By Angela Ryan Lee, MD 

 Medically reviewed by Lindsay Cook, PharmD

Refractory heart failure, also known as end stage or advanced heart failure, is a condition in which heart failure symptoms persist despite taking prescribed medications. This includes symptoms while at rest or frequent hospitalization for heart failure symptoms. Many medications help with heart failure and its symptoms, but not everyone responds adequately.

This article discusses refractory heart failure and its symptoms, causes, and treatment.

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What Is Heart Failure?

The heart is responsible for pumping oxygen and nutrients throughout the body. In heart failure, the heart is not able to adequately perform its function, either due to problems with filling or pumping blood.

The term "low cardiac output" describes the situation in which the blood flow out of the heart is insufficient. This leads to symptoms ranging from fatigue and shortness of breath to lightheadedness and fainting.

Refractory Heart Failure Symptoms

Symptoms of heart failure are caused by the backup or congestion of blood in the lungs and body, and the insufficient delivery of oxygen and nutrients to organs.

Symptoms include:¹

• Shortness of breath

• Persistent coughing (producing white or pink blood-tinged mucus), or wheezing

• Decreased exercise tolerance

• Abdominal pain

• Nausea, decreased appetite

• Swelling in the feet, legs, abdomen, and/or groin

• Tiredness or Fatigue

• Lightheadedness

• Confusion, impaired thinking

• Palpitations (increased heart rate)

Causes

Refractory heart failure has many causes. In general, heart failure may be caused by a problem with the heart's muscle called cardiomyopathy, and by structural abnormalities of the heart or heart valves.

Some of the main causes of heart failure include:

• Inherited cardiomyopathy

• Coronary artery disease

• High blood pressure

• Toxins like alcohol, cocaine, and certain medications

• Inflammatory disease including sarcoidosis and viral myocarditis

• Arrhythmias

• Amyloidosis due to misfolded protein collecting in the heart

• Heart valve problems such as narrow (stenotic) or leaky (regurgitant) valves

• Congenital heart abnormalities

Diagnosis

Diagnosing heart failure is based on symptoms, a physical examination, and multiple complementary tests.

Refractory heart failure does not require any specific testing beyond the tests for heart failure in general. Heart failure is considered to be refractory when symptoms are persistent despite being on medical therapy for heart failure. This includes having symptoms while at rest or having repeated hospitalizations for heart failure.

Heart failure is staged according to the American College of Cardiology and American Heart Association (ACC/AHA) staging system and New York Heart Association (NYHA) class.²

The stages include:

• Stage A: At risk of heart failure with no structural abnormality

• Stage B: Structural abnormality or abnormal function without heart failure symptoms

• Stage C: Symptoms of heart failure currently or previously

• Stage D: Symptoms at rest, recurrent hospitalizations or requiring specialized therapies (also called advanced or end-stage heart failure)

The NYHA classes include:³

• Class I: No activity limitation

• Class II: Mild activity limitation, symptoms with ordinary exertion

• Class III: Significant activity limitation, symptoms with less than ordinary exertion

• Class IV: Marked activity restriction, symptoms at rest

Treatment

Sometimes heart failure improves with treating the underlying cause, such as congenital abnormalities, valvular problems, coronary artery disease, and arrhythmias. Otherwise, medications are the primary treatment option for heart failure.

Refractory heart failure is managed with specialized devices and advanced therapies.

Nonpharmacologic Therapy

Nonpharmacologic therapy refers to treatment strategies that do not involve medications.

People with heart failure symptoms are recommended to limit sodium and fluid intake. They must also monitor for signs of fluid overload such as weight gain, leg swelling, and shortness of breath. Noticing these signs early on and discussing a plan with a healthcare provider can improve symptoms and help prevent hospitalization for heart failure.

