Inhibition of the renin-angiotensin-aldosterone system (RAASi) is recommended in a range of clinical guidelines, both for heart failure (HF)1,2,3 and chronic kidney disease (CKD).4 Medications which inhibit the RAAS include angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARBs), angiotensin II receptor/neprilysin inhibitors (ARNI) and mineralocorticoid receptor antagonists (MRAs). But what are the barriers to RAASi therapy, and do their benefits outweigh potential risks such as hyperkalaemia?
This article provides an overview of the effect of RAASi therapy both on the heart and kidneys in patients with HF and CKD, emphasising the importance of guidelines-directed dosing of these agents to achieve the best patient outcomes.
Benefits for heart failure patients
Over 30 years ago the CONSENSUS trial was the first study to show the significant benefits of an ACE-I (enalapril) in patients with NYHA class IV HF with ejection fraction less than 35% and HF symptoms.5 Alongside a reduction in risk of all-cause mortality by 27% vs placebo (p=0.003), patients also experienced an improvement in their NYHA classification and a reduction in requirements for other HF medication.5
It is not only those with severe HF who benefit from ACE-I; in patients with asymptomatic HF, the SOLVD-Prevention study reported a 20% reduction in the incidence of death or hospitalisation due to HF with use of an ACE-I (enalapril) vs placebo (p<0.001), in patients not receiving other HF treatment.6
The results from MRA trials were similar. The 1999 RALES study in patients with severe HF and ejection fraction <35% demonstrated that blockade of aldosterone receptors with an MRA (spironolactone), in addition to standard therapy, substantially reduced the risk of death by 30% compared with placebo. This reduction was attributed to a lower risk of death from progressive HF and sudden death from cardiac causes. Spironolactone also significantly reduced the risk of hospitalisation for worsening HF vs placebo.7
Patients enrolled in the EMPHASIS-HF study had less severe (NYHA class II) HF and were required to be receiving an ACE-I, and ARB, or both, and a beta-blocker. The addition of an MRA (eplerenone) resulted in a reduced risk of both cardiovascular death or hospitalisation for HF compared to placebo.8 The benefits of combining RAASis were also examined in an extensive meta-analysis, which concluded that the greatest reduction in mortality for HF patients is achieved through combination therapy.9
Reflecting these, and other, studies, the European Society of Cardiology (ESC), the National Institute for Health and Care Excellence UK (NICE), the American College of Cardiology (ACC), the American Heart Association (AHA) and the Heart Failure Society of America (HFSA), are consistent in recommending RAASi in patients with HF with reduced ejection fraction:10,2,3
- ACE-I is recommended, in addition to a beta-blocker, for symptomatic patients with HF and reduced ejection fraction2
- ARB is recommended when ACE-I is not tolerated
- MRA is recommended for patients with HF and reduced ejection fraction, who remain symptomatic despite treatment with an ACE-I and a beta-blocker
- Highest tolerated targeted doses are recommended10,3
Benefits for renal patients
Due to its central role in regulating intravascular volume, blood pressure and tissue repair,11 the RAAS is a target for both cardiovascular and renal disease. While it was thought that antihypertensives slowed renal disease progression, in 1993 the Collaborative Study Group showed a protective effect of ACE-I (captopril) on renal function in Type I diabetics, independent to that of its impact on blood pressure.12 Captopril was associated with a 48% reduction in the risk of doubling of baseline creatinine, and a 50% reduction in the risk of the combined endpoint of death, dialysis and transplantation.12 This was a landmark clinical trial in nephrology.
Examining the effects of ARB therapy in patients with Type II diabetes and nephropathy, the RENAAL and IDNT studies also showed a reduction in kidney disease progression (measured as doubling of baseline serum creatinine levels or end-stage renal disease).13,14 Data from RENAAL demonstrated the renoprotective effect of losartan through a significant 16% reduction in the risk of primary composite endpoint (defined as doubling of the base-line serum creatinine concentration, the onset of end-stage renal disease, or death from any cause) versus placebo,14 while data from IDNT demonstrated the renoprotective effect of irbesartan through a 20% relative risk reduction compared with placebo for the primary composite endpoint.13 In patients with Type II diabetes and microalbuminuria, the IRMA2 study reported a significant reduction in progression to diabetic nephropathy and restoration of normoalbuminuria with 300mg of irbesartan
The Collaborative Study Group’s initial landmark trial was in Type I diabetic nephropathy patients, but this independent renoprotective effect of ACE-I therapy was later also demonstrated in patients with non-diabetic nephropathy.16 The REIN study showed a significant decrease in the speed of glomerular filtration rate decline with ramipril vs placebo in patients with chronic nephropathy also receiving conventional antihypertensive medication.16
Relevant renal associations have thus incorporated these results in their guidelines. The International Society of Nephrology, the Kidney Disease, Improving Global Outcomes (ISN / KDIGO), the National Kidney Foundation USA (NKF) and NICE, as well as many local guidelines, all recommend RAASi use to slow the progression of kidney disease4,17 and reduce proteinuria,17,18 (as a surrogate marker of renoprotection), concluding that RAASi:
- Are valuable in CKD and strongly indicated in proteinuria4,18
- Have known beneficial effects in diabetic nephropathy18
- Are more effective at reducing kidney function decline than other blood pressure-lowering drugs17
Challenges with RAASi therapy
The positive effects of RAASi have been repeatedly demonstrated in many studies using different compounds within the drug classes, and across a range of patients.19–22 However, the difficulties in maintaining the maximum tolerated, guideline recommended doses of RAASis have also become apparent, particularly with regard to the risk of hyperkalaemia.23 A study of the association between outcomes and serum potassium levels in patients with impaired renal function found that a hyperkalaemic event was associated with a cessation (rather than a dose reduction) of RAASi therapy, regardless of underlying kidney function.23 The authors also noted that amongst those who had their RAASi stopped, 50% remained without RAASi therapy for the remainder of the study, depriving them of access to these important drugs.23
The impact of suboptimal dosing was also demonstrated in the BIOSTAT-HF study in which patients with HF and reduced ejection fraction who achieved <50% of recommended dose of ACE-I or ARB demonstrated a greater risk of death compared with patients reaching or exceeding the recommended dose.24 Patients who did not reach the recommended dose due to symptoms, side effects or non-cardiac organ dysfunction had the highest risk of death.24 The association between hyperkalaemia and suboptimal use or dosage of RAASi is discussed further in this recent COMPACT RENAL article.
