Acute Hereditary Angioedema Attacks Research Articles

Interventions for the treatment of acute hereditary angioedema attacks

Interventions for the treatment of acute hereditary angioedema attacks

Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors

The lectin pathway (LP) of the complement system is an important antimicrobial defense mechanism, but it also contributes significantly to ischemia reperfusion injury (IRI) associated with myocardial infarct, stroke, and several other clinical conditions. Mannan-binding lectin–associated serine proteinase 2 (MASP-2) is essential for LP activation, and therefore, it is a potential drug target. We have previously developed the first two generations of MASP-2 inhibitors by in vitro evolution of two unrelated canonical serine proteinase inhibitors. These inhibitors were selective LP inhibitors, but their nonhuman origin rendered them suboptimal lead molecules for drug development. Here, we present our third-generation MASP-2 inhibitors that were developed based on a human inhibitor scaffold. We subjected the second Kunitz domain of human tissue factor pathway inhibitor 1 (TFPI1 D2) to directed evolution using phage display to yield inhibitors against human and rat MASP-2. These novel TFPI1-based MASP-2 inhibitor (TFMI-2) variants are potent and selective LP inhibitors in both human and rat serum. Directed evolution of the first Kunitz domain of TFPI1 had already yielded the potent kallikrein inhibitor, Kalbitor® (ecallantide), which is an FDA-approved drug to treat acute attacks of hereditary angioedema. Like hereditary angioedema, acute IRI is also related to the uncontrolled activation of a specific plasma serine proteinase. Therefore, TFMI-2 variants are promising lead molecules for drug development against IRI.

PRO24 COST-EFFECTIVENESS OF LANADELUMAB AND C1-INHIBITORS FOR PROPHYLAXIS AGAINST ACUTE ATTACKS OF HEREDITARY ANGIOEDEMA

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent episodes of body tissue swelling. We evaluated the cost-effectiveness of lanadelumab and the C1-inhibitors, Cinryze and Haegarda, for long-term prophylaxis against acute HAE attacks versus no prophylaxis in adult patients with HAE type 1/2 from a US health system perspective. We developed a Markov model with two health states: alive with HAE and dead with monthly cycles over a life-time horizon. Baseline characteristics were: mean age of 39.6 years, 68.4% female, mean weights of 88.8kg (male) and 76.4 kg (female), and a baseline attack rate of 3.39 per month. We tracked number of attacks, time attack free, survival, quality-of-life, and costs. Parameters were obtained from publicly available databases, published literature, and expert opinion. Outcomes included discounted (3% per year) quality-adjusted life-years (QALYs) and costs (2018 US$), and incremental cost per QALY gained (ICER). We conducted univariate and probabilistic sensitivity analyses, and scenario analyses. Expected QALYs were 17.47 for no prophylaxis, and ranged from 18.21 (Cinryze) to 18.66 (lanadelumab) for patients receiving prophylaxis. Expected costs were $9,953,000 for no prophylaxis and ranged from $10,343,000 (Haegarda) to $14,396,000 (Cinryze) yielding ICERs ranging from $328,000 (Haegarda) to $5,954,000 (Cinryze). ICERs were extremely sensitive to drug acquisition costs, the baseline attack rate and treatment effects. The probability that Haegarda and lanadelumab were cost-effective at a $150,000/QALY threshold was 36% and 5%, respectively. A scenario analysis showed that 75% of patients would need to be switched to every four-week dosing for lanadelumab to be cost-effective at a $150,000/QALY threshold. In the base case, drugs for prophylaxis against acute attacks of HAE were likely to exceed the cost-effectiveness threshold of $150,000/QALY. However, the model outcomes were highly sensitive to changes in model inputs and assumptions and should be interpreted with caution.

