Novel Oral Anticoagulants
New oral anticoagulants (rivaroxaban, apixiban and dabigatran) have been approved by FDA for reducing the risk of stroke in patients with nonvalvular atrial fibrillation. In addition, rivaroxaban can be used for prevention of deep vein thrombosis. The common mechanism of these new drugs is reversible blockage of the active enzyme site of thrombin (Factor IIa) or Factor Xa. Unlike warfarin, the anticoagulant effect of these new oral anticoagulants is not dependent on decreased synthesis of coagulation factors. Unlike heparin, their anticoagulant effect is not dependent on accelerating the effect of antithrombin.
These drugs have many advantages compared with warfarin including rapid onset of anticoagulation, lack of dietary restrictions, fewer drug to drug interactions and more predictable pharmacokinetics. Like all drugs, they also have some disadvantages including dosing dependent on renal function; lack of a rapid reversal agent; and the unavailability of FDA approved companion diagnostic tests to measure their concentration or anticoagulant effect. Another problem is that these drugs interfere with routine coagulation tests in an unpredictable fashion.
All of the new oral anticoagulants (NOAC) are given at fixed doses and do not require routine coagulation monitoring because of their predictable pharmacokinetics. Measurement of the anticoagulant effect of one of these drugs in an asymptomatic, stable patient on long term therapy could actually be harmful if a slightly elevated result prompted the clinician to deviate from the approved dose. The clinical significance of slightly elevated coagulation results with these new oral anticoagulant drugs is unknown.
Unlike warfarin, which has a long-lasting effect and can be monitored with an INR drawn at any time, NOAC are reversible and have short half lives. Knowing the timing of the last dose is critical for interpretation of results. For example, Rivaroxaban will significantly elevate the Protime 4 hours after the last dose, but not at 12 hours. The potential to misinterpret a single measurement is worrisome. Also, because of their rapid onset and short half lives, it may be difficult to assess patient compliance if a patient has skipped several doses and resumed treatment the day before testing. Therefore, ordering of coagulation tests for patients receiving NOAC should be reserved for clinical situations such as life threatening bleeding, before invasive procedures or suspected overdose or noncompliance.
Rivaroxaban
Rivaroxaban (Xarelto®) is an oral direct factor Xa inhibitor recently approved by the FDA for the prevention of deep vein thrombosis in patients undergoing hip or knee replacement surgery and to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Rivaroxaban reversibly inhibits both free Factor Xa as well as clot-bound FXa activity. Inhibition of FXa enzyme activity prevents the conversion of prothrombin to thrombin and reduces the rate of fibrin clot formation.
Rivaroxaban dosing varies depending on indication. For prevention of deep vein thrombosis, the dose is 10mg by mouth daily, with or without food, for patients with normal renal function. First dose should be given at least 6-10 hours after surgery once hemostasis is established, and continued for 35 days in hip surgery and 12 days in knee surgery. Renal function should be assessed prior to treatment to determine appropriate dose. Rivaroxaban should not be used for patients with renal impairment (CrCl< 30mL/min) or those undergoing dialysis. For patients with atrial fibrillation, the recommended dose is 20mg by mouth daily during the evening meal. For patients with decreased renal function (CrCl 15-50 mL/min) the dose should be reduced to 15mg.
Rivaroxaban is rapidly absorbed. Time to peak concentration is 2-4 hours. Circulating half-life is 5-9 hours in younger patients and 11-13 hours in the elderly. Oral bioavailability is increased with food and dose-dependent (80-100% for 10mg; 66% for 20mg). Expected plasma levels of rivaroxaban after therapeutic doses have been determined in phase II clinical trials. Peak levels were measured 2-4 hours after dosing and trough levels were measured at 24 hours.
Rivaroxaban is contraindicated for use with all strong inducers and inhibitors of the CYP3A4 enzyme. Drugs that inhibit CYP3A4 lead to increased concentrations of rivaroxaban. Inhibitors of this enzyme include protease inhibitors, ketoconazole, and macrolide antibiotics. Inducers cause subtherapeutic levels of rivaroxaban and include anticonvulsants, St. John’s wort and rifampicin
Rivaroxaban has rates of major bleeding events compared to warfarin, but reduced rates of intracranial and fatal bleeding. However, there has been a higher incidence of GI bleeding and bleeding resulting in transfusion of ≥ 2 units of blood with rivaroxaban compared to warfarin.
