The benefits of Renin Angiotensin Aldosterone System Inhibitors (RAASi) in cardio-renal protection are well-established, and as such their use is recommended by both heart failure1–3 and chronic kidney disease (CKD)4 association guidelines. These guidelines recommend the highest-tolerated targeted doses of RAASi in order to replicate the positive clinical outcomes from clinical trials.1–4
For symptomatic patients with heart failure, guidelines recommend angiotensin-converting enzyme inhibitors (ACEi) at the highest-tolerated target doses, in addition to beta-blockers, based on existing clinical evidence. For patients who continue to remain symptomatic, additional treatment with mineral receptor antagonists are the preferred option. Angiotensin receptor blockers (ARBs) are recommended in situations where ACE inhibitors are not tolerated.1–3
CKD guidelines recommend RAAS inhibition (ACEi or ARBs) to slow the progression of CKD by controlling blood pressure and reducing proteinuria. RAAS inhibition (ACEi or ARBs) has been shown to be more effective at slowing decline in kidney function in patients with proteinuria than other drugs that lower blood pressure. Treating early diabetic kidney disease by lowering blood pressure can reduce kidney function decline by between 30-70%.4,5
The real world
Clinical trials, however, do not always accurately reflect the situation in everyday clinical practice. Analysis of real-world data suggests that patients with cardio-renal conditions (chronic kidney disease, heart failure, or diabetes) are less likely to receive the recommended dose of RAASi as suggested by guidelines, with over 50% of patients prescribed below the recommended dose.6
Why the low dosing?
The kidneys are the principal regulator of potassium balance. With normal renal function, 90% of dietary potassium is excreted by the kidneys to maintain homeostasis.7 As kidney function declines, the prevalence of hyperkalaemia increases, especially in moderate to advanced CKD, reflecting the critical role the kidney exerts in normal potassium balance.8 The importance of the RAAS in regulating potassium means that disturbance at any point along the system can result in an increased risk of hyperkalaemia.7
Risks of Hyperkalaemia
Hyperkalaemia is a serious, recurrent disorder with potentially lethal clinical consequences.9,10 Patients are often asymptomatic until sudden serious events that require emergency admission and hospitalizations, including arrhythmias such as ventricular fibrillation, or sudden death.9-11 Patients may present with muscle weakness, twitching, cramping or paralysis or ECG changes, although some may be entirely asymptomatic without ECG abnormalities.10,11
‘Patients who are known to derive the greatest benefit from these drugs are the same patients who are at highest risk of developing hyperkalaemia’. Epstein, 20166
The benefits of RAASi may be great, but do not outweigh the negative effects of hyperkalaemia.12,13 Accordingly, guidelines provide a series of recommendations in relation to the level of serum potassium, including dose reduction or cessation of RAASi treatment if serum potassium values exceed > 5.5 mEq/L, and cessation of RAASi therapy if hyperkalaemia (>6.0 mEq/L). 1–4
A retrospective analysis of 279 patients’ medical records, from a single-centre, found that hyperkalaemia was one of the main reasons for stopping RAASi therapy in CKD patients:
- 67% of patients discontinued RAASi therapy because of hyperkalaemia
- 14% of patients were not started on RAASi therapy because of hyperkalaemia9
These changes in RAASi therapy, however, simply shift the risk without removing it entirely; patients who discontinued therapy or received sub-maximum doses of RAASi have been shown to have worse outcomes than those on the recommended target dose.10 A recent prospective European study of heart failure patients reported that those prescribed less than the recommended RAASi dose experienced higher mortality rates than those on the optimal dose.11
To optimise the overall treatment benefits of RAASi for patients, there is an urgent need for long-term control of serum potassium levels in order to maintain RAASi use at recommended doses. However, until recently the treatment options were limited. Dietary restriction of potassium intake is difficult as many healthy foods are rich in potassium and contradicts the Dietary Approaches to Stop Hypertension (DASH) diet. The use of sodium polystyrene sulfonate and calcium polystyrene sulfonate for treatment of hyperkalaemic episodes is another option, however, patient compliance is poor and gastrointestinal side effects are quite common.14
Does the future look brighter?