A Study of Icatibant for Acute Attacks of Hereditary Angioedema in Japanese Participants

A Study of Icatibant for Acute Attacks of Hereditary Angioedema in Japanese Participants

Chemotherapy in Patients with Hereditary Angioedema

Hereditary angioedema (HAE) is an autosomal dominant hereditary disorder characterized by episodic swelling of many body regions (especially throat and abdomen), potentially triggered by medication. No data are available for HAE in patients with cancer assigned to standard chemotherapy. The aim of our study was to identify circulating mediators potentially predictive of acute HAE attacks during chemotherapy. Repeated blood testing (approximately every week) for complement system members (C3, C4, CH50, C1 inhibitor, C1-inhibitor functional C1Q), D-dimers and for routine haematochemistry were performed in a 42-year-old male affected by type 2 HAE during standard adjuvant oxaliplatin/fluorouracil-based chemotherapy administered for stage III radically resected rectal cancer. Pre-medication with 1,000 U Berinert inhibitor C1 was administered every week throughout treatment. Mann-Whitney U-test was used to determine statistical differences in measures between the first 30 days of therapy and beyond day 30 of therapy. Pre-chemotherapy values of tested variables (day 0) were: C3: 101 mg/dl, C4: 5.71 mg/dl, CH50: 74%, C1 inhibitor: 43.4 mg/dl, C1-inhibitor functional: 18%, C1Q: 150 mg/dl, and D-dimers: 113 g/ml. A significant change in circulating values was observed for C3, D-dimers and C1-inhibitor functional. Four HAE attacks were observed, they started from the forth cycle of treatment and all were manageable. Changes in C3, D-dimers and C1-inhibitor functional preceded the attacks. The stress induced by chemotherapy such a standard oxaliplatin/fluorouracil increases the risk of attacks in patients with HAE. However, circulating biomarkers such as D-dimers, C3 and C1-inhibitor functional may serve as early predictors of acute HAE crisis.

PSY13 - THE TREATMENT OPTIONS FOR ACUTE ATTACK OF HEREDITARY ANGIOEDEMA (HAE): A SYSTEMATIC LITERATURE REVIEW AND NETWORK META-ANALYSIS

Hereditary angioedema (HAE) is a rare inherited disease with unpredictable attacks of anywhere in body including larynx, which can be fatal. The purpose of this systematic review was to compare the efficacy and safety of currently available medications for the treatment of acute attack of HAE. A systematic search was conducted using MEDLINE and The Cochrane Library from January 2003 through June 2018. To be included, studies had to evaluate the efficacy and safety of the medications that could be used to treat acute attack of HAE. Then, we performed indirect treatment comparison of the efficacy using ‘time to onset of symptom relief (hours)’ as outcome measure with placebo or supportive care as a common control group. The random effect model was applied to meta-analysis because of the heterogeneity of studies included. The safety profile of the included studies reported different measures, therefore we performed qualitative synthesis. A total of 230 studies that investigated treatment for HAE were identified. Seven placebo-controlled studies among three medication groups (ecallantide, icatibant, C1-INH concentrate) for the treatment of acute attack were included network meta-analysis. All of medications were generally tolerable in the clinical studies. Each of the medications showed a statistically significant early onset of symptom relief compared with the control group; icatibant (mean difference, MD -8.93, p=0.03), C1-INH (MD -2.74, p=0.002), and ecallantide (MD -1.63, p=0.003). However, there were no statistically significant superiority of efficacy among the medications in each pair of indirect comparison. Currently, available treatments generally have good efficacy and tolerability compared to placebo, but no relative superiority among treatments can be found. However, because of the nature of such a rare disease, all of the included studies had a relatively small number of patients, therefore further studies are needed to identify the relative efficacy and cost-effectiveness of these treatments.

Treatment of Hereditary Angioedema Attacks with Icatibant and Recombinant C1 Inhibitor During Pregnancy.

