Prophylaxis Of Bleeding Research Articles

CO62 Prophylaxis Treatment for Patients With Hemophilia A Without Inhibitors: Experience Monitoring Survey on the Use of Damoctocog Alfa Pegol

Damoctocog alfa pegol (Jivi® Bayer) is an extended half-life recombinant factor VIII (rFVIII) approved for the treatment and prophylaxis of bleeding in previously treated hemophilia A patients aged ≥12 years. The clinical efficacy and safety of damoctocog alfa pegol were demonstrated in the PROTECT VIII Phase II/III international multicenter trial. An experience monitoring survey was performed to evaluate physicians’ experience with damoctocog alfa pegol.

Moroctocog Alfa (AF-CC) for Prophylaxis and Treatment of Bleeding Episodes in Previously Treated Patients with Hemophilia A in India.

Hemophilia A is an X-linked congenital disorder, characterized by factor VIII (FVIII) deficiency. Globally, India has the highest population of patients with hemophilia, and there is a clear unmet need for appropriate and effective treatment for this patient population. This multicenter, open-label, post-approval study evaluated the safety and efficacy of moroctocog alfa in patients with moderate or severe congenital hemophilia A in India. Intravenous moroctocog alfa was administered 30 ± 5 IU/kg 3 times weekly for bleeding prophylaxis, according to the local product document. Participants were treated for up to 8 weeks, with an up to 4-week screening period and a subsequent post-treatment, 28-day safety observation period. Patients continued in the study until at least 24 exposure days or a period of up to 8 weeks on moroctocog alfa. A total of 50 participants were enrolled, and 48 (85.7%) completed the study. No participants developed FVIII inhibitors during the study. The mean (SD) annualized bleeding rate during moroctocog alfa prophylaxis was 0.79 (2.0) with a median (range) of 0.00 (0.0, 6.8). The mean (SD) annualized total factor consumption (TFC) per participant was 287,432 (93,866) IU; the mean (SD) annualized TFC by weight per participant was 4176 (858) IU/kg. Moroctocog alfa was well tolerated with no reported treatment-emergent adverse event-related dose reductions, discontinuations, or serious adverse events. Moroctocog alfa was safe, effective, and well tolerated in Indian participants with congenital moderate to severe hemophilia A. No participant developed FVIII inhibitors during the study.

Pharmacokinetics, Efficacy and Safety Evaluation of FRSW107 in Previously Treated Hemophilia a Patients: A Multicentre, Open-Label, Non-Randomized Phase III Study

Background: FRSW 107, a novel homodimer recombinant factor VIII (rFVIII) Fc fusion protein, is the first domestic extended half-life (EHL) rFVIII under development in China，and is currently at stage of Biologics License Application (BLA) in NMPA for the prophylaxis and treatment of bleeding episodes in adolescent and adult (≥12 yr) with hemophilia A (HA). Aims: This phase III (NCT04456387, CTR20201212), open-label, non-randomized, multicenter trial aimed to evaluate the pharmacokinetics (PK), safety, and clinical efficacy of FRSW 107 for prophylaxis and treatment of bleeding in previously treated HA patients ≥12 yr. Methods: Eligible patients included male severe HA (FVIII:C< 1%) ≥12 yr, previous treatment with FVIII concentrates for ≥150 exposure days (EDs), and absence of FVIII inhibitors (＜0.6 Bethesda Units/mL). A total of 119 patients received FRSW 107 for prophylaxis treatment (n=83) or on-demand treatment (n=36). The patients in the prophylaxis group were administered one dose of 50 IU/kg of FRSW 107 every three days for at least 50 EDs for a minimum period of 6 months, and the primary efficacy endpoint was annualized bleeding rate (ABR). The patients in the on-demand treatment group received 30 to 50 IU/kg of FRSW 107 over 6 months, according to the severity and location of the bleeding, and the primary efficacy endpoint was hemostatic effect (excellent, good). The single-dose and repeat dose PK parameters of 15 patients in the prophylaxis group were analyzed at ED1 and ED35, respectively. Results: In the prophylaxis group, the mean and median annualized bleeding rate (ABR) were 1.61±3.74 and 0.00 (IQR, 0.00-2.02), decreased by 95.01% versus the baseline 32.24±23.98 and 26.00 (IQR, 16.00-46.00), and 56 (67.5%) patients had no bleeds during the trial. Detailed ABR data for prophylaxis group was included in the table below. In the on-demand treatment group, hemostatic efficacy was rated as "excellent” or "good” for 98.9% of bleeds. 97.9% of 721 reported bleeds were treated with ≤2 injections. No FVIII inhibitors have been reported in this study. Drug-related adverse events (AEs) occurred in 10.1% of the patients. No SAE was judged to be related to FRSW107 treatment. No thromboembolic events were reported, and there are no unexpected safety concerns. The terminal half-life of FRSW 107 ranged between 20 to 22 hours. The incremental recovery (IR) was approximately 2.14 (IU/dL)/(IU/kg). The PK parameters and profiles remained consistent between ED1 and the repeated dosing at ED35. Conclusions: The data indicate that FRSW 107 was safe and effective for prophylaxis and treatment of bleeding episodes in previously treated adolescent and adult HA patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characteristics and Prevalence of Posttraumatic Stress Disorder and Posttraumatic Stress Symptoms Among Adults with Hemophilia a and B

