Evaluating the cost-effectiveness of diagnosing and treating phantom cows in seasonal-calving dairy herds.

The objective of this study was to explore the cost-effectiveness of using a progesterone-based synchrony program to manage phantom cows on seasonal-calving dairy farms. Phantom cows were defined as cows that had been artificially inseminated ≤14 d after mating start date (MSD), were not subsequently detected in estrus, and were diagnosed nonpregnant at a pregnancy diagnosis conducted approximately 49 d after MSD. Decision-tree analysis was applied to data from a previous randomized controlled trial in which phantom cows (n = 378) from spring-calving dairy farms were randomly allocated to an untreated control group or were immediately treated with a 10-d progesterone-based synchrony program with fixed-time artificial insemination. The net economic return of treating all cows presented by the farmer for pregnancy diagnosis that were diagnosed nonpregnant was compared with no intervention. The net return was calculated per cow present at MSD because the decision trees followed all cows present at MSD through to mating end date to account for farmers inadvertently presenting ineligible cows for pregnancy diagnosis and possible treatment. Probabilities, costs, and benefits of reproductive outcomes were based on published data and expert opinion. The effects of key variables on the economic return were tested by sensitivity analysis. Phantom cow intervention delivered a net return of NZ$4.451 (at the time of the study, NZ$1 = US$0.6629) per cow present at MSD. The sensitivity of pregnancy diagnosis, the proportion of ineligible cows presented by the farmer for pregnancy diagnosis, and the prevalence of phantom cows were highly influential on the net economic return from phantom cow intervention. These findings suggest that treatment of phantom cows in seasonal-calving dairy farms using a progesterone-based synchrony program is economically viable based on the current model assumptions. Accurate cow selection and pregnancy diagnosis are essential to success, and veterinarians and animal health advisors can improve the net economic return of intervention by selecting farms likely to have a higher prevalence of phantom cows based on the presence of observable risk factors.

Effect of treatment of phantom cows with a progesterone-based synchrony programme.

Aim: To determine the effect of a progesterone-based synchrony programme on the daily hazard of conception and the probability of being pregnant at the end of the seasonal mating period in cows not observed in oestrus within 35-49 days of insemination and that were diagnosed non-pregnant (phantom cows) on seasonally calving New Zealand dairy farms. Secondary aims were to determine the prevalence of phantom cows and estimate the proportion of phantom cows with a functional corpus luteum (CL) at enrolment. Methods: Phantom cows from 14 New Zealand commercial dairy farms were enrolled in a randomised, controlled trial. Cows that were artificially inseminated ≤14 days after mating start date and were not subsequently detected in oestrus, were presented for pregnancy diagnosis approximately 49 days after mating start date. Non-pregnant cows were diagnosed as phantom cows and randomly allocated to treatment and control groups. A milk sample was collected for progesterone assay to determine the presence of a functional CL. Treatment consisted of an injection of buserelin and insertion of an intravaginal device containing progesterone on Day 0, injections of dinoprost and equine chorionic gonadotrophin, and removal of the intravaginal device on Day 7, injection of buserelin on Day 9, and fixed time artificial insemination on Day 10. Treatment group cows were then mixed with bulls for the remainder of the seasonal mating period. Cows allocated to the control group were mated naturally by bulls. Statistical models were constructed to determine the effect of treatment on the daily hazard of conception and the probability of being pregnant at the end of the seasonal mating period. Results: A total of 378/4,214 (9.0%) cows presented for pregnancy diagnosis were diagnosed as phantom cows. A functional CL was diagnosed in 257/362 (71.0%) phantom cows. Median predicted enrolment to conception intervals were 33 (95% CI = 30-45) and 30 (95% CI = 28-33) days, for cows in the control and treatment groups, respectively. The odds of being pregnant at the end of mating were 1.70 (95% CI = 1.34-2.17) times greater for treated phantom cows than untreated phantom cows. Estimated marginal mean proportion pregnant at mating end date were 59.5 (95% CI = 47.9-70.1)% and 71.5 (95% CI = 62.6-79.0)% for control and treatment group cows, respectively. Conclusions: Treatment with a progesterone-based synchrony programme significantly increased the probability of phantom cows being pregnant at the end of the seasonal mating period.