Hereditary angioedema (HAE) is a rare disease caused by a C1 inhibitor (C1-INH) deficit. Clinically, HAE is manifested by repeated episodes of localized subcutaneous or submucosal oedema attacks. Managing HAE patients in pregnancy is challenging, since there are only limited data on the safety and efficacy of various therapeutic approaches. We present our clinical experience treating acute HAE attacks during pregnancy in six consecutive patients. During the pregnancies, 79 HAE attacks occurred. The most frequent were abdominal 53 (67.1%) followed by peripheral 21 (26.6%), facial 10 (12.7%), and laryngeal 10 (12.7%) oedemas; 13 (16.5%) attacks were combined. Fifty (63.3%) attacks were treated with recombinant human C1-INH (rhC1-INH); 17 (21.5%) with plasma-derived, pasteurized, nanofiltered C1-INH (pnfC1-INH); 13 (16.5%) with icatibant; and 1 (1.3%) with plasma-derived, nanofiltered C1-INH (nfC1-INH). Treatment had to be repeated in 5 attacks (6.3%). All six deliveries (one caesarean section and five spontaneous vaginal deliveries) were complication free. All pregnancies went to the full term and the patients delivered healthy babies with a birth weight ranging from 2850 to 3690g. No congenital abnormalities were detected in the neonates. No abortions occurred. Our results show good C1-INH or icatibant treatment efficacy for HAE attacks in pregnancy. The treatment by the first drug used was effective in 93.7% of all attacks. In 6.3% of attacks, a second treatment had to be used. No adverse effects were observed.

Recombinant human C1-esterase inhibitor for the prevention of acute hereditary angioedema attacks: a case report

Background: Prophylaxis may be considered for frequent acute attacks of hereditary angioedema (HAE); moreover, prophylaxis efficacy may impact direct costs associated with medical utilization/medication.Objectives: To present data on the efficacy and cost savings of investigational prophylactic treatment with recombinant human C1-esterase inhibitor (rhC1-INH).Methods: Retrospective chart review of patient with HAE.Results: A white female aged 52 years who had experienced HAE attack symptoms since age 16 years was diagnosed at age 37 years with type 1 HAE. She received danazol 400 mg/d; attempts to lower her dose were unsuccessful. She continued to experience daily extremity swelling and had abdominal edema with intense pain severe enough to warrant hospitalization every 2–3 months. In 2012, she began prophylaxis with plasma-derived C1-INH (pdC1-INH) 1000 IU 3 times weekly (TIW) at a weekly cost of ∼$16,500. During a 12-month period (September 2013 to September 2014), authors documented 13 emergency room (ER) visits for acute HAE attacks, but other records suggest there were several additional ER visits. The pdC1-INH dose was increased to 1500 IU TIW in October 2014 at a weekly cost of ∼$24,829, and the number of ER visits declined (n = 9 during a 14-month period). In December 2015, patient began prophylaxis TIW with rhC1-INH 2100 IU for an annual cost savings of $400,660 versus pdC1-INH. From initiation of rhC1-INH to October 2017, patient required only 1 ER visit.Conclusions: rhC1-INH prophylaxis for HAE reduced occurrence of ER visits and provided potential cost benefits for both drug costs and medical utilization.

Recombinant human C1 esterase inhibitor (Conestat alfa) for prophylaxis to prevent attacks in adult and adolescent patients with hereditary angioedema

ABSTRACTIntroduction: Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a debilitating and potentially lethal disease. Management includes on-demand treatment of angioedema and their prophylaxis. Plasma derived C1-INH is an established treatment for both on demand and prophylaxis of HAE. Conestat alfa is a recombinant form of human C1-INH (rhC1-INH) produced in transgenic rabbits. It has granted drug’s registration as treatment option for acute HAE attacks in adults and adolescents in Europe, America, and other countries. Long-term prophylaxis with rhC1-INH received recent consideration in clinical trials.Areas covered: This review will critically appraise available information about rhC1-INH (conestat alfa) prophylactic treatment in adult and adolescent patients with congenital C1-INH deficiency. Results from a phase II randomized placebo-controlled trial for prophylaxis of severe HAE evidenced positive treatment outcomes for its application, both twice or once weekly.Expert commentary: Phase II clinical studies suggest that rhC1-INH is a viable option for prophylaxis of HAE. Safety and tolerability data are comparable to other available HAE specific drugs, zeroing the possibility for blood-born viral transmission. Sustainability of modern technologies is granting a practically stable and continuous recombinant production process. With other available options, rhC1-INH facilitates tailoring HAE treatment to patients’ needs.

