Wednesday, May 3, 2017

SCCM VCCR Podcast - ACEi Angioedema Plus Sacubitril and DPP-IV inhibitors


I had the chance to talk with Sean P. Kane, PharmD, BCPS about angiotensin-converting enzyme (ACE) inhibitor-induced angioedema. And it was recorded!

As part of the SCCM VCCR podcast, this episode we spoke about a variety of treatment approaches for ACE inhibitor-induced angioedema are discussed, including fresh frozen plasma, ecallantide, icatibant, and conventional therapies for undifferentiated angioedema. Here is the link, and some show notes to go along with it.


Compared to a type 1 IGE mediated angioedema, ACEi associated angioedema (AAE)  is a result of bradykinin and B2 receptor activation causing vascular endothelial dysfunction. Therefore, antihistamines, corticosteroids, and epinephrine to not play a role in ACEi-angio.(1-3)



Additionally, the proposed MOA isn't simply accumulation of bradykinin, since this occurs in all patients taking ACEi. In those 0.7% in whom Angio develops, it is theorized that there are abnormalities in the additional metabolic pathways of bradykinin, namely neutral endopeptidase (NEP), aminopeptidase P, and DPP-IV.(4)


Why this is important is several fold. The number of patients taking ACEi is increasing as a result of increasing role in therapy for hypertension, diabetes and heart failure. As this knowledge translation takes place, we are in fact seeing an increase in ACEi usage and AAE. In a retrospective observational study of patients presenting to the ED for angioedema saw a significant increase in the occurrence of angioedema cases over the study's 5 year period; from ~5.8 per 10,000 presentations to 11.3 per 10,000. (5)


By no means is this any reason to not use ACEi or commentary that we are using too many. In fact, we are likely not prescribing these drugs enough. But as we do, we must be cautious of both ADRs and drug interactions that unnecessarily  increase this risk. This is particularly important given the multitude of new drugs that are, and have come to market that may play a role in the pathophysiology of AAE. These drugs, namely NEP inhibitors and DPP-IV inhibitors, are going unrecognized in their risk in increasing the risk of AAE.


Sacubitril is the latest addition in the drug therapy cache for addressing the neurohormonal imbalance in our current understanding of heart failure (HF) pathophysiology. This drug is by no means hot off the press, since the PARADIGM-HF trial was published back in 2014, it is picking up steam and starting to show up on medication profiles of HF folks in the ED.(6) With the high hopes of improved mortality, reduced hospitalization of this drug (which is co-formulated with valsartan) compared to a non-optimized dose of enalapril, this drug has an ugly side in terms of cost and drug interactions.
Sacubitril’s active metabolite inhibits neprilysin (aka neutral endopeptidase, NEP) allowing for prolonged exposure natriuretic peptides. It’s co-formulated with an ARB (valsartan) rather than an ACE-inhibitor because of whopping increase in the risk of angioedema.
The ill fated predecessor of sacubitril, omapatrilat (a NEP and ACE inhibitor) demonstrated a 2.17% incidence of angioedema compared to 0.68% with ACE-inh (enalapril) alone. This should be of no surprise after reviewing the proposed mechanisms of ACE-inh angioedema.
Briefly, accumulation of bradykinin, causing increased vascular permeability from interaction with the bradykinin-2 receptor and substance P mediated edema, both as a result of ACEi.  Since not all patients receiving ACEi develop angioedema, it is theorized that those who are affected also have deficiencies/abnormalities related to the other enzymes that metabolized bradykinin, namely aminopepdidase P (APP), NEP, DPP-IV, carboxypeptidase N. (7-9)


Looking further into NEP, it is a plasma membrane-bound zinc metalloprotease that catalyzes the metabolism of endothelin 1 (ET-1) and angiotensin II (AngII), as well as the metabolism of other peptides, including bradykinin, ANP, brain and C-type natriuretic peptides (BNP and CNP, respectively), and substance P. NEP is also involved in the enzymatic conversion of big ET-1 to its active form, ET-1. Therefore, the balance of effects of NEP inhibition on vascular tone will depend on whether the predominant substrate degraded by NEP are vasodilators or vasoconstrictors and on the extent of NEP involvement in the processing of big ET-1.(10) Furthermore, when combined with ARB, Ang-II receptor unopposed, thus more vasodilation. However, knocking out two of these pathways with ACE-inh and NEP, increases the risk of angioedema, as demonstrated as a trend in the OVERTURE study and a positive relationship in the OCTAVE study. (11, 12) There is also concern that NEP inhibition itself can potentiate angioedema. In fact, more patients in the treatment arm developed angioedema than did in the enalapril arm of the PARADIGM-HF trial (0.5% versus 0.2%. (6)


Practically speaking, there is a listed drug interaction with ACE-inh and sacubitril to avoid combination therapy and to wait 36 hours from discontinuation of any ACE-inh before initiating sacubitril. (13) However, this interaction has slowly made its way to the third party provided alert software and may not alert providers who are trying to initiate enalaprilat in the ED for patients with acute HF on sacubitril. That is, if they alert isn’t lost among the countless other alerts and “best practice advisories.”


The dipeptidyl peptidase IV (DPPIV) inhibitors are a group of medications used in the management of type 2 diabetes. Inhibition of dipeptidyl peptidase IV (DPP-IV) results in prolonged active incretin levels. Incretin hormones (eg, glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and decreasing glucagon secretion from pancreatic alpha cells. (14) Under normal physiologic circumstances, incretin hormones are released by the intestine throughout the day and levels are increased in response to a meal. These hormones are kept in balance by rapid inactivation by DPP-IV.


Sitagliptin, saxagliptin, and linagliptin are available in the United States and often used in combination with ACE inhibitor and ARB therapy. However, the incidence and prevalence of DPPIV inhibitor associated angioedema is unknown. Never-the-less, healthcare providers should be aware that angioedema has been associated with DPP-IV inhibitors, either alone or when used concomitantly with certain classes of medications, including ACE inhibitors and ARBs.(15-17) In one analysis of vildagliptin (not available in US) with an ACEi compared to an ACEi alone, there was a significant increase in the risk of angioedema to the tune of a 4.57 odds ratio (95% CI 1.57 to 13.28). (18)


If AAE does occur and is as a result of one of these interactions, the treatment options are varied. Depending on the clinical scenario, early intubation may be required to secure the airway, but other strategies are hardly ‘reversal’ strategies, but rather aim to sway the pendulum back to a balanced state by either preventing the production of bradykinin (C1-INH, FFP), enhance breakdown (FFP) or block its activity (Icatibant).  Ultimately, we hope these mechanism would translate into the prevention of airway compromise (which occurs in roughly 4% of Angio cases) or reduction in hospital LOS (which is about 4.8 days).(5)  However, the perceptions of the efficacy in terms of patient-oriented outcomes are often poorly formed as a result of a paucity of high quality evidence. This causes these drugs to be veiled in myth and legend.


Despite the available observational studies, the literature is heavily influenced by publication bias of case reports where these interventions have been linked to positive outcomes. With purified C1-inhibitor concentrate, this story holds true in that they have been effective in case reports (19-23).  This agent appears to be more popular in Europe, with inclusion in the French guidelines for management of ACEI-AAG (24).  Currently there is an ongoing phase III study of C1-inhibitor concentrate so this may change (NCT01843530).


The evidence supporting FFP appears more plentiful, but still subject to publication bias.(25-29). The most common proposed alternative to C1INH or icatibant is FFP. FFP has several advantages that make it a reasonable option; it contains ACE (to breakdown bradykinin) as well as other enzymes (AAP, NEP, etc), additional plasma proteins, relatively inexpensive vs alternatives, and readily available in most hospitals. Unfortunately, FFP does also contain kallikrein, bradykinin itself which can potentially worsen angioedema, the volume required to be administered can be significant to patients with underlying cardiac disease (TACO), requires type/screen, and infusion reactions (TRALI).  Furthermore, there are no controlled trials evaluating the safety and efficacy of FFP in this scenario.


Ecallantide (an expensive recombinant protein that inhibits Kallikrein) has been investigated for management of AAG. One phase 2, double blind dose ranging study of ecallantide in patients with ACEi-AE was stopped early due to futility.(30) While a similarly designed, phase 2, blinded study comparing ecallantide to placebo showed a 10% increase in ability to discharge patients earlier from the emergency department which did not meet the predetermined expected reduction of 50%.(31)  For the price of a pretty decent car the clinical results with Ecallantide have been unimpressive.


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.


Recently Bas et al. published a prospective RCT in the New England Journal of Medicine comparing Icatibant to antihistamine plus 500 mg of prednisolone plus clemastine 2 mg for management of ACEI-AAG.(32)  All patients were eligible to receive an open label dose of icatibant plus prednisolone if there were no reduction in symptoms by 6 hours after initial treatment.  The primary endpoint was the time to complete resolution of edema as evaluated on the basis of investigator-assessed and patient-assessed symptom scores and investigator's assessment of the severity of angioedema based on physical exam.  Although the study only included 27 patients in its analysis, it did meet power and was able to demonstrate a significant reduction in the duration of edema in patients who received icatibant compared to standard therapy (8.0 hrs IQR(3.0-16.0) vs 27.1 hrs (20.3-48.0); p=0.002). While hospital admission, LOS and disposition data was not reported, 3 patients in the standard therapy arm required rescue therapy with open label drug administration and one of these patients underwent tracheotomy. 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.


What is absent from the literature entirely is the utility of these agents in patients with AAE that persists after intubation. In these patients it is not known whether preventing the production of bradykinin (C1-INH, FFP), enhance breakdown (FFP) or block its activity (Icatibant) will shorten the duration of MV and thereby the associated risks to the patient (infection, thrombosis, delirium, etc) as well as the significant cost. A return on investment analysis should take place when considering these drugs in this setting at the hospital administration level. Here at CTMFHC, we took a similar approach with sugammadex, another drug that appears to shorten certain parameters but does not impact patient oriented outcomes (LOS, morbidity or mortality).




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  13. Entresto (sacubitril and valsartan) [prescribing information]. East Hanover, NJ: Novartis; August 2015
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  15. Brown NJ, et al. Dipeptidyl Peptidase-IV Inhibitor Use Associated With Increased Risk of ACE Inhibitor-Associated Angioedema. Hypertension. 2009;54:516-523
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  17. Gosmanov AR. Sitagliptin-Associated Angioedema. Diabetes Care Aug 2012, 35 (8) e60
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  31. Bernstein JA, Moellman JJ, Collins SP, Hart KW, Lindsell CJ. Effectiveness of ecallantide in treating angiotensin-converting enzyme inhibitor-induced angioedema in the emergency department. Ann Allergy Asthma Immunol. 2015 Mar;114(3):245-9
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