Pharmacology Consult

A look at coagulation assays for target-specific oral anticoagulants

Target-specific oral anticoagulants have emerged as alternative therapeutic options for the management of thrombembolic disorders.

Before the development of target-specific oral anticoagulants (TSOACs), the oral vitamin K antagonist warfarin was the mainstay of treatment and prophylaxis for thromboembolism. Although effective, the use of oral vitamin K antagonists requires routine laboratory monitoring, owing to their narrow therapeutic index, slow onset of action, and potential for multiple drug-drug and food interactions. Frequent laboratory monitoring and dose adjustment result in poor patient compliance and difficulty maintaining patients within a therapeutic window. These limitations led to the development of TSOACs (see Table 1).

Owing to their predictable pharmacokinetic and pharmacodynamic responses, TSOACs are promising in many regards, such as a fixed-dose regimen without the need for routine coagulation monitoring, fewer drug and food interactions, and improved efficacy profile. However, there remain certain areas of TSOAC use that are continually being explored.

Indications for monitoring

Although TSOACs are presented as having predictable response, a reliable laboratory assay that could measure the plasma levels or anticoagulant effects of these agents may be necessary in certain clinical circumstances, such as before emergency surgery or other invasive procedures, when there is suspicion of overdose, in acute thrombosis, when proof of compliance is required and in potential drug interactions. In addition, assessment of TSOAC response also may be vital in patients with extreme body weight (< 50 kg or > 110 kg), with hepatic and renal impairment, in case of comorbidities or in elderly patients.

Shreya Patel, PharmD, BCPS

Shreya Patel

Eyerusalem Befkadu, PharmD candidate

Eyerusalem Befkadu

Hence, the advantage of being “unmonitored” may only apply to relatively healthy, young patients with thromboembolic disorders. Clinicians may want to determine the anticoagulant effects of TSOACs in high-risk patients and in emergent clinical circumstances.

Coagulation screening assays

Routine therapeutic drug monitoring of TSOACs is not recommended. However, in certain situations, measurement of anticoagulant activity may be necessary.

Available coagulation assays for qualitative assessment of TSOACs include prothrombin time (PT) and activated partial thromboplastin time (aPTT), provided reagents are sensitive to detect the effects of TSOACs. Thrombin time (TT) also provides qualitative assessment, but its use is dependent on ease of accessibility to clinicians. Anti-Factor Xa and ecarin clotting time (ECT) provide quantitative assessment of anticoagulant effect. Quantitative assessment may be useful in emergency or urgent clinical situations, in patients presenting with renal or hepatic insufficiencies and in cases of suspected overdosing. However, it is important to note that these quantitative tests may not be readily available for use in clinical practice.

Table 1. FDA-approved target-specific oral anticoagulants

Table 1. Click the image for a larger one.

Tables provided by: Shreya Patel and Eyerusalem Befkadu.

Before selection of a coagulation test, clinicians should have a comprehensive understanding of available assays and know how to interpret them in patients treated with TSOACs.

In addition, variables that can lead to coagulation assay prolongation and influence laboratory results should be carefully identified. Examples of factors that can influence coagulation test results include clotting-factor deficiencies, vitamin K deficiency, liver disease, disseminated intravascular coagulation and antiphospholipid antibody syndrome. When interpreting a coagulation assay, a clinical profile of the patient should be taken into account along with the pharmacokinetic profile of the TSOACs (Table 1 provides the pharmacokinetic profile of each TSOAC). It is important to know when the TSOAC was administered relative to the timing of when the blood sample was obtained. Blood samples obtained at peak level will result in much larger impact on coagulation tests than when performed at trough level. TSOACs have a short half-life compared with oral vitamin K antagonists, and the plasma concentration is sufficiently low or undetectable after four to five half-lives have elapsed from the time the drug was last administered. Certain patient factors such as presence of renal or hepatic insufficiencies and increased age can prolong the elimination half-life of TSOACs. Careful determination, selection and interpretation of coagulation assay is key in the emergency management of patients on TSOACs.

Oral direct thrombin inhibitor: Dabigatran

There are currently no FDA-approved coagulation assays for monitoring of dabigatran (Pradaxa, Boehringer Ingelheim), but a number of routine coagulation tests may aid clinicians in monitoring its anticoagulant effect.

