Heparin Requirements Research Articles

Individualized heparin monitoring and management reduces protamine requirements in cardiac surgery on minimal invasive extracorporeal circulation; A prospective randomized study.

Individualized heparin and protamine management is increasingly used as a strategy to reduce coagulation activation and bleeding complications. While it is associated with increased heparin requirements during Cardiopulmonary Bypass (CPB), the impact on protamine administration remains controversial. We aim to investigate the effect of heparin level-guided monitoring on protamine dosing during cardiac surgery where low-anticoagulation protocols are implemented. This is a prospective, randomized, controlled trial. A total of 132 patients undergoing elective full-spectrum cardiac surgery with Minimal Invasive Extracorporeal Circulation (MiECC) were recruited. All patients were managed by the same anaesthetic, surgical and perfusion team. Patients were randomly allocated in two groups; the individualized heparin-protamine titration (IHPT) group and the conventional heparinization and reversal group by using ACT (cACT) with a 0.75:1, protamine: heparin ratio. Titration was accomplished with the Hepcon HMS Plus (Medtronic, Minneapolis, MN) system. The primary outcome of the study was the total protamine dose used. Secondary outcomes comprised of the total heparin dose, the percentage of patients achieving target ACT, 24-h transfusion requirements, postoperative bleeding, duration of mechanical ventilation, major morbidity and length of hospital stay. Patients in each group were divided in two subgroups according to the target ACT; those operated for coronary artery bypass grafting (CABG) using a target ACT >300s and the rest (non-CABG) patients operated with a target ACT >400s, respectively. Protamine requirements were significantly reduced when IHPT was implemented; CABG (118 ± 24mg vs 163 ± 61 mg; p < 0.001) and non-CABG cases (151 ± 46mg vs 197 ± 45mg; p < 0.001). Moreover, heparin requirements were significantly higher in the non-CABG subgroup managed with IHPT (34,539 ± 7658 IU vs 29,893 ± 9037 IU; p = 0.02). In overall, no significant differences were detected with respect to postoperative bleeding, transfusion of RBC or other blood products. Individualized heparin monitoring and management reduces protamine requirements in cardiac surgery with MiECC implementing reduced anticoagulation strategy. clinicaltrials.gov; NCT04215588.

Impact of corticosteroids on the procoagulant profile of critically ill COVID-19 patients: a before-after study.

Several studies have reported an increased risk of thrombotic events in COVID-19 patients, but the pathophysiology of this procoagulant phenotype remains poorly understood. We hypothesized that corticosteroids may attenuate this procoagulant state through their anti-inflammatory effects. The aim of this study was to evaluate the impact of dexamethasone (DXM) on the coagulation profile of severely ill COVID-19 patients. We conducted a retrospective, observational before/after bi-centric cohort study among ICU patients hospitalized for severe COVID-19 and receiving therapeutic anticoagulation by unfractionated heparin (UFH). Before and after the standardized use of DXM, we compared inflammatory and coagulation profiles, as well as the kinetics of heparin requirement, adjusted for weight and anti-Xa activity. Eighty-six patients were included, 35 in the no-DXM group, and 51 in the DXM group. At admission, CRP and fibrinogen levels were not different between groups, neither were UFH infusion rates. At day 3 after ICU admission, CRP (178±94 mg/L vs. 99±68 mg/L, P<0.001) and fibrinogen (7.2±1.4 g/L vs. 6.1±1.4 g/L, P=0.001) significantly decreased in the DXM group, but not in the no-DXM group. Over time, UFH infusion rates were lower in the DXM group (P<0.001) without any significant difference in plasma anti-Xa activity. CRP variations correlated with heparin dose variations between Day 0 and Day 3 (r=0.39, P=0.009). Finally, the incidence of venous thromboembolic events during in-ICU stay was significantly reduced in the DXM group (4 vs. 43%, P<0.0001). In critically ill COVID-19 patients, dexamethasone use was associated with a decrease in both pro-inflammatory and procoagulant profile.

Low-Dose Heparin Protocol in Type A Aortic Dissection Surgeries.

