Introduction
0
ACE-inhibitor induced angioedema (ACEI-AAG) accounts for about a third of angioedema cases presenting to the emergency department. ACE inhibitors are increasingly popular, with the new JNC 8 guidelines up-grading them to a first-line drug for hypertension. Thus, ACEI-AAG may represent a growing problem. Unfortunately, this is often treated incorrectly, with a medication regimen directed against allergic angioedema (i.e., corticosteroids and antihistamines).
0
Physiology of ACEI-AAG
0
0
ACEI-AAG is due to excessive accumulation of bradykinin. The reason that only a small fraction of patients treated with ACE inhibitors develop ACEI-AAG may relate to genetic variations in bradykinin metabolism. During treatment with ACE inhibitors, various alternative enzymatic pathways for metabolism of bradykinin become critical (e.g. plasma aminopeptidase P). Individuals with lower activity of these alternative clearance pathways may be at increased risk of bradykinin accumulation and ACEI-AAG (Campo 2013).
0
A brief word on diagnosis
0
There should be a high index of suspicion for ACEI-AAG for any patient with angioedema taking an ACE inhibitor. Although ACEI-AAG usually occurs soon after starting ACEi, it may occur years later. There is a higher incidence among women and a five-fold higher incidence among African Americans (Byrd 2008).
0
The following clinical features may help differentiate ACEI-AAG from histamine-mediated allergic angioedema (note however that ACEI-AAG has many clinical features in common with other forms of bradykinin-induced angioedema such as C1-esterase inhibitor deficiency).
0
0
0
- Lack of allergic trigger (in contrast, ACEI-AAG may occur after minor trauma)
- Starts with focal swelling (e.g. isolated swelling of tongue or lips, often asymmetric)
- Evolves over hours (slower progression than histamine-mediated angioedema)
- Absence of urticaria or itching
- Failure to respond to antihistamines, steroid, epinephrine
0
Steroids, antihistamines, and epinephrine are ineffective for ACEI-AAG.
0
ACEI-AAG is due to impaired metabolism of bradykinin. Standard treatments for allergen-induced angioedema (epinephrine, steroid, and anti-histamines) do not affect this. There is no persuasive evidence that these treatments are effective, as stated in several consensus guidelines (Cicardi 2014, Zuraw 2013, Lang 2012):
0
As with management of acute angioedema in patients with C1-inhibitor deficiency, administration of antihistamines, corticosteroids, or epinephrine is not associated with benefit and is not recommended
– International consensus on hereditary and acquired angioedema, Lang 2012.
0
0
Disease-modifying treatments: Fresh Frozen Plasma (FFP), Icatibant (FIRAZYR), C1-inhibitor concentrate
0
0
FFP contains multiple enzymes which degrade bradykinin, addressing the underlying disorder in ACEI-AAG. This has never been studied in a prospective RCT. Nonetheless, there are several publications describing cases or case series of patients with rapid improvement following ~2-4 units of FFP, often after repeated failure of steroid, epinephrine, and antihistamine (Karim 2002, Warrier 2004, Stewart 2012, Bolton 2012, Hassen 2013, Shiber 2014). FFP has similarly been found to be effective in other forms of bradykinin-mediated angioedema such as C1-esterase deficiency.
0
Icatibant (FIRAZYR) is a very small peptide which blocks bradykinin-receptors. Until now, Icatibant was supported by case reports and one uncontrolled study. Icatibant has some potential advantages over FFP because it is formulated in a lower amount of volume and does not risk viral transmission. However, it is extremely expensive ($23,000 for 30 mg according to Epocrates; local costs will vary).
0
0
0
Ecallantide (an expensive recombinant protein that inhibits Kallikrein; figure above) has been investigated for management of ACEI-AAG. Bernstein 2014 was terminated early due to futility, while Lewis 2015 showed a 10% increase in ability to discharge patients earlier from the emergency department. Overall, clinical results with Ecallantide have been unimpressive.
0
Purified C1-inhibitor concentrate has been effective in case reports (Nielsen 2006). This agent appears to be more popular in Europe, with inclusion in the French guidelines for management of ACEI-AAG (Nosbaum 2013). Only one case report describing the use of C1-inhibitor concentrate exists in the English literature. Currently the evidence supporting FFP appears more robust, but there is an ongoing phase III study of C1-inhibitor concentrate so this may change (NCT01843530).
