Author + information
- Received January 13, 2014
- Revision received May 21, 2014
- Accepted May 26, 2014
- Published online September 16, 2014.
- Adam Cuker, MD, MS∗∗ (, )
- Deborah M. Siegal, MD, MSc†,
- Mark A. Crowther, MD, MSc† and
- David A. Garcia, MD‡
- ∗Department of Medicine and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- †Department of Medicine, McMaster University, Hamilton, Ontario, Canada
- ‡Department of Medicine, University of Washington, Seattle, Washington
- ↵∗Reprint requests and correspondence:
Dr. Adam Cuker, Hospital of the University of Pennsylvania, 3 Dulles, 3400 Spruce Street, Philadelphia, Pennsylvania 19014.
Background Non–vitamin K oral anticoagulants (NOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations.
Objectives This study’s objective was to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban.
Methods We searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2).
Results We identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R2 = 0.92 to 0.99) and ecarin-based assays (R2 = 0.92 to 1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. For rivaroxaban and apixaban, anti-Xa activity is linear (R2 = 0.89 to 1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification.
Conclusions Dabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in NOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed.
Dabigatran etexilate, an oral prodrug of the direct thrombin inhibitor dabigatran, and the oral direct inhibitors of factor Xa, rivaroxaban and apixaban, are approved in the United States, Europe, and Canada to prevent stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). They are also variably licensed for treatment of venous thromboembolism (VTE) and prevention of VTE after major orthopedic surgery (MOS) in certain jurisdictions. We refer to these agents collectively as non–vitamin K oral anticoagulants (NOACs) in this paper. Synonymous terms preferred by other researchers include direct-acting oral anticoagulant agents and new, novel, or target-specific oral anticoagulant agents (1).
Unlike warfarin and other vitamin K antagonists (VKAs), the NOACs are administered in fixed doses and do not require routine laboratory monitoring (2–4). However, measurement of their anticoagulant activity may be desirable in special clinical settings such as bleeding; the pre-operative state; breakthrough thrombosis; and suspected overdose, noncompliance, or drug interactions and in certain populations, including those with extremes in body weight and in the elderly and patients with renal insufficiency in whom there is a risk of drug accumulation. Assessment of anticoagulant effect may also be important in patients with AF presenting with acute ischemic stroke before administration of thrombolytic therapy (5).
Numerous studies on use of coagulation assays for measurement of NOAC activity have been published recently, although a systematic review has not been undertaken. The objective of our analysis was to summarize current evidence regarding laboratory measurement of NOAC anticoagulant activity and to provide evidence-based guidance to practicing cardiologists on the interpretation of coagulation tests in NOAC-treated patients.
We performed a systematic review of the literature to examine current evidence for laboratory measurement of the NOACs. A search of PubMed and Web of Science from inception through December 1, 2013, was undertaken separately for dabigatran, rivaroxaban, and apixaban using the following key words: “name of drug” AND ((laboratory measurement) OR (laboratory monitoring)).
Articles were examined, first by title and abstract and then by review of the complete paper as indicated. Additional articles were sought by reviewing bibliographies. Liquid chromatography/tandem mass spectrometry (LC-MS/MS) is the reference method for measurement of the plasma concentration of NOACs (6). Studies that reported the relationship between drug (or active metabolite) levels in human plasma, as measured directly using LC-MS/MS or indirectly using LC-MS/MS–validated calibration standards and 1 or more clinical coagulation assays, were eligible for inclusion. We excluded animal studies, abstracts only, and non–English language publications.
We extracted key characteristics from eligible studies and recorded them in an evidence table. These included author, year of publication, setting, NOAC (i.e., dabigatran, rivaroxaban, or apixaban), reference method for measurement of drug levels, range of drug concentrations studied, test material (i.e., ex vivo patient plasma, ex vivo healthy control plasma, or spiked normal plasma), dose (for studies using ex vivo plasma only), indication (for studies using ex vivo patient plasma only), number of samples (for studies using individual [i.e., unpooled] plasma only), coagulation assays and reagents, and descriptors of the relationship between drug level and coagulation assay (e.g., R2 values, range of linearity).
