Introduction
Deep vein thrombosis (DVT) and pulmonary embolism (PE) are two manifestations of venous thromboembolism (VTE), and they share the same predisposing factors.1 Rivaroxaban is a highly selective, direct factor Xa inhibitor with high oral bioavailability.2 The recommended dosage is 15 mg administered orally twice daily for three weeks, followed by 20 mg once daily, for the continued treatment of VTE.2 The duration of therapy should be a minimum of three months; however, it could be extended over a longer period of time if the benefits exceed the risk of bleeding.2,3
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| Indication under review |
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| Treatment of venous thromboembolic events (deep vein thrombosis [DVT], pulmonary embolism [PE]) and prevention of recurrent DVT and PE |
| Listing criteria requested by sponsor |
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| Use of XARELTO (15 mg and 20 mg tablets) for the treatment of PE for up to six (6) months |
The objective of this report is to perform a systematic review of the beneficial and harmful effects of rivaroxaban 15 mg and 20 mg for the treatment of DVT and/or PE.
Results and Interpretation
Included Studies
Two published, manufacturer-sponsored, open-label, randomized controlled trials (RCTs) were included in this systematic review: EINSTEIN DVT (N = 3,449),4,5 and EINSTEIN PE (N = 4,832).6,7 The two trials evaluated the non-inferiority of rivaroxaban versus an established standard treatment with enoxaparin and a vitamin K antagonist (VKA) for symptomatic recurrent VTE, defined as the composite outcome of recurrent DVT or non-fatal or fatal PE. The non-inferiority margin was based on a meta-analysis of 14 studies that provided four different values of the non-inferiority margin (NIM); these values were hazard ratios ranging from 1.54 to 2.00, depending on the calculation method. The manufacturer used the most liberal value estimated from the meta-analysis and did not specify any clear justification for the choice of this NIM.8 A review of the basis of this estimate revealed some discrepancies in data and methods used for the NIM estimation; the revision of these issues led to an estimated NIM that ranged from 1.49 to 2.28, depending on the calculation method. Other outcomes included health care resources utilization and clinically relevant bleeding.
Efficacy
The overall incidence of death was similar for rivaroxaban and enoxaparin/VKA; the differences between the two groups did not reach statistical significance in the individual trials.
Results from EINSTEIN DVT met the pre-specified and the revised NIMs with an observed hazard ratio of ▬▬▬▬ in the PP population; results were similar for the intention-to-treat [ITT] analysis). On the other hand, results from EINSTEIN PE trial met the pre-specified and the revised NIMs based on the arithmetic scale; the trial failed to meet the revised margins when they were estimated on the geometric scale. The observed hazard ratio was ▬▬▬▬ in the PP population; results were similar for ITT).
Hospitalization and length of hospitalization were reported in the EINSTEIN trials as part of the health care utilization assessment. ▬▬▬▬ These differences were not tested statistically.
Harms
The overall incidence of adverse events, serious adverse events, and withdrawals due to adverse events during the EINSTEIN trials did not differ significantly between rivaroxaban and enoxaparin/VKA, and were not higher than would be expected in this patient population in clinical practice.
Clinically relevant bleeding was the primary safety outcome and was defined as a composite of major and clinically relevant non-major bleeding. In both trials, results were similar between treatment groups for this composite outcome. Results for major bleeding events varied for the two trials; in the EINSTEIN DVT trial (rivaroxaban: 14 [0.8%] versus enoxaparin/VKA: 20 [1.2%]); however, in the EINSTEIN PE trial, major bleeding events were significantly lower with rivaroxaban than with comparator treatment (26 [1.1%] versus 52 [2.2%]).
Pharmacoeconomic Summary
Rivaroxaban (Xarelto) is available as 15 mg and 20 mg tablets. The manufacturer has priced rivaroxaban at $2.84 per tablet regardless of strength (flat pricing), or at $5.68 daily (days 1 to 21) and $2.84 daily (day 22 onward). The manufacturer assumed equal efficacy and harms compared with low-molecular-weight heparins plus VKA (based on the EINSTEIN PE trial) and submitted a cost-minimization analysis. It considered treatment regimens used in the EINSTEIN PE trial and treatment durations of three, six, and 12 months. The manufacturer concluded that rivaroxaban is cost saving at three and six months, with results driven by the lower monitoring costs for rivaroxaban. However, given that the cost of rivaroxaban is significantly greater than that of VKA, for longer treatment duration of ≥ 12 months (indicated for a considerable proportion of patients), rivaroxaban is more costly.
