Recombinant von Willebrand factor prophylaxis in patients with severe von Willebrand disease: phase 3 study results.

International guidelines conditionally recommend long-term prophylaxis in patients with von Willebrand disease (VWD) and severe and frequent bleeding. As recombinant von Willebrand factor (rVWF; vonicog alfa) may reduce the frequency of treated spontaneous bleeding events (BEs), we investigated the efficacy and safety of rVWF prophylaxis in adults with severe VWD. Patients with BEs requiring VWF therapy in the past year (on-demand VWF therapy [prior on-demand group] or plasma-derived VWF prophylaxis [pdVWF; switch group]) were enrolled in a prospective, open-label, nonrandomized, phase 3 study. The planned duration of rVWF prophylaxis was 12 months; starting rVWF dose was 50 ± 10 VWF: ristocetin cofactor (VWF:RCo) IU/kg twice weekly (prior on-demand group) or based on prior pdVWF weekly dose/dosing frequency (switch group). The primary endpoint was annualized bleeding rate (ABR) of treated spontaneous BEs (sABR) during rVWF prophylaxis. Over the 12-month study period, treated sABR decreased by 91.5% on-study vs historical sABR in 13 patients in the prior on-demand group, and by 45.0% in 10 patients in the switch group (model-based analysis ratio, 0.085; 95% confidence interval [CI], 0.021-0.346 and 0.550; 95% CI, 0.086-3.523, respectively). No treated spontaneous BEs were recorded in 84.6% (11/13) and 70.0% (7/10) of patients, respectively. The safety profile of rVWF was consistent with the previously established profile, with no new adverse drug reactions identified. Findings suggest that rVWF prophylaxis can reduce treated spontaneous BEs in patients previously receiving on-demand VWF therapy and maintains at least the same level of hemostatic control in patients who switch from prophylaxis with pdVWF to rVWF, with a favorable safety profile. This trial was registered at www.clinicaltrials.gov (#NCT02973087) and www.clinicaltrialsregister.eu (#EudraCT 2016-001478-14).

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.

An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension.

BACKGROUND: Hereditary angioedema (HAE) is characterized by recurrent attacks of subcutaneous or submucosal edema. Attacks are unpredictable, debilitating, and have a significant impact on quality of life. Patients may be prescribed prophylactic therapy to prevent angioedema attacks. Current prophylactic treatments may be difficult to administer (i.e., intravenously), require frequent administrations or are not well tolerated, and breakthrough attacks may still occur frequently. Lanadelumab is a subcutaneously-administered monoclonal antibody inhibitor of plasma kallikrein in clinical development for prophylaxis of hereditary angioedema attacks. A Phase 1b study supported its efficacy in preventing attacks. A Phase 3, randomized, double-blind, placebo-controlled, parallel-arm study has been completed and an open-label extension is currently ongoing. METHODS/DESIGN: The primary objective of the open-label extension is to evaluate the long-term safety of repeated subcutaneous administrations of lanadelumab in patients with type I/II HAE. Secondary objectives include evaluation of efficacy and time to first angioedema attack to determine outer bounds of the dosing interval. The study will also evaluate immunogenicity, pharmacokinetics/pharmacodynamics, quality of life, characteristics of breakthrough attacks, ease of self-administration, and safety/efficacy in patients who switch to lanadelumab from another prophylactic therapy. The open-label extension will enroll patients who completed the double-blind study ("rollover patients") and those who did not participate in the double-blind study ("non-rollover patients"), which includes patients who may or may not be currently using another prophylactic therapy. Rollover patients will receive a single 300 mg dose of lanadelumab on Day 0 and the second dose after the patient's first confirmed angioedema attack. Thereafter, lanadelumab will be administered every 2 weeks. Non-rollover patients will receive 300 mg lanadelumab every 2 weeks regardless of the first attack. All patients will receive their last dose on Day 350 (maximum of 26 doses), and will then undergo a 4-week follow-up. DISCUSSION: Prevention of attacks can reduce the burden of illness associated with HAE. Prophylactic therapy requires extended, repeated dosing and the results of this study will provide important data on the long-term safety and efficacy of lanadelumab, a monoclonal antibody inhibitor of plasma kallikrein for subcutaneous administration for the treatment of HAE. Trial registration NCT02741596.

Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema.

