Dr. Nicolas Werner
Prof. Michael Bohm
The use of inhibitors of the renin angiotensin system (RAS) can significantly reduce mortality and morbidity in patients with cardiovascular disease 1-7. In addition, in patients with and without diabetes, angiotensin-converting-enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB) slow progression of nephropathy 8-10. However, in clinical practice the use of inhibitors of the RAS in appropriate doses is limited due to dose-related changes in serum creatinine and potassium levels in patients with advanced renal insufficiency.
Why do ACE-I increase serum creatinine levels? ACE-I reduce the intraglomerular pressure. In combination with a decreased effective arterial blood volume which results in a reduced pressure in the afferent arteriole, the single nephron is no longer able to maintain glomerular filtration pressure and filtration rate (GFR). The combination of ACE-I therapy and hypoperfusion of the kidneys (e.g. after aggressive diuretic therapy in patients with low output heart failure) with the loss of the kidneys' ability for pressure autoregulation, are the most common causes for an acute rise in serum creatinine following RAS inhibition 11.
In large-scale prospective clinical ACE-I trials, patients with advanced renal insufficiency were excluded for the above mentioned reasons and consequently data on renal outcome and change of cardiovascular risk has not been determined in this group of patients.
Hou and collegues recently investigated the effect of benazepril in 422 Chinese patients with non-diabetic renal insufficiency 12. The patients were divided according to their creatinine levels: Group 1 included patients with creatinine levels of 1.5 to 3.0 mg/dl (n=104) while group 2 included patients with levels of 3.1 to 5.0 mg/dl (n=224). After a 8 week run-in, patients in group 1 received 10mg benazepril bid whereas patients in group 2 received 10mg benazepril or placebo (n=112 each). Patients were followed for a mean of 3.4 years. In order to achieve a blood pressure of less than 130/80 mmHg the use of antihypertensive drugs other than ACE-I or ARB was allowed. The primary outcome was a combined end point consisting of a doubling of serum creatinine levels, end-stage renal disease or death. Secondary end points were the rate of urinary protein excretion, and the progression of renal disease (creatinine level, clearance, GFR).
102 patients (22%) in group 1, 44 patients (41%) in group 2 (benazepril), and 65 patients (60%) in group 2 (placebo) reached the primary endpoint. Treatment with benazepril significantly reduced the occurrence of the primary endpoint compared to placebo. However, patients with creatinine levels of 1.5-3.0 mg/dl (group 1) had a significant better outcome with benazepril treatment compared to patients with creatinine levels between 3.1 and 5.0 mg/dl (group 2) under the same dose of benazepril (p=0.003). Compared with placebo treatment, benazepril resulted in a significant risk reduction (43%, p=0.005) in group 2 patients independently of blood pressure reduction (p=0.009). Interestingly, benazepril was able to reduce the risk for end-stage renal disease by 40% (p=0.02) and significantly improved secondary endpoints.
The results of the study demonstrate that benazepril mediates renal protection even in advanced stages of renal disease in non-diabetic patients. This effect was blood pressure independent. Health care providers may reconsider the restricted use of inhibitors of the RAS in patients with chronic renal disease. By any means, treatment with ACE-I in renal insufficiency requires close monitoring of renal function and serum potassium levels. Absolute contraindications for ACE-I are bilateral renal stenosis, the occurrence of a Quincke edema during therapy with ACE-I, and serum potassium levels of >5.5 mmol/L. Further studies are necessary to demonstrate whether renoprotection is a class effect of ACE-I in advanced renal disease and whether data can be transferred to the Caucasian population.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. Brenner BM, Cooper ME, Zeeuw DD, Grunfeld JP, Keane WF, Kurokawa K, McGill JB, Mitch WE, Parving HH, Remuzzi G, Ribeiro AB, Schluchter MD, Snavely D, Zhang Z, Simps R. The losartan renal protection study - rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan). J Renin Angiotensin Aldosterone Syst. 2000;1:328-335. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11967819&query_hl=30&itool=pubmed_docsum 2. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-1675. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11759645&query_hl=32&itool=pubmed_docsum 3. Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet. 2002;360:752-760. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12241832&query_hl=34&itool=pubmed_docsum 4. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759-766. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=13678871&query_hl=36&itool=pubmeddocsum 5. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-1435. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2883575&query_hl=41&itool=pubmed_docsum 6. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2057034&query_hl=43&itool=pubmed_docsum 7. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10639539query_hl=45&itool=pubmed_DocSum 8. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11565517&query_hl=48&itool=pubmed_docsum 9. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456-1462. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8413456&query_hl=50&itool=pubmed_docsum 10. Ihle BU, Whitworth JA, Shahinfar S, Cnaan A, Kincaid-Smith PS, Becker GJ. Angiotensin-converting enzyme inhibition in nondiabetic progressive renal insufficiency: a controlled double-blind trial. Am J Kidney Dis. 1996;27:489-495. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8678058&query_hl=52&itool=pubmed_docsum 11. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160:685-693. 12. Hou FF, Zhang X, Zhang GH, Xie D, Chen PY, Zhang WR, Jiang JP, Liang M, Wang GB, Liu ZR, Geng RW. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med. 2006;354:131-140. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16407508&query_hl=54&itool=pubmed_docsum
N. Werner1,2 and M. Böhm2 1 Medizinische Klinik und Poliklinik Klinik für Innere Medizin II Universitätsklinikum Bonn 53105 Bonn
2 Klinik für Innere Medizin III Universitätsklinikum des Saarlandes 66421 Homburg-Saar
Correspondence: Nikos Werner, MD Medizinische Klinik und Poliklinik Innere Medizin II Universitätsklinikum Bonn Sigmund-Freud-Str. 25 53105 Bonn phone +49-228-287-5217/5218 fax +49-228-287-6423 Email: firstname.lastname@example.org
Our mission: To reduce the burden of cardiovascular disease
© 2018 European Society of Cardiology. All rights reserved