Impact of plasma potassium normalization on short-term mortality in patients with hypertension and hypokalemia or low normal potassium.

BACKGROUND: Hypokalemia is common in patients treated with antihypertensive drugs, but the impact of correcting hypokalemia is insufficiently studied. We examined the consequences of hypokalemia and borderline hypokalemia correction in patients with hypertension. METHODS: We identified 8976 patients with hypertension and plasma potassium concentrations ≤3.7 mmol/L within 100 days from combination antihypertensive therapy initiation. The first measurement between 6 and 100 days after the episode with potassium ≤3.7 mmol/L was retained. We investigated all-cause and cardiovascular mortality within 60-days from the second potassium measurement using Cox regression. Mortality was examined for seven predefined potassium intervals derived from the second measurement: 1.5-2.9 mmol/L (n = 271), 3.0-3.4 mmol/L (n = 1341), 3.5-3.7 (n = 1982) mmol/L, 3.8-4.0 mmol/L (n = 2398, reference), 4.1-4.6 mmol/L (n = 2498), 4.7-5.0 mmol/L (n = 352) and 5.1-7.1 mmol/L (n = 134). RESULTS: Multivariable analysis showed that potassium concentrations 1.5-2.9 mmol/L, 3.0-3.4 mmol/L, 4.7-5.0 mmol/L and 5.1-7.1 mmol/L were associated with increased all-cause mortality (HR 2.39, 95% CI 1.66-3.43; HR 1.36, 95% CI 1.04-1.78; HR 2.36, 95% CI 1.68-3.30 and HR 2.62, 95% CI 1.73-3.98, respectively). Potassium levels <3.0 and > 4.6 mmol/L were associated with increased cardiovascular mortality. The adjusted standardized 60-day mortality risks in the seven strata were: 11.7% (95% CI 8.3-15.0%), 7.1% (95% CI 5.8-8.5%), 6.4% (95% CI 5.3-7.5%), 5.4% (4.5-6.3%), 6.3% (5.4-7.2%), 11.6% (95% CI 8.7-14.6%) and 12.6% (95% CI 8.2-16.9%), respectively. CONCLUSIONS: Persistent hypokalemia was frequent and associated with increased all-cause and cardiovascular mortality. Increase in potassium to levels > 4.6 mmol/L in patients with initial hypokalemia or low normal potassium was associated with increased all-cause and cardiovascular mortality.

The relationship between serum potassium concentrations and electrocardiographic characteristics in 163,547 individuals from primary care.

AIMS: Potassium disturbances are common and associated with increased morbidity and mortality, even in patients without prior cardiovascular disease. We examined six electrocardiographic (ECG) measures and their association to serum potassium levels. METHODS AND RESULTS: From the Copenhagen General Practitioners' Laboratory, we identified 163,547 individuals aged ≥16 years with a first available ECG and a concomitant serum potassium measurement during 2001-2011. Restricted cubic splines curves showed a non-linear relationship between potassium and the Fridericia corrected QT (QTcF) interval, T-wave amplitude, morphology combination score (MCS), PR interval, P-wave amplitude and duration. Therefore, potassium was stratified in two intervals K: 2.0-4.1 mmol/L and 4.2-6.0 mmol/L for further analyses. Within the low potassium range, we observed: QTcF was 12.8 ms longer for each mmol/L decrease in potassium (p < 0.0001); T-wave amplitude was 43.1 µV lower for each mmol/L decrease in potassium (p < 0.0001); and MCS was 0.13 higher per mmol/L decrease in potassium (p < 0.001). Moreover, P-wave duration and PR interval were prolonged by 2.7 and 4.6 ms for each mmol/L decrease in potassium (p < 0.0001), respectively. Within the lowest potassium range (2.0-4.1 mmol/L) P-wave amplitude was 3.5 µV higher for each mmol/L decrease in potassium (p < 0.0001). Within the high potassium range associations with the above-mentioned ECG parameters were much weaker.

Short-term mortality risk of serum potassium levels in hypertension: a retrospective analysis of nationwide registry data.

