- Email: [email protected]
Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema
Accepted Manuscript Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema Brittany T. Straka, M.D, Claudia E. Ramirez, M.D, James B. Byrd, M.D., M.S, Elizabeth Stone, R.N, Alencia Woodard-Grice, Ph.D, Hui Nian, M.S, Chang Yu, Ph.D, Aleena Banerji, M.D, Nancy J. Brown, M.D. PII:
S0091-6749(16)31376-8
DOI:
10.1016/j.jaci.2016.09.051
Reference:
YMAI 12474
To appear in:
Journal of Allergy and Clinical Immunology
Received Date: 11 July 2016 Revised Date:
23 August 2016
Accepted Date: 19 September 2016
Please cite this article as: Straka BT, Ramirez CE, Byrd JB, Stone E, Woodard-Grice A, Nian H, Yu C, Banerji A, Brown NJ, Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema, Journal of Allergy and Clinical Immunology (2016), doi: 10.1016/j.jaci.2016.09.051. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema
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Abbreviated title: B2R in ACE inhibitor-associated angioedema
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Brittany T. Straka, M.D.,1 Claudia E. Ramirez, M.D.,1 James B. Byrd, M.D., M.S.,1 Elizabeth
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Stone, R.N.,1 Alencia Woodard-Grice, Ph.D.,1 Hui Nian, M.S.,2 Chang Yu, Ph.D.,2 Aleena
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Banerji, M.D.,3 Nancy J. Brown, M.D.1
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From the 1Department of Medicine and the 2Department of Biostatistics, Vanderbilt University
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Medical Center, Nashville, TN 37232, USA, and 3Massachussetts General Hospital, Boston, MA
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Correspondence:
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Nancy J. Brown, M.D.
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D-3100 Medical Center North
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Vanderbilt University School of Medicine
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Nashville, TN 37232-2358
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615-343-8701
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[email protected]
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ClinicalTrials.gov Identifiers: NCT00517582, NCT01574248
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Abstract
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Background: The B2 receptor antagonist icatibant is approved for treatment of attacks of
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hereditary angioedema. Icatibant has been reported to decrease time-to-resolution of angiotensin-
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converting enzyme (ACE) inhibitor-associated angioedema in one study of European patients.
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Methods: Patients with ACE inhibitor-associated angioedema (defined as swelling of lips,
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tongue, pharynx or face during ACE inhibitor use and no swelling in the absence of ACE
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inhibitor use) were enrolled at Vanderbilt University Medical Center from October 2007 through
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September 2015 and at Massachusetts General Hospital in 2012. C1 inhibitor deficiency and
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patients with bowel edema only were excluded. Patients were randomized within six hours of
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presentation to subcutaneous icatibant 30 mg or placebo at zero and six hours later. Patients
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assessed severity of swelling using a visual analog scale serially following study drug
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administration or until discharge.
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Results: Thirty-three patients were randomized and 31 received treatment, with 13 receiving
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icatibant and 18 receiving placebo. One patient randomized to icatibant did not complete the
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visual analog scale and was excluded from analyses. Two-thirds of patients were African
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American and two-thirds were women. Time-to-resolution of symptoms was similar in placebo
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and icatibant treatment groups (p=0.19 for the primary symptom and p>0.16 for individual
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symptoms of face, lip, tongue, or eyelid swelling). Frequency of administration of H1 and H2
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blockers, corticosteroids, and epinephrine was similar in the two treatment groups. Time-to-
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resolution of symptoms was similar in black and white patients.
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Conclusions: This study does not support clinical efficacy of a bradykinin B2 receptor antagonist
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in ACE inhibitor-associated angioedema.
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Key Messages
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The study does not support the clinical efficacy of bradykinin B2 receptor blockade in
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angiotensin-converting enzyme inhibitor-associated angioedema.
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Black and white patients differed in the site-specific severity of swelling.
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Capsule Summary
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This randomized, placebo-controlled double-blind study does not shown any benefit of
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administration of the bradykinin B2 receptor antagonist icatibant in patients presenting with
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angiotensin-converting enzyme inhibitor-associated angioedema. This contrasts studies in
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hereditary angioedema.
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Key Words
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Angiotensin-converting enzyme
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Angioedema
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Bradykinin
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Icativant
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Substance P
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Abbreviations
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ACE, angiotensin-converting enzyme
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CRC, Clinical Research Center
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DSMC, Data and Safety Monitoring Committee
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GLS, generalized least squares
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OCTAVE, Omapatrilat Cardiovascular Treatment Assessment vs Enalapril
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VAS, visual analog scale
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Introduction Angioedema is a potentially life-threatening side effect sometimes seen in patients taking
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angiotensin-converting enzyme (ACE) inhibitors, and is characterized by well-demarcated
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edema of the lips, tongue, mucous membranes of the throat, nose, or other parts of the face, and
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occasionally the hands or gastrointestinal mucosa.(1) The incidence of angioedema among ACE
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inhibitor users ranges from 0.7 to 1.3 episodes per thousand person-years of exposure in whites
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and 3.3 to 4.6 person-years of exposure in blacks.(2)
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The mechanism of angioedema is not fully understood but is presumed to involve
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bradykinin. Activation of the kallikrein-kinin system contributes to the pathogenesis of
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hereditary angioedema.(3) ACE or kininase II catalyzes the formation of angiotensin II from
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angiotensin I but is also involved in the breakdown of bradykinin to inactive metabolites. ACE
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inhibitors potentiate the effects of bradykinin through its action at the B2 receptor.(4;5) Stimulation
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of B2 receptors induces vasodilation and vascular permeability and also stimulates the release of
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substance P from sensory fibers.(6) Substance P increases vascular permeability and contributes
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to ACE inhibitor-associated angioedema in rodent models.(7;8)
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The standard-of-care for ACE inhibitor-associated angioedema has been non-specific and
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consists of discontinuation of the ACE inhibitor, observation, and airway management.
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Antihistamines, corticosteroids, and epinephrine are often administered but ineffective in this
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non-allergic form of angioedema.(1) Icatibant or HOE 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8])
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bradykinin is a selective bradykinin B2 receptor antagonist, which has been used in human
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studies to delineate the contribution of bradykinin to the beneficial effects of ACE
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inhibitors.(4;5;9) Icatibant reduces the time-to-resolution of symptoms in patients with hereditary
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angioedema(10;11) and has been approved by the FDA for this indication. Recently Bas and
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colleagues reported that icatibant significantly decreases time-to-complete resolution of ACE
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inhibitor-associated angioedema in patients of European descent.(12) Whether these findings can
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be applied to a more heterogeneous patient population remains to be determined. The purpose of
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this study was to test the hypothesis that administration of icatibant decreases the duration and
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severity of ACE inhibitor-associated angioedema.
Material and Methods
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Subjects
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Patients age 18 to 65 years with ACE inhibitor-associated angioedema were enrolled at
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Vanderbilt University Medical Center between October 2007 and August 2011 (NCT00517582)
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and at Massachusetts General Hospital (a single case enrolled in 2012) and VUMC between
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August 2011 and September 2015 (NCT01574248). Two other sites initiated the study but did
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not consent any patients. Patients were defined as having ACE inhibitor-associated angioedema
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if they had swelling of the lips, pharynx or face while taking an ACE inhibitor and had never had
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swelling in the absence of ACE inhibitor use. Patients with hereditary angioedema were
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excluded. Cases of ACE inhibitor-associated bowel edema were excluded because it would be
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difficult to define time of onset and time-to-resolution accurately. Patients who presented with
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features of hypersensitivity, such as pruritus or urticaria, were not considered as having ACE
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inhibitor-associated angioedema. Patients who had presented to medical care more than six hours
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prior to screening and randomization were excluded. Pregnant women were excluded by
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measurement of urine beta-human chorionic gonadotropin (HCG) on enrollment; initiation of
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oral contraceptive therapy within six months of presentation was also a criterion for exclusion.
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Study Protocol The double-blind, placebo-controlled study protocol was approved by the Institutional
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Review Boards of the participating institutions in accordance with the Declaration of Helsinki.
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All patients provided written informed consent prior to enrollment.
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After consent was obtained patients underwent a baseline history and assessment of their
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angioedema. Patients were randomized in a one-to-one ratio to receive icatibant 30 mg (Firazyr,
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Jerini AG/Shire Human Genetic Therapies, Inc) or matching placebo (normal saline) at zero and
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six hours using a permuted-block randomization algorithm. Randomization was stratified by
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race. The Vanderbilt Investigational Drug Service was responsible for the storage, preparation
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and labeling of study drug. Study medication was delivered in two 1.5 mL syringes and was
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administered subcutaneously in the abdominal region by the nurse caring for the patient, so that
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investigators would remain blinded if there was any local irritation. Patients were not questioned
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about irritation at the injection site and nurses were instructed not to tell research personal if a
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patient commented on irritation so as to maintain blinding. Blood pressure and heart rate were
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measured prior to and every 15 minutes following study drug administration for one hour and
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then with each assessment of angioedema severity.
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In addition to study drug, patients received standard-of-care medical therapy at the
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discretion of the treatment team and administration of anti-histamines, steroids, or epinephrine
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was recorded as a secondary endpoint. In all cases, the patient’s ACE inhibitor was stopped and
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the patient was given a list of ACE inhibitors so that he or she could avoid re-exposure.
