Risk Of Excessive Bleeding Research Articles

Safety of Direct Oral Anticoagulants and Vitamin K Antagonists in Oldest Old Patients: A Prospective Study

ObjectiveThe safety of direct oral anticoagulants (DOACs) in oldest old patients with nonvalvular atrial fibrillation (NVAF) in daily clinical practice has not been systematically assessed. This study examined the safety of DOACs and dicumarol (a vitamin K antagonist) in NVAF geriatric patients. DesignProspective study from January 2010 through June 2015, with follow-up through January 2016. SettingGeriatric medicine department at a tertiary hospital. ParticipantsA total of 554 outpatients, 75 years or older, diagnosed of NVAF and starting oral anticoagulation. MeasurementsThe main outcome was bleeding, which was classified into major (including those life-threatening) and nonmajor episodes. Statistical analyses were performed with Cox regression. ResultsA total of 351 patients received DOACs and 193 dicumarol. Patients on DOACs were older, with more frequent comorbidities, mobility limitation and disability in activities of daily living, as well as higher mortality, than those treated with dicumarol. The incidence of any bleeding was 19.2/100 person-years among patients on DOACs and 13.7/100 person-years on dicumarol; corresponding figures for major bleeding were 5.2 for those on DOACs, and 3.3 for those on dicumarol. In crude analyses, hazard ratios (95% confidence intervals) for any bleeding, and for mayor bleeding in patients on DOACs vs dicumarol were 1.60 (1.04-2.44) and 2.22 (0.88-5.59), respectively. Excess risk of bleeding associated with DOACs vs dicumarol disappeared after adjustment for clinical characteristics, so that corresponding figures were 1.19 (0.68-2.08) and 1.01 (0.35-2.93). Results did not vary across subgroups of high-risk patients. ConclusionIn very old patients with NVAF, the higher risk of bleeding associated with DOACs vs dicumarol could be mostly explained by the worse clinical profile of patients receiving DOACs. Risk of bleeding was rather high, and warrants close clinical monitoring.

DAPT plus anticoagulant therapy: The difficult coexistence post-ACS in older patients with atrial fibrillation.

Atrial fibrillation (AF) and coronary artery disease requiring percutaneous coronary intervention (PCI) and stenting often coexist in older patients. This poses the difficult problem of concurrent anticoagulant and double antiplatelet therapy (triple therapy). Current treatment guidelines do recommend triple therapy, especially in the course of acute coronary syndrome (ACS), with limitations due to an excessive risk of bleeding associated with this therapeutic regimen. This review summarizes randomized clinical trials and observational studies that compared triple therapy with a variety of different therapeutic options. Although the available evidence is not completely satisfactory and other studies are urgently needed, alternative regimens to triple therapy in AF patients undergoing PCI and stenting are promising, at least in terms of safety.

Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients

AbstractThe noninferiority of direct oral factor Xa (FXa) inhibitors (rivaroxaban, apixaban, and edoxaban) in treatment of atrial fibrillation were demonstrated compared with warfarin by several large clinical trials; however, subsequent meta-analyses reported a higher risk of major bleeding with rivaroxaban than with the other FXa inhibitors. In the present study, we first estimated the changes of prothrombin time (PT) in 5 randomized trials based on reported population pharmacokinetic and pharmacodynamic models and then carried out a model-based meta-analysis to obtain models describing the relationship between PT changes and the event rates of ischemic stroke/systemic embolism (SE) and of major bleeding. By using the models, we simulated the optimal therapeutic doses for each FXa inhibitor. It was suggested that dose reduction of rivaroxaban from the current 20 mg/d to 10 mg/d would decrease patient deaths from major bleeding (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.64-0.74) with little increase in those for ischemic stroke/SE (HR, 1.11; 95% CI, 1.07-1.20). The overall decrease in the mortality caused by both events was estimated as 5.81 per 10 000 patient-years (95% CI, 3.92-8.16), with an HR of 0.87 (95% CI, 0.83-0.91). For apixaban and edoxaban, no distinct change in the overall mortality was simulated by dose modification. This study suggested that the current dose of rivaroxaban might be excessive and would need to be reduced to decrease the excess risk of major bleeding.

