cardiac resynchronization therapy ( crt ) is an effective therapy in symptomatic , optimally treated heart failure ( hf ) patients with prolonged qrs duration and low ejection fraction ( ef ) .
long - term results of crt on exercise tolerance and disease progression , as evaluated by reversal of maladaptive remodelling process , are rather limited and mostly reported in patients with sinus rhythm ( sr ) .
permanent atrial fibrillation ( af ) is a common arrhythmia in hf patients and is associated with increased morbidity and mortality .
some studies have reported significant acute and short - term benefits of crt in af patients with hf .
we recently emphasized the importance of atrio - ventricular junction ( avj ) ablation in order to optimize crt in patients with permanent af .
pure resynchronization effect which translates into significant long - term improvement in left ventricular function and remodelling .
such a reverse remodelling effect has been shown to correlate with improved survival in hf patients with normal sr treated with crt over mid - term follow - up .
to date , there is no information regarding this aspect in hf patients with af .
the aim of the present study was two - fold : first , to investigate the effect of crt on long - term survival in hf patients with permanent af compared with sr patients ; second , to investigate whether the adjunct of avj ablation may influence long - term outcome in the af patient subgroup .
for the purpose of the present study , the data were derived from the multicentre longitudinal observational study ( milos ) and included all consecutive patients undergoing crt pacemaker ( crt - p ) or crt defibrillator ( crt - d ) device implant from 1 august 1995 to 1 august 2004 . among the 1303 patients enrolled in the registry
, 18 had incomplete data or were lost to follow - up : the remaining 1285 patients , who represent the study population , were regularly followed in outpatient clinic settings ( at 2 , 6 , and every 6 months thereafter ) , where the physicians were 
blinded to the avj ablation therapeutic scheme ; all presented complete information about cardiac rhythm and survival status ; the last follow - up was scheduled on november 2004 .
aetiology was assessed in all cases by coronary angiography , and causes of hf amenable to surgery or intervention were corrected at least 6 months before device implantation . because indication for cardioverter 
defibrillator therapy changed over time , patients received the most appropriate device on the basis of current available evidence and guidelines .
two hundred and forty - three ( 19% ) patients had permanent af at the time of implant , whereas the remaining 1042 were in sr .
immediately after crt device implantation , every af patient received negative chronotropic drugs , and the rate adaptive mode plus specific pacing features ( such as ventricular rate regularization and/or trigger function ) were activated in order to maximize biventricular stimulation .
for all centres , the choice of performing avj ablation was mainly based on the detection of inadequate bvp% derived from device counters at 2 month post - implant control . in the earlier phases ,
the evidence of frequent fusion , pseudo - fusion , or competitive spontaneous beats detected from standard , dynamic , or stress test ecg monitoring was utilized to further indicate avj ablation .
therefore , in patients with bvp%  85 , avj ablation was performed ; digoxin and amiodarone were subsequently suspended ( amiodarone was continued only if significant ventricular tachyarrhythmias were present ) , whereas beta - blocker therapy was maintained . on the contrary , patients with bvp%
> 85 continued throughout the follow - up the  rate - control treatment regimen combining chronotropic negative drugs with activation of device features .
because avj ablation was not a standardized clinical care , formal approval was obtained from the review boards of each institution .
all patients gave their written informed consent to undergo the ablation procedure under the understanding that irreversible complete atrio - ventricular block would be created with subsequent pacemaker dependency .
outcome data were collected at each participating centre by reviewing outpatient clinical files or by phone interviews with relatives and/or family doctors . at each centre ,
an adjudication committee was established to perform chart review and assign , by consensus , the mode of cardiac death .
the adjudication committee was blinded to the strategy undertaken to achieve rate control in af patients as well as to the type of implanted device .
cardiac deaths were classified as sudden ( not preceded by hf or ischaemic symptoms ) or due to hf according to epstein et al .
patients undergoing left ventricle assist device or urgent heart transplant were classified as hf deaths . when the cause of death could not be determined using all available sources , it was classified as unknown .
