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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Heart failure medical management has blossomed in recent years, particularly for heart failure with reduced ejection fraction (HFrEF), although the gains for HF with preserved ejection fraction (HFpEF) have been all the more meaningful because of the scarcity of proven agents.

HFrEF

Inhibition of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has long been a staple of HFrEF management. But with the advent of angiotensin receptor/neprilysin inhibition (ARNI) -- combining an ARB and an inhibitor of an enzyme that degrades natriuretic peptides and other vasoactive peptides -- guidelines now recommend those as the top choice for first-line therapy for patients with New York Heart Association (NYHA) class II to III symptoms.

An ACE inhibitor is the next best option when an ARNI isn't feasible, and an ARB can take over as a third choice if patients have intolerable cough with an ACE inhibitor or have a history of angioedema.

When switching between an ACE inhibitor and ARNI, stopping the prior drug for at least 36 hours is necessary to avoid risk of angioedema.

The second pillar of HFrEF treatment, beta blockade, also reduces risk of mortality. However, the class 1 recommendation applies only to bisoprolol, sustained-release metoprolol (succinate), and carvedilol (Coreg), not the entire class of beta-blockers.

"Even when asymptomatic, or when symptoms are mild or improve with other therapies, beta-blocker therapy is important and should not be delayed until symptoms return or disease progression is documented," the guidelines note.

The third pillar, mineralocorticoid receptor antagonists (MRAs), are recommended for patients with NYHA class II to IV symptoms if kidney function isn't impaired (eGFR >30 mL/min/1.73 m²) and serum potassium is over 5.0 mEq/L. As a more selective MRA for the aldosterone receptor, eplerenone is safer than spironolactone, with fewer adverse effects like gynecomastia or vaginal bleeding.

"Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely monitored thereafter to minimize risk of hyperkalemia and renal insufficiency," the HF guidelines caution.

In practical terms, a noted that doses of the drugs should be adjusted every week or 2, with the general principle that it "may be performed more rapidly in non-congested patients with normal blood pressure than in those with frailty or borderline hypotension." Also, reducing the dose of loop diuretics may be advisable for non-congested patients when starting the ARNI sacubitril/valsartan (Entresto) to reduce the risk for hypotension.

Even though uptitration can be more challenging in a real-world population of patients than in the clinical trials, the reviewers urged pushing doses as close to optimal as possible no matter how long it takes to get there.

"Clinicians must recognize that even when perceived stable, patients with HFrEF have a high risk for complications from their diagnosis and benefit from achieving guideline-directed medical therapy," the authors stated. "The fallacy of the 'stable patient with HFrEF' should be avoided in order to achieve optimal titration."

The latest iteration of the , released in 2022, added a : sodium-glucose cotransporter 2 (SGLT2) inhibition. While these drugs started out as type 2 diabetes medications, they gained a class 1 recommendation for all chronic, symptomatic HF patients, regardless of diabetes status.

The reduction in combined risk of cardiovascular death or HF hospitalization with SGLT2 inhibitors in the DAPA-HF and EMPEROR-Reduced trials was about 25%.

Additional Considerations in HFrEF

However, uptake has been poor. In one from 2023, SGLT2 inhibitors were prescribed to less than 15% of even high-risk patients with an indication for them due to having both type 2 diabetes and HF along with atherosclerotic cardiovascular disease.

And that's been true for all the pillars, according to an published by the American College of Cardiology (ACC).

Utilization has been "dismal with large observational studies suggesting that pharmacotherapies are not being used at their optimal dosing, or worse, not being prescribed at all," the document states. "Current estimates suggest that ACE-I/ARB usage in HFrEF is about 60-80%; ARNI usage is just above 10%; BB [beta blocker] usage is about 60-80%; and MRA usage is about 30-60%. Worse still, target dosing is as low as 10-20% for ACE-I/ARB, 10% for ARNI, 10-20% for BB, and 60-80% for MRA."

Electronic health record alerts in the PROMPT-HF study showed that highlighting which of the four pillars of guideline-directed medical therapy were missing for patients with HFrEF yielded a relative 41% boost in the number of patients who added one or more of those classes to their regimen.

In , an automated, electronic health record-embedded tool to alert clinicians when a patient was eligible to take an MRA more than doubled prescription rates, but the improvement was from a dismal 11.7% to a still low 29.6%.

A that aimed to get patients titrated on all four classes within 4 weeks after an exacerbation of HFrEF either in the community or following hospitalization achieved this in 76% of eligible patients and with a 6% rate of significant adverse events.

Starting all four pillars while in the hospital has also proven effective. In the STRONG-HF trial, initiating heart failure medications before patients headed home from an acute HF hospitalization and rapid uptitration afterward reduced 180-day HF readmission or death from any cause by a relative 34% compared with usual care.

Beyond those foundational therapies, ivabradine is indicated for patients in sinus rhythm with a heart rate of 70/min or greater, despite a maximally tolerated beta-blocker. For Black patients with persistent NYHA class III-IV symptoms despite guideline-directed medical therapy at maximally tolerated doses, isosorbide dinitrate and hydralazine can be an option individually or in fixed-dose combination.

Vericiguat (Verquvo) also gained an indication to lower cardiovascular events in HFrEF patients who have recently been hospitalized or have received intravenous diuretic therapy.

When HFrEF treatments work to cut symptoms and bring left ventricular EF (LVEF) above 40%, patients move into the HF with improved EF (HFimpEF) category. But that is no reason to lighten up on treatment, guidelines caution.

They give a class 1 recommendation to continued guideline-directed medical therapy to prevent relapse and LV dysfunction, even if patients become asymptomatic.