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Disposition was also determined by the treatment team. Patients who were discharged home
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were offered the option of being admitted to the Vanderbilt Clinical Research Center (CRC) to
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complete study procedures up to 48 hours after study drug administration. Patient’s electronic
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medical records were also reviewed for recurrence of angioedema after discontinuation of ACE
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inhibitor use and study medication until completion of the study; one patient in the placebo
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group and one patient in the icatibant group were lost to follow-up.
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Angioedema severity assessment
Patients were given a 10-cm non-hatched visual analog scale (VAS) that had been
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developed for trials of icatibant in hereditary angioedema to assess severity of face, lip, tongue
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and eyelid swelling, as well as shortness of breath, difficulty speaking, difficulty swallowing,
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and voice change.(10-12) Patients completed the VAS at baseline and 1, 2, 4, 6, 8, 16, 24, 48 hours
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following study drug administration or until discharge. Patients were provided with a mirror to
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view their swelling if desired prior to using the VAS and graded symptom score. At the same
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times, patients were also asked to contrast the current severity of their signs and symptoms to the
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prior time point with a graded symptom score using the following verbal descriptors: “none,”
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“much less,” “a little less,” “about the same,” “a little more,” and “much more.”
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The investigator or research nurse independently assessed the severity of angioedema
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using a graded sign and symptom score, assigning a score equal to zero for “absence of
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symptoms,” 1 for “mild,” 2 for “moderate,” and 4 for “severe” symptom or signs. The study
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personnel completed this scale at baseline and 1, 2, 4, 6, 8, 16, 24, 48 hours after study drug or at
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discharge.
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Laboratory Analysis
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Blood for complete blood count, metabolic panel, prothrombin and partial thromboplastin
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time were collected at enrollment and at discharge and measured in the clinical laboratory. Blood
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for measurement of C1 esterase inhibitor and complement levels was collected at baseline. C1
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esterase inhibitor protein was determined by quantitative nephelometry at a third party laboratory
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(ARUP Laboratories, Salt Lake City, UT), and C1 esterase inhibitor activity was determined
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using a commercially available chromogenic assay (Technoclone GmbH, Vienna, Austria). C3
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and C4 levels were assessed by immunoturbidimetric method at the Vanderbilt Pathology
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Laboratory. Blood samples for future research assays were collected at baseline and 6, 24, 48
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hours (or at discharge) after study drug administration and immediately centrifuged at 5°C for 20
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minutes. Serum and plasma were then separated and stored at -80°C until the time of assay.
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Statistical Analysis
The calculated sample size for the study was 16 patients per study arm. This sample size
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had a 0.8 power to detect a difference in the median times to resolution of 8.5 hours versus 23.3
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hours between treatment based on a log-rank test with two-sided type I error rate of 0.05. The
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expected median times were based on time-to-resolution following treatment with icatibant
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versus placebo in hereditary angioedema.(10)
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In February 2015, the principal investigator convened the Data and Safety Committee
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(DSMC) of the study to seek input regarding continuation of the study after Bas et al published
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the report of a randomized trial comparing the effect of icatibant to prednisolone/clemastine
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comparator on time-to-resolution of ACE inhibitor-induced angioedema.(12) The DSMC
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concluded that equipoise still existed and that the study should continue, based on important
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differences in outcomes and participant demographics between the published study and the
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current study. After the publication of the Bas trial, however, enrollment declined and, in
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September 2015, it was decided to discontinue the study after consultation with the DSMC.
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An intention-to-treat analysis was completed in all patients who received any study drug.
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The primary analyses were 1) survival analysis using a log-rank test to assess the time-to-
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resolution of symptoms, and 2) generalized least squares (GLS) linear regression analysis of the
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VAS measurement of the primary (most severe) sign or symptom over time. In the log-rank test,
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signs or symptoms with a VAS measurement below or equal to one cm were defined as resolved.
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Data were also analyzed using a Cox proportional hazards model which controlled for severity at
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baseline (VAS score at time 0) and race.
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Secondary outcomes included the frequency of concomitant medications, the incidence of
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admission to the intensive care unit, the incidence of intubation, the effect of treatment on blood
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pressure, and the frequency of adverse events.
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A two-sided p-value less than 0.05 was considered statistically significant. All the analyses were performed using R 3.1.2.
Among thirty-three eligible participants, 33 were randomized to study drug (15 to
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Results
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icatibant and 18 to placebo) (supplemental Figure 1). The imbalance resulted from
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incompletely filled randomization blocks within strata during both the Vanderbilt single-center
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study stage and the multi-center study stage. Two patients randomized to icatibant withdrew
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consent prior to study drug administration. All but one patient were enrolled at Vanderbilt. The
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single patient enrolled at the Massachusetts General Hospital was intubated and sedated and not
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able to complete the VAS; this patient, randomized to icatibant, was excluded from the final
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analysis. Two patients in the placebo group did not receive a second dose of study drug at six
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hours. (In one case, the patients symptoms had improved and he elected not to stay at the CRC.
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In the other, the patient’s plasma troponin I was elevated.) These patients are included in the
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analysis. Baseline characteristics were similar in the two treatment groups (Table 1). Two-thirds of
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patients presenting with ACE inhibitor-associated angioedema were women and two-thirds were
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African American. All but one patient had hypertension and 47% were diabetic. One diabetic
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patient in the placebo group was taking a dipeptidyl peptidase 4 inhibitor and had taken this for
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five years. Fifty-three percent of patients presenting with ACE inhibitor-associated angioedema
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were current or former smokers; forty-seven percent had a history of seasonal allergies. No
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patient presented with pruritus; one patient in the placebo group has a small area of urticaria on
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his right thigh, which was observed after he had been randomized and treated. Six patients (20%)
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were taking an immunosuppressant or carried a diagnosis of immunodeficiency. In the placebo
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group this included two heart transplant patients, one renal transplant patient, a patient taking
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prednisone for chronic lung disease, and a patient with rheumatoid arthritis; one patient in the
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icatibant group carried the human immunodeficiency virus. Two patients had a history of prior
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angioedema while taking an ACE inhibitor. One patient with multiple myeloma in the placebo
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group had a low C4 level and C1 inhibitor activity with a normal C3 level and C1 inhibitor
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concentration. This patient had no prior history of angioedema or any episodes of angioedema
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during two years of follow-up following discontinuation of ACE inhibition. This patient was
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included in the final analysis, because exclusion did not change the findings. No patient had
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recurrent angioedema after discontinuation of his or her ACE inhibitor with a mean follow-up of
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4.36±2.19 years.
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Although patients were treated with study drug within six hours of presentation to the
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hospital, the mean time from onset of symptoms to administration of study drug was 10.3 hours 11
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in the icatibant group. Figure 1 shows the Kaplan-Meier curves for time from treatment to
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complete resolution (symptoms less than one cm on the VAS) by treatment group. The time-to-
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resolution was similar in the placebo and icatibant treatment groups. There was also no
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significant effect of treatment on time-to-resolution in a Cox Proportional Hazards model in
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which we controlled for race and baseline severity (p=0.20 for the primary symptom and p>0.09
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for all individual symptoms). Figure 2 shows mean symptom scores using the VAS over time
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following initiation of study drug. In a GLS model analysis, there was no significant effect of
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treatment on the amount of swelling over time (p=0.95 for the primary site of swelling). There
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were also no significant differences between treatment arms in the time course of patient-
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assessed changes in symptoms or physician-assessed severity of symptoms.
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The frequency of administration of H1 and H2 blockers, corticosteroids, and epinephrine was similar in the two treatment groups (Table 2).
Blood pressure trended down slightly over time after treatment and was similar in the two
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treatment groups (supplemental Table 1).
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Relationship between race and presenting symptoms or time-to-resolution of ACE inhibitor-
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associated angioedema
The demographic characteristics of blacks and whites presenting with ACE inhibitor-
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associated angioedema were similar with one exception. Seventy-five percent of blacks
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presenting with ACE inhibitor-associated angioedema were women, whereas forty percent of
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whites presenting with angioedema were women (Table 3); this difference did not reach
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statistical significance.
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At presentation, lip swelling was more severe among black patients while angioedema of
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the tongue was more prominent in white patients (Table 3). White patients were significantly
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more likely to receive epinephrine. There were no other differences in the frequencies of
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treatments administered. In addition, the time-to-resolution of symptoms following
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administration of study drug was similar in the black and white patients presenting with ACE
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inhibitor-associated angioedema (p=0.53 for effect of race on resolution of the primary symptom
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in the Cox Proportional Hazards model, p=0.45 in the longitudinal analysis). There was also no
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effect of icatibant on time-to-resolution when analyzed separately in blacks or whites or in
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women or men (p>0.20 for time to resolution of the primary symptom in all subgroups).
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There were no serious adverse events. One patient in the placebo arm, a transplant patient
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taking immunosuppressive drugs, reported having a low sperm count measured one month after
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completion of the study. Unbeknownst to the investigators, the patient and his wife had been
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undergoing an evaluation for infertility prior to the study; the research team consulted with the
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patient’s nephrologist who did not request unblinding of study medication. One patient in the
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placebo group had elevated troponin levels. One patient in the icatibant arm developed
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leukocytosis; this was attributed to concurrent administration of systemic steroids.
