Treatment Of Acute Angioedema Attacks Research Articles

Treatment of Hereditary Angioedema.

Hereditary angioedema due to C1-esterase inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease. In the last decade, new drugs and new indications for old drugs have played a role in the management of C1-INH-HAE. This review examines current therapy for C1-INH-HAE and provides a brief summary of drugs that are under development. Increased knowledge of the pathophysiology of C1-INH-HAE has been crucial for advances in the field, with inhibition of the kallikrein-kinin system (plasma kallikrein, activated factor XII) as a key area in the discovery of new drugs, some of which are already marketed for treatment of C1-INH-HAE. Pharmacological treatment is based on 3 pillars: treatment of acute angioedema attacks (on-demand treatment), short-term (preprocedure) prophylaxis, and long-term prophylaxis. The 4 drugs that are currently available for the treatment of acute angioedema attacks (purified plasma-derived human C1 esterase inhibitor concentrate, icatibant acetate, ecallantide, recombinant human C1 esterase inhibitor) are all authorized for self-administration, except ecallantide. Purified plasma-derived human C1 esterase inhibitor concentrate is the treatment of choice for short-term prophylaxis. Tranexamic acid, danazol, intravenous and subcutaneous nanofiltered purified plasma-derived human C1 esterase inhibitor concentrate, and lanadelumab can be used for long-term prophylaxis. New drugs are being investigated, mainly as long-term prophylaxis, and are aimed at blocking the kallikrein-kinin system by means of antiprekallikrein, antikallikrein, and anti-activated FXII action.

Administration of Conestat Alfa, Human C1 Esterase Inhibitor and Icatibant in the Treatment of Acute Angioedema Attacks in Adults with Hereditary Angioedema Due to C1 Esterase Inhibitor Deficiency. Treatment Comparison Based on Systematic Review Results

Introduction: Hereditary angioedema (HAE) is a genetic disease caused by C1-esterase inhibitor deficiency, characterized by recurrent attacks of intense, massive, localized subcutaneous oedema that can involve all parts of the body. The aim of this study is a comparison of the clinical effectiveness of conestat alfa, human C1 esterase inhibitor (C1INH) and icatibant in the treatment of acute angioedema attacks in adults with HAE. Materials and methods: A systematic review of literature published up to May 2012 was performed to assess the efficacy and safety of conestat alfa, C1INH and icatibant in the treatment of acute angioedema attacks in adults with HAE. Databases were searched at MEDLINE (PubMed), EMBASE and Cochrane. The general search structure was designed as a combination of keywords or synonyms: (hereditary angioedema) AND (conestat alfa OR human C1 esterase inhibitor concentrate or synonyms OR icatibant). Only randomized clinical studies were selected. Results: Systematic review yielded no clinical trials directly comparing the therapeutic options mentioned. Two randomized clinical trials were found which compared each of the following: conestat alfa, C1INH and icatibant with placebo. Based on the gathered evidence it was demonstrated that taking any of the medicinal substances mentioned in the treatment of acute angioedema attack results in a shorter time to the start of symptom relief and the time to reduce symptoms, the probability of treatment response after 4 hours is increased and the safety profile is comparable to placebo. Conclusions: Due to the significant heterogeneity of the identified trials, the scientific evidence available was insufficient to identify the most effective therapeutic option in the treatment of acute oedemas in HAE.

Cost-utility analysis of Ruconest(®) (conestat alfa) compared to Berinert(®) P (human C1 esterase inhibitor) in the treatment of acute, life-threatening angioedema attacks in patients with hereditary angioedema.

IntroductionAdministration of human C1 esterase inhibitor (Berinert® P) from target import is the most widespread treatment strategy for patients with hereditary angioedema (HAE). However, a therapeutic health program including Ruconest® (conestat alfa) could shorten a patient's expectancy for a life-saving treatment.AimTo evaluate the cost-utility of Ruconest® (conestat alfa) financed from public funds within the newly introduced therapeutic health program compared with Berinert® P (human C1 esterase inhibitor) in the treatment of acute angioedema attacks in adults with HAE.Material and methodsThe cost-utility analysis from the Polish healthcare payer's perspective was performed for 1 year (2012). The costs and health outcomes were simulated for three pairs of eligible HAE patient groups (active treatment and corresponding placebo). The incremental costs of each intervention compared with placebo were listed together (direct or indirect comparisons between options were impossible due to limited clinical data available).ResultsThe incremental cost-utility ratios (ICURs) for the evaluated interventions compared with placebo were as follows: EUR 15,226 per QALY (Ruconest®) and EUR 27,786 per QALY (Berinert® P). The probability of cost-utility (ICUR < EUR 24,279 per QALY) assessed for Ruconest® administered in the case of acute angioedema attack was 61% and 41% for Berinert® P.ConclusionsThe administration of Ruconest® in acute life-threatening angioedema attacks is economically justified from the Polish healthcare payer's perspective, results in lower costs and is characterized by higher cost-utility probability compared with Berinert® P.