conventional ventricular leads were positioned in the right ventricular apex in all patients implanted with crt systems , and conventional atrial leads were used only in sr patients . in those patients in whom implantable defibrillator was necessary ,
transvenous left ventricular lead positioning was guided by coronary sinus venogram , preferring a lateral or postero - lateral vein as implantation site . in case of failure or technical difficulties by the transvenous approach ( phrenic nerve stimulation , inability to cannulate the coronary sinus , etc . ) , epicardial screw - in or steroid - eluting passive lead was implanted through limited thoracotomy .
the latter was the elective approach used before transvenous leads became routinely available . in patients with preserved sr , devices were programmed in ddd modality , usually with a minimum heart rate of 50 b.p.m . , and
rate adaptive response was activated in any af patient and the maximum rate was set at 85% of the theoretical maximum heart rate ; moreover , in order to achieve the higher biventricular pacing percentage , ventricular rate stabilization and/or ventricular rate regulation ( vrr ) and trigger mode were activated when available .
descriptive statistics were computed as mean and standard deviation for continuous variables and as counts and percentage for categorical variables .
patients characteristics were compared between groups with unpaired t - test or one - way analysis of variance and with fisher 's exact test , respectively .
median follow - up and its 2575th percentiles were computed by means of the inverse kaplan  meier method .
the rates of fatal and of cardiac events per 100 person - year and their 95% confidence intervals ( 95% cis ) were calculated .
cox regression was used to assess the prognostic role of the presence of af when compared with sr and , among af patients , the presence or absence of avj ablation , while adjusting for a series of potential baseline confounders ( age , gender , left ventricular ef , aetiology , qrs duration , functional nyha class , and the type of implanted device 
crt - p or crt - d ) , in a multivariable model stratified for centre .
avj ablation was treated as a time - dependent variable . to better characterize the prognostic role of af and avj ablation on the different causes and modes of death ,
separate cox models were fitted for cardiac death , death from hf , and sudden death . in these cases , to avoid overfitting , confounding was addressed by including the quintiles of the propensity score ( ps ) in the cox model stratified by centre .
the ps is a measure of the likelihood for a patient to undergo avj , given its presenting characteristics , derived from a multivariable logistic model . to build the ps
, we included in the model all the demographic and clinical variables collected ( age , gender , left ventricular ef , aetiology , qrs duration , functional nyha class , the type of implanted device , and centre ) , together with their two - way interactions , as well as the drug regimen administered ( table  1 ) . the balancing property of the ps was satisfied and the c - statistic for the model was computed to 0.80 .
moreover , the ability of the ps to control for confounding in the subsequent cox models was confirmed by its lack of statistical significance .
baseline characteristics of global permanent atrial fibrillation patient population compared with sinus rhythm patients mean ( sd ) for continuous variables ; n ( % ) for categorical variables
. sr , sinus rhythm ; af , atrial fibrillation ; crt - d , cardiac resynchronization therapy pacemaker with defibrillator ; arbs , angiotensin receptor blockers .
stata 9 ( statacorp , college station , tx , usa ) was used for computation . a two - sided p - value < 0.05 was considered statistically significant .
for the purpose of the present study , the data were derived from the multicentre longitudinal observational study ( milos ) and included all consecutive patients undergoing crt pacemaker ( crt - p ) or crt defibrillator ( crt - d ) device implant from 1 august 1995 to 1 august 2004 .
among the 1303 patients enrolled in the registry , 18 had incomplete data or were lost to follow - up : the remaining 1285 patients , who represent the study population , were regularly followed in outpatient clinic settings ( at 2 , 6 , and every 6 months thereafter ) , where the physicians were 
blinded to the avj ablation therapeutic scheme ; all presented complete information about cardiac rhythm and survival status ; the last follow - up was scheduled on november 2004 .
aetiology was assessed in all cases by coronary angiography , and causes of hf amenable to surgery or intervention were corrected at least 6 months before device implantation . because indication for cardioverter 
defibrillator therapy changed over time , patients received the most appropriate device on the basis of current available evidence and guidelines .
