ACE-Inhibitors, Azotemia & NSAIDs
ACVIM 2008
Clarke E. Atkins, DVM, DACVIM (Internal Medicine & Cardiology)
Raleigh, NC, USA

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, imidipril, 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 15 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, 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 is little veterinary data, nephrotoxicity with NSAIDS is relatively rare in humans and is precipitated by:


 Blood loss

 Congestive heart failure*

 Hepatic cirrhosis

 Diuretic use*

 Dietary sodium restriction*

 Use of ACE-I?*

 Pre-existing 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 patients. This risk rose with advancing age of the patients.21 Furthermore, 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 to may diminish the efficacy of ACE-I. This is because such drugs diminish the production of prostaglandins, which are enhanced by the inhibition of kinin breakdown 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, 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, delaying the onset of CHF, 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.

Speaker Information
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Clarke Atkins, DVM, DACVIM (Internal Medicine & Cardiology)
North Carolina State University
Raleigh, NC