Acute Bleeding Events Research Articles

Association of acute kidney injury and bleeding events with mortality after radial or femoral access in patients with acute coronary syndrome undergoing invasive management: secondary analysis of a randomized clinical trial.

In the Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) trial, adults with acute coronary syndrome undergoing coronary intervention who were allocated to radial access had a lower risk of bleeding, acute kidney injury (AKI), and all-cause mortality, as compared with those allocated to femoral access. The mechanism of the mortality benefit of radial access remained unclear. We used multistate and competing risk models to determine the effects of radial and femoral access on bleeding, AKI and all-cause mortality in the MATRIX trial and to disentangle the relationship between these different types of events. There were large relative risk reductions in mortality for radial compared with femoral access for the transition from AKI to death [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.31-0.97] and for the pathway from coronary intervention to AKI to death (HR 0.49, 95% CI 0.26-0.92). Conversely, there was little evidence for a difference between radial and femoral groups for the transition from bleeding to death (HR 1.05, 95% CI 0.42-2.64) and the pathway from coronary intervention to bleeding to death (HR 0.84, 95% CI 0.28-2.49). The prevention of AKI appeared predominantly responsible for the mortality benefit of radial as compared with femoral access in the MATRIX trial. There was little evidence for an equally important, independent role of bleeding.

Macrophage Polarization Is Impaired in Hemophilia

Macrophages are master regulators of inflammation and wound healing. As such they play an important role in hemophilia, which is commonly associated with delayed tissue regeneration and bleeding-induced joint inflammation. The objective of this study is to determine if macrophage function is deregulated in hemophilia and whether this affects the physiological balance of tissue regeneration and inflammation.For this study, we analyzed monocytes and plasma from a cohort of 26 adult patients with hemophilia A or B that visited our clinic for their annual routine check-up. Patients with acute bleeding events were excluded. The majority of patients had severe forms of hemophilia with factor VIII or IX activity < 1% and, therefore, received prophylactic factor replacement therapy (recombinant or plasmatic) but we also included patients with moderate to mild hemophilia, which were only treated in case of bleeding. Corresponding control samples stemmed from healthy male individuals that we recruited randomly from our blood donor center.To assess macrophage differentiation, we isolated monocytes from the peripheral blood of hemophilia patients as well as healthy controls and began treatment with M-CSF or GM-CSF for 7 days. Macrophage differentiation was confirmed by phase contrast and fluorescence microscopy, which revealed a spread and elongated cell phenotype in donor monocytes in the presence of M-CSF and, to a lesser extent, GM-CSF. Hemophilia monocytes, on the other hand, failed to spread properly in response to either of the cytokines suggesting that macrophage polarization is diminished in patients with reduced activity of coagulation factor VIII or IX.As hemophilia macrophages failed to spread in response to M-CSF, they also failed to express TNFα and CD163, which are macrophage differentiation markers typically induced by M-CSF. In contrast, GM-CSF-induced differentiation was only mildly suppressed suggesting that hemophilia macrophages specifically resist the differentiating stimulus of M-CSF. Consequently, we experienced a significant impairment in M-CSF-induced regenerative macrophage functions such as clot infiltration and red blood cell phagocytosis in hemophilia. Intriguingly, while monocyte invasion was impaired, protein expression in response to M-CSF was regained with respect to CD163 and CD206 after embedding hemophilia monocytes in clotted plasma from healthy blood donors suggesting that a functioning coagulation system has positive effects on regenerative macrophage functions.The inability of hemophilia macrophages to promote M-CSF-mediated signals correlates with a marked down regulation of the M-CSF receptor CSF-1R on hemophilia monocytes as determined in citrated whole blood by flow cytometry. Alongside with a modest reduction of GM-CSF-R, we also detected a substantial reduction of CD163 and Tie2, which are specifically expressed on regenerative monocytes/macrophages, suggesting that clotting deficiencies impair the immune function either directly or indirectly. To further analyze the immune status of hemophilia patients, we performed a cytokine array on plasma samples from hemophiliacs versus healthy blood donors, which revealed the down regulation of a large spectrum of anti-inflammatory and regenerative cytokines in the blood of hemophilia patients.Among the few cytokines upregulated in the blood of hemophiliacs, the adipokine leptin was the most prominent (6-fold, hemophiliac vs. donor). Since leptin has been shown to cause deregulation of the innate immunity, we treated the human monocyte cell line THP1 with recombinant leptin and found a significant inhibitory effect of M-CSF-induced spreading and clot invasion. Therefore, these data suggest that high leptin levels in the blood can reiterate the changes in monocyte function we observed in hemophilia. Together, we conclude that macrophage differentiation is deregulated in hemophilia as a result of resistance towards the cytokine M-CSF. Consequently, hemophilia macrophages are unable to properly perform regenerative functions such as clot invasion and red blood cell phagocytosis. The hemophilic monocyte/macrophage phenotype we describe can be induced by high levels of leptin and mitigated by correcting the clotting dysfunction suggesting a two prone approach to prevent delayed wound healing and persistent inflammation in hemophilia. DisclosuresNo relevant conflicts of interest to declare.

