Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study—A Randomized Clinical Trial

Abstract

BackgroundPimobendan is effective in treatment of dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD). Its effect on dogs before the onset of CHF is unknown.Hypothesis/ObjectivesAdministration of pimobendan (0.4–0.6 mg/kg/d in divided doses) to dogs with increased heart size secondary to preclinical MMVD, not receiving other cardiovascular medications, will delay the onset of signs of CHF, cardiac‐related death, or euthanasia.Animals360 client‐owned dogs with MMVD with left atrial‐to‐aortic ratio ≥1.6, normalized left ventricular internal diameter in diastole ≥1.7, and vertebral heart sum >10.5.MethodsProspective, randomized, placebo‐controlled, blinded, multicenter clinical trial. Primary outcome variable was time to a composite of the onset of CHF, cardiac‐related death, or euthanasia.ResultsMedian time to primary endpoint was 1228 days (95% CI: 856–NA) in the pimobendan group and 766 days (95% CI: 667–875) in the placebo group (P = .0038). Hazard ratio for the pimobendan group was 0.64 (95% CI: 0.47–0.87) compared with the placebo group. The benefit persisted after adjustment for other variables. Adverse events were not different between treatment groups. Dogs in the pimobendan group lived longer (median survival time was 1059 days (95% CI: 952–NA) in the pimobendan group and 902 days (95% CI: 747–1061) in the placebo group) (P = .012).Conclusions and Clinical ImportanceAdministration of pimobendan to dogs with MMVD and echocardiographic and radiographic evidence of cardiomegaly results in prolongation of preclinical period and is safe and well tolerated. Prolongation of preclinical period by approximately 15 months represents substantial clinical benefit.

A prospective, randomized, double‐blind, placebo‐controlled pilot study of sacubitril/valsartan (Entresto) in dogs with cardiomegaly secondary to myxomatous mitral valve disease

“…Dogs were excluded from the study if they had congenital cardiac disease or acquired cardiac disease other than MMVD, clinically relevant arrhythmias, or echocardiographic evidence of clinically relevant pulmonary hypertension (PH) defined as a right ventricular‐to‐right atrial pressure gradient (RV : RA PG) > 65 mm Hg 29. Dogs were excluded if they had previous or current evidence of left‐sided CHF.…”

“…Congestive heart failure was defined as radiographic evidence of cardiogenic pulmonary edema denoted by an interstitial or alveolar pulmonary pattern in the caudodorsal lung fields, as well as contemporaneous clinical signs (eg, tachypnea, dyspnea, cough, and increased sleeping respiratory rate) that would require furosemide treatment. Dogs were excluded if they were being treated with ACEI, other cardiovascular medication(s) other than pimobendan, or non‐cardiovascular medications with known effects on the RAAS, such as corticosteroids 29. Dogs with clinically relevant diseases, or diseases suspected to affect the RAAS (ie, chronic renal disease, hyperadrenocorticism) were excluded.…”

Plasma and tissue angiotensin‐converting enzyme 2 activity and plasma equilibrium concentrations of angiotensin peptides in dogs with heart disease

“…Further classification of dogs in stage B occurred depending on the absence (stage B1) or presence (stage B2) of heart enlargement on echocardiography defined as LVIDdN ≥ 1.7 and LA:Ao ≥ 1.6. 17 Venipuncture, blood collection, and storage were performed as previously described. Healthy dogs were recruited as described above.…”

Clinical Trials in Veterinary Medicine: A New Era Brings New Challenges

“…The use and reporting of ITT and PP methods in both the human42, 46, 47 and veterinary3, 4, 5, 6, 7, 8, 9, 13 medical literature varies widely. In many studies, key pieces of information, including original number of patients recruited and randomized, how missing data was treated, and exactly which analysis methods and data sets were used, are lacking 48, 49.…”

“…A glance through recent issues of the Journal of Veterinary Internal Medicine identifies prospective randomized clinical trials (RCTs) involving dogs,1, 2, 3, 4, 5, 6, 7, 8, 9 cats,10, 11, 12, 13 cows,14, 15 and horses16, 17 that cover the fields of neurology,1, 8 oncology,3, 5 cardiology,4, 6, 12 and internal medicine 2, 9, 10, 11, 13, 14, 15, 16, 17. Collectively, these findings suggest that we have entered into an era of prospective veterinary RCTs.…”