icatibant and Angioedemas--Hereditary

Topics: Adolescent; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Child; Humans; Treatment Outcome

Hereditary angioedema (HAE) is a disorder affecting bradykinin regulation presenting as recurrent cutaneous or mucosal swelling. Treatment options include plasma-derived or human-recombinant C1-inhibitor, icatibant, or ecallantide. Due to the lack of knowledge and experience on the topic, the treatment of choice in pregnancy is plasma-derived C1-inhibitor, and reporting any new experience is recommended. This review presents current guidelines for HAE treatment with a focus on pregnancy and reviews all experience with icatibant use during pregnancy.. Our experience of treating a pregnant nC1-INH HAE patient with icatibant is presented, with no adverse effects or abnormalities, to add to the growing knowledge of icatibant use during pregnancy. Considering the limited number of attacks that our patient usually experiences, which continued at more or less the same frequency during pregnancy, we feel icatibant to be a safe choice for on-demand HAE treatment during pregnancy for such cases.

Topics: Angioedemas, Hereditary; Bradykinin; Complement C1 Inhibitor Protein; Female; Humans; Pregnancy; Treatment Outcome

Hereditary angioedema (HAE) is characterized by unpredictable, recurring and painful swelling episodes that can be disabling or even life-threatening. Awareness of HAE has progressively grown worldwide, and options for treatment of acute attacks and prevention of future attacks continue to expand; however, unmet needs in diagnosis and treatment remain. In Japan, recognition of HAE within the medical community remains low, and numerous obstacles complicate diagnosis and access to treatment. Importance of timely treatment of HAE attacks with on-demand therapies is continually demonstrated; recommended agents per the WAO/EAACI treatment guidelines published in 2018 include C1 inhibitor (C1-INH) concentrate, ecallantide, and icatibant. In Japan, multiple factors contribute to delayed HAE treatment (potentially leading to life-threatening consequences), including difficulties in finding facilities at which C1-INH agents are readily available. Recognition of challenges faced in Japan can help promote efforts to address current needs and expand access to effective therapies. Icatibant, a potent, selective bradykinin B

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Disease Management; Disease Progression; Disease Susceptibility; Humans; Japan; Practice Guidelines as Topic; Public Health Surveillance; Treatment Outcome

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.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Humans; Kallikrein-Kinin System; Peptides; Recombinant Proteins

Topics: Angioedemas, Hereditary; Antibodies, Monoclonal, Humanized; Biological Therapy; Bradykinin; Complement C1 Inhibitor Protein; Humans; Kallikreins; Peptides; Receptor, Bradykinin B2; Recombinant Proteins

Acquired angioedema with C1-inhibitor deficiency is a rare and peculiar entity belonging to the spectrum of bradykinin angioedemas. It usually occurs in subjects over 60 years old, and is mostly associated with a B-cell lymphoid hemopathy or a monoclonal gammopathy. The diagnosis relies on at least one angioedema episode, lasting more than 24 h, and on the decrease of functional C1-inhibitor. Low C1q is observed in 90% of patients, and an anti C1-inhibitor antibody is found in 50% of patients. The treatment of severe attacks relies on icatibant or C1-inhibitor perfusions. Long term prophylaxis in patients with frequent attacks requires treatment of the associated hemopathy if so. In case of idiopathic angioedema, tranexamic acid and danazol may be used, provided that there is-no thrombophilia; as well as rituximab as second-line treatment. Inhibitors of kallikrein still need to be evaluated in this therapeutic indication.

Topics: Angioedema; Angioedemas, Hereditary; Bradykinin; Chemoprevention; Comorbidity; Diagnosis, Differential; Diagnostic Techniques and Procedures; France; Hematologic Diseases; Humans; Internal Medicine; Middle Aged; Reference Standards; Rituximab; Societies, Medical; Tranexamic Acid

Hereditary angioedema (HAE) is a rare group of genetic disease characterized by non-itchy swelling of subcutaneous and submucosal tissues of the extremities, genitalia, gastrointestinal tract, and upper airways, which can be life threatening. Moreover, unpredictability and recurrence of HAE attacks significantly affect patients' quality of life. Short- and long-term prophylaxis is used to decrease the severity and frequency of attacks, but during severe or potentially severe acute episodes, treatment with C1-INH replacement or icatibant is mandatory. Icatibant is a selective bradykinin B2 receptor antagonist that has been licensed for self-administration at home, resulting in earlier treatment of the attack and quicker recovery, less emergency admittance with a significant improvement of patients' quality of life, and decrease of health care costs. The authors present a case of a young woman, affected by Type I HAE, who has been successfully treated with icatibant on demand at home, resulting in reduction of emergency admissions and improvement of quality of life. The authors also review the different types HAE, their clinical aspects, diagnosis, and management.

Topics: Acute Disease; Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Female; Humans; Self Administration

Hereditary angioedema is characterized by severe, episodic edema of the subcutaneous and mucosal tissue. The disease carries significant morbidity and mortality due to involvement of the gastrointestinal tract and upper airway. Recent advances in the treatment of hereditary angioedema include new techniques used to isolate and purify human-derived C1 inhibitor, the production of a recombinant form of C1 inhibitor, and the development of drugs that target the kallikrein-kinin pathway. This paper reviews the mechanisms, efficacy, and adverse reactions associated with these medications.

Topics: Angioedemas, Hereditary; Bradykinin; Complement C1 Inhibitor Protein; Humans; Peptides

Hereditary angioedema (HAE) is a rare genetic disease defined by recurrent attacks of edema, causing a substantial burden for patients, with morbidity, mortality, and reduced quality of life. This burden is increased by delayed diagnosis, inappropriate treatment, and suboptimal follow-up and patient education. Several novel therapeutics have recently been approved or are currently under evaluation for prevention of HAE attacks.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Humans; Kallikreins; Peptides; Recombinant Proteins

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a genetic disorder that clinically manifests with attacks of angioedema in the subcutaneous and submucosal tissues, mainly in the extremities, abdomen, and upper airway. During attacks, vascular permeability is increased due to increased bradykinin (BK). This means that special therapies are needed for attacks that do not respond to traditional antiallergic therapies involving antihistamines, corticosteroids, and epinephrine. The recurring attacks may disable patients and lead to frequent visits to emergency rooms where misdiagnoses are common. HAE attacks may be fatal when upper-airway edema occurs, if proper treatment with a C1 inhibitor concentrate or BK receptor antagonist is not administered or an emergency tracheostomy is not performed. We propose a mnemonic method for the warning signs of HAE for the use as a diagnostic tool, i.e., the so-called "ABC" of the warning signs of HAE. The letters represent the following: A = Angioedema, B = Bradykinin, C = C1 inhibitor, D = Distress factors, E = Epinephrine nonresponsive, F = Family history, and G = Glottis/Gastrointestinal edema. To avoid fatalities, medical staff and patients, including family members, must be aware of HAE. An alphabetical mnemonic method has been developed and we hope it may benefit patients.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Capillary Permeability; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Genetic Predisposition to Disease; Humans; Receptors, Bradykinin

To evaluate the place in therapy of fresh frozen plasma (FFP), C1 esterase concentrate (C1-INH), ecallantide, and icatibant in the management of angiotensin-converting enzyme inhibitor-induced angioedema (ACEI-IA).. A literature search was performed using PubMed (1946 through August 2015) and Embase (<1966 through August 2015). References from identified articles were reviewed.. Consensus papers, practice guidelines, case reports/series, clinical trials, and meeting abstracts published in English and involving humans were included.. No medications are currently Food and Drug Administration-approved for managing ACEI-IA. Emerging evidence suggests that FFP and medications approved for management of acute attacks of hereditary angioedema, another bradykinin-mediated event, may be effective for use in ACEI-IA. Positive efficacy results were reported with FFP and C1-INH while mixed results have been seen with ecallantide. Off-label icatibant has the most evidence supporting its use in ACEI-IA with rapid symptom resolution (10 minutes to 6 hours) and avoidance of intubation and tracheotomy in several cases. These agents were well-tolerated in ACEI-IA.. ACEI-IA is typically a self-limiting event. First-line therapies include ACEI discontinuation, observation, and supportive medications (eg, corticosteroids, antihistamines, and epinephrine). Symptom progression can be life-threatening and may require interventions such as tracheotomy and intubation. Off-label use of FFP and medications approved for hereditary angioedema have resulted in rapid resolution of symptoms and avoidance of intubation. Among these agents, icatibant has the most supporting evidence and has been incorporated into practice guidelines and algorithms as a second-line agent for serious life-threatening ACE-IA.

Topics: Angioedema; Angioedemas, Hereditary; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Complement C1s; Humans; Off-Label Use; Peptides; Plasma; United States

Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare disease, characterized by recurrent, unpredictable episodes of cutaneous and/or mucosal edema. Bradykinin, released by the activation of the contact system, binds to bradykinin B2 receptors on the endothelial cell surface to enhance vascular permeaility, which leads to angioedema.. C1-INH-HAE therapy is aimed at the inhibition of bradykinin release, as well as at the blockage of its effects mediated by its receptor. Three controlled trials, three open-label extensions, and two open-label studies, and a prospective, observational study have confirmed the safety and efficacy of the bradykinin B2 receptor antagonist, icatibant administered as acute treatment for HAE attacks in adult patients with C1-INH-HAE. Expert commentary: The ready-to-use, pre-filled syringes of icatibant can be self-administered easily, effectively, safely and, importantly, conviently. - This has resulted in patients being able to quickly treat an attack and realize a dramatic change for the better in their lives.

Topics: Adult; Angioedemas, Hereditary; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Humans; Receptor, Bradykinin B2; Self Administration

Hereditary angioedema (HAE) is a chronic disease with unpredictable and severe acute attacks that are potentially life threatening. The treatment of HAE has two main objectives: treat acute attacks and limit their occurrence in the short term and long term. The acute treatment should be administered as soon as possible for better efficiency and patient safety. Self-administration should be encouraged for greater patient autonomy and safety (reducing delay to receive treatment injection). Long-term prophylaxis treatments should be set up to limit acute attacks occurrences and finally improve patients' quality of life and safety. Short-term prophylaxis treatments are required and should be thoroughly applied in case of exposure to known potential triggers (surgery, dental care…). CREAK protocols are available. The HAE National Educational Therapeutic Program "Educreak" is in place to allow the patient and his close family or partners to acquire skills for greater autonomy in day to day disease management.

Topics: Angioedemas, Hereditary; Bradykinin; Chemoprevention; Complement C1 Inhibitor Protein; Humans; Patient Education as Topic; Prognosis

Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent attacks of self-limiting tissue swelling. The management of HAE has transformed dramatically with recently approved therapies in the United States. However, there is lack of awareness among physicians about these new modalities. The aim of this review is to update the practicing physician about various therapeutic options available for HAE patients. An exhaustive literature search of PubMed and OVID was performed to develop this article. Management of HAE is traditionally classified into treatment of acute attacks or on-demand therapy, short-term (preprocedural) prophylaxis, and long-term prophylaxis. Newer therapies include C1 esterase inhibitor (C1-INH) and contact system modulators, namely, ecallantide and icatibant. Recombinant C1-INH, which is available in Europe, is awaiting approval in the United States. C1-INH concentrate is approved for prophylaxis as well as on-demand therapy while ecallantide and icatibant are approved for acute treatment only. Effective HAE management further includes patient education, reliable access to specific medications, and regular follow-up to monitor therapeutic response and safety.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Humans; Peptides; Practice Guidelines as Topic

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.. 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.. 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 shorter time to beginning of relief of symptoms, time to minimal symptoms, the probability of the treatment response after 4 hours is increased, and the safety profile is comparable to placebo.. Due to significant heterogeneity of identified trials, the scientific evidence available was insufficient to point out the most effective therapeutic option in the treatment of acute oedemas in HAE.

Topics: Adult; Aged; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Humans; Middle Aged; Randomized Controlled Trials as Topic; Recombinant Proteins; Secondary Prevention; Treatment Outcome

Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a rare genetic disease characterized by recurrent swellings of the subcutaneous and submucosal tissues that can manifest as cutaneous edema, abdominal pain and laryngeal edema with airway obstruction. These symptoms have a significant impact on patients' quality of life. The reduction in C1-INH function leads to uncontrolled activation of the contact system and generation of bradykinin, the mediator of increased vascular permeability and edema formation. In the past, few treatment options were available; however, several new therapies with proven efficacy have recently become available to treat and prevent HAE attacks, such as plasma-derived and recombinant C1-INHs that replace the deficient protein, bradykinin receptor antagonist (icatibant) that blocks bradykinin activity and kallikrein inhibitor (ecallantide) that prevents bradykinin release. Such therapies can improve disease outcome. This article reviews the therapeutic management of HAE, which involves the treatment of acute attacks and prophylaxis.

