Baseline Bleeding Research Articles

Safety and Efficacy of Selective, Clopidogrel-Based Strategies in Patients With Acute Coronary Syndrome: A Systematic Review and Meta-Analysis

Background: Selective, clopidogrel-based therapies after percutaneous coronary intervention (PCI) have been investigated to reduce the bleeding risk while maintaining an adequate anti-ischemic protection. However, single studies may be underpowered for events at low incidence, mainly major bleeding or ischemic complications. Methods: We performed an updated meta-analysis and meta-regression of randomized trials comparing outcome with unguided de-escalation to clopidogrel or guided clopidogrel therapy vs conventional treatment with potent oral P2Y12 inhibitors in patients undergoing PCI, especially for acute coronary syndrome (ACS). The primary safety endpoint was major bleeding. The primary efficacy endpoint was the incidence of major adverse cardiovascular events (MACE, cardiovascular death, myocardial infarction, stroke). Stent thrombosis was also an outcome measure. Findings: We considered six randomized trials, three on unguided de-escalation (N=3473) and three on guided clopidogrel therapy (N=7533). Control groups received conventional treatment with ticagrelor/prasugrel in all studies. The incidence of major bleeding was significantly lower with unguided de-escalation (1·0% vs 2·0% with conventional treatment; OR 0·53, 95% CI 0·30-0·95, p=0·03) and non-significantly reduced with guided de-scalation clopidogrel therapy (2·2% vs 3·6%; OR 0·79, 95% CI 0·49-1·27, p=0·33). Both unguided (3·3% vs 4·4%; OR 0·74, 95% CI 0·52-1·05, p=0·09) and guided clopidogrel therapy (2·8% vs 2·7%; OR 1·09, 95% CI 0·79-1·51, p=0·61) were associated with similar incidence of MACE vs conventional treatment. A trend towards an increased risk of stent thrombosis was observed in studies on guided clopidogrel therapy (OR 2·27, 95% CI 0·72-7·16, p=0·16). Meta-regression indicated greater safety and similar ischemic protection of the two alternatives clopidogrel-based therapies, regardless of baseline bleeding and ischemic risk. Interpretation: As compared with prasugrel/ticagrelor treatment, unguided de-escalation to clopidogrel, but no a guided clopidogrel therapy, decreases bleeding complications among patients with ACS undergoing PCI. Both unguided de-escalation and guided clopidogrel therapy appear as effective as in preventing MACE. Funding Information: None. Declaration of Interests: G.P.: speaker/consultant fee from Abbott, Astra Zeneca, Sanofi, Amgen, Menarini, Bayer, Pfizer, BMS, Daiichi Sankyo, PIAM, Malesci, Sigma Tau, Chiesi, Medtronic, MSD, Boehringer Ingelheim, Servier. L.G., E.G.S., A.R., M.M.: none.

Antithrombotic therapy according to baseline bleeding risk in patients with atrial fibrillation undergoing percutaneous coronary intervention: applying the PRECISE-DAPT score in RE-DUAL PCI.

Patients with atrial fibrillation undergoing coronary intervention are at higher bleeding risk due to the concomitant need for oral anticoagulation and antiplatelet therapy. The RE-DUAL PCI trial demonstrated better safety with dual antithrombotic therapy (DAT: dabigatran 110 or 150 mg b.i.d., clopidogrel or ticagrelor) compared to triple antithrombotic therapy (TAT: warfarin, clopidogrel or ticagrelor, and aspirin). We explored the impact of baseline bleeding risk based on the PRECISE-DAPT score for decision-making regarding DAT vs. TAT. A score ≥25 points qualified high bleeding risk (HBR). Comparisons were made for the primary safety endpoint International Society of Thrombosis and Haemostasis major or clinically relevant non-major bleeding, and the composite efficacy endpoint of death, thrombo-embolic events, or unplanned revascularization, analysed by time-to-event analysis. PRECISE-DAPT was available in 2336/2725 patients, and 37.9% were HBR. Compared to TAT, DAT with dabigatran 110 mg reduced bleeding risk both in non-HBR [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.31-0.57] and HBR (HR 0.70, 95% CI 0.52-0.94), with a greater magnitude of benefit among non-HBR (Pint = 0.02). Dual antithrombotic therapy with dabigatran 150 mg vs. TAT reduced bleeding in non-HBR (HR 0.60, 95% CI 0.45-0.80), with a trend toward less benefit in HBR patients (HR 0.92, 95% CI 0.63-1.34; Pint = 0.08). The risk of ischaemic events was similar on DAT with dabigatran (both 110 and 150 mg) vs. TAT in non-HBR and HBR patients (Pint = 0.45 and Pint = 0.56, respectively). PRECISE-DAPT score appeared useful to identify AF patients undergoing PCI at further increased risk of bleeding complications and may help clinicians identifying the antithrombotic regimen intensity with the best benefit-risk ratio in an individual patient.

Baseline hemoglobin and bleeding risk in patients with myocardial infarction treated with PCI

