Post-hoc analysis on the long-term response to fixed-dose prophylaxis with N8-GP in patients with haemophilia A.

INTRODUCTION: Challenges with personalised prophylaxis in haemophilia remain, including designing unique dosing schedules that require continual adjustments and monitoring using complex sampling procedures. AIM: To assess long-term efficacy and pharmacokinetic outcomes with fixed-dose N8-GP prophylaxis. METHODS: Descriptive analyses were performed on data from the pathfinder 2 and pathfinder 5 trials of patients with severe haemophilia A. Bleed frequency and reoccurrence were assessed in relation to several clinical criteria of interest. Bleed risk relative to time since last dose was assessed using calculated annualised bleeding rate (ABR). Long-term ABR and mean factor VIII (FVIII) trough levels were assessed in patients who received consistent N8-GP prophylaxis every 4 days (Q4D). RESULTS: During pathfinder 2, 117/136 patients with study-drug exposure of ≥600 days experienced bleeding episodes; 8.6% of bleeds were reoccurring bleeds; bleed reoccurrence decreased over time. For patients who received consistent Q4D prophylaxis across the trial (n = 61), mean ABR decreased from 3.5 bleeds/year (Year 1) to 1.6 bleeds/year (Year 6); mean FVIII trough levels stabilised at approximately 5% (Year 6). Across patients who received prophylaxis at some point during pathfinder 2 (n = 177), 125/126 (99%) reoccurring bleeds were joint bleeds. For patients receiving Q4D prophylaxis, bleeding risk generally increased as the time since the last prophylaxis dose increased. A similar reduction in ABR and stabilisation of trough level was observed in pathfinder 5. CONCLUSION: Long-term exposure (> 5 years) to fixed-dose N8-GP prophylaxis resulted in a protective haemostatic effect, with reduction in bleed frequency and reoccurrence, and stabilisation of FVIII trough level over time.

Clinical outcomes after joint surgery in patients on turoctocog alfa pegol (N8-GP) prophylaxis: A post hoc analysis.

INTRODUCTION: Joint damage in haemophilia often requires surgical correction. However, the surgery effect on bleeding rates and other clinical joint outcomes can be unclear. AIM: To investigate the effects of joint surgery on joint annualized bleeding rates (JABRs) and physical health outcomes in patients with haemophilia A undergoing N8-GP prophylaxis. METHODS: Patients in the pathfinder 2 trial received N8-GP prophylaxis, enrolling in the pathfinder 3 trial for indicated surgery. Patients returned to pathfinder 2 post-surgery, continuing N8-GP prophylaxis until end-of-trial. JABRs were calculated from bleeding across all joints for pre-surgery (immediately before surgery) and post-surgery (to pathfinder 2 study end) periods. Joint-health-related outcomes were derived from patient records. RESULTS: Data (41 joint surgeries; n = 30) were analysed statistically using datamining and descriptively. Pre-surgery mean JABR was higher in patients who later were operated than in 146 non-operated patients (p = .004). In operated patients, mean JABR decreased from 1.33 pre-surgery to .37 post-surgery (p = .011). In all but three patients, JABR improved or remained the same post-surgery. In the three patients whose JABR remained at one (all with multiple joint arthropathy), post-surgery bleeds were mostly at non-operated sites. Two of the three patients whose JABR increased post-surgery had undergone surgery for reasons unlikely to improve JABR. Mobility parameters often improved in patients whose JABR remained at zero. CONCLUSION: Patients with haemophilia treated with N8-GP prophylaxis benefit from surgeries. However, this analysis could not differentiate the relative contributions of surgical interventions and prophylactic treatment to the improvement of JABR.

Predictive Modeling Identifies Total Bleeds at 12-Weeks Postswitch to N8-GP Prophylaxis as a Predictor of Treatment Response.

