Anticoagulation in Hospitalized Patients

Once the oral anticoagulant rivaroxaban becomes available, I believe it will revolutionize the way that U.S. hospitalists manage patients who require an anticoagulant in the hospital.

The drug, already approved in Canada and the European Union, is expected to be approved by the Food and Drug Administration following a 15–2 vote by the FDA's Cardiovascular and Renal Drugs Advisory Committee that the drug has a favorable risk-benefit profile for prophylaxis of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery. This is the first indication reviewed by the FDA; other indications are being studied in phase III trials, including a multinational study of VTE prevention in medically ill hospitalized patients. I am familiar with rivaroxaban in my role as principal investigator in this study at the University of Miami, one of the study sites.

The drug is important for hospitalists because we work closely with orthopedic surgeons in caring for patients undergoing hip and knee replacement. It will provide an alternative to existing drugs for preventing VTE, a common complication in these patients, including warfarin (Coumadin); low-molecular-weight heparin (LMWH), such as enoxaparin sodium (Lovenox); and fondaparinux sodium (Arixtra). About half of these patients receive LMWH for prophylaxis, about 30%–40% receive warfarin, and a smaller proportion receive fondaparinux.

Promising data were reported in a study published last year, which compared rivaroxaban to enoxaparin after hip arthroplasty. The VTE rate was a little over 3.5% among those on enoxaparin, but was closer to 1% among those on 10 mg of rivaroxaban a day, a significant difference. Rivaroxaban was associated with an absolute risk reduction in VTE of approximately 2.6%, and the number of patients needed to treat to prevent one case of VTE was about 38 (N. Engl. J. Med. 2008;358:2765–75).

In addition to its efficacy, a great benefit of this drug is that it's taken once daily and, unlike LMWH, is not given parenterally. Compliance decreases when patients must take a drug twice a day or more often. Also, no monitoring is needed, so rivaroxaban has several advantages over warfarin, the only other oral anticoagulant available. Warfarin has a narrow therapeutic index, requires regular INR monitoring, interacts with many drugs and with some food, and is cleared by the cytochrome P450 system.

More patients are undergoing surgery than ever before, and joint replacement surgeries are becoming ever more frequent, so rivaroxaban holds great promise for our aging population.

Excess bleeding and potential hepatoxicity were the adverse events considered in the FDA panel's discussion of the drug's risk-benefit profile. Although the risk of major bleeding may be slightly increased, the rate of major bleeding in pooled clinical trials was 0.4% in those on rivaroxaban and 0.2% in those on enoxaparin, which was not a significant difference. Signs of potential hepatoxicity also were uncommon (0.15% in rivaroxaban-treated patients vs. 0.11% in those on enoxaparin, not a significant difference). I don't believe that hepatoxicity will be an issue with this drug.

The recommended dose of rivaroxaban is 10 mg a day, its onset of action is anywhere from 2.5 to 4 hours, it lasts for 24 hours, and it has a half-life of 6–9 hours. It is cleared by the kidneys, and patients with creatine clearances under 3 mL/min were not enrolled in trials. Rivaroxaban should be avoided in patients on drugs that inhibit the cytochrome P450 3A4 (CYP 3A4), such as ketoconazole and protease inhibitors, and vice versa. Rivaroxaban should be avoided in patients with severe renal disease (creatinine clearance below 30 mL/min) or severe liver disease.

We have just enrolled our first patient in the study that is comparing 10 mg of rivaroxaban a day (for up to 39 days) with 40 mg of enoxaparin once a day (for up to 14 days) for preventing VTE in medically ill hospitalized patients. Also, as one of the sites for a study of rivaroxaban for treating deep vein thrombosis and pulmonary embolism, we plan to start enrolling patients in that trial soon. For now, the FDA is looking at approving rivaroxaban only for VTE prevention in patients undergoing hip or knee replacement. But this indication itself will make the drug the first new oral anticoagulant since warfarin was discovered to treat VTE more than 50 years ago.