Study quality was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2), a standardized tool for quality assessment of studies of diagnostic accuracy. The tool comprises 4 domains: patient selection, index test, reference standard, and flow and timing. Risk of bias is assessed across all domains; the first 3 domains are also assessed with respect to applicability to clinical practice (7).
Dabigatran etexilate, an oral nonpeptide prodrug, is rapidly converted to the active drug dabigatran by ubiquitous esterases. Dabigatran directly inhibits both free and clot-bound thrombin. It has relatively poor bioavailability (approximately 6.5%) and is eliminated predominantly by the kidneys (80%). In individuals with normal renal function, the half-life of dabigatran is 12 to 14 h. Prolonged clearance and bioaccumulation are observed in patients with renal insufficiency (8). In patients with nonvalvular AF and normal kidney function, the dose is 150 mg twice daily, which is reduced in patients with renal insufficiency.
Peak levels of dabigatran occur 2 to 3 h after ingestion. Steady-state peak and trough concentrations in patients with AF and normal renal function taking dabigatran 150 mg twice daily are shown in Table 1 (8). Substantial interindividual variability in drug exposure is observed. In the PETRO (Prevention of Embolic and Thrombotic Events in Patients With Persistent Atrial Fibrillation) study, the range (5th to 95th percentile) in peak and trough concentrations in patients taking 150 mg twice daily was 64 to 443 ng/ml and 31 to 225 ng/ml, respectively (9,10).
Our literature search yielded 160 articles. Nine additional references were identified from bibliographies. A total of 152 articles were excluded: 135 did not report an original research study, 14 did not report drug levels measured by LC-MS/MS, and 3 were published as abstracts only. The remaining 17 articles (11–27) met eligibility criteria (Figure 1). Eligible studies were collectively conducted in 9 different countries across a range of dabigatran concentrations from 0 to 1,886 ng/ml. Only 4 studies used ex vivo plasma from dabigatran-treated patients; the remainder involved ex vivo healthy volunteer plasma or normal plasma spiked in vitro with dabigatran as the test material (Table 2).
Activated partial thromboplastin time
Twelve eligible studies reported a relationship between the activated partial thromboplastin time (APTT) and dabigatran levels. Three used ex vivo patient plasma, 2 ex vivo healthy volunteer plasma, and 7 normal plasma spiked with dabigatran in vitro (Table 2). Dabigatran prolonged the APTT in a concentration-dependent manner in both ex vivo and in vitro studies. The dose response was linear up to a concentration of 200 to 300 ng/ml and then flattened out at higher drug levels (17,28). This curvilinear relationship did not permit quantitative assessment of dabigatran levels, particularly at higher concentrations.
Commercial APTT reagents differ widely in their sensitivity to dabigatran. The APTT of plasma spiked with dabigatran 120 ng/ml ranged from 26.0 to 91.9 s in a cross-validation study of 9 different APTT methods (27). These findings suggest that coagulation laboratories should perform dose-response studies using calibration standards to determine the sensitivity of their particular APTT method to dabigatran and communicate the results to clinicians. The least sensitive reagents required a dabigatran concentration of approximately 400 ng/ml to produce a 2-fold prolongation in the APTT over control (19). The APTT may not be prolonged in the presence of typical on-therapy trough levels (Table 1), particularly if a relatively insensitive reagent is used. In a study of ex vivo plasma from patients taking dabigatran 150 mg twice daily, 18% of participants had a normal APTT at trough (25). In another study of patients with AF, some samples had an APTT within the normal range despite dabigatran concentrations as high as 60 ng/ml (23).