Association of preoperative plasma fibrinogen level with postoperative bleeding after on-pump coronary bypass surgery: does plasma fibrinogen level affect the amount of postoperative bleeding?

Our primary aim was to investigate the association between the preoperative concentration of plasma fibrinogen and the volume of postoperative bleeding. Our secondary aim was to identify whether there is a possible correlation between the patients' different characteristics and haemostatic laboratory variables and the postoperative amount of bleeding after on-pump coronary artery bypass grafting procedures. A total of 550 adult patients undergoing isolated coronary artery bypass grafting on cardiopulmonary bypass in our hospital were enrolled and investigated retrospectively. The total amount of chest tube drainage within the first 24 postoperative hours or until the patient was re-explored for bleeding was assessed. Excessive bleeding was defined as more than 500 ml drainage in the first 24 h. The patients were divided into 2 groups: Group 1: the patients who bled ≤500 ml in the first 24 h and Group 2: the patients who bled >500 ml in the first 24 h. A preoperative fibrinogen threshold associated with excessive bleeding was investigated by receiver operating characteristic curve analyses, revealing a calculated cutoff value of 3.1 g/l. Risk factors for increased bleeding were analysed by a logistic regression model that revealed male gender (P < 0.001), body mass index ≤28.3 kg/m2 (P < 0.001), platelet count ≤233 × 103/µl (P < 0.001), estimated glomerular filtration rate ≤90.8 ml/min (P < 0.001) and fibrinogen ≤3.1 g/l (P = 0.01) as significant predictors. A preoperative plasma fibrinogen concentration <3.1 g/l was associated with increased risk of excessive bleeding in patients undergoing on-pump coronary artery bypass grafting. The amount of postoperative blood loss can be roughly predicted with simple preoperative blood tests.

Risk scoring for prediction of postoperative bleeding in cardiac surgery

BackgroundMorbidity and mortality after cardiac surgery can be caused by excessive bleeding which is a common and preventable cause. Excessive bleeding after cardiac operations can be classified to surgical or medical causes. The Papworth Bleeding Risk Score can be helpful in predicting the high risk patients for excessive bleeding.The objective of this study was the evaluation of the ability of Papworth Bleeding Risk Score for prediction of excessive early bleeding after cardiac surgery in Egypt. MethodsIn this prospective single-center observational study carried out from September 2017 till December 2017, at National Heart Institute of Egypt enrolled 100 consecutive patients.Adult patients who were plnned to undergo cardiac surgery with cardiopulmonary bypass were included. Exclusion criteria were Off pump surgeries, congenital heart diseases and known bleeding disorders. The aim was to identify patients with expected risk of an adverse excessive postoperative bleeding according to Papworth bleeding risk score. Postoperative bleeding, reopening and death were calculated. ResultsTotal number of the bleeders were 17 cases, (4 high risk, 11 medium risk and 2 low risk). Three patients were reopened with only one patient because of surgical cause. ConclusionsWe consider this bleeding score as a simple, effective and discriminative modality to stratify cases into three risk groups to take the prophylactic measures with high risk patients and to avoid side effects of these measures in low risk patients.

Transcatheter Aortic Valve Replacement and Atrial Fibrillation: Impact of Antithrombotic Strategy on Clinical Outcomes

Antithrombotic recommendations following transcatheter aortic valve replacement (TAVR) are largely based on previous trial protocols. The efficacy and risk of anticoagulation has not been systematically assessed. The aim of this study was to determine the efficacy and safety of oral anticoagulation in patients with atrial fibrillation (AF) following TAVR with the Lotus Valve System (Boston Scientific, Marlborough, MA, USA). Consecutive patients with severe aortic stenosis who underwent Lotus valve implantation were prospectively recruited (n=164). Atrial fibrillation patients prescribed oral anticoagulation (standard AF therapy) were compared to non-AF patients prescribed aspirin and clopidogrel (standard non-AF therapy). Twenty (20) of 164 patients were excluded, as they were not prescribed standard therapy. The primary endpoint was 6-month incidence of death, myocardial infarction, stroke/transient ischaemic attack (TIA) or major/life-threatening bleeding. Secondary endpoints included each component of the primary endpoint, defined according to VARC-2. Overall, the primary endpoint occurred in 20.8% and 17.7% of the standard AF and standard non-AF therapy groups respectively (p=0.82). There was no statistically significant difference in bleeding (12.5% versus 9.4%, p=0.77) or stroke/TIA (2.1% versus 8.3%, p=0.27) between the standard AF and standard non-AF therapy groups respectively. This study supports the safety of anticoagulation in AF patients, which did not result in excess risk of bleeding or stroke/TIA compared with dual antiplatelet therapy in non-AF patients.

