Table 1.
Baseline characteristics stratified by renal dysfunction, anaemia and iron deficiency
| Variables | Total cohort (n = 2151) | No renal dysfunction | Renal dysfunction | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Anaemic | Not anaemic | Anaemic | Not anaemic | ||||||||||
| No ID | ID | p‐value | No ID | ID | p‐value | No ID | ID | p‐value | No ID | ID | p‐value | ||
| (n = 76) | (n = 231) | (n = 398) | (n = 430) | (n = 106) | (n = 365) | (n = 209) | (n = 336) | ||||||
| Anaemia alone | IDA | No comorbidities | ID alone | CRAS | CRAIDS | CKD alone | CRIDS | ||||||
| Clinical parameters | |||||||||||||
| Age (years) | 70.5 [61.4–78.1] | 68.9 [58.2–73.9] | 72.0 [63.8–77.7] | 0.060 | 64.6 [56.3–73.6] | 63.6 [55.3–73.9] | 0.658 | 76.2 [67.6–81.0] | 75.4 [68.7–80.6] | 0.689 | 73.0 [65.3–80.2] | 73.3 [65.1–79.4] | 0.625 |
| Women | 575 (26.7%) | 9 (11.8%) | 56 (24.2%) | 0.033 | 69 (17.3%) | 124 (28.8%) | <0.001 * | 16 (15.1%) | 104 (28.5%) | 0.008 * | 64 (30.6%) | 133 (39.6%) | 0.043 |
| BMI (kg/m2) | 27.9 (5.58) | 27.1 (4.24) | 27.7 (5.42) | 0.380 | 28.2 (5.84) | 28.0 (5.94) | 0.707 | 26.7 (5.56) | 27.6 (5.28) | 0.147 | 27.9 (4.86) | 28.3 (5.87) | 0.397 |
| NYHA class | 0.035 | <0.001 * | 0.017 | <0.001 * | |||||||||
| I | 46 (2.20%) | 3 (3.95%) | 3 (1.35%) | 14 (3.64%) | 10 (2.43%) | 3 (2.88%) | 4 (1.13%) | 5 (2.45%) | 4 (1.21%) | ||||
| II | 734 (35.2%) | 37 (48.7%) | 75 (33.6%) | 191 (49.6%) | 137 (33.3%) | 31 (29.8%) | 87 (24.6%) | 84 (41.2%) | 92 (27.8%) | ||||
| III | 1053 (50.4%) | 29 (38.2%) | 115 (51.6%) | 153 (39.7%) | 209 (50.9%) | 64 (61.5%) | 206 (58.2%) | 101 (49.5%) | 176 (53.2%) | ||||
| IV | 255 (12.2%) | 7 (9.21%) | 30 (13.5%) | 27 (7.01%) | 55 (13.4%) | 6 (5.77%) | 57 (16.1%) | 14 (6.86%) | 59 (17.8%) | ||||
| Heart rate (bpm) | 80.2 (19.6) | 75.0 (17.3) | 81.7 (19.9) | 0.005 * | 79.5 (18.8) | 85.7 (22.4) | <0.001 * | 74.4 (16.2) | 78.3 (17.7) | 0.033 | 75.3 (17.4) | 81.3 (19.7) | <0.001 * |
| Estimated protein intake (g/day) | 54.9 (11.2) | 56.2 (13.4) | 54.9 (11.0) | 0.472 | 58.5 (12.7) | 55.5 (11.1) | <0.001 * | 51.4 (9.46) | 52.0 (8.96) | 0.576 | 55.9 (11.0) | 53.0 (10.1) | 0.004 * |
| Ischaemic aetiology | 957 (45.2%) | 28 (37.3%) | 108 (48.2%) | 0.133 | 147 (37.8%) | 171 (40.2%) | 0.520 | 61 (58.1%) | 193 (53.8%) | 0.501 | 104 (51.0%) | 145 (43.3%) | 0.099 |
| Systolic blood pressure (mmHg) | 125 (21.9) | 123 (22.1) | 123 (20.5) | 0.811 | 125 (19.2) | 128 (24.7) | 0.027 | 118 (20.6) | 124 (21.9) | 0.004 * | 125 (20.2) | 124 (23.1) | 0.628 |
