records were collected between november 2004 and february 2010 , 
 from 197 client - owned dogs with documented pulmonary edema . we evaluated the records of the first onset of pulmonary edema ( dyspnea , cough and tachypnea ) in dogs with mitral regurgitation , retrospectively . dogs were 
 included , if they had been diagnosed with mmvd via a 2-d echocardiographic examination which showed thickening of the mitral valve leaflets , + / evidence of 
 chordal rupture and left ventricular and left atrial dilatation within the first 3 days of hospitalization . measurements , including fractional shortening   and the la / ao ratio , were obtained from the right parasternal short axis using the 2d view . thoracic radiographs ( standard lateral 
 and dorsal  ventral ( dv)/ventral  dorsal ( vd ) views ) had to be taken within the initial 3 days of hospitalization for chf to verify the presence of pulmonary edema . the patients were required to have current radiographic evidence of pulmonary edema and cardiomegaly ( vertebral heart score ( vhs ) 10.5 ) . during the initial hospitalization period for stabilization of the left side chf ( l - chf ) , dogs were excluded from the study , if they died without responses to acute therapy during the initial onset of pulmonary edema . after treatment and recovery of chf , the dogs were treated with a combination of diuretics , aceis , digoxin , pimobendan , antiarrhythmics as needed and cough 
 suppressants . the dogs were divided into one of the following treatment groups for the study : conventional therapy group ( n=84 ) : aceis administered according to the manufacturer s recommended dosages , furosemide ( 2 mg / kg q12hr ) or other loop diuretics at 
 the manufacturer s recommended dosages , and other drugs as needed . low dose pimobendan ( low - pimo ) group ( n=49 ) : aceis administered according to the manufacturer s recommended dosages , furosemide ( 2 mg / kg q12hr ) or other loop 
 diuretics at the manufacturer s recommended dosages , pimobendan at half the manufacturer s recommended dose ( 0.13 mg / kg [ range 0.050.19 mg / kg ] ) q12hr , and other 
 drugs as needed . standard dose pimobendan ( standard - pimo ) group ( n=64 ) : aceis administered according to the manufacturer s recommended dosages , furosemide ( 2 mg / kg q12hr ) or 
 other loop diuretics , pimobendan at the recommended dose ( 0.24 mg / kg [ range 0.200.48 mg / kg ] ) q12hr , and other drugs as needed . the dogs were followed individually , and drug dosages were adjusted according to the needs of each patient . however , neither the aceis nor the pimobendan dosages 
 ( low or standard dose ) were changed . seventy dogs ( 29 from the low - pimo group and 41 from the standard - pimo group ) were treated with pimobendan immediately after the initial onset of pulmonary 
 edema . eleven dogs ( eight from the low - pimo group and three from the standard - pimo group ) were treated with pimobendan more than 1 month after initial onset of 
 pulmonary edema . thirty - two dogs ( 12 from the low - pimo group and 20 from the standard - pimo group ) were treated with pimobendan after the reoccurrence of pulmonary 
 edema . the primary endpoint was defined as death resulting from an underlying mitral regurgitation , i.e. , death at home with signs of fatal pulmonary edema , or sudden 
 cardiac death likely to have been caused by a fatal arrhythmia or rehospitalization with l - chf and severe pulmonary edema considered unmanageable following up 
 to 3 days of intensive therapy , leading to euthanasia . survival was calculated as the number of days from the first occurrence of l - chf until the verified day 
 of all cause death . the secondary endpoint of the study was defined as the reoccurrence ( second episode ) of clinical and radiographic signs of l - chf . additionally , a log - rank test 
 was used to evaluate whether the reoccurrence of pulmonary edema was associated with a worse prognosis . age , body weight , grade of heart murmur , vhs , la / ao and fs are expressed as the mean  standard deviation . statmate iii ( statmate iii , atms , co. , ltd . , tokyo , 
 japan ) all continuous baseline variables were compared using bartlett s test and one - way 
 analysis of variance ( one - way anova ) . for categorical data , a  or fisher the kaplan - meier method was used to estimate the 
 median time to end point for each treatment group and to plot time to event curves . a log - rank test was used to determine whether there were any significant 
 differences between each group . the primary endpoint was defined as death resulting from an underlying mitral regurgitation , i.e. , death at home with signs of fatal pulmonary edema , or sudden 