We aim to compare the heparin dose regimen in terms of bleeding, reoperation rate due to severe bleeding, and the amount of transfusion of the blood products in patients who underwent surgery for type A aortic dissection (TAAD). Between January 2018 and August 2021, 90 adult patients who underwent for TAAD were included. Primary outcome measures were postoperative bleeding amount and blood product transfusion requirements. Two different protocols performed in TAAD surgery in our clinic. In this pre- and postimplementation study, before October 2019, the standard-dose heparin protocol (SH group) was used and after November 2019, the low-dose heparin protocol (LH group) was used and two groups were compared. Mechanical ventilation duration, length of intensive care unit and hospital stay, postoperative drainage volumes, blood product transfusions, reoperations due to bleeding, and in-hospital mortality rates were recorded. The dosages of heparin and activated clotting time values, as well as the additional heparin requirement, were significantly different between the two groups (p < 0.001). Standard-dose heparinization was needed only in 33.3% of patients in the LH group. In the SH group, postoperative total drainage and red blood cell (RBC) transfusion were significantly higher than the LH group (p = 0.036 and p = 0.046, respectively). We found that the low-dose heparin regimen resulted in significantly less postoperative total drainage and RBC transfusion requirement in patients who underwent for TAAD.

Uninterrupted DOACs Approach for Catheter Ablation of Atrial Fibrillation: Do DOACs Levels Matter?

Most patients present for catheter ablation of atrial fibrillation (CAAF) with residual or full effect of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). In daily practice, it has been observed that the activated clotting time (ACT) was actually poorly sensitive to the effect of DOACs and that patients on DOACs required more unfractionated heparin (UFH) to achieve the ACT target of 300 s during the procedure, leading some authors to worry about potential overdosing. Conversely, we hypothesize that these higher doses of UFH are necessary to achieve adequate hemostasis during CAAF regardless of the residual effect of DOACs. During CAAF, thrombosis is promoted mainly by the presence of thrombogenic sheaths and catheters in the bloodstream. Preclinical data suggest that only high doses of DOACs are able to mitigate catheter-induced thrombin generation, whereas low dose UFH already do so. In addition, the effect of UFH seems to be lower in patients on DOACs, compared to patients on VKAs, explaining part of the differences observed in heparin requirements. Clinical studies could not identify increased bleeding risk in patients on DOACs compared to those on VKAs despite similar efficacy during CAAF procedures. Moreover, targeting a lower ACT was associated with an increased periprocedural thrombotic risk for both DOAC and VKA patients. Therefore, the low sensitivity of the ACT to the residual effect of DOACs should not be a major concern in its use in the interventional cardiology laboratory.

Coronary angioplasty and COVID-19: are heparin requirements and thrombotic complications increasing?

Funding AcknowledgementsType of funding sources: None.BackgroundCovid-19 infection is associated with coagulopathy and possible heparin resistance, raising concerns that routine heparin during percutaneous coronary intervention (PCI) is failing to achieve adequate anticoagulation. We examined heparin requirements and efficacy in patients treated by PCI before and after the first reported UK case of Covid-19 (January 31st 2020).MethodsWe retrospectively compared heparin dose, Activated Clotting Time (ACT) and coronary flow (TIMI grade) for PCI procedures at a London cardiac centre in the 3 months before the UK pandemic and the three months afterwards. Testing for COVID was not routinely performed. Pre-specified analyses in patients with STEMI, NSTEMI and Stable angina were undertaken.ResultsOf 1227 PCI procedures performed over the period of observation, 690 were pre-pandemic and 537 were afterwards. Overall median heparin dose per case was 11000units versus 11500units (p = 0.137) and maximum ACTs were 291s versus 305s, respectively (p = 0.135). Pre-PCI TIMI 3 flow was lower during the pandemic than before (60% v 65%, p = 0.005) but Post-PCI flow was similar (96% versus 96%, p = 0.839). There were no statistically significant differences in heparin dose or achieved ACT among patients with STEMI, NSTEMI or Stable presentations.ConclusionIn spite of the increasing evidence that COVID-19 infection causes thrombosis, it appears that standard heparin management during PCI is sufficient to achieve effective anticoagulation and avoid peri-procedural thrombotic complications. Group 1 Pre PandemicGroup 2 PandemicP valueNumber of doses given3 (3 to 4)3 (3 to 4)0.952Total Heparin dose (units)11000 (8000 to 14000)11500 (9000 to 14000)0.137Number of ACTs measured2 (1 to 2)2 (1 to 2)0.194First ACT (seconds)240 (199 to 318)248 (206 to 326)0.256Maximum ACT (seconds)291 (230 to 368)305 (239 to 369)0.135Heparin dose and Activated Clotting Times (ACT) in patients undergoing PCI before Covid-19 pandemic (Group 1) and during pandemic (Group 2); median and interquartile ranges Figure. Clinical Presentation

Differences in activated coagulation times and heparin requirements during ablation procedures in patients with different oral anticoagulant drug regimens