PCN3 - REAL WORLD EVIDENCE OF METASTATIC BREAST CANCER TREATMENT: A COMPARISON OF ADVERSE EFFECTS BETWEEN PALBOCICLIB TREATMENT AND ENDOCRINE THERAPY

Palbociclib (PC) is a CDK4/6 inhibitor for ER(+)/HER2(-), metastatic breast cancer (MBC). Studies show progression-free survival is better among palbociclib patients than among patients receiving endocrine therapy. Evidence on whether the frequency of adverse effects (AEs) differs between PC patients and patients on other endocrine therapies is lacking. Data from a health research network representing over 19M female patient-lives was used to compare: (1) the occurrence of AEs in PC+letrozole(L) patients versus patients receiving an aromatase inhibitor (AI); and (2) the occurrence of AEs in PC+fulvestrant(F) patients versus patients receiving second-line endocrine therapy (ET). Patients had to be 50+ years old, have an MBC diagnosis between 2013-2017, and be ER(+)/HER2(-). The following AEs were defined by an ICD and/or LOINC code: neutropenia, anemia, acute respiratory infections, osteoporosis, fractures, weakness, bleeding events and mood disorders. We report the RRs and 95% CIs. The mean ages of PC+L(n=755), PC+F(n=447), AIs(n=7,600) and ET(n=1,821) patients were comparable (ages 66-67). PC+L and PC+F patients had a significantly higher risk of neutropenia and anemia than AI and ET patients. Compared to AI patients, PC+L patients had a lower risk of osteoporosis (RR=0.5;0.4-0.7) and mood disorders (RR=0.8;0.7-0.9), and a higher risk of bleeding events (RR=1.4;1.1-1.9). PC+L patients did not significantly differ from AI patients with respect to acute respiratory infections, fractures, or weakness or fatigue. Compared to ET patients, PC+F patients only had a significantly lower risk of osteoporosis (RR=0.7;0.5-0.9). Adjusting for treatment history and other confounders did not meaningfully impact the results. Although studies have demonstrated benefits to PC treatment over endocrine therapies, PC patients may have an increased risk of infection and bleeding. As PC, and other newly approved therapies in the same class, become more common, further analyses should assess whether these differences raise concern for patient safety.

Emergencies in Hemophilia

Hemophilia is a severe congenital bleeding disorder associated with both spontaneous and traumatic bleeding episodes that can require emergent medical evaluation. Many persons with hemophilia (PWH) utilize the emergency department for the initial management of acute bleeding events. Prompt administration of factor replacement products is crucial in controlling acute bleeds and minimizing potential associated morbidity. PWH who have inhibitory antibodies can be especially difficult to treat, as they often require by-passing agent therapies to obtain hemostatic control. Although consultation with an experienced hematologist is always warranted, initial management of acute complications in hemophilia is emergent, which necessitates emergency care providers to have a strong understanding of the current treatment principles in this complex condition.

Volume-replacement ratio for crystalloids and colloids during bleeding and resuscitation: an animal experiment

BackgroundFluid resuscitation remains a cornerstone in the management of acute bleeding. According to Starling's “Three-compartment model”, four-times more crystalloids have the same volume effect as colloids. However, this volume-replacement ratio remains a controversial issue as it may be affected by the degradation of the endothelial glycocalyx layer, a situation often found in the critically ill. Our aim was to compare colloid and crystalloid based fluid resuscitation during an experimental stroke volume index (SVI) guided hemorrhage and resuscitation animal model.MethodsAnesthetized and mechanically ventilated pigs were randomized to receive a colloid (Voluven®,HES, n=15) or crystalloid (Ringerfundin®,RF, n=15) infusion. Animals were bled till baseline SVI (Tbsl) dropped by 50% (T0), followed by resuscitation until initial SVI was reached (T4) in four steps. Invasive hemodynamic measurements, blood gas analyses and laboratory tests were performed at each assessment points. Glycocalyx degradation markers (Syndecan-1/hematocrit ratio, Glypican/hematocrit ratio) were determined at Tbsl, T0 and T4.ResultsSimilar amounts of blood were shed in both groups (HES group: 506±159 mls blood, RF group: 470±127 mls blood). Hemodynamic changes followed the same pattern without significant difference between the groups. Animals received significantly less resuscitation fluid in the HES compared to the RF-group: 425 [320-665], vs 1390 [884-1585] mls, p <0.001. The volume replacement ratio was 0.92 [0.79-1.54] for HES; and 3.03 [2.00-4.23] for the RF-group (p <0.001). There was no significant difference between the groups in the glycocalyx degradation markers.ConclusionIn this moderate bleeding-resuscitation animal model the volume-replacement ratio for crystalloids and colloids followed similar patterns as predicted by Starling's principle, and the glycocalyx remained intact. This indicates that in acute bleeding events, such as trauma or during surgery, colloids may be beneficial as hemodynamic stability may be achieved more rapidly than with crystalloids.