Meta-Analysis of Studies Comparing Dual- Versus Mono-Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation

Current guidelines recommend dual-antiplatelet therapy (DAPT) after transcatheter aortic valve implantation (TAVI), although some studies suggest mono-antiplatelet therapy is equally efficacious with an improved safety profile. We performed a meta-analysis of studies comparing DAPT with mono-antiplatelet therapy after TAVI. Study quality and heterogeneity were assessed using Jadad score, Newcastle-Ottawa Scale, and Cochran's Q statistics. Mantel-Haenszel odds ratios (ORs) were calculated using fixed effect models as the primary analysis. Eight studies including 2,439 patients met the inclusion criteria. At 30 days, DAPT was associated with an increased risk of all-cause mortality (OR 2.06, 95% confidence interval [CI] 1.34 to 3.18, p = 0.001), major or life-threatening bleeding (OR 2.04, 95% CI 1.60 to 2.59, p <0.001), and major vascular complications (OR 2.15, 95% CI 1.51 to 3.06, p <0.001). There was no difference in the rate of the combined end point of stroke or transient ischemic attack, or myocardial infarction. Outcome data up to 6 months were available in 5 studies; all-cause mortality and stroke were similar between groups, although major or life-threatening bleeding was more frequent with DAPT. In conclusion, in patients undergoing TAVI, DAPT is associated with increased risk at 30 days of all-cause mortality, major or life-threatening bleeding, and major vascular complications without a decrease in ischemic complications; at 6 months, the excess bleeding risk persisted. These data suggest a safety concern with DAPT and justify further investigation of the optimal antiplatelet therapy regimen after TAVI.

6-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomised, open-label, non-inferiority trial

Current guidelines recommend dual antiplatelet therapy (DAPT) of aspirin plus a P2Y12 inhibitor for at least 12 months after implantation of drug-eluting stents (DES) in patients with acute coronary syndrome. However, available data about the optimal duration of DAPT in patients with acute coronary syndrome undergoing percutaneous coronary intervention are scant. We aimed to investigate whether a 6-month duration of DAPT would be non-inferior to the conventional 12-month or longer duration of DAPT in this population. We did a randomised, open-label, non-inferiority trial at 31 centres in South Korea. Patients were eligible if they had unstable angina, non-ST-segment elevation myocardial infarction, or ST-segment elevation myocardial infarction, and underwent percutaneous coronary intervention. Enrolled patients were randomly assigned, via a web-based system by computer-generated block randomisation, to either the 6-month DAPT group or to the 12-month or longer DAPT group, with stratification by site, clinical presentation, and diabetes. Assessors were masked to treatment allocation. The primary endpoint was a composite of all-cause death, myocardial infarction, or stroke at 18 months after the index procedure in the intention-to-treat population. Secondary endpoints were the individual components of the primary endpoint; definite or probable stent thrombosis as defined by the Academic Research Consortium; and Bleeding Academic Research Consortium (BARC) type 2-5 bleeding at 18 months after the index procedure. The primary endpoint was also analysed per protocol. This trial is registered with ClinicalTrials.gov, number NCT01701453. Between Sept 5, 2012, and Dec 31, 2015, we randomly assigned 2712 patients; 1357 to the 6-month DAPT group and 1355 to the 12-month or longer DAPT group. Clopidogrel was used as a P2Y12 inhibitor for DAPT in 1082 (79·7%) patients in the 6-month DAPT group and in 1109 (81·8%) patients in the 12-month or longer DAPT group. The primary endpoint occurred in 63 patients in the 6-month DAPT group and in 56 patients in the 12-month or longer DAPT group (cumulative event rate 4·7% vs 4·2%; absolute risk difference 0·5%; upper limit of one-sided 95% CI 1·8%; pnon-inferiority=0·03 with a predefined non-inferiority margin of 2·0%). Although all-cause mortality did not differ significantly between the 6-month DAPT group and the 12-month or longer DAPT group (35 [2·6%] patients vs 39 [2·9%]; hazard ratio [HR] 0·90 [95% CI 0·57-1·42]; p=0·90) and neither did stroke (11 [0·8%] patients vs 12 [0·9%]; 0·92 [0·41-2·08]; p=0·84), myocardial infarction occurred more frequently in the 6-month DAPT group than in the 12-month or longer DAPT group (24 [1·8%] patients vs ten [0·8%]; 2·41 [1·15-5·05]; p=0·02). 15 (1·1%) patients had stent thrombosis in the 6-month DAPT group compared with ten (0·7%) in the 12-month or longer DAPT group (HR 1·50 [95% CI 0·68-3·35]; p=0·32). The rate of BARC type 2-5 bleeding was 2·7% (35 patients) in the 6-month DAPT group and 3·9% (51 patients) in the 12-month or longer DAPT group (HR 0·69 [95% CI 0·45-1·05]; p=0·09). Results from the per-protocol analysis were similar to those from the intention-to-treat analysis. The increased risk of myocardial infarction with 6-month DAPT and the wide non-inferiority margin prevent us from concluding that short-term DAPT is safe in patients with acute coronary syndrome undergoing percutaneous coronary intervention with current-generation DES. Prolonged DAPT in patients with acute coronary syndrome without excessive risk of bleeding should remain the standard of care. Abbott Vascular Korea, Medtronic Vascular Korea, Biosensors Inc, and Dong-A ST.

