Acute Angioedema Attacks Research Articles

Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema

Hereditary angioedema (HAE) results from a genetic deficiency of C1-inhibitor. Two similar independent, randomized, saline controlled, double-blind studies were conducted to evaluate the efficacy and safety of recombinant human C1-inhibitor (rhC1INH) as a treatment of acute angioedema attacks in patients with HAE. Analysis of pooled study results. Patients with an eligible attack were randomized to a single intravenous dose of rhC1INH or saline. Efficacy was assessed by using patient-reported visual analog scale outcomes, and safety was assessed by using adverse events and immunogenicity of rhC1INH. rhC1INH at 100 (n= 29) and 50 (n= 12) U/kg body weight resulted in a significant reduction for both the primary endpoint time to the beginning of relief of symptoms compared with saline (n= 29): median, 66 (95% CI, 61-122) minutes, 122 (72-136) minutes, and 495 (245-520) minutes, P< .001 and P= .013, respectively; and for the secondary endpoint time to minimal symptoms, median, 266 (242-490) minutes, 247 (243-484) minutes, and 1210 (970-1500) minutes, P< .001 and P= .001, respectively. Therapeutic failure occurred in 59% (17/29) of the saline group compared with 0% (0/12) of the 50 U/kg group and 10% (3/29) of the 100 U/kg group. Treatment-emergent adverse events were unremarkable and tended to be reported more frequently in the saline group. No postexposure antibody responses against rhC1INH or host-related impurities were observed. Administration of rhC1INH at 100 or 50 U/kg was highly effective as a treatment of acute attacks in patients with HAE and appeared to be safe and well tolerated.

Ecallantide for the Treatment of Acute Attacks in Hereditary Angioedema

Hereditary angioedema is a rare genetic disorder characterized by acute, intermittent, and potentially life-threatening attacks of edema of the skin and mucosa. We evaluated ecallantide, a newly developed recombinant plasma kallikrein inhibitor, for the treatment of acute attacks of angioedema. In this double-blind, placebo-controlled trial, patients with hereditary angioedema presenting with an acute attack were randomly assigned, in a 1:1 ratio, to receive subcutaneous ecallantide, at a dose of 30 mg, or placebo. Two measures of patient-reported outcomes were used to assess the response: treatment outcome scores, which range from +100 (designated in the protocol as significant improvement in symptoms) to -100 (significant worsening of symptoms), and the change from baseline in the mean symptom complex severity score, which range from +2 (representing a change from mild symptoms at baseline to severe symptoms after) to -3 (representing a change from severe symptoms at baseline to no symptoms after). The primary end point was the treatment outcome score 4 hours after study-drug administration. Secondary end points included the change from baseline in the mean symptom complex severity score at 4 hours and the time to significant improvement. A total of 71 of the 72 patients completed the trial. The median treatment outcome score at 4 hours was 50.0 in the ecallantide group and 0.0 in the placebo group (interquartile range [IQR], 0.0 to 100.0 in both groups; P=0.004). The median change in the mean symptom complex severity score at 4 hours was -1.00 (IQR, -1.50 to 0.00) with ecallantide, versus -0.50 (IQR, -1.00 to 0.00) with placebo (P=0.01). The estimated time to significant improvement was 165 minutes with ecallantide versus more than 240 minutes with placebo (P=0.14). There were no deaths, treatment-related serious adverse events, or withdrawals owing to adverse events. Four hours after administration of ecallantide or placebo for acute attacks of angioedema in patients with hereditary angioedema, patient-reported treatment outcome scores and mean symptom complex severity scores were significantly better with ecallantide than with placebo. (Funded by Dyax; ClinicalTrials.gov number, NCT00262080.)

Successful treatment of acute angioedema attacks with a bradykinin receptor-2 antagonist (Icatibant) in a patient with acquired C1 inhibitor deficiency

Immune modulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) has shown great success in inducing immune tolerance in a large cohort of enzyme replacement therapy (ERT)-naïve infantile Pompe disease patients. Antibody-dependent cellular cytotoxicity, the principal mechanism by which rituximab depletes B-cells, requires CD20 binding by Fab’2 of rituximab on B-cells and the concomitant binding of its Fc region to Fc receptors on effector cells or to complement. To protect patients against microbial infections when using rituximab, IVIG was added to the immunomodulation regimen used in Pompe disease. Administration of IVIG can saturate neonatal Fc receptors (FcRn), which recycle endogenous as well as administered polyclonal/monoclonal antibodies via the binding of the Fc moiety to FcRn. As such, the administration of IVIG prior to rituximab, a chimeric mouse-human monoclonal antibody, may sharply reduce the half-life of rituximab and in turn, its efficacy. Based on this understanding, it is vital to understand the optimal timing of IVIG administration in relation to rituximab administration for the purposes of inducing immune tolerance.

