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New research looks at spironolactone + benazepril for CHF associated with canine mitral valve disease: the BESST study

J Vet Intern Med . 2021 Jul;35(4):1673-1687
Clinical efficacy of a benazepril and spironolactone combination in dogs with congestive heart failure due to myxomatous mitral valve disease: The BEnazepril Spironolactone STudy (BESST)
Melissa Coffman, Emilie Guillot, Thomas Blondel, Catherine Garelli-Paar, Shuo Feng , Susanne Heartsill , Clarke E Atkins 

https://onlinelibrary.wiley.com/doi/full/10.1111/jvim.16155

Prepare to be confronted with a renewed wave of marketing as the latest canine heart medication research hits the street. This is a big multi-centre, randomised, double-blinded study -and, as such, it ticks a lot of evidence-based medicine boxes.

Perhaps I’m just an old cynic, and I know it’s inevitable that these studies are always funded by the companies selling the product in question, but I feel that we know enough about the realities of clinical research to be aware that the outcomes always warrant serious scrutiny.  They are routinely backed by the endorsement of very highly qualified clinicians -and that in itself shouldn’t give the published findings a ‘free pass’.  Even without conspiracy theories, the annals of medical research are full of impressive findings which subsequently prove not to fulfil their initial promise.

So, the published punchline here is that….

‘The combination of spironolactone and benazepril is effective, safe, and superior to benazepril alone, when used with furosemide for the management of mild, moderate or severe CHF caused by MMVD in dogs‘

OK, that seems fair enough.  The big issue is how this translates into practice.

Neither the benazepril + frusemide nor the benazepril + frusemide + spironolactone groups were allowed pimobendan.  Given that the QUEST study, which showed convincing superiority of frusemide + pimobendan over frusemide + benazepril,  was published in 2008 it seems a bit lame to say that ‘study designers grappled with the ethics of a CHF study not including pimobendan, which had, at the time, been recently shown to benefit dogs in CHF with MMVD‘.

Apart from the ethical side of things, this immediately leaves us with the whopping unanswered issue of ‘is frusemide + pimobendan + benazepril + spironolactone any better than frusemide + pimobendan’?

 The latest on the ACEi front prior to BESST is that according to the VALVE study:

J Vet Intern Med 2020 Nov;34(6):2232-2241
Efficacy of adding ramipril (VAsotop) to the combination of furosemide (Lasix) and pimobendan (VEtmedin) in dogs with mitral valve degeneration: The VALVE trial
Gerhard Wess 1, Jan-Gerd Kresken 2, Ralph Wendt 3, Juliane Gaugele 1, Markus Killich 1, Lisa Keller 1, Julia Simak 1, Peter Holler 1, Alexander Bauer 4, Helmut Küchenhof 4, Tony Glaus

https://onlinelibrary.wiley.com/doi/abs/10.1111/jvim.15863

….frusemide + pimobendan + ramipril did not confer improved outcomes versus frusemide + pimobendan.

The case for ACEi in canine CHF generally rests heavily on three studies: VALVE, BENCH and LIVE.

Essentially, VALVE found no added benefit with ACEi. 

The conclusions drawn by the authors of BENCH, as viewed from 2021, seem open to question given that median survival for the frusemide + benazepril group was 436 days and some of these dogs were reported to have had clinical signs for up to 5 years before entering the study.  Given that inclusion criteria were ISACHC heart failure stage II or III (and that stage II might include dogs with, for instance, cough), in the light of our subsequently evolved understanding of canine cardiorespiratory medicine in the subsequent two decades it seems justifiable to query whether all of the dogs were actually in CHF.

Broadly-speaking BESST, QUEST and BENCH each included a group of MMVD dogs treated with frusemide + benazepril.  There are slight differences in end-point designations but, essentially, each looked at time to cardiac death or deterioration of CHF such that additional interventions were necessary.

Median time to endpoint for the three studies were 69, 111 days and 436 days respectively.  The discrepancy speaks for itself.

LIVE has also been questioned

Advances in Sm. Anim. Med. & Surg. February 2020;33(2):1-3

Angiotensin-Converting Enzyme Inhibitors and Cardiac Disease: Have They Had Their Day?

Mark Rishniw. 

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

All in all, the case for ACEi in canine MMVD-associated CHF is highly debatable. 

I suspect that on the back of BESST we are now going to be urged with renewed authority to treat CHF due to MMVD with frusemide + pimobendan + ACEi + spironolactone.  And it will be based on an EBVM-friendly RCT.

Personally, I’m not convinced that we really know whether we should routinely do more than loop diuretic + pimobendan in stage C.  In end-stage disease I fully accept that there’s little to lose by adding everything we’ve got in the cupboard.

It will be interesting to see how the debate unfolds.