Anticoagulation Practices Using Activated Clotting Time in Veno-Venous Extracorporeal Membrane Oxygenation for Patients with Respiratory Failure: A Systematic Review and Met-Analysis

Background Veno-Venous Extracorporeal Membrane Oxygenation (ECMO) technology provides as a alternative approach in the intensive care of patients with respiratory failure due to varied causes who are not responsive to conventional treatment. As per the 2014 Extracorporeal Life Support Organization (ELSO) guidelines, in order to to maintain circuit patency and minimize thromboembolic complications, anticoagulation is used, but the optimal strategy remains to be defined. Activated clotting time (ACT) is the most utilized bedside test to adjust anticoagulation. Therefore, we performed an extended analysis of all published studies on the incidence of thromboembolic and bleeding events in patients with acute respiratory distress syndrome who were put on ECMO. Methods A comprehensive search of several databases from inception to November 25, 2020, limited to English language and excluding animal studies, was conducted. The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. The studies were classified into low anticoagulation target (ACT<180) or high anticoagulation target (ACT>180). A meta-analysis was performed of all eligible studies with the data on the incidences of thromboembolic and bleeding complications in patients with ARDS on VV-ECMO during different intensities of anticoagulation. Results A total of 6 eligible studies (4 retrospective and 2 case series) were identified, including in total 190 patients for 100 patient years. Our study showed that there is two times higher chances of bleeding when ACT goal is >180 versus a lower ACT range of <180 (Risk ratio 2.07, 95% CI 1.23-3.46, P 0.0056). The incidence of thrombosis did not change in the two group (Risk ratio 1.17, 95% CI 0.45-3, P 0.7516). Conclusions Currently there is a lack of data for anticoagulation strategies during VV-ECMO for patients in respiratory failure. Our study aimed to find an appropriate anticoagulation target for this patient group. The results show that although anticoagulation is required for circuit patency, there is an increased risk of bleeding when higher anticoagulation targets are set. Disclosures No relevant conflicts of interest to declare.

Efficacy of the hemostatic device VasoSTAT and the study of hemostatic factor

Recently, trans-radial intervention has gained popularity as a common procedure to reduce hemorrhagic complications. However, the cuff-type hemostatic device (TR Band) previously used at our institution required 6 h to achieve hemostasis. Since July 2016, we have been using the VasoSTAT, a new hemostatic device that could achieve hemostasis in 4 h. In a verification study, we found that prolonged activated clotting time (ACT) was related to transient hemorrhage occurrence after the hemostatic procedure. Therefore, we designed a hemostatic protocol based on ACT and evaluated its efficacy. In this retrospective and observational study, 78 and 111 patients used the VasoSTAT and TR Band, respectively, from July 2015 to May 2017. In the VasoSTAT group, the ACTs were significantly lower in the hemostasis success (246 ± 46 s) than in the failure group patients (327 ± 59 s) (P < 0.01). Therefore, we applied the hemostatic protocol to 271 patients from May 2017 to March 2020. The hemostasis success rate was 96% in the post-protocol applied group patients, which was significantly higher than the 82% success rate in the pre-protocol applied group patients (P < 0.01). VasoSTAT resulted in adequate hemostasis in 4 h. Further, ACT was predictive of adequate hemostasis.

Clinical monitoring of activated clotting time during cardiothoracic surgery: comparing the Hemochron® Response and Hemochron® Signature Elite

