Coagulation Testing For New Oral Anticoagulants
Asc. Prof. Mehmet Demir
Cardiology Department, Bursa Yüksek İhtisas Education and Research Hospital Bursa,Turkey.
Atrial fibrillation is the most common and important cardiac rhythm disorder, which increases the risk of stroke and mortality. New oral anticoagulants are an alternative for vitamin K antagonists to prevent stroke in patients with non-valvular atrial fibrillation. New oral anticoagulants do not require routine monitoring of coagulation. However, the quantitative assessment of the anticoagulant effect drug levels may be needed in emergency situations, such as a serious bleeding or need for urgent surgery, or in patient with renal or hepatic insufficiency. In the paper we focus on the coagulation testing for new oral anticoagulants.
Key Words : New Oral Anticoagulants, Stroke, Atrial Fibrillation.
Correspondence to: Dr. Mehmet Demir,
Adres: yaseminpark sit 4E D11 osmangazi 16100
Bursa/Turkey.
Atrial fibrillation (AF) is the most common cardiac rhythm disorder. The estimated prevalence of AF ranges from 0.4% to 2% in the general population and increases by age. AF is associated with a five-fold risk of stroke and a three-fold incidence of congestive heart failure, and higher mortality.1,2,3,4
New oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with non-valvular AF.
The NOACs for stroke prevention in AF fall into two classes: the oral direct thrombin inhibitors (dabigatran) and oral direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban). In contrast to VKAs, which block the formation of multiple active vitamin K-dependent coagulation factors (factors II, VII, IX, and X), these drugs block the activity of one single step in coagulation.4
The NOACs so far tested in clinical trials have all shown non- inferiority compared with VKAs, with better safety, consistently limiting the number of intracranial hemoraji. On this basis, ESC guideline recommends them as broadly preferable to VKA in the vast majority of patients with non-valvular AF.4
NOACs do not require routine monitoring of coagulation. However, the quantitative assessment of the anticoagulant effect drug levels may be needed in emergency situations, such as a serious bleeding and thrombotic events, need for urgent surgery, or in special clinical situations such as patients who present with renal or hepatic insufficiency, suspected overdosing because of drugs interactions.
The maximum effect of the NOACs on the clotting test will occur at its maximal plasma concentration, which is approximately 2-3 h after intake of drugs. A coagulation assay obtained on a blood sample taken 2-3 h after the ingestion of the drugs.5
The activated partial thromboplastin time (aPTT) may provide a qualitative assessment of the presence of dabigatran and the pro- thrombin time (PT) for rivaroxaban (and likely other factor Xa inhibitors), but these respective tests are not sensitive for the quantitative assessment of the NOAC. Quantitative tests for direct thrombin inhibitors (DTIs) and FXa inhibitors do exist, but they may not be routinely available in most hospitals. Point of care tests should not be used to assess the international normalized ratio (INR) in patients on NOACs An overview of the inter- pretation of all the coagulation tests for different NOACs can be found in Table 1.
Direct Thrombin Inhibitors (Dabigatran)
For dabigatran, the ecarin clotting time (ECT) and thrombin
clotting time are useful tests, and directly reflect thrombin inhibition;
however, an activated partial thromboplastin time (aPTT) can also
be used (especially in an emergency setting).6 The aPTT may provide
a qualitative assessment of dabigatran (direct thrombin inhibitor)
level and activity. The relation between dabigatran and the aPTT
is curvilinear. Nevertheless, the sensitivity of the different aPTT
reagents varies greatly. In patients receiving chronic therapy with
dabigatran 150 mg twice daily (bid), the median peak aPTT was
approximately two-fold that of control. Twelve hours after the last
dose, the median aPTT was 1.5-fold that of control.
Therefore, if the aPTT level exceeds two times the upper limit of
normal, this may be associated with a higher risk of bleeding, and
may warrant caution especially in patients with bleeding risk factors.
