Los Angeles—In recent years, three new oral anticoagulants have entered the market. In a standing-room-only session at the annual meeting of the Hematology/Oncology Pharmacy Association, pharmacists were given an overview of the agents and cued into some of the challenges they may face in using them for managing venous thromboembolism (VTE) in cancer patients.

“Cancer patients can benefit from these agents because they have ease of administration, less drug interactions compared with warfarin and monitoring is not required,” said Surabhi Palkimas, PharmD, who presented the data. Hypercoagulability state and bleeding, however, are risks, said Dr. Palkimas, a benign hematology pharmacy coordinator at University of Virginia Health System, Charlottesville..

The Path to Approval

In 2010, the FDA approved dabigatran (Pradaxa, Boehringer Ingelheim) for atrial fibrillation (AF). In 2011, the agency approved rivaroxaban (Xarelto, Bayer) for both prevention of VTE in patients undergoing knee or hip replacement surgery and for AF; in 2012, rivaroxaban received additional indications for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). The newest addition to the anticoagulant arsenal is apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), approved for AF in 2013.

Rivaroxaban, given once daily, and apixaban, given twice daily, are direct factor Xa inhibitors that are absorbed rapidly and have a bioavailability of approximately 50%. Dabigatran, which is a prodrug, is given twice daily, is a direct factor IIa inhibitor, requires an acidic environment for absorption and has a bioavailability of 6%.

These drugs have quick onset and offset of action, but differ with regard to metabolism, dosing frequency and a variety of other factors (Table 1).

Table 1. Pharmacokinetic and Pharmacodynamic Properties

Dabigatran Rivaroxaban Apixaban
Time to peak, h 1.25-3 2-4 3-4
Half-life, h 12-17 5-9 8-15
Dosing frequency bid qd bid
Metabolism Conjugation CYP3A4 (primary)
CYP232, oxidation
Elimination Renal (80%)
Biliary (20%)
Renal (66%)
Biliary/Fecal (25%)
Renal (~27%)
Fecal (25%)
Plasma protein binding, % 35 >90 ~87
Binding to catalytic site Reversible Reversible Reversible
bid, twice daily; CYP, cytochrome P450; qd, once daily

“They are all reversible agents, but something we don’t have with all three drugs is an antidote,” Dr. Palkimas said. “With warfarin, if someone comes in with a bleed, we have vitamin K. With [the other agents], we don’t have that. But these agents have a short half-life and quick time to peak compared with warfarin, so do we really need an antidote?” She pointed out that the procoagulant reversal agents noted in the package inserts for these drugs, including prothrombin complex concentrate (PCC or aPCC) and recombinant factor VIIa (rFVIIa), are not supported by evidence-based medicine.

Pharmacists, she said, need to be really smart when thinking about drug–drug interactions. Dabigatran’s FDA label warns that it interacts with ketoconazole, droneclarone (Multaq, Sanofi), amiodarone (Nexterone, Baxter), quinidine, verapamil, rifampicin and St. John’s wort. Rivaroxaban and apixaban interact with ketoconazole, clarithromycin, ritonavir (Norvir, Abbott) and St. John’s wort.

Looking Beyond the Label For a True Picture of Risk

The labels, however, don’t tell the whole story. The lists of drug interactions are much longer on the Canadian and European labels of the three drugs, according to Dr. Palkimas. “As pharmacists, we need to be diligent and look at the metabolism of concomitant drugs to assess potential drug–drug interactions,” she said. For example, because dabigatran is a substrate of P-glycoprotein, pharmacists need to think about all the drugs that affect its metabolism—there are approximately 21 of them. With rivaroxaban and apixaban, pharmacists need to take precautions when patients are on drugs that inhibit P-glycoprotein and cytochrome P450 3A4. Pharmacists also need to be aware that these oral drugs require different dosing for different creatinine clearance rates.

Dr. Palkimas pointed out that the MAGELLAN and ADOPT VTE prevention trials include few cancer patients. In these trials, rivaroxaban and apixaban were evaluated for VTE prophylaxis in medically ill patients and shown to be noninferior to enoxaparin (Lovenox, Sanofi) but resulted in higher rates of major bleeding events. In the MAGELLAN trial that evaluated rivaroxaban, 7% of patients had cancer. In the ADOPT trial, 3.5% of patients receiving apixaban had active cancer and 6.1% had remote cancer. Dabigatran has not been evaluated for VTE prevention in medically ill patients.

Table 2. Cancer Patients in VTE Treatment Trials
Trial/Arm Patients Receiving New Oral Agent, %
EINSTEIN-DVT, rivaroxaban 6.3
EINSTEIN-PE, rivaroxaban 4.7
AMPLIFY-EXT, apixaban Not included
RECOVER, dabigatran 5
VTE, venous thromboembolism

VTE treatment trials also include few cancer patients (Table 2). The EINSTEIN and RECOVER trials pitted the new oral agents against the standard treatment of starting patients on enoxaparin for five days and then switching them over to warfarin. In EINSTEIN, rivaroxaban was shown to be noninferior to standard therapy. Although the incidence of major and non-major bleeding was similar in both treatment groups, rivaroxaban was associated with a significantly lower risk for major bleeding compared with standard therapy. In RECOVER, dabigatran was noninferior to warfarin and had similar bleeding risks. In the AMPLIFY-EXT trial, apixaban was superior to placebo.

“At our institution, we started using rivaroxaban for VTE treatment [in some cancer patients] since its approval for that indication,” Dr. Palkimas said. She added that pharmacists should consider offering the new oral anticoagulants to cancer patients with VTE who have difficulty getting their international normalized ratio (INR) test or difficulty staying in their INR therapeutic range, who also have normal renal function and are not taking medications that interact with the new oral anticoagulants.

Cost could be a stumbling block for some patients, Dr. Palkimas noted, pointing out that a month’s supply of dabigatran and rivaroxaban is approximately $290 and $320, respectively.

A Note of Caution

Asked to comment on the three new oral anticoagulants, Agnes Lee, MD, the director of the thrombosis program at Vancouver General Hospital and an associate professor of medicine at the University of British Columbia, in Vancouver, said she would be hesitant to use the drugs in oncology patients because so few cancer patients were included in the trials. “None of these drugs have been studied in depth in cancer patients,” Dr. Lee said. “There could be potential interactions with chemotherapeutic drugs.”

Patients on chemotherapy, she said, tend to have gastrointestinal problems that lead to unpredictable absorption, and these drugs could increase the risk for gastrointestinal bleeding. “I would really like to see these drugs tested in a clinical trial of cancer patients,” she said. “It is desperately needed.”

Dr. Palkimas had no relevant disclosures. Dr. Lee reported honoraria and advisory board involvement with BMS, and honoraria from Bayer and Boehringer Ingelheim.