Abstract Background Bleeding is one of the major complications of the modern treatment of myocardial infarction (MI). The data on admission hemoglobin (aHb) and bleeding in patients with MI who underwent percutaneous intervention (PCI) are scarce. Purpose We aimed to investigate the association between the graded aHb level and hospital bleeding in patients with MI who underwent PCI. Methods A single-center retrospective study was performed at our university, a tertiary referral hospital with a 24/7 PCI service. We analyzed 7315 MI patients. The patients were treated according to the published guidelines for the management of MI. The PCI strategy and concomitant medication were left to the discretion of the operator and the attending physician. The groups, stratified at 10g/L intervals according to the Hb level on admission, were compared. The criteria of the Bleeding Academic Research Consortium (BARC) 3a bleeding (an aHb drop of 30–50 g/L or any transfusion) were used. Data were analyzed using descriptive statistics. The interval with the most patients (130–139 g/L) was used as the reference group. The aHb value was used not only as a categorical variable but also as a continuous variable. Results The rates of bleeding were significantly higher in the groups with lower baseline aHb compared to the groups with higher aHb levels (p<0.0001). A nonlinear inverse relationship was observed between the aHb and bleeding (Figure 1). Higher values of aHb were associated with a lower risk of bleeding (adjusted OR 0.76; 95% CI 0.72 to 0.81; p<0.0001). We observed that there was an ∼7.5-fold and an ∼2-fold lower odds of bleeding in the lowest aHb level groups (<100g/L and 100–109 g/L) compared to the reference group, respectively (adjusted OR 7.54; 95% CI 5.38 to 10.56; p<0.0001 and 2.01; 95% CI 1.38 to 2.92) after adjustment for potential confounders. Patients with aHb levels equal to or greater than 110 g/L had a similar bleeding risk to the reference group. Conclusion We found that a graded decrease in the aHb level is associated with a progressively increased risk of hospital bleeding. Patients with aHbs lower than 110 g/L are particularly prone to bleed. Up to now, no consensus has been reached as to whether interventions aimed at correcting anemia could improve the outcome in these patients. Therefore, preventive measures to minimize additional bleeding (radial access, thinner sheaths, the use of selective GPIIb/IIIa receptor antagonists, proton-pump inhibitors) should be used. Even bare-metal stents may be selected, based on the evaluation of the bleeding/thrombosis risk for each patient. In general, the lower the aHb, the greater the bleeding risk. Admission Hb and bleeding Funding Acknowledgement Type of funding source: None

Acute kidney injury after transcatheter aortic valve replacement: predictors and prognostic impact from a single, high-volume centre

Abstract Background Acute kidney injury (AKI) represents a common complication of transcatheter aortic valve replacement (TAVR), occurring in a variable proportion (from 10% to 30%) and being associated with an increased length of hospital stay and a 2- to 6-fold higher risk of mortality. Purpose We sought to identify pre-procedural and procedural variables independently associated with AKI and to analyze AKI impact on 1-month and 1-year all-cause mortality. Methods We prospectively collected consecutive patients undergoing TAVR at our centre. AKI was defined according to the Valve Academic Research Consortium (VARC)-2 criteria, as an increase of at least 0.3 mg/dL in serum creatinine or a urine output worsening (<0.5 mL/kg for <12 hours) occurring within 7 days after the procedure. Results From 664 consecutive TAVR conducted between January 2010 and December 2018 we excluded 19 (2.9%) patients for unsuccessful procedure according to VARC-2 criteria leading to a population of 645 patients. The mean follow-up was 9.6±4.3 months, age was 83.2±5.3, 270 (41.9%) were men. AKI complicated TAVR procedure in 141 (21.9%) patients. All-cause mortality occurred in 14 (2.2%) at 1-month and 51 (7.9%) patients at 1-year. AKI was more likely to complicate TAVR in patients who died within 1-month (4.7% vs. 0.8%, p=0.003) and 1-year (14.1% vs. 5.3%, p<0.001) follow-up period. Multivariable regression analysis showed that baseline creatinine (OR: 1.46, 95% CI: 1.20–1.78, p<0.001) and VARC-2 bleeding complications (OR: 1.49, 95% CI: 1.04–2.12, p=0.029) were independently associated with AKI incidence, while non-significant covariates were: age, gender, contrast volume, use of self-expandable valve and peri-procedural rapid pacing. Multivariable analysis adjusted for age and sex showed that AKI (HR: 3.02, 95% CI: 1.03–8.90, p=0.045) and chronic obstructive pulmonary disease (COPD) (HR: 4.12, 95% CI: 1.37–12.40, p=0.012) were independently associated with 1-month all-cause mortality. After 1 month, landmark analysis adjusted for age and sex showed that AKI (HR: 2.41, 95% CI: 1.17–4.96, p=0.017) and peri-procedural myocardial injury (HR: 2.36, 95% CI: 1.05–5.31, p=0.037) were independent predictors of 1-year all-cause mortality, while COPD, non-transfemoral route, and bleeding complications were not independently associated. Conclusions In a contemporary cohort of consecutive patients undergoing TAVR, AKI complicated ∼1 out of 5 procedures and is linked with about 4-fold adjusted risk of short-term death at 1-month and about 2-fold adjusted risk of subsequent death events up to 1-year follow-up. Baseline creatinine and bleeding complications, but not contrast volume were independently associated with AKI incidence. Landmark analysis for 1-year mortality Funding Acknowledgement Type of funding source: None

The predictor role of worsening renal function in patients with new onset atrial fibrillation on direct oral anticoagulant

Abstract Background Chronic kidney disease (CKD) is an important outcome predictor in patients with atrial fibrillation (AF). Moreover, renal function at baseline is used to guide oral anticoagulant (OA) selection and dosing at initial treatment. The prognostic role of worsening renal function (WRF) during treatment with direct oral anticoagulants (DOACS) has been poorly explored. Purpose To estimate the prognostic role of WRF in terms of major adverse cardiovascular events (MACEs) in a series of patients with newly diagnosed non-valvular AF (NVAF) treated with DOACs. Methods Among all patients with newly diagnosed NVAF and indication for OA between January 2017 and December 2018, we enrolled those treated with DOACs. Renal function at baseline and during follow-up was assessed with estimated glomerular filtration rates (eGFR). eGFR was calculated as a mean value of Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. The hemorrhagic risk at baseline was estimated with the main available scores (HAS-BLED, ATRIA and ORBIT). WRF was defined as a decrease in eGFR of at least 20%. MACEs were evaluated according to the type of DOAC and the WRF. Major bleedings (MB) were defined according to the ISTH definition. Results The study population was constituted by 249 patients with newly diagnosed NVAF started on DOAC and followed for a median time of 14.1±8.6 months. Overall, WRF was observed in 58 cases (23.3%). Patients with WRF had significative higher rates of death (10.3% versus 3.1%, p=0.025) and MB (13.8% versus 4.7%, p=0.016). The incidence of bleeding events, acute coronary syndromes and stroke was not affected by WRF. Interestingly, CG formula better predicted the incidence of MB as compared to the other formulas (p=0.006). The type of DOAC did not significantly impact the observed renal impairment and had no effect on the occurrence of MACEs in patients showing WRF. The predictors of WRF were found to be age, female sex, low hemoglobin level and left ventricle end telediastolic volume. At multivariate analysis, WRF was identified as an independent predictor of MB (OR 3.1, 95% C.I, 1.12–8.58), regardless of the baseline bleeding risk. Conclusion This is the first prospective study to evaluate the impact of worsening renal function on cardiovascular events in patients with atrial fibrillation treated with DOACs. A significant WRF emerged as an independent predictor of death and MB. The specific DOAC did not affect either the entity of worsening renal function or the incidence of cardiovascular events. Funding Acknowledgement Type of funding source: None

