Successful treatment of post-pericardiotomy syndrome via C1 inhibitor replacement therapy in a hereditary angioedema patient with Marfan syndrome.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (HAE-C1INH) is caused by dysfunctional C1-INH protein due to mutations in the SERPING1 gene encoding C1-INH. Marfan syndrome is a genetic connective tissue disease that affects the cardiovascular and ocular systems along with the skeletal system. In this case, we present the successful treatment of post-pericardiotomy syndrome unresponsive to classical therapy, which has not been described in the literature. The syndrome developed in a patient with hereditary angioedema (HAE) who underwent open heart surgery due to cardiac involvement in Marfan syndrome. CASE: A nine-year-old male HAE-C1INH patient underwent open heart surgery secondary to cardiac involvement caused by Marfan syndrome. To prevent HAE attacks, 1000 units of C1 inhibitor concentrate therapy were given 2 hours before and 24 hours after the operation. Post-pericardiotomy syndrome was diagnosed on the postoperative second day and ibuprofen 15 mg/kg/day (3 weeks) was started. Since there was no response to classical treatment on the 21st postoperative day, C1 inhibitor concentrate treatment was planned as 1000 units/ dose for 2 days a week considering a prolonged hereditary angioedema attack. In the second week of treatment, complete recovery was achieved for pericardial effusion with a total of 4 doses. CONCLUSIONS: We emphasize that in patients with hereditary angioedema undergoing this treatment, care should be taken in terms of complications that may be associated with the disease even if short-term prophylaxis is given before operations and that longer-term use of C1 inhibitor concentrate has a place in treatment.

Short-term prophylaxis for children and adolescents with hereditary angioedema.

Background: Hereditary Angioedema (HAE) is a rare, autosomal dominant, life threatening disease, secondary to the deficiency of C1-inhibitor, dysfunction of C1-inhibitor or inadequate control of the contact pathway. Presentation includes recurrent swelling of the skin, upper airway and the abdomen. Trauma can precipitate attacks, which in the airway can lead to asphyxia. For this reason, short term prophylaxis (STP) may be indicated before medical, surgical and dental procedures. The goal of the manuscript is to review short term prophylaxis for children of all ages. Methods: We searched the following search words: children, pediatric, adolescent, plasma derived C1-inhibitor, recombinant C1-inhibitor, surgery, medical procedures, prophylaxis, dental, Hereditary Angioedema, tranexamic acid, androgens, fresh frozen plasma, short term prophylaxis, lanadelumab, subcutaneous C1-inhibitor in Google Scholar and in PubMed to develop our results. Results: STP should be discussed at every visit. Plans should be individualized based upon the procedure, therapies available and shared decision making with patient/parent. For high risk procedures plasma derived C1-inhibitor should be used at 20 units/kg just prior to the procedure. Alternative agents for STP include recombinant C1-inhibitor, fresh frozen plasma, androgens, or tranexamic acid. In all cases, with or without the use of STP, 2 doses of on-demand therapy should be available in case of an attack. Conclusion: Herein, we review the published data on STP for pediatric patients with HAE and discuss first-line options, and off label use of medications, as well as review the guidelines pertaining to short term prophylaxis.

Assessing the cost and quality-of-life impact of on-demand-only medications for adults with hereditary angioedema.

Background: Novel subcutaneous (SC) prophylactic therapies are transforming the treatment landscape of hereditary angioedema (HAE). Although questions are being raised about their cost, little attention has been paid to the cost and quality of life (QoL) impact of using on-demand-only medications. Objective: We assessed the overall economic burden of on-demand-only treatment for HAE and compared patient QoL with patients who received novel SC prophylactic therapies. Methods: US Hereditary Angioedema Association members were invited to complete an anonymous online survey to profile attack frequency, treatment use, and the presence of comorbidities as well as economic and socioeconomic variables. We modeled on-demand treatment costs by using net pricing of medications in 2018, indirect patient and caregiver costs, and attack-related direct billed costs for emergency department admissions, physician office visits, and/or hospitalizations. QoL was assessed by using the Angioedema Quality of Life questionnaire. Results: A total of 1225 patients (31.4%) responded. Of these, 737 adults with HAE (type I or II) met the inclusion criteria and completed the survey. Per patient/year direct costs associated with modeled on-demand-only treatment totaled $363,795, with additional indirect socioeconomic costs of $52,576 per patient/year. The greatest improvement in QoL was seen in patients who used novel SC prophylactic therapies, with a 59.5% (p < 0.01) improvement in median impairment scores versus on-demand-only treatment. In addition, patients who used novel SC prophylactic therapies reported a 77% reduction in the number of attacks each year when compared with those who used on-demand-only treatment. Conclusion: Our real-world patient data showed the cost and QoL burden of HAE treatment with on-demand-only therapy. Use of novel SC prophylaxis can lead to sizeable reductions in attack frequency and statistically significant and clinically relevant improvements in QoL. These data could be useful to clinicians and patients as they consider therapy options for patients with HAE.

