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 too has 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 initial concern regarding the renal safety of these compounds^6-8 and all ACE-I, which have enjoyed extensive clinical use, have been associated with renal dysfunction, usually temporary⁹. 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, while benazepril has been marketed in Asia, 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 20 years of veterinary clinical experience with ACE-I (mainly benazepril 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 with resultant hypotension. Typically, cessation or dosage reduction of diuretics 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, 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 intraglomerular 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 disease²⁰.

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, inappetance, weakness, lassitude, and precipitating digitalis intoxication by reducing renal elimination.

The advent of a group of very effective NSAIDs has opened the door for the interaction of NSAIDs and ACE-I, as both are frequently utilized in older patients. This polypharmacy, particularly in dogs with heart failure on diuretics, causes concern because of the potential for added nephrotoxicity. Although there are few veterinary data, nephrotoxicity with NSAIDs is relatively rare in humans and is precipitated by:

 Dehydration

 Blood loss

 Congestive heart failure

 Hepatic cirrhosis

 Diuretic use

 Dietary sodium restriction

 Use of ACE-I?

 Preexisting renal disease

The bolded phrases, risk factors associated with cardiac disease, indicate that concern/caution is warranted. NSAIDs were shown to increase the odds ratio for hospitalization for renal disease to 2.2 when added acutely to ACE-I-treated human patients. This risk rose with advancing age.²¹ Additionally, more severe renal dysfunction has been shown to exist in people admitted to the hospital, particularly if receiving ACE-I, NSAIDs and diuretics.²²

Another concern is that the addition of NSAIDs may diminish the efficacy of ACE-I. This is because such drugs diminish the production of prostaglandins, which are pharmacologically enhanced by kininase inhibition with ACE-I. Prostaglandins are thought to be involved in the vasodilatory effect of ACE-I. It has been shown that aspirin at 300 mg reduces ACE-I control of hypertension in humans.²³ This effect is not universal among the drug group, has not been evaluated in veterinary NSAIDs, and is likely class/agent, dosage, and species-dependent. Nevertheless, in patients receiving ACE-I, NSAIDs should be used cautiously, at the lowest dosage, and with the lowest frequency that keeps the patient comfortable.

In conclusion, ACE-I are effective in treating CHF, probably delaying the onset of CHF and improving survival, managing hypertension, and in treating renal disease. There is little evidence of nephrotoxicity alone or with NSAIDs, but caution and monitoring are advisable. There is potential for nephrotoxicity with concurrent use of these drugs and there is the possibility that concurrent use may render ACE-I ineffective.

References

1.  Acute and short-term hemodynamic, echocardiographic, and clinical effects of enalapril maleate in dogs with naturally acquired heart failure: results of the Invasive Multicenter PROspective Veterinary Evaluation of Enalapril study. The IMPROVE Study Group. J Vet Intern Med. 1995;9:234–242.

2.  Controlled clinical evaluation of enalapril in dogs with heart failure: results of the Cooperative Veterinary Enalapril Study Group. The COVE Study Group. J Vet Intern Med. 1995;9:243–252.

3.  Ettinger SJ, Benitz AM, Ericsson GF, et al. Effects of enalapril maleate on survival of dogs with naturally acquired heart failure. The Long-Term Investigation of Veterinary Enalapril (LIVE) Study Group. J Am 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 (BENazepril in Canine Heart disease) 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 Contin Educ Pract 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. Am J Hypertens. 1998;11:1080–1186.

10. MacDonald JS, Bagdon AJ, Peter, CP, et al. Renal effects of enalapril in dogs. Kidney Int. 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. Am 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. N Engl 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 (abstract). 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 (abstract). 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. Am J Vet Res. 1999;60:1516–1525.

21. Bouvy ML, Heerdink ER, Hoes AW, Leufkens HG. Effects of NSAIDs on the incidence of hospitalisations for renal dysfunction in users of ACE inhibitors. Drug Saf. 2003;26:983–989.

22. Loboz KK, Shenfield GM. Drug combinations and impaired renal function - the 'triple whammy.' Br J Clin Pharmacol. 2004;59:239–243.

23. Guazzi MD, Campodonico J, Celeste F, et al. Antihypertensive efficacy of angiotensin converting enzyme inhibition and aspirin counteraction. Clin Pharm Ther. 1998;63:79–86.