For qualitative assessment of dabigatran, aPTT is the recommended coagulation test. A normal aPTT level indicates lack of relevant pharmacologic anticoagulant effect. An aPTT of approximately 1.5-fold prolongation at trough is the expected level of anticoagulation. According to the European Heart Rhythm Association practical guide, an aPTT level two times the upper limit of normal suggests an excess risk for bleeding if obtained 12 to 24 hours after administration of last dose. It is important to note that aPTT results may vary based on reagents used and are not useful for quantification of drug levels.

A more precise method of measuring the quantitative anticoagulant effect of dabigatran is ECT. ECT has a close linear relationship with the plasma concentration of dabigatran; however, it is not approved for clinical use in the United States.

The TT coagulation assay is too sensitive and may display a prolonged coagulation at low doses. This may be useful in detecting very low or undetectable levels of dabigatran, but is not ideal in emergency situations. The Hemoclot direct thrombin inhibitor assay, which has a similar turnaround time as aPTT, is available in the United States, but reserved for research use only. Other routine coagulation tests such as PT and INR are not reliable for assessment of anticoagulant effects of dabigatran. False elevation in point-of-care INR values has been reported.

Until quantitative coagulation assays for measurement of dabigatran activity are available in the United States, the preferred coagulation assay is aPTT, which has variable sensitivity depending on the reagent used. Clinicians can choose to obtain both aPTT and TT for careful interpretation of the anticoagulant effect of dabigatran. A normal aPTT and TT suggests absence of anticoagulant effect. A prolonged aPTT and abnormal TT indicates presence of direct thrombin inhibitor at low levels, whereas a prolonged aPTT and TT indicates presence of anticoagulant effect.

Oral Factor Xa inhibitors: Rivaroxaban, apixaban, edoxaban

The preferred test for measuring the coagulation effect of oral Factor Xa inhibitors is the drug-specific calibrated chromogenic anti-Factor Xa level. At this time, none are FDA-approved for use in the United States, but some individual centers are performing these tests.

Factor Xa inhibitors have varying effects on PT and aPTT. Monitoring of aPTT levels is generally not recommended due to its weak prolongation, variability of assays and paradoxical response at low doses. PT is a more reliable method for qualitative assessment of the inhibitory effect of rivaroxaban (Xarelto, Janssen Pharmaceuticals) and is prolonged in a concentration-dependent manner when sensitive reagents are used. A normal PT value suggests that rivaroxaban level is not high, but does not exclude its presence. As with low–molecular-weight heparin (LMWH), the PT cannot estimate the intensity of the anticoagulation effects of rivaroxaban. For the most sensitive reagents, PT may only inform the clinician if the patient is taking the drug. On the other hand, PT is not sensitive enough to ensure an accurate estimation of the anticoagulation effect of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer). The drug-specific anti-Factor Xa chromogenic assay is preferred to assess anticoagulant effect of apixaban. There are limited data on the coagulation assay of choice for edoxaban (Savaysa, Daiichi Sankyo), but in vitro studies suggest that the variability in aPTT prolongation among reagents used is much smaller than that of PT.

With appropriate calibrators and controls, anti-Factor Xa assays are far more useful and reliable for assessing the quantitative anticoagulant effect of Factor Xa inhibitors. Studies show a linear concentration-dependent relationship between Factor Xa inhibitor concentration and specific drug calibrated anti-Factor Xa activity. Even when commercial anti-Xa assays were used with LMWH calibrators, rather than specific drug calibrators, the relationship remained linear. Thus, anti-Factor Xa measured using Factor Xa inhibitors or LMWH calibrators can provide a quantitative measure of Factor Xa inhibitor concentration. However, there is no established range to guide clinicians in decision making. In addition, access to specific anti-Factor Xa assays in a timely fashion is limited in clinical practice. Measurement of INR to assess anticoagulant effect of Factor Xa inhibitors is completely unreliable and not recommended.

Clinician preference

Routine monitoring of coagulation for patients receiving TSOACs is not necessary based on their predictable pharmacokinetic and pharmacodynamic response. However, routine coagulation tests can be utilized to determine anticoagulant effect in emergency situations.