Background: Studies show that the prevalence of illness-induced Posttraumatic Stress Disorder (PTSD) ranges from 12-25%, but little is known about the prevalence of PTSD or Posttraumatic Stress Symptoms (PTSS) among adults with hemophilia. We hypothesized that persons with hemophilia (PWH) would be particularly at risk for PTSD and PTSS given their bleeding diathesis, bleeding disorder treatment and prophylaxis requirements, and history of viral contamination of their treatments. After experiencing a traumatic event, symptoms of PTSD include intrusive memories, avoidance of reminders of the traumatic event, negative alterations in cognitions and mood, and marked alterations in arousal and reactivity. Aims:Determine the prevalence of PTSD and PTSS among PWH.Characterize the traumatic experiences of PWHs. Methods: Using REDCap, a self-administered survey tool was offered to all adult PWH aged 20+ at the time of their annual comprehensive visit to their Hemophilia Treatment Center (HTC). Three large academic HTCs (Boston Hemophilia Center, MA; Mount Sinai Hemophilia Center, NY; M Health Fairview Center for Bleeding and Clotting Disorders, MN) participated in the study. The tool for this study had two components: (i) Participant Characteristics was used to collect demographic information and specifics about participants’ hemophilia and comorbidities. Participants were also given the opportunity to provide a description of any hemophilia-related traumatic experience. The second component of the tool was the (ii) PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 (PCL-5): The PCL-5 is a validated, 20-item, self-report questionnaire that assesses the four DSM-5 symptom clusters of PTSD and their severity. In this study, it was used to screen for PTSS and/or provide a provisional diagnosis of PTSD based on their identified hemophilia-related trauma. Results: 178 participants were included in the analysis. Total scores on the PCL-5 ranged from 0-66 with a median of 8. 11.8% of participants (n=21) met criteria for a provisional PTSD diagnosis based on either PCL-5 score ≥ 31 or if the participant endorsed each PTSD symptom cluster. This included 6 participants (31.6%) with a self-reported established PTSD diagnosis. 101 participants (56.7%) identified a traumatic event related to living with hemophilia. The following themes of trauma emerged from their subjective trauma descriptions: non-infectious medical events, psychosocial, pain, hepatitis, and HIV/AIDS. 63 participants (35.4%) endorsed at least one Posttraumatic Stress Symptom (PTSS) by reporting a traumatic event and meeting clinical diagnostic criteria for at least one PTSD symptom cluster. Intrusion symptoms were experienced most frequently by participants (32%). A higher burden of PTSD symptomatology was significantly associated with lower education levels (p = 0.003), being unemployed (p = 0.003), having a history of previous hospitalization (p<0.001) and having two or more previously identified mental health disorders (p<0.001). Age (p = 0.18), sex (p = 0.14), comorbidities (p=0.16) and severity of hemophilia (p = 0.67) were not significantly associated with PTSD symptomatology or PTSS. Conclusion: PTSD and PTSS are commonly experienced by PWH regardless of disease severity and appear to exist at a higher rate than among the general population. These findings warrant the need for routine trauma screening, trauma informed care, and further investigation into trauma prevention. This research was supported by the 2021 National Hemophilia Foundation's Social Work Excellence Fellowship Award.

Real Pandemic World Results of Personalized Prophylaxis of Bleeds in Polish Children and Adolescents with Severe Hemophilia a

