Horizon Scanning Research May 2015 & Intelligence Centre

Patiromer for hyperkalaemia – first line

SUMMARY NIHR HSRIC ID: 6958

Patiromer is intended for the treatment of acute and/or chronic hyperkalaemia in patients with chronic disease, type 2 diabetes or chronic heart failure. If licensed, patiromer will offer a novel treatment option This briefing is for hyperkalaemia in this patient group who currently have few well-tolerated based on effective therapies available. Patiromer is a non-absorbed cation-exchange information polymer that binds potassium predominantly in the lumen of the colon where available at the time potassium is the most abundant cation. Patiromer does not currently have of research and a Marketing Authorisation in the EU for any indication. limited literature search. It is not The incidence of hyperkalaemia varies between 1.1% and 10% of hospital intended to be a patients, of which 77% of cases are thought to be due to renal failure, 63% to definitive statement prescribed drugs, and 49% to hyperglycaemia. Hyperkalaemia is the reason for emergency haemodialysis in 24% of haemodialysis patients and accounts on the safety, for 3-5% of deaths in this patient group. In 2013-14, there were 7,214 efficacy or hospital admissions for hyperkalaemia in England, resulting in 20,725 bed effectiveness of the days and 9,942 finished consultant episodes. health technology covered and should There is limited good quality evidence on the role of drug treatment in not be used for hyperkalaemia. Aside from reducing potassium intake, treatment options commercial largely focus on reducing cardiac cell membrane excitability, shifting of purposes or potassium from the extracellular to the intracellular domain and reducing total commissioning body potassium. Patiromer has completed a phase III comparing without additional its effect on serum potassium against treatment with placebo. information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] m.ac.uk Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Hyperkalaemia: acute or chronic; in patients with not yet receiving dialysis, type 2 diabetes or heart failure – first line (in addition to intravenous treatment options in acute hyperkalaemia).

TECHNOLOGY

DESCRIPTION

Patiromer (ILY-105, RLY5016) is a non-absorbed cation-exchange polymer that binds potassium predominantly in the lumen of the colon where potassium is the most abundant cation. This increases faecal potassium , leading to removal of potassium from the body and lowering of serum potassium levels in patients with hyperkalaemia. Patiromer consists of uniformly sized spherical beads of a salt formulated with a proprietary polymer, optimised to minimise gastrointestinal side effects and enhance palatability. Patiromer is intended for the treatment of acute and/or chronic hyperkalaemia in patients with chronic kidney disease (CKD) not yet receiving dialysis, type 2 diabetes or heart failure (HF).

Patiromer is administered orally as a powder mixed with water. The proposed starting doses of patiromer are 8.4g or 16.8g, based on serum potassium level, taken once daily with food; doses may be titrated up or down as required.

Patiromer does not currently have Marketing Authorisation in the EU for any indication.

INNOVATION and/or ADVANTAGES

If licensed, patiromer will offer a novel treatment option for hyperkalaemia in patients with CKD, diabetes or chronic HF, who currently have few well-tolerated effective therapies available.

DEVELOPER

Relypsa.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

An abnormally high serum potassium level is termed hyperkalaemia1. Extracellular potassium is tightly maintained between 3.5 and 5.0mmol/L by a complex system of potassium excretion and consumption2,3. Levels above 7mmol/L can cause significant haemodynamic and neurological consequences, while levels over 8mmol/L cause respiratory paralysis and cardiac arrest, which is rapidly fatal2.

2 Horizon Scanning Research & Intelligence Centre

Hyperkalaemia can cause a rapid reduction in resting membrane potential which can lead to increased cardiac depolarisation and muscle excitability, which in turn leads to electrocardiographic (ECG) changes4. The risk of arrhythmias increases with levels of potassium greater than 6.5mmol/L; even small increases of potassium above this level can lead to rapid progression from peaked T waves on ECG to ventricular fibrillation or asystole4.

