Efficacy and Safety of Donidalorsen for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25. RESULTS: A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity. CONCLUSIONS: Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.).

Inhibition of Prekallikrein for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is characterized by recurrent and unpredictable swellings that are disabling and potentially fatal. Selective inhibition of plasma prekallikrein production by antisense oligonucleotide treatment (donidalorsen) may reduce the frequency of attacks and the burden of disease. METHODS: In this phase 2 trial, we randomly assigned, in a 2:1 ratio, patients with hereditary angioedema with C1 inhibitor deficiency to receive four subcutaneous doses of either donidalorsen (80 mg) or placebo, with one dose administered every 4 weeks. The primary end point was the time-normalized number of investigator-confirmed angioedema attacks per month (attack rate) between week 1 (baseline) and week 17. Secondary end points included quality of life, as measured with the Angioedema Quality of Life Questionnaire (scores range from 0 to 100, with higher scores indicating worse quality of life), and safety. RESULTS: A total of 20 patients were enrolled, of whom 14 were randomly assigned to receive donidalorsen and 6 to receive placebo. The mean monthly rate of investigator-confirmed angioedema attacks was 0.23 (95% confidence interval [CI], 0.08 to 0.39) among patients receiving donidalorsen and 2.21 (95% CI, 0.58 to 3.85) among patients receiving placebo (mean difference, -90%; 95% CI, -96 to -76; P<0.001). The mean change from baseline to week 17 in the Angioedema Quality of Life Questionnaire score was -26.8 points in the donidalorsen group and -6.2 points in the placebo group (mean difference, -20.7 points; 95% CI, -32.7 to -8.7). The incidence of mild-to-moderate adverse events was 71% among patients receiving donidalorsen and 83% among those receiving placebo. CONCLUSIONS: Among patients with hereditary angioedema, donidalorsen treatment resulted in a significantly lower rate of angioedema attacks than placebo in this small, phase 2 trial. (Funded by Ionis Pharmaceuticals; ISIS 721744-CS2 ClinicalTrials.gov number, NCT04030598.).

Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein-kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema. METHODS: VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged ≥12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (≤17 years vs >17 years) and baseline attack rate (1 to <3 attacks per month vs ≥3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and ClinicalTrials.gov, NCT04656418. FINDINGS: Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0·27, 95% CI 0·05 to 0·49) than in the placebo group (2·01, 1·44 to 2·57; p<0·0001), corresponding to a percentage difference in means of -87% (95% CI -96 to -58; p<0·0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0·00-0·31) for garadacimab and 1·35 (1·00-3·20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events. INTERPRETATION: Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults. FUNDING: CSL Behring.

A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality-of-life (ISIS721744-CS2, NCT04030598). We report the 2-year interim analysis of the phase 2 open-label extension (OLE) study (ISIS 721744-CS3, NCT04307381). METHODS: In the OLE, the on-treatment study period consisted of fixed (weeks 1-13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17-105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments. RESULTS: Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02-0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94-3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0-1.7; 95% CI, -0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen. CONCLUSION: The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.

Pain trajectories after bilateral orthotopic lung transplantation surgery performed via a clamshell incision.

INTRODUCTION: The nature, intensity, and progression of acute pain after bilateral orthotopic lung transplantation (BOLT) performed via a clamshell incision has not been well investigated. We aimed to describe acute pain after clamshell incisions using pain trajectories for the study cohort, in addition to stratifying patients into separate pain trajectory groups and investigating their association with donor and recipient perioperative variables. METHODS: After obtaining IRB approval, we retrospectively included all patients ≥18 years old who underwent primary BOLT via clamshell incision at a single center between January 1, 2017, and June 30, 2022. We modeled the overall pain trajectory using pain scores collected over the first seven postoperative days and identified separate pain trajectory classes via latent class analysis. RESULTS: Three hundred one adult patients were included in the final analysis. Three separate pain trajectory groups were identified, with most patients (72.8%) belonging to a well-controlled, stable pain trajectory. Uncontrolled pain was either observed in the early postoperative period (10%), or in the late postoperative period (17.3%). Late postoperative peaking trajectory patients were younger (p = .008), and sicker with a higher lung allocation score (p = .005), receiving preoperative mechanical ventilation (p < .001), or VV-ECMO support (p < .001). CONCLUSION: Despite the extensive nature of a clamshell incision, most pain trajectories in BOLT patients had a well-controlled stable pain profile. The benign nature of pain profiles in our patient population may be attributed to the routine institutional practice of early thoracic epidural analgesia for BOLT patients unless contraindicated.

