Please see the links below for important safety information for patients on Pradaxa® presenting in emergency and surgery situations.
Evaluation of anticoagulant activity
In emergency situations it is advisable to assess the anticoagulation status of a patient receiving PRADAXA. There is a close correlation between the plasma concentration of PRADAXA and the degree of anticoagulant effect. The half-life of PRADAXA is 12-14 hours; 80% of PRADAXA is renally cleared. Please be aware that in patients with renal impairment the half-life of PRADAXA will be prolonged accordingly.1,2
Recommended tests: quantitative
Calibrated Hemoclot® Thrombin Inhibitor assay (HYPHEN BioMed, Neuville-sur-Oise, France): A diluted Thrombin Time (dTT) measure with the calibrated Hemoclot® assay of >200 ng/mL dabigatran plasma concentration prior to the next drug intake after 150 mg twice-daily dosing (trough measure, eg, 10–16 hours after the previous dose) is associated with a higher risk of bleeding. The table below shows the expected plasma levels of PRADAXA after intake of approved dosages1,4-6:
Recommended tests: semi-quantitative
Activated Partial Thromboplastin Time test: An aPTT >80 seconds or approximately 2-3-fold prolongation at trough (when the next dose is due) is associated with a higher risk of bleeding. An aPTT of approximately 1.5-fold prolongation at trough is the expected level of anticoagulation after the intake of PRADAXA 150mg bid. It should be noted that aPTT may also be prolonged by heparin and its derivatives.The combined effect is not known.2
Ecarin Clotting Time and Thrombin Time: ECT and TT tests assess the anticoagulant activity of direct thrombin inhibitors, such as PRADAXA. Due to the lack of standardization both assays may be prone to substantial interlaboratory variability. Therefore, no reference values for local laboratories can be provided.2
Please see full Summary of Product Characteristics.
To manage bleeding in patients receiving PRADAXA
Apply the same measures as for patients treated with vitamin K antagonists, excluding vitamin K application. Dialysis is an additional option to eliminate PRADAXA from the blood plasma.1,2
a) Prothrombin complex concentrates (PCC) (e.g. nonactivated or activated)
b) Recombinant activated factor VIIa (rFVIIa)
c) Platelet concentrates may be considered when thrombocytopenia is present or long-acting antiplatelet drugs (e.g. acetylsalicylic acid or clopidogrel) have been used
Serial measurements of anticoagulation tests may provide a guide to the relative clearance of PRADAXA. It is important to note that coagulation assays such as the aPTT and ECT may remain elevated despite PCC administration.7
Patients on PRADAXA who undergo surgery or invasive procedures are at increased risk of bleeding. In these circumstances surgical interventions may require a temporary discontinuation of PRADAXA.
PRADAXA should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established.
Chart adapted with permission from van Ryn J, Stangier J, Haertter S et al. Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103:1116–1127.
Patients on PRADAXA who undergo surgery or invasive procedures are at increased risk of bleeding. In these circumstances surgical interventions may require a temporary discontinuation of PRADAXA. PRADAXA should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established.
PRADAXA should be discontinued at least 24 hours before elective invasive or surgical procedures. In patients at higher risk of bleeding, or in major surgery where complete hemostasis may be required, consider stopping PRADAXA 2-4 days before surgery. Clearance of dabigatran in patients with renal insufficiency may take longer. This should be considered in advance of any procedures.
If an acute intervention is required, PRADAXA should be temporarily discontinued. A surgery/intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed, the risk of bleeding may be increased. This risk of bleeding should be weighed against the urgency of intervention. 1
Coagulation tests and their interpretation 2
Pradaxa ® treatment does not need routine clinical monitoring, neither for short-term nor for long-term treatment. However, in cases of suspected overdose or in patients treated with Pradaxa ® presenting in emergency departments or prior to surgery it may be advisable to assess the anticoagulation status of a patient treated with Pradaxa ®. There is a close correlation between plasma dabigatran concentration and degree of anticoagulant effect. The following tests may serve to assess the risk of bleeding (see Figure 2):
NOTE: INR is very insensitive to the dabigatran treatment and cannot be recommended as a coagulation test. In emergency situations the Hemoclot ® test or the aPTT test can be used for clotting time determination. 2,5
Figure 2: Illustration of the situation in a once-daily dosing of Pradaxa ®. Example of correlation of coagulation parameters with dabigatran clearance of a 200-mg dose. 8
At recommended doses, dabigatran prolongs coagulation time as measured by the activated partial thromboplastin time (aPTT), thrombin time (TT) and ecarin clotting time (ECT). In patients who are bleeding due to excess activity of dabigatran, these coagulation tests would be expected to be elevated and may be helpful in assessing anticoagulant activity of dabigatran, if necessary. The aPTT is generally less sensitive to anticoagulant activity than either TT or ECT. 1
The actual Thrombin Time (TT) test measure will depend on the coagulometer and of the thrombin lot used for the measurement. It is therefore advisable to use the calibrated Hemoclot ® Thrombin Inhibitor assay (a diluted TT assay, Hyphen BioMed, Neuville-sur-Oise, France) with dabigatran standards to calculate the dabigatran concentration rather than to determine TT only. 2,5 The SPC recommends that a diluted Thrombin Time (dTT) test be performed. If the dTT is used, dabigatran concentrations above 200 ng/ml, measured at trough after 150 mg twice daily dosing (10-16 hours after the previous dose), are associated with an increased risk of bleeding. 1
However, the aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. In patients who are bleeding or at risk of bleeding, the aPTT test may be useful to assist in determining an excess of anticoagulant activity. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of anticoagulant effect, especially at high plasma concentrations of dabigatran. High aPTT values should be interpreted with caution. 1
1. Pradaxa ® Summary of Product Characteristics, 2011. Boehringer Ingelheim.
2. van Ryn J et al. Thromb Haemost 2010; 103:1116–1127.
3. van Ryn J et al. Am J Med 2011, in press.
4. Peyrafitte M et al. J Thromb Haemost 2011; 9(Suppl 2):660 Abstract P-WE-445.
5. Hemoclot ® Thrombin Inhibitor assay (HYPHEN BioMed, Neuville-sur-Oise, France). www.hyphen-biomed.com.
6. Boehringer Ingelheim. Data on file.
7. Feiba ® Prescribing Information, 2009. Baxter Healthcare Corporation.
8. Stangier J et al. Br J Clin Pharmacol 2007; 64:292-303.