A total of 1,208,815 patients met the study criteria, with 161,849 (13%) having HK. Compared to patients without HK, HK patients were older (mean age 60 ± 18 years vs 43 ± 18 years), more often male (51% vs 41%), had a higher Charlson Comorbidity Index (CCI; 3.5 ± 2.8 vs 1.7 ± 1.4; P < 0.001), and were more likely to have renal insufficiency (16.3% vs 0.7%; P < 0.001). Atherosclerotic CV disease (CVD), HF, and atrial fibrillation were among the highest prior diagnoses in patients with HK (21%, 20%, and 14%, respectively) and significantly higher than in the no-HK group (4%, 2%, and 2%, respectively). Baseline characteristics stratified by the presence of HK are presented in Table 1. At baseline, all assessed medication use was more common in the HK group, K+-binder use was low overall (< 1%); sodium polystyrene sulfonate (SPS) was used in 0.4% of patients with HK and 0.04% of patients without HK (P < 0.001); and patiromer use was insufficient to evaluate. At 3-year follow-up, major adverse CV events (MACEs) were higher in the HK vs no-HK group (18.8% vs 3.2%; P < 0.001), which persisted after adjustment (multivariable HR = 1.60; P < 0.001; Table 1, Fig. 1A).
Table 1
Overall Population – Baseline Characteristics and Post-Index Outcomes
| No-HK n = 1,046,966 | HK n = 161,849 |
Mean age (years)* | 43 ± 18 | 60 ± 18 |
< 65 years | 86% | 56% |
65–74 years | 8% | 20% |
≥ 75 years | 6% | 24% |
Sex (male)* | 41% | 51% |
CCI* | 1.7 ± 1.4 | 3.5 ± 2.8 |
Mean baseline sK (mmol/L)*,† | 4.07 ± 0.39 | 5.38 ± 0.48 |
Traditional CV Risk Factors |
Hypertension* | 20% | 63% |
Hyperlipidaemia* | 17% | 55% |
Diabetes* | 7% | 33% |
Smoking* | 13% | 26% |
Renal insufficiency* | 0.7% | 16% |
BMI, kg/m2, n = 662,888* | 28.4 ± 7.4 | 29.7 ± 8.1 |
BMI ≥ 30 | 33% | 40% |
Maximum SBP (mm Hg)* | 139.2 ± 71.6 | 162.8 ± 73.7 |
EF (%)* | 60.9 ± 10.2 | 58.0 ± 12.9 |
Prior Diagnoses |
ASCVD* | 4% | 21% |
CAD* | 1% | 7% |
MI* | 0.6% | 4% |
Stroke* | 0.3% | 2% |
TIA* | 0.7% | 4% |
PVD* | 0.1% | 1.0% |
Heart failure* | 2% | 20% |
Atrial fibrillation* | 2% | 14% |
Baseline Medications |
Statin* | 7% | 39% |
Other anti-diabetic* | 1% | 10% |
Insulin* | 2% | 24% |
Metformin* | 3% | 18% |
Sulfonylurea* | 1% | 11% |
NSAID* | 39% | 62% |
ACEi* | 8% | 39% |
ARB* | 3% | 16% |
Aldosterone inhibitor* | 0.6% | 6% |
Beta-blocker* | 6% | 32% |
Diuretic* | 9% | 42% |
CCB* | 4% | 22% |
Furosemide* | 3% | 24% |
Torsemide* | 0.1% | 1.2% |
SPS* | 0.04% | 0.4% |
Patiromer | 0% | 0% |
3-Year Post-Index Outcomes (n = 1,128,582) |
| n = 983,409 | n = 145,173 |
MACE* | 3.2% | 18.8% |
Death* | 2.9% | 16.7% |
MI* | 0.05% | 0.2% |
Stroke* | 0.2% | 0.9% |
HFH* | 0.2% | 2.8% |
Multivariable Hazard Ratio (95% CI) for 3-Year MACE‡ |
No-HK vs HK* | 1.60 (1.57, 1.63) |
Post-Index Average Costs/Year (n = 1,208,815) |
ED Cost ± SD* Median (IQR) | $207 ± 1,930 11 (0, 187) | $552 ± 7,574 56 (0, 408) |
Inpatient Cost ± SD* Median (IQR) | $1,477 ± 21,423 0 (0, 740) | $10,956 ± 93,026 0 (0, 4585) |
Age ≥ 60 years Post-Index Average Costs/Year (n = 290,972) |
ED Cost ± SD* Median (IQR) | $222 ± 2,747 18 (0, 219) | $561 ± 7,098 72 (0, 444) |
