Bruce Ritchie

Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.)

Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks.

BACKGROUND Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder. OBJECTIVE To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema. METHODS This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours. RESULTS Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus. CONCLUSION C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief.

WAO Guideline for the Management of Hereditary Angioedema

Hereditary Angioedema (HAE) is a rare disease and for this reason proper diagnosis and appropriate therapy are often unknown or not available for physicians and other health care providers. For this reason we convened a group of specialists that focus upon HAE from around the world to develop not only a consensus on diagnosis and management of HAE, but to also provide evidence based grades, strength of evidence and classification for the consensus. Since both consensus and evidence grading were adhered to the document meets criteria as a guideline. The outcome of the guideline is to improve diagnosis and management of patients with HAE throughout the world and to help initiate uniform care and availability of therapies to all with the diagnosis no matter where the residence of the individual with HAE exists.

Clinical perspectives of emerging pathogens in bleeding disorders

Summary As a result of immunological and nucleic-acid screening of plasma donations for transfusion-transmissible viruses, and the incorporation of viral reduction processes during plasma fractionation, coagulation-factor concentrates (CFC) are now judged safe in terms of many known infectious agents, including hepatitis B and C viruses, HIV, and human T-cell lymphotropic virus. However, emerging pathogens could pose future threats, particularly those with blood-borne stages that are resistant to viral-inactivation steps in the manufacturing process, such as non-lipid-coated viruses. As outlined in this Review, better understanding of infectious diseases allows challenges from newly described agents of potential concern in the future to be anticipated, but the processes of zoonotic transmission and genetic selection or modification ensure that plasma-derived products will continue to be subject to infectious concerns. Manufacturers of plasma-derived CFC have addressed the issue of emerging infectious agents by developing recombinant products that limit the need for human plasma during production. Such recombinant products have extended the safety profile of their predecessors by ensuring that all reagents used for cell culture, purification steps, and stabilisation and storage buffers are completely independent of human plasma.

Canadian hereditary angioedema guideline

Hereditary angioedema (HAE) is a disease which is associated with random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased Health Related Quality of Life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada is neither optimal nor uniform across the country. It lags behind other countries where there are more organized models for HAE management, and where additional therapeutic options are licensed and available for use. The objective of this guideline is to provide graded recommendations for the management of patients in Canada with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. It is anticipated that by providing this guideline to caregivers, policy makers, patients and their advocates, that there will be an improved understanding of the current recommendations regarding management of HAE and the factors that need to be considered when choosing therapies and treatment plans for individual patients. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency physicians, gastroenterologists, dentists and otolaryngologists, who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.

Activated prothrombin complex concentrate for dabigatran-associated bleeding

A humanized antibody fragment to reverse the oral thrombin inhibitor dabigatran is currently under development (Schiele et al, 2013). The absence of a specific reversal agent has caused apprehension over the use of this anticoagulant (Cotton et al, 2011). Prothrombin complex concentrate (PCC) and activated factor VII seemed ineffective in recently reported cases (Lillo-Le Louet et al, 2012), and animal models and ex vivo studies have provided conflicting results Majeed & Schulman, 2013). Although dabigatran has a low degree of binding to plasma proteins and is dialyzable (Khadzhynov et al, 2013), it may take many hours to eliminate this drug from the circulation. We treated four patients with potentially life-threatening dabigatran-associated bleeding with activated PCC (FEIBA, Baxter AG, Vienna, Austria), two in Hamilton, Ontario and two in Edmonton, Alberta. The laboratory and transfusion data are shown in Fig 1. Creatinine clearance was estimated with the Cockroft-Gault formula. An 84-year-old male (Hamilton 1) with a medical history of atrial fibrillation, hypertension and chronic renal insufficiency was urgently referred to our tertiary care hospital with subdural haematoma. He had fallen at home 1 month earlier and, at the time of presentation, had a 3-day history of headache and progressive left sided weakness. Computed tomography (CT) showed acute on chronic right parietal subdural haematoma with associated midline shift (Fig 2). The last dose of dabigatran, 110 mg, was 2 d before transfer to our hospital. On admission the thrombin time (TT) was 127 s (normal range 20–30 s), activated partial thromboplastin time (aPTT) was 46 s (normal 22–35 s), prothrombin time – international normalized ratio (INR) was 1 2, dabigatran concentration (with Hemoclot ) was 50 ng/ml, and creatinine 135 lmol/l with calculated creatinine clearance of 45 ml/min. The neurosurgeon elected to defer haematoma drainage until dabigatran had been eliminated. The patient received 4600 units (50 units/kg) of aPCC, whereafter the weakness improved without immediate change in the coagulation profile. The thrombin time normalized 3 d later and he underwent uneventful craniotomy with evacuation of 100 ml of blood. Repeat imaging demonstrated resolution of the bleed and he was discharged home the next day. At 1month follow-up, there was complete resolution of the weakness. An 81-year-old female (Hamilton 2) with atrial fibrillation and hypertension woke up in the morning, 12 h after her last dabigatran dose (110 mg), and felt normal but 1 h later she fell off the toilet and was disoriented, unsteady and had right-sided weakness and slurred speech. When the paramedics arrived, 20 min later, her blood pressure was 196/100. CT, 70 min after onset showed acute intra-axial haemorrhage