Prothrombin time/international normalized ratio
Eleven studies reported a relationship between dabigatran levels and the prothrombin time/international normalized ratio (PT/INR). Eight used spiked plasma, 2 ex vivo patient plasma, and 1 ex vivo plasma from healthy volunteers (Table 2). Dabigatran prolonged the PT in a concentration-dependent manner, as defined by an exponential (i.e., nonlinear) relationship (17). The PT/INR was less sensitive to dabigatran than the APTT. In an ex vivo study of patients with AF, an INR of 1.2 or greater was only observed with dabigatran concentrations in excess of 400 ng/ml (23).
As with APTT, commercial PT reagents differ in their sensitivity to dabigatran. In a survey of 71 coagulation laboratories, the PT of plasma spiked to a concentration of 300 ng/ml ranged from 15.7 to 50.2 s, depending on the reagent (27). PT may be measured using 2 assay types. The Quick method is influenced by the entire extrinsic and common pathways of coagulation, whereas the Owren method is affected only by factors II, VII, and X. In studies of spiked plasma, Quick PT reagents were more sensitive to dabigatran than Owren reagents (14,27).
Point-of-care devices are available for measuring the INR (POC-INR) in whole blood in VKA-treated patients. In one study assessing the relationship between dabigatran levels and a single POC-INR system, the POC system yielded INR values 2- to 4-fold higher than those obtained using a laboratory PT/INR method. Dabigatran concentrations >500 ng/ml were beyond the POC system’s limit of detection (22).
Six studies reported a relationship between thrombin time (TT) and dabigatran levels (Table 2). The TT (in unmodified form) was inordinately sensitive in both ex vivo and in vitro studies. Depending on the reagent, dabigatran concentrations of as little as 25 and up to 150 ng/ml exceeded the limits of detection (15–17,28).
In the dilute TT assay, the excessive sensitivity of the TT is overcome by diluting the plasma sample (21). Seven studies reported a relationship between the dilute TT and dabigatran concentration (Table 2). Two studies used an in-house modification of the TT (15,20); 5 used the HEMOCLOT thrombin inhibitor assay (HYPHEN BioMed, Neuvillesur-Oise, France), a commercially available dilute TT test (17,21,23–25). Dabigatran prolonged the assay in a concentration-dependent manner. The relationship showed a high degree of linearity, with R2 values ranging between 0.92 and 0.99 in both in vitro and ex vivo studies. The lower limit of detection according to the manufacturer is 50 ng/ml (21). Two studies determined the assay to be less accurate and more variable at concentrations below 50 to 100 ng/ml (15,21). The dilute TT is currently not widely available; in a recent survey in Australia and New Zealand, only 9 of 592 laboratories reported using it (29).
Ecarin is a snake venom that cleaves prothrombin to form meizothrombin, an unstable intermediate of thrombin. Dabigatran inhibits the thrombin-like activity of meizothrombin (24). Two assays use ecarin as an activator: the ecarin clotting time (ECT) and ecarin chromogenic assay (ECA).
Six studies reported a relationship between ECT and dabigatran levels (Table 2). Both in vitro and ex vivo studies demonstrated a high degree of linearity, with R2 values ranging between 0.92 and 1.00. Loss of linearity was observed in 2 studies at dabigatran levels in excess of 470 to 500 ng/ml (17,19). A relationship between ECA and drug levels was reported in 4 studies (Table 2). The relationship was linear, with R2 values of 0.94 to 0.99 in in vitro and ex vivo samples. One study identified greater variability at dabigatran concentrations <50 ng/ml (23). The ECT and ECA are hampered by lack of standardization, variability in sensitivity to dabigatran among different lots of ecarin, and limited availability (17,20).
Relationships between dabigatran level and the dilute PT, prothrombinase-induced clotting time (PiCT), and activated clotting time (ACT) were each reported in a single study. Both the dilute PT and PiCT evinced a complex nonlinear dose-response curve (17). As with heparin, the ACT proved insensitive to lower concentrations of dabigatran. In an ex vivo study, the ACT was normal in 40% of trough samples despite on-therapy dabigatran levels (25).
