In the current era, extracorporeal membrane oxygenation (ECMO) is widely used in patients with refractory cardiogenic shock or respiratory failure.1–3 With current technology, anticoagulation remains a necessity to prevent pump thrombosis and thromboembolic events that occur as a result of hemoactivation secondary to blood contact with ECMO circuit components. Bleeding complications leave the clinician in a perpetual balancing act of preventing both bleeding and thrombosis, placing an emphasis on utilizing an anticoagulation strategy with the most favorable safety and efficacy profile.4
The 2014 extracorporeal life support organization (ELSO) Anticoagulation Guideline offers no specific recommendation for anticoagulation selection in either veno-arterial (VA) or veno-venous (VV) ECMO.4 , 5 A 2013 survey of ECMO centers found all respondents (121 of 187 possible sites) were utilizing unfractionated heparin and 97% reported serial activated clotting times as their preferred method of anticoagulation monitoring.6 Although unfractionated heparin clearly remains the first-line anticoagulant in ECMO, there is emerging data demonstrating that the direct thrombin inhibitors (DTI) argatroban and bivalirudin are non-heparinoid alternatives, which potentially better balance bleeding and thrombosis risk as has been seen in the acute coronary syndrome population.7–9 In addition to their potentially favorable pharmacokinetic and risk profiles, DTIs do not carry the risk of heparin-induced thrombocytopenia (HIT). This is of considerable significance in a population in which unabated thrombosis could be catastrophic. The primary objective of this study was to determine whether bivalirudin offers distinct clinical benefits as the anticoagulant of choice in ECMO when employing an activated partial thromboplastin time (aPTT)–based monitoring approach.
This was a retrospective study approved by the Allina Health Institutional Review Board. Given the nature of the study and the sole intent of quality improvement, the requirement for obtaining individual informed consent was waived. Data were gathered manually from the patient’s electronic medical record and through an electronic data warehouse report specified to collect predetermined discrete variables and demographic characteristics.
Adult patients, aged ≥18 years, supported with VA or VV ECMO between January 2012 and September 2015 were eligible for inclusion. Continuous anticoagulation during the first 96 hours of initiating the systemic agent was required. Patients transitioned from heparin to bivalirudin or vice versa during this time frame were excluded from review. During the study period, the Thoratec CentriMag Blood Pump (Levinotrix CentriMag. Acquired by Thoratec, Pleasanton, CA in 2011) and the Jostra Rota Flow pump (Maquet Cardiopulmonary AG, Hirrlingen, Germany) were utilized. The Quadrox-D (Maquet, Jostra Medizintechnik AG, Hirrlingen, Germany) has been the oxygenator of choice at our center. Our circuits were heparin coated. All patients received a heparin bolus of 80 unit/kg at the time of cannulation. Subsequently, patients receiving heparin and bivalirudin were maintained on protocols ranging in the intensity of anticoagulation. Continuous infusion anticoagulation was initiated in the intensive care unit in the absence of excessive bleeding post-cannulation and post-procedure aPTT of <70 sec. Heparin was initiated per protocol without a bolus using a blood volume–based dosing strategy that correlated with an initial infusion rate of 8–12 units/kg/hour. Available aPTT-based heparin protocols were low intensity (45–65 sec correlating to a heparin anti-Xa activity of 0.1–0.29 IU/mL) and high intensity (65–90 sec correlating to a heparin anti-Xa activity of 0.3–0.5 IU/mL). Bivalirudin was initiated per protocol without a bolus at 0.04 mg/kg/hour. Bivalirudin, in similar fashion, was available as both a low-intensity (45–65 sec) and high-intensity (60–80 sec) infusion. Patients who transitioned to and from low- and high-intensity infusions during the first 96 hours were included in the analysis as this is common in clinical practice driven by the dynamic nature of bleeding and thrombotic risks. Based on the infusion intensity, the patient spent the most time receiving during the initial 96 hours of ECMO support predicated if they were stratified as constant, low, or high-intensity for analysis.
The primary end points of the study were thrombotic event rates between heparin and bivalirudin during 3 time periods: the initial 96 hours of anticoagulation, anytime during the entire ECMO run, and at any time during the admission and in-hospital and 30 day mortality. Secondary end points included percent time in therapeutic range (%TTR), aPTT perturbations, neurologic events, vascular complications, major and minor bleeding, blood product use, and total cost of stay. For the sake of standardization and to calculate %TTR, we defined a therapeutic aPTT as being >50 sec. The Rosendaal method was extrapolated for the purpose of %TTR calculations.10 This method uses linear interpolation to calculate the aPTT in between aPTT lab draws to assess the percent time a patient spent above a predefined therapeutic range (aPTT > 50 for the purposes of this study). It should be noted that Rosendaal has only been validated in patient populations receiving chronic warfarin.