Inpatient Cost ± SD* Median (IQR) | $3,765 ± 35,137 0 (0, 2307) | $13,844 ± 109,257 1,277 (0, 6678) |
ACEi: angiotensin-converting enzyme inhibitor; ARB: angiotensin-II receptor blockers; ASCVD: atherosclerotic cardiovascular disease; BMI: body mass index; CAD: coronary artery disease; CCB: calcium channel blocker; CCI: Charlson Comorbidity Index; CV: cardiovascular; ED: emergency department; EF: ejection fraction; HFH: heart failure hospitalization; HK: hyperkalaemia; IQR: interquartile range; MACE: major adverse CV event; MI: myocardial infarction; NSAID: nonsteroidal anti-inflammatory drug; PVD: peripheral vascular disease; SBP: systolic blood pressure; SD: standard deviation; sK: serum potassium; SPS: sodium polystyrene sulfonate; TIA: transient ischaemic attack. |
Models adjusted by baseline characteristics, risk factors, and medications. |
*P < 0.001. |
†Taken within ± 1 month of index date (baseline sK level). |
‡MACE is the composite of death, MI, stroke, and HFH. |
Table 2 describes baseline characteristics and outcomes by HK frequency. Persistent HK represented only 3% of the total HK population, whereas a large majority showed either intermittent or transient patterns (45% and 52%, respectively). Relative to other HK patterns, persistent HK was more common in older patients (mean age 68 ± 17 years) and was the dominant pattern (40%) in those age ≥ 75 years. Persistently recurring HK was also associated with the highest CCI (4.3 ± 3.1) as well as greater rates of renal insufficiency (30%) and HF (30%). At baseline and relative to more frequent patterns, all medication use was generally lowest among transient HK, with the exception of nonsteroidal anti-inflammatory drugs (NSAIDs). SPS use was low in each group (0.1% of transient HK, 0.7% of intermittent HK, 1% of persistent HK). Substantially higher than other patterns, 3-year MACE was highest (44.8%) with persistently recurring HK, achieving statistical significance (persistent vs transient HK multivariable HR = 2.31 [95% CI, 2.20, 2.43], P < 0.001). A smaller difference was observed between less frequently occurring patterns (intermittent vs transient HK multivariable HR = 1.02 [95% CI, 0.99, 1.05], P = not significant; Table 2, Fig. 1B). Each of the four individual MACE components (death, myocardial infarction [MI], stroke, and HF hospitalization) influenced risk.
Table 2
HK Frequency – Baseline Characteristics and Post-index Outcomes
| Transient n = 82,307 (52%) | Intermittent n = 72,382 (45%) | Persistent n = 5,150 (3%) |
Mean age (years)* | 57 ± 19 | 63 ± 16 | 68 ± 17 |
< 65 years | 64% | 48% | 40% |
65–74 years | 16% | 24% | 20% |
≥ 75 years | 20% | 28% | 40% |
Sex (male)* | 49% | 53% | 56% |
CCI* | 3.1 ± 2.7 | 3.8 ± 2.8 | 4.3 ± 3.1 |
Mean baseline sK (mmol/L)*,† | 5.3 ± 0.5 | 5.4 ± 0.5 | 5.6 ± 0.6 |
Traditional CV Risk Factors |
Hypertension* | 52% | 74% | 73% |
Hyperlipidaemia* | 49% | 63% | 55% |
Diabetes* | 23% | 43% | 43% |
Smoking* | 24% | 29% | 27% |
Renal insufficiency* | 10% | 23% | 30% |
BMI ≥ 30 | 37% | 43% | 40% |
Maximum SBP* (mm Hg) | 158 ± 82 | 168 ± 64 | 168 ± 49 |
EF (%)* | 58 ± 13 | 57 ± 14 | 58 ± 13 |
Prior Diagnoses |