Efficacy of recombinant human C1 esterase inhibitor across anatomic locations in acute hereditary angioedema attacks.

Hereditary angioedema (HAE) may occur at or spread to multiple anatomic locations during an acute attack. Recombinant human C1 esterase inhibitor (rhC1-INH) is approved for treating acute HAE attacks. To examine the time to the beginning of symptom relief with rhC1-INH by attack location. Data for patients ≥12 years of age with an acute HAE attack who received rhC1-INH 50 IU/kg or placebo were pooled from two double-blind clinical trials with open-label extensions. The time to the beginning of symptom relief was defined as the first time point that the visual analog scale severity score at an attack location decreased by ≥20 mm versus baseline, with persistence. Data were reported as median time values (95% confidence interval [CI]). For abdominal attacks, the median time to the beginning of symptom relief was 60.0 minutes (95% CI, 47.0-62.0 minutes; n = 194 attacks) with rhC1-INH versus 240.0 minutes (95% CI, 45.0-720.0 minutes; n = 15 attacks) with placebo. The median time to the beginning of symptom relief for peripheral attacks was 105.0 minutes (95% CI, 90.0-120.0 minutes; n = 169 attacks) with rhC1-INH versus 303.0 minutes (95% CI, 180.0-720.0 minutes; n = 17 attacks) with placebo. For oro-facial-pharyngeal-laryngeal attacks or urogenital attacks, the median time to the beginning of symptom relief with rhC1-INH was 64.5 minutes (95% CI, 60.0-120.0 minutes; n = 36 attacks) and 119.0 minutes (95% CI, 40.0-270.0 minutes; n = 13 attacks), respectively, versus 306.0 minutes (95% CI, 30.0-495.0 minutes; n = 6 attacks) and 320.0 minutes (n = 1 attack) with placebo. In shortening the median time to the beginning of symptom relief of acute HAE attacks, rhC1-INH 50 IU/kg was efficacious, regardless of attack location.

A transcriptomics study of hereditary angioedema attacks

Hereditary angioedema (HAE) caused by C1-inhibitor deficiency is a lifelong illness characterized by recurrent acute attacks of localized skin or mucosal edema. Activation of the kallikrein/bradykinin pathway at the endothelial cell level has a relevant pathogenetic role in acute HAE attacks. Moreover, other pathways are involved given the variable clinical expression of the disease in different patients. We sought to explore the involvement of other putative genes in edema formation. We performed a PBMC microarray gene expression analysis on RNA isolated from patients with HAE during an acute attack and compared them with the transcriptomic profile of the same patients in the remission phase. Gene expression analysis identified 23 genes significantly modulated during acute attacks that are involved primarily in the natural killer cell signaling and leukocyte extravasation signaling pathways. Gene set enrichment analysis showed a significant activation of relevant biological processes, such as response to external stimuli and protein processing (q<0.05), suggesting involvement of PBMCs during acute HAE attacks. Upregulation of 2 genes, those encoding adrenomedullin and cellular receptor for urokinase plasminogen activator (uPAR), which occurs during an acute attack, was confirmed in PBMCs of 20 additional patients with HAE by using real-time PCR. Finally, invitro studies demonstrated the involvement of uPAR in the generation of bradykinin and endothelial leakage. Our study demonstrates the increase in levels of adrenomedullin and uPAR in PBMCs during an acute HAE attack. Activation of these genes usually involved in regulation of vascular tone and in inflammatory response might have a pathogenic role by amplifying bradykinin production and edema formation in patients with HAE.

Plasma Prekallikrein: Its Role in Hereditary Angioedema and Health and Disease.

