Argatroban for Anticoagulation in Patients Requiring Venovenous Extracorporeal Membrane Oxygenation in Coronavirus Disease 2019

Abstract

OBJECTIVES:

A significant proportion of patients with coronavirus disease 2019 requiring venovenous extracorporeal membrane oxygenation at our institution demonstrated heparin resistance, which in combination with a heparin shortage resulted in the transition to argatroban with or without aspirin as an alternative anticoagulation strategy. The optimal anticoagulation strategy for coronavirus disease 2019 patients requiring venovenous extracorporeal membrane oxygenation is unknown, and therefore, we sought to evaluate the efficacy and safety of argatroban with or without aspirin as an alternative anticoagulation strategy in this patient population.

DESIGN:

Retrospective cohort.

SETTING:

Single-center tertiary-care facility in Fort Sam Houston, TX, from 2020 to 2021.

PATIENTS:

Twenty-four patients who were cannulated for venovenous extracorporeal membrane oxygenation due to respiratory failure secondary to coronavirus disease 2019.

INTERVENTIONS:

Argatroban, with or without aspirin, was substituted for heparin in coronavirus disease 2019 patients requiring venovenous extracorporeal membrane oxygenation.

MEASUREMENTS AND MAIN RESULTS:

Eighty percent of our coronavirus disease 2019 patients requiring venovenous extracorporeal membrane oxygenation demonstrated heparin resistance, and patients who were initially started on heparin were significantly more likely to require a change to argatroban than vice versa due to difficulty achieving or maintaining therapeutic anticoagulation goals (93.4% vs 11.1%; p < 0.0001). The time to reach the therapeutic anticoagulation goal was significantly longer for patients who were initially started on heparin in comparison with argatroban (24 vs 6 hr; p = 0.0173). Bleeding and thrombotic complications were not significantly different between the two cohorts.

CONCLUSIONS:

Argatroban, with or without aspirin, is an effective anticoagulation strategy for patients who require venovenous extracorporeal membrane oxygenation support secondary to coronavirus disease 2019. In comparison with heparin, this anticoagulation strategy was not associated with a significant difference in bleeding or thrombotic complications, and was associated with a significantly decreased time to therapeutic anticoagulation goal, likely as a result of high rates of heparin resistance observed in this patient population.

With the advent of coronavirus disease 2019 (COVID-19) pneumonia causing severe acute respiratory distress syndrome (ARDS), venovenous extracorporeal membrane oxygenation (V-V ECMO) support has been increasingly used (1–4). However, the use of ECMO is associated with significant thrombotic and bleeding complications regardless of indication, with particularly high occurrence rates published recently in COVID-19 patients (5–10).

The optimal management of anticoagulation for COVID-19 patients both on and off ECMO is unknown. Although the majority of published reports describe the use of heparin for anticoagulation on V-V ECMO, both for COVID-19 and non-COVID-19 patients, some reports have demonstrated significant hemorrhagic and thrombotic complications in COVID-19 patients compared with non-COVID-19 patients, as well as an increased occurrence rate of heparin resistance (11–16). Previous reports in non-COVID-19 critically ill patients have demonstrated that direct thrombin inhibitors, such as bivalirudin and argatroban, are an effective alternative when heparin resistance occurs (15, 17).

A significant proportion of patients at our institution with COVID-19 requiring V-V ECMO support demonstrated difficulty achieving therapeutic heparin levels, which in combination with a concomitant heparin shortage resulted in increasing use of argatroban as an alternative to heparin. The aim of this study was to retrospectively describe the rate of thrombotic and hemorrhagic complications in this patient population. We hypothesized that complication rates in our cohort would be similar to those previously published with heparin and argatroban use, respectively, in V-V ECMO patients prior to the COVID-19 pandemic.

MATERIALS AND METHODS

Study Population

This is a single-center retrospective observational cohort study of patients who were cannulated for V-V ECMO by the Department of Defense ECMO team and transferred to the Brooke Army Medical Center (BAMC), Fort Sam Houston, TX, between June 2020 and January 2021 for the management of ARDS due to COVID-19 and who were decannulated with a final disposition prior to data analysis. BAMC is a tertiary-care academic referral center and accepts nonmilitary trauma, burn, and ECMO patients; all patients included in this study were nonmilitary. One patient who did not receive anticoagulation for 8 days after being started on ECMO due to a life-threatening hemorrhage associated with cannulation was not included. The patients were analyzed consecutively, and the diagnosis of COVID-19 pneumonia was determined by reverse transcription-polymerase chain reaction assays in conjunction with chest imaging. ARDS was defined using the 2012 Berlin definition. ECMO was initiated according to institutional protocol in patients who failed to improve despite management with standard ARDS therapy including lung-protective ventilation, volume optimization, prone positioning, and neuromuscular blockade.