Dabigatran has little effect on the PT and INR at clinically relevant
plasma concentrations. Prolongation of the PT is related linearly
and dose-dependently to the plasma dabigatran concentration, but
the responsiveness is low. The INR is therefore unsuitable for the
quantitative assessment of the anticoagulant activity of DTIs.7
ECT prolongations above the basal value are related linearly and
dose-dependently to the dabigatran concentration; responsiveness
is also adequate. The ECT assay provides a direct measure of the
activity of DTIs. ≥3 times elevated ECT at trough is associated with
a higher risk of bleeding in patients taking dabigatran.8
Thrombin time results depend on the coagulometer and the
thrombin lot used. Unlike diluted thrombin time (dTT) test can
more accurately predict the coagulation state. A dTT has been
developed, with appropriate calibrators for interpretation in the
context of dabigatran use (Hemoclotw). The dTT is suitable for the
quantitative assessment of dabigatran concentrations. A normal dTT
measurement indicates no clinically relevant anticoagulant effect
of dabigatran. When dabigatran is used with twice daily dosing,
a dTT measured at trough (≥12 h after the previous dose) with
the Hemoclotw of <200 ng/ml dabigatran plasma concentration
(dTT approximately <65 s), is associated with an increased risk of
bleeding.13 still that there are no data on a cut-off dTT below which
elective or urgent surgery is ‘safe’, and therefore its use in this respect
cannot be recommended at this time.5
Table 1. Coagulation assays for NOACs
|
Dabigatran |
Rivaroxaban |
Apixaban |
Edoxaban |
Plasma peak/trough
level (after ingestion) |
2h/12-24h |
2-4h/16-24h |
1-4h/12-24h |
1-2h/12-24h |
PT |
Cannot be used
Advantage: linearity of dose-response curve, availabilty.
Disadvantage: standardization and responsiveness to
drug concentration problem |
Prolonged
Advantage: linearity of dose-response curve,
availabilty and responsiveness to drug concentration
Disadvantage: standardization ? |
Cannot be used |
prolonged |
INR |
Cannot be used |
Cannot be used |
Cannot be used |
Cannot be used |
aPTT |
At trough:>2xULNSuggest bleeding risk
Advantage: responsiveness to drug concentration,
availabilty.
Disadvantage: standardization and linearity of doseresponse
curve problem |
Cannot be used
Advantage: linearity of dose-response curve,
availabilty and responsiveness to drug concentration
Disadvantage: standardization problem |
Cannot be used |
Prolonged but bleeding risk? |
dTT |
At trough:>200 ng/ml or >65s Suggest bleeding risk
Advantage: linearity of dose-response curve, availabilty
and responsiveness to drug concentration
Disadvantage: standardization ? |
Cannot be used |
Cannot be used |
Cannot be used |
ECT |
At trough:>3xULN
Suggest bleeding risk
Advantage:responsiveness to drug concentration,
linearity of dose-response curve |
Not affected |
Not affected |
Not affected |
Anti-FXa assay |
Not applicable |
Quantitative; threshold values for bleeding?
Advantage: linearity of dose-response curve,
responsiveness to drug concentration
Disadvantage: standardization, availabity |
Quantitative; threshold
values for bleeding? |
Quantitative; threshold values for bleeding? |
PT, prothrombin time; INR, international normalized ratio; aPTT, activated partial thromboplastin time; dTT, diluted thrombin time; ULN, upper limit of normal.
Factor Xa Inhibitors (Rivaroxaban, Apixaban, Edoxaban)
Factor Xa-inhibitors prolongs the prothrombin time (PT) and
aPTT varying degree and this might be used as a rough estimate
of an anticoagulation effect. But the aPTT cannot be used for
evaluation of FXa inhibitory effect because of the weak corelation
and variability of assays.
The prolongation of the PT is related linearly and dose-dependently
to the Factor Xa-inhibitor concentration, and the responsiveness is
adequate. Nevertheless the effect on the PT depends both on the
assay and on the FXa inhibitor. For rivaroxaban, the PT may provide
some quantitative information, but the sensitivity of the different PT
reagents varies greatly.
The INR is unreliable for the evaluation of FXa inhibitory activity.
A better estimate for an anticoagulant effect for the oral Factor Xa
inhibitors is an anti-Xa assay.4,5,9
Anti-FXa ‘chromogenic assays’ have been developed to assess
plasma concentrations of the FXa-inhibitors and are commercially
available. However, there are currently no data that associate a
coagulation parameter or a drug level at trough or at peak with
bleeding risk or risk for thrombo-embolism.
Impact Of NOACs On Coagulation System Assessment
The NOACs interfere with routine coagulation tests, thrombophilia
tests or the measurement of coagulation factors. Abnormal coagulation
tests should be interpreted with caution if the time window between
blood sampling and NOAC intake is unknown. Therefore, a time
window of at least 24 h is recommended between the last intake
of a NOAC and blood sampling to assess coagulation parameters
and this time window may be even longer for lupus anticoagulant
measurements (≥48 h).10
Because NOACs may have an additional impact on the INR
(especially the FXa inhibitors), influencing the measurement while
on combined treatment during the overlap phase, it is important
that the INR be measured just before the next intake of the NOAC
during concomitant administration, and be retested 24 h after the
last dose of the NOAC (during sole VKA therapy).