Safety and efficacy of antithrombotic therapy according to stroke and bleeding risk in patients with atrial fibrillation and acute coronary syndrome or PCI: insights from AUGUSTUS

Abstract Background The AUGUSTUS trial showed that patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) and/or PCI treated with a P2Y12 inhibitor and apixaban resulted in less bleeding and comparable ischemic events compared with regimens that included a vitamin K antagonist (VKA), aspirin, or both. We assessed the effect of apixaban versus VKA and aspirin versus placebo according to patients' baseline risk of stroke and bleeding. Methods AUGUSTUS randomized 4614 patients in a two-by-two factorial design to open label apixaban or VKA and blinded aspirin or placebo. The primary endpoint was major or clinically relevant nonmajor (CRNM) bleeding over 6 months of follow-up. The effects were assessed stratified by baseline CHA2DS2-VASc and HAS-BLED score using Cox proportional hazards models. Results 4386 patients were included for this analysis. The median age was 71 (64–77) years, 29.4% were female, 81.7% had a CHA2DS2-VASc score≥3, and 66.8% a HAS-BLED score≥3. As shown in the table, rates of bleeding were lower with apixaban (vs VKA) irrespective of baseline bleeding risk (p-value interaction: 0.23). Aspirin (vs placebo) was associated with increased bleeding irrespective of baseline risk (p-value interaction: 0.88). Apixaban use was associated with a lower risk of death or hospitalization without a significant interaction with stroke risk (p-value of interaction=0.53). No differences were found for ischemic outcomes. Conclusion An antithrombotic regimen including a P2Y12 inhibitor and apixaban is associated with less bleeding and hospitalization compared to a regimen with VKA, aspirin, or both with results consistent across CHA2DS2-VASc, and HAS-BLED scores. Our findings support the use of apixaban and a P2Y12 inhibitor without aspirin during the first 6 months for most patients with AF and ACS and/or PCI, regardless of stroke and bleeding risk. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): The Augustus trial was sponsored by Bristol-Myers Squibb and Pfizer, Inc

Utilization of anticoagulants and predictors of treatment among hospitalized patients with atrial fibrillation in the USA

Objective To evaluate utilization of anticoagulants (ACs) and the predictors of treatment of patients with a diagnosis of atrial fibrillation (AF) during a hospital stay in the USA. Methods Patients (≥18 years of age) who had a primary or secondary discharge diagnosis code of AF during a hospitalization (without a diagnosis of venous thromboembolism) were identified from the Premier Hospital database (1 January 2016–30 September 2017). AC treatments were examined during hospitalizations to assign AF patients into 3 study cohorts: those who received an oral AC (OAC), those who received parenteral AC only, and those who did not receive AC therapy. Multivariable logistic regression analyses were carried out to evaluate potential predictors of receiving parenteral AC only vs. OAC therapy, no AC therapy vs. OAC therapy, as well as the specific OAC drug choices. Results Of the patients hospitalized with an AF diagnosis (n = 482,729; mean age: 74.7 years; 46.8% female; 82.9% White; 79.4% with Medicare), 42.6% received OAC therapy (most commonly, warfarin or apixaban), 35.3% parenteral AC only, and 22.2% no AC therapy. A key predictor of not receiving OAC therapy was having an AF diagnosis in the second position (applicable to 87.4% of study population). Greater comorbidity level and prior baseline bleeding were strong predictors of receiving parenteral AC only or not receiving any AC therapy vs. receiving OAC therapy. Predictors of receiving warfarin vs. apixaban included higher stroke risk and prior baseline bleeding. Limitations OAC utilization may have been underestimated since outpatient OAC utilization was not included in the analysis. Conclusions A substantial portion of hospitalized AF patients did not receive any AC therapy, particularly those patients with an AF diagnosis in the second position on hospital records. The predictors of inpatient AC treatment that were identified may be helpful in the clinical decision-making process for patients who are hospitalized with AF.

Outpatient management of deep vein thrombosis using direct oral anticoagulants is safe and efficient

AbstractDirect oral anticoagulants (DOACs) are increasingly becoming the treatment of choice for venous thromboembolism (VTE). To ensure safe prescription and prevent delay of supply for dischargeable patients with deep venous thrombosis (DVT) presenting to the Emergency Department (ED) outside pharmacy hours, we implemented a “Rivaroxaban after‐hours pack” system, that requires prescribers to assess suitability via criteria detailed in a decision support system GuidanceMS, prior to pack provision. Pharmacist and clinic follow up is also provided. To assess the safety and effectiveness of the program, a retrospective case series review was undertaken of DVT patients discharged from the ED with an after‐hours pack from April 2015 to December 2017. Patients were assessed for compliance with recommendations for treatment from their baseline demographics, biochemistry, medication history, bleeding and thrombotic risk. Any bleeding episodes or clot extension were recorded. The number of admissions for hospital DVT treatment for the study period was compared to the preceding 30 months. Of the 120 patients reviewed, all patients had adequate renal function, 96.3% had liver function tests <3× the upper limit normal. Three patients (2.5%) had active malignancy and no patients had a mechanical valve or antiphospholipid syndrome. All patients received a pharmacist telephone follow‐up education conversation and referral to Thrombosis Outpatients. Twelve patients reported clinically relevant non‐major bleeding, while two patients had clot extension despite compliance. There was marked reduction in hospital and/or hospital‐in‐the‐home admissions compared to the previous 30 months (P < 0.001). In conclusion, all DVT patients were safely prescribed Rivaroxaban using this system, with a reduction in hospital and/or hospital‐in‐the‐home admissions. This system is efficient in ensuring safe provision of Rivaroxaban outside of pharmacy hours, with potential for extension to the primary care setting.

