The impact of direct oral anticoagulants on viscoelastic testing – A systematic review
Sebastian D. Sahli1† 
Clara Castellucci1† 
Tadzio R. Roche1 
Julian Rössler2 Donat R. Spahn1 Alexander Kaserer1*- 1Institute of Anesthesiology, University and University Hospital Zurich, Zurich, Switzerland
- 2Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic, Cleveland, OH, United States
Background: In case of bleeding patients and in acute care, the assessment of residual direct oral anticoagulant (DOAC) activity is essential for evaluating the potential impact on hemostasis, especially when a timely decision on urgent surgery or intervention is required. Viscoelastic tests are crucial in a modern goal-directed coagulation management to assess patients’ coagulation status. However, the role of viscoelastic test to detect and quantify residual DOAC plasma levels is controversially discussed. The aim of this review was to systematically summarize the evidence of viscoelastic tests for the assessment of residual DOAC activity.
Method: PubMed, Embase, Scopus, and the Cochrane Library were searched for original articles investigating the effect of rivaroxaban, apixaban, edoxaban, or dabigatran plasma levels on different viscoelastic tests of the adult population from database inception to December 31, 2021.
Results: We included 53 studies from which 31 assessed rivaroxaban, 22 apixaban, six edoxaban, and 29 dabigatran. The performance of viscoelastic tests varied across DOACs and assays. DOAC specific assays are more sensitive than unspecific assays. The plasma concentration of rivaroxaban and dabigatran correlates strongly with the ROTEM EXTEM, ClotPro RVV-test or ECA-test clotting time (CT) and TEG 6s anti-factor Xa (AFXa) or direct thrombin inhibitor (DTI) channel reaction time (R). Results of clotting time (CT) and reaction time (R) within the normal range do not reliable exclude relevant residual DOAC plasma levels limiting the clinical utility of viscoelastic assays in this context.
Conclusion: Viscoelastic test assays can provide fast and essential point-of-care information regarding DOAC activity, especially DOAC specific assays. The identification and quantification of residual DOAC plasma concentration with DOAC unspecific viscoelastic assays are not sensitive enough, compared to recommended anti-Xa activity laboratory measurements.
Systematic review registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=320629], identifier [CRD42022320629].
Introduction
Direct oral anticoagulants (DOACs) are prescribed for stroke prevention in atrial fibrillation, for the prevention and treatment of venous thromboembolism and for secondary cardiovascular prevention (1, 2). Currently, five substances are approved with regional differences for clinical use by medical regulatory authorities: rivaroxaban, apixaban, edoxaban, and dabigatran (3). The prescription and use of DOACs is steadily increasing since the introduction in 2008 (4). They are taken orally as fixed-dose regimens with no regular monitoring required (5).
In acute care, the assessment of residual DOAC activity is essential for evaluating the potential impact on hemostasis, especially when a timely decision on urgent surgery or intervention is required (6–9). Residual DOAC plasma levels can be quantified by high-pressure liquid chromatography-tandem mass spectrometry (HPLC-MS) or by chromogenic anti-Xa and anti-IIa assays (10). However, both measurements are more time-consuming compared to point-of-care assays. HPLC-MS measurement requires on average 2 h, whereas specific DOAC anti-Xa assays deliver results within 30 min. No standardized point-of-care test is currently available to evaluate the anticoagulant effects of DOACs (7, 8). Viscoelastic tests are crucial in a modern-goal directed coagulation management to assess patients’ coagulation status (11, 12). The role of viscoelastic test to detect residual DOAC plasma levels in acute care is controversially discussed. Therefore, this systematic review compiles the existing evidence on the accuracy of point-of-care viscoelastic tests to assess residual DOAC effects.