ASCVD* | 15% | 26% | 25% |
CAD* | 5% | 10% | 9% |
MI* | 3% | 5% | 4% |
Stroke* | 1% | 2% | 2% |
TIA* | 3% | 4% | 4% |
PVD* | 0.7% | 1% | 1% |
Heart failure* | 13% | 27% | 30% |
Atrial fibrillation* | 10% | 17% | 19% |
Baseline Medications |
Statin* | 33% | 46% | 41% |
Other anti-diabetic* | 6% | 13% | 14% |
Insulin* | 17% | 32% | 33% |
Metformin* | 13% | 22% | 23% |
Sulfonylurea* | 7% | 16% | 18% |
NSAID* | 61% | 65% | 59% |
ACEi* | 30% | 47% | 48% |
ARB* | 13% | 20% | 18% |
Aldosterone inhibitor* | 25% | 39% | 37% |
Beta-blocker* | 4% | 9% | 8% |
Diuretic* | 33% | 52% | 50% |
CCB* | 17% | 27% | 28% |
Furosemide* | 17% | 32% | 34% |
Torsemide* | 0.7% | 2% | 2% |
SPS* | 0.1% | 0.7% | 1% |
Patiromer | 0% | 0% | 0% |
3-Year Post-Index Outcomes (n = 145,173) |
| n = 73,036 | n = 67,486 | n = 4,651 |
MACE*,‡ | 14.8% | 21.3% | 44.8% |
Death* | 14.1% | 17.7% | 44.2% |
MI* | 0.1% | 0.3% | 0.04% |
Stroke* | 0.6% | 1.2% | 0.5% |
HFH* | 0.9% | 5% | 1.8% |
Multivariate Hazard Ratio (95% CI) for 3-Year MACE‡ |
Persistent vs transient HK* | 2.31 (2.20, 2.43) |
Intermittent vs transient HK | 1.02 (0.99, 1.05) |
Post-Index Average Costs/Year |
ED | | | |
Cost ± SD* | $422 ± 4,221 | $620 ± 2,305 | $1,737 ± 37,846 |
Median (IQR) | 0 (0, 274) | 165 (0, 580) | 0 (0, 70) |
1-year visit* (primary diagnosis) | 0.01% | 0.3% | 0.7% |
Inpatient | | | |
Cost ± SD* | $5,047 ± 51,691 | $16,478 ± 108,826 | $30,011 ± 245,519 |
Median (IQR) | 0 (0, 1347) | 2681 (0, 9661) | 0 (0, 1488) |
1-year visit* (primary diagnosis) | 0.004% | 0.3% | 0.9% |
ACEi: angiotensin-converting enzyme inhibitor; ARB: angiotensin-II receptor blockers; ASCVD: atherosclerotic cardiovascular disease; BMI: body mass index; CAD: coronary artery disease; CCB: calcium channel blocker; CCI: Charlson Comorbidity Index; CV: cardiovascular; ED: emergency department; EF: ejection fraction; HFH: heart failure hospitalization; HK: hyperkalaemia; IQR: interquartile range; MACE: major adverse CV event; MI: myocardial infarction; NSAID: nonsteroidal anti-inflammatory drug; PVD: peripheral vascular disease; SBP: systolic blood pressure; SD: standard deviation; sK: serum potassium; SPS: sodium polystyrene sulfonate; TIA: transient ischaemic attack. |
Models adjusted by baseline characteristics, risk factors, and medications. |
*P < 0.001. |
†Taken within ± 1 month of index date (baseline sK level). |
‡MACE is the composite of death, MI, stroke, and HFH. |
Table 3 identifies baseline characteristics and post-index outcomes by HK severity. Of total HK patients, only 3% had severe HK; most had mild (81%) or moderate (16%) HK. Severity patterns were similar across age groups. Moderate and severe HK were associated with higher baseline disease burden based on CCI. At baseline, SPS use was low regardless of HK severity (0.8% each of moderate and severe HK, 0.3% of mild HK). MACE risk at 3 years positively correlated with HK severity; multivariable HR was 1.31 (95% CI, 1.23, 1.40; P < 0.001) for severe vs mild groups and 1.29 (95% CI, 1.25, 1.33; P < 0.001) for moderate vs mild groups (Table 3, Fig. 1C). Death and HF hospitalization were the primary drivers of MACE risk.
Table 3
HK Severity – Baseline Characteristics and Post-Index Outcomes
| Mild HK n = 131,509 (81%) | Moderate HK n = 25,380 (16%) | Severe HK n = 4,960 (3%) |
Mean age (years)* | 60 ± 18 | 60 ± 19 | 58 ± 19 |
< 65 years | 56% | 55% | 59% |
65–74 years | 20% | 19% | 18% |
≥ 75 years | 24% | 26% | 23% |
Sex (male)* | 51% | 50% | 48% |
CCI* | 3.2 ± 2.7 | 3.9 ± 2.9 | 4.1 ± 3.0 |
Mean baseline sK (mmol/L)*,† | 5.2 ± 0.1 | 5.8 ± 0.2 | 7.3 ± 1.1 |
Traditional CV Risk Factors |
Hypertension* | 62% | 65% | 65% |
Hyperlipidaemia* | 56% | 51% | 47% |
Diabetes* | 32% | 36% | 37% |
Smoking* | 25% | 29% | 33% |
Renal insufficiency* | 14% | 24% | 38% |
BMI ≥ 30 | 40% | 40% | 40% |
Maximum SBP (mm Hg)* | 162 ± 77 | 166 ± 59 | 166 ± 52 |
EF (%)* | 38 ± 13 | 57 ± 14 | 58 ± 13 |
Prior Diagnosis |
ASCVD* | 20% | 22% | 19% |
CAD* | 7% | 8% | 7% |
MI* | 3% | 4% | 3% |
Stroke* | 1% | 2% | 2% |
TIA* | 4% | 4% | 3% |
PVD* | 1% | 1% | 0.9% |
Heart failure* | 18% | 24% | 26% |
Atrial fibrillation* | 13% | 16% | 17% |
Baseline Medications |
Statin* | 40% | 37% | 33% |
Other anti-diabetic | 10% | 10% | 9% |
Insulin* | 23% | 29% | 31% |
Metformin‡ | 18% | 17% | 16% |
Sulfonylurea* | 11% | 12% | 10% |
NSAID* | 63% | 61% | 60% |
ACEi* | 38% | 39% | 36% |
ARB | 16% | 16% | 15% |
Aldosterone inhibitor* | 6% | 8% | 9% |
Beta-blocker* | 31% | 34% | 32% |
Diuretic* | 41% | 46% | 45% |
CCB* | 21% | 24% | 23% |
Furosemide* | 23% | 29% | 30% |
Torsemide* | 1% | 2% | 1% |
SPS* | 0.3% | 0.8% | 0.8% |
Patiromer | 0% | 0% | 0% |
3-Year Post-Index Outcomes (n = 145,173) |
| n = 117,902 | n = 22,879 | n = 4392 |
MACE*,§ | 17.2% | 25.1% | 27.9% |
Death* | 15.2% | 22.7% | 25.9% |
MI | 0.2% | 0.2% | 0.2% |
Stroke | 0.9% | 1% | 0.7% |
HFH* | 2.6% | 3.6% | 3.3% |
Multivariable Hazard Ratio (95% CI) for 3-Year MACE§ |
Moderate vs mild HK* | 1.29 (1.25, 1.33) |
Severe vs mild HK* | 1.31 (1.23, 1.40) |
Post-Index Annualized Acute Care Trends |
ED | | | |
Mean cost ± SD* | $519 ± 7,819 | $701 ± 6,936 | $668 ± 2,100 |
Median (IQR) | 54 (0, 391) | 67 (0, 477) | 68 (0, 554) |
1-year visit* (primary diagnosis) | 0.1% | 0.4% | 0.7% |
Inpatient | | | |
Mean cost ± SD* | $9,626 ± 73,418 | $16,328 ± 155,262 | $18,743 ± 125,932 |
Median (IQR) | 0 (0, 4235) | 0 (0, 6222) | 788 (0, 7332) |
1-year visit* (primary diagnosis) | 0.1% | 0.4% | 1.1% |
ACEi: angiotensin-converting enzyme inhibitor; ARB: angiotensin-II receptor blockers; ASCVD: atherosclerotic cardiovascular disease; BMI: body mass index; CAD: coronary artery disease; CCB: calcium channel blocker; CCI: Charlson Comorbidity Index; CV: cardiovascular; ED: emergency department; EF: ejection fraction; HFH: heart failure hospitalization; HK: hyperkalaemia; IQR: interquartile range: MACE: major adverse CV event; MI: myocardial infarction; NSAID: nonsteroidal anti-inflammatory drug; PVD: peripheral vascular disease; SBP: systolic blood pressure; SD: standard deviation; sK: serum potassium; SPS: sodium polystyrene sulfonate; TIA: transient ischaemic attack. |
Models adjusted by baseline characteristics, risk factors, and medications. |
*P ≤ 0.001. |
†Taken within ± 1 month of index date (baseline sK level). |
‡P ≤ 0.01. |
§MACE is the composite of death, MI, stroke, and HFH. |
ED and inpatient costs in the HK and no-HK groups were compared (Table 1), with substantial divergence of medians and median ranges in older patients. In the overall HK population, average annual costs were $552 ± 7,574 for ED and $10,956 ± 93,026 for inpatient visits; in the no-HK group, costs were $207 ± 1,930 for ED and $1,477 ± 21,423 for inpatient visits. Notably, in patients age ≥ 60 years, average annual ED and inpatient costs were significantly higher in HK patients ($561 ± 7,098 for ED and $13,844 ± 109,257 for inpatient) relative to those without HK ($222 ± 2,747 for ED and $3,765 ± 35,137 for inpatient) (Table 1).