Exploring the Postpartum Pyrexia Related to Inherited Coagulopathies in a Cohort of Iranian Women

Background: Postpartum pyrexia results from various causes with bacterial infection heading the list. However, there are many other possible causes such as bleeding. Congenital deficiency of the coagulation factors causes inherited coagulopathies most of which are rare. Following delivery, the reduction in coagulation factors puts these mothers at greater risk ‎of postpartum excessive bleeding. Objectives: We aimed to assess ‎postpartum pyrexia in bleeding disorder mothers. ‎Methods: This ‎study was conducted on 98 bleeding disorder patients and 199 controls. Using a standardized questionnaire, the data were collected by consulting a specialist. The subject`s medical records during pregnancy and labor were also reviewed. Postpartum fever ‎was defined as temperature >‎ 38°C ‎in the first 10 days after delivery ‎‎‎excluding the first day.‎ The data were analyzed using Chi-square statistical analysis and P < 0.05 was considered statistically ‎significant. Results: Postpartum pyrexia was detected in 11.2% of the patients compared to 4% of the controls. The statistical analysis revealed a significantly higher incidence of postpartum fever among the coagulation disorder patients (P = 0.019). Considering the infection, our data showed that in the patient group, fever was mostly due to (unknown) reasons other than infection. Conclusions: Our results revealed that besides hemorrhagic complications in inherited bleeding disorders, postpartum fever could also be a sign of threat. Early identification and diagnosis of these threats greatly improve the childbirth outcomes in high-risk mothers.

Development and validation of a predictive model for excessive postpartum blood loss: A retrospective, cohort study

Backgroundpostpartum haemorrhage is one of the leading causes of maternal morbidity and mortality worldwide. Despite the use of uterotonics agents as preventive measure, it remains a challenge to identify those women who are at increased risk of postpartum bleeding. Objectiveto develop and to validate a predictive model to assess the risk of excessive bleeding in women with vaginal birth. Designretrospective cohorts study. Setting“Mancha-Centro Hospital” (Spain). Participantsthe elaboration of the predictive model was based on a derivation cohort consisting of 2336 women between 2009 and 2011. For validation purposes, a prospective cohort of 953 women between 2013 and 2014 were employed. Women with antenatal fetal demise, multiple pregnancies and gestations under 35 weeks were excluded Methodswe used a multivariate analysis with binary logistic regression, Ridge Regression and areas under the Receiver Operating Characteristic curves to determine the predictive ability of the proposed model. Resultsthere was 197 (8.43%) women with excessive bleeding in the derivation cohort and 63 (6.61%) women in the validation cohort. Predictive factors in the final model were: maternal age, primiparity, duration of the first and second stages of labour, neonatal birth weight and antepartum haemoglobin levels. Accordingly, the predictive ability of this model in the derivation cohort was 0.90 (95% CI: 0.85–0.93), while it remained 0.83 (95% CI: 0.74–0.92) in the validation cohort. Conclusionsthis predictive model is proved to have an excellent predictive ability in the derivation cohort, and its validation in a latter population equally shows a good ability for prediction. This model can be employed to identify women with a higher risk of postpartum haemorrhage.