two hundred and forty - three ( 19% ) patients had permanent af at the time of implant , whereas the remaining 1042 were in sr .
immediately after crt device implantation , every af patient received negative chronotropic drugs , and the rate adaptive mode plus specific pacing features ( such as ventricular rate regularization and/or trigger function ) were activated in order to maximize biventricular stimulation .
for all centres , the choice of performing avj ablation was mainly based on the detection of inadequate bvp% derived from device counters at 2 month post - implant control . in the earlier phases ,
the evidence of frequent fusion , pseudo - fusion , or competitive spontaneous beats detected from standard , dynamic , or stress test ecg monitoring was utilized to further indicate avj ablation .
therefore , in patients with bvp%  85 , avj ablation was performed ; digoxin and amiodarone were subsequently suspended ( amiodarone was continued only if significant ventricular tachyarrhythmias were present ) , whereas beta - blocker therapy was maintained . on the contrary , patients with bvp% > 85 continued throughout the follow - up the  rate - control treatment regimen combining chronotropic negative drugs with activation of device features .
because avj ablation was not a standardized clinical care , formal approval was obtained from the review boards of each institution .
all patients gave their written informed consent to undergo the ablation procedure under the understanding that irreversible complete atrio - ventricular block would be created with subsequent pacemaker dependency .
outcome data were collected at each participating centre by reviewing outpatient clinical files or by phone interviews with relatives and/or family doctors . at each centre ,
an adjudication committee was established to perform chart review and assign , by consensus , the mode of cardiac death .
the adjudication committee was blinded to the strategy undertaken to achieve rate control in af patients as well as to the type of implanted device .
cardiac deaths were classified as sudden ( not preceded by hf or ischaemic symptoms ) or due to hf according to epstein et al .
patients undergoing left ventricle assist device or urgent heart transplant were classified as hf deaths . when the cause of death could not be determined using all available sources , it was classified as unknown .
conventional ventricular leads were positioned in the right ventricular apex in all patients implanted with crt systems , and conventional atrial leads were used only in sr patients . in those patients in whom implantable
transvenous left ventricular lead positioning was guided by coronary sinus venogram , preferring a lateral or postero - lateral vein as implantation site . in case of failure or technical difficulties by the transvenous approach ( phrenic nerve stimulation , inability to cannulate the coronary sinus , etc . ) , epicardial screw - in or steroid - eluting passive lead was implanted through limited thoracotomy .
the latter was the elective approach used before transvenous leads became routinely available . in patients with preserved sr
, devices were programmed in ddd modality , usually with a minimum heart rate of 50 b.p.m . , and
rate adaptive response was activated in any af patient and the maximum rate was set at 85% of the theoretical maximum heart rate ; moreover , in order to achieve the higher biventricular pacing percentage , ventricular rate stabilization and/or ventricular rate regulation ( vrr ) and trigger mode were activated when available .
descriptive statistics were computed as mean and standard deviation for continuous variables and as counts and percentage for categorical variables .
patients characteristics were compared between groups with unpaired t - test or one - way analysis of variance and with fisher 's exact test , respectively .
median follow - up and its 2575th percentiles were computed by means of the inverse kaplan  meier method .
the rates of fatal and of cardiac events per 100 person - year and their 95% confidence intervals ( 95% cis ) were calculated .
cox regression was used to assess the prognostic role of the presence of af when compared with sr and , among af patients , the presence or absence of avj ablation , while adjusting for a series of potential baseline confounders ( age , gender , left ventricular ef , aetiology , qrs duration , functional nyha class , and the type of implanted device 
crt - p or crt - d ) , in a multivariable model stratified for centre .
avj ablation was treated as a time - dependent variable . to better characterize the prognostic role of af and avj ablation on the different causes and modes of death
, separate cox models were fitted for cardiac death , death from hf , and sudden death . in these cases , to avoid overfitting , confounding was addressed by including the quintiles of the propensity score ( ps ) in the cox model stratified by centre .
the ps is a measure of the likelihood for a patient to undergo avj , given its presenting characteristics , derived from a multivariable logistic model . to build the ps , we included in the model all the demographic and clinical variables collected ( age , gender , left ventricular ef , aetiology , qrs duration , functional nyha class , the type of implanted device , and centre ) , together with their two - way interactions , as well as the drug regimen administered ( table  1 ) . the balancing property of the ps was satisfied and the c - statistic for the model was computed to 0.80
moreover , the ability of the ps to control for confounding in the subsequent cox models was confirmed by its lack of statistical significance .