The randomized TRED-HF trial showed that patients with dilated cardiomyopathy whose LVEF had improved from less than 40% to at least 50% along with normalization of LV end-diastolic volume and N-terminal pro-B-type natriuretic peptides (NT-proBNP) were likely to have their LVEF drop substantially if they stopped their medications. Secondary analyses showed worsening quality of life as well with withdrawal of HF medications.

HFmrEF

For HF with mildly reduced EF in the 41-49% range (HFmrEF), the evidence is less definitive.

And that's because there haven't been any randomized clinical trials specifically done in this population -- only post-hoc or subset analyses from HF trials that included this relative newcomer to HF classifications, typically HFpEF trials with an LVEF cutoff of 40% or 45% or higher.

Thus, the 2022 HF guidelines give a 2a recommendation for SGLT2 inhibitors to reduce risk of HF hospitalization and cardiovascular mortality. For example, the SGLT2 inhibitor sotagliflozin (Inpefa) reduced combined risk of cardiovascular deaths and hospitalizations or urgent visits for HF by about 30% across the LVEF spectrum for patients recently hospitalized for worsening HF (SOLOIST-WHF) and for those with type 2 diabetes, reduced kidney function, or risks for cardiovascular disease (SCORED), leading to a recent FDA approval for cardiovascular prevention without restriction on LVEF.

For patients who are or have been symptomatic, the guidelines also give 2b recommendations to the beta-blockers used for HFrEF (bisoprolol, sustained-release metoprolol, and carvedilol), ARNI, ACE inhibitor or ARB, and MRAs. These might help reduce the risk of HF hospitalization and cardiovascular mortality.

Notably, the benefit appears to vary across the LVEF spectrum in HFmrEF, as patients whose LVEF is closer to the 40% threshold for HFrEF appear to respond to medical therapies similarly to patients with HFrEF.

For example, in the CHARM program, looking at EF as a continuous variable showed that candesartan's benefit started to decline when the EF increased above 50%. And in the PARAGON-HF trial, treatment with sacubitril/valsartan held benefit when LVEF was at or below the median of 57%, leading to expansion of the ARNI's indication. For recently decompensated heart failure patients in the 40-60% LVEF range, sacubitril/valsartan improved clinical outcomes in the PARAGLIDE-HF trial as well.

"Thus, it may be reasonable to treat these patients with GDMT [guideline-directed medical therapy] used for treatment of HFrEF," the guidelines noted.

Indeed, a 2022 review in noted that "HFrEF medication use in registries is high in the population of patients with HFmrEF, which might be explained by the role of these therapies in treating risk factors and comorbidities that are frequent in HF regardless of EF, such as hypertension, diabetes, chronic kidney disease, IHD [ischemic heart disease] and atrial fibrillation."

"Diuretic use is also high in patients with HFmrEF, presumably for symptom relief, which is indicated regardless of EF," the document added.

HFpEF

After many years of one failed therapeutic trial after another in HFpEF, treatment options have finally begun to emerge: "the success of recent SGLT2i trials has shown that HFpEF is treatable," noted an American College of Cardiology .

Empagliflozin (Jardiance) in the EMPEROR-Preserved trial and dapagliflozin (Farxiga) in the DELIVER trial reduced HF hospitalization or cardiovascular death by 18-21% among HF patients with LVEF over 40%.

The SOLOIST-WHF and SCORED trials showed sotagliflozin lowered by about 30% the combined risk of cardiovascular death, hospitalization, and urgent visits for HF among patients recently hospitalized for worsening HF and for those with type 2 diabetes, reduced kidney function, or risks for cardiovascular disease. Almost 21% of participants in both trials had HFpEF, and the benefit of sotagliflozin appeared consistent across the range of ejection fractions.

Across the trials, benefits from SGLT2 inhibitors have generally applied similarly to patients with and without diabetes, and across the spectrum of EF. All three drugs are guideline-recommended (class 2a) and FDA-approved treatments for HF without limitations on left ventricular ejection fraction.

With regard to ARNI treatment, patients with an LVEF of 45% or more didn't benefit overall in the PARAGON-HF trial. Sacubitril/valsartan missed statistical significance (P=0.06) in reducing the risk of HF hospitalization or cardiovascular death. The at which sacubitril/valsartan stopped showing a trend for benefit was around 60% for men but nearer to 70% for women.

But starting sacubitril/valsartan for recently decompensated HF with LVEF over 40% improved the key prognostic marker NT-proBNP and, for those in the 40-60% range, clinical outcomes as well, the PARAGLIDE-HF trial showed.

Guidelines give a lower, class 2b recommendation for ARNI use in HFpEF. The same is true for MRA and ARB medications. All three come with the disclaimer that their effects are "particularly among patients with LVEF on the lower end of this spectrum."

Diuretics also help relieve congestive symptoms in HFpEF, but routine use of nitrates and phosphodiesterase-5 inhibitors are specifically noted in guidelines as of no benefit.

"Despite numerous major differences between HFpEF and HFrEF indicating that these are two distinct syndromes, [cases like the SGLT2 inhibitors] also open up the possibility of EF-agnostic HF therapeutics," the ACC scientific statement on HFpEF noted. Like SGLT2 inhibitors, "some therapies developed for HFpEF may be beneficial to all HF patients, especially as we understand that the comorbidity-inflammation-endothelial dysfunction paradigm may extend to many patients with HFrEF as well."

Read previous installments of this series:

Part 1: Heart Failure: A Look at Low Ejection Fraction

Part 2: Exploring Heart Failure With Preserved Ejection Fraction

Part 3: Heart Failure With Reduced Ejection Fraction: Diagnosis and Evaluation

Part 4: Case Study: Lightheadedness, Fatigue in Man With Hypertension

Part 5: Heart Failure With Preserved Ejection Fraction: Diagnosis and Evaluation

Up next: Comorbidity Management