Viscoelastic assays
Different from standard coagulation assays, viscoelastic tests are point-of-care systems analyzing in whole blood the process of clot formation and subsequent lysis in real time with on-line graphic display. The rotational thrombelastic system (ROTEM, Werfen, Bedford, MA, USA) and thrombelastographic system (TEG, Haemonetics Corporation, Boston, MA, USA) provide similar information but operate with different techniques. While ROTEM delta uses a rotating pin, the TEG 5000 uses a cup oscillating around the pin. The new ROTEM sigma operates by the same principle as delta but is automated with ready-to-use cartridges for simultaneous testing. The new TEG 6s system uses a resonance method, is fully automated and uses prefabricated cartridges, too. Differences in the terminology of the results between both devices are shown in Figure 1. ClotPro (Haemonetics Corporation, Boston MA, USA; formerly enicor GmbH, Munich, Germany) provides six channels for parallel testing. It has a unique Active-Tip technology with the dried reagents contained in a sponge at the pipette tip.
Figure 1. The difference in the terminology of the most important results between ROTEM and TEG. ROTEM parameters: CT, clotting time; CFT, clot formation time; α, α angle; MCF, maximum clot firmness; LI (30/60), lysis index 30 and 60 min after CT. TEG parameters: R, reaction time; k, kinetics; α, α angle; MA, maximum amplitude; CL (30/60), clot lysis after 30 and 60 min (89). With reprint permission by Georg Thieme Verlag KG.
With the different viscoelastic systems, several assays can be performed depending on the clinical question (13). For ROTEM and ClotPro, the clotting time (CT) and for TEG the reaction time (R) is defined as the time from the beginning of the test until a clot firmness amplitude of 2 mm is achieved which reflects the velocity of thrombin generation.
Methods
This systematic review follows the guidelines of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) (Figure 2). We defined the PICO question for this review as “In adult patients taking DOACs (Population), are results in point-of-care viscoelastic tests (Intervention) compared to standardized laboratory tests or DOAC naïve blood (Control) altered by the drug (Outcome)?” This work was registered on the international prospective register of systematic reviews PROSPERO (registration ID # CRD42022320629).
Figure 2. Clinical questions for evidence-based practice.
Eligibility criteria and study selection
We included original articles addressing the coagulation profile of DOACs assessed with viscoelastic assays of the adult population (>18 years old) from database inception to December 31, 2021. Articles were excluded if they did not consider apixaban, edoxaban, rivaroxaban, and dabigatran; did not involve whole blood viscoelastic assays; instruments for measuring activated clotting time (ACT) solely; or referred to animal studies. Non-commercially available assays were considered beyond the scope of this review and are mentioned, but not further described. Poster abstracts and case reports were excluded too.
Search strategy
Four electronic databases have been queried: US National Library of Medicine (MEDLINE via PubMed), Excerpta Medica Database (EMBASE), Scopus database by Elsevier, and the Cochrane Library for Trials. We used following keywords and operators: (ROTEM or TEG or sonoclot or clotpro or reorox or viscoelastic or “viscoelastic hemostatic assay” or “viscoelastic test” or thrombelastometry or thrombelastography or thrombelastography or “hemostatic assay”) AND (DOAC or “direct oral anticoagulant” or NOAC or “new oral anticoagulants” or “non-vitamin k anticoagulants” or rivaroxaban or dabigatran or apixaban or edoxaban).
References of articles were retrieved for the inclusion of related articles. Publications in English and German language were considered.
Selection process
Two reviewers (CC and SDS) examined studies independently by reading the titles and abstracts. The studies corresponding to the inclusion criteria were read and the reviewers abstracted data. Any discrepancies between the reviewers were resolved by discussion.
Data items
A standard form was used to extract the following data: author(s), year of publication, study site and country, study design, number of overall patients, anticoagulant(s) examined, viscoelastic test(s) used, plasma concentrations of anticoagulant(s), main findings.
Risk of bias
The methodological quality of each included article was evaluated by the Newcastle Ottawa Scale (NOS) (14) (Supplementary Table 1). Three independent authors performed the evaluation (SDS, CC, and TRR). Disagreement was solved by discussion.
Statistics
We labeled the strength of the association, for absolute values of r, the following: 0 to 0.19 is regarded as very weak, 0.2 to 0.39 as weak, 0.40 to 0.59 as moderate, 0.6 to 0.79 as strong and 0.8 to 1 as very strong correlation (15). Regression analyses values of R2 were converted into an effect size f according to Cohen (16), where f = 0.10 represents a weak effect, f = 0.25 a moderate effect and f = 0.40 a strong effect (17).