BACKGROUND: Predicting annualized bleeding rate (ABR) during factor VIII (FVIII) prophylaxis for severe hemophilia A (SHA) is important for long-term outcomes. This study used supervised machine learning-based predictive modeling to identify predictors of long-term ABR during prophylaxis with an extended half-life FVIII. METHODS: Data were from 166 SHA patients who received N8-GP prophylaxis (50 IU/kg every 4 days) in the pathfinder 2 study. Predictive models were developed to identify variables associated with an ABR of ≤1 versus >1 during the trial's main phase (median follow-up of 469 days). Model performance was assessed using area under the receiver operator characteristic curve (AUROC). Pre-N8-GP prophylaxis models learned from data collected at baseline; post-N8-GP prophylaxis models learned from data collected up to 12-weeks postswitch to N8-GP, and predicted ABR at the end of the outcome period (final year of treatment in the main phase). RESULTS: The predictive model using baseline variables had moderate performance (AUROC = 0.64) for predicting observed ABR. The most performant model used data collected at 12-weeks postswitch (AUROC = 0.79) with cumulative bleed count up to 12 weeks as the most informative variable, followed by baseline von Willebrand factor and mean FVIII at 30 minutes postdose. Univariate cumulative bleed count at 12 weeks performed equally well to the 12-weeks postswitch model (AUROC = 0.75). Pharmacokinetic measures were indicative, but not essential, to predict ABR. CONCLUSION: Cumulative bleed count up to 12-weeks postswitch was as informative as the 12-week post-switch predictive model for predicting long-term ABR, supporting alterations in prophylaxis based on treatment response.

Illustrative Cases from the Pathfinder Clinical Trials of Patients with Hemophilia A Treated with Turoctocog Alfa Pegol (N8-GP).

PURPOSE: To illustrate the benefits of the extended half-life (EHL) recombinant factor VIII product N8-GP (Esperoct®, turoctocog alfa pegol) by describing individual cases of patients with severe hemophilia A treated with N8-GP in the pathfinder clinical trial program. PATIENTS AND METHODS: This manuscript presents selected patient cases from the pivotal pathfinder clinical trial program, which included a number of clinical studies in adults (pathfinder 2 and 3) and children (pathfinder 5); overall results published previously. Clinical data and outcomes described in this manuscript are more detailed and derived from several interesting patient cases (five adults from pathfinder 2 and two children from pathfinder 5), who received N8-GP as prophylaxis (PPX) for their severe hemophilia A. Three of the five adults described here also underwent multiple major surgeries (for which they moved from pathfinder 2 into pathfinder 3 and later returned to pathfinder 2). New analyses on pediatric joint health from pathfinder 5 are also summarized here. Outcomes assessed included bleeding complications, improvements in quality of life, intraoperative hemostatic response, blood loss during surgery, number of blood transfusions, and annualized bleeding rates. For the pediatric patients, target joint resolution, adverse events, and annualized joint bleeding rate were also assessed, all by the treating physician. RESULTS: Considerable improvements in treatment adherence, bleeding rates, and overall physical activity levels were demonstrated in two adult cases from the pathfinder 2 trial. N8-GP demonstrated good or excellent hemostatic coverage in three adult patients undergoing multiple major surgeries. The benefits of N8-GP for joint health and in support of children and adolescents with evolving active lifestyles were reported for several pediatric cases. CONCLUSION: These patient cases highlight the benefits of EHL products, such as N8-GP, for patients with severe hemophilia A. They include more challenging scenarios relating to improvements in previously poor adherence to PPX, children with active sporting lifestyles, and patients requiring multiple major surgeries.

Association of In-Hospital Surgical Bleeding Events with Prolonged Hospital Length of Stay, Days Spent in Critical Care, Complications, and Mortality: A Retrospective Cohort Study Among Patients Undergoing Neoplasm-Directed Surgeries in English Hospitals.

PURPOSE: To evaluate the association of in-hospital surgical bleeding events with the outcomes of hospital length of stay (LOS), days spent in critical care, complications, and mortality among patients undergoing neoplasm-directed surgeries in English hospitals. PATIENTS AND METHODS: This is a retrospective cohort study using English hospital discharge data (Hospital Episode Statistics [HES]) linked to electronic health records (Clinical Practice Research Datalink [CPRD]). HES includes information on patient demographics, admission and discharge dates, diagnoses and procedures, days spent in critical care, and discharge status. CPRD includes information on patient demographics, diagnoses and symptoms, drug exposures, vaccination history, and laboratory tests. Patients aged ≥18 years who underwent selected neoplasm-directed surgeries between 1-Jan-2010 and 29-February-2016: hysterectomy, low anterior resection (LAR), lung resection, mastectomy, and prostate surgery were included. The primary independent variable was in-hospital surgical bleeding events identified by diagnosis of haemorrhage and haematoma complicating a procedure or reopening/re-exploration and surgical arrest of postoperative bleeding. Outcomes included LOS, days spent in critical care, in-hospital complications (diagnoses of infections, acute renal failure, vascular events), and in-hospital mortality, identified during surgery through discharge. Multivariable regression was used to examine the adjusted association of bleeding events with outcomes. RESULTS: The study included 26,437 neoplasm-directed surgeries (hysterectomy=6092; LAR=2957; lung=1538; mastectomy=12,806; prostate=3044). Incidence proportions of bleeding events were: hysterectomy=1.9% (95% confidence interval=1.1-2.5%); LAR=3.0% (CI=2.3-3.6%); lung=1.8% (CI=1.1-2.5%); mastectomy=1.6% (CI=1.3-1.8%); prostate=1.0% (CI=0.6-1.3%). In adjusted analyses, bleeding events were associated with: prolonged LOS: 3.1 (CI=1.1-6.3) mastectomy to 5.7 (CI=3.6-8.2) LAR days longer; more days spent in critical care: 0.4 (CI=0.03-0.27) mastectomy to 6.5 (CI=2.5-13.6) hysterectomy days more; and higher incidence proportions of all examined complications; all P<0.05. CONCLUSION: This study quantifies a substantial clinical and healthcare resource utilization burden associated with surgical bleeding among patients undergoing neoplasm-directed surgery in England hospitals.