Subcutaneous Immunoglobulin 16.5% (Cutaquig®) in Primary Immunodeficiency Disease: Safety, Tolerability, Efficacy, and Patient Experience with Enhanced Infusion Regimens.

PURPOSE: To achieve reductions in infusion time, infusion sites, and frequency, a prospective, open-label, multicenter, Phase 3 study evaluated the safety, efficacy, and tolerability of subcutaneous immunoglobulin (SCIG) 16.5% (Cutaquig®, Octapharma) at enhanced infusion regimens. METHODS: Three separate cohorts received SCIG 16.5% evaluating volume, rate, and frequency: Cohort 1) volume assessment/site: up to a maximum 100 mL/site; Cohort 2) infusion flow rate/site: up to a maximum of 100 mL/hr/site or the maximum flow rate achievable by the tubing; Cohort 3) infusion frequency: every other week at twice the patient's weekly dose. RESULTS: For Cohort 1 (n = 15), the maximum realized volume per site was 108 mL/site, exceeding the currently labeled (US) maximum (up to 40 mL/site for adults). In Cohort 2 (n = 15), the maximum realized infusion flow rate was 67.5 mL/hr/site which is also higher than the labeled (US) maximum (up to 52 mL/hr/site). In Cohort 3 (n = 34), the mean total trough levels for every other week dosing demonstrated equivalency to weekly dosing (p value = 0.0017). All regimens were well tolerated. There were no serious bacterial infections (SBIs). Most patients had mild (23.4%) or moderate (56.3%) adverse events. The majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens and reported that switching to SCIG 16.5% was easy. CONCLUSIONS: SCIG 16.5% (Cutaquig®), infusions are efficacious, safe, and well tolerated with reduced infusion time, fewer infusion sites, and reduced frequency. Further, the majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens.

Pain Trajectories After Valve Surgeries Performed via Midline Sternotomy Versus Mini-Thoracotomy.

OBJECTIVES: Controlling moderate-to-severe pain remains a major challenge after cardiothoracic surgery. Several outcomes have been compared extensively after valve surgery performed via midline sternotomy versus mini-thoracotomy, but postoperative pain (POP) was not adequately examined. Therefore, the authors tested the hypothesis that there is no difference in POP trajectories in patients undergoing valve surgery via midline sternotomy versus mini-thoracotomy. DESIGN: An Institutional Review Board-approved retrospective study. SETTING: At a single, large academic medical center. PARTICIPANTS: Adult patients who underwent mitral or aortic valve surgeries over a 5-year period. INTERVENTIONS: The authors compared the characteristics of pain between valve surgery patients receiving either midline sternotomy or mini-thoracotomy. To identify pain score trajectories, the authors employed latent class linear mixed models and then used multinomial regression models to study the association between incision type and pain trajectory class. MEASUREMENTS AND MAIN RESULTS: The authors' cohort consisted of 1,660 surgical patients-544 (33%) received a midline sternotomy, and 1,116 (66%) received a mini-thoracotomy. The authors identified the following 4 pain trajectory classes: stationary, rapidly improving, slowly improving, and acute worsening pain. Compared to the rapidly improving class, the odds of belonging to the stationary (adjusted odds ratio [aOR] [95% CI] 1.45 [1.01- 2.08]; p = 0.04) or the acute worsening class (aOR [95% CI] 1.71 [1.10-2.67] p = 0.02) were significantly higher for sternotomy patients compared to mini-thoracotomy. CONCLUSIONS: Midline sternotomies are associated with higher odds of having an acute worsening or stationary versus a rapidly improving pain trajectory compared to mini-thoracotomies. Therefore, the choice of incision may play an important role in determining POP trajectory after valve surgery.

Conventional Ultrafiltration During Elective Cardiac Surgery and Postoperative Acute Kidney Injury.