Definition of Events
Thrombotic events were defined as clinically documented venous or arterial thromboembolism or thrombus within the ECMO circuit. Major bleeding was defined as any bleeding event associated with a drop in hemoglobin of at least 3 mg/dL within the prior 24 hours. Minor bleeding events were those associated with less than a 3 mg/dL drop in hemoglobin during the preceding 24 hours. Neurologic events were defined as acute ischemic or hemorrhagic stroke. Vascular complications were defined as the need for stitching or packing, limb ischemia, limb loss, fasciotomy, or any operating room intervention. Confirmed HIT required both a positive heparin antibody test and serotonin-release assay (SRA) result. An aPTT perturbation included any deviation from a therapeutic aPTT to an aPTT outside of the predefined goal range for the anticoagulant.
Descriptive statistics are displayed as means and SDs for continuous variables; number and percentage with characteristic are given for categorical variables. When continuous variables had skewed distributions (time variables and laboratory values), data are summarized with medians and 25th and 75th percentiles. Categorical variables were analyzed using Pearson’s χ2 or Fisher’s exact tests. Continuous variables were analyzed using Student’s t test for normally distributed variables or Kruskal–Wallis tests for continuous variables with non-normal distribution. A value of p < 0.05 was considered significant, and p values are two-sided where possible. All statistical calculations and plots were done with Stata 11.2 (College Station, TX).
A total of 72 patients receiving VA or VV ECMO support between January 2012 and September 2015 were analyzed, including 28 receiving heparin and 44 receiving bivalirudin. A majority of patients (75%) were cannulated in the cardiac catheterization laboratory, and VA ECMO (92%) constituted the majority of our study population. Cardiogenic shock (71%) was the predominant etiology. Baseline patient characteristics and laboratory values before cannulation are depicted in Table 1. The only significant differences between the groups were related to etiology of shock (cardiogenic, 50% vs. 84%; septic, 39.1% vs. 0%; respiratory, 3.6% vs. 6.8%; mixed, 7.1% vs. 9.1%; p < 0.001) and baseline median aPTT (47 vs. 37 sec, p = 0.02). The latter was potentially related to slight differences in anticoagulation dosing at the time of cannulation or the timing of the baseline aPTT relative to the cannulation.
The decision to use heparin versus bivalirudin was made based on provider preference for ECMO anticoagulation. In the heparin group, 18 (64%) patients received the high-intensity protocol, 6 (21%) patients received low-intensity, and 4 (14%) patients were placed on constant-rate infusion. The bivalirudin group had 26 (59%) patients on a high-intensity protocol and 18 received low-intensity (41%). The co-primary end points of thrombotic events during the initial 96 hours of anticoagulation, over the course of their entire ECMO run, and at any time during the admission were not significant between patient’s anticoagulated with heparin as compared with bivalirudin (Table 2). In addition, there was no difference in in-hospital and 30-day mortality (Table 2). Secondary clinical outcomes, notably, %TTR and major/minor bleeding events did not vary significantly between the treatment groups (Table 2). One patient from the heparin group did have SRA-confirmed HIT, and none required supplementation with antithrombin III (AT III). See Figure 1 for detailed hematologic and coagulation parameters during the first 96 hours of support in which there were no statistically significant differences between groups. Pump flow rates tended to be higher for bivalirudin, particularly during the first 48 hours of support (Table 3). Overall, blood product use (RBCs, plasma, platelets, cryoprecipitate) was similar between groups (Table 3).
An analysis of patients solely receiving high-intensity heparin or high-intensity bivalirudin (Table 4) did reveal a statistically significant difference in respect to %TTR (81% vs. 95%; p = 0.033). Patients treated with bivalirudin also had fewer perturbations from a therapeutic to sub-therapeutic aPTT and accordingly spent less time under-anticoagulated. However, this corresponded with no difference in thrombotic or neurologic events between the two groups (Table 4). Rates of major/minor bleeding and vascular complications also did not vary (Table 4). There was a trend toward higher total cost in the bivalirudin group ($144,900 vs. $181,700; p = 0.93) but did not reach statistical significance.