Introduction and aim of the study: In the autumn of 2020, the new nationwide protocol of bleeding prophylaxis in Polish plasma-derived FVIII (pdFVIII) previously treated patients (PTPs) with severe hemophilia A (sHA) was introduced, resulting in the necessity of switching from pdFVIII to recombinant FVIII (octocog-alpha; rFVIII). It created the opportunity to perform the study aiming to: 1. assess the safety of switching from pdFVIII to rFVIII 2. assess the safety and efficacy of pharmacokinetically-based (PK-based) personalized prophylaxis in children and adolescents with severe hemophilia A. Patients and methods: A total of one hundred fifty-one patients (median age 166 [93-209] months) receiving prophylaxis with a standard dose (40 U/kg 3 x weekly) of pdFVIII were included in this study. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were analyzed for all patients before enrollment. Using myPKFiT application, pharmacokinetic (PK) analysis followed by the selection of optimal (dosing and timing) model of prophylaxis was performed in all patients. All pros and cons of two possible models of prophylaxis (standard-dose rFVIII versus PK-based rFVIII) were discussed with parents/guardians and/or patients leaving the choice to their decision. Episodes of bleeds in two study groups were reported by parents/guardians using e-diaries and verified by local hemophilia treaters. Screening for inhibitor (INH) development was performed every three months and in every case of clinical suspicion. ABR and AJBR were prospectively analyzed again after a minimum follow-up time of 26 weeks with respect to models of prophylaxis and a type of FVIII used. Rates of bleedings were compared using the Student's t-test. Results: Due to COVID-19 pandemic-related problems, 141/151 (93.4%) patients completed the study. Thirty-four patients decided to continue standard prophylaxis with rFVIII (Group I), whereas one hundred seven were switched to PK-based prophylaxis (Group II). The risk of INH development could be assessed in 137/151 (90.7%) patients. Only 2/137 (1.47%) patients (both on PK-based prophylaxis) developed low-titer inhibitors (0.8 BU/ml after 120 exposure days (EDs) and 1.8 BU/ml after 78 EDs, respectively) with no clinical manifestation and with spontaneous elimination of the inhibitor in both cases. The retrospective analysis of bleeds during last 12 months of standard pdFVIII prophylaxis revealed that patients who decided to continue standard prophylaxis (Group I) had better ABR and AJBR than those who started PK-based personalized prophylaxis (Group II). After a minimum of 26 weeks, ABR and AJBR improved significantly in both groups. There was no significant difference in ABR and AJBR between Group I and Group II during the follow-up period, however the rate of reduction of ABR and AJBR was higher in patients on PK-based personalized prophylaxis (Group II). The prophylaxis results are presented in Figure 1. Conclusions: 1. Switching from pdFVIII to rFVIII (octocog-alpha) in PTPs with sHA is safe, 2. PK-based personalized prophylaxis may decrease ABR and AJBR in children and adolescents with sHA, especially in those in whom results of previous prophylaxis were unsatisfactory. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Nupower Study: Nuwiq for Perioperative Management of Patients with Haemophilia a on Emicizumab Regular Prophylaxis

Background: Surgery and other invasive procedures have the potential for excessive, uncontrolled bleeding in patients with hemophilia A. Simoctocog alfa (Nuwiq®) has been shown to be highly efficacious at controlling bleeding during and after surgery in hemophilia A patients. Sufficient factor VIII (FVIII) must be available for the surgery and to maintain postoperative coverage. Emicizumab is indicated for the prophylaxis of bleeding in patients with hemophilia A, but additional hemostatic cover may be required to manage bleeding during surgery, particularly major surgeries. To date, there are limited data available on the use of FVIII to provide additional hemostatic cover for surgery in patients on emicizumab. Aims: To evaluate the overall haemostatic efficacy of simoctocog alfa during major surgery in hemophilia A patients on regular emicizumab prophylaxis. Methods: NuPOWER is a prospective, open-label, single-arm, multicenter study to be conducted at approximately 15 study centers worldwide. Previously treated male patients ≥12 years of age with severe hemophilia A (FVIII:C <1%) and no current or past FVIII inhibitors, who have been on regular emicizumab prophylaxis for at least 3 months and scheduled for major elective surgery are eligible for the study. Simoctocog alfa will be administered once within 3 hours prior to surgery and repeated as necessary every 8-24 hours to achieve a FVIII plasma level of 80-100 IU/dL until adequate wound healing has been achieved. Simoctocog alfa dosing will continue for at least another 7 days to maintain a FVIII plasma level of 30-60 IU/dL (Figure 1). The primary endpoint is the overall perioperative hemostatic efficacy ("success" or "failure") of simoctocog alfa. Hemostatic efficacy will be assessed at the end of surgery and at the end of the postoperative period (i.e. up to 24 hours after the last injection of simoctocog alfa), both using an objective 4-point ordinal scale, and adjudicated by the Independent Data Monitoring Committee using a pre-defined algorithm. Secondary endpoints include thrombin generation potential, and incidence of adverse events including thrombotic events and inhibitor formation. Target enrollment is 23 patients to document 26 major surgeries. Each subject can have multiple independent surgeries that will be counted as separate procedures. Study start is planned for Q4, 2022. Conclusions: Results from the NuPOWER study will provide valuable data on the use of simoctocog alfa in patients on emicizumab prophylaxis who need to undergo major surgery. The data will help healthcare professionals to develop evidence-based guidelines for the management of bleeding in hemophilia A patients on emicizumab during surgery. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effectiveness of Proton Pump Inhibitors as a Gastrointestinal Bleeding Prophylaxis in Intensive Care Unit: Systematic Review and Meta-Analysis