OBJECTIVE: Conventional ultrafiltration (CUF) during cardiopulmonary bypass (CPB) serves to hemoconcentrate blood volume to avoid allogeneic blood transfusions. Previous studies have determined CUF volumes as a continuous variable are associated with postoperative acute kidney injury (AKI) after cardiac surgery, but optimal weight-indexed volumes that predict AKI have not been described. DESIGN: Retrospective cohort. SETTING: Single-center university hospital. PARTICIPANTS: A total of 1,641 consecutive patients who underwent elective cardiac surgery between June 2013 and December 2015. INTERVENTIONS: The CUF volume was removed during CPB in all participants as part of routine practice. The authors investigated the association of dichotomized weight-indexed CUF volume removal with postoperative AKI development to provide pragmatic guidance for clinical practice at the authors' institution. MEASUREMENTS AND MAIN RESULTS: Primary outcomes of postoperative AKI were defined by the Kidney Disease: Improving Global Outcomes staging criteria and dichotomized, weight-indexed CUF volumes (mL/kg) were defined by (1) extreme quartiles (Q3) and (2) Youden's criterion that best predicted AKI development. Multivariate logistic regression models were developed to test the association of these dichotomized indices with AKI status. Postoperative AKI occurred in 827 patients (50.4%). Higher CUF volumes were associated with AKI development by quartiles (CUF >Q3 = 32.6 v CUF < Q1 = 10.4 mL/kg; odds ratio [OR] = 1.68, 95% CI: 1.19-2.3) and Youden's criterion (CUF ≥ 32.9 v CUF <32.9 mL/kg; OR = 1.60, 95% CI: 1.21-2.13). Despite similar intraoperative nadir hematocrits among groups (p = 0.8), higher CUF volumes were associated with more allogeneic blood transfusions (p = 0.002) and longer lengths of stay (p < 0.001). CONCLUSIONS: Removal of weight-indexed CUF volumes > 32 mL/kg increased the risk for postoperative AKI development. Importantly, CUF volume removal of any amount did not mitigate allogeneic blood transfusion during elective cardiac surgery. Prospective studies are needed to validate these findings.

Berotralstat (BCX7353) is a novel oral prophylactic treatment for hereditary angioedema: Review of phase II and III studies.

Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable and potentially life-threatening episodes of swelling in various parts of the body. These attacks can be painful and debilitating, and affect a patient's quality of life. Every patient who experiences an attack should be treated with on-demand medication to mitigate attack severity and duration. Many patients with HAE also receive long-term prophylaxis to reduce the frequency and severity of edema episodes. Although long-term prophylaxis reduces the disease burden for patients with HAE, available intravenous and subcutaneous treatments are accompanied by a significant treatment burden because of the logistical, emotional, and physical challenges posed by their long-term parenteral nature. Androgens are an effective oral prophylactic treatment; however, they are associated with significant adverse events and are not suitable for all patients. Thus, the HAE community has expressed interest in the development of alternative oral prophylactic therapies for preventing HAE attacks. Objective: Here, we review the phase II and III clinical data of berotralstat (BCX7353), which was approved by the U.S. Food and Drug Administration in December 2020. Results: Berotralstat is an oral, second-generation, synthetic, small-molecule plasma kallikrein inhibitor taken once daily for the prevention of HAE attacks in patients ages ≥ 12 years. Results from the APeX studies (APeX-1 NCT02870972, APeX-2 NCT03485911, APeX-S NCT03472040, APex-J NCT03873116) demonstrated the efficacy of berotralstat as long-term prophylaxis for patients with HAE, which showed a reduction in the attack rate and on-demand medication usage. Berotralstat was well tolerated, and gastrointestinal treatment-emergent adverse events were generally mild and self-limited. Conclusion: Oral berotralstat is an effective and safe long-term prophylactic treatment for patients with HAE that will provide patients unable to tolerate parenteral therapies with the option of disease control. Berotralstat may be associated with reduced treatment burden compared with injectable therapies, highlighting the importance of patient preference with regard to the administration route of their HAE prophylactic treatment.

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 .).

An FDA analysis of clinical hold deficiencies affecting investigational new drug applications for oncology products.

A systematic analysis of new commercial investigational new drug applications (IND) submitted to the FDA's Office of Hematology and Oncology Products (OHOP) in the Center for Drug Evaluation and Research was conducted to quantify the most common reasons INDs for oncology indications go on clinical hold. In OHOP, less than 10% of INDs went on hold or were withdrawn within the 30-day safety review period. Of INDs that were placed on hold, deficiencies were mainly clinical, followed by concerns related to pharmaceutical quality and nonclinical development. INDs were also characterized based on phase of development, product type, sponsors' regulatory experience, and occurrence of a pre-IND meeting. INDs that were placed on hold were mostly for first-in-human trials or submitted by sponsors with limited regulatory experience. INDs that went on hold or were safe-to-proceed had pre-IND meetings with comparable rates but sponsors with substantial experience appeared to benefit more from pre-IND meetings compared to those with limited experience. The time interval between the pre-IND meeting and the IND submission was longer for INDs that went on hold. To obtain useful FDA feedback on product development, it is essential to provide focused questions and supporting information in pre-IND meeting packages.

Hereditary angioedema: Differential diagnosis, diagnostic tests, and family screening.

