Breakthrough: a first-in-class virtual simulator for dose optimization of ACE inhibitors in translational cardiovascular medicine.

The renin-angiotensin-aldosterone-systems (RAAS) play a central role in the pathophysiology of congestive heart failure (CHF), justifying the use of angiotensin converting enzyme inhibitors (ACEi) in dogs and humans with cardiac diseases. Seminal studies in canine CHF had suggested that the pharmacological action of benazepril was relatively independent of doses greater than 0.25 mg/kg P.O, thereby providing a rationale for the European labeled dose of benazepril in dogs with CHF. However, most of these earlier studies relied on measures of ACE activity, a sub-optimal endpoint to characterize the effect of ACEi on the RAAS. The objectives of this study were (i) to expand on previous mathematical modeling efforts of the dose-exposure-response relationship of benazepril on biomarkers of the RAAS which are relevant to CHF pathophysiology and disease prognosis; and (ii) to develop a software implementation capable of simulating clinical trials in benazepril in dogs bedside dose optimization. Our results suggest that 0.5 mg/kg PO q12h of benazepril produces the most robust reduction in angiotensin II and upregulation of RAAS alternative pathway biomarkers. This model will eventually be expanded to include relevant clinical endpoints, which will be evaluated in an upcoming prospective trial in canine patients with CHF.

'The Mercury Challenge': feline systolic blood pressure in primary care practice - a European survey.

OBJECTIVES: The aim of this study was to collect data from a substantial number of older cats having their systolic blood pressure (SBP) measured in a variety of clinical practices, to describe the findings and assess variables that affected the duration of assessment and the values obtained. METHODS: An international (European-based) multicentre convenience sample survey of cats ⩾7 years of age attending veterinary clinics and having SBP measured as part of their clinical assessment. Information gathered included details of the cat, concomitant disease(s) or therapies, SBP results, device used, time taken to assess SBP and the demeanor of the cat. RESULTS: Useable data were available from 8884 cats aged 7-26 years, from 811 clinics across 16 countries. The device used to measure SBP was Doppler in 47.4% and oscillometry in 48.5%. The demeanor of the cat was reported to be calm in 45.7%, anxious in 41.9% and nervous in 8.9%; and the duration of assessment was reported to be <5 mins in 50.4%, 5-10 minutes in 41.7% and >10 mins in 7.9%. Concomitant chronic kidney disease (CKD) was reported in 21.8%, hyperthyroidism in 12.0% or both in 3.1%. The median SBP was 150 mmHg (range 80-310), with 18.6% classified as hypertensive (SBP 160-179 mmHg) and 21.1% as severely hypertensive (SBP ⩾180 mmHg). The measured SBP was significantly affected by the cat's demeanor, duration of SBP assessment, presence of CKD and/or hyperthyroidism, the cat's sex and age, and the presence of concomitant therapy. The duration of SBP assessment was significantly affected by the cat's demeanor. CONCLUSIONS AND RELEVANCE: In veterinary clinics, SBP can be measured in most cats within a short period of time using either Doppler or oscillometric equipment. The presence of CKD or hyperthyroidism was associated with significantly higher SBP values, and anxious or nervous cats had higher SBP values and took longer to obtain SBP assessments.

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).

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS), when chronically activated, is harmful and RAAS-suppressive drugs are beneficial in the treatment of congestive heart failure (CHF). Mineralocorticoid receptor antagonists are widely used in the treatment of CHF in people. HYPOTHESIS/OBJECTIVES: To determine if a mineralocorticoid receptor antagonist (spironolactone) is beneficial and safe in CHF due to myxomatous mitral valve disease (MMVD) of varying severity, we hypothesized that, when combined with furosemide, a combination product (S+BNZ) containing the ACE inhibitor (ACE-I), benazepril, and spironolactone, would be superior to benazepril alone. ANIMALS: Five hundred and sixty-nine client-owned dogs, with MMVD and CHF (ACVIM Stage C) of ≤10-days' duration. METHODS: After initial stabilization, dogs were randomized into a positive-controlled, double-blind, multicenter trial, to receive furosemide plus S+BNZ or furosemide plus benazepril. The primary outcome variable was the percentage of dogs reaching cardiac endpoint before Day 360. Cardiac endpoint was defined as cardiac death or euthanasia, recurrence of pulmonary edema, necessity for nonauthorized cardiac drug(s) or a furosemide dosage >8 mg/kg/d. RESULTS: A significantly lower percentage of dogs treated with S+BNZ reached the primary outcome variable by Day 360 (OR = 0.56; 95% CI, 0.32-0.98; P = .04) and risk of dying or worsening from cardiac causes, was significantly reduced (HR = 0.73; 95% CI = 0.59-0.89, P = .002) vs benazepril alone. Adverse events, potentially associated with treatment, were rare and equal between groups. CONCLUSION AND CLINICAL IMPORTANCE: The combination of S+BNZ 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.