Efficacy and safety of Nuwiq® (human-cl rhFVIII) in patients with severe haemophilia A undergoing surgical procedures.

Haemophilia A patients are at a high risk of excess bleeding during surgeries. The aim of haemostatic therapy during the perioperative period is to normalize FVIII level perioperatively and postoperatively to maintain normal haemostasis until wound healing is complete. To examine the efficacy of Nuwiq® (simoctocog alfa, human-cl rhFVIII), a 4th generation recombinant FVIII produced in a human cell line, for surgical prophylaxis in patients with severe haemophilia A. This analysis assessed the efficacy of Nuwiq® during surgical procedures and in the postoperative period in seven clinical studies of previously treated patients (PTPs) with severe haemophilia A. Thirty-six patients, aged 3-55years, received surgical prophylaxis with Nuwiq® for 60 surgeries (28 major and 32 minor). Efficacy was evaluated for 52 surgeries (25 major and 27 minor). The success rate of Nuwiq® treatment was 98.1% (51 of 52 evaluated surgeries); haemostatic efficacy was assessed as "excellent" or "good" in all but one major surgery (assessed as "moderate"). The number of infusions ranged from 1 to 19 for minor surgeries and from 3 to 76 for major surgeries. The median (range) daily doses were 42.0 (28.2-100.9) IUkg-1 for minor surgeries and 69.3 (43.3-135.6) IUkg-1 for major surgeries. There were no serious treatment-related adverse events, and none of the patients developed FVIII inhibitors. The results of this pooled analysis show that Nuwiq® was efficacious in maintaining haemostasis during and after major and minor surgical procedures in PTPs with severe haemophilia A.

Dermoscopy and Pigmented Lesions of Oral Cavity

Dear editor, Pigmented lesions are relatively rare in the oral cavity. They represent a variety of entities ranging from racial pigmentation to manifestation of systemic illness (Addison’s disease), to benign (hemangioma, lymphangioma, melanotic nevi) and malignant neoplasms (Kaposi’s sarcoma, malignant melanoma, pigmented basal cell carcinoma). 1 Biopsy is usually avoided in vascular lesions like hemangioma, Kaposi’s sarcoma etc. by general dentists owing to the risk of excessive bleeding due to the possibility of their association with a feeder vessel. A color Doppler ultrasonography is sometime required in order to rule out this association; otherwise sclerosing agents are used for diagnostic and therapeutic purposes. 2 Melanotic lesions like malignant melanoma or melanotic nevi are sometimes seen in the oral cavity; some clinicians believe that incisional biopsy of a melanoma might disseminate the disease. 3 A guideline of biopsy taking for melanoma has been issued. It includes a full thickness excisional biopsy allowing assessment of the Breslow thickness, but preliminary biopsies are only advisable in case of acral melanoma; however, shave and punch biopsy are no more recommended, but hesitation of clinicians for taking biopsy from pigmented lesions cannot be ignored. 4 Dermoscopy is a non – invasive technique that allows a visualization of morphological features of the lesion that are not visible to a naked eye. This is useful in dermatology for making an early differential diagnosis of different pigmented lesions. 5 Despite their popularity in dermatology, they are not very popular in investigation of the mucosal lesions of lip and oral cavity. 6 Dermoscopy can be extremely helpful in making demarcation between melanotic nevi and malignant melanoma (Figure 1). There is a need to intensify the research pertaining to the use of dermoscopy in oral mucosal lesions, also a criterion has to be introduced for the diagnosis of oral pigmented lesions on dermoscopy. It minimizes the risk of the exposure of the patient to excisional biopsy that may be resulting in facial disfigurement. This procedure can be easily adopted by dentists working in private sectors and corporate sectors. Dental curriculum has to be enhanced with the use of dermoscopes in diagnosing pigmented oral lesions on graduate and post-graduate level.