 cardiac death likely to have been caused by a fatal arrhythmia or rehospitalization with l - chf and severe pulmonary edema considered unmanageable following up 
 to 3 days of intensive therapy , leading to euthanasia . survival was calculated as the number of days from the first occurrence of l - chf until the verified day 
 of all cause death . the secondary endpoint of the study was defined as the reoccurrence ( second episode ) of clinical and radiographic signs of l - chf . additionally , a log - rank test 
 was used to evaluate whether the reoccurrence of pulmonary edema was associated with a worse prognosis . age , body weight , grade of heart murmur , vhs , la / ao and fs are expressed as the mean  standard deviation . statmate iii ( statmate iii , atms , co. , ltd . , tokyo , 
 japan ) all continuous baseline variables were compared using bartlett s test and one - way 
 analysis of variance ( one - way anova ) . for categorical data , a  or fisher the kaplan - meier method was used to estimate the 
 median time to end point for each treatment group and to plot time to event curves . a log - rank test was used to determine whether there were any significant 
 differences between each group . the most commonly recruited breeds were shih tzu ( n=49 ) , maltese ( n=36 ) , chihuahua ( n=18 ) , cavalier 
 king charles spaniel ( n=12 ) , yorkshire terrier ( n=11 ) , miniature dachshund ( n=8 ) , toy poodle ( n=7 ) and pomeranian ( n=7 ) . there were 15 additional breeds and 34 
 mixed - breed dogs . the median age at initial presentation was 11.8 years ( range , 4.918.1 years ) , and the median body weight was 6.1  3.7 kg ( range , 1.521.1 
 kg ) . there were no statistically significant differences in the signalment , physical examination , heart size or echocardiographic findings between the 3 groups 
 at initial presentation . ( table 1table 1.initial clinical data from dogs in the three treatment groupsconventional grouplow - dose pimobendan groupstandard - dose pimobendan groupp - valueage ( years)11.7  2.511.8  2.511.9  2.50.89body weight ( kg)5.9  3.86.1  3.66.5  3.70.68sex ( m / nm / f / nf ) ( % ) 42/12/12/1828/4/12/534/11/10/90.35(50/14/14/22)(57/8/25/10)(53/17/16/14)grade of heart murmur4.2  0.84.0  0.64.0  0.70.23thoracic radiographyvhs ( v)11.9  1.111.9 1.012.1 0.80.40echocardiographyla / ao2.3  0.62.4  0.42.1  0.40.08fs ( % ) 47.2 10.147.7  9.945.5  7.80.53presence of tr ( % ) 3826510.09 m , male ; nm , neutered male ; f , female ; nf , neutered female . ) . m , male ; nm , neutered male ; f , female ; nf , neutered female . there was a significant difference in the number of dogs in the low - pimo group ( 28/49 : 57% ) treated with spironolactone compared to the standard - pimo group 
 ( 16/64 : 25% ) and the conventional group ( 5/84 : 6% ) ( p<0.001 ) . there were significantly fewer dogs ( p<0.01 ) treated with 
 bronchodilators in the standard - pimo group ( 9/64 : 14% ) than in the low - pimo ( 15/49 : 31% ) and conventional ( 31/84 : 37% ) groups . 150 dogs ( 76% ) died spontaneously of cardiac related causes , 2 dogs ( 1% ) were 
 euthanized for cardiac related causes , 5 dogs ( 3% ) died of renal failure , and 1 dog ( 0.5% ) died from a neoplasm . thirty - nine dogs ( 21% ) were censored , because 
 37 dogs ( 19% ) were alive at the termination of the study and 2 dogs ( 1% ) had received mitral valve repair surgery . in both of the groups administered pimobendan , the survival times were significantly prolonged compared to the conventional group ( p<0.001 ) 
 ( fig . 1.kaplan-meier survival curve . in both of the groups administered pimobendan , the survival times were significantly longer than those in the conventional 
 group . ) . the median survival times for the standard - pimo , low - pimo and conventional groups were 334 , 277 and 136 days , and the 1-year survival rates were 46% , 
 37% and 23% , respectively . there was no significant difference between the standard- and low - pimo groups . kaplan - meier survival curve . in both of the groups administered pimobendan , thirty - two dogs ( 12 from the low - pimo group and 20 from the standard - pimo group ) were excluded from the analysis , because pimobendan was initiated after the 
 reoccurrence of pulmonary edema . the reoccurrence rates of pulmonary edema for the standard - pimo , low - pimo and conventional groups were 43% ( 19/44 ) , 59% ( 22/37 ) 
 and 62% ( 52/84 ) , respectively . the standard - pimo group showed a significant reduction in the reoccurrence of pulmonary edema compared to the low - pimo and 
 conventional groups . the death rates from the reoccurrence of pulmonary edema were as follows : standard ( 9% ) , low ( 11% ) and conventional ( 24% ) therapy . thus , 