Plasma prekallikrein (PK) has a critical role in acute attacks of hereditary angioedema (HAE). Unlike C1 inhibitor, its levels fall during HAE attacks with resultant cleaved high-molecular-weight kininogen. Cleavage of high-molecular-weight kininogen liberates bradykinin, the major biologic peptide that promotes the edema. How prekallikrein initially becomes activated in acute attacks of HAE is not known. PK itself is negatively associated with cardiovascular disease. High prekallikrein is associated with accelerated vascular disease in diabetes and polymorphisms of prekallikrein that reduce high-molecular-weight kininogen binding are associated with protection from cardiovascular events. Prekallikrein-deficient mice have reduced thrombosis risk and plasma kallikrein (PKa) inhibition is associated with reduced experimental gastroenterocolitis and arthritis in rodents. In sum, prekallikrein and its enzyme PKa are major targets in HAE providing much opportunity to improve the acute and chronic management of HAE. PKa inhibition also may be a target to ameliorate cardiovascular disease, thrombosis risk, and inflammation as in enterocolitis and arthritis.

Sustained response of recombinant human C1 esterase inhibitor for acute treatment of hereditary angioedema attacks

BackgroundSymptoms of hereditary angioedema (HAE) attacks can recur soon after initial treatment; the durability of response for recombinant human C1 esterase inhibitor (rhC1INH) treatment is unknown. ObjectiveTo examine the efficacy and durability of rhC1INH for acute HAE attacks. MethodsIn this pooled post hoc analysis of 2 trials, patients with type I or II HAE (functional C1INH levels <50% of normal) and a baseline visual analog scale score of at least 50 mm were included if they had received at least 1 intravenous dose of 50 IU/kg of rhC1INH. Response was defined as symptom relief within 4 hours after treatment with persistence (≥20-mm decrease in visual analog scale scores [0 mm {“no symptoms at all”} to 100 mm {“extremely disabling”}] at 2 consecutive time points) during the 4 hours. Durability was the response without an increase of at least 20 mm in the minimum post-treatment visual analog scale score up to 24 hours. Recurrence and new attack symptoms were determined for patients with 72-hour post-treatment data. ResultsData were analyzed for 127 patients treated with 50 IU/kg of rhC1INH in 2 studies. Most attacks (90.7%) responded within 4 hours, with differences in response rates among attack locations (61.5%–94.4%). The median time to the beginning of symptom relief was 75.0 minutes (95% confidence interval 65.0–80.0). No relapse occurred during 24 hours for attacks that initially responded. Only 7.1% of attacks were associated with symptom recurrence within 72 hours of initial rhC1INH treatment. ConclusionThis integrated analysis supports the efficacy of rhC1INH for treatment of acute HAE across multiple attacks, with a sustained response for at least 3 days. Trial RegistrationClinicalTrials.gov Identifiers: NCT00225147 and NCT00262301.

Recombinant Human C1-Esterase Inhibitor to Treat Acute Hereditary Angioedema Attacks in Adolescents

Recombinant human C1-esterase inhibitor (rhC1-INH) is efficacious and well tolerated for managing hereditary angioedema (HAE) attacks in adults. However, there are insufficient data on its efficacy and safety in adolescents. To evaluate the efficacy and safety profiles of rhC1-INH for acute HAE attacks in adolescents. Adolescents (aged 12-18 y) with HAE enrolled in 2 randomized controlled trials and 2 open-label extension trials were included and received intravenous rhC1-INH for acute attacks. Times to the beginning of sustained symptom relief (visual analog scale change from baseline ≥20 mm) and minimal symptoms (visual analog scale score of <20 mm across locations) were assessed. Safety parameters included hypersensitivity reactions, anti-rhC1-INH antibodies, and host-related impurities. Sixteen adolescents (50 attacks, aged 14-18 y) received rhC1-INH. Attacks were managed with single-dose rhC1-INH 50 U/kg (46.0%) and single-dose rhC1-INH 2100 U (16%), and 32.0% were treated with additional doses after receiving an initial rhC1-INH 2100 U dose (total dose, 4200-6300 U). Most attacks (88.0%) occurred at a single location; 59.1% (26 of 44) were abdominal. Across the first 5 attacks, median times to the beginning of symptom relief ranged from 19.0 to 78.5 minutes; median times to minimal symptoms ranged from 120 to 190 minutes. Pharmacokinetics showed that rhC1-INH restored functional plasma C1-esterase inhibitor levels to the normal (>70%) range for almost all evaluable patients. No severe or drug-related adverse events or hypersensitivity reactions occurred. No treatment-emergent antibodies to rhC1-INH or host-related impurities were observed. rhC1-INH is efficacious and well tolerated among adolescents with HAE.