( sd ) for continuous variables ; n ( % ) for categorical variables . sr , sinus rhythm ; af , atrial fibrillation ; crt - d , cardiac resynchronization therapy pacemaker with defibrillator ; arbs , angiotensin receptor blockers .
stata 9 ( statacorp , college station , tx , usa ) was used for computation . a two - sided p - value < 0.05 was considered statistically significant .
the characteristics of the 1042 patients in sr are compared with those of the 243 patients with permanent af in table  1 .
the two groups had similar severity of symptoms as shown by their nyha class and need of intravenous inotropic therapy .
patients with af were older , with a greater prevalence of female gender , less coronary artery disease , slightly higher ef , and marginally shorter qrs duration .
af patients received less crt - d devices and were more often treated with digoxin , amiodarone , and negative chronotropic drugs ( to achieve a higher percentage of biventricular pacing time ) . during a median follow - up of 34 months ( interquartile range : 1040 months )
, 170/1042 and 39/243 patients in the sr and af groups died , with a mortality rate of 8.4 ( 95% ci 7.29.8 ) and 8.9 ( 95% ci 6.512.2 ) per 100 person - year ( figure  1a ) , respectively .
multivariable analysis confirmed similar mortality of sr and af patients ( hr 0.90 , 95% ci 0.571.42 , p = 0.64 ) .
comparison of kaplan  meier estimates of overall ( a ) , cardiac ( b ) , and heart failure ( c ) survival between sinus rhythm and the global atrial fibrillation population .
the p - values presented derive from the adjusted hazards ratio analysis stratified according to the corresponding cause of death .
the cause of death could not be established in only six cases ( four patients in sr and two in af ) and were therefore classified as unknown .
one hundred and sixty - nine patients died from cardiac death , 135/1042 and 34/243 in the sr and af groups , respectively .
cardiac death rates were 6.7 ( 95% ci 5.67.9 ) and 7.7 ( 95% ci 5.510.8 ) per 100 person - year in sr and af patients , respectively ( figure 1b ) .
no difference in cardiac mortality was found between patients in sr and af both at univariable and multivariable analyses ( adjusted hr 1.00 , 95% ci 0.601.66 , p = 0.991 ) .
worsening hf was the most important mode of death in both groups accounting for 105/1042 deaths in sr patients and for 28/243 deaths in patients with af , a mortality rate of 5.2 ( 95% ci 4.36.3 ) and 6.3 ( 95% ci 4.49.2 ) per 100 person - year , respectively ( figure 1c ) .
no difference in adjusted hr for hf death ( 1.18 , 95% ci 0.672.06 , p = 0.564 ) was found .
the af population was subdivided depending on whether the modality used to control heart rate was by negative chronotropic drugs ( af - drugs ) or avj ablation ( avj - abl ) .
the two groups were similar with respect to some of their main baseline characteristics ( table 2 ) , including age , gender , aetiology , nyha class , and pharmacological therapy .
patients in the avj - abl group had a shorter qrs duration and less frequently received crt - d .
moreover , the use of negative chronotropic drugs , in the first 23 months after crt implant , was similar between the two groups and dosages were adequate .
of the 243 patients , 240 were still alive at the 2 month follow - up : three af patients died before this scheduled visit ( two on drug therapy and one extremely compromised patient , who underwent avj ablation soon after crt implantation and died from refractory hf before discharge ) .