Association of Blood Type With Postsurgical Mucosal Bleeding in Pediatric Patients Undergoing Tonsillectomy With or Without Adenoidectomy

Blood type (BT) O has been identified as a risk factor for bleeding complications, while non-O BTs may increase risk for thromboembolic events. Limited data are available in children undergoing tonsillectomy with or without adenoidectomy. To determine whether BT O is associated with hemorrhage after tonsillectomy with or without adenoidectomy. Retrospective cohort study of patients younger than 22 years who underwent tonsillectomy with or without adenoidectomy at a single institution between January 1, 2008, and August 7, 2017. Statistical analysis was performed from November 2017 to January 2019. Prevalence of hemorrhage following surgery was defined as any bleeding requiring cauterization up to 1 month after the procedure. Data on sex, age, von Willebrand disease (VWD) status, BT, white blood cell counts, and platelet counts closest to date of surgery were collected from an electronic medical record system, and the association of these factors with hemorrhage following surgery was investigated. A total of 14 951 pediatric patients (median [range] age, 5.6 [0.8-21.9] years; 6956 [46.5%] female) underwent tonsillectomy with or without adenoidectomy. Prevalence of hemorrhage following the procedure was 3.9% (578 patients) for the full cohort and 2.8% (362 of 13 065) for patients with no BT identified or preprocedure VWD panel results at baseline. Children who had a BT identified and/or a VWD panel before surgery had higher bleeding rates (BT only, 14.9% [172 of 1156]; preprocedure VWD panel only, 4.6% [28 of 607]; and BT and preprocedure VWD panel, 13.0% [16 of 123]), all of which were significantly different from the baseline bleeding rate (P < .001). While the bleeding rates in children with BT O were not statistically different from those with non-O BT (14.8% and 14.6%, respectively; P > .99), mean von Willebrand factor values were statistically different (mean [SD] von Willebrand factor antigen level in O group, 86.9 [42.4] IU/dL in the O group vs 118.0 [53.8] IU/dL in the non-O group; P = .002; and mean [SD] von Willebrand factor ristocetin-cofactor in the O group, 72.2 [44.3] IU/dL vs 112.6 [68.0] IU/dL in the non-O group; P = .001). In addition, children older than 12 years had increased bleeding rates in the full cohort (8.3% vs 3.2%), in the testing-naive cohort (6.5% vs 2.3%), and in those with a preprocedure VWD panel only (13.5% vs 3.1%) compared with children aged 12 years or younger. Type O blood was not a risk factor associated with hemorrhage after tonsillectomy with or without adenoidectomy despite lower baseline von Willebrand factor antigen and von Willebrand factor ristocetin-cofactor values in children with BT O vs those with non-O BT in our study cohort. No association was found between VWD status and bleeding, and there was no difference in VWD panel values in those who experienced hemorrhage vs those who did not within BT groups. Further studies elucidating the utility of von Willebrand factor values for children undergoing tonsillectomy with or without adenoidectomy are needed.

Glycemic status and risks of thromboembolism and major bleeding in patients with atrial fibrillation

BackgroundStudies specifically examining the association between glycated hemoglobin A1c (HbA1c) levels and ischemic stroke/systemic thromboembolism (IS/SE) risk in atrial fibrillation (AF) patients are limited. Here, we investigated the association between HbA1c levels and the risk of IS/SE, as well as major bleeding, among AF patients with or without oral anticoagulants (OACs). We also compared the effectiveness and safety of warfarin and direct oral anticoagulants (DOACs) in different HbA1c categories.MethodsWe utilized medical data from a multi-center healthcare provider in Taiwan, which included 34,036 AF patients with serum HbA1c data available within 3 months after AF being diagnosed. Patients were divided into seven study groups according to their HbA1c levels: < 5.4%, 5.4%–5.6%, 5.7%–5.9%, 6.0%–6.4%, 6.5%–6.9%, 7.0%–7.9%, and ≥ 8.0%. The risks of IS/SE and major bleeding were compared among the groups after adjusting for baseline stroke and bleeding risk factors.ResultsCompared with the patients with HbA1c level < 5.4%, IS/SE risk significantly increased at HbA1c levels higher than 6.5% [adjusted hazard ratio (HR): 1.20, 95% confidence interval (CI): 1.00–1.43 for HbA1c level 6.5%–6.9%; 1.32, (95% CI 1.11–1.57) for HbA1c level 7.0%–7.9%; and 1.48 (95% CI 1.25–1.76) for HbA1c level ≥ 8.0%]. These results were generally consistent in AF patients without OACs (n = 24,931). However, among 9105 patients receiving OACs, IS/SE risk was not higher for patients having higher HbA1c levels. The risk of major bleeding was comparable across all HbA1c categories. Compared with warfarin, DOACs were associated with lower risks of IS/SE (adjusted HR: 0.61, 95% CI 0.49–0.75) and major bleeding (adjusted HR: 0.30, 95% CI 0.21–0.42) without interactions across different HbA1c categories (all P interactions > 0.05).ConclusionFor AF patients, IS/SE risk significantly increased once HbA1c levels exceeded 6.5%, and OACs may attenuate these associations. Compared with warfarin, DOACs were more effective and safer across broad HbA1c categories. Therefore, in addition to prescribing DOACs when indicated, more aggressive glycemic control to achieve an HbA1c level < 6.5% may be considered for eligible AF patients and should be tested in further prospective studies.