Outcomes

The primary outcomes of this study were bleeding and thrombotic complications. Secondary outcomes included time to therapeutic range of anticoagulation and mortality. Patients were analyzed retrospectively, and bleeding and thrombotic complications were identified through daily chart review along with review of imaging tests and blood product transfusion history. Severity of bleeding complications was determined using the Bleeding Academic Research Consortium grading system (Table 1) (18). Time to therapeutic range was determined by comparing the time at which systemic anticoagulation was ordered with that of when the anticoagulation goal was achieved as defined by the standard partial thromboplastin time (PTT) and anti-Xa protocols defined below.

TABLE 1.

Bleeding Academic Research Consortium Definitions for Bleeding

Bleeding Type	Definition
Type 0	No bleeding
Type 1	Bleeding that is nonactionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment
Type 2	Any overt, actionable sign of hemorrhage that does not fit the criteria for type 3, 4 or 5, but does meet one of the following criteria:
	Requiring nonsurgical, medical intervention
	Leading to hospitalization or increased level of care
	Prompting evaluation
Type 3a	Overt bleeding plus hemoglobin drop of 3 to <5 g/dL (provided hemoglobin drop is related to bleed) or any transfusion with overt bleeding
Type 3b	Overt bleeding plus hemoglobin drop ≥ 5 g/dL (provided hemoglobin drop is related to bleed), cardiac tamponade, bleeding requiring surgical intervention for control,a or bleeding requiring IV vasoactive agents
Type 3c	Intracranial hemorrhage,b subcategories confirmed by autopsy or imaging or lumbar puncture, or intraocular bleed compromising vision
Type 4	Bleeding related to coronary artery bypass grafting
Type 5a	Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious
Type 5b	Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation

^aExcluding dental/nasal/skin/hemorrhoid.

^bExcluding microbleeds or hemorrhagic transformation does include intraspinal.

Anticoagulation

During V-V ECMO support, all adjustments regarding anticoagulation management were made by the treating ECMO physician. Either argatroban or unfractionated heparin (UFH) was administered continuously per standard protocol to achieve therapeutic goals of PTT 60–80 seconds or anti-Xa 0.2–0.4 international units (IU)/mL, as determined by the treating ECMO physician. Thromboelastography was not routinely used, nor were antithrombin III levels routinely measured. Heparin and argatroban dosing was determined using total body weight, with a starting dose of 12 U/kg/hr or 0.5 µg/kg/min, respectively. Specific dose adjustments were not made for obese patients. Concomitant aspirin was used in some cases at the discretion of the treating physician. No additional anticoagulants, antithrombotic agents, or thrombolytics were administered. Upper and lower extremity ultrasounds were obtained in all patients 72 hours after ECMO decannulation to screen for deep venous thrombosis (DVT) per institutional protocol. Heparin resistance was defined as requiring more than 35,000 total units of UFH over a 24-hour period to reach the therapeutic goal (19).

Statistical Analysis

Nonparametric statistical tests were used due to the small sample size and based on visual assessments of continuous data. Continuous data were reported as median (interquartile range [IQR]) and categorical data as percentages. Mann-Whitney U tests and Fisher exact tests were used to compare continuous or categorical data, respectively. Effect sizes were determined and used to calculate odds ratios (ORs) and 95% CIs. The Kaplan-Meier method was used to create a survival curve for time to therapeutic range for each anticoagulant, with the curves compared using the log-rank test. A p value of less than 0.05 was considered statistically significant.

Study approval was obtained from the Regional Health Command-Central Institutional Review Board (IRB), reference number C.2017.152d. Waiver of consent was obtained prospectively for all patients included in this study after IRB approval. Demographic information, anticoagulation strategies, ECMO characteristics, laboratory data, and clinical data were collected and analyzed.

RESULTS

Demographics

This study included a total of 24 patients who were cannulated for V-V ECMO due to respiratory failure secondary to COVID-19 and were decannulated prior to data analysis. A total of 535 days on ECMO were observed, with 48 days on heparin and 487 days on argatroban. The duration of ECMO support ranged from 5 to 87 days. Of the 24 patients, 16 patients were initially started on heparin for anticoagulation, whereas the remaining eight were started on argatroban. One patient had two separate ECMO runs and was started on heparin for the first run and argatroban for the second run. Demographic variables, Sequential Organ Failure Assessment (SOFA) and Respiratory ECMO Survival Prediction (RESP) scores, and d-dimer levels did not vary significantly between the two groups when recorded (Table 2). No patients in either group had a prior bleeding or thrombotic event before ECMO cannulation aside from the patient that underwent a second ECMO run, who suffered both bleeding and thrombotic events prior to the second cannulation.

