Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban
ABSTRACTThe new oral anticoagulants dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) have predictable pharmacokinetic and pharmacodynamic profiles and are alternatives to warfarin. However, many physicians are wary of these drugs, since there is limited evidence on how to manage bleeding in patients taking them, and since no specific antidote is known to reverse their anticoagulant effect. Management requires careful adherence to first principles of bleeding care. Unapproved and untested reversal strategies may be required in patients with life-threatening bleeding.
KEY POINTS
- Thromboprophylaxis with anticoagulants is an important aspect of managing patients at risk of systemic or pulmonary embolization.
- Dabigatran is a direct inhibitor of thrombin (factor IIa); rivaroxaban and apixaban inhibit factor Xa.
- Monitoring of coagulation function is not routinely necessary with the new drugs but may be useful in emergencies.
- Nonspecific hemostatic agents that have been suggested for off-label use in reversing excessive bleeding in patients taking the new oral anticoagulants include recombinant factor VIIa, three-factor and four-factor prothrombin complex concentrate, and activated prothrombin complex concentrate.
THE NEW ORAL ANTICOAGULANTS AND BLOOD COAGULATION ASSAYS
Assessment of the anticoagulant activity of the new oral anticoagulants is not necessary in routine clinical practice, but it may be useful in planning intervention in patients with major bleeding, those with drug overdose, or those who need emergency surgery.
The activated partial thromboplastin time
The activated partial thromboplastin time (aPTT) is a measure of the activity of the intrinsic pathway of the coagulation cascade.
Dabigatran. There is a curvilinear relationship between the aPTT and the plasma concentration of dabigatran and other direct thrombin inhibitors, although the aPTT prolongation appears to vary with different reagents and coagulometers.9,14,15 However, Stangier et al9 found a linear relationship between the aPTT and the square root of the dabigatran plasma concentration.
Rivaroxaban prolongs the aPTT in a dose-dependent manner, but there is no standard for calibration of this assay. Hence, the aPTT is not recommended for monitoring rivaroxaban in clinical practice.
Apixaban may also prolong the aPTT, but there are limited data on its reactivity with different reagents.
The prothrombin time and international normalized ratio
The prothrombin time and international normalized ratio (INR) are measures of the extrinsic pathway of the coagulation cascade.
Dabigatran. The INR has a linear response to the dabigatran concentration, but it is insensitive.9 Hence, it is not suitable for monitoring the anticoagulant effects of direct thrombin inhibitors.
Rivaroxaban. The prothrombin time correlates strongly with the plasma concentration of rivaroxaban in healthy trial participants11 and in patients undergoing total hip arthroplasty or total knee arthroplasty.16 Samama et al17 noted that, unlike with vitamin K antagonists, the INR cannot be used to monitor patients on rivaroxaban because the prothrombin time results varied with different reagents. They used a standard calibration curve to express the prothrombin time results in plasma concentrations of rivaroxaban rather than in seconds or the INR.
Apixaban increases the INR in a dose-dependent manner.18 Its effect on different reagents remains unknown.
The thrombin time
The thrombin time reflects the activity of thrombin in the plasma. The amount of thrombin and the concentration of thrombin inhibitors in the plasma sample determine the time to clot formation.
Dabigatran. The thrombin time displays a linear dose-response to dabigatran, but only over the range of therapeutic concentrations. At a dabigatran concentration greater than 600 ng/mL, the test often exceeds the maximum measurement time of coagulometers.9 Hence, this test is too sensitive for emergency monitoring, especially in cases of drug overdose. However, it is well suited for determining if any dabigatran is present.
Rivaroxaban and apixaban have no effect on the thrombin time.
The Hemoclot direct thrombin inhibitor assay and dabigatran
The Hemoclot direct thrombin inhibitor assay (Hyphen BioMed, France) is a sensitive diluted thrombin time assay that can be used for quantitative measurement of dabigatran activity in plasma. This test is based on inhibition of a constant amount of highly purified human alpha-thrombin by adding it to diluted test plasma (1:8 to 1:20) mixed with normal pooled human plasma.19,20
Stangier et al19 found that the Hemoclot assay was suitable for calculating a wide range of dabigatran concentrations up to 4,000 nmol/L (1,886 ng/mL). Although this finding has not been confirmed in larger studies, this test may provide a rapid and accurate assessment of dabigatran’s anticoagulant activity in cases of emergency surgery or overdose.
The ecarin clotting time and dabigatran
The ecarin clotting time is a measure of the activity of direct thrombin inhibitors, but not the factor Xa inhibitors.
Ecarin is a highly purified metalloprotease isolated from the venom of a snake, Echis carinatus, and it generates meizothrombin from prothrombin.21 Meizothrombin facilitates clot formation by converting fibrinogen to fibrin and, like thrombin, it can be inactivated by direct thrombin inhibitors, thereby prolonging the clotting time.
The limitations of the ecarin clotting time include dependence on the plasma levels of fibrinogen and prothrombin.
The ecarin chromogenic assay and dabigatran
The ecarin chromogenic assay is an improvement on the principle of the ecarin clotting time that can be used to measure the activity of direct thrombin inhibitors.22 In this test, ecarin is added to a plasma sample to generate meizothrombin, and the amidolytic activity of meizothrombin towards a chromogenic substrate is then determined.
Results of the ecarin chromogenic assay are not influenced by the levels of fibrinogen or prothrombin. Another advantage is that this assay can be used in automated and manual analyzers, thus enabling its use at the bedside. However, to our knowledge, it is not being regularly used to monitor direct thrombin inhibitors in the clinical setting, and there is no standard calibration of the ecarin clotting time method.
Assays of factor Xa activity
A variety of assays to monitor the anticoagulant activity of factor Xa inhibitors have been proposed.23–25 All measure inhibition of the activity of factor Xa using methods similar to those used in monitoring heparin levels. All require calibrators with a known concentration of the Xa inhibitor; many are easily adapted for laboratories currently providing measurement of factor Xa inhibition from heparin.23 These assays have been suggested as a better indicator of plasma concentration of factor Xa inhibitor drugs than the prothrombin time.25
CONTROLLING BLEEDING IN PATIENTS ON THE NEW ORAL ANTICOAGULANTS
Bleeding is an anticipated adverse event in patients taking anticoagulants. It is associated with significant morbidity and risk of death.26,27
Many physicians still have limited experience with using the new oral anticoagulants and managing the attendant bleeding risks. Hence, we recommend that every health institution have a treatment policy or algorithm to guide all clinical staff in the management of such emergencies.
Prevention of bleeding
Management of bleeding from these agents should begin with preventing bleeding in the first place.
The physician should adhere to the recommended dosages of these medications. Studies have shown that the plasma concentration of these drugs and the risk of bleeding increase with increasing dosage.1,28,29
In addition, these medications should be used for the shortest time for which anticoagulation is required, especially when used for preventing deep vein thrombosis. Prolonged use increases the risk of bleeding.30,31
Most patients who need anticoagulation have comorbidities such as heart failure, renal failure, diabetes mellitus, and hypertension. Although the kidneys play a major role in the excretion of dabigatran and, to some extent, rivaroxaban and apixaban, patients with severe renal impairment were excluded from the major trials of all three drugs.1–3 Hence, to avoid excessive drug accumulation and bleeding, these medications should not be used in such patients pending further studies. Further, patients taking these medications should be closely followed to detect new clinical situations, such as acute renal failure, that will necessitate their discontinuation or dose adjustment.
