Number Of Bleeding Events Research Articles

Case Series: Outcome and Cost Analysis of Rituximab Versus Non-Targeted Immunosuppression As First Line Inhibitor Eradication in Acquired Hemophilia a

Introduction Acquired hemophilia A (AHA) is a rare bleeding disorder where autoantibodies interfere with factor VIII activity. AHA causes severe bleeding in 90% of affected individuals and carries a high mortality rate (8-22%). The initial factor level and inhibitor titre do not correspond to bleeding severity, and the risk of severe and fatal hemorrhage persists until the inhibitor has been eradicated. Therefore, treatment must concurrently address bleeding (with hemostatic and bypassing agents) and inhibitor eradication. Immunosuppressive therapy (IST) aims to normalize factor VIII levels by achieving the latter. With a median age of 78 years at diagnosis, AHA patients typically have more comorbidities, lower reserve, and are more susceptible to adverse events secondary to IST. In 2015, local availability of Rituximab improved via the Short Term Exceptional Drug Therapy program, allowing upfront Rituximab treatment for AHA. Prior to 2015, standard IST was steroids and cyclophosphamide as published randomized control trials comparing IST regimens are lacking. The purpose of this study was to compare Rituximab (R) to non-Rituximab (non-R) IST. Primary outcomes were time to inhibitor eradication, number of infections, and number of bleeding events. Secondary outcomes included number of hospital and emergency department (ED) admissions, mortality and relapse rate, and cost analysis. Methods A retrospective chart review was performed on all AHA patients diagnosed and treated at the Southern Alberta Rare Blood & Bleeding Disorders Comprehensive Care Clinic (SARBBDC). Data was extracted from electronic and paper medical records from the time of diagnosis to the time of death, or December 2018, whichever occurred first. Descriptive statistics were used to summarize relevant demographics and outcomes. Mann-Whitney and t-tests were used to compare groups. Kaplan Meier curves and log-rank test was used for time to inhibitor eradication. Pricing for cost analysis was obtained from the local hospital billing office, Canadian Blood Services, and the Alberta Health Services Provincial Drug Formulary (current as of April 1, 2019). Results Between 1998 and 2018, 17 AHA patients were treated at the SAARBBDC. Ten (59%) were female and seven (41%) were male. In seven (41%) of the cases, there was an underlying cause: three related to autoimmune disease, three to malignancy, and one to pregnancy. All patients received prednisone as a part of initial IST. Seven patients received R IST and 10 received non-R. Table 1 describes IST regimens and patient characteristics. The average PTT and inhibitor titre at diagnosis were greater in the R group (p=0.006, p=0.02). There were no other statistically significant differences between the groups. Median time to inhibitor eradication was greater in the R group but was not statistically significant (Figure 1, p=0.69). There were more ED visits and infections per patient in the non-R group, although not statistically significant. There were more bleeding events per patient in the R group, but the cost of bleeding treatment per patient was greater in the non-R group. Overall, there were no deaths secondary to bleeding. Mortality rate was greater in the non-R group (10% v 0%). Relapse rate was greater in the R group (14% v 10%). There was a significantly different cost for IST per kilogram between non-R and R-groups ($23.20/kg v $167.71/kg, p=0.004); no significant difference in cost for bleeding treatment per kilogram ($1479/kg v $1406/kg, p=0.41). The overall average cost per patient was greater in the non-R group despite a significantly greater cost for IST in the R group. This was mainly driven by the cost of bleeding treatment. Conclusion Overall, median time to inhibitor eradication and number of bleeding events were greater in the R group. However, the number of infections, emergency department visits, and mortality rate was greater in the non-R group despite a younger median age, suggesting the toxicity of the IST may be clinically significant. Although the cost of Rituximab is significant, there is a $13,000 cost savings on average for the treatment of an AHA patient with Rituximab-containing IST. This evidence can be used to guide clinical decision making at the local level and has the potential to reduce overall burden on our health care system. Disclosures No relevant conflicts of interest to declare.

Peripheral leukocyte count and risk of bleeding in patients with non-valvular atrial fibrillation taking dabigatran: a real-world study.

Background:The association between peripheral leukocyte count and bleeding events in nonvalvular atrial fibrillation (NVAF) patients treated with dabigatran remains unclear. This study aimed to explore the association between leukocyte count and bleeding events after excluding other confounders in NVAF patients taking dabigatran.Methods:A total of 851 NVAF patients treated with dabigatran (110 mg bid) were recruited from 12 centers in China from February 2015 to December 2017. Follow-up was completed by May 2018. The exposure and outcome variables were leukocyte count measured at baseline and the number of bleeding events within the subsequent 6 months. Multivariate Cox proportional hazards models were constructed to analyze independent associations, and a Cox proportional hazards regression with cubic spline functions and smooth curve fitting (penalized spline method) was used to address nonlinearity between leukocyte count and bleeding. The inflection point was calculated using a recursive algorithm, and then a two-piecewise Cox proportional hazards model for both sides of the inflection point was constructed.Results:During 6-month follow-up, 87 participants occurred bleeding events. For every 1 × 109/L increase in leukocyte count, the risk of bleeding increased by 11% (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 0.99–1.25). The smooth curve showed nonlinear relationship between leukocyte count and bleeding events. The inflection point of the leukocyte count was 6.75 × 109/L. For leukocyte counts < 6.75 × 109/L, the HR (95% CI) was 0.88 (0.69–1.13), and for leukocyte counts ≥ 6.75 × 109/L, the HR (95% CI) was 1.28 (1.09–1.51).Conclusion:This study found a J-shaped association between baseline leukocyte count and risk of bleeding in NVAF patients treated with dabigatran.Clinical trial registration:NCT02414035, https://clinicaltrials.gov.