baseline characteristics at the time of cardiac resynchronization therapy implant of the permanent atrial fibrillation patient population divided according to atrio - ventricular junction ablation ( avj - abl ) or drugs ( af - drugs ) for rate control mean ( sd ) for continuous variables ;
n ( % ) for categorical variables . avj - abl , atrial fibrillation patients who underwent atrio - ventricular junction ablation ; af - drugs , atrial fibrillation patients who did not undergo atrio - ventricular junction ablation ; crt - d , cardiac resynchronization therapy pacemaker with defibrillator ; arbs , angiotensin receptor blockers . for post hoc comparisons ,
scheff 's test was used after one - way anova ; after fisher 's exact test , the level of significance was set to 0.017 for bonferroni correction . at the 2-month control ,
123 patients reached bvp% > 85 ( mean 89.4  2.4% ) and continued negative chronotropic drugs throughout the follow - up to maintain adequate bvp% ( af - drugs group ) . the other 117 af patients with bvp%  85 at 2 months ( mean 74.2  4.2% ) underwent avj ablation within 3 months from device implant ( avj - abl group ) .
once ablation of the avj was performed , digoxin and amiodarone were discontinued ( amiodarone was continued only in cases presenting relevant ventricular tachyarrhythmias ) , whereas beta - blockers were maintained . at the following control after avj ablation , device counters revealed full biventricular pacing effectiveness , with bvp% nearing 100 ( mean 98.7  1.8% ) .
the evaluation of drug therapy modifications in the af group was performed after 1 year of crt .
dosage of beta - blockers increased compared with baseline ( carvedilol increased from 14.6 to 19.5 mg / day , p < 0.001 ) .
no differences were detected in either beta - blocker or ace - inhibitor usage between the two af patient groups .
of these events , 28/125 patients were observed in the af - drugs group and 11/118 patients in avj - abl group ( figure 2a ) , with mortality rates of 14.2 ( 95% ci 9.720.5 ) and 4.6 ( 95% ci 2.58.2 ) per 100 person - year , respectively ( figure 2a ) .
total mortality was therefore significantly better in the avj - abl group compared with the af - drugs group ( adjusted hr 0.26 , 95% ci 0.090.73 , p = 0.010 , figure 3 ) .
comparison of kaplan  meier estimates of overall ( a ) , cardiac ( b ) , and heart failure ( c ) survival between atrial fibrillation patients who underwent atrio - ventricular junction ablation ( avj - abl ) and atrial fibrillation patients treated only with negative chronotropic drugs ( af - drugs ) .
the p - values presented derive from the adjusted hazards ratio analysis stratified according to the corresponding cause of death .
hazard ratio estimates stratified according to cause of death between atrial fibrillation patients who underwent atrio - ventricular junction ablation ( avj - abl ) and atrial fibrillation patients treated with negative chronotropic drugs ( af - drugs ) ; hazard ratio estimates were adjusted for centre , age , gender , aetiology , nyha class , qrs width , left ventricular ejection fraction , and device type .
corresponding hazard ratio values for each cause of death are indicated with a square , the bar represents 95% confidence interval range , and the p - value for each estimate is presented on the right of the figure . with respect to the cause of death , cardiac deaths occurred in 24/125 patients of the af - drugs group compared with 10/118 patients in the avj - abl group ( figure 2b ) , with cardiac mortality rates of 12.1 ( 95% ci 8.118.1 ) and 4.1 ( 95% ci 2.27.7 ) per 100 person - year , respectively ( figure 2b ) , and an adjusted hr of 0.31 ( 95% ci 0.100.99 , p = 0.048 ) for avj - abl vs. af - drugs patients ( figure 3 ) .
a total of 28 events ( death or urgent heart transplant or left ventricular assist device positioning ) occurred as a result of worsening hf with an incidence of 22/125 in the af - drugs group , as opposed to only 6/118 in the avj - abl group , with a mortality rate of 11.1 per 100 person - year ( 95% ci 7.316.9 ) in the af - drugs group and of only 2.5 ( 95% ci 1.15.5 ) per 100 person - year in the avj - abl group ( figure 2c ) ( adjusted hr 0.15 , 95% ci 0.030.70 , p = 0.016 ) ( figure 3 ) .