Rivaroxaban is an oral inhibitor of free and clot-associated factor Xa through reversible, competitive interactions with its active site (30). Bioavailability following oral administration is dose dependent (80% to 100% following a 10-mg dose; 66% following a 20-mg dose). It is highly bound to plasma proteins (>90%) (31); plasma levels peak 2 to 4 h following oral administration (32,33). Partially excreted by the kidneys (36%), rivaroxaban has a half-life of 6 to 13 h depending on dose and age (31–35). Table 1 shows expected peak and trough plasma concentrations in patients with AF treated with 20 mg daily (36).
Our literature search yielded 134 unique rivaroxaban articles. Two additional references were identified from bibliographies. We excluded 121 articles: 108 did not report an original research study, 12 did not report a relationship between a coagulation assay and drug levels measured by LC-MS/MS, and 1 was published as an abstract only. The remaining 15 articles (27,37–50) met eligibility criteria (Figure 1). Rivaroxaban concentrations in eligible studies ranged from 0 to >1,000 ng/ml. Four studies used ex vivo plasma from rivaroxaban-treated patients, 1 incorporated ex vivo plasma from healthy controls, and the remainder used normal plasma spiked in vitro with rivaroxaban (Table 3).
We found 11 studies evaluating the effect of rivaroxaban on PT (Table 3). In general, rivaroxaban prolonged the PT in a concentration-dependent, linear fashion in plasma spiked with rivaroxaban and in plasma from patients receiving rivaroxaban for approved indications. On-therapy rivaroxaban concentrations showed a modest effect on PT. Typical trough (41 to 60 ng/ml) and peak (219 to 305 ng/ml) concentrations increased PT by 6% to 19% and 50% to 135%, respectively (27,38,42,47). Assay sensitivity varied significantly among thromboplastin reagents. Interassay variability was reduced by use of an international sensitivity index specific for rivaroxaban but not by conversion to an INR used for monitoring VKA therapy (38,42). These observations suggest that coagulation laboratories should perform dose-response studies using calibration standards to determine the sensitivity of their particular PT method for rivaroxaban and communicate the results to clinicians.
Activated partial thromboplastin time
Five studies evaluated the effect of rivaroxaban on APTT (Table 3). Whereas rivaroxaban prolonged APTT in a dose-dependent manner, the overall relationship between rivaroxaban concentration and APTT prolongation was nonlinear, with studies reporting conflicting data regarding the concentration ranges over which nonlinearity was most pronounced (27,41,45). Similar to PT results, there was significant variability among reagents and among individual laboratories in a multicenter study (27,45). Hillarp et al. (41) reported that the APTT assay was insensitive at the lowest drug level studied (25 ng/ml).
Ten studies assessed the effect of rivaroxaban on anti-Xa activity (Table 3). In general, the studies showed a linear, concentration-dependent relationship between rivaroxaban concentration and anti-Xa activity over a wide range of concentrations (e.g., 20 to 660 ng/ml) when they were measured using a standard curve generated with rivaroxaban calibrators and controls with R2 values ranging from 0.95 to 1.00 (39,43,44,49,50). The correlation was less robust at concentrations <100 ng/ml (49). However, Samama et al. (46) demonstrated that low rivaroxaban concentrations could be measured with a modified anti-Xa test using less diluted samples. Investigators found a greater degree of assay imprecision at higher rivaroxaban concentrations (800 ng/ml) in one study (45). In a multicenter study, both intralaboratory and interlaboratory precision were satisfactory except at the lower limit of detection (20 ng/ml); use of a centrally distributed reagent reduced interlaboratory variability (46). Mathematical modeling also decreased interassay variability resulting from different sensitivities of individual reagents to rivaroxaban (40). When commercial anti-Xa assays were used with unfractionated or low-molecular-weight heparin (LMWH) calibrators (rather than rivaroxaban calibrators), the relationship remained linear up to a rivaroxaban concentration of 500 ng/ml (38,41).