Association between emergency admission for peptic ulcer bleeding and air pollution: a case-crossover analysis in Hong Kong's elderly population

Air pollution increases intestinal permeability, alters the gut microbiome, and promotes inflammation, which might contribute towards gastrointestinal bleeding. In the present study, we aim to examine whether short-term elevations in air pollution are associated with increased numbers of emergency hospital admissions for peptic ulcer bleeding in Hong Kong. Daily air pollution (particulate matter with aerodynamic diameter less than 2·5 μm [PM2·5], nitric oxide [NO2], sulpher dioxide [SO2], and ozone [O3]) data during 2005-10 were collected from the Environmental Protection Department and emergency admission data for peptic ulcer bleeding in elderly people (aged 65 years or older) from the Hospital Authority of Hong Kong. A time stratified case-crossover analysis with conditional logistic regression was used to estimate the excess risk of peptic ulcer bleeding associated with each air pollutant, in single-pollutant and multi-pollutant models. Cardiorespiratory diseases were used as positive controls. 8566 emergency admissions for peptic ulcer bleeding were recorded among Hong Kong's elderly population during 2005-10; the daily number of admissions ranged from 0 to 13. An IQR increment of 5-day moving average (lag04) of NO2 concentration (25·8 μg/m3) was associated with a 7·6% (95% CI 2·2-13·2) increase in emergency admissions for peptic ulcer bleeding. Multi-pollutant models confirmed the robustness of the risk estimates for NO2. Other pollutants (PM2·5, SO2, and O3) were not associated with peptic ulcer bleeding admissions. Short-term elevation in ambient NO2 might trigger peptic ulcer bleeding events and increase the risk of emergency admissions for peptic ulcer bleeding in Hong Kong's elderly population. These findings strengthen the hypothesis that air pollution affects not just cardiopulmonary diseases, but also certain diseases of the digestive system. None.

Becoming Reconciled to MedRec

Becoming Reconciled to MedRec

Impact of six versus 12 months of dual antiplatelet therapy in patients with drug-eluting stent implantation after risk stratification with the residual SYNTAX score: Results from a secondary analysis of the I-LOVE-IT 2 trial.

The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation remains undetermined, especially for those at high risk of cardiac events postprocedure. This study was aimed to investigate the impact of 6 versus 12 months of DAPT after DES implantation based on risk stratification with the residual SYNTAX score (rSS). A total of 2737 patients in the I-LOVE-IT 2 trial were grouped according to rSS status (low rSS [rSS = 0, n = 1474] versus high rSS [rSS > 0, n = 1263]) and DAPT duration (6 months vs. 12 months). The primary endpoint was 12-month target lesion failure (TLF), and the major secondary endpoints were 12-month net adverse clinical events (NACE) and major bleeding. Incidences of TLF (5.2 vs. 7.4%, P = 0.01) and NACE (9.2 vs. 13.4%, P < 0.001) at 12 months were significantly higher in patients with high rSSs compared with patients with low rSSs. Landmark analysis showed that, in patients with high rSS, 12-month DAPT was associated with slightly lower risks of TLF (3.0% vs. 1.6%, P = 0.08) and NACE (7.0 vs. 4.4%, P = 0.054) compared with 6-month DAPT within 6 to 12 months after PCI. Patients with different DAPT durations had similar risks of bleeding both in the low and high rSS groups. Patients with high rSSs have an increased risk of TLF and NACE at 12 months after DES implantation. Twelve-month DAPT might be superior to 6-month DAPT in patients with high rSS for reducing adverse events within 6 to 12 months after PCI without excessive risk of bleeding. © 2017 Wiley Periodicals, Inc.