Introduction: The Activated Clotting Time (ACT) is commonly used to manage anticoagulation during cardiac surgery. The aim of this study was to compare the older manually operated Hemochron® Response and the automated Hemochron® Signature Elite. Methods: In this observational study the clinically relevant differences of both devices were investigated simultaneously, using duplicate measurements, in 29 patients who underwent a Coronary Artery Bypass Grafting (CABG) or Aortic Valve Replacement (AVR) in order to determine reliability, bias, and to detect which method has the lowest variation. Blood samples were obtained from the arterial line prior to surgery, after administration of 300 IU/kg heparin, 5 minutes after initiation of cardiopulmonary bypass and successively every 30 minutes, and after protamine administration. Results: A total of 202 measurements were performed. Of these 10 measurements were out of range in the Response and 9 in the Elite. About 27 single unstable magnet errors were seen in the Response versus no measurement errors in the Elite. No statistically significant differences between the Response (p = 0.22, Wilcoxon rank) and Elite (p = 0.064) duplicates were observed. The Response values were consistently higher during heparinization than the Elite measurements (p = 0.002, repeated measurements) with an average positive bias of around 56 seconds during heparinization (Bland-Altman). Overall, the coefficient of variation (CoV) increased during heparinization. Conclusion: The Elite was more reliable, but the variation was higher for the Elite than the Response. The observed positive bias in the Response compared to the Elite could affect heparin administration during surgery making the two systems not interchangeable.

Running after Activated Clotting Time Values in Patients Receiving Direct Oral Anticoagulants: A Potentially Dangerous Race. Results from a Prospective Study in Atrial Fibrillation Catheter Ablation Procedures

Background: Activated Clotting Time (ACT) guided heparinization is the gold standard for titrating unfractionated heparin (UFH) administration during atrial fibrillation (AF) ablation procedures. The current ACT target (300 s) is based on studies in patients receiving a vitamin K antagonist (VKA). Several studies have shown that in patients receiving Direct Oral Anticoagulants (DOACs), the correlation between ACT values and UFH delivered dose is weak. Objective: To assess the relationship between ACT and real heparin anticoagulant effect measured by anti-Xa activity in patients receiving different anticoagulant treatments. Methods: Patients referred for AF catheter ablation in our centre were prospectively included depending on their anticoagulant type. Results: 113 patients were included, receiving rivaroxaban (n = 30), apixaban (n = 30), dabigatran (n = 30), and VKA (n = 23). To meet target ACT, a higher UFH dose was required in DOAC than VKA patients (14,077.8 IU vs. 9565.2 IU, p < 0.001), leading to a longer time to achieve target ACT (46.5 min vs. 27.3 min, p = 0.001). The correlation of ACT and anti-Xa activity was tighter in the VKA group (Spearman correlation ρ = 0.53), compared to the DOAC group (ρ = 0.19). Despite lower ACT values in the DOAC group, this group demonstrated a higher mean anti-Xa activity compared to the VKA group (1.56 ± 0.39 vs. 1.14 ± 0.36; p = 0.002). Conclusion: Use of a conventional ACT threshold at 300 s during AF ablation procedures leads to a significant increase in UFH administration in patients treated with DOACs. This increase corresponds more likely to an overdosing than a real increase in UFH requirement.

Assessing Anticoagulation in Neonates With Congenital Diaphragmatic Hernia During Extracorporeal Membrane Oxygenation: Does Anti-Factor Xa or Thromboelastometry Provide Additional Benefit?

Objective: The optimal management of anticoagulation in neonatal/pediatric patients during extracorporeal membrane oxygenation (ECMO) has not been established yet and varies greatly among ECMO centers worldwide. Therefore, we aimed to assess whether the use of anti-factor Xa assay and/or thromboelastometry correlate better than activated clotting time with heparin dose in newborns with congenital diaphragmatic hernia during ECMO. We also examined whether these coagulation assays correlate with thrombotic and/or hemorrhagic complications, when the management of anticoagulation is based only on activated clotting time values.Methods: A prospective observational study in a neonatal ECMO center was conducted. We included all neonates with congenital diaphragmatic hernia born in our institution between March 2018 and January 2019 and requiring support with venoarterial ECMO. A total of 26 ECMO runs were analyzed. During the study, the heparin dose was still adjusted according to activated clotting time values. Measurements of anti-factor Xa assay, activated partial thromboplastin time, and a thromboelastometry from the same blood specimen were performed twice a day.Results: Anti-factor Xa levels showed a moderate correlation with heparin dose, whereas the other tests showed a weak correlation. Four patients (17.4%) had thrombotic complications, 2 patients (8.7%) experienced life-threatening bleeding, and in 11 patients (47.8%) disseminated intravascular coagulation (DIC) occurred. Anti-factor Xa levels were lower in the group with thrombotic complications (0.23 vs. 0.27 IU/ml; p = 0.002), while activated partial thromboplastin time was higher in the group with hemorrhagic complications (69.4 s vs. 59.8 s; p = 0.01). In patients experiencing DIC, heparin dose and anti-factor Xa levels were lower, while no difference in activated clotting time and clotting time in INTEM and INTEM-HEPTEM were shown.Conclusions: Anti-factor Xa levels correlate better to heparin dose than activated clotting time. The use of anti-factor Xa assay instead of activated clotting time for dosing of unfractionated heparin could reduce thrombotic complications in neonates with congenital diaphragmatic hernia on ECMO support. The thromboelastometry showed no additional benefit for this purpose.

