Many customers have reached out to our customer support team lately with questions about switching to a new heart failure treatment recommended by their healthcare providers after years on the same therapy. Some are concerned that this may be an indication that the old medication does not work for them anymore or that their condition has worsened. It’s our role as pharmacists to always try to explain in lay terms what may have been the reasons for the doctor’s choice so that the patient can understand and cope with the implications. The recent questions are coming from patients who had been recommended a new heart failure with reduced ejection fraction medicine (technically known as an HFrEF treatment) and who are now being prescribed a drug called Entresto (generic sacubitril/valsartan).
From our research, we can tell them that the main driver for the switch away from the older forms of treatment to Entresto is a new recommendation by the American College of Cardiology (ACC) in its consensus decision pathway for the treatment of heart failure with reduced ejection fraction. This change elevates Entresto’s status above traditional ACE inhibitors (such as Vasotec, Zoprotec, Vasodip Combo or Altace) and ARBs (for example, Diovan, Edarbi, Cozaar, Atacand, Hyzaar, Entresto, or Avapro). The following paragraphs will try to explain some of the more technical issues in simple language.
Understanding Entresto’s Mechanism
Entresto is part of a newer class of drugs known as angiotensin receptor-neprilysin inhibitors (ARNIs). It is a unique combination of sacubitril and valsartan. This sets it apart from traditional therapies like ACE inhibitors and ARBs. Sacubitril, a neprilysin inhibitor, works by preventing the breakdown of natriuretic peptides, which promote vasodilation and sodium excretion, and reduce changes in the heart’s size and shape that occur in response to cardiac disease or cardiac damage (remodeling). By inhibiting neprilysin, sacubitril helps the body maintain these beneficial effects. However, neprilysin also breaks down angiotensin II, a potent vasoconstrictor. To prevent the undesirable increase in angiotensin II, sacubitril is combined with valsartan, an ARB that blocks the effects of angiotensin II on blood vessels, thus lowering blood pressure.
This dual action makes Entresto more effective than older treatments like ACE inhibitors or ARBs alone, which only affect the renin-angiotensin-aldosterone system (RAAS), which regulates long-term blood pressure and blood volume. Entresto provides a more comprehensive approach to managing HFrEF by addressing both controls. This superior mechanism was discovered in the PARADIGM-HF trial, where Entresto significantly reduced cardiovascular deaths and heart failure hospitalizations compared to Vasotec. This ACE inhibitor has been widely prescribed for over forty years.
The Shift From ACE/ARB to ARNI
For nearly fifty years, ACE inhibitors and ARBs have been the cornerstone of heart failure management. These drugs work by interrupting the RAAS, preventing the harmful actions of angiotensin II (vasoconstriction and sodium retention,) which can worsen heart failure. While they are effective, ACE inhibitors and ARBs only address one aspect of the complex pathophysiology of HFrEF.
The ACC’s 2024 update represents a significant shift in practice by recommending ARNI therapy with Entresto as the first-line treatment for most patients with HFrEF. For patients currently being treated with an ACE inhibitor or ARB, the recommendation is to transition to an ARNI, provided they can tolerate it. This change is based on the substantial evidence from clinical trials showing Entresto’s superiority in reducing hospitalizations and mortality. Patients previously stabilized on ACE inhibitors or ARBs are now being encouraged to switch to Entresto unless it is contraindicated for prior angioedema or renal impairment.
Managing Common Comorbidities
Addressing other health issues, which are common in HFrEF patients, is a major consideration in heart failure management. These can include conditions like diabetes, hypertension, and chronic kidney disease. The ACC guidelines emphasize that while Entresto has shown broad benefits across different patient groups, careful monitoring is required, particularly in those with kidney impairment or low blood pressure.
For patients with chronic kidney disease (CKD), there may be concerns about the potential for worsening renal function with ARNI therapy. However, recent studies suggest that Entresto can be safely used in patients with mild to moderate kidney disease, with the proviso that kidney function and potassium levels must be closely monitored. The benefits of improved heart failure outcomes generally outweigh the risks.
In patients with diabetes, Entresto’s vasodilatory effects may enhance blood flow and reduce afterload, which could be beneficial for glucose control. Additionally, Entresto has been found to reduce hospitalizations for heart failure, even in patients without diabetes.
For patients with hypertension, it is essential to monitor blood pressure closely, especially when starting Entresto, as it has a more pronounced hypotensive effect than ACE inhibitors or ARBs alone. We advise our customers to adhere closely to their dosing schedules and to follow up with their healthcare provider regularly to adjust medications as needed.