Aims: Diuretics and renin­angiotensin­aldosterone system inhibitors are central in the treatment of hypertension, but may cause serum potassium abnormalities. We examined mortality in relation to serum potassium in hypertensive patients. Methods and Results: From Danish National Registries, we identified 44 799 hypertensive patients, aged 30 years or older, who had a serum potassium measurement within 90 days from diagnosis between 1995 and 2012. All-cause mortality was analysed according to seven predefined potassium levels: <3.5 (hypokalaemia), 3.5­3.7, 3.8­4.0, 4.1­4.4, 4.5­4.7, 4.8­5.0, and >5.0 mmol/L (hyperkalaemia). Outcome was 90-day mortality, estimated with multivariable Cox proportional hazard model, with the potassium interval of 4.1­4.4 mmol/L as reference. During 90-day follow-up, mortalities in the seven strata were 4.5, 2.7, 1.8, 1.5, 1.7, 2.7, and 3.6%, respectively. Adjusted risk for death was statistically significant for patients with hypokalaemia [hazard ratio (HR): 2.80, 95% confidence interval (95% CI): 2.17­3.62], and hyperkalaemia (HR: 1.70, 95% CI: 1.36­2.13). Notably, normal potassium levels were also associated with increased mortality: K: 3.5­3.7 mmol/L (HR: 1.70, 95% CI: 1.36­2.13), K: 3.8­4.0 mmol/L (HR: 1.21, 95% CI: 1.00­1.47), and K: 4.8­5.0 mmol/L (HR: 1.48, 95% CI: 1.15­1.92). Thus, mortality in relation to the seven potassium ranges was U-shaped, with the lowest mortality in the interval of 4.1­4.4 mmol/L. Conclusion: Potassium levels outside the interval of 4.1­4.7 mmol/L were associated with increased mortality risk in patients with hypertension.

Associations of serum potassium levels with mortality in chronic heart failure patients.

AIMS: Medication prescribed to patients suffering from chronic heart failure carries an increased risk of impaired potassium homeostasis. We examined the relation between different levels of serum potassium and mortality among patients with chronic heart failure. METHODS AND RESULTS: From Danish National registries, we identified 19 549 patients with a chronic heart failure diagnosis who had a measurement of potassium within minimum 90 days after initiated medical treatment with loop diuretics and angiotensin converting enzyme inhibitors or angiotensin-II receptor blockers. All-cause mortality was examined according to eight predefined potassium levels: 2.8-3.4 mmol/L, 3.5-3.8 mmol/L, 3.9-4.1 mmol/L, 4.2-4.4 mmol/L, 4.5-4.7 mmol/L, 4.8-5.0 mmol/L, 5.1-5.5 mmol/L, and 5.6-7.4 mmol/L. Follow-up was 90 days from potassium measurement. We estimated the risk of all-cause mortality using multivariable adjusted Cox proportional hazard model, with normal serum potassium level at 4.2-4.4 mmol/L as reference. After 90 days, the mortality in the eight strata was 14.4, 8.0, 6.3, 5.0, 5.8, 7.9, 10.3, and 21.1% respectively. In multivariable adjusted analysis, patients with potassium levels of 2.8-3.4 mmol/L [hazard ratio (HR): 3.16; confidence interval (CI): 2.43-4.11], 3.5-3.8 mmol/L (HR: 1.62; CI: 1.31-1.99), 3.9-4.1 mmol/L (HR: 1.29; CI: 1.08-1.55), 4.8-5.0 mmol/L (HR: 1.34; CI: 1.10-1.63), 5.1-5.5 mmol/L (HR: 1.60; CI: 1.29-1.97), and 5.6-7.4 mmol/L (HR: 3.31; CI: 2.61-4.20) had an increased risk of all-cause mortality. CONCLUSION: Levels within the lower and upper levels of the normal serum potassium range (3.5-4.1 mmol/L and 4.8-5.0 mmol/L, respectively) were associated with a significant increased short-term risk of death in chronic heart failure patients. Likewise, potassium below 3.5 mmol/L and above 5.0 mmol/L was also associated with increased mortality.

Risk of developing hyperkalemia in patients with hypertension treated with combination antihypertensive therapy - a retrospective register-based study.

