When to Use and Not to Use ACE Inhibitors
World Small Animal Veterinary Association World Congress Proceedings, 2014
Clarke Atkins, DVM, DACVIM (Internal Medicine and Cardiology)
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA

Our understanding of the pathogenesis and management of heart failure has markedly changed over the last 20 years. During this time we have learned that the heart may fail due to diastolic dysfunction, as well as systolic dysfunction; that hemodynamic alterations and their management are less important than the body's own maladaptive neurohormonal response to a fall in cardiac output; that drugs which improve hemodynamics may actually result in long-term harm; and that the greatest clinical benefits result from therapies which blunt the body's neurohormonal response in heart failure. In addition, there has been a plethora of new procedures, drugs, and even drug classes introduced for the management of cardiac disease.

Some of the most important clinical ramifications of heart failure, such as dyspnea (due to pulmonary edema or pleural effusion) and ascites, are directly attributable to sodium and fluid retention resulting from activation of the renin-angiotensin-aldosterone system (RAAS). Management of the signs of congestive heart failure (CHF) has relied upon the use of natriuretic diuretics (furosemide), restriction of dietary sodium, and more recently angiotensin-converting enzyme inhibitors (ACE-I) which, by blocking aldosterone production, combat sodium retention and congestion. In addition, as vasodilators, ACE-I unload the heart, improving cardiac output and exercise, normalize electrolyte aberrations, and blunt the pathological cardiovascular remodeling produced by angiotensin II and aldosterone.

While off-loading therapy with the aforementioned drug groups can be lifesaving, their use can be associated with adverse side effects. Most notable of these are hypotension, azotemia, renal failure, and arrhythmias. Certain complications are more apt to occur when combinations of drugs are used. Because of the potential for such side effects, these drugs are best employed in specific sequence and combinations. The following discussion relates to their use in the management of chronic heart failure.

Angiotensin-Converting Enzyme Inhibitors

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. Exercise capacity is also improved in dogs with experimental mitral insufficiency. Benazepril has likewise been shown to improve survival. 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 compounds and all ACE-I, which have enjoyed extensive clinical use, have been associated with renal dysfunction, usually temporary. 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. To date, veterinary clinicians have had experience with enalapril, captopril, benazepril, 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 Japan, 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. 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.

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. 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.

In fact, it is now well accepted that ACE-I are administered chronically to both human and veterinary patients with naturally occurring and experimental renal failure. 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. Enalapril has recently been shown to reduce urine protein loss and reduce blood pressure in naturally occurring canine glomerulonephritis. Likewise, benazepril reduced azotemia and proteinuria in a short-term study of experimental and naturally occurring renal insufficiency in cats and lowered BUN and creatinine concentrations and blood pressure in cats with polycystic kidney disease.

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.

ACE inhibitors have received the majority of attention in asymptomatic MR. There are studies which support and refute the activation of the RAAS prior to CHF in MR, leaving the question to be answered by clinical trials. Two studies have prospectively evaluated enalapril in dogs with asymptomatic MR. The first (SVEP) was carried out in Northern Europe in Cavalier King Charles spaniels. This double-blind, placebo-controlled (DBPC) study was unable to demonstrate a benefit in time to onset of CHF when the drug was compared to placebo in mildly to moderately affected dogs; however, the dosage used was suboptimal and the dogs were mildly affected The second (VETPROOF), a DBPC trial carried out in the U.S., has recently been completed (to both CHF and death as endpoints). This study showed benefits in time dogs remained in the study without CHF, number of dogs CHF-free at 500 days and study termination. The Kaplan-Meier "survival" curves demonstrate a strong, but not statistically significant, trend toward an increase in time to onset of heart failure. An unpublished VETPROOF substudy of survival revealed that early ACE-Inhibitor therapy provided a significant survival benefit (> 9 months). Both the SVEP and VETPROOF demonstrated the safety of enalapril in aged dogs with compensated heart disease. Finally, a retrospective trial demonstrated improvement in all-cause mortality in asymptomatic MR dogs, treated with benazepril. There was no benefit in time to onset of signs, however.

This author offers ACE-I therapy to dogs with asymptomatic MR and radiographic and/or echocardiographic evidence of remodeling (VHS > 11). Reasons for this approach include the proven hemodynamic improvement in human MR, the results of the VETPROOF, the strong safety record, and potential for benefit in reducing mitral regurgitation and in blunting remodeling initiated by the RAAS. Careful scrutiny of renal function, blood pressure, and serum potassium concentration is provided initially and periodically during therapy. In addition, the owner is advised as to cost, the potential for life-time administration, the risk of hypotension, and the varied results of clinical trials.

Aldosterone-Receptor Blockers

Spironolactone and eplerenone, aldosterone receptor blockers, used in the treatment of heart failure in humans, are thought to be effective by blocking the remodeling effects of aldosterone. It has been shown in people, and recently in the author's laboratory in dogs, that aldosterone and angiotensin II "escape" or "break through" from ACE-inhibitor suppression weeks to months after institution of therapy. Multiple studies have shown that spironolactone has benefits in both human and canine heart failure. Studies in our laboratory have shown that breakthrough occurs early and most likely spironolactone should be instituted at the time that ACE inhibitors are added. As yet, unpublished studies by Rausch et al. at NCSU demonstrated no risk for hyperkalemia in dogs treated concurrently with enalapril and spironolactone. Likewise, Thomasin et al. showed that with concurrent ACE inhibition, spironolactone was safe and produced no electrolyte aberrations in asymptomatic cardiac disease. The dosage used by this author for aldosterone receptor blockade is 2.0 mg/kg once daily.


Of the commonly used therapeutic strategies, loop-diuretic therapy has the greatest potential for adverse side effects (hypotension, azotemia, activation of RAAS, electrolyte disturbances, and fatal arrhythmias). Therefore, except in emergencies, furosemide should not be used as a monotherapy and should be used at the lowest dosage preventing signs of CHF. Salt restriction has similar, but lesser effects on RAAS activation, and potentiates diuretic- and ACE-I-induced tendencies toward azotemia. Therefore, moderate, rather than severe salt restriction, is indicated until signs of heart failure become refractory. Of the off-loading therapies under discussion, only ACE-I have been shown to benefit heart failure while blunting other pathophysiological processes (RAAS activation, electrolyte abnormalities, aldosterone- and angiotension II-induced cardiac remodeling, and renal dysfunction). Therefore, if either azotemia or hypotension is noted in a patient being managed for heart failure, the diuretic should first be discontinued or the dosage reduced, being reinstituted as necessary. Reduction or cessation of ACE-I is employed only if altering the diuretic dosage is ineffectual. Though ACE-I are generally safe, BUN and creatinine, as well as serum potassium concentration and systemic blood pressure, should be monitored periodically, particularly if sodium restriction and/or diuretic therapy are utilized concurrently. Finally, when any of these agents are utilized, either alone or in combination, if caution is exercised and hypotension avoided, there is little risk of significant renal impairment. Beta-blockers are indicated in DCM (NYHA Phase I, II, and III). Although theoretically indicated, a recent trial failed to show benefit in asymptomatic MR. Aldosterone-receptor blockers are useful in CHF and probably should be used whenever an ACE inhibitor is employed.


Speaker Information
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Clarke Atkins, DVM, DACVIM (Internal Medicine and Cardiology)
College of Veterinary Medicine
North Carolina State University
Raleigh, NC, USA