First Factor Xa Inhibitor Approved for DVT Prevention

BY ELIZABETH MECHCATIE
Elsevier Global Medical News

With the recent approval of rivaroxaban for an orthopedic indication, there are now two new oral anticoagulants available in the United States, after a more-than-half-century lapse since warfarin was approved.

The Food and Drug Administration approved rivaroxaban (a factor Xa inhibitor that is taken orally) for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. The recommended dosage is 10 mg orally, once daily, for 35 days in patients undergoing hip surgery and for 12 days for those undergoing knee surgery. The initial dose should be taken at least 6-10 hours after surgery, “once hemostasis has been established,” according to the prescribing information.

Rivaroxaban is the first drug in this class to be approved. Dabigatran, an orally administered direct thrombin inhibitor marketed as Pradaxa by Boehringer Ingelheim Pharmaceuticals, was approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation in 2010 – the first oral anticoagulant approved since warfarin was approved in 1954. Neither requires international normalized ratio monitoring.

Rivaroxaban is a small-molecular-weight drug that works by inhibiting direct factor Xa, which lowers thrombin production and prolongs prothrombin time. At a meeting in 2009, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 15-2 that the data from clinical trials demonstrated that the drug had a favorable risk-benefit profile for this indication. At the meeting, panelists were concerned that the drug might be used off label, and stressed that clinicians should avoid prescribing the drug for longer periods and for unapproved indications.

The drug is also being studied in patients with acute coronary syndrome. The manufacturer, Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, is marketing the drug as Xarelto.

More than 6,000 patients undergoing hip or knee replacement surgery have been treated with rivaroxaban in clinical trials, according to the FDA statement announcing the approval.

Among patients undergoing knee replacement surgery, almost 10% of those who were treated with rivaroxaban had a venous thromboembolic event (VTE), compared with 18.8% of those who were treated with enoxaparin (Lovenox), according to the statement. In two studies of patients undergoing a hip replacement, 1.1% and 2% of patients who received rivaroxaban developed a VTE, compared with 3.9% and 8.4% of those who received enoxaparin, respectively.

Bleeding was the most common adverse event associated with rivaroxaban. The label includes warnings about the increased risk of bleeding that can be serious and fatal, as well as a boxed warning about the risk of a spinal or epidural hematoma in surgical settings in patients who are anticoagulated and are receiving neuraxial anesthesia or undergoing a spinal puncture. The manufacturer has been asked to conduct a postmarketing study on the risk factors, clinical management, and outcome of major bleeding cases associated with rivaroxaban use, according to the FDA’s approval letter.

Rivaroxaban “doesn”t appear to have a great liability in patients with organ impairment, so it can be used in patients with mild or moderate renal or hepatic dysfunction,” Dr. Peter Kowey said in an interview. There is a large amount of information available on rivaroxaban for various indications, “and like dabigatran, the once-a-day dosing will have an impact on compliance,” he added. The two drugs, however, cannot be directly compared because there are no head-to-head studies of the two drugs, and cross-study comparisons are treacherous, noted Dr. Kowey, a cardiologist and professor of medicine and clinical pharmacology at Jefferson Medical College, Philadelphia.

With the possible approval of other novel anticoagulants over the next 1-2 years, the choice of which one to prescribe may prove to be a challenge for clinicians. The potential for additional new anticoagulants on the market “will create a tremendous burden” to provide the education, information, and other resources that physicians will need “in order to make an intelligent decision about choice of therapy,” he said. These drugs have different mechanisms of action, pharmacologies, drug interactions, and dosing schemes – and dosing of the same drug differs by indication, “so there”s a lot to learn and a lot to digest when choosing one of these new drugs for an individual patient,” he said.

The availability of these newer agents will result in a lot more patients being anticoagulated, “some appropriately,” Dr. Kowey said. However, there is concern that because of the excitement over these new anticoagulants, some low-risk patients who probably should not receive anticoagulants will end up on treatment.

Although he expects that the use of warfarin will “diminish dramatically” with the availability of these new anticoagulants, warfarin will continue to be used to treat certain patients, such as those in whom it is important to know their precise level of anticoagulation for various reasons (such as a history of bleeding), and for indications for which the new anticoagulants have not yet been proved to be safe and effective (such as mechanical heart valve prophylaxis or treatment of pulmonary embolism). And there are those clinicians – and patients – who prefer to wait until the newer drugs have been available for awhile before they switch, he said.

Dr. Kowey said that another possible benefit of having several agents on the market is that competition will reduce their costs.

A Johnson & Johnson spokesperson said that the cost of rivaroxaban is $6.75 a day, the same as dabigatran in November 2010.

Dr. Kowey consults for every company that is developing a new anticoagulant: J&J, Merck, Portola, BMS, Daiichi-Sankyo, Boehringer Engelheim, Sanofi, and AstraZeneca. He is not an investigator for any and he does not own stock – all fee for service consultation.

COMMENTARY
Dr. Jeana O’Brien, FCCP, comments: This article brings information regarding the approval of another new oral anticoagulant. Rivaroxaban, a direct inhibitor of factor Xa, has been approved for DVT prophylaxis in orthopedic patients with expectations for additional indications in the near future. This drug joins dabigatran, another oral anticoagulant approved last year for prevention of ischemic stroke. Neither of these drugs require INR monitoring; however, they cost much more than warfarin. There are no comparative studies available at present between these drugs, or between the newer agents and warfarin in terms of safety and efficacy. The addition of newer agents to the market is always exciting. Their niche will need to be determined, and their use should be informed and carefully considered.