Turoctocog alfa pegol provides effective management for major and minor surgical procedures in patients across all age groups with severe haemophilia A: Full data set from the pathfinder 3 and 5 phase III trials.

INTRODUCTION: Turoctocog alfa pegol is a glycoPEGylated recombinant factor VIII (FVIII) with an extended half-life developed for prophylaxis, treatment of bleeds and perioperative management in patients with haemophilia A. AIM: Evaluate the efficacy and safety of turoctocog alfa pegol treatment for major and minor surgeries in the pathfinder 3 and 5 phase III trials. METHODS: Adults/adolescents aged ≥12 years with severe haemophilia A (FVIII <1%) received perioperative turoctocog alfa pegol treatment planned to achieve FVIII activity levels >80% during major surgery (pathfinder 3). The primary end point was haemostatic efficacy during surgery; secondary end points were blood loss, haemostatic effect postsurgery, consumption, transfusions, safety and health economics. Children (0-11 years) undergoing minor surgeries received 20-75 IU/kg turoctocog alfa pegol at Investigator's discretion (pathfinder 5). RESULTS: pathfinder 3 included 35 patients undergoing 49 major surgeries. Haemostasis was successful in 47/49 (95.9%) surgeries; two had moderate haemostatic responses. Median (mean) blood loss during major surgery was 75 (322.6) mL. Four bleeds were reported postsurgery; three were successfully treated with turoctocog alfa pegol (one was not evaluated). On the day of surgery, overall mean (median) dose was 75.5 (74.5) IU/kg and mean (median) number of doses was 1.7 (2.0). Five procedures required 11 transfusions on the day of surgery or days 1-6. No safety concerns or inhibitors were identified. Forty-five minor surgeries in 23 children were performed without complications. CONCLUSION: Turoctocog alfa pegol was effective for perioperative haemostatic management of major and minor surgeries in patients across age groups with severe haemophilia A.

Real world usage of PCC to "rapidly" correct warfarin induced coagulopathy.

BACKGROUND: Life threatening bleeding and emergency procedures in patients on vitamin K antagonists are indications for urgent reversal with prothrombin complex concentrate and vitamin K. Rapid reversal in these situations is emphasized in the literature and guidelines, but only very limited information is available on its real life use, especially on the timing of treatment in relation to presentation. MATERIALS AND METHODS: We retrospectively audited emergency warfarin reversal in 131 consecutive patients. We studied the indication, use of vitamin K, time between presentation and administration of vitamin K and PCC, effectiveness in INR reduction and clinical outcome. RESULTS: The median PCC dose was 26.8 IU/kg. The median INR was reduced from 3.1 to 1.2. Vitamin K (5 mg) was given in 91.6% of evaluable patients. We found significant delays in administration of PCC and vitamin K. The median time between presentation and administration of vitamin K/PCC was 3.6 and 5.2 hours respectively. The times in intracranial haemorrhage were 2.7 and 3.0 hours and in emergency procedures 17.4 and 15.9 hours respectively. Mortality related to bleeding was 7.6% overall but in patients with intracranial haemorrhage 22.8%. The thrombotic rate within 7 days of reversal was 1.5%. DISCUSSION: The local protocol for reversal with PCC and vitamin K was adhered to well but the delay in pre-procedural patients, suggests that intravenous vitamin K alone may be sufficient in many cases and PCC administration can be avoided by better planning. Intracranial haemorrhage in warfarinised patients carries a high mortality. Treatment delays should be avoided by making PCC stocks available within emergency departments, simple dosing structures independent of INR and administering PCC without waiting for INR and CT scan results in those with strong suspicion of intracranial haemorrhage and clear trauma. Future reports and studies should always include the time from presentation to PCC treatment.

