This study provides insights into the use of Argatroban as primary anticoagulant during vvECMO support with respect to safety, efficacy and complications in comparison to a propensity-score matched group of patients without HIT and anticoagulation with UFH.
In summary, Argatroban was non-inferior to UFH in view of clinically relevant complications such as major bleeding and major thrombosis. Similar results were seen for minor bleeding and minor thrombosis. Technical complications were also comparable. Of note, the decline in platelet count was more pronounced in the UFH group than in the Argatroban group despite receiving more platelet transfusions. Costs for the anticoagulant were substantially higher in the Argatroban group; yet, after accounting for blood transfusions and HIT testing in the UFH group, expenses were aligning.
Complications
Anticoagulation during vvECMO therapy is much scrutinized because the device per se may cause both clotting and hemorrhagic complications [
16]. Systemic anticoagulation is necessary to lessen potential lethal complications such as thromboembolism [
4] but also increases the risk of bleeding [
17,
18]. The ELSO anticoagulation guideline does not include any specific recommendations on anticoagulation during vvECMO support [
19]. According to a recent survey, 264 out of 273 ECMO centers routinely use UFH as primary anticoagulant [
20].
In the current analysis, Argatroban and UFH did not differ regarding the composite endpoint of major bleeding and major thrombosis. Although bleeding complications are common during ECMO support, the reported incidence varies between 0 and 91% [
18,
21]. Besides potential differences in treatment algorithms, these variations are most likely due to differing definitions and methods for assessing bleeding [
5,
18,
21]. In our study, the rate of bleeding complications was numerically relatively high but was mainly related to the chosen definition of bleeding according to the ELSO classification [
5] that is liberal compared to other definitions [
22,
23]. Considering only patients with either a drop in hemoglobin of ≥ 2 g/dl/day or a transfusion of ≥ 2 RBC/day, the incidence of major bleeding in our study was below 30%. The average number of RBC transfusions during ECMO support amounted to 0.3/day. Compared with data from a recent meta-analysis including 18 studies, this number is in the lower range [
18]. In line with our results, Mazzeffi et al. reported that only the number of transfused blood products but not the bleeding episodes per se were associated with mortality during ECMO support [
24]. Also, the incidence of cerebral hemorrhage in both our cohorts was low compared to other reports [
25,
26]. The occurrence of bleeding, among others, depends on the pursued level of anticoagulation. Both our patient groups showed similar median aPTT levels of about 50 s throughout ECMO support. To accomplish this level, more aPTT checks per day were necessary in the Argatroban group. In our study, Argatroban doses had to be increased if markers for sepsis were dropping. We did not observe any clear threshold for aPTT or Argatroban-plasma concentration at which the rate of complications increased.
Severe bleeding with suggested standard dosing (2 µg/kg/min) of argatroban has been reported in critically ill patients on vvECMO [
8]. Therefore, equally to others, initiating dose was set to 0.2 µg/kg/min in this study [
8,
12]. In general, bleeding events are not uncommon during ECMO therapy [
24]. Thus, the use of argatroban might be of advantage due to the shorter half-life time compared to UFH but in contrast to UFH an antidot is not available and the choice of how to monitor argatroban dosing is controversial [
27]. Still, aPTT is commonly used for controlling anticoagulation with Argatroban [
8,
11,
12,
28] and it also was shown that the target range of aPTT in vvECMO patients was more frequently achieved with argatroban compared to UFH [
12].
Interestingly, the decline in the platelet count was more pronounced in the UFH group. This often described phenomenon of decreasing platelet numbers [
5,
9] seems to be related to the ECMO device, possibly the pump unit, itself [
29]. Whether heparin has an additional, independent effect on platelets—which may not occur with Argatroban—needs to be investigated in more detail, in particular due to the numerical inclusion imbalances between the Argatroban and the UFH group.
Besides bleeding, other complications with an important impact on outcome are thromboembolism [
4,
30] and technical issues of the ECMO device caused by clotting. The incidence of thrombosis in patients requiring vvECMO support ranges from 0 to 85% [
4]. Most previous studies reporting on the use of Argatroban during ECMO therapy included patients with type II HIT [
8,
12]. However, HIT is associated with high rates of thromboembolism and hence lower survival rates [
10]; therefore, a direct comparison with the current analysis that excludes patients with HIT is not feasible. The largest study on thromboembolism during vvECMO therapy to date reports incidences of any type of thrombosis of 62% [
4], and the fraction of 28% clinically significant thromboembolic events was comparable to that of the Argatroban group in this study. Eventually, Argatroban may be an alternative in cohorts with a high risk for thromboembolism such as COVID-19 patients [
31] due to its antithrombotic action, presumably also working in already formed clots, and its potential anti-inflammatory, and theoretical antiviral characteristics [
32]. Technical complications related to clotting were similar. In 2004, Young et al. [
33] found decreased thrombin generation in ECMO patients anticoagulated with Argatroban in comparison to UFH, but this observation has not been transferred into clinical practice so far.
It is likely that aPTT is not the best parameter to monitor anticoagulation with Argatroban and other parameters such as ecarin clotting time may be superior [
28]. Yet, aPTT is widely available in clinical practice and has been frequently used to control anticoagulation with Argatroban in ECMO and non-ECMO patients [
8,
11,
12,
34]. Alternatives such as Argatroban concentration or plasma-diluted thrombin time that are not influenced by various other factors such as D-Dimers and coagulopathy have no ceiling effect like aPTT and remain valid at higher ranges [
10,
27,
35,
36]. In the current analysis, Argatroban concentrations only moderately correlated with aPTT levels. However, a therapeutic target range according to clinical efficacy has not yet been defined. In their case report, Kennedy et al. suggested a range of 0.4–1.2 μg/ml but did not provide any further evidence [
37]. Technical complications such as pump or oxygenator failure were comparable between the two groups in our analysis and similar to previous reports [
38]. By trend, successful discharge from hospital was higher in the Argatroban group; however, our study was not powered for outcome.
Limitations
This single-center retrospective study was conducted by staff with considerable experience in the use of Argatroban. Therefore, some singularities of Argatroban were known before the initiation of the study, for instance the need of a very low initiation dose and a stepwise increase during the further treatment course. A direct causal relationship cannot be inferred due to the study’s design. Patients with cardiogenic shock during veno-arterial (va) ECMO therapy were excluded a priori to avoid cases of liver failure, for which Argatroban is contraindicated. A systematic bias may have occurred since the classification of bleeding events is limited in retrospective studies. To address this issue, we also reported the daily need of RBC transfusion. Our study included patients from a time period of 13 years. We cannot exclude that some details of management had changed over time; however, standards of care, persons in charge and technical set-up remained essentially the same so that outcome data are comparable to results previously published by our research group.
Finally, due to the limited number of patients treated with Argatroban, small effects and differences may have been missed, and future prospective studies should involve larger cohorts.