Results
We identified 512 records in the mentioned databases of which 190 duplicates were automatically removed (Figure 3). The remaining 322 records were screened for suitability and a total of 148 full-text articles were proofread. A total of 53 studies met the pre-defined quality and inclusion criteria.
Figure 3. PRISMA flow chart of the selection process.
Viscoelastic analysis of direct factor Xa inhibitors
Rivaroxaban
We identified 31 studies describing rivaroxaban action in whole blood with viscoelastic methods (18–48) (Supplementary Tables 2.1–2.3). Except for the well-documented viscoelastic parameters clotting time (CT) and reaction time (R), rivaroxaban showed either no significant influence or was not analyzed for other parameters besides individual and heterogenous nominations. The CT and R in relation to the rivaroxaban plasma concentration are shown in Figure 4.
Figure 4. Reported clotting time (CT) and reaction time (R) in relation to the DOAC plasma concentration of the included studies for the ROTEM EXTEM and TEG 5000 kaolin assays. [c] DOAC plasma concentration in ng/ml. The dashed lines represent the lower and upper reference values for ROTEM EXTEM CT [42, 72 s (88)] and TEG 5000 R [3, 6 min (90)].
Rivaroxaban and rotational thrombelastometry
Seventeen studies assessed rivaroxaban measurements in whole blood with ROTEM (Werfen, Bedford, MA, USA) (18, 19, 23, 24, 27, 28, 30, 31, 34, 36, 39–41, 44, 45, 47, 48) (Supplementary Table 2.1). A significant correlation between rivaroxaban plasma concentration and duration of clotting time (CT) was shown for EXTEM (strong to very strong correlation) (24, 28, 30, 34, 44, 45), INTEM (moderate to strong correlation) (24, 28, 30, 34, 45), NATEM (strong correlation) (19), FIBTEM (strong correlation) (44), and HEPTEM (strong correlation) (28) assays (Table 1.1). One study did not find any significant effect of rivaroxaban on ROTEM parameters (31).
Table 1.1. Study defined ROTEM clotting time (CT) thresholds for detection of the residual DOAC plasma concentration stratified by assays.
Three studies examined modified ROTEM assays (18, 40, 48). Some of these non-commercially available modified ROTEM activators showed promising results in detecting rivaroxaban plasma levels (Table 2.1).
Table 1.2. Study defined TEG 6s reaction time (R) thresholds for detection of residual DOAC plasma concentration stratified by assays.
Table 1.3. Study defined ClotPro clotting time (CT) thresholds for detection of residual DOAC plasma concentration stratified by assays.
Table 2.1. Correlation of DOAC plasma concentration and ROTEM clotting time (CT) for different assays.
Rivaroxaban and thrombelastography
Thirteen studies described rivaroxaban action in whole blood with TEG (Haemonetics Corporation, Boston MA, U.S.A.) (20–22, 25, 26, 31–33, 35, 37, 42, 43, 46) (Supplementary Table 2.2). Of these, four studies did not report the exact rivaroxaban concentration under which conditions the viscoelastic tests were performed (22, 25, 32, 33). Four studies investigated with the new cartridge-based anti-factor-Xa [AFXa] channel of TEG 6s (20–22, 25), to the best of our knowledge not yet commercially available at the time of manuscript preparation (Table 1.2).
A significant correlation between rivaroxaban plasma concentration and reaction time (R) have been reported for the specific anti-factor-Xa channel [AFXa] (strong to very strong correlation) (20, 21, 37), and for citrated kaolin channel (moderate to strong correlation) (35, 37).
The study of Kaaber et al. mentions that approximately 65% of the patients treated with rivaroxaban presented with RapidTEG™ activated clotting time within the normal reference, but that those with an activated clotting time above this level had a significantly increased risk of severe bleeding with high transfusion demands (33). Three studies did not find any significant effect of rivaroxaban on TEG 5000 parameters (31, 32, 42). One study compared the results descriptively only (46) (Table 2.2).