Anticoagulation during percutaneous catheter ablation should be closely monitored with Activated Clotting Time (ACT). However, VKA or direct oral anticoagulant drugs (DOAC) may act differently on ACT and thus on heparin needs. The aim of this study was to compare ACT and heparin requirements during catheter ablation under various oral anticoagulant drug regimens and in controls. Sixty consecutive patients referred for ablation were retrospectively included: group 1 ( n = 15, VKA), group 2 ( n = 15, uninterrupted rivaroxaban), group 3 ( n = 15, uninterrupted apixaban) and group 4 ( n = 15, controls). Heparin requirements and ACT were compared throughout the procedure. Heparin requirements during the procedure were significantly lower in patients under VKA compared to DOAC and lower in DOAC patients compared to controls. First and averaged ACT values were significantly higher in patients under VKA compared to DOAC and similar in DOAC patients compared to controls. Furthermore, anticoagulation control as evaluated by the number/proportion of ACT > 300 as well as the time passed over 300 sec was significantly better in patients under VKA versus DOAC, but the differences were not significant between DOAC versus controls. Finally, the number of patients/ACT with excessive ACT values was significantly higher in VKA versus DOAC patients versus controls. There was no significant difference between DOAC drugs for ACT or heparin dosing throughout the procedure. VKA allowed less heparin requirement despite reaching higher ACT values and more efficient anticoagulation control (although with a higher risk for excessive values) compared to patients under long-term DOAC therapy and to controls.

Periprocedural anticoagulation in the uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation (ELIMINATE-AF) trial.

Aims This post hoc analysis of ELIMINATE-AF evaluated requirements of unfractionated heparin (UFH) and procedure-related bleeding in atrial fibrillation (AF) patients undergoing ablation with uninterrupted edoxaban or vitamin K antagonist (VKA) therapy.Methods and results Patients were randomized 2:1 to once-daily edoxaban 60 mg (or dose-reduced 30 mg) or dose-adjusted VKA (target international normalized ratio: 2.0–3.0). Uninterrupted anticoagulation was mandated for 21–28 days’ pre-ablation and 90 days’ post-ablation. During ablation, UFH administration targeted an activated clotting time (ACT) of 300–400 s. Periprocedural bleeding was differentiated between procedure-related (bleeding at puncture side, cardiac tamponade) and unrelated events. Of 614 randomized patients, 553 received study drug and underwent catheter ablation (edoxaban n = 375; VKA n = 178). The median (Q1–Q3) time from last dose to ablation procedure was 14.8 (13.3–16.5) vs. 16.5 (14.8–19.5) h (edoxaban vs. VKA group, respectively). Mean ACT (SD) ≥300 s was observed in 52% edoxaban- vs. 76% VKA-treated patients, despite a higher mean (SD) UFH dose in the edoxaban vs. VKA group [14 261 (6397) IU vs. 11 473 (4300) IU; exploratory P-value < 0.0001]. In the edoxaban group, 13 patients (3.5%) had procedure-related bleeds of whom 9 had received an UFH dose above the median (13 000 IU). In the VKA arm, 7 patients (3.9%) had procedure-related bleeds of whom 3 had received an UFH dose above the median (10 225 IU).Conclusion The rate of procedure-related major/clinically relevant non-major bleeding did not differ between the treatment arms despite higher doses of UFH used with edoxaban vs. VKA to achieve a target ACT during AF ablation.

A Randomized Controlled Trial of Antithrombin Supplementation During Extracorporeal Membrane Oxygenation.

Supplementation of antithrombin might decrease the amount of heparin needed to achieve a given anticoagulation target during extracorporeal membrane oxygenation. However, exogenous antithrombin itself may increase the risk of bleeding. We conceived a study to evaluate the effect of antithrombin supplementation in adult patients requiring venovenous extracorporeal membrane oxygenation for respiratory failure on heparin dose, adequacy of anticoagulation, and safety. Prospective randomized controlled trial. ICUs of two Italian referral extracorporeal membrane oxygenation centers. Adult patients requiring venovenous extracorporeal membrane oxygenation for severe respiratory failure and unfractionated heparin for systemic anticoagulation. Before extracorporeal membrane oxygenation start, patients were randomized to either receive antithrombin concentrate to maintain a plasmatic level 80-120% (treatment) or not (control) during the extracorporeal membrane oxygenation course. The primary outcome was the total amount of heparin required to maintain activated partial thromboplastin time ratio 1.5-2. Secondary outcomes were anti-factor Xa, the incidence of hemorrhagic and thrombotic events, and the amount of blood products transfused. Twenty-four patients in the treatment group and 24 in the control group were included in the intention-to-treat analysis. Antithrombin was 109.5% (93.0-123.0%) in the treatment group and 84.0% (68.5-98.0%) in the control group (p = 0.001). Supplementation of antithrombin did not decrease heparin dose (13.5 international units/kg/hr [9.6-17.9 international units/kg/hr] vs 15.1 international units/kg/hr [10.7-18.3 international units/kg/hr] in the treatment and control group, respectively; p = 0.33) and anti-Factor Xa levels (0.4 international units/mL [0.3-0.5 international units/mL] vs 0.3 international units/mL [0.2-0.5 international units/mL] in the treatment group and control group respectively; p = 0.65). Bleeding, blood product transfusions, and thrombosis were not different in the two groups. Antithrombin supplementation may not decrease heparin requirement nor diminish the incidence of bleeding and/or thrombosis in adult patients on venovenous extracorporeal membrane oxygenation.