Inhibition of Factor Xa by Rivaroxaban at the recommended dose of 10 to 20 mg once daily usually elevates the Protime. The sensitivity of the protime to Rivaroxaban is dependent on the thromboplastin reagent used for coagulation testing. Some protime reagents will not detect low Rivaroxaban concentrations. Rivaroxaban increases the protime in a linear and concentration dependent manner when using Stago Neoplastin CI Plus® reagents. Using this reagent, the protime is increased 1.5 times above normal by a plasma concentration of 200 ug/L and increased two times normal at a plasma concentration of 300 ug/L. Laboratories using other thromboplastin reagents may not show the same linear effect, but the protime may still be useful to qualitatively identify the presence or absence of rivaroxaban. INR does not correct for differences in assay sensitivities and is unreliable.
Rivaroxaban elevates the APTT in a concentration dependent manner. A plasma concentration of 200 ug/dL prolongs the APTT by 1.5 times normal. Different APTT reagents vary in their responsiveness to Rivaroxaban. Siemens Actin FS reagent is the most responsive and Stago PTT-A the least. Protime is preferred over APTT.
Rivaroxaban elevates dRVVT, but this test has not been standardized for this purpose. A plasma concentration of 200 ug/dL increases dRVVT approximately 2.5 times normal.
Since FXa is the target of Rivaroxaban, the anti-Factor Xa assay should be the test of choice. This test is based on measuring residual Factor Xa activity with a synthetic chomogenic pepide after addition of excess Factor Xa to the patient’s plasma sample. Rivaroxaban interferes with the anti-factor Xa assay calibrated to monitor heparin. A low result can be used to rule out a clinically relevant rivaroxaban concentration, but an elevated result does not provide an accurate drug level since this assay was calibrated with heparin. Stago is developing a new anti-Factor Xa assay that uses rivaroxaban calibrator and controls and can measure rivaroxaban concentrations between 20-500 ug/L.
No specific antidote is available for management of bleeding. No clinical trials have evaluated the efficacy of reversing the anticoagulant effect with plasma or coagulation factor concentrates. One study demonstrated normalization of prolonged protime and aPTT in healthy nonbleeding volunteers with a dose of 50 units/kg of 4 factor prothrombin complex.
Apixaban
Apixaban (Eliquis) is an oral direct inhibitor of factor Xa that was approved by the FDA to reduce the risk of embolism in patients with atrial fibrillation. The recommended dose is 5 mg by mouth twice daily. A lower dose of 2.5 mg twice daily is recommended for individuals who are 80 years or older, weigh less than or equal to 60 kg, or have reduced kidney function. The bioavailability of apixaban is about 50%, with peak plasma concentrations occurring 1 to 2 hours after dosing. Food does not affect the absorption of apixaban. Circulating half-life is 8 to15 hours.
About 75% of apixaban is metabolized by the CYP3A4 enzyme pathway, while approximately 25% is eliminated unchanged by the kidneys. Drugs that increase the breakdown of apixaban reduce its blood level and effectiveness. Examples include carbamazepine (Tegretol, Tegretol XR, Equetro, Carbatrol), rifampin, St. John's Wort, and phenytoin.
Unlike Rivaroxaban, Apixiban, given at the recommended doses, has little effect on the protime and is not helpful in determining the presence or absence of drug. Apixiban elevates the APTT in a concentration dependent manner, but the changes are small and variable. APTT lacks sensitivity to accurately assess the anticoagulant effect of apixiban. Theoretically, an anti-factor Xa assay using specific calibrator should be able to quantitate plasma concentration of apixiban, but efficacy has not been proven.
Apixaban will interfere with a chromogenic anti-factor Xa assay calibrated to monitor heparin. A low result can be used to rule out clinically relevant Apixaban concentration. An anti-Factor Xa assay using apixaban calibrator should be able to measure apixaban concentrations reliably, but are not commercially available.
Compared to warfarin, apixiban has a lower risk of major bleeding. No specific antidote is available for management of bleeding. No clinical trials have evaluated the efficacy of reversing the anticoagulant effect with plasma or coagulation factor concentrates. Since apixaban has the same anti-FXa activity as rivaroxaban, it is expected that 4 factor prothrombin complex will correct prolonged protime and aPTT at a dose of 50 units/kg
Dabigatran
Dabigatran Etexilate (Pradaxa®) is an oral direct thrombin (factor IIa) inhibitor approved by the FDA in 2010 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Dabigatran etexilate is a prodrug that is rapidly absorbed from the GI tract and then converted to its active form, dabigatran. Dosing for patients with normal renal function is 150 mg by mouth twice daily. Therapeutic levels are reached within 30 minutes to two hours following oral administration. Steady state is reached within 2 to 3 days. The drug is largely excreted unchanged by the kidneys (~80%) with the remainder excreted in bile. Circulating half life is 12-17 hours.