Table 2. Effect of target-specific oral anticoagulants on routine coagulation assays

Table 2. Click the image for a larger one.

Tables provided by: Shreya Patel and Eyerusalem Befkadu.

Due to their rapid turnaround time and universal accessibility, aPTT and PT are the methods of choice. However, this must be weighed against their poor sensitivity and specificity and the lack of consensus regarding the most suitable reagents and analyzers. The more complex ECT, TT and the anti-Factor Xa assays, although preferable, are less accessible and slower. Until a more precise method becomes commercially available for each TSOAC, clinicians should have a thorough understanding of the effect of TSOACs on available coagulation assays (see Table 2 for a summary of the effect of routine coagulation assays on TSOACs).

Clinicians should also take into consideration patient factors that may lead to abnormal test results before interpretation of coagulation assays. Further research is warranted to determine the correlation between coagulation assays and clinical outcome in patients treated with TSOACs.

References:

Blann AD, et al. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2014.07.010.

Brunetti L, et al. Ann Pharmacother. 2013;doi:10.1345/aph.1R720.

Cuker A, et al. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2014.05.065.

Douxfils J, et al. Thromb J. 2014;doi:10.1186/1477-9560-12-24.

Heidbuchel H, et al. Europace. 2013;doi:10.1093/europace/eut083.

Miyares MA, et al. Am J Health Sys Pharm. 2012;doi:10.2146/ajhp110725.

For more information:

Shreya Patel, PharmD, BCPS, is assistant professor at Touro College of Pharmacy in New York, New York. Eyerusalem Befkadu is a PharmD candidate at Touro College of Pharmacy. Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is professor of clinical pharmacy and the residency and industry fellowship programs coordinator at Philadelphia College of Pharmacy at University of the Sciences in Philadelphia. Spinler is the Cardiology Today Pharmacology Consult column editor. She can be reached at Philadelphia College of Pharmacy at University of the Sciences, 600 S. 43rd St., Philadelphia, PA 19104; email: s.spinle@usciences.edu.

Disclosures: The authors report no relevant financial disclosures.

Target-specific oral anticoagulants have emerged as alternative therapeutic options for the management of thrombembolic disorders.

Before the development of target-specific oral anticoagulants (TSOACs), the oral vitamin K antagonist warfarin was the mainstay of treatment and prophylaxis for thromboembolism. Although effective, the use of oral vitamin K antagonists requires routine laboratory monitoring, owing to their narrow therapeutic index, slow onset of action, and potential for multiple drug-drug and food interactions. Frequent laboratory monitoring and dose adjustment result in poor patient compliance and difficulty maintaining patients within a therapeutic window. These limitations led to the development of TSOACs (see Table 1).

Owing to their predictable pharmacokinetic and pharmacodynamic responses, TSOACs are promising in many regards, such as a fixed-dose regimen without the need for routine coagulation monitoring, fewer drug and food interactions, and improved efficacy profile. However, there remain certain areas of TSOAC use that are continually being explored.

Indications for monitoring

Although TSOACs are presented as having predictable response, a reliable laboratory assay that could measure the plasma levels or anticoagulant effects of these agents may be necessary in certain clinical circumstances, such as before emergency surgery or other invasive procedures, when there is suspicion of overdose, in acute thrombosis, when proof of compliance is required and in potential drug interactions. In addition, assessment of TSOAC response also may be vital in patients with extreme body weight (< 50 kg or > 110 kg), with hepatic and renal impairment, in case of comorbidities or in elderly patients.

Shreya Patel, PharmD, BCPS

Shreya Patel

Eyerusalem Befkadu, PharmD candidate

Eyerusalem Befkadu

Hence, the advantage of being “unmonitored” may only apply to relatively healthy, young patients with thromboembolic disorders. Clinicians may want to determine the anticoagulant effects of TSOACs in high-risk patients and in emergent clinical circumstances.

Coagulation screening assays

Routine therapeutic drug monitoring of TSOACs is not recommended. However, in certain situations, measurement of anticoagulant activity may be necessary.