| LVEF (%) | 30.0 [25.0–37.0] | 30.0 [25.0–36.0] | 30.0 [25.0–39.0] | 0.730 | 30.0 [25.0–35.0] | 28.0 [21.5–35.0] | 0.460 | 33.0 [25.0–40.0] | 31.0 [25.0–40.0] | 0.634 | 30.0 [25.0–37.0] | 30.0 [24.0–35.0] | 0.020 |
| HF subgroup | 0.283 | 0.238 | 0.262 | 0.257 | |||||||||
| HFrEF | 1544 (80.3%) | 58 (84.1%) | 152 (75.2%) | 318 (85.9%) | 323 (82.6%) | 67 (72.0%) | 220 (70.7%) | 156 (80.0%) | 250 (85.6%) | ||||
| HFmrEF | 248 (12.9%) | 8 (11.6%) | 32 (15.8%) | 38 (10.3%) | 43 (11.0%) | 20 (21.5%) | 54 (17.4%) | 25 (12.8%) | 28 (9.59%) | ||||
| HFpEF | 131 (6.81%) | 3 (4.35%) | 18 (8.91%) | 14 (3.78%) | 25 (6.39%) | 6 (6.45%) | 37 (11.9%) | 14 (7.18%) | 14 (4.79%) | ||||
| Successful completion of 6MWT | 1318 (63.4%) | 56 (74.7%) | 126 (57.0%) | 0.010 * | 309 (80.1%) | 274 (65.7%) | <0.001 * | 57 (55.3%) | 179 (51.1%) | 0.524 | 129 (63.5%) | 188 (58.0%) | 0.243 |
| 6MWT (m) | 203 (172) | 253 (177) | 173 (164) | 0.001 * | 280 (173) | 225 (178) | <0.001 * | 159 (159) | 140 (139) | 0.273 | 207 (173) | 168 (162) | 0.011 * |
| KCCQ overall summary score | 48.5 (22.3) | 56.8 (20.5) | 46.9 (22.1) | 0.001 * | 56.9 (22.5) | 49.2 (21.9) | <0.001 * | 47.3 (22.6) | 40.0 (19.7) | 0.004 * | 54.2 (21.2) | 42.6 (21.1) | <0.001 * |
| Previous hospitalization for HF | 670 (31.1%) | 25 (32.9%) | 65 (28.1%) | 0.519 | 104 (26.1%) | 101 (23.5%) | 0.424 | 44 (41.5%) | 159 (43.6%) | 0.792 | 66 (31.6%) | 106 (31.5%) | 1.000 |
| Hepatomegaly | 310 (14.5%) | 10 (13.2%) | 30 (13.0%) | 1.000 | 52 (13.1%) | 57 (13.3%) | 1.000 | 27 (25.7%) | 69 (19.0%) | 0.169 | 20 (9.57%) | 45 (13.5%) | 0.215 |
| Pulmonary congestion | 1135 (54.0%) | 36 (48.6%) | 130 (57.3%) | 0.246 | 150 (39.1%) | 239 (57.2%) | <0.001 * | 49 (48.0%) | 236 (65.9%) | 0.002 * | 91 (44.2%) | 204 (61.6%) | <0.001 * |
| Comorbidities | |||||||||||||
| Atrial fibrillation | 984 (45.7%) | 33 (43.4%) | 101 (43.7%) | 1.000 | 159 (39.9%) | 156 (36.3%) | 0.310 | 55 (51.9%) | 198 (54.2%) | 0.750 | 103 (49.3%) | 179 (53.3%) | 0.413 |
| COPD | 370 (17.2%) | 11 (14.5%) | 39 (16.9%) | 0.753 | 50 (12.6%) | 72 (16.7%) | 0.110 | 18 (17.0%) | 94 (25.8%) | 0.082 | 33 (15.8%) | 53 (15.8%) | 1.000 |
| Renal disease | 616 (28.6%) | 7 (9.21%) | 22 (9.52%) | 1.000 | 14 (3.52%) | 29 (6.74%) | 0.053 | 62 (58.5%) | 244 (66.8%) | 0.141 | 78 (37.3%) | 160 (47.6%) | 0.023 |
| Peripheral arterial disease | 236 (11.0%) | 5 (6.58%) | 24 (10.4%) | 0.448 | 24 (6.03%) | 44 (10.2%) | 0.038 | 7 (6.60%) | 73 (20.0%) | 0.002 * | 22 (10.5%) | 37 (11.0%) | 0.972 |
| Hypertension | 1339 (62.3%) | 41 (53.9%) | 133 (57.6%) | 0.674 | 228 (57.3%) | 253 (58.8%) | 0.703 | 64 (60.4%) | 257 (70.4%) | 0.067 | 135 (64.6%) | 228 (67.9%) | 0.489 |