Once the oral anticoagulant rivaroxaban becomes available, I believe it will revolutionize the way that U.S. hospitalists manage patients who require an anticoagulant in the hospital.

The drug, already approved in Canada and the European Union, is expected to be approved by the Food and Drug Administration following a 15–2 vote by the FDA's Cardiovascular and Renal Drugs Advisory Committee that the drug has a favorable risk-benefit profile for prophylaxis of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery. This is the first indication reviewed by the FDA; other indications are being studied in phase III trials, including a multinational study of VTE prevention in medically ill hospitalized patients. I am familiar with rivaroxaban in my role as principal investigator in this study at the University of Miami, one of the study sites.

The drug is important for hospitalists because we work closely with orthopedic surgeons in caring for patients undergoing hip and knee replacement. It will provide an alternative to existing drugs for preventing VTE, a common complication in these patients, including warfarin (Coumadin); low-molecular-weight heparin (LMWH), such as enoxaparin sodium (Lovenox); and fondaparinux sodium (Arixtra). About half of these patients receive LMWH for prophylaxis, about 30%–40% receive warfarin, and a smaller proportion receive fondaparinux.

Promising data were reported in a study published last year, which compared rivaroxaban to enoxaparin after hip arthroplasty. The VTE rate was a little over 3.5% among those on enoxaparin, but was closer to 1% among those on 10 mg of rivaroxaban a day, a significant difference. Rivaroxaban was associated with an absolute risk reduction in VTE of approximately 2.6%, and the number of patients needed to treat to prevent one case of VTE was about 38 (N. Engl. J. Med. 2008;358:2765–75).

In addition to its efficacy, a great benefit of this drug is that it's taken once daily and, unlike LMWH, is not given parenterally. Compliance decreases when patients must take a drug twice a day or more often. Also, no monitoring is needed, so rivaroxaban has several advantages over warfarin, the only other oral anticoagulant available. Warfarin has a narrow therapeutic index, requires regular INR monitoring, interacts with many drugs and with some food, and is cleared by the cytochrome P450 system.

More patients are undergoing surgery than ever before, and joint replacement surgeries are becoming ever more frequent, so rivaroxaban holds great promise for our aging population.

Excess bleeding and potential hepatoxicity were the adverse events considered in the FDA panel's discussion of the drug's risk-benefit profile. Although the risk of major bleeding may be slightly increased, the rate of major bleeding in pooled clinical trials was 0.4% in those on rivaroxaban and 0.2% in those on enoxaparin, which was not a significant difference. Signs of potential hepatoxicity also were uncommon (0.15% in rivaroxaban-treated patients vs. 0.11% in those on enoxaparin, not a significant difference). I don't believe that hepatoxicity will be an issue with this drug.

The recommended dose of rivaroxaban is 10 mg a day, its onset of action is anywhere from 2.5 to 4 hours, it lasts for 24 hours, and it has a half-life of 6–9 hours. It is cleared by the kidneys, and patients with creatine clearances under 3 mL/min were not enrolled in trials. Rivaroxaban should be avoided in patients on drugs that inhibit the cytochrome P450 3A4 (CYP 3A4), such as ketoconazole and protease inhibitors, and vice versa. Rivaroxaban should be avoided in patients with severe renal disease (creatinine clearance below 30 mL/min) or severe liver disease.

We have just enrolled our first patient in the study that is comparing 10 mg of rivaroxaban a day (for up to 39 days) with 40 mg of enoxaparin once a day (for up to 14 days) for preventing VTE in medically ill hospitalized patients. Also, as one of the sites for a study of rivaroxaban for treating deep vein thrombosis and pulmonary embolism, we plan to start enrolling patients in that trial soon. For now, the FDA is looking at approving rivaroxaban only for VTE prevention in patients undergoing hip or knee replacement. But this indication itself will make the drug the first new oral anticoagulant since warfarin was discovered to treat VTE more than 50 years ago.