the occurrence of sudden cardiac death was very rare and accounted for only two events in the af - drugs ( 1.01 , 95% ci 0.34.1 per 100 person - year ) and four events in the avj - abl group ( 1.7 , 95% ci 0.64.4 per 100 person - year ) .
the characteristics of the 1042 patients in sr are compared with those of the 243 patients with permanent af in table  1 .
the two groups had similar severity of symptoms as shown by their nyha class and need of intravenous inotropic therapy .
patients with af were older , with a greater prevalence of female gender , less coronary artery disease , slightly higher ef , and marginally shorter qrs duration .
af patients received less crt - d devices and were more often treated with digoxin , amiodarone , and negative chronotropic drugs ( to achieve a higher percentage of biventricular pacing time ) . during a median follow - up of 34 months ( interquartile range : 1040 months )
, 170/1042 and 39/243 patients in the sr and af groups died , with a mortality rate of 8.4 ( 95% ci 7.29.8 ) and 8.9 ( 95% ci 6.512.2 ) per 100 person - year ( figure  1a ) , respectively .
multivariable analysis confirmed similar mortality of sr and af patients ( hr 0.90 , 95% ci 0.571.42 , p = 0.64 ) .
comparison of kaplan  meier estimates of overall ( a ) , cardiac ( b ) , and heart failure ( c ) survival between sinus rhythm and the global atrial fibrillation population .
the p - values presented derive from the adjusted hazards ratio analysis stratified according to the corresponding cause of death .
the cause of death could not be established in only six cases ( four patients in sr and two in af ) and were therefore classified as unknown .
one hundred and sixty - nine patients died from cardiac death , 135/1042 and 34/243 in the sr and af groups , respectively .
cardiac death rates were 6.7 ( 95% ci 5.67.9 ) and 7.7 ( 95% ci 5.510.8 ) per 100 person - year in sr and af patients , respectively ( figure 1b ) .
no difference in cardiac mortality was found between patients in sr and af both at univariable and multivariable analyses ( adjusted hr 1.00 , 95% ci 0.601.66 , p = 0.991 ) .
worsening hf was the most important mode of death in both groups accounting for 105/1042 deaths in sr patients and for 28/243 deaths in patients with af , a mortality rate of 5.2 ( 95% ci 4.36.3 ) and 6.3 ( 95% ci 4.49.2 ) per 100 person - year , respectively ( figure 1c ) .
no difference in adjusted hr for hf death ( 1.18 , 95% ci 0.672.06 , p = 0.564 ) was found .
the af population was subdivided depending on whether the modality used to control heart rate was by negative chronotropic drugs ( af - drugs ) or avj ablation ( avj - abl ) .
the two groups were similar with respect to some of their main baseline characteristics ( table 2 ) , including age , gender , aetiology , nyha class , and pharmacological therapy .
patients in the avj - abl group had a shorter qrs duration and less frequently received crt - d .
moreover , the use of negative chronotropic drugs , in the first 23 months after crt implant , was similar between the two groups and dosages were adequate .
of the 243 patients , 240 were still alive at the 2 month follow - up : three af patients died before this scheduled visit ( two on drug therapy and one extremely compromised patient , who underwent avj ablation soon after crt implantation and died from refractory hf before discharge ) .
baseline characteristics at the time of cardiac resynchronization therapy implant of the permanent atrial fibrillation patient population divided according to atrio - ventricular junction ablation ( avj - abl ) or drugs ( af - drugs ) for rate control mean ( sd ) for continuous variables ; n ( % ) for categorical variables .