On the horizon are two new potassium binders, sodium zirconium cyclosilicate and patiromer. Sodium zirconium cyclosilicate is a crystal which is highly selective for potassium, binding potassium throughout the gastrointestinal tract. Trials have shown sodium zirconium cyclosilicate to be effective at maintaining normokalaemia in hyperkalaemic patients.15 Patiromer is a non-absorbable polymer which exchanges calcium for potassium in the colon, increasing faecal excretion.16 Clinical trials have confirmed patiromer’s ability to achieve normokalaemia in hyperkalaemic patients on active therapy and it was approved by the FDA in 2015 and the EMA in July 2017.17 Both therapies have an established safety profile based on their clinical programmes,18,19 with additional data recently presented at the 2017 American Society of Nephrology Kidney Week congress.
Data on these potential treatments were also presented at the 2017 ERA-EDTA congress, a summary of which can be found here. Our recent Expert Round Table video also provides further discussion on the current controversies and evolving challenges of managing hyperkalaemia in the cardio-renal patient.
- Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACCF/AHA Focused update to the 2013 ACCF/AHA guideline for the management of heart failure: A report of the american college of cardiology foundation/american heart association task force on practice guidelines. JACC. 2017; 70(6). DOI: 10.1016/j.jacc.2017.04.025.
- Ponikowski P, Voors A, Anker S, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;18:891-975. DOI: 10.1093/eurheartj/ehw128.
- Lindenfeld J, Albert N, Boehmer J, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010;16(6):1-94.
- KDIGO. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3(1):4-4. doi:10.1038/kisup.2012.76.
- National Institute for Health and Care Excellence. Chronic kidney disease (CG73): Early identification and management of chronic kidney disease in adults in primary and secondary care. 2008. Available at: http: //www.nice.org.ul/CG73.
- Epstein M. Hyperkalemia constitutes a constraint for implementing renin-angiotensin-aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena. Kidney Int Suppl. 2016;6(1):20-28. doi:http://dx.doi.org/10.1016/j.kisu.2016.01.004.
- Palmer BF, Clegg DJ. Physiology and pathophysiology of potassium homeostasis. Adv Physiol Educ. 2016;40(4):480-490. doi:10.1152/advan.00121.2016.
- Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009;169(12):1156-62. doi:10.1001/archinternmed.2009.132.
- Yildrim T, Arici M, et al. Major barrier against renin-angiotensin-aldosterone system blocker use in chronic kidney disease stages 3-5 in clinical practice: a safety concern? Ren Fail. 2012;34(9):1095-9. doi: 10.3109/0886022X.2012.717478
- Kraft MD, Btaiche IF, Sacks GS, Kudsk KA, et al. Treatment of electrolyte disorders in adult patients in the intensive care unit. Am J Health Syst Pharm. 2005;62(16):1663-82. doi: 10.2146/ajhp040300
- Weisberg LS. Management of severe hyperkalemia. Crit Care Med. 2008; 36: 3246-51. doi: 10.1097/CCM.0b013e31818f222b.
- Moranne O, Froissart M, Rossert J, et al; and NephroTest Study Group. Timing of onset of CKD-related metabolic complications. J Am Soc Nephrol. 2009;20(1):164-171.
- Collins AJ, Pitt B, Reaven N, et al. Association of Serum Potassium with All-Cause Mortality in Patients with and without Heart Failure, Chronic Kidney Disease, and/or Diabetes. Am J Nephrol. 2017; 46:213-221. doi:10.1159/000479802.
- Epstein M, Reaven NL, Funk SE, Mcgaughey KJ, Oestreicher N, Knispel J. Evaluation of the Treatment Gap Between Clinical Guidelines and the Utilization of Renin-Angiotensin- Aldosterone System Inhibitors. Am J Manag Care. 2015;V21, No11(September):212-220.
- Ouwerkerk W, Voors AA, Anker SD, et al. Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: A prospective European study. Eur Heart J. 2017;38(24):1883-1890. doi:10.1093/eurheartj/ehx026.
- Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in Patients with Kidney Disease and Hyperkalemia Receiving RAAS Inhibitors. N Engl J Med. 2015;372(3):211-221. doi:10.1056/NEJMoa1410853.
- Sterns RH, Grieff M, Bernstein PL. Treatment of hyperkalemia: Something old, something new. Kidney Int. 2016;89(3):546-554. doi:10.1016/j.kint.2015.11.018.
- European Medicines Agency. Veltassa 8.4g, 16.8g & 25.2g – Summary of Product Characteristics (SmPC). 2017 [Online] Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004180/WC500232689.pdf [Accessed 24 Nov 2017]
- European Medicines Agency. CHMP Summary of Positive Opinion for Lokelma 5g & 10g. 2017 [Online] Availble at: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/004029/WC500222241.pdf [Accessed 24 Nov 2017]