Only two percent of total body potassium is found in the extracellular domain, while 95% of potassium is present in the intracellular domain3. In a 70kg male, this equates to about 59mmol/L of potassium in the extracellular domain3. On average, the daily intake of potassium through diet is about 70-100mmol/L5, but can be up to 200mmol/L, so the body removes extracellular potassium quickly to avoid hyperkalaemia3. Excretion of potassium takes place mainly via the kidneys, while about 5-10% is excreted in the digestive system and through sweat2,3.

Hyperkalaemia is predominantly caused by kidney failure, drugs or disorders that inhibit the renin-angiotensin-aldosterone system, deficiency or direct tissue trauma1,2,6; the majority of cases of hyperkalaemia are due to patients prescribed angiotensin converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) in conjunction with spironolactone with pre-existing or new renal impairment6. Most other cases occur because of potassium supplementation and prescription of potassium sparing drugs or diuretics6, such as trimethoprim, spironolactone and epleronone5. The condition can occur in both hospitalised patients and outpatients1. Symptoms of hyperkalaemia can include muscle weakness, fatigue, distal paraesthesia, respiratory depression and cardiac arrhythmias1,2.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • NHS England. 2013/14 NHS Standard Contract for Ex-vivo Partial Nephrectomy Service (Adult). A06/S(HSS)b. • NHS England. 2013/14 NHS Standard Contract for Renal Dialysis: Hospital and Satellite (Adult). A06/S/a. • NHS England. 2013/14 NHS Standard Contract for Renal Dialysis: Home (Adult). A06/S/b. • NHS England. 2013/14 NHS Standard Contract for Renal Dialysis: Peritoneal (Adult). A06/S/c. • NHS England. 2013/14 NHS Standard Contract for Acute Kidney Injury (Adult). A06/S/d. • NHS England. 2013/14 NHS Standard Contract for Renal Assessment (Adult). A06/S/e.

CLINICAL NEED and BURDEN OF DISEASE

Hyperkalaemia usually occurs in patients with acute or chronic renal failure4. In 2011-12, the recorded prevalence of chronic kidney disease (CKD) among those aged 18 years and over was 4.3% in England; an estimated 1.9 million people7. However, the underlying prevalence of stage 3-5 CKD in England has been estimated at 6.8%, which equates to about three million adults7.

The incidence of hyperkalaemia varies between 1.1% and 10% of hospital patients4,8, of which 77% of cases are thought to be due to renal failure, 63% to prescribed drugs, and 49% to hyperglycaemia, although in clinical practice there may be a combination of factors contributing to the disease4. Renin-angiotensin-aldosterone blocking drugs have been particularly implicated in the occurrence of hyperkalaemia; it may occur in as many as 10% of outpatients within a year of starting treatment, and is the underlying cause in 10-25%5 of patients admitted to hospital for hyperkalaemia4. Clinically significant hyperkalaemia is

3 Horizon Scanning Research & Intelligence Centre

present in 5-10% of patients requiring regular haemodialysis (although this is more common when there is a long gap between dialysis)5 and has been reported in 10% of pre-dialysis samples in patients with end-stage renal disease4. Hyperkalaemia is the reason for emergency haemodialysis in 24% of haemodialysis patients and accounts for 3-5% of deaths in this patient group4.

In 2013-14, there were 7,214 hospital admissions for hyperkalaemia (ICD-10 E87.5) in England, resulting in 20,725 bed days and 9,942 finished consultant episodes9. In 2013, there were 19 deaths registered, in England and Wales due to hyperkalaemia; 12 males and 7 females10. However, these numbers underestimate the size of the problem as many patients who are reported as dying from sudden unexpected cardiac death may have been affected by hyperkalaemia5.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE clinical guideline. Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care (CG182). July 2014. • NICE clinical guideline. Intravenous fluid therapy in adults in hospital (CG174). December 2013. • NICE clinical guideline. Acute kidney injury: Prevention, detection and management of acute kidney injury up to the point of renal replacement therapy (CG169). August 2013. • NICE clinical guideline. Hypertension: Clinical management of primary hypertension in adults (CG127). August 2011.