 the inclusion of pimobendan in addition to conventional therapy for chf was negatively correlated to death as a result of reoccurring pulmonary edema . the group that had reoccurrence of pulmonary edema ( n=93 ) had significantly shorter survival times compared with the group that had non - reoccurrence ( n=72 ) 
 ( p<0.05 ) . the most commonly recruited breeds were shih tzu ( n=49 ) , maltese ( n=36 ) , chihuahua ( n=18 ) , cavalier 
 king charles spaniel ( n=12 ) , yorkshire terrier ( n=11 ) , miniature dachshund ( n=8 ) , toy poodle ( n=7 ) and pomeranian ( n=7 ) . there were 15 additional breeds and 34 
 mixed - breed dogs . the median age at initial presentation was 11.8 years ( range , 4.918.1 years ) , and the median body weight was 6.1  3.7 kg ( range , 1.521.1 
 kg ) . there were no statistically significant differences in the signalment , physical examination , heart size or echocardiographic findings between the 3 groups 
 at initial presentation . ( table 1table 1.initial clinical data from dogs in the three treatment groupsconventional grouplow - dose pimobendan groupstandard - dose pimobendan groupp - valueage ( years)11.7  2.511.8  2.511.9  2.50.89body weight ( kg)5.9  3.86.1  3.66.5  3.70.68sex ( m / nm / f / nf ) ( % ) 42/12/12/1828/4/12/534/11/10/90.35(50/14/14/22)(57/8/25/10)(53/17/16/14)grade of heart murmur4.2  0.84.0  0.64.0  0.70.23thoracic radiographyvhs ( v)11.9  1.111.9 1.012.1 0.80.40echocardiographyla / ao2.3  0.62.4  0.42.1  0.40.08fs ( % ) 47.2 10.147.7  9.945.5  7.80.53presence of tr ( % ) 3826510.09 m , male ; nm , neutered male ; f , female ; nf , neutered female . ) . m , male ; nm , neutered male ; f , female ; nf , neutered female . there was a significant difference in the number of dogs in the low - pimo group ( 28/49 : 57% ) treated with spironolactone compared to the standard - pimo group 
 ( 16/64 : 25% ) and the conventional group ( 5/84 : 6% ) ( p<0.001 ) . there were significantly fewer dogs ( p<0.01 ) treated with 
 bronchodilators in the standard - pimo group ( 9/64 : 14% ) than in the low - pimo ( 15/49 : 31% ) and conventional ( 31/84 : 37% ) groups . 150 dogs ( 76% ) died spontaneously of cardiac related causes , 2 dogs ( 1% ) were 
 euthanized for cardiac related causes , 5 dogs ( 3% ) died of renal failure , and 1 dog ( 0.5% ) died from a neoplasm . thirty - nine dogs ( 21% ) were censored , because 
 37 dogs ( 19% ) were alive at the termination of the study and 2 dogs ( 1% ) had received mitral valve repair surgery . in both of the groups administered pimobendan , the survival times were significantly prolonged compared to the conventional group ( p<0.001 ) 
 ( fig . 1fig . 1.kaplan-meier survival curve . in both of the groups administered pimobendan , the survival times were significantly longer than those in the conventional 
 group . ) . the median survival times for the standard - pimo , low - pimo and conventional groups were 334 , 277 and 136 days , and the 1-year survival rates were 46% , 
 37% and 23% , respectively . there was no significant difference between the standard- and low - pimo groups . kaplan - meier survival curve . in both of the groups administered pimobendan , thirty - two dogs ( 12 from the low - pimo group and 20 from the standard - pimo group ) were excluded from the analysis , because pimobendan was initiated after the 
 reoccurrence of pulmonary edema . the reoccurrence rates of pulmonary edema for the standard - pimo , low - pimo and conventional groups were 43% ( 19/44 ) , 59% ( 22/37 ) 
 and 62% ( 52/84 ) , respectively . the standard - pimo group showed a significant reduction in the reoccurrence of pulmonary edema compared to the low - pimo and 
 conventional groups . the death rates from the reoccurrence of pulmonary edema were as follows : standard ( 9% ) , low ( 11% ) and conventional ( 24% ) therapy . thus , 
 the inclusion of pimobendan in addition to conventional therapy for chf was negatively correlated to death as a result of reoccurring pulmonary edema . the group that had reoccurrence of pulmonary edema ( n=93 ) had significantly shorter survival times compared with the group that had non - reoccurrence ( n=72 ) 
 ( p<0.05 ) . pimobendan is frequently added to the conventional treatment regimen in dogs with clinical signs associated with mmvd . however , there has been no study 
 documenting the efficacy of pimobendan in combination therapy . we retrospectively investigated the survival times after the initial onset of pulmonary edema in 
 dogs with mmvd . the present study compared the impact of two different dose ranges of pimobendan with the efficacy of conventional treatment . the prognosis of dogs diagnosed with severe mitral regurgitation is very poor , and the median survival time is less than 7 months [ 5 , 19 ] . therefore , the efficacy of new treatment regimens was evaluated by observing whether there was an 