Double or triple antithrombotic therapy after coronary stenting and atrial fibrillation: A systematic review and meta-analysis of randomized clinical trials

AimsDouble or triple antithrombotic therapy (DAT/TAT) including or excluding aspirin in association with oral anticoagulant and P2Y12 inhibitor are currently two available options in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). We evaluated efficacy and safety outcomes for DAT vs. TAT. Methods and resultsFour non-vitamin K oral anticoagulants (NOAC)-based randomized controlled trials comparing DAT vs. TAT with a total of 10,938 patients were pooled. Bleeding events occurred more frequently than ischemic events. DAT as compared to TAT was associated to an increased risk of stent thrombosis (RR 1.54, 95% CI 1.10–2.14; p = 0.03), myocardial infarction (RR 1.23, 95% CI 1.04–1.46; p = 0.03) and cardiovascular mortality (RR 1.09, 95% CI 1.01–1.19; p = 0.04) and to a reduced risk of ISTH major or clinically relevant non-major bleeding (RR 0.59, 95% CI 0.62–0.93; p = 0.03). A consistent effect was observed in all safety endpoints. Intracranial haemorrhage was numerically reduced by DAT. No difference for all-cause death was observed. ConclusionAntithrombotic treatment in patients with AF undergoing PCI represents a trade-off between ischemia and bleeding. A careful patient selection based on baseline ischemic and bleeding risk may optimize the net clinical balance in this population.

Beliefs, Opinions, and Impact of Emicizumab on Hemophilia Patients: A National U.S. Survey

Introduction : As the first in a new class of substitutive, non-factor hemophilia A therapy, acceptance of emicizumab by patients with hemophilia is unclear. Impact of emicizumab on treatment adherence, pursuit of athletic activity, psychosocial connection to the hemophilia patient community, and patient satisfaction have not been assessed. Additionally, reasons for choosing to initiate or not initiate emicizumab in patients who have been offered it have not been evaluated. This patient survey study addresses these questions. Methods : A voluntary, anonymous 22-item survey was electronically distributed to hemophilia patients throughout the United States through hemophilia treatment centers and the National Hemophilia Foundation. Recipients were instructed to take the survey only if they were a patient with hemophilia A who has been offered bleeding prophylaxis (or the parent of such a patient under age 18). Skip logic was employed such that individual respondents answered 15 or fewer items based on their familiarity with and use of emicizumab. Results to items utilizing a 5-point Likert scale were converted to weighted average scores (ranging from 1, lowest to 5, highest) for comparison between groups of respondents. Results : 126 respondents (67 adults and 59 parents of children age &lt;18) answered the survey, 82% without an inhibitor and 18% who currently have an inhibitor (Table 1). 89% of respondents were familiar with emicizumab, of whom 43% were using and 57% had never used emicizumab. Table 1 describes respondent demographics and baseline bleeding and prophylaxis characteristics by emicizumab use and inhibitor status. Patients using emicizumab had higher reported median annualized bleeding rates (ABR) prior to emicizumab than those not using emicizumab regardless of inhibitor status (5 bleeds/year vs. 2 bleeds/year) and patients using emicizumab reported lower adherence with prior factor prophylaxis than current emicizumab prophylaxis (76.7% vs. 96.8 described adherence as good or excellent). Non-inhibitor patients emphasized subcutaneous administration [score 4.33, 21% cited as most important reason (MIR) for initiating emicizumab] and ability to dose ≤1 time per week (4.24, 6%) as equally or more important than safety (4.27, 15%) and effectiveness in bleed prevention (4.15, 24%), Table 2. By contrast, the top concern of inhibitor patients was effectiveness in bleed prevention (4.27, 46%) and safety (4.18, 9%), with lifestyle concerns such as subcutaneous administration (3.82, 0%) less important. In consideration of the impact of emicizumab on wellbeing, most patients were highly satisfied with their decision to start emicizumab (Table 3). Emicizumab use did not result in perceived distancing from the hemophilia patient community. Non-inhibitor patients deciding not to initiate emicizumab (Table 4) cited safety concerns (score 4.38, MIR 45%), unknowns of a new treatment (4.22, 33%), and lack of lab monitoring of emicizumab effect (4.10, 15%) as the primary reasons to forego emicizumab; effectiveness (3.35, 0%) was not a major concern. Of the 64 respondents not using emicizumab, 60% had discussed it with their hemophilia doctor; of these patients, 90% chose to wait for more experience with its use and 10% would have started it but could not due to insurance denial. Of the 40% who had not discussed emicizumab with their hemophilia doctor, 67% felt they learned enough about emicizumab from patient groups or marketing and had decided not to begin the agent; 33% felt they did not have enough information to make a decision about using it. Conclusions : Most U.S. hemophilia A patients requiring prophylaxis are familiar with emicizumab. Regardless of inhibitor status, patients with higher ABR and worse compliance with infusion-based prophylaxis are more likely to use emicizumab. From the non-inhibitor patient perspective, ease of administration with subcutaneous dosing ≤1 time per week was at least as important as effectiveness and safety of the drug in their decision to switch to emicizumab, whereas this was much less important to inhibitor patients. Patients using emicizumab were highly satisfied with their decision to switch to this agent. Patients choosing not to switch to emicizumab are concerned about safety, unknowns with a new treatment, and lack of lab monitoring, although one-third of patients felt they lacked the information to decide whether to use it. Disclosures Al-Samkari: Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. Croteau:Octapharma: Honoraria; Bayer: Consultancy, Honoraria; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; Spark Therapeutics: Research Funding; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Research Funding.

Correlations between von Willebrand Factor Antigen Levels and Factor VIII Pharmacokinetics Are Similar across Different FVIII Products in Patients with Severe Hemophilia A

