Response to letter to the editor regarding “Efficacy of adding ramipril (VAsotop) to the combination of furosemide (Lasix) and pimobendan (VEtmedin) in dogs with mitral valve degeneration: The VALVE trial”

Dear editor, We appreciate the interest in our VALVE trial by Dr Atkins and others. The authors open an important discussion and raise several interesting questions that we would like to address. However, we would like to point out that their letter to the editor appears to start with a misunderstanding. The aim or the primary hypothesis of the VALVE trial was not to address whether pimobendan “is all that is needed beyond loop diuretics to manage CHF in MMVD. ” The only aim of the VALVE trial was to answer the question in dogs with MMVD that had reached the stage of congestive heart failure (CHF), ACVIM stage C or D, if the addition of an angiotensin converting enzyme inhibitor (ACEI) to the basic treatment of a loop diuretic combined with pimobendan is superior to this basic treatment. It is our opinion that this question has been considered clinically relevant by the veterinary community for quite some time. Please allow us to further elaborate on the historical background of the ACEI issue and the underlying evidence. Approximately 30 years ago, ACEI found their way into veterinary cardiology and their use made pathophysiological sense. Subsequently, the IMPROVE, LIVE, and BENCH studies led to the approval of ACE inhibitors for dogs. These trials were groundbreaking in veterinary cardiovascular medicine, being large controlled clinical multicenter trials. However, it should be noted that they do not meet the CONSORT recommendations, which is mandatory for trials of this size conducted today. At about the same time, the term “evidence-based medicine,” first mentioned in 1990 in human medicine, also found its way into the veterinary community, and was further defined in 2005. For many years, ACEI use in veterinary medicine was based on good evidence, the evidence being based on pathophysiological logic, experimental animals, extrapolation from human medicine, small veterinary studies, and expert opinion. In fact, ACEI had been advised and used for many years to treat preclinical heart disease in dogs. However, subsequently it was shown that the systemic RAAS system was not measurably activated in MMVD, if furosemide was not part of the treatment. This raised the question as to whether ACEI were beneficial in dogs with MMVD before the development of congestion and before the use of diuretics. Nevertheless, ACEI inhibitors continued to be widely used in dogs with preclinical MMVD (ACVIM stage B) for many years, and still are. Then came the SVEP trial, a prospective randomized study which failed to show any benefit of enalapril in dogs with MMVD, when administered before the clinical occurrence of congestion. There was no measurable benefit demonstrated, neither in dogs with normal heart size (which today would be called ACVIM stage B1), nor in dogs with demonstrable compensatory left ventricular volume overload (which today would be classified as ACVIM stage B2). Despite this evidence, ACEI were still recommended in dogs with MMVD in the noncongested phase. Some arguments for ignoring the results of the SVEP trial were inadequate dosage and the inclusion of only one breed, the Cavalier King Charles Spaniel, which might not be representative of other breeds with the same disease. Next came a study similar to the SVEP trial, performed and published by Atkins et al. This trial had some different aspects from the SVEP trial, specifically multiple breeds were enrolled and a reasonable dosage of ACEI was chosen. This second prospective randomized trial did not show a statistical difference between dogs on an ACEI and those on placebo concerning the primary endpoint. In this publication, the authors carefully analyzed the data and offered plausible reasons to explain this unexpected result. One consideration was the possibility that starting ACEI treatment could be harmful to a certain subgroup of dogs with MMVD, and that if these dogs were excluded from the study, a benefit might be shown. One major problem with that argument is the fact that no known parameter could identify the proposed subgroup of dogs, at least at the present time to our knowledge. Despite statistical nonsuperiority of ACEI over placebo in this second study, ACEI still are widely used in dogs with MMVD in ACVIM stages B1 and B2. In dogs with MMVD and decompensation (which today would be called ACVIM stage C), the usefulness of ACEI was not questioned, and they were still broadly recommended and used. Received: 12 January 2021 Accepted: 12 January 2021