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Discussion
This study compared the effect of placebo versus the bradykinin B2 receptor antagonist
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icatibant on symptoms of ACE inhibitor-associated angioedema in a mixed race population of
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patients. The study does not support the clinical efficacy of B2 receptor blockade in this form of
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angioedema.
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The findings contrast those of Bas et al, who reported that administration of icatibant
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reduced the duration of symptoms of ACE inhibitor-associated angioedema in Europeans of
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Caucasian descent.(12) The present study differs from that study in several important aspects. Bas
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et al utilized active comparator treatment and it is not possible to exclude the interpretation that
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treatment worsens ACE inhibitor-associated angioedema. In contrast, the current study was
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placebo-controlled and administration of other therapies was considered a secondary outcome. In
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the earlier study, all of the patients were white and sixty-two percent were male. Patients enrolled
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in the present study were more representative of previously published risk factors for ACE
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inhibitor-induced angioedema in that the majority or patients were of African descent and
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female.(13;14) It is possible that the effect of icatibant differs in whites and blacks, or in men and
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women, but we did not find this in post-hoc analyses. Whereas in the Bas trial 57% of patients in
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the standard therapy group were taking ramipril and the majority in the icatibant group were
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taking ramipril (38%) or enalapril (38%),(12) the majority of patients in the present study were
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taking lisinopril. Bas et al reported that investigator-assessed injection-site reactions were more
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common in the icatibant group than in the standard therapy group.(12) Patients who were asked to
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assess injection site inflammation may have become biased or inadvertently conveyed
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information to investigators resulting in unblinding. In the present study, study drug was
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administered by a nurse who was not part of the study so that investigators could remain masked
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to therapy.
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In contrast, our findings are similar to those of Sinert et al, who recently presented the
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results of a randomized, double-blind, placebo-controlled study in 121 patients at 31 centers.(15)
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In that study, the mean time from onset of angioedema to treatment with icatibant was 7.9 hours.
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The primary outcome was time to meeting discharge criteria and the median was 4.0 hours in
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both icatibant and placebo treatment groups. As in our study, the frequency of administration of
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antihistamine, steroids, and epinephrine was similar in the treatment groups. Our findings are
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also consistent with the observation that ecallantide, a kallikrein inhibitor which decreases the
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production of endogenous bradykinin, does not have significant effect on ACE inhibitor-
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associated angioedema.(16;17) The present study is smaller in size compared to these prior negative
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studies, a limitation, but similar in size to the study of Bas et al.(12)
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The lack of effect of bradykinin receptor antagonism on symptoms in patients with ACE
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inhibitor-associated angioedema also contrasts the efficacy of the drug in hereditary
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angioedema.(10;11) There are several possible explanations for this divergence. First, hereditary
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angioedema results from excess formation of bradykinin whereas ACE inhibitor-associated
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angioedema results from decreased degradation of bradykinin as well as other vasoactive
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substrates of ACE such as substance P.(1;3) Unopposed effects of substance P or other peptide
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substrates of ACE may contribute to angioedema even when the B2 receptor is blocked.(8;18)
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Second, patients with hereditary angioedema often recognize their symptoms and can be given
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icatibant early in the course of angioedema, whereas patients who take ACE inhibitors may not
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present for medical attention immediately. In the present study, for example, patients did not
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receive icatibant until a mean of 10.3 hours after the onset of symptoms. In the Bas study, the
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median time from the onset of angioedema to treatment with icatibant was 6.1 hours.(12)
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We compared the presentation and natural history of ACE inhibitor-associated
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angioedema in blacks and white patients enrolled in our study. Interestingly, the two groups
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differed in the site-specific severity of swelling involving the lips and tongue. White patients
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presenting with angioedema were more likely to receive epinephrine, perhaps reflecting concern
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regarding airway obstruction due to more severe tongue involvement. The tongue was also the
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most common site of angioedema involvement among European patients studied by Bas et al.(12)
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Importantly, even though ACE inhibitor-associated angioedema is more common in individuals
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of African descent than in those of Caucasian or Asian descent,(13) we found no relationship
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between race and the duration of symptoms. Forty-seven percent of patients presenting with ACE inhibitor-associated angioedema in
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the present study had a history of seasonal allergies and six of 33 patients were
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immunosuppressed. Previous studies have reported an association between seasonal allergies and
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increased risk of ACE inhibitor associated angioedema. For example in the Omapatrilat
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Cardiovascular Treatment Assessment vs Enalapril (OCTAVE) Trial, seasonal allergies were
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associated with a significantly increased risk of angioedema during treatment with enalapril (OR,
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1.79; 95% CI, 1.06-3.00).(14) Likewise, several groups have reported an increased incidence of
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ACE inhibitor-associated angioedema among transplant patients or patients taking an
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immunosuppressant.(19;20)
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Of note, the average duration of ACE inhibitor use among patients presenting with
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angioedema in this study exceeded two years. This is consistent with prior studies indicating that
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while the risk of angioedema is highest shortly after initiation of therapy, angioedema often
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occurs after prolonged therapy,(2;13;21) likely due to an event that increases production of
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vasoactive substrates of ACE. This delay in onset can confound recognition of ACE inhibitor-
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associated angioedema by patients and their physicians.(22;23) Indeed, two patients had had prior
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episodes of angioedema while taking an ACE inhibitor and had been continued or restarted on an
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ACE inhibitor prior to enrollment in this study.
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Acknowledgements
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The investigators wish to thank the many physicians and nurses who contacted us when patients
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presented with ACE inhibitor-associated angioedema, as well as the patients who generously
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gave of their time.
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Disclosures
354
Dr. Brown is a consultant for Novartis Pharmaceuticals and serves on the Scientific Advisory
355
Board of Alynylam Pharmaceuticals. Dr. Brown has recently served as a consultant to Shire
356
Pharmaceuticals, Inc. Dr. Brown has received research funding from New Haven
357
Pharmaceuticals as well as funding from Shire Pharmaceuticals, Inc.
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Funding Sources
360
This study was partially supported by UL1 RR024975 and R01HL079184 from the National
361
Institutes of Health, and the Investigator-Initiated Research Program from Jerini AG/Shire
362
Pharmaceuticals, Inc. Drs. Straka, Byrd, and Woodard-Grice were funded by T32GM007569.
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References (1)
Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-
associated angioedema. Immunol Allergy Clin North Am 2006; 26(4):725-37. (2)
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Burkhart DG, Brown NJ, Griffin MR, Ray WA, Hammerstrom T, Weiss S.
Angiotensin converting enzyme inhibitor-associated angioedema: higher risk in blacks than
368
whites. Pharmacoepidemiol Drug Saf 1996; 5(3):149-54. (3)
Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med 2008;
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359(10):1027-36.
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Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin-
receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive
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and hypertensive subjects. N Engl J Med 1998; 339(18):1285-92.
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(5)
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Pretorius M, Rosenbaum D, Vaughan DE, Brown NJ. Angiotensin-converting
enzyme inhibition increases human vascular tissue-type plasminogen activator release through
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endogenous bradykinin. Circulation 2003; 107(579):585.
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(6)
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Seyedi N, Maruyama R, Levi R. Bradykinin activates a cross-signaling pathway
between sensory and adrenergic nerve endings in the heart: a novel mechanism of ischemic
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(7)
Sulpizio AC, Pullen MA, Edwards RM, Brooks DP. The effect of acute
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angiotensin-converting enzyme and neutral endopeptidase 24.11 inhibition on plasma
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extravasation in the rat. J Pharmacol Exp Ther 2004; 309(3):1141-7.
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(8)
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Byrd JB, Shreevatsa A, Putlur P, Foretia D, McAlexander L, Sinha T et al.
Dipeptidyl peptidase IV deficiency increases susceptibility to angiotensin-converting enzyme
385
inhibitor-induced peritracheal edema. J Allergy Clin Immunol 2007; 120(2):403-8. (9)
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Witherow FN, Helmy A, Webb DJ, Fox KA, Newby DE. Bradykinin contributes
to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with
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heart failure. Circulation 2001; 104(18):2177-81. (10)
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Cicardi M, Banerji A, Bracho F, Malbran A, Rosenkranz B, Riedl M et al.
Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med 2010;
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363(6):532-41. (11)
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Lumry WR, Li HH, Levy RJ, Potter PC, Farkas H, Moldovan D et al.
Randomized placebo-controlled trial of the bradykinin B(2) receptor antagonist icatibant for the
394
treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma
395
Immunol 2011; 107(6):529-37. (12)
396
Bas M, Greve J, Stelter K, Havel M, Strassen U, Rotter N et al. A randomized
trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med 2015; 372(5):418-25. (13)
Brown NJ, Ray WA, Snowden M, Griffin MR. Black americans have an
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increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin
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Pharmacol Ther 1996; 60(1):8-13. (14)
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Kostis JB, Kim HJ, Rusnak J, Casale T, Kaplan A, Corren J et al. Incidence and
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characteristics of angioedema associated with enalapril. Arch Intern Med 2005; 165(14):1637-
403
42.