The risk of hyperkalemia in relation to different combinations of antihypertensive therapy remains to be elucidated. In this Danish register-based study, we aimed to investigate the risk of developing hyperkalemia in relation to different combinations of antihypertensive therapy. Using incidence density matching, we matched a hyperkalemic patient to five normokalemic patients on eGFR groups, age, sex, and time between study entry and date of potassium measurement. Combination therapies were subdivided into eight groups: beta blockers (BB) + calcium channel blockers (CCB), BB + renin angiotensin system inhibitors (RASi), BB + RASi + mineralocorticoid receptor antagonists (MRA), CCB + RASi, CCB + RASi + thiazides, CCB + thiazides, RASi + thiazides, and other combinations. Multivariable conditional logistic regression was used to estimate the odds of hyperkalemia within 90 days for each of the eight antihypertensive combination therapies. A total of 793 patients with hyperkalemia were matched to 3598 normokalemic patients. In multivariable analysis, odds of developing hyperkalemia when being treated with BB + RASi + MRA was 1.95 (95% CI, 1.39-2.72) compared to RASi + thiazides (reference). CCB + thiazides (OR, 0.76 [95% CI, 0.45-1.28]) and CCB + RASi + Thiazid (OR 0.81 [95% CI, 0.51-1.28]) were among the others not significantly associated with hyperkalemia. Combinations of BB + RASi + MRA were significantly associated with an increased risk of developing hyperkalemia within 90 days of initiating treatment. Patients treated with BB + RASi + MRA within 90 days of treatment initiation, were associated with an increased hyperkalemia risk. When treating hypertensive patients with combination antihypertensive therapy, identifying and monitoring patients with a high risk of dyskalemias is a crucial goal to avoid serious adverse effects and detrimental outcomes related to dyskalemia.

Short-term prognosis of changes in plasma potassium following an episode of hyperkalaemia in patients with chronic heart failure.

BACKGROUND/AIM: There is an increasing prevalence of chronic heart failure (HF). It is well known that patients with HF and disturbances in the potassium level have an increased mortality risk. The aim of this study was to investigate the prognosis of a second plasma-potassium measurement after an episode with hyperkalaemia on short-term mortality in patients with chronic HF. METHODS AND RESULTS: From Danish national registers, 2,339 patients with chronic HF and hyperkalaemia (>4.6 mmol/L) at first potassium measurement within 14-365 days from concomitant treatment were identified. To be included, a second measurement was required within 6-30 days subsequent to the first measurement and the 60-day mortality was observed. Based on the second measurement, the patients were divided into five groups: <3.5 mmol/L (n = 257), 3.5-4.0 mmol/L (n = 709), 4.1-4.6 mmol/L (n = 1,204, reference), 4.7-5.0 mmol/L (n = 89) and >5.0 mmol/L (n = 80). To assess all-cause and cardiovascular mortality, we used the Cox regression model. The multivariable analysis showed that patients with potassium concentrations <3.5 mmol/L (hazard ratio (HR): 3.03; 95% CI: 2.49-3.70) and 3.5-4.0 mmol/L (HR: 1.81; 95% CI: 1.54-2.14) had a worse prognosis compared to the reference. We observed similar results when calculating the risk of cardiovascular mortality. A restricted cubic spline curve showed a U-shaped relationship between plasma-potassium and all-cause mortality. CONCLUSION: Patients with chronic HF and hyperkalaemia who became hypokalaemic after 6-30 days were associated with a higher 60-day all-cause and cardiovascular mortality compared to the reference. This also applied for patients with low normal potassium concentrations (3.5-4.0 mmol/L).

Correction: Hypertension genetic risk score is associated with burden of coronary heart disease among patients referred for coronary angiography.

[This corrects the article DOI: 10.1371/journal.pone.0208645.].

External validation of the simple NULL-PLEASE clinical score in predicting outcomes of out-of-hospital cardiac arrest in the Danish population - A nationwide registry-based study.