Use of two- and three-dimensional echocardiography for assessment of the left ventricular outflow tract and aortic orifice areas in dogs.

INTRODUCTION/OBJECTIVES: In clinical practice, dogs are screened for subaortic stenosis (SAS) using two-dimensional (2DE) and Doppler echocardiography. There is no accepted antemortem diagnostic criterion to distinguish between mild SAS and unaffected, therefore additional means of evaluating the left ventricular outflow tract (LVOT) and aorta may be desirable. This study sought to determine and compare LVOT and aortic orifice areas using 2DE and three-dimensional echocardiography (3DE) in apparently healthy dogs of various breeds and somatotypes. ANIMALS, MATERIALS, AND METHODS: Sixty-nine healthy, privately-owned dogs. The LVOT and aortic orifice areas were determined using 2DE aortic valve (AV) diameter-derived area; the continuity equation (CE); and 3DE planimetry of the LVOT, AV, sinus of Valsalva, and sinotubular junction. Orifice areas were indexed to body surface area (BSA). RESULTS: Obtaining 3DE images and performing planimetry were feasible in all dogs. The mean indexed area measured using the 2DE AV diameter (2.85 cm2/m2) was significantly lower than that derived from 3DE AV planimetry (3.85 cm2/m2; mean difference, 1.00 cm2/m2; P<0.001). There was poor agreement between the effective area calculated using the CE and the anatomic areas calculated using 2DE AV diameter and 3DE planimetry. The area calculated using the CE was less than all other calculations of area. Interobserver and intraobserver repeatability and reproducibility for 3DE planimetry were excellent. CONCLUSIONS: Methods for determining aortic orifice areas in dogs are not interchangeable, and this must be taken into account if these methods are investigated in the evaluation of dogs with SAS in the future.

Prospective clinical trial evaluating spironolactone in Doberman pinschers with congestive heart failure due to dilated cardiomyopathy.

INTRODUCTION/OBJECTIVES: Whether the aldosterone antagonist spironolactone has beneficial survival effects in dogs with dilated cardiomyopathy (DCM) is not known. The primary objective of the study was to evaluate the effect of spironolactone, when added to conventional therapy, on survival time in Doberman pinschers with congestive heart failure (CHF) due to DCM. ANIMALS: Sixty-seven client-owned Doberman pinschers with CHF due to DCM. MATERIALS AND METHODS: The trial design was prospective, randomized, blinded, and placebo controlled. Dogs were randomized to receive 50-75 mg of spironolactone twice daily (n = 34) or a placebo (n = 33), in addition to standard CHF therapy. Follow-up visits were targeted every one-six weeks until endpoint. Quality-of-life questionnaire and physical examination were performed at every visit, while renal biochemistry, ECG, echocardiography, and thoracic radiography were reassessed as needed. The primary endpoint was time to cardiac death, defined as death or euthanasia from CHF or sudden death. RESULTS: Median time to primary endpoint in the spironolactone group (183 days) was not statistically significantly different than that for the placebo group (124 days) (P = 0.254). The development of atrial fibrillation (AF) was significantly less frequent in the spironolactone group (n = 7) than the placebo group (n = 15, P = 0.037). CONCLUSIONS: While median time to cardiac death in the spironolactone group was not statistically significantly different than that in the placebo group, adding spironolactone to conventional therapy resulted in reduced occurrence of AF.

Total bilirubin is an independent predictor of death in dogs with degenerative valvular disease and dilated cardiomyopathy.