The value of Sonoclot detection technology to guide the clinical medication of the perioperative anticoagulation and antiplatelet therapy in patients with acute myocardial infarction undergoing emergent PCI.

The value of Sonoclot detection technology to guide the clinical medication of the perioperative anticoagulation and antiplatelet therapy in patients with acute myocardial infarction (AMI) undergoing emergent percutaneous coronary intervention (PCI) was estimated. One hundred and twenty-eight patients were randomly divided into control group and observation group with 64 cases in each group. Control group adopted routine blood coagulation indexes, including prothrombin time, activated partial thromboplastin time, fibrinogen and plasma thrombin time, platelet count and platelet aggregation turbidity analysis; observation group adopted Sonoclot detection technology, including activated clotting time, coagulation rate and platelet function. Anticoagulant therapy selected was of low molecular weight heparin calcium perioperatively, intraoperative unfractionated heparin, and clopidogrel (75 mg) combined with aspirin enteric-coated tablets (100 mg) as antiplatelet drugs. The therapy was administered in accordance with blood coagulation results. The blood coagulation time, postoperative creatine kinase isoenzyme MB, cardiac troponin I and B-type natriuretic peptide levels in the observation group are significantly lower than those in the control group (P<0.05) though the operating time and specifications of the stenting did not show any significant difference (P>0.05). The incidence of recurrent myocardial infarction, microembolism, acute and subacute thrombosis and bleeding events in the observation group are significantly lower than those in the control group (P<0.05). In the control group, there is no difference in the coagulation indexes of the patients with thrombosis events or bleeding events or no event (P>0.05). Whereas, in the observation group, there is significant difference in coagulation indexes of the patients with thrombosis events or bleeding events or no event (P<0.05). In conclusion, Sonoclot detection technology instructs emergent PCI treatment in AMI patients to shorten the detection time of blood coagulation, reduce the degree of myocardial injury, reduce the incidence of perioperative thrombosis and bleeding events. Furthermore, it has great value in guiding the clinical medication of anticoagulation and antiplatelet therapy.

IVC filters-Trends in placement and indications, a study of 2 populations.

Inferior vena cava filter (IVCF) placement appears to be expanding over time despite absence of clear directing evidence.Two populations were studied. The first population included patients who received an IVCF between January 2005 and August 2013 at our community hospital center. Demographic information, indications for placement, and retrieval rate was recorded among other variables. The second population comprised of patients receiving an IVCF from 2005 to 2012 according to the Nationwide Inpatient Sample (NIS) using ICD-9CM coding. Patients were divided into 2 groups based on the year of admission for comparison, that is, first group from 2005 to 2008 and the second from 2009 to 2012. In addition, we analyzed annual trends in filter placement, acute venothromboembolic events (VTE) and several underlying comorbidities within this population.At our center, 802 IVCFs were placed (55.2% retrievable); 34% for absolute, 61% for relative, and 5% for prophylactic indications. Major bleeding (27.5%), minor self-limited bleeding (13.7%), and fall history (11.2%) were the commonest indications. Periprocedural complication rate was 0.7%, and filter retrieval rate was 7%. The NIS population (811,487 filters) saw a decline in IVCF placement after year 2009, following an initial uptrend (Ptrend < 0.01). IVCF use among patients with neither acute VTE nor bleeding among prior VTE saw a 3-fold absolute reduction from 2005 to 2012 (33,075-11,655; Ptrend < 0.01). Patients from 2009 to 2012 were more likely to be male and had higher rates of acute VTE, thrombolytic use, cancer, bleeding, hypotension, acute cardiorespiratory failure, shock, prior falls, blood product transfusion, hospital mortality including higher Charlson comorbidity scores. The patients were younger, had shorter length of stay, and were less likely to be associated with strokes including hemorrhagic or require ventilator support. Prior falls (adjusted odds ratio-aOR 2.8), thrombolytic use (aOR 1.76), and shock (aOR 1.45) were most predictive of IVCF placement between 2009 and 2012 on regression analysis.Recent trends suggest that a higher proportion of patients receive temporary IVCF, for predominantly relative indications. Nationally, the number of filters being placed is decreasing, especially among those who did not experience acute VTE or bleeding events. Prior falls, thrombolytic therapy, and shock were most predictive of IVCF placement in latter half of the study period.