Thalidomide Use Reduces Risk of Refractory Gastrointestinal Bleeding in Patients with Continuous Flow Left Ventricular Assist Devices.

Gastrointestinal (GI) bleeding is a common complication seen in patients with implanted continuous flow left ventricular assist devices (CF-LVAD), often attributed to arteriovenous malformations (AVMs). Whether thalidomide reduces recurrent GI bleeding risk in CF-LVAD patients has been incompletely evaluated. We conducted a retrospective review of all CF-LVAD patients at our institution with GI bleeding from AVMs who had a trial both off and on thalidomide. The primary endpoint was time to rebleed, while secondary endpoints included overall GI bleeding events, packed red blood cell (PRBC) transfusion requirements, and adverse events related to thalidomide. We report on 24 patients with recurrent AVM-associated GI bleeding who met criteria for and received thalidomide therapy, of which 17 had sufficient follow-up to be ultimately included for final analysis. We found the risk of rebleeding was significantly reduced in those on thalidomide therapy versus off (hazard ratio = 0.23, p = 0.022). The median number of GI bleeds per year was reduced from 4.6 to 0.4 (p = 0.0008) and the PRBC requirement was lower (36.1 vs. 0.9 units per year, p = 0.004) in those on thalidomide therapy. The adverse event rate with thalidomide was 59%, with symptoms resolution in most following dose reduction without increased bleeding. Thalidomide reduced the risk of AVM-associated GI rebleeding, number of bleeding events, and PRBC requirements in CF-LVAD patients. When initiating therapy, potential side effects and overall clinical context should be considered.

Effect of hypothermia on haemostasis and bleeding risk: a narrative review.

It must be remembered that clinically important haemostasis occurs in vivo and not in a tube, and that variables such as the number of bleeding events and bleeding volume are more robust measures of bleeding risk than the results of analyses.In this narrative review, we highlight trauma, surgery, and mild induced hypothermia as three clinically important situations in which the effects of hypothermia on haemostasis are important. In observational studies of trauma, hypothermia (body temperature <35°C) has demonstrated an association with mortality and morbidity, perhaps owing to its effect on haemostatic functions. Randomised trials have shown that hypothermia causes increased bleeding during surgery. Although causality between hypothermia and bleeding risk has not been well established, there is a clear association between hypothermia and negative outcomes in connection with trauma, surgery, and accidental hypothermia; thus, it is crucial to rewarm patients in these clinical situations without delay. Mild induced hypothermia to ≥33°C for 24 hours does not seem to be associated with either decreased total haemostasis or increased bleeding risk.

Comparative efficacy and safety of local and peripheral venous thrombolytic therapy with urokinase for thrombosed hemodialysis arteriovenous fistulas.

Arteriovenous fistula (AVF) thrombosis is a common complication in patients undergoing hemodialysis, and early intervention is required. Urokinase has been used as a thrombolytic agent for declotting the thrombosed access. However, the optimal route for infusing urokinase remains to be determined. In the present retrospective observational study, 49 patients who underwent local venous infusion and 57 patients with peripheral venous infusion of urokinase were included. A urokinase dosage of 300,000 U was administered until successful thrombolysis, which was a maximum of three times. Age, sex, period of dialysis, time of AVF placement, systolic and diastolic blood pressure and thrombus age were similar between the two groups. The efficacy of urokinase infusion via the two routes in resolving thrombosed AVFs, defined as successful fibrinolysis, and the safety, defined as the number of bleeding events, was compared. The cumulative thrombolysis success rate following three sessions of thrombolytic therapy in the local venous thrombolysis group was higher compared with that in the peripheral venous thrombolysis group (85.7 vs. 68.4%; P=0.04). The local thrombolysis group exhibited less ecchymosis (4.1 vs. 14.0%; P=0.07), epistaxis (2.0 vs. 10.5%; P=0.08) and gingival bleeding (4.1 vs. 19.3%; P=0.02) events compared with the peripheral thrombolysis group. Further analyses demonstrated that systolic [odds ratio (OR)=1.10; 95% confidence interval (CI), 1.03-1.17; P<0.01] and diastolic (OR=1.08; 95% CI, 1.02-1.14; P<0.05) blood pressure were protective factors, whereas thrombus age (OR=0.91; 95% CI, 0.84-0.99; P<0.05) was a risk factor for thrombolysis success among patients who underwent local thrombolytic therapy. Overall, the results suggest that local venous infusion of urokinase is superior to peripheral venous infusion for the treatment of patients with thrombosed fistulas.