In summary, RAAS inhibition has demonstrated a significant impact in reducing morbidity and mortality in HF patients with reduced ejection fraction, as well as a renoprotective effect in CKD patients, with the greatest benefits obtained at guideline recommended doses.3,10 However, in the presence of hyperkalaemia, a reduction in RAASi dose is recommended,2–4,10 while clinically treatment is often discontinued altogether.25 New potassium lowering medications may open new opportunities for escalation of RAASi doses and the achievement of maximum beneficial clinical and biochemical effects.
- Yancy CW, Jessup M, Bozkurt B, et al. 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. Circulation. 2013;128(16). doi:10.1161/CIR.0b013e31829e8776.
- Lindenfeld J, Albert N, Boehmer J, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010;16(6):1-94.
- 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:doi:10.1093/eurheartj/ehw128.
- 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.
- CONSENSUS Trial Study Group. Effects of Enalapril on mortality in severe congestive heart failure. N Engl J Med. 1987;316(23):1429-1435.
- Investigators TS. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327(10):685-691.
- Pitt P, ZANNAD F, REMME W, et al. The Effect of Spironolactone on Morbidity and Mortality in Patients With Severe Heart Failure. N Engl J Med. 1999;341(10):709-717. doi:10.1056/NEJM199909023411001.
- Zannad F, McMurray J, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21.
- Burnett H, Earley A, Voors AA, et al. Thirty Years of Evidence on the Efficacy of Drug Treatments for Chronic Heart Failure with Reduced Ejection Fraction: A Network Meta-Analysis. Circ Hear Fail. 2017;10(1). doi:10.1161/CIRCHEARTFAILURE.116.003529.
- Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. Circulation. 2017;136:e137-e161. doi:10.1161/CIR.0000000000000509.
- Mentz R, Bakris GL, Waeber B, et al. The past, present and future of renin-angiotensin aldosterone system inhibition. Int J Cardiol. 2013;167(5):1677-1687. doi:10.1109/TMI.2012.2196707.Separate.
- Lewis E, Hunsicker L, Bain R, Rohde R. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329:1456-1462.
- Lewis E, Hunsicker L, Clarke W, et al. Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy due to Type 2 Diabetes. N Engl J Med. 2001;345(12):851-860.
- BRENNER B, COOPER M, DE ZEEUW D, et al. EFFECTS OF LOSARTAN ON RENAL AND CARDIOVASCULAR OUTCOMES IN PATIENTS WITH TYPE 2 DIABETES AND NEPHROPATHY. N Engl J Med. 2001;345(12):861-869.
- Parving H, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. THE EFFECT OF IRBESARTAN ON THE DEVELOPMENT OF DIABETIC NEPHROPATHY IN PATIENTS WITH TYPE 2 DIABETES. N Engl J Med. 2001;345(12):870-878.
- The GISEN Group. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet. 1997;349:1857-1863. doi:10.1016/S0140-6736(96)11445-8.
- NICE. National Institute for Health and Clinical Excellence (NICE) [UK]. Chronic kidney disease (partial update): Early identification and management of chronic kidney disease in adults in primary and secondary care. 2014. Available at: https://www.nice.org.uk/guidance/cg182/evidence/update-full-guideline-191905165.
- KDOQI. K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis. 2004;43(5):S1-290. Available at: http://www2.kidney.org/professionals/KDOQI/guidelines_bp/guide_7.htm.
- Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med. 1996;334(15):939-45. Available at: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed4&NEWS=N&AN=1998045211.
- Wright JT, Bakris G, Greene T, et al. Effect of Blood Pressure Lowering and Antihypertensive Drug Class on Progression of Hypertensive Kidney Disease. J Am Med Assoc. 2002;288(19):2421-2432.
- Hou F, Zhang X, Zhang G, et al. Efficacy and Safety of Benazepril for Advanced Chronic Renal Insufficiency. N Engl J Med. 2006;354(2):131-140.
- Bakris GL, Barnhill BW, Sadler R. Treatment of arterial hypertension in diabetic humans: Importance of therapeutic selection. Kidney Int. 1992;41(4):912-919. doi:10.1038/ki.1992.139.
- Luo J, Brunelli SM, Jensen DE, Yang A. Association between serum potassium and outcomes in patients with reduced kidney function. Clin J Am Soc Nephrol. 2016;11(1):90-100. doi:10.2215/CJN.01730215.
- 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.
- Yildirim T, Arici M, Piskinpasa S, et al. Major Barriers against Renin–Angiotensin–Aldosterone System Blocker Use in Chronic Kidney Disease Stages 3–5 in Clinical Practice: A Safety Concern? Ren Fail. 2012;34(July):1095-1099. doi:10.3109/0886022X.2012.717478.