Notfallsituation akutes Angioödem

Angioedema is an oedematous swelling of the mucosa or submucosa of the skin. Acute angioedema represents a clinical emergency when the pharynx or larynx are involved and breathing of the patient is impaired. For rapid and effective treatment it is necessary to differentiate between allergic and non-allergic angioedema. Three of the five subforms of non-allergic angioedema are mediated by bradykinin: renin-angiotensin-aldosterone system (RAAS)-blocker-induced angioedema (RAE), hereditary angioedema (HAE) and acquired angioedema (AAE). Antihistamines, corticosteroids and adrenalin can be used to treat allergic angioedema but are ineffective in acute attacks of non-allergic angioedema. In these events the bradykinin-B2-receptor antagonist icatibant (in HAE, or RAE) or C1-INH concentrate (in HAE, or AAE) are therapeutic options for rapid alleviation of acute angioedema. The following article gives an overview of the diagnostics and treatment in the emergency situation of "acute angioedema", especially if swelling of the head-and-neck region is present.

Plasma biomarkers of acute attacks in patients with angioedema due to C1‐inhibitor deficiency

Cl-inhibitor (C1-INH) deficiency leads to recurrent attacks of mucocutaneous edema and may be inherited (hereditary angioedema [HAE]) or acquired (acquired angioedema [AAE]), which have the same clinical picture characterized by angioedema involving the skin, gastrointestinal tract, and larynx. Although cutaneous swelling is evident, abdominal angioedema is still a diagnostic challenge and attacks can mimic surgical emergencies. There is currently no laboratory marker for identifying angioedema attacks. As coagulation and fibrinolysis are activated during angioedema attacks, we assessed if plasma measurements of prothrombin fragment F1 + 2 (marker of thrombin generation) and D-dimer (marker of fibrin degradation) can be useful for the diagnosis of angioedema because of C1-INH deficiency, especially in case of hidden locations as abdominal attacks. In addition to complement, we measured plasma levels of F1 + 2 and D-dimer in 28 patients with C1-INH deficiency during acute attacks and remission, 35 patients without C1-INH deficiency during abdominal colics, and 20 healthy subjects. Plasma F1 + 2 levels were higher in patients with C1-INH deficiency during remission than in healthy controls (P = 0.001), and further increased during cutaneous and abdominal attacks (P = 0.0001); patients without C1-INH deficiency had normal F1 + 2 levels during abdominal colics. Plasma D-dimer levels were higher in patients with C1-INH deficiency during remission than in controls (P = 0.012) and increased during angioedema attacks, reaching higher levels than in patients without C1-INH deficiency during colics (P = 0.002). During acute angioedema attacks, patients with C1-INH deficiency have high prothrombin fragment F1 + 2 and D-dimer levels, the measurement of which may have an important diagnostic value.

Pharmacokinetics, Clinical Efficacy and Safety of Plasma-Derived Nanofiltered C1 Inhibitor Concentrate for Treatment of Hereditary and Acquired Angioedema.