Conclusions
The review included two open-label RCTs, EINSTEIN DVT and EINSTEIN PE. The two trials compared the anticoagulation effects of rivaroxaban and enoxaparin/VKA for the treatment and prevention of recurrence of DVT and/or PE. Overall survival in the two trials showed similar incidence of all-cause mortality between the two study treatments. The EINSTEIN DVT trial showed that rivaroxaban was non-inferior to enoxaparin and a VKA for the treatment of DVT in patients without symptomatic PE. However, although rivaroxaban was found to be non-inferior to enoxaparin/VKA in the treatment and prevention of recurrent VTE based on the pre-specified NIM for EINSTEIN PE, there is uncertainty around the NIM used. CADTH Common Drug Review re-evaluation of the margin suggests a tighter and more conservative one than that used in EINSTEIN PE. Rivaroxaban appeared similar to enoxaparin/VKA with respect to clinically relevant harms outcomes such as bleeding and serious adverse events. The incidence of adverse events did not differ significantly between treatment groups in either trial.
Table 1Summary of Results
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| Outcome | EINSTEIN DVT | EINSTEIN PE |
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| Rivaroxaban | Enoxaparin/VKA | Rivaroxaban | Enoxaparin/VKA |
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| All-cause death, ITT |
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| n/N (%) | 38/1,731 (2.2) | 49/1,718 (2.9) | 58/2,419 (2.7) | 50/2,413 (2.1) |
| Hazard ratio (95% CI) | 0.67 (0.44 to 1.02) | 1.13 (0.77 to 1.65) |
Symptomatic recurrent VTE
(composite of recurrent DVT or non-fatal or fatal PE – primary efficacy outcome), PP |
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| n/N (%) | ▬▬▬▬ | ▬▬▬▬ | ▬▬▬▬ | ▬▬▬▬ |
| Hazard ratio (95% CI) | ▬▬▬▬ | ▬▬▬▬ |
Symptomatic recurrent VTE
(composite of recurrent DVT or non-fatal or fatal PE – primary efficacy outcome), ITT |
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| n/N (%) | 36/1,731 (2.1) | 51/1,718 (3.0) | 50/2,419 (2.1) | 44/2,413 (1.8) |
| Hazard ratio (95% CI) | 0.68 (0.44 to 1.04) | 1.12 (0.75 to 1.68) |
| Symptomatic recurrent VTE: 3-month treatment durations, ITT |
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| n/N (%) | 5/208 (2.4) | 3/203 (1.5) | 6/127 (4.7) | 2/122 (1.6) |
| Hazard ratio (95% CI) | ▬▬▬▬ | ▬▬▬▬ |
| Symptomatic recurrent VTE: 6-month treatment durations, ITT |
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| n/N (%) | 25/1,083 (2.3) | 29/1,083 (2.7) | 27/1,387 (1.9) | 24/1,387 (1.7) |
| Hazard ratio (95% CI) | ▬▬▬▬ | ▬▬▬▬ |
| Symptomatic recurrent VTE: 12-month treatment durations, ITT |
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| n/N (%) | 6/440 (1.4) | 19/432 (4.4) | 17/905 (1.9) | 18/904 (2.0) |
| Hazard ratio (95% CI) | ▬▬▬▬ | ▬▬▬▬ |
| Safety results |
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| Withdrawals; Total/N (%) | 298/1,731 (17.2) | 338/1,718 (19.7) | 258/2,419 (10.7) | 297/2,413 (12.3) |
| WDAEs; n/N (%) | 85/1,718 (4.9) | 81/1,711 (4.7) | 123/2,412 (5.1) | 99/2,405 (4.1) |
| SAEs; n/N (%) | 207/1,718 (12.0) | 233/1,711 (13.6) | 504/2,412 (20.9) | 497/2,405 (20.7) |
| AEs; n/N (%) | 1,078/1,718 (62.7) | 1,080/1,711 (63.1) | 1,937/2,412 (80.3) | 1,901/2,405 (79.0) |
| First major/clinically relevant non-major bleeding |
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| n/N (%) | 139/1,718 (8.1) | 138/1,711 (8.1) | 249/2,412 (10.3%) | 274/2,405 (11.4%) |
| Major bleeding only |
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| n/N (%) | 14/1,718 (0.8) | 20/1,711 (1.2) | 26/2,412 (1.1%) | 52/2,405 (2.2%) |
AEs = adverse events; CI = confidence interval; DVT = deep vein thrombosis; ITT = intention-to-treat; PE = pulmonary embolism; PP = per protocol; SAEs = serious adverse events; VKA = vitamin K antagonist; VTE = venous thromboembolic event; WDAEs = withdrawal due to adverse events.