Efficacy of oral torasemide in dogs with degenerative mitral valve disease and new onset congestive heart failure: The CARPODIEM study.

BACKGROUND: Torasemide is a potent loop diuretic with potential to treat congestive heart failure (CHF) in dogs. OBJECTIVE: Evaluate the efficacy and safety of torasemide compared to furosemide in dogs with first occurrence of CHF caused by degenerative mitral valve disease (DMVD). ANIMALS: Three hundred and nineteen dogs with new onset CHF attributable to DMVD. METHODS: Double-blinded randomized noninferiority study of PO torasemide vs furosemide in addition to standard CHF treatment. The primary efficacy criterion was decreased pulmonary edema and cough and no worsening of dyspnea or exercise tolerance at day 14. Secondary endpoints included clinical response at day 84 and time to death, euthanasia, or premature study withdrawal for cardiac reasons. RESULTS: Torasemide q24h (n = 161) was noninferior to furosemide q12h (n = 158); percentage of dogs meeting primary efficacy criterion at day 14 was similar between groups (torasemide, 74.4% [95% confidence interval (CI), 66.8%-81.0%] vs. furosemide, 73.5% [95% CI, 65.7%-80.4%]; risk ratio [RR], 1.01; 95% CI, 0.89-1.15; P = .87). Efficacy at day 84 showed similar results (RR, 1.05; 95% CI, 0.88-1.25; P = .6). Dogs receiving torasemide had a longer time to endpoint and were less than half as likely to experience death, euthanasia, or premature study withdrawal (hazard ratio, 0.36; 95% CI, 0.19-0.65; P = .001) than dogs receiving furosemide at any time during the study. CONCLUSION AND CLINICAL IMPORTANCE: Torasemide was noninferior to furosemide as first line PO treatment for new onset CHF caused by DMVD. Torasemide significantly decreased risk of cardiac-related death or premature study withdrawal for cardiac reasons compared to furosemide.

The SEISICAT study: a pilot study assessing efficacy and safety of spironolactone in cats with congestive heart failure secondary to cardiomyopathy.

INTRODUCTION: The pathophysiology of heart failure involves activation of several neurohormonal systems including the renin-angiotensin-aldosterone system. The mineralocorticoid receptor antagonist spironolactone has been shown to be beneficial in humans and dogs with heart failure. The objective of this pilot study was to investigate the efficacy and safety of spironolactone in cats with heart failure secondary to cardiomyopathy already treated with furosemide and an angiotensin-converting enzyme inhibitor. ANIMALS: Twenty cats with heart failure due to cardiomyopathy. METHODS: The study was a double-blind, randomised, placebo-controlled, multicentre clinical study assessing the effect of spironolactone on survival and clinical parameters in cats with heart failure due to cardiomyopathy. The primary end point was mortality, defined as death (spontaneous or by euthanasia) due to cardiac causes. RESULTS: Twenty cats were enrolled: 9 in the spironolactone group and 11 in the placebo group of which 56% (5/9) and 0% (0/11) completed the 15-month period respectively. At inclusion, differences in systemic blood pressure, body condition score, electrocardiographic abnormalities and LA/Ao ratio suggested that disease may be less severe in the spironolactone group. Twenty-two percent (2/9) of cats in the spironolactone group and 82% (9/11) in the control group reached the primary end point (Fisher's exact test, p = 0.0216). No safety issues were identified in either group. CONCLUSIONS: This study suggests that spironolactone is well tolerated, and preliminary results support further investigation to evaluate the efficacy of spironolactone in the treatment of cats with cardiac failure due to cardiomyopathy.