Table 1.
Outcomes of interest within RCTs evaluating factor Xa inhibitors: apixaban, rivaroxaban, or edoxaban vs. warfarin
| Outcome of Interest | Randomized Controlled Trial | |||
|---|---|---|---|---|
| ARISTOTLE (N=18,201) (Apixaban vs. Warfarin) |
ROCKET AF (N=14,264) (Rivaroxaban vs. Warfarin) |
ENGAGE AF (High Dose Edoxaban vs. Warfarin) (N=14,071) |
ENGAGE AF (Low Dose Edoxaban vs. Warfarin) (N=14,070) |
|
| Stroke or Systemic Embolism | In the ITT population: 1.27% of patients per year with apixaban, 1.60% of patients per year in the warfarin group (HR 0.79; 95% CI 0.66 to 0.95, p=0.01) NNT = 167/2 years |
In the ITT population: 2.1% of patients per year in the rivaroxaban group and 2.4% of patients per year with warfarin (HR 0.88; 95% CI 0.7 to 1.03; p<0.001 for noninferiority; p=0.12 for superiority) In the per-protocol population,: 1.7% per year in the rivaroxaban group and 2.2% with warfarin (noninferiority HR 0.79; 95% CI 0.66 to 0.96; p<0.001; superiority HR 0.79; 95% CI 0.65 to 0.95; p=0.01) |
In the ITT analysis in the overall study period, event rates were higher in all groups and there were no statistically significant differences (1.80% per year for warfarin, 1.57%/year for high dose edoxaban [HR 0.87; 97.5% CI 0.73–1.04 as compared to warfarin]) In the modified ITT: 1.5% of patients per year with warfarin, 1.18% of patients per year in the high-dose edoxaban group (HR 0.79; 97.5% CI 0.63–0.99, p < 0.001 for noninferiority and p=0.02 for superiority) |
In the ITT analysis in the overall study period, event rates were higher in all groups and there were no statistically significant differences (2.04%/year for low dose edoxaban [HR 1.13; 97.5% CI 0.96 to 1.34 as compared to warfarin]) In the modified ITT: 1.61% of patients per year in the low-dose edoxaban group (HR1.07; 97.5% CI 0.87 to 1.31, p=0.005 for noninferiority and p=0.44 for superiority). |
| Ischemic or Uncertain Stroke | 0.97% per year for apixaban and 1.05% per year for warfarin HR 0.92; 95% CI 0.74 to 1.13; p=0.42 |
1.34% per year for rivaroxaban and 1.42% per year for warfarin HR 0.94; 95% CI 0.75 to 1.17; p=0.58 |
1.25% per year for warfarin and 1.25% per year for edoxaban, HR1.00; 95% CI 0.83 to 1.19 | 1.77% per year for edoxaban and 1.25% per year for warfarin, HR 1.41; 95% CI 1.19 to 1.67 |
| Hemorrhagic Stroke | 0.24% per year for apixaban and 0.47% per year for warfarin HR 0.51; 95% CI 0.35 to 0.75; p<0.001 |
0.26% per year for rivaroxaban and 0.44% per year for warfarin HR 0.59; 95% CI 0.37 to 0.93; p=0.024 |
0.26% of patients per year, HR 0.54; 95% CI 0.38 to 0.77 0.47% patients per year for warfarin |
0.16% of patients per year, HR 0.33; 95% CI 0.22 to 0.50 0.47% patients per year for warfarin |
| Any Stroke or TIA | NA | NA |
Any stroke 1.49% of patients per year, HR 0.88; 95% CI 0.75 to 1.03 1.69% patients per year for warfarin |
Any stroke 1.91% of patients per year, HR 1.13; 95% CI 0.97 to 1.31 1.69% patients per year for warfarin |
| Systemic Embolism | 0.09% per year for apixaban and 0.10% per year for warfarin HR 0.87; 95% CI 0.44 to 1.75; p=0.70 |
0.04% per year for rivaroxaban and 0.19% per year for warfarin HR 0.23; 95% CI 0.09 to 0.61; p=0.003 |
0.08% of patients per year, HR 0.65; 95% CI 0.34 to 1.20 0.12% of patients per year for warfarin Subanalysis: Geller, 2015 (23): there was no difference in nonfatal systemic embolic or fatal events between high dose edoxaban compared with warfarin. |
0.15% of patients per year, HR 1.24; 95% CI 0.72 to 2.15 0.12% of patients per year for warfarin Subanalysis: Geller, 2015 (23): there was no difference in nonfatal systemic embolic or fatal events between low dose edoxaban compared with warfarin. |
| Major Bleeding | 2.13% per year for apixaban and 3.09% per year for warfarin HR 0.69; 95% CI 0.60 to 0.80; p<0.001 |
3.6% per year for rivaroxaban and 3.4% per year for warfarin HR 1.04; 95% CI 0.90 to 1.20; p=0.58 |
2.75% of patients per year, HR 0.80; 95% CI 0.71 to 0.91 3.43% patients per year for warfarin |
1.61% of patients per year, HR 0.47; 95% CI 0.41 to 0.55 3.43% patients per year for warfarin |
| Major, NMCR and Minor Bleeding |
Major or NMCR bleeding: 4.07% per year in the apixaban group and 6.01% per year in the warfarin group HR 0.68; 95% CI 0.61 to 0.75 Non-major bleeding: 6.4% per year for apixaban, 9.4 %per year for warfarin HR 0.69; 95% CI 0.63 to 0.75 |
Major or NMCR bleeding: 14.9% per year in the rivaroxaban group and 14.5% per year years for warfarin HR 1.03; 95% CI 0.96 to 1.11 NMCR bleeding: 11.8% per year in the rivaroxaban group and 11.4% per year for warfarin HR 1.04; 95% CI 0.96 to 1.13 |