Rivaroxaban Prophylaxis in Severe Congenital Protein C Deficiency

INTRODUCTIONProtein C is a vitamin K-dependent coagulation inhibitor produced by the hepatocytes. It is activated by the Thrombin-Thrombomodulin Complex, and in association with its cofactor, Protein S, induces proteolysis and inactivates Factor Va and Factor VIIIa thus limiting thrombin production.Congenital protein C deficiency may be inherited as an autosomal dominant disorder. Asymptomatic Protein C deficiency has been reported to be prevalent in 1 in 200 to 500 of healthy individuals, whereas the incidence of symptomatic deficiency is 1 in 20000. Autosomal recessive inheritance has been estimated to be around 1 in 4 million.CASE REPORTWe report a case of a 19 year old male, ex 33 week-premature first twin baby from Thailand, diagnosed with severe Protein C Deficiency after presenting to a local hospital with an acute manifestation of bilateral leg swelling and purpura fulminans when he was 2 years old. At that time, his Protein C activity was 2%. He was initially treated with quarantined FFP replacement 10-15ml/kg weekly and LMWH and later warfarin. MRI done at that time showed evidence of prior ischemic events.Upon arrival to the US at 16 years of age his treatment with warfarin was continued. During the following year, he presented several times with complications including deep venous thrombosis, warfarin skin necrosis, bleeding and transient neurological deficits. He was started on rivaroxaban - a direct thrombin inhibitor- 20mg orally daily at 17 years of age. For the following two years he did well and had no other acute thrombotic, bleeding events or medication side effects. Follow up brain MRI showed no new areas of infarct.DISCUSSIONNo well-defined general guidelines are available for the treatment of symptomatic patients with severe congenital protein C deficiency. Current treatment for this condition focuses on to Protein C replacement with Fresh Frozen Plasma or an infusion of a human plasma-derived, viral inactivated protein C concentrate - such as ceprotin.It has been shown that patients with severe congenital Protein C deficiency were more effectively treated with Protein C concentrates than those treated with FFP or conventional anticoagulants. Nevertheless, Protein C concentrates requires supervision of an experienced physician and long-term treatments require the need of a central venous access. Side effects include higher risk of infections due to frequent transfusions, fluid overload, allergic reactions, high sodium intake, heparin induced thrombocytopenia and high cost. New anticoagulation medications open a window of possibilities for management of this medical condition.There is no literature on the use of rivaroxaban in children. Few studies have been done and most of them are case reports. In 2013, Martinelli et al published a case report of a 6 year old girl with severe protein S deficiency. Initially started on warfarin but had recurrent episodes of warfarin-induced skin necrosis. Her hypercoagulable state was due to warfarin-induced reduction of protein C so the switch of anticoagulant therapy to rivaroxaban resulted in the disappearance of skin necrosis at 1 year of follow-up.Our case demonstrates an autosomal recessive Protein C deficiency successfully managed with the use of direct Xa inhibitor- rivaroxaban- given orally on a daily basis. This treatment approach appears to be safe and effective and could be studied in prospective large cohorts of patients with Protein C deficiency. DisclosuresNo relevant conflicts of interest to declare.

Clinical Application and Pharmacodynamic Monitoring of Apixaban in a Patient with End-Stage Renal Disease Requiring Chronic Hemodialysis

Despite prescribing guidance, limited data exist to describe the use of apixaban in patients with end-stage renal disease (ESRD) requiring hemodialysis (HD). Current apixaban dosing recommendations for this patient population are based largely on a single-dose pharmacokinetic study of eight patients. We describe the clinical application and pharmacodynamic monitoring of apixaban in a 62-year-old 156-kg African-American woman with nonvalvular atrial fibrillation and ESRD requiring hemodialysis who developed calciphylaxis while receiving warfarin therapy. Based on a multidisciplinary clinical judgment decision due to concern for drug accumulation after multiple doses in patients with ESRD receiving HD, she was anticoagulated with apixaban 2.5 mg twice/day, as opposed to 5 mg twice/day as recommended by the package insert. Antifactor Xa monitoring was used, and resultant peak and trough apixaban concentrations were above the upper limit of detection for our clinical laboratory (more than 2.00 IU/ml). On day 7 of her hospitalization, the patient developed gastrointestinal bleeding, and apixaban was discontinued; no further clinical signs of bleeding occurred during her subsequent hospitalization course. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 6) between apixaban exposure and the manifestation of gastrointestinal bleeding. The patient ultimately died 44 days after the acute bleeding event; however, coagulation concerns were not implicated in the patient's death. To our knowledge, this is the first case report that describes apixaban use and associated antifactor Xa monitoring in a patient with ESRD receiving HD, and it provides concern for current apixaban dosing recommendations in this patient population. Further pharmacokinetic and clinical data are likely necessary to better characterize apixaban use in these patients to optimize safety and efficacy.

