SGLT2 Inhibitors Added to ESC Guidelines for Treatment of Chronic HFrEF

Sodium glucose co-transporter 2 (SGLT2) inhibitors empagliflozin (Jardiance) and dapagliflozin (Farxiga) are now recommended for treatment of chronic heart failure with reduced ejection fraction (HFrEF), according to the latest 5-year update of the European Society of Cardiology (ESC) Guidelines in acute and chronic heart failure, which were released early Friday during the ESC Congress 2021.

The ESC Congress, being held in a virtual format for the second year due to COVID-19, runs today through Monday.

ESC updates guidelines in various treatment areas on 5-year cycles and releases them throughout its annual Congress. Other updates scheduled this year are valvular heart disease (Saturday), cardiac pacing (Sunday), and cardiovascular disease prevention (Monday). The heart failure guidelines were simultaneously published in the European Heart Journal.

Chronic heart failure is a condition where the heart is unable to pump blood around the body properly. It usually occurs because the heart has become too weak or stiff. Ejection fraction, which is the percentage of the blood within the ventricles that is ejected during the cardiac cycle, is the most important measure in heart failure.

Heart failure with preserved ejection fraction (HPpEF), also called diastolic heart failure, involves impaired relaxation of the left ventricle. Heart failure with reduced ejection fraction (HFrEF), or systolic systolic heart failure, involves impaired contraction of the left ventricle.

HFpEF is on the rise in the United States and worldwide, given that its likelihood rises with age and high blood pressure. According to ESC, prevalence rises from 1% among those age 55 and under to more than 10% among those aged 70 and older. Symptoms include breathlessness, ankle swelling, and tiredness. Once diagnosed, patients are typically hospitalized once each year and 50% die within 5 years.

Heart failure is linked to hospitalization and has been a major source of rising health care costs; in 2014, the mean cost of a hospitalization was pegged at $11,552, with total costs nationwide estimated at $11 billion. Under the Affordable Care Act, Medicare developed systems of penalizing hospitals that readmitted too many patients for heart failure within 30 days of discharge, thus fueling the need for therapies to treat this condition.

The update recognizes that patients with heart failure typically have other conditions such as atrial fibrillation and valvular heart disease, and gives treatment recommendations. “It is crucial to treat the underlying causes of heart failure and its comorbidities,” said task force chairperson Marco Metra, MD, of the University of Brescia, Italy, in a statement. “Proper treatment of high blood pressure, diabetes, and coronary artery disease can prevent the development of heart failure. Atrial fibrillation, valvular heart disease, diabetes, chronic kidney disease, iron deficiency and other comorbidities frequently co-exist with heart failure and the adoption of specific treatments may have a major impact on the clinical course of our patients.”

The rise of SGLT2 inhibitors in heart failure

Several evidence-based treatments have been developed to improve survival in HFrEF, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor neprilysin inhibitors (ARNIs), beta-blockers and mineralocorticoid receptor antagonists (MRAs). But in recent years, SGLT2 inhibitors, first introduced in 2013 to treat type 2 diabetes (T2D), have reshaped cardiometabolic care across diabetes, heart failure, and renal disease.

The 2015 EMPA-REG OUTCOME trial, designed to meet FDA requirements for empagliflozin’s approval in T2D, stunned both the diabetes and cardiology community when the drug showed cardiovascular (CV) benefits, and soon separate trials in heart failure and renal disease were under way across the drug class.

Two of these trials were EMPEROR-Reduced and EMPEROR-Preserved, which examined empagliflozin in HFrEF and HFpEF, respectively. Both EMPEROR-Reduced and the DAPA-HF trial in dapagliflozin showed significant reductions in a composite of cardiovascular death or heart failure hospitalization, leading to the new ESC guidelines.

Findings for EMPEROR-Preserved will be unveiled later Friday during the ESC Congress, and topline results suggest they will be significant. As noted during a press conference held ahead of the presentation on EMPEROR-Preserved, the latest heart failure guideline update could be outdated literally within hours. The 2021 ESC Guidelines state, “To date, no treatment has been shown to convincingly reduce mortality and morbidity in patients with HFpEF, although improvements have been seen for some specific phenotypes of patients within the overall HFpEF umbrella.”

“Every guideline we write is out of date a few days after it's published,” said Milton Packer, MD, of Baylor University Medical Center, who is presenting one of the studies on Friday.

Acknowledging that he was exaggerating a bit, Packer continued: “The guidelines are dynamic documents. They represent what we know at the time that they're written. And then new information comes out, and they have to be updated. And that takes time. It's a process and we all understand that process, there is no real concept of finality here. We do the best we can with the data we have.”

Changes from 2016

The ESC guidelines in heart failure were last updated in 2016. The authors highlight several concepts incorporated across the guidelines, including:

• A change from “heart failure with mid-range ejection fraction” to the term “heart failure with mildly reduced ejection fraction” (HFmrEF) to describe patients with left ventricle ejection fraction (LVEF) of 41% to 49%
• A modified classification for acute HF
• The addition of key quality indicators

Therapies. The updated guidelines recommend empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and sotagliflozin for patients with T2D who are at risk of CV events “to reduce hospitalizations for HF, major CV events, end-stage renal dysfunction, and CV death.” Separately, dapagliflozin, empagliflozin, and sotagliflozin were recommended for those with T2D and HFrEF to reduce hospitalizations for heart failure and CV death. Sotagliflozin, which is an SGLT1/2 inhibitor, has not yet been approved by FDA.

Of note, new Level 1 recommendations—which means there is evidence or general agreement that a treatment or procedure is beneficial, useful and effective—call for giving patients evidence-based oral medications, including SGLT2 inhibitors, before discharge from the hospital. Guidelines call for patients to be evaluated for congestion before they leave so that physicians can find optimal oral therapy regimens. Follow-up visits are recommended at 1 to 2 weeks to increase doses if necessary.

Strategies. Beyond the recommendations for the use of specific therapies, other updates—if embedded into clinical practice—could make a major impact on patient care. Additional Level 1 recommendations cover the following:

1. HFpEF. Screening for, and treatment of, etiologies, and CV and non-CV comorbidities are recommended in patients with HFpEF.
2. Prevention and screening. (1) Self-management strategies are recommended to reduce the risk of HF hospitalization and mortality. (2) Either home-based and/or clinic-based programs improve outcomes and are recommended to reduce the risk of HF hospitalization and mortality.
3. Management for advanced HF. (1) Patients being considered for long-term mechanical circulatory support must be able to handle the device and have support systems in place; (2) Heart transplants are recommended for those with advanced HF and refractory to medical/device therapy and who do not have absolute contraindications.
4. Management of patients with HF and valvular heart disease. (1) Aortic valve intervention, transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR) is recommended in patients with HF and severe high-gradient aortic stenosis to reduce mortality and improve symptoms. (2) The choice between TAVI and SAVR should be made based on individual patient preference and features that include age, surgical risk, clinical, anatomical and procedural aspects, weighing the risks and benefits of each approach.
5. Patients with HF and iron deficiency. Patients with HF must be screened for anemia and iron deficiency with a full blood count, serum ferritin concentration, and transferrin saturation.
6. Patients with HF and cancer. Those with cancer who are at increased risk for cardi-otoxicity, defined by a history or risk factors of CV disease, previous cardiotoxicity or exposure to cardiotoxic agents, should undergo CV evaluation before scheduled anticancer therapy, preferably by a cardiologist with experience in cardio-oncology.
7. HF and amyloidosis. (1) The guidelines recommend tafamidis (Vyndamax) for patients with transthyretin amyloidosis-cardiac amyloidosis (CA) with genetic testing proven hereditary hTTR-CMP and NYHA class I or II symptoms, and (2) to for patients with wtTTR-CA and NYHA class I or II symptoms to reduce symptoms, CV hospitalization and mortality.

Reference

McDonagh TA, Metra M, Adamo M, Gardner RS. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021; [published online August 26, 2021]. doi:10.1093/eurheartj/ehab368