Total Bleeding Rate Research Articles

Clinical and Economic Impact of a Multisciplinary Intervention to Reduce Bleeding Risk in Patients With Acute Coronary Syndrome

Introduction and objectivesTo evaluate the clinical and economic impact of a multidisciplinary program to reduce bleeding events in patients with acute coronary syndrome through optimization of antithrombotic therapy. MethodsWe designed a preintervention (PRE) and postintervention (POST) quasi-experimental study using a retrospective analysis of 2 cohorts. The first cohort was analyzed to detect correctable measures contributing to bleeding (PRE). Afterward, a quality improvement intervention with a bundle of recommendations was implemented. Finally, a second cohort of patients was evaluated to investigate the impact of the measures on bleeding reduction (POST). The impact on health outcomes was evaluated through comparison of the percentage of in-hospital bleeding events and 30-day readmissions between the 2 cohorts. The economic analysis took into account the costs associated with the implementation of the program and the cost-savings associated with the prevention of bleeding events and 30-day readmissions. ResultsA total of 677 patients were included (377 in PRE and 300 in POST). The total bleeding rate was reduced after the implementation of the bundled intervention by 29.2% (31.6% in POST vs 22.3% in PRE; OR, 0.62; 95%CI, 0.44-0.88) while 30-day readmission rates were 7.7% in PRE and 5% in POST (P=.20). The estimated avoided cost was €95 113.6 per year, meaning that €10.1 would be obtained in return for each euro invested during the first year and €36.3 during the following years. ConclusionsThis multidisciplinary program has proven to be effective in reducing bleeding events and is economically attractive.

Use of dabigatran vs. warfarin with low-molecular-weight heparin bridging in catheter ablation for atrial fibrillation patients with a low CHADS2 score.

The purpose of the present study was to compare the efficacy and safety of dabigatran and interrupted warfarin with low-molecular-weight heparin bridging in non-valvular atrial fibrillation (AF) catheter ablation. Previously, there has been concerns that bridging therapy increases bleeding events without the benefit of stroke prevention. It has been suggested that bridging therapy should be considered only for patients at high-risk of thrombosis. Nevertheless, bridging therapy in AF patients with a low CHADS2 score may be safe and effective. The authors performed a prospective, observational study that included consecutive 240 patients undergoing AF ablation in P.R. China. A total of 139 patients received 110 mg dabigatran twice daily and 101 patients took dose-adjusted warfarin that had been bridged with low-molecular-weight heparin. The mean patient age was 55.48 years with 72.1% being men and 74.2% having paroxysmal AF. One thromboembolic complication occurred in the dabigatran group compared to none in the warfarin group. Both the groups presented a similar major bleeding rate, total bleeding rate, and bleeding and thromboembolic complications. In patients undergoing AF ablation, the risk of bleeding or thromboembolic complications was similar for both dabigatran and interrupted warfarin with bridging therapy. Bridging therapy appeared to be safe and effective for the low-risk population.

Evaluating cardioversion outcomes for atrial fibrillation on novel oral anticoagulants versus warfarin: experience at a tertiary referral centre.

Current guidelines recommend anticoagulation prior to cardioversion in patients with atrial fibrillation of >48h or unknown duration to reduce thromboembolic risk. Therapeutic anticoagulation with warfarin, with INR between 2 and 3, is consistently achieved in approximately 60% of patients. We evaluated outcomes and assessed differences in direct current cardioversion (DCCV) in patients treated with warfarin and novel oral anticoagulants (NOAC) at our institution. A retrospective analysis of consecutive DCCV at a tertiary referral over 18months was conducted. Analysis of cardioversion records allowed completion of a standardised dataset. Clinical variables recorded included (1) CHADSVASC score, (2) anticoagulant use, and (3) bleeding complications. During this period 187 DCCVs were scheduled; 119 on warfarin and 68 on NOAC. DCCV was deferred in 26% (n=31) of the warfarin group and 4.4% (n=3) of the NOAC group (p=0.0002). The average time interval between referral and DCCV was 144.43 and 109.32days for the warfarin and NOAC groups, respectively (p value=0.023). 7.56% (n=9) of the warfarin population had a bleeding event compared to a 2.94% total bleeding rate in NOAC group (p=0.213). Deferral of elective DCCV and additional anticoagulant monitoring was estimated at €1160 per procedure. In elective cardioversions, the group anticoagulated with NOAC was less likely to have subtherapeutic anticoagulation and hence deferred procedures and had reduced health care consumption when compared to the group anticoagulated with warfarin.

