This was a subgroup analysis of a retrospective cohort study that compared the risk of major bleeding and stroke/systemic embolism (SE) events between apixaban and warfarin in Japanese patients with nonvalvular atrial fibrillation (NVAF) who were naïve to oral anticoagulants based on their baseline creatinine clearance (CrCl) (≥ 15 to < 30, ≥ 30 to < 50, ≥ 50 to < 80, and ≥ 80 mL/min). In addition, the association between renal function decline during the study period and clinical outcomes of apixaban versus warfarin was investigated. |
After propensity score matching, patients treated with apixaban had generally lower incidence rates of major bleeding and stroke/SE events than those treated with warfarin across the CrCl subgroups. The incidence rates of major bleeding and stroke/SE events generally increased with an increasing annual decline in CrCl in both treatment groups. |
This real-world study revealed that the safety and effectiveness of apixaban and warfarin in Japanese patients with NVAF were consistent across different renal function subgroups, including those with severe renal impairment, and emphasized the importance of monitoring variations in renal function over time in patients with NVAF. |
1 Introduction
2 Methods
2.1 Study Design and Eligibility Criteria
2.2 Outcomes and Definitions
2.3 Statistical Analyses
3 Results
3.1 Patient Disposition
3.2 Demographics and Baseline Clinical Characteristics
Variable | CrCl ≥ 15 to < 30 mL/min | CrCl ≥ 30 to < 50 mL/min | CrCl ≥ 50 to < 80 mL/min | CrCl ≥ 80 mL/min | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Apixaban [n = 313] | Warfarin [n = 313] | SMD | Apixaban [n = 1049] | Warfarin [n = 1049] | SMD | Apixaban [n = 1816] | Warfarin [n = 1816] | SMD | Apixaban [n = 1207] | Warfarin [n = 1207] | SMD | |
Female sex | 210 (67.1) | 206 (65.8) | 0.027 | 567 (54.1) | 528 (50.3) | 0.074 | 692 (38.1) | 707 (38.9) | 0.017 | 295 (24.4) | 288 (23.9) | 0.014 |
Age, years | 85.2 ± 6.8 | 84.4 ± 7.6 | 0.105 | 80.9 ± 6.6 | 80.7 ± 6.8 | 0.039 | 73.4 ± 7.9 | 73.0 ± 7.9 | 0.050 | 62.5 ± 9.7 | 61.8 ± 9.7 | 0.067 |
≥ 75 to < 85 | 105 (33.5) | 102 (32.6) | 567 (54.1) | 557 (53.1) | 732 (40.3) | 710 (39.1) | 118 (9.8) | 92 (7.6) | ||||
≥ 85 | 182 (58.1) | 174 (55.6) | 322 (30.7) | 319 (30.4) | 116 (6.4) | 110 (6.1) | 0 (0.0) | 6 (0.5) | ||||
Body weight, kg | 48.04 ± 10.15 | 48.66 ± 11.25 | 0.059 | 52.66 ± 9.7 | 53.04 ± 10.4 | 0.038 | 60.27 ± 10.31 | 60.06 ± 10.13 | 0.021 | 72.05 ± 13.24 | 71.84 ± 12.83 | 0.016 |
≤ 40.0 | 73 (23.3) | 68 (21.7) | 97 (9.2) | 94 (9.0) | 26 (1.4) | 35 (1.9) | 2 (0.2) | 2 (0.2) | ||||
