Background
Methods
Study data and patient population
Study design and data structuring
Statistical analyses
Results
Patient demographics and characteristics at baseline
Variable | All | Serum potassium at baseline (mmol/L)a | ||||||
---|---|---|---|---|---|---|---|---|
< 3.5 | 3.5 to < 4.0 | 4.0 to < 4.5 | 4.5 to < 5.0 | 5.0 to < 5.5 | 5.5 to < 6.0 | ≥6.0 | ||
Number of patients | 191,964 | 3635 | 17,662 | 50,065 | 48,543 | 18,454 | 4250 | 1026 |
Follow-up time (years), mean (SD) | 4.96 (2.76) | 4.65 (3.06) | 5.17 (2.86) | 5.14 (2.80) | 5.02 (2.79) | 4.83 (2.81) | 4.62 (2.85) | 4.25 (2.94) |
Patient demographics, mean (SD)b | ||||||||
Age (years) | 72.48 (12.26) | 73.46 (13.08) | 72.45 (12.59) | 71.63 (12.39) | 72.03 (12.12) | 72.53 (11.80) | 72.67 (11.87) | 71.97 (13.48) |
Male, n (%) | 75,611 (39.39%) | 1145 (31.50%) | 6365 (36.04%) | 19,000 (37.95%) | 19,958 (41.11%) | 8118 (43.99%) | 1987 (46.75%) | 480 (46.78%) |
Current smoker, n (%) | 27,078 (16.1%) | 530 (16.20%) | 2511 (15.50%) | 7047 (15.31%) | 7577 (16.87%) | 2987 (17.48%) | 762 (19.35%) | 192 (20.3%) |
Body mass index (kg/m2) | 28.53 (5.89) | 27.80 (6.50) | 28.32 (5.92) | 28.44 (5.75) | 28.69 (5.90) | 28.71 (6.05) | 28.38 (6.14) | 28.41 (7.13) |
Systolic blood pressure (mmHg) | 139.77 (19.96) | 138.87 (21.95) | 140.33 (20.24) | 140.07 (20.05) | 139.82 (19.92) | 139.61 (20.09) | 139.86 (21.05) | 138.42 (23.69) |
eGFR (mL/min/1.73m2) | 50.96 (8.43) | 49.93 (8.84) | 51.59 (7.63) | 51.88 (7.54) | 51.14 (8.15) | 49.63 (9.45) | 47.00 (11.47) | 42.17 (14.48) |
Serum potassium (mmol/L) | 4.47 (0.53) | 3.20 (0.24) | 3.76 (0.13) | 4.22 (0.14) | 4.68 (0.14) | 5.15 (0.14) | 5.64 (0.13) | 6.36 (0.51) |
Serum phosphorus (mmol/L) | 1.14 (0.94) | 1.06 (0.24) | 1.08 (0.21) | 1.13 (1.32) | 1.14 (0.21) | 1.17 (0.24) | 1.23 (0.30) | 1.32 (0.39) |
Clinical history at baseline, n (%)c | ||||||||
History of diabetes | 28,089 (14.63%) | 330 (9.08%) | 1778 (10.07%) | 5658 (11.30%) | 7437 (15.32%) | 3719 (20.15%) | 1025 (24.12%) | 284 (27.68%) |
History of myocardial infarction | 6277 (3.27%) | 74 (2.04%) | 419 (2.37%) | 1433 (2.86%) | 1661 (3.42%) | 802 (4.35%) | 192 (4.52%) | 46 (4.48%) |
History of stroke | 12,087 (6.30%) | 251 (6.91%) | 1114 (6.31%) | 2969 (5.93%) | 2875 (5.92%) | 1198 (6.49%) | 272 (6.40%) | 73 (7.12%) |
History of arrhythmia | 14,835 (7.73%) | 313 (8.61%) | 1416 (8.02%) | 3812 (7.61%) | 3767 (7.76%) | 1482 (8.03%) | 327 (7.69%) | 83 (8.09%) |
History of peripheral vascular disease | 4620 (2.41%) | 76 (2.09%) | 374 (2.12%) | 1057 (2.11%) | 1174 (2.42%) | 507 (2.75%) | 148 (3.48%) | 40 (3.90%) |
History of chronic pulmonary disease | 18,401 (9.59%) | 381 (10.48%) | 1727 (9.78%) | 5003 (9.99%) | 4805 (9.90%) | 1911 (10.36%) | 414 (9.74%) | 95 (9.26%) |
History of malignancy | 17,658 (9.20%) | 443 (12.19%) | 1700 (9.63%) | 4658 (9.3%) | 4497 (9.26%) | 1814 (9.83%) | 404 (9.51%) | 122 (11.89%) |