Measuring Activated Clotting Time during Cardiac Catheterization and PCI: The Effect of the Sampling Site

Background/Purpose. We aimed to investigate the influence of the sampling site on the variability of ACT measurement. Activated clotting time (ACT) has been used for decades in cardiac surgery and interventional cardiology to assess unfractionated heparin activity. However, standardized protocols for the use of ACT measurement in the catheterization laboratory are lacking. Methods/Materials. After elective cardiac catheterization, ACT measurements were collected in simultaneously obtained blood samples from three different sample sites: the arterial catheter, arterial sheath, and peripheral intravenous line. Measurements were performed using the i-Stat® device (Abbott, Princeton, NJ, USA). The study was conducted with approval of the local medical ethical committee. Results. In 100 patients (mean age 67.1, 65% male), no significant differences were observed in ACT values obtained from the guiding catheter and arterial sheath (mean difference (MD) −18.3 s; standard deviation (SD) 96 s; P = 0.067 ). Contrarily, ACT values obtained from the intravenous line were significantly lower as compared to values obtained from the guiding catheter (MD 25.7 s; SD 75.5; P = 0.003 ) and arterial sheath (MD 39 s; SD 102.8; P < 0.001 ). Furthermore, ACT measurements from the arterial sheath showed a statistically significant proportional bias when compared to the other sampling sites (sheath vs. catheter, r = 0.761, P = 0.001 ; sheath vs. IVL, r = 1.013, P < 0.001 ). Conclusions. The present study shows statistical significance and possibly clinically relevant variations between ACT measurements from different sample sites. Bias in ACT measurements may be minimized by using uniform protocols for ACT measurement during cardiac catheterization.

Heparin Monitoring with an Anti-Xa Protocol Compared to Activated Clotting Time in Patients on Temporary Mechanical Circulatory Support

Background: Temporary mechanical circulatory support (tMCS) devices are used for patients with severe cardiac or respiratory failure; however, these patients are at high risk for clotting and bleeding. The best method to monitor heparin in these patients has not been established. Objective: To determine the risks for bleeding and clotting while monitoring heparin with either anti-Xa or activated clotting time (ACT) in tMCS patients. Methods: A retrospective cohort study was conducted on tMCS patients who received heparin adjusted according to an anti-Xa or ACT protocol. The primary outcome was incidence of major bleeding. Pertinent secondary outcomes were individual components of the primary outcome, clotting events, and time to therapeutic range. Results: There were 103 patients included in the study: 53 in the ACT group and 50 in the anti-Xa group. Overall, there were 30 (56.6%) patients with major bleeding in the ACT group, compared with 16 (32%) patients in the anti-Xa group ( P = 0.017). An anti-Xa–based protocol was associated with a decreased hazard of major bleeding (hazard ratio = 0.388 [0.215-0.701]; P = 0.002) in the univariate analysis. In the multivariable analysis, an anti-Xa protocol remained associated with a significantly lower hazard of bleeding. Findings were similar when broken down into more discrete subgroups of the entire cohort, extracorporeal membrane oxygenation life support (ECMO), and non-ECMO groups. Conclusion and Relevance: Anti-Xa monitoring was associated with a lower hazard of bleeding during tMCS compared to an ACT-based protocol. Further studies should evaluate if anti-Xa monitoring should be preferentially used in tMCS.