INTRODUCTION: There is little published regarding the association between canine cardiovascular disease and the hepatic system. The objective of the study was to evaluate the relationship between hepatic parameters, survival, and disease stages of dogs with either dilated cardiomyopathy (DCM) or degenerative valvular disease (DVD). ANIMALS, MATERIALS, AND METHODS: Retrospective study analyzing hepatic parameters in dogs with DVD or DCM in American College of Veterinary Internal Medicine stage B or C and healthy control dogs. Associations between liver parameters, type and stage of disease, and survival were investigated. RESULTS: Ninety-nine dogs were included in the study: 61 DVD, 22 DCM, and 16 controls. Differences in liver parameter concentrations between DCM, DVD, and disease stages were found. Univariate analysis identified alanine aminotransferase (P < 0.001), aspartate aminotransferase (P = 0.02), and total bilirubin (P = 0.005) as predictors of mortality. In the multivariate analysis, total bilirubin remained an independent predictor of mortality. CONCLUSIONS: The observed differences between DCM, DVD, and disease stages are likely consistent with disease-specific hemodynamics and progression of disease. This and the role of total bilirubin as an independent predictor for mortality indicate that in dogs with DVD and DCM the cardiovascular-hepatic interaction might be of relevance for disease progression and outcome, as reported for humans with cardiac disease. Further studies into the role of hepatic function in canine cardiac disease are required.

Heart rate distribution in dogs with third degree atrioventricular block and rate responsive pacemakers.

INTRODUCTION: In dogs, single lead ventricular pacing, ventricular sensing, inhibition response, rate adaptive (VVIR) pacemakers are routinely used to treat third degree atrioventricular block. The objectives of this study were to investigate the heart rate distribution in dogs with VVIR pacemakers, and report changes when activity settings were adjusted. ANIMALS: Eighteen client-owned dogs with VVIR pacemakers for third degree atrioventricular block. MATERIALS AND METHODS: This observational study consisted of a review of medical records of dogs with VVIR pacemakers. For dogs with >50% of paced beats at the lower pacing rate, the activity daily living (ADL) and exertion responses were increased. Re-evaluations were performed after 6-12 months. RESULTS: Heart rate distribution similar to healthy dogs was absent for all dogs. In nine dogs, the ADL and exertion responses were increased to the highest level. Of these, three dogs showed no improvement in heart rate distribution; for two dogs, one with an epicardial pacemaker, several activity settings were adjusted and pacing at higher heart rates was observed at re-evaluation. Four dogs died or were lost to follow-up. Clinical signs had resolved for all dogs after pacemaker implantation. CONCLUSION: Default activity settings of VVIR pacemakers do not result in heart rate distribution equivalent to healthy dogs. Increasing the ADL and exertion response settings to the highest levels did not improve the pacemaker rate response. Further investigations into the role of dog size, generator positioning, pacemaker settings, and whether rate responsiveness is required for dogs' quality and quantity of life are warranted.

Efficacy of benazepril hydrochloride to delay the progression of occult dilated cardiomyopathy in Doberman Pinschers.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACEIs) are recommended in people to treat asymptomatic (occult) dilated cardiomyopathy (DCM). Efficacy of therapy in occult DCM in dogs is unknown. HYPOTHESIS: ACEIs, specifically benazepril hydrochloride (BH), will delay the onset of overt DCM in Doberman Pinschers. ANIMALS: Ninety-one Doberman Pinschers were studied, 57 dogs received BH, and 34 dogs no ACEI. METHODS: Retrospective study of the medical records of all Doberman Pinschers with occult DCM that received BH or no ACEI between April 1989 and February 2003. Two criteria of left ventricular enlargement were used for enrollment: one independent of body weight (BW) (C1) and the other indexed to BW (C2). Cox proportional hazards analyses were used to identify variables associated with the onset of overt DCM. RESULTS: On univariate analysis the median time to onset of overt DCM was significantly longer for the benazepril group (for C1: 425 days for BH, 95% confidence interval [CI] 264-625 days; 339 days for no ACEI, CI 172-453 days, P= .02; for C2: 454 days for BH, CI 264-628 days; 356 days for no ACEI, CI 181-547 days, P= .02). The hazard ratio (HR) (benazepril/no ACEI) was 0.57, CI 0.35-0.94, P= .03 for C1; HR = 0.56, CI 0.34-0.93, P= .02 for C2. On multivariate analysis, BH significantly delayed onset of overt DCM (HR [benazepril/no ACEI] = 0.45, CI 0.26-0.78, P < .01, for C1; HR = 0.36, CI 0.21-0.63, P < .01, for C2). CONCLUSIONS: BH in particular and ACEIs in general might delay the progression of occult DCM. Prospective studies are warranted to test this theory.