Major or NMCR bleeding: 11.1% of patients per year, HR 0.86; 95% CI 0.80 to 0.92 13.02% patients per year for warfarin Minor bleeding:4.12% of patients per year, HR 0.84; 95% CI 0.76 to 0.94 4.89% patients per year for warfarin |
Major or NMCR bleeding: 7.97% of patients per year, HR 0.62; 95% CI 0.57 to 0.67 13.02% patients per year for warfarin Minor bleeding:3.52% of patients per year, HR 0.72; 95% CI 0.65 to 0.81 4.89% patients per year for warfarin |
| Gastrointestinal Bleeding | NA | 3.61% per year for rivaroxaban and 2.60% per year; HR 1.42; 95% CI 1.22 to 1.66 | NA | NA |
| Intracranial Bleeding | Lower intracranial bleeding in patients treated with apixaban compared to warfarin HR 0.42; 95% CI 0.30 to 0.58; p<0.001 |
Overall event rate of 0.67% per year Lower intracranial bleeding in patients treated with rivaroxaban compared to warfarin HR 0.67; 95% CI 0.47 to 0.93; p=0.023 |
0.39% of patients per year, HR 0.47; 95% CI 0.34 to 0.63 0.85% patients per year for warfarin |
0.26% of patients per year, HR 0.30; 95% CI 0.21 to 0.43 0.85% patients per year for warfarin |
| All-Cause Mortality | 3.52% per year for apixaban and 3.94% per year in the warfarin group HR 0.89; 95% CI 0.80 to 0.998; p=0.047 |
In the ITT analysis: 4.5% per year in the rivaroxaban group and 4.9% per year for warfarin HR 0.92; 95% CI 0.82 to 1.03; p=0.15 In treatment per protocol analysis: 1.9% per year for rivaroxaban and 2.2% per year for warfarin HR 0.85; 95% CI 0.70 to 1.02; p=0.07 |
3.99% of patients per year, HR 0.92; 95% CI 0.83 to 1.01 4.35% patients per year for warfarin |
3.80% of patients per year, HR 0.87; 95% CI 0.79 to 0.96 4.35% patients per year for warfarin |
| Death from Cardiovascular Causes | 1.8% per year for apixaban and 2.02% per year for the warfarin group HR 0.89; 95% CI 0.76 to 1.04 |
1.53% per year for the rivaroxaban group and 1.71 %per year for warfarin HR 0.89; 95% CI 0.73 to 1.10; p=0.289 |
2.74 % patients per year, HR 0.86; 95% CI 0.77 to 0.97 3.17% patients per year for warfarin |
2.71% patients per year, HR 0.85; 95% CI 0.76 to 0.96 3.17% patients per year for warfarin |
| Myocardial Infarction | 0.53% per year for apixaban and 0.61% per year for warfarin HR 0.88; 95% CI 0.66 to 1.17; p=0.37 |
0.9% per year for rivaroxaban and 1.1% per year in the warfarin group HR 0.81; 95% CI 0.63 to 1.06; p=0.12 |
0.70% of patients per year, HR 0.94; 95% CI 0.74 to 1.19 0.75% patients per year for warfarin |
0.89% of patients per year, HR 1.19; 95% CI 0.95 to 1.49 0.75% patients per year for warfarin |
| Specific Subgroups of Interest | ||||
| Prior Stroke | No statistically significant interaction was found between prior stroke/TIA and treatment for stroke or systemic embolism, cardiovascular death, disabling or fatal stroke, all-cause mortality, major bleeding (24). | No statistically significant interaction was found between prior stroke/TIA and treatment for stroke or systemic embolism, major or non-major clinically relevant bleeding (25). | No statistically significant interaction was found between prior stroke/TIA and treatment (high dose edoxaban vs. warfarin) for stroke or systemic embolic event, any stroke, hemorrhagic stroke, ischemic stroke, any cause death, or cardiovascular death (26). | NA |
| Aspirin Treatment | No statistically significant interactions between treatment and use of aspirin vs. none on stroke or systemic embolism, ischemic stroke, MI, death, major bleeding, hemorrhagic stroke, major or clinically-relevant non-major bleeding or any bleeding (27). | No statistically significant interactions between treatment and use of aspirin versus none on stroke or systemic embolism, major bleeding or all-cause death (28). | No statistically significant interactions between treatment and use of single antiplatelet drug vs. none on stroke or systemic embolic events, ischemic stroke, hemorrhagic stroke, MI, cardiovascular death, major bleeding, intracranial bleeding, or any bleeding (29). | No statistically significant interactions between treatment and use of single antiplatelet drug vs. none on stroke or systemic embolic events, ischemic stroke, hemorrhagic stroke, MI, cardiovascular death, major bleeding, intracranial bleeding, or any bleeding (29). |
Abbreviations: ARISTOTLE=Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial; CI=confidence interval; ENGAGE AF-TIMI 48=Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 trial; HR=hazard ratio; ITT=intent to treat; MI=myocardial infarction; NA=not applicable; NMCR=nonmajor clinically relevant; RE-LY=Randomized Evaluation of Long-term Anticoagulation Therapy trial; ROCKET AF=Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; TIA=transient ischemic attack