BACKGROUND: Upper airway angioedema is a rare, unpredictable, and at times life-threatening adverse effect of angiotensin-converting enzyme inhibitors (ACE-Is) with no existing effective pharmacologic treatment. Icatibant is a bradykinin B2 receptor antagonist that may be beneficial in patients with ACE-I-induced angioedema. OBJECTIVE: We aimed to evaluate the efficacy of icatibant in subjects with ACE-I-induced angioedema. METHODS: At 31 centers in 4 countries, adults on ACE-Is who presented within 12 hours of the onset of at least moderately severe angioedema were randomized 1:1 to icatibant 30 mg or placebo administered subcutaneously. The primary efficacy end point was time to meeting discharge criteria after study drug administration, based on the severity of airway symptoms assessed hourly by a blinded physician using clinical ratings across 4 domains. RESULTS: A total of 121 subjects were randomized (icatibant, n = 61; placebo, n = 60); 118 received treatment a median of 7.8 hours from symptom onset. We observed no difference in time to meeting discharge criteria between groups (median, 4.0 hours in each group; P = .63). There also was no difference in time to onset of symptom relief (median, icatibant, 2.0 hours; placebo, 1.6 hours; P = .57) or any other secondary end point. Similar findings were noted in prespecified and post hoc subgroup analyses stratified by symptom severity, time interval to treatment, age, and other clinical covariates. No new safety signals were detected. CONCLUSIONS: Icatibant was no more efficacious than placebo in at least moderately severe ACE-I-induced angioedema of the upper airway.

Icatibant for Multiple Hereditary Angioedema Attacks across the Controlled and Open-Label Extension Phases of FAST-3.

BACKGROUND: 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). METHODS: 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). RESULTS: 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. CONCLUSIONS: Icatibant was efficacious and generally well tolerated across multiple HAE attacks, including laryngeal attacks.

Ferumoxytol for treating iron deficiency anemia in CKD.

Iron deficiency is an important cause of anemia in patients with chronic kidney disease (CKD), but intravenous iron is infrequently used among patients who are not on dialysis. Ferumoxytol is a novel intravenous iron product that can be administered as a rapid injection. This Phase III trial randomly assigned 304 patients with CKD in a 3:1 ratio to two 510-mg doses of intravenous ferumoxytol within 5 +/- 3 d or 200 mg of elemental oral iron daily for 21 d. The increase in hemoglobin at day 35, the primary efficacy end point, was 0.82 +/- 1.24 g/dl with ferumoxytol and 0.16 +/- 1.02 g/dl with oral iron (P < 0.0001). Among patients who were not receiving erythropoiesis-stimulating agents, hemoglobin increased 0.62 +/- 1.02 g/dl with ferumoxytol and 0.13 +/- 0.93 g/dl with oral iron. Among patients who were receiving erythropoiesis-stimulating agents, hemoglobin increased 1.16 +/- 1.49 g/dl with ferumoxytol and 0.19 +/- 1.14 g/dl with oral iron. Treatment-related adverse events occurred in 10.6% of patients who were treated with ferumoxytol and 24.0% of those who were treated with oral iron; none was serious. In summary, a regimen of two doses of 510 mg of intravenous ferumoxytol administered rapidly within 5 +/- 3 d was well tolerated and had the intended therapeutic effect. This regimen may offer a new, efficient option to treat iron deficiency anemia in patients with CKD.

Pancreatic adenocarcinoma: value of multidetector CT angiography in preoperative evaluation.

PURPOSE: To retrospectively assess the sensitivity and specificity of multidetector computed tomographic (CT) angiography in the preoperative evaluation of pancreatic adenocarcinoma by using surgical findings as the reference standard. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant study; informed consent was waived. We reviewed CT reports, surgical notes, and pathology reports from 114 patients with pancreatic or distal cholangiocarcinoma who underwent multidetector CT angiography and surgery at our institution between March 2003 and March 2006. When CT findings and surgical reports were discordant, radiologists experienced in pancreatic imaging retrospectively reviewed images for lesion resectability; four-, eight-, 16-, and 64-row CT scanners were used in 54, 19, 25, and 16 patients, respectively. Collimation of 1.25 mm was used for four- and eight-row CT and 0.5 or 0.625 mm for 16- and 64-row CT. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for resectability were calculated for initial clinical interpretation and blinded retrospective review. RESULTS: Eighty-eight patients had resectable lesions according to CT angiographic criteria (group A: 46 women, 42 men; mean age, 67 years; age range, 39-85 years): resection was aborted in 10 patients (11%). Twenty-six patients underwent surgery despite lesion unresectability assessed according to CT angiographic criteria (group B: 16 women, 10 men; mean age, 62 years; age range, 33-83 years); all lesions were confirmed as unresectable. The initial clinical interpretation of CT angiographic scans in all 114 patients had 100% sensitivity in the detection of resectability, 72% specificity, 89% PPV, and 100% NPV. These parameters did not appear to vary among different types of scanner. With the blinded retrospective evaluation by experienced readers, specificity increased to 94% and PPV to 98%, with no difference in sensitivity and NPV. CONCLUSION: Multidetector CT angiography is an effective preoperative tool that reduces the number of aborted pancreatic resections; there is no evidence from this retrospective study suggesting varying results from the various generations of multidetector CT scanners used.