The relationship between rivaroxaban concentration and the dilute PT, dilute Russell viper venom time (dRVVT), and PiCT was evaluated in a single study (38). Researchers uncovered a linear, dose-dependent relationship between rivaroxaban and the dilute PT. Rivaroxaban increased the dRVVT ratio (expressed as ratio vs. baseline) in a concentration-dependent but nonlinear manner. At low concentrations of rivaroxaban (<200 ng/ml), there was a paradoxical shortening of PiCT, whereas PiCT was prolonged in a concentration-dependent fashion at higher concentrations.
Like rivaroxaban, apixaban is a small, orally available, direct inhibitor of coagulation factor Xa (51). It has 50% bioavailability and, in healthy volunteers, reaches its maximum plasma concentration approximately 3 h after ingestion. Apixaban is highly protein bound in plasma, and concomitant food intake has little impact on its pharmacokinetics (52). Metabolized through multiple routes, apixaban is less dependent on renal clearance than dabigatran and rivaroxaban. In persons with normal renal function, apixaban has a half-life of approximately 12 h (53). As measured by LC-MS/MS, the expected steady-state concentrations of apixaban have been published by Frost et al. (52) and are shown in Table 1.
Our literature search for apixaban yielded 70 articles; 3 additional references were identified from bibliographies. Sixty-nine articles were excluded: 68 did not report an original research study and 1 was published as an abstract only. The remaining 4 articles (37,54–56) met eligibility criteria (Figure 1). Eligible studies collectively evaluated apixaban across a range of concentrations from 0 to 2,500 ng/ml (Table 4).
Prothrombin time/international normalized ratio
We found 3 studies that reported the relationship between the PT and apixaban levels. One study used both spiked normal plasma and ex vivo plasma from apixaban-treated patients (37), another used spiked plasma as well as ex vivo plasma from healthy volunteers taking apixaban (55), and the third study included only spiked normal plasma samples (56) (Table 4). For the 2 studies that used ex vivo plasma, the relationship was linear in one (37) and curvilinear in the other (55). Correlation was modest, with R2 values of 0.36 and 0.41, respectively. Across in vitro and ex vivo samples and for a variety of reagents, the PT was inadequately sensitive to apixaban, not only below, but also above the expected trough concentration of 50 ng/ml.
Activated partial thromboplastin time
Only 1 study compared apixaban concentrations with APTT (Table 3), which was measured using 10 different APTT reagents in normal plasma samples spiked with 10 different concentrations of apixaban. The sensitivity of the APTT was unacceptably low; all assays yielded a ratio of 1.1 times control when the spiked apixaban concentration was 100 ng/ml (i.e., twice the expected trough concentration).
Three studies compared anti-Xa activity measurements with the plasma concentration of apixaban (Table 4). In 2 of the studies (37,54), ex vivo patient samples were used, whereas the third study (56) included only spiked samples of normal plasma. In general, the relationship was linear at all apixaban concentrations, with R2 values ranging from 0.89 to 0.97. Available evidence suggests that an anti-Xa assay calibrated with LMWH standards will also correlate linearly with apixaban concentrations (37,54).
Assessment of study quality using QUADAS-2 criteria (7) highlighted several recurrent methodological concerns among eligible studies (Table 5). Many studies used in vitro samples or ex vivo samples from healthy controls rather than ex vivo patient samples. Concern about the applicability of these studies to clinical practice within the patient selection domain was judged to be high. Some studies examined assays not widely available to clinicians (e.g., ECA, ECT, dilute TT). Concern regarding applicability of these studies to clinical practice across the index test domain was judged to be high. Because data correlating plasma NOAC levels and clinical outcomes are scarce, concern about the applicability of the reference standard (plasma drug concentration) to clinical practice was judged to be high for all eligible studies.