Hereditary angioedema is a rare, autosomal dominant genetic disorder that leads to sporadic episodes of swelling, which can affect any part of the body. With a prevalence of 1 in 10,000 to 1 in 50,000, there are other, more common causes of angioedema. Differentiating between bradykinin-mediated and histamine-mediated causes of swelling remains a major challenge. It is critical to develop an appropriate differential diagnosis, work through the various conditions, and obtain the pertinent laboratory evaluation to rule in or out the proposed diagnosis. As an autosomal dominant genetic disorder, there is a 50% chance with each pregnancy of passing on the genetic mutation in the SERPING1 gene. This review addressed the differential diagnosis to consider, the appropriate laboratory evaluation, and the importance of family screening.

Patterns and trends in OSHA occupational noise exposure measurements from 1979 to 2013.

OBJECTIVES: Noise is one of the most common exposures, and occupational noise-induced hearing loss (NIHL) is highly prevalent. In addition to NIHL, noise is linked to numerous non-auditory health effects. The Occupational Safety and Health Administration (OSHA) maintains the Integrated Management Information System (IMIS) database of compliance-related measurements performed in various industries across the USA. The goal of the current study was to describe and analyse personal noise measurements available through the OSHA IMIS, identifying industries with elevated personal noise levels or increasing trends in worker exposure over time. METHODS: Through a Freedom of Information Act request, we obtained OSHA's noise measurements collected and stored in IMIS between 1979 and 2013 and analysed permissible exposure limit (PEL) and action level (AL) criteria measurements by two-digit industry code. RESULTS: The manufacturing industry represented 87.8% of the 93 920 PEL measurements and 84.6% of the 58 073 AL measurements. The highest mean noise levels were found among the agriculture, forestry, fishing and hunting industry for PEL (93.1 dBA) and the mining, quarrying and oil and gas extraction group for AL (93.3 dBA). Overall, measurements generally showed a decreasing trend in noise levels and exceedances of AL and PEL by year, although this was not true for all industries. CONCLUSIONS: Our results suggest that, despite reductions in noise over time, further noise control interventions are warranted both inside and outside of the manufacturing industry. Further reductions in occupational noise exposures across many industries are necessary to continue to reduce the risk of occupational NIHL.

What Does a Red Meat Allergy Have to Do With Anesthesia? Perioperative Management of Alpha-Gal Syndrome.

Over the past decade, there has been a growing awareness of a new allergic syndrome known as alpha-gal allergy or alpha-gal syndrome, commonly recognized as a red meat allergy. We performed a review of the literature to identify articles that provide both background on this syndrome in general and any reports of reactions to medications or medical devices related to alpha-gal syndrome. Alpha-gal syndrome results from IgE to the oligosaccharide galactose-α-1,3-galactose, expressed in the meat and tissues of noncatarrhine mammals. It is triggered by the bite of the lone star tick and has been implicated in immediate-onset hypersensitivity to the monoclonal antibody cetuximab and delayed-onset hypersensitivity reactions after the consumption of red meat. There is growing recognition of allergic reactions in these patients to other drugs and medical devices that contain alpha-gal. Many of these reactions result from inactive substances that are part of the manufacturing or preparation process such as gelatin or stearic acid. This allergy may be documented in a variety of ways or informally reported by the patient, requiring vigilance on the part of the anesthesiologist to detect this syndrome, given its serious implications. This allergy presents a number of unique challenges to the anesthesiologist, including proper identification of a patient with alpha-gal syndrome and selection of anesthetic and adjunctive medications that will not trigger this allergy.

Perioperative Anesthetic and Transfusion Management of Veno-Venous Extracorporeal Membrane Oxygenation Patients Undergoing Noncardiac Surgery: A Case Series of 21 Procedures.