A multi-center clinical observation on safety and efficacy of a plasma derived coagulator factor Ⅷ for treatment of patients with hemophilia A

To evaluate the efficacy and safety of homemade plasma derived coagulation factor Ⅷ in patients with hemophilia A. Patients with congenital hemophilia A who met the inclusive and exclusive criteria were enrolled in the study after informed consent. The doses of factor Ⅷ were calculated according to the weight, disease severity etc. FⅧ activity and infusion efficacy value at 10 min and 60 min after infusion were recorded, as well as adverse events and validity rating according to the improvement of clinical syndromes. Viral infections including HBV, HCV, HIV and FⅧ inhibitor were determined after 3 and 6 months. A total of 65 patients were enrolled in this study, all of whom were evaluable for drug safety. Treatment efficacy was evaluated in 60 patients and 57 cases completed the trial finally. In this 57 cases, most (52/57) subjects were of middle and severe hemophilia A mainly characterized by joint bleeding. Overall response rate of acute bleeding events was classified as "excellent" (70.00%) or "better" (30.00%). The non-responder was 0. FⅧ activity and infusion efficiency value of first administration after 10 min and 60 min improved significantly [10 min: (123.66±47.54)%; 60 min: (108.05±43.24)%]. The incidence of adverse events was 1.54%. Neither allergic reaction nor reactivation of HBV, HCV, HIV was detected after treatment of 3 and 6 months. No FⅧ inhibitor negative patients converted to positive during follow-up. This homemade plasma derived coagulation factor Ⅷ is safe and effective for the treatment of acute bleeding in patients with hemophilia A.

Volunteer Case Series of a New Telemetric Sensor for Blood Detection in the Upper Gastrointestinal Tract: The HemoPill.

An acute upper gastrointestinal bleeding event is an emergency situation which requires immediate endoscopic assessment and treatment. A new telemetric real-time intracorporeal bleeding sensor can help in the timely diagnosis of an acute upper gastrointestinal bleeding event: The sensor capsule, HemoPill, is swallowed by the patient if gastrointestinal bleeding is suspected. Information about the bleeding status is displayed by telemetric communication of the capsule with an extracorporeal receiver. This is the first evaluation of the HemoPill to detect blood in the upper human gastrointestinal tract. A voluntary test person ate a defined meal with or without the adjunct of his own blood for a total of eight times and afterward swallowed the sensor capsule. The collected spectrometric receiver data were analyzed to assess whether the sensor system was capable of detecting blood and to evaluate the effect of stomach content as an artifact. With its optical sensor, the HemoPill was able to reliably indicate the ingested blood in the stomach. The data transmission from the swallowed sensor capsule to the extracorporeal receiver was achieved consistently. The evaluation of diverse concentrations of ingested blood and the respective sensor signals led to an exponential relationship of these variables. This relationship allows to define thresholds for categories indicating the likelihood of blood presence in the gastrointestinal tract. The HemoPill is a valuable tool to detect an acute upper gastrointestinal bleeding event without the need of endoscopy.

Clinical Perspectives and Pearls from the 2015 ESC NSTE-ACS Guidelines.

Four years after the latest edition, the 2015 non-ST-segment elevation acute coronary syndromes guidelines of the European Society of Cardiology have been published. Novel aspects include a new diagnostic algorithm for non-ST-segment elevation myocardial infarction using high-sensitivity cardiac troponins as well as guidance on cardiac rhythm monitoring duration. A large section is dedicated to antiplatelet therapy including initiation and duration of dual-antiplatelet therapy as well as the management of patients requiring, at the same time, long-term oral anticoagulation. New sections include the management of antiplatelet agent in patients requiring coronary artery bypass surgery and of acute bleeding events related to antiplatelet agents, vitamin K antagonist (VKA), and non-VKA oral anticoagulant drugs. Current evidence supports the radial access over the femoral one for coronary angiography and percutaneous revascularization.

Platelet Function Tests in Bleeding Disorders.

