A new wave of oral anticoagulants has been approved by the US Food and Drug Administration over the last several years, and their use has become more common in both the general and oncology populations.
These new medications include the direct thrombin inhibitor dabigatran (Pradaxa®) and factor Xa inhibitors apixaban (Eliquis®) and rivaroxaban (Xarelto®). Many of these products are advertised as having advantages over warfarin and other non-oral anticoagulants; however, careful review of their properties is needed in order to avoid potential problems when they are administered to patients with cancer.
Dabigatran, an oral direct thrombin inhibitor, is approved for prevention of stroke in non-valvular atrial fibrillation, as well as for prevention and treatment of venous thromboembolism (VTE).1 Dabigatran is dosed at 150 mg twice daily and is primarily cleared renally. Therefore, in patients with decreased renal clearance, caution must be used and the dose must be adjusted accordingly. Patients with creatinine clearance (CrCl) less than 30 mL/min must use 75 mg twice daily; similarly, patients with CrCl between 30 and 50 mL/min can also be given this reduced dose. These adjustments are particularly important in elderly patients (>75-80 years old) with cancer or those who are receiving concomitant chemotherapy that could be nephrotoxic.
Some of the more common nephrotoxic chemotherapy agents include platinum-based compounds (ie, cisplatin, carboplatin, and oxaliplatin), antimetabolites (ie, methotrexate, hydroxyurea, and capecitabine), and alkylating agents (ie, cyclophosphamide and bendamustine). Renal clearance must be closely followed if it is not already secondary to the patient’s cancer or age. Dabigatran does not have any CYP450 interactions; however, it is a P-glycoprotein (P-gp) substrate so caution must be used when using medications that affect this efflux pump. Another important consideration in the use of dabigatran is that there is no antidote in the case of an overdose, which has caused some controversy over its use, especially in the elderly.
Rivaroxaban is an oral factor Xa inhibitor that is approved for the prevention of stroke in non-valvular atrial fibrillation; for the prevention of deep vein thrombosis (DVT) and for the treatment of DVT and pulmonary embolism.2 This medication also undergoes renal clearance and should not be used in patients with CrCl less than 15 to 30 mL/min, depending on the indication. A patient’s renal function must be evaluated prior to administration of rivaroxaban in addition to reviewing the nephrotoxicity potential of the chemotherapy. Rivaroxaban has significant drug interactions with medications that are strong inhibitors and inducers of both the P-gp transporter and CYP3A4 system, such as the azole antifungals and ritonavir. Drug interactions with chemotherapeutic agents must be vigilantly checked prior to administration. Similar to dabigatran, there is no antidote for rivaroxaban.
In addition to these clinical considerations, rivaroxaban has a boxed warning for an increased risk of stroke when the medication is discontinued in patients with non-valvular atrial fibrillation. If rivaroxaban needed to be stopped in a scenario other than excessive bleeding, the transition to a different anticoagulant should be considered. There is another boxed warning for increased risk of spinal or epidural hematomas in patients undergoing lumbar punctures or neuraxial anesthesia, which are both procedures that patients with cancer often undergo.
Another available oral factor Xa inhibitor is apixaban, which is approved for the prevention of stroke in non-valvular atrial fibrillation and for the prevention of VTE.3 It has many of the same properties and warnings as rivoroxaban. Additionally, dose adjustment is recommended for patients who have two of the following characteristics: 80 years or age or older; serum creatinine of 1.5 mg/dL or greater; and body weight of 60 kg or less. Apixaban has similar drug interactions as rivaroxaban, with concurrent use of CYP3A4 and P-gp inhibitors requiring a dose reduction. Apixiban has the same boxed warning as rivoroxaban for elevated stroke risk after discontinuation in non-valvular atrial fibrillation patients, but not for spinal or epidural hematomas.
These new oral anticoagulants have shown promise in their use in non-valvular atrial fibrillation and the prevention and/or treatment of VTE. In order to avoid the consistent monitoring required when using warfarin, increasing numbers of patients with cancer may be started on these new agents. However, many of these agents do not have extensive post-marketing data as of yet; therefore, caution is urged. A more formal recommendation on their use in patients with cancer will need to be made once additional data is available.
1. Dabigatran (Pradaxa ®) Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT. January 2013.
2. Rivoroxaban (Xarelto ®) Prescribing Information. Janssen Pharmaceuticals, Inc. Titusville, NJ. March 2013.
3. Apixiban (Eliquis ®) Prescribing Information. Bristol-Myers Squibb Company, Princeton, NJ. December 2012.