Protamine reversal of low molecular weight heparin: clinically effective?

Low molecular weight heparins (LMWHs) are frequently used in the prophylaxis or treatment of venous thrombosis, acute coronary syndromes and peri-operative bridging. Major bleeding occurs in 1-4% depending on dose and underlying condition. Protamine is recommended for reversal but only partially reverses the anti-Xa activity and there are very limited data on clinical effectiveness. We retrospectively studied the effect of emergency reversal of LMWH with protamine in actively bleeding patients and patients requiring emergency surgery in our institution. Eighteen patients were identified through haematology referral/pharmacy records of protamine prescriptions between 1998 and 2009. Case notes were checked for the reversal indication, type/dose of LMWH, dose and clinical response to protamine, timing in relation to the last dose of LMWH and anti-Xa levels before and after protamine. All but one patient received enoxaparin. Fourteen were actively bleeding, three required emergency surgery without active bleeding and one had an accidental overdose without bleeding. The three patients requiring surgery had an uneventful procedure. In 12 of 14 patients with active bleeding, protamine could be evaluated. Bleeding stopped in eight. In the four with continuing bleeding, one had an additional coagulopathy. Protamine only partially affected anti-Xa levels. Protamine may be of use in reversing bleeding associated with LMWH but not in all patients. Anti-Xa levels were useful to assess the amount of anticoagulation before protamine administration but unhelpful in assessing its effect. Better reversal agents and methods to monitor LMWH therapy are required.

Blood product support for delivery in severe factor X deficiency: the use of thrombin generation to guide therapy.

BACKGROUND: Severe FX deficiency is a rare disorder with a variable bleeding tendency but spontaneous life threatening haemorrhage can occur. Treatment for invasive procedures and spontaneous bleeding is with prothrombin complex concentrates (PCC). When used in large or repetitive doses these are associated with a thrombotic tendency. FX:C levels of 0.15 - 0.30 IU/ mL are thought to be haemostatic during surgery . There is only limited information on the outcome and management of pregnancy in severe FX deficiency. Caesarean section is suggested as delivery mode to reduce the risk of intracranial/abdominal neonatal haemorrhage, but successful vaginal deliveries are also described. The calibrated automated thrombin generation assay (CAT) is a global coagulation test that measures the time course of thrombin generation. It has been reported to correlate with prothrombotic states and the severity of bleeding in rare coagulation disorders. The variability in phenotype, the uncertainty of the minimal haemostatic FX:C concentration and the association of PCC's with thrombosis make thrombin generation of interest in the management of FX deficient patients. PATIENT: We describe the use of CAT as a possible means to monitor treatment with PCC (Beriplex) in a patient with severe FX deficiency (FX:C < 0.01 IU/mL) during successful vaginal delivery and epidural anaesthesia. RESULTS: Thrombin generation was normal at FX:C 0.80 IU/mL but only borderline normal at FX:C 0.25 IU/mL. Repetitive doses over 3 days increased thrombin generation to the upper limit of normal at FX:C 0.25 IU/mL consistent with a prothrombotic tendency after multiple doses. The increase in thrombin generation was not related to prothrombin levels. CONCLUSION: The data suggest that CAT may be used to monitor treatment with PCC in FX deficiency. Higher levels than previously thought may be needed to normalize thrombin generation. Further studies into the correlation with bleeding or thrombosis are needed before the approach can be accepted in clinical practice.

Assuring the quality of high-stakes undergraduate assessments of clinical competence.

In the UK, and in many Commonwealth countries, a university degree is accepted by registration bodies as an indication of competence to practice as a PRHO or intern. Concerns have been raised that the quality of university examinations may not always be sufficient for such high-stakes decision-making. Assessments of clinical competence are subject to many potential sources of error. The search for standardization, and high validity and reliability, demands the identification and reduction of measurement errors and biases due to poor test design or variation in test items, judges, patients or examination procedures. Generalizability and other research studies have identified where the likely sources of error might arise and have been taken into account in the development of published guidelines on international best practice, which institutions should strive to follow. The purpose of this paper is to describe the development of the integrated final-year assessment of clinical competence at the University of Sheffield. The aim was to introduce a range of strategies to ensure the examination met the best practice guidelines. These included blueprinting the assessment to achieve a high degree of content validity; lengthening the examination by adding a written component to the OSCE component to ensure an adequate level of reliability; providing training and feedback for examiners and simulated patients; paying attention to item development; and providing statistical information to assist the examination committee in standard setting and decision-making. This evidence-based approach should be readily achievable by all medical schools.