Table 3.
Principal published phase III, randomized clinical trials data for rivaroxaban in its approved indications [42, 47, 57, 59, 67, 78]
| Indication | Study | Design | Patients randomized (n) | Study drugs | Treatment duration | Primary efficacy outcome | Principal safety outcome |
|---|---|---|---|---|---|---|---|
| Prevention of VTE in patients undergoing total hip or knee replacement | RECORD1–3 | Multicenter, randomized, double-blind, superiority, pooled analysis | 9,581 | Rivaroxaban oral 10 mg vs enoxaparin s.c. 40 mg od | Rivaroxaban: 31–39 days (hip) or 10–14 days (knee) Enoxaparin: 10–40 days (hip) or 11–15 days (knee) | VTE plus all-cause mortality on treatment: 0.4 vs 0.8 %; p = 0.005 | Major bleeding on treatment (14 days): 0.2 vs 0.2 % |
| RECORD1–4 | Multicenter, randomized, double-blind, superiority, pooled analysis | 12,729 | Rivaroxaban oral 10 mg vs enoxaparin s.c. 40 mg od or 30 mg bid | Rivaroxaban: 31–39 days (hip) or 10–14 days (knee) Enoxaparin: 11–40 days (hip) or 10–15 days (knee) | Symptomatic VTE plus all-cause mortality on treatment: 0.5 vs 1.0 %; p = 0.001 | Major bleeding on treatment (12 ± 2 days): 0.3 vs 0.2 %; p = 0.23 Clinically relevant bleeding on treatment (12 ± 2 days):a 2.8 vs 2.5 %; p = 0.19 | |
| Treatment and secondary prevention of VTE | EINSTEIN DVT | Multicenter, randomized, open-label, non-inferiority | 3,449 | Rivaroxaban oral 15 mg bid for 3 weeks followed by 20 mg od vs standard enoxaparin/VKAb | 3, 6, or 12 months | Symptomatic, recurrent VTE: 2.1 vs 3.0 % (p < 0.001 for non-inferiority) | Clinically relevant bleeding:a 8.1 vs 8.1 % (p = 0.77) Major bleeding: 0.8 vs 1.2 % (p = 0.21) |
| EINSTEIN PE | Multicenter, randomized, open-label, non-inferiority | 4,832 | As above | 3, 6, or 12 months | Symptomatic, recurrent VTE: 2.1 vs 1.8 % (p = 0.003 for non-inferiority) | Clinically relevant bleeding:a 10.3 vs 11.4 % (p = 0.23) Major bleeding: 1.1 vs 2.2 % (p = 0.003) | |
| EINSTEIN EXT | Multicenter, randomized, double-blind, superiority | 1,197 | Rivaroxaban oral 20 mg od or placebo | 6 or 12 months | Symptomatic, recurrent VTE: 1.3 vs 7.1 % (p < 0.001) | Major bleeding: 0.7 vs 0.0 % (p = 0.11) Clinically relevant bleeding:a 6.0 vs 1.2 % (p < 0.001) | |
| Prevention of stroke and systemic embolism in patients with non-valvular AF and risk factors for stroke | ROCKET AF | Multicenter, randomized, double-blind, non-inferiority | 14,264 | Rivaroxaban oral 20 mg odc or dose-adjusted warfarin | Median 590 days | Stroke or systemic embolism: 1.7 vs 2.2 % per year (p < 0.001 for non-inferiority; per-protocol population) | Clinically relevant bleeding:a 14.9 vs 14.5 % per year (p = 0.44) Major bleeding: 3.6 vs 3.4 % per year (p = 0.58) Intracranial bleeding: 0.5 vs 0.7 % per year (p = 0.02) Fatal bleeding: 0.2 vs 0.5 % per year (p = 0.003) |
| Prevention of cardiovascular events in patients with recent ACS | ATLAS ACS 2 TIMI 51 | Multicenter, randomized, double-blind, superiority | 15,526 | Dual antiplatelet therapy plus either rivaroxaban oral 2.5 mg bid or 5 mg bid or placebo | Mean 31 months | Death from CV causes, MI or stroke: 8.9 vs 10.7 % (p = 0.008) | Major bleeding:d 2.1 vs 0.6 % (p < 0.001) Intracranial bleeding: 0.6 vs 0.2 % (p = 0.009) Fatal bleeding: 0.3 vs 0.2 % (p = 0.66) |
ACS acute coronary syndrome, AF atrial fibrillation, bid twice daily, CrCl creatinine clearance, CV cardiovascular, INR international normalized ratio, MI myocardial infarction, od once daily, s.c. subcutaneous, VKA vitamin K antagonist, VTE venous thromboembolism
aComposite of major and non-major clinically relevant bleeding
bEnoxaparin s.c. 1.0 mg/kg bid for ≥5 days, discontinued when the INR was ≥2.0 for 2 consecutive days, plus VKA started ≤48 h after randomization
c15 mg od in patients with CrCl 30–49 mL/min
dNot related to coronary artery bypass grafting