Rivaroxaban ( Xarelto ) is indicated for the treatment of deep vein thrombosis ( DVT ), and prevention of recurrent DVT and pulmonary embolism ( PE ) following an acute deep vein thrombosis in adults.
For the initial treatment of acute deep vein thrombosis, the recommended dosage of Rivaroxaban is 15 mg twice daily for the first 21 days followed by 20 mg once daily for continued treatment and prevention of recurrence.
The duration of treatment recommended in the summary of product characteristics depends on bleeding risk and other clinical criteria: short-term treatment ( 3 months ) is recommended for those with transient risk factors such as recent surgery and trauma, and longer treatment for permanent risk factors or idiopathic ( unprovoked ) deep vein thrombosis.
The summary of product characteristics further states that experience with Rivaroxaban in this indication for more than 12 months is limited.
A reduced dosage of 15 mg twice daily for 21 days followed by 15 mg once daily should be used in people with moderate ( creatinine clearance 30–49 ml/min ) or severe ( creatinine clearance 15–29 ml/min ) renal impairment.
The key clinical evidence in the manufacturer's submission came from 2 trials ( EINSTEIN-DVT and EINSTEIN-Ext ).
EINSTEIN-DVT was an open-label non-inferiority study that compared Rivaroxaban ( 15 mg twice daily for 3 weeks, then 20 mg once daily for 3, 6 or 12 months ) with Enoxaparin followed by a vitamin K antagonist ( either Warfarin or Acenocoumarol ) for treating patients with acute symptomatic deep vein thrombosis without any symptoms of pulmonary embolism, and for preventing recurrent deep vein thrombosis and pulmonary embolism. Enoxaparin was given until a vitamin K antagonist had brought the international normalised ratio ( INR ) into the target range, and was then stopped. Based on individual patient risk factors, patients were either assigned to 3, 6 or 12 months of treatment as determined by the treating physician.
EINSTEIN-Ext was a randomised placebo-controlled superiority trial that compared Rivaroxaban ( 20 mg once daily; n=602 ) with placebo once daily ( n=594 ) in patients with confirmed symptomatic deep vein thrombosis or pulmonary embolism that had been treated for 6 or 12 months with a vitamin K antagonist ( Warfarin or Acenocoumarol ) or Rivaroxaban up to the moment of randomisation. Patients were recruited if the risks and benefits of further anticoagulation were finely balanced, that is, there was clinical equipoise for the decision to continue anticoagulation.
About 60% of patients recruited into EINSTEIN-Ext were assigned to 6 months of treatment, about 40% were assigned to 12 months of treatment and 28% had previously used Rivaroxaban.
Some people were excluded from the EINSTEIN-DVT and EINSTEIN-Ext trials, such as those with a creatinine clearance of less than 30 ml/min, clinically significant liver disease, high blood pressure ( systolic more than 180 mmHg or diastolic more than 110 mmHg ), active bleeding or at high risk of bleeding.
The primary efficacy endpoint was a composite of deep vein thrombosis or pulmonary embolism ( symptomatic, recurrent venous thromboembolism ). Pulmonary embolism included both fatal and non-fatal pulmonary embolism. The primary safety endpoint was a composite of major bleeding and other clinically relevant non-major bleeding ( clinically relevant bleeding ) for EINSTEIN-DVT and major bleeding for EINSTEIN-Ext. A range of secondary composite endpoints were also included.
In EINSTEIN-DVT, the primary efficacy endpoint of symptomatic recurrent venous thromboembolism occurred in 2.1% ( n=36 ) of patients in the Rivaroxaban group compared with 3.0% ( n=51 ) in the Enoxaparin and vitamin K antagonist group ( hazard ratio, HR=0.68; 95% confidence interval [ CI ] 0.44 to 1.04, p less than 0.001 for non-inferiority and p=0.076 for superiority ).
The overall hazard ratio for Rivaroxaban was 0.97 ( 95% CI 0.76 to 1.22, p=0.77 ) for the primary safety endpoint of clinically relevant bleeding and 0.67 ( 95% CI 0.44 to 1.02, p=0.06 ) for death from all causes.
Recurrent deep vein thrombosis occurred less frequently in patients treated with Rivaroxaban than with Enoxaparin and a vitamin K antagonist ( 14 compared with 28 ). Pulmonary embolisms ( fatal and non-fatal ) did not differ between treatment groups.
A time in therapeutic range for the comparator Enoxaparin and a vitamin K antagonist of 57.7% across all centres and 59.7% in western European centres was reported.
Guidelines from the National Patient Safety Agency and the Scottish Executive Health Department recommend a time in therapeutic range of at least 60%.
It also noted there was no statistical interaction observed in EINSTEIN-DVT between time in therapeutic range and treatment effect.
In EINSTEIN-Ext, patients taking Rivaroxaban experienced fewer recurrences of venous thromboembolism ( 1.3%, n=8 ) than patients taking placebo ( 7.1%, n=42 ) ( HR=0.18, 95% CI 0.09 to 0.39, p less than 0.0001 ).
The numbers of clinically relevant non-major bleeding events were significantly higher in the Rivaroxaban arm than in the placebo arm ( 32 patients [ 5.3% ] compared with 7 patients [ 1.2% ], p less than 0.001 ).
There were more major bleeding events in patients taking Rivaroxaban ( 4 patients compared with no patients ), although this did not reach statistical significance.
A mixed treatment comparison for the subgroup of patients with cancer was reported. This compared the relative effectiveness of Rivaroxaban with dual low molecular weight heparin ( LMWH ) and a vitamin K antagonist, long-term LMWH compared with LMWH and a vitamin K antagonist, and Rivaroxaban compared with long-term LMWH.
The manufacturer provided 3 analyses. The primary analysis used data from a systematic review of long-term anticoagulation in patients with cancer reported by Akl et al ( 2011 ) and from the whole EINSTEIN-DVT trial population. Secondary analysis 1 used data from a trial by Lee et al ( 2003 ) evaluating the LMWH Dalteparin for the prevention of recurrent venous thromboembolism in patients with cancer and the data from the whole EINSTEIN-DVT trial population. Similarly, secondary analysis 2 used data from Akl et al ( 2011 ) and effectiveness data from the cancer subgroup of EINSTEIN-DVT.
Results from the primary analysis indicated that for patients with active cancer, the venous thromboembolism recurrence hazard ratio for Rivaroxaban compared with long-term LMWH was 1.44 ( 95% credible intervals 0.07 to 31.4 ). Secondary analysis 2 showed that Rivaroxaban was less effective than LMWH at preventing venous thromboembolism recurrence ( HR=1.32, 95% credible intervals 0.06 to 32.3 ) but induced fewer major bleeding events ( OR=0.24, 95% credible intervals 0.00 to 9.44 ). However, the mixed treatment comparison had credible intervals with wide margins for the efficacy and safety of Rivaroxaban compared with long-term LMWH.
Adverse events from EINSTEIN-DVT and EINSTEIN-Ext that were experienced in at least 4% of any treatment group were reported.
The most common adverse events across both EINSTEIN trials were headache, pain in extremity, nasopharyngitis and nosebleed.
The reported incidences of post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension were low in both arms of EINSTEIN-DVT and EINSTEIN-Ext. ( Xagena )
Source: NICE, 2012