Análisis de los resultados económicos y en salud de un programa dirigido a la reducción de hemorragia en pacientes con síndrome coronario agudo

Introduction and objectivesTo evaluate the clinical and economic impact of a multidisciplinary program to reduce bleeding events in patients with acute coronary syndrome through optimization of antithrombotic therapy. MethodsWe designed a preintervention (PRE) and postintervention (POST) quasi-experimental study using a retrospective analysis of 2 cohorts. The first cohort was analyzed to detect correctable measures contributing to bleeding (PRE). Afterward, a quality improvement intervention with a bundle of recommendations was implemented. Finally, a second cohort of patients was evaluated to investigate the impact of the measures on bleeding reduction (POST). The impact on health outcomes was evaluated through comparison of the percentage of in-hospital bleeding events and 30-day readmissions between the 2 cohorts. The economic analysis took into account the costs associated with the implementation of the program and the cost-savings associated with the prevention of bleeding events and 30-day readmissions. ResultsA total of 677 patients were included (377 in PRE and 300 in POST). The total bleeding rate was reduced after the implementation of the bundled intervention by 29.2% (31.6% in POST vs 22.3% in PRE; OR = 0.62; 95%CI, 0.44-0.88) while 30-day readmission rates were 7.7% in PRE and 5% in POST (P = .20). The estimated avoided cost was 95 113.6€ per year, meaning that 10.1€ would be obtained in return for each euro invested during the first year and 36.3€ during the following years. ConclusionsThis multidisciplinary program has proven to be effective in reducing bleeding events and is economically attractive.Full English text available from:www.revespcardiol.org/en

Coagulation Factor IX (Recombinant), Albumin Fusion Protein (Albutrepenonacog Alfa; Idelvion®): A Review of Its Use in Haemophilia B.

Albutrepenonacog alfa (Idelvion®), a fusion protein that genetically fuses recombinant factor IX (rFIX) with recombinant human albumin (rAlbumin), is indicated in the treatment of haemophilia B. This narrative review discusses the pharmacological properties and clinical data related to the use of this novel fusion protein, hereafter referred to as rIX-FP. The fusion of rFIX to rAlbumin prolongs the elimination half-life of rIX-FP in the circulation, allowing routine prophylaxis to be administered once every 7-14 days. In the pivotal phase 3 clinical trials in previously treated patients with moderately severe to severe haemophilia B, routine rIX-FP prophylaxis (administered once every 7 days in children, and once every 7-14 days in adolescents and adults) was associated with low annualized spontaneous, total and joint bleeding rates, and was associated with significantly fewer bleeding episodes than on-demand treatment. rIX-FP was also effective in controlling bleeding episodes when used as on-demand treatment and in maintaining haemostasis in the perioperative setting. rIX-FP was well tolerated in the clinical trials, with no reports of inhibitor development. In conclusion, rIX-FP provides an effective, well-tolerated option for the treatment and management of haemophilia B that, by virtue of its extended half-life, is less burdensome than conventional FIX products.

Dosing of Rviii-Singlechain Based on Clinical Bleeding Phenotypes Results in Low Bleeding Rates and Low Consumption in Patients Treated with Prophylaxis Two or Three Times Weekly

Introduction: Safety and efficacy of rVIII-SingleChain (AFSTYLA) was investigated in two pivotal and one extension study, comprising the Affinity program. The study design and instructions provided to the investigators allowed the physician to freely choose the dose assignment and regimen, based on the FVIII treatment regimen used prior to enrollment, and the subject's clinical bleeding phenotype. Adjustments of dose and schedule were allowed at any time during the study.Methods: This analysis investigates initial and final dose assignment and the corresponding total and spontaneous bleeding rates in subjects in the adult and adolescent study assigned to prophylaxis two or three times weekly (>80% of the subjects on prophylaxis therapy) in dosing brackets of 20 to <30 IU/kg, 30 to <40 IU/kg and 40 to ≤50 IU/kg.Results: In the final dose assignment, 43 subjects were assigned a dose of 20 to <30 IU/kg, 62 subjects were assigned a dose of 30 to <40 IU/kg, and 38 subjects were assigned a dose of 40 to ≤50 IU/kg. No differences were observed in the analysis by dose brackets in the adult and adolescent (12-65) population (complete or stratified by age); neither in the initial nor the final dose assignment analysis. The median annualized bleeding rate for the dosing brackets of 20 to <30 IU/kg, 30 to <40 IU/kg and 40 to ≤50 IU/kg was 1.93, 1.05 and 2.21, respectively. The median annualized spontaneous bleeding rate was 0, 0 and 0.50, respectively (final dose assignment).Conclusions: This data shows that dosing of rVIII-SingleChain based on clinical bleeding phenotypes results in low bleeding rates and low consumption in patients treated with prophylaxis two or three times weekly, with more than 70% of subjects being maintained at doses of <40 IU/kg. DisclosuresSt Ledger:CSL Behring: Employment. Blackman:CSL Behring: Employment. Veldman:CSL Behring: Employment. Pabinger:CSL Behring: Consultancy.

Optimisation of antithrombotic therapy in patients with acute coronary syndrome to reduce bleeding episodes.

The aim of the study was to evaluate the effectiveness of a multidisciplinary intervention to reduce the risk of bleeding associated with antithrombotic drugs in patients with acute coronary syndrome (ACS). We designed a pre-post quasi-experimental intervention study using retrospective cohorts. The first cohort was analysed to detect correctable measures contributing to bleeding (PRE: January-July 2010). Second, a bundle of interventions was implemented and third, a second cohort of patients was evaluated to investigate the impact of our measures in bleeding reduction (POST: September 2011-February 2012). A total of 677 patients were included (377 in PRE and 300 in POST). The bundle of interventions was: Overdose avoidance measures: the percentage of patients overdosed was reduced by 66.3% (p < 0.001). Institutional protocol update to include the latest recommendations regarding bleeding prevention: In POST, the percentage of patients treated with fondaparinux increased (2.4% vs. 50.7%; p < 0.001). In PRE, 11 patients were treated with the combination of abciximab and bivalirudin; whereas in POST, only one patient received the combination (p = 0.016). Mandatory measurement of body weight: the percentage of patients with unknown body weight was reduced by 35% (p = 0.0001). In POST, the total bleeding rate was reduced by 29.2% (31.6% in PRE vs. 22.4%, p < 0.05, OR: 0.62; 95% CI: 0.44-0.88). It was necessary to implement the interventions in 11 patients to prevent one bleeding episode (95% CI: 7-39). The multidisciplinary programme has been effective in reducing bleeding episodes. The interventions were effective in reducing antithrombotic drugs overdosage, incorporating the use of fondaparinux to the NSTE-ACS therapeutic arsenal, limiting the use of bivalirudin with abciximab and obtaining body weight for most patients.

Comparison of Short-Term Tertiary Prophylaxis at Low-Dose and Intermediate-Dose for Adults with Severe Hemophilia a in China

▪Background: Low-dose prophylaxis and intermediate-dose prophylaxis in hemophilia A both had been proved in reducing bleedings in some developing country, but there was rare attention in terms of the Health-related Quality of life (HRQoL) and patients' adherence. So we initiated a retrospective study to compare the differecen between low-dose and intermediate-dose regimen of tertiary prophylaxis for adults with severe hemophilia A.Methods: Data collected from the hemophilia treatment centre at Nanfang hospital from July 2010 to February 2015(median 2 years of follow-up), a total of 40 adult patients with severe hemophilia A (FVIII < 1%) who are receiving prophylaxis treatment≥1 year and treatment data available were eligible for enrollment in the study, including 25 patients in low-dose regimen(F‡[8-15 IU/kg 1-2times weekly or weekly<30IU/kg), and 15 patients in intermediate-dose regimen( F‡[ 15-20 IU/kg 2-3 times weekly or weekly≥40IU/kg and <75 IU/kg). Collect the data with patients' characteristics, previous condition and treatment, annual total bleeding rate(ABR). Use SF36 to evaluate patients' quality of life, use the difference between the beginning of this study and one year ago of SF36 score to represent the improvement of quality of life. Use "hemophilia bleeding and factor injection record handbook" to collect information about patients' bleeding and injection record, use HO's measuring method to evaluate adherence.Results: 1. There were no statistical differences between two groups in age, weight, age at first bleeding, age at first treatment, family history of hemophilia and history of hepatitis.(the range of P-value was 0.221-1.000). 2.The Health-related Quality of life (HRQoL) in patients with severe hemophilia A were measured by the SF-36. Only on bodily pain(P=0.965) and vitality(P=0.101)the differences did not exist between two groups ,beyond that intermediate-dose group were better in other aspects(included total SF36, physical functioning, role-physical, general health, social functioning, role-emotional and mental health) than low-dose group(the range of P-value was 0.000-0.045, P<0.05),which inferred that the improvement of quality of life was better in patients in intermediate-dose group. 3. Used HO's measuring method for adherence to evaluate the 40 patients in two groups. The dosage and dosing intervals adherence of low-dose group were 78.6A88.5 respectively, while the intermediate-dose group were 90.3A95.2 respectively, the differences in dosage and dosing intervals adherence between two groups were statistically significant(P=0.003). Intermediate-dose prophylaxis treatment reduced the annual total bleeding rate(ABR) than the low-dose group(median 13 vs. 5.5,P=0.000), while poor dosage adherence correlates with more ABR(B=-0.555,P=0.000), which meant worse adherence was association with much bleeding, but there was no correlation between dosing intervals adherence and ABR(B=0.171,P=0.507).Conclusion: 1. Compared to low-dose regimen, intermediate-dose regimen for short-term tertiary prophylaxis in adults with severe hemophilia A would improve quality of life. 2.Patients in intermediate-dose prophylaxis regimen had better adherence than low-dose regimen. There are negative correlation between dosage adherence and ABR, which means poor adherence lead to more bleeding events, while there's no correlation between dosing intervals adherence and ABR. DisclosuresNo relevant conflicts of interest to declare.

Effect of Intracoronary Plus Low-Dose Intravenous Tirofiban in Elderly Patients with Acute Myocardial Infarction

To investigate the efficacy and safety of low-dose tirofiban in elderly patients undergoing primary percutaneous coronary intervention (PPCI) for acute myocardial infarction (AMI). One hundred and four patients aged 70 years and above undergoing PPCI for AMI were divided into control (n=52) and study (n=52) groups. All patients received bolus intracoronary injection of tirofiban (10μg/kg), which was followed by intravenous infusion at 0.15μg/kg/min in the control group and at 0.075μg/kg/min in the study group for 24h. There was no statistically significant difference between the study group and the control group in patients with complete ST segment resolution (84.2% vs. 85.7%, P=0.851), peak high-sensitive cardiac troponin T level (5.1±1.9 vs. 5.8±2.6μg/L, P=0.123), scores of thrombus in the infarct-related artery (0.98±0.51 vs. 1.12±0.59, P=0.214), and patients with TIMI grade 3 flow (86.0% vs. 88.2%, P=0.737) after PPCI. There were no statistically significant differences between the two groups in left ventricular ejection fraction (57.1±6.3 vs. 57.7±6.1, P=0.611) and composite major adverse cardiovascular events rate (P =0.778) at 90 days after PCI. The total bleeding rate in the study group was lower than in the control group (P=0.048). In elderly patients with AMI undergoing primary PCI, low and standard dose of tirofiban exerts similar effects on platelet aggregation, coronary flow, infarct size, left ventricular systolic function and short-term clinical outcomes. Low dose regimen is associated with a lower bleeding rate than the standard dose.

Assessment of Risk of Thromboprophylaxis Failure in Hospitalized Patients with Cancer (Artic Study)

▪Background: Venous thromboembolism (VTE) remains the major cause of morbidity and mortality in hospitalized patients. Three randomized placebo controlled trials have demonstrated the superiority low molecular weight heparin (LMWH) and 1 heparinoid in the prevention of VTE in hospitalized medical patients with a 50% absolute risk reduction in VTE compared to placebo, but an overall failure rate of 5%. Current guidelines suggest that hospitalized cancer patients receive venous thromboprophylaxis with LMWH, if their hospital stay is longer than 3 days. In this study we sought to evaluate the incidence of VTE in hospitalized patients with cancer receiving VTE prophylaxis with subcutaneous 5000 units of dalteparin daily during the admission period.Methods: This is a single centre retrospective cohort study (London, Canada). We collected data from adult patients with active cancer admitted for acute medical reasons who received VTE prophylaxis with LMWH during their hospital stay. We considered failure of prophylaxis if objective diagnosis of pulmonary embolism or deep venous thrombosis occurred: a) during hospitalization; b) within 1 month or 3 months of most recent discharge from hospital.We included patients 18 years old or older; with any type of active cancer (except basal cell and squamous cell carcinoma of the skin) admitted for at least 3 days for treatment of an acute medical reason directly associated to their cancer or not. We did not include patients admitted at the intensive care unit.We need 713 patients to demonstrate a 5 to 7.5% failure rate in VTE prophylaxis (MCID 2.5%) in hospitalized patients with cancer with a 0.025 one-sided alpha and 80% power.Results: Between January 2011 and December 2013 our hospital registered 4262 admissions of patients with active malignancy for treatment of an acute medical illness. 875 patients (total 1132 admissions) fulfilled our eligibility criteria. 434 were males (49.5%), mean age 64.3 (SD= 13.5). There were 180 (20%) hematological and 695 (80%) solid malignancies. The most frequent tumor sites were genitourinary (n=170), lung (n=158), colorectal (n=128) and others (n= 239). 559 (70%) patients with solid tumors had stage III or IV. Reason for admission was failure to thrive (n=232); fever/ infection (n= 202); need for cancer treatment (n= 154); pain control (n=126); respiratory distress (n=108) or CNS symptoms (n=53). Mean hospitalization days were 14.7 (±12). 491 (56%) patients had a single admission.VTE occurred in 70 of 875 patients (8.0%). The incidence of VTE was most frequent during the hospitalization period [34 of 70 patients (48.0%)] compared to 1 month [14 (20.0%)] or 3 months [22 (31.5%)] following the most recent hospitalization. Univariate analysis suggested that being male (OR= 1.69; 95%CI: 1.03 – 2.78; p=0.039); age 65 or older (OR=1.39; 95%CI: 0.4 -1.8; p=0.052); admission due to respiratory distress (OR=2.61; 95%CI: 0.9 – 6.8; p=0.052) or failure to thrive (OR=2.52; 95%CI: 1.1 – 5.9; p=0.036) were significantly associated with VTE risk. Having pancreas or colorectal cancer approached significance (Table).Total bleeding rate was 18 of 875 (2%) with 5 major bleeding events. 175 (20%) patients died during the study period: 125 (75%) due to malignancy progression.Conclusion: Hospitalized patients with active cancer are at high risk for VTE prophylaxis failure (8%). It appears that reason of admission, age and male sex are significant risk factors of VTE prophylaxis failure. Having colorectal or pancreatic cancer may also pose a risk for VTE. New VTE prophylactic strategies for this population should be investigated in future prospective studies.TableUnivariate analysis to assess potential risk factors for LMWH prophylaxis failure in hospitalized patients with cancerRisk FactorsOdds Ratio (95% CI)p-valueMale0.95 (0.6 -1.5)0.808Age ≥651.39 (0.4 -1.8)0.052Stage I - IIStage III - IV1.03 (0.4 -2.5)1.27 (0.7 -2.4)0.9090.478Primary tumor site*LungColorectalBreastPancreasOthers1.79 (0.8 - 7.4)2.67(0.9 - 4.7)1.63 (0.9 -10.7)3.11 (0.6 - 3.8)1.33 (0.9 - 5.6)0.1690.0600.3630.0730.452Reason for admission^FeverCNS symptomsRespiratory distressPainFailure to thrive1.32 (0.5 - 3.4)1.703 (0.5 - 6.0)2.61 (0.9 - 6.8)1.79 (0.7 - 4.8)2.52 (1.1 - 5.9)0.5720.4110.0520.2480.036Number of admissions**<4≥ 41.21 (0.7 - 2.0)1.46 (0.4 -5.0)0.4620.553Reference: *hematological; ^anticancer treatment**single admission DisclosuresNo relevant conflicts of interest to declare.

PCV94 - Economic evaluation of apixaban for venous thromboembolism in total knee and total hip replacement in Guatemala

Due to the aging of the population, musculoskeletal diseases, particularly articular diseases and fragility fractures, have been constantly increasing. For this reason, total hip replacement (THR) and total knee replacement (TKR) have also increased. These procedures impact the quality of life and imply high risk of venous thromboembolism (VeT). VeT events have a high mortality in the elderly, 21% on hospitalized patients and up to 39% one year after the surgery. Prophylaxis for VeT is as a major strategy to minimize the consequences on patients undergoing TKR and THR. The aim of this study was to assess the cost-effectiveness (CE) of apixaban against dabigatran, rivaroxaban, fondaparinux, and enoxaparin for VeT prevention on these patients in Guatemala, from the private health care perspective. A simulated cohort of 1,000 patients subjected to THR/TKR entered a decision-tree model to compare costs and effectiveness of apixaban (2.5 mg/12 hours), dabigatran (220 mg/day), rivaroxaban (10 mg/day), fondaparinux (2.5 mg/day) and enoxaparin (30 mg/12 hours). Effectiveness measures were: total VeT events, bleeding rates and deaths. The model used a 5 year time horizon and only direct medical costs were considered (inpatient costs, medication expenses, adverse events, tests). Effectiveness and epidemiologic data were retrieved from published literature. Local costs (2012 US$) were gathered from the 3 private hospitals of Guatemala official databases. The total VeT events were 69 for Apixaban, 55 for Rivaroxaban, 112 for Dabigatran, 86 for Enoxaparin and 45 for Fondoparinux. The estimated bleeds were 71 (Apixaban), 85 (Rivaroxaban), 85 (Dabigatran), 73 (Enoxaparin) and 31 (Fondaparinux). Apixaban dominated enoxaparin and dabigatran while rivaroxaban and fondaparinux had an ICER of US$104,177/QALY and US$103,933/QALY, respectively. In the acceptability curves, Apixaban appeared with the highest probability of being cost-effective. . Apixaban resulted as the cost-effective therapy for VeT prevention for adult patients in Costa Rica.

Human-Cl Rhfviii Effectively and Safely Prevents Bleeding Episodes in Previously Treated Adult Patients with Severe Haemophilia A

AbstractAbstract 1132The main purpose of this prospective, multi-center, open-label phase 3 study was to assess the efficacy of prophylactic treatment with Human-cl rhFVIII, the first human cell-line derived recombinant FVIII, in previously treated patients (PTPs) with severe haemophilia A.Patients were to receive 30–40 international units (IU) FVIII of Human-cl rhFVIII per kg every other day for 6 months. Efficacy of preventing and treating bleeds were judged using objective criteria taking the monthly bleeding rate and the number of infusions needed to manage a break-through bleed into account. In-vivo recovery (IVR) was determined at the beginning of the study and after 3 and 6 months. FVIII:C was measured by validated chromogenic (CHR) and one-stage (OS) assays in a central laboratory, which also assigned drug potencies. Inhibitor activity was determined using the Nijmegen modification of the Bethesda assay before the first administration and at defined intervals thereafter. Thirty-two patients between 18 and 75 years of age were enrolled from 11 centres in Europe and treated prophylactically for 6.0±0.9 months (mean ± SD) with a mean prophylactic dose of 32.8 IU/kg. Sixteen patients never bled, 11 patients bled once and 5 more than once. The mean total and spontaneous monthly bleeding rate was 0.188±0.307 and 0.095±0.211, respectively. Efficacy of the prophylactic treatment was “excellent” in all patients for spontaneous BEs and “excellent” or “good” in all patients but one for all types of bleeds. All treatments of bleeds were rated as “excellent” (71.4%) or “good” (28.6%). The IVR at baseline was 2.6±0.5 % per IU/kg for the CHR and 2.2±0.5 % per IU/kg for the OS assay and remained stable during the study. A total of 2921 infusions were given in the study. Human-cl rhFVIII was well tolerated and no patient experienced a related serious adverse event. No FVIII inhibitors were detected. Conclusion:The data indicate that Human-cl rh FVIII is safe and efficacious in preventing and treating bleeds in PTPs with severe haemophlia A. Disclosures:Knaub:Octapharma AG: Employment. Lissitchkov:Octapharma AG: PI Other. Tuddenham:College London: Consultancy, Employment, Gene therapy for hemophilia A, Gene therapy for hemophilia A Patents & Royalties, Research Funding. Collins:Octapharma AG: Consultancy. Oldenburg:d and e: Baxter, Bayer, Biotest, CSL-Behring, Grifols, Inspiration, NovoNordisk, Octapharma, Pfizer e: Biogen IDec, Swedish Orphan Biovitrum: Honoraria, Research Funding. Bichler:Octapharma AG: Employment.

Efficacy, PK and Safety Results of a Phase I/II Clinical Trial of Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP) in Previously Treated Patients with Haemophilia B (PROLONG - 9FP)

AbstractAbstract 1121Factor IX (FIX) replacement therapy is the standard of care for patients with haemophilia B. FIX products currently available have a relatively short half-life, requiring 2–3 times a week intravenous prophylactic treatment to achieve a significant bleeding reduction. A recombinant FIX albumin fusion protein (rIX-FP) was generated by genetic fusion of human recombinant albumin to rFIX to extend the half life of FIX. A Phase I/II open-label, multicenter, clinical study of rIX-FP has been completed in previously treated patients with severe hemophilia B (FIX ≤ 2%) as part of the PROLONG - 9FP clinical developmental program. The objectives of the study were to evaluate the prevention of bleeding episodes during once weekly prophylaxis and to assess the hemostatic efficacy of rIX-FP for the treatment of bleeding, in addition to safety and pharmacokinetic (PK) assessments.The study consisted of a 10 to 14 day PK evaluation period, and a 3 to 12 month safety and efficacy evaluation period, during which subjects received either on-demand or prophylaxis treatment. Subjects receiving weekly prophylactic treatment were initially treated with a dose based upon the subject's PK profile, bleeding phenotype, and physical activity level. The dose could be adjusted based on clinical outcome, while maintaining a 7 day treatment interval. Subjects receiving on-demand treatment were treated with a dose based upon the subject's PK profile and WFH recommendations for treatment of bleeding episodes.Seventeen study subjects from hemophilia treatment centers in Israel and Bulgaria participated in the study, 13 of whom received weekly prophylaxis treatment and 4 of whom received on-demand treatment. Following a single infusion of 25 IU/kg rIX-FP (n=13), the PK parameters (t1/2 = 94 hrs, AUC0-inf= 3414 hr*IU/dL) were comparable to those previously reported from the Phase I study (Blood prepublished Aug 2, 2012). In addition, rIX-FP maintained a baseline-corrected mean trough level of 3.8% and 2.7% at Day 7 and Day 14, respectively, after 25 IU/kg rIX-FP administration. There were no AEs considered as possibly related to rIX-FP. There were no allergic reactions, inhibitors to FIX or antibodies to rIX-FP reported. All 10 prophylaxis subjects who were previously receiving routine prophylaxis with FIX were maintained successfully on weekly treatment with rIX-FP for the entire study. Furthermore, three prophylaxis subjects who were previously treated on-demand were maintained successfully on weekly prophylaxis treatment with rIX-FP with at least 85% reduction in the annualized spontaneous and total bleeding rate compared to the annualized bleeding rate prior to study entry. All of the bleeding events were treated successfully, including approximately 90% of the events with a single infusion of rIX-FP. The mean weekly product consumption of rIX-FP (IUs) was reduced compared to the consumption of the previous FIX product (IUs). No subject was withdrawn from the study due to safety concerns or lack of hemostatic efficacy. This Phase I/II study has demonstrated the clinical efficacy of rIX-FP for once weekly routine prophylaxis to prevent spontaneous bleeding episodes and treatment of bleeding episodes, in addition to the excellent safety characteristics and improved PK profile. A detailed analysis of the efficacy of weekly routine prophylaxis and treatment of bleeding episodes, improved PK and safety properties of rIX-FP will be presented. Disclosures:Martinowitz:CSL Behring: Honoraria, Investigator for CSL clinical study of rIX-FP Other. Lubetsky:CSL Behring: Investigator for CSL clinical trial of rIX-FP Other. Santagostino:CSL Behring: Honoraria, Investigator for CSL Behring clinical trial of rIX-FP Other, Research Funding, Speakers Bureau. Jotov:CSL Behring: sub-investigator for CSL clinical trial of rIX-FP Other. Barazani-Brutman:CSL Behring: study coordinator for CSL Behring clinical trial of rIX-FP Other. Voigt:CSL Behring: Employment. Moises:CSL Behring: Employment. Jacobs:CSL Behring: Employment. Lissitchkov:CSL Behring: Investigator for CSL Behgring clinical trial of rIX-FP Other.

Sa1644 Outcomes and Long Term Prognosis of Endoscopic Submucosal Dissection for Early Gastric Cancer

Outcomes and Long Term Prognosis of Endoscopic Submucosal Dissection for Early Gastric Cancer Ken Ohnita*, Hajime Isomoto, Kayoko Matsushima, Yuko Akazawa, Naoyuki Yamaguchi, Hitoshi Nishiyama, Eiichiro Fukuda, Fuminao Takeshima, Saburo Shikuwa, Kazuhiko Nakao Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan; Internal Medicine, Sankokai Miyazaki Hospital, Isahaya, Japan Backgrounds: Endoscopic submucosal dissection (ESD) yields high rate of curative resection of early gastric cancer (EGC). However, little information is available on the long term outcomes of ESD in a large number of patients. Patients and method: A total of 1332 EGCs in 1209 consecutive patients were treated by ESD from January 2001 to December 2010. The indication criteria (group A) were defined as differentiated -type mucosal cancer without ulceration 2 cm in diameter. Expanded indication criteria (group B) were defined as follows; differentiated -type mucosal cancer without ulceration irrespective of tumor size, differentiated -type mucosal cancer with ulceration 3 cm in diameter, differentiated -type minute ( 500 m from the muscularis mucosae, sm1) submucosal invasive cancer 3 cm in size, and undifferentiated-type mucosal cancer without ulceration 2 cm in diameter with no lymphaticvascular involvement. Out of indication (group C) were defined as except for group A and B. The early outcomes (perforation and bleeding rate and curability) were assessed in 1209 patients. Resections were considered curative when a tumor was excised by en bloc and was within the indication or expanded indication criteria with tumor-free lateral and vertical margins and no lymphovascular invasion. Long-term outcomes were assessed in 319 patients for over 5-year follow-up. Overall survival rates among the three groups were compared. We compared the overall survival rates in different age groups. Results: Short-term outcomes were as follows; The 617 (46.3%) lesions were defined as group A , 507 (38.1%) lesions were defined as group B, and the 208 (15.6%) lesions were defined as group C. Curative resection rate were 96.6% (596/617) in group A and 91.5% (464/507) in group B. Total perforation rate was 2.9% (39/1332), which was higher in group B than in group A (4.3% [22/507] versus 1.8% [11/617], p 0.05). Total bleeding rate was 2.0% (26/1332), which was significantly higher in group C than in group A (4.8% [10/208] versus 1.1% [7/617], p 0.01) and in group B (4.8% [10/208] versus 1.8% [9/507], p 0.05). In analysis of long term outcomes, median term of observation was 66 months (1106 months). In the 53 patients out of group C, 26 patients had additional surgery. Of the 266 patients with group A or group B, 41 patients died of nongastric cancer disease. Of the 53 patients with group C, 11 patients died (one patient died of gastric cancer). The 5-year survival rates in three groups were not significantly different. However, the 5-year survival rates in the patients over 80 years old (59.2%) were lower than the younger age-group (under 60 years old; 88.4%, sixties; 93.5%, seventies; 82.7%) (p 0.01). Conclusions: Expanded indication of ESD for early gastric cancer is appropriate, but it is necessary to consider the basal disease in elder patients.

Feasibility and Safety of Dabigatran Versus Warfarin for Periprocedural Anticoagulation in Patients Undergoing Radiofrequency Ablation for Atrial Fibrillation: Results From a Multicenter Prospective Registry

The purpose of this study was to evaluate the feasibility and safety of periprocedural dabigatran during atrial fibrillation (AF) ablation. AF ablation requires optimal periprocedural anticoagulation for minimizing bleeding and thromboembolic complications. The safety and efficacy of dabigatran as a periprocedural anticoagulant for AF ablation are unknown. We performed a multicenter, observational study from a prospective registry including all consecutive patients undergoing AF ablation in 8 high-volume centers in the United States. All patients receiving dabigatran therapy who underwent AF ablation on periprocedural dabigatran, with the dose held on the morning of the procedure, were matched by age, sex, and type of AF with an equal number of patients undergoing AF ablation with uninterrupted warfarin therapy over the same period. A total of 290 patients, including 145 taking periprocedural dabigatran and an equal number of matched patients taking uninterrupted periprocedural warfarin, were included in the study. The mean age was 60 years with 79% being male and 57% having paroxysmal AF. Both groups had a similar CHADS(2) score, left atrial size, and left ventricular ejection fraction. Three thromboembolic complications (2.1%) occurred in the dabigatran group compared with none in the warfarin group (p = 0.25). The dabigatran group had a significantly higher major bleeding rate (6% vs. 1%; p = 0.019), total bleeding rate (14% vs. 6%; p = 0.031), and composite of bleeding and thromboembolic complications (16% vs. 6%; p = 0.009) compared with the warfarin group. Dabigatran use was confirmed as an independent predictor of bleeding or thromboembolic complications (odds ratio: 2.76, 95% confidence interval: 1.22 to 6.25; p = 0.01) on multivariate regression analysis. In patients undergoing AF ablation, periprocedural dabigatran use significantly increases the risk of bleeding or thromboembolic complications compared with uninterrupted warfarin therapy.

Combined intracoronary tirofiban and manual thrombectomy during primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction

To investigate the efficacy and safety of low-dose tirofiban in elderly patients undergoing primary percutaneous coronary intervention (PPCI) for acute myocardial infarction (AMI).One hundred and four patients aged 70 years and above undergoing PPCI for AMI were divided into control (n=52) and study (n=52) groups. All patients received bolus intracoronary injection of tirofiban (10 μg/kg), which was followed by intravenous infusion at 0.15 μg/kg/min in the control group and at 0.075 μg/kg/min in the study group for 24 h.There was no statistically significant difference between the study group and the control group in patients with complete ST segment resolution (84.2% vs. 85.7%, P = 0.851), peak high-sensitive cardiac troponin T level (5.1±1.9 vs. 5.8±2.6 μg/L, P = 0.123), scores of thrombus in the infarct-related artery (0.98±0.51 vs. 1.12±0.59, P = 0.214), and patients with TIMI grade 3 flow (86.0% vs. 88.2%, P=0.737) after PPCI. There were no statistically significant differences between the two groups in left ventricular ejection fraction (57.1±6.3 vs. 57.7±6.1, P=0.611) and composite major adverse cardiovascular events rate (P =0.778) at 90 days after PCI. The total bleeding rate in the study group was lower than in the control group (P = 0.048).In elderly patients with AMI undergoing primary PCI, low and standard dose of tirofiban exerts similar effects on platelet aggregation, coronary flow, infarct size, left ventricular systolic function and short-term clinical outcomes. Low dose regimen is associated with a lower bleeding rate than the standard dose.

The EFFect of hIgh-dose ClopIdogrel treatmENT in patients with clopidogrel resistance (The EFFICIENT Trial)

ObjectivesThe aim of this study was to evaluate the effect of high-dose clopidogrel continuation treatment on the development of MACCE after elective PCI in patients with clopidogrel resistance. MethodsThe study group consisted of 192 patients. Of these, 98 participants without resistance served as the control group (Group 1) and received 75mg/day clopidogrel for 1month. Ninety-four patients with resistance were randomly divided into two groups: 47 patients in the standard-dose group (Group 2) received 75mg/day continuation therapy, whereas 47 patients in the high-dose group (Group 3) received 150mg/day continuation therapy for 1month. Clopidogrel resistance was evaluated with the VerifyNow P2Y12 test. Patients with a platelet inhibition value lower than 40% were classified as resistant. ResultsDuring the 6-month follow-up for MACCE, the event-rate in Group 2 was significantly higher than both Groups 1 and 3 (Group 1 vs Group 2; p=0.019, Group 1 vs Group 3; p=0.82, Group 2 vs Group 3; p=0.045). Total bleeding rate in all groups were similar (Group 1 vs Group 2; p=0.54, Group 1 vs Group 3; p=0.27, Group 2 vs Group 3; p=0.16). The rate of NACE was similar in all groups (Group 1 vs Group 2; p=0.08, Group 1 vs Group 3; p=0.50, Group 2 vs Group 3; p=0.39). ConclusionIn patients who underwent elective PCI and had clopidogrel resistance, high-dose clopidogrel continuation therapy was more efficient in preventing MACCE than the standard dose. High-dose continuation therapy did not increase the risk of bleeding complication (The EFFICIENT Trial; ClinicalTrials.gov number: NCT01032668).

Cilostazol reduces the progression of carotid intima-media thickness without increasing the risk of bleeding in patients with acute coronary syndrome during a 2-year follow-up

Cilostazol, a phosphodiesterase III inhibitor, is known to have anti-proliferative activity. We investigated the effects of cilostazol 200mg, in addition to aspirin 100mg and clopidogrel 75mg, on carotid intima-media thickness (IMT) progression during a 2-year follow-up period in patients with acute coronary syndrome (ACS) requiring stent implantation. Patients with ACS (n=130) were randomly assigned to the cilostazol group (n=64) or the control group (n=66). Longitudinal images of left and right carotid IMT were measured at baseline, at 6, 12, and 24months using a 10-MHz linear vascular probe. The primary endpoint was to compare the changes in maximum carotid IMT at 2years. Other parameters such as inflammatory markers [interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP), and adiponectin] and bleeding risk were also compared. The carotid IMT showed no significant progression from baseline in the cilostazol group compared to significant progression in the control group at 12months (0.78±0.38 and 0.85±0.41mm, p=0.034, respectively) and 24months (0.82±0.41 and 0.96±0.39mm, p=0.022, respectively). Major bleeding (p=1.00), minor bleeding (p=0.68), and total bleeding rates (p=0.74) were similar between the two groups during the 2-year follow-up. Decreases from baseline in IL-6 (-2.79±2.83 and -2.14±3.36pg/ml, p=0.010, respectively) and TNF-α (-2.81±1.97 and -2.21±2.68pg/ml, p=0.029, respectively) were significantly greater in the cilostazol group than the control group during the follow-up. Cilostazol treatment, with greater anti-inflammatory effect, inhibited the progression of carotid IMT without increasing the risk of bleeding in patients with ACS during the 2-year follow-up.

Dabigatran etexilate: advances in anticoagulation therapy

Evaluation of: Schulman S, Kearon C, Kakkar AK et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N. Engl. J. Med. 361, 2342–2352 (2009).Venous thromboembolism (VTE) is associated with significant morbidity and mortality. The need for anticoagulation therapy is well recognized, but treatment is frequently suboptimal owing to limitations of current agents. The RE-COVER™ trial compared 150 mg twice-daily dabigatran etexilate (herafter referred to as dabigatran) with warfarin for 6 months in patients with acute VTE; dabigatran was as effective as warfarin in preventing recurrent VTE, with comparable major bleeding and significantly lower total bleeding rates. The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY®) trial on stroke prevention in patients with atrial fibrillation has also been completed recently, and dabigatran at higher doses showed superior efficacy in preventing stroke and systemic embolism, with lower bleeding than warfarin. Dabigatran provides convenient fixed-dose treatment without the need for monitoring, and has the potential to change the management of venous and arterial thromboembolism.

Influence of the Interfacial Transition Zone Properties on Chloride Corrosion in Reinforced Concrete-Characterization of ITZ

Influence of the Interfacial Transition Zone Properties on Chloride Corrosion in Reinforced Concrete-Characterization of ITZ