Intra-procedural anticoagulation and post-procedural hemoglobin fall in atrial fibrillation ablation with minimally interrupted direct oral anticoagulants: comparisons across 4 drugs.

Thromboembolic or hemorrhagic complications related to atrial fibrillation (AF) ablation are rare, and thus, it is difficult to compare their frequency across different direct oral anticoagulants (DOACs). We aimed to compare the intra-ablation blood coagulability and post-procedural hemoglobin fall as alternatives to those complications across 4 DOACs. We enrolled AF patients younger than 65years old in 3 cardiovascular centers who skipped a single dose of apixaban, dabigatran, edoxaban, and rivaroxaban, prior to the ablation. Endpoints included the activated clotting time (ACT), heparin requirement during the ablation, and drop in the hemoglobin level 24h after the procedure. The time-course curves of the ACT differed significantly across the patients with apixaban (N = 113), dabigatran (N = 130), edoxaban (N = 144), and rivaroxaban (N = 81), with its highest level in the dabigatran group (P < 0.001). The average ACT was greater in the dabigatran group than in the other groups (312.3 ± 34, 334.4 ± 44, 308.1 ± 41, and 305.8 ± 34.7s; P < 0.001). A significant difference was noted in total heparin requirement across the patient groups (3990.2 ± 1167.9, 3890.4 ± 955.3, 4423.8 ± 1051.6, and 3972 ± 978.7U/m2/h; P < 0.001), with its greatest amount in the edoxaban group. The reduction in the hemoglobin level was similar (- 0.93 ± 0.92, - 0.88 ± 0.79, - 0.89 ± 0.97, - 0.95 ± 1.23g/dL; P = 0.94). No inter-group difference was noted in the rate of major or minor bleedings (0.9%, 2.3%, 1.4%, and 3.7%; P = 0.51), and no thromboembolic events were encountered. A difference in DOACs may have an impact on intra-ablation anticoagulation; however, it may not be on the procedural blood loss in the setting of a single skip.

Remaining activity of temporary interrupted direct oral anticoagulants and its impact on intra-ablation heparinization in patients with atrial fibrillation: Comparisons across four drugs and two dose regimens.

Atrial fibrillation (AF) ablation with minimally interrupted direct oral anticoagulants (DOACs) may raise a concern about their remaining activity. We tested the residual activity of four different DOACs and its impact on intraprocedural heparinization in patients undergoing AF ablation. We measured the anti-factor Χa activity for rivaroxaban, apixaban, and edoxaban, and serum DOAC concentration for rivaroxaban, apixaban, and dabigatran, 24 hours after the last intake in patients undergoing AF ablation treated with standard or reduced doses of DOACs. The heparin requirement during the procedure was also measured. We enrolled 34 patients with rivaroxaban, 35 with apixaban, 32 with edoxaban, and 31 with dabigatran, and among them, 30 were treated with reduced doses. The anti-factor Χa activity was the highest in the apixaban group among the patients with standard doses. The DOAC concentration was paradoxically lower in patients with standard doses than in those with reduced doses among the patients with rivaroxaban (34.3 ± 19.8 vs 56.6 ± 7.7 ng/mL; P = .01) and dabigatran (12.6 ± 10.6 vs 23.4 ± 14.7 ng/mL; P = .03). The total heparin requirement per body surface area had significant correlations with the anti-factor Χa activity (r = -.36) and DOAC concentration (r = -.32). Two different multiple linear regression models (adjusted R2 = 0.56 and 0.6, respectively) revealed that the anti-factor Χa activity (β = -.28; P = .002) and DOAC concentration (β = -.38; P < .001) were independent determinants of the total heparin requirement. Factors determining residual DOAC activity may include its type and dose regimen, and it may influence the heparin requirement during AF ablation.