This systematic review sought to examine evidence for laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban. Although data on the relationship between plasma NOAC levels and clinical outcomes are beginning to emerge (57), there is, as yet, no evidence that routine monitoring or dose titration will improve outcomes. Nevertheless, measurement may be useful in 3 circumstances: 1) to determine if very high levels are present (in the case of suspected excess effect [e.g., due to overdose or bioaccumulation]); 2) to determine if drug is present in typical on-therapy ranges (e.g., in the case of suspected therapeutic failure); and 3) to determine if any clinically relevant drug effect is present (e.g., in the case of bleeding or planned invasive procedures). An ideal assay would thus show adequate linearity, sensitivity, and reproducibility to enable quantification across a broad range of drug levels. Apart from LC-MS/MS, a test generally restricted to select reference laboratories, no single coagulation assay meets these idealized standards. Therefore, it is important for clinicians to be aware of how coagulation tests perform at NOAC concentrations below, within, and above typical on-therapy ranges (Central Illustration).
The effect of dabigatran on various coagulation assays is summarized in the Central Illustration. The TT is exquisitely sensitive to dabigatran. A normal TT excludes the presence of clinically relevant drug levels; however, the assay is too sensitive for quantification within and above the on-therapy range. The dilute TT, ECT, and ECA show a high degree of linearity at drug levels >50 ng/ml and are thus useful for quantification across the entire on-therapy range. They may be unreliable at concentrations below this threshold. The APTT is relatively insensitive to dabigatran; a normal APTT may not exclude clinically relevant below or within on-therapy drug levels. The curvilinear response of APTT at higher drug levels does not permit accurate quantification. The PT has even poorer sensitivity and may be normal within much of the on-therapy range.
Anti-Xa activity measured using chromogenic substrates and rivaroxaban or heparin/LMWH calibrators correlates linearly with rivaroxaban over a wide range of concentrations (20 to 660 ng/ml) (Central Illustration). When rivaroxaban calibrators are used, anti-Xa assays can provide a quantitative measure of rivaroxaban concentration. A negative anti-Xa assay likely excludes clinically relevant rivaroxaban levels. Although rivaroxaban prolongs the PT, assay results vary markedly with different thromboplastin reagents. A normal PT does not rule out the presence of clinically significant below or within on-therapy rivaroxaban concentrations; however, a prolonged PT qualitatively indicates the drug’s presence. The APTT is not suitable for measuring rivaroxaban due to the nonlinear relationship with rivaroxaban concentration, poor sensitivity, and significant variability between reagents.
Although both the PT and APTT may be prolonged in the presence of apixaban, neither is sufficiently sensitive to exclude the presence of clinically relevant on-therapy drug concentrations (Central Illustration). Anti-Xa activity measurements demonstrate a strong linear correlation with apixaban concentration; the absence of detectable anti-Xa activity (whether the standard curve is established with apixaban or LMWH) likely excludes the presence of physiologically important apixaban activity.
Suggestions and comparisons with guidance documents
Recommendations for laboratory measurement of the NOACs differ by drug and clinical objective. The findings of our systematic review support the suggestions summarized in Table 6. These suggestions align with recommendations provided in drug labels and published guidance documents, with 2 notable exceptions. First, we found strong evidence from studies of ex vivo patient samples that a normal APTT does not definitively exclude on-therapy dabigatran concentrations (23,25). This observation is at variance with guidelines from the American Society of Hematology (ASH) and the British Committee for Standards in Haematology (BCSH), which state that a normal APTT is likely to exclude therapeutic intensity dabigatran (58) or contribution of dabigatran to bleeding (59). Second, we found that a normal PT does not exclude clinically relevant rivaroxaban levels. The BCSH statement, in contrast, comments that a normal PT ratio with most reagents excludes therapeutic intensity rivaroxaban (58). The ASH and BCSH statements were published in 2011 and 2012, respectively. Discrepancies between our findings and these statements may reflect availability of new information since their publication regarding a wider variety of test reagents and their sensitivity to the NOACs.