Effect of pimobendan on case fatality rate in Doberman Pinschers with congestive heart failure caused by dilated cardiomyopathy.

BACKGROUND: Despite traditional therapy of a diuretic, angiotensin converting enzyme inhibitor, digoxin, or a combination of these drugs, survival of dogs with dilated cardiomyopathy (DCM) is low. Pimobendan, an inodilator, has both inotropic and balanced peripheral vasodilatory properties. HYPOTHESIS: Pimobendan when added to conventional therapy will improve morbidity and reduce case fatality rate in Doberman Pinschers with congestive heart failure (CHF) caused by DCM. ANIMALS: Sixteen Doberman Pinschers in CHF caused by DCM. METHODS: A prospective randomized, double-blind, placebo-controlled study with treatment failure as the primary and quality of life (QoL) indices as secondary outcome variables. Therapy consisted of furosemide (per os [PO] as required) and benazepril hydrochloride (0.5 mg/kg PO q12h) and dogs were randomized in pairs and by sex to receive pimobendan (0.25 mg/kg PO q12h) or placebo (1 tablet PO q12h). RESULTS: Pimobendan-treated dogs had a significant improvement in time to treatment failure (pimobendan median, 130.5 days; placebo median, 14 days; P= .002; risk ratio = 0.35, P= .003, lower 5% confidence limit = 0.13, upper 95% confidence limit = 0.71). Number and rate of dogs reaching treatment failure in the placebo group precluded the analysis of QoL. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan should be used as a first-line therapeutic in Doberman Pinschers for the treatment of CHF caused by DCM.

Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study.

BACKGROUND: Myxomatous mitral valve disease (MMVD) continues to be an important cause of morbidity and mortality in geriatric dogs despite conventional therapy. HYPOTHESIS: Pimobendan in addition to conventional therapy will extend time to sudden cardiac death, euthanasia for cardiac reasons, or treatment failure when compared with conventional therapy plus benazepril in dogs with congestive heart failure (CHF) attributable to MMVD. ANIMALS: Two hundred and sixty client-owned dogs in CHF caused by MMVD were recruited from 28 centers in Europe, Canada, and Australia. METHODS: A prospective single-blinded study with dogs randomized to PO receive pimobendan (0.4-0.6 mg/kg/d) or benazepril hydrochloride (0.25-1.0 mg/kg/d). The primary endpoint was a composite of cardiac death, euthanized for heart failure, or treatment failure. RESULTS: Eight dogs were excluded from analysis. One hundred and twenty-four dogs were randomized to pimobendan and 128 to benazepril. One hundred and ninety dogs reached the primary endpoint; the median time was 188 days (267 days for pimobendan, 140 days for benazepril hazard ratio = 0.688, 95% confidence limits [CL]=0.516-0.916, P= .0099). The benefit of pimobendan persisted after adjusting for all baseline variables. A longer time to reach the endpoint was also associated with being a Cavalier King Charles Spaniel, requiring a lower furosemide dose, and having a higher creatinine concentration. Increases in several indicators of cardiac enlargement (left atrial to aortic root ratio, vertebral heart scale, and percentage increase in left ventricular internal diameter in systole) were associated with a shorter time to endpoint, as was a worse tolerance for exercise. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan plus conventional therapy prolongs time to sudden death, euthanasia for cardiac reasons, or treatment failure in dogs with CHF caused by MMVD compared with benazepril plus conventional therapy.

Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo: The EPIC Study.

BACKGROUND: Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described. OBJECTIVES: To investigate the effect of pimobendan on clinical variables and the relationship between a change in heart size and the time to congestive heart failure (CHF) or cardiac-related death (CRD) in dogs with MMVD and cardiomegaly. To determine whether pimobendan-treated dogs differ from dogs receiving placebo at onset of CHF. ANIMALS: Three hundred and fifty-four dogs with MMVD and cardiomegaly. MATERIALS AND METHODS: Prospective, blinded study with dogs randomized (ratio 1:1) to pimobendan (0.4-0.6 mg/kg/d) or placebo. Clinical, laboratory, and heart-size variables in both groups were measured and compared at different time points (day 35 and onset of CHF) and over the study duration. Relationships between short-term changes in echocardiographic variables and time to CHF or CRD were explored. RESULTS: At day 35, heart size had reduced in the pimobendan group: median change in (Δ) LVIDDN -0.06 (IQR: -0.15 to +0.02), P < 0.0001, and LA:Ao -0.08 (IQR: -0.23 to +0.03), P < 0.0001. Reduction in heart size was associated with increased time to CHF or CRD. Hazard ratio for a 0.1 increase in ΔLVIDDN was 1.26, P = 0.0003. Hazard ratio for a 0.1 increase in ΔLA:Ao was 1.14, P = 0.0002. At onset of CHF, groups were similar. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan treatment reduces heart size. Reduced heart size is associated with improved outcome. At the onset of CHF, dogs treated with pimobendan were indistinguishable from those receiving placebo.

Cognitive problems following hematopoietic stem cell transplant: relationships with sleep, depression and fatigue.

Cognitive problems are a significant, persistent concern for patients undergoing hematopoietic stem cell transplant (HSCT). Sleep is important for many cognitive tasks; however, the relationship between sleep and cognitive problems for HSCT patients is unknown. This study examined the relationship between sleep and cognitive problems for HSCT patients from pre to post transplant. Patients undergoing HSCT (N=138) completed questionnaires at pre-transplant and during the 12 months following transplant. Questionnaires assessed sleep and cognitive problems as well as commonly co-occurring symptoms: depressive symptoms, fatigue and pain. Post hoc analyses examined the relationship of specific sleep problems with cognitive problems. Sleep problems covaried with cognitive problems even after controlling for depressive symptoms, fatigue and pain. Depressive symptoms and fatigue were also uniquely related to cognitive problems. Post hoc analyses suggest that sleep somnolence, shortness of breath, snoring and perceptions of inadequate sleep may contribute to the association found between sleep and cognitive problems. Findings suggest that sleep problems are associated with and may contribute to cognitive problems for HSCT patients. However, sleep problems are rarely screened for or discussed during clinic visits. Assessing and treating specific sleep problems in addition to depressive symptoms and fatigue may have implications for improving cognitive problems for HSCT patients.

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

BACKGROUND: Pimobendan 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/OBJECTIVES: Administration 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. ANIMALS: 360 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. METHODS: Prospective, 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. RESULTS: Median 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 IMPORTANCE: Administration 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.

Efficacy of pimobendan in the prevention of congestive heart failure or sudden death in Doberman Pinschers with preclinical dilated cardiomyopathy (the PROTECT Study).

BACKGROUND: The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported. HYPOTHESIS: That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival. ANIMALS: Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America. METHODS: The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint. RESULTS: The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441-1152 days) versus the placebo group (441 days, IQR 151-641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491-1531 days) versus the placebo group (466 days, IQR 236-710 days) (log-rank P = .034). CONCLUSION AND CLINICAL IMPORTANCE: The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome.