Table 3 Systematic review of the treatment effectiveness for bradykinin-induced angioedema [30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48, 50,51,52]
From: Bradykinin-induced angioedema in the emergency department
Treatment | Author and journal | Study type and population | Description | Findings |
|---|---|---|---|---|
HAE | ||||
C1-INH | Bork and Barnstedt 2001 [30] | - Prospective study - Series of 95 patients with HAE and functional deficiency of C1-INH | - 42 patients experienced a total of 517 laryngeal episodes over a 20-year observation period - In 193 of these episodes, the patient received C1-INH | - C1-INH was effective in all laryngeal edemas - Duration of laryngeal edema was 15.3 ± 9.3 h in episodes treated with C1-INH versus 100.8 ± 26.2 h in episodes not treated with C1-INH - Mean interval from C1-INH injection to symptom relief was 42.2 ± 19.9 min (ranged: 10 min to 4 h) |
Craig et al. 2010 [31] | - Prospective, multicentre, open-label study - 16 patients with HAE type 1 or II | - 39 emergency laryngeal attacks were treated with C1- INH | - Median time to onset of symptom relief was 15 min—onset of relief observed in at least 95% of attacks within 1 h of treatment - Median time to complete resolution of symptoms was 8.25 h (range: 0.6–48.9 h) | |
Gurmen et al. 2017 [32] | - Case report - 34-year-old woman admitted to ED for facial swelling with a known diagnosis of HAE - No continuous use of any medical products | - No response to anaphylaxis treatment - Patient refused FFP - C1-INH was administered | - Symptom regression observed at the end of 10-min C1-INH infusion | |
Yigit et al. 2018 [33] | - Case report - 48-year-old-woman admitted to ED with oropharyngeal and facial swelling - No known history of HAE or use of ACEi | - No response to epinephrine and antihistamine - C1-INH was administered | - Swelling resolved completely within 60 min of administration - Diagnosis of HAE type I confirmed after the emergency event | |
FFP | Pekdemir et al. 2007 [35] | - Case series of three patients presenting at ED with HAE attack - Case 1: 35-year-old woman - Case 2: 21-year-old woman - Case 3: 33-year-old woman | - Case 1: Symptoms persisted after conventional therapy of steroid, antihistamine and epinephrine at two different medical centres before FFP was administered - Case 2: FFP was administered - Case 3: Received FFP and developed allergic reaction so infusion stopped; FFP administration restarted after allergic reaction regressed | - Case 1: Symptoms resolved in first 4 h and patient discharged after 24 h - Case 2: Symptoms resolved within 4 h and patient discharged after 12 h - Case 3: Symptoms began to resolve and patient left ED on her own accord; follow up determined symptoms completely resolved within 5 days |
Wentzel et al. 2019 [34] | - Retrospective study - 43 HAE patients with acute swelling episodes necessitating ED attendance | - 176 acute episodes observed - 98 episodes treated with FFP—observed time to resolution and length of hospital stay | - In 96/98 episodes, FFP led to resolution of symptoms - Median time to resolution was 4 h (IQR: 2–12) - Five transfusion reactions and no deaths occurred (5%) | |
Drug-induced angioedema | ||||
C1-INH | Erickson and Coop 2016 [36] | - Case report - 59-year-old man on > 5 years of ACEi therapy presenting with angioedema of the tongue and difficulty swallowing | - Received conventional therapy of antihistamine, steroids and epinephrine but condition continued to deteriorate - C1-INH was administered | - Patient experienced rapid resolution of symptoms, which avoided airway complications |
Greve et al. 2015 [37] | - Case-control study - Ten adult patients presenting with ACEi-induced angioedema based on patient history and thorough clinical examination - Historical control group included 47 adult patients with ACEi-induced angioedema who had been treated with corticosteroids and antihistamines intravenously at the same institution over the prior 8 years | Assessed time to complete resolution of symptoms following C1-INH | Ten patients in the C1-INH group had shorter time to resolution of symptoms compared with the 47 patients in the control group (10.1 ± 3.0 h versus 33.1 ± 19.4 h; p value not reported) - No intubation or tracheotomy was needed in the C1-INH group (0/10), compared to 3/47 patients from the control group requiring tracheotomy, and 2/47 who were intubated | |
Leibfried and Kovary 2016 [38] | - Case series - Two cases of ACEi-induced angioedema - Case 1: 60-year-old male with angioedema secondary to lisinopril treatment - Case 2: 64-year-old male with angioedema secondary to enalapril | - Both patients were unsuccessfully treated with conventional treatment (antihistamine, methylprednisolone, epinephrine, FFP) | - Case 1: C1-INH administered with clinical improvement, but symptoms returned 4 h later, and patient underwent tracheotomy - Case 2: Endotracheal tube placement was unsuccessful and C1-INH was administered, resulting in improvement of symptoms | |
Rasmussen and Bygum 2013 [39] | - Case report - 63-year-old man taking ACEi presenting with severe angioedema of the tongue and floor of the mouth | - Initially treated with drugs for anaphylaxis (epinephrine, antihistamine and corticosteroids) but angioedema progressed and began to involve soft palate and uvula - C1-INH was administered | - Swelling regressed within 20 min following treatment | |
Icatibant | Bartal and Stavi 2015 [40] | - Case report - 76-year-old woman presenting with laryngeal edema and dyspnea admitted to ED - Two weeks before the episode, she had begun treatment with enalapril | - Unsuccessfully treated with adrenaline, methylprednisolone, ranitidine and promethazine - Became more dyspneic and agitated, respiratory distress aggravated - During preparation for intubation, icatibant was administered | - Dyspnea was relieved within minutes of treatment, and swelling largely resolved after 30 min - Discharged after 48 h |
Bas et al. 2010 [41] | - Case series with historical control - 8 patients presenting with ACEi-induced angioedema - Retrospectively identified group of 47 patients with similar diagnosis formed the historical comparison group | - Patients were treated with icatibant - Examined for time to first improvement of symptom relief and time to complete symptom relief from treatment - Historical group underwent intensive care interventions and received methylprednisolone and clemastine | - Mean interval to first symptom improvement after icatibant administration was 50.6 ± 21 min - Mean time to complete relief of symptoms in icatibant treatment | |
group was 4.4 ± 0.8 h compared with the historical group of 33 ± 19.4 h - In the icatibant treatment group, no patients received tracheal intubation or tracheotomy - In the historical group, 3/47 received tracheotomy and 2/47 were intubated | ||||
Baş et al. 2015 [46] | - Double-blind, multicentre, randomised phase 2 study - 30 patients with ACEi-induced angioedema from two treatment groups were analysed: icatibant (n = 15) or placebo with standard treatment of glucocorticoid and antihistamine (n = 15) - 27 patients were included in the analysis | - Primary efficacy endpoint was median time to complete resolution of angioedema - Secondary endpoints included time to onset of symptom relief | - Complete resolution of angioedema was 8.0 h (IQR: 3.0–16.0 h) for icatibant and 27.1 h (IQR: 20.3–48.0 h) for placebo (p = 0.002)—one patient from the placebo group required tracheotomy—time to onset of symptom relief was 2.0 h (95% CI: 1.0–8.1) for icatibant and 11.7 h (95% CI: 8.0–18.0) for placebo (p = 0.03) | |
Bova et al. 2015 [42] | - Case series - 13 patients on ACEi seen in ED with angioedema involving face, lips or the upper airways - Initially received standard treatment (antihistamine, corticosteroid, epinephrine) - Lack of response and worsening severity of symptoms | - Patients received icatibant - Time to first and complete symptom relief from treatment were examined and compared with time from previous attacks treated with corticosteroids, antihistamines and/or not treated (10 patients) | - All patients experienced improvement with symptom relief reported at 30 min (IQR: 27.5–70 min) - Complete resolution of symptoms at 5 h (IQR: 4–7 h) - Previous attacks without icatibant treatment had higher median time to complete resolution of 54 h (IQR: 33–63 h; p = 0.002) - No patients required tracheal intubation or tracheotomy - All discharged within 24 h | |
Crooks et al. 2014 [43] | - Case report - 75-year-old woman presenting with massive tongue and lip swelling secondary to ACEi-induced angioedema | - Awake fibreoptic intubation performed due to impending airway obstruction - No improvement in symptoms after 72 h - Icatibant was administered | - Patient’s trachea successfully extubated 36 h following treatment | |