> 40.0 to ≤ 50.0 | 121 (38.7) | 128 (40.9) | 347 (33.1) | 362 (34.5) | 280 (15.4) | 276 (15.2) | 38 (3.1) | 32 (2.7) | ||||
> 50.0 to ≤ 60.0 | 82 (26.2) | 73 (23.3) | 375 (35.7) | 360 (34.3) | 618 (34.0) | 633 (34.9) | 171 (14.2) | 148 (12.3) | ||||
BMI, kg/m2 | 21.48 ± 3.77a | 21.57 ± 4.01a | 0.023 | 22.08 ± 3.55b | 22.28 ± 3.45b | 0.058 | 23.54 ± 3.46c | 23.63 ± 3.49c | 0.025 | 25.99 ± 4.32d | 26.13 ± 4.38d | 0.034 |
SBP, mmHg | 126.2 ± 24.9e | 124.7 ± 21.5e | 0.061 | 128.8 ± 21.5f | 127.3 ± 20.0f | 0.071 | 130.2 ± 19.8g | 129.6 ± 19.9g | 0.029 | 132.1 ± 18.9h | 131.3 ± 19.4h | 0.039 |
DBP, mmHg | 71.6 ± 15.7e | 70.3 ± 14.6e | 0.088 | 73.1 + 14.6i | 73.3 ± 14.5i | 0.011 | 76.7 ± 14.2j | 76.6 ± 14.0j | 0.007 | 81.3 ± 14.9k | 80.4 ± 13.8k | 0.069 |
CrCl, mL/min | 23.8 ± 3.9 | 23.5 ± 4.1 | 0.067 | 40.5 ± 5.7 | 40.4 ± 5.6 | 0.030 | 63.8 ± 8.5 | 63.8 ± 8.6 | 0.009 | 102.3 ± 23.0 | 102.5 ± 23.9 | 0.009 |
≥ 15 to < 30 | 313 (100) | 313 (100) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | ||||
≥ 30 to < 50 | 0 (0.0) | 0 (0.0) | 1049 (100) | 1049 (100) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | ||||
Paroxysmal AF | 123 (39.3) | 101 (32.3) | 0.147 | 444 (42.3) | 393 (37.5) | 0.099 | 823 (45.3) | 688 (37.9) | 0.151 | 498 (41.3) | 449 (37.2) | 0.083 |
CHADS2 score | 3.0 [2.0–3.0] | 3.0 [2.0–3.0] | 0.038 | 2.0 [2.0–3.0] | 2.0 [2.0–3.0] | 0.003 | 2.0 [1.0–3.0] | 2.0 [1.0–3.0] | 0.002 | 1.0 [1.0–2.0] | 1.0 [1.0–2.0] | 0.024 |
CHA2DS2-VASc score | 5.0 [4.0–5.0] | 5.0 [4.0–5.0] | 0.052 | 4.0 [3.0–5.0] | 4.0 [3.0–5.0] | 0.049 | 3.0 [2.0–4.0] | 3.0 [2.0–4.0] | 0.005 | 2.0 [1.0–3.0] | 2.0 [1.0–3.0] | 0.013 |
HAS-BLED score | 3.0 [2.0–4.0] | 3.0 [2.0–4.0] | 0.039 | 2.0 [2.0–3.0] | 2.0 [2.0–3.0] | 0.016 | 2.0 [2.0–3.0] | 2.0 [1.0–3.0] | 0.037 | 1.0 [1.0–2.0] | 1.0 [1.0–2.0] | 0.006 |
Comorbidities | 303 (96.8) | 308 (98.4) | 0.105 | 984 (93.8) | 994 (94.8) | 0.041 | 1629 (89.7) | 1617 (89.0) | 0.021 | 1010 (83.7) | 1027 (85.1) | 0.039 |
CHF | 161 (51.4) | 168 (53.7) | 0.045 | 354 (33.7) | 360 (34.3) | 0.012 | 413 (22.7) | 442 (24.3) | 0.038 | 243 (20.1) | 265 (22.0) | 0.045 |
Hypertension | 273 (87.2) | 274 (87.5) | 0.010 | 861 (82.1) | 849 (80.9) | 0.029 | 1380 (76.0) | 1383 (76.2) | 0.004 | 854 (70.8) | 854 (70.8) | 0.00 |
Diabetes | 71 (22.7) | 70 (22.4) | 0.008 | 218 (20.8) | 225 (21.4) | 0.016 | 378 (20.8) | 370 (20.4) | 0.011 | 266 (22.0) | 280 (23.2) | 0.028 |
Dyslipidemia | 83 (26.5) | 89 (28.4) | 0.043 | 320 (30.5) | 300 (28.6) | 0.042 | 567 (31.2) | 544 (30.0) | 0.027 | 356 (29.5) | 345 (28.6) | 0.020 |