Diagnostic Yield of Endoscopy Procedures in the Management of Left Ventricular Assist Device Recipients Presenting with Gastrointestinal Bleeding

Purpose Left ventricular assist device (LVAD) patients are predisposed to gastrointestinal bleeding (GIB) due to a combination of anticoagulation/antiplatelet medications and continuous flow physiology of LVADs, resulting in arteriovenous malformations. The workup for GIB often includes multiple endoscopic procedures resulting in prolonged hospital length of stay (LOS). Methods A single center retrospective review was performed on adult patients between 2011 and 2017 for patients receiving LVAD and having a GIB event within 1 year after implantation. The types of procedure, clinical findings, and endoscopy results were recorded. Results We included 54 subjects, accounting for 164 endoscopies from 111 GIB events. The most utilized exam was upper GI endoscopy (UGE; 50% of all procedures). Diagnostic yield leading to treatment was highest for double balloon enteroscopy (DBE) (65%; Fig 1A) and lowest for UGE (40%) with similar frequencies for lesion identification (Fib 1B). There were 50 patients presenting with their first GIB concerning for an upper GI source, of which 42 received UGE. A lesion was identified in 25 (50%) of these cases, and treatment administered in 13 (25%). For subsequent endoscopy procedures, diagnostic yield for push enteroscopy (PE) was 76% and 71% for DBE. There were 28 (52%) patients that had re-bleeding within 1 year; the median number of bleeding events per person was 2 [1, 2.75] and the median number of endoscopies needed per person was 2 [2, 4]. There were 117 (71%) endoscopies that identified culprit lesions and 79 (48%) resulted in 1 or more treatment. Median LOS for patients who received DBE was 8 days, compared to 5 days for those with no DBE. Conclusion Initial endoscopic evaluation with DBE or PE rather than UGE would serve to increase the yield of finding a culprit lesion and decrease LOS in patients with LVAD admitted for GIB. Additional studies to identify patients at high risk of recurrent GIB are needed.

Clopidogrel bisulfate (Plavix) does not increase bleeding complications in patients undergoing rubber band ligation for symptomatic hemorrhoids

BackgroundThe incidence of postprocedural bleeding in patients undergoing rubber band ligation (RBL) for symptomatic internal hemorrhoids while taking clopidogrel bisulfate is unknown. To determine the postprocedural bleeding risk of RBL for patients taking clopidogrel compared with age- and sex-matched controls. Materials and methodsThis is a retrospective case-controlled cohort study analyzing data from 2005 to 2013 conducted at a single tertiary care academic center. The study included a total of 80 rubber bands placed on 41 patients taking clopidogrel bisulfate and 72 bands placed on 41 control patients not taking clopidogrel matched for age and sex. The 30-d rates of significant and insignificant bleeding events after RBL were recorded. A bleeding event was considered significant if the patient required admission to the hospital, transfusion of blood products, or additional procedures to stop the bleeding. Insignificant bleeding was defined as passage of blood or clots per rectum with spontaneous cessation and no need for additional intervention. ResultsThere was no significant difference in the number of bleeding events per band placed in the clopidogrel group when compared with the control group (3.75% versus 2.78%, P = 0.7387). The rate of significant (2.5% versus 1.39%, P = 0.6244) and insignificant bleeding events (1.25% versus 1.39%, P = 0.9399) was also similar between the two groups. Two significant bleeding events occurred in the clopidogrel group requiring intervention: cauterization in one patient and colonoscopy and transfusion in the other. ConclusionsThe risk of a bleeding complication after RBL for hemorrhoids does not appear to be increased in patients taking clopidogrel. Our results support the practice of continuing clopidogrel bisulfate in the periprocedural period as the associated risk of thrombosis is greater than the risk of bleeding.

Bleeding Events in Thrombocytopenic Patients With Cancer Undergoing Acute Rehabilitation

Objectives: To determine incidence of bleeding in thrombocytopenic patients with cancer undergoing acute inpatient rehabilitation. Design: This is an observational cross-sectional retrospective study. Setting: Acute inpatient academic rehabilitation facility. Participants: Adult patients admitted to acute inpatient rehabilitation with functional impairments secondary to cancer. Methods: Electronic records were reviewed for thrombocytopenic patients with cancer to determine platelet counts, bleeding events during rehabilitation, and anticoagulant medications prescribed. Main outcomes measurements: Type and number of bleeding events, severity of bleeding by World Health Organization criteria. Results: Of the 278 patients with cancer admitted to acute rehabilitation over a 27-month time frame, 119 had at least one platelet count &lt;150 000/µL. In all, 37 (31.1%) had a history of a bleeding event prior to the rehabilitation admission and 34 (28.6%) had at least one bleeding complication during their stay. Most events (87.5%) were of low grade (Grade 1 and 2 World Health Organization criteria). There was no association between platelet counts &lt;11 000 or counts 11 000 to 20 000/µL and the occurrence of bleeding ( P = .106 and P = .319, respectively). Although anticoagulants were common, there was no association found with a bleeding event and either anticoagulation status (receiving or not on such agents), specific anticoagulant or antiplatelet agents, or a combination. Conclusions: Bleeding events in patients with cancer with thrombocytopenia during acute rehabilitation stay are not uncommon but are typically mild in severity and not associated with the degree of thrombocytopenia. Patients taking anticoagulants when platelet levels rose did experience bleeding events, but not at a statistically greater rate than those not taking such medications.