• NICE quality standard. Acute kidney injury (QS76). December 2014. • NICE quality standard. Renal replacement therapy services (QS72). November 2014. • NICE quality standard. Intravenous fluid therapy in adults in hospital (QS66). August 2014. • NICE quality standard. Chronic kidney disease (QS5). March 2011.

Other Guidance

• The Renal Association. Treatment of Acute Hyperkalaemia in Adults. 20144. • Nottingham University Hospitals. Guideline for the Management of Acute Hyperkalaemia in Adults. 201311. • Scottish Intercollegiate Guidelines Network. Diagnosis and Management of Chronic Kidney Disease (103). 200812. • Clinical Resource Efficiency Support Team (CREST). Guidelines for the treatment of hyperkalaemia in adults. 20056.

CURRENT TREATMENT OPTIONS

There is controversy about the role of drug treatment in hyperkalaemia due to few or no high quality clinical trials on which to base recommendations, which results in clinical inconsistencies4. When pseudohyperkalaemia has been ruled out, increased potassium intake should be stopped; this includes food/drink and potassium supplements (intravenous and oral)4,6,11. Significant acute hyperkalaemia may be managed by the following4,6,11: • Reduction in cardiac cell membrane excitability:

4 Horizon Scanning Research & Intelligence Centre

o Calcium gluconate should be given to protect the heart although it does not decrease the serum potassium levels. • Shifting of potassium from the extracellular to the intracellular domain: o Administration of rapid acting insulin will reduce serum potassium by 0.65- 1.0mmol/L. To avoid hypoglycaemia, 10-50% should be given first5. o Sodium bicarbonate is not recommended as there is little support for its use and should only be given if the pH is <7.2. o Nebulised salbutamol reduces serum potassium by 0.62-0.8mmol/L, but response is not always consistent and should be avoided in patients with ischaemic heart disease. • Reduction in total body potassium: o Increase patient hydration with fluids via oral or intravenous route although there is little evidence to support this practice in hyperkalaemia associated with acute kidney injury. o Ion-exchange resins, such as resins (e.g. calcium resonium) are given to remove serum potassium. o Dialysis is required for patients not responding to the above treatments and for patients that are on long-term dialysis or have advanced CKD.

EFFICACY and SAFETY

Trial NCT01810939, RLY5016- NCT01371747, RLY5016- RLY5016-103; patiromer; 301, 2012-001956-20, 205, 2011-000165-12, phase I. OPAL-HK; patiromer vs AMETHYST-DN; patiromer placebo; phase III. with losartan vs patiromer with current ACEi and/or ARB, and spironolactone; phase II. Sponsor Relypsa Inc. Relypsa Inc. Relypsa Inc. Status Published. Published in abstract. Published in abstract. Source of Publication13, trial Poster15, trial registry16, Poster17, manufacturer. information registry14, manufacturer. manufacturer. Location EU (not UK), USA, EU (not UK), Georgia and Georgia and Bulgaria. Georgia, Serbia and Serbia. Ukraine. Design Randomised, placebo- Randomised. Non-randomised. controlled. Participants n=243; aged 18-80 years; n=304; aged 30-80 years; n=25; aged 18-80 years; hyperkalaemia, CKD, and CKD with hyperkalaemia Part A: CKD stage 3a, 3b type 2 diabetes, who were defined as eGFR 15 to <90 2 or 4; hyperkalaemia receiving ACEi and/or ARB mL/min/1.73m ; serum defined as serum drugs with or without potassium 5.5-6.2mmol/L potassium 5.1 to spironolactone at screening (diet run-in <6.5mmolL; taking an entry) and 5.5-<6.5mmol/L angiotensin converting at baseline (treatment enzyme inhibitor (ACEi), initiation); on a stable dose angiotensin II receptor of ≥1 RAASi for 28 days blockers (ARB) or prior to screening. aldosterone antagonist (AA).

Part B: Serum potassium levels of 5.5 to <6.5mmol/L at part A baseline and 3.8 to <5.1mmol/L at the end

5 Horizon Scanning Research & Intelligence Centre

of Part A week 4 and on patiromer and renin- angiotensin-aldosterone system inhibitors (RAASi). Schedule Part A: patiromer given Stratum 1: subjects with Eligible subjects received 4 with meals at an initial entry serum potassium > doses of patiromer over a dose of: 8.4g/day (4.2g 5.0 to 5.5mmol/L were 34 hour period. The first twice a day) in subjects randomised to starting dose of 8.4g patiromer was with baseline serum doses of 8.4, 16.8, or administered with the potassium 5.1 to < 25.2g/day patiromer (taken morning meal on the first 5.5mmol/L; or in equally divided doses treatment day followed by 16.8g/day (8.4g twice a twice a day) for 52 weeks 3 more doses of 8.4g day) in subjects with patiromer each with meals baseline serum potassium Stratum 2: subjects with over a course of 2 days at 5.5 to < 6.5mmol/L for 4 entry serum potassium > 10, 24 and 34 hours after weeks. 5.5 to < 6.0mmol/L were the initial dose, Dose titrated based on randomised to starting respectively. subject response. doses of 16.8, 25.2, or Part B: subjects 33.6g/day patiromer for 52 randomised to continue on weeks patiromer or stop patiromer and receive placebo for 8 Dose titrated based on weeks. subject response Follow-up Active treatment period up Active treatment period 52 Active treatment period 2 to 12 weeks (part A 4 weeks, follow-up period 56 days, follow-up period 6 weeks, part B 8 weeks) weeks. days. and follow-up period up to 14 weeks. Primary Part A: change from Change from baseline in Change from baseline in outcome/s baseline in serum serum potassium at serum potassium during potassium week 4 or prior to dose the 48 hours following the Part B: between group titration (if occurs before first dose of patiromer. difference in the change week 4). from Part B baseline in serum potassium. Secondary Part A: proportion with Proportion of patients Change from baseline in outcome/s serum potassium levels in maintaining starting serum potassium levels for the range 3.8 to patiromer dose at week 4 each of two baseline <5.1mmol/L; and 8; mean time to first potassium subgroups (5.5 Part B: recurrence of patiromer titration; mean to 6.0mmol/L versus > 6.0 hyperkalaemia defined as number of patiromer to < 6.5mmol/L), where the serum potassium titrations; proportion of number of subjects in the ≥5.5mmol/L or serum patients who maintain subgroup was ≥ 5. potassium ≥5.1mmol/L. serum potassium at 3.5 to 5.5mmol/L or 4.0 to 5.0mmol/L; mean change in blood pressure; mean change in urine albumin to creatinine ratio (ACR); proportion of patients with ≥35% reduction in urine ACR; proportion of patients with urine ACR ≥500mg/g at screening who achieve urine ACR <500mg/g at week 4 and 8; safety.

