Dose reduction or discontinuation of renin-angiotensinaldosterone system inhibitor (RAASI) therapy in the setting of hyperkalaemia remains common despite expert recommendations against this as a routine practice. At a recent summit organized by AstraZeneca and moderated by Professor Daniel Tak-Mao Chan, Chair Professor and Chief of Nephrology at the University of Hong Kong (HKU), a multidisciplinary panel of local experts identified key issues related to suboptimal RAASI therapy and hyperkalaemia management, and proposed strategies to avoid inappropriate RAASI dose reduction or discontinuation especially in cardiorenal patients.
RAASIs and the challenges of hyperkalaemia
The benefits of continued therapy with maximally tolerated RAASI dose in
protecting both cardiovascular and renal systems in at-risk patients are well established.“However, RAASIs also reduce
potassium excretion, increasing the risk of hyperkalaemia in an already vulnerable
population,” said meeting chair, Professor
Andrew Coats of the University of Warwick in Warwick, UK.
“Hyperkalaemia is not an acute complication but a predictable one
that should be managed proactively,” added meeting co-chair, Dr Andrew Frankel
of the Impe rial College Healthcare National Health Service Trust in London, UK. [J
Manag Care Pharm 2007;13:9-20; J Am Coll Cardiol 2014;63:853-871;
Eur Heart J Cardiovasc Pharmacother 2015;1:126-131;
J Am Heart Assoc 2019;8:e014500]
Hyperkalaemia (defined as serum potassium level ≥5.0 mmol/L) has been associated with increased all-cause mortality in patients with heart failure (HF), chronic kidney disease (CKD) or diabetes mellitus (DM). In real-world clinical practice, hyperkalaemia detection in patients on RAASIs is frequently followed by RAASI dose reduction or discontinuation immediately without fully utilizing other means of potassium management, despite guideline recommendations and robust clinical evidence supporting the cardiorenal benefits of continued therapy and highlighting the potential adverse outcomes of RAASI discontinuation. [Am J Nephrol 2017;46:213-221;
Am J Manag Care 2015;21:S212-S220; Eur Heart J 2021;42:3599-3726;
J Am Coll Cardiol 2022;79:e263-e421; Kidney Int 2021;99:S1-S87;
Nephrology (Carlton)2020;25:12-45; Kidney Int 2020;98:S1-S115;
Diabetes Care 2022;45:S144-S174]
“RAASI dose reduction or discontinuation is not an innocent decision since this is linked with higher mortality rates vs continued treatment at maximally tolerated doses,” stressed Coats. In fact, RAASI dose reduction or discontinuation was associated with more than doubling of mortality rates in patients with HF, DM or stage 3–4 CKD. [Am J Manag Care 2015;21:S212-S220]
“RAASI dose adjustments or discontinuation should only be considered in the event of life-threatening hyperkalaemia or as a last resort after all possible interventions to lower potassium levels have been exhausted [eg, dietary changes, adjustment of other concurrent medications, and use of diuretics, sodium bicarbonate or potassium binders],” added Frankel. [Kidney Int 2020;98:S1-S115;
Nephrology (Carlton) 2020;25:12-45]
In particular, the European Society of Cardiology’s guidelines for the diagnosis and treatment of acute and chronic HF proactively recommends the initiation of an approved potassium-lowering agent upon detection of potassium level >5.0 mmol/L. [Eur Heart J 2021;42:3599-3726]
While suboptimal RAASI therapy is commonly prescribed in clinical practice due to hyperkalaemia, an international Delphi consensus among more than 500 cardiorenal specialists showed general agreement that hyperkalaemia is a manageable side effect of RAASIs, and that RAASI de-escalation or discontinuation should be avoided until alternative hyperkalaemia management strategies have already been optimized. [Eur J Heart Fail 2022;doi:10.1002/ejhf.2612]
“Strategies to reinforce the importance of staying on guideline-recommended RAASI therapy in the setting of hyperkalaemia should be implemented,” Frankel suggested. In the PROMPT-HF trial, compared with usual care, the use of a real-time, targeted and tailored emergency health record–based alerting system for outpatients with HF and reduced ejection fraction led to significantly higher rates of guidelinedirected medical therapy [GDMT]. [J Am Coll Cardiol 2022;79:2203-2213]
Local perspectives on RAASI therapy and hyperkalaemia management: A multidisciplinary approach
Locally, the incidence rate of hyperkalaemia among patients receiving RAASIs is approximately
in the range of 25–30 percent, based on preliminary 2018–2021 data from
the Hong Kong West Cluster (n=14,206). “Importantly, follow-up data showed a significant 4-fold increase in 3-year mortality
rate among patients on RAASIs who experienced hyperkalaemia vs those who did
not [25.5 percent vs 6.2 percent; p<0.001], highlighting an urgent need to improve the
management of these high-risk patients,” noted Dr Desmond Yat-Hin Yap, Clinical
Associate Professor and Specialist in Nephrology at the Queen Mary Hospital, Hong
Kong. [Yap D, et al, unpublished]
The following is a summary of observations and suggestions from local experts in Emergency Medicine, Cardiology, Endocrinology, and Nephrology regarding RAASI therapy in the setting of hyperkalaemia.