Coagulation and heparin requirements during ablation in patients under oral anticoagulant drugs.

BackgroundAnticoagulation during catheter ablation should be closely monitored with activated clotting time (ACT). However vitamin K antagonists (VKA) or direct oral anticoagulant drugs (DOAC) may act differently on ACT and on heparin needs. The aim of this study was to compare ACT and heparin requirements during catheter ablation under various oral anticoagulant drugs and in controls.MethodsSixty consecutive patients referred for ablation were retrospectively included: group I (n = 15, VKA), group 2 (n = 15, uninterrupted rivaroxaban), group 3 (n = 15, uninterrupted apixaban), and group 4 (n = 15, controls). Heparin requirements and ACT were compared throughout the procedure.ResultsHeparin requirements during the procedure were significantly lower in patients under VKA compared to DOAC, but similar between DOAC patients and controls.Activated clotting time values were significantly higher in patients under VKA compared to DOAC and similar in DOAC patients versus controls. Furthermore, anticoagulation control as evaluated by the number/proportion of ACT> 300 as well as the time passed over 300 seconds was significantly better in patients under VKA versus DOAC, without significant differences between DOAC and controls. Finally, the number of patients/ACT with excessive ACT values was significantly higher in VKA versus DOAC patients versus controls.There was no significant difference between rivaroxaban and apixaban for ACT or heparin dosing throughout the procedure.ConclusionVitamin K antagonists allowed less heparin requirement despite reaching higher ACT values and more efficient anticoagulation control (with more excessive values) compared to patients under DOAC therapy and to controls. There was no difference in heparin requirements or ACT between DOAC patients and controls.

Extra-Corporeal Membrane Oxygenation for Neonatal Respiratory Support

To review our experience with Extra-Corporeal Membrane Oxygenation (ECMO) for respiratory support in neonates. From 1989 to 2018 2114 patients underwent respiratory ECMO support, with 764 (36%) neonates. Veno-Venous (V-V) cannulation was used in 428 (56%) neonates and Veno-Arterial (V-A) in 336 (44%). Historically V-V ECMO was our preferred modality, but due to lack of suitable cannula in the last 7 years V-A was used in 209/228 (92%) neonates. Mean and inter-quartile range of ECMO duration was 117 hours (inter-quartile range 90 to 164 hours). Overall 724 (95%) neonates survived to ECMO decannulation, with 640 (84%) hospital discharge. Survival varied with underlying diagnosis: meconium aspiration 98% (354/362), persistent pulmonary hypertension 80% (120/151), congenital diaphragmatic hernia 66% (82/124), sepsis 59% (35/59), pneumonia 86% (6/7), other 71% (43/61). Survival was 86% with V-V and 80% with V-A cannulation, better than ELSO Registry with 77% V-V and 63% V-A. Major complications: cerebral infarction/hemorrhage in 4.7% (31.1% survival to discharge), renal replacement therapy in 17.6% (58.1% survival to discharge), new infection in 2.9%, with negative impact on survival (30%). Following a circuit design modification and subsequent reduction in heparin requirement, intracerebral hemorrhage decreased to 9/299 (3.0%) radiologically proven cerebral infarction/hemorrhage. We concluded (1) outcomes from neonatal ECMO in our large case series were excellent, with better survival and lower complication rate than reported in ELSO registry. (2) These results highlight the benefits of ECMO service in high volume units. (3) The similar survival rate seen in neonates with V-A and V-V cannulation differs from the ELSO register; this may reflect the change in cannulation enforced by lack of suitable V-V cannula and all neonates undergoing V-A cannulation.

Effects of rivaroxaban on activated clotting time in catheter ablation for atrial fibrillation in Chinese patients.