CAD | 67 (21.4) | 66 (21.1) | 0.008 | 182 (17.3) | 190 (18.1) | 0.020 | 289 (15.9) | 307 (16.9) | 0.027 | 156 (12.9) | 154 (12.8) | 0.005 |
PADl | 17 (5.4) | 16 (5.1) | 0.014 | 56 (5.3) | 46 (4.4) | 0.044 | 75 (4.1) | 85 (4.7) | 0.027 | 34 (2.8) | 40 (3.3) | 0.029 |
Medical history | 135 (43.1) | 113 (36.1) | 0.144 | 365 (34.8) | 373 (35.6) | 0.016 | 487 (26.8) | 460 (25.3) | 0.034 | 226 (18.7) | 209 (17.3) | 0.037 |
Stroke/TIA | 64 (20.4) | 58 (18.5) | 0.048 | 178 (17.0) | 180 (17.2) | 0.005 | 185 (10.2) | 175 (9.6) | 0.018 | 76 (6.3) | 80 (6.6) | 0.013 |
Bleedingm | 4 (1.3) | 5 (1.6) | 0.027 | 17 (1.6) | 18 (1.7) | 0.007 | 27 (1.5) | 25 (1.4) | 0.009 | 15 (1.2) | 12 (1.0) | 0.024 |
Concomitant medication | ||||||||||||
Antiplatelet drugs | 126 (40.3) | 120 (38.3) | 0.039 | 343 (32.7) | 356 (33.9) | 0.026 | 448 (24.7) | 471 (25.9) | 0.029 | 199 (16.5) | 221 (18.3) | 0.048 |
ACE inhibitor or ARB | 165 (52.7) | 166 (53.0) | 0.006 | 489 (46.6) | 507 (48.3) | 0.034 | 782 (43.1) | 804 (44.3) | 0.024 | 435 (36.0) | 457 (37.9) | 0.038 |
β-blocker | 75 (24.0) | 71 (22.7) | 0.030 | 198 (18.9) | 200 (19.1) | 0.005 | 334 (18.4) | 323 (17.8) | 0.016 | 213 (17.6) | 190 (15.7) | 0.051 |
Amiodarone | 9 (2.9) | 11 (3.5) | 0.036 | 20 (1.9) | 20 (1.9) | 0.0 | 13 (0.7) | 16 (0.9) | 0.019 | 18 (1.5) | 22 (1.8) | 0.026 |
PPI or H2 receptor antagonist | 150 (47.9) | 138 (44.1) | 0.077 | 351 (33.5) | 336 (32.0) | 0.030 | 498 (27.4) | 454 (25.0) | 0.055 | 221 (18.3) | 193 (16.0) | 0.062 |
NSAIDs | 22 (7.0) | 22 (7.0) | 0.0 | 68 (6.5) | 62 (5.9) | 0.024 | 78 (4.3) | 69 (3.8) | 0.025 | 34 (2.8) | 36 (3.0) | 0.010 |
Apixaban dose | ||||||||||||
5 mg bid | 26 (8.3) | NA | 237 (22.6) | NA | 1123 (61.8) | NA | 1008 (83.5) | NA | ||||
2.5 mg bid | 278 (88.8) | NA | 797 (76.0) | NA | 674 (37.1) | NA | 176 (14.6) | NA | ||||
Other | 9 (2.9) | NA | 15 (1.4) | NA | 19 (1.0) | NA | 23 (1.9) | NA |
3.3 Clinical Outcomes of Apixaban Versus Warfarin Stratified by Baseline CrCl
Event/CrCl (mL/min) | Apixaban | Warfarin | Cox proportional hazards regressionb | ||||||
---|---|---|---|---|---|---|---|---|---|
Number of eventsa | Person-yearsa | Incidence ratea (95% CI) | Number of eventsa | Person-yearsa | Incidence ratea (95% CI) | HR (95% CI) | p value | ||
Major bleeding | |||||||||
≥ 15 to < 30 mL/minc | 16 | 427 | 3.75 (2.14–6.09) | 34 | 464 | 7.34 (5.08–10.25) | 0.48 (0.26–0.87) | 0.02 | |
≥ 30 to < 50 mL/mind | 33 | 1813 | 1.82 (1.25–2.56) | 38 | 1768 | 2.15 (1.52–2.95) | 0.85 (0.53–1.36) | 0.50 | |
≥ 50 to < 80 mL/mine | 24 | 3277 | 0.73 (0.47–1.09) | 35 | 3385 | 1.03 (0.72–1.44) | 0.71 (0.42–1.20) | 0.20 | |