Main obstacles to optimal RAASI therapy
In a multidisciplinary panel of 10 experts in Hong Kong, six doctors agreed
that RAASI treatment discontinuation after hyperkalaemia detection is an important
obstacle to optimal RAASI use. Three doctors noted that failure to reintroduce RAASI
therapy after its discontinuation due to hyperkalaemia
is also a key issue, while one doctor suggested that failure to escalate
RAASI dosing in the first place also contributes
to suboptimal RAASI therapy. (Table 1)
“Hyperkalaemia at 5.5–6.0 mmol/L is not infrequent among patients with DM,”
shared Professor Kathryn Choon-Beng Tan, Chief of Endocrinology, Diabetes &
Metabolism at HKU. According to the panel, despite guideline-recommended
management, RAASI dose reduction or discontinuation is common and likely
over-used in clinical practice, specifically
among junior colleagues. Also, despite resolution of hyperkalaemia, RAASI therapy
is often not reintroduced or remains at a suboptimal dose.
“Some clinicians may hesitate to aim for maximal RAASI dosing to avoid the risk of hyperkalaemia. In private practice, it is easier to intervene more promptly than in a busy public clinic, for example with novel potassium-lowering agents such as sodium zirconium cyclosilicate [SZC], which may not be readily accessible in public hospitals,” noted Dr David Chung-Wah Siu, Specialist in Cardiology in private practice.
The panel added that consideration of treatment cost is a significant issue, even in the private sector, because patients requiring RAASI therapy often have multiple comorbidities and are likely receiving other medications. Polypharmacy may complicate hyperkalaemia management and increase treatment costs, especially since long-term treatment may be necessary.
The experts also noted that access to and availability of effective hyperkalaemia treatments affect optimal RAASI therapy, especially in the emergency care setting. “Readily available potassium binders such as sodium polystyrene sulfonate have a relatively slow onset of action and may not be useful in the emergency setting. Novel potassium binders such as SZC are better tolerated and have faster onset of action, but are not yet readily available at our hospital pharmacy,” said Dr Wing-Fai Pang, Specialist in Nephrology at the Prince of Wales Hospital. [Mayo Clin Proc 2020;95:339-354]
“At the emergency room, we often encounter patients with severe hyperkalaemia [eg, >6.00 mmol/L] who require prompt treatment,” noted Dr Matthew Sik-Hon Tsui, Consultant Specialist in Emergency Medicine at Queen Mary Hospital. “Careful adherence to GDMT helps us avoid inappropriate discontinuation of beneficial concurrent medications such as RAASIs. Along with sodium bicarbonate to correct metabolic acidosis, SZC has become a useful adjunct for patients requiring acute hyperkalaemia management in Accident and Emergency Departments.”
Solutions to optimize RAASI therapy and hyperkalaemia management
Experts in the discussion panel agreed that a multidisciplinary approach
is needed to ensure consistent implementation of guideline-supported RAASI
therapy and avoid inappropriate dose reduction or discontinuation in the setting
of hyperkalaemia. This implies multispecialty coordination that goes beyond
communication between individual clinicians, but one that includes all parties
involved in patient management, such as nurses, pharmacists and the patients
Solutions proposed to address suboptimal RAASI therapy in the context of hyperkalaemia management are roughly categorized under strategies to reinforce patient education, use of recommended pharmacotherapeutic approaches to treat or prevent hyperkalaemia, and proactive monitoring of potassium level. Table 2 summarizes these proposed measures, and the anticipated challenges as well as suggested strategies to overcome these potential barriers.
“[In terms of patient education,] we need to be more careful with choice of words when discussing hyperkalaemia with patients. We must avoid branding RAASIs as medicines that could lead to hyperkalaemia that ‘could kill’. Instead, one should remind patients about the life-saving benefits of continued RAASI therapy, and that hyperkalaemia is a known but manageable potential side effect,” stressed Dr Walter Wai- Chee Chen, Specialist in Cardiology in private practice.
For pharmacotherapeutic strategies to treat hyperkalaemia and reinforcement of regular potassium level monitoring, the panel stressed the importance of a multidisciplinary approach involving all relevant healthcare providers (ie, from physicians to pharmacists) to ensure consistent message and that management strategies are streamlined, standardized and applied across all points of care.
“These strategies may be incorporated in a locally based consensus or protocol on acute and chronic hyperkalaemia management during optimal RAASI therapy, which should be consistently cascaded to all healthcare professionals,” noted Chen.
Local experts from Hong Kong agree that inappropriate RAASI treatment discontinuation and failure to reintroduce therapy, and failure to optimize dosing, are obstacles to optimal RAASI use in the context of hyperkalaemia management. There is a need to reinforce guideline-directed hyperkalaemia management strategies to minimize their occurrence under circumstances that do not call for these actions. Overcoming these obstacles may be achieved through a multidisciplinary consensus to ensure consistent messaging and care implementation across all points of care.