Successful perioperative management of three patients with hereditary angioedema without C1 esterase inhibitor therapy: A developing country perspective.

BACKGROUND: Hereditary angioedema (HAE) is a rare inherited disorder characterized by sudden and unpredictable appearance of swelling. Surgical procedures, even minor ones, are known to precipitate an attack in these patients. C1 esterase inhibitor (C1-INH) therapy may be effective for short term prophylaxis in such situations. However, there is limited experience with short term prophylaxis in countries where C1-INH therapy is not available. METHODS: To report our experience of using short term prophylaxis for a dental procedure, a Cesarean section and a major hip surgery in one patient each with HAE in resource constrained settings. RESULTS: All 3 patients were given FFP before and during the procedure. While the first (a 6-year-old girl) and third patient (a 60-year-old male) were already taking stanozolol and the dose was doubled 5 days before the surgery, the second patient (28-year-old woman) was not taking any prophylaxis and she was initiated on stanozolol on the day of Cesarean section. The first patient was also given additional FFP one day after the dental procedure. After the procedure, the dose of stanozolol was decreased to baseline in patient 1 and 3 while it was discontinued in patient 3. All 3 patients tolerated the procedures well and had no related episodes of angioedema. CONCLUSIONS: Dental and other major surgical procedures in patients with HAE are known to precipitate an episode of angioedema. In countries where C1-INH therapy is not available, attenuated androgens and FFP may be used to prevent these episodes.

Exogenous hormones and hereditary angioedema.

Gonadal hormones, estrogen and androgen are strongly involved in the control of the bradykinin production. Estrogen may worsen whereas androgen can be part of the long-term prophylactic treatment. In this review, we will describe the potential impact of estrogen in the pathophysiology of hereditary angioedema (HAE). Then we will review the different hormone treatments and their implication on the course of HAE in women and men: contraception, Assisted Reproductive Technology (ART), menopause, hormone dependent cancers in women and men, treatment of hyperandrogenism in women.

Current and emerging therapies to prevent hereditary angioedema attacks.

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.

Population pharmacokinetics of subcutaneous C1-inhibitor for prevention of attacks in patients with hereditary angioedema.

BACKGROUND: Long-term prophylaxis with subcutaneous (SC) administration of a highly concentrated plasma-derived C1-esterase inhibitor (C1-INH) formulation was recently approved by the Food and Drug Administration for hereditary angioedema (HAE) attack prevention. OBJECTIVE: To characterize the population pharmacokinetics of C1-INH (SC) (HAEGARDA® ; CSL Behring) in healthy volunteers and HAE patients, and assess the variability and influence of covariates on pharmacokinetics. METHODS: C1-INH functional activity data obtained after administration of various C1-INH (intravenous; IV) and C1-INH (SC) doses from 1 study in healthy volunteers (n = 16) and 2 studies in subjects with HAE (n = 108) were pooled to develop a population pharmacokinetic model (NONMEM v7.2). Pharmacokinetic parameters derived from steady-state simulations based on the final model were also evaluated. RESULTS: C1-INH functional activity following C1-INH (SC) administration was described by a linear one-compartment model with first-order absorption and elimination, with inter-individual variability in all parameters tested. The mean population bioavailability of C1-INH (SC), and pharmacokinetic parameters for clearance (CL), volume of distribution, and absorption rate were estimated to be ~43%, 1.03 mL/hour/kg, 0.05 L/kg and 0.0146 hour-1 , respectively. The effect of bodyweight on CL of C1-INH functional activity was included in the final model, estimated to be 0.74. Steady-state simulations of C1-INH functional activity vs time profiles in 1000 virtual HAE patients revealed higher minimum functional activity (Ctrough ) levels after twice-weekly dosing with 40 IU/kg (~40%) and 60 IU/kg (~48%) compared with 1000 IU IV (~30%). Based on the population pharmacokinetic model, the median time to peak concentration was ~59 hours and the median apparent plasma half-life was ~69 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Twice-weekly bodyweight-adjusted dosing of C1-INH (SC) exhibits linear pharmacokinetics and dose-dependent increases in Ctrough levels at each dosing interval. In this analysis, SC dosing led to maintenance of higher Ctrough levels than IV dosing.

Management of Children With Hereditary Angioedema Due to C1 Inhibitor Deficiency.

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.

Perioperative course in patients with hereditary or acquired angioedema.