Table 2.2. Correlation of DOAC plasma concentration and TEG reaction time (R) for different assays.
Rivaroxaban and ClotPro analyzer
Two studies reported results from the ClotPro analyzer (29, 38) (Supplementary Table 2.3). The commercially available Russel’s viper venom test (RVV-test) for the detection of factor Xa antagonists showed strong to very strong correlations between rivaroxaban plasma concentration and clotting time (CT) (29, 38) (Tables 1.3, 2.3).
Viscoelastic thresholds for rivaroxaban concentrations
Rivaroxaban plasma concentrations between 30 and 150 ng/ml can be detected by threshold values of the viscoelastic parameters CT and R (18–22, 24, 30, 38, 40) (Figure 5 and Tables 1.1–1.3). In particular, the RVV-test of ClotPro and the AFXa channel of TEG 6s show high sensitivity and specificity. It is important to mention that the study of Bliden et al. analyzed the results of rivaroxaban and apixaban in a pooled setting (22).
Figure 5. Detection of residual DOAC plasma concentrations with ROTEM, TEG, and ClotPro assays coded for test accuracy by sensitivity. (A) EXTEM, ROTEM assay extrinsic activated; INTEM, ROTEM assay intrinsic activated; NATEM, ROTEM assay natively activated; (B) DTI, direct thrombin inhibitor channel of TEG 6s; AFXa, anti-factor-Xa channel of TEG 6s; (C) ECA, ecarin-activated ClotPro test; RVV, Russell’s viper venom-activated ClotPro test. References: [1] Henskens et al. (30); [2] Taune et al. (69); [3] Artang et al. (21); [4] Artang et al. (20); [5] Bliden et al. (22); [6] Oberladstätter et al. (38).
Apixaban
Twenty-two studies were identified analyzing the effects if apixaban on viscoelastic testing (18, 20–22, 25–27, 29, 32, 33, 35, 38, 40, 45, 46, 48–54) (Supplementary Tables 2.1–2.3). The CT and R in relation to the apixaban plasma concentration are shown in Figure 4.
Apixaban and rotational thrombelastometry
We revealed nine studies assessing the effects of apixaban on ROTEM (18, 27, 40, 45, 48–52) (Supplementary Table 2.1). Out of these, three studies used modified or ad hoc designed assays (18, 40, 48), whereas the other studies focused on the EXTEM (27, 45, 49–52), INTEM (27, 45), NATEM (50) and FIBTEM (45) assays. Apixaban caused a statistically significant prolongation of CT in EXTEM (27, 49, 51), with a greater sensitivity than CT in INTEM (27, 45). In comparison to the other factor Xa inhibitors, apixaban had the lowest effect on CT, often requiring supra-therapeutic doses to achieve a significant CT prolongation (27, 45). Also, apixaban plasma levels beneath 50 ng/ml could not be detected by EXTEM CT changes (45, 51). The significance of a dose dependent effect of apixaban plasma concentrations on CT length was shown for EXTEM [strong correlation (45)], INTEM [strong correlation (45)], and NATEM [weak correlation (50)] assays (Table 2.1).
Our search identified four studies analyzing modified ROTEM assays (18, 40, 48, 50). Overall, the experimental changes to ROTEM resulted in CT prolongation, with some studies requiring lower concentrations than those done with commercially available channels (Table 1.1).
Apixaban and thrombelastography
Ten studies investigated the effects of apixaban on TEG with a focus on R value, using either the TEG 6s anti-factor Xa channel [AFXa] (20–22, 25), or TEG 5000 system (26, 32, 33, 35, 46, 53, 54) (Supplementary Table 2.2). A statistically significant, dose-dependent correlation of reaction time (R) and apixaban plasma concentration was shown with the anti-factor Xa channel [very strong correlation (20, 21)] and kaolin-TEG [moderate correlation (35)] (Tables 1.2, 2.2).
Two studies reported no statistically significant effect of apixaban plasma levels on reaction time (R) (32, 53).