History of metastatic tumour | 4296 (2.24%) | 121 (3.33%) | 466 (2.64%) | 1243 (2.48%) | 1082 (2.23%) | 421 (2.28%) | 108 (2.54%) | 31 (3.02%) |
History of rheumatic disease | 6377 (3.32%) | 155 (4.26%) | 784 (4.44%) | 1884 (3.76%) | 1538 (3.17%) | 538 (2.92%) | 119 (2.80%) | 30 (2.92%) |
History of peptic ulcer | 1649 (0.86%) | 30 (0.83%) | 126 (0.71%) | 410 (0.82%) | 405 (0.83%) | 178 (0.96%) | 34 (0.80%) | 7 (0.68%) |
History of dementia | 4749 (2.47%) | 179 (4.92%) | 561 (3.18%) | 1235 (2.47%) | 1009 (2.08%) | 360 (1.95%) | 80 (1.88%) | 35 (3.41%) |
Medication use at baseline, n (%)d | ||||||||
ACE inhibitors | 67,886 (35.36%) | 1116 (30.70%) | 5912 (33.47%) | 17,604 (35.16%) | 18,859 (38.85%) | 7970 (43.19%) | 1926 (45.32%) | 467 (45.52%) |
ARBs | 26,517 (13.81%) | 482 (13.26%) | 2465 (13.96%) | 6952 (13.89%) | 6850 (14.11%) | 2926 (15.86%) | 682 (16.05%) | 151 (14.72%) |
Renin inhibitors | 68 (0.04%) | 0 (0.00%) | 10 (0.06%) | 15 (0.03%) | 17 (0.04%) | 9 (0.05%) | 0 (0.00%) | 0 (0.00%) |
MRAs | 4911 (2.56%) | 200 (5.50%) | 445 (2.52%) | 1106 (2.21%) | 1330 (2.74%) | 744 (4.03%) | 281 (6.61%) | 103 (10.04%) |
Any RAASi therapye | 92,267 (48.06%) | 1630 (44.84%) | 8235 (46.63%) | 23,931 (47.80%) | 25,102 (51.71%) | 10,567 (57.26%) | 2566 (60.38%) | 613 (59.75%) |
CCBs (DHP) | 45,640 (23.78%) | 1227 (33.76%) | 5106 (28.91%) | 12,191 (24.35%) | 11,294 (23.27%) | 4362 (23.64%) | 1117 (26.28%) | 290 (28.27%) |
CCBs (non-DHP) | 7568 (3.94%) | 148 (4.07%) | 798 (4.52%) | 2093 (4.18%) | 1885 (3.88%) | 745 (4.04%) | 184 (4.33%) | 31 (3.02%) |
NSAIDs | 26,739 (13.93%) | 466 (12.82%) | 2453 (13.89%) | 7277 (14.54%) | 7424 (15.29%) | 2993 (16.22%) | 695 (16.35%) | 159 (15.50%) |
Diuretics | 77,143 (40.19%) | 2842 (78.18%) | 10,850 (61.43%) | 21,548 (43.04%) | 16,819 (34.65%) | 6182 (33.5%) | 1478 (34.78%) | 407 (39.67%) |
Beta blockers | 48,570 (25.3%) | 994 (27.35%) | 4608 (26.09%) | 12,655 (25.28%) | 12,898 (26.57%) | 5277 (28.60%) | 1280 (30.12%) | 326 (31.77%) |
Statins | 82,815 (43.14%) | 1456 (40.06%) | 7479 (42.35%) | 21,479 (42.90%) | 22,269 (45.87%) | 9210 (49.91%) | 2103 (49.48%) | 481 (46.88%) |
Bronchodilators | 21,771 (11.34%) | 493 (13.56%) | 2059 (11.66%) | 5843 (11.67%) | 5879 (12.11%) | 2435 (13.19%) | 581 (13.67%) | 123 (11.99%) |
RAASi agent | Number of patients | RAASi dosing at baseline, n (%)a | ||
---|---|---|---|---|
≥100% of target | 50% to < 100% of target | < 50% of target | ||
ACE inhibitorsb | 53,571 | 19,345 (36.11%) | 14,202 (26.51%) | 20,024 (37.38%) |
ARBsc | 18,671 | 613 (3.28%) | 6953 (37.24%) | 11,105 (59.48%) |
MRAsd | 3770 | 1358 (36.02%) | 2412 (63.98%) | 0 (0.00%) |
Serum potassium and hyperkalaemia
Statistic | Serum potassium interval to define hyperkalaemiaa | ||
---|---|---|---|
≥5.0 mmol/L to < 5.5 mmol/L | ≥5.5 mmol/L to < 6.0 mmol/L | ≥6.0 mmol/L | |
Incidence of hyperkalaemia | |||
Total hyperkalaemia episodes | 234,339 | 59,688 | 14,291 |
Mean number of hyperkalaemia episodes per patient (SD) | 1.22 (2.29) | 0.31 (1.05) | 0.07 (0.44) |