≥ 80 mL/minf | 16 | 1921 | 0.83 (0.48–1.35) | 21 | 2184 | 0.96 (0.60–1.47) | 0.85 (0.44–1.63) | 0.63 | |
Stroke/SE | |||||||||
≥ 15 to < 30 mL/minc | 10 | 422 | 2.37 (1.14–4.36) | 11 | 473 | 2.33 (1.16–4.16) | 0.96 (0.41–2.28) | 0.93 | |
≥ 30 to < 50 mL/mind | 28 | 1819 | 1.54 (1.02–2.23) | 47 | 1750 | 2.69 (1.97–3.57) | 0.58 (0.36–0.92) | 0.02 | |
≥ 50 to < 80 mL/mine | 41 | 3261 | 1.26 (0.90–1.71) | 55 | 3356 | 1.64 (1.23–2.13) | 0.76 (0.51–1.14) | 0.19 | |
≥ 80 mL/minf | 10 | 1931 | 0.52 (0.25–0.95) | 16 | 2185 | 0.73 (0.42–1.19) | 0.67 (0.31–1.48) | 0.32 |
3.4 Clinical Outcomes of Apixaban Versus Warfarin in Patients with CrCl Decline During the Study Period
Cohort | Quartile | Number of patients | Change in CrCl per year (mL/min) | ||||
---|---|---|---|---|---|---|---|
Minimum | Q1 | Median | Q3 | Maximum | |||
Apixaban | 1 | 968 | − 2.22 | − 1.62 | − 1.09 | − 0.53 | 0 |
2 | 968 | − 5.10 | − 4.17 | − 3.48 | − 2.84 | − 2.22 | |
3 | 968 | − 12.55 | − 9.56 | − 7.54 | − 6.14 | − 5.10 | |
4 | 967 | − 9697.67 | − 95.58 | − 36.92 | − 19.39 | −12.56 | |
Warfarin | 1 | 659 | − 2.28 | − 1.73 | − 1.10 | − 0.55 | 0 |
2 | 659 | − 5.38 | − 4.48 | − 3.65 | − 2.97 | − 2.28 | |
3 | 659 | − 14.00 | − 9.98 | − 7.85 | − 6.42 | − 5.40 | |
4 | 658 | − 8577.44 | − 112.73 | − 40.40 | − 20.71 | − 14.04 |
Event | Group | Quartile | Number of patients at risk | Number of first eventsa (95% CI)b | Incidence ratea (95% CI) | HR (95% CI) |
---|---|---|---|---|---|---|
Major bleeding | Apixaban | 1c | 968 | 0.66 (0.38–1.07) | 1.97 (1.20–3.22) | – |
2 | 968 | 0.95 (0.60–1.44) | 2.64 (1.73–4.02) | 1.43 (0.75–2.72) | ||
3 | 968 | 1.47 (0.98–2.11) | 4.23 (2.88–6.19) | 2.14 (1.16–3.95) | ||
4 | 967 | 3.75 (2.53–5.35) | 7.06 (4.50–10.97) | 4.46 (2.40–8.29) | ||
Warfarin | 1c | 659 | 1.21 (0.74–1.87) | 3.57 (2.31–5.50) | – | |
2 | 659 | 0.90 (0.50–1.48) | 2.61 (1.57–4.32) | 0.74 (0.38–1.45) | ||
3 | 659 | 1.38 (0.83–2.16) | 4.25 (2.70–6.66) | 1.13 (0.60–2.12) | ||
4 | 658 | 4.98 (3.28–7.25) | 9.66 (5.94–15.52) | 3.42 (1.88–6.21) | ||
Stroke/SE | Apixaban | 1c | 968 | 0.79 (0.48–1.23) | 2.23 (1.42–3.50) | – |
2 | 968 | 0.82 (0.50–1.28) | 2.33 (1.48–3.66) | 1.03 (0.55–1.95) | ||
3 | 968 | 1.27 (0.82–1.87) | 3.90 (2.59–5.84) | 1.55 (0.85–2.81) | ||
4 | 967 | 2.23 (1.32–3.52) | 3.20 (1.88–5.42) | 2.31 (1.19–4.46) | ||
Warfarin | 1c | 659 | 0.91 (0.51–1.50) | 2.44 (1.48–4.03) | – | |
2 | 659 | 1.32 (0.83–1.99) | 4.04 (2.67–6.10) | 1.45 (0.75–2.80) | ||
3 | 659 | 1.91 (1.25–2.79) | 5.42 (3.67–7.97) | 2.04 (1.08–3.85) | ||
4 | 658 | 4.48 (2.87–6.66) | 7.51 (4.65–12.03) | 4.05 (2.09–7.83) |