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ACE inhibitors in canine heart disease: are we giving the right dose?

Datasheets for both Fortekor Flavour and Benazecare state that they should be prescribed for dogs with CHF at a dose range 0.25-0.5mg benazepril hydrochloride/kg body weight once daily. And that ‘the dose may be doubled, still administered once daily, to a minimum dose of 0.5 mg/kg (range 0.5-1.0), if judged clinically necessary and advised by the veterinary surgeon.’

This paper, hot off the JVIM press, raises the question of whether we should be giving more:

J Vet Intern Med 2021 Sep;35(5):2102-2111. 
Retrospective evaluation of a dose-dependent effect of angiotensin-converting enzyme inhibitors on long-term outcome in dogs with cardiac disease
Jessica L Ward, Yen-Yu Chou, Lingnan Yuan, Karin S Dorman, Jonathan P Mochel 

https://onlinelibrary.wiley.com/doi/full/10.1111/jvim.16236

This sets the cat back amongst the pigeons.  Just when the pigeons thought they’d about done with all that.

To summarise very briefly:

• there is limited and conflicting data on the pharmacokinetics of ACEi in dogs
• there’s some evidence of circadian rhythm in RAAS biomarkers
• at the end of the day, regardless of theoretical concepts, we lack real-world evidence of relative benefits of difference ACEi doses and dose frequencies in canine heart disease
• this has been the source of some debate.  For example:

Angiotensin-Converting Enzyme Inhibitors and Cardiac Disease: Have They Had Their Day? Mark Rishniw. Advances in Sm. Anim. Med. & Surg. February 2020;33(2):1-3

https://www.sciencedirect.com/science/article/abs/pii/S1041782620300189?via%3Dihub

• Ward et al. looked retrospectively at 144 dogs prescribed benazepril or enalapril for heart disease (a mix of DMVD, DCM and other conditions; in various stages).
• They looked at outcomes (onset of CHF, survival) related to variables including total daily ACEi dose, dose frequency, diagnosis, stage (B2 vs C) and blood pressure.
• Interestingly and illuminatingly, ACEi dose varied very widely from 0.2-0.3mg/Kg/day to >1.2mg/Kg/day.
• Neither ACEI dose nor dose frequency were significant predictors of 2-year survival in the full study sample (i.e. when dogs were included who were not in CHF at the time when ACEi were first prescribed )
• Survival was strongly associated with total ACEi dose for dogs in CHF (those in CHF at first visit and for those who reached CHF during the study).  You’ll have to look at fig 4 in the paper, but the Kaplan-Meier curve looks subjectively quite convincing to the non-statistical eye. 

There are complex statistical considerations here because dogs on twice daily dosing were much more likely to be on higher total daily dose (unsurprisingly).  In final, multivariable, models twice daily dosing emerged as a predictor of improved 2 year survival….but, the authors acknowledge that

‘It is therefore impossible to determine whether the survival benefit found in our study was associated with higher ACEI dose, q12h dose frequency, or both‘.

The authors conclude

‘Administration of ACEI at a median dose of 0.84 mg/kg/day was well-tolerated in this large group of dogs with cardiac disease. These findings provide a potential explanation for the failure of clinical trials to identify a clinical benefit of ACEI in dogs with cardiovascular disease, because all such previous trials have utilized ACEI dosages <0.5 mg/kg q24h‘

There are obvious, important caveats in such a limited, retrospective study: a fact freely conceded by the authors. However, in my eyes and pending prospective studies, this paper provides reasonable justification for using ACEi (benazepril or enalapril) in dogs with CHF at 0.25-0.5mg/Kg bid.  

….another overhaul of prescribing recommendations, sigh!