Apixaban and ClotPro analyzer
Using the ClotPro analyzer, Oberladstätter et al. (38) found a statistically strong correlation between apixaban plasma concentrations and clotting time (CT), which, compared to the other anti-factor Xa inhibitors used in the study, showed weaker correlation (Tables 1.3, 2.3, and Supplementary Table 2.3).
Table 2.3. Correlation of DOAC plasma concentration and ClotPro clotting time (CT) for different assays.
Viscoelastic thresholds for apixaban concentrations
There is no result with ROTEM EXTEM and INTEM for apixaban thresholds detection. Apixaban plasma concentrations of ≥30 and of ≥50 ng/ml can be detected by threshold values of the AFXa channel by TEG 6s and RVV-test by ClotPro (20–22, 38) (Figure 5 and Tables 1.1–1.3). No differences in R times between apixaban peak and through samples were found in another study (25).
Edoxaban
Six studies (25, 29, 38, 45, 46, 55) were identified analyzing the effects if edoxaban on viscoelastic testing (Supplementary Tables 2.1–2.3). The CT and R in relation to the edoxaban plasma concentration are shown in Figure 4.
Edoxaban and rotational thrombelastometry
By the time literature review was concluded there were only two studies assessing the effects of edoxaban on ROTEM showing significant prolongations of EXTEM clotting time (CT) even in therapeutic doses (45, 55) (Table 2.1).
Edoxaban and thrombelastography
Two studies described effects of edoxaban on the anti-factor-Xa channel [AFXa] of the TEG 6s and TEG 5000 system (Supplementary Table 2.2). The one study reported a pooled analysis of various DOACs together, not allowing for an individual result analysis (56). The other reported a change in parameters at doses several times higher than peak plasma levels (46) (Table 2.1).
Edoxaban and ClotPro analyzer
Alterations of ClotPro parameters by edoxaban were found in two studies (Supplementary Table 2.3). Main changes occurred to CT of the russel viper venom test, showing high sensitivity and specificity for a low threshold (38). Further, a statistically significant prolongation of the CT for this test was only seen in patients taking edoxaban compared to the other anti-factor Xa inhibitors rivaroxaban and apixaban (29) (Tables 1.3, 2.3).
Viscoelastic thresholds for edoxaban concentrations
Edoxaban plasma concentrations of 50 and 100 ng/ml can be detected by threshold values of clotting time (CT) (38) (Figure 5 and Table 1.2).
Viscoelastic analysis of direct factor II inhibitor
Dabigatran
29 studies described dabigatran action in whole blood with viscoelastic methods (20–22, 25–27, 29–31, 34, 35, 38, 45, 48, 57–71) (Supplementary Tables 2.1–2.3). As already mentioned for the factor Xa inhibitors, dabigatran showed either no significant influence or was not analyzed for other parameters except for the viscoelastic parameters clotting time (CT) and reaction time (R). The CT and R in relation to the dabigatran plasma concentration are shown in Figure 4.
Dabigatran and rotational thrombelastometry
Fourteen studies assessed dabigatran in whole blood with ROTEM (27, 30, 31, 45, 48, 58, 60, 61, 68–71) (Supplementary Table 2.1). Out of these, one study did not report the exact dabigatran concentration under which conditions the viscoelastic tests were performed (48). Most studies analyze the EXTEM (27, 30, 31, 34, 45, 58, 60, 64, 68–70) and INTEM (27, 30, 31, 34, 45, 58, 60, 64, 68, 70) original assays, with less data published on NATEM (61, 68) and FIBTEM (34, 45, 58, 70). Four studies reported results obtained from ad hoc designed or modified original assays (48, 60, 69, 70).
The majority of studies describe a correlation between plasma dabigatran concentrations with a linear increase of clotting time (CT), some highlighting a higher sensitivity of EXTEM over INTEM (27, 31, 34, 45, 58, 64, 68, 70, 72). In detail, a significant correlation between dabigatran plasma concentration and duration of clotting time (CT) varied from strong [EXTEM (34), INTEM (34, 70)] to very strong [EXTEM (45, 58, 64, 70), INTEM (45, 58, 60, 64) and FIBTEM (58, 70)] (Table 2.1).