OBJECTIVES: To analyze the perioperative management of veno-venous extracorporeal membrane oxygenation (VV ECMO) in patients undergoing major noncardiac surgical procedures, which is poorly described in the literature. In doing so, perioperative challenges related to hemodynamic instability, impaired gas exchange, bleeding, and coagulopathy will be quantified. DESIGN: Retrospective, nonrandomized, observational study. SETTING: A single, university-affiliated, quaternary medical center. PARTICIPANTS: Fourteen patients who underwent 21 noncardiac surgical procedures during the period of January 1, 2014, through April 1, 2016. Approval for this study was obtained from the Duke University Medical Center Institutional Review Board (study Pro00072723). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fifty percent of subjects were alive at 1 year after ECMO cannulation. Anesthetic type was variable with an inhaled anesthetic utilized in 71.4% of events, a presurgical continuous sedative was continued in 81.0% of cases, fentanyl was utilized in 100% of encounters, and midazolam was utilized in 71.4% of encounters. Intraoperatively, 50% of encounters resulted in an oxygen desaturation with a peripheral oxygen saturation assessed by pulse oximetry (SpO2)<90%, and 15% of procedures resulted in a SpO2 <80%. A vasopressor, most commonly epinephrine, was used during 66.7% of procedures. Intraoperatively, blood was administered in 52.4% of procedures, fresh frozen plasma was administered in 23.8% of procedures, and platelets were administered in 28.6% of procedures. Hemoglobin levels remained stable throughout the perioperative period, averaging 9.5 g/dL preoperatively, 9.7 g/dL immediately postoperatively, and 9.5 g/dL 24 hours after surgery. CONCLUSIONS: VV ECMO patients can be anesthetized using either inhalational or intravenous anesthetics. Patient hemodynamics, oxygenation, and decarboxylation require frequent interventions, but can typically be optimized to meet clinically acceptable thresholds.

Defining Value-Based Care in Cardiac and Vascular Anesthesiology: The Past, Present, and Future of Perioperative Cardiovascular Care.

Health care reimbursement models are transitioning from volume-based to value-based models. Value-based models focus on patient outcomes both during the hospital admission and postdischarge. These models place emphasis on cost, quality of care, and coordination of multidisciplinary services. Perioperative physicians are challenged to evaluate traditional practices to ensure coordinated, cost-effective, and evidence-based care. With the Centers for Medicare and Medicaid Services planned introduction of bundled payments for coronary artery bypass graft surgery, cardiovascular anesthesiologists are financially responsible for postdischarge outcomes. In order to meet these patient outcomes, multidisciplinary care pathways must be designed, implemented, and sustained, a process that is challenging at best. This review (1) provides a historical perspective of health care reimbursement; (2) defines value as it pertains to quality, service, and cost; (3) reviews the history of value-based care for cardiac surgery; (4) describes the drive toward optimization for vascular surgery patients; and (5) discusses how programs like Enhanced Recovery After Surgery assist with the delivery of value-based care.

Management of Patients With Left Ventricular Assist Devices Requiring Teeth Extraction: Is Halting Anticoagulation Appropriate?

PURPOSE: An increasing number of patients with end-stage heart failure are supported with left ventricular assist device (LVAD) implantation and must be maintained on a consistent anticoagulation regimen. Pre-emptive extraction of carious teeth in these patients is necessary to prevent seeding of the implanted device and endocarditis. Thus, the objective of this study was to evaluate bleeding complications after minor oral surgery, specifically teeth extractions, in this unique patient population requiring long-term anticoagulation. MATERIALS AND METHODS: This study was a retrospective single-center review. Adult patients supported on an implanted continuous-flow LVAD from January 1, 2007 to December 31, 2016 were included. Baseline characteristics were collected by retrospective chart review and the institutional LVAD registry. All extractions were performed in the operating room under local anesthesia with moderate sedation or general anesthesia with nasal intubation, and LVAD settings were monitored by a trained perfusionist. Preoperative and postoperative hematology laboratory values, such as hemoglobin and international normalized ratio (INR), were collected by chart review. Continuous variables were presented as mean ± standard deviation and compared using the Student t test. Categorical variables were presented as proportion and percentage and compared using the χ2 test or Fisher exact test as appropriate. Statistical significance was established at a P value less than .05. RESULTS: After screening 798 patients, 32 (4%) were found to have undergone dental extractions after LVAD implantation. The sample was composed of 32 patients with a mean age of 60.13 years and 81.25% were men. The average time from LVAD implantation to extraction was 445.19 ± 1,108.53 days. Average preoperative INR was 1.76 ± 0.47. Preoperative fresh frozen plasma was not administered to any patients. Twenty-eight patients (87.5%) were on Coumadin (warfarin) preoperatively. In 11 of these 28 patients (39.3%), Coumadin was held preoperatively. The average postoperative change in hemoglobin level was -0.79 ± 1.45. Only 1 patient (3%) required postoperative blood transfusion for a hemoglobin level of 7.6 that responded appropriately. There were no reoperations for bleeding. CONCLUSIONS: Minor oral surgical procedures can be performed safely for patients being supported on LVAD therapy. With primary closure of the gingiva at the site of extraction, dental extractions can be performed without the full reversal of anticoagulation.

Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial.

Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations. Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks. Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized. Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments. Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period. Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab). Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy. Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.