One-year and longer dual antiplatelet therapy after an acute coronary syndrome: a Belgian position paper

Acute coronary syndrome patients receive DAPT up to one year after their initial event. Exceptions to the guideline-recommended one-year rule, however, are not uncommon. The reasoning behind shorter treatments, such as unacceptable bleeding risk or urgent surgery, should be well documented in the patient’s charts and discharge letter. Based on recent evidence, patients at high risk for repetitive events should continue on low-dose ticagrelor without a significant interruption at one year and indefinitely in the absence of excess bleeding risk. As there is currently no reimbursement, policy makers and insurers should be made aware of the continuing risk and unmet clinical need in this patient population. Nevertheless, many unsolved questions need to be answered, both through additional analyses from recent trials such as PEGASUS-TIMI 54 or DAPT, as well as new carefully designed clinical studies.

Living donor hepatectomy in female donors with ongoing menstruation

Purpose: The purpose of this study was to study the safety of the major hepatectomy in female donors with ongoing menstruation in situations where the recipient needs urgent liver transplantation and its impact on menstrual bleeding and subsequent menstrual cycles. Materials and Methods: Fifty-eight female donors that underwent adult-to-adult living donor liver transplantation were enrolled in this study and were categorized into two groups. Group A comprised 49 female donors with normal physiological state and Group B comprised nine female donors with ongoing menstruation during the surgery. All the donors in the cohort underwent right hepatectomy including the middle hepatic vein without any blood transfusion in perioperative period. Results: Preoperative international normalized ratio (INR) in Group A and B was 1.05 ± 0.08 and 1.07 ± 0.08, respectively, while INR at postoperative day 7 in Group A donors was 1.72 ± 0.22 while in Group B donors, it was 1.75 ± 0.26. Perioperative hemoglobin drop in Group A and B was statistically insignificant (1.59 ± 0.83 g% vs 1.68 ± 1.51 g%, P = 0.78). The menstrual blood loss in both the groups was statistically comparable. Conclusions: Our study shows safety of right lobe living donation in female donors with ongoing menstruation with no increased risk of intraoperative excessive bleeding and postoperative physiological impact on their general health.

The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial

The APEX trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among hospitalized, acutely ill medical patients. The 80-mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P-glycoprotein inhibitor. This analysis assessed the pharmacokinetics, efficacy, and safety of full- (80 mg) and reduced-dose (40 mg) betrixaban relative to enoxaparin in the APEX trial. The median concentration of betrixaban among subjects administered the 80-mg dose was higher than that of the 40-mg dose (19 ng/mL vs 11 ng/mL, P<.001). In the primary analysis cohort 1 (d-dimer ≥2× upper limit of normal), the primary efficacy outcome (asymptomatic proximal deep vein thrombosis, symptomatic proximal or distal deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or venous thromboembolism-related death) was significantly reduced among subjects treated with 80 mg of extended-duration betrixaban versus enoxaparin (6.27% [95/1516] vs 8.39% [130/1549], relative risk reduction=0.26 [0.04-0.42], P=.023), and similarly in the entire primary efficacy outcome population (4.87% [122/2506] vs 7.06% [181/2562], relative risk reduction=0.30 [0.13-0.44], P=.001). There was no difference in the primary outcome for subjects treated with 40 mg betrixaban vs enoxaparin across cohorts. In addition, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin. The 80-mg betrixaban dose achieves higher plasma concentrations than the 40-mg dose and, in contrast to the 40-mg dose, is associated with improved efficacy across all cohorts relative to standard-dose enoxaparin without an excess risk of major bleeding in the management of medically ill subjects.

The Safety and Efficacy of Full Versus Reduced Dose Betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) Trial