Is true FISP imaging reliable in the evaluation of venous thrombosis?

OBJECTIVE: The objective of our study was to evaluate the accuracy of true fast imaging with steady-state precession (FISP) in the diagnosis of venous thrombosis using gadolinium-enhanced 3D T1-weighted gradient-echo images and correlative imaging as the gold standard. MATERIALS AND METHODS: Twenty-five MR examinations were retrospectively reviewed independently by two radiologists to rule out thrombosis in the central veins of the body. The presence of venous thrombus was assessed separately in 80 veins using true FISP and gadolinium-enhanced T1-weighted images. Diagnosis was confirmed by another imaging technique (sonography, CT, and/or conventional venography) in all positive cases. Negative examinations were confirmed using imaging, clinical follow-up, or both. RESULTS: Venous thrombosis was present in 25 veins in 18 patients. True FISP images had a lower sensitivity (66%) and specificity (70.9%) for the diagnosis of venous thrombosis than gadolinium-enhanced MR images (p < 0.01). CONCLUSION: True FISP images have lower sensitivity and specificity in the diagnosis of venous thrombosis than gadolinium-enhanced T1-weighted gradient-echo images. True FISP images should not be used exclusively for the diagnosis of venous thrombosis.

Tissue-print and print-phoresis as platform technologies for the molecular analysis of human surgical specimens: mapping tumor invasion of the prostate capsule.

Molecular profiling of human biopsies and surgical specimens is frequently complicated by their inherent biological heterogeneity and by the need to conserve tissue for clinical diagnosis. We have developed a set of novel 'tissue print' and 'print-phoresis' technologies to facilitate tissue and tumor-marker profiling under these circumstances. Tissue printing transfers cells and extracellular matrix components from a tissue surface onto nitrocellulose membranes, generating a two-dimensional anatomical image on which molecular markers can be visualized by specific protein and RNA- and DNA-detection techniques. Print-phoresis is a complementary new electrophoresis method in which thin strips from the print are subjected to polyacrylamide gel electrophoresis, providing a straightforward interface between the tissue-print image and gel-based proteomic techniques. Here we have utilized these technologies to identify and characterize markers of tumor invasion of the prostate capsule, an event generally not apparent to the naked eye that may result in tumor at the surgical margins ('positive margins'). We have also shown that tissue-print technologies can provide a general platform for the generation of marker maps that can be superimposed directly onto histopathological and radiological images, permitting molecular identification and classification of individual malignant lesions.

Increased prevalence of coronary artery calcification in patients with suspected pulmonary embolism.

RATIONALE AND OBJECTIVES: The authors explored the possibility that patients with suspected pulmonary embolism are at high risk for coronary artery disease. To this purpose, they compared the presence of coronary artery calcification on computed tomography (CT) in patients suspected of pulmonary embolism with age- and gender-matched controls. MATERIALS AND METHODS: The CT scans of 214 patients were reviewed. Of those, 107 consecutive patients (50%) had pulmonary CT angiography for suspected pulmonary embolism (PE group). The remaining 107 age- and gender-matched patients were scanned for reasons other than pulmonary embolism (non-PE group). All CT scans were performed with the same 8-detector-row multislice scanner. Two radiologists reviewed scans of 5-mm slices using a five-grade modified coronary calcium scoring system: 1 = no calcification; 2 = minimal calcification; 3 = mild calcification; 4 = moderate calcification; and 5 = severe calcification. The Marginal Homogeneity test was used to compare the distribution and severity of calcification in the two groups. RESULTS: Of 107 patients in the PE group, seven (6.54%) had pulmonary embolism detected on CT. Coronary artery calcification was detected in 61 patients (57%) in the PE group compared with 42 patients (39%) in the non-PE group. The Marginal Homogeneity test showed that patients with pulmonary embolism symptoms were 2.9 times more likely to have calcification detected compared with those patients who had chest CT for some other reason (P = .0034). However, in patients in whom coronary artery calcification was detected, the distribution of severity of calcification was the same in both groups. CONCLUSION: Assuming coronary artery calcification indicated coronary atherosclerosis, patients undergoing CT for suspected pulmonary embolism may be at high risk for coronary artery disease.