 percent do not show any abnormalities unless the test includes using an exercise bike to elicit changes. (Studies show that infusing saline or lifting someone's leg can also help when patients cannot safely use a bike.)

"It is amazingly instructive for a clinician," Goldberg says. "Within two minutes, the pressures elevate and it is clear the patient has HFpEF."

Not all practices have exercise bikes for RHC, though, and they are not always available, even at heart failure programs. At Penn, the heart failure team uses exercise RHC to look not only at filling pressures on both sides of the heart, but also heart rate, blood pressure and other parameters to guide treatment plans.

When warranted, the team can also turn to further specialized testing such as cardiac MRI and pyrophosphate (PYP) scans to rule out other heart failure causes. Other possible etiologies include cardiac amyloidosis (10 percent to 15 percent of patients), sarcoid and hypertrophic cardiomyopathy.

New Options for HFpEF Such as SGLT2 Inhibitors Aid Treatment after Diagnosis

Unlike with other forms of heart failure, clinical trials to treat HFpEF with medical therapy historically failed to show efficacy, sometimes even causing harm. Those setbacks faded after successful trials for sodium-glucose cotransporter-2 (SGLT2) inhibitors, a new heart failure drug class subsequently added to revised management guidelines in 2022.

Part of a wave of heart failure advances in recent years, the trials were the first to clearly meet their primary endpoints for HFpEF. They followed investigations of SGLT2 inhibitors for guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction, or LVEF less than 40 percent.

In the EMPEROR-Preserved trial, investigators looked at the SGLT2 inhibitor empagliflozin for HFpEF, and in DELIVER they looked at dapagliflozin. A subsequent combined meta-analysis confirmed significantly reduced hospitalizations and urgent care visits for heart failure, regardless of diabetes status. While the analysis showed a lesser impact on cardiovascular mortality, hospitalization is tied to a worse prognosis for heart failure.

The SGLT2 inhibitor results gained the drugs a Class 2A recommendation for HFpEF in the guidelines and FDA approval for empagliflozin. Approval for dapagliflozin is expected.

"It's one of the main tools that I'm using in this patient population," Prenner says of the new drug class, adding that it also helps with diabetes and chronic kidney disease, common comorbidities. Contraindications, possible side effects and monitoring are similar to GDMT use.

The trial for another drug class, ARNi, at first appeared disappointing, with the primary end point unmet. But a post-hoc analysis of PARAGON-HF revealed the benefits of using the sacubitril-valsartan combination for certain populations, as opposed to valsartan alone. The pairing seemed to help patients with LVEF between 50 percent and 57 percent, as well as women more broadly. It can also help slow renal decline when needed. It has a Class 2B recommendation and FDA approval.

How Heart Failure Specialists Can Help Community Physicians Care for HFpEF

Among other HFpEF support, heart failure programs can help get patients on the latest drugs. At Penn, the heart failure team gained early experience with the medications during trials and quickly developed protocols for implementation. Patients can come for a one-time consultation or a series of visits, while still receiving the bulk of their cardiology care in the community.

Penn can also implant a sensor in the pulmonary artery for remote filling pressure monitoring. While the overall evidence for PA monitors is mixed, Prenner says, they can help certain high-risk patients avoid rehospitalization. In addition to experience with patient selection, Penn has the capacity to track and quickly incorporate sensor data.

Perhaps the greatest outstanding needs come from the formidable list of comorbidities seen with HFpEF:

  • Atrial fibrillation
  • Chronic kidney disease
  • Diabetes
  • Hypertension
  • Ischemic heart disease
  • Obesity
  • Sleep apnea

HFpEF patients often have more than one comorbidity. In response, Prenner and his heart failure colleagues coordinate with specialists across Penn Medicine, including in nephrology, endocrinology, sleep medicine, gastroenterology and bariatric surgery.

Among other investigator-initiated HFpEF trials at Penn, nationally recognized researchers are exploring the effect calcium channel blockers and beta blockers can have on hypertension. Hypertension is potentially one of the more modifiable risk factors for the development and progression of HFpEF.

Penn researchers are also taking part of a trial looking at whether semaglutide injections can help patients lose weight when they have HFpEF and obesity. Shedding pounds in such cases can support exercise tolerance and quality of life, research shows. It can also improve RHC results and actually help the heart unstiffen. Unfortunately, the newer HFpEF drugs have not shown a weight loss benefit, so Prenner says that Penn is investigating further options.

"You can't succeed in these patients if you're not addressing their other medical conditions," he says.

Contact the Penn Heart Failure Program

To reach the Penn heart failure team, please call 215-615-0800.

Penn Medicine, Philadelphia, PA 800-789-7366 © , The Trustees of the University of Pennsylvania

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