Dabigatran and thrombelastography
Four studies investigated dabigatran action with the new cartridge-based direct thrombin inhibitor [DTI] channel of TEG 6s (20–22, 25), to our knowledge not yet commercially available at the time of manuscript preparation. Of these, two (22, 25) did not report the exact dabigatran concentration under which conditions the viscoelastic tests were performed.
The further studies investigated parameters with the TEG 5000 system (26, 31, 35, 57, 62, 63, 65–67) (Supplementary Table 2.2).
Dabigatran treated whole blood led to a significant prolongation of reaction time (R) when compared to baseline or control values in regard to the direct thrombin inhibitor channel (20), the citrated kaolin channel (26, 35, 67, 73), RapidTEG™ channel (26, 62), and calcium chloride (CaCl2) channel (63). One study did not find any effect of dabigatran on TEG 5000 parameters (57).
A significant correlation between dabigatran plasma concentration and reaction time (R) was shown for the direct thrombin inhibitor channel [very strong correlation (20, 21)], for the citrated kaolin channel [strong to very strong correlation (35, 65, 67)], and calcium chloride channel [moderate correlation (63)] (Table 2.2).
Dabigatran and ClotPro analyzer
The three studies performed with ClotPro showed moderate (59) to very high (29, 38) correlation between plasma dabigatran concentration and clotting time (CT) of pathway, specific for the detection of factor IIa antagonist (Supplementary Table 2.3).
Viscoelastic thresholds for dabigatran concentrations
Dabigatran plasma concentrations between 20 and 100 ng/ml can be detected by threshold values of the viscoelastic parameters CT and R (20–22, 30, 38, 69) (Figure 5; Tables 1.1–1.3). In particular, the ECA-test of ClotPro and the DTI channel of TEG 6s show consistent statistical sensitivity and specificity.
Impact of andexanet alfa and idarucizumab on viscoelastic testing
The specific antagonists andexanet alfa and idarucizumab have been developed for the reversal of direct oral anticoagulants. There is limited to no published information on viscoelastic coagulation testing for specific DOAC reversal (3) despite this method being of particular importance, as the treatment monitoring after administration of andexanet alfa should not be based on commercial anti-FXa activity assays (74, 75). In these assays, the FXa inhibitor dissociates from andexanet alfa resulting in the detection of falsely elevated anti-FXa activity levels.
We found two studies reporting viscoelastic testing after the specific reversal of DOAC (68, 76). No data is available for ROTEM on behalf of andexanet alfa. Takeshita et al. investigated the reversal of dabigatran by adding idarucizumab, which resulted in both INTEM and EXTEM clotting time reversal toward reference ranges (68). Oberladstätter et al. investigated the specific reversal of dabigatran with ClotPro ecarin clotting time (ECA-test CT) and apixaban, edoxaban, and rivaroxaban with ClotPro Russell’s viper venom test clotting time (RVV-test CT) (76). Idarucizumab substantially reduced ECA-CT, whereas andexanet alfa did not normalize the RVV-CT. Andexanet alfa spiking of non-anticoagulated blood prolonged RVV-CT, potentially as a consequence of a competitive antagonism with human factor Xa.
Discussion
This review shows the effect of the DOACs rivaroxaban, apixaban, edoxaban, and dabigatran on viscoelastic point-of-care tests. A total of 53 studies were included and qualitatively analyzed. Mainly, studies report ROTEM and TEG measurement methods, with rivaroxaban and dabigatran being the most studied.