Topics: Angioedemas, Hereditary; Bradykinin; Disease Management; Hereditary Angioedema Types I and II; Humans; Peptides; Treatment Outcome

To review the pharmacology, pharmacokinetics, clinical trials, and safety of icatibant, a recently approved bradykinin B(2) receptor antagonist for treatment of acute attacks of hereditary angioedema (HAE).. Articles indexed in MEDLINE (1948-June 2012), International Pharmaceutical Abstracts (1970-May 2012), and Cumulative Index to Nursing and Allied Health Literature (1981-June 2012) were identified using the search terms icatibant, bradykinin B(2) receptor antagonist, and hereditary angioedema. Additional references were identified from the reference lists of the articles identified.. English-language articles were reviewed.. Icatibant was evaluated in 3 Phase 3 clinical trials and found to be a safe and effective option for treatment of acute HAE. Icatibant was compared to placebo in 2 clinical trials (FAST-1 and FAST-3) and to tranexamic acid in the FAST-2 trial. Patients receiving icatibant in FAST-1 did not experience a significant improvement in median time to clinically significant relief of the index symptom (p = 0.14), whereas patients receiving icatibant in FAST-3 experienced a significant improvement in median time to at least 50% reduction in symptom severity (p < 0.001). When icatibant was compared to tranexamic acid in FAST-2, the median time to clinically significant relief of the index symptom was shorter for patients receiving icatibant (p < 0.001). The most common adverse events associated with the administration of icatibant were injection-site reactions, which were mild to moderate and transient. These data suggest that icatibant is a safe and effective treatment for acute attacks of HAE. Although direct comparisons of recently approved alternatives for treatment of acute attacks are lacking, there are administration advantages of icatibant over other agents. Additionally, the cost of icatibant is comparable to that of the C1 esterase inhibitor Berinert and less expensive than ecallantide.. Available efficacy data support that icatibant should be considered a safe and effective treatment for acute attacks of HAE. Additionally, limited treatment options for this rare condition, ease of administration, and comparable cost profile support its consideration for formulary inclusion.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin Receptor Antagonists; Clinical Trials, Phase III as Topic; Complement C1 Inhibitor Protein; Humans; Peptides; Tranexamic Acid

Hereditary angioedema (HAE) is a rare disorder generally caused by a deficit in the activity of C1-esterase inhibitor (C1-INH). Symptoms manifest as recurrent episodes of nonallergic, nonpruritic, and nonpitting edema. Attacks commonly occur on the extremities, trunk, genitalia, abdomen, or head and neck--the latter 2 locations are associated with the greatest morbidity and mortality. In the United States, there has been a considerable void in effective HAE treatments and emergency management guidelines. Clinical outcomes using agents such as fresh-frozen plasma, attenuated androgens (danazol), or plasmin inhibitors (aminocaproic acid) have not been ideal. Recent years have seen progress with US Food and Drug Administration (FDA) approval of several products for acute HAE treatment. Plasma concentrate of C1-INH has long been the treatment of choice in many parts of the world, and a pasteurized formula received FDA approval in October 2009 for treating attacks. Ecallantide, a plasma kallikrein inhibitor, and icatibant, a bradykinin receptor antagonist, were approved in December 2009 and August 2011, respectively, for treatment of acute attacks. A recombinant C1-INH product is in late development stages for treating acute attacks. These new treatments provide symptom relief within hours, dramatically shorten attack duration, and decrease mortality from airway compromise. For the first time, US physicians have rapid-acting and highly effective treatments for managing acute HAE attacks.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Emergency Treatment; Humans; Peptides; Practice Guidelines as Topic; United States

The 2 most commonly encountered primary immunodeficiency syndromes in adult practice are antibody deficiency disorders and hereditary angioedema.Immunologic therapy for these disorders has significantly improved patient management. Therapy with immunoglobulin leads to improvement in overall quality of life. With increasing survival rates and decreasing levels of life-threatening infections in patients with primary antibody deficiencies, disease complications are more commonly encountered. Treatment of these complications with monoclonal antibody therapy seems promising and is likely to increase in the future. More recently,several additional agents have become available, including novel drugs targeted at different elements of the disease process.

Topics: Adrenergic beta-Antagonists; Anemia, Hemolytic, Autoimmune; Angioedemas, Hereditary; Bradykinin; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Cost-Benefit Analysis; Delayed Diagnosis; Disease Transmission, Infectious; Filtration; Granuloma; Home Infusion Therapy; Humans; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Immunization, Passive; Immunoglobulin G; Immunoglobulins; Immunologic Deficiency Syndromes; Infections; Kallikreins; Nanotechnology; Peptides; Purpura, Thrombocytopenic, Idiopathic; Quality Control; Quality of Life; Recombinant Proteins; Self Administration; Technology, Pharmaceutical

The aim of treatment of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (HAE-C1-INH) is either treating acute attacks or preventing attacks by using prophylactic treatment. For treating acute attacks, plasma-derived C1 inhibitor (C1-INH) concentrates, a bradykinin B2 receptor antagonist, and a recombinant human C1-INH are available in Europe. In the United States, a plasma-derived C1-INH concentrate, a bradykinin B2 receptor antagonist, and a plasma kallikrein inhibitor have been approved. Fresh frozen plasma is also available for treating acute attacks. Short-term prophylactic treatment focuses on C1-INH and attenuated androgens. Long-term prophylactic treatments include attenuated androgens such as danazol, stanozolol, and oxandrolone, antifibrinolytics, and a plasma-derived C1-INH concentrate. Plasma-derived C1-INH and a bradykinin B2 receptor antagonist are permitted for self-administration and home therapy. The number of management options has increased considerably within the last few years, thus helping to diminish the burden of HAE.

Topics: Angioedemas, Hereditary; Bradykinin; Complement C1 Inhibitor Protein; Danazol; Disease Management; Humans; Oxandrolone; Peptides; Plasma; Recombinant Proteins; Stanozolol

Hereditary angioedema (HAE) is a potentially life-threatening autosomal dominant disease characterized by recurrent episodes of oedema, commonly occurring in the skin, abdomen, and upper respiratory tract. After many years during which limited treatment options were available, a range of newer therapies with proven efficacy have been approved in Europe by the European Commission for the treatment of HAE attacks. However, due to differing legislation and financial restrictions, these treatment options are not available in all countries. Home therapy and self-administration of treatment are recommended in order to minimize the burden of disease upon the patient, with the ideal treatment option being effective, well-tolerated, and easy to prepare and administer. Recently, the Hereditary Angioedema International Working Group (HAWK) consensus recommended early, on-demand treatment for HAE. This article reviews the current treatment options available, and considers the need for treatment guidelines to recommend the appropriate therapy.

Topics: Airway Obstruction; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Costs and Cost Analysis; Europe; Health Knowledge, Attitudes, Practice; Hospitalization; Humans; Insurance Coverage; Insurance, Pharmaceutical Services; Legislation, Drug; Peptides; Practice Guidelines as Topic; Practice Patterns, Physicians'; Self Administration

Hereditary Angioedema (HAE) is a rare disease characterized by recurrent, self-limiting episodes of swelling. New therapies have recently emerged and are now available; however, many physicians are not aware of the new medications, and their indications and contraindications.. To update allergists and primary care physicians on new advances in HAE therapies.. A PubMed literature search was used to develop this manuscript.. English language peer-reviewed angioedema articles were selected. High quality Phase II and III placebo-controlled clinical trials were reviewed and summarized.. Until 2008, therapy for HAE consisted of symptom relief with narcotics, hydration and fresh frozen plasma (FFP). Androgens and FFP are frequently used despite multiple, significant side effects. Newer therapies include C1-inhibitor--both human plasma derived and recombinant--as well as contact system modulators such as ecallantide and icatibant. All of these products can be used for treatment of acute attacks of HAE, and C1-inhibitors can also be used for prophylaxis.. New, disease-specific therapies have recently emerged which are more efficacious, are proven to work by placebo-controlled studies, have minimal adverse effects, and can be utilized for the treatment of HAE.

Topics: Androgens; Angioedemas, Hereditary; Bradykinin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Complement C1 Inhibitor Protein; Databases, Bibliographic; Drug Administration Schedule; Humans; Narcotics; Peptides; Placebos; Plasma; Recombinant Proteins

To review and update the management and understanding of hereditary angioedema (HAE), while integrating insights into pediatric subtleties that exist in practice.. Major advances have recently been made in HAE treatment. Ecallantide (a kallikrein inhibitor approved for use in the United States in December 2009) and icatibant (a selective bradykinin B2 receptor antagonist approved for use in the United States in August 2011) represent novel subcutaneous therapies for acute HAE exacerbations. Recombinant human C1 esterase inhibitor (C1INH) serves as a promising future alternative to current mainstay acute and prophylactic treatment with plasma-derived C1INH. Recent guidelines have outlined new algorithms for short-term and long-term prophylaxis against HAE exacerbations.. The evolving standard of care for HAE management involves not only treatment of acute exacerbations but also individualized patient preference-sensitive short-term and long-term prophylaxis. Updated international consensus guidelines provide useful protocols, whereas recent clinical reviews have raised awareness of HAE. Further advances will likely focus on improving patient access to convenient acute and prophylactic treatment with C1INH.

Topics: Adolescent; Algorithms; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Child; Child, Preschool; Complement C1 Inhibitor Protein; Evidence-Based Medicine; Female; Humans; Infant; Kallikreins; Male; Peptides; Practice Guidelines as Topic; Treatment Outcome; United States

Hereditary angioedema (HAE) is a rare autosomal dominant disease characterized by episodic swelling of the face, extremities, larynx, gastrointestinal tract or genitals. Three different subtypes have been identified so far. Type I and II HAE are caused by mutations in the C1 inhibitor gene leading to decreased or dysfunctional C1 inhibitor, respectively. Type III is caused by a mutation in the coagulation factor XII. In addition, acquired forms or forms with no known etiology exist. Increased bradykinin production leading to increased vessel permeability is common to all HAE types. Treatment of HAE has evolved dramatically during the last years as self-administration of C1 inhibitor concentrate and bradykinin-2 receptor antagonist icatibant have become available.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Factor XII; Humans; Mutation

Androgen derivatives are regarded as standard in the long-term prophylaxis of swelling attacks in patients with hereditary angioedema (HAE). Because of their relatively slow onset of action, they are not suitable for acute therapy. Long-term prophylaxis with androgen derivatives must be regarded critically, especially on account of their androgenic and anabolic effects, some of which are severe. The risk of adverse events increases with the daily dose and the duration of treatment. Thus, treatment always calls for close monitoring of patients with regard to potential adverse events. In addition, androgens are subject to numerous contraindications and they show interactions with a large number of other drugs. Off-label use, doping issues, clarification of reimbursement and the need to import the androgen derivatives, which are no longer marketed in Germany, result in additional effort for the treating physician in terms of logistics and time involved. In symptomatic treatment of acute attacks the intravenous substitution of C1-INH and - since 2008 - subcutaneous administration of icatibant are available. The two substances are well tolerated and their effect occurs rapidly and, when the diagnosis has been confirmed, reliably. In the light of these two treatment options for controlling acute attacks, prophylactic treatment of HAE patients with androgen derivatives such as danazol should be reassessed. Patients might benefit from a dose reduction or the withdrawal of androgen prophylaxis and attacks can be controlled with demand-oriented acute treatment using C1-INH or icatibant.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Dose-Response Relationship, Drug; Humans; Longitudinal Studies; Testosterone Congeners; Treatment Outcome

Hereditary angioedema (HAE) is characterized by acute attacks of edema with multiple localizations, the laryngeal angioedema being the most potentially lethal. In HAE, C1-INH impairments cause episodic increase in kallikrein activity leading to attacks of angioedema. Several therapies have recently become available to treat or to prevent HAE attacks, and others are under evaluation for this indication. Plasma-derived C1-INH, bradykinin receptor antagonists (icatibant), kallikrein inhibitors (ecallantide), or recombinant C1-INH is authorized on the market for HAE attack therapy or prophylaxis. Some of these compounds can be used exclusively to treat HAE attacks, whereas others can also be used as prophylactic therapies. Such therapies, although not available worldwide, can improve disease outcome due to their different mechanisms of action.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Clinical Trials as Topic; Complement C1 Inhibitor Protein; Disease Progression; Humans; Kallikreins; Peptides; Recombinant Proteins

Hereditary angioedema (HAE) is a rare condition. Its prognosis depends on whether there is laryngeal involvement with a risk of asphyxia, which is present in 25% of such cases. Improved understanding of the pathophysiology of this disease has resulted in the development of targeted therapies including icatibant, which acts as an antagonist at bradykinin B2 receptors. This agent has been shown to be effective in the treatment of attacks of HAE in three Phase III randomized double-blind published studies. Efficacy data have been collected in all types of attack: cutaneous, abdominal and laryngeal. Safety data are also encouraging. Icatibant is administered subcutaneously, with the potential for patients to self-administer. In the future, this therapy may offer increased independence for HAE patients.

Topics: Angioedemas, Hereditary; Bradykinin; Clinical Trials, Phase III as Topic; Double-Blind Method; Humans; Randomized Controlled Trials as Topic; Vasodilator Agents

A short-cut review was carried out to establish whether icatibant is effective in the treatment of hereditary angioedema. A total of 168 papers were found using the reported search, of which one represented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of this best paper are tabulated. The clinical bottom line is there is promising evidence for the use of the bradykinin receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema.

Topics: Adolescent; Adrenergic beta-Antagonists; Angioedemas, Hereditary; Bradykinin; Evidence-Based Medicine; Female; Humans

Icatibant (Firazyr(®)) is a novel subcutaneous treatment recently licensed in the European Union for acute hereditary angioedema. Hereditary angioedema, resulting from inherited partial C1 inhibitor deficiency, is a disabling condition characterized by intermittent episodes of bradykinin-mediated angioedema. Icatibant blocks bradykinin B2 receptors, attenutating the episode. Randomized double-blind, placebo-controlled trials of icatibant, showed significant superiority over oral tranexamic acid in 74 European patients and a trend to improvement in a similar US trial comparing icatibant with placebo in 55 patients. Outcomes for several endpoints did not reach significance in the US trial, perhaps because of low participant numbers and confounding factors: a further trial is planned. Open label studies have shown benefit in multiple treatments for attacks at all sites. Approximately 10% of patients require a second dose for re-emergent symptoms, usually 10 to 27 hours after the initial treatment. Its subcutaneous route of administration, good tolerability and novel mode of action make icatibant a promising addition to the limited repertoire of treatments for hereditary angioedema.

