Clarke E. Atkins, DVM, DACVIM (Internal Medicine & Cardiology)
Department of Clinical Sciences, North Carolina State University, College of Veterinary Medicine
In landmark veterinary studies of enalapril in NYHA phase III and IV heart disease (moderate to severe heart failure), due to mitral regurgitation (MR) and dilated cardiomyopathy (DCM), enalapril improved survival by >100% as well as reducing pulmonary edema and, improving quality of life scores.1-3 Exercise capacity is also improved in dogs with experimental mitral insufficiency.4 Benazepril has likewise been shown to improve survival.5 ACE-I have proven to provide additional benefits in human patients by blocking pathological remodeling, presumably slowing progression of heart disease and by normalizing serum electrolyte concentrations. Today, ACE-I represent the cornerstone in the chronic management of CHF. They are indicated in virtually all cases of systolic heart failure in which they are tolerated.
There was early concern regarding the renal safety of these compounds6-8 and all ACE-I, which have enjoyed extensive clinical use, have been associated with renal dysfunction, usually temporary.9 There has been speculation that, at very high doses (180x the clinical dosage), ACE-I have direct nephrotoxic effects but it is generally felt that the major impact of ACE-I on the kidney, with clinically relevant dosages, is through production of hypotension, with reduced renal perfusion pressure and resulting in worsening of azotemia.10 To date, veterinary clinicians have had experience with enalapril, captopril, benazepril, imidapril, ramipril and lisinopril. Of these, only enalapril has been extensively studied and is licensed for use in management of heart failure in the United States, though benazepril has been marketed in Europe and Canada. The active metabolite of benazepril is reportedly excreted both in the bile and in the urine so that lower serum concentrations are evident in experimental renal disease.11 The clinical relevance of this is unclear. Over 10 years of veterinary clinical experience with ACE-I (mainly captopril and enalapril) have taught us that their impact on kidney function is minimal even in the face of severe heart failure. When azotemia is observed, ACE-I are almost always being used in conjunction with diuretics and sodium restriction and hypotension results. Typically, cessation of diuretic therapy or reduction in the dosage results in the reversal of azotemia.9
In studies of enalapril in NYHA phase III and IV heart disease (moderate to severe heart failure), due to MR and DCM, there was actually a lower incidence of azotemia in the enalapril-treated group than the placebo-treated group.1-3,12 Furthermore, in a study of enalapril's role in the delay or prevention of heart failure due to naturally-occurring MR, showed that enalapril at the standard dosage of 0.5 mg/kg daily had no effect on serum creatinine concentrations, as compared to placebo.13
In fact, evidence is building to prove benefit when ACE-I are administered chronically to both human and veterinary patients with naturally-occurring and experimental renal failure.14-20 Mechanisms for this improvement are postulated to be the antihypertensive effect, reduction of angiotensin II-induced mesangial cell proliferation, and renal vasodilatory effects of ACE-I, the latter related to a fall in renal filtration pressure and proteinuria.14-16 Enalapril has recently been shown to reduce urine protein loss and reduce blood pressure in naturally-occurring canine glomerulonephritis.18 Likewise, benazepril reduced azotemia and proteinuria in a short-term study of experimental and naturally-occurring renal insufficiency in cats19 and lowered BUN and creatinine concentrations and blood pressure in cats with polycystic kidney disease.20
As mentioned above, ACE-I have the potential to produce symptomatic hypotension. This is due to the mixed vasodilatory effect of this group of drugs and is typically observed when ACE-I are used in conjunction with other off-loading therapies, such as vasodilators, diuretics, and sodium restriction. Hypotension is reversed by altering drug therapies but may be problematic in producing azotemia, inappetence, weakness, lassitude, and precipitating digitalis intoxication by reducing renal elimination.
1. Improve Study Group. Acute and short-term hemodynamic, echocardiographic, and clinical effects of enalapril maleate in dogs with naturally occurring acquired heart failure: Results of invasive multicenter prospective veterinary evaluation of enalapril study. J Vet Intern Med 1995; 9:234-242.