Available coagulation assays for qualitative assessment of TSOACs include prothrombin time (PT) and activated partial thromboplastin time (aPTT), provided reagents are sensitive to detect the effects of TSOACs. Thrombin time (TT) also provides qualitative assessment, but its use is dependent on ease of accessibility to clinicians. Anti-Factor Xa and ecarin clotting time (ECT) provide quantitative assessment of anticoagulant effect. Quantitative assessment may be useful in emergency or urgent clinical situations, in patients presenting with renal or hepatic insufficiencies and in cases of suspected overdosing. However, it is important to note that these quantitative tests may not be readily available for use in clinical practice.

Table 1. FDA-approved target-specific oral anticoagulants

Table 1. Click the image for a larger one.

Tables provided by: Shreya Patel and Eyerusalem Befkadu.

Before selection of a coagulation test, clinicians should have a comprehensive understanding of available assays and know how to interpret them in patients treated with TSOACs.

In addition, variables that can lead to coagulation assay prolongation and influence laboratory results should be carefully identified. Examples of factors that can influence coagulation test results include clotting-factor deficiencies, vitamin K deficiency, liver disease, disseminated intravascular coagulation and antiphospholipid antibody syndrome. When interpreting a coagulation assay, a clinical profile of the patient should be taken into account along with the pharmacokinetic profile of the TSOACs (Table 1 provides the pharmacokinetic profile of each TSOAC). It is important to know when the TSOAC was administered relative to the timing of when the blood sample was obtained. Blood samples obtained at peak level will result in much larger impact on coagulation tests than when performed at trough level. TSOACs have a short half-life compared with oral vitamin K antagonists, and the plasma concentration is sufficiently low or undetectable after four to five half-lives have elapsed from the time the drug was last administered. Certain patient factors such as presence of renal or hepatic insufficiencies and increased age can prolong the elimination half-life of TSOACs. Careful determination, selection and interpretation of coagulation assay is key in the emergency management of patients on TSOACs.

Oral direct thrombin inhibitor: Dabigatran

There are currently no FDA-approved coagulation assays for monitoring of dabigatran (Pradaxa, Boehringer Ingelheim), but a number of routine coagulation tests may aid clinicians in monitoring its anticoagulant effect.

For qualitative assessment of dabigatran, aPTT is the recommended coagulation test. A normal aPTT level indicates lack of relevant pharmacologic anticoagulant effect. An aPTT of approximately 1.5-fold prolongation at trough is the expected level of anticoagulation. According to the European Heart Rhythm Association practical guide, an aPTT level two times the upper limit of normal suggests an excess risk for bleeding if obtained 12 to 24 hours after administration of last dose. It is important to note that aPTT results may vary based on reagents used and are not useful for quantification of drug levels.

A more precise method of measuring the quantitative anticoagulant effect of dabigatran is ECT. ECT has a close linear relationship with the plasma concentration of dabigatran; however, it is not approved for clinical use in the United States.

The TT coagulation assay is too sensitive and may display a prolonged coagulation at low doses. This may be useful in detecting very low or undetectable levels of dabigatran, but is not ideal in emergency situations. The Hemoclot direct thrombin inhibitor assay, which has a similar turnaround time as aPTT, is available in the United States, but reserved for research use only. Other routine coagulation tests such as PT and INR are not reliable for assessment of anticoagulant effects of dabigatran. False elevation in point-of-care INR values has been reported.

Until quantitative coagulation assays for measurement of dabigatran activity are available in the United States, the preferred coagulation assay is aPTT, which has variable sensitivity depending on the reagent used. Clinicians can choose to obtain both aPTT and TT for careful interpretation of the anticoagulant effect of dabigatran. A normal aPTT and TT suggests absence of anticoagulant effect. A prolonged aPTT and abnormal TT indicates presence of direct thrombin inhibitor at low levels, whereas a prolonged aPTT and TT indicates presence of anticoagulant effect.

PAGE BREAK

Oral Factor Xa inhibitors: Rivaroxaban, apixaban, edoxaban

The preferred test for measuring the coagulation effect of oral Factor Xa inhibitors is the drug-specific calibrated chromogenic anti-Factor Xa level. At this time, none are FDA-approved for use in the United States, but some individual centers are performing these tests.