Understanding Heart Failure with Reduced Ejection Fraction (HFrEF)
Heart failure with reduced ejection fraction (HFrEF) is a condition in which the heart is unable to pump blood efficiently due to weakened heart muscle contractions. In HFrEF, the heart’s ejection fraction (EF)—the percentage of blood the left ventricle pumps out with each contraction—is typically 40% or lower. This reduced ability to pump blood effectively leads to inadequate oxygen and nutrient delivery to the body’s tissues, resulting in the symptoms and complications associated with heart failure.
How HFrEF Differs from HFpEF
There are two primary types of heart failure, distinguished by ejection fraction:
- HFrEF (Heart Failure with Reduced Ejection Fraction): This occurs when the heart muscle is weakened and cannot contract forcefully enough to pump enough blood into the arteries. The prominent signature of HFrEF is an ejection fraction of 40% or less, which means that less than half of the chamber’s blood is ejected with each beat.
- HFpEF (Heart Failure with Preserved Ejection Fraction): In this form of heart failure, the heart muscle contracts normally, and the ejection fraction is preserved (typically above 50%), but the heart’s ventricles become stiff and are unable to relax properly. As a result, the chamber cannot fill with enough blood between beats, leading to fluid buildup and congestion, even though the pumping function remains relatively standard.
The key distinction between the two lies in the underlying cause of heart failure. HFrEF is primarily a problem of pumping function, while HFpEF is more of a volume issue. HFpEF is more commonly seen in older female patients with secondary conditions like hypertension and diabetes. In contrast, HFrEF often occurs after a heart attack (myocardial infarction) or other events that directly damage heart muscle.
The Timeline and Development of Heart Failure
Heart failure, including HFrEF, can develop slowly over time or appear suddenly, depending on the underlying cause. The progression of heart failure generally follows a predictable trajectory. It often starts with conditions that put excess strain on the heart, eventually leading to structural and functional changes that impair its ability to pump blood efficiently.
Early Stages (At-Risk Phase)
The early stages of heart failure often involve risk factors or conditions that place a strain on the heart, such as:
- Hypertension (high blood pressure)
- Coronary artery disease (narrowing or blockage of heart arteries)
- Diabetes
- Obesity
- Previous heart attacks
Structural damage to the heart may not be evident at this stage, and patients may feel no symptoms. However, if these risk factors are left untreated, they can lead to heart muscle damage, eventually resulting in symptomatic heart failure.
Progression to HFrEF (Stage C)
Over time, continuous stress on the heart muscle causes it to weaken and enlarge (a condition called dilated cardiomyopathy). At this point, patients may begin to develop symptoms such as:
- Shortness of breath
- Fatigue
- Swelling in the legs and ankles
- Difficulty performing daily activities
This phase marks the transition into Stage C heart failure, where symptoms become apparent, and treatment is required to manage the condition.
End-Stage Heart Failure (Stage D)
If HFrEF continues to progress without adequate treatment, it can lead to end-stage heart failure, where the heart is no longer able to pump sufficient blood to meet the body’s needs, even at rest. At this point, patients may require advanced treatments such as ventricular assist devices (VADs) or a heart transplant.
The Main Causes of HFrEF
There are several primary causes of HFrEF, many of which are linked to underlying cardiovascular conditions:
- Coronary Artery Disease (CAD) is the most common cause of HFrEF. CAD restricts blood flow to the heart muscle, leading to ischemia and myocardial infarction (heart attack). Damage from a heart attack often weakens the heart’s pumping ability.
- High Blood Pressure (Hypertension) forces the heart to work harder to pump blood, eventually leading to weakening and enlargement of the heart muscle.
- Cardiomyopathy can directly weaken the heart muscle, leading to HFrEF. Causes of cardiomyopathy include viral infections, alcohol abuse, genetic factors, and some medications.
- In cases of Valvular Heart Disease, defective or damaged heart valves can require the heart to work harder to maintain normal circulation, leading to heart muscle damage and eventual HFrEF.
- Abnormal heart rhythms (arrhythmias), especially persistent atrial fibrillation, can impair the heart’s efficiency and lead to heart failure over time.
- Toxins, medications, excessive alcohol consumption, use of illicit drugs (such as cocaine and speed), and some medications (such as some chemotherapy drugs) can damage the heart muscle and result in HFrEF.