AIM: The NULL-PLEASE score (Nonshockable rhythm, Unwitnessed arrest, Long no-flow or Long low-flow period, blood pH < 7.2, Lactate > 7.0 mmol/L, End-stage renal disease on dialysis, Age ≥85 years, Still resuscitation, and Extracardiac cause) may identify patients with out-of-hospital cardiac arrest (OHCA) unlikely to survive. We aimed to validate the NULL-PLEASE score in a nationwide setting. METHODS: We used Danish nationwide registry data from 2001 to 2019 and identified OHCA survivors with return of spontaneous circulation (ROSC) or ongoing cardiopulmonary resuscitation at hospital arrival. The primary outcome was 1-day mortality. Secondary outcomes were 30-day mortality and the combined outcome of 1-year mortality or anoxic brain damage. The risks of outcomes were estimated using logistic regression with a NULL-PLEASE score of 0 as reference (range 0-14). The predictive ability of the score was examined using the area under the receiver operating characteristics (AUCROC) curve. RESULTS: A total of 3,881 patients were included in the analyses. One-day mortality was 35%, 30-day mortality was 61%, and 68% experienced the combined outcome. For a NULL-PLEASE score ≥9 (n = 244) the absolute risks were: 1-day mortality: 80.7% (95% confidence interval [CI]: 75.8-85.7%); 30-day mortality: 98.0% (95% CI: 96.2-99.7%); and the combined outcome: 98.4% (95% CI: 96.8-100.0%). Corresponding AUCROC values were 0.800 (95% CI: 0.786-0.814) for 1-day mortality, 0.827 (95% CI: 0.814-0.840) for 30-day mortality, and 0.828 (95% CI: 0.815-0.841) for the combined outcome. CONCLUSIONS: In a nationwide OHCA-cohort, AUCROC values for the predictive ability of NULL-PLEASE were high for all outcomes. However, some survived even with high NULL-PLEASE scores.

Association between intravenous iron therapy and short-term mortality risk in older patients undergoing hip fracture surgery: an observational study.

BACKGROUND: Anemia is common among ortho-geriatric hip fracture patients and is associated with prolonged recovery and increased postoperative mortality rate. Intravenous iron seems to increase hemoglobin recovery and reduce the mortality rate in patients undergoing orthopedic surgeries. This study investigated the association between short-term mortality risk and intravenous iron therapy in older patients undergoing hip fracture surgery. METHODS: This observational study included 210 patients undergoing hip fracture surgery from July 2018 to May 2020. These 210 patients were alive and had a hemoglobin ≤ 6.5 mmol/L on the 3rd postoperative day. In May 2019, a local intravenous iron therapy protocol was implemented and recommended intravenous iron (Monofer©) if hemoglobin on the 3rd postoperative day was ≤ 6.5 mmol/L. According to the treatment of postoperative anemia between the 1st and 3rd day post-surgery, the patients were divided into four groups: no treatment (n=52), blood transfusion (n=38), IV Monofer (n=80), and blood transfusion and IV Monofer (n=40). Primary outcome was 30-day mortality post-surgery. The secondary outcome was the impact on hemoglobin level 14-30 days postoperatively. Multivariable Cox regression was used to estimate the 30-day mortality standardized for covariates. RESULTS: Of 210 patients, 17 (8.1%) died within 30 days after surgery. There was a significantly lower mortality among the patients who received IV Monofer compared to those who received no treatment (HR 0.17, 95% CI [0.03-0.93], P = 0.041). Among the 86 patients with available hemoglobin measurements within 14 to 30 days post-surgery, there was no significant difference in hemoglobin level between the various treatment groups (mean 6.6 mmol/L, P = 0.1165). CONCLUSION: IV Monofer on the 3rd postoperative day in older hip fracture patients seemed to reduce 30-day mortality compared with no treatment. No significant differences in hemoglobin levels between 14 and 30 days post-surgery across treatment groups were found, although this was assessed in a subset of patients with available hemoglobin levels warranting further study.

Increased 5-year risk of stroke, atrial fibrillation, acute coronary syndrome, and heart failure in out-of-hospital cardiac arrest survivors compared with population controls: A nationwide registry-based study.

AIM: Long-term risks of stroke, atrial fibrillation, or flutter (AF), acute coronary syndrome (ACS), and heart failure (HF) among survivors of out-of-hospital cardiac arrest (OHCA) are unknown. We aimed to examine 5-year risks of these outcomes among 30-day survivors of OHCA. METHODS: Thirty-day survivors of OHCA without a prior (or within 30 days after cardiac arrest) history of stroke, AF, ACS, or HF and population controls without a prior history of these conditions were identified using Danish nationwide registries. Five-year risks of stroke, AF, ACS, and HF standardized to the distributions of age, sex, and comorbidities among OHCA survivors and controls were obtained using multivariable regression. RESULTS: Of 4,362 30-day OHCA-survivors, 1,051 were stroke-, AF-, ACS-, and HF-naïve and matched with controls using age, sex, and time of OHCA event. Absolute five-year risks for OHCA survivors vs. controls were for stroke: 6.3% [95% confidence interval (CI) 4.1-8.5] vs. 2.0% [1.6-2.5], AF: 7.9% [5.7-10.2] vs. 2.6% [2.1-3.1], ACS: 5.0% [3.2-6.8] vs. 1.5% [1.1-1.9], and HF: 12.7% [10.1-15.4] vs. 1.2% [0.9-1.6], respectively. Corresponding relative risks were 3.18 [95% CI 1.76-4.61] for stroke, 3.03 [1.93-4.14] for AF, 3.23 [1.69-4.77] for ACS, and 10.40 [6.57-14.13] for HF. CONCLUSION: When compared with population controls, OHCA survivors had significantly increased five-year risks of incident stroke, AF, ACS, and HF.

Incident atrial fibrillation and risk of psychoactive drug redemptions and psychiatric hospital contacts: a Danish Nationwide Register-based Follow-up Study.

AIMS: To investigate whether incident atrial fibrillation or flutter (AF) diagnosis increases the risk of psychiatric outcomes compared with the general population. METHODS AND RESULTS: First-time AF patients and population controls naive to psychiatric disease or filled prescriptions for psychotropic drugs were identified in Danish nationwide registries during 2005-14. AF patients were matched 1:2 with exposure density matching. Patients and controls were compared for 1-year cumulative incidences of depression, anxiety, and stress disorders, and for filled drug prescriptions for antidepressant, anxiolytic, selected antipsychotics, and hypnotics. Lastly, we examined 1-year cumulative incidences of a composite endpoint of the above-mentioned diagnoses or drug redemptions. We included 146 377 AF patients and 292 754 matched controls, 55% men and median age 74 (25-75% 65-82) years. AF patients had significantly higher cumulative incidences of composite endpoints. Furthermore, filled prescriptions for anxiolytics and hypnotics were significantly higher for AF patients compared with healthy population controls. The cumulative incidence of the composite endpoint was significantly higher in AF patients relative to controls 11.1% vs. 8.3%. For the composite endpoint, a significantly higher risk was apparent both in unadjusted (HR: 2.76, 95% CI: 2.67-2.85) and adjusted (HR: 2.51, 95% CI: 2.43-2.60) models for AF patients vs. controls in the first 3 months after study inclusion. CONCLUSION: First-time AF patients were significantly more likely to have psychiatric outpatient or hospital contacts and to fill prescriptions for psychotropic drugs compared with healthy population controls. The risk was significantly elevated only during the first 3 months after AF diagnosis.

Insulin resistance genetic risk score and burden of coronary artery disease in patients referred for coronary angiography.

AIMS: Insulin resistance associates with development of metabolic syndrome and risk of cardiovascular disease. The link between insulin resistance and cardiovascular disease is complex and multifactorial. Confirming the genetic link between insulin resistance, type 2 diabetes, and coronary artery disease, as well as the extent of coronary artery disease, is important and may provide better risk stratification for patients at risk. We investigated whether a genetic risk score of 53 single nucleotide polymorphisms known to be associated with insulin resistance phenotypes was associated with diabetes and burden of coronary artery disease. METHODS AND RESULTS: We genotyped patients with a coronary angiography performed in the capital region of Denmark from 2010-2014 and constructed a genetic risk score of the 53 single nucleotide polymorphisms. Logistic regression using quartiles of the genetic risk score was performed to determine associations with diabetes and coronary artery disease. Associations with the extent of coronary artery disease, defined as one-, two- or three-vessel coronary artery disease, was determined by multinomial logistic regression. We identified 4,963 patients, of which 17% had diabetes and 55% had significant coronary artery disease. Of the latter, 27%, 14% and 14% had one, two or three-vessel coronary artery disease, respectively. No significant increased risk of diabetes was identified comparing the highest genetic risk score quartile with the lowest. An increased risk of coronary artery disease was found for patients with the highest genetic risk score quartile in both unadjusted and adjusted analyses, OR 1.21 (95% CI: 1.03, 1.42, p = 0.02) and 1.25 (95% CI 1.06, 1.48, p<0.01), respectively. In the adjusted multinomial logistic regression, patients in the highest genetic risk score quartile were more likely to develop three-vessel coronary artery disease compared with patients in the lowest genetic risk score quartile, OR 1.41 (95% CI: 1.10, 1.82, p<0.01). CONCLUSIONS: Among patients referred for coronary angiography, only a strong genetic predisposition to insulin resistance was associated with risk of coronary artery disease and with a greater disease burden.

Serum Potassium and Mortality in High-Risk Patients: SPRINT.

[Figure: see text].

Update on management of hypokalaemia and goals for the lower potassium level in patients with cardiovascular disease: a review in collaboration with the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.

Hypokalaemia is common in patients with cardiovascular disease. In this review, we emphasize the importance of tight potassium regulation in patients with cardiovascular disease based on findings from observational studies. To enhance the understanding, we also describe the mechanisms of potassium homeostasis maintenance, the most common causes of hypokalaemia and present strategies for monitoring and management of low potassium levels. We propose elevation of potassium in asymptomatic patients with lower normal concentrations and concurrent cardiovascular disease. These proposals are intended to assist clinicians until more evidence is available.

Impact of Plasma Potassium Normalization on Short-Term Mortality in Patients With Hypertension and Hyperkalemia.

Background Hyperkalemia can be harmful, but the effect of correcting hyperkalemia is sparsely studied. We used nationwide data to examine hyperkalemia follow-up in patients with hypertension. Methods and Results We identified 7620 patients with hypertension, who had the first plasma potassium measurement ≥4.7 mmol/L (hyperkalemia) within 100 days of combination antihypertensive therapy initiation. A second potassium was measured 6 to 100 days after the episode of hyperkalemia. All-cause mortality within 90 days of the second potassium measurement was assessed using Cox regression. Mortality was examined for 8 predefined potassium intervals derived from the second measurement: 2.2 to 2.9 mmol/L (n=37), 3.0 to 3.4 mmol/L (n=184), 3.5 to 3.7 mmol/L (n=325), 3.8 to 4.0 mmol/L (n=791), 4.1 to 4.6 mmol/L (n=3533, reference), 4.7 to 5.0 mmol/L (n=1786), 5.1 to 5.5 mmol/L (n=720), and 5.6 to 7.8 mmol/L (n=244). Ninety-day mortality in the 8 strata was 37.8%, 21.2%, 14.5%, 9.6%, 6.3%, 6.2%, 10.0%, and 16.4%, respectively. The multivariable analysis showed that patients with concentrations >5.5 mmol/L after an episode of hyperkalemia had increased mortality risk compared with the reference (hazard ratio [HR], 2.27; 95% CI, 1.60-3.20; P<0.001). Potassium intervals 3.5 to 3.7 mmol/L and 3.8 to 4.0 mmol/L were also associated with increased risk of death (HR, 1.71; 95% CI, 1.23-2.37; P<0.001; HR, 1.36; 95% CI, 1.04-1.76; P<0.001, respectively) compared with the reference group. We observed a trend toward increased risk of death within the interval 5.1 to 5.5 mmol/L (HR, 1.29; 95% CI, 0.98-1.69). Potassium concentrations <4.1 mmol/L and >5.0 mmol/L were associated with increased risk of cardiovascular death. Conclusions Overcorrection of hyperkalemia to levels <4.1 mmol/L was frequent and associated with increased all-cause and cardiovascular mortality. Potassium concentrations >5.5 mmol/L were also associated with an increased all-cause and cardiovascular mortality.

Association between serum potassium levels and short-term mortality in patients with atrial fibrillation or flutter co-treated with diuretics and rate- or rhythm-controlling drugs.

AIMS: We investigated the association between potassium levels and 90-day all-cause mortality in atrial fibrillation or flutter (AF) patients co-treated with diuretics and rate- or rhythm-controlling drugs. METHODS AND RESULTS: During 2000-12, first-time AF patients treated with beta-blockers, amiodarone, sotalol, verapamil, or digoxin combined with any diuretic within 90 days post-AF discharge were included. Following co-treatment, a potassium measurement within 90 days after initiating diuretic treatment was required. Mortality risk associated with potassium <3.5, 3.5-3.7, 3.8-4.0, 4.5-4.7, 4.8-5.0, and >5.0 mmol/L (reference: 4.1-4.4 mmol/L) was assessed using multivariable Cox regression. In total, 14 425 AF patients were included (median age: 78 years; women: 52%). Patients most often received beta-blocker monotherapy (29%), beta-blockers and digoxin combined (25%), digoxin monotherapy (24%), amiodarone monotherapy (3%), and verapamil monotherapy (3%). Increased 90-day mortality risk was associated with <3.5 mmol/L [hazard ratio (HR) 2.05, 95% confidence interval (CI) 1.68-2.50], 3.5-3.7 mmol/L (HR 1.28, 95% CI 1.05-1.57), 4.5-4.7 mmol/L (HR 1.20, 95% CI 1.02-1.41), 4.8-5.0 mmol/L (HR 1.37, 95% CI 1.14-1.66), and >5.0 mmol/L: (HR 1.84, 95% CI 1.53-2.21). Compared with beta-blocker monotherapy, rate- or rhythm-controlling drugs did not modify the association between potassium groups and mortality risk. CONCLUSION: In addition to hypo- and hyperkalaemia, low and high normal range potassium levels were associated with increased 90-day mortality risk in AF patients co-treated with diuretics and rate- or rhythm-controlling drugs. These associations were independent of rate- or rhythm-controlling drugs.

Risk of Developing Hypokalemia in Patients With Hypertension Treated With Combination Antihypertensive Therapy.

Little is known about the occurrence of hypokalemia due to combination therapy for hypertension. Using data from Danish administrative registries, we investigated the association between different combinations of antihypertensive therapy and risk of developing hypokalemia. Using incidence density matching, 2 patients without hypokalemia were matched to a patient with hypokalemia (K, <3.5 mmol/L) on age, sex, renal function, and time between index date and date of potassium measurement. Combination therapies were subdivided into 10 groups including ß-blockers (BB)+thiazides (BB+thiazides), calcium channel blockers (CCB)+renin angiotensin system inhibitors (RASi)+thiazides (CCB+RASi+Thiazides), calcium channel blockers+thiazides (CCB+thiazides), and ß-blockers+renin angiotensin system inhibitors+thiazides (BB+RASi+thiazides). We used conditional logistic regression to estimate the odds of developing hypokalemia for different combinations of antihypertensive drugs within 90 days of combination therapy initiation. We matched 463 patients with hypokalemia to 926 patients with normal potassium concentrations. The multivariable analysis showed 5.82× increased odds of developing hypokalemia if administered CCB+thiazides (95% CI, 3.06-11.08) compared with CCB+RASi. Other combinations significantly associated with increased hypokalemia odds were BB+thiazides (odds ratio, 3.34 [95% CI, 1.67-6.66]), CCB+RASi+thiazides (odds ratio, 3.07 [95% CI, 1.72-5.46]), and BB+RASi+thiazides (odds ratio, 2.78 [95% CI, 1.41-5.47]). Combinations of thiazides with CCB, RASi, or BB were strongly associated with increased hypokalemia risk within 90 days of treatment initiation.

Prognostic role of serum sodium levels across different serum potassium levels in heart failure patients: A Danish register-based cohort study.