Optimization of the isolation and effective use of mRNA from rat mast cells

To define the molecular regulation of mast cell phenotype and function optimized procedures must be available to study mRNA from mast cells freshly isolated from tissues. However, rat peritoneal mast cells (PMC) contain large amounts of the proteoglycan heparin, and unfortunately, this molecule which is a potent inhibitor of reverse transcriptase (RT) and Taq polymerase and thus RT-PCR, copurifies with RNA. Here we describe an optimized protocol for extracting and amplifying RNA from rat PMC. Mast cells were isolated from rat peritoneum and a method modified from that of Chomczynski and Sacchi (1987) was used to extract the RNA. Following the removal of heparin by heparinase digestion, first strand cDNA synthesis was primed with oligo-dT and the resulting cDNA was quantified by rapid paper chromatography. The use of a detection system for the reverse transcription reaction ensured that the production of cDNA had occurred and allowed subsequent PCR testing to be optimal. cDNA thus produced can be used to detect relatively specific (histidine decarboxylase) and non-specific (beta-actin) mast cell products. Our PCR studies have shown a 300-fold increase in sensitivity over RNA processed by other methods.

Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor

BACKGROUND Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS We conducted an international, prospective, multicenter, randomized, double‐blind, placebo‐controlled, dose‐ranging, phase 3 trial to evaluate the efficacy and safety of self‐administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2‐month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16‐week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, –2.42 attacks per month; 95% confidence interval [CI], –3.38 to –1.46; and mean difference with 60 IU, –3.51 attacks per month; 95% CI, –4.21 to –2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40‐IU group and 90% (95% CI, 77 to 96) in the 60‐IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40‐IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60‐IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013‐000916‐10, and ClinicalTrials.gov number, NCT01912456.)

Population pharmacokinetics of plasma-derived C1 esterase inhibitor concentrate used to treat acute hereditary angioedema attacks

BACKGROUND C1 esterase inhibitor (C1-INH) replacement is recommended as a first-line therapy for acute edema attacks in hereditary angioedema (HAE). Only limited pharmacokinetic analyses of the administered C1-INH in plasma are available. OBJECTIVE To investigate retrospectively the population pharmacokinetics of a plasma-derived C1-INH (pC1-INH) concentrate used to treat acute HAE attacks in a randomized, placebo-controlled phase 2/3 study in patients with HAE. METHODS Acute abdominal and facial attacks were treated with either a pC1-INH concentrate (Berinert) at single intravenous doses of 10 or 20 U/kg body weight or placebo. Plasma sampling was conducted 0, 1, and 4 hours after dosing. A nonlinear retrospective population pharmacokinetic model was obtained using the assumption of a 1-compartment model. RESULTS The final population pharmacokinetic model was based on data from 97 patients treated with 10 or 20 U/kg of pC1-INH concentrate. The estimated mean half-life was 32.7 hours (90% confidence interval, 16.6-48.8 hours), and the estimated mean clearance was 0.92 mL/kg/h (90% confidence interval, 0.50-1.33 mL/kg/h). CONCLUSIONS The half-life of the same pC1-INH concentrate reported in a previous study was confirmed by this retrospective population pharmacokinetic analysis in patients treated for acute HAE attacks. In contrast to other treatment options with shorter half-lives, the long half-life of pC1-INH concentrate may provide an extended period of protection, even after the symptoms of an attack have subsided.

Chronic immune thrombocytopenic purpura in children: a survey of the canadian experience.

Background Immune thrombocytopenic purpura (ITP) in children is a common pediatric bleeding disorder with heterogeneous manifestations and a natural history that is not fully understood. To better understand the natural history of chronic ITP and detect response trends and outcomes of therapy, we conducted a 10-year retrospective survey of children from age 1 to 18 years with a diagnosis of chronic ITP. Results Data on 198 patients from 8 Canadian Pediatric Hematology/Oncology centers were analyzed. The majority of patients were female (58%), and were previously diagnosed with acute (primary) ITP (85%). The age at diagnosis of chronic ITP ranged from 1.1 to 17.2 years with a mean of 8.2±4.4 years. Ninety percent of patients received some form of treatment. Untreated patients had a higher mean platelet count at diagnosis of chronic ITP (P=0.009) despite similarities in mean age at first presentation and mean duration of follow-up. Thirty-four (17%) patients underwent splenectomy. Splenectomized patients tended to be significantly older, had a lower mean platelet count at diagnosis of chronic ITP, and had a longer duration of follow-up. Conclusions The results from this study are consistent with published reports.