0
Purified C1-inhibitor concentrate has been effective in case reports (Nielsen 2006). This agent appears to be more popular in Europe, with inclusion in the French guidelines for management of ACEI-AAG (Nosbaum 2013). Only one case report describing the use of C1-inhibitor concentrate exists in the English literature. Currently the evidence supporting FFP appears more robust, but there is an ongoing phase III study of C1-inhibitor concentrate so this may change (NCT01843530).
0
Recent Bas et al. study compares Icatibant vs. Steroid/Antihistamine
0
Recently Bas et al. published a prospective RCTin the New England Journal of Medicine comparing Icatibant to antihistamine plus 500 mg of prednisolone for management of ACEI-AAG. These authors didn't mention FFP at any point in the paper, but instead stated that steroid plus antihistamine was “standard therapy” for ACEI-AAG. As might be expected, Icatibant was more effective than steroid plus antihistamine, with substantially faster resolution of angioedema.
0
As discussed above steroid plus antihistamine is not “standard therapy” for ACEI-AAG, but is actually ineffective. The concept that steroid and antihistamine are indicated for ACEI-AAG may be best regarded as a myth. At Genius General Hospital we have previously treated ACEI-AAG successfully with FFP. Currently there may not be any universal “standard therapy” for ACEI-AAG. The use of FFP is controversial, but it is a more rational and evidence-based therapy than steroid plus antihistamine.
0
By comparing Icatibant to steroid/antihistamine, this trial is effectively comparing Icatibant to a placebo. Unfortunately, by failing to compare Icatibant to FFP, this study is not very helpful for most clinicians. Icatibant is enormously expensive and is not widely available. A study evaluating the utility of FFP would be much more useful to most clinicians throughout the world, especially in less affluent regions.
0
Industry-driven research agenda
0
Potential treatments of ACEI-AAG include extremely expensive peptides such as Icatibant and Ecallantide. There is substantial funding and pressure from industry to perform trials on these drugs and promote their use. Unfortunately there is no incentive to perform trials of FFP. This has led to a lopsided investigational approach towards ACEI-AAG, with six trials listed on ClinicalTrials.gov investigating designer peptides compared to zero investigating FFP.
0
To date, all industry-sponsored trials have avoided using FFP as a comparator. At this point, Bas 2015 has demonstrated the superiority of Icatibant compared to ineffective therapy (steroid/antihistamine), with one patient in the control group requiring tracheostomy. The ethics of replicating this trial is questionable, given significant risk of harm among patients not receiving Icatibant. Nonetheless, two studies comparing Icatibant to placebo are listed as ongoing (NCT01343823and NCT01919801). Future trials would ideally be designed comparing Icatibant to FFP, rather than placebo or steroid/antihistamine.
0
Conclusions
0
0
- Angioedema due to ACE inhibitors (ACEI-AAG) may be life-threatening, and will probably become more common with expanding use of ACE inhibitors.
- ACEI-AAG is due to excessive bradykinin. This is not responsive to treatments for allergic angioedema (e.g., epinephrine, steroid, antihistamines).
- Until recently, case reports suggested that fresh frozen plasma (FFP) or Icatibant may be effective for ACEI-AAG. FFP contains enzymes which metabolize bradykinin, whereas Icatibant blocks bradykinin receptors (figure above).
- Bas et al. performed a prospective RCT comparing Icatibant to steroid/antihistamine. As expected, Icatibant was superior.
- Icatibant is extremely expensive and not widely available. Alternatively, FFP is universally available at a fraction of the cost. Further information is needed to determine the relative efficacy of these therapies.
- If Icatibant is unavailable, consider early administration of 2-4 units FFP.
Image credits: https://en.wikipedia.org/wiki/Compact_car#/media/File:CVC2012aaa.jpg
Latest posts by Josh Farkas (see all)
- PulmCrit Blogitorial – Use of ECGs for management of (sub)massive PE - March 24, 2024
- PulmCrit Wee: Propofol induced eyelid opening apraxia – the struggle is real - March 20, 2024
- PulmCrit wee: Why I like central lines for GI bleed resuscitation - March 13, 2024
Tranexamic acid has no role in the acute management of angioedema regardless of the cause. The postulated effect of TXA is to inhibit C1 and plasmin activation. This results in “sparing” of C1 esterase inhibitor. This takes days to have any appreciable effect but explains why it works as a prophylactic treatment for patients with hereditary angioedema due to a deficiency in C1-INH.
Tranexamic acid has no role in the acute management of angioedema regardless of the cause. The postulated effect of TXA is to inhibit C1 and plasmin activation. This results in “sparing” of C1 esterase inhibitor. This takes days to have any appreciable effect but explains why it works as a prophylactic treatment for patients with hereditary angioedema due to a deficiency in C1-INH.
Really… The risk of vital transmission of FFP is minimal, fluid overload is not occurring in a majority of pts w a couple units of FFP (even 4 for that matter) and trali is much more rare now given the change in donation guidelines. Personally, I will never order one of the $$$$ medications over FFP. I do agree that the majority of these pts I have seen in the ED do fine – I haven't seen any issues in those intubated in the ICU either. But I think the argument of the negatives of FFP is extremely overblown.
What are your thoughts and experiences using TXA as a treatment?
This dosen't make sense. At least steroid + benadryl is low risk and cheap with little evidence of benefit. FFP is high risk and expensive with little evidence of benefit (TRALI, fluid overload, viral transmission). Most of these patients get better with no treatment so anecdotes are of little value. Blood products should not be used indiscriminately.
Thankyou for writing this article. I have been pushing FFP for long and often fruitless time as the only available effective treatment for ACEI-AAG and C1 est def. I recall a while back an Author ( sorry lost) mooting that ACE-AAG was relative C1 est inh deficiency and had anecdotal success using that for ACE-AAG.
I use FFP now in any potential airway threatening presentation, but do get push back by the steroid anti histamine brigade
The benadryl and pepcid divisions of the anti-histamine brigade are quite powerful even more than the epinephrine battalion.
Is there any benefit to changing ACE inhibitors periodically in an effort to prevent this from occurring or will the build up of bradykinin be the same even with varying the ACEi?
I think it’s a class effect, so my guess would be that this doesn’t help.
My question is: what will save intubations? Will need a huge study, probably multiple arms of randomization. But I don’t really care about a swollen lip that gets better in 8hrs. I care about do I need to intimate them. At this point, I can’t hang my hat on any of these, so if it’s concerning, they get intubated. If it’s less concerning, we monitor and consider intubation. Until this question is answered, how do you justify spending any money on one of these therapies?
Doubtful that FFP will ever be studied in this fashion because it’s not pharma-sponsored. Agree that mild cases require no treatment and severe cases require intubation. However, there may be a middle-ground of patients who show up with mild swelling and are getting worse. They don’t require intubation now, but they are moving in the wrong direction. Perhaps these patients could benefit from FFP. There is no level-I evidence, so you’re free to practice however you feel best.
How long does it take the FFP to work / show any definitive amelioration of angioedema.?
As an anesthesia provider, I am curious if I can avoid intubation in the acute presentation with potential for airway for compromise.
Hi Josh,
I’m interested what you think about the 2018 AHA Stroke Recommendations related to treatment of a tPA-associated angioedema, They recommend discontinuation of alteplase infusion, administration of methylprednisolone, diphenhydramine, rantidine and epi “if necessary.’ Is it too much of a bleeding edge to say it’s reasonable to give FFP (if Icatibant not availble) in the acute ischemic stroke patient who is potentially losing their airway due to angioedema?
Thank you for your time,
Erin
Link to 2018 AHA recommendations (pg. 25)
http://stroke.ahajournals.org/content/strokeaha/early/2018/01/23/STR.0000000000000158.full.pdf
This happened to me after six months on Lisinopril. Angioedema was periocular and not life threatening at time of diagnosis,v thought temporarily disfiguring. In most hospitals , FFP is in such supply that they will not use it unless the condition is life threatening. Driver am hope to the ER only to find they are unwilling to administer FFP. They said steroids might help and we a script that I did not fill as I understand excess bradykinin will not respond. Just stopped there Lisinopril and things got better over three days. Problem was accompanied by serious muscle pain, mild… Read more »
Hello. Does Danatrol help?
Thanks, this article is very helpful and explains the poor response I’ve seen to current treatment for angioedema caused by lisinopril.
As a blood banker, I need to know if the elements in FFP desired to treat angioedema are stable over the 5 days of storage after thawing that are now more common in plasma products or if it is important that these patients receive plasma that has been thawed for less than 24 hours.
Thank you for this article. I do have angioedema and this is horrible. End up in the emergency room and admitted in hospital for a week. Allergic to the class of blood pressure medicine called ACE inhibitors. I do not take any chronic medicine afterwards. Six months later I get it from certain foods that I ate. Almost with every meal. My face is most of the time swollen and out of proportion. Cannot breath normal and itching al over my body with severe knobs. Please, take that drug of the market from scratch and do not play with people’s… Read more »