Scenario:
To support the pre-approved use of sodium zirconium cyclosilicate (Lokelma) through the Non Formulary Request process in NHS Borders.
Background:
Hyperkalaemia (defined as a serum potassium of >5.5mmol/L) is a frequent complication of chronic kidney disease (CKD). Sodium zirconium cyclosilicate (ZS-9) is a novel cation exchange resin that binds potassium in the gut for excretion. ZS-9 is currently approved by the Scottish Medicines Consortium for the management of hyperkalaemia (serum potassium of >6mmol/L) in adult patients with CKD stage 3b to 5 and/or heart failure, who would otherwise need to down-titrate or discontinue renin angiotensin aldosterone system inhibitor (RAASi) to maintain a clinically acceptable serum potassium level (normokalaemia) (Scottish Medicines Consortium. Advice 2288).
Assessment:
Hyperkalaemia is also frequently encountered in patients with acute kidney injury (AKI) and patients with end-stage kidney disease on haemodialysis. In AKI, medical management of hyperkalaemia is an
appropriate first step but if this fails, dialysis is usually required. Conventional medical management of hyperkalaemia has a very limited role in patients established on renal replacement therapy (RRT) where the optimal treatment is dialysis. In both groups of patients however, there are situations where achieving normokalaemia might allow a safe temporary delay in dialysis until either vascular access is obtained or renal recovery occurs. A limited course of ZS-9 in selected patients in these situations may prevent unnecessary procedures and reduce morbidity associated with temporary central venous access and dialysis itself; also providing more patient centred care and will save money.
Advantages of ZS-9:
Reduces total body potassium by promoting gut K excretion. Oral administration as dissolvable granules is key strength. In addition, it works quickly, the potassium lowering effect can be seen as early as 4 hours after ingestion with peak effects by 24 hours. ZS-9 is better tolerated by patients than other potassium binders such as calcium resonium which greatly aids clinical efficacy.
Disadvantages of ZS-9:
Main reported adverse effects are mild constipation and hypokalaemia. Cost of new drug. Limited efficacy in AKI.
Alternatives to ZS-9:
Insulin – Shifts K into cells temporarily to hyperkalemia so is only a temporary holding measure. Requires IV administration, high risk of drug errors with several reports of iatrogenic overdose. Inherent risks of hypoglycaemia even when given with dextrose as is standard of care which means frequent blood glucose monitoring required. Frequent reports of patient harm from hypoglycaemia due following insulin and dextrose.
Salbutamol - Shifts K into cells temporarily to hyperkalemia so is only a temporary holding measure. Requires nebulised administration. Risk of triggering cardiac ischaemia as side effect of beta-adrenoceptor agonist induced tachycardia.
Calcium resonium – Binds potassium in the gut to promote gut K excretion. Oral or per-rectum administration Poorly tolerated by patients due to unpleasant taste. Frequently causes constipation even when given alongside laxatives leading to high rates of discontinuation and takes 24-48hrs to work.
Sodium bicarbonate – can promote urinary potassium loss and shift into cells. IV or oral administration. Contains a significant sodium load which can exacerbate salt and volume overload.
Can also cause hypocalcaemia.
Dialysis – requires central venous access with associated high costs, significant risks, patient discomfort and admission to critical care.
Recommendation:
We recommend the extended clinical use of sodium zirconium cyclosilicate (Lokelma) in the clinical scenarios outlined below. We suggest use of a limited course (typically no more than 7 days) of ZS-9 to control hyperkalaemia in:
1. Patients on renal replacement therapy with
- Serum potassium >5.5mmol/L
AND - No dialysis access due to access failure or removal (for instance due to catheter-associated infection)
AND - Require a ‘plastic free’ period to minimise risk of seeding infection
OR - Temporary dialysis catheter insertion is not feasible or desirable
AND - Definitive vascular access (permanent dialysis catheter) is planned
Real case example: A haemodialysis patient was admitted with a dialysis catheter-related bacteraemia. Antibiotics were started and the dialysis catheter removed. Potassium 24hrs after line removal was 5.7mmol/L. Typically dialysis would be required within the next 24hrs, necessitating insertion of temporary dialysis catheter which carries the risks of pain, arterial injury, pneumothorax and seeding infection. ZS-9 was started alongside fluid restriction and dietary advice. Potassium fell to <5.0mmol/L after 24hrs and remained under 6mmol/L until a new tunnelled catheter was inserted 6 days later. The patient was well throughout and was discharged to complete outpatient antibiotic treatment.
Dosage: 10g every 8hrs for 24hrs then 5g daily. Dose can be increased to 10g daily depending on clinical response.
Indicative cost: ~ £80 for 7 days treatment at suggested dosage.
2. Patients with AKI of any KDIGO stage with
- Serum potassium >6mmol/L despite appropriate medical management (insulin, salbutamol, sodium bicarbonate, culprit medication discontinuation, fluid resuscitation)
AND - No other urgent indication for dialysis (fluid overload, uraemia, acidosis etc) is present
AND - Renal recovery is expected to occur within a reasonable time frame (up to 72hrs)
AND/OR - Dialysis is inappropriate as determined by the responsible senior clinician
All criteria should be met. Use of ZS-9 in this circumstance has been approved by NICE (TA599) in Sept 2019.
Real case example: An elderly patient was admitted with AKI after a diarrhoeal illness whilst on several potentially contributory medications (ACEi, MRA, trimethoprim). Serum potassium was 6.8 mmol/L with oliguria despite repeated medical management. Calcium resonium was
poorly tolerated and declined. ZS-9 is started and potassium fell to under 6mmol/L. 72 hrs later, her urine output improved, renal function recovered, normokalaemia ensued and she was discharged.
Dosage: 10g every 8hrs for 72hrs then 5g daily. Dose can be increased to 10g daily depending on clinical response.
Indicative cost: ~£128 for 72hrs treatment at suggested dosage.
3. Patients with pre-dialysis CKD with
- Serum potassium >6mmol/L despite standard medical management (insulin, salbutamol, sodium bicarbonate, culprit medication discontinuation, fluid resuscitation)
AND - Pre-emptive living donor renal transplantation within 48-72 hrs
OR - Definitive dialysis access (permanent dialysis catheter) is planned within a reasonable time frame (for example 48-72hrs)
AND - Avoiding temporary dialysis catheter insertion is a highly desirable
Real case example: A patient was admitted the day before planned living donor renal transplantation. He has no dialysis access. His admission blood tests showed a further decline in renal function and a potassium of 6.2mmol/L. From an anaesthetic perspective his serum potassium has to be <6.0mmol/L prior to transplantation. Insulin & salbutamol therapy reduced serum potassium to 5.9 mmol/L but there was concern about potential rebound in serum potassium ahead of surgery so two doses of ZS-9 were given. Potassium 12 hours later is 4.7mmol/L and surgery proceeded as planned.
Dosage: 10g every 8hrs for 24hrs then 5g daily. Dose can be increased to 10g daily depending on clinical response.
Indicative cost: ~£50 for 48hrs treatment at suggested dosing
4. Patients on renal replacement therapy with
- An average pre-dialysis serum potassium 4.9 mmoL/L
AND - face a delay in usual scheduled dialysis session due to dialysis unit staffing issues due to COVID-19 pandemic or extreme adverse weather
OR - face a delay in usual scheduled dialysis session due to technical issues with delivery of dialysis (for example water or power supply failure)
Dosage: 10g every 8hrs for 24hrs then 5g daily. Dose can be increased to 10g daily depending on clinical response.
Indicative cost: ~£60 for 4days treatment at suggested dosing
Associated materials:
NHS Borders clinical guidelines