The most significant drug interaction for dabigatran is with p-glycoprotein enzyme inducers and inhibitors which decrease and increase its bioavailability respectively. Commonly used medications that increase serum dabigatran concentrations include verapamil, ketoconazole, amiodarone. In contrast, carbamazepine, dexamethasone, prazosin, trazodone decrease dabigatran concentrations.
Supra-therapeutic concentrations of dabigatran result in modest elevations of the protime and INR (<2.0). However the effect on INR is variable and unpredictable. Different laboratories may get different results depending on the thromboplastin used to perform the assay. An elevated protime/INR may be evidence that the patient is anticoagulated, but the protime and INR should not be used as a measure of the anticoagulant effect of dabigatran.
There is a reasonable, non-linear correlation between dabigatran plasma concentration and the activated plasma thromboplastin time (aPTT). Dabigatran prolongs the aPTT to 1.5 – 2.5 times normal. At a dose of 150 mg bid, less than 10% of patients have aPTTs greater than 65 sec (or 2 times normal) when measured 12 hours after dosing. An aPTT >2.5 x control may indicate over-anticoagulation. APTT can be used to detect an anticoagulant effect, but it cannot be used for quantitation of dabigatran concentration.
Thrombin Time is significantly prolonged even with low concentrations of dabigatran. Thrombin time may be elevated as much as 10 to 20 times control in patients with therapeutic plasma concentrations of dabigatran. Thrombin time is too sensitive for routine monitoring of dabigatran because in many instances an endpoint is never reached. However a normal thrombin time can be used to rule out clinically significant concentrations of dabigatran.
A properly calibrated dilute thrombin time can yield a linear correlation with the plasma concentration of dabigatran that spans the therapeutic range. Stago and Hemoclot (Aniara) offer commercially available versions of the dilute thrombin time that use dabigatran calibrators and can measure dabigatran concentration between 50 and 2000 ng/mL.
Dabigatran affects the activated clotting time (ACT) as do other direct thrombin inhibitors but no systematic investigation of their efficacy has been undertaken.
Ecarin clotting time (ECT) is a specific test that shows a close linear correlation with the plasma concentrations of direct thrombin inhibitors, including dabigatran. However, this test is not generally available in hospital laboratories. ECT ratios of 2-4 have been observed for plasma concentrations of dabigatran with doses of 150 mg bid.
The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial demonstrated lower bleeding and hemorrhagic stroke rates with dabigatran than with heparin. However, the incidence of dyspepsia and major GI bleeding were higher with dabigatran than warfarin. Bleeding risk is increased with concomitant use of antiplatelet medications.
Patients with therapeutic levels of dabigatran are at increased risk of bleeding during invasive procedures or surgery. Dabigatran should be discontinued at least 24 hours prior to elective surgery depending on the degree of renal impairment and risk of bleeding. In patients with normal renal function and a standard bleeding risk, discontinuation of dabigatran 24 hours before surgery will decrease plasma levels to approximately 12-25% of steady state trough levels. Plasma levels are decreased to 15% at 36 hours and 5-10% at 48 hours before surgery. Dabigatran should probably be discontinued for 2-4 days prior to surgery for patients at higher risk of bleeding or for major surgery. For patients at high risk of bleeding, a thrombin time can be performed 6-12 hours before surgery. An elevated thrombin time, in the absence of heparin or other direct thrombin inhibitors, is an indication of the continued presence of dabigatran.
Reversal
Currently, no antidote is available to reverse the anticoagulant effect of dabigatran. No clinical trials have evaluated the efficacy of reversing the anticoagulant effect with plasma or coagulation factor concentrates. The off label use of recombinant activated factor VII (NovoSeven®) or nonactivated four factor prothrombin complex concentrates (KCentra®) may reverse the anticoagulant effect but have not been adequately studied.
Preoperative Cessation
The timing of cessation of NOAC before an elective procedure depends on two factors: bleeding risk and renal function. The American College of Chest Physicians (ACCP) guidelines categorize bleeding risk as either low or high based on the type of procedure. Procedures considered high risk have a bleeding risk greater than 1.5%.
NOACs should be stopped four to five half lives for a procedure with high bleed risk so that there is minimal residual anticoagulant effect. NOACs can be stopped two to three half-lives before a procedure with low bleeding risk. Elimination half-lives of NOACs increases as creatinine clearance (CrCl) decreases. The following table lists the recommended minimum time interval between the last NOAC dose and start of an invasive procedure based on both renal function and procedure bleeding risk.