Introduction: GI bleeding is a serious illness that can lengthen the time spent in the Intensive Care Unit (ICU) and increase morbidity and death by up to four times. Proton Pump Inhibitors (PPIs) are agents commonly used in patients to prevent Gastrointestinal (GI) bleeding in ICU. However, nowadays, the use of PPIs to prevent GI bleeding is being concerned due to the emergence of various studies regarding the side effects caused by PPIs. We conducted a systematic review and meta-analysis to see the magnitude of the effectiveness and validate the safety of PPIs.&#x0D; Methods: We searched through PubMed, ScienceDirect, GARUDA Portal, Clinical Key, and Google Scholar databases to identify randomized controlled trials (RCTs) that compared the effects of PPI administration on the PPI and placebo groups in adults ICU patients.&#x0D; Results: From a total of 8 studies, this meta-analysis shows the effectiveness of PPIs as prophylactic GI bleeding significantly with p &lt; 0.0001, RR = 0.52 (95% CI 0.38-0.71). Regarding safety, PPIs did not significantly increase the risk of pneumonia (p = 0.30, RR = 1.31 (95% CI 0.78-2.20)); and C. difficile infection (p = 0.90, RR = 0.91 (95% CI 0.21-3.85); and it does not impact on the mortality event (p = 0.78; RR 1.01 (95% CI 0.93-1.10).&#x0D; Conclusions: PPIs reduce GI bleeding in ICU patients over the age of 18. PPIs are also safe to use as preventative GI bleeding with no increased risk of pneumonia and C. difficile infection. PPI does not, however, significantly affect the death rates.

Advances in Acquired Hemophilia A.

Acquired Hemophilia A (AHA) is a rare, life-threatening bleeding disorder from autoantibodies against clotting factor VIII. These autoantibodies occur with increasing incidence with advanced age and are often associated with other medical conditions such as autoimmune diseases and malignancy. Not uncommonly, AHA presents as a new bleeding disorder in a person with prior thrombosis or thrombotic risk. Treatment of AHA focuses on managing and preventing bleeding, as well as immunosuppression with the goal to eradicate the autoantibody. Despite current treatment approaches, morbidity, and mortality are high due to complications from bleeding, immunosuppression, and underlying comorbidities. The most pressing needs to improved outcome for this disease are better bleeding prophylaxis in the outpatient setting and reduction of the need for intense immunosuppression. Because of the rare nature of this disease, there is limited prospective data and most treatment standards have been based on case series. The field has recently focused on improved diagnostics and advanced risk stratification, with a potential of tailoring the need and intensity of immunosuppression. Case reports of off label use of emicizumab, a factor FVIII mimetic approved for congenital hemophilia A, suggest emicizumab may provide effective and safe bleeding prophylaxis in the outpatient setting; this could permit reducing immunosuppression and decreasing the risk of treatment related infections. Two ongoing prospective clinical trials of emicizumab will help clarify the safety and efficacy in AHA.

S652 Prophylactic Epinephrine Injections for the Prevention of Postpolypectomy Bleeding: A Meta-Analysis