6 Horizon Scanning Research & Intelligence Centre

Key results Part A: mean change Mean serum potassium The study reached its (±SE) in serum potassium reduction after week 4 primary endpoint in which levels from baseline to (±SE): an early onset of week 4, -1.01±0.03mmol/L Stratum 1, -0.47±0.601 potassium lowering action (95%CI -1.07 to -0.95) p<0.001; was observed. From a p<0.001; number of Stratum 2, -0.92±0.748 mean (±SE) baseline participants with serum p<0.001. serum potassium of potassium levels in target Mean reductions from 5.93±0.04mmol/L, a range at week 4, 76% baseline to day 3 (±SD): significant reduction (95%CI 70 to 81). Mild hyperkalaemia: (p=0.002) in mean serum Part B: for patiromer and -0.29±0.42mmol/L, potassium occurred 7 hrs placebo groups, p<0.001; moderate after the first dose of respectively: median hyperkalaemia: patiromer. change in serum -0.59±0.45mmol/L, Significant reductions potassium from start of p<0.001. occurred in each of the Part B to week 4, baseline potassium 0.72mmol/L and 0mmol/L, Mean serum potassium subgroups. between group difference was ≤5.0mmol/L at day 3 0.72mmol/L (95%CI 0.46 (mild hyperkalaemia) and to 0.99), p<0.001; number week 1 (moderate of participants with at least hyperkalaemia) and was one potassium value of maintained for 52 weeks. ≥5.5mmol/L, 15% (95%CI 6 to 24) and 60% (95%CI % of patients with serum 47 to 74), p<0.001; potassium 3.8-5.0mmol/L number of participants with at visits between weeks at least one potassium 12-52 ranged from 77-95% value of ≥5.1mmol/L, 91% for the overall population (95%CI 83 to 99) and 43% (mild and moderate (95%CI 30 to 56), p<0.001. hyperkalaemia patients combined). Adverse Part A: number of The most common AEs Treatment with patiromer effects participants reporting ≥1 (occurred in ≥5.0% of for 2 days was well (AEs) AE, 47%; most common patients in either baseline tolerated, with no deaths, (occurred in ≥3%) AEs, hyperkalaemia group) or serious or severe , diarrhoea, during the 52-week study treatment-emergent hypomagnesaemia, were hypomagnesaemia, adverse events (TEAEs) nausea, anaemia, chronic worsening of hypertension, reported, and no TEAEs renal failure; number of worsening of CKD, leading to discontinuation. participants reporting ≥1 diarrhoea, constipation, TEAEs occurred in 28% of serious AE, 1%. hypoglycaemia; number of subjects, with mild Part B: for patiromer and participants reporting ≥1 constipation (8%) and mild placebo, respectively: serious AE in the mild hypotension (8%) being number of participants hyperkalaemia group was the most frequently reporting ≥1 AE, 47% and 13% and 18% in the reported events. 50%; most common moderate hyperkalaemia (occurred in ≥4%) AEs, group. headache, supraventricular extrasystoles, constipation, Mean change in serum diarrhoea, nausea; number from baseline of participants reporting ≥1 to week 52 was -0.09 to serious AE, 0% and 2%. -0.14mg/dL with 13 (4%) patients having serum magnesium <1.2mg/dL (none <1.0 mg/dL).

Mean eGFR and albuminuria overall (±SE) were

7 Horizon Scanning Research & Intelligence Centre

42.5±17.7mL/min/1.73m2 and 995±1641mg/g, respectively, at baseline. Changes from baseline to week 52 were: eGFR, +1.8±16.3mL/min/1.72m2; albuminuria: -27±1422mg/g.

No AEs of worsening of CKD were considered by the principal investigator as being related to study drug

Trial NCT01130597, RLY5016-204; patiromer NCT00868439, RLY-5016-202, PEARL- and spironolactone; phase II. HF; patiromer or placebo, both with spironolactone; phase II. Sponsor Relypsa Inc. Relypsa Inc. Status Complete, but unpublished. Published. Source of Trial registry18, manufacturer. Publication19, trial registry20. information Location Georgia and Slovenia. EU (not UK), USA, Georgia, Russia and Ukraine. Design Uncontrolled, single arm. Randomised, placebo-controlled. Participants n=63; aged 18 years and older; chronic n=120; aged 18 years and older; history HF; clinically indicated to receive of chronic HF; an indication to initiate spironolactone; serum potassium 4.3 to spironolactone therapy; serum potassium 5.1mmol/L; CKD (eGFR concentration of 4.3-5.1mmol/L at <60mL/min/1.73m2); on at least one HF screening; must have either (i) CKD with therapy (ACEi, ARB or beta-blockers). estimated glomerular filtration rate (eGFR) <60ml/min and receiving one or more HF therapies (ACEi, ARBs, beta- blockers), or (ii) documented history of hyperkalaemia that led to discontinuation of therapy with an AA, ACEi, ARB or beta- blocker in 6 months prior to baseline visit. Schedule Patiromer 16.8g/day (8.4g twice a day) Patients received patiromer 15mg or starting dose; up- or down-titrated by 8.4 placebo, both oral twice daily, and mixed g/day to maintain serum potassium with water or low potassium food, and between 4.0 and 5.1mmol/L; and both in combination with spironolactone spironolactone 25mg/day starting dose 25mg daily. Spironolactone increased increased to 50mg/day at first occurrence after 2 weeks to 50mg a day if potassium of potassium value ≤ 5.1mmol/L after day serum levels >3.5 to ≤5.1mmol/L, or kept 3. at 25mg if potassium serum levels >5.1 to ≤5.5mmol/L. Patients discontinued from treatment if potassium serum levels ≤3.5 or >5.5mmol/L. Follow-up Active treatment period 8 weeks, follow- Active treatment and follow-up period 4 up period 64 days. weeks. Primary Proportion of patients with serum Mean change in serum potassium. outcome/s potassium 3.5 to 5.5mmol/L. Secondary Effect of patiromer on serum potassium in Proportion of patients: with serum outcome/s HF subjects with CKD; safety and potassium >5.5mmol/L at any point and tolerability. whose spironolactone dose could be increased to 50mg/day; safety.