Topics: Acute Disease; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Humans; Injections, Subcutaneous; Randomized Controlled Trials as Topic; Secondary Prevention

Hereditary angioedema is a severe genetic disorder due to C1 esterase inhibitor deficiency, which leads to an excess of bradykinin. It is characterised by attacks of subcutaneous or mucosal oedema, which can carry a risk of asphyxiation if the larynx is involved. The first-choice symptomatic treatment for attacks is intravenous C1 esterase inhibitor administration. Tranexamic acid is sometimes used. Icatibant, a decapeptide bradykinin B2 receptor antagonist, is now authorised in the European Union for use in this situation. We found no trials comparing icatibant versus C1 esterase inhibitor. The two principal clinical trials were both comparative trials, one versus tranexamic acid (74 patients), and the other versus placebo (56 patients). No mortality data were reported in either trial. Icatibant seemed to be more effective than tranexamic acid in relieving symptoms and also yielded a higher response rate. However, these positive results were not confirmed in the placebo-controlled trial. Both trials suffer from several biases, ruling out firm conclusions on the efficacy of icatibant, the trials were underpowered, some criteria were difficult to measure, the blinding was incomplete, and tranexamic acid was given at a lower dose than that recommended. The main adverse effects of icatibant are reactions at the injection site, which occur in almost all patients. A potential risk of cardiac disorders (especially angina) needs to be investigated. Subcutaneous administration of icatibant requires a large volume of solution (3 ml). In practice, in the absence of head-to-head comparisons, it remains to be shown whether or not icatibant has a better risk-benefit balance than C1 esterase inhibitor. Due to inconsistencies between the results and numerous biases in the two main clinical trials, the evidence supporting the efficacy of icatibant is weak. C1 esterase inhibitor remains the first-choice treatment for patients with acute attacks of hereditary angioedema.

Topics: Adrenergic beta-Antagonists; Angioedemas, Hereditary; Bradykinin; Complement C1 Inactivator Proteins; Complement Inactivating Agents; Humans; Randomized Controlled Trials as Topic

To determine when newer agents, such as C1 esterase inhibitor protein (C1-INH), should be considered as prophylaxis to decrease hereditary angioedema (HAE) attacks as an alternative to androgens, which have significant adverse events.. A literature review (PubMed, Google, and Ovid), guideline review, expert panel meeting, and group discussion were performed to decide when prophylaxis is indicated.. Articles addressing HAE therapy published in the peer-reviewed literature were selected.. The retrieved studies demonstrate that C1-INH is effective and that the half-life makes it attractive for prophylactic use. The short half-lives of ecallantide, icatibant, and recombinant human C1-INH limit their use as prophylactic agents. Patients with severe anxiety, more than 1 attack per month, rapid progression of attacks, limited access to health care, more than 10 days lost from work or school per year, previous laryngeal swelling, more than 3 emergency department visits per year, more than 1 hospitalization per year, previous intubation, previous intensive care unit care, significant compromise in quality of life, or narcotic dependency should be considered for androgen or C1-INH prophylaxis therapy.. Patients with HAE with frequent attacks, severe attacks, past laryngeal attacks, excessive loss of work or school, significant anxiety, and poor quality of life should be considered for C1-INH prophylaxis, especially those who fail, are intolerant of, have adverse reactions to, or are not candidates for androgen therapy.

Topics: Androgens; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Clinical Trials as Topic; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Humans; Kallikreins; Mortality; Peptides

Hereditary angioedema (HAE) is an autosomal dominant, potentially life-threatening disease, characterized by recurrent self-limiting bouts of edema mainly involving the extremities, genitalia, face, intestines and airways. The prevalence of HAE in the general population has been estimated to be in the range of 1:10,000 to 1:150,000. Currently, acute attacks of HAE are treated mainly symptomatically, with poor outcomes. Recently, it has been demonstrated that bradykinin (BK) is responsible for most of the symptoms of HAE. Icatibant (Firazyr, HOE 140, JE049) is a potent, specific and selective B2 BK receptor antagonist that has recently been approved by the EMEA for the treatment of HAE. In phase III clinical trials, 30 mg of subcutaneous icatibant demonstrated rapid and stable relief from symptoms in cutaneous, abdominal or laryngeal HAE attacks. Local site reactions after subcutaneous injection of icatibant were observed, however, these reactions were mild to moderate in severity and resolved spontaneously and quickly. Icatibant is a new, safe and effective treatment for acute attacks of HAE.

Topics: Angioedemas, Hereditary; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans

There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Humans; Kallikrein-Kinin System; Respiratory Tract Diseases

Hereditary angioedema (HAE) is an autosomal-dominant condition, characterized by episodic recurrent attacks of angioedema, which can be occasionally life-threatening. Therapy for HAE consists of three points: treatment of acute attacks and both short- and long-term prophylaxis. Authors describe the methods which should be performed during the attacks of angioedema and drugs for those situations. Besides we describe the main rules of prophylaxis including potentially triggering events. Finally authors present future therapeutic options including new drugs being in clinical trial at present. In the near future, such drugs will be available to provide more effective treatment for HAE attacks with fewer adverse effects than the currently available treatment options.

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Complement C1 Inhibitor Protein; Female; Humans; Kallikreins; Male; Primary Prevention; Recombinant Proteins

Hereditary angioedema is a rare genetic disorder, manifested by recurrent edema leading to disfigurement, organ dysfunction and life-threatening respiratory impairment that may become fatal. The hallmark of HAE is C1 esterase inhibitor deficiency, but recent evidence points at bradykinin as the main mediator that causes hyperpermeability of small vasculature, leading to accumulation of edema fluid. Current therapeutic options for HAE are limited, and consist of drugs, replacement therapy, and supportive treatment. In view of many disadvantages of the current therapeutic modalities, new approaches to the treatment of HAE are now being offered. This review summarizes our experience with a new line of medications developed for the treatment of acute exacerbations and prophylaxis of HAE--icatibant: bradykinin receptor antagonist, ecallantide: kallikrein inhibitor, and two C1 INH preparations: Berinert-P, human plasma-derived concentrate, and Rhucin: novel recombinant C1-INH produced in transgenic rabbits. Preliminary results of these studies are encouraging and may bring new hope to the patients with this distressing condition. The exact number of HAE patients in Israel is unknown and because patients are treated individually and comprehensive laboratory assessment is partial, many cases might be missed or not treated according to accepted guidelines. We offer a new specialty center for HAE patients, addressing the medical and psychosocial needs of patients and their families.

Topics: Abdominal Pain; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Kallikreins; Male; Multicenter Studies as Topic; Nausea; Peptides; Treatment Outcome

To review the evolution of our understanding of hereditary angioedema (HAE) from the first historical reference to the present day.. MEDLINE and PubMed were searched using the following keywords: history of HAE, C1 inhibitor, complements system, genetics of HAE, mechanisms of HAE, and treatment of HAE.. Information was selected that outlines the advances made in complementology, the first report of HAE, and subsequent studies that elucidated the underlying mechanisms of this disease, leading to current therapy of this orphan disease.. Generational research efforts in HAE have focused on the following: (1) several new clinical presentations, (2) acquired forms of non-histamine-induced angioedema, (3) the genetic basis for the inherited forms, (4) the effects of C1 inhibitor on contact phases of coagulation-fibrinolytic pathways, and (5) various therapies for short- and long-term control of the disease.. The progress made in understanding the pathogenesis and treatment of HAE is an excellent example of the "bench to the bedside" paradigm involving the collaboration between clinicians and researchers.

Topics: Adrenergic beta-Antagonists; Angioedemas, Hereditary; Animals; Bradykinin; Clinical Trials as Topic; Complement C1 Inactivator Proteins; Complement C2; Danazol; Disease Models, Animal; Factor XIIa; Genetic Linkage; Humans; Kallikreins; Mice; Peptides; Research

To provide a comprehensive overview on clinical trial design and results of emerging therapies for the treatment of hereditary angioedema (HAE).. MEDLINE or PubMed literature searches were conducted to identify double-blind, placebo-controlled trials investigating C1 esterase replacement, kallikrein inhibitor, and bradykinin receptor 2 antagonist therapies.. Ongoing trials or those just recently completed from all companies developing a product for the treatment of HAE are discussed.. All of these agents are believed to be effective when tested in patients in phase 1 or phase 2 trials. The studies have many features in common, including being placebo-controlled and blinded; having a preliminary screening visit at which the diagnosis is confirmed; having either low circulating C1 inhibitor protein levels or low levels of functional C1 inhibitor, low C4 levels, and normal C1q levels; enrolling individuals who are relatively early in attacks (4-6 hours from the onset); and stipulating that patients continue taking the medications that they have been taking in the long term. The type of attack acceptable for each treatment protocol varies from study to study. Some allow peripheral edema attacks, some facial attacks, and in some studies, the Food and Drug Administration has allowed purified serum C1 inhibitor to be used as a rescue medication if the patient remains in difficulty after the study drug has been used and found to be ineffective.. The outlook for new, effective short-term therapy appears to be excellent. In the near future, a whole new therapeutic armamentarium to care for patients with HAE should be available in the United States.

Topics: Angioedemas, Hereditary; Animals; Animals, Genetically Modified; Bradykinin; Bradykinin Receptor Antagonists; Clinical Trials as Topic; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Complement C1q; Complement C4; Double-Blind Method; Humans; Injections, Intravenous; Injections, Subcutaneous; Kallikreins; Rabbits; Receptors, Bradykinin; Recombinant Proteins; United States

To provide an overview on the current status of emerging therapies for hereditary angioedema (HAE) in the United States.. Summary statements were obtained from each pharmaceutical company regarding their agent.. Each agent is undergoing or has completed phase 3, double-blind, placebo-controlled trials.. Berinert P, a purified, virus-inactivated, human plasma-derived C1 inhibitor (C1-INH) concentrate, is being investigated in 2 international, multicenter, prospective trials. Experience with this agent in Europe and Canada indicates it is effective and safe. Cinryze is a nanofiltered C1-INH replacement therapy demonstrated to be effective and safe in acute and prophylactic arms of a phase 3, double-blind, placebo-controlled study. Rhucin, a recombinant human C1-INH replacement therapy from transgenic rabbits, has been shown to be effective and safe in phase 2 and phase 2/3 studies, with an additional phase 3 study ongoing. DX-88 or ecallantide, a potent and specific inhibitor of plasma kallikrein, achieved all primary and secondary efficacy end points in a placebo-controlled, double-blind, phase 3 study, with a second phase 3 study ongoing. Icatibant, a potent and specific peptidomimetic bradykinin 2 receptor antagonist, was studied in 2 phase 3 trials: FAST 1 (For Angioedema Subcutaneous Treatment) did not achieve statistical significance for the primary end point but did so for secondary end points, whereas FAST 2 achieved statistical significance for primary and secondary end points.. The future treatment of HAE in the United States appears promising based on progress being made in drug development for this orphan disease.

Topics: Adrenergic beta-Antagonists; Angioedemas, Hereditary; Animals; Animals, Genetically Modified; Attention; Bradykinin; Clinical Trials, Phase III as Topic; Complement C1 Inhibitor Protein; Controlled Clinical Trials as Topic; Filtration; Global Health; Humans; Kallikreins; Nanoparticles; Peptides; Rabbits; Recombinant Proteins; Treatment Outcome

ACE-inhibitor induced angioedema is a non-allergic drug-related side effect. Inhibited bradykinin degradation leads to an unphysiological enhanced bradykinin plasma level with vascular leakage and, consequently, to angioedema. ACE-inhibitor induced angioedema develop rapidly in the head and neck region. Typical sites of manifestation are lips, tongue, and larynx. Novel pharmacotherapies may allow a causal treatment of the ACE-inhibitor induced angioedema in the future.

Topics: Adrenal Cortex Hormones; Algorithms; Angioedema; Angioedemas, Hereditary; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Bradykinin Receptor Antagonists; Forecasting; Histamine Antagonists; Humans; Laryngeal Edema; Laryngoscopy; Magnetic Resonance Imaging; Time Factors; Tomography, X-Ray Computed

We evaluated the safety, efficacy, and pharmacokinetics of subcutaneous weight-adjusted icatibant for the treatment of acute hereditary angioedema attacks in Japanese pediatric patients. Two patients (aged 10-13 and 6-9 years) received icatibant for a total of four attacks. Each attack was abdominal and/or cutaneous and was treated with a single icatibant injection. Mild or moderate injection-site reactions were the only adverse events reported. Time to onset of symptom relief was 0.9-1.0 h. Icatibant was rapidly absorbed, with a pharmacokinetic profile consistent with previous studies. Simulated exposure levels were consistent with non-Japanese pediatric patients. These results support the safety and efficacy of icatibant in Japanese pediatric patients.

Topics: Adolescent; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Child; East Asian People; Humans; Injections, Subcutaneous; Treatment Outcome

Hereditary angioedema (HAE) is a genetic disease characterized by recurrent swelling episodes affecting the skin, gastrointestinal mucosa, and upper respiratory tract.. A phase 3, single-arm, open-label study was performed to evaluate a selective bradykinin B. Eight patients who had an attack affecting the skin (n = 4), abdomen (n = 3), or larynx (n = 1) were treated with icatibant (3 of the injections were self-administered). The median time to onset of symptom relief was 1.75 h (95% confidence interval, 1.00-2.50), and all patients had symptom relief within 5 h after administration. The time to maximum plasma concentration of icatibant was 1.79 h, and the maximum plasma concentration was 405 ng/ml. Seven patients experienced an injection site reaction, and 3 patients had adverse events (2 patients had a worsening or repeat HAE attack 29.0 and 18.3 h after icatibant administration, respectively, and 1 had headache).. Although the number of patients is small, the efficacy and tolerability of icatibant for acute attacks were demonstrated in Japanese patients with HAE, regardless of self-administration or administration by healthcare professional.