Correlation of direct oral anticoagulant plasma concentration with viscoelastic tests
Direct oral anticoagulants (DOACs) show a clear influence on CT and R, resulting in being the main focus of studies. Other ROTEM and TEG parameters (e.g., MCF, A10, LI 60, or alpha angle) were either not further analyzed or showed no to minor changes in the reported studies. By using different activators, viscoelastic tests distinguish extrinsic, intrinsic or total pathways of coagulation in relation to the DOAC effect. The most specific results are produced by viscoelastic assays that reflect thrombin generation by measuring the physiological constitutional change of blood from the viscous to the clotted state. In principle, this reflects the length of CT as well as R. Accordingly, most significant concentration-dependent changes are described for ROTEM INTEM/EXTEM-CT and for TEG AFXa/DTI as well as CK channel R time. Overall, the results of the analyzed studies were trending toward DOACs showing a higher correlation of CT with drug concentration in the EXTEM channel over INTEM and FIBTEM. With TEG, the greatest affinity resulted with the AFXa or DTI channel, which are currently not yet available. Stronger correlations were demonstrated in assays with alternative not commercially available activators, but these are isolated examples and beyond the scope of this review. Not only is it important to consider the right cartridge and channel, but also the mechanism of action of the DOAC, distinguishing between dabigatran and factor-Xa inhibitors. In regards to the latter, the two most analyzed drugs, rivaroxaban and apixaban, show distinct differences in their affinity, even in identical conditions, potentially explaining the discrepancies in CT with apixaban (77). ROTEM tests were only poorly impacted by low levels of rivaroxaban, edoxaban or dabigatran, and apixaban had only a low effect even at high concentrations.
Detection of clinically relevant direct oral anticoagulant plasma concentrations with viscoelastic tests
Of particular interest are threshold values of clotting time CT or reaction time R at which a certain DOAC concentration must be assumed. It was shown that a cut-off value of 50 ng/ml does not exacerbate ongoing hemorrhage in bleeding patients (78, 79). For surgery with high bleeding risk, a preoperative DOAC concentration less than 30 ng/ml is proposed (78, 80, 81). In surgery with high expected blood loss, a calculated rivaroxaban concentration of greater than 100 ng/ml was associated with a significant increase of perioperative red blood cell loss (82). For thrombolysis in patients with acute ischemic stroke, plasma concentrations up to 100 ng/ml have been suggested to be acceptable (83). According to current guidelines, administration of reversal agents in bleeding patients on DOACs should be considered if plasma concentrations exceed 50 ng/ml (80). Most of the research regarding perioperative bleeding thresholds focuses on rivaroxaban, as this is the most prescribed DOAC (79, 81). We are not aware of any study investigating the interchangeability of above mentioned perioperative bleeding thresholds between different DOACS.
Most data are available for rivaroxaban and dabigatran. We revealed a good sensitivity of viscoelastic parameters in patients using DOAC and might therefore be a good candidate for emergency testing. The added advantage is that the results are readily available and there is uniform performance. But it must be assumed that viscoelastic methods are not sensitive enough to determine specific DOAC concentrations. Results within the normal reference range do not reliably exclude relevant residual DOAC plasma levels and limit their clinical implications. Further, traditional viscoelastic coagulation monitoring assays were not designed to measure the effects of DOACs. Of interest, the costs of DOAC specific laboratory measurements, such as anti-Xa-activity or liquid-chromatography mass-spectrometry (a more accurate method compared to HP-LC) are $40USD and $130USD, with a turnaround time of approximately 30–60 min and 2-4 h, respectively. Moreover, liquid-chromatography mass-spectrometry measurements may not be available 24/7. Viscoelastic tests cost on average about $70USD per analysis and provide first results within minutes. However, there may be price differences depending on the manufacturer and country-specific health system.
Monitoring the specific direct oral anticoagulant reversal
The use of commercially available anti-FXa assays to measure rivaroxaban or apixaban concentrations in patients after reversal with andexanet alfa has limitations. One of the limitations is the large sample dilution in the assay set-up, which causes dissociation of the inhibitor from the andexanet alfa-inhibitor complex, resulting in an erroneous elevation of the anti-FXa activity (5). For rivaroxaban, the residual drug concentration 4 h after treatment with andexanet alfa was approximately 42% lower than the pretreatment concentration (84). A concentration that can still affect hemostasis. Thus, viscoelastic testing may play an important role in monitoring after andexanet alfa reversal (85).