Crude rate of hyperkalaemia per 1000 patient-years (95% CI) | 246.02 (245.03, 247.02) | 62.66 (62.16, 63.17) | 15.00 (14.76, 15.25) |
Number patients experiencing hyperkalaemia episodes (%) | |||
No hyperkalaemia episodes | 105,273 (54.84%) | 161,335 (84.04%) | 182,524 (95.08%) |
Exactly one hyperkalaemia episode | 38,323 (19.96%) | 18,765 (9.78%) | 6985 (3.64%) |
Exactly two hyperkalaemia episodes | 18,253 (9.51%) | 5683 (2.96%) | 1449 (0.75%) |
Exactly three hyperkalaemia episodes | 10,352 (5.39%) | 2606 (1.36%) | 490 (0.26%) |
Four or more hyperkalaemia episodes | 19,763 (10.30%) | 3575 (1.86%) | 516 (0.27%) |
To first episode (among patients experiencing 1+ episodes) | 1.80 (0.72, 3.61) | 2.58 (1.13, 4.62) | 3.09 (1.41, 5.17) |
First to second episode (among patients experiencing 2+ episodes) | 0.99 (0.40, 1.99) | 0.84 (0.24, 1.87) | 0.65 (0.12, 1.66) |
Second to third episode (among patients experiencing 3+ episodes) | 0.76 (0.31, 1.48) | 0.59 (0.19, 1.31) | 0.41 (0.10, 1.13) |
Third to fourth episode (among patients experiencing 4+ episodes) | 0.61 (0.26, 1.18) | 0.48 (0.15, 1.06) | 0.30 (0.08, 0.84) |
Incidence of death, MACE, and RAASi discontinuation
Explanatory variable | Estimate | SE | t statistic | P-value |
---|---|---|---|---|
Incidence of death | ||||
Constant | −4.1733 | 0.2272 | −18.37 | < 0.0001 |
Serum potassium: < 3.5 mmol/L | 0.9137 | 0.0300 | 30.47 | < 0.0001 |
Serum potassium: 3.5 to < 4.0 mmol/L | 0.2385 | 0.0171 | 13.96 | < 0.0001 |
Serum potassium: 4.0 to < 4.5 mmol/L | 0.0184 | 0.0127 | 1.45 | 0.1395 |
Serum potassium: 5.0 to < 5.5 mmol/L | 0.1304 | 0.0159 | 8.20 | < 0.0001 |
Serum potassium: 5.5 to < 6.0 mmol/L | 0.4689 | 0.0262 | 17.91 | < 0.0001 |
Serum potassium: ≥6.0 mmol/L | 1.0578 | 0.0499 | 21.20 | < 0.0001 |
Age at baseline (years) | 0.0715 | 0.0008 | 95.05 | < 0.0001 |
Sex at baseline: Female | −0.3021 | 0.0111 | −27.18 | < 0.0001 |
Smoker at baseline: Yes | 0.4211 | 0.0157 | 26.90 | < 0.0001 |
Time with CKD (years) | 0.0994 | 0.0022 | 44.71 | < 0.0001 |
Time-updated eGFR (mL/min/1.73m2; truncated at 60 mL/min/1.73m2) | − 0.0240 | 0.0006 | −43.32 | < 0.0001 |
Time-updated prescribed RAASi: Yes | −0.7887 | 0.0113 | −69.54 | < 0.0001 |
Time-updated history of HF: Yes | 0.8336 | 0.0213 | 39.08 | < 0.0001 |
History of diabetes at baseline: Yes | 0.3289 | 0.0160 | 20.58 | < 0.0001 |
History of cancer at baseline: Yes | 0.3858 | 0.0171 | 22.60 | < 0.0001 |
History of PVD at baseline: Yes | 0.2370 | 0.0290 | 8.17 | < 0.0001 |
History of dementia at baseline: Yes | 0.7182 | 0.0251 | 28.67 | < 0.0001 |
History of MACE at baseline: Yes | 0.2946 | 0.0133 | 22.12 | < 0.0001 |
Natural logarithm of baseline BMI (kg/m2) | −0.9316 | 0.0601 | −15.51 | < 0.0001 |
Natural logarithm of baseline haemoglobin (g/cL) | −0.8928 | 0.0392 | −22.76 | < 0.0001 |
Prescribed diuretics ±3 months of baseline: Yes | 0.1574 | 0.0119 | 13.28 | < 0.0001 |