Progress of HFrEF Without and With Treatment
The prognosis of HFrEF varies significantly depending on how early the condition is detected and proper treatment begins. Without treatment, heart failure tends to advance continuously, leading to progressive symptoms and repeated hospitalizations, and it carries a high risk of mortality.
Outcomes Without Treatment
- Left untreated, patients with HFrEF may experience rapid progression of symptoms, including increased shortness of breath, swelling, and fatigue.
- As heart function declines, patients often have to be hospitalized for acute exacerbations of heart failure, where fluid builds up in the lungs (pulmonary edema) or elsewhere in the body.
- The mortality rate for untreated heart failure is high. Studies have shown that without proper medical management, the five-year survival rate for heart failure patients can be as low as 50%, and it is even lower for patients with HFrEF.
Outcomes With Treatment
Modern treatments for HFrEF can substantially improve both survival and quality of life for patients. These treatments aim to relieve symptoms, reduce hospitalizations, and slow the progression of the disease. Key therapies include:
- ARNI (Entresto): As discussed earlier, Entresto is now a first-line treatment for HFrEF and has been shown to reduce both hospitalizations and mortality by 20% compared to ACE inhibitors.
- Beta-blockers like Tenormin, Bystolic, Lopressor, Zebeta, or Coreg help slow the heart rate, reduce blood pressure, and prevent further damage to the heart muscle. One study published by the American College of Cardiology showed that beta-blockers can produce better outcomes in heart failure patients with HFrEF than those with HFpEF.
- SGLT2 inhibitors like Farxiga, Jardiance, and Synjardy, originally used to treat diabetes, have been shown to reduce the risk of heart failure hospitalization and cardiovascular death in HFrEF patients, regardless of whether or not they have diabetes.
- Diuretics such as aldactone and Inspra help reduce fluid retention, improve symptoms, and prevent the progression of heart failure by blocking the effects of aldosterone.
- Patients who make relatively simple lifestyle modifications tend to have better outcomes. Changes such as reducing salt intake, managing fluid levels, maintaining a healthy weight, and adhering to prescribed exercise regimens are easy to make.
- In advanced cases, patients may benefit from implantable cardioverter-defibrillators (ICDs) or left ventricular assist devices (LVADs). In some cases, a heart transplant may be an option for end-stage heart failure.
Considering Costs
The cost of newer HFrEF treatment medications like Entresto can be a significant concern for patients. This is where IsraelPharm can play a major role in helping patients make the switch to Entresto. Since no generic options are available, the choice may come down to giving up the strong advantages of the new meds if your insurance will not cover the additional cost.
Although Entresto is more expensive than older therapies, we ensure patients can benefit from this superior therapy without incurring extra costs. The table below shows a comparison between the retail cost of typical ACE and ARB medications as well as Entresto from US pharmacies and the same drugs from IsraelPharm:
Brand | Strength | US Retail
per tablet |
IsraelPharm
per tablet |
Enalapril (ACE) | 20 mg | $1.30 | $0.57 |
Diovan (ARB) | 160 mg | $12.23 | $1.17 |
Farxiga (SGLT2) | $16.17 | $1.10 | |
Entresto | 50 mg
100 mg 200 mg |
$12.25
$13.10 $13.10 |
$6.36
$6.27 $6.82 |
Answering Patient Concerns About HFrEF treatment
Patients switching to a new type of HFrEF treatment, such as from an ACE inhibitor or ARB to Entresto, may have concerns about side effects or how the new medication will interact with their current regimen. Entresto has proven benefits in improving survival rates and slowing the progression of heart failure.
The most commonly reported side effects include dizziness (coming from hypotension) and kidney function changes, particularly when starting the medication. We advise people to report any severe dizziness, swelling (angioedema), or signs of kidney problems (such as reduced urine output or swelling in the legs) to their healthcare providers. Prescribers will generally monitor kidney function and electrolytes in the first few weeks of therapy.
Patients transitioning from an ACE inhibitor to Entresto need a 36-hour washout period before starting the new drug. This washout is necessary to avoid the risk of life-threatening angioedema, a known risk when neprilysin inhibitors are combined with ACE inhibitors.
Prognosis with the New HFrEF Treatment
With the combination of medications and lifestyle changes, many patients with HFrEF can live longer and enjoy a better quality of life. The introduction of quadruple therapy (ARNI, beta-blocker, diuretic, and SGLT2 inhibitor) has significantly improved survival rates. Some studies show a reduction in all-cause mortality by up to 40%, allowing patients to spend more time enjoying normal lives.