For dabigatran reversal, there appears to be a rebound or dissociation effect after 12 to 24 h (5). Measurements of dabigatran may predict the need for secondary dosing of this reversal agent. In a retrospective study, it has been shown that no plasma dabigatran rebound was observed after reversal in patients with dabigatran plasma level <264 ng/mL at baseline (86). Further, in a case of ongoing bleeding by chronic accumulation of dabigatran showed impressively ongoing redistribution of dabigatran necessitates repetitive application of idarucizumab to neutralize dabigatran (87). Accordingly, repeated and timely coagulation monitoring is required.
Limitation
The studies are heterogeneous, and their replication of results was not constant. For apixaban in particular, there are heterogeneous data for the effect on CT EXTEM in ROTEM. This may be attributed to methodological differences in the work of Escolar et al. and Pujadas-Mestres et al. (49, 51). Most studies are based on a small study population or sample collection. The analyses reflect different populations including healthy volunteers with spiked samples and in vitro analyses. Furthermore, there is a lack of international reference values among the different tests. On the other hand, this work includes a large number of studies. Direct conclusions for the treatment of patients under DOAC can be made for clinical use from this review. We omitted betrixaban from our review as the drug was discontinued by the manufacturer in April 2020 for independent business reasons and never received approval from the European Medicines Agency.
Conclusion
Viscoelastic test assays can provide fast and essential point-of-care information regarding residual DOAC activity, especially DOAC specific assays. Even with strong correlation between the DOAC plasma concentration and viscoelastic parameter clotting time (CT) or reaction time (R), the results could be within the normal reference range. The quantification of residual DOAC plasma concentration with DOAC unspecific viscoelastic assays is not sensitive enough, compared with recommended anti-Xa activity laboratory measurements.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
SDS, DRS, and AK contributed to conception and design of the study. SDS and CC organized the database. SDS wrote the first draft and processed the manuscript. CC wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.
Acknowledgments
DRS acknowledges grant support from the Swiss National Science Foundation, the Swiss Society of Anesthesiology and Perioperative Medicine (SSAPM), and the Swiss Foundation for Anesthesia Research via his department.
Conflict of interest
AK received honoraria for lecturing from Bayer AG Switzerland. DRS’s academic department receives grant support from Vifor SA, and Vifor (International) AG. He is co-chair of the ABC-Trauma Faculty, sponsored by unrestricted educational grants from Novo Nordisk Health Care AG, CSL Behring GmbH, LFB Biomédicaments, and Octapharma AG. He has received honoraria/travel support for consulting or lecturing from: Alexion Pharmaceuticals Inc., AstraZeneca AG, Bayer AG, B. Braun Melsungen AG, CSL Behring GmbH, Celgene International II Sàrl, Daiichi Sankyo AG, Haemonetics, Instrumentation Laboratory (Werfen), LFB Biomédicaments, Merck Sharp & Dohme, Novo Nordisk Health Care AG, PAION Deutschland GmbH, Pharmacosmos A/S, Pfizer AG, Pierre Fabre Pharma, Portola Schweiz GmbH, Roche Diagnostics International Ltd, Sarstedt AG & Co., Shire Switzerland GmbH, Takeda, Tem International GmbH, Vifor Pharma, Vifor (International) AG, and Zuellig Pharma Holdings.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
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Keywords: DOAC, point-of-care, ROTEM, TEG, ClotPro, FXa inhibitor, FII inhibitor
Citation: Sahli SD, Castellucci C, Roche TR, Rössler J, Spahn DR and Kaserer A (2022) The impact of direct oral anticoagulants on viscoelastic testing – A systematic review. Front. Cardiovasc. Med. 9:991675. doi: 10.3389/fcvm.2022.991675
Received: 26 July 2022; Accepted: 03 October 2022;
Published: 07 November 2022.
Edited by:
Jianyong Ma, University of Cincinnati, United StatesReviewed by:
Dimitrios Tsakiris, University of Basel, SwitzerlandNicolas Gendron, Hôpital Européen Georges Pompidou, France
Copyright © 2022 Sahli, Castellucci, Roche, Rössler, Spahn and Kaserer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Alexander Kaserer, alexander.kaserer@usz.ch
†These authors share first authorship