PURPOSE: Two types of bradykinin-mediated angioedema, hereditary angioedema (HAE) and acquired angioedema (AAE), result from deficiency or dysfunction of C1 esterase inhibitor, leading to an overproduction of bradykinin, which can lead to vascular permeability and life-threatening angioedema of the airway. The objective of this study was to review perioperative outcomes in a series of patients with HAE and AAE and to review current knowledge about anesthetic complications in patients with HAE or AAE. METHODS: Medical records were retrospectively reviewed for perioperative complications in patients with HAE or AAE who underwent general anesthesia from January 1, 2000, to December 31, 2014, at our institution. RESULTS: Twenty-four patients (13 with HAE, 10 with AAE, and 1 with unspecified angioedema) underwent 38 instances of general anesthesia with airway manipulation. All except 4 received prophylactic therapy. One patient, a 67-year-old woman who was pretreated with stanozolol and fresh frozen plasma required reintubation after postoperative airway edema developed. CONCLUSION: Life-threatening episodes of angioedema of the airway occur infrequently, but they can occur in patients who received pretreatment and in patients who have previously undergone anesthesia uneventfully. Anesthesiologists must be ready to emergently manage a difficult airway and must be familiar with recommendations provided in consensus guidelines for the treatment of HAE and AAE patients.

Escalating doses of C1 esterase inhibitor (CINRYZE) for prophylaxis in patients with hereditary angioedema.

BACKGROUND: Nanofiltered C1 inhibitor (human) is approved in the United States for routine prophylaxis of angioedema attacks in patients with hereditary angioedema, a rare disease caused by a deficiency of functional C1 inhibitor. OBJECTIVE: To assess the safety of escalating doses of nanofiltered C1 inhibitor (human) in patients who were not adequately controlled on the indicated dose (1000 U every 3 or 4 days). METHODS: Eligible patients had >1 attack/month over the 3 months before the trial. Doses were escalated to 1500 U every 3 or 4 days for 12 weeks, at which point, the patients were evaluated. If treatment was successful (≤1 attack/mo) or at the investigator's discretion, the patients entered a 3-month follow-up period. The patients with an average of >1 attack/month were eligible for further escalation to 2000 U and then 2500 U. RESULTS: Twenty patients started at 1500 U; 13 were escalated to 2000 U, and 12 were escalated to 2500 U. Eighteen patients reported adverse events. Two patients reported 4 serious adverse events (cerebral cystic hygroma, laryngeal angioedema attack, anemia, and bile duct stone) that were considered by investigators to be unrelated to treatment. Notably, there were no systemic thrombotic events or discontinuations due to adverse events. Fourteen patients were treated successfully (70%), continued to the follow-up period at the investigator's discretion, or experienced a reduction in attacks of >1.0/month. CONCLUSIONS: Dose escalation of nanofiltered C1 inhibitor (human) up to 2500 U was well tolerated and reduced attack frequency in the majority of patients.

High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency.

BACKGROUND: The inherited deficiency of C1-inhibitor (C1-INH), which can be quantitative (type I) or qualitative (type II), is characterized by recurrent attacks of oedema, and it is known as hereditary angioedema due to C1-INH deficiency (HAE-C1-INH). The frequency of symptoms varies widely among patients and in the same patient during life. OBJECTIVE: To identify laboratory markers of disease severity in HAE-C1-INH patients. METHODS: We studied 162 patients with differently severe HAE-C1-INH during remission, 31 HAE-C1-INH patients during attacks, and 81 normal controls, evaluating complement parameters, spontaneous plasma kallikrein activity, the capacity of plasma to inhibit exogenous kallikrein activity, and cleavage of high-molecular-weight kininogen (HK). Sixty-five HAE-C1-INH patients were screened for mutations in the C1-INH gene. RESULTS: As expected, plasma C1-INH levels and activity and C4 levels were low in the HAE-C1-INH patients. Spontaneous plasma kallikrein activity in patients in remission was higher than in controls (P = 0.001) and increased during acute attacks (P = 0.01), whereas the capacity of inhibiting kallikrein activity was lower in patients in remission than in controls (P = 0.001) and further reduced during attacks (P = 0.001). HAE-C1-INH patients in remission had higher levels of cleaved HK than controls (P = 0.001), and these further increased during acute attacks (P = 0.001). Cleaved HK levels were higher in highly symptomatic HAE-C1-INH patients than in those with less frequent attacks (P = 0.001). Thirty-five different mutations in the C1-INH gene were equally distributed in patients with different attack frequencies. CONCLUSIONS: Measuring plasma levels of cleaved HK may be a sensitive mean of assessing disease severity in HAE-C1-INH patients.

Bradykinin B2 receptor antagonist off label use in short-term prophylaxis in hereditary angioedema.