Topics: Acute Disease; Adult; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Disease Progression; Female; Humans; Injections, Subcutaneous; Japan; Male; Middle Aged; Self Administration; Treatment Outcome

Icatibant, a selective bradykinin B2 receptor antagonist for the treatment of acute hereditary angio-oedema (HAE) attacks in adults, can be administered by health care professionals (HCPs) or self-administered. This analysis compared characteristics and outcomes of acute HAE attacks treated with self-administered and HCP-administered icatibant in a real-world setting.. The Icatibant Outcome Survey (Shire, Zug, Switzerland; NCT01034969) is an international observational study monitoring the safety and effectiveness of icatibant treatment. Descriptive retrospective analyses were performed (February 2008 to December 2012).. Icatibant was used in 652 attacks in 170 patients with HAE type I/II. Most icatibant injections were self-administered (431/652, 68.5%). The proportion of self-treated attacks increased over time (40.3% in 2009 vs. 89.7% in 2012). The median time to administration was significantly shorter in self- versus HCP-treated attacks (1.5 vs. 2.4 h; p = 0.016). Earlier treatment (<2 h after onset) was significantly associated with a shorter median time to resolution (2.5 vs. 5.0 h; p = 0.032) and attack duration (3.0 vs. 14.0 h; p < 0.0001), regardless of administration method. Patients self-administered icatibant for attacks of all severities; overall, 34.7% of severe and 30.2% of very severe attacks were HCP treated. Logistic regression analysis did not find use of long-term prophylaxis, attack location or gender to be predictive for self-administration.. The proportion of HAE attacks treated with self-administered icatibant increased over time. Patients successfully self-administered icatibant for a wide variety of HAE attacks, demonstrating that icatibant is generally well tolerated and effective for self-administration. Self-administration of icatibant provides a complementary option to HCP administration, enabling optimization of patient care.

Topics: Adolescent; Adult; Aged; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Data Collection; Female; Humans; Male; Middle Aged; Prospective Studies; Retrospective Studies; Self Administration; Treatment Outcome; Young Adult

In randomized, controlled, double-blind, multicenter phase 3 studies, one icatibant injection was efficacious and generally well tolerated in patients with a single hereditary angioedema (HAE) attack. Here, the efficacy and safety of icatibant for multiple HAE attacks was evaluated across the controlled and open-label extension phases of the For Angioedema Subcutaneous Treatment (FAST)-3 study (NCT00912093).. In the controlled phase, adults with HAE type I or II were randomized (1:1) to receive a single subcutaneous injection of icatibant 30 mg or placebo within 6 h of an attack becoming mild (laryngeal) or moderate (cutaneous/abdominal). Open-label icatibant was administered for severe laryngeal symptoms. In the open-label extension phase, patients could receive up to three icatibant injections per attack. Efficacy and safety were analyzed for the first five icatibant-treated attacks at any location (prospective analysis) and laryngeal attacks (post hoc analysis) across both phases. Efficacy outcomes were based on patient-reported symptom severity (visual analog scale).. In groups of patients with one to five icatibant-treated attacks at any location (n = 88), the median times to onset of symptom relief, onset of primary symptom relief and almost complete symptom relief were 1.9-2.1, 1.5-2.0 and 3.5-19.7 h, respectively. The same outcomes for laryngeal attacks (n = 25) were 1.0-2.0, 1.0-2.0 and 1.5-8.1 h, respectively. The most frequently reported adverse events were a worsening or recurrence of HAE attack, headache and nasopharyngitis. Two serious adverse events (arrhythmia and noncardiac chest pain) were considered to be related to icatibant.. Icatibant was efficacious and generally well tolerated across multiple HAE attacks, including laryngeal attacks.

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Double-Blind Method; Female; Humans; Injections, Subcutaneous; Male; Prospective Studies; Recurrence; Treatment Outcome

Historically, treatment for hereditary angioedema (HAE) attacks has been administered by healthcare professionals (HCPs). Patient self-administration could reduce delays between symptom onset and treatment, and attack burden. The primary objective was to assess the safety of self-administered icatibant in patients with HAE type I or II. Secondary objectives included patient convenience and clinical efficacy of self-administration.. In this phase IIIb, open-label, multicenter study, adult patients were trained to self-administer a single 30-mg icatibant subcutaneous injection to treat their next attack. Icatibant-naïve patients were treated by an HCP prior to self-administration. Evaluations included adverse event (AE) reporting, a validated questionnaire for convenience, and visual analog scale for efficacy.. A total of 151 patients were enrolled; 104 had an attack requiring treatment during the study, and 97 patients (19 naïve) were included in the self-administration cohort. Recurrence or worsening of HAE symptoms (22 of 97) was the most commonly reported AE; rescue medications including icatibant (N = 3) and C1-inhibitor concentrate (N = 6) were used in 13 cases. Overall, 89 of 97 patients used a single injection of icatibant. No serious AEs or hospitalizations were reported. Most patients (91.7%) found self-administration preferable to administration in the clinic. The median time to symptom relief (3.8 h) was comparable with results from controlled trials of icatibant.. With appropriate training, patients were successfully able to recognize HAE attacks and decide when to self-administer icatibant. This, coupled with the patient-reported high degree of satisfaction, convenience and ease of use supports the adoption of icatibant self-administration in clinical practice.

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Disease Progression; Female; Hereditary Angioedema Types I and II; Humans; Male; Middle Aged; Patient Satisfaction; Recurrence; Risk Factors; Self Administration; Treatment Outcome

Hereditary angioedema (HAE) is characterized by potentially life-threatening recurrent episodes of oedema. The open-label extension (OLE) phase of the For Angioedema Subcutaneous Treatment (FAST)-1 trial (NCT00097695) evaluated the efficacy and safety of repeated icatibant exposure in adults with multiple HAE attacks. Following completion of the randomized, controlled phase, patients could receive open-label icatibant (30 mg subcutaneously) for subsequent attacks. The primary end-point was time to onset of primary symptom relief, as assessed by visual analogue scale (VAS). Descriptive statistics were reported for cutaneous/abdominal attacks 1-10 treated in the OLE phase and individual laryngeal attacks. Post-hoc analyses were conducted in patients with ≥ 5 attacks across the controlled and OLE phases. Safety was evaluated throughout. During the OLE phase, 72 patients received icatibant for 340 attacks. For cutaneous/abdominal attacks 1-10, the median time to onset of primary symptom relief was 1·0-2·0 h. For laryngeal attacks 1-12, patient-assessed median time to initial symptom improvement was 0·3-1·2 h. Post-hoc analyses showed the time to onset of symptom relief based on composite VAS was consistent across repeated treatments with icatibant. One injection of icatibant was sufficient to treat 88·2% of attacks; rescue medication was required in 5·3% of attacks. No icatibant-related serious adverse events were reported. Icatibant provided consistent efficacy and was well tolerated for repeated treatment of HAE attacks.

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Female; Humans; Male; Middle Aged; Retreatment; Treatment Outcome; Young Adult

Hereditary angioedema (HAE) with C1 inhibitor deficiency manifests as recurrent episodes of edema involving the skin, upper respiratory tract and gastrointestinal tract. It can be lethal due to asphyxia. The aim here was to evaluate the response to therapy for these attacks using icatibant, an inhibitor of the bradykinin receptor, which was recently introduced into Brazil.. Prospective experimental single-cohort study on the efficacy and safety of icatibant for HAE patients.. Patients with a confirmed HAE diagnosis were enrolled according to symptoms and regardless of the time since onset of the attack. Icatibant was administered in accordance with the protocol that has been approved in Brazil. Symptom severity was assessed continuously and adverse events were monitored.. 24 attacks in 20 HAE patients were treated (female/male 19:1; 19-55 years; median 29 years of age). The symptoms were: subcutaneous edema (22/24); abdominal pain (15/24) and upper airway obstruction (10/24). The time taken until onset of relief was: 5-10 minutes (5/24; 20.8%); 10-20 (5/24; 20.8%); 20-30 (8/24; 33.4%); 30-60 (5/24; 20.8%); and 2 hours (1/24; 4.3%). The time taken for complete resolution of symptoms ranged from 4.3 to 33.4 hours. Adverse effects were only reported at injection sites. Mild to moderate erythema and/or feelings of burning were reported by 15/24 patients, itching by 3 and no adverse effects in 6.. HAE type I patients who received icatibant responded promptly; most achieved improved symptom severity within 30 minutes. Local adverse events occurred in 75% of the patients.

Topics: Adult; Age Distribution; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Brazil; Cohort Studies; Edema; Female; Gastrointestinal Tract; Humans; Male; Middle Aged; Prospective Studies; Subcutaneous Tissue; Time Factors; Treatment Outcome; Young Adult

The For Angioedema Subcutaneous Treatment (FAST)-3 study was a phase III, randomized, double-blind, placebo-controlled study of icatibant (bradykinin B(2) receptor antagonist) in subjects with hereditary angioedema (HAE) resulting from C1-INH deficiency or dysfunction (type I/II).. To investigate icatibant efficacy and safety in subjects with acute HAE attacks.. Subjects with moderate to very severe cutaneous or abdominal symptoms received icatibant (n = 43) or placebo (n = 45). Five subjects with laryngeal (mild-to-moderate) first attacks received icatibant (n = 3) or placebo (n = 2), and 5 subjects with severe laryngeal first attacks received open-label icatibant.. Cutaneous or abdominal attacks: icatibant significantly reduced median times (vs placebo) to 50% or more reduction in symptom severity (2.0 vs 19.8 hours; P < .001, primary endpoint), onset of primary symptom relief (1.5 vs 18.5 hours; P < .001, key secondary endpoint), or almost complete symptom relief (8.0 vs 36.0 hours; P = .012) and provided a shorter time to initial symptom relief (0.8 vs 3.5 hours; P < .001). For laryngeal attacks, median time to 50% or more reduction in symptom severity was 2.5 hours (icatibant) and 3.2 hours (placebo). No icatibant-treated subject required rescue medication before symptom relief occurred. The incidence of adverse events (AEs) was similar in icatibant- and placebo-treated subjects (41% and 52%, respectively). All icatibant-treated subjects experienced injection site reactions, but none reported clinically relevant changes in safety parameters or serious AEs.. FAST-3 demonstrated that icatibant was effective and generally well tolerated in subjects with acute HAE attacks.. Clinicaltrials.gov Identifier: NCT00912093.

Topics: Adult; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Double-Blind Method; Female; Humans; Injections, Subcutaneous; Kaplan-Meier Estimate; Male

Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist.. In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms.. A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported.. In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

Topics: Acute Disease; Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Double-Blind Method; Female; Humans; Injections, Subcutaneous; Intention to Treat Analysis; Male; Statistics, Nonparametric; Tranexamic Acid

C1-inhibitor (C1INH) concentrates and the selective bradykinin B2 receptor antagonist icatibant are approved only for treating hereditary angioedema with C1INH deficiency. Yet, they are regularly prescribed off label in other types of bradykinin-mediated angioedema including angiotensin-converting enzyme inhibitor (ACEi)-related and undetermined angioedema. We conducted a retrospective chart review of inpatient prescriptions of C1INH concentrates and icatibant between 2016 and 2020 in the University Hospital of Angers. The first outcome was the proportion of prescriptions with explicit indication. Then, we determined the compliance of prescriptions with European Medicines Agency approvals and the French bradykinin-mediated angioedema reference center guidelines. Finally, we estimated the economic impact of inappropriate prescribing. The therapeutic indication was explicit in 90.4% of prescriptions (n = 66/73). Only 17.8% of prescriptions were for hereditary angioedema with C1INH deficiency, while 31.5% were for ACEi-related and 28.7% for undetermined angioedema. However, most off-label prescriptions were consistent with the French bradykinin-mediated angioedema reference center guidelines (73.3%). We estimated that 13% of drug expenditures were potentially excessive. The predominance of off-label prescriptions may be explained by the infrequency of hereditary angioedema and the absence of approved alternatives in other types of bradykinin-mediated angioedema. Most attacks were related to ACEis. Epinephrine was rarely prescribed as first-line therapy in attacks of unknown origin. Given the high prices of these drugs, we advocate the development of a readily available management algorithm of angioedema to reduce inappropriate prescriptions in our center. In addition, we think that the drug prescription circuit should be redesigned to ensure the traceability of prescribed vials in the dispensing areas.

Topics: Angioedema; Angioedemas, Hereditary; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Humans; Off-Label Use; Prescriptions; Retrospective Studies

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Humans; Treatment Outcome

Topics: Angioedemas, Hereditary; Bradykinin; Complement C1 Inhibitor Protein; Humans; Registries

Hereditary angioedema due to C1 inhibitor deficiency (HAE-1/2) is a chronic and debilitating disease. The unpredictable clinical course represents a significant patient burden.. To analyse longitudinal registry data from the Icatibant Outcome Survey (IOS) in order to characterize temporal changes in disease activity in patients with HAE-1/2.. Icatibant Outcome Survey (NCT01034969) is an international observational registry monitoring the clinical outcomes of patients eligible for icatibant treatment. The current analyses are based on data collected between July 2009 and July 2019. Retrospective data for attacks recorded in the 12 months prior to IOS enrolment and for each 12-month period up to 7 years were analysed.. Included patients reported angioedema attacks without long-term prophylaxis (LTP; n = 315) and with LTP (n = 292) use at the time of attack onset. Androgens were the most frequently used LTP option (80.8%). At the population level, regardless of LTP use, most patients (52-80%) reporting <5 attacks in Year 1 continued experiencing this rate; similarly, many patients (25-76%) who reported high attack frequency continued reporting ≥10 attacks/year. However, year on year, 31-51% of patients experienced notable changes (increase/decrease of ≥5 attacks) in annual attack frequency. Of patients who reported an absolute change of ≥10 attacks from Year 1 to 2, 17-50% continued to experience a change of this magnitude in subsequent years.. At the population level, attack frequency was generally consistent over 7 years. At the small group level, 28.8-34.5% of patients reported a change in attack frequency of ≥5 attacks from Year 1 to Year 2; up to half of these patients continued to experience this magnitude of variation in disease activity in later years, reflecting high intra-patient variability.