2. Cove Study Group. Controlled clinical evaluation of enalapril in dogs with heart failure: Results of the cooperative veterinary enalapril study group. J Vet Intern Med 1995; 9:234-242.
3. LIVE Study Group. Effects of enalapril on survival in dogs naturally acquired heart disease: Results of long-term investigation of veterinary enalapril (LIVE) study group. J Amer Vet Med Assoc 1998; 213:1573-1577.
4. Hamlin, RL, Benitz, AM, Ericsson, GF, et al.: Effects of enalapril on exercise tolerance and longevity in dogs with heart failure produced by iatrogenic mitral regurgitation. J Vet Intern Med 1996; 10:85-87.
5. Bench Study Group: The effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: Results of a multicenter, prospective, randomized, double-blinded, placebo-controlled, long-term clinical trial. J Vet Cardiol 1999; 1:7-18.
6. Packer M, Leen WH, Medina N, et al. Functional renal insufficiency during long-term therapy with captopril and enalapril in severe, chronic, heart failure. Ann Intern Med 1987; 106:346-352.
7. Schlessinger DP, Rubin, SI. Potential adverse effects of angiotensin-converting enzyme inhibitors in the treatment of congestive heart failure. Compend Cont Ed Pact Vet 1994; 16:275-283.
8. Roudebush P, Allen TA. The effect of combined therapy with captopril, furosemide, and a sodium-restricted diet on serum electrolyte concentrations and renal function in normal dogs and dogs with congestive heart failure. J Vet Intern Med 1994; 8:337-342.
9. Wynckel A, Ebikili, B, Melin, JP, et al. Long-term follow-up of acute renal failure caused by angiotensin converting enzyme inhibitors. Amer J Hypertens 1998; 11:1080-1187.
10. MacDonald JS, Bagdon AJ, Peter, CP, et al. Renal effects of enalapril in dogs. Kidney International 1987; S20:148-153.
11. Lefebvre, HP, Laroute, V, Concordet, D, Toutain, P. Effects of renal impairment on the disposition of orally administered enalapril, benazepril, and their metabolites. J Vet Intern Med 1999; 13:21-27.
12. Merck AgVet. Enacard package insert. 1994.
13. Atkins CE, Brown WA, Coats JR, et al. Effects of long-term administration of enalapril on clinical indicators of renal function in dogs with compensated mitral regurgitation.J Am Vet Med Assoc. 2002; 221:654-658.
14. Abraham PA, Opsahl JA, Halstenson CE, et al. Efficacy and renal effects of enalapril therapy for hypertensive patients with chronic renal insufficiency. Arch Intern Med 1988; 148:2358-2362.
15. Praga M, Hernandez, E, Montoyo, C, et al. Long-term beneficial effects of angiotensin-converting enzyme inhibition in patients with nephrotic proteinuria. Amer J Kidney Dis 1992; 20:240-248.
16. Maschio G, Alberti, D, Gerard, J, et al. Effect of the angiotensin-converting enzyme-inhibitor benazepril on the progression of chronic renal failure. New Eng J Med 1996; 334:939-945.
17. Brown SA, Brown CA, Jacobs G, et al. Hemodynamic effects of angiotensin converting enzyme inhibition (benazepril) in cats (abst). J Vet Intern Med 1999; 13:250.
18. Grauer GF, Creco, DS, Getzy, DM, et al. Effects of enalapril versus placebo as a treatment for canine idiopathic glomerulonephritis. J Vet Intern Med. 2000; 14:526-533.
19. Watanabe T, Mishina M, Wakao, Y. Studies of the ACE inhibitor benazepril in an experimental model and in clinical cases of renal insufficiency in cats (abst). J Vet Intern Med 1999; 13:252.
20. Miller RH, Lehmkuhl, LB, Smeak, DD, et al. Effect of enalapril on blood pressure, renal function, and the renin-angiotensin-aldosterone system in cats with autosomal dominant polycystic kidney disease. Amer J Vet Res 1999; 60:1516-1525.