Multiple retrospective analysis of survival and evaluation of cardiac death predictors in a population of dogs affected by degenerative mitral valve disease in ACVIM class C treated with different therapeutic protocols

Clinical records of dogs with spontaneous degenerative mitral valve disease (DMVD) with clinical signs related to congestive heart failure (CHF) that had been recruited during routine clinical practice, between 2001 and 2018 at the Cardiology Unit of the Veterinary Teaching Hospital (University of Milan) were included in this retrospective cohort study. Baseline echocardiographic data were evaluated. Median survival times (MSTs) were calculated. Data on therapeutic treatment, ISACHC or ACVIM classes were reviewed based on the inclusion period and type of endpoint (i.e. cardiac death or death for other causes). The main goal of this data review was to retrospectively evaluate 259 clinical records of subjects belonging to ACVIM C class examined between 2001 to 2018 together with the 202 examined between 2010 to 2018. The MSTs of these subjects was 531 d (2001-2018) and 335.5 d (2010-2018), respectively. Univariate survival regression analysis for subjects included from 2010 to 2018 showed the following variables as being significantly related to cardiac death (CD): LA/Ao ratio (HR 2.754, p=0.000), E wave (HR 2.961, p=0.000), E/A ratio (HR 1.372, p=0.000), EDVI (HR 1.007, p=0.000), ESVI (HR 1.012, p=0.026), Allo(d) (HR 4.018, p=0.000) and Allo(s) (HR 2.674, p=0.049), age (HR 1.006, p=0.009) and PH severity (HR=1.309, p=0.012). Multivariate analysis, adjusted for age, showed that the only variable that determined a statistically significant difference in MST was PH severity (HR 1.334, p=0.033). The type of therapeutic treatment within this class was not significant for the MST of the subjects.


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Abstract: 28 Clinical records of dogs with spontaneous degenerative mitral valve disease (DMVD) with 29 clinical signs related to congestive heart failure (CHF) that had been recruited during routine Introduction 53 Degenerative mitral valve disease is the most common heart disease in middle-old aged and 54 medium-sized dogs. It is characterized by a slow progression over years, and in many affected 55 dogs, because of the age of onset, does not always progress to clinical signs of congestive 56 heart failure (CHF) [1,2,3]. Some authors have reported a survival time of between 5 to 14 57 months after the onset of clinical signs [4,5]. Although DMVD has been studied for more than 58 40 years, its treatment remains a challenge for the clinician. 59 Many advances have been made regarding diagnosis, imaging, medical and surgical therapy,  The aim of DMVD treatment is to modulate hemodynamic and neurohormonal disorders, 65 including high venous pressures, reduce the systolic function, activate the sympathetic and 66 renin-angiotensin-aldosterone systems, and also release cytokines and vasopressin [1,2]. 67 Treatment of CHF due to DMVD consists of a diuretic (loop diuretic, ++ furosemide) and 68 additional agents (angiotensin-converting enzyme inhibitors, inodilators and aldosterone 69 receptor antagonists) [8,9]. Angiotensin-converting enzyme inhibitors (ACE-Is), benazepril or 70 enalapril, combined with furosemide improve the quality of life [4,10]. The administration of 71 pimobendan, an inodilator, has been evaluated in dogs with CHF due to DMVD [5,11]. survived longer than dogs that did not [5,13]. Improved survival and reduction of risk for a 78 cardiac event have also been shown in dogs affected by DMVD and CHF treated with 79 spironolactone [14,15]. 80 The main goal of this study was to retrospectively investigate the survival time of a 81 population of dogs affected by DMVD belonging to ACVIM class C and treated with 82 different combinations of drugs including furosemide, ACE-I (benazepril or enalapril), 83 pimobendan, and spironolactone.

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The effects of the different therapeutic protocols on MST, and the prognostic value of the 85 echocardiographic variables were also evaluated. Committee because this is a retrospective study carried out on data collected in subjects 94 routinely brought to a clinical examination by the owners.

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From the beginning of the study to 2009, the admitted dogs were classified according to 96 ISACHC classes [16], and from 2010 to 2018 according to the ACVIM classification [9]. In 97 order to compare the subjects, a univocal classification was needed, and the patients classified  The clinical records were selected according to the following inclusion criteria: complete 108 clinical findings including signalment, history, physical examination, thoracic radiographs, 109 electrocardiogram (ECG) and a diagnosis of DMVD ACVIM class C based on 110 echocardiographic, and Doppler evaluation associated with clinical signs (increased resting 111 respiratory rate, cough, dyspnoea, ascites) [17]. In all subjects the presence and severity of PH 112 were evaluated, based on the TRV. The PH was classified as reported in the literature [18,19].