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(15)
Sinert R, Levy P, Bernstein JA, Body R, Sivilotti MLA, Moellman J et al. Phase
3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Study Evaluating the
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Safety and Efficacy of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced
407
Angioedema in Adults. Academic Emergency Medicine 23[S1], S11. 2016.
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(16)
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Bernstein JA, Moellman JJ, Collins SP, Hart KW, Lindsell CJ. Effectiveness of
ecallantide in treating angiotensin-converting enzyme inhibitor-induced angioedema in the
410
emergency department. Ann Allergy Asthma Immunol 2015; 114(3):245-9. (17)
Lewis LM, Graffeo C, Crosley P, Klausner HA, Clark CL, Frank A et al.
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Ecallantide for the acute treatment of angiotensin-converting enzyme inhibitor-induced
413
angioedema: a multicenter, randomized, controlled trial. Ann Emerg Med 2015; 65(2):204-13.
414
(18)
Emanueli C, Grady EF, Madeddu P, Figini M, Bunnett NW, Parisi D et al. Acute
ACE inhibition causes plasma extravasation in mice that is mediated by bradykinin and
416
substance P. Hypertension 1998; 31(6):1299-304.
417
(19)
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Duerr M, Glander P, Diekmann F, Dragun D, Neumayer HH, Budde K. Increased
incidence of angioedema with ACE inhibitors in combination with mTOR inhibitors in kidney
419
transplant recipients. Clin J Am Soc Nephrol 2010; 5(4):703-8.
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(20)
Byrd JB, Woodard-Grice A, Stone E, Lucisano A, Schaefer H, Yu C et al.
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Association of angiotensin-converting enzyme inhibitor-associated angioedema with transplant
422
and immunosuppressant use. Allergy 2010; 65(11):1381-7.
20
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(21)
Miller DR, Oliveria SA, Berlowitz DR, Fincke BG, Stang P, Lillienfeld DE.
Angioedema incidence in US veterans initiating angiotensin-converting enzyme inhibitors.
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Hypertension 2008; 51(6):1624-30.
427
428
(22)
Brown NJ, Snowden M, Griffin MR. Recurrent angiotensin-converting enzyme
inhibitor-associated angioedema. JAMA 1997; 278(3):232-3. (23)
Loftus PA, Tan M, Patel G, Lin J, Helman S, Badhey A et al. Risk factors
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associated with severe and recurrent angioedema: an epidemic linked to ACE-inhibitors.
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Laryngoscope 2014; 124(11):2502-7.
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Table 1: Baseline Characteristics by Treatment Group Icatibant
N=18
N=12
60.7±10.8
56.3±13.4
Female
12 (67%)
Male
6 (33%)
White Black Sites with swelling at presentation* Lip
Face Eyelid
EP
Smoker
Diabetes
AC C
Never
5 (42%)
0.43
7 (39%)
3 (25%)
11 (61%)
9 (75%)
12 (67%)
10 (83%)
0.31
11 (61%)
5 (45%)
0.41
9 (50%)
7 (58%)
0.65
3 (17%)
3 (25%)
0.58
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Tongue
7 (58%)
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Race
Current
0.36
0.64
Gender
Past
P-value
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Age
Placebo
SC
434
0.43 10 (56%)
4 (33%)
4 (22%)
5 (42%)
4 (22%)
3 (25%) 0.54
No
10 (56%)
8 (67%)
Yes
8 (44%)
4 (33%) 0.41
Hypertension 22
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No
1 (6%)
0
Yes
17 (94%)
12 (100%) 0.77
Seasonal allergy 10 (56%)
6 (50%)
Yes
8 (44%)
6 (50%)
0.19
13 (72%)
Yes
5 (28%)
Prior angioedema while taking an ACE inhibitor No Yes
Enalapril Benazapril
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Fosinopril
EP
Lisinopril
Quinapril
1 (8%)
18 (100%)
10 (83%)
0
2 (17%)
1903±1912
791±852
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Duration ACE inhibitor use (days)
11 (92%)
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No
SC
Immunosuppressed†
ACE inhibitor
RI PT
No
0.07
0.19 0.51
12 (67%)
11 (92%)
2 (11%)
1 (8%)
2 (11%) 1 (6%) 1 (6%)
435
*Site was defined as involved with swelling if the patient marked the zero to ten cm visual
436
analog scale for swelling at least one cm. More than one site may have been involved with
437
swelling. †Immunosuppressants in the placebo group were prednisone (N=4), methotrexate
23
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438
(N=1), tacrolimus (N=1). One patient in the icatibant group was infected with the human
439
immunodeficiency virus.
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440
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Table 2: Concurrent Treatment by Treatment Group Icatibant
N=18
N=12
12.7 ± 8.1
10.3 ± 5.6
0.55
H1 blocker, N (%)
16 (88.9%)
11 (92%)
0.80
H2 blocker, N (%)
14 (78%)
11 (92%)
0.32
Corticosteroids, N (%)
16 (88.9%)
11 (92%)
0.80
Symptom onset to study drug (hours)
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Other Treatment
Epinephrine, N (%) ICU admission, N (%) Intubation, N (%)
0
0.14
6 (33%)
6 (50%)
0.36
1 (6%)
2 (17%)
0.32
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3 (17%)
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P-value
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Placebo
SC
441
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Table 3: Baseline Characteristics and Concurrent Treatment by Racial Group
444
White
(N=20)
(N=10)
57.7±12.0
61.6±11.9
0.4
Female
15 (75%)
4 (40%)
0.06
Male
5 (25%)
Gender
6 (60%)
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Smoker
SC
Age
Never Past Current
No Yes Hypertension
EP
No
AC C
Yes
8 (40%)
6 (60%)
7 (35%)
2 (20%)
5 (25%)
2 (20%)
12 (60%)
6 (60%)
8 (40%)
4 (40%)
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Diabetes
Yes
0.56
1.00
0.15
0
1 (10%)
20 (100%)
9 (90%) 0.80
Seasonal allergy No
P-value
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Black
11 (55%)
5 (50%)
9 (45%)
5 (50%) 0.33
Immunosuppression No
15 (75%)
9 (90%)
Yes
5 (25%)
1 (10%)
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0.60
Prior angioedema 19 (95%)
9 (90%)
Yes
1 (5%)
1 (10%)
Duration ACE inhibitor use (days)
1521±1829
1143±955
0.82
Symptom onset to study drug (hours)
11.6±6.6
12.0±8.7
0.82
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No
0.22
10 (50%)
Tongue, N (%)
6 (30%)
Face, N (%)
4 (20%)
Baseline patient ranking of swelling Lip, cm on VAS
2 (20%) 6 (60%) 2 (20%)
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Lip, N (%)
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Primary site of swelling
6.6±3.8
3.4±3.7
0.03
2.7±3.5
6.4±3.9
0.02
2.96±3.85
4.08±3.07
0.32
1.34±2.80
0.42±0.92
0.65
17 (85%)
10 (100%)
0.20
16 (80%)
9 (90%)
0.49
18 (90%)
9 (90%)
1.00
Epinephrine, N (%)
0
3 (30%)
0.01
ICU admission, N (%)
7 (35%)
5 (50%)
0.43
Intubation, N (%)
1 (5%)
2 (20%)
0.20
Tongue, cm
Other treatment H1 blocker, N (%) H2 blocker, N (%)
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Corticosteroids, N (%)
EP
Eyelid, cm
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Face, cm
445
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Figure Legends
447
Figure 1: Kaplan-Meier Curve showing time-to-resolution of primary symptom, as assessed by
448
patients using visual analog scale in patients treated with placebo (dotted line) or icatibant (solid
449
line). Symptoms were deemed resolved when the patient marked the severity as less than one on
450
a ten centimeter visual analog scale. P=0.192 for effect of treatment.
451
Figure 2: Time-course of symptom severity after treatment with placebo (grey line) or icatibant
452
(red line) as indicated by patient on a visual analog scale. Data are presented as means ± standard
453
error of the mean.