Functional disorders of platelets can involve any aspect of platelet physiology, with many different effects or outcomes. These include platelet numbers (thrombocytosis or thrombocytopenia); changes in platelet production or destruction, or capture to the liver (Ashwell receptor); altered adhesion to vascular injury sites and/or influence on hemostasis and wound healing; and altered activation or receptor functions, shape change, spreading and release reactions, procoagulant and antifibrinolytic activity. Procoagulant membrane alterations, and generation of thrombin and fibrin, also affect platelet aggregation. The above parameters can all be studied, but standardization and quality control of assay methods have been limited despite several efforts. Only after a comprehensive clinical bleeding assessment, including family history, information on drug use affecting platelets, and exclusion of coagulation factor, and tissue deficits, should platelet function testing be undertaken to confirm an abnormality. Current diagnostic tools include blood cell counts, platelet characteristics according to the cell counter parameters, peripheral blood smear, exclusion of pseudothrombocytopenia, whole blood aggregometry (WBA) or light transmission aggregometry (LTA) in platelet-rich plasma, luminescence, platelet function analysis (PFA-100) for platelet adhesion and deposition to collagen cartridges under blood flow, and finally transmission electron microscopy to exclude rare structural defects leading to functional deficits. The most validated test panels are included in WBA, LTA, and PFA. Because platelets are isolated from their natural environment, many simplifications occur, as circulating blood and interaction with vascular wall are omitted in these assays. The target to reach a highly specific platelet disorder diagnosis in routine clinical management can be exhaustive, unless needed for genetic counseling. The elective overall assessment of platelet function disorder primarily aims at better management of hemostasis in case of emergency surgery or other interventions and acute bleeding events.

Angiopoietin-2 in acute myocardial infarction complicated by cardiogenic shock--a biomarker substudy of the IABP-SHOCK II-Trial.

Angiopoietin-2 (Ang-2) is a mediator of capillary leakage, and increased Ang-2 levels were associated with poor in-hospital outcome in a pilot study in cardiogenic shock (CS). In this larger study, we followed this hypothesis and aimed at assessing the predictive role of Ang-2 on short- and long-term mortality, investigating the effect of intra-aortic balloon pump (IABP) treatment on Ang-2 levels, and identifying clinical and procedural predictors of increased Ang-2. In the IABP-SHOCK II-trial, 600 patients with CS complicating acute myocardial infarction were assigned to therapy with or without IABP. This substudy included 189 randomized patients with serial blood sampling performed at days 1, 2, and 3. No significant differences in Ang-2 levels were found between patients with or without IABP. The Ang-2 levels above the median at day 1 were associated with 30-day [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.26-3.10, P = 0.002) and 1-year mortality (HR 2.21, 95% CI 1.49-3.27, P < 0.001). Stratification of patients according to Ang-2 levels at day 3 increased these associations (30 days HR 5.15, 95% CI 2.80-9.45, P < 0.001; 1 year HR 5.24, 95% CI 3.19-8.58, P < 0.001). The Ang-2 concentrations were independent predictors for mortality in multivariate analysis (30 days HR 4.82, 95% CI 1.52-15.23, P = 0.007; 1 year HR 2.01, 95%CI 1.24-3.24, P = 0.005). Predictors of increased Ang-2 levels at day 3 were baseline Ang-2, development of acute kidney injury, bleeding events or transfusion, and impaired reperfusion. In CS, high levels of Ang-2 are independently associated with poor short- and long-term outcome and associated with the reperfusion success as well as complications. URL: www.clinicaltrials.gov; unique identifier: NCT00491036.

PCV66 - Economic Evaluation Of Dabigatran Etexilate Versus Warfarin, Rivaroxaban And Apixaban In Stroke Prevention In Atrial Fibrilation

To determine the economic value of dabigatran for stroke prevention in atrial fibrillation (SPAF) compared to other reimbursed oral anticoagulants warfarin, rivaroxaban and apixaban from a perspective of Mexican public institutions. A Markov disease model with three month cycles length was developed. A number of clinically relevant events, including acute thromboembolic and bleeding events, as well as long-term consequences such as stroke, intracranial hemorrhage and acute myocardial infarction, were followed in the model within the lifetime horizon (mean 10 years from diagnosis for Mexican patients). Identical hypothetical cohorts of patients entered the model, following a disease background of atrial fibrillation (2500 simulations per treatment arm). Published results of head to head clinical trials or relative efficacy derived in network meta-analysis and indirect comparisons were used to populate the model. Public institutional direct medical costs (2014 purchases and price tabulators) where retrieved to adopt the national health system perspective. Model outputs included total costs, event rates and life-years gained. Mean life-years saved for dabigatran, apixaban, rivaroxaban and warfarin were 69.435, 69.219, 68.737 and 68.373 respectively. Estimated cost of treatment for dabigatran, warfarin, rivaroxaban and apixaban were 110,942 USD, 108,757 USD, 124,718 USD and 112,373 USD, respectively. ICER showed that dabigatran is a cost-saving alternative versus rivaroxaban and apixaban, and a cost-effective one versus warfarin (defined by a one GDP per capita threshold in the country). These results where robust to changes in discount rates. From a perspective of Mexican public institutions, the treatment with dabigatran was found to be cost-effective when compared with warfarin and economically dominant versus rivaroxaban and apixaban as it resulted in highest projected life years gained at lower costs.