Topics: Angioedemas, Hereditary; Bradykinin; Hereditary Angioedema Types I and II; Humans; Retrospective Studies; Treatment Outcome

Topics: Angioedema; Angioedemas, Hereditary; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Humans; N-Methyl-3,4-methylenedioxyamphetamine

Elevated bradykinin levels are responsible for the development of clinical symptoms in patients with hereditary angioedema (HAE). Icatibant is a bradykinin type 2 receptor antagonist indicated for the acute treatment of HAE attacks. A population modeling and simulation approach was used to examine sources of variability impacting icatibant pharmacokinetics (PK) and provide guidance on icatibant dosing in pediatric patients with HAE. An exposure-response analysis was performed for the time to onset of symptom relief (TOSR). Data from 141 adults (133 healthy, 8 with HAE) who received subcutaneous icatibant 30 mg and 31 pediatric patients with HAE who received 0.4 mg/kg (capped at 30 mg) were included in the analysis. Icatibant PK was described by a 2-compartment model with linear elimination. Complete absorption of icatibant was expected within 1 hour of dosing. The apparent clearance and central volume of distribution were 15.4 L/h and 20.4 L, respectively. Icatibant PK was mainly dependent on body weight. The mean TOSR was very short (1.38 hours). A flat exposure-response was observed, confirming that the relationship plateaued at the level of exposure observed in pediatric patients. Simulations confirmed that weight band-based dosing regimens (10 mg [12-25 kg], 15 mg [26-40 kg], 20 mg [41-50 kg], 25 mg [51-65 kg], and 30 mg [>65 kg]) resulted in exposure similar to the 0.4-mg/kg dose. This analysis showed that icatibant undergoes rapid absorption, reaches levels required for therapeutic response, and promptly relieves HAE symptoms. A weight band-based dosing regimen is appropriate in pediatric patients with HAE.

Topics: Adolescent; Adult; Angioedemas, Hereditary; Body Weight; Bradykinin; Bradykinin B2 Receptor Antagonists; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Models, Biological; Young Adult

Topics: Adolescent; Angioedemas, Hereditary; Bradykinin; Humans; Treatment Outcome

Hereditary angioedema (HAE) is a rare C1-inhibitor (C1-INH) deficiency disease. Low levels of functional C1-INH can lead to recurrent attacks of severe swelling occurring in areas such as the limbs, face, gastrointestinal tract, and throat. These attacks are both painful and disabling and, if not treated promptly and effectively, can result in hospitalization or death. Agents targeting the specific physiologic pathway of HAE attacks can offer improved outcomes with limited side effects compared with nonspecific therapies. However, these treatments display varying efficacy in HAE patients, including the need to redose or seek additional care if the treatment does not resolve symptoms effectively.. To analyze the expected cost and utility per HAE attack when treated on-demand with HAE therapies indicated for the treatment of acute attacks.. A decision-tree model was developed using TreeAge Pro software. Four on-demand HAE treatments were included: ecallantide, icatibant, plasma-derived (pd)C1-INH, and recombinant human (rh)C1-INH. The model uses probabilities for redosing, self-administration versus health care provider administration, and risk of hospitalization. Costs within the model consisted of the HAE treatments and associated health care system expenses. Nonattack baseline utility and attack utility were implemented for effectiveness calculations; time to attack resolution was considered as well. Effectiveness and overall costs per attack were calculated and used to estimate cost per quality-adjusted life-year (QALY). Variability and ranges in cost-effectiveness were determined using probabilistic sensitivity analyses. Finally, a budget impact model for a health plan with 1 million covered lives was also developed.. The base case model outputs show costs and calculated effectiveness per attack at $12,905 and 0.806 for rhC1-INH, $14,806 and 0.765 for icatibant, $14,668 and 0.769 for pdC1-INH, and $21,068 and 0.792 for ecallantide, respectively. Cost per QALY was calculated using 26.9 attacks per person-year, leading to results of $420,941 for rhC1-INH, $488,349 for icatibant, $483,892 for pdC1-INH, and $689,773 for ecallantide. Sensitivity analyses demonstrate that redose rates (from 3% for rhC1-INH to 44% for icatibant) are a primary driver of variability in cost-effectiveness. Annual health plan costs from the budget impact model are calculated as $6.94 million for rhC1-INH, $7.97 million for icatibant, $7.90 million for pdC1-INH, and $11.33 million for ecallantide.. Accounting for patient well-being and additional cost components of HAE attacks generates a better estimation of cost-effectiveness than drug cost alone. Results from this model indicate that rhC1-INH is the dominant treatment option with lower expected costs and higher calculated effectiveness than comparators. Further analyses reinforce the idea that low redose rates contribute to improved cost-effectiveness.. Funding support was contributed by Pharming Healthcare. Relan and Adams are employed by Pharming Healthcare. Tyson and Magar are employed by AHRM, which received fees to perform the analysis and develop the manuscript. Bernstein reports grants, personal fees, and nonfinancial support from Shire, CSL Behring, and Pharming Healthcare; grants and personal fees from Biocryst; and nonfinancial support from HAEA, unrelated to this study.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Cost-Benefit Analysis; Decision Trees; Humans; Models, Economic; Peptides; Quality-Adjusted Life Years; Recombinant Proteins; Treatment Outcome

C1INH-deficiency hereditary angioedema (HAE) is characterized by recurrent episodes of potentially severe oedema. Icatibant for SC injection will soon be approved for use in children and it is necessary to train parents in recognising severe episodes of AOH and in the technique for injection of icatibant. Simulation in healthcare (SH) is a set of educational methods for improving skills in a safe environment. We wished to assess the feasibility of a therapeutic training session (TTS) involving scripted scenarios for the parents of children with HAE.. The TTS session included pre- and post-training testing on AOH, two scenarios (calling emergency services for lingual AO; gastrointestinal AO) involving actors and a volunteer parent, a workshop for learning the SC injection technique, and a satisfaction questionnaire. We analysed the answers on the questionnaire and noted down parents' verbatim observations during debriefing sessions.. Eight parents from 5 families took part in this session. Parents rated their overall satisfaction as 9.3/10. The parents commented that during the simulations, they felt "in the thick of it" and that they "experienced stress while viewing the scenes", thus attesting to the realism and relevance of the simulated scenarios.. This session met the parents' expectations in terms of being able to cope and having adequate know-how, based on both the simulations and the level of knowledge acquired. The main limitation lay in the parents' difficulty in confronting certain situations reminiscent of traumatic past experiences. TTS shares many common features with SH for the parents of sick children. The place of the latter in TTS must be evaluated.

Topics: Adolescent; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Child; Child, Preschool; Female; Humans; Injections, Subcutaneous; Male; Parents; Severity of Illness Index; Simulation Training

Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) is a rare genetic disease that runs in the family. As a result of the disease, acute swellings of the subcutaneous tissue and mucous membranes of the digestive and respiratory systems, including the larynx, occur. Any attack of the disease involving the throat and larynx is particularly dangerous and requires knowledge of clinical determinants of the disease and its proper management.. The study included adult consecutive HAE-C1INH patients having follow-up visits in our centre. The group was examined with a structured clinical questionnaire, concerning the last 6 months and focusing particularly on laryngeal swelling attacks.. 55 subjects (F/M - 35/20, age range - 18-76) were included in the study. Laryngeal attacks occurred in 19 individuals (34.5%): 1-3, 4-6, and ≥7 attacks in 9, 8 and 2 patients, respectively, two of whom required intubation. In comparison to other patients, subjects with laryngeal attacks were characterised by significantly more frequent: (1) facial attacks, (2) severe disease activity, (3) the occurrence of female patients, (4) mental stress as a trigger of attacks. All patients with laryngeal attacks had a rescue medication at home and 15/19 (78%) patients could use it at home. Most of them used plasma-derived C1-inhibitor 17/19 (89.5%) and icatibant, 8/19 (42.1%).. HAE-C1INH patients with laryngeal attacks require particular attention. Proper training regarding the identification of these patients, adequate management, access to emergency services and emergency drugs are essential to ensure the safety of subjects with this localization of HAE-C1INH attacks.

Topics: Adolescent; Adult; Aged; Angioedemas, Hereditary; Bradykinin; Female; Humans; Laryngeal Edema; Male; Middle Aged; Surveys and Questionnaires; Vasodilator Agents; Young Adult

Topics: Adolescent; Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Delayed Diagnosis; General Practitioners; Humans; Pediatricians; Specialization; Surveys and Questionnaires; Treatment Outcome; Young Adult

The Icatibant Outcome Survey (IOS; NCT01034969) is a Shire-sponsored, international, observational study monitoring the safety and effectiveness of icatibant, a bradykinin B2 receptor antagonist approved for the acute treatment of adults with hereditary angioedema with C1 inhibitor deficiency (HAE-C1-INH).. To report IOS data comparing demographic and icatibant treatment outcomes in patients with HAE-C1-INH from Germany to HAE-C1-INH patients from 11 other IOS countries.. A descriptive, retrospective, comparative analysis of data from 685 IOS patients with HAE-C1-INH from seven centres in Germany (n = 93) vs. centres from Austria, Brazil, Czech Republic, Denmark, France, Greece, Israel, Italy, Spain, Sweden and the United Kingdom (n = 592, July 2009-January 2017). Icatibant treatment outcomes were retrieved from patients with complete attack outcome data for time to treatment, time to resolution and attack duration (160 attacks in 42 German patients and 1442 attacks in 251 patients from other IOS countries).. German patients reported significantly fewer severe/very severe attacks (38.7% vs. 57.5%, respectively; P < 0.001). The proportion of attacks treated with a single icatibant injection was significantly higher in German patients (97.1% vs. 91.6%, P = 0.0003). The median time to treatment (0.0 h vs. 1.5 h), time to resolution (3.0 h vs. 7.0 h) and attack duration (4.3 h vs. 10.5 h) in German patients vs. other IOS countries were all significantly shorter (all P < 0.0001). No meaningful differences were identified between patients from Germany and other countries with regard to sex, median age at enrolment, median age at symptom onset and median age at diagnosis.. German IOS patients share similar demographic characteristics to patients from other IOS countries yet treat their attacks with icatibant significantly earlier and have markedly fewer severe or very severe attacks. Factors including regional access to and availability of icatibant may drive these outcomes and warrant further investigation.

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Female; Germany; Health Surveys; Humans; Male; Middle Aged; Retrospective Studies; Symptom Flare Up; Time Factors; Time-to-Treatment

Qualitative and quantitative determination of amino acid composition using amino acid analysis (AAA) is an important quality attribute and considered an identity of therapeutic peptide drugs by the regulatory agencies. Although huge literature is available on pre- and post- column derivatization AAA methods, arriving at an appropriate hydrolysis protocol coupled with adequate separation of the derivatized/underivatized amino acids is always challenging. Towards achieving a facile and comprehensive protocol for AAA, the present work is geared towards developing a deeper understanding of the extent of hydrolysis of peptide, and the nature and stability of amino acids present in the peptide backbone. This defines the suitability of the method in meeting the end goals and the regulatory requirement. Analysis of historical data generated during the method optimization of AAA for icatibant acetate (ICT) using head space oven hydrolysis (HSOH) and microwave-assisted hydrolysis (MAH) methods helped in arriving at fast (< 1 h) and efficient hydrolysis (0.9-1.1 of theoretical residue) conditions. Better separations for the natural and unnatural amino acids were achieved using 3.45 ≤ pH ≤ 10.85, and a column oven gradient program. This approach was useful in meeting the method quality attributes [resolution (R

Topics: Amino Acids; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Chromatography, High Pressure Liquid; Data Accuracy; Hot Temperature; Humans; Hydrogen-Ion Concentration; Hydrolysis; Ninhydrin; Osmolar Concentration; Time

Ever-expanding armamentarium of treatments for hereditary angioedema (HAE) are associated with various adverse effects, issues with vascular access, or lack of self-administration.. To understand patients' impressions and confidence in their past and present treatments, and identifying adverse events while also directly asking patients to reveal their hope for the future of HAE management and treatments.. After institutional review board approval, all subjects with laboratory-confirmed HAE were mailed a survey that they completed and returned to the researchers, and data were collected and entered into a secure online web application for surveys. Medication confidence data were summarized and expressed as means, medians, standard deviations, and quartiles by using a 5-point Likert scale. Analyses were performed by using statistical software.. Of 150 surveys, 38 (25.3%) were completed. Among 36 subjects, 27 (75.0%) were female subjects, and the mean age was 50.1 years. Cinryze and Berinert (both C1-esterase inhibitors) had the highest median scores (5.0) for patient confidence, followed by ecallantide (4.5), icatibant (4.0), and androgens (2.0). For Cinryze, 64.3% selected it as the most effective and 57.1% tolerated it best. For Berinert, 50% of the subjects found it to be most effective and 59.1% tolerated it best. Some subjects listed androgens as most effective (33.3%) or best tolerated (16.7%), and many reported that this class caused the most adverse effects (44.4%). Among those who answered, 50% preferred a noninvasive method of administration, such as oral (24%), subcutaneous (18%), or not intravenous (8%) routes.. Determining patient predilections and the reasoning behind them can be valuable for determining specific therapies to achieve each individual's personal goals.

Topics: Adolescent; Adult; Androgens; Angioedemas, Hereditary; Bradykinin; Drug Administration Routes; Female; Forecasting; Humans; Male; Middle Aged; Patient Satisfaction; Peptides; Surveys and Questionnaires

Management of patients with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is evolving worldwide. Evaluating the Israeli experience may provide valuable insights.. To compare demographics and icatibant treatment patterns and outcomes in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey (IOS) in Israel with those in other countries.. The IOS is an ongoing observational study that prospectively monitors real-world icatibant safety/tolerability and treatment outcomes.. By July 2016, 58 patients from Israel and 594 patients from other countries were enrolled. Median age at diagnosis (16.7 vs. 21.3 years, P = 0.036) and median delay between symptom onset and diagnosis (0.8 vs. 6.6 years, P = 0.025) were lower in Israel compared with other countries, respectively. Differences in attack severity were not significant (P = 0.156); however, during follow-up, Israeli patients were less likely to miss > 7 days of work/school due to C1-INH-HAE-related complications (P = 0.007). A trend was also shown in Israel for earlier time to treatment (median 0.5 vs. 1.3 hours, P = 0.076), attack duration was shorter (median 5.0 vs. 9.0 hours, P = 0.026), and patients more often self-administered icatibant (97.2% vs. 87.5%, P = 0.003), respectively. However, Israeli patients were less likely to treat attacks (P = 0.036). Whereas patients in Israel reported exclusive use of danazol for long-term prophylaxis, those in other countries used various agents, including C1-INH.. Recognition of C1-INH-HAE and timeliness of icatibant treatment appear more favorable, and attack duration shorter, in Israel compared with other countries.

