Diuretics and renin–angiotensin–aldosterone 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.
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), 3.5–3.7, 3.8–4.0, 4.1–4.4, 4.5–4.7, 4.8–5.0, and >5.0 mmol/L (hyperkalaemia). Outcome was 90-day mortality, estimated with multivariable Cox proportional hazard model, with the potassium interval of 4.1–4.4 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): 2.17–3.62, and hyperkalaemia (HR: 1.70, 95% CI: 1.36–2.13). Notably, normal potassium levels were also associated with increased mortality: K: 3.5–3.7 mmol/L (HR: 1.70, 95% CI: 1.36–2.13), K: 3.8–4.0 mmol/L (HR: 1.21, 95% CI: 1.00–1.47), and K: 4.8–5.0 mmol/L (HR: 1.48, 95% CI: 1.15–1.92). Thus, mortality in relation to the seven potassium ranges was U-shaped, with the lowest mortality in the interval of 4.1–4.4 mmol/L.
Potassium levels outside the interval of 4.1–4.7 mmol/L were associated with increased mortality risk in patients with hypertension.
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.
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.
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.
Recent GWAS studies have identified more than 300 SNPs associated with variation in blood pressure. We investigated whether a genetic risk score constructed from these variants is associated with ...burden of coronary heart disease.
From 2010-2014, 4,809 individuals admitted to coronary angiography in Capital Region of Copenhagen were genotyped. We calculated hypertension GRS comprised of GWAS identified SNPs associated with blood pressure. We performed logistic regression analyses to estimate the risk of hypertension and prevalent CHD. We also assessed the severity of CHD associated with the GRS. The analyses were performed using GRS quartiles. We used the Inter99 cohort to validate our results and to investigate for possible pleiotropy for the GRS with other CHD risk factors.
In COGEN, adjusted odds ratios comparing the 2nd, 3rd and 4th cumulative GRS quartiles with the reference were 1.12(95% CI 0.95-1.33), 1.35(95% CI 1.14-1.59) and 1.29(95% CI 1.09-1.53) respectively, for prevalent CHD. The adjusted multinomial logistic regression showed that 3rd and 4th GRS quartiles were associated with increased odds of developing two(OR 1.33, 95% CI 1.04-1.71 and OR 1.36, 95% CI 1.06-1.75, respectively) and three coronary vessel disease(OR 1.77, 95% CI 1.36-2.30 and OR 1.65, 95% CI 1.26-2.15, respectively). Similar results for incident CHD were observed in the Inter99 cohort. The hypertension GRS did not associate with type 2 diabetes, smoking, BMI or hyperlipidemia.
Hypertension GRS quartiles were associated with an increased risk of hypertension, prevalent CHD, and burden of coronary vessel disease in a dose-response pattern. We showed no evidence for pleiotropy with other risk factors for CHD.
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.
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;
<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;
<0.001; HR, 1.36; 95% CI, 1.04-1.76;
<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.
The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not ...well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography.
1599 individuals (mean age 64 years min-max 29-96 years, 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010-2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies.
Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively.
Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a "missing heritability" in early-onset CAD warrants more research.
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 β-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 β-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.
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.
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).
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.
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.
Abstract
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.
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