Cardiac rehabilitation is a structured program involving a cohesive treatment team and structured exercise therapy that can help optimize activity levels for people with heart failure.⁴

Medical Therapy

Medical therapy for heart failure is prescribed to improve the heart's function, delay progression of heart failure, and treat heart failure symptoms.

There are several medications prescribed for heart failure, including:

• Diuretics such as Lasix (furosemide) help with symptoms of shortness of breath and swelling

• Beta blockers (specifically bisoprolol, carvedilol, and metoprolol succinate)

• Neprilysin inhibitors such as Entresto (sacubitril/valsartan combination pill)

• ACE-inhibitors or angiotensin receptor blockers (such as lisinopril or valsartan)

• Aldosterone antagonists (such as spironolactone or eplerenone) in selected people

• Vasodilators such as Bidil (hydralazine and nitrate combination pill) in selected people

• Ivabradine in selected people whose heart rate remains high despite beta blockers

• SGLT2 inhibitors such as Jardiance (empagliflozin), a newer class of medication that has been shown to decrease heart failure

• Digoxin, which is sometimes used in selected people with ongoing symptoms despite other treatment

In addition, specific medications exist for specific types of heart failure. For example, cardiac amyloidosis is a type of heart failure caused by misfolded proteins. A medication called tafamidis stabilizes the misfolded proteins to prevent further accumulation in the heart.

Medication Considerations

Keep in mind that some people may not be able to tolerate some of these medications or may have contraindications to taking them. Some of these medications have specific indications and are not recommended for all people with heart failure. The specific therapy for heart failure should be discussed with a cardiologist.

Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) is recommended for people who meet specific criteria of heart failure and have electrocardiogram (ECG) abnormalities.

In CRT, a device called an implanted cardiac defibrillator is placed under the skin of the upper chest with wires that sit in the heart. The device acts as a pacemaker to stimulate the heart and help portions of the heart contract with specific timing to optimize the pumping of the heart.

Inotropic Therapy

Inotropes are medications that improve the heart's contractility, including milrinone and dobutamine. They are given as a continuous intravenous infusion. They are used temporarily for managing low cardiac output in people hospitalized with heart failure, but some people can benefit from ongoing home infusion.

These medications do not improve survival, and they increase the risk of life-threatening arrhythmias, so they are not routinely prescribed. However, they can be of great benefit for symptom relief in selected people with refractory heart failure.

Mechanical Support Devices

Mechanical circulatory support refers to the use of implanted devices that assist the heart in pumping blood. They act as motors to physically assist blood flow out of the heart to the aorta.

While some of these devices are temporarily used during hospitalizations, a long-term or "durable" device called left ventricular assist device (LVAD) can be surgically implanted in some people with refractory heart failure. The LVAD is powered by a battery pack that the person must wear at all times and requires the use of blood thinning medication to prevent blood clots.

Another device called a total artificial heart (TAH) can be implanted in people waiting for a heart transplant.

Heart Transplant

Heart transplants are performed in some people with refractory heart failure. This surgery replaces the failing heart with a heart from an organ donor.

A successful transplant requires a team of healthcare providers and extensive planning. Lifelong immunosuppressive medication is needed to prevent the body from rejecting the transplanted organ.

Palliative Care

Palliative care is an important part of treating refractory heart failure with the goal of improving quality of life. Palliative care provides symptom relief and support for people dealing with symptoms of refractory heart failure and support for their family members.⁵

Prognosis

Without a heart transplant or durable LVAD, the prognosis of refractory heart failure is poor. Prognosis is worse in later stages.

However, advances in LVAD and transplant have significantly improved survival rates. People who receive LVAD as definitive therapy without a plan for transplant have survival rates of 51% at 7 years.⁶ The median survival rate after a heart transplant is 12-13 years.⁷

Living with heart failure symptoms can be difficult both physically and mentally. Refractory heart failure can bring anxiety and stress from fear of complications and death to the challenges of managing medication and treatment devices. Support from family, friends, and a treatment team is an important part of dealing with a chronic illness like heart failure.