Topics: Adult; Aged; Aged, 80 and over; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Danazol; Delayed Diagnosis; Female; Follow-Up Studies; Humans; Israel; Male; Middle Aged; Prospective Studies; Registries; Self Administration; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Treatment Outcome; Young Adult

Angioedema (AE) is a potentially life-threatening event. We investigated the etiology of AE, with the emphasis on bradykinininduced angioedema treatment in emergency medicine.. The retrospective study included 237 patients with AE, who were examined and treated in two hospitals (group A and B) in Croatia from 2009 to 2016. The location and duration of AE, data about chronic diseases and treatment, potential causative agents (food, drugs, insect bites and chemicals), physical examination data and the subsequent treatment were analyzed.. There was no statistical difference regarding age or comorbidities but there was a statistically significant difference in etiology between the groups (Chi-square, P=0.03). Renin-angiotensin-aldosterone system (RAAS) blocker induced AE was the main cause of emergency attendance in group A (37.5%) and among the leading causes in group B (18.8%). Bradykinin-induced AE (hereditary angioedema (HAE) and RAAS-AE) were the leading causes in a total of 75 (31.5%) patients. RAAS-AE was treated with glucocorticoids and antihistamines. HAE attacks in both groups (2/7 patients, 1.5/6%) were treated with specific therapy. Other causes of AE in groups A/B were insect bites (15/23 patients, 13.5/20%), use of antibiotics/analgetics (11/17 patients, 9/15%), gastroesophageal reflux disease (10/11 patients, 8/9%), neoplasms (5/6 patients, 4/5%) and idiopatic (32/31 patients, 26.5/26%). 21% of patients were hospitalized.. Bradykinin-mediated AE was the main cause of emergency attendance associated with AE. Advances in the treatment of HAE, with case reports of patients with RAAS-AE treated with C1 esterase inhibitor concentrate or bradykinin receptor antagonist, may prove to be a new, reliable and efficacious therapy option.

Topics: Adult; Aged; Angioedema; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Complement C1 Inhibitor Protein; Complement C1s; Croatia; Emergency Medicine; Female; Gastroesophageal Reflux; Hospitalization; Hospitals; Humans; Incidence; Insect Bites and Stings; Male; Middle Aged; Neoplasms; Prevalence; Renin-Angiotensin System; Retrospective Studies

Topics: Adolescent; Adult; Angioedemas, Hereditary; Bradykinin; Cohort Studies; Complement C1 Inhibitor Protein; Female; France; Humans; Male; Middle Aged; Prospective Studies; Retrospective Studies; Young Adult

To explore treatment behaviours in a cohort of Italian patients with hereditary angioedema due to complement C1-inhibitor deficiency (C1-INH-HAE), and to estimate how effects and costs of treating attacks in routine practice differed across available on-demand treatments.. Cost analyses and survival analyses using attack-level data collected prospectively for 1 year.. National reference centre for C1-INH-HAE.. 167 patients with proved diagnosis of C1-INH-HAE, who reported data on angioedema attacks, including severity, localisation and duration, treatment received, and use of other healthcare services.. Attacks were treated with either icatibant, plasma-derived C1-INH (pdC1-INH) or just supportive care.. Treatment efficacy in reducing attack duration and the direct costs of acute attacks.. Overall, 133 of 167 patients (79.6%) reported 1508 attacks during the study period, with mean incidence of 11 attacks per patient per year. Only 78.9% of attacks were treated in contrast to current guidelines. Both icatibant and pdC1-INH significantly reduced attack duration compared with no treatment (median times from onset 7, 10 and 47 hours, respectively), but remission rates with icatibant were 31% faster compared with pdC1-INH (HR 1.31, 95% CI 1.14 to 1.51). However, observed treatment behaviours suggest patterns of suboptimal dosing for pdC1-INH. The average cost per attack was €1183 (SD €789) resulting in €1.58 million healthcare costs during the observation period (€11 912 per patient per year). Icatibant was 54% more expensive than pdC1-INH, whereas age, sex and prophylactic treatment were not associated to higher or lower costs.. Both icatibant and pdC1-INH significantly reduced attack duration compared with no treatment, however, icatibant was more effective but also more expensive. Treatment behaviours and suboptimal dosing of pdC1-INH may account for the differences, but further research is needed to define their role.

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Complement C1 Inhibitor Protein; Cost-Benefit Analysis; Female; Humans; Immunologic Factors; Italy; Male; Middle Aged; Plasma; Prospective Studies; Treatment Outcome

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 3690 g. 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.

Topics: Adult; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Complement C1 Inhibitor Protein; Delivery, Obstetric; Disease Progression; Female; Humans; Pregnancy; Pregnancy Complications; Pregnancy Trimesters; Recombinant Proteins; Risk Factors; Treatment Outcome; Young Adult

Real-world data on usage and associated outcomes with hereditary angioedema (HAE)-specific medications introduced to the United States (US) market since 2009 are very limited. The purpose of this retrospective study was to evaluate real-world treatment patterns of HAE-specific medications in the US and to assess their impact on healthcare resource utilization (HCRU). This analysis used IMS PharMetrics PlusTM database records (2006-2014) of patients with HAE, ≥1 insurance claim for an HAE-specific medication, and continuous insurance enrollment for ≥3 months following the first HAE prescription claim.. Of 631 total patients, 434 (68.8%) reported C1-INH(IV) use; 396 (62.8%) reported using ecallantide and/or icatibant. There were 306 episodes of prophylactic use of C1-INH(IV) (defined by continuous refills averaging ≥1500 IU/week for ≥13 weeks) in 155 patients; use of ≥1 on-demand rescue medication was implicated during 53% (163/306) of those episodes. Sixty-eight (20.2%) of 336 C1-INH(IV) users eligible for the HCRU analysis were hospitalized at least once, and 191 (56.8%) visited the emergency department (ED). Eighteen patients (5.4%) had a central venous access device (CVAD); of these, 5 (27.7%) required hospitalization and 14 (77.7%) had an ED visit. The adjusted relative risk of hospitalization and/or ED visits for patients with a CVAD was 2.6 (95% CI: 0.17, 39.23) compared to C1-INH(IV) users without a CVAD.. Despite widespread availability of modern HAE medications in the US, we identified a subset of patients requiring long-term prophylaxis who continue to be burdened by frequent rescue medication usage and/or complications related to the use of CVADs for intravenous HAE medication.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Humans; Patient Acceptance of Health Care; Peptides; Retrospective Studies; United States

Hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) is a rare, potentially fatal, bradykinin-mediated disease. Icatibant is a bradykinin B2 receptor antagonist originally approved in 2008 in the European Union and 2011 in the United States as an acute therapy option for HAE attacks in adults.. To compare demographics, disease characteristics and treatment outcomes of icatibant-treated HAE attacks in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey across six European countries: Austria, France, Germany, Italy, Spain and the UK.. The Icatibant Outcome Survey [IOS; Shire, Zug, Switzerland (NCT01034969)] is an international observational study monitoring the safety and effectiveness of icatibant. Descriptive, retrospective analyses compared IOS country data derived during July 2009-April 2015.. Overall, 481 patients with C1-INH-HAE provided demographic data. A significant difference across countries in age at onset (P = 0.003) and baseline attack frequency (P < 0.001) was found although no significant differences were found with respect to gender (majority female; P = 0.109), age at diagnosis (P = 0.182) or delay in diagnosis (P = 0.059). Icatibant was used to treat 1893 attacks in 325 patients with majority self-administration in all countries. Overall, significant differences (all P < 0.001) were found across countries in time to treatment [median 1.8 h; median range: 0.0 (Germany-Austria) to 4.4 (France) h], time to resolution [median 6.5 h; median range: 3 (Germany-Austria) to 12 (France) h] and attack duration [median 10.5 h; median range: 3.1 (Germany-Austria) to 18.5 (France) h].. These data form the first European cross-country comparison of disease characteristics and icatibant use in patients with C1-INH-HAE who are enrolled in IOS. International variation in icatibant practice and treatment outcomes across the six European countries assessed highlight the need to further investigate the range of country-specific parameters driving regional variations in icatibant use.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Europe; Female; Humans; Male; Registries; Retrospective Studies; Treatment Outcome

The benefits of the worldwide approval of new drugs for the treatment of acute C1-INH-HAE attacks may still not reach all patients. Identifying the current barriers in the access to medication, as well as conducting a detailed assessment of the progress in this area, is essential to achieve universal treatment. Two hundred and twenty five patients registered in the Argentina Hereditary Angioedema Patient Association (AHAEPA) were randomly selected and invited to participate in a web based questionnaire on accessibility to icatibant and pdC1-INH, self-treatment, delay to treatment, and coverage. The data retrieved was compared to our previous reports in 2008 and 2013. We collected 156/225 answers. One hundred and eighteen (76%) patients have either pdC1-INH (n = 86), icatibant (n = 10) or both (n = 22), while 38 (24%) do not have access to treatment. In 2008, 26% had access while 82% had it in 2013. Thirty-two subjects (22%) self-inject themselves, similar to 29% in 2013, even though between studies, widespread self-injection training activities have taken place. However, considering injections by proxy, home treatment reached 56%. Only half of the patients decide to receive treatment early during the attack. Ninety-nine patients (63%) have full coverage, thirty (19%) have no coverage at all and the rest only obtain partial reimbursement. Twenty-nine families (31%) share a single treatment dose of the medication, better than 36% in 2013. Argentina's C1-INH-HAE patients had a sustained improvement in their access to medication. Efforts should continue to further improve accessibility and optimal management of HAE acute attacks to all patients in the country.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Argentina; Bradykinin; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Female; Health Services Accessibility; Humans; Male; Surveys and Questionnaires

Topics: Aged, 80 and over; Angioedema; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inactivator Proteins; Female; Humans; Immunologic Factors; Lymphoma; Male; Middle Aged; Paraproteinemias; Peptides; Rituximab; Treatment Outcome

Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1-INH-HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor deficiency (C1-INH-AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1-INH-AAE and compare disease characteristics with those with C1-INH-HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6-month intervals during patient follow-up visits. In the icatibant-treated population, 16 patients with C1-INH-AAE had 287 attacks and 415 patients with C1-INH-HAE types I/II had 2245 attacks. Patients with C1-INH-AAE versus C1-INH-HAE types I/II were more often male (69 versus 42%; P = 0·035) and had a significantly later mean (95% confidence interval) age of symptom onset [57·9 (51·33-64·53) versus 14·0 (12·70-15·26) years]. Time from symptom onset to diagnosis was significantly shorter in patients with C1-INH-AAE versus C1-INH-HAE types I/II (mean 12·3 months versus 118·1 months; P = 0·006). Patients with C1-INH-AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P = 0·064). Overall, angioedema attacks were more severe in patients with C1-INH-HAE types I/II versus C1-INH-AAE (61 versus 40% of attacks were classified as severe to very severe; P < 0·001). Median total attack duration was 5·0 h and 9·0 h for patients with C1-INH-AAE versus C1-INH-HAE types I/II, respectively.

Topics: Adult; Aged; Aged, 80 and over; Angioedema; Angioedemas, Hereditary; Bradykinin; Disease Progression; Female; Follow-Up Studies; Humans; Male; Middle Aged; Phenotype; Retrospective Studies; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome

The clinical characteristics and icatibant-treatment outcomes of patients with hereditary angioedema with normal C1 inhibitor (HAE-nC1 INH) are limited.. We retrospectively analyzed data from French HAE patients enrolled in the Icatibant Outcome Survey registry (from July 2009 to September 2013) to compare disease characteristics and the effectiveness and safety of acute icatibant-treated angioedema attacks in patients with HAE-nC1 INH, HAE with C1 INH deficiency (type I), or dysfunction (type II).. One center in Grenoble contributed 22 patients with HAE-nC1 INH and a family history of HAE while 15 centers across France contributed 153 patients with HAE type I and seven patients with HAE type II. Patients with HAE-nC1 INH compared to HAE type I, respectively, were more likely to be female (88.1% vs. 63.4%), older at median age of disease onset (21 years vs. 15 years), and have a greater rate of abdominal (80% vs. 61%) and laryngeal (23% vs. 14%) attacks. Icatibant was effective in both groups though the median time to resolution of attack was significantly longer in the HAE-nC1 INH group (20.0 h, 37 attacks) versus the HAE type I group (14.0 h, 67 attacks). Icatibant was self-administered for 96.1% of attacks in patients with HAE-nC1 INH and 75.8% in patients with HAE type I. No serious adverse side effects related to icatibant were reported.. These data help further define the disease characteristics of HAE-nC1 INH in the French population and extend the limited data reporting the safe and effective use of icatibant in acute treatment of angioedema in French patients diagnosed with HAE-nC1 INH.

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Female; France; Humans; Male; Middle Aged; Treatment Outcome

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Female; Humans; Male; Middle Aged; Prospective Studies

Hereditary angioedema resulting from C1-inhibitor deficiency (C1-INH-HAE) is a rare, autosomal dominant disorder, characterized by recurrent attacks of edema formation. The management of pregnant patients with C1-INH-HAE is often a challenge for the physician. There is limited experience with novel therapies. Plasma-derived nanofiltered C1-INH (pnfC1-INH) is the only recommended therapeutic option during pregnancy. In our 26-year-old female patient with type II C1-INH-HAE, pregnancy was confirmed in the sixth week of gestation. During this period, the patient received the bradykinin B2-receptor antagonist, icatibant, on five occasions, as acute treatment. She experienced 119 attacks, for which she received 108 vials of pnfC1-INH during her pregnancy. The patient gave birth to a healthy baby. No side effects were detected with either treatment. No reports have been published to date on multiple dosing with icatibant during the first trimester of pregnancy. This therapy proved effective and free of maternal or fetal adverse effects.

