Are ACE inhibitors effective in treating heart disease?

Angiotensin-converting enzyme inhibitors are among the most studied therapeutics in veterinary cardiology, which gives us more data than usual to evaluate their use

Examining all interventions critically from the perspective of the best available evidence is an important principle in evidence-based medicine. This applies to well-established and widely practiced therapies as much as to novel or unusual ones. As new evidence becomes available, revisiting established treatments and revising or abandoning them when indicated are key to curating the most effective, evidence-based set of clinical practices possible.

The use of angiotensin-converting enzyme (ACE) inhibitors in dogs and cats with cardiac disease is a long-standing treatment that has been reevaluated periodically as new evidence is developed. Many practitioners approach the use of these drugs as they were taught to in veterinary school. Given the substantive change over time in the evidence and the controversies about the role of ACE inhibitors in the treatment of heart disease, I believe it is worthwhile to review the rationale and the available evidence.

What are ACE inhibitors and what do they do?

The myriad effects of the renin-angiotensin-aldosterone system (RAAS) are complex, but in brief, ACE inhibitors block the conversion of angiotensin I to angiotensin II. This reduces the effects of angiotensin II, which include direct vasoconstriction and indirect effects through aldosterone release. Less aldosterone leads to reduced renal sodium retention and lower levels of antidiuretic hormone, both of which promote diuresis and reduced blood volume. ACE inhibitors also cause increased levels of bradykinin, which is a vasodilator and mild diuretic.1,2

These effects are believed to benefit patients with cardiac disease by reducing blood volume and vascular resistance. However, predicting the clinical impact of medications based on physiologic rationale alone is often unsuccessful; determining the true risks and benefits of drug therapies requires the use of clinical research.

In addition to a plausible physiologic rationale, there is evidence from experimental animal models suggesting ACE inhibitors should be beneficial for patients with cardiac disease.1,2 There is also clinical trial research in humans showing benefits of various ACE inhibitors for patients with heart failure and some types of heart disease without heart failure.3-5 That said, the application of such human clinical trial evidence to veterinary patients is always problematic. While evidence in humans is often much more extensive and robust than veterinary research, differences in physiology and in the causes and treatment of human and veterinary patients make direct extrapolation of human studies to dogs and cats unreliable.

Use in dogs with congestive heart failure

ACE inhibitors are among the most studied therapeutics in veterinary cardiology. This gives us more data than usual to evaluate, but it also forces us to contend with contradictory findings and interpretations of the available studies.

The balance of the evidence suggests ACE inhibitors added to standard therapy improve survival and clinical symptoms in dogs with congestive heart failure (CHF) secondary to mitral valve disease (MVD) or dilated cardiomyopathy (DCM).1,2,6-10 The COVE study randomized dogs with MVD or DCM to standard treatment and either enalapril or placebo for 28 days and found a significant increase in survival in those given the ACE inhibitor.6 The IMPROVE study also found the same benefit with enalapril,9 and the BENCH study found significant survival benefits from benazepril compared with placebo in a similar population.8

The LIVE study found a survival benefit for enalapril plus standard therapy compared to standard treatment and placebo in dogs with CHF due to MVD and DCM.7 However, there is some controversy about this study, and it has been noted by several cardiologists that prepublication data presented at conferences and the data in the final journal publication differ in significant ways that alter the study’s conclusions. There is evidence that industry-sponsored research tends to be favorable to the interests of the sponsor,11,12 and this could be a factor in the inconsistencies of the data from this study.

One study, which has been reported at a conference but not yet published, compared treatment with furosemide and pimobendan alone to treatment with these medications and an ACE inhibitor (ramipril); it found no benefit from addition of the ACE inhibitors for dogs in left-sided CHF.13 This contradicts some of the other existing studies, so while the preponderance of evidence suggests ACE inhibitors probably benefit patients with CHF, there is room for reasonable doubt. All conclusions based on scientific evidence are probabilistic, not absolute, so it is more useful to evaluate medical therapies in terms of the strength of the evidence and our degree of confidence in our conclusions than it is to talk about treatments being “proven” effective or ineffective.

Use in dogs without congestive heart failure

While existing evidence supports a relatively high degree of confidence in the benefits of ACE inhibitors in patients with CHF, the evidence is less compelling in patients with heart disease who are not yet in heart failure. In humans, ACE inhibitors do have some benefits in patients with left ventricular dysfunction without CHF.14,15 However, research in veterinary patients has largely failed to find such a benefit.

The SVEP study randomized more than 200 Cavalier King Charles spaniels with MVD to placebo or enalapril and monitored for the development of CHF. Only about 40 percent of the dogs in either group developed CHF over approximately three years, and there was no difference between those on enalapril and those receiving placebo, regardless of the presence of left atrial enlargement.16

The VETPROOF study also randomly assigned dogs with MVD to enalapril or placebo; it found no effect on the primary outcome of time to onset of CHF. A number of secondary outcomes did differ between the groups, and there is debate about whether this suggests the treatment may benefit dogs with MVD prior to CHF despite the lack of effect on the primary endpoint.10

Another study compared outcomes in dogs with MVD not in CHF given benazepril or given no treatment. The authors found no difference in the time to onset of CHF. Several other outcomes were reported purporting to show benefits of benazepril treatment in dogs other than Cavalier King Charles spaniels; however, the methodological limitations of this study cast significant doubt on these claims.17,18

Use in cats

There is very limited research evidence evaluating ACE inhibitors in cats. One small study of cats with hypertrophic cardiomyopathy (HCM) and not CHF found no significant effect of treatment with ramipril.19 Another study evaluated benazepril on cats with various types of heart disease both with and without CHF and found no evidence of any benefits.20

Bottom line

Though there is a plausible physiologic rationale for use of ACE inhibitors in veterinary patients with heart disease, there is limited research evidence showing clinical benefits. There is moderate evidence ACE inhibitors improve symptoms and prolong survival in dogs with CHF, though not all studies have found such benefits. ACE inhibitors probably do not delay the onset of CHF in dogs with MVD, and it is doubtful whether they provide any other benefits in such patients. Very limited research in cats has found no evidence of benefits from ACE inhibitors in with or without CHF.

Despite the uncertainty about their benefits, the risks of ACE inhibitors appear to be small. Adverse renal effects can occur, but these are rare, and there is evidence ACE inhibitors can improve some aspects of renal disease in dogs and cats. Hypotension can also occur with ACE inhibitors, especially combined with diuretics or other drugs that lower blood pressure. Overall, ACE inhibitors appear to be well tolerated by most patients.2

Brennen McKenzie, MA, MSc, VMD, cVMA, discovered evidence-based veterinary medicine after attending the University of Pennsylvania School of Veterinary Medicine and working as a small animal general practice veterinarian. He has served as president of the Evidence-Based Veterinary Medicine Association and reaches out to the public through his SkeptVet blog, the Science-Based Medicine blog, and more. He is certified in medical acupuncture for veterinarians. Columnists’ opinions do not necessarily reflect those of Veterinary Practice News.