Fok et al. 2015 [44] | - Case series - 13 consecutive ED patients presenting with ACEi-associated upper respiratory tract angioedema - No improvement with adrenaline and/or corticosteroids | - Treated with icatibant - Time from ED presentation to receiving icatibant ranged from 30 min to 3 days (median 3 h) | - Four patients were intubated in the D before or after treatment; three of these were extubated within 24 h of treatment - Eight patients did not require intubation - Time to onset of symptom improvement after icatibant ranged from 15 min to 7 h (median 2 h) | |
Sinert et al. 2017 [47] | - Double-blind, multicentre, Phase 3 RCT - 121 patients with ACEi-induced angioedema were randomised to two groups: icatibant (n = 61) or placebo (n = 60) | - Primary efficacy study endpoint was time to achieving discharge criteria (no difficulty breathing or swallowing, and mild or absent voice change, and tongue swelling) | - No difference in meeting primary endpoint between the two treatment groups - Median time to discharge criteria in the icatibant treatment group was 4.0 h (95% CI: 3.0–5.0) and placebo treatment group was 4.0 h (95% CI: 2.0–5.0) (p = 0.63) | |
Straka et al. 2017 [48] | - Prospective, double-blind, RCT - 33 patients with ACEi-induced angioedema were randomised to two groups: icatibant (n = 15) or placebo (n = 18) - 30 patients were included in the analysis | - Primary analyses included time to resolution of symptoms, using survival analysis, and symptom severity (swelling of face, lip, tongue, eyelid) over time using regression analysis | - Survival analysis revealed time to resolution of symptoms was similar between the two treatment groups (p = 0.192) - Regression analysis revealed severity of symptoms over time was similar between the two treatment groups (p > 0.16) | |
Icatibant or C1-INH | Javaud et al. 2015 [45] | - Prospective, multicentre, observational study - Consecutive enrollment of 62 patients with ACEi-induced angioedema attacks across ED of four hospitals | - 41 patients were given subcutaneous icatibant (30/41) or C1-INH (11/41), depending upon availability - Reported duration from symptom onset to ED arrival, from symptom onset to treatment decision, from ED arrival to specific treatment, and from specific treatment to onset of symptom relief | - A favourable course was observed in all patients - Median time to onset of symptom relief after C1-INH or icatibant was 0.5 h (IQR: 0.5–1.0), which was significantly shorter than in patients receiving standard treatments (2.9 h (IQR: 2.5–7.0); p < 0.0001) |
Ecallantide | Bernstein et al. 2015 [50] | - Triple-blinded, phase 2 RCT - Patients experiencing ACEi-induced angioedema not responsive to standard treatment (H1 or H2 antagonists, corticosteroids and epinephrine) within 2 h - 52 patients were randomised to two groups: conventional therapy with ecallantide (n = 25) or conventional therapy with placebo (n = 27) - 50 patients were included in the analysis | - Primary efficacy study endpoint was achieving discharge criteria from the ED within 4 h after initiating study-related treatment | - Objective discharge criteria met in ≤ 4 h for 5/24 (21%) patients receiving placebo and for 8/26 (31%) of patients receiving ecallantide - Difference in meeting discharge eligibility endpoint criteria between the two groups was not statistically significant |
Lewis et al. 2015 [51] | - Multicentre, double-blind phase 2 RCT - 79 patients with suspected ACEi-induced angioedema in the ED were randomised to placebo with physician- directed conventional therapy or 10, 30 and 60 mg of ecallantide - 76 patients were included in the analysis | - Primary endpoint defined as meeting discharge eligibility criteria within 6 h of study drug administration - Discharge criteria included improvement of angioedema, stable vital signs, absence of stridor, absence of dyspnea or use of accessory muscles during respiration, absence of drooling and ability to drink without difficulty | - The discharge eligibility endpoint was met by 72% of placebo group, and 85%, 89% and 89% of 10, 30 and 60 mg ecallantide groups, respectively - Difference in meeting discharge eligibility endpoint criteria between treatment groups was not statistically significant | |
FFP | Hassen et al. 2013 [52] | - Case series - Seven patients treated for progressive and refractory presumed ACEi-induced angioedema in the ED | - Refractory to antihistamines, corticosteroids and epinephrine - FFP was administered | - Symptoms improved with treatment in all patients - Avoided intubation in one patient with tongue swelling; stopped progression of facial and lip swelling in five patients; reduced facial and lip swelling in one patient |