Background: Prophylactic treatment with replacement factor VIII (FVIII) is the standard of care for patients with severe hemophilia A to prevent bleeding and subsequent joint damage and chronic arthropathy. Because of variability in patient characteristics and clinical needs, it is recommended that prophylaxis is tailored to individual patient needs based on their baseline characteristics, bleeding history, and FVIII pharmacokinetic (PK) parameters. Endogenous levels of von Willebrand factor antigen (VWF:Ag) are known to influence the PK of FVIII. This analysis investigates the relationship between FVIII PK parameters and VWF:Ag levels, as well as between VWF:Ag levels and age, in patients with severe hemophilia A treated with various recombinant FVIII products using data obtained from multiple clinical trials. Patients/Methods: This integrated regression analysis is based on data with five FVIII products from six clinical trials. The products were: PEGylated recombinant FVIII BAY 94-9027 (damoctocog alfa pegol, Jivi®); sucrose-formulated recombinant FVIII (rFVIII-FS; Kogenate®-FS); BAY 79-4980 (liposomal version of Kogenate®-FS); unmodified full-length recombinant FVIII BAY 81-8973 (Kovaltry); and recombinant antihemophilic factor plasma/albumin-free method rAHF-PFM (octocog alfa, Advate®). The trials were: NCT01184820, NCT01029340, NCT00623727, NCT01233258, NCT02483208, and NCT01580293. PK parameters were estimated by means of a non-compartmental analysis based on densely sampled single-dose profiles measured by one-stage and chromogenic assays, and following a dose of 25-60 IU/kg. The primary regression analysis was performed using the log-transformed PK parameters (half-life [t1/2], clearance [CL], and dose-normalized area under the curve [AUCnorm]) as dependent variables and the VWF:Ag levels as the independent variable in a mixed model including fixed treatment effects and random patient effects. In addition, the impact of age on VWF:Ag levels was investigated. One-stage assay results are reported. Results based on the chromogenic assay were in line with those reported for the one-stage assay. Results: Data from 104 patients from six studies were used to investigate the relationship of the dose-independent PK-parameter, t1/2 vs VWF:Ag levels, and of VWF:Ag levels vs age. Median age was 31 years (range 12-64 years). For the analyses of the PK parameters AUCnorm and CL, data from 77 patients from five studies were analyzed. Median age was 32 years (range 12-64 years). Some patients participated in multiple studies. The primary regression analyses across all products and studies on the log-transformed PK parameters showed significant associations between PK parameters and VWF:Ag levels. Significant positive correlations vs VWF:Ag levels were observed for t1/2 (n = 155 observations in 104 patients, P &amp;lt; 0.001) and AUCnorm (n = 117 observations in 77 patients, P &amp;lt; 0.001), resulting in a negative correlation with CL (Figure 1). Other factors, such as age and the interaction of treatment with the VWF:Ag-PK effect, were found to be redundant and were not included in the final model. Analysis of VWF:Ag levels vs age using a simple linear regression that did not incorporate the dependencies of multiple observations in patients, revealed a positive correlation between age and VWF:Ag levels (Spearman coefficient , r = 0.290 [P = 0.0029]; Pearson coefficient, r = 0.334 [P = 0.0005]). Comparable results were observed in a mixed model with random patient effects. Conclusions: In this combined analysis across five FVIII products, FVIII PK parameters (t1/2, AUCnorm, and CL) were significantly correlated with endogenous VWF:Ag levels which were also correlated with age. Moreover, while there were differences in the average PK parameters between products (represented by the intercept for treatment), all five FVIII products demonstrated similar VWF-PK relationships. It is well known that a patient's VWF:Ag level influences the PK of rFVIII, but this analysis suggests that the quantitative relationship between FVIII PK and VWF:Ag is similar for modified and unmodified FVIII products. This finding can be used, for example, to support selection of adequate treatment regimens when a patient is switching rFVIII product. Disclosures Maas Enriquez: Bayer: Employment. Delesen:Bayer: Employment. Solms:Bayer: Employment, Equity Ownership. Croteau:Novo Nordisk: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; Octapharma: Honoraria; CSL Behring: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Berntorp:Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Research Funding; Shire: Consultancy, Honoraria, Research Funding; Sobi/Bioverativ: Research Funding; Octapharma: Consultancy, Honoraria.

Medical Management of Retained Inferior Vena Cava Filters

Background Venous thromboembolism (VTE) is a common and often fatal medical event. VTE management often includes inferior vena cava filter (IVCF) placement when anticoagulation fails or is contraindicated. Controversial indications for IVCF placement include adjunctive treatment for deep vein thrombosis (DVT) without pulmonary embolism (PE) and VTE prophylaxis for high-risk patients (Deyoung and Minocha, 2016; Ho et al., 2019). Numerous device-associated mechanical and medical complications have been described (Ayad et al., 2019) and guidelines recommend early retrieval (Morales et al., 2013). There is limited evidence, however, to guide anticoagulation practices while IVCFs are retained. We aimed to characterize IVCF placement, retrieval, and interim medical management at our institution. Methods Retrospective chart review was performed for all patients who underwent IVCF placement at the University of Virginia Medical Center from January to December 2016. Data were collected from time of IVCF placement until either IVCF removal or 18 months post-placement, whichever occurred first. Indication for IVCF placement, baseline patient characteristics, IVCF complications, anticoagulation regimens, and bleeding and clotting events were identified. Baseline characteristics were recorded for all patients. Patients who did not survive the admission during which the IVCF was placed, underwent IVCF removal prior to discharge, or lacked adequate outpatient records during the period of IVCF retention were excluded from the event analysis cohort. Results IVCFs were placed in 140 patients during the study period (Table 1). A majority of patients were admitted to a surgical service, frequently following trauma (49 patients, 35%). IVCFs were placed for several indications, most commonly diagnosed VTE with a contraindication to anticoagulation (70 patients, 50%) and prophylaxis for high risk of VTE (44 patients, 31%). By the end of the study period, 88 patients (63%) had confirmed IVCF removal while 35 patients (25%) retained the IVCF for a clinical consideration. 33 patients (24%) lacking an adequately documented period of outpatient IVCF retention were excluded from the event analysis. Of the 107 patients included in the event analysis cohort, 76 patients (71%) underwent IVCF removal. Removal occurred &gt;60 days after placement in 82% of these cases and median time to removal was 95 days (Table 2). Outpatient follow up and anticoagulation management varied widely, though 75 patients (70%) received a therapeutic dose anticoagulant during the period of IVCF retention and only 15 patients (14%) were not exposed to either a prophylactic or therapeutic dose anticoagulant. 50 patients (47%) had at least one regimen change. Bleeding and/or clotting events occurred for 15 patients (14%, Table 3). All 8 bleeding events occurred during anticoagulant exposure. Patients were exposed to a therapeutic dose anticoagulant during 4 of the 6 observed major or clinically relevant non-major bleeding events. Of the 12 observed clotting events, 8 occurred in the absence of anticoagulation. Isolated DVT was the most common clotting event (8 events in 7 patients, 7%) and IVCF thrombus was observed in 2 patients (2%). Bleeding and clotting events were observed in patients with a wide range of indications for IVCF placement, including patients whose IVCFs were placed prophylactically. Conclusions The optimal medical management of retained IVCFs is uncertain. This retrospective study characterizes IVCF placement, removal, and interim medical management for a diverse patient population at a single institution. Outpatient follow up varied widely and anticoagulant exposure during IVCF retention was inconsistent. Despite considerable anticoagulant exposure across the cohort, major bleeding events were infrequent. Thrombotic events, often in the absence of anticoagulation and potentially preventable, were more common. Standardization of medical management during IVCF retention would likely benefit this heterogeneous patient population at high risk of both bleeding and thrombotic complications. Ongoing statistical modeling for the study cohort will seek to inform anticoagulant decision making by assessing for associations between anticoagulant exposure and these clinical events. Disclosures No relevant conflicts of interest to declare.