Prescribed bronchodilators ±3 months of baseline: Yes | 0.3514 | 0.0154 | 22.81 | < 0.0001 |
Prescribed insulin ±3 months of baseline: Yes | 0.3265 | 0.0338 | 9.66 | < 0.0001 |
Prescribed statins ±3 months of baseline: Yes | −0.1796 | 0.0116 | −15.49 | < 0.0001 |
Incidence of MACE | ||||
Constant | −5.7072 | 0.0967 | −59.01 | < 0.0001 |
Serum potassium: < 3.5 mmol/L | 0.3126 | 0.0416 | 7.52 | < 0.0001 |
Serum potassium: 3.5 to < 4.0 mmol/L | 0.1117 | 0.0199 | 5.62 | < 0.0001 |
Serum potassium: 4.0 to < 4.5 mmol/L | 0.0257 | 0.0140 | 1.84 | 0.0731 |
Serum potassium: 5.0 to < 5.5 mmol/L | −0.0110 | 0.0182 | − 0.61 | 0.3322 |
Serum potassium: 5.5 to < 6.0 mmol/L | 0.0722 | 0.0353 | 2.05 | 0.0492 |
Serum potassium: ≥6.0 mmol/L | 0.1426 | 0.0825 | 1.73 | 0.0897 |
Age at baseline (years) | 0.0407 | 0.0007 | 55.07 | < 0.0001 |
Sex at baseline: Female | −0.2540 | 0.0148 | −17.18 | < 0.0001 |
Smoker at baseline: Yes | 0.0628 | 0.0198 | 3.17 | 0.0027 |
Time with CKD (years) | 0.0714 | 0.0027 | 26.33 | < 0.0001 |
Time-updated eGFR (mL/min/1.73m2) | −0.0032 | 0.0007 | −4.88 | < 0.0001 |
History of diabetes at baseline: Yes | 0.0518 | 0.0208 | 2.49 | 0.0181 |
History of MACE at baseline: Yes | 0.7804 | 0.0174 | 44.80 | < 0.0001 |
History of rheumatologic disease at baseline: Yes | 0.0930 | 0.0364 | 2.55 | 0.0153 |
History of CPD at baseline: Yes | 0.2485 | 0.0220 | 11.29 | < 0.0001 |
Natural logarithm of baseline total cholesterol (mmol/L) | −0.1001 | 0.0345 | −2.91 | 0.0066 |
Prescribed CCBs ±3 months of baseline: Yes | 0.1042 | 0.0152 | 6.86 | < 0.0001 |
Prescribed insulin ±3 months of baseline: Yes | 0.2142 | 0.0416 | 5.14 | < 0.0001 |
Prescribed beta blockers ±3 months of baseline: Yes | 0.2504 | 0.0156 | 16.06 | < 0.0001 |
Incidence of RAASi discontinuation | ||||
Constant | −1.6740 | 0.0254 | −65.84 | < 0.0001 |
Serum potassium: < 3.5 mmol/L | 0.0316 | 0.0329 | 0.96 | 0.2519 |
Serum potassium: 3.5 to < 4.0 mmol/L | −0.1005 | 0.0144 | −6.96 | < 0.0001 |
Serum potassium: 4.0 to < 4.5 mmol/L | −0.0653 | 0.0095 | −6.87 | < 0.0001 |
Serum potassium: 5.0 to < 5.5 mmol/L | 0.1148 | 0.0115 | 10.00 | < 0.0001 |
Serum potassium: 5.5 to < 6.0 mmol/L | 0.3858 | 0.0192 | 20.09 | < 0.0001 |
Serum potassium: ≥6.0 mmol/L | 1.0271 | 0.0352 | 29.16 | < 0.0001 |
Sex at baseline: Female | −0.1364 | 0.0094 | −14.45 | < 0.0001 |
Time with CKD (years) | 0.0161 | 0.0017 | 9.44 | < 0.0001 |
Time-updated eGFR (mL/min/1.73m2; truncated at 60 mL/min/1.73m2) | −0.0205 | 0.0004 | −45.54 | < 0.0001 |
History of diabetes at baseline: Yes | 0.2476 | 0.0128 | 19.32 | < 0.0001 |
History of rheumatologic disease at baseline: Yes | 0.1235 | 0.0227 | 5.45 | < 0.0001 |
History of MACE at baseline: Yes | 0.1432 | 0.0112 | 12.76 | < 0.0001 |
Prescribed diuretics ±3 months of baseline: Yes | 0.2374 | 0.0096 | 24.60 | < 0.0001 |
Prescribed insulin ±3 months of baseline: Yes | 0.1519 | 0.0239 | 6.34 | < 0.0001 |
Prescribed CCBs ±3 months of baseline: Yes | 0.1197 | 0.0099 | 12.14 | < 0.0001 |