Introduction: Bleeding is the most common major complication from colonoscopic polypectomy. We performed a meta-analysis to evaluate whether submucosal epinephrine injections prevent postpolypectomy bleeding. Methods: The dataset was defined by searching PubMed for randomized controlled and retrospective studies published before December 2021 that compared the use of epinephrine (alone or with another preventative measure) to no prophylaxis for bleeding. Groups were defined as either epinephrine injection only (group A), mechanical prophylaxis via detachable snare and/or clip only (group B), combined therapy group (group C), and a control group. Group differences were analyzed by using a random-effects models. Effect sizes were calculated as Cohen’s d for continuous data or a log of the odds ratio (OR) for percentage (binary) data. Results: In all, we identified ten studies: six used in a prior meta-analysis and four additional studies (Table). Overall, 2,125 patients with 2,287 total polyps were included in nine randomized controlled trials and one retrospective chart review. Overall bleeding was lower in group A than in controls on the basis of five studies (OR, -1.038; confidence interval [CI] -1.560 to -0.515; p≤0.001). One study indicated that overall bleeding was lower in group B than in the controls (OR, -1.524; CI, -2.799 to -0.249; p=0.019) (Figure A). Early bleeding was lower in group A than in the controls on the basis of five studies (OR, -1.626; CI, -2.535 to -0.718; p≤0.001) and lower in group B on the basis of one study (OR, -2.719; CI, -4.175 to -1.263; p≤0.001) (Figure B). There were no significant group differences associated with late onset bleeding. Group A was significantly older than group C (Figure C) and had larger polyps than group B (Figure D). Homogeneity tests indicated homogeneity among the effect sizes suggesting examination of moderating variables was not necessary and there were no differences among the groups in terms of patient sex, polyp histology, polyp morphology, or stalk size. Conclusion: The results indicate that epinephrine prophylaxis reduces overall and early postpolypectomy bleeding but does not affect late bleeding.Figure 1.: Comparison of (A) overall and (B) early postpolypectomy bleeding in the epinephrine and control group. (C) Group A was significantly older than Group C. (D) Group A identified larger polyp size than Group B. Table 1. - Study Characteristics (NA, not available; mm, millimeters) Study Population Group Comparisons Number of patients Age (year) Number of polyps Polyp size (mean) (mm) Rohde NA A: Epinephrine B: No prophylaxis NA A: 70 (53–88), B: 65 (33–78) 40 A: 15 (7–28), B: 15 (11–35) Lee SH. Multicenter A: Epinephrine B: No prophylaxis 486 A: 51.6 ± 11.4, B: 56.8 ± 11.3 561 A: 14.5 ± 5.7, B: 15.0 ± 6.8 Hsieh Yh. Single center A: Epinephrine B: No prophylaxis 129 A: 62.9 (59.8–62.1), B: 64.9 (62.1–67.8) 151 A: 8.0 (8–13), B: 8.0 (8–11) Dobrowolski S. Single center A: Epinephrine B: No prophylaxis 69 A: 63.7 ± 9.7, B: 66.8 ± 11.5 100 A: 16.3 ± 5.4, B: 16.1 ± 5.9 Paspatis GA. Multicenter A: Combined therapy (detachable snare with epinephrine) B: Epinephrine 159 A: 61.7 ± 13.8, B: 64.5 ± 11 159 A: 27.1 ± 8.9, B: 26.3 ± 8.1 Kouklakis G. Single center A: Mechanical therapy (Endoloop with postpolypectomy clipping) B: Epinephrine 64 A: 57.9 ± 9.7, B: 58.8 ± 11.2 64 A: 25.6 ± 12.0, B: 27.0 ± 11.0 Di Giorgio P. Single center A: Mechanical therapy (detachable snare) B: Epinephrine C: No prophylaxis 488 A: 64 ± 9.2, B: 63 ± 8.9, C: 62 ± 9.0 488 A: 22.2 ± 5.9, B: 24.7 ± 5.3, C: 21.6 ± 4.8 Yamaguchi Single center A: Epinephrine B: No prophylaxis 204 A: 73.7 ± 8.7, B: 73.7 ± 8.3 204 A: 10.0 ± 5.8, B: 10.0 ± 5.0 Bahin Multicenter A: Combined therapy (epinephrine and succinylated gelatin injection with electrocoagulation) B: Epinephrine and succinylated gelatin injection 347 A: 66.0, B: 70.0 347 A: 39.5, B: 39.8 Park Multicenter A: Combined therapy (clipping with epinephrine) B: Mechanical therapy (clipping) 148 A: 59 ± 11, B: 60 ± 10 173 A: 17.5 ± 6.7, B: 17.2 ± 6.6

Feasibility of transbronchial lung cryobiopsy in patients with veno-venous extracorporeal membrane oxygenation support.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is essential life support in patients with severe acute hypoxaemic respiratory failure. However, biopsies should be considered for some patients with unknown aetiology. This study aims to evaluate the feasibility of transbronchial lung cryobiopsy (TBLC) in such patients. All patients with acute hypoxaemic respiratory failure of unknown aetiology who underwent TBLC with VV-ECMO support were retrospectively reviewed. Patients' characteristics, ventilation settings, procedure parameters, complications, pathological diagnosis and survival were summarised and analysed. Eight female and five male patients with VV-ECMO support underwent TBLC. The median age was 58 (interquartile range (IQR) 38-67) years old. Concurrent diseases were present in 10 of the 13 patients, seven of which were immunosuppressed. The median time between biopsy and VV-ECMO establishment was 2.0 (IQR 0.5-6.5) days. No patient died from the procedure. Neither pneumothorax nor severe bleeding occurred in any of the patients. Five of the 13 patients experienced moderate bleeding, and all bleeding events were successfully controlled with prophylactic balloon blockers. Pathological diagnosis by TBLC was obtained in all patients, and the diagnosis of diffuse alveolar damage was made in nine of them. In patients with VV-ECMO support, the TBLC procedure is generally safe when standardised bleeding prophylaxis is in place. TBLC contributes to identifying underlying aetiologies in patients with acute hypoxaemic respiratory failure of unknown aetiology.

The Use of Proton Pump Inhibitors in Intensive Care Units

Abstract The bleeding from the upper gastrointestinal tract represent a significant medical but also socio-economic problem.A special group of patients et increased risk consists of critically ill patients in intensive care units. Particularly significant cause of bleeding in intensive care unit patients is bleeding resulting from the stress ulcers caused by damage of themucosa of the stomach and duodenum. The purpose of this review is to present current experience in prevention of upper gastrointestinal tract bleeding using proton pump inhibitors in intensive care units. Combination of endoscopic hemostatic methods and proton pump inhibitors represents golden standard in most cases. Despite some adverse effects treatment with proton pump blockers is essential when upper gastrointestinal tract bleeding appears in critically ill patients in intensive care units. Proton pump inhibitors are more effective in acid suppression, as well as in the prevention of recurrent bleeding after endoscopic hemostasis than histamine 2 receptor blockers. The efficacy of proton pump blockers is higher in the case of a continuous intravenous infusion than in the intermittent mode of administration of the drug. The need for highly elaborate strategy for the prophylaxis of bleeding from the upper parts of gastrointestinal tract in intensive care units is essential, because when it occurs in intensive care units, mortality is high, and therapeutic options become narrow.