It has been observed that patients on rivaroxaban require more heparin and frequent activated clotting time (ACT) monitoring throughout the catheter ablation of atrial fibrillation, but the strategy of heparin injection varies in different studies. We sought to examine the determinants of heparin dosage in Chinese patients on rivaroxaban. We reviewed consecutive patients who received rivaroxaban before atrial fibrillation ablation and compared them to patients on no anticoagulant. The dosage of heparin required to achieve ACT > 300 s was evaluated. We then tested determinants of heparin dosage prospectively. There were 124 patients on rivaroxaban (R group) and 42 on no anticoagulant (NA group) in retrospective study. Heparin dosage required to achieve target ACT was 0.89 ± 0.01 mg/kg in R group and 0.60 ± 0.01 mg/kg in NA group, P < 0.05. The bolus heparin dosage required was 0.77 ± 0.01 mg/kg (96.1 ± 1.1 U/kg) when baseline ACT > 200 s. In the prospective study, 80/90(88.9%) of patients in R group and 79/90(87.8%) in NA group achieved an ACT > 300 s after initial bolus injection of heparin. The ACT 60 min after target ACT (ACT60) in R group was higher than that in NA group (287.5 ± 28.3 VS 238.9 ± 29.5, P < 0.05). Rivaroxaban was the only independent predictor of ACT60. There was no significant difference in ACT or heparin dosage in patients with different duration on or withdrawal of rivaroxaban. In patients undergoing atrial fibrillation ablation on rivaroxaban, the effective duration of heparin is prolonged and the procedural heparin requirement is significantly greater. Heparin dosage can be predicted by baseline ACT, but not influenced by duration on or withdrawal of rivaroxaban.

Cirrhosis, Thrombosis, Finding FaXts about Doses: Dosing of Unfractionated Heparin for Venous Thromboembolism in Cirrhosis.

Background: Despite known disease-specific alterations to anti-factor Xa (AXA) levels, the physiological response of patients with cirrhosis to unfractionated heparin (UFH) infusions is not well established in clinical settings. Objective: The purpose of this study was to characterize the dosing and safety profile of UFH in patients with varying degrees of cirrhosis when treated for venous thromboembolism (VTE). Methods: This retrospective observational study was conducted at a single academic medical center in the United States. Patients with a diagnosis of cirrhosis who received UFH infusions for greater than 48 hours for treatment of VTE were included. Comparisons between heparin infusion rates, AXA levels, and safety outcomes based on severity of cirrhosis were made to define differences between those groups. Results: When compared by compensation status or by Child-Turcotte-Pugh (CTP) class, patients with more severe disease trended toward lower initial AXA levels on heparin initiation and higher heparin requirements to achieve therapeutic levels and were significantly less likely to achieve therapeutic levels than patients with less severe disease (P = 0.001 for compensation, P = 0.017 for CTP). Additionally, bleeding rates were higher in patients with more severe disease, without reaching statistical significance. Conclusion and Relevance: Patients with severe cirrhosis required higher doses of heparin to achieve the same therapeutic AXA levels, but also tended to have higher rates of bleeding compared with less severe cirrhosis. These results represent further evidence of changes in heparin response as cirrhosis severity increases and may suggest that current monitoring methods are suboptimal in this patient population.

P1860Unfractionated heparin dose and complication rate in catheter ablation of atrial fibrillation, a comparison between uninterrupted therapy with phenprocoumon and direct oral anticoagulants

Abstract Background Catheter ablation of atrial fibrillation is known for the combining risks of thromboembolism (TE) and major bleedings. This urges a better understanding and optimization of the intraprocedural anticoagulation management. Differences in unfractionated heparin (UFH) requirements and anticoagulation time (ACT) levels between patients on different uninterrupted oral anticoagulation (OAC) agents have been studied. However, the clinical relevance, in terms of periprocedural TE and bleeding events, of UFH administration according to ACT monitoring among patients on different OAC agents, needs to be addressed. Objective To evaluate how the ACT monitoring and differences in intraprocedural UFH requirements among different anticoagulant agents, may translate to clinical outcome, in terms of periprocedural incidence of thromboembolic and bleeding events. Methods We retrospectively studied 1571 cases who underwent catheter ablation for atrial fibrillation between January 2011 and May 2017. Cases were on an uninterrupted oral OAC therapy of Vitamin K Antagonists (VKA)(713), Rivaroxaban (RG)(385), Dabigatran (DG)(260), Apixaban (AG)(192) and Edoxaban (EG)(21). First ACT measurements after the initial bolus of UFH (1ehz748.0610U), mean ACT measurements, total UFH doses/kg (Body Weight)/min (duration of procedure) and incidence of major periprocedural events were compared among the above OAC groups. Results The mean ACT (sec) was significantly lower in the AG and greater in the VKA (313,7±47 vs 340,5±49, p&lt;0,001). Significantly lower UFH doses (U/kg/min) were required to reach the target ACT in VKA compared to RG, DG, AG and EG (0,69±0,4 vs 1,41±0,76; 1,42±0,7; 1,63±0,8; 1,37±0,4 respectively, p&lt;0,001) The proportion of patients who achieved a target ACT value within 30 minutes after the fixed first UFH Bolus of 10 000 U was significantly lower in DG and AG compared to VKA, EG and RG group (51,5% and 49% vs 53%, 71,4%, and 61,8% respectively p=0,005). The incidence of periprocedural TE events and bleedings showed no significant difference among OAC groups. However, the 22 patients with a periprocedural TE event had significantly lower UFH doses (U)/ Duration of catheter ablation (min) compared to the ones without periprocedural TE (62,71±44,5 vs 94,4±66,4, p=0,026), despite equivalent mean ACT values between these two groups. Patients with a periprocedural TE had also a significantly older Age (69,6±10 vs 64±10 p=0,01, higher CHADSVASC Score (3,64±1,76 vs 2,63±1,7 p=0,006), longer duration of procedure (188,9±79,1 vs 144,9±57 p=0,0001) and higher pre-Ablation INR values (2,2±0,6 vs 1,7±0,6 p=0,002). Conclusions The average UFH doses required to reach the target ACT were lower in VKA than in NOAC- groups. The incidence of periprocedural TE events and bleedings was equivalent among OAC groups. Patients with TE showed a lower UFH requirement compared to no-TE group, with both groups having mean ACT ≥300 sec.