| Diabetes mellitus | 692 (32.2%) | 21 (27.6%) | 91 (39.4%) | 0.087 | 97 (24.4%) | 104 (24.2%) | 1.000 | 40 (37.7%) | 163 (44.7%) | 0.248 | 51 (24.4%) | 125 (37.2%) | 0.003 * |
| Laboratory indices | |||||||||||||
| Transferrin saturation (%) | 16.7 [10.9–24.2] | 26.5 [22.6–33.3] | 9.95 [6.63–14.3] | <0.001 * | 27.7 [23.5–34.8] | 13.3 [9.95–16.4] | <0.001 * | 26.5 [22.7–33.9] | 11.4 [8.29–15.3] | <0.001 * | 27.1 [23.2–31.0] | 13.3 [9.53–16.8] | <0.001 * |
| Ferritin (mg/L) | 102 [50.0–192] | 150 [88.8–242] | 65.0 [27.5–142] | <0.001 * | 144 [83.5–255] | 94.0 [50.2–175] | <0.001 * | 127 [72.2–316] | 69.0 [31.0–150] | <0.001 * | 130 [74.0–209] | 83.0 [46.0–171] | <0.001 * |
| Iron (mg/dl) | 44.7 [27.9–72.6] | 67.0 [54.5–90.8] | 22.3 [16.8–39.1] | <0.001 * | 83.8 [67.0–106] | 39.1 [27.9–50.3] | <0.001 * | 61.5 [50.3–83.8] | 27.9 [16.8–39.1] | <0.001 * | 78.2 [61.5–101] | 39.1 [27.9–50.3] | <0.001 * |
| sTfR (mg/L) | 1.53 [1.17–2.11] | 1.24 [0.92–1.78] | 1.81 [1.35–2.84] | <0.001 * | 1.30 [1.04–1.63] | 1.55 [1.21–2.05] | <0.001 * | 1.36 [1.00–1.92] | 1.84 [1.30–2.46] | <0.001 * | 1.37 [1.06–1.70] | 1.73 [1.35–2.29] | <0.001 * |
| Transferrin (mg/dl) | 200 [160–250] | 185 [138–240] | 190 [140–240] | 0.550 | 210 [180–240] | 220 [180–270] | 0.014 * | 160 [130–210] | 180 [130–240] | 0.051 | 200 [160–250] | 210 [170–260] | 0.090 |
| Mean corpuscular volume (fL) | 90.8 [86.5–95.2] | 92.0 [87.0–97.9] | 88.5 [82.1–93.4] | 0.005 * | 92.2 [88.6–96.4] | 90.1 [86.2–93.5] | <0.001 * | 93.9 [88.7–99.3] | 89.8 [84.7–94.7] | <0.001 * | 92.9 [89.3–96.3] | 89.9 [86.6–94.5] | <0.001 * |
| Haemoglobin (g/dl) | 13.2 (1.90) | 11.8 (1.09) | 11.4 (1.05) | 0.011 * | 14.7 (1.18) | 14.2 (1.18) | <0.001 * | 11.2 (1.25) | 11.1 (1.15) | 0.239 | 14.3 (1.34) | 14.0 (1.16) | 0.011 * |
| Haematocrit (%) | 40.0 (5.38) | 35.6 (3.33) | 35.2 (3.15) | 0.322 | 44.0 (3.62) | 42.7 (3.59) | <0.001 * | 34.4 (3.92) | 34.4 (3.56) | 0.977 | 42.9 (3.95) | 42.4 (3.47) | 0.124 |
| IL‐6 (pg/ml) | 5.40 [2.90–10.6] | 3.45 [1.87–8.10] | 7.00 [3.92–13.2] | <0.001 * | 2.95 [1.80–5.30] | 5.80 [3.10–11.6] | <0.001 * | 5.30 [3.30–11.1] | 7.85 [4.80–15.0 | <0.001 * | 3.90 [2.42–7.27] | 6.40 [3.90–13.9] | <0.001 * |
| CRP (mg/L) | 19.8 (19.1) | 15.5 (17.5) | 25.9 (20.9) | <0.001 * | 12.3 (14.5) | 21.6 (19.3) | <0.001 * | 17.8 (19.0) | 24.6 (20.1) | 0.002 * | 14.3 (16.0) | 22.3 (19.6) | <0.001 * |
| NT‐proBNP (ng/ml) | 2838 [1252–5990] | 1692 [716–4038] | 3037 [1470–5898] | 0.001 * | 1448 [641–2613] | 2408 [1099–4742] | <0.001 * | 3914 [1899–9754] | 5227 [2274–10 721] | 0.158 | 2470 [1163–4654] | 4134 [2260–8448] | <0.001 * |