RATIONALE: From the early 70's, C1 inhibitor concentrate manufactured from pooled human plasma has been available to patients with hereditary and acquired angioedema (HAE and AAE) and in 1997 a highly purified C1 inhibitor (Cetor®) was introduced. Many precautions have been taken to minimize the potential risk of viral transmission (e.g. rigorously controlled whole blood collection systems, extensive screening of each individual donation for a variety of blood-borne viruses, pasteurisation). To further minimize the potential risk of viral transmission, a 15 nm filtration was implemented in the manufacturing process giving rise to C1-inhibitor-N (anofiltered).DESIGN: A randomised, double-blind, controlled cross-over phase II study was conducted in which our primary objective was to compare the pharmacokinetics of the newly developed concentrate with conventional C1-inhibitor concentrate in HAE patients without signs of an attack of angioedema. Secondly, an open-label phase III study in patients with an HAE attack was performed to investigate whether the introduction of the virus reducing 15nm filtration step in the manufacturing process of the concentrate did not affect the efficacy and safety of the product.RESULTS: Thirteen patients were enrolled in the phase II study. No differences between conventional C1-inhibitor concentrate and nanofiltered C1-inhibitor concentrate were detected with regard to the primary pharmacokinetic parameters clearance, volume of distribution, and the fraction of C1-inhibitor-N detected by the antigen assay relative to the functional assay. Therefore incremental recovery, mean residence time, half-life and the area under curve were equivalent for both products. In the phase III study, 8 HAE patients were enrolled. In these 8 patients, 14 attacks qualified as acute angioedema attack. The mean time-to-relief for attacks treated with new C1-inhibitor concentrate was 3.0 (SD 2.5) hours. Historical data showed that treatment with conventional C1-inhibitor concentrate resulted in time-to-relief of 3.9 (SD 6.2) hours, whereas for untreated attacks this was 24.7 (SD 19.9) hours. The attacks treated with new C1-esterase inhibitor concentrate had a mean time-to-resolve of 18.6 hours (SD 13.1) whereas medical history showed an time-to-resolve of 17.8 hours (SD 17.2) for conventional C1-inhibitor. Untreated attacks showed a mean time-to-resolve of 63.6 hours (SD 31.0).CONCLUSION: The newly developed nanofiltered C1-esterase inhibitor has equal pharmacokinetic properties compared to the conventional concentrate. The viral reduction step (15 nm filtration) in the production process of Cetor did not induce changes in the efficacy and safety in the treatment of acute angioedema attacks and in the pharmacokinetic parameters.

New treatments addressing the pathophysiology of hereditary angioedema

Hereditary angioedema is a serious medical condition caused by a deficiency of C1-inhibitor. The condition is the result of a defect in the gene controlling the synthesis of C1-inhibitor, which regulates the activity of a number of plasma cascade systems. Although the prevalence of hereditary angioedema is low – between 1:10,000 to 1:50,000 – the condition can result in considerable pain, debilitation, reduced quality of life, and even death in those afflicted. Hereditary angioedema presents clinically as cutaneous swelling of the extremities, face, genitals, and trunk, or painful swelling of the gastrointestinal mucosa. Angioedema of the upper airways is extremely serious and has resulted in death by asphyxiation.Subnormal levels of C1-inhibitor are associated with the inappropriate activation of a number of pathways – including, in particular, the complement and contact systems, and to some extent, the fibrinolysis and coagulation systems.Current findings indicate bradykinin, a product of contact system activation, as the primary mediator of angioedema in patients with C1-inhibitor deficiency. However, other systems may play a role in bradykinin's rapid and excessive generation by depleting available levels of C1-inhibitor.There are currently no effective therapies in the United States to treat acute attacks of hereditary angioedema, and currently available agents used to treat hereditary angioedema prophylactically are suboptimal. Five new agents are, however, in Phase III development. Three of these agents replace C1-inhibitor, directly addressing the underlying cause of hereditary angioedema and re-establishing regulatory control of all pathways and proteases involved in its pathogenesis. These agents include a nano-filtered C1-inhibitor replacement therapy, a pasteurized C1-inhibitor, and a recombinant C1-inhibitor isolated from the milk of transgenic rabbits. All C1-inhibitors are being investigated for acute angioedema attacks; the nano-filtered C1-inhibitor is also being investigated for prophylaxis of attacks. The other two agents, a kallikrein inhibitor and a bradykinin receptor-2 antagonist, target contact system components that are mediators of vascular permeability. These mediators are formed by contact system activation as a result of C1-inhibitor consumption.

Recombinant human C1‐inhibitor in the treatment of acute angioedema attacks

Patients with hereditary C1-inhibitor deficiency have recurrent attacks of angioedema, preferably treated with C1-inhibitor concentrate. A recombinant human C1-inhibitor (rHuC1INH) was developed, derived from milk from transgenic rabbits. This study was undertaken to investigate the effects of rHuC1INH in the treatment of acute angioedema attacks in patients with a hereditary C1-inhibitor deficiency. Patients with hereditary C1-inhibitor deficiency were treated with rHuC1INH (at a dose of 100 U/kg) within 8 hours after onset of an acute attack. Time to initiation of relief and time to minimal symptoms were reported by both the patient and the treating physician. Thirteen severe angioedema attacks in 9 patients with hereditary C1-inhibitor deficiency were treated with rHuC1INH. There was rapid improvement of clinical conditions for all attacks, with approximately 80 percent of treated patients experiencing symptom relief within 2 hours and minimal symptoms within 12 hours. There were no drug-related adverse events or immunogenic reactions to C1-inhibitor or rabbit proteins. The transgenically produced rHuC1INH was successfully used in the treatment of acute angioedema attacks in patients with hereditary C1-inhibitor deficiency.

