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Rivaroxaban (Xarelto)

An oral factor Xa inhibitor.

Trade name Xarelto

Fixed dose drug for acute deep vein thromboembolism and maintenance, without monitoring.

Rivaroxaban therapy for a DVT associated with lower rates of post thrombotic syndrome compared with warfarin.

Effective in preventing venous thromboembolism after orthopedic surgery.

Approved anticoagulation for knee and hip replacements, and nonvalvular atrial fibrillation.

Once daily oral dosing.

One-third eliminated by the kidneys unchanged and the remainder as inactive metabolizes after liver transformation.

Half-life 5 to 9 hours and 11-13 hours in the elderly.

Renal elimination 35%.

Not recommended in those with moderate-severe renal impairment with moderate/severe hepatic impairment, especially with coagulopathy.

Hepatic metabolism occurs primarily by the cytochrome P-450 system (CYP) and includes 3A4 and 2J2 families of enzymes.

Levels can becomes elevated or reduced by inhibitors or inducers of CYP3A4.

Elimination also dependent on P-gp resulting in fluctuating levels of anticoagulation when administered with meds that impair P-gp systems.

It is not inferior to enoxaparin followed by warfarin in a study involving patients with established venous thrombosis.

Has no food interactions and few drug interactions.

Approved for the treatment of DVT, pulmonary embolism, and for the reduction in the risk of recurrent recurrence of DVT and PE following the initial six months treatment for DVT and or PE.

Short half-life of 7-11 hours compared to warfarin which has a 20-60 hour half-life.

RECORD2 trial compared this agent with subcutaneous enoxaparin for the prevention of venous thromboembolism after orthopedic surgery: with rivaroxaban 2%, had a deep vmein thrombosis or non-fatal pulmonary embolus up to 30-42 days while in the enoxaprin group this number was 9.3%, resulting in an absolute risk reduction of 7.3% with similar bleeding rates.

Randomized studies oral rivaroxaban 15 mg BID for three weeks, followed by 20 mg a day compared with subcutaneous enoxaparin followed by vitamin K antagonists for three, six, or 12 months in patients with acute, symptomatic DVT, and a parallel study comparing rivaroxiban at 20 mg a day alone with placebo for an additional six or 12 months in patients who have completed 6 to 12 months of treatment for venous thromboembolism:Rivaroxaban group had 2.1% recurrent DVT while the enoxaparin-vitamin K antagonist group had 3% recurrent DVT, and in the continued-treatment study group rivaroxaban had a superior efficacy 1.3% versus 7.1% with the placebo (The EINSTEIN Investigators).

Rivaroxaban 15mg bid as initial therapy for PE for 3 weeks as failure to provide adequate initial therapy leads to unacceptable recurrence rates, and use of twice daily leads to earlier steady state, higher trough rates and better thrombus regression at 3 weeks than once daily treatment.

In the Stroke Prevention Using Rivaroxaban Compared With Warfarin in Patients With Non-valvular Atrial Fibrillation:demonstrated noninferiority for preventing stroke in emboli, without increase in bleeding risk, and decreased intracranial and fatal bleeding. (ROCKET AF trial).

In patients with atrial fibrillation and bioprosthetic mitral valve, rivaroxaban is not inferior to warfarin with respect to the mean time until the primary outcome of death, major cardiovascular events, or major bleeding at 12 months (RIVER trial investigators).

Among patients with AF and stage four or five chronic kidney disease or undergoing hemodialysis, rivaroxaban appears it associated with significantly less major bleeding compared to warfarin.

EINSTEIN-PE Investigators study of oral rivaroxaban for the treatment of symptomatic pulmonary embolism provided protection from recurrent venous thromboembolism similar to the protection provided by standard therapy, with similar bleeding rates: during the mean study duration of approximately 9 months there was a recurrence in 2.1% in the rivaroxaban group and 1.8% in the standard therapy group.

Discontinuing this agent in nonvalvular AF increases risk of thrombotic events, and other agents should be considered if the drug needs to be discontinued for reasons other than pathologic bleeding.

Oral Rivaroxaban is noninferior to standard therapy for initial and long term treatment of PE, with a non major bleeding rate of 10.3% in the rivaroxaban group and 11.4% in the standard therapy group, and major bleeding in 1.1% and 2.2% of patients, respectively (EINSTEIN-PE Investigators).

Patients 40 years or older hospitalized for acute medical ilness were randomized to receive subcutaneous enoxaparin 40 mg once daily for 10+ and -4 days and oral placebo for 35+ and -4 days or to receive subcutaneous placebo for 10+ and -4 days and oral Rivaroxaban 10 mg once daily for 35+ or -4 days: Rivaroxaban: Rivaroxaban was noninferior to enoxaparin for standard duration thromboprophylaxis(Cohen AT et al).

In the MAGELLAN study patients older than 40 years who were hospitalized for medical illness were randomized to receive subcutaneous enoxaparin or to receive subcutaneous placebo or to receive oral Rivaroxaban 10 mg a day or oral placebo:Rivaroxaban was non-inferior to enoxaparin for standard duration thrombophylaxis.

Extended duration Rivaroxaban was associated with increased risk of bleeding, but reduced the risk of venous thromboembolism.

Oral 20 mg once daily with evening meal, and 15 mg for patients with CrCl 15 mL/min to 50 mL/min.

Rivaroxaban should be taken with the evening meal.

Should be disontinued 24 hours prior to anticipated surgery.

In a randomized trial, patients with atrial fibrillation undergoing elective cardioversion were randomized to either rivaroxaban or warfarin and both agents appeared to be equally safe.

In a randomized trial of 1504 patients with atrial fibrillation and cardioversion this agent was safe and effectively prevented the risk of stroke (Cappato R et al).

In the above study Rivaroxaban’s 2-4 hour action allows for a more rapid conversation than vitamin K antagonists.

The cumulative incidence risk in the above study for composite outcome of stroke, non-CNS embolism, TIA, myocardial infarction, and all- cause mortality was 0.61% with Rivaroxaban and 1.22% in patients receiving vitamin K antagonists.

DosageReduction in Risk of Stroke in Nonvalvular Atrial Fibrillation with CrCl >50 mL/min:20 mg once daily with the evening meal

CrCl 15 to 50 mL/min:15 mg once daily with the evening meal

Treatment of DVT and treatment of PE 15 mg twice daily with food, for first 21 days.

Affter 21 days, transition to 20 mg once daily with food, for remaining treatment.

Reduction in the risk of recurrence of DVT and of PE 20 mg once daily with food.

Prophylaxis of DVT Following hip or knee replacement surgery: Hip replacement:10 mg once daily for 35 days, Knee replacement:10 mg once daily for 12 days.

For stroke prevention in nonvalvular atrial fibrillation 20 mg orally daily with creatinine clearance gr>50ml per minute and 15 mg orally with creatinine clearance 15-50 ml per minute

Cassini trial of high-risk ambulatory patients with cancer treatment with rivaroxaban did not result in significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180 day trial period.

Following revascularization the use of rivaroxaban plus aspirin is associated with a significant lower incidence of acute limb ischemia, major amputations for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular disease causes than aspirin alone.

Among individuals 65 years or older with atrial fibrillation treatment with  rivaroxaban compared with apixaban was associated with significant increased risk of major ischemic or hemorrhagic events.

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