Secondary prophylaxis with anti-inhibitor coagulant complex (AICC) : from anecdote to reality.

Background. Evidence of prophylaxis benefit in patients without inhibitors to reduce hemarthrosis and severe bleeding have not been demonstrate in patients with hemophilia A (HA) and inhibitors, however, we could assume the reduction in bleeding episodes. Several publications have shown good results of secondary prophylaxis with AICC agents to reduce safely the number of bleeding events. We report the results in hemophilia treatment centers of two cities in a developing country, with access difficulties related to the high cost of this therapy to the health system. Objective. To describe the frequency of hemarthrosis and other bleeding episodes in patients with HA and inhibitors under AICC (Feiba®) prophylaxis.

Assessment of venous thromboembolism treatment in patients with cancer on low molecular weight heparin, warfarin, and the direct oral anticoagulants.

Direct oral anticoagulants (DOACs) are not recommended for venous thromboembolism (VTE) treatment in patients with cancer because their safety and efficacy have not been compared to low molecular weight heparin (LMWH) in large trials. Routine anti-Xa monitoring in cancer patients on LMWH is also not recommended due to limited data correlating anti-Xa levels and outcomes. Compare the safety and efficacy of DOACs to LMWH and warfarin and assess the relationship of anti-Xa monitoring and outcomes in patients with cancer taking LMWH in an urban university setting. This retrospective, cohort study analyzed the recurrence of VTE and number of bleeding events in patients with cancer. There were 131 patients included in the analysis. There was no difference seen in the rate of recurrent VTEs between the LMWH, warfarin and DOAC groups (9.3%, 5.9%, 9.1%, p = 0.89). There was also no difference in the rate of bleeding between groups (10.5%, 14.7%, 9.1%, p = 0.576). There was an increased rate of mortality seen in the LMWH group (26.7% vs. 2.9% vs. 18.2%, p = 0.006). There was no difference seen in recurrent VTE (10.3% vs. 8.5%, p = 0.53) or bleeding (10.3% vs. 10.7%, p = 0.661) between the monitored and unmonitored LMWH patients. Results of this analysis suggest DOACs may be as safe and effective as LMWH and warfarin for the treatment of VTE in patients with cancer, and there may be no clinical benefit to routine anti-Xa monitoring in patients on LMWH treatment. However, larger studies are needed to confirm these observations.

Implications of an inpatient warfarin dosing nomogram on safety outcomes post-discharge.

Many hospitals have implemented warfarin dosing nomograms to improve patient safety. To our knowledge, no study has assessed the impact inpatient warfarin initiation has in both medical and surgical patients, on safety outcomes post discharge. To evaluate the impact of a suggested institutional nomogram for the initiation of warfarin, the primary endpoint was the incidence of bleeding throughout follow up. Secondary endpoints included the composite of INR changes ≥0.5/day and INR >4. Patients were followed for a period of 2weeks post-discharge. The composite endpoint was evaluated for an effect on reaching therapeutic INR, time to reach therapeutic INR, and bleeding events throughout follow up. A single center retrospective study comparing the safety of adherence vs. non-adherence to a warfarin nomogram. A total of 206 patients were included, 73 patients in the nomogram adherence vs. 133 in the nonadherence arm. There was no difference in the proportion of patients who bled throughout the follow up period, adherence 9.6% vs. nonadherence to the nomogram 13.5%, p = 0.407. There was however a statistical difference in the mean total number of bleeding events, 0.096 (7/73) in the adherence vs. 0.158 (21/133) in the non-adherence arm, p = 0.022. There was also no difference in the composite endpoint, 19.2% in the adherence vs. 28.6% in the non-adherence arm p = 0.180. A positive correlation between the inpatient composite and risk of bleeding throughout follow up was noted. The findings of this study support adherence to the nomogram as opposed to non-adherence.