Hereditary angioedema type I (HAE-C1-INH) is an inherited disorder characterized by repeated severe angioedema attacks mostly triggered by traumas, emotional stress, increased estrogen levels or surgical procedures, in particular, odontostomatological interventions. Icatibant, a bradykinin B2 receptor antagonist, has been approved for treatment of HAE attacks. In this paper we describe the “off label” administration of icatibant as short-term prophylaxis of dental extraction in a patient with HAE with the aim of preventing perioperative angioedema attacks. The drug showed an effective and safe profile. Thus, a short-term prophylaxis of angioedema attacks in patients with HAE may be arranged on a multidisciplinary basis, according to the clinical history of each single patients.

Management and prevention of hereditary angioedema attacks.

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.

Recent advances in the management of hereditary angioedema.

Hereditary angioedema (HAE) is a rare genetic condition that manifests as painful and potentially life-threatening episodic attacks of cutaneous and submucosal swelling. It results from functional deficiency of C1 inhibitor (C1 INH), which is a regulator of the complement, fibrinolytic, kinin (contact), and coagulation systems. In patients with HAE, the low plasma concentration of functional C1 INH leads to overactivation of the kinin cascade and local release of bradykinin. Bradykinin is responsible for the pain, vascular permeability changes, and edema associated with HAE. Until recently, therapeutic options for HAE have been very limited. Many new therapies have emerged, however, such as C1 INH replacement drugs and medications aimed at components of the contact system (eg, plasma kallikrein inhibitor and bradykinin B2 receptor antagonist). The authors review current and novel treatments for patients with HAE.

Preprocedural administration of nanofiltered C1 esterase inhibitor to prevent hereditary angioedema attacks.

Patients with hereditary angioedema (HAE) may have attacks triggered by dental, medical, or surgical procedures. This analysis evaluated the efficacy and safety of preprocedural administration of nanofiltered C1 esterase inhibitor (C1 INH-nf; human) for the prevention of HAE attacks during and after dental, medical, or surgical procedures. Data were reviewed retrospectively from two acute treatment trials in which at least 1000 U of C1 INH-nf was administered i.v. within 24 hours before an emergency or noncosmetic medical, surgical, or dental procedure. Dosing data, HAE attacks reported within 72 hours, and adverse events (AEs) reported within 7 days after a preprocedural dose of C1 INH-nf were analyzed to assess efficacy and safety. Forty-one unique subjects (8 children and 33 adults) received C1 INH-nf for 91 procedures (40 in children and 51 in adults). The majority of procedures (56%) involved dental work and 44% involved a variety of surgical or medical procedures. A single 1000-U dose of C1 INH-nf was administered for 96% of procedures. An HAE attack did not occur within 72 hours after C1 INH-nf dosing for 98% (89/91) of procedures. Two HAE attacks were reported after the procedure, and both were treated with C1 INH-nf and achieved relief. None of the reported AEs were judged to be related to C1 INH-nf or were associated with an HAE attack. This analysis supports the efficacy and safety of preprocedural administration of C1 INH-nf for the prevention of HAE attacks.

Assessment of rebound and relapse following ecallantide treatment for acute attacks of hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease characterized by unpredictable and recurring attacks of angioedema. This study assessed potential attack rebound and relapse following treatment with ecallantide, a plasma kallikrein inhibitor approved for HAE attack treatment. METHODS: Results were integrated from 2 double-blind, placebo-controlled studies of ecallantide treatment for HAE: EDEMA3-DB and EDEMA4. Symptoms were assessed by treatment outcome score (TOS), mean symptom complex severity (MSCS) score, and global response. Patients with improvement at 4 h post-dosing in all three measures followed by any sign of worsening at 24 h were considered to show potential rebound if worsening was beyond baseline or potential relapse if not beyond baseline. Likeliness of rebound or relapse was determined by the number of measures showing worsening and the magnitude of worsening. Patients receiving placebo who met the criteria for rebound/relapse were evaluated for descriptive comparison only. RESULTS: Significantly more ecallantide-treated patients (42 of 70) compared to placebo (26 of 71) showed improvement in three measures at 4 h and were thus eligible for rebound/relapse (P = 0.006). Of the nine ecallantide-treated patients with signs of worsening at 24 h, none were likely rebound, one was assessed as possible rebound, one as likely relapse, and two as possible relapse. No patient with potential rebound/relapse experienced new symptoms after dosing. Medical intervention was required in one ecallantide-treated patient. CONCLUSION: Ecallantide was efficacious for treating acute HAE attacks. Relapse was observed in a small proportion of patients, and there was little evidence of rebound.

Update on treatment of hereditary angioedema.

BACKGROUND: 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. OBJECTIVE: To update allergists and primary care physicians on new advances in HAE therapies. DATA SOURCES: A PubMed literature search was used to develop this manuscript. STUDY SELECTIONS: English language peer-reviewed angioedema articles were selected. High quality Phase II and III placebo-controlled clinical trials were reviewed and summarized. RESULTS: 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. CONCLUSION: 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.