TABLE 2.

Demographic Data

Baseline Characteristics	Argatroban (n = 9)	Heparin (n = 16)	p	OR (95% CI)
Age (yr)	44 (32–55)	45 (38–51)	0.9124	0.95 (0.22–4.2)
Gender (% male)	77.8	87.5	0.6016	0.81 (0.11–6.0)
Weight (kg)	88.3 (69.4–136)	101.6 (94.3–125)	0.3370	0.67 (0.15–3.0)
Height (cm)	164 (158.5–182)	175 (167–179)	0.2225	0.30 (0.07–1.4)
Active smoker (%)	11.1	18.8	1.000	0.54 (0.05–6.1)
Preexisting diabetes mellitus (%)	44.4	50	1.000	0.80 (0.16–4.1)
Preexisting hypertension (%)	22.2	37.5	0.6608	0.48 (0.07–3.1)
Admission Sequential Organ Failure Assessment (score)	6 (5–8.5)	7 (5.5–8.5)	0.3371	0.48 (0.11–2.1)
Admission Respiratory ECMO Survival Prediction (score)	4 (1–4.5)	4 (2.5–4)	0.8026	0.66 (0.15–2.9)
Admission d-dimer (µg/mL)	4.4 (2.7–6.6)	2.0 (1.3–3.1)	0.0524	4.6 (0.72–29)

OR = odds ratio.

Anticoagulation Management

At the time of anticoagulation initiation, patients on argatroban were managed with a PTT goal of 60–80 seconds. Patients on heparin were managed with a PTT goal of 60–80 seconds (10 patients) or anti-Xa goal 0.2–0.4 IU/mL (six patients). The anticoagulation goal was determined by the ordering provider. Patients on heparin were significantly more likely to require a modification to their anticoagulation goal (p = 0.0028). Modifications were either transitioning from goal PTT 60–80 seconds to anti-Xa 0.2–0.4 IU/mL or vice versa. For 19 of the 25 ECMO runs, the patient was also treated with aspirin 81 mg once daily, with no significant difference in use between patients started on heparin compared to those started on argatroban (p = 0.3644) (Table 3).

TABLE 3.

Modifications to Anticoagulation by Initial Anticoagulant

Outcomes	Argatroban (n = 9)	Heparin (n = 16)	p	OR (95% CI)
Total extracorporeal membrane oxygenation days (n)	453	48
Concurrent antiplatelet drug (%)	88.9	68.8	0.3644	3.6 (0.35–37)
Change in anticoagulation goal (%)	0	62.5	0.0028	Not applicable
Unable to reach anticoagulation goal (%)	11.1	18.8	1.000	0.54 (0.05–6.1)
Time to goal (hr)	6 (0–7.5)	24 (11–48)	0.0173	0.16 (0.03–0.96)
Change to other anticoagulant (%)	11.1	93.4	0.0001	0.008 (0.0005–0.15)

OR = odds ratio.

Event rate represents the median (IQR) of the number of events per day on ECMO for each individual multiplied by 100.

Patients started on heparin were significantly more likely to be switched to argatroban than vice versa (p = 0.0001), and the majority of these patients (80%) met criteria for heparin resistance. The documented reason for the switch was difficulty achieving or maintaining the therapeutic goal in all patients switched from heparin to argatroban. The development of or concern for heparin-induced thrombocytopenia (HIT) was not a reason for switching to argatroban for any of the studied patients. One patient was switched from argatroban to heparin because of the development of hepatic failure. The time to reaching the therapeutic goal also was significantly longer for patients started initially on heparin in comparison with argatroban (p = 0.0173), with a median time to therapeutic range of 24 hours for patients on heparin and 6 hours for patients on argatroban (Fig. 1). One patient was previously on argatroban before cannulation and was excluded from this analysis. After switching from heparin to argatroban, the median time to therapeutic range (PTT goal 60–80 s for all) was 9 hours (7–12 hr).

Figure 1.

Time to therapeutic range by initial anticoagulant. Censored patients are indicated by the ticks at the time of censoring; patients were censored when they were switched to the alternative anticoagulant prior to meeting the therapeutic goal. The two survival curves were significantly different (p = 0.0204, log-rank test).