Correlation of Coagulation Markers and 4F-PCC-Mediated Reversal of Rivaroxaban in a Rabbit Model of Acute Bleeding

IntroductionRivaroxaban is an oral, selective direct factor Xa inhibitor approved for several indications in patients at risk of thrombotic events. One limitation of its clinical use is the lack of data pertaining to its reversal in situations where urgent response is critical (e.g. acute bleeding events or emergency surgery). Materials and methodsThis study assessed the effectiveness of a four-factor prothrombin complex concentrate (4F-PCC; Beriplex®/Kcentra®) for the reversal of rivaroxaban-associated bleeding in an in vivo rabbit model, and evaluated the correlations between in vitro coagulation parameters and haemostasis in vivo. ResultsAdministration of single intravenous doses of rivaroxaban (150–450μg/kg) resulted in increased and prolonged bleeding following standardised kidney incision. Pre-incision treatment with 4F-PCC (25–100IU/kg) resulted in a dose-dependent reversal of rivaroxaban (150 and 300μg/kg)-associated increases in time to haemostasis and blood loss; no reversal was seen at the highest rivaroxaban dose (450μg/kg). Of the in vitro biomarkers tested, thrombin generation and whole-blood clotting time correlated well with in vivo measures of 4F-PCC-mediated effects. Thrombin generation was highly reagent-dependent, with the assay initiated using the phospholipid-only reagent being the most predictive of effective haemostasis in vivo. ConclusionsIn summary, in a rabbit model of acute bleeding, treatment with 4F-PCC reduced bleeding to control levels following rivaroxaban 150μg/kg and 300μg/kg administration.

Prevalence of superficial siderosis following singular, acute aneurysmal subarachnoid hemorrhage.

Superficial siderosis is presumably a consequence of recurrent bleeding into the subarachnoid space. The objective of this study was to assess the prevalence of superficial siderosis after singular, aneurysmal subarachnoid hemorrhage (SAH) in the long term. We retrospectively identified all patients who presented with a singular, acute, aneurysmal SAH at our institution between 2010 and 2013 and in whom a magnetic resonance imaging (MRI) including T2*-weighted imaging was available at least 4 months after the acute bleeding event. MRI scans were judged concerning the presence and distribution of superficial siderosis. Influence of clinical data, Fisher grade, localization, and cause of SAH as well as the impact of neurosurgical interventions on the occurrence of superficial siderosis was tested. Seventy-two patients with a total of 117 MRIs were included. Mean delay between SAH and the last available MRI was 47.4 months (range 4-129). SAH was Fisher grade 1 in 2 cases, 2 in 4 cases, 3 in 10 cases, and 4 in 56 cases. Superficial siderosis was detected in 39 patients (54.2%). In all patients with more than one MRI scan, localization and distribution of superficial siderosis did not change over time. Older age (p = 0.02) and higher degree of SAH (p = 0.03) were significantly associated with the development of superficial siderosis. Superficial siderosis develops in approximately half of patients after singular, aneurysmal SAH and might be more common in patients with an older age and a greater amount of blood. However, additional factors must play a role in whether a patient is prone to develop superficial siderosis or not.

Four-Factor Prothrombin Complex Concentrate (4F-PCC) Effectively Reverses Rivaroxaban Induced Bleeding in a Rabbit Model of Acute Bleeding

