What is angioedema?

I recently started taking Entresto, the new heart failure drug.  The product information insert that comes with the Estresto lists the following side effects and instructions: “Angioedema that may cause trouble breathing and death. Get emergency medical help right away if you have symptoms of angioedema or trouble breathing. Do not take ENTRESTO again if you have had angioedema while taking ENTRESTO. People who are Black or who have had angioedema and take ENTRESTO may have a higher risk of having angioedema”. 

Trust me, this is a notice that will get a heart failure patient’s attention immediately.  Heart failure routinely comes with shortness of breath, so needless to say trouble breathing and death are both huge concerns for heart failure patients.  But I did not know what angioedema was, or why it might cause a patient to have difficulty breathing.  I wondered if it might be helpful to include a description of angioedema in the product information insert.   
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Additionally, I also recalled that the word angioedema is used during Entresto commercials, but I do not believe it provides a description of the condition.  I do know what edema is, having taken diuretics for a number of years to deal with the water retention that comes with heart failure.  So I figured that angioedema might also be a condition that has something to do with water.  I also looked up “angio” in several online dictionaries and found that it means blood vessel.  I concluded it must be a condition where water impacts the blood vessels.

I researched online for a better, more learned definition of angioedema and found the following on the Webster Dictionary website.  It is quite detailed and a little intimidating:

• ​“An acute or chronic disorder that affects the mucous membranes and deepest layers of the skin along with underlying tissue and that is marked by rapid swelling, large welts, and pain   NOTE:  Swelling results from a buildup of fluid leaking out of blood vessels with walls that have become abnormally permeable. The lips, mouth, throat, eyes, hands, and feet are most commonly affected. Swelling of the throat may interfere with breathing and can be life-threatening. Angioedema may be caused by an allergic reaction (as to food or drugs), is sometimes due to a hereditary condition (hereditary angioedema), but is often of unknown cause.
• —called also angioneurotic edema, giant urticaria, Quincke's disease,Quincke's edema

Wow – that’s a mouthful!  I also wondered who the Quincke was of Quincke’s disease or Quincke’sedema.  It turns out that this term appears to be linked to Heinrich Quincke, a German doctor whose specialty was research of pulmonary medicine.  When you think about it, it makes sense that he is associated with angioedema, a condition which can result in trouble breathing.  This makes sense because pulmonary relates to the lungs or the respiratory system.

According to the Mayo Clinic, the following are potential causes of angioedema:  food, medications, common allergens, environmental factors, underlying medical conditions (for example, lupus, certain thyroid conditions, etc.), and genetics.  The Mayo Clinic also says that almost any medication can cause angioedema, but specifically mentions:  penicillin, aspirin, ibuprofen, naproxen and blood pressure medications.  With respect to the blood pressure medications that might cause angioedema, this may cover many of the ACE inhibitors taken for high blood pressure as well as for heart failure.  (In fact, I used to take a blood pressure medication for my  heart failure).  

Here is what the website Webmd lists as what appears to be an angioedema type of side effect for an ACE inhibitor:

• A very serious allergic reaction to this drug is rare. However, get medical help right away if you experience any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

What does an ACE inhibitor do?  According to the website of the Texas Heart Institute:  "These medicines block an enzyme in the body that is responsible for causing the blood vessels to narrow. If the blood vessels are relaxed, your blood pressure is lowered and more oxygen-rich blood can reach your heart.
ACE inhibitors lower the amount of salt and water in your body, which also helps to lower your blood pressure."

How does Entresto work?  According to a packet of materials I received as part of the the Entresto Central Support program, one ingredient, valsartan, reduces blood vessel tightening and the buildup of sodium and fluid.  The other ingredient, sacubitril (only found in Entresto), helps relax blood vessels and decreases sodium and fluid in the body.

You may ask what is in an ACE inhibitor or Entresto that causes angioedema.  Well, the webpage for angioedema on the National Jewish Organization website says that there are two main subtypes of angioedema: mast-cell mediated and bradykinin-mediated angioedema.   The one that comes into play with both ACE inhibitors and Entresto is apparently is bradykinin-mediated angioedema. 

According to the same webpage, “Bradykinin-mediated angioedema is more likely to occur without associated symptoms, although flushing or blotchiness of the skin can occur.  It is sometimes the result of a commonly used class of heart and blood pressure medications called ACE inhibitors, which include lisinopril, captopril, and enalapril. Angioedema related to the use of these medications is rare but can happen at any time a person is taking the medicine, even years after he or she has been taking it.”

What is the likelihood that someone taking an ACE Inhibitor will have angioedema as a side effect?  An April 2011 paper on the American Nurse website addressed the angioedema, and the higher risk in African Americans:

• Overall, angioedema occurs in only about 0.1% to 0.2% of patients receiving angiotension-converting enzyme (ACE) inhibitors. But the incidence is higher among African-Americans. A study of more than 12,000 patients taking enalapril found black patients were about three times more likely to develop angioedema within 6 months of starting therapy (1.62% versus .55% of white patients). In other research, the mean age of patients who experienced angioedema from ACE inhibitors or angiotensin receptor blockers (ARBs) was 60, with a higher incidence in women (60%) and African-Americans (69%).

What is the likelihood that someone on Entresto may have the side effect of angioedema?  An article on the angioedema news website (yes, there really is one) says:  Entresto (sacubitril/valsartan) — an approved medication for heart failure — does not significantly increase the risk of angioedema compared with standard therapy Vasotec  (enalapril), data from a Phase 3 trial show.  (Note:  Vasotec is an ACE inhibitor).
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I would also note that since I have enrolled in the Entresto Central Support Program, I continue to receive very helpful information by postal mail and e-mail on Entresto as well as on how to manage with heart failure.  I think it is important to note that the information on angioedema has more detail than the product information insert that came with the drug.  It says that Entresto may cause serious side effects including:  Serious allergic reactions causing swelling of your face, lips, tongue, and throat (angioedema) that may cause trouble breathing and death.  Get emergency medical help right away if you have symptoms of angioedema or trouble breathing. 
 
Again, I can honestly say that I do not recall experiencing angioedema in the time that I have been taking either an ACE inhibitor or the Entresto.  But I continue at this early stage to take keep an eye out for any possible signs of angioedema.  I will also continue to study the information I receive from the Entresto central support program .  Because in all things related to heart failure, I would rather be well informed and on the lookout for symptoms than to be taken by surprise.