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SC
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446
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EP
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454
28
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0.2
TE D
0.4
0.6
M AN U
SC
0.8
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Placebo Icatibant
0.0
Resolution Probability
1.0
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0
10
20
30
Time (hours)
40
50
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1
Supplemental Table 1: Systolic and diastolic blood pressures prior to and following
2
treatment
Placebo
Icatibant
Placebo
N=18
N=12
Baseline
139±21
137±11
0.94
76±15
1 hour
133±17
134±13
0.58
75±13
78±13
0.31
2 hours
135±14
134±16
0.79
75±15
75±15
1.00
3 hours
129±14
134±24
4 hours
137±18
135±18
6 hours
131±18
139±19
8 hours
136±25
125±25
16 hours
139±26
24 hours
135±19
48 hours
135±11
P-value
Icatibant
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P-value
N=12
82±11
SC
N=18
RI PT
Diastolic Blood Pressure, mmHg
0.32
73±12
75±11
0.92
0.98
74±15
74±11
0.46
0.45
70±10
79±14
0.09
0.40
78±18
68±10
0.18
126±22
0.30
74±14
80±15
0.36
124±16
0.23
73±7
66±8
0.14
126±14
0.33
68±8
68±10
0.75
TE D
0.63
AC C
3
Systolic Blood Pressure, mmHg
EP
Time
1
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1
Supplemental Figure 1: Study Flow Diagram
Enrollment
SC
Assessed for eligibility (n=33)
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2
M AN U
Randomized (n=33)
Allocation
Allocated to placebo (n=18) ♦ Received allocated intervention (n=18) ♦ Did not receive allocated intervention (n=0)
TE D
Allocated to icatibant (n=15) ♦ Received allocated intervention (n=13) ♦ Did not receive allocated intervention (n=2) because withdrew consent
Follow-Up
Analysis
AC C
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Visual analog scale not completed by intubated participant (n= 1)
Analyzed (n=12) ♦ Excluded from analysis due to missing primary endpoint data (n=1)
Analyzed (n=18) ♦ Excluded from analysis (n=0)
1
S0091-6749(16)31376-8
DOI:
10.1016/j.jaci.2016.09.051
Reference:
YMAI 12474
To appear in:
Journal of Allergy and Clinical Immunology
Received Date: 11 July 2016 Revised Date:
23 August 2016
Accepted Date: 19 September 2016
Please cite this article as: Straka BT, Ramirez CE, Byrd JB, Stone E, Woodard-Grice A, Nian H, Yu C, Banerji A, Brown NJ, Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema, Journal of Allergy and Clinical Immunology (2016), doi: 10.1016/j.jaci.2016.09.051. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
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Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema
2 3
Abbreviated title: B2R in ACE inhibitor-associated angioedema
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Brittany T. Straka, M.D.,1 Claudia E. Ramirez, M.D.,1 James B. Byrd, M.D., M.S.,1 Elizabeth
6
Stone, R.N.,1 Alencia Woodard-Grice, Ph.D.,1 Hui Nian, M.S.,2 Chang Yu, Ph.D.,2 Aleena
7
Banerji, M.D.,3 Nancy J. Brown, M.D.1
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From the 1Department of Medicine and the 2Department of Biostatistics, Vanderbilt University
10
Medical Center, Nashville, TN 37232, USA, and 3Massachussetts General Hospital, Boston, MA
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02114
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Correspondence:
14
Nancy J. Brown, M.D.
15
D-3100 Medical Center North
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Vanderbilt University School of Medicine
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Nashville, TN 37232-2358
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615-343-8701
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[email protected]
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ClinicalTrials.gov Identifiers: NCT00517582, NCT01574248
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Abstract
24
Background: The B2 receptor antagonist icatibant is approved for treatment of attacks of
25
hereditary angioedema. Icatibant has been reported to decrease time-to-resolution of angiotensin-
26
converting enzyme (ACE) inhibitor-associated angioedema in one study of European patients.
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23
27
Methods: Patients with ACE inhibitor-associated angioedema (defined as swelling of lips,
29
tongue, pharynx or face during ACE inhibitor use and no swelling in the absence of ACE
30
inhibitor use) were enrolled at Vanderbilt University Medical Center from October 2007 through
31
September 2015 and at Massachusetts General Hospital in 2012. C1 inhibitor deficiency and
32
patients with bowel edema only were excluded. Patients were randomized within six hours of
33
presentation to subcutaneous icatibant 30 mg or placebo at zero and six hours later. Patients
34
assessed severity of swelling using a visual analog scale serially following study drug
35
administration or until discharge.
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Results: Thirty-three patients were randomized and 31 received treatment, with 13 receiving
38
icatibant and 18 receiving placebo. One patient randomized to icatibant did not complete the
39
visual analog scale and was excluded from analyses. Two-thirds of patients were African
40
American and two-thirds were women. Time-to-resolution of symptoms was similar in placebo
41
and icatibant treatment groups (p=0.19 for the primary symptom and p>0.16 for individual
42
symptoms of face, lip, tongue, or eyelid swelling). Frequency of administration of H1 and H2
43
blockers, corticosteroids, and epinephrine was similar in the two treatment groups. Time-to-
44
resolution of symptoms was similar in black and white patients.
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45
Conclusions: This study does not support clinical efficacy of a bradykinin B2 receptor antagonist
46
in ACE inhibitor-associated angioedema.
47
49
Key Messages
50
•
The study does not support the clinical efficacy of bradykinin B2 receptor blockade in
•
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angiotensin-converting enzyme inhibitor-associated angioedema.
51 52
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Black and white patients differed in the site-specific severity of swelling.
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Capsule Summary
56
This randomized, placebo-controlled double-blind study does not shown any benefit of
57
administration of the bradykinin B2 receptor antagonist icatibant in patients presenting with
58
angiotensin-converting enzyme inhibitor-associated angioedema. This contrasts studies in
59
hereditary angioedema.
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Key Words
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Angiotensin-converting enzyme
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Angioedema
65
Bradykinin
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Icativant
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Substance P
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Abbreviations
69
ACE, angiotensin-converting enzyme
70
CRC, Clinical Research Center
71
DSMC, Data and Safety Monitoring Committee
72
GLS, generalized least squares
73
OCTAVE, Omapatrilat Cardiovascular Treatment Assessment vs Enalapril
74
VAS, visual analog scale
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Introduction Angioedema is a potentially life-threatening side effect sometimes seen in patients taking
77
angiotensin-converting enzyme (ACE) inhibitors, and is characterized by well-demarcated
78
edema of the lips, tongue, mucous membranes of the throat, nose, or other parts of the face, and
79
occasionally the hands or gastrointestinal mucosa.(1) The incidence of angioedema among ACE
80
inhibitor users ranges from 0.7 to 1.3 episodes per thousand person-years of exposure in whites
81
and 3.3 to 4.6 person-years of exposure in blacks.(2)
SC
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The mechanism of angioedema is not fully understood but is presumed to involve
83
bradykinin. Activation of the kallikrein-kinin system contributes to the pathogenesis of
84
hereditary angioedema.(3) ACE or kininase II catalyzes the formation of angiotensin II from
85
angiotensin I but is also involved in the breakdown of bradykinin to inactive metabolites. ACE
86
inhibitors potentiate the effects of bradykinin through its action at the B2 receptor.(4;5) Stimulation
87
of B2 receptors induces vasodilation and vascular permeability and also stimulates the release of
88
substance P from sensory fibers.(6) Substance P increases vascular permeability and contributes
89
to ACE inhibitor-associated angioedema in rodent models.(7;8)
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The standard-of-care for ACE inhibitor-associated angioedema has been non-specific and
91
consists of discontinuation of the ACE inhibitor, observation, and airway management.
92
Antihistamines, corticosteroids, and epinephrine are often administered but ineffective in this
93
non-allergic form of angioedema.(1) Icatibant or HOE 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8])
94
bradykinin is a selective bradykinin B2 receptor antagonist, which has been used in human
95
studies to delineate the contribution of bradykinin to the beneficial effects of ACE
96
inhibitors.(4;5;9) Icatibant reduces the time-to-resolution of symptoms in patients with hereditary
97
angioedema(10;11) and has been approved by the FDA for this indication. Recently Bas and
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colleagues reported that icatibant significantly decreases time-to-complete resolution of ACE
99
inhibitor-associated angioedema in patients of European descent.(12) Whether these findings can
100
be applied to a more heterogeneous patient population remains to be determined. The purpose of
101
this study was to test the hypothesis that administration of icatibant decreases the duration and
102
severity of ACE inhibitor-associated angioedema.
Material and Methods
105
Subjects
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103
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Patients age 18 to 65 years with ACE inhibitor-associated angioedema were enrolled at
107
Vanderbilt University Medical Center between October 2007 and August 2011 (NCT00517582)
108
and at Massachusetts General Hospital (a single case enrolled in 2012) and VUMC between
109
August 2011 and September 2015 (NCT01574248). Two other sites initiated the study but did
110
not consent any patients. Patients were defined as having ACE inhibitor-associated angioedema
111
if they had swelling of the lips, pharynx or face while taking an ACE inhibitor and had never had
112
swelling in the absence of ACE inhibitor use. Patients with hereditary angioedema were
113
excluded. Cases of ACE inhibitor-associated bowel edema were excluded because it would be
114
difficult to define time of onset and time-to-resolution accurately. Patients who presented with
115
features of hypersensitivity, such as pruritus or urticaria, were not considered as having ACE
116
inhibitor-associated angioedema. Patients who had presented to medical care more than six hours
117
prior to screening and randomization were excluded. Pregnant women were excluded by
118
measurement of urine beta-human chorionic gonadotropin (HCG) on enrollment; initiation of
119
oral contraceptive therapy within six months of presentation was also a criterion for exclusion.
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Study Protocol The double-blind, placebo-controlled study protocol was approved by the Institutional
123
Review Boards of the participating institutions in accordance with the Declaration of Helsinki.
124
All patients provided written informed consent prior to enrollment.
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After consent was obtained patients underwent a baseline history and assessment of their
126
angioedema. Patients were randomized in a one-to-one ratio to receive icatibant 30 mg (Firazyr,
127
Jerini AG/Shire Human Genetic Therapies, Inc) or matching placebo (normal saline) at zero and
128
six hours using a permuted-block randomization algorithm. Randomization was stratified by
129
race. The Vanderbilt Investigational Drug Service was responsible for the storage, preparation
130
and labeling of study drug. Study medication was delivered in two 1.5 mL syringes and was
131
administered subcutaneously in the abdominal region by the nurse caring for the patient, so that
132
investigators would remain blinded if there was any local irritation. Patients were not questioned
133
about irritation at the injection site and nurses were instructed not to tell research personal if a
134
patient commented on irritation so as to maintain blinding. Blood pressure and heart rate were
135
measured prior to and every 15 minutes following study drug administration for one hour and
136
then with each assessment of angioedema severity.