Management of dental extraction in patients undergoing anticoagulant oral direct treatment: a pilot study

The main goal of this study was to compare the incidence of postoperative bleeding events after dental extractions between patients treated with direct oral anticoagulants (DOACs) and those treated with vitamin K antagonists (VKAs) without withdrawal of oral anticoagulant therapy (OAT). Our second objective was to evaluate the risk factors affecting postoperative hemorrhage after tooth extraction in patients taking DOACs. This prospective observational study included 51 patients who were being treated with oral anticoagulants and required dental extractions. They were divided into two groups: 31 patients receiving a DOAC and 20 control patients taking VKA with an international normalized ratio between 2.0 and 3.0. In both groups, extractions were performed under continued OAT, and the same local hemostatic measures were applied. All procedures were performed in an outpatient facility. A bleeding event was defined as persistent oozing or marked hemorrhage over 20minutes after tooth extraction despite local hemostasis procedures or all bleeding episode occurring during the first postoperative week. Five patients taking DOACs had seven bleeding episodes, and four patients receiving VKAs had five bleeding episodes during the postoperative follow-up period. The difference in the number of bleeding events between the two groups was not statistically significant (adjusted odds ratio=0.77; 95% confidence interval 0.19-3.19; P=.723). Eleven (91.67%) bleeding events were mild and controlled by mechanical compression with gauzes, and one (8.33 %) was managed with a revision of the wound, application of fibrin glue, and resuturing. No bleeding required hospitalization or blood transfusion. All bleeding episodes occurred during the first 3 postoperative days. According to our preliminary outcome data, dental extractions can be performed safely in an outpatient facility in patients treated with DOAC by applying local hemostatic measures, without interrupting or modifying OAT.

Abstract WP347: Clopidogrel Plus Aspirin in Patients With Different Types of Single Small Subcortical Infarction_Subgroup Analysis of CHANCE Trial

Objective: We aim to investigate the effects and safety of clopidogrel plus aspirin in patients with different types of single small subcortical infarction(SSSI) in the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial. Methods: In this subgroup analysis, SSSI was defined as single DWI lesion of ≤2.0 cm and SSSI with stenosis of any degree of the parent artery was regarded as a SSSI+PAD. We assessed the interaction of the treatment effects of clopidogrel plus aspirin versus aspirin alone among patients with and without PAD. Efficacy was assessed by intention to treat analysis and safety was assessed in the on-treatment population. Results: A total of 338 patients with SSSI were included in the final analysis,105 with SSSI+PAD and 233 SSSI-PAD. In SSSI+PAD patients, 10.9% (5/46) had recurrent stroke in the clopidogrel-aspirin group as compared to 13.6% (8/59) in the aspirin group (adjusted hazard ratio, 0.66; 95% confidence interval, 0.20-2.20; P=0.50). In SSSI-PAD patients, 8.9% (11/124) had recurrent stroke in the clopidogrel-aspirin group as compared 7.3% (8/109) in the aspirin group (adjusted hazard ratio, 1.64; 95% confidence interval, 0.61- 4.38; P=0.32). The number of bleeding events was similar between the clopidogrel-aspirin group and aspirin group regardless of SSSI+PAD or SSSI-PAD. Conclusions: Although dual antiplatelet therapy did not significantly reduce the risk of recurrent stroke than aspirin alone in patients with SSSI. It was potentially beneficial to the patients with SSSI+PAD. Dual antiplatelet treatment did not increase the risk of bleeding in patients with any kind of SSSI.

Advances in Diagnosis and Treatments for Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired hemorrhagic condition characterized by the accelerated clearance of platelets caused by antiplatelet autoantibodies. A platelet count in peripheral blood <100 × 109/L is the most important criterion for the diagnosis of ITP. However, the platelet count is not the sole diagnostic criterion, and the diagnosis of ITP is dependent on additional findings. ITP can be classified into three types, namely, acute, subchronic, and persistent, based on disease duration. Conventional therapy includes corticosteroids, intravenous immunoglobulin, splenectomy, and watch-and-wait. Second-line treatments for ITP include immunosuppressive therapy [eg, anti-CD20 (rituximab)], with international guidelines, including rituximab as a second-line option. The most recently licensed drugs for ITP are the thrombopoietin receptor agonists (TRAs), such as romiplostim and eltrombopag. TRAs are associated with increased platelet counts and reductions in the number of bleeding events. TRAs are usually considered safe, effective treatments for patients with chronic ITP at risk of bleeding after failure of first-line therapies. Due to the high costs of TRAs, however, it is unclear if patients prefer these agents. In addition, some new agents are under development now. This manuscript summarizes the pathophysiology, diagnosis, and treatment of ITP. The goal of all treatment strategies for ITP is to achieve a platelet count that is associated with adequate hemostasis, rather than a normal platelet count. The decision to treat should be based on the bleeding severity, bleeding risk, activity level, likely side effects of treatment, and patient preferences.

Azacitidine (AZA) Combined with Idarubicin in Higher Risk MDS - Results of a Phase I/II Study By the Groupe Francophone Des Myelodysplasies (GFM)