Recombinant C1-Inhibitor

Recombinant human C1-inhibitor (rhC1INH; Ruconest®) has been developed for treatment of acute angioedema attacks in patients with hereditary angioedema (HAE) due to heterozygous deficiency of C1INH. Previous reports suggest that administration of plasma-derived C1INH products may be associated with an increased risk for thromboembolic complications. Our aim is to evaluate the effects of rhC1INH on coagulation and fibrinolysis in symptomatic HAE patients. Levels of various coagulation and fibrinolytic parameters were determined in pre- and post-exposure plasma samples from HAE patients included in a randomized clinical trial. Patients were treated with either saline, or 50 or 100 U/kg rhC1INH for an acute angioedema attack. Prior to rhC1INH treatment, the majority of patients had low to normal activated partial thromboplastin times (aPTT) and increased levels of prothrombin fragment 1+2, thrombin-antithrombin complexes, D-dimers and plasmin-antiplasmin complexes, all of which indicate activation of both coagulation and fibrinolysis. Infusion of rhC1INH at doses up to 100 U/kg did not affect these parameters except for a dose-dependent prolongation of aPTT, confirming that rhC1INH is an inhibitor of the contact system, and that F1+2 levels decreased. Coagulation and fibrinolytic systems are activated in HAE patients suffering from an acute angioedema attack. Treatment with rhC1INH at 50 or 100 U/kg had no effect on parameters reflecting activation of these systems except for a significant effect on aPTT, which likely reflects a pharmacodynamic effect of rhC1INH, and a reduction on plasma levels of the prothrombin activation fragment F1+2. We conclude that these results argue against a prothrombotic effect of treatment with this rhC1INH product in HAE patients.

84 Immuno-Safety of Recombinant Human C1 Inhibitor in Patients With Hereditary Angioedema

BackgroundRecombinant C1 inhibitor (rhC1INH) is a novel therapeutic option for the treatment of acute angioedema attacks in patients with hereditary angioedema (HAE). The amino acid sequence of rhC1INH is identical to that of endogenous C1INH. However, any recombinant protein may elicit antibodies against the protein and/or host related impurities (HRI). Clinical consequences of these antibodies can theoretically range from no clinical symptoms to allergic reactions and reduced C1INH activity due to neutralizing antibodies.ObjectiveTo analyze the immuno-safety of rhC1INH in symptomatic patients with HAE.MethodsPlasma samples were collected pre-treatment and 22 and 90 days post-treatment of an acute angioedema attack. Plasma samples were tested for the presence of antibodies against plasma-derived C1INH and rhC1INH using 6 different, validated enzyme-linked immunosorbent assays (ELISAs), to detect IgM, IgG and IgA antibodies against plasma-derived C1INH or rhC1INH. Antibodies against HRI in plasma samples were measured in an ELISA testing for all antibody classes. Plasma samples from normal healthy controls and HAE patients, never exposed to rhC1INH, were used to estimate cut off levels of the assays. Plasma samples with antibody levels above the cut-off level in the screening assays were tested in confirmatory displacement assay in case of anti-HRI antibodies and in an assay for neutralizing antibodies in case of antibodies against C1INH.ResultsData from 155 symptomatic HAE patients having received a total of 424 administrations of rhC1INH were analyzed. The frequency of anti-C1INH antibody levels above the assay cut-off was low and similar in pre- and post-exposure samples (1.7 and 1.8%, respectively). Results above the assay cut-off were sporadic and transient. Occurrence of anti-C1INH antibodies did not correlate with repeated treatment or time since last treatment. No neutralizing antibodies were detected. A total of 5/155 (3%) rhC1INH-treated patients had confirmed anti-HRI antibodies; these included 1 patient with presence of anti-HRI antibodies prior to exposure to rhC1INH. The presence of anti-C1INH and anti-HRI antibodies was not associated with clinical symptoms. The presence of anti-C1INH antibodies did not affect clinical efficacy.ConclusionsrhC1INH used for the treatment of acute HAE attacks has a low potential to induce antibodies and has a reassuring immuno-safety profile.

Standard care impact on angioedema because of hereditary C1 inhibitor deficiency: a 21-month prospective study in a cohort of 103 patients

Hereditary angioedema (HAE) due to the deficiency of C1 inhibitor (C1-INH) causes chronically recurrent cutaneous, abdominal and laryngeal angioedema that are disabling and potentially life-threatening. We designed a prospective study to quantify the residual disease in patients with HAE treated according to the existing consensus documents. Data were collected from diaries recording occurrence, duration, location and treatment of acute angioedema attacks. A total of 386 semesters properly completed were analyzed. Forty-seven of 103 patients were on prophylactic treatment, 41 with attenuated androgens and six with tranexamic acid. A total of 1532 angioedema attacks (one every 45.3 days) were registered. Peripheral attacks were the most frequent (698), followed by abdominal (503) and combined locations (232), laryngeal edema was less common (99). Patients on prophylaxis with attenuated androgens had 7.7 attacks/year lasting 1.47 days, those on tranexamic acid had 8.1 attacks/year lasting 1.59 days, and those without prophylaxis had 8.9 attacks/year lasting 1.68. Plasma-derived C1-INH was used by 44 patients to treat a total of 376 acute attacks that resolved faster (1.1 day) than those not treated (1.85 day) or treated with tranexamic acid (1.79 day). No adverse events related to C1-INH infusion were reported. Our data demonstrate that tranexamic acid is not effective in the treatment of acute attacks and indicate that under the current therapeutic approach, the HAE related disability is effectively but partially reduced. Incomplete success does not appear to depend on limited efficacy of the drugs but on their limited use that can be overcome by implementing specific treatment strategies.

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.

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.

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.

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.

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.