Once the oral anticoagulant rivaroxaban becomes available, I believe it will revolutionize the way that U.S. hospitalists manage patients who require an anticoagulant in the hospital.

The drug, already approved in Canada and the European Union, is expected to be approved by the Food and Drug Administration following a 15–2 vote by the FDA's Cardiovascular and Renal Drugs Advisory Committee that the drug has a favorable risk-benefit profile for prophylaxis of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery. This is the first indication reviewed by the FDA; other indications are being studied in phase III trials, including a multinational study of VTE prevention in medically ill hospitalized patients. I am familiar with rivaroxaban in my role as principal investigator in this study at the University of Miami, one of the study sites.

The drug is important for hospitalists because we work closely with orthopedic surgeons in caring for patients undergoing hip and knee replacement. It will provide an alternative to existing drugs for preventing VTE, a common complication in these patients, including warfarin (Coumadin); low-molecular-weight heparin (LMWH), such as enoxaparin sodium (Lovenox); and fondaparinux sodium (Arixtra). About half of these patients receive LMWH for prophylaxis, about 30%–40% receive warfarin, and a smaller proportion receive fondaparinux.

Promising data were reported in a study published last year, which compared rivaroxaban to enoxaparin after hip arthroplasty. The VTE rate was a little over 3.5% among those on enoxaparin, but was closer to 1% among those on 10 mg of rivaroxaban a day, a significant difference. Rivaroxaban was associated with an absolute risk reduction in VTE of approximately 2.6%, and the number of patients needed to treat to prevent one case of VTE was about 38 (N. Engl. J. Med. 2008;358:2765–75).

In addition to its efficacy, a great benefit of this drug is that it's taken once daily and, unlike LMWH, is not given parenterally. Compliance decreases when patients must take a drug twice a day or more often. Also, no monitoring is needed, so rivaroxaban has several advantages over warfarin, the only other oral anticoagulant available. Warfarin has a narrow therapeutic index, requires regular INR monitoring, interacts with many drugs and with some food, and is cleared by the cytochrome P450 system.

More patients are undergoing surgery than ever before, and joint replacement surgeries are becoming ever more frequent, so rivaroxaban holds great promise for our aging population.

Excess bleeding and potential hepatoxicity were the adverse events considered in the FDA panel's discussion of the drug's risk-benefit profile. Although the risk of major bleeding may be slightly increased, the rate of major bleeding in pooled clinical trials was 0.4% in those on rivaroxaban and 0.2% in those on enoxaparin, which was not a significant difference. Signs of potential hepatoxicity also were uncommon (0.15% in rivaroxaban-treated patients vs. 0.11% in those on enoxaparin, not a significant difference). I don't believe that hepatoxicity will be an issue with this drug.

The recommended dose of rivaroxaban is 10 mg a day, its onset of action is anywhere from 2.5 to 4 hours, it lasts for 24 hours, and it has a half-life of 6–9 hours. It is cleared by the kidneys, and patients with creatine clearances under 3 mL/min were not enrolled in trials. Rivaroxaban should be avoided in patients on drugs that inhibit the cytochrome P450 3A4 (CYP 3A4), such as ketoconazole and protease inhibitors, and vice versa. Rivaroxaban should be avoided in patients with severe renal disease (creatinine clearance below 30 mL/min) or severe liver disease.

We have just enrolled our first patient in the study that is comparing 10 mg of rivaroxaban a day (for up to 39 days) with 40 mg of enoxaparin once a day (for up to 14 days) for preventing VTE in medically ill hospitalized patients. Also, as one of the sites for a study of rivaroxaban for treating deep vein thrombosis and pulmonary embolism, we plan to start enrolling patients in that trial soon. For now, the FDA is looking at approving rivaroxaban only for VTE prevention in patients undergoing hip or knee replacement. But this indication itself will make the drug the first new oral anticoagulant since warfarin was discovered to treat VTE more than 50 years ago.