| Hepcidin (nmol/L) | 6.50 [2.20–16.9] | 7.85 [4.35–20.0] | 4.00 [0.90–12.1] | <0.001 * | 9.00 [4.50–20.5] | 5.60 [2.10–15.6] | <0.001 * | 8.90 [3.90–25.2] | 4.50 [1.00–14.8] | <0.001 * | 8.80 [4.10–21.4] | 4.50 [1.40–11.9] | <0.001 * |
| Albumin (g/L) | 32.0 (8.80) | 31.4 (9.05) | 28.4 (8.76) | 0.014 * | 35.6 (7.47) | 33.3 (7.83) | <0.001 * | 29.2 (10.0) | 28.1 (9.21) | 0.320 | 34.2 (8.14) | 32.2 (8.22) | 0.006 * |
| Renal function | |||||||||||||
| eGFR (MDRD) (ml/min/1.73 m2) | 61.7 [46.7–78.0] | 77.5 [67.1–91.4] | 75.4 [66.3–87.4] | 0.258 | 78.1 [69.2–92.7] | 77.9 [68.4–91.2] | 0.622 | 41.0 [31.9–48.6] | 42.0 [30.6–50.6] | 0.420 | 48.8 [40.4–55.2] | 48.6 [38.6–54.6] | 0.527 |
| Creatinine (µmol/ml) | 103 [84.0–130] | 88.0 [75.8–97.4] | 87.0 [74.0–98.5] | 0.853 | 87.0 [74.0–97.2] | 83.0 [72.5–97.2] | 0.167 | 152 [130–184] | 142 [120–181] | 0.049 | 124 [114–147] | 125 [112–147] | 0.677 |
| Urea (mmol/L) | 11.4 [7.60–18.4] | 9.70 [7.10–15.4] | 10.1 [6.20–15.4] | 0.734 | 8.40 [6.10–13.0] | 8.10 [6.07–12.9] | 0.519 | 19.5 [12.8–28.8] | 16.5 [11.4–25.7] | 0.121 | 11.7 [8.55–19.0] | 13.6 [9.43–22.1] | 0.078 |
| Plasma NGAL (ng/ml) | 60.3 [37.7–97.2] | 54.2 [34.6–78.9] | 52.3 [34.2–80.2] | 0.777 | 44.8 [27.8–69.6] | 45.8 [31.8–64.3] | 0.977 | 96.1 [58.1–167] | 95.2 [60.7–154] | 0.772 | 71.9 [45.6–116] | 73.1 [44.6–109] | 0.461 |
| Cystatin C (ng/ml) | 15 012 [10 183–21 902] | 14 695 [9544–21 694] | 12 446 [8390–18 762] | 0.042 | 14 068 [9881–21 132] | 13 441 [8948–18 863] | 0.012 * | 19 606 [13 464–29 116] | 17 311 [12 446–25 280] | 0.123 | 16 690 [11 865–23 494] | 15 187 [10 507–22 247] | 0.049 |
| Aldosterone (pg/ml) | 93.5 [43.0–194] | 87.0 [44.0–198] | 61.0 [26.2–146] | 0.018 | 109 [55.2–201] | 81.0 [44.0–170] | 0.001 * | 71.0 [32.0–238] | 91.0 [37.0–190] | 0.582 | 125 [65.5–235] | 100 [50.0–223] | 0.032 |
| Renin (µIU/ml) | 88.7 [28.4–255] | 81.7 [26.4–270] | 83.2 [27.4–270] | 0.986 | 71.4 [27.3–209] | 59.2 [19.5–191] | 0.068 | 112 [33.1–460] | 116 [40.8–294] | 0.574 | 125 [39.8–293] | 101 [28.8–290] | 0.210 |
| PENK (pmol/L) | 85.9 [63.7–120] | 67.9 [55.3–91.7] | 76.6 [61.4–94.7] | 0.145 | 66.5 [54.4–82.4] | 66.3 [53.5–85.3] | 0.932 | 143 [105–200] | 136 [103–192] | 0.503 | 100 [79.6–127] | 102 [80.2–133] | 0.660 |
| FGF23 (RU/ml) | 224 [120–602] | 138 [89.1–220] | 283 [154–822] | <0.001 * | 118 [87.3–179] | 189 [108–432] | <0.001 * | 348 [168–964] | 523 [255–1456] | 0.012 * | 195 [117–374] | 387 [177–1162] | <0.001 * |
| KIM‐1(NPX) | 8.47 (1.05) | 8.27 (0.92) | 8.38 (0.92) | 0.391 | 8.11 (0.88) | 8.18 (0.94) | 0.287 | 8.98 (1.10) | 8.96 (1.07) | 0.904 | 8.58 (0.92) | 8.62 (1.24) | 0.698 |