Antithrombin supplementation during extracorporeal membrane oxygenation: study protocol for a pilot randomized clinical trial

BackgroundNormal levels of plasma antithrombin (AT) activity might decrease heparin requirements to achieve an adequate level of anticoagulation during treatment with extracorporeal membrane oxygenation (ECMO). Acquired AT deficiency during ECMO is common, but formal recommendations on target, timing, and rate of AT supplementation are lacking. Thus, we conceived a pilot trial to evaluate the feasibility and safety of prolonged AT supplementation in patients requiring veno-venous ECMO for respiratory failure.MethodsGrifols Antithrombin Research Awards (GATRA) is a prospective, randomized, single blinded, multicenter, controlled two-arm trial. Patients undergoing veno-venous ECMO will be randomized to either receive AT supplementation to maintain a functional AT level between 80 and 120% (AT supplementation group) or not (control group) for the entire ECMO course. In both study groups, anticoagulation will be provided with unfractionated heparin following a standardized protocol. The primary endpoint will be the dose of heparin required to maintain the ratio of activated partial thromboplastin time between 1.5 and 2. Secondary endpoints will be the adequacy of anticoagulation and the incidence of hemorrhagic and thrombotic complications.DiscussionGATRA is a pilot trial that will test the efficacy of a protocol of AT supplementation in decreasing the heparin dose and improving anticoagulation adequacy during ECMO. If positive, it might provide the basis for a future larger trial aimed at verifying the impact of AT supplementation on a composite outcome endpoint including hemorrhagic events, transfusion requirements, and mortality.Trial registrationClinicalTrials.gov, NCT03208270. Registered on 5 July 2017.

When is it appropriate to stop non-vitamin K antagonist oral anticoagulants before catheter ablation of atrial fibrillation? A multicentre prospective randomized study.

Although a recent expert consensus statement has recommended periprocedural uninterrupted (UI) non-vitamin K antagonist oral anticoagulants (NOACs) during catheter ablation of atrial fibrillation (AF) as a Class I indication, there have been no clear randomized trials. We investigated the safety and efficacy of UI, procedure day single-dose skipped (SDS), and 24-hour skipped (24S) NOACs in patients undergoing AF ablation. In this prospective, open-label, randomized multicentre trial, 326 patients (75% male, 58 ± 11 years old) scheduled for AF catheter ablation were randomly assigned in a 1:1:1 ratio to UI, SDS, and 24S at three tertiary hospitals. Bridging with low molecular weight heparin was carried out in the patients with persistent AF who were assigned to the 24S group. Dabigatran, rivaroxaban, and apixaban were assigned in order after randomization. The primary endpoint was the incidence of bleeding events within 1 month after ablation. The secondary endpoints included thrombo-embolic and other procedure-related complications. The intra-procedural heparin requirement was higher in the 24S group than others (P < 0.001), and the mean activated clotting time was comparable among the groups (P = 0.139). The incidence of major bleeding up to 1 month after ablation and a post-procedural reduction in the haemoglobin levels did not significantly differ among the treatment groups and different NOACs (P > 0.05). There were no fatal events or thrombo-embolic complications in all the three groups. In patients undergoing AF ablation, UI NOACs and SDS or double dose skipped NOACs had a comparable efficacy and safety, regardless of the type of NOAC.