Background: Hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and must be further improved. In addition, AZA yields only about 30% of marrow responses (including CR+PR+marrow CR). Intensive chemotherapy combining Idarubicin (IDA) and AraC yields 30 to 50 % CR in higher risk MDS (Beran and all, cancer 2001) and IDA, as single agent, induces about 30% CR in elderly AML patients (Carella, haematologica 1990). We designed a phase I/II study evaluating the safety and efficacy of the combination of AZA and IDA (1 day during each AZA cycle) in higher risk MDS patients (NCT01305135).Methods: Main Inclusion criteria were: (1) IPSS int-2 or high MDS, or CMML with WBC < 13 G/l and marrow blasts > 10%, or AML with 20-30% marrow blasts (2) Age ≥ 18 years (3) Performance Status (PS) <=2 (4) no prior treatment, except ESAs. Patients received AZA 75 mg/m2/d SC x7d every 4 weeks combined, on day 8 of each cycle (for the first 9 cycles), with IDA 5 mg/m2 (IV) in a first cohort of 10 patients, escalated to 10 mg/m2 IV in a second cohort of 10 patients, followed by an extension study in 21 patients with the IDA 10 mg/m2 schedule. The primary endpoint of the study was response after 6 cycles according to IWG 2006 criteria.Results: Between Dec 2010 and Jan 2014, 41 patients (from 13 centers) were enrolled, including 13 women and 28 men with a median age of 74 years [IQR 70; 76]. At inclusion, WHO classification was RCMD in 1 pt, CMML in 2 pts, RAEB-1 in 10 pts, RAEB-2 in 13 pts, AML in 12 pts and unclassified MDS in 3 pts. Median marrow blast % was 9.5 [IQR: 6-19.9] and karyotype according to IPSS was favorable in 12 (29%), intermediate in 9 (22%) and unfavorable in 18 pts (44%) (2 cytogenetic failures). IPSS was int-2 and high in 56% and 44%, respectively. PS was 0 in 39%, 1 in 55% and 2 in 6% pts.10 patients received 5 mg/m2 of idarubicin (cohort 1) and 31 received 10 mg/m2 (cohort 2). 375 cycles of AZA were administered (219 of them with AZA+IDA, as IDA was used only for the first 9 cycles), with a median number of 6 cycles/patient (median 6 in the IDA 5 mg/m2 cohort and 4 in the 10 mg/m2 cohort (p=0.9).Of the 41 patients enrolled, 20(48.8%, 95%CI: 32.9-64.9) achieved response (6 CR, 7 PR, 4 mCR and 3 stable disease with HI) with no difference between the two cohorts (50% vs 48%) and a marrow response rate (CR + PR + mCR) of 41,5%. Thirteen of the 22 patients with abnormal karyotype were evaluable for cytogenetic response: 5 achieved cytogenetic response (4 complete, 1 partial), 1 in cohort 1 and 4 in cohort 2. With a median follow up of 14 months, 9 of the 20 responders had relapsed. Median response duration was 11 months [3.2-42.7], with no difference between the two cohorts.Median OS was 14.3 months [IC95%: 12.5; NA] and 2y OS was 24.8%, with no significant difference between the 2 cohorts (p=0.43).By univariate analysis no baseline parameter including gender, karyotype, marrow blast %, IPSS and IDA dosage (5 or 10 mg/m2), had any significant impact on response or survival.45 SAEs were reported in 26 patients, including febrile neutropenia (n=25), bleeding (n=7) and 2 non-clinically significant reductions in left ventricular ejection fraction (1 transient, and 1 persisting without symptoms). The number of infections per cycle [9/85 (10%) in the IDA 5 mg/m2 arm and 38/281 (14%) in the IDA 10 mg/m2 arm] and the number of bleeding events (9% vs 17%) did not significantly differ between the two cohorts.Conclusion: In our experience, Idarubicin (on day 8 of each cycle) can be combined to Azacitidine without any additional toxicity. The marrow response rate obtained with the combination (41.5%) may be higher than with AZA alone. We are currently comparing in higher risk MDS patients this AZA-IDA combination versus AZA alone (and other combinations of AZA with other drugs) in a prospective randomized GFM trial. DisclosuresSebert:Celgene: Research Funding. Fenaux:Celgene: Research Funding.

Endoscopic mucosal resection of early oesophageal neoplasia in patients requiring anticoagulation: is it safe?

Endoscopic mucosal resection (EMR) has become the standard treatment for early oesophageal neoplasia. The mucosal defect caused by EMR usually takes several weeks to heal. Despite guidelines on high-risk endoscopic procedures in patients on anticoagulation, evidence is lacking whether EMR is safe in such patients. We investigated the immediate and delayed bleeding risk in patients undergoing diagnostic or therapeutic oesophageal EMR comparing patients requiring warfarin anticoagulation with a control group. Warfarin was stopped 5days before the planned EMR and restarted on the evening following the procedure. Patients with high-risk conditions, such as recent pulmonary thromboemboli, received bridging with low molecular weight heparin. All EMRs were performed when the INR was <1.5. Bleeding events on the day of the EMR and within 3months post-procedure were documented. One hundred and seventeen consecutive patients with early oesophageal neoplasia were included. Sixty-eight EMRs were performed in 15 patients requiring anticoagulation. One patient on warfarin was readmitted 10days after EMR with haematemesis and melaena. Out of 400 EMRs in 102 controls, 26 immediate bleeding events occurred requiring endoscopic intervention. One delayed bleeding event (melaena) occurred in the control group. The number of bleeding events did not differ between groups [p=0.99; odds ratio 1.01 (0.30-3.44)], neither for acute (p=0.76) nor delayed bleeding (p=0.24). EMR of early oesophageal neoplasia can be safely performed in patients requiring anticoagulation when warfarin is discontinued 5days before the endoscopic intervention and reinstituted on the evening of the procedure day.