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In addition to study drug, patients received standard-of-care medical therapy at the
138
discretion of the treatment team and administration of anti-histamines, steroids, or epinephrine
139
was recorded as a secondary endpoint. In all cases, the patient’s ACE inhibitor was stopped and
140
the patient was given a list of ACE inhibitors so that he or she could avoid re-exposure.
141
Disposition was also determined by the treatment team. Patients who were discharged home
142
were offered the option of being admitted to the Vanderbilt Clinical Research Center (CRC) to
143
complete study procedures up to 48 hours after study drug administration. Patient’s electronic
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medical records were also reviewed for recurrence of angioedema after discontinuation of ACE
145
inhibitor use and study medication until completion of the study; one patient in the placebo
146
group and one patient in the icatibant group were lost to follow-up.
148
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Angioedema severity assessment
Patients were given a 10-cm non-hatched visual analog scale (VAS) that had been
150
developed for trials of icatibant in hereditary angioedema to assess severity of face, lip, tongue
151
and eyelid swelling, as well as shortness of breath, difficulty speaking, difficulty swallowing,
152
and voice change.(10-12) Patients completed the VAS at baseline and 1, 2, 4, 6, 8, 16, 24, 48 hours
153
following study drug administration or until discharge. Patients were provided with a mirror to
154
view their swelling if desired prior to using the VAS and graded symptom score. At the same
155
times, patients were also asked to contrast the current severity of their signs and symptoms to the
156
prior time point with a graded symptom score using the following verbal descriptors: “none,”
157
“much less,” “a little less,” “about the same,” “a little more,” and “much more.”
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The investigator or research nurse independently assessed the severity of angioedema
159
using a graded sign and symptom score, assigning a score equal to zero for “absence of
160
symptoms,” 1 for “mild,” 2 for “moderate,” and 4 for “severe” symptom or signs. The study
161
personnel completed this scale at baseline and 1, 2, 4, 6, 8, 16, 24, 48 hours after study drug or at
162
discharge.
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Laboratory Analysis
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Blood for complete blood count, metabolic panel, prothrombin and partial thromboplastin
166
time were collected at enrollment and at discharge and measured in the clinical laboratory. Blood
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for measurement of C1 esterase inhibitor and complement levels was collected at baseline. C1
168
esterase inhibitor protein was determined by quantitative nephelometry at a third party laboratory
169
(ARUP Laboratories, Salt Lake City, UT), and C1 esterase inhibitor activity was determined
170
using a commercially available chromogenic assay (Technoclone GmbH, Vienna, Austria). C3
171
and C4 levels were assessed by immunoturbidimetric method at the Vanderbilt Pathology
172
Laboratory. Blood samples for future research assays were collected at baseline and 6, 24, 48
173
hours (or at discharge) after study drug administration and immediately centrifuged at 5°C for 20
174
minutes. Serum and plasma were then separated and stored at -80°C until the time of assay.
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Statistical Analysis
The calculated sample size for the study was 16 patients per study arm. This sample size
178
had a 0.8 power to detect a difference in the median times to resolution of 8.5 hours versus 23.3
179
hours between treatment based on a log-rank test with two-sided type I error rate of 0.05. The
180
expected median times were based on time-to-resolution following treatment with icatibant
181
versus placebo in hereditary angioedema.(10)
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In February 2015, the principal investigator convened the Data and Safety Committee
183
(DSMC) of the study to seek input regarding continuation of the study after Bas et al published
184
the report of a randomized trial comparing the effect of icatibant to prednisolone/clemastine
185
comparator on time-to-resolution of ACE inhibitor-induced angioedema.(12) The DSMC
186
concluded that equipoise still existed and that the study should continue, based on important
187
differences in outcomes and participant demographics between the published study and the
188
current study. After the publication of the Bas trial, however, enrollment declined and, in
189
September 2015, it was decided to discontinue the study after consultation with the DSMC.
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An intention-to-treat analysis was completed in all patients who received any study drug.
191
The primary analyses were 1) survival analysis using a log-rank test to assess the time-to-
192
resolution of symptoms, and 2) generalized least squares (GLS) linear regression analysis of the
193
VAS measurement of the primary (most severe) sign or symptom over time. In the log-rank test,
194
signs or symptoms with a VAS measurement below or equal to one cm were defined as resolved.
195
Data were also analyzed using a Cox proportional hazards model which controlled for severity at
196
baseline (VAS score at time 0) and race.
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Secondary outcomes included the frequency of concomitant medications, the incidence of
198
admission to the intensive care unit, the incidence of intubation, the effect of treatment on blood
199
pressure, and the frequency of adverse events.
200 201
A two-sided p-value less than 0.05 was considered statistically significant. All the analyses were performed using R 3.1.2.
Among thirty-three eligible participants, 33 were randomized to study drug (15 to
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Results
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icatibant and 18 to placebo) (supplemental Figure 1). The imbalance resulted from
206
incompletely filled randomization blocks within strata during both the Vanderbilt single-center
207
study stage and the multi-center study stage. Two patients randomized to icatibant withdrew
208
consent prior to study drug administration. All but one patient were enrolled at Vanderbilt. The
209
single patient enrolled at the Massachusetts General Hospital was intubated and sedated and not
210
able to complete the VAS; this patient, randomized to icatibant, was excluded from the final
211
analysis. Two patients in the placebo group did not receive a second dose of study drug at six
212
hours. (In one case, the patients symptoms had improved and he elected not to stay at the CRC.
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In the other, the patient’s plasma troponin I was elevated.) These patients are included in the
214
analysis. Baseline characteristics were similar in the two treatment groups (Table 1). Two-thirds of
216
patients presenting with ACE inhibitor-associated angioedema were women and two-thirds were
217
African American. All but one patient had hypertension and 47% were diabetic. One diabetic
218
patient in the placebo group was taking a dipeptidyl peptidase 4 inhibitor and had taken this for
219
five years. Fifty-three percent of patients presenting with ACE inhibitor-associated angioedema
220
were current or former smokers; forty-seven percent had a history of seasonal allergies. No
221
patient presented with pruritus; one patient in the placebo group has a small area of urticaria on
222
his right thigh, which was observed after he had been randomized and treated. Six patients (20%)
223
were taking an immunosuppressant or carried a diagnosis of immunodeficiency. In the placebo
224
group this included two heart transplant patients, one renal transplant patient, a patient taking
225
prednisone for chronic lung disease, and a patient with rheumatoid arthritis; one patient in the
226
icatibant group carried the human immunodeficiency virus. Two patients had a history of prior
227
angioedema while taking an ACE inhibitor. One patient with multiple myeloma in the placebo
228
group had a low C4 level and C1 inhibitor activity with a normal C3 level and C1 inhibitor
229
concentration. This patient had no prior history of angioedema or any episodes of angioedema
230
during two years of follow-up following discontinuation of ACE inhibition. This patient was
231
included in the final analysis, because exclusion did not change the findings. No patient had
232
recurrent angioedema after discontinuation of his or her ACE inhibitor with a mean follow-up of
233
4.36±2.19 years.
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Although patients were treated with study drug within six hours of presentation to the
235
hospital, the mean time from onset of symptoms to administration of study drug was 10.3 hours 11
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in the icatibant group. Figure 1 shows the Kaplan-Meier curves for time from treatment to
237
complete resolution (symptoms less than one cm on the VAS) by treatment group. The time-to-
238
resolution was similar in the placebo and icatibant treatment groups. There was also no
239
significant effect of treatment on time-to-resolution in a Cox Proportional Hazards model in
240
which we controlled for race and baseline severity (p=0.20 for the primary symptom and p>0.09
241
for all individual symptoms). Figure 2 shows mean symptom scores using the VAS over time
242
following initiation of study drug. In a GLS model analysis, there was no significant effect of
243
treatment on the amount of swelling over time (p=0.95 for the primary site of swelling). There
244
were also no significant differences between treatment arms in the time course of patient-
245
assessed changes in symptoms or physician-assessed severity of symptoms.
248 249
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The frequency of administration of H1 and H2 blockers, corticosteroids, and epinephrine was similar in the two treatment groups (Table 2).
Blood pressure trended down slightly over time after treatment and was similar in the two
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treatment groups (supplemental Table 1).
250
Relationship between race and presenting symptoms or time-to-resolution of ACE inhibitor-
252
associated angioedema
The demographic characteristics of blacks and whites presenting with ACE inhibitor-
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254
associated angioedema were similar with one exception. Seventy-five percent of blacks
255
presenting with ACE inhibitor-associated angioedema were women, whereas forty percent of
256
whites presenting with angioedema were women (Table 3); this difference did not reach
257
statistical significance.