Plasmatic Markers Of Coagulation And Fibrinolysis In Patients With C1 Inhibitor Deficiency During Acute Attacks Of Angioedema

RATIONALE: C1-INH controls protease activity in complement, contact, coagulation and fibrinolytic systems. Its deficiency causes recurrent angioedema of the skin, bowel mucosa and upper airway. Aim of this study was the identification of plasmatic markers to distinguish angioedema due to C1-INH deficiency. Since activation of fibrinolytic system and generation of thrombin occur during angioedema in C1-INH deficiency, we used commonly available methods to measure prothrombin fragment F1+2 and fibrin fragment D-Dimer as markers of thrombin generation and fibrinolysis.

A novel therapeutic concept for the treatment of acute angioedema attacks in hereditary angioedema patients: multiple successful treatments even in severe swelling attacks with the bradykinin-B2 receptor antagonist Icatibant

Several forms of angioedema seem to be induced by elevated bradykinin (BK) concentrations. They are either caused by increased BK production, as is the case in hereditary angioedema (HAE) involving the lack of a functional C1-esterase inhibitor, or by reduced BK inactivation (e.g. during ACE-inhibitor treatment). BK-induced angioedema does not respond to the current standard treatment for angioedema caused by increased histamine levels, corticosteroids and antihistamines. Until now acute attacks of HAE have been treated with intravenously administered C1-esterase inhibitor concentrate derived from human plasma. However, no specific treatment has been approved for ACE-inhibitor-induced angioedema. It would be necessary that such an approach inhibits directly the activation of the bradykinin-B2 receptor by BK. During the ongoing international phase III HAE study FAST2, we treated several HAE patients subcutaneously with Icatibant, a specific bradykinin-B2 receptor antagonist. In the open-label part of this study we administered Icatibant for the treatment of 21 acute HAE attacks. Eleven attacks were located in the head-neck region, of which three involved the laryngeal area, six the abdominal and four the genital area. Following treatment with Icatibant, patients reported rapid onset of symptom relief and complete remission of symptoms within a few hours. We were especially impressed by the successful treatment of the edema involving the laryngeal area. The study drug was safe and well tolerated. We have noted short-lived local injection site reactions, which resolved spontaneously without intervention. In our hands Icatibant showed high efficacy for the treatment of acute HAE attacks with a rapid onset of symptom relief. Subcutaneous administration might improve the quality of life for HAE patients. Icatibant could also represent a new therapeutic paradigm for the treatment of ACE-inhibitor-induced angioedema cases but this hypothesis needs to be tested in a clinical study.

C1 inhibitor concentrate therapy in 473 patients with hereditary and acquired angioedema

Rationale C1 inhibitor deficiency is a rare, potentially lethal condition that can be either inherited (hereditary angioedema, HAE) or acquired (acquired angioedema, AAE). Substitutive therapy with C1-INH concentrate is the treatment of choice for severe acute attacks of angioedema in Europe. Methods We report the need and effect of C1-INH concentrate in 448 patients with HAE and 25 with AAE. Time to beginning of resolution of attacks, side effects were recorded. Results We recorded 326 infusions of C1 inhibitor plasma concentrate in 127 HAE patients (mean infusion/patient 2.5, range 1-17) and 89 infusion in 8 AAE patients (mean infusion/patient 11.1, range 1-27). Dose of concentrate ranged from 500U to 2000U for HAE, 1000U-12000U for AAE. Time to beginning of resolution was 1 hour in 303 (93%), between 1 and 2 hours in 7 and between 2 and 12 hours in the remaining 16 patients. One HAE patient underwent tracheostomy for laryngeal edema despite treatment with C1-INH concentrate. In 5 patients with AAE (54 infusions) beginning of resolution was always within one hour; in the remaining 3 patients (35 infusions) the response became progressively slow 3 (3 hours or more) requiring higher doses of C1-INH concentrate. One anaphylactic reaction and 2 generalized cutaneous reactions were reported in 2 patients with HAE. Transmission of HCV has been recorded before introduction of virucidal methods. Conclusions C1 inhibitor concentrate is effective and safe for treatment of severe symptoms in the majority of patients with HAE. Patients with AAE may become resistant to the treatment.