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The accepted administered drugs were a combination of diuretics (furosemide), ACE-I 114 (benazepril, enalapril and ramipril), inodilator (pimobendan), and spironolattone. The 115 therapeutic protocol applied was clearly reported on the clinical record from the first to the 116 last examiner, as well as whether the owner was willing to be interviewed by telephone. In 117 this study all genders, weights and breeds were included, except for Cavalier King Charles   Incomplete clinical records or with missing information on the therapeutic protocol adopted 126 were also excluded.   The survival analysis was performed considering different end points such as death due to 146 other causes (OC), death related to the studied heart pathology (CD -cardiac death), first and 147 following therapy changes and moving to more advanced gravity class. The survival time in 148 the CD group was also analysed in relation to the therapeutic scheme.  were mixed breed, 20.5 (7.9%) Poodle, 20 (7.7%) Yorkshire Terrier, 13 (5.1%) Dachshund, 7

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The therapeutic groups considered in the first analysis are reported in Table 1. Table 2  MST was 318 days (Table 3). 204 Univariate regression analysis showed the following variables to be statistically significant:           235 The therapy groups in the ACVIM class C were 1, 2 and 3 (Table 1).  The MST of subjects that died of CD was 665 days in group 1, 487 days in group 2, and 447 242 days in group 3.

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The univariate analysis revealed a positive correlation among the LA/Ao ratio, administration 244 of therapy (yes or no), E wave, E/A ratio, EDVI, ESVI, Allo(d) and Allo(s)), and CD. The 245 univariate analysis of the aforementioned variables was statistically significant for MST, 246 whose increase, increased the risk of death (Table 3).

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The multivariate analysis for subjects in class ACVIM C showed that only LA/Ao led to a 248 statistically significant difference in MST, and significantly increased (2.5 times) the risk of 249 CD, as described in Table 3.

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MSTs were also evaluated together with the influence of individual parameters on the MST 251 using univariate analysis and ANOVA tests between subjects with different types of therapy. increased the risk of CD, as did some of the other variables considered (Table 3).  The relationship between PH and CD was then investigated in each therapeutic group.  The distribution of PH severity among the three groups of dogs who died of CD is reported in 284 The regression model applied to each group of therapy evidenced different significant 294 correlations. In group 1 the following correlated significantly to CD: E wave, E/A ratio, 295 FS%, Allo(d) and Allo(s) and PH severity. In group 2 the following correlated significantly to 296 CD: LA/Ao ratio, E wave, E/A ratio, EDVI, ESVI and Allo(d) and Allo(s), In group 3 these 297 variables were LA/Ao ratio, EDVI, Allo(d). In groups 1 and 2 considered together as a single 298 group, the variables correlating significantly to CD were LA/Ao ratio, E wave, E/A wave, 299 EDVI, ESVI, Allo(d) and Allo(s) and PH severity. 300 We found a significant model only in therapeutic group 3, containing predictor LA/Ao 301 (HR=5.867, p=0.014) adjusted for age.

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An analysis of the three different endpoints (EP) was performed for each group: CD, first and 303 following therapy changes and moving to more advanced gravity class.  The difference in the tricuspid regurgitation velocity between the first and last visits was the 309 only parameter to be statistically significant (p=0.008) in animals subjected to a therapeutic 310 change in ACVIM C.

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In veterinary medicine, in order to improve the diagnostic and therapeutic approach to CHF, 329 two classification schemes have been proposed: the ISACH classification and the ACVIM 330 classification [9,16,34]. In this study, it was assumed that for the records included from 2010 331 to 2018, there was a more standardised classification, not affected by conversion errors.

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While the majority of dogs died or were euthanized because of worsening heart failure,  The inclusion criteria of the patients were very strict. However, this is a retrospective study, 396 thus biases cannot be as well controlled as in a well-designed prospective study. Patients who 397 had already been treated with cardioactive therapy were recruited which justifies the 398 variability in therapeutic groups of the overall population.

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The echocardiographic values, associated with ACVIM class of DMVD, were useful from a 400 prognostic point of view, and to answer any of the owners' questions.

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The PH severity also correlated strongly to CD and therapeutic groups. In addition, we 402 believe that our study indicates that data regarding therapeutic choices and any variations after 403 the initial diagnosis should be monitored in clinical practice in order to assess the prognosis 404 and modulate the treatment of animals with DMVD.

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The retrospective evaluation of the medical records of patients visited over a very long period