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Potential Role of Entresto (sacubitril-valsartan) in Barth Syndrome Cardiac Management, presented by Dr. John Jefferies, University of Tennessee Health Sciences Center



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February 19th, 2020

Describing and Defining Heart Failure

What is heart failure?
Heart failure (HF) is associated with decreased quality of life and early mortality in Barth syndrome. HF is defined as a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle (one of the chambers of the heart) to fill with or eject blood, and as a result can’t pump enough blood to meet the body’s needs. The issue can occur due to a problem with the heart’s ability to “squeeze” (systolic function), “relax” (diastolic function), or both.

Heart failure is classified by the ACC (American College of Cardiology) and the AHA (American Heart Association) in stages progressing from patients who are “at-risk” to those who have end-stage heart failure. Four stages are described:

  • Stage A: Patients at high risk for HF but without structural heart disease or symptoms of HF.
  • Stage B: Patients with structural heart disease but without signs of symptoms of HF
  • Stage C: Patients with structural heart disease who also have prior or current symptoms of HF
  • Stage D: Patients who have marked symptoms at rest despite maximal medical therapy (these patients are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions). 

Therapeutic strategies vary depending on the patient’s stage of HF; the goal is to keep patients in Stage A, or at least Stage B, thereby preventing further progression of disease and symptoms.

Heart failure in Barth syndrome

HF can be caused by a variety of reasons, one of which is a genetically triggered cardiomyopathy such as Barth syndrome. It is important to recognize in this context that inherited cardiomyopathies are typically progressive (worsen over time) and may be life-limiting as these are life-long exposures with a cumulative impact as compared to acquired disease like a myocardial infarction (heart attack).

Inherited cardiomyopathies include:

Dilated cardiomyopathy (DCM)

Patients with DCM typically have an enlarged and weak heart muscle. DCM is the most common type of cardiomyopathy worldwide; about 40% of genetic causes of DCM have been identified involving over 30 genes. The TAZ gene associated with Barth syndrome is one of these genes. DCM is characterized by left ventricular dilation and systolic dysfunction. DCM commonly progresses to heart failure; however, there are approved and effective therapies that help improve heart function.

Hypertrophic cardiomyopathy (HCM)

HCM is an abnormal thickening (or hypertrophy) of the heart muscle. In patients with HCM the heart not only doesn’t relax but there can be physical obstructions of the heart muscle as well. There are multiple genetic triggers that can cause HCM including mitochondrial disease. HCM causes congestion of blood in the heart causing obstruction (blood can’t get out of the heart) or sudden cardiac death. Unfortunately, there are no approved medications that improve HCM.  The medical therapies currently used are targeted at improving symptoms and managing arrhythmias.  Some patients with Barth syndrome may have HCM, which is of importance due to the potential risk of sudden cardiac death.

Normal ejection fraction (the volume of blood pumped by the heart) is 55-70%; people with HCM typically have a higher EF (75-80%) due to the heart pumping too efficiently. Surveillance is extremely important in patients with genetic diseases that cause HCM in order to avoid sudden cardiac death.

Left Ventricular Noncompaction Cardiomyopathy (LVNC)

LVNC is a very common cardiac phenotype in Barth syndrome. In patients with LVNC, the heart is structurally abnormal and looks like a honeycomb or sponge as seen in early gestational development. These abnormalities persist over time. LVNC can be seen in conjunction with other cardiomyopathies including DCM, HCM and restrictive cardiomyopathy (RCM). Many patients with LVNC, similar to HCM, have abnormal heart rhythms and have a higher stroke risk than with other types of cardiomyopathy. Previously thought to be a very rare form of cardiomyopathy, increased awareness and improvements in diagnostic imaging have resulted in more reported cases such that LVNC accounts for approximately 9% of newly diagnosed pediatric cardiomyopathies currently.

All of these genetic cardiomyopathies impair the optimal function of the heart and can cause heart failure.

Approaches to Treatment

Heart failure is a major problem in the general population as well as a primary issue for patients with Barth syndrome. In general, studies have demonstrated that every heart failure related hospital admission is directly related to a decrease in survival over time. Therefore, managing heart failure and preventing progression of disease is extremely important and a driver in medication and therapeutic strategies.

Pathophysiology and pharmacology

Atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP) are both elevated in chronic heart failure; BNP is the more important of the two indicators and is more often used as a diagnostic tool. In the setting of decompensated HF, BNP elevated (above normal or increased compared to the typical baseline for the patient).

Chronic heart failure, as caused by the cardiomyopathies described above, is typically accompanied by negative changes to the structure of the heart called pathologic or unfavorable remodeling. Therapies to treat remodeling vary depending on the size and thickness of the heart and the heart muscle function. Ideally, pharmacologic approaches to heart failure management strive to improve multiple systems (neurohormonal, renal, hemodynamic) causing impaired heart function, as well as reverse the negative remodeling that is occurring.

Again, based on the stages of disease (A, B, C, D) mentioned earlier, the goal of treatment is to identify patients when they are asymptomatic but intervene immediately when there is evidence of disease in order to prevent further progression and hospitalization/necessity of specialized medical management. Additionally, current Guidelines such as those published by the New York Heart Association suggest that treatment should be directed toward helping patients stay in a compensated state where they do not have symptoms.

Common drugs used to treat heart failure

Heart disease, blood vessel constriction and kidney function are all important when managing heart failure.  Commonly used drugs to treat heart failure include beta-blockers, diuretics (such as Lasix), ACE inhibitors (i.e. lisonopril, enalapril, ramipril), angiotensin receptor blockers (ARB) (i.e. losartan, valsartan, candesartan) and finally the class of drugs which includes Entresto (sacubitril-valsartan), angiotensin receptor neprilysin inhibitors (ARNis). Of importance, ARNis have helpful effects on the heart, kidneys and the blood vessels; note also that Entresto is a combination therapy that includes an ARB (valsartan) as well as a neprilysin inhibitor.

Multiple studies have evaluated the safety and efficacy of various therapies and outcomes in adults with HF. ACE inhibitors, ARBs, ARNis, beta-blockers all improve survival and have been shown to reduce hospitalizations.   Most of this information has been generated from adult populations; however, there is some positive data in pediatric patients. 

Use of Entresto

The individualized pharmacologic choice of drug to treat heart failure is based on a classification system using levels of evidence and a risk-benefit ratio. For example, a Class IA recommendation would be quite strong where the potential benefit of the drug outweighs the risk, and high-quality evidence from randomized clinical trials (RCT) also supports the potential for improvement. Until the recent approval of Entresto, ACE inhibitors and ARB were the most frequently used Class I drugs to treat HF.

Clinical trials using Entresto to treat various types and stages of heart failure (A, B, C, D); for purpose of discussion most of the data is focused on Stage C. As a reminder, patients with Stage C heart failure have heart muscle disease AND have symptoms. 2017 HF (ACC/AHA) Guidelines help clinicians with guideline directed medical therapy. Based on the type of abnormality, clinicians may consider an ARB, an ACE inhibitor, or more recently, Entresto (an ARNi). Because Entresto is a combination therapy that includes an ARB (valsartan), patients would not be treated with an ACE inhibitor and/or an ARB and Entresto.  For patients taking an ACE inhibitor, they would undergo a washout phase before beginning treatment with the ARNi (in the United States Entresto is the FDA-approved ARNi indicated for treatment of HF).  Those on an ARB can transition directly to Entresto.

Clinical Trials evaluating Entresto

PARADIGM-HF: Angiotensin-Neprilysin Inhibition vs Enalapril in Heart Failure (NEJM, 2014) 

The PARADIGM-HF trial was stopped early given the favorable findings and expedited to approval by FDA due to evidence of the obvious benefit of Entresto as a treatment of HF. When compared to patients using enalapril, the Entresto group had a 21% reduced risk of hospitalization for HF, a significant decrease of symptoms and physical limitations of HF, and an overall decrease in the rate of death from cardiovascular causes. In other words, ALL of the endpoints in the trial were favorably impacted by use of Entresto. As a result, changes in ACC/AHA treatment guidelines were established so that Entresto is a Class I drug of choice for patients with evidence of heart muscle disease and HF symptoms.

PIONEER-HF: Angiotensis-Neprilysin Inhibition in Acute Decompensated Heart Failure (NEJM, 2019)

In the PIONEER-HF trial, patients hospitalized for HF were treated with Entresto and then followed over time.  The focus of this study was not mortality or hospital admission but rather a biomarker called NT pro-BNP. Levels of NT pro-BNP are a strong predictor of readmission and mortality; the lower the NT pro-BNP level the better for the patient.  Those patients treated with Entresto had a more significant drop in NT pro-BNP than those treated with enalapril.  As compared to treatment with enalapril, the side effect profile was very similar.

PARAGON-HF Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction (NEJM, 2019)

This trial reviewed patients with preserved ejection fraction, or a problem with the relaxation of the heart as opposed to the heart’s ability to squeeze. Some populations showed more improvement but overall the trial did not show a statistically significant benefit as compared to use of valsartan alone.

Additional considerations for HF management include:

  • Control anemia
  • Control blood pressure (less than 130/80 in adults)
  • Treat sleep disorders such as sleep apnea

Use of Entresto in children

A small recent trial (PANORAMA) evaluated that Entresto can be used in children over 1 year of age with LV dysfunction and symptoms, although the children in the study did not specifically have Barth syndrome.  

Use of Entresto in patients with heart transplant

Immunosuppression drugs have an impact on kidney function and this presents the greatest potential area of risk for use of Entresto in patients with heart transplant. Although there are no current indications or clinical trial data on the use of Entresto for transplanted individuals, it should be considered just as other HF drugs based on the patient’s individualized presentation and level of risk for progression of disease and/or sudden cardiac death.

In summary, Entresto can be used in both the outpatient and hospital setting to treat HF, specifically in patients with a cardiomyopathy that impairs the heart’s ability to squeeze. The potential exists today for further study to evaluate the specific use and potential benefit of ARNIs in genetic cardiomyopathy such as Barth syndrome, especially considering the cumulative effect of worsening HF in these conditions.

About Dr. Jefferies:
Dr. John L. Jefferies is the appointed Jay M. Sullivan Endowed Chair in Cardiovascular Medicine and Chief of Cardiology at the University of Tennessee Health Science Center (UTHSC) and Director for the newly formed UT Methodist Institute for Cardiovascular Science. Prior to joining the University of Tennessee Health Science Center, Dr. Jefferies spent more than eight years with the University of Cincinnati College of Medicine and Cincinnati Children’s, where he was an Associate Professor of Adult Cardiovascular Diseases and Pediatric Cardiology from 2010-2015, Professor of Adult Cardiovascular Disease and Pediatric Cardiology from 2015-2018, and Professor of Human Genetics from 2015-2018.

Of immense value to our community, Dr. Jefferies was the Director of the Advanced Heart Failure and Cardiomyopathy Services in the Heart Institute at Cincinnati Children’s Hospital Medical Center where he played a primary role in BTHS patient heart transplantation cases.

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