Mortality after transjugular intrahepatic portosystemic shunt in older adult patients with cirrhosis: A validated prediction model.

Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) improves survival in patients with cirrhosis with refractory ascites and portal hypertensive bleeding. However, the indication for TIPS in older adult patients (greater than or equal to 70 years) is debated, and a specific prediction model developed in this particular setting is lacking. The aim of this study was to develop and validate a multivariable model for an accurate prediction of mortality in older adults. We prospectively enrolled 411 consecutive patients observed at four referral centers with de novo TIPS implantation for refractory ascites or secondary prophylaxis of variceal bleeding (derivation cohort) and an external cohort of 415 patients with similar indications for TIPS (validation cohort). Older adult patients in the two cohorts were 99 and 76, respectively. A cause-specific Cox competing risks model was used to predict liver-related mortality, with orthotopic liver transplant and death for extrahepatic causes as competing events. Age, alcoholic etiology, creatinine levels, and international normalized ratio in the overall cohort, and creatinine and sodium levels in older adults were independent risk factors for liver-related death by multivariable analysis. After TIPS implantation, mortality is increased by aging, but TIPS placement should not be precluded in patients older than 70 years. In older adults, creatinine and sodium levels are useful predictors for decision making. Further efforts to update the prediction model with larger sample size are warranted.

The Profile of Markers of Bone Turnover, Inflammation and Extracellular Neutrophil Traps on Bone Mass in Haemophilia and the Development of Haemophilic Arthropathy.

Background: The aim of the study is to evaluate selected biomarkers of bone turnover, inflammation, neutrophil trap and factors predisposing haemophiliacs to bone loss, and to analyse their relationship with clinical features, treatment and complications. Methods: The levels of interleukin 6 (IL-6); citrullinated histone (CH3); osteocalcin (BGLAP); bone alkaline phosphatase (BALP); N-terminal procollagen type I propeptide (P1NP); and C-terminal collagen type I telopeptide (C1CP) were examined in 60 patients with haemophilia. Results: The cut-off value for BGLAP is 26.41 ng/mL, and 929.7 pg/mL for CH3. There is a statistically significant difference between BGLAP, BALP, C1CP and CH3 concentrations, depending on the prophylaxis used. The median concentration of BGLAP in patients taking the factor on demand is 28.0 ng/mL, BALP 322.5 U/L, C1CP 191.2 ng/mL and CH3 1114.4 pg/mL. In patients taking recombinant coagulation factor VIII/IX as prophylaxis of bleeding, the median BGLAP concentrations are 35.9 ng/mL, BALP 280.9 U/L, C1CP 161.6 ng/mL and CH3 952.5 pg/mL. BGLAP and BALP concentrations are dependent on the development of haemophilic arthropathic. Conclusions: The concentrations of selected markers of bone turnover and NETs may help to identify patients at particular risk of developing haemophilic arthropathy and bone metabolic turnover abnormalities.

Novel blood derived hemostatic agents for bleeding therapy and prophylaxis.

Hemorrhage is a major cause of preventable death in trauma and cancer. Trauma induced coagulopathy and cancer-associated endotheliopathy remain major therapeutic challenges. Early, aggressive administration of blood-derived products with hypothesized increased clotting potency has been proposed. A series of early- and late-phase clinical trials testing the safety and/or efficacy of lyophilized plasma and new forms of platelet products in humans have provided light on the future of alternative blood component therapies. This review intends to contextualize and provide a critical review of the information provided by these trials. The beneficial effect of existing freeze-dried plasma products may not be as high as initially anticipated when tested in randomized, multicenter clinical trials. A next-generation freeze dried plasma product has shown safety in an early phase clinical trial and other freeze-dried plasma and spray-dried plasma with promising preclinical profiles are embarking in first-in-human trials. New platelet additive solutions and forms of cryopreservation or lyophilization of platelets with long-term shelf-life have demonstrated feasibility and logistical advantages. Recent trials have confirmed logistical advantages of modified plasma and platelet products in the treatment or prophylaxis of bleeding. However, their postulated increased potency profile remains unconfirmed.