A Clinical Prediction Score for Course of Disease in Newly Diagnosed Childhood Immune Thrombocytopenia

Background Newly diagnosed childhood immune thrombocytopenia (ITP), an acquired autoimmune bleeding disease, has a good prognosis: 60-70% of patients recover spontaneously 3 months after diagnosis (transient ITP), whereas 10-20% remain thrombocytopenic beyond 12 months (chronic ITP). A key clinical challenge is the early identification of a patient's disease course to counsel families, inform treatment decisions, and guide additional diagnostics, e.g. screening for systemic autoimmune diseases, immunodeficiencies or genetic thrombocytopenia. Several clinical predictors have been proposed (Heitink-Pollé et al. Blood 2014;142(22)), but it is unclear how they can be integrated to predict disease outcomes. Objective To develop and validate a clinical prediction model for transient vs. prolonged disease courses in children with newly diagnosed ITP, using clinical characteristics at diagnosis. Study design Model development and validation in a multinational prospective observational cohort; external validation in a multicenter randomized controlled trial. Methods Using modern statistical methods, we extended a score by Edslev et al. (BJH 2007; 138) into an updated, multivariate prediction score, using individual patient data from newly diagnosed childhood ITP patients included in the observational, prospective Nordic Pediatric Hematology-Oncology ITP study (NOPHO; N=377; data shared by original investigators). Transient ITP was defined as complete recovery by platelet count 3 months after diagnosis (NOPHO, ≥150x109/L; TIKI, ≥100x109/L). The model was developed by penalized regression (Ridge) with ten-fold cross-validation in patients included during the first half of the NOPHO study period (derivation cohort, N=233) and subsequently validated in the second half (validation cohort, N=144). External validation was performed on children with newly diagnosed ITP included in the Dutch randomized controlled trial Treatment With or Without IVIg for Kids With ITP (TIKI; N=200; N=100 randomized to IVIg and N=100 carefully observed; Heitink-Pollé et al.Blood 2018; 132(9)). Inclusion criteria of both studies included a diagnosis platelet count ≤20x109/L and age below 16 years. Results Case-mix analyses showed that TIKI and NOPHO cohorts had comparable baseline characteristics, considering age, gender, preceding infections and bleeding. The rate of transient ITP was 67% (NOPHO) and 73% (TIKI). Seven predictors were included in the model: age (years; penalized odds ratio [OR] for transient ITP, 0.97), male gender (OR, 1.07), presence of mucosal bleeding (OR, 1.27), preceding infection (OR, 1.27) or vaccination (OR, 0.99), insidious disease onset (&gt; 14 days; OR, 0.41) and diagnosis platelet count (x109/L; OR, 0.99). We evaluated the clinical prediction model in two independent groups: patients with transient ITP were discriminated with a receiver-operating characteristic AUC of 0.72 (95% CI, 0.61 - 0.84) for the NOPHO validation cohort and 0.71 (95% CI, 0.62 - 0.80) for the TIKI cohort. Additional analyses in the TIKI cohort revealed a similar classification accuracy for patients randomized to IVIg and observation only. At a posterior probability ≥65%, the positive predictive value for transient ITP was 0.85 and negative predictive value was 0.41. For long-term follow-up, when patients were grouped in low, intermediate and high score terciles (obtained in the NOPHO derivation cohort), the rate of persistent ITP after six months was 60/36/14 % (low/medium/high scores; NOPHO) and 50/27/10 % (TIKI). Furthermore, the rate of chronic ITP at twelve months follow-up was 27/16/6 % for the same score terciles (TIKI). Finally, the model score correlated with cessation of mucosal bleeding as well as any bleeding during five clinical follow-up visits during twelve months after diagnosis. Conclusion The updated clinical prediction model for transient ITP, i.e. recovery from ITP three months after diagnosis, showed adequate performance in two independent validation cohorts. Next to short-term recovery, long-term recovery six and twelve months after diagnosis and bleeding symptoms were predicted. This prediction model may allow the targeting of intensive monitoring or additional diagnostic efforts to children with low scores. On the other hand, in children with high scores, the rate for persistent and chronic ITP is low and they could be monitored `hands-off`, if this is intended. Disclosures No relevant conflicts of interest to declare.

An International Multicenter Study of Intravenous Bevacizumab for the Treatment of Chronic Bleeding and Anemia in Hereditary Hemorrhagic Telangiectasia: The Inhibit-Bleed Study

An International Multicenter Study of Intravenous Bevacizumab for the Treatment of Chronic Bleeding and Anemia in Hereditary Hemorrhagic Telangiectasia: The Inhibit-Bleed Study

Abstract # 3238 Gustatory-immune integration in the insular cortex

Pregnancy may be complicated by the presence of congenital or acquired bleeding disorders that increase the risk of postpartum hemorrhage. Because factor VIII (FVIII) and von Willebrand factor (VWF) increase during pregnancy, von Willebrand disease and FVIII deficiency should be managed using desmopressin (DDAVP) or VWF concentrates according to the VWF and FVIII levels at term and the women's response to desmopressin. Factors IX (FIX) and XI (FXI) do not increase with pregnancy; therefore, treatment of women with FIX or FXI deficiency is based on baseline factor levels and bleeding history. Factor VII (FVII) also increases during normal pregnancy and only women with severely reduced FVII levels at term will require treatment. Of the acquired bleeding disorders, thrombocytopenia is the most common, although etiologies are diverse and consequences range from benign to life-threatening. Treatment depends on the underlying cause—options include observation, corticosteroids or immunoglobulin, plasma exchange, and delivery of the fetus.

