Table 3.
Phase 3 RCTs reporting hazards of cardiovascular events (Intention-to-treat population) in RCTs of hypoxia-inducible factor stabilisers (HIF-PHIs) in anaemic non-dialysis and dialysis CKD patients
| Trial | N | Age (years) | DM/CVD (% pts) | Follow-up | Trial arms | Achieved Hb (g/dL) | Cardiovascular endpoints | CV risk (HR, 95% CI) |
|---|---|---|---|---|---|---|---|---|
| Non-dialysis | ||||||||
| Pooled: ALPS, ANDES, OLYMPUS [117] | 4277 | 62 | 54/37 | 52 weeks | Roxadustat Placebo |
Weeks 28–52: 11.0 ± 0.8 Weeks 28–52: 9.2 ± 1.1 |
MACE (ACM, nonfatal MI or stroke) MACE+ (MACE, unstable angina, HHF) |
1.10 (0.96–1.27) 1.07 (0.94–1.21) |
| DOLOMITES [37] | 616 | 66 | 34/48 | 104 weeks | Roxadustat Darbepoetin-α |
Weeks 104: 11.0–11.5 in either arm |
MACE (ACM, nonfatal MI or stroke) MACE + (MACE, unstable angina, HHF) |
0.89 (0.60–1.33) 0.93 (0.65–1.32) |
| PRO2TECT [44] | 3471 | 66 | 64/46 | 1.7 years | Vadadustat Darbepoetin-α |
Weeks 40–52: ↑ 1.52* ↑ 1.48* |
MACE (ACM, nonfatal MI or stroke) MACE + (MACE, HHF, TE event) CV DEATH |
1.17 (1.01–1.36) 1.11 (0.97–1.27) 1.01 (0.79–1.29) |
| ASCEND-ND [41] | 3872 | 67 | 57/37 | 1.9 years | Daprodustat Darbepoetin-α |
Weeks 28–52: ↑ 0.74° ↑ 0.66° |
MACE (ACM, nonfatal MI or stroke) MACE or TE event MACE or HHF |
1.03 (0.89–1.19) 1.06 (0.93–1.22) 1.09 (0.95–1.24) |
| Dialysis | ||||||||
| Pooled DD (90 %)-ID: SIERRAS PYRENEES, ROCKIES, HIMALAYAS [131] | 4714 | 56 | 34/NR | 43 weeks | Roxadustat Epoetin alfa-α |
Weeks 28–36: ↑ 2.4 ID, 0.7 DD# ↑ 2.1 ID, 0.4 DD# |
MACE (ACM, nonfatal MI or stroke) MACE+ (MACE, unstable angina, HHF) |
1.09 (0.95–1.26) 0.98 (0.86–1.11) |
| INNO2VATE [47] | 3923 | 58 | 55/49 | 1.2 years | Vadadustat Darbepoetin-α |
Weeks 40–52: ↑ 1.42§ ↑ 1.50§ |
MACE (ACM, nonfatal MI or stroke) MACE+ (MACE, HHF, TE event) CV DEATH |
0.96 (0.83–1.11) 0.96 (0.84–1.10) 0.96 (0.77–1.20) |
| ASCEND-D [54] | 2964 | 58 | 42/45 | 2.5 years | Daprodustat Epoetin alfa-α |
Weeks 28–52: ↑ 0.28^ ↑ 0.10^ |
MACE (ACM, nonfatal MI or stroke) MACE or TE event MACE or HHF |
0.93 (0.81–1.07) 0.88 (0.78–1.00) 0.97 (0.85–1.11) |
ACM all-cause mortality, CI confidence interval (in bold are highlighted the significant HRs), CVD cardiovascular disease, DD dialysis-dependent patients, DM diabetes mellitus; ESA erythropoiesis stimulating agent, Hb haemoglobin, HHF hospitalisation for heart failure, HR hazard ratio, ID patients incident in dialysis, MACE major adverse CV events, MI myocardial infarction, NR not reported, TE thromboembolic events, y years
*Change from the basal level (9.1 ± 0.8 and 10.4 ± 0.9 in ESA untreated and treated, respectively, for either arm); °Change from the basal level (9.9 ± 0.9 and 9.8 ± 0.9 in Dapro and Darbe arms, respectively); #Change from the basal level (8.8 ± 1.2 and 10.3 ± 1.0 in ID and DD, respectively, for either arm); §Change from the basal level (9.3 ± 1.1 and 10.4 ± 0.9 in ID-10% and DD-90%, respectively, for either arm); ^Change from the basal level (10.4 ± 1.0 in either arm)