Factor Xa inhibitors have varying effects on PT and aPTT. Monitoring of aPTT levels is generally not recommended due to its weak prolongation, variability of assays and paradoxical response at low doses. PT is a more reliable method for qualitative assessment of the inhibitory effect of rivaroxaban (Xarelto, Janssen Pharmaceuticals) and is prolonged in a concentration-dependent manner when sensitive reagents are used. A normal PT value suggests that rivaroxaban level is not high, but does not exclude its presence. As with low–molecular-weight heparin (LMWH), the PT cannot estimate the intensity of the anticoagulation effects of rivaroxaban. For the most sensitive reagents, PT may only inform the clinician if the patient is taking the drug. On the other hand, PT is not sensitive enough to ensure an accurate estimation of the anticoagulation effect of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer). The drug-specific anti-Factor Xa chromogenic assay is preferred to assess anticoagulant effect of apixaban. There are limited data on the coagulation assay of choice for edoxaban (Savaysa, Daiichi Sankyo), but in vitro studies suggest that the variability in aPTT prolongation among reagents used is much smaller than that of PT.

With appropriate calibrators and controls, anti-Factor Xa assays are far more useful and reliable for assessing the quantitative anticoagulant effect of Factor Xa inhibitors. Studies show a linear concentration-dependent relationship between Factor Xa inhibitor concentration and specific drug calibrated anti-Factor Xa activity. Even when commercial anti-Xa assays were used with LMWH calibrators, rather than specific drug calibrators, the relationship remained linear. Thus, anti-Factor Xa measured using Factor Xa inhibitors or LMWH calibrators can provide a quantitative measure of Factor Xa inhibitor concentration. However, there is no established range to guide clinicians in decision making. In addition, access to specific anti-Factor Xa assays in a timely fashion is limited in clinical practice. Measurement of INR to assess anticoagulant effect of Factor Xa inhibitors is completely unreliable and not recommended.

Clinician preference

Routine monitoring of coagulation for patients receiving TSOACs is not necessary based on their predictable pharmacokinetic and pharmacodynamic response. However, routine coagulation tests can be utilized to determine anticoagulant effect in emergency situations.

Table 2. Effect of target-specific oral anticoagulants on routine coagulation assays

Table 2. Click the image for a larger one.

Tables provided by: Shreya Patel and Eyerusalem Befkadu.

Due to their rapid turnaround time and universal accessibility, aPTT and PT are the methods of choice. However, this must be weighed against their poor sensitivity and specificity and the lack of consensus regarding the most suitable reagents and analyzers. The more complex ECT, TT and the anti-Factor Xa assays, although preferable, are less accessible and slower. Until a more precise method becomes commercially available for each TSOAC, clinicians should have a thorough understanding of the effect of TSOACs on available coagulation assays (see Table 2 for a summary of the effect of routine coagulation assays on TSOACs).

Clinicians should also take into consideration patient factors that may lead to abnormal test results before interpretation of coagulation assays. Further research is warranted to determine the correlation between coagulation assays and clinical outcome in patients treated with TSOACs.

References:

Blann AD, et al. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2014.07.010.

Brunetti L, et al. Ann Pharmacother. 2013;doi:10.1345/aph.1R720.

Cuker A, et al. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2014.05.065.

Douxfils J, et al. Thromb J. 2014;doi:10.1186/1477-9560-12-24.

Heidbuchel H, et al. Europace. 2013;doi:10.1093/europace/eut083.

Miyares MA, et al. Am J Health Sys Pharm. 2012;doi:10.2146/ajhp110725.

For more information:

Shreya Patel, PharmD, BCPS, is assistant professor at Touro College of Pharmacy in New York, New York. Eyerusalem Befkadu is a PharmD candidate at Touro College of Pharmacy. Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is professor of clinical pharmacy and the residency and industry fellowship programs coordinator at Philadelphia College of Pharmacy at University of the Sciences in Philadelphia. Spinler is the Cardiology Today Pharmacology Consult column editor. She can be reached at Philadelphia College of Pharmacy at University of the Sciences, 600 S. 43rd St., Philadelphia, PA 19104; email: s.spinle@usciences.edu.

Disclosures: The authors report no relevant financial disclosures.

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