Quality assessment highlighted several key limitations of eligible studies (Table 5). First, on-therapy ranges (Table 1) were derived from pharmacokinetic analyses. We resisted the term “therapeutic range” because data on how these ranges correlate with clinical outcomes are sparse, although they are beginning to emerge (57). Second, many eligible studies used either ex vivo or spiked plasma samples from healthy controls rather than ex vivo samples from NOAC-treated patients. Reassuringly, results obtained with patient samples generally aligned with those from healthy controls. Third, we identified only 4 eligible apixaban studies, just 2 of which used ex vivo patient samples. Because apixaban was the most recent NOAC to receive regulatory approval, we expect that additional studies of its laboratory measurement will be forthcoming. Such studies are also needed for NOACs not yet approved in North America and Europe (e.g., edoxaban).
A relatively large number of published studies have assessed the relationship between coagulation tests and levels of dabigatran, rivaroxaban, and apixaban. Each drug produces unique effects on coagulation assays. Our systematic review provides guidance to the clinician on how to use and interpret coagulation test results in NOAC-treated patients. Further studies are needed to define the relationship between drug levels, coagulation test results, and clinical outcomes.
COMPETENCY IN MEDICAL KNOWLEDGE 1: Prothrombin time (PT) and activated partial thromboplastin time (APTT) do not show sufficient sensitivity or linearity for quantification of dabigatran, rivaroxaban, or apixaban. A normal PT and/or APTT may not exclude clinically relevant anticoagulant effects of these drugs.
COMPETENCY IN MEDICAL KNOWLEDGE 2: A normal thrombin time likely excludes clinically relevant plasma levels of the direct thrombin inhibitor dabigatran. Dilute thrombin time and ecarin-based assays may be used to measure dabigatran activity.
COMPETENCY IN MEDICAL KNOWLEDGE 3: An anti-Xa assay using drug-specific calibrators may be used to measure the activity of the factor Xa inhibitors rivaroxaban and apixaban.
COMPETENCY IN PATIENT CARE: The NOACs dabigatran, rivaroxaban, and apixaban do not require laboratory monitoring of coagulation during routine clinical use, but measurement of their anticoagulant effect may be desirable in certain circumstances.
TRANSLATIONAL OUTLOOK: Development of laboratory assays for measurement of the anticoagulant activity of these NOACs is a high priority. Ideally, these assays should be sufficiently sensitive to detect all clinically relevant drug concentrations, show linearity across a wide range of concentrations to permit quantification, and be reproducible and simple to perform at the point of care.
This work was supported by grant HL112903 (National Heart, Lung, and Blood Institutehttp://dx.doi.org/10.13039/100000050) to Dr. Cuker. Dr. Cuker has served as a consultant for Baxter, Bayer, and Genzyme; has served on advisory boards for Daiichi Sankyo and Genzyme; and has received research support from Diagnostica Stago. Dr. Crowther has served on advisory boards for and/or received consulting fees from Boehringer Ingelheim, Portola, Viropharm, and AKP America; has received research funding from Leo Pharma (McMaster University); and has received funding for presentations from Bayerhttp://dx.doi.org/10.13039/100004326, Celgenehttp://dx.doi.org/10.13039/100006436, Shire, and CSL Behring. Dr. Garcia has served as a consultant to Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, Pfizer, and Roche. Dr. Siegal has reported that she has no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- activated clotting time
- atrial fibrillation
- activated partial thromboplastin time
- ecarin chromogenic assay
- ecarin clotting time
- non–vitamin K oral anticoagulant
- prothrombinase-induced clotting time
- point of care
- prothrombin time/international normalized ratio
- thrombin time
- vitamin K antagonist
- Received January 13, 2014.
- Revision received May 21, 2014.
- Accepted May 26, 2014.
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