Higher HK frequency correlated with greater ED and inpatient costs (Table 2), with greatest impact on inpatient costs. For transient, intermittent, and persistent HK patterns, ED costs were $422 ± 4,221, $620 ± 2,305, and $1,737 ± 37,846, respectively; and inpatient costs were $5,047 ± 51,691, $16,478 ± 108,826, and $30,011 ± 245,519, respectively. For patients with a primary diagnosis of HK, visits within 1 year increased in parallel with greater HK frequency.
Increasing severity showed similar trend patterns but with lower magnitudes of cost increases (Table 3). The severe-HK group incurred the highest mean annual inpatient costs ($18,743 ± 125,932; P < 0.001) and 1-year hospitalization rate (1.1%; P < 0.001). The moderate-HK group averaged the highest annual ED costs ($701 ± 6,936; P < 0.001), albeit a modest numeric difference from other groups.
The general trends suggest that inpatient costs trended upward with both severity and frequency of HK, while ED costs trended upward with frequency but not severity. Persistently recurring HK diverged from other frequencies and any severity with regard to impact on both ED and inpatient costs.
A HyperK Risk Score was calculated for a total of 1,077,306 patients using clinical risk predictors from standard factors from the electronic health record. Baseline characteristics among the derivation and validation cohorts are shown in Table 4. Of patients who were given HyperK Risk Scores, 754,109 (70.0%) were in the derivation cohort. Within the derivation cohort, 732,936 (97.2%) did not have HK (defined as sK < 5.0 mmol/L) and 21,173 (2.8%) had HK (defined as sK > 5.5 mmol/L). Among the derivation cohort, 334,504 (44.4%) were considered low-risk, 337,335 (44.7%) were moderate, and 82,270 (10.9%) were high-risk. 323,197 (30.0%) were applied in a validation cohort, of which 314,030 (97.2%) did not have HK and 9,167 (2.8%) had HK (sK > 5.5 mmol/L). Patients with an intermediate sK between > 5.0 and 5.5 mmol/L were excluded. In the validation cohort, 143,328 (44.3%) were low-risk, 144,990 (44.9%) were moderate, and 34,879 (10.8%) were high-risk.
Table 4
HyperK – Baseline Characteristics
| Derivation n = 754,109 | Validation n = 323,197 |
Mean age (years) | 43.1 ± 18.4 | 43.0 ± 18.4 |
< 65 years | 85.1% | 85.2% |
65–74 years | 8.4% | 8.3% |
≥ 75 years | 6.5% | 6.5% |
Sex (male)* | 41.7% | 41.5% |
Hypertension | 21.5% | 21.4% |
Hyperlipidaemia | 18.0% | 17.9% |
Diabetes | 7.4% | 7.3% |
Smoking | 13.0% | 12.9% |
ASCVD | 4.2% | 4.1% |
Heart failure | 2.6% | 2.6% |
Atrial fibrillation | 2.5% | 2.5% |
Renal failure | 1.5% | 1.5% |
Dialysis* | 0.2% | 0.2% |
ACEi | 5.6% | 5.6% |
ARB | 2.2% | 2.2% |
Beta-blocker | 4.5% | 4.5% |
Aldosterone | 0.6% | 0.6% |
NSAID | 25.3% | 25.3% |
Furosemide | 2.2% | 2.3% |
Torsemide | 0.1% | 0.1% |
ACEi: angiotensin-converting enzyme inhibitor; ARB: angiotensin-II receptor blockers; ASCVD: atherosclerotic cardiovascular disease; NSAID: nonsteroidal anti-inflammatory drug. |
*P < 0.05. |
Significant predictors of HK (Fig. 2) as validated within this population are consistent with other bodies of evidence and include advancing age, male gender, comorbidities (eg, DM, HTN, HF, renal failure), and medications associated with altered K+ homeostasis (eg, RAASi’s, diuretics, beta-blockers, NSAIDs). Area under the curve c-statistics and 95% CIs for the derivation and validation cohorts were 0.850 (0.847, 0.853) and 0.853 (0.848, 0.858), respectively. ORs for incident HK in patients in the derivation cohort were evaluated in moderate- vs low-risk (OR = 2.64; P < 0.001) and high- vs low-risk (OR = 32.49; P < 0.001). In the validation cohort, OR for incident HK was evaluated in moderate- vs low-risk (OR = 2.81; P < 0.001) and high- vs low-risk (OR = 34.79; P < 0.001).