Background: The exposure of all the currently licenced DOACs is increased in renal impairment and by certain drug interactions. The Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among acutely ill medical patients. The full 80 mg dose of betrixaban was halved to 40 mg among subjects with severe renal insufficiency (calculated creatinine clearance <30ml/min), or receiving a concomitant strong P-glycoprotein (P-gp) inhibitor.Objectives and Methods: The goal of this analysis is to assess the efficacy and safety of full (80 mg) and reduced dose (40 mg) betrixaban relative to enoxaparin in the APEX trial. Subjects were stratified into the two dose groups prior to randomization according to the pre-specified dosing criteria. The primary efficacy outcome was the composite of asymptomatic proximal and symptomatic venous thromboembolism (proximal or distal deep-vein thrombosis, symptomatic nonfatal pulmonary embolism, or death from venous thromboembolism). The principal safety outcome was major bleeding.Results: The median concentration of betrixaban among subjects administered the 80 mg dose was higher than that of the 40 mg dose (19 ng/ml vs 11 ng/ml, p<0.0001). In the primary analysis Cohort 1 (the elevated D-dimer +ve patients), the primary efficacy outcome was significantly reduced among subjects treated with 80 mg of extended dose betrixaban vs enoxaparin [6.3% (95/1516) vs 8.4% (130/1549), RRR = 0.26 (0.04-0.42), p=0.023]. A similar reduction was observed in the entire modified Intention to Treat (mITT) population [4.87% (122/2506) vs 7.06% (181/2562), RRR = 0.30 (0.13 - 0.44), p=0.001]. In contrast, among subjects receiving 40 mg of betrixaban there was no significant difference in the primary outcomes compared with enoxaparin across Cohorts 1, 2, and 3. There was no excess of major bleeding associated with administration of either the full 80 mg dose or the reduced 40 mg dose of betrixaban as compared with enoxaparin.Conclusion: For extended duration prophylaxis against VTE in hospitalized medically ill patients, the full 80 mg dose of extended duration betrixaban achieves higher serum concentrations than the 40 mg dose and is associated with improved efficacy across all cohorts relative to standard dose enoxaparin, without an excess risk of major bleeding. Based upon the approximate halving of plasma concentrations in this analysis and the lack of improvement in clinical outcomes, the reduced 40 mg dose may have been excessively downwardly adjusted. Conversely, the 80 mg dose was efficacious in all cohorts, including cohort 1. The inclusion of the 40 mg dose in the primary analysis may explain at least in part the marginal statistical result in the original report. DisclosuresCohen:Takeda: Consultancy; Medscape: Speakers Bureau; XO1: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Portola: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; NHS: Membership on an entity’s Board of Directors or advisory committees; Lifeblood: Membership on an entity’s Board of Directors or advisory committees; Department of Health: Membership on an entity’s Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Janssen: Consultancy; Aspen: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; Colation to Prevent Venous Thromboembolism: Other: Founder; Leo Pharma: Consultancy; UK Government Health Select Committee: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria. Goldhaber:Portola: Consultancy. Hull:Portola: Consultancy. Hernandez:Portola: Consultancy. Gold:Portola Pharmaceuticals: Employment. Wiens:Portola: Employment, Equity Ownership. Harrington:Portola: Consultancy. Gibson:Portola: Consultancy.

Low-factor consumption for major surgery in haemophilia B with long-acting recombinant glycoPEGylated factor IX.

Surgery in patients with haemophilia B carries a high risk of excessive bleeding and requires adequate haemostatic control until wound healing. Nonacog beta pegol, a long-acting recombinant glycoPEGylated factor IX (FIX), was used in the perioperative management of patients undergoing major surgery. To evaluate the efficacy and safety of nonacog beta pegol in patients with haemophilia B who undergo major surgery. This was an open-label, multicentre, non-controlled surgery trial aimed at assessing peri- and postoperative efficacy and safety of nonacog beta pegol in 13 previously treated patients with haemophilia B. All patients received a preoperative nonacog beta pegol bolus injection of 80 IU kg-1 . Postoperatively, the patients received fixed nonacog beta pegol doses of 40 IU kg-1 , repeated at the investigator's discretion. Safety assessments included monitoring of immunogenicity and adverse events. Intraoperative haemostatic effect was rated 'excellent' or 'good' in all 13 cases. Apart from the preoperative injection, none of the patients needed additional doses of nonacog beta pegol on the day of surgery. The median number of postoperative doses of nonacog beta pegol was 2.0 from days 1 to 6 and 1.5 from days 7 to 13. No unexpected intra- or postoperative complications were observed including deaths or thromboembolic events. No patients developed inhibitors. These results indicated that nonacog beta pegol was safe and effective in the perioperative setting, allowing major surgical interventions in patients with haemophilia B with minimal peri- and postoperative concentrate consumption and infrequent injections as reported with standard FIX products.