8 Horizon Scanning Research & Intelligence Centre

Key results Serum potassium levels were controlled For patiromer and placebo groups, in 90.5% (95% CI 80.4% to 96.4%) of respectively: difference between groups in subjects at the end of the 8-week study mean change in serum potassium, - treatment period. 0.45mmol/L, p<0.001; % of patients with serum potassium >5.5mmol/L, 7% and 25%, p=0.015; % of patients with spironolactone dose increased, 91% and 74%, p=0.019. Adverse A total of 36 (57.1%) subjects had at least For patiromer and placebo, respectively: effects one AE. Gastrointestinal disorders were AEs 54% and 31%; serious AEs 4% in (AEs) most frequently reported (10 [15.9%] both groups, none of which were subjects), the most frequently reported considered to be related to treatment. AEs were abdominal discomfort (4 [6.3%] subjects), and flatulence, headache, hypertension, renal failure acute and renal impairment (3 [4.8%] subjects each).

ESTIMATED COST and IMPACT

COST

The cost of patiromer is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other: the absolute reduction in potassium is  No impact identified difficult to determine across all studies, but is likely to be moderate; many gastrointestinal side-effects – exchange resins reduce potassium by inducing nausea and reducing potassium intake with a negative impact on nutritiona. The company suggest patiromer may be particularly useful in patients with advanced CKD stages 3b or worse, including those with diabetes, hypertension or HF where there is widespread use of ARBs, ACEi or aldosterone antagonists. Patiromer may be the preferred choice in patients susceptible to fluid overload who cannot tolerate even small increases in sodium load.

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services: has the potential to decrease emergency department visits in patients with advanced CKD.

 Re-organisation of existing services  Need for new services

 Other:  None identified

a Expert personal opinion.

9 Horizon Scanning Research & Intelligence Centre

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs: oral treatment option. Patiromer may allow for the continuation and/or maximal dosing of ACEi and/or ARB – therapies which have demonstrated delays in the onset of end- stage renal disease and dialysis.

 Other: uncertain unit cost compared to  None identified existing treatments

Other Issues

 Clinical uncertainty or other research question  None identified identifiedb: clinical necessity for patiromer is limited; differentiation of a biochemical abnormality (serum potassium >5mmol/L) vs clinical problem (the point at which the potassium level requires treatment); current guidance on when to treat is difficult to reconcile and it is this uncertainty which would provide a market for this product, much more so than actual clinical need; clinicians will use patiromer, but principally this will be limited to those patients who are risk averse.