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Female; Humans; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Treatment Outcome

To characterize the management and outcomes of life-threatening laryngeal attacks of hereditary angioedema (HAE) treated with icatibant in the observational Icatibant Outcome Survey (NCT01034969) registry.. This retrospective analysis was based on data from patients with HAE type I/II who received healthcare professional-administered or self-administered icatibant to treat laryngeal attacks between September 2008 and May 2013.. Twenty centers in seven countries contributed data. Overall, 42 patients with HAE experienced 67 icatibant-treated laryngeal attacks. Icatibant was self-administered for 62.3% of attacks (healthcare professional-administered, 37.7%). One icatibant injection was used for 87.9% of attacks, with rescue or concomitant medication used for 9.0%. The median time to treatment was 2.0 h (n=31 attacks) and the median time to resolution was 6.0 h (n=35 attacks).. This analysis describes successful use of icatibant for the treatment of laryngeal HAE attacks in a real-world setting.

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Female; Hereditary Angioedema Types I and II; Humans; Injections, Subcutaneous; Laryngeal Diseases; Male; Retrospective Studies; Surveys and Questionnaires; Treatment Outcome

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) causes swelling in the skin and upper airways and pain in the abdomen because of mucosal swelling. C1-INH-HAE is frequently misdiagnosed, leading to delays in diagnosis, inadequate treatment, and unnecessary procedures.. To evaluate the history of misdiagnosis in patients participating in the Icatibant Outcome Survey (IOS).. The IOS is an observational study in which safety and effectiveness of icatibant have been evaluated since 2009. As part of the IOS, patients record any misdiagnoses received before being diagnosed as having C1-INH-HAE.. In January 2016, a total of 418 of 633 IOS patients with C1-INH-HAE type I or II had provided misdiagnosis data. Of these, 185 of 418 (44.3%) received 1 or more prior misdiagnoses. The most common misdiagnoses were allergic angioedema (103 of 185) and appendicitis (50 of 185). A variety of other misdiagnoses were reported, including a substantial number of gastrointestinal disorders (excluding appendicitis). Misdiagnosis rates were similar between males (41.1%) and females (46.5%) and between C1-INH-HAE type I (43.7%) and type II (51.6%). Patients with family members diagnosed as having C1-INH-HAE were significantly less likely to be misdiagnosed than patients without a family history (140 of 366 [41.7%] vs 38 of 58 [65.5%], respectively; P = .001). Patients with a prior misdiagnosis had longer median delay to C1-INH-HAE diagnosis (13.3 years) than patients without (1.7 years; P < .001).. From this large database, approximately 50% of patients with C1-INH-HAE type I or II have previously had their conditions misdiagnosed, most commonly as allergic angioedema or appendicitis. Misdiagnosis results in marked delays in receiving the correct diagnosis, during which time patients cannot access effective, lifesaving treatment.. ClinicalTrials.gov: NCT01034969.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Child; Child, Preschool; Diagnostic Errors; Female; Humans; Infant; Male; Middle Aged; Young Adult

Information on F12 mutation hereditary angioedema (HAE) is still limited, but Spain is now recognized as having one of the highest concentrations of cases in Western Europe.. To describe unique features of HAE in Spanish carriers of the F12 mutation and investigate a potential role for angiotensin-converting enzyme (ACE) and aminopeptidase-P polymorphisms in disease expression.. This was a prospective observational cohort study of 35 individuals (80% females) from 9 unrelated families carrying the p.Thr309Lys mutation. We analyzed detailed medical records and complement activity (C4, C1q, C1 inhibitor) and screened for mutations in exon 9 of the F12 gene and 2 polymorphisms: XPNPEP2 c-2399A and the ACE insertion/deletion polymorphism.. The p.Thr309Lys mutation was found in all individuals. Three of the 9 index patients had a clinically negative family history, and 72% of males and 29% of females were asymptomatic. Sixteen females (44% estrogen dependent, 56% estrogen sensitive) were clearly symptomatic. The most common locations of attacks were the abdomen (63%), face (25%), and peripheral structures (6%). Triggers other than hyperestrogenic states included stress and minor trauma or pressure. Short-term treatment with C1-inhibitor concentrate and icatibant and long-term prophylaxis with tranexamic acid were useful. The combination of the I allele and A allele was detected in 17% of patients.. The polymorphisms analyzed were not a major determinant of disease expression in our population. We recommend searching for F12 mutations in women with edema attacks without associated wheals and with normal C1-inhibitor levels, particularly when they develop symptoms during hyperestrogenic states or are of Western European or African origin.

Topics: Adolescent; Adult; Aminopeptidases; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Antifibrinolytic Agents; Bradykinin; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Factor XII; Female; Humans; Male; Mutation; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prospective Studies; Spain; Tranexamic Acid; White People; Young Adult

Hereditary angioedema (HAE) is a potentially life-threatening inherited disease characterized by attacks of skin swelling, severe abdominal pain, and upper airway swelling. Attacks typically begin in childhood, but the appropriate diagnosis is often missed. Attacks do not respond to epinephrine, antihistamines, or glucocorticoids. Recently, many effective drugs have been approved for treatment of adults with HAE, and the Medical Advisory Board of the HAE Patient's Association has developed and reported treatment recommendations for adults. Only 1 medication is approved for treatment of children <12 years of age, and there are no reported consensus recommendations for treatment of young children in the United States. The 11-member Medical Advisory Board, with extensive experience in the treatment of children, in concert with the leaders of the HAE Patient's Association, has developed these consensus recommendations to help in recognition, diagnosis, treatment of attacks, and prophylaxis of children with HAE.

Topics: Adolescent; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Antifibrinolytic Agents; Bradykinin; Child; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Danazol; Genetic Testing; Humans; Patient Care Team; Patient Education as Topic; Peptides; Recombinant Proteins; Tranexamic Acid

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Disease Progression; Female; Humans; Male; Prodromal Symptoms; Prospective Studies; Registries; Risk Factors; Stress, Psychological; Time Factors; Treatment Outcome

Sporadic and familiar forms of non-histaminergic angioedema and normal C1 inhibitor encompass a group of disorders possibly caused by bradikinin. We aimed to study the subgroups of hereditary angioedema with FXII mutation (FXII-HAE), unknown genetic defect (U-HAE) and idiopathic non-histaminergic acquired angioedema (InH-AAE). We screened the F12 locus in our cohort and delineated the clinical, laboratory and genetic features. Four families carried the p.Thr309Lys mutation in F12 gene. Haplotyping confirmed the hypothesis of a common founder. Six families were affected by U-HAE and 13 patients by sporadic InH-AAE. C4 levels were significantly lower in FXII-HAE than in InH-AAE. In the FXII-HAE group, none had attacks exclusively in high estrogenic states; acute attacks were treated with icatibant. Prophylaxis with tranexamic acid reduced the attack frequency in most patients. Our study provides new data on the diagnosis, clinical features and treatment of non-histaminergic angioedema, underlying the role of the screening for F12 mutations.

Topics: Adolescent; Adult; Aged; Angioedema; Angioedemas, Hereditary; Antifibrinolytic Agents; Bradykinin; Bradykinin B2 Receptor Antagonists; Cohort Studies; Complement C4; Factor XII; Female; Genetic Predisposition to Disease; Genetic Testing; Humans; Italy; Male; Middle Aged; Pedigree; Polymorphism, Single Nucleotide; Tranexamic Acid; Young Adult

Acute attacks of hereditary angioedema are characterized by recurrent localized edema. These attacks can be life threatening and are associated with substantial morbidity and mortality.. To determine factors associated with hospital admission of patients with an acute attack of hereditary angioedema presenting at the emergency department.. This was a multicenter prospective observational study of consecutive patients (January 2011 through December 2013) experiencing an acute hereditary angioedema attack and presenting at the emergency department at 1 of 4 French reference centers for bradykinin-mediated angioedema. Attacks requiring hospital admission were compared with those not requiring admission.. Of 57 attacks in 29 patients, 17 (30%) led to hospital admission. In multivariate analysis, laryngeal and facial involvements were associated with hospital admission (odds ratio 18.6, 95% confidence interval 3.9-88; odds ratio 7.7, 95% confidence interval 1.4-43.4, respectively). Self-injection of icatibant at home was associated with non-admission (odds ratio 0.06, 95% confidence interval 0.01-0.61). The course was favorable in all 57 cases. No upper airway management was required.. Most patients attended the emergency department because they were running out of medication and did not know that emergency treatment could be self-administered. Risk factors associated with hospital admission were laryngeal and facial involvement, whereas self-injection of icatibant was associated with a return home.

Topics: Adult; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Emergency Service, Hospital; Female; France; Humans; Male; Patient Admission; Prospective Studies

Topics: Adult; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Female; Humans; Pregnancy; Pregnancy Complications

Experiences from a Danish patient cohort with hereditary angioedema are reported with focus on home therapy and burden of illness. Eighty patients have been prospectively followed over 11 years, having experienced a total of 7,809 attacks over 469 patient years. More than half of the patients stopped long-term prophylaxis with danazol or tranexamic acid and changed treatment regimen to on-demand treatment with C1 inhibitor concentrate or icatibant. At least 10% of the attacks remained un-treated. More than half of the patients felt that hereditary angioedema had a significant psychological impact on their lives and restricted their physical activities. By December 2012, a total of 39 patients (49%) were practicing home treatment of acute attacks. Home therapy reduced the mean number of acute hospital visits by 84% and significantly improved burden of illness items. In conclusion, home therapy has profoundly improved the lives of hereditary angioedema patients.

Topics: Activities of Daily Living; Administration, Cutaneous; Adult; Aged; Angioedemas, Hereditary; Bradykinin; Complement C1 Inhibitor Protein; Cost of Illness; Danazol; Denmark; Dermatologic Agents; Disease Progression; Drug Administration Schedule; Female; Home Care Services; Hospitalization; Humans; Male; Middle Aged; Motor Activity; Prospective Studies; Quality of Life; Registries; Time Factors; Tranexamic Acid; Treatment Outcome

In the world, hereditary angioedema (HAE) affects 1 every 50000 persons. It is characterized by highly disabling and recurrent episodes of cutaneous, abdominal and laryngeal episodes of angioedema. Asphyxia related mortality ranges from 15 to 50%. In Argentina a plasma derived C1 inhibitor concentrate (pdC1INH) has been available for the treatment of acute attacks for many decades, however, only15 (26%) out of 58 patients had received pdC1INH at least once until 2008, and only2 (3.4%) had used it regularly. After worldwide approval of the new drugs for the treatment of acute HAE attacks, adding icatibant to pdC1INH in Argentina, and after publication of the therapeutic guide for the country, 42 (82%) out of 51 patients from the original group has pdC1INH available to treat their next attack. However, 16 (18%) patients continue without access to medication and other 15 (35.7%) obtain their therapy spuriously through some other affected relative in their environment. Only 12 (28.6%) patients of the group self-treated at home. Access to treatment has greatly improved, but needs to be extended to all patients and self-treatment at home should be encouraged.

Topics: Acute Disease; Angioedemas, Hereditary; Argentina; Bradykinin; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Health Services Accessibility; Humans; Surveys and Questionnaires

No published data presently exist concerning hereditary angioedema (HAE) in Greece. The aim of this study was to present the results from patients recorded by the Greek Hereditary Angioedema Registry over the last 3 years (July 2010 to June 2013).. A systematic recording of HAE cases was undertaken following a physician awareness campaign and confirmation of diagnosis. A questionnaire was also used for the assessment of key parameters of the patients' disease-specific quality of life.. One hundred and sixteen patients from 41 non-related families were recorded. There were 33 (80.5%) families with type I HAE, 7 (17%) with type II HAE and 1 (2.5%) with non-C1 inhibitor (C1-INH), non-FXII HAE. Two further non-C1-INH, non-FXII HAE sporadic cases were recorded. An investigation of non-symptomatic family members revealed another 6 asymptomatic individuals with C1-INH deficiency. The average delay in diagnosis was 16.5 years and the incidence of death in the families of patients was 1 for every 2 families. The use of newer therapeutic agents seems to fall significantly short of the existing needs. HAE was found to affect the quality of life slightly in 14%, greatly in 63% and significantly in 23% of the patients.. Until recently, there has been a significant degree of underdiagnosis of HAE in Greece. Very low compliance with the provisions of the applicable international guidelines and consensus positions, with adverse consequences on the patients' quality of life, was also observed. The centralized model we used to uncover the patients could be effective in other countries presenting with comparable disease characteristics.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Child; Child, Preschool; Danazol; Estrogen Antagonists; Female; Follow-Up Studies; Greece; Humans; Male; Middle Aged; Quality of Life; Registries; Surveys and Questionnaires; Young Adult

Hereditary angioedema is a rare and potentially fatal autosomal dominant disorder characterised by unpredictable skin, gastrointestinal tract or respiratory tract oedema. Plasma-derived C1-esterase inhibitors are effective in the prophylaxis or treatment of hereditary angioedema type I and II attacks, but must be administered intravenously. This may be problematic in patients with venous access difficulties. Icatibant, a bradykinin B2-receptor antagonist, is administered subcutaneously. In July 2008 icatibant received approval for healthcare professional-administered treatment of hereditary angioedema attacks in adults. In 2011 it received European Medicines Agency and US Food and Drug Administration licences for patient-administered treatment of hereditary angioedema attacks. Given these approvals, and with the appropriate training, icatibant could provide the opportunity for patients to self-administer treatment. This is one of the first long-term follow-up reports of patients with hereditary angioedema using self-administered icatibant. During follow-up, icatibant remained effective and patient satisfaction was high.