Recombinant Human C1 Inhibitor (rHC1INH) Is Efficacious and Well Tolerated As Prophylaxis for Prevention of Hereditary Angioedema (HAE) Attacks: A Randomized, Phase 2 Trial

rhC1INH is currently administered for the treatment of acute HAE attacks. Repeat rhC1INH treatment for recurrent attacks during open-label extension studies have maintained efficacy while being well tolerated, supporting a potential role for rhC1INH in prophylaxis. A randomized, double-blind, 3-period, crossover study was conducted in patients ≥13 years of age with functional C1INH levels <50% of normal and ≥4 HAE attacks during the previous 3 months. Patients received rhC1INH 50 IU/kg (max, 4200 IU) once or twice weekly or placebo in three, 4-week periods; each treatment was separated by 1 week and symptoms monitored by a daily diary. Primary endpoint was number of HAE attacks per 4-week period. Additional endpoints included percentage of patients with ≥25%, ≥50% (clinical response), or ≥75% reduction in number of HAE attacks versus placebo and number of days with HAE symptoms. Thirty-two patients were randomized (mean age, 45.9 years [range, 16.9–73.5 years]). Mean number of HAE attacks was reduced from 7.2 (placebo) to 4.4 (rhC1INH once weekly; P=0.0004) and 2.7 (rhC1INH twice weekly; P<0.0001). Percentage of patients with ≥25%, ≥50%, and ≥75% reduction in HAE attacks versus placebo was 64.5%, 41.9%, and 19.4% for rhC1INH once weekly and 80.6%, 74.2%, and 41.9% rhC1INH twice weekly, respectively. Number of days with HAE symptoms was lower with rhC1INH twice weekly (5.1 days) and once weekly (8.0 days) versus placebo (10.2 days). rhC1INH was efficacious for the prevention of HAE attacks and data support continued investigation of rhC1INH as prophylaxis.

Novel usage of fresh frozen plasma in hereditary angioedema.

Hereditary angioedema (HAE) is a rare and potentially life threatening autosomal dominant disease characterized by recurrent episodes of cutaneous and mucosal oedema. It results from reduced expression or loss of function of CI-esterase inhibitors (C1-INH). As opposed to the more common histamine-mediated angioedema, HAE does not respond well to conventional treatments with anti-histamines, steroids and adrenaline. Early recognition and timely intervention with the correct treatment are crucial particularly preventing airway obstruction. New disease specific treatment including plasma derived or recombinant C1-INH, ecallantide and icatibant have recently emerged and its appropriate use can reduce HAE-associated mortality and morbidity. However due to its costs, these disease specific treatments have yet to reach Malaysia. Despite that no randomized clinical trial on FFP has been performed, its efficacy in treating acute attacks of HAE is only demonstrated in case studies. This case report illustrates the successful treatment of acute HAE episode with FFP in a Malaysian government hospital setting.

Complements Are Not Always a Good Thing: Novel Therapies for Angioedema.

Hereditary angioedema attacks are rare, but emergency care providers must be aware of the clinical presentation and treatment of these patients because the emergency department remains the most common setting where these patients seek treatment. If providers are not aware of the past medical history of these patients, they are likely to receive standard therapies for respiratory distress and anaphylaxis including antihistamines, corticosteroids, and epinephrine. However, these medications may not work in these patients, given the pathophysiology of their underlying disease. Since 2009, several new therapies have been approved for the treatment of acute hereditary angioedema attacks. This article discusses pathophysiology, clinical presentation, and use of novel therapies for the management of angioedema.

Subcutaneous Icatibant for the Treatment of Acute Attacks of Hereditary Angioedema: Comparison of Self-Administration to Administration at a Medical Facility

Subcutaneous Icatibant for the Treatment of Acute Attacks of Hereditary Angioedema: Comparison of Self-Administration to Administration at a Medical Facility

C1-Esterase Inhibitor Concentrate for Acute Laryngeal Hereditary Angioedema (HAE) Attacks: Different Treatment Response Based on Dosing Regimen?

For acute treatment of hereditary angioedema (HAE) attacks, international consensus guidelines recommend plasma-derived C1-inhibitor concentrate (pdC1-INH) both at fixed and body weight-adjusted doses. Since fast response to treatment with a single dose is paramount for potentially life-threatening laryngeal HAE attacks, we compared available efficacy data with different pdC1-INH dosing regimens. We performed an indirect, descriptive comparison of treatment response with pdC1-INH at fixed doses of 500 or 1000 IU and body weight-adjusted doses of 20 IU/kg, using data from clinical studies with 1000 IU Cinryze®, and 500 or 1000 IU and 20 IU/kg Berinert®. Data were compared descriptively, using a Kaplan-Meier analysis, and by a Wilcoxon test. Median time to onset of symptom relief (95% confidence interval [CI]) was 15 minutes (14; 25) with 20 IU/kg Berinert (N=48), 30 minutes (30; 40) with 500 IU Berinert (N=48), 40 minutes (40; 40) with 1000 IU Berinert (N=145), and 45 minutes (30; 75) with 1000 IU Cinryze (N=82) (per-attack analysis). A similar difference was seen in a per-patient analysis, with significantly shorter median average time to onset of symptom relief with 20 IU/kg compared with fixed pdC1-INH doses (26 versus 43 minutes; p=0.019). No re-dosing was needed with body weight-adjusted dosing, while a second dose was used in up to 62% of attacks treated with 1000 IU. Available data suggest body weight-adjusted dosing with pdC1-INH at 20 IU/kg as preferred treatment choice over fixed dosing to ensure optimal treatment response for acute laryngeal HAE attacks.

Efficacy of Different Medical Therapies for the Treatment of Acute Laryngeal Attacks of Hereditary Angioedema due to C1-esterase Inhibitor Deficiency

BackgroundHereditary angioedema (HAE) is a rare disease characterized by C1-esterase inhibitor (C1-INH) deficiency, resulting in periodic attacks of acute edema, which can be life-threatening if they occur in the upper airway. No head-to-head comparisons of different treatment options for acute HAE attacks are available. Because immediate symptom relief is critical for potentially life-threatening laryngeal attacks, it is important to determine the treatment option that provides optimal treatment response. ObjectiveReview and compare data from clinical studies that evaluated the efficacy and safety of treatments for laryngeal HAE attacks. MethodsWe conducted an indirect comparison of clinical outcomes from prospective studies for treatment of 881 acute laryngeal attacks with plasma-derived C1-INH concentrate (pdC1-INH) at fixed doses (500 or 1000 U) or a body weight-adjusted dose (20 U/kg), recombinant C1-INH concentrate at a fixed dose (2100 U), or a body weight-adjusted dose (50 U/kg), icatibant (30 mg), or ecallantide (30 mg). Comparisons included time to onset of symptom relief and need for re-dosing or emergency procedures. ResultsThe median time to onset of symptom relief ranged between 15 min and approximately 2 h, and was shortest with body weight-adjusted doses of pdC1-INH. The proportion of laryngeal attacks with re-dosing ranged between 0% and 72%. No re-dosing was needed after treatment with a single body weight-adjusted dose of pdC1-INH (48 attacks). ConclusionsAvailable data suggest that among different HAE treatments, body weight-adjusted pdC1-INH (20 U/kg) provides the most reliable treatment response for treatment of laryngeal HAE attacks.