REFERENCES

1 Batterink J, Cessford, TA and Taylor RA. Pharmacological interventions for treating acute hyperkalaemia in adults. The Cochrane Library 2013; DOI: 10.1002/14651858.CD010344. 2 Lederer E. . Medscape April 2014. http://emedicine.medscape.com/article/240903- overview Accessed 30 April 2015. 3 Parham WA, Mehdirad AA, and Fredman CS. Hyperkalaemia revisited. Texas Heart Institute Journal 2006;33(1):40-47. 4 The Renal Association. Treatment of Acute Hyperkalaemia in Adults. March 2014. http://www.renal.org/guidelines/joint-guidelines/treatment-of-acute-hyperkalaemia-in- adults#sthash.EAbz9fkT.dpbs Accessed 30 April 2015. 5 NIHR Horizon Scanning Centre. Sodium Zirconium cyclosilicate for hyperkalaemia – first line. University of Birmingham, March 2015. http://www.hsc.nihr.ac.uk/ 6 Clinical Resource Efficiency Support Team. Guidelines for the treatment of hyperkalaemia in adults. August 2005. http://www.dhsspsni.gov.uk/hyperkalaemia-booklet.pdf Accessed 30 April 2015. 7 National Institute for Health and Care Excellence. Costing statement: Chronic kidney disease implementing the NICE guideline on chronic kidney disease (CG182). London: NICE; July 2014. 8 Rajan T, Widmer N, Kim H et al. A quality improvement project to enhance the management of hyperkalemia in hospitalized patients. British Colombia Medical Journal 2012;54(1)29-33. 9 Health and Social Care Information Centre, Hospital Episode Statistics for England. Inpatient statistics, 2013-14. www.hscic.gov.uk 10 Office for National Statistics. Deaths Registered in England and Wales (series DR). 2013. http://www.ons.gov.uk/ 11 Nottingham University Hospitals. Guideline for the management of acute hyperkalaemia in adults. Nottingham: NUH; April 2013. 12 Scottish Intercollegiate Guidelines Network. Diagnosis and management of chronic kidney disease. National Clinical Guideline 103. Edinburgh: SIGN; June 2008.

b Expert personal opinion.

10 Horizon Scanning Research & Intelligence Centre

13 Weir MR, Barkis GL, Bushinsky DA et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. The New England Journal of Medicine 2015;372(2):211- 221. 14 ClinicalTrials.gov. A two-part, single-blind, phase 3 study evaluating the efficacy and safety of patiromer for the treatment of hyperkalemia (OPAL-HK). https://clinicaltrials.gov/ct2/show/NCT01810939?term=NCT01810939&rank=1 Accessed 30 April 2015. 15 Pitt B, Bushinsky D, Garza D et al. 1-year safety and efficacy of patiromer for hyperkalemia in heart failure patients with chronic kidney disease on renin-angiotensin-aldosterone system inhibitors. American College of Cardiology. March 2015. 1145-184. Poster. 16 ClinicalTrials.gov. RLY5016 in the treatment of hyperkalemia in patients with hypertension and diabetic nephropathy (AMETHYST-DN). https://www.clinicaltrials.gov/ct2/show/NCT01371747?term=rly-5016&rank=1&submit_fld_opt= Accessed 5 May 2015. 17 Bushinsky DA, Bakris GL, Williams G et al. Patiromer induced a rapid and sustained K+ lowering throughout the dosing period in CKD patients with hyperkalaemia. American Society of Nephrology Kidney Week. November 2014. SA-PO153. 18 ClinicalTrials.gov. Evaluation of RLY5016 titration in heart failure patients with chronic kidney disease. https://www.clinicaltrials.gov/ct2/show/NCT01130597?term=NCT01130597&rank=1 Accessed 5 May 2015. 19 Pitt B, Anker SD, Bushinsky DA et al. Evaluation of the efficacy and safety of RLY5016, a polymeric , in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. European Heart Journal 2011;32:820-828. 20 ClinicalTrials.gov. Evaluation of RLY5016 in heart failure patients (PEARL-HF). https://www.clinicaltrials.gov/ct2/show/study/NCT00868439?term=rly-5016&rank=2 Accessed 5 May 2015.

11