Effectiveness of Palliative Hemostatic Radiotherapy for Hemoptysis; A Prospective Single Arm Observational Study

Palliative external beam radiotherapy is commonly used for malignancy associated hemoptysis. Few studies have focused on the effectiveness of radiotherapy in a cohort of patients with uncontrolled bleeding. The purpose of this study is to determine radiotherapy control probability, durability and influencing factors. This is a single institution prospective observational study that included patients ≥18 years with any lung malignancy and active hemoptysis at time of presentation. Hemoptysis severity was captured and monitored via an in-house developed patient reported outcome tool. The tool captures bleeding description, amount and frequency within 1 week prior to presentation and assigns a cumulative score ranging from 0-12. Patients were interviewed at enrollment, 2 weeks, 3 months and 6 months post treatment. Definition of a complete response was a total score of 0, partial response was a decrease from baseline score but >0, and progression was an increase from baseline score. Descriptive statistics, Kaplan-Meier method, Wilcoxon signed-rank test and Cox regression models were used. From April 2016 to November 2018, 41 patients were enrolled. One patient withdrew consent and was excluded. Median age was 68 years. The majority of patients were male (67%) with stage 4 (87%), lung primary (85%) disease and ECOG performance status 2 (55%). Prior to enrollment, 15% of patients received a blood transfusion and 5% had a bleeding associated intervention. Median baseline bleeding score was 7 (IQR; 5-8). Most common fractionation scheme (72.5%) was 2000 cGy in 5 fractions. Median Planning Target Volume (PTV) was 364 cc. Median follow up was 6.1 months (range 0.9-6.2). Forty patients had scores available at baseline versus 32, 19 and 10 scores at 2 weeks, 3 and 6 months. Complete response was achieved in 17 (53%) of surviving patients at 2 weeks (z= -4.2, p<0.001), 15 (79%) at 3 months (z= -3.5, p<0.001) and 8 (80%) at 6 months (z= -2.6, p=0.004). Of the patients with complete hemoptysis response, 2 (20%) recurred at 3 months and 1 (16%) at 6 months. The 6-month OS was 26% (95% CI 0.13, 0.41). No patient received re-radiation for their hemoptysis. On univariate analysis, ECOG status (p=0.012) and prior radiation (p=0.006) were strongly associated with freedom from hemoptysis survival, while baseline hemoptysis score was borderline (p=0.072). Multivariate analysis was not performed due to small sample size. Hemostatic radiotherapy is an effective modality for controlling hemoptysis in a poor prognosis population with acceptable durability and no re-treatments required. However, a larger sample size is required to assess the impact of influencing factors.

The furcation tunnel preparation—A prospective 5‐year follow‐up study

The aim of this study was to prospectively follow furcation tunnelled molars over a 5-year period of supportive periodontal therapy (SPT) and to identify factors associated with tooth loss. A total of 32 patients with 42 furcation tunnelled molars (all class III prior tunnelling) were recruited upon commencing SPT following active periodontal therapy. Clinical registrations, bacterial samples and standardised radiographs were taken at baseline, year 1 (no radiographs), 2 and 5. Total viable counts, total streptococci, Streptococcus sanguinis and mutans streptococci (MS) were identified through culture, a panel of periodontal pathogens through the checkerboard technique. After 5years, 29 molars (69%) were still in function. Of the lost molars, eight were upper and five lower molars. Recurrent periodontal disease and caries were reasons for tooth loss. A multilevel regression analysis showed that a smoking habit, bleeding on probing and the presence of MS in furcations were associated with an increased risk of tooth loss. Furcation tunnelled molars can in most cases be kept over a period of 5years of SPT. A smoking habit, baseline bleeding scores and the presence of MS in the furcation were risk indicators for loss.

Serotonergic Antidepressants and Hospitalization for Bleeding in Patients with LVAD

Purpose Serotonergic antidepressants (SA) are commonly used for a variety of indications in patients supported with durable left ventricular assist devices (LVAD). Reduced serotonin reuptake with SAs leads to platelet dysfunction and is associated with an increased risk of bleeding across diverse populations. There is limited data on the bleeding risk with SAs in the LVAD population prone to hemorrhagic complications due to other mechanisms. Methods We performed a retrospective analysis of LVAD patients (pts) managed at our institution from January 2016 to August 2018. Pertinent demographics and clinical variables related to bleeding were collected at the time of discharge from LVAD implantation and on admission for a bleeding event. Pts were divided into those prescribed an SA at discharge from LVAD implantation or admitted for a bleeding event with documented SA use prior to admission (Group 1) and those without SA exposure after implant (Group 2). Primary and secondary endpoints included incidence of bleeding requiring hospitalization, time from implant to first hospitalization for a bleeding event, and incidence rate of hospitalizations for bleeding per patient years. Results A preliminary analysis of 20 randomly selected pts out of 95 total implants performed. Ten pts were prescribed an SA (Group 1) and 10 were not (Group 2). Baseline demographics and bleeding risk factors were similar between the (two) 2 groups. Trazodone and sertraline were the most commonly prescribed SAs (35% each) and multiple SA use was common (50%). Acid suppressive therapy was used in all pts at discharge. In Group 1, 50% of the pts were hospitalized for a bleeding event compared to 10% of pts in Group 2 (p=0.1). At 1 year, 60% of pts remained free from hospitalization for a bleeding event in Group 1 compared to 100% in Group 2 (p=0.16). The number of bleeds per patient-year in Group 1 vs. those in Group 2 was 0.79 vs 0.4, respectively (p=0.26). Gastrointestinal (6 vs. 3 events) and intracranial (2 vs. 0 events) bleeding was more common in Group 1. Conclusion A preliminary analysis of patients with an LVAD treated with SA therapy demonstrated a trend towards an increased rate of hospitalization due to bleeding and a shorter time to first hospitalization compared to those who were not treated with an SA. Our final analysis will expand to all 95 patients to determine the significance of these findings.