Complications

A total of 17 bleeding events occurred in 12 patients, with two patients experiencing bleeding events on both heparin and argatroban. None of the bleeding events were life-threatening, and the majority of events were minor (type I or II) (Table 4). No instances of intracranial bleeding occurred. At the time of bleeding event, 67% of patients were at a therapeutic PTT, with the remaining subtherapeutic. No patients had a supratherapeutic PTT at the time of a bleeding event. For patients who suffered a bleeding event while on argatroban, the median PTT was 63.6 seconds (IQR, 60.5–69.8 s). The use of aspirin was not associated with the occurrence of a bleeding event (p = 0.6609; OR, 1.8 [0.26–12]).

TABLE 4.

Complications by Anticoagulant at the Time of the Event

Complication	Argatroban			Heparin			p	OR (95% CI)
	Patients (n)	Events (n)	Event Rate	Patients (n)	Events (n)	Event Rate
Bleeding (all)	10	14	0 (0–7.3)	2	3	0 (0–0)	0.1802	0.65 (0.21–2.0)
Bleeding type I or II	6	8	0 (0–0.82)	2	2	0 (0–0)	0.5892	0.57 (0.18–1.8)
Bleeding type IIIa–Vb	5	6	0 (0–0)	1	1	0 (0–0)	0.4654	0.94 (0.30–2.9)
Thrombotic event	8	8	0 (0–5.12)	1	1	0 (0–0)	0.1164	1.80 (0.58–5.6)

OR = odds ratio.

Patients who suffered a bleeding event required more packed RBC transfusions than did patients who did not suffer a bleeding event—8 units (5–12) compared with 1 unit (0–2) (p = 0.0003; OR, 20 [3.8–100]). Transfusions of other products were less common and were not associated with the occurrence of bleeding events. Having experienced a bleeding complication was not significantly associated with an increased risk of mortality while on ECMO (p = 1.0000; OR, 0.94 [0.16–5.5]).

Thrombotic complications, not including the need for a circuit change, occurred in nine patients, with no significant difference by anticoagulant (p = 0.1164; OR, 1.80 [0.58–5.6]). All events occurred while the patient was at a therapeutic PTT. None of the events were fatal, and none required treatment other than continuing anticoagulation. The use of aspirin was not associated with the occurrence of a thrombotic event (p = 0.6300; OR, 0.46 [0.07–3.0]). A total of 10 patients underwent between one and four circuit changes during their ECMO run, with 0.21 exchanges per week of ECMO therapy. Having experienced a thrombotic complication or undergone a circuit change was not associated with an increased risk of mortality while on ECMO (p = 1.000; OR, 1.3 [0.19–8.4]). After decannulation, DVTs were noted on screening exams in nine of the 17 ECMO survivors. In five of the nine patients, the noted DVT was also present while on ECMO. Overall, ECMO mortality was 29.2% (7/24), with an inhospital mortality of 33.3% (8/24).

DISCUSSION

There are limited data on the use of argatroban in V-V ECMO, and to the authors’ knowledge, this report is the first to focus on argatroban use in V-V ECMO for patients with ARDS secondary to COVID-19. This retrospective observational review focused on describing the therapeutic efficacy and safety of argatroban in comparison with heparin. Overall, the patients in this cohort had significant difficulty achieving therapeutic anticoagulation with heparin, and as a result, many received argatroban, with outcomes suggesting that argatroban is a safe and efficacious anticoagulation strategy in this patient population.

This study included patients requiring V-V ECMO support for treatment of ARDS due to COVID-19 at a single center. Due to the retrospective nature of the study, patients were not matched between the heparin and argatroban groups. However, patient characteristics, comorbidities, and demographics did not differ significantly between the groups. Illness severity was also comparable, as estimated by median RESP and SOFA scores at the time of admission. None of the patients had experienced bleeding or thrombotic complications prior to ECMO cannulation, indicating that prior coagulopathy was likely not a confounding factor.

Overall, argatroban demonstrated a favorable profile compared with heparin. The time to therapeutic anticoagulation was shorter with argatroban compared with heparin. Heparin was switched to argatroban in significantly more patients than vice versa, with significantly decreased time to achieving the therapeutic target with argatroban after the switch despite the finding that the majority of patients initially anticoagulated with heparin met criteria for heparin resistance. Argatroban additionally requires a lower volume of infusion compared with heparin, which may be an additional benefit (using standard concentrations at starting doses for the median patient weight of 99.2 kg and heparin requires 571 mL/d compared with argatroban with 71 mL/d).