BACKGROUND: In heart failure (HF), evidence on the prognosis of simultaneously abnormal sodium and potassium levels remains unknown. Therefore, we investigated associations between sodium levels and 90-day all-cause mortality across potassium levels in HF patients. METHODS: Using Danish registers, we identified HF patients with sodium and potassium levels within 90 days following a redeemed loop diuretic prescription from 2000 to 2012. We grouped sodium (<139, 139-143, >143 mmol/L) and potassium levels (<3.5 [hypokalemia], 3.5-4.0, 4.1-4.6, 4.7-5.0, >5.0 mmol/L [hyperkalemia]). First, by adjusting for potassium groups using multivariable Cox regression, we compared mortality of sodium <139 mmol/L and >143 mmol/L with 139-143 mmol/L as reference. Second, by combining sodium and potassium groups, we compared mortality of the resulting 15 combinations using sodium 139-143 mmol/L and potassium 4.1-4.6 mmol/L as reference. RESULTS: We included 16,343 HF patients (median age: 77.0 years; males: 53.7%). When adjusting for potassium groups, sodium <139 mmol/L and >143 mmol/L were associated with excess mortality (hazard ratio [HR]: 1.91, 95% confidence interval [CI]: 1.74-2.09; HR: 1.45, 95% CI: 1.25-1.68; respectively). When stratifying across potassium groups (interaction term: P = 0.291), we observed excess mortality with hyperkalemia for sodium <139 mmol/L (HR: 3.30, 95% CI: 2.76-3.96) and >143 mmol/L (HR: 3.46, 95% CI: 2.31-5.18), whereas mortality risk was lower for sodium 139-143 mmol/L (HR: 1.67, 95% CI: 1.30-2.14). Correspondingly, hypokalemia was associated with excess mortality (<139 mmol/L: HR: 3.53, 95% CI: 2.76-4.52; 139-143 mmol/L: HR: 2.47, 95% CI: 1.88-3.24; >143 mmol/L: HR: 2.67, 95% CI: 1.73-4.12). Lowest mortality risk appeared with sodium 139-143 mmol/L combined with remaining potassium groups. CONCLUSION: Abnormal sodium is an important risk factor for mortality in HF patients receiving diuretics, and the importance is independent of potassium levels.

Short-term mortality risk of serum potassium levels in acute heart failure following myocardial infarction.

AIMS: Diuretic treatment is often needed in acute heart failure following myocardial infarction (MI) and carries a risk of abnormal potassium levels. We examined the relation between different levels of potassium and mortality. METHODS AND RESULTS: From Danish national registries we identified 2596 patients treated with loop diuretics after their first MI episode where potassium measurement was available within 3 months. All-cause mortality was examined according to seven predefined potassium levels: hypokalaemia <3.5 mmol/L, low normal potassium 3.5-3.8 mmol/L, normal potassium 3.9-4.2 mmol/L, normal potassium 4.3-4.5 mmol/L, high normal potassium 4.6-5.0 mmol/L, mild hyperkalaemia 5.1-5.5 mmol/L, and severe hyperkalaemia: >5.5 mmol/L. Follow-up was 90 days and using normal potassium 3.9-4.2 mmol/L as a reference, we estimated the risk of death with a multivariable-adjusted Cox proportional hazard model. After 90 days, the mortality rates in the seven potassium intervals were 15.7, 13.6, 7.3, 8.1, 10.6, 15.5, and 38.3%, respectively. Multivariable-adjusted risk for death was statistically significant for patients with hypokalaemia [hazard ratio (HR): 1.91, confidence interval (95%CI): 1.14-3.19], and mild and severe hyperkalaemia (HR: 2, CI: 1.25-3.18 and HR: 5.6, CI: 3.38-9.29, respectively). Low and high normal potassium were also associated with increased mortality (HR: 1.84, CI: 1.23-2.76 and HR: 1.55, CI: 1.09-2.22, respectively). CONCLUSION: Potassium levels outside the interval 3.9-4.5 mmol/L were associated with a substantial risk of death in patients requiring diuretic treatment after an MI.