As a hematology/oncology clinician, there is perhaps no drug I hate more than Coumadin (warfarin sodium). Venous thromboembolism (VTE) is an unfortunate, all-too-common complication in cancer patients, and thus, many wind up on short-term (i.e., six months) or life-long anticoagulation, typically in the form of Coumadin.
As you may know, patients on Coumadin are a bit of a nightmare to manage. Coumadin seems to interact with just about every drug out there, especially antibiotics (which our patients frequently need). And vitamin K rich foods (think green/leafy) counteract the effects of Coumadin. All of this interaction often leads to sub-therapeutic (too low) INR levels, which increase risk for repeated clots or supra-therapeutic (too high) INR levels, leading to increased risk of bleeding.
At least once weekly I think to myself, "When will we no longer have to use this drug? When will there be a better and/or safer option?!" Well, the answer to that question may just lie in the new drug rivaroxaban.
Rivaroxaban (Xarelto) was first approved by the FDA in July 2011 to prevent VTE in patients undergoing knee/hip replacement surgery. Now the FDA, as of November 2012, has approved rivaroxaban for first-line treatment of deep vein thrombosis and pulmonary embolism (PE). This latest approval came after the global Einstein research study, which encompassed three large trials evaluating the safety and efficacy of the drug.
One of the sub-trials, Einstein-PE, looked at 4,382 patients with PE from 263 sites in 38 countries. Half the patients were assigned to receive oral rivaroxaban, with the dosing consisting of 15mg twice a day for three weeks followed by 20mg once daily thereafter (this is now the current dosing recommendation as well). The other half of study patients received standard therapy in the form of low-molecular-weight heparin (LMWH) plus Coumadin until the patient reached a therapeutic INR level, at which time LMWH was discontinued.
Rivaroxaban demonstrated non-inferiority for both efficacy and safety compared to standard therapy. Specifically, there was essentially equal efficacy in terms of VTE recurrence between the two groups. From a safety standpoint, there was actually a slightly lower risk of bleeding events in the rivaroxaban group.
Other exciting facts about this drug include:
- It is active within one to three hours of oral intake. Therefore, unlike Coumadin, which takes up to seven days to become therapeutic in the system (and thus requires bridging of LMWH), this drug is up and running in your body within hours of VTE diagnosis.
- It has a relatively short half-life of five to nine hours. This is important when a patient needs to hold anticoagulation for surgery (be it planned or emergency circumstances).
Now for the big catch: Currently rivaroxaban is not approved for patients with cancer or renal complications. Only 5 percent to 6 percent of patients in the Einstein-PE trial had malignancy. Consequently, good conclusions about this drug's usage in oncology patients cannot yet be determined. Much more focused study is needed before you will see this drug used in your own practice settings.
Another limitation requiring further study is there is no reversal agent for this drug. Thus major bleeding episodes cannot be easily reversed. This is, of course, concerning for our patients, many of whom already have potentially low platelet counts or are at increased risk for falls.
With all that said, I am hopeful. I think there is great promise for drugs like rivaroxaban and also dabigatran etexilate (Pradaxa) to cause a paradigm shift, moving us away from the frustrations of Coumadin and moving us toward treatment that is safer, equally or perhaps even more efficacious (i.e., having consistent anticoagulation rather than fluctuating levels of drug coverage), and easier to manage from a clinician standpoint.
- Abrams, C., Buller, H., Goldhaber, S., Huisman, M., Konstantinides, S., Moll, S., Sharifi, M. (2012). Rivaroxaban expected to have huge impact on management of DVT, PE. HemOnc Today, November 2012, 1, 12-14.