Bradykinin and the pathophysiology of angioedema

Angioedema has different causes and different clinical presentations. Some types of angioedema may be mediated by bradykinin. We measured plasma levels of bradykinin-(1–9)nonapeptide by radioimmunoassay after high-performance liquid chromatography in patients with different types of angioedema during acute attacks and/or in remission, i.e. hereditary C1-inhibitor deficiency, angiotensin converting enzyme (ACE) inhibitor treatment, idiopathic non histaminergic and responders to antihistamines. Eleven patients with the deficiency of C1-inhibitor had very high levels of bradykinin during acute attacks of angioedema (18.0–90.0 pM) (normal range 0.2–7.1 pM). In three patients with history of ACE inhibitor-related angioedema, plasma bradykinin was high during ACE inhibitor treatment (62.0, 8.9 and 27.0 pM) and in a fourth patient was 47.0 pM during an acute attack and decreased by 93% to 3.2 pM after withdrawal of the ACE inhibitor. The patient with idiopathic angioedema, during an acute attack involving the right arm, had high levels of bradykinin in the venous blood refluent from the angioedematous arm (20.0 pM) while in the contralateral arm bradykinin levels were normal (6.6 pM), similarly to what we previously observed in cases of brachial angioedema due to C1-inhibitor deficiency. The four patients with angioedema responsive to antihistamines had normal levels of bradykinin even during acute attacks (5.7, 3.4, 4.7 and 1.2 pM). In one of these patients who had a brachial angioedema, bradykinin levels were normal in the venous blood refluent from both arms. Bradykinin is involved in hereditary C1-inhibitor deficiency angioedema, in ACE inhibitor-related angioedema, and in idiopathic non-histaminergic angioedema, while bradykinin is not related to allergen-dependent or idiopathic angioedema that are responsive to antihistamines.

In vitro interaction of C1-inhibitor with thrombin.

Previous observations of increased generation of thrombin during acute attacks of angioedema in plasma of patients with C1-inhibitor (C1-INH) deficiency prompted us to evaluate the interaction of C1-INH with thrombin in both purified systems and human plasma. For this purpose, we used several methods: (1) sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting analysis; (2) enzyme-linked immunosorbent assays to measure complexes between C1-INH and thrombin and inactivated C1-INH; and (3) kinetic studies using a chromogenic assay. We found that the interaction of purified C1-INH with thrombin is associated with the formation of bimolecular complexes of molecular weight (Mr) 130 000 and 120 000 as well as with the appearance of a cleaved form of C1-INH of Mr 97 000. The kinetic studies of inhibition of thrombin by C1-INH showed an average second-order rate constant of 19/s per mol/l, which was significantly increased in the presence of heparin. The addition of thrombin to human plasma was not associated with detectable C1-INH-thrombin complex formation or with cleavage of C1-INH. In conclusion, our data demonstrate that C1-INH upon interaction with thrombin, in part, forms enzyme-inhibitor complexes and, in part, is cleaved. The low second-order rate constant and the lack of a significant interaction in plasma suggest that the inhibition of thrombin by C1-INH has a minor role in circulating blood; however, its role might be important at the endothelial surface, where high concentrations of glycosaminoglycans occur.

Haemostasis contact system and fibrinolysis in hereditary angioedema (C1-inhibitor deficiency).

Factors of the classical complement pathway, the contact system and fibrinolysis were evaluated both with functional and immunochemical methods, in patients with inherited deficiency of C1-inhibitor. Evaluations were performed under basal conditions, during acute attacks and during prophylaxis with low doses of anabolic steroids. Patients in the basal state showed no significant abnormalities of any of the parameters that we investigated. During acute attacks a slightly reduced prekallikrein concentration was registered. During treatment with low doses of danazol and stanozolol, protein C and plasminogen were found to be increased. Our data suggest that C1-inhibitor deficiency per se does not lead to a derangement of the fibrinolysis and coagulation contact system, and that the kinin system may be involved during acute attacks of angioedema.