Major complications examined in this cohort were thrombosis, including primarily DVT/pulmonary embolism and bleeding events; the number of circuit changes was additionally evaluated as a surrogate marker of thrombosis. Though the clinical significance of circuit changes remains largely unknown, it is a well-described complication of ECMO and often occurs despite therapeutic anticoagulation (8, 11). An increased occurrence rate of venous thromboembolism has been described in the COVID-19 population, which is thought to be secondary to a state of inflammation resulting in microthrombi and disseminated intravascular coagulation (5, 20). Studies in the COVID-19 ECMO population primarily describe the use of heparin for anticoagulation, with significant complications reported, including thrombosis despite therapeutic anticoagulation (27–76.9%), severe intracranial hemorrhage (6–40%), and HIT (12.5–23.1%) (7, 9, 12–14, 21, 22). Study of argatroban in V-V ECMO and critical illness prior to the COVID-19 pandemic suggested that argatroban is a safe and effective alternative to heparin for anticoagulation (15, 23). In COVID-19 ECMO patients, the study of argatroban has thus far been limited to the treatment of HIT. By comparison, argatroban was used empirically in this study, with no patients developing HIT.

In this cohort, there was no statistically significant difference between anticoagulant groups with respect to the rate of thrombotic events, which is consistent with results of a study comparing argatroban with heparin in V-V ECMO performed by Menk et al (15) prior to the COVID-19 pandemic. In general, the rate of thrombotic events was similar to rates reported in previous studies of patients with COVID-19 requiring V-V ECMO, in which the vast majority of patients were anticoagulated with heparin (7, 13, 14, 21). In this cohort, 0.21 circuit changes occurred per week of therapy, which is less than the 0.44 exchanges per week previously reported in heparin use for COVID-19 patients on V-V ECMO (13). In our cohort, DVTs were identified via ultrasound in 52.9% of patients that survived to decannulation, all of whom were anticoagulated with argatroban at the time of DVT diagnosis. This is consistent with DVT rates previously described in non-COVID-19 on V-V ECMO and is equivalent to or lower than rates reported in COVID-19 patients (7, 9, 10, 13). In fact, previous reports on patients with COVID-19 requiring V-V ECMO suggest an increased occurrence rate of thrombotic events in general, with up to a 100% rate of DVTs identified via CT reported in one study by Parzy et al (9) in ECMO patients after decannulation.

Patients in this cohort anticoagulated with argatroban experienced a bleeding event rate similar to the rates previously reported with argatroban utilization in V-V ECMO prior to the COVID-19 pandemic (15). Importantly, there were no CNS bleeds in this study, which is a complication that has been of particular concern in COVID-19 patients (14). None of the bleeding complications occurred in the context of a supratherapeutic anticoagulation target, which is consistent with prior studies demonstrating lack of correlation between PTT values and bleeding events in argatroban (15). Major bleeding events (e.g., type IIIa or higher) occurred in only five of 24 patients, with no deaths presumed to be secondary to severe hemorrhage.

Interestingly, aspirin was coadministered empirically with both anticoagulants in the majority of patients in this cohort, with emerging evidence supporting use of aspirin in patients with COVID-19 (24). There was no statistically significant difference in aspirin utilization between patients initially treated with heparin versus argatroban, and aspirin was not associated with increased bleeding or thrombotic complications. In general, neither thrombotic nor bleeding complications were associated with decreased ECMO survival in this cohort. Overall ECMO and inhospital mortality were also comparable with a prior study in COVID-19 patients requiring V-V ECMO (33.3% vs 37% inhospital mortality) (21).

This study has several limitations, perhaps the most significant of which is concurrent aspirin utilization in the majority of patients, which may confound interpretation of the data. However, bleeding and thrombotic complication rates were similar to those previously reported in argatroban use, and aspirin use was not significantly associated with increased bleeding complications, thrombotic complications, or mortality. This study is also limited in terms of sample size, heterogeneity, and generalizability, as it is a single-center retrospective observational study. Larger, prospective studies are needed to confirm the finding that argatroban is an efficacious, safe alternative to heparin for anticoagulation in COVID-19 patients requiring V-V ECMO support, as well as to determine the influence of other factors, such as sepsis and fluid balance on the optimal argatroban dosing strategy.

CONCLUSIONS

Significant heparin resistance was present in patients requiring V-V ECMO support due to ARDS secondary to COVID-19. Argatroban with or without aspirin appears to be a safe and effective anticoagulant in this patient population, with bleeding and thrombotic complication rates similar to those previously reported with both argatroban and heparin utilization and a faster time to therapeutic anticoagulation compared with heparin.