Fresh frozen plasma: A solution to heparin resistance during extracorporeal membrane oxygenation (ECMO)

ObjectiveThe management of Heparin resistance in patients undergoing ECMO is still uncertain. We sought to assess the efficacy and safety of Fresh frozen plasma to optimize the anticoagulation in these patients. MethodsWe studied 42 adults undergoing VA-ECMO. Heparin infusion was increased incrementally to achieve target ACT in HG group and plasma administered in FFPG group in heparin resistance (HR) patients. Statistical comparison was performed between these two groups and results compared with non-heparin resistance (Non-HR) patients. ResultsOverall 36% survived and 64% suffered bleeding complications. There was no difference in age (p = 0.118) or average ECMO duration (p = 0.393). The heparin requirement was significantly less in FFPG (p = 0.008) and average ACT difference of 159.2 (20.3) was highly significant (p < 0.001). Clinically the survival was higher in FFPG (50% vs 10%) without statistical difference (p = 0.07) probably due to small sample size. Twenty HR compared to 22 Non-HR patients. The survival rate (41% vs 30%) was not statistically significant (p = 0.340). However, more bleeding 80% vs 50% recorded in HR (p = 0.043) even though heparin doses between them was not different. ConclusionsThe heparin requirement was high in patients treated with heparin alone. Fresh frozen plasma effectively increased ACT to therapeutic target in HR patients. There was no difference in the heparin dose, significantly higher bleeding complications were recorded in HR patients. Clinically, survival was better in Non-heparin resistance and plasma treated patients that was not found to be statistically significant.

Assessment of Anticoagulation in Patients Receiving Ultrasound-Assisted Catheter-Directed Thrombolysis for Treatment of Pulmonary Embolism.

Ultrasound-assisted, catheter-directed thrombolysis (USAT) has emerged as a popular treatment option for submassive pulmonary embolism (PE). The optimal strategy for transitioning patients from full-intensity to reduced-intensity heparin during the procedure has yet to be established. The goal of this study was to evaluate the anticoagulation management in patients receiving catheter-directed thrombolysis with USAT. A retrospective chart review was conducted of patients who received USAT for the treatment of PE. Institutional review board approval was obtained. The primary objective was to determine the proportion of patients with a therapeutic activated partial thromboplastin time (aPTT) prior to and during tissue-plasminogen activator (tPA) infusion. Secondary outcomes included heparin requirements, the rate of bleeding complications, and the appropriateness of long-term venous thromboembolism management. A therapeutic aPTT value was achieved in 32 patients (54.2%) prior to USAT and 35 patients (59.3%) during tPA infusion. Heparin requirements were reduced from 15.1 ± 4.1 to 12.8 ± 4.2 U/kg/h for patients who achieved a therapeutic aPTT both prior to and during tPA infusion. Bleeding occurred in 34.4% of patients and tended to be minimal (20.3%) or minor (10.9%). The majority of patients were discharged on a direct oral anticoagulant (63%), followed by warfarin (32%) and enoxaparin (5%). Conclusion and Relevance: To our knowledge, this is the first study that has assessed heparin management in the setting of USAT. The results of these data may aid in empirically dose adjusting unfractionated heparin to ensure safe and effective anticoagulation for patients receiving USAT.

Management of Intraprocedural Anticoagulation in Patients on Non-Vitamin K Antagonist Oral Anticoagulants Undergoing Catheter Ablation for Atrial Fibrillation

Catheter ablation has gained a prominent role in the management of atrial fibrillation (AF), with recent data providing positive evidence on hard outcomes, including hospitalization and mortality. Ablation, however, exposes the patient to a rather unique situation, combining risks for both major bleeding and thromboembolic events. In this setting, the critical importance of rigorous anticoagulation during the procedure has been underlined, and the latest international guidelines now recommend performing AF catheter ablation with uninterrupted non-vitamin K antagonist oral anticoagulants (NOACs) and concomitant administration of unfractionated heparin adjusted to achieve and maintain a target activated clotting time of ≥300 seconds. Whereas observational studies and randomized controlled trials support the safety and efficacy of uninterrupted NOAC strategy for AF catheter ablation, recent experiences have questioned this point, showing a greater unfractionated heparin requirement in NOAC-treated patients compared with vitamin K antagonists-treated patients to achieve the target activated clotting time. Important gaps in evidence regarding optimal intraprocedural anticoagulation management need to be acknowledged. A thorough appreciation of the physiology of anticoagulation during AF catheter ablation and the relevant differences between vitamin K antagonists and NOACs is required, while also understanding the limitations of activated clotting time measurement with regard to accurate intraprocedural anticogulation monitoring. This review aims to provide a critical look at this relatively ignored aspect of AF catheter ablation, especially pitfalls in NOAC monitoring, and to identify gaps in knowledge that need to be addressed in the near future.