Topics: Adult; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Female; Humans; Middle Aged; Patient Satisfaction; Self Administration

Hereditary angioedema (HAE) is a rare genetic syndrome caused by a deficiency in functional C1 inhibitor that results in recurrent episodes of nonpruritic swelling of the hands, feet, arms, legs, trunk, face, genitalia, bowels, and larynx beginning in childhood or adolescence and continuing throughout the patient's lifetime. Treatment for acute HAE attacks in the United States has been transformed by new therapies that inhibit the underlying mechanisms of angioedema- notably ecallantide, a potent and specific inhibitor of plasma kallikrein, and icatibant, a selective bradykinin receptor antagonist. These treatments, combined with safer formulations of plasma-derived C1 esterase inhibitor concentrate for HAE prophylaxis and acute treatment, have greatly improved the quality of life for people with HAE, many of whom can now lead fairly normal lives. This article reviews the current therapeutic landscape for HAE, including treatment for acute angioedema attacks, short- and long-term HAE prophylaxis, and home-based therapy.

Topics: Adolescent; Angioedemas, Hereditary; Bradykinin; Child; Clinical Trials as Topic; Cost of Illness; Female; Humans; Male; Peptides; Pregnancy; Secondary Prevention; Treatment Outcome; United States; Young Adult

The For Angioedema Subcutaneous Treatment (FAST)-2, a phase III, double-blind, randomized, multicenter, placebo-controlled study (ClinicalTrials.gov identifier: NCT00500656), established the efficacy and safety of single injections of icatibant, a bradykinin B₂ receptor antagonist, in the treatment of hereditary angioedema (HAE) attacks. Here, we evaluate the efficacy and safety of repeated treatment with icatibant in adult patients experiencing HAE attacks during the FAST-2 open-label extension (OLE) phase.. Patients completing the controlled phase were eligible to participate in the OLE phase and receive open-label icatibant (30 mg subcutaneously) for the treatment of cutaneous, abdominal, and/or laryngeal HAE attack(s) severe enough to warrant treatment. Time to onset of symptom relief was calculated for each attack. Descriptive analyses (median, 95% CIs) were performed for all attacks; post hoc analyses were conducted in patients with at least five icatibant-treated attacks throughout the FAST-2 OLE phase. Safety was also monitored.. Fifty-four patients received icatibant for 374 attacks (176 cutaneous, 168 abdominal, and 30 laryngeal). For cutaneous and/or abdominal attacks (attacks 2-5), the median times to onset of symptom relief ranged between 2.0 and 2.5 h. For all laryngeal attacks, the median times to regression (start of improvement) of symptoms ranged between 0.3 and 4.0 h. Post hoc analyses showed that the overall median time to onset of symptom relief was 2.0 h. Overall, 89.8% of attacks resolved with a single icatibant injection. No drug-related serious adverse events were reported.. These findings have demonstrated the efficacy and safety of repeated icatibant treatment for HAE attacks.

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Clinical Trials, Phase III as Topic; Cohort Studies; Double-Blind Method; Female; Humans; Injections, Subcutaneous; Male; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Secondary Prevention; Treatment Outcome

Angioedema owing to hereditary deficiency of C1 inhibitor (HAE) is a rare, life-threatening, disabling disease. In the last 2 years, the results of well-designed and controlled trials with existing and new therapies for this condition have been published, and new treatments reached the market. Current guidelines for the treatment for HAE were released before the new trials and before the new treatments became available and were essentially based on observational studies and expert opinion. To provide evidence-based HAE treatment guidelines supported by the new studies, a conference was held in Gargnano del Garda, Italy, from September 26 to 29, 2010. The meeting hosted 58 experienced HAE expert physicians, representatives of pharmaceutical companies and representatives of HAE patients' associations. Here, we report the topics discussed during the meeting and evidence-based consensus about management approaches for HAE in adult/adolescent patients.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Humans; Kallikreins; Peptides

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Disease Progression; Feasibility Studies; Female; Health Personnel; Humans; Injections, Subcutaneous; Male; Middle Aged; Pruritus; Recurrence

Hereditary angioedema (HAE) is a rare, potentially life-threatening autosomal dominant disease characterized by recurrent angioedema attacks that affect the skin, gastrointestinal tract, and airway, including the larynx. Pharmacologic developments in HAE treatment have culminated in the recent introduction of 4 new HAE-specific therapies in the United States.. In light of these new therapeutic options, this commentary outlines historical US HAE therapy choices, discusses the potential effect of the 4 recently approved HAE treatments, and considers strategies for optimizing their use in line with international treatment recommendations.. Treatment options for HAE in the United States have been limited to attenuated androgens and antifibrinolytic agents for long-term prophylaxis and FFP and supportive therapy for the management of acute attacks. The 4 new therapies that have recently become available (ie, 2 plasma-derived C1 esterase inhibitor (C1-INH) concentrates, the kallikrein inhibitor ecallantide, and the bradykinin β(2)-antagonist icatibant) have provided an opportunity to change routine HAE treatment. In 2009, despite the availability of 2 of the new treatments (ie, the plasma-derived C1-INH concentrates), a large survey of US physicians suggested that wide variability still existed in the treatment of patients with HAE. Since this survey was undertaken, clinical experience with all 4 new treatments has increased significantly, and because 3 of these agents (ie, 2 plasma-derived C1-INH concentrates and icatibant) can be self-administered by trained patients, physicians can now provide individualized care that is proven effective and more aligned with international guidance.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Disease Management; Humans; Kallikreins; Peptides; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; United States

We evaluated the efficacy and safety of icatibant self-administration in 15 patients with hereditary angioedema (HAE) types I or III, for 55 acute attacks (mostly severe or very severe). Icatibant self-administration was generally effective: first symptom improvement occurred in 5 min-2 h (HAE type I; n = 17) and 8 min-1 h (HAE type III; n = 9) for abdominal attacks and 5-30 min (HAE type I; n = 4) and 10 min-12 h (HAE type III; n = 6) for laryngeal attacks. Complete symptom resolution occurred in 15 min-19 h (HAE type I; n = 8) and 15 min-48 h (HAE type III; n = 9) for abdominal attacks and 5-48 h (HAE type I; n = 3) and 8-48 h (HAE type III; n = 5) for laryngeal attacks. No patient required emergency hospitalization. The only adverse events were mild, spontaneously resolving injection site reactions. Patients reported that carrying icatibant with them gave them greater confidence in managing their condition.

Topics: Acute Disease; Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Disease Progression; Erythema; Female; Humans; Male; Middle Aged; Prospective Studies; Quality of Life; Self Administration; Surveys and Questionnaires; Young Adult

We present the case of a 28-year-old female with a previous diagnosis of C1 esterase inhibitor deficiency presenting for dental extractions under general anaesthesia. Following prophylaxis with a new bradykinin receptor 2 antagonist (icatibant), surgery was carried out uneventfully with an unremarkable postoperative course.

Topics: Adult; Anesthesia, General; Angioedema; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1s; Female; Humans; Molar, Third; Monitoring, Intraoperative; Oral Surgical Procedures; Perioperative Care; Preoperative Care

Hereditary angio-oedema (HAE) is a rare genetic disease caused by deficiency of complement C1 inhibitor. It is characterised by recurrent episodes of subcutaneous or submucosal oedema typically involving the extremities, bowel, face or larynx. Within the latest years it has become evident that the active mediator of HAE attacks is an increased level of bradykinin and various new treatment modalities have been developed. The aim of this paper is to give an update from the Danish HAE Comprehensive Care Centre on current treatment possibilities and address some of the challenges when diagnosing HAE.

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Diagnosis, Differential; Erythema; Female; Humans; Kallikreins; Laryngeal Edema; Peptides; Receptor, Bradykinin B2; Recombinant Proteins

Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is characterized by recurrent edema attacks in various organs. The objective of the present study was to assess the efficacy and safety of weekly long-term replacement treatment with one or more injections of plasma-derived C1-INH concentrate per week (WLTC) in patients with HAE-C1-INH.. Nineteen patients with HAE-C1-INH underwent WLTC for 9 years on average. The benefits and risks were determined based on regular recording by the patients of the severity and number of attacks at the beginning and the end of the study.. All patients reported that all or most of their attacks were much less severe: the percentage of severe attacks was 93.3% without and 3.8% with treatment. In 8 of the 14 patients undergoing WLTC, the monthly number of attacks was lower at the end of the study than before the study, higher in 5 patients, and unchanged in 1 patient. The mean number of attacks per week in 6 patients (1 patient initially received weekly on-demand treatment for 2 years and then shifted to WLTC) with weekly on-demand treatment was 4.3 (SD 1.9) at the beginning and 8.0 (SD 3.1) at the end of the study.. HAE-C1-INH can be significantly improved by one or more injections of C1-INH concentrate per week. However, patients have to accept a large number of intravenous injections and, in some cases, an increase in disease activity.

Topics: Adult; Aged; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Complement C1 Inhibitor Protein; Drug Administration Schedule; Humans; Male; Middle Aged; Prospective Studies

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Humans; Kallikreins; Peptides; Self Administration

Hereditary angioedema is a disease which develops as a result of a deficiency or dysfonction of C1-inhibitor, a key regulator of the complement, coagulation and contact cascades, resulting among others in excessive release of bradykinin. This disease mortality rate is high in absence of immediate and effective treatment, in particular in presence of acute attacks of the upper respiratory tract (laryngeal edema). Until now only administration of a purified C1-inhibitor extract was effective against these symptoms. This paper aims to synthesise essentials knowledge concerning news drugs, in particular icatibant, a selective bradykinin B2- receptor antagonist whose use should be widened to the treatment of angioedema with ACE-inhibitors intolerance.

Topics: Adrenergic beta-Antagonists; Angioedemas, Hereditary; Bradykinin; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Humans

Topics: Adult; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Diagnosis, Differential; Female; Humans; Hypovolemia; Kinins; Shock; Tomography, X-Ray Computed

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Clinical Trials as Topic; Humans

Topics: Adrenergic beta-Antagonists; Angioedemas, Hereditary; Bradykinin; Cost-Benefit Analysis; Drug Costs; Humans; Managed Care Programs; United States

Topics: Angioedemas, Hereditary; Anti-Inflammatory Agents; Bradykinin; Complement C1 Inhibitor Protein; Drug Utilization; Half-Life; Humans; Recombinant Proteins; Time Factors; Treatment Outcome

The bradykinin B2 receptor antagonist icatibant has recently become available for treating hereditary angioedema. Our observations demonstrate icatibant to be effective and safe for the treatment of both, abdominal and cutaneous attacks in a practice setting beyond clinical studies.

Topics: Adult; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin Receptor Antagonists; Female; Humans; Male; Middle Aged; Treatment Outcome

Icatibant is a selective antagonist of the bradykinin type 2 receptor. In the randomized, double-blind, multicentre, FAST-1 trial, the difference in the median time to the onset of symptom relief (primary endpoint) did not reach statistical significance between a single dose of subcutaneous icatibant 30 mg and placebo in adults with moderate to very severe acute abdominal or cutaneous episodes of hereditary angioedema. However, icatibant was effective with regard to several other endpoints, providing significantly greater reductions from baseline in symptom severity scores 4 and 12 hours after administration, and eliciting significantly shorter times to both first symptom improvement and overall patient improvement than placebo. In the similarly designed, active comparator-controlled, FAST-2 trial, a single dose of subcutaneous icatibant 30 mg was associated with a significantly shorter median time to onset of symptom relief (primary endpoint) than oral tranexamic acid in adults with acute abdominal or cutaneous episodes of hereditary angioedema, and was also more effective than tranexamic acid in terms of most other endpoints. Across both FAST-1 and -2, the efficacy of subcutaneous icatibant 30 mg in the treatment of laryngeal episodes of hereditary angioedema was generally consistent with that seen for abdominal and cutaneous episodes, with a median time to first symptom improvement of 0.6-1.0 hours. Subcutaneous icatibant was generally well tolerated in adult patients with hereditary angioedema in the FAST trials, with the most common adverse events being injection-site reactions that were generally of mild severity, transient in nature and resolved spontaneously without treatment.

Topics: Adult; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Bronchodilator Agents; Calcium Channel Blockers; Chemistry, Pharmaceutical; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Humans; Infusions, Intravenous; Injections, Intravenous; Meta-Analysis as Topic; Pain Measurement; Pain, Postoperative; Serotonin Receptor Agonists; Tooth Extraction; Treatment Outcome

Topics: Adrenergic beta-Antagonists; Angioedemas, Hereditary; Bradykinin; Complement C1 Inactivator Proteins; Humans; Male; Middle Aged; Treatment Outcome

Topics: Acute Disease; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Humans

Topics: Acute Disease; Angioedemas, Hereditary; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Humans; Kallikreins; Peptides

Hereditary angioedema (HAE) is an autosomal dominant disease associated with episodic attacks of nonpitting edema that may affect any external or mucosal body surface. Attacks most often affect the extremities, causing local swelling, the GI tract, leading to severe abdominal pain, and the mouth and throat, at times causing asphyxiation. Most patients with HAE have low levels of the plasma serine protease inhibitor C1 inhibitor. The edema in these patients is caused by unregulated generation of bradykinin. Effective chronic therapy of patients with impeded androgens or plasmin inhibitors has been available for decades, but in the United States, we do not have therapy for acute attacks. Five companies have completed or are in the process of conducting phase 3 clinical trials, double-blind, placebo-controlled studies of products designed to terminate acute attacks or to be used in prophylaxis. Two companies, Lev Pharmaceuticals and CSL Behring, have preparations of C1 inhibitor purified from plasma that have been used in Europe for decades (trade names Cinryze and Berinert P, respectively). One company, Pharming, has developed a recombinant C1 inhibitor preparation. One company, Dyax, is testing a kallikrein inhibitor (ecallantide), and one company, Jerini, is completing testing of a bradykinin type 2 receptor antagonist (Icatibant). Although little has been published thus far, all of these products may prove effective. It is likely that HAE treatment will change dramatically within the next few years.

Topics: Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Clinical Trials, Phase III as Topic; Complement C1 Inhibitor Protein; Controlled Clinical Trials as Topic; Double-Blind Method; Humans; Kallikreins; Peptides; Recombinant Proteins; United States