| Medications | |||||||||||||
| β‐blocker | 1773 (82.4%) | 65 (85.5%) | 181 (78.4%) | 0.233 | 352 (88.4%) | 349 (81.2%) | 0.005 * | 93 (87.7%) | 287 (78.6%) | 0.051 | 179 (85.6%) | 267 (79.5%) | 0.088 |
| ACE/ARB baseline | 1544 (71.8%) | 58 (76.3%) | 168 (72.7%) | 0.641 | 324 (81.4%) | 318 (74.0%) | 0.013 * | 74 (69.8%) | 232 (63.6%) | 0.284 | 149 (71.3%) | 221 (65.8%) | 0.212 |
| Aldosterone antagonist | 1134 (52.7%) | 41 (53.9%) | 127 (55.0%) | 0.981 | 246 (61.8%) | 232 (54.0%) | 0.027 | 52 (49.1%) | 167 (45.8%) | 0.624 | 100 (47.8%) | 169 (50.3%) | 0.640 |
| Loop diuretic | 2141 (99.5%) | 76 (100%) | 229 (99.1%) | 1.000 | 397 (99.7%) | 428 (99.5%) | 1.000 | 106 (100%) | 363 (99.5%) | 1.000 | 208 (99.5%) | 334 (99.4%) | 1.000 |
| Digoxin | 406 (18.9%) | 9 (11.8%) | 38 (16.5%) | 0.433 | 84 (21.1%) | 96 (22.3%) | 0.733 | 12 (11.3%) | 63 (17.3%) | 0.187 | 34 (16.3%) | 70 (20.8%) | 0.228 |
| Acenocoumarol | 817 (38.4%) | 30 (40.0%) | 82 (35.8%) | 0.606 | 143 (36.7%) | 152 (35.7%) | 0.826 | 39 (37.5%) | 146 (40.1%) | 0.714 | 82 (39.6%) | 143 (42.9%) | 0.501 |
| Antiplatelets | 1094 (51.4%) | 38 (50.7%) | 119 (52.0%) | 0.950 | 198 (50.8%) | 229 (53.8%) | 0.434 | 54 (51.9%) | 187 (51.4%) | 1.000 | 95 (45.9%) | 174 (52.3%) | 0.178 |
| Insulin | 285 (41.2%) | 3 (14.3%) | 33 (36.3%) | 0.092 | 35 (36.1%) | 42 (40.4%) | 0.630 | 12 (30.0%) | 92 (56.4%) | 0.005 * | 24 (47.1%) | 44 (35.2%) | 0.195 |
| Oral anti‐diabetics | 432 (62.4%) | 16 (76.2%) | 70 (76.9%) | 1.000 | 65 (67.0%) | 68 (65.4%) | 0.925 | 28 (70.0%) | 83 (50.9%) | 0.046 | 28 (54.9%) | 74 (59.2%) | 0.722 |
6MWT, 6‐min walk test; ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CRAIDS, cardio‐renal anaemia iron deficiency syndrome; CRAS, cardio‐renal anaemia syndrome; CRIDS, cardio‐renal iron deficiency syndrome; CRP, C‐reactive protein; eGFR, estimated glomerular filtration rate; FGF23, fibroblast growth factor‐23; HF, heart failure; HFmrEF, heart failure with mid‐range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; ID, iron deficiency; IDA, iron deficiency anaemia; IL‐6, interleukin 6; KCCQ, Kansas City Cardiomyopathy Questionnaire; KIM‐1, kidney injury molecule‐1; LVEF, left ventricular ejection fraction; MDRD, Modification of Diet in Renal Disease; NGAL, neutrophil gelatinase‐associated lipocalin; NPX, Normalized Protein eXpression (Olink's arbitrary unit which is in log2 scale); NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; PENK, proenkephalin; sTfR, soluble transferrin receptor.
*
False discovery rate ≤0.05