Rivaroxaban is an oral, selective direct factor Xa inhibitor approved for several indications in patients at risk of thrombotic events. One limitation of this agent is the lack of data pertaining to its reversal in situations where urgent response is critical (e.g. acute bleeding events or emergency surgery).This study therefore evaluated the effectiveness of a four-factor prothrombin complex concentrate (4F-PCC; Beriplex® P/N, Kcentra®, CSL Behring), for the reversal of rivaroxaban-associated bleeding in an in vivo rabbit model of acute bleeding. In addition, the study evaluated the correlation between in vitro coagulation parameters and haemostasis in vivo in order to gain more information on the predictivity of in vitro markers for effective bleeding reversal.Administration of single intravenous doses of rivaroxaban (150–450 μg/kg) resulted in increased and prolonged bleeding following standardised kidney injury compared to a vehicle treated control group as determined by measurements of total blood loss and time required to achieve full hemostasis. Subsequent treatment with 4F-PCC (25−100 IU/kg) resulted in a dose-dependent reversal of rivaroxaban-associated bleeding signals. Of the in vitro coagulation markers tested, thrombin generation (TGA) and whole blood clotting time (WBCT) correlated well with in vivo measures of PCC-mediated effects. Thrombin generation was highly reagent-dependent, with the assay initiated using tissue factor reagent being most sensitive to the anticoagulant effects induced by Rivaroxaban, while the phospholipid-only reagent being the most predictive of 4F-PCC mediated effective haemostasis in vivo.In summary, in a rabbit model of acute bleeding, 4F-PCC was able to effectively reduce bleeding to control levels following rivaroxaban 150 μg/kg and 300 μg/kg administrations. The 4F-PCC mediated bleeding reversal correlated best with the in vitro endpoints thrombin generation and whole blood clotting time. DisclosuresHerzog:CSL Behring GmbH: Employment. Off Label Use: The use of Beriplex P/N for reversal of Rivaroxaban anticoagulation represents off-label use. Mueller-Cohrs:CSL Behring GmbH: Employment. Kaspereit:CSL Behring GmbH: Employment. Krege:CSL Behring GmbH: Employment. Niebl:CSL Behring GmbH: Employment. Doerr:CSL Behring GmbH: Employment. Schulte:CSL Behring GmbH: Employment. Dickneite:CSL Behring GmbH: Employment.

Comparison of the Cost-effectiveness of New Oral Anticoagulants for the Prevention of Stroke and Systemic Embolism in Atrial Fibrillation in a UK Setting

PurposeThree new oral anticoagulants (NOACs) have recently become available in the United Kingdom as an alternative to warfarin in the prevention of stroke and systemic embolism in atrial fibrillation. This study examines the relative cost-effectiveness of dabigatran (BID dosing of 150 mg or 110 mg based on patient age), rivaroxaban, and apixaban from a UK payer perspective. MethodsA previously published model that follows up patients through treatment of atrial fibrillation during a lifetime was adapted to allow comparison of the 3 NOACs and warfarin. Acute thromboembolic and bleeding events, as well as long-term consequences of stroke, intracranial hemorrhage, and acute myocardial infarction, were tracked. Relative efficacy was calculated from a formal indirect treatment comparison using data from the 3 key trials (Randomized Evaluation of Long-Term Anticoagulation Therapy, Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation, and Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) of the NOACs. Data from the rivaroxaban trial were adjusted for the difference in international normalized ratio control among warfarin patients versus the other 2 trials. Model outputs included total costs, event rates, and quality-adjusted life-years. FindingsAmong the patients taking NOACs, those taking dabigatran had the highest total QALYs (7.68 QALYs), followed by apixaban (7.63 QALYs) and rivaroxaban (7.47 QALYs). Patients taking dabigatran had the lowest total lifetime costs (£23,342), followed by apixaban (£24,014) and rivaroxaban (£25,220). The differences between dabigatran and apixaban were modest but consistent in sensitivity analyses, with the directionality only changing at the limits of the CIs for the relative risks of ischemic stroke or intracranial hemorrhage or when assuming that both treatment discontinuation and post-event disability rates differ by drug. ImplicationsDabigatran was found to be economically dominant over rivaroxaban and apixaban in the UK setting. These economic findings are based on relative clinical efficacy from an indirect treatment comparison and would benefit from any data of direct comparisons of the NOACs in the future.

Illustrating the impact of mild/moderate and severe haemophilia on health-related quality of life: hypothesised conceptual models.

Haemophilia and its treatment have a significant impact on patients' lives. The study objectives were to understand the impacts of haemophilia and its treatment from the patient perspective and to inform the development of comprehensive health-related quality-of-life (HRQL) conceptual models to illustrate these impacts. The study included two phases. Phase I involved a review of literature published from 1995 to 2010, qualitative analysis of six patient (N = 31) and three healthcare provider (N = 15) focus group transcripts, and interviews with two experts to inform draft conceptual models of mild/moderate and severe haemophilia. Phase II involved interviews with 20 haemophilia patients and qualitative analysis of transcripts to confirm the concepts and structure of the conceptual models. The literature search resulted in 66 publications assessing HRQL, four of which were qualitative studies on the impact of haemophilia from the patient perspective. Results from Phase I indicated that acute bleeding events result in pain, swelling, bruising and restricted joint movement; repeated joint bleeds result in chronic symptoms, such as pain and arthropathy. Acute bleeds cause interruptions in daily activities and interfere with work/school. Patients have fears about having bleeds, which can affect their participation in activities, such as sports or crowded events. Patients also expressed feelings of depression, frustration, isolation and embarrassment. Results of Phase II corroborated findings from Phase I. The conceptual models illustrate the substantial impact of haemophilia and its treatments on patients' lives and can help inform clinical study design and the selection of endpoints to assess treatment benefit.