Abstract 13846: The Relationship of Platelet Function Measurements with Bleeding Outcomes During Long-term Treatment with Dual Antiplatelet Therapy in Medically Managed NSTE-ACS Patients

Introduction: The relationship of low “on-treatment” platelet reactivity to longitudinal risks of major bleeding following acute coronary syndromes (ACS) has not been clearly delineated. Methods: We analyzed 2428 patients with non-ST-elevation ACS (NSTE ACS) from the TRILOGY ACS trial who were managed without revascularization and had platelet reactivity measurements (P2Y12 reaction units [PRUs]) collected in a platelet function substudy. Patients received aspirin + prasugrel (10 mg/d; 5 mg/d for those ≥75 y or &lt;75 y and &lt;60 kg) or clopidogrel (75 mg/d). Non-CABG severe/moderate GUSTO bleeding and non-CABG TIMI major/minor bleeding were ascertained through 30 months. Contal’s method was used to investigate whether a PRU cut point could distinguish high vs low bleeding risk. Multivariable Cox proportional hazard models were used to evaluate the association between PRU and time to first bleed. Results: Through 30 months, there were 27 GUSTO severe/moderate bleeds and 37 TIMI major/minor bleeds, with gastrointestinal bleeding the most common. Baseline characteristics were stratified by tertiles of PRU values at 5 d, and significant differences were seen across tertiles (Table). Unadjusted bleeding rates appeared highest among those in the lowest PRU tertile but no reliable PRU cut point was found that significantly distinguished bleeding risk. Unadjusted analyses showed continuous measures of PRUs were not associated with GUSTO (HR=1.00, 95% CI: 0.96-1.04) or TIMI bleeding (HR=1.03, 95% CI: 0.99-1.06). This relationship did not change after multivariable adjustment. Conclusions: Among NSTE-ACS patients managed without revascularization and receiving dual antiplatelet therapy, PRU values were not significantly associated with long-term bleeding risk. The relatively small number of bleeding events accrued limited study power, but these results suggest that low “on-treatment” platelet reactivity does not independently predict post-ACS bleeding risk.

Pre-Procedure Desmopressin Acetate to Reduce Bleeding in Renal Failure: Does It Really Work?

Background: Desmopressin (DDAVP) is often used prior to procedures to minimize bleeding in patients with renal failure; however, there is little evidence to support this practice. The objectives of this study were to evaluate the practice of administration of DDAVP prior to procedures within our division and to determine the number of bleeding episodes for patients who received DDAVP compared to those who did not. Methods: Hospital records of patients who underwent renal biopsy or central line placement between April 2006 and March 2008 were reviewed. Patients with glomerular filtration rate (GFR) <60 ml/min/1.73 m² were identified and subcategorized into three groups: group A GFR <15 ml/min/1.73 m², group B GFR 15-29 ml/min/1.73 m², and group C GFR 30-60 ml/min/1.73 m². The number of bleeding events was noted in each group. Results: No significant difference was found in the number of bleeding events between those who received and did not receive DDAVP overall and in each GFR group. A possible trend towards the benefit with treatment in group A was observed. Conclusion: There was no significant reduction in bleeding for those who received DDAVP which questions the validity of this practice. Patients with GFR <15 ml/min/1.73 m² may possibly derive benefit.

Sustained pro-haemostatic activity of rFVIIa in plasma and platelets in non-bleeding pigs may explain the efficacy of a once-daily prophylaxis in humans

Recombinant factor VIIa (rFVIIa) is registered for treatment of inhibitor-complicated haemophilia, and a once-daily prophylactic administration of rFVIIa is successful in reducing the number of bleeding events. This suggests that a single rFVIIa dose has a pro-haemostatic effect up to 24 hours (h), which is difficult to explain given its half-life of 2 h. In this study, six pigs received a 90 µg/kg rFVIIa bolus. Plasma was collected and platelets were isolated at various time points up to 48 h, and analysed for FVIIa levels and associated haemostatic activity. Elevated plasma FVIIa levels were detected up to 24 h post-administration (36 (32-56) mU/ml [median (interquartile range [IQR]), 24 h] vs 2 (2-14) mU/ml [baseline]). Corresponding prothrombin time (PT) values remained shortened compared to baseline until 24 h post-administration (9.4 (9.3-9.9) seconds (s) [24 h] vs 10.5 (10.2-11.0) s [baseline], p ≤0.01). The lag time in thrombin generation testing as well as clotting times in plasma-based assays were shortened up to 12 or 24 h post-administration, respectively (lag times 1.8 (1.7-2.1) minutes (min) [12 h] vs 2.3 (2.3-2.6) min [baseline], p ≤0.01 and clotting times 3.8 (3.2-3.9) min [24 h] vs 5.2 (4.6-5.5) min [baseline], p ≤0.001). Platelet FVIIa levels were elevated up to 48 h (7.7 (3.4-9.0) ng VIIa/mg actin [48 h] vs 2.5 (0.7-4.8) ng VIIa/mg actin [baseline]). In conclusion, elevated and haemostatically active plasma and platelet FVIIa levels are detectable up to 24-48 h following rFVIIa administration in pigs. This prolonged pro-haemostatic effect of FVIIa may explain the prophylactic efficacy of a once-daily rFVIIa treatment.

