Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks

Background: For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). Objective: To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). Methods: Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). Results: A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. Conclusions: In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms

Safety and Usage of C1-Inhibitor in Hereditary Angioedema: Berinert Registry Data

BackgroundThe plasma-derived, highly purified, nanofiltered C1-inhibitor concentrate (Berinert; “pnfC1-INH”) is approved in the United States for treating hereditary angioedema (HAE) attacks and in many European countries for attack treatment and short-term prophylaxis.ObjectiveThe objective of this study was to describe safety and usage patterns of pnfC1-INH.MethodsA multicenter, observational, registry was conducted between 2010 and 2014 at 30 United States and 7 European sites to obtain both prospective (occurring after enrollment) and retrospective (occurring before enrollment) safety and usage data on subjects receiving pnfC1-INH for any reason.ResultsOf 343 enrolled patients, 318 received 1 or more doses of pnfC1-INH for HAE attacks (11,848 infusions) or for prophylaxis (3142 infusions), comprising the safety population. Median dosages per infusion were 10.8 IU/kg (attack treatment) and 16.6 IU/kg (prophylaxis). Approximately 95% of infusions were administered outside of a health care setting. No adverse events (AEs) were reported in retrospective data. Among prospective data (n = 296 subjects; 9148 infusions), 252 AEs were reported in 85 (28.7%) subjects (rate of 0.03 events/infusion); 9 events were considered related to pnfC1-INH. Two thromboembolic events were reported in subjects with thrombotic risk factors. No patient was noted to have undergone viral testing for suspected blood-borne infection during registry participation.ConclusionsThe findings from this large, international patient registry documented widespread implementation of pnfC1-INH self-administration outside of a health care setting consistent with current HAE guidelines. These real-world data revealed pnfC1-INH usage for a variety of reasons in patients with HAE and showed a high level of safety regardless of administration setting or reason for use

Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks

Background For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). Objective To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). Methods Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). Results A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. Conclusions In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms

Propofol or benzodiazepines for short- and long-term sedation in intensive care units? An economic evaluation based on meta-analytic results

Lorenzo Pradelli,1 Massimiliano Povero,1 Hartmut Bürkle,2 Tim-Gerald Kampmeier,3 Giorgio Della-Rocca,4 Astrid Feuersenger,5 Jean-Francois Baron,6 Martin Westphal5 1AdRes HE&OR, Torino, Italy; 2Department of Anaesthesiology and Critical Care Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, 3Clinic for Anesthesiology and Surgical Intensive Care Medicine, University Hospital Münster, Münster, Germany; 4Department of Anaesthesia and Intensive Care Medicine, Medical School of the University of Udine, Udine, Italy; 5Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany; 6Fresenius Kabi ELAMA, Paris Cedex, France Purpose: This evaluation compares propofol and benzodiazepine sedation for mechanically ventilated patients in intensive care units (ICUs) in order to identify the potential economic benefits from different payers’ perspectives. Methods: The patient-level simulation model incorporated efficacy estimates from a structured meta-analysis and ICU-related costs from Italy, Germany, France, UK, and the USA. Efficacy outcomes were ICU length of stay (LOS), mechanical ventilation duration, and weaning time. We calculated ICU costs from mechanical ventilation duration and ICU LOS based on national average ICU costs with and without mechanical ventilation. Three scenarios were investigated: 1) long-term sedation >24 hours based on results from randomized controlled trials (RCTs); 2) long-term sedation based on RCT plus non-RCT results; and 3) short-term sedation <24 hours based on RCT results. We tested the model’s robustness for input uncertainties by deterministic (DSA) and probabilistic sensitivity analyses (PSA).Results: In the base case, mean savings with propofol versus benzodiazepines in long-term sedation ranged from €406 (95% confidence interval [CI]: 646 to 164) in Italy to 1,632 € (95% CI: 2,362 to 880) in the USA. Inclusion of non-RCT data corroborated these results. Savings in short-term sedation ranged from €148 (95% CI: 291 to 2) in Italy to €502 (95% CI: 936 to 57) in the USA. Parameters related to ICU and mechanical ventilation had a stronger influence in the DSA than drug-related parameters. In PSA, propofol reduced costs and ICU LOS compared to benzodiazepines in 94%–100% of simulations. The largest savings may be possible in the UK and the USA due to higher ICU costs.Conclusion: Current ICU sedation guidelines recommend propofol rather than midazolam for mechanically ventilated patients. This evaluation endorses the recommendation as it may lead to better outcomes and savings for health care systems, especially in countries with higher ICU-related costs. Keywords: critically ill patients, mechanical ventilation, anesthetics, length of stay, costs, health care syste