Carvedilol Achieves Higher Hemodynamic Response and Lower Rebleeding Rates Than Propranolol in Secondary Prophylaxis

Carvedilol induces stronger decreases in hepatic venous pressure gradient (HVPG) than conventional nonselective β-blockers (ie, propranolol). Limited data exist on the efficacy of carvedilol in secondary prophylaxis of variceal bleeding. Patients undergoing paired HVPG measurements for guiding secondary prophylaxis with either carvedilol or propranolol were included in this retrospective analysis. All patients also underwent band ligation. Changes in HVPG and systemic hemodynamics were compared between the 2 groups. Long-term follow-up data on rebleeding, acute kidney injury, nonbleeding decompensation, and liver-related death were analyzed applying competing risk regression. Eighty-seven patients (carvedilol/propranolol, n= 45/42) were included in our study. The median baseline HVPG was 21 mm Hg (interquartile range, 18-24 mm Hg), and 39.1%/48.3%/12.6% had Child-Turcotte-Pugh A/B/C cirrhosis, respectively. Upon nonselective β-blocker initiation, HVPG decreased more strongly in carvedilol users (median relative decrease, -20% [interquartile range: -29% to -10%] vs -11% [-22% to -5%] for propranolol; P= .027), who also achieved chronic HVPG response more often (53.3% vs 28.6%; P= .034). Cumulative incidences for rebleeding (Gray test, P= .027) and liver-related death (P= .036) were significantly lower in patients taking carvedilol compared with propranolol. Notably, ascites development/worsening also was observed less commonly in carvedilol patients (P= .012). Meanwhile, acute kidney injury rates did not differ between the 2 groups (P= .255). Stratifying patients by HVPG response status yielded similar results. The prognostic value of carvedilol intake was confirmed in competing risk regression models. Carvedilol induces more marked reductions in HVPG than propranolol in secondary prophylaxis of variceal bleeding, and thus is associated with lower rates of rebleeding, liver-related death, and further nonbleeding decompensation.

Acute hemodynamic response to propranolol predicts bleeding and nonbleeding decompensation in patients with cirrhosis.

Nonselective beta‐blockers are used as prophylaxis for variceal bleeding in patients with advanced chronic liver disease (ACLD). The acute hemodynamic response to intravenous propranolol (i.e., ≥10% reduction in hepatic venous pressure gradient [HVPG]) is linked to a decreased risk of variceal bleeding. In this study, we aimed to investigate the overall prognostic value of an acute response in compensated and decompensated ACLD. We analyzed the long‐term outcome of prospectively recruited patients with ACLD following a baseline HVPG measurement with an intraprocedural assessment of the acute hemodynamic response to propranolol. Overall, we included 98 patients with ACLD (mean ± SD age, 56.4 ± 11.5 years; 72.4% decompensated; 88.8% varices; mean ± SD HVPG, 19.9 ± 4.4 mm Hg) who were followed for a median of 9.6 (interquartile range, 6.5–18.2) months. Fifty‐seven patients (58.2%) demonstrated an acute hemodynamic response to propranolol that was associated with a decreased risk of variceal bleeding (at 12 months, 3.6% vs. 15% in nonresponder; log‐rank, p = 0.038) and hepatic decompensation (at 12 months, 23% vs. 33% in nonresponder; log‐rank, p = 0.096). On multivariate analysis, the acute response was an independent predictor of first/further hepatic decompensation (adjusted hazards ratio, 0.31; 95% confidence interval [CI], 0.13–0.70; p = 0.005). Importantly, there was a tendency toward a prolonged transplant‐free survival in acute responders compared to nonresponders (34.2; 95% CI, 29.2–39.2 vs. 25.2; 95% CI, 19.8–30.6 months; log‐rank, p = 0.191). Conclusions: Patients with ACLD who achieve an acute hemodynamic response to intravenous propranolol experience a lower risk of variceal bleeding and nonbleeding hepatic decompensation events compared to nonresponders. An assessment of the acute hemodynamic response to intravenous propranolol provides important prognostic information in ACLD.

FRI533 - Carvedilol is associated with superior hemodynamic response and rebleeding rates in comparison to propranolol in secondary prophylaxis of variceal bleeding

FRI533 - Carvedilol is associated with superior hemodynamic response and rebleeding rates in comparison to propranolol in secondary prophylaxis of variceal bleeding

Spleen Transient Elastography and Damping Index Identify a Subgroup of Patients Without an Acute or Chronic Response to Beta-Blockers.

Background and AimsMonitoring of acute or chronic response to beta-blockers in patients with liver cirrhosis is based on the measurement of the HVPG. Our aim was to evaluate the response to beta-blockers with non-invasive techniques.Patients and MethodsThis is a prospective observational study. Consecutive patients with an indication of primary or secondary prophylaxis of variceal bleeding who did not meet exclusion criteria were included. Acute response and chronic response were evaluated. Baseline and after acute and chronic response hepatosplenic measurements of TE and ARFI were obtained. Contrast-enhanced Doppler ultrasound was performed before and after acute and chronic responses.ResultsFrom June 2015 to May 2018, 55 patients (14 with exclusion criteria) were included. We analyzed 41 patients, mean age 57 (SD: 8), 82.9% men, alcohol 43.9%, children A/B/C 78%/17.1%/4.9%, and 87.8% on primary prophylaxis. In all, the acute response was performed and was positive in 68.3% (CI 95: 55–85%). The chronic response was performed in 30 (73.2%) and was positive in 36.7% (CI 95: 18–55%). Basal measurements significantly related to acute response were spleen TE [responders 58.4 (SD: 23.0) KPa vs. non-responders 75 (SD: 0) KPa; p = 0.02] and damping index [non-responders 0.96 (0.8) vs. responders 0.44 (0.4), p = 0.01], and with chronic response, the spleen TE [responders 58.1 (SD: 21.4) KPa vs. non-responders 73.2 (SD: 5.5) KPa; p = 0.02], and damping index [non-chronic responders 0.8 (0.7) vs. chronic responders 0.4 (0.4), p = 0.04]. A spleen TE ≥ 74 KPa had a high sensitivity of 100% and specificity of 60% and a high NPV100% for predicting poor acute response to beta-blockers. The damping index > 0.6 showed moderate sensitivity of 67% and specificity of 69% with a high NPV of 82% for predicting poor acute response to beta-blockers. The combination of both measurements for predicting poor acute response to beta-blockers had an AUC of 0.8 (CI 95: 0.5–0.9). A spleen TE ≥ 74 KPa had a high sensitivity of 87% and specificity of 71% with a high NPV of 71% for predicting poor chronic response to beta-blockers. A damping index > 0.6 had moderate sensitivity of 60%, specificity of 82%, and NPV of 56% for predicting poor chronic response to beta-blockers. The combination of both measurements for predicting poor chronic response to beta-blockers had an AUC of 0.8 (CI 95: 0.7–0.9).ConclusionSpleen TE and damping index can identify a subgroup of patients with poor acute or chronic response to beta-blockers.

Efficacy and Safety of Endoscopic Primary Prophylaxis of Bleeding in Children With High-Risk Gastroesophageal Varices.

Primary prophylaxis of bleeding is debated in children with gastroesophageal varices; one of the reasons is the limited number of studies concerning its efficacy and safety. We report our experience with endoscopic primary prophylaxis. From 2006 to 2019, 145 children (median age, 3.5 years; cirrhosis, n = 116) with high-risk gastroesophageal varices underwent primary prophylaxis (banding, n = 114; sclerotherapy n = 31, primarily in smaller children). We observed the eradication of varices in 93% of children after a mean of 6 months, at least one recurrence of varices in 45% after eradication, and gastrointestinal bleeding in 17% of children. Irrespective of the cause of portal hypertension, grade 3 esophageal varices, presence of gastric varices along the cardia and a lower composite score of endoscopic severity were associated with a worse probability of eradication, a longer time to eradication and a lower risk of a first recurrence and of bleeding following the procedure, respectively. Ten-year probabilities of overall survival and of bleeding-free survival were 95% and 75%, respectively. Endoscopic primary prophylaxis of variceal bleeding is reasonably effective and safe in children with high-risk gastroesophageal varices. Worse results are observed in children with more advanced endoscopic features. This pleads for endoscopic screening in children with portal hypertension and early detection of varices warranting primary prophylaxis.

Propranolol vs. band ligation for primary prophylaxis of variceal hemorrhage in cirrhotic patients with ascites: a randomized controlled trial.

Recent studies have debated the utility of beta-blockers to prevent variceal hemorrhage (V.H.) in cirrhosis patients with ascites. We aimed to evaluate the safety and efficacy of propranolol (PPL) compared to endoscopic variceal ligation (EVL) for V.H. primary prevention in patients with ascites. Cirrhosis patients with ≥ grade 2 ascites and varices needing primary prophylaxis were randomly assigned to receive either PPL (n = 80) or EVL (n = 80). Patients were followed monthly until 12months or transplant or death. The primary endpoint was 12-month transplant-free-survival (TFS). Secondary endpoints were the incidence of V.H., acute kidney injury (AKI), and control of ascites. Baseline characteristics were similar between the groups. PPL-group had a lower 12-month TFS (76.0% vs. 89.7%; p = 0.02) as compared with EVL-group. Mean arterial pressure ≤ 82mmHg and MELD-sodium were the independent predictors of mortality. Incidence of VH was comparable between PPL and EVL-groups [6 (7.5%) vs. 2 (2.5%), p = 0.13]. In PPL vs. EVL-group, more patients had worsening of ascites (15% vs. 5%; p = 0.03), developed refractory ascites (13.7% vs.3.7%; p = 0.02), relapse of ascites (37.1% vs. 16.4%, p < 0.01), and AKI (26.2% vs. 12.5%; p = 0.02). Side effects were comparable between the two groups. Primary VH-prophylaxis with PPL is associated with lower survival, poor control of ascites, and increased risk of AKI in cirrhosis patients with ≥ grade 2 ascites. PPL and EVL are equally effective in preventing V.H. Serial monitoring of blood pressures and renal functions is needed in cirrhosis patients with ascites on PPL (NCT02649335).