Association Of Bleeding Tendency With Time Under Target FIX Activity Levels In Severe Hemophilia B Patients Treated With Recombinant Factor IX Fc Fusion Protein

IntroductionThe goal of prophylactic treatment with coagulation factor replacement in hemophilia patients has been to convert severe hemophilia, defined as <1% endogenous factor activity levels, to moderate (1% to 5%) and mild (5 to 40%) disease. It has been reported that increased time spent under 1% FVIII activity was associated with an increase in total bleeding episodes and hemarthroses in patients with severe hemophilia A (Collins PW, J Thromb Haemost 2009). Since no studies to date have documented this association for FIX activity in patients with severe hemophilia B, we examined the bleeding tendency in relation to FIX activity using data from the B-LONG study. The B-LONG study evaluated the pharmacokinetics (PK), safety, and efficacy of a recombinant FIX Fc fusion protein (rFIXFc) in severe hemophilia B patients (Powell J, J Thromb Haemost 2013). Briefly, the B-LONG study had 4 treatment arms: weekly prophylaxis, tailored prophylaxis, episodic treatment, and perioperative management. The corresponding median annualized bleeding rates for the first 3 treatment arms were 2.95, 1.38, and 17.69, respectively. MethodsA 3-compartmental population PK model of rFIXFc was developed based on activity-time profiles in 12 subjects from a Phase 1/2a study and 123 subjects (>12 years) from B-LONG, collected over ≤ 52 weeks of treatment (Diao L, EAHAD 2013). Individual post-hoc PK parameters were then derived to construct continuous FIX activity-time profiles for each dose administered over the course of the study for all subjects in B-LONG. The cumulative time under target 1%, 3%, and 5% FIX level for each individual on study was calculated and normalized to obtain annualized time under the respective target FIX level. Negative binomial regression models were used to evaluate associations between the number of bleeding events (overall, spontaneous, traumatic, and joint) and annualized time (days) under 1%, 3%, and 5% of FIX activity for all subjects in B-LONG. Models were adjusted for age, body mass index, baseline HIV and HCV status, FIX genotype, number of bleeding episodes in the 12 months prior to study entry, and each subject's time on study. ResultsThe multivariable negative binomial regression analysis estimated that overall bleeding events increased with increased time spent under 1% of FIX activity (p<0.001). The association, however, is largely driven by subjects on episodic treatment. The median annualized time under 1% for subjects on episodic treatment was 171 days, in contrast to the median of 0 days for subjects on either weekly prophylaxis or tailored prophylaxis, respectively, as the tailored PK-driven dosing regimens were designed to maintain a target trough above 1%. The association is consistent with the distribution of bleeding events, most of which occurred at predicted FIX activity levels under 1% in subjects on episodic treatment. Since the distribution of predicted FIX trough levels in subjects on prophylaxis were largely in the range of 1% to 5%, the analysis was repeated for cumulative time under 3% and 5%. Both analyses found statistically significant increases in predicted bleeding events as time spent below the respective FIX activity levels increased (Figure 1). The significant association was also observed for spontaneous, traumatic, or joint bleeds analyzed separately for all 3 target FIX activity levels. When comparing across thresholds (1% vs. 3% vs. 5%), the predicted bleeding rate was significantly reduced and the predicted probability of being bleed-free improved as the trough increased. Additionally, the odds of having joint bleeds increased significantly with increasing time spent under the respective target trough (1%, 3%, or 5%). [Display omitted] [Display omitted] ConclusionsThis is the first study to demonstrate a correlation between increased time spent under a target therapeutic FIX activity level (1%, 3% or 5%) and increased bleeding tendency, as well as a reduced probability of being bleed-free in patients treated with rFIXFc, suggesting that rFIXFc can provide protection from bleeding in a manner similar to endogenous FIX. These findings also confirm the importance of a minimum therapeutic threshold of 1% and provide additional support for establishing effective rFIXFc prophylaxis using population PK simulation. Disclosures:Shapiro:Baxter: Consultancy, Global steering committees Other, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Global steering committees, Global steering committees Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Inspiration: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; Biogen Idec: Research Funding. Potts:Biogen Idec: Employment. Li:Biogen Idec: Employment. Valentino:Baxter Healthcare: Consultancy; Bayer: Consultancy; Biogen Idec: Consultancy; GTC Biotherapeutics: Consultancy; Inspiration Biopharmaceuticals: Consultancy; Novo Nordisk: Consultancy. Diao:Biogen Idec: Employment, Equity Ownership. Wang:Biogen Idec: Employment. Robinson:Biogen Idec: Employment. Pierce:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership.