Serum potassium and clinical outcomes in heart failure patients: results of risk calculations in 21 334 patients in the UK

Abstract

Aims At present, the clinical burden of hypokalaemia and hyperkalaemia among European heart failure patients, and relationships between serum potassium and adverse clinical outcomes in this population, is not well characterized. The aim of this study was to investigate associations between mortality, major adverse cardiac events, and renin–angiotensin–aldosterone system inhibitor (RAASi) discontinuation across serum potassium levels, in a UK cohort of incident heart failure patients. Methods and results This was a retrospective observational cohort study of newly diagnosed heart failure patients listed in the Clinical Practice Research Datalink, with a first record of heart failure (index date) between 2006 and 2015. Hypokalaemia and hyperkalaemia episodes were defined as the number of serum potassium measurements exceeding each threshold (<3.5, ≥5.0, ≥5.5, and ≥6.0 mmol/L), without such a measurement in the preceding 7 days. Risk equations developed using Poisson generalized estimating equations were utilized to estimate adjusted incident rate ratios (IRRs) relating serum potassium and clinical outcomes (death, major adverse cardiac event, and RAASi discontinuation). Among 21,334 eligible heart failure patients, 1969 (9.2%), 7648 (35.9%), 2725 (12.8%), and 763 (3.6%) experienced episodes of serum potassium <3.5, ≥5.0, ≥5.5, and ≥6.0 mmol/L, respectively. The adjusted IRRs for mortality exhibited a U‐shaped association pattern with serum potassium. Relative to the reference category (4.5 to <5.0 mmol/L), adjusted IRRs for mortality were estimated as 1.98 (95% confidence interval: 1.69–2.33), 1.23 (1.12–1.36), 1.35 (1.14–1.60), and 3.02 (2.28–4.02), for patients with serum potassium <3.5, ≥5.0 to <5.5, ≥5.5 to <6.0, and ≥6.0 mmol/L, respectively. The adjusted IRRs for major adverse cardiac events demonstrated a non‐statistically significant relationship with serum potassium. Discontinuation of RAASi therapy exhibited a J‐shaped trend in association with serum potassium. Compared with the reference category (4.5 to <5.0 mmol/L), adjusted IRRs were estimated as 1.07 (0.89–1.28) in patients with serum potassium <3.5 mmol/L, increasing to 1.32 (1.14–1.53) and 2.19 (1.63–2.95) among those with serum potassium ≥5.5 to <6.0 and ≥6.0 mmol/L, respectively. Conclusions In UK patients with new onset heart failure, both hypokalaemia and hyperkalaemia were associated with increased mortality risk, and hyperkalaemia was associated with increased likelihood of RAASi discontinuation. Our results demonstrate the potential importance of serum potassium monitoring for heart failure outcomes and management.

Generalized Mixed Modeling in Massive Electronic Health Record Databases: What is a Healthy Serum Potassium?

“… This lack of precision limits rational use of both potassium replacement in patients with low K + (hypokalemia) and potassium binding drugs in those with elevated K + (hyperkalemia). Existing and emerging therapies for hypertension [19], congestive heart failure [20][21][22] and therapies for diabetic kidney disease [23,24], require the use of drugs e.g. the mineralocorticoid receptor antagonists that will variably elevate the potassium level [25].…”

Hyperkalemia in heart failure: current treatment and new therapeutic perspectives

“…Use of MRA can bring with it a risk of hyperkalemia but, as demonstrated in the RALES trial (Juurlink et al, 2004;Pitt et al, 1999), which tested the use of spironolactone in HF, there is a benefit in terms of mortality when K + levels remain ≤ 5.5 mml/L. Data from a retrospective observational study conducted in the U.K. on new onset HF patients suggest that not only hyperkalemia brings an increased mortality risk, but is also correlated with a greater probability of RAASi suspension (Linde et al, 2019). Similarly, it has been recently seen that in the context of non-dialysis chronic kidney disease, hyperkalemia generates a greater probability of evolution toward end-stage forms, particularly when associated with RAASi non-use or discontinuation, while it does not increase mortality (Provenzano et al, 2018).…”

Frequency and clinical impact of hyperkalaemia within a large, modern, real‐world heart failure population

“…HK may lead to potentially lethal arrhythmias or to discontinuation of RAASi's, potentially diminishing their clinical benefits. 4 Heart failure patients are particularly susceptible to HK from HF-associated reductions in renal blood flow, as well as the aforementioned confounding co-morbidities and RAASi use. In 2013, an estimated 3.7 million US adults had HK, and prevalence has increased since 2010.…”

“…Renin‐angiotensin‐aldosterone system inhibitors (RAASi's) are common treatments for these co‐morbidities and may increase HK risk. HK may lead to potentially lethal arrhythmias or to discontinuation of RAASi's, potentially diminishing their clinical benefits 4 …”