Table 3.
Efficacy and safety results (patients aged ≥75 years) in trials of NOACs for reduction in the risk of stroke in NVAF
| Characteristic | RE-LY
|
RE-LY
|
ROCKET AF
|
ENGAGE AF-TIMI 48
|
ENGAGE AF-TIMI 48
|
ARISTOTLE
|
AVERROES
|
|---|---|---|---|---|---|---|---|
| Dabigatran 110 mg32 | Dabigatran 150 mg32 | Rivaroxaban 20 mg33,a | Edoxaban 30 mg29,b | Edoxaban 60 mg29,b | Apixaban 5 mg27,34,c | Apixaban 5 mg31,36,d | |
| N (aged ≥75 years) | 7,258 | 6,229 | 8,474 | 5,678 | 1,898 | ||
| Comparator | Warfarin, target INR 2.0–3.0 | Warfarin, target INR 2.0–3.0 | Warfarin, target INR 2.0–3.0 | Warfarin, target INR 2.0–3.0 | Warfarin, target INR 2.0–3.0 | Warfarin, target INR 2.0–3.0 | Aspirin 81–324 mg |
| Efficacy | |||||||
| Stroke or SE | 1.89 vs 2.14; RR: 0.88 (0.66–1.17) | 1.43 vs 2.14; RR: 0.67 (0.49–0.90) | 2.29 vs 2.85; HR: 0.80 (0.63–1.02) | 2.55 vs 2.31 | 1.91 vs 2.31 | 1.56 vs 2.19; HR: 0.71 (0.53–0.95) | 2.0 vs 6.1; HR: 0.33 (0.20–0.54) |
| Stroke, SE, vascular death | 5.27 vs 5.74; HR: 0.92 (0.78–1.087) | ||||||
| Stroke, SE, MI, vascular death | 6.07 vs 6.68; HR: 0.91 (0.78–1.06) | ||||||
| Hemorrhagic stroke | 0.34 vs 0.49; HR: 0.70 (0.39–1.25) | ||||||
| Ischemic stroke | 1.71 vs 1.95; HR: 0.88 (0.67–1.16) | 1.6 vs 5.0; HR: 0.33 (0.18–0.56) | |||||
| Stroke (undetermined) | 0.09 vs 0.16; HR: 0.55 (0.19–1.65) | ||||||
| All-cause mortality | 5.42 vs 5.97; HR: 0.91 (0.77–1.07) | 5.6 vs 7.8; HR: 0.71 (0.50–0.99) | |||||
| Safety | |||||||
| Major bleeding | 4.43 vs 4.37; RR: 1.01 (0.83–1.23) | 5.10 vs 4.37; RR: 1.18 (0.98–1.42) | 4.86 vs 4.40; HR: 1.11 (0.92–1.34) | 2.26 vs 4.83 | 4.01 vs 4.83 | 3.33 vs 5.19; HR: 0.64 (0.52–0.79) | 2.6 vs 2.2; HR: 1.21 (0.69–2.12) |
| Hb drop | 3.85 vs 2.98; HR: 1.29 (1.03–1.61) | ||||||
| Transfusion | 2.28 vs 1.86; HR: 1.23 (0.93–1.64) | ||||||
| Clinical organ | 1.07 vs 1.42; HR: 0.75 (0.52–1.08) | ||||||
| Fatal bleeding | 0.28 vs 0.61; HR: 0.45 (0.23–0.87) | ||||||
| Intracranial hemorrhage | 0.37 vs 1.00; RR: 0.37 (0.21–0.64) | 0.41 vs 1.00; RR: 0.42 (0.25–0.70) | 0.66 vs 0.83; HR: 0.80 (0.50–1.28) | 0.43 vs 1.29; HR: 0.34 (0.20–0.57) | 0.6 vs 0.7; HR: 0.84 (0.28–2.41) | ||
| Major or CRNM bleeding | 19.83 vs 17.55; HR: 1.13 (1.02–1.25) | 6.7 vs 5.3; HR: 1.26 (0.88–1.80) | |||||
| GI bleeding | 2.19 vs 1.59; RR: 1.39 (1.03–1.98) | 2.80 vs 1.59; RR: 1.79 (1.35–2.37) | |||||
| Extracranial hemorrhage | 4.10 vs 3.44; RR: 1.20 (0.97–1.48) | 4.68 vs 3.44; RR: 1.39 (1.13–1.70) | |||||
| Non-GI extracranial hemorrhage | 2.00 vs 1.95; RR: 1.02 (0.76–1.36) | 2.26 vs 1.95; RR: 1.16 (0.88–1.53) | |||||
| Any bleeding | 23.5 vs 33.7; HR: 0.71 (0.65–0.78) | ||||||
| Net clinical events | 8.91 vs 10.9; HR: 0.82 (0.72–0.93) | ||||||
Notes: All columns show NOAC vs warfarin except AVERROES, which compared apixaban vs aspirin. All data are presented as annual rates per 100 patients and RRs/HRs with 95% confidence intervals. Population numbers represent subjects in the total randomized population who were aged ≥75 years at baseline.
Fifteen milligrams daily for those with moderately impaired renal function (CrCl 30–49 mL/min). The 2,950 (20.7%) patients with CrCl 30–49 mL/min had a mean age of 79 years.62
For patients in either group, dose was halved if any of the following characteristics were present at the time of randomization or during the study: estimated CrCl 30–50 mL/min; body weight ≤60 kg; or the concomitant use of verapamil, quinidine, or dronedarone.
A reduced dose of apixaban 2.5 mg twice daily or placebo was administered in 790 patients ≥75 years of age (13.9% of patients ≥75 years).
A reduced dose of apixaban (2.5 mg twice daily) was used throughout the study for patients who met two of the following criteria: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 μmol/L). A total of 6% of the patients in the apixaban group and 7% in the aspirin group received 2.5 mg twice a day according to protocol. A daily dose of 81 mg of aspirin or aspirin placebo was used in 65% of patients in the apixaban group and 64% in the aspirin group.
Abbreviations: ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; AVERROES, Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; CrCl, creatinine clearance; CRNM, clinically relevant nonmajor; ENGAGE AF-TIMI 48, Evaluation of Efficacy and Safety of Edoxaban versus Warfarin in Subjects with Atrial Fibrillation – Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation; HR, hazard ratio; INR, international normalized ratio; MI, myocardial infarction; NOAC, non-vitamin K antagonist oral anticoagulant; NVAF, non-valvular atrial fibrillation; RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy; 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; RR, relative risk; SE, systemic embolism.