Updates on Treating Congestive Heart Failure, Part 1: Is Spironolactone a Game Changer?

Dr. Simon Dennis
BVetMed, MVM, DECVIM (Cardiology)

The Renin-Angiotensin-Aldosterone System (RAAS)
Most veterinarians familiar with the pathophysiology of congestive heart failure will be familiar with the Renin-Angiotensin-Aldosterone System (RAAS).  The RAAS is activated in congestive heart failure, particularly when Furosemide (Lasix) is started.  While the short-term effects of RAAS activation are beneficial to cardiovascular homeostasis, the chronic effects on the heart, vasculature and kidneys are harmful (1).  Consequently, pharmacological RAAS inhibition has been a mainstay of congestive heart failure treatment since these effects were identified more than 30 years ago.  ACE inhibitors (such as Enalapril and Benazepril) and angiotensin-receptor antagonists (such as Telmisartan) have established roles in veterinary medicine for treating congestive heart failure and chronic renal disease.  Both classes of drug target the angiotensin arm of the RAAS.  

Angiotensin II is a vasoconstrictor and a mediator for progression of renal disease.  Hence the role for ACE inhibitors and angiotensin-receptor antagonists in systemic hypertension and chronic renal disease.  Angiotensin II receptors are also present in the heart, where chronic activation causes myocardial cell death.  Over time, this leads to cardiac remodeling, which manifests as heart enlargement, systolic dysfunction and arrhythmias.  Consequently, ACE inhibitors are used to treat congestive heart failure.  

Aldosterone binds to mineralocorticoid receptors in the kidney and heart.  This binding is inhibited by Spironolactone.  The main effect of Spironolactone on the kidneys, mild diuresis, is widely known.  The effects of Spironolactone on the heart are less well known.  Over recent years, there has been an increasing body of evidence that aldosterone has an important role in the progression of heart disease.  As with angiotensin II, the chronic effect aldosterone on the heart is myocardial cell death and subsequent cardiac remodeling.  A study following 162 dogs with chronic degenerative valvular disease over 6 to 18 months found a significant association between urinary aldosterone concentration and increase in left ventricular size over time (2).  This provides good evidence for the association of aldosterone and cardiac remodeling in naturally occurring heart disease in dogs.  

Cardiac Remodeling and “Aldosterone breakthrough”
In theory, both ACE inhibitors (Enalapril, Benazepril) and mineralocorticoid-receptor antagonists (Spironolactone) should inhibit aldosterone-mediated cardiac remodeling; ACE inhibitors by preventing aldosterone production, Spironolactone by blocking the binding of aldosterone to receptors on the heart.  However, treatment with ACE inhibitors does not always prevent aldosterone production.  This phenomenon of “Aldosterone breakthrough” has been found to occur in dogs receiving either Enalapril (3) or Benazepril (4).  If aldosterone breakthrough occurs in dogs with chronic degenerative valvular disease, we would expect to see ACE inhibitors having little to no effect on heart size.  Studies have shown this to be the case.  No studies have shown a beneficial effect of ACE inhibitors on heart size in dogs with chronic degenerative valvular disease (5,6,7).  Whereas, in a small, randomized, controlled, clinical trial in dogs with valvular disease and left heart enlargement, the rate of increase in left ventricular size was slowed by the administration of Spironolactone (8).  This study also found that the rate of increase in NT-proBNP concentrations was also slowed by Spironolactone.  A supportive finding since NT-proBNP, a marker of myocardial wall stress, is also associated with left heart size in dogs.  This suggests at least some action of Spironolactone on cardiac remodeling.  What about the effect of both an ACE inhibitor and Spironolactone?  Perhaps both are required to fully inhibit RAAS-mediated cardiac remodeling.  Evidence for this can be found in a large, randomized, controlled, clinical trial published in 2020 (9).  In this prospective study involving 184 dogs with chronic degenerative valvular disease and left heart enlargement, administration of both Benazepril and Spironolactone did not just slow the rate of increase, but actually resulted in a significant decrease in left heart size, echocardiographic markers of left atrial pressure, and concentrations of NT-proBNP.  This provides strong evidence that both Benazepril and Spironolactone inhibit cardiac remodeling more effectively than either drug alone.  If this is the case, perhaps the addition of Spironolactone to a patient with congestive heart failure that is receiving Furosemide (Lasix) and an ACE inhibitor will have a clinical benefit.  

