The association between serum potassium and mortality in patients with hypertension: ‘a wake-up call’

This editorial refers to ‘Short-term mortality risk of serum potassium levels in hypertension: a retrospective analysis of nationwide registry data’†, by M. Krogager et al., on page 104. There has been considerable focus on the risks of hyperkalaemia, especially in patients with chronic kidney disease (CKD), diabetes mellitus, and/or heart failure.1–3 Although the exact level of serum potassium (K+) that is associated with an increase in mortality remains controversial, increasing evidence suggests that in patients with CKD, diabetes mellitus, and/or heart failure, especially the elderly, a K+ >5.0 mmol/L is associated with an increased risk of death.4 Conversely, while a K+ <3.5 mmol/L is thought by many to be associated with an increase in mortality in patients with heart failure, there is evidence that a K+ <4.0 mmol/L is associated with an increase in mortality and that most deaths due to hypokalaemia in patients with heart failure occur with a K+ <4.0–3.5 mmol/L.5,6 Despite this evidence in patients with heart failure and/or CKD a K+ <4.0 mmol/L is often not corrected. The level of K+ at which clinicians should be concerned about the risk of death in patients with hypertension both with hyperkalaemia and with hypokalaemia has received less attention, with many physicians becoming concerned only at a K+ <3.5 and >5.5 mmol/L. In this issue of the journal, Krogager et al.7 used the Danish National Patient Registry to examine the association between K+ and all-cause mortality over 90 days in >40 000 patients with hypertension taking a dual single antihypertensive drug. Patients with renal insufficiency, those with missing serum creatinine values, as well as those who prior to the administration of two concomitant antihypertensives were diagnosed with CKD, including proteinuria or primary aldosteronism, were excluded. Co-morbid conditions such as atrial fibrillation, heart failure, and acute myocardial infarction were present at a rate of ∼10% each, while somewhat more than 10% of patients were receiving antidiabetic drugs. The authors found a U-shaped relationship between a K+ <4.1 and >4.7 mmol/L and all-cause mortality. After adjusting for age, sex, biologically relevant co-morbidities, and concomitant medications, as well as when patients with a history of myocardial infarction or heart failure were excluded from the analysis, the results were similar. The authors emphasize the fact that patients whose levels of K+ are often considered within the normal range, from 3.5 to 3.7, 3.8 to 4.0, and 4.8 to 5.0 mmol/L, had a significant increase in mortality with hazard ratios of 1.49, 1.14, and 1.38, respectively. Several limitations of their study are noted, including: its observational nature; lack of information on the cause of death; and potential misclassification of some patients as hypertensives; and they also point out that they cannot determine whether the increase in mortality that they have observed is due to potassium's influence on the membrane potential or other processes. While future prospective studies will be required to verify the exact level of K+ associated with death in a broader population of patients with hypertension, the fact remains that K+ levels considered within the normal range by many clinicians, and often ignored, are associated with an increased risk of death. In view of the finding of an increase in mortality in these patients with hypertension at a K+ >4.7 mmol/L within 90 days of measurement, it would seem prudent in those at risk for hyperkalaemia, such as those patients with a history of CKD, diabetes mellitus, and/or the elderly to be provided with dietary counselling regarding a low potassium diet. Many physicians do not have the knowledge or time to advise their patients properly regarding foods that have a high potassium content and should therefore routinely refer their patients with hypertension to a dietician. The DASH diet,8 while often recommended to patients with hypertension, unfortunately has a high K+ content. If despite dietary counselling the K+ remains elevated, one might consider adding a thiazide diuretic at appropriate doses [or a loop diuretic in patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1/73 m2] to the patient's regimen, if not already present. Alternatively, switching from a renin–angiotensin–aldosterone system inhibitor- (RAAS-I) based strategy to a strategy not associated with hyperkalaemia such as a calcium channel blocking agent should be considered, since the evidence that a RAAS-I-based strategy is superior to other classes of antihypertensive therapy is lacking for most patients with hypertension at low cardiovascular risk and for those with diabetes mellitus.9 If, however, hypertension is complicated by CKD and/or heart failure with a reduced left ventricular ejection fraction (HFREF), the situation is more complex in that RAAS-Is have been shown to be of benefit. Therefore, reducing the dose of the RAAS-I or discontinuing it could place the patient at increased risk for death. In this situation, one might consider the use of a K+-lowering agent while continuing a RAAS-I. Unfortunately sodium polystyrene sulphonate (SPS), an available K+-lowering agent, has been associated with an increased risk of bowel necrosis and exchanges potassium for sodium, which could increase the risk for volume overload in a patient with HFREF.10 The recent availability, at least in the USA, of the non-absorbed potassium-lowering polymer Patiromer and the likely availability within the year of the potassium-binding agent ZS9 provide an opportunity to maintain a RAAS-I in patients with hypertension.11 While both Patiromer and ZS9 have been shown to be effective in reducing K+ to normal levels in patients with hyperkalaemia and to be relatively well tolerated, it will be necessary to evaluate their long-term efficacy on cardiovascular outcomes while maintaining a RAAS-I in comparison with switching to another class of antihypertensive agent. It will also be important to compare the long-term efficacy and safety of Patiromer with those of ZS9 since while Patiromer exchanges potassium for calcium ZS9 exchanges potassium for sodium, raising the possibility that similarly to SPS, ZS9 could lead to an increase in sodium absorption and volume overload. Potential hypokalaemia and hyperkalaemia treatment patterns. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RAAS-I, renin–angiotensin–aldosterone system inhibitor. In conclusion, we are indebted to Krogager et al.7 for focusing our attention on the risks of both hyper- and hypokalaemia in patients with hypertension and pointing out that we should be concerned about K+ levels currently thought by many to be within the normal range. Their study should be a ‘wake-up call’, prompting further studies to prevent the deviations in K+ above and below the levels associated with all-cause death in patients with hypertension. While the relative risks of death related to deviations in K+ within the ‘normal range’, both <4.0 and >4.7 mmol/L, are relatively low, the potential absolute number of deaths is staggering given the growing incidence of hypertension in our ageing population and the recent evidence suggesting the need for more intensive blood pressure lowering.15 Conflict of interest: P.R. received travel grants from Pfizer Inc. He is a consultant to AstraZeneca, Novartis, Relypsa, Vifor Fresenius Medical Care Renal Pharma, and Stealth Peptides, and has received speakers fees from CVRx and Bayer. He is co-founder of CardioRenal. B.P. is a consultant to Relypsa, scPharmaceuticals, Tricida, pharMain, Aurasense, KBP biosciences, and DaVinci Therapeutics, for which he also hass stock options; and to Bayer, AstraZeneca, Boehringer Ingelheim, Merck, Forrest Laboratories, and Stealth Peptides. He serves on the Data Monitoring Boards of Novartis, Johnson & Johnson, and Tenax, and on the Clinical Events Committee of Juventas. He has a patent pending on the site-specific delivery of eplerenone to the myocardium.