Anticoagulation remains a necessity in the ECMO population to prevent circuit thrombosis and thromboembolic events. Counterbalancing this need with the inherent challenge of maintaining hemostasis weighs heavy on clinicians given the circuit’s propensity for mechanical consumption and induction of coagulopathy. Based on the most recent ELSO Registry data in adult population, the prevalence of ischemic stroke is 3.8%, limb ischemia 3.6%, and oxygenator thrombosis 8.2%. This has a major clinical implication, with significantly lower overall survival to discharge of 23%, 28%, and 40%, respectively. As we await a circuit void of requiring anticoagulation, the answer for the optimal agent, desired intensity, timing of anticoagulation, and appropriate laboratory monitoring remains elusive.
Heparin is often cited as a flawed anticoagulant when used in patients supported with ECMO for a variety of reasons. Variable, nonlinear therapeutic response and duration of effect occurs from indiscriminant binding to plasma proteins, endothelial cells, and macrophages, as well as elimination through a combination of rapid endothelial cell/macrophage metabolism and slow renal clearance.11 In addition, AT III, a necessary co-factor for heparin efficacy, can be reduced in severe illness, resulting in drastic interpatient variability in the amount of heparin required to achieve therapeutic anticoagulation. This can extend the time a patient is out of therapeutic range until heparin resistance is recognized. Repletion of AT III is a feasible but expensive endeavor for large ECMO centers given the need for constant re-supplementation. This can also result in oscillations in heparin sensitivity and dosing variability. The potential for HIT, a devastating event in the already critically ill patient, also exists with heparin exposure. Overall, HIT rates in the general population treated with unfractionated heparin are low, as noted in a meta-analysis by Martel et al. 12 with an overall incidence of 2.6%. This number potentially underestimates the true rate of HIT in the ECMO population as patients are thought to be more prone to develop immunogenic complications. Likewise, given mechanical consumption, coagulopathies, and criticality of the patient, the threshold for HIT antibody testing is much lower with ECMO patients.
Bivalirudin and DTIs, as a class, represent an alternative anticoagulant option to heparin able to avoid the previously mentioned pitfalls. Bivalirudin directly binds to the active site of thrombin without the need for AT III or other cofactors. It does not bind to red blood cells or to plasma proteins other than thrombin. Metabolism and elimination is more predicable, with 80% of the active drug metabolized through proteolysis and the remaining unchanged drug eliminated through the kidneys. This results in a strong correlation between bivalirudin plasma levels and anticoagulant effects. Bivalirudin is not structurally related to heparin and does not complex with platelet factor 4; therefore, there is no risk of HIT.13 Several studies suggest a reduction in bleeding seen with bivalirudin compared with heparin in the ACS population and there is thought this benefit could translate to the ECMO population.7–9 , 14 , 15 Cautious optimism has surrounded the use of bivalirudin in ECMO given the possibility for intracardiac thrombus, however.16 The heart can act as a natural reservoir for blood stagnation during ECMO support, leading to local hypermetabolism of bivalirudin within the heart chambers via proteolysis and thrombus formation. Although not the same mechanism of metabolism, this phenomenon has also been described with heparin.17
Definitive clinical data to guide anticoagulation decisions in ECMO patients is limited to retrospective analyses and case reports, many of which are found in pediatric literature and involve argatroban use.6 , 18–23 Prior analyses by Pieri et al. 18 and Ranucci et al. 19 represent the largest published evaluations of bivalirudin versus heparin, which assessed a combined total of 41 ECMO patients (nine of which were children). Pieri et al. determined that bivalirudin reduced variability in aPTT values and the intensity of dosing adjustments as opposed to heparin in 20 adult ECMO patients, but this conferred no statistically significant difference in bleeding, thromboembolic events, ECMO duration, mortality, or the number of aPTT values > 80 sec compared with heparin. Similarly, Ranucci et al. concluded that in 21 (12 adult and 9 children) post-cardiotomy ECMO patients, bivalirudin decreased blood loss and product use, although no difference in thromboembolic events was noted. A centrally cannulated, post-cardiotomy patient population represents a distinct bleeding risk profile because of the exposure to cardiopulmonary bypass and a recent invasive cardiothoracic procedure. This population, along with the inclusion of children, makes broad extrapolation of bivalirudin’s benefit challenging. Although these analyses offer evidence suggesting bivalirudin and heparin may be at least interchangeable, they are limited to small sample sizes.