References

  1. Ames MK, Atkins CE, Pitt B. The renin-angiotensin-aldosterone system and its suppression. J Vet Intern Med. 2019;33(2):363-382. doi:10.1111/jvim.15454
  2. Lefebvre H, Brown S, Chetboul V, King J, Pouchelon J-L, Toutain P. Angiotensin-Converting Enzyme Inhibitors in Veterinary Medicine. Curr Pharm Des. 2007;13(13):1347-1361. doi:10.2174/138161207780618830
  3. McKelvie RS. Heart failure. BMJ Clin Evid. 2011;2011. http://www.ncbi.nlm.nih.gov/pubmed/21878135. Accessed December 14, 2019.
  4. Weintraub RG, Semsarian C, Macdonald P. Dilated cardiomyopathy. Lancet. 2017;390(10092):400-414. doi:10.1016/S0140-6736(16)31713-5
  5. Strauss CE, Duval S, Pastorius D, Harris KM. Pharmacotherapy in the treatment of mitral regurgitation: A systematic review. J Heart Valve Dis. 2012;21(3):275-285.
  6. Woodfield JA. 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(4):243-252. doi:10.1111/j.1939-1676.1995.tb01075.x
  7. 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(11):1573-1577. http://www.ncbi.nlm.nih.gov/pubmed/9838955. Accessed December 14, 2019.
  8. 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(1):7-18. doi:10.1016/S1760-2734(06)70025-X
  9. Sisson DD. 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(4):234-242. doi:10.1111/j.1939-1676.1995.tb01074.x
  10. Atkins CE, Keene BW, Brown WA, et al. Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency. J Am Vet Med Assoc. 2007;231(7):1061-1069. doi:10.2460/javma.231.7.1061
  11. Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsorship and research outcome. Cochrane database Syst Rev. 2017;2:MR000033. doi:10.1002/14651858.MR000033.pub3
  12. Mandrioli D, Kearns CE, Bero LA. Relationship between research outcomes and risk of bias, study sponsorship, and author financial conflicts of interest in reviews of the effects of artificially sweetened beverages on weight outcomes: A systematic review of reviews. PLoS One. 2016;11(9). doi:10.1371/journal.pone.0162198
  13. Wess G. The VALVE Study – Is Triple Therapy Superior to Double Therapy for Heart Failure Treatment Due to Endocardiosis? – Vasotop® (Ramipril) in Addition to Lasix® and Vetmedin® in Canine Endocardiosis (VALVE Study). In: 2017 American College of Veterinary Internal Medicine Forum. National Harbor, MD; 2017.
  14. Konstam MA. Angiotensin converting enzyme inhibition, in asymptomatic left ventricular systolic dysfunction and early heart failure. Eur Heart J. 1995;16(suppl N):59-64. doi:10.1093/eurheartj/16.suppl_n.59
  15. Reed B, Sueta C. Stage B: What is the Evidence for Treatment of Asymptomatic Left Ventricular Dysfunction? Curr Cardiol Rev. 2014;11(1):18-22. doi:10.2174/1573403×09666131117164352
  16. Kvart C, Häggström J, Pedersen HD, et al. Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation. J Vet Intern Med. 16(1):80-88. http://www.ncbi.nlm.nih.gov/pubmed/11822810. Accessed December 14, 2019.
  17. Pouchelon J-L, Jamet N, Gouni V, et al. Effect of Benazepril on Survival and Cardiac Events in Dogs with Asymptomatic Mitral Valve Disease: A Retrospective Study of 141 Cases. J Vet Intern Med. 2008;22(4):905-914. doi:10.1111/j.1939-1676.2008.0105.x
  18. Kittleson M, Rishniw M, Pion P. Correspondence. J Vet Intern Med. 2009;23(3):445-446. doi:10.1111/j.1939-1676.2009.0294.x
  19. MacDonald KA, Kittleson MD, Larson RF, Kass P, Klose T, Wisner ER. The effect of ramipril on left ventricular mass, myocardial fibrosis, diastolic function, and plasma neurohormones in Maine Coon cats with familial hypertrophic cardiomyopathy without heart failure. J Vet Intern Med. 2006;20(5):1093-1105. doi:10.1892/0891-6640(2006)20[1093:TEOROL]2.0.CO;2
  20. King JN, Martin M, Chetboul V, et al. Evaluation of benazepril in cats with heart disease in a prospective, randomized, blinded, placebo‐controlled clinical trial. J Vet Intern Med. 2019;33(6):2559-2571. doi:10.1111/jvim.15572
Comments
Post a Comment

Comments