 increase in survival times . in the present study , the median survival times for the standard - pimo , low - pimo and conventional groups were 334 , 277 and 136 days , 
 respectively . this study showed that pimobendan administered in addition to conventional treatment increased the survival of dogs with chf due to mmvd by 2.5 
 times . these results are consistent with previously reported studies that have examined the effects of pimobendan monotherapy . at similar doses , although it is difficult to directly compare previous 
 studies due to the differences in study criteria , our data suggest that the combination therapy of pimobendan with conventional treatment ( including aceis ) is 
 more effective than conventional therapy alone ( including aceis ) . a previous study suggested that pimobendan may increase mr under clinical conditions and may induce ventricular hypertrophy . another study reported that pimobendan may worsen valve regurgitation in dogs with asymptomatic mmvd compared to aceis . the efficacy of pimobendan in asymptomatic dogs with mmvd still needs to be 
 confirmed . in our study , symptomatic dogs with mmvd demonstrated a longer survival time when on either the standard dose or low dose pimobendan . the clinical 
 signs associated with high - dose ( 2.621.3 mg / kg ) pimobendan toxicosis have been reported   and include cardiovascular 
 abnormalities , such as severe tachycardia , hypotension and hypertension . however , these adverse effects of pimobendan were not observed in any of the dogs in this 
 study . the other drugs did not show any influence on the survival time in the multivariate analysis . previous reports have indicated the effectiveness of aceis as a 
 medical treatment for mmvd [ 2 , 11 ] , and the guidelines for diagnosis and treatment of 
 canine chronic valvular heart disease recommend the use of diuretics and aceis in the treatment of chf . at present , 
 these medications make up the standard drug treatment regimen for dogs with chf . aceis and loop diuretics were used in the treatment of many dogs in this study . thus , the current study is important in clarifying the efficacy of combining pimobendan with other conventional therapies . the positive inotropic effect of digoxin leads to increased oxygen consumption by 
 the myocardium , however , studies on the effect of combined pimobendan and digoxin therapy have not yet been published . spironolactone is an aldosterone antagonist 
 that has a positive effect on survival in dogs with naturally occurring mr caused by mmvd . our study does not address the effect of combination therapy with 
 pimobendan and digoxin or aldosterone antagonists , such as spironolactone or torsemide , and further studies are required to address the impact of combined 
 pimobendan and concomitant drug therapy . our study showed that the reoccurrence 
 rate of pulmonary edema was associated with a shorter survival time . the present study investigated the efficacy of combination therapy including pimobendan to 
 reduce the reoccurrence of pulmonary edema . we found that the standard dose range of pimobendan ( 0.200.48 mg / kg ) was associated with a significantly lower rate 
 of reoccurrence of pulmonary edema compared to conventional treatment . these data are consistent with the fact that pimobendan reduces left atrial diameter   and left atrial pressure . the positive inotropic effects of pimobendan have 
 been observed using 0.1 mg / kg administered orally , and pimobendan was administered at this concentration . in addition , 
 a higher dose ( 0.5 mg / kg ) of pimobendan has been shown to decrease left atrial pressure to a higher degree . this retrospective study supports the benefits of adding the standard dose ( 0.25 mg / kg q12hr ) 
 of pimobendan to a conventional therapy regimen to reduce pulmonary edema and improve disease prognosis . this was a retrospective study , and therefore , we did not have any control over the composition and dosage 
 of the conventional treatment or of the dosage and timing of pimobendan introduction into the treatment regimen . these factors brought considerable variability 
 into the analysis of the combination treatment . nonetheless , this study confirmed the benefits of pimobendan and supports the use of standard - dose pimobendan and 
 combination therapy over conventional treatment . another limitation in this study is that sodium intake in each individual patient was not measured . in conclusion , pimobendan in combination with conventional therapy significantly prolongs the survival time after the initial onset of pulmonary edema in dogs 
 with chf caused by mmvd .