258
At presentation, lip swelling was more severe among black patients while angioedema of
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the tongue was more prominent in white patients (Table 3). White patients were significantly
260
more likely to receive epinephrine. There were no other differences in the frequencies of
261
treatments administered. In addition, the time-to-resolution of symptoms following
262
administration of study drug was similar in the black and white patients presenting with ACE
263
inhibitor-associated angioedema (p=0.53 for effect of race on resolution of the primary symptom
264
in the Cox Proportional Hazards model, p=0.45 in the longitudinal analysis). There was also no
265
effect of icatibant on time-to-resolution when analyzed separately in blacks or whites or in
266
women or men (p>0.20 for time to resolution of the primary symptom in all subgroups).
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There were no serious adverse events. One patient in the placebo arm, a transplant patient
268
taking immunosuppressive drugs, reported having a low sperm count measured one month after
269
completion of the study. Unbeknownst to the investigators, the patient and his wife had been
270
undergoing an evaluation for infertility prior to the study; the research team consulted with the
271
patient’s nephrologist who did not request unblinding of study medication. One patient in the
272
placebo group had elevated troponin levels. One patient in the icatibant arm developed
273
leukocytosis; this was attributed to concurrent administration of systemic steroids.
274
276
Discussion
This study compared the effect of placebo versus the bradykinin B2 receptor antagonist
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icatibant on symptoms of ACE inhibitor-associated angioedema in a mixed race population of
278
patients. The study does not support the clinical efficacy of B2 receptor blockade in this form of
279
angioedema.
280
The findings contrast those of Bas et al, who reported that administration of icatibant
281
reduced the duration of symptoms of ACE inhibitor-associated angioedema in Europeans of
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Caucasian descent.(12) The present study differs from that study in several important aspects. Bas
283
et al utilized active comparator treatment and it is not possible to exclude the interpretation that
284
treatment worsens ACE inhibitor-associated angioedema. In contrast, the current study was
285
placebo-controlled and administration of other therapies was considered a secondary outcome. In
286
the earlier study, all of the patients were white and sixty-two percent were male. Patients enrolled
287
in the present study were more representative of previously published risk factors for ACE
288
inhibitor-induced angioedema in that the majority or patients were of African descent and
289
female.(13;14) It is possible that the effect of icatibant differs in whites and blacks, or in men and
290
women, but we did not find this in post-hoc analyses. Whereas in the Bas trial 57% of patients in
291
the standard therapy group were taking ramipril and the majority in the icatibant group were
292
taking ramipril (38%) or enalapril (38%),(12) the majority of patients in the present study were
293
taking lisinopril. Bas et al reported that investigator-assessed injection-site reactions were more
294
common in the icatibant group than in the standard therapy group.(12) Patients who were asked to
295
assess injection site inflammation may have become biased or inadvertently conveyed
296
information to investigators resulting in unblinding. In the present study, study drug was
297
administered by a nurse who was not part of the study so that investigators could remain masked
298
to therapy.
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In contrast, our findings are similar to those of Sinert et al, who recently presented the
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300
results of a randomized, double-blind, placebo-controlled study in 121 patients at 31 centers.(15)
301
In that study, the mean time from onset of angioedema to treatment with icatibant was 7.9 hours.
302
The primary outcome was time to meeting discharge criteria and the median was 4.0 hours in
303
both icatibant and placebo treatment groups. As in our study, the frequency of administration of
304
antihistamine, steroids, and epinephrine was similar in the treatment groups. Our findings are
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also consistent with the observation that ecallantide, a kallikrein inhibitor which decreases the
306
production of endogenous bradykinin, does not have significant effect on ACE inhibitor-
307
associated angioedema.(16;17) The present study is smaller in size compared to these prior negative
308
studies, a limitation, but similar in size to the study of Bas et al.(12)
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The lack of effect of bradykinin receptor antagonism on symptoms in patients with ACE
310
inhibitor-associated angioedema also contrasts the efficacy of the drug in hereditary
311
angioedema.(10;11) There are several possible explanations for this divergence. First, hereditary
312
angioedema results from excess formation of bradykinin whereas ACE inhibitor-associated
313
angioedema results from decreased degradation of bradykinin as well as other vasoactive
314
substrates of ACE such as substance P.(1;3) Unopposed effects of substance P or other peptide
315
substrates of ACE may contribute to angioedema even when the B2 receptor is blocked.(8;18)
316
Second, patients with hereditary angioedema often recognize their symptoms and can be given
317
icatibant early in the course of angioedema, whereas patients who take ACE inhibitors may not
318
present for medical attention immediately. In the present study, for example, patients did not
319
receive icatibant until a mean of 10.3 hours after the onset of symptoms. In the Bas study, the
320
median time from the onset of angioedema to treatment with icatibant was 6.1 hours.(12)
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We compared the presentation and natural history of ACE inhibitor-associated
322
angioedema in blacks and white patients enrolled in our study. Interestingly, the two groups
323
differed in the site-specific severity of swelling involving the lips and tongue. White patients
324
presenting with angioedema were more likely to receive epinephrine, perhaps reflecting concern
325
regarding airway obstruction due to more severe tongue involvement. The tongue was also the
326
most common site of angioedema involvement among European patients studied by Bas et al.(12)
327
Importantly, even though ACE inhibitor-associated angioedema is more common in individuals
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328
of African descent than in those of Caucasian or Asian descent,(13) we found no relationship
329
between race and the duration of symptoms. Forty-seven percent of patients presenting with ACE inhibitor-associated angioedema in
331
the present study had a history of seasonal allergies and six of 33 patients were
332
immunosuppressed. Previous studies have reported an association between seasonal allergies and
333
increased risk of ACE inhibitor associated angioedema. For example in the Omapatrilat
334
Cardiovascular Treatment Assessment vs Enalapril (OCTAVE) Trial, seasonal allergies were
335
associated with a significantly increased risk of angioedema during treatment with enalapril (OR,
336
1.79; 95% CI, 1.06-3.00).(14) Likewise, several groups have reported an increased incidence of
337
ACE inhibitor-associated angioedema among transplant patients or patients taking an
338
immunosuppressant.(19;20)
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Of note, the average duration of ACE inhibitor use among patients presenting with
340
angioedema in this study exceeded two years. This is consistent with prior studies indicating that
341
while the risk of angioedema is highest shortly after initiation of therapy, angioedema often
342
occurs after prolonged therapy,(2;13;21) likely due to an event that increases production of
343
vasoactive substrates of ACE. This delay in onset can confound recognition of ACE inhibitor-
344
associated angioedema by patients and their physicians.(22;23) Indeed, two patients had had prior
345
episodes of angioedema while taking an ACE inhibitor and had been continued or restarted on an
346
ACE inhibitor prior to enrollment in this study.
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Acknowledgements
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The investigators wish to thank the many physicians and nurses who contacted us when patients
350
presented with ACE inhibitor-associated angioedema, as well as the patients who generously
351
gave of their time.
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Disclosures
354
Dr. Brown is a consultant for Novartis Pharmaceuticals and serves on the Scientific Advisory
355
Board of Alynylam Pharmaceuticals. Dr. Brown has recently served as a consultant to Shire
356
Pharmaceuticals, Inc. Dr. Brown has received research funding from New Haven
357
Pharmaceuticals as well as funding from Shire Pharmaceuticals, Inc.
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Funding Sources
360
This study was partially supported by UL1 RR024975 and R01HL079184 from the National
361
Institutes of Health, and the Investigator-Initiated Research Program from Jerini AG/Shire
362
Pharmaceuticals, Inc. Drs. Straka, Byrd, and Woodard-Grice were funded by T32GM007569.
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associated angioedema. Immunol Allergy Clin North Am 2006; 26(4):725-37. (2)
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Burkhart DG, Brown NJ, Griffin MR, Ray WA, Hammerstrom T, Weiss S.
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Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med 2008;
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Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin-
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Pretorius M, Rosenbaum D, Vaughan DE, Brown NJ. Angiotensin-converting
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Seyedi N, Maruyama R, Levi R. Bradykinin activates a cross-signaling pathway
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Sulpizio AC, Pullen MA, Edwards RM, Brooks DP. The effect of acute
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angiotensin-converting enzyme and neutral endopeptidase 24.11 inhibition on plasma
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Byrd JB, Shreevatsa A, Putlur P, Foretia D, McAlexander L, Sinha T et al.
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Witherow FN, Helmy A, Webb DJ, Fox KA, Newby DE. Bradykinin contributes
to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with
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Cicardi M, Banerji A, Bracho F, Malbran A, Rosenkranz B, Riedl M et al.
Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med 2010;
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363(6):532-41. (11)
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Lumry WR, Li HH, Levy RJ, Potter PC, Farkas H, Moldovan D et al.
Randomized placebo-controlled trial of the bradykinin B(2) receptor antagonist icatibant for the
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treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma
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Immunol 2011; 107(6):529-37. (12)
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Bas M, Greve J, Stelter K, Havel M, Strassen U, Rotter N et al. A randomized
trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med 2015; 372(5):418-25. (13)
Brown NJ, Ray WA, Snowden M, Griffin MR. Black americans have an
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increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin
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Kostis JB, Kim HJ, Rusnak J, Casale T, Kaplan A, Corren J et al. Incidence and
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characteristics of angioedema associated with enalapril. Arch Intern Med 2005; 165(14):1637-
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42.
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Sinert R, Levy P, Bernstein JA, Body R, Sivilotti MLA, Moellman J et al. Phase
3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Study Evaluating the
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Safety and Efficacy of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced
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Bernstein JA, Moellman JJ, Collins SP, Hart KW, Lindsell CJ. Effectiveness of
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Lewis LM, Graffeo C, Crosley P, Klausner HA, Clark CL, Frank A et al.
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Emanueli C, Grady EF, Madeddu P, Figini M, Bunnett NW, Parisi D et al. Acute
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Duerr M, Glander P, Diekmann F, Dragun D, Neumayer HH, Budde K. Increased
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Byrd JB, Woodard-Grice A, Stone E, Lucisano A, Schaefer H, Yu C et al.
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Association of angiotensin-converting enzyme inhibitor-associated angioedema with transplant
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and immunosuppressant use. Allergy 2010; 65(11):1381-7.
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Miller DR, Oliveria SA, Berlowitz DR, Fincke BG, Stang P, Lillienfeld DE.
Angioedema incidence in US veterans initiating angiotensin-converting enzyme inhibitors.
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Hypertension 2008; 51(6):1624-30.
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Brown NJ, Snowden M, Griffin MR. Recurrent angiotensin-converting enzyme
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Loftus PA, Tan M, Patel G, Lin J, Helman S, Badhey A et al. Risk factors
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associated with severe and recurrent angioedema: an epidemic linked to ACE-inhibitors.
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Laryngoscope 2014; 124(11):2502-7.
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Table 1: Baseline Characteristics by Treatment Group Icatibant
N=18
N=12
60.7±10.8
56.3±13.4
Female
12 (67%)
Male
6 (33%)
White Black Sites with swelling at presentation* Lip
Face Eyelid
EP
Smoker
Diabetes
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Never
5 (42%)
0.43
7 (39%)
3 (25%)
11 (61%)
9 (75%)
12 (67%)
10 (83%)
0.31
11 (61%)
5 (45%)
0.41
9 (50%)
7 (58%)
0.65
3 (17%)
3 (25%)
0.58
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Tongue
7 (58%)
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Race
Current
0.36
0.64
Gender
Past
P-value
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Age
Placebo
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0.43 10 (56%)
4 (33%)
4 (22%)
5 (42%)
4 (22%)
3 (25%) 0.54
No
10 (56%)
8 (67%)
Yes
8 (44%)
4 (33%) 0.41
Hypertension 22
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No
1 (6%)
0
Yes
17 (94%)
12 (100%) 0.77
Seasonal allergy 10 (56%)
6 (50%)
Yes
8 (44%)
6 (50%)
0.19
13 (72%)
Yes
5 (28%)
Prior angioedema while taking an ACE inhibitor No Yes
Enalapril Benazapril
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Fosinopril
EP
Lisinopril
Quinapril
1 (8%)
18 (100%)
10 (83%)
0
2 (17%)
1903±1912
791±852
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Duration ACE inhibitor use (days)
11 (92%)
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No
SC
Immunosuppressed†
ACE inhibitor
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No
0.07
0.19 0.51
12 (67%)
11 (92%)
2 (11%)
1 (8%)
2 (11%) 1 (6%) 1 (6%)
435
*Site was defined as involved with swelling if the patient marked the zero to ten cm visual
436
analog scale for swelling at least one cm. More than one site may have been involved with
437
swelling. †Immunosuppressants in the placebo group were prednisone (N=4), methotrexate
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438
(N=1), tacrolimus (N=1). One patient in the icatibant group was infected with the human
439
immunodeficiency virus.
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440
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Table 2: Concurrent Treatment by Treatment Group Icatibant
N=18
N=12
12.7 ± 8.1
10.3 ± 5.6
0.55
H1 blocker, N (%)
16 (88.9%)
11 (92%)
0.80
H2 blocker, N (%)
14 (78%)
11 (92%)
0.32
Corticosteroids, N (%)
16 (88.9%)
11 (92%)
0.80
Symptom onset to study drug (hours)
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Other Treatment
Epinephrine, N (%) ICU admission, N (%) Intubation, N (%)
0
0.14
6 (33%)
6 (50%)
0.36
1 (6%)
2 (17%)
0.32
EP AC C
443
3 (17%)
TE D
442
P-value
RI PT
Placebo
SC
441
25
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Table 3: Baseline Characteristics and Concurrent Treatment by Racial Group
444
White
(N=20)
(N=10)
57.7±12.0
61.6±11.9
0.4
Female
15 (75%)
4 (40%)
0.06
Male
5 (25%)
Gender
6 (60%)
M AN U
Smoker
SC
Age
Never Past Current
No Yes Hypertension
EP
No
AC C
Yes
8 (40%)
6 (60%)
7 (35%)
2 (20%)
5 (25%)
2 (20%)
12 (60%)
6 (60%)
8 (40%)
4 (40%)
TE D
Diabetes
Yes
0.56
1.00
0.15
0
1 (10%)
20 (100%)
9 (90%) 0.80
Seasonal allergy No
P-value
RI PT
Black
11 (55%)
5 (50%)
9 (45%)
5 (50%) 0.33
Immunosuppression No
15 (75%)
9 (90%)
Yes
5 (25%)
1 (10%)
26
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0.60
Prior angioedema 19 (95%)
9 (90%)
Yes
1 (5%)
1 (10%)
Duration ACE inhibitor use (days)
1521±1829
1143±955
0.82
Symptom onset to study drug (hours)
11.6±6.6
12.0±8.7
0.82
RI PT
No
0.22
10 (50%)
Tongue, N (%)
6 (30%)
Face, N (%)
4 (20%)
Baseline patient ranking of swelling Lip, cm on VAS
2 (20%) 6 (60%) 2 (20%)
M AN U
Lip, N (%)
SC
Primary site of swelling
6.6±3.8
3.4±3.7
0.03
2.7±3.5
6.4±3.9
0.02
2.96±3.85
4.08±3.07
0.32
1.34±2.80
0.42±0.92
0.65
17 (85%)
10 (100%)
0.20
16 (80%)
9 (90%)
0.49
18 (90%)
9 (90%)
1.00
Epinephrine, N (%)
0
3 (30%)
0.01
ICU admission, N (%)
7 (35%)
5 (50%)
0.43
Intubation, N (%)
1 (5%)
2 (20%)
0.20
Tongue, cm
Other treatment H1 blocker, N (%) H2 blocker, N (%)
AC C
Corticosteroids, N (%)
EP
Eyelid, cm
TE D
Face, cm
445
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Figure Legends
447
Figure 1: Kaplan-Meier Curve showing time-to-resolution of primary symptom, as assessed by
448
patients using visual analog scale in patients treated with placebo (dotted line) or icatibant (solid
449
line). Symptoms were deemed resolved when the patient marked the severity as less than one on
450
a ten centimeter visual analog scale. P=0.192 for effect of treatment.
451
Figure 2: Time-course of symptom severity after treatment with placebo (grey line) or icatibant
452
(red line) as indicated by patient on a visual analog scale. Data are presented as means ± standard
453
error of the mean.
M AN U
SC
RI PT
446
AC C
EP
TE D
454
28
AC C
EP
0.2
TE D
0.4
0.6
M AN U
SC
0.8
RI PT
Placebo Icatibant
0.0
Resolution Probability
1.0
ACCEPTED MANUSCRIPT
0
10
20
30
Time (hours)
40
50
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
1
Supplemental Table 1: Systolic and diastolic blood pressures prior to and following
2
treatment
Placebo
Icatibant
Placebo
N=18
N=12
Baseline
139±21
137±11
0.94
76±15
1 hour
133±17
134±13
0.58
75±13
78±13
0.31
2 hours
135±14
134±16
0.79
75±15
75±15
1.00
3 hours
129±14
134±24
4 hours
137±18
135±18
6 hours
131±18
139±19
8 hours
136±25
125±25
16 hours
139±26
24 hours
135±19
48 hours
135±11
P-value
Icatibant
M AN U
P-value
N=12
82±11
SC
N=18
RI PT
Diastolic Blood Pressure, mmHg
0.32
73±12
75±11
0.92
0.98
74±15
74±11
0.46
0.45
70±10
79±14
0.09
0.40
78±18
68±10
0.18
126±22
0.30
74±14
80±15
0.36
124±16
0.23
73±7
66±8
0.14
126±14
0.33
68±8
68±10
0.75
TE D
0.63
AC C
3
Systolic Blood Pressure, mmHg
EP
Time
1
ACCEPTED MANUSCRIPT
1
Supplemental Figure 1: Study Flow Diagram
Enrollment
SC
Assessed for eligibility (n=33)
RI PT
2
M AN U
Randomized (n=33)
Allocation
Allocated to placebo (n=18) ♦ Received allocated intervention (n=18) ♦ Did not receive allocated intervention (n=0)
TE D
Allocated to icatibant (n=15) ♦ Received allocated intervention (n=13) ♦ Did not receive allocated intervention (n=2) because withdrew consent
Follow-Up
Analysis
AC C
EP
Visual analog scale not completed by intubated participant (n= 1)
Analyzed (n=12) ♦ Excluded from analysis due to missing primary endpoint data (n=1)
Analyzed (n=18) ♦ Excluded from analysis (n=0)
1