Is Spironolactone beneficial for patients with congestive heart failure?
Two, large, multicentered, randomized, controlled, clinical trials have demonstrated a significant clinical benefit for Spironolactone in treating congestive heart failure in dogs with chronic degenerative valvular disease when added to Furosemide and an ACE inhibitor (10,11).  Both studies found that the addition of Spironolactone resulted in a longer median survival time.  For the one study in which clinical improvement was also evaluated (11), the addition of Spironolactone resulted in a faster improvement in signs of coughing and decreased activity.  Both studies were large, 123 dogs (10) and 414 dogs (11), and both followed dogs over 12 months, which is a clinically relevant time-period for dogs with congestive heart failure.  The fact that two large, interventional studies, conducted in separate populations, in 2 different continents, each found that the addition Spironolactone to Furosemide and an ACE inhibitor lengthens life in dogs with chronic degenerative valvular disease and congestive heart failure is noteworthy.  The results of these studies have significant clinical relevance for dogs with congestive heart failure, and their results can be considered reliable.  Just as important, no adverse effects of adding Spironolactone were found in either study.  In neither study were there any adverse effects on markers of renal function by the addition of Spironolactone to Furosemide (Lasix) and an ACE inhibitor.  In the most recent study (11), Spironolactone and Benazepril were administered as a single flavored tablet (Cardalis) once daily with voluntary compliance in 88% of dogs.  For me, the survival benefit, the lack of adverse effects, and the ease of administration provide compelling evidence that the combination of Spironolactone and Benazepril is more beneficial for dogs with congestive heart failure than giving an ACE inhibitor alone.  

1. Ames MK, Atkins CE, Pitt B. 2019. The renin-angiotensin-aldosterone system and its suppression. J Vet Intern Med. 33(2):363-382.  
2. Hezzell MJ, Boswood A, Chang Y-M, et al. Associations among serum N-terminal procollagen type III concentration, urinary aldosterone-to-creatinine ratio, and ventricular remodeling in dogs with myxomatous mitral valve disease. Am J Vet Res 2012; Nov; 73(11), 1765-1774.  
3. Lantis AC, Ames MK, Werre S, et al. The effect of enalapril on furosemide-activated renin-angiotensin-aldosterone system in healthy dogs.  J Vet Pharmacol Ther 2015; 38(5), 513-517.  
4. Lantis AC, Ames MK, Atkins CE, et al. Aldosterone breakthrough with benazepril in furosemide-activated renin-angiotensin-aldosterone system in normal dogs.  J Vet Pharmacol Ther 2015; 38(1), 65-73. 
5. The IMPROVE Study Group. 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. J Vet Intern Med 1995; 9(4), 234-242. 
6. Haggstrom J, Lord PF, Hoglund K, et al. Short-term hemodynamic and neuroendocrine effects of pimobendan and benazapril in dogs with myxomatous mitral valve disease and congestive heart failure. J Vet Intern Med 2013; 27(6), 1452-1462.
7. Haggstrom J, Boswood A, O’Grady M, et al. Longitudinal analysis of quality of life, clinical, radiographic, echocardiographic, and laboratory variables in dogs with myxomatous mitral valve disease receiving pimobendan or benazepril: the QUEST study. J Vet Intern Med 2013; 27(6), 1441-1451. 
8. Hezzell MJ, Boswood A, Lopez-Alvarez J, et al. Treatment of dogs with compensated myxomatous mitral valve disease with spironolactone – a pilot study. J Vet Cardiol 2017; 19(4), 325-338.  
9. Borgarelli M, Ferasin L, Lamb K, et al. DELay of Appearance of sYmptoms of Canine Degenerative Mitral Valve Disease Treated with Spironolactone and Benazepril: the DELAY Study. J Vet Cardiol 2020; 27, 34-53. 
10. Bernay F, Bland JM, Haggstrom J, et al. Efficacy of Spironolactone on Survival in Dogs with Naturally Occurring Mitral Regurgitation Caused by Myxomatous Mitral Valve Disease. J Vet Intern Med 2010; 24, 331-341. 
11. Freedom of Information Summary, NADA #141-538 (July 27, 2020), CARDALIS.