The enhanced pharmacokinetic profile of bivalirudin demonstrated in previous retrospective analyses by Pieri et al. 18 and Ranucci et al. 19 was confirmed in our study. In both the composite and high-intensity analysis, bivalirudin demonstrated an enhanced %TTR and overall reduction in coagulation parameter perturbations. The %TTR difference in the high-intensity group was found to be statistically significant (p = 0.033). A greater percentage of bivalirudin-initiated patients began with a therapeutic aPTT (>50 sec), but this was not statistically significant compared with heparin in either the composite or high-intensity analysis. Although bivalirudin seemingly conferred an advantageous pharmacodynamic profile compared with heparin, there were no differences in clinical outcomes. Pump and patient thrombosis, overall thrombosis, neurologic events, and mortality were no different in the groups. We also found that both major and minor bleeding, in addition to vascular complications and blood product use, were similar between both the composite and high-intensity groups.
Our analysis had one case of SRA-confirmed HIT in the heparin group. The preliminary diagnosis of HIT was established after the initial 96-hour time period had passed. This patient was eventually transitioned to bivalirudin and had no thrombotic complications. The incidence of HIT seen in this study coincides with the conclusion reached by Martel et al.12 HIT antibody testing (ELISA, etc.) must be pragmatically used in clinical practice, however, as there is a high tendency for false positives that are never confirmed by SRA testing. For example, Marler et al. 24 analyzed 85 hospitalized patients at their institution from 2011 to 2013 with a positive ELISA antibody screen (optical density value < 1.0). Of these, none were found to have SRA-confirmed HIT. Additionally, Glick et al. found that 1 of 119 ECMO patients at their institution had functional assay–confirmed HIT.25 Of the 23 patients with an optical density score performed, 23 (87%) were less than 0.4 and all were less than 1. With this in mind, an SRA must always be ordered for a positive HIT antibody test to not only confirm the diagnosis, but to not limit future anticoagulant options if necessary. There was also no use of AT III in this study. If aPTT values were not moving toward goal range after at least two draws, off-protocol adjustments were made to heparin doses at the discretion of the attending provider. Any perceived heparin resistance was overcome through judicious clinical decision making and heparin dose adjustments.
Although our study lends further support to using bivalirudin as an alternative anticoagulant in adult VA ECMO patients, we did not demonstrate a significant clinical advantage to its use in our adult, predominantly peripherally cannulated patient population with shock not related to cardiotomy. With no notable difference in outcomes, cost of care is an important consideration. Although we did not see statistically significant differences in terms of total cost of stay, a bivalirudin first approach in every ECMO patient could have detrimental pharmacoeconomic impact, given the drug’s high cost relative to heparin in the absence of AT III replacement. Unless clinical events and their associated costs are avoided, a heparin-first approach would be prudent to reduce the cost of care.
Inherent limitations of this study include its retrospective design and relatively small study size. Although, to the best of our knowledge, this study represents the largest comparative analysis of bivalirudin versus heparin in the combined VA and VV ECMO population, we had very few patients on VV ECMO, making it difficult to draw similar conclusions in this patient population. No children were included. Also, the majority of our clinical outcomes were assessed in the first 96 hours of systemic anticoagulation, which we considered the most tenuous period of anticoagulation. Once out of this window, stability in anticoagulation status often ensues as was seen with Ranucci et al.19 Our conclusion of equality between heparin and bivalirudin for anticoagulation in the ECMO population is hypothesis generating and requires further validation in a head to head, appropriately powered, prospective trial. Given the variety of monitoring practices, anticoagulation algorithms individual institutions employ, and overall lack of standardization, pursuing multicenter data for a retrospective analysis would be very challenging.6
Our study suggests that bivalirudin does not offer a distinct clinical benefit when compared with heparin as the initial anticoagulant of choice in adult patients supported by ECMO. Given the vast majority of patients observed in this study received VA support, conclusions cannot be extrapolated to the VV population. While the pharmacokinetic advantages of bivalirudin were seemingly reaffirmed, this resulted in no difference in clinical outcomes. These results do lend further support for bivalirudin as a viable anticoagulant in patients supported by ECMO. Given the pharmacoeconomic implications of bivalirudin compared with heparin without AT III monitoring and replacement, heparin remains the first-line anticoagulant for ECMO in patients without a history of HIT. Prospective, multicenter, randomized trials are still needed to determine the most appropriate approach to anticoagulation in the VA and VV ECMO populations.
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