avj - abl , atrial fibrillation patients who underwent atrio - ventricular junction ablation ; af - drugs , atrial fibrillation patients who did not undergo atrio - ventricular junction ablation ; crt - d , cardiac resynchronization therapy pacemaker with defibrillator ; arbs , angiotensin receptor blockers . for post hoc comparisons ,
scheff 's test was used after one - way anova ; after fisher 's exact test , the level of significance was set to 0.017 for bonferroni correction . at the 2-month control ,
123 patients reached bvp% > 85 ( mean 89.4  2.4% ) and continued negative chronotropic drugs throughout the follow - up to maintain adequate bvp% ( af - drugs group ) . the other 117 af patients with bvp%  85 at 2 months ( mean 74.2  4.2% ) underwent avj ablation within 3 months from device implant ( avj - abl group ) .
once ablation of the avj was performed , digoxin and amiodarone were discontinued ( amiodarone was continued only in cases presenting relevant ventricular tachyarrhythmias ) , whereas beta - blockers were maintained . at the following control after avj ablation , device counters revealed full biventricular pacing effectiveness , with bvp% nearing 100 ( mean 98.7  1.8% ) .
the evaluation of drug therapy modifications in the af group was performed after 1 year of crt .
dosage of beta - blockers increased compared with baseline ( carvedilol increased from 14.6 to 19.5 mg / day , p < 0.001 ) .
no differences were detected in either beta - blocker or ace - inhibitor usage between the two af patient groups .
of these events , 28/125 patients were observed in the af - drugs group and 11/118 patients in avj - abl group ( figure 2a ) , with mortality rates of 14.2 ( 95% ci 9.720.5 ) and 4.6 ( 95% ci 2.58.2 ) per 100 person - year , respectively ( figure 2a ) .
total mortality was therefore significantly better in the avj - abl group compared with the af - drugs group ( adjusted hr 0.26 , 95% ci 0.090.73 , p = 0.010 , figure 3 ) .
comparison of kaplan  meier estimates of overall ( a ) , cardiac ( b ) , and heart failure ( c ) survival between atrial fibrillation patients who underwent atrio - ventricular junction ablation ( avj - abl ) and atrial fibrillation patients treated only with negative chronotropic drugs ( af - drugs ) .
the p - values presented derive from the adjusted hazards ratio analysis stratified according to the corresponding cause of death .
hazard ratio estimates stratified according to cause of death between atrial fibrillation patients who underwent atrio - ventricular junction ablation ( avj - abl ) and atrial fibrillation patients treated with negative chronotropic drugs ( af - drugs ) ; hazard ratio estimates were adjusted for centre , age , gender , aetiology , nyha class , qrs width , left ventricular ejection fraction , and device type .
corresponding hazard ratio values for each cause of death are indicated with a square , the bar represents 95% confidence interval range , and the p - value for each estimate is presented on the right of the figure . with respect to the cause of death , cardiac deaths occurred in 24/125 patients of the af - drugs group compared with 10/118 patients in the avj - abl group ( figure 2b ) , with cardiac mortality rates of 12.1 ( 95% ci 8.118.1 ) and 4.1 ( 95% ci 2.27.7 ) per 100 person - year , respectively ( figure 2b ) , and an adjusted hr of 0.31 ( 95% ci 0.100.99 , p = 0.048 ) for avj - abl vs. af - drugs patients ( figure 3 ) .
a total of 28 events ( death or urgent heart transplant or left ventricular assist device positioning ) occurred as a result of worsening hf with an incidence of 22/125 in the af - drugs group , as opposed to only 6/118 in the avj - abl group , with a mortality rate of 11.1 per 100 person - year ( 95% ci 7.316.9 ) in the af - drugs group and of only 2.5 ( 95% ci 1.15.5 ) per 100 person - year in the avj - abl group ( figure 2c ) ( adjusted hr 0.15 , 95% ci 0.030.70 , p = 0.016 ) ( figure 3 ) .
the occurrence of sudden cardiac death was very rare and accounted for only two events in the af - drugs ( 1.01 , 95% ci 0.34.1 per 100 person - year ) and four events in the avj - abl group ( 1.7 , 95% ci 0.64.4 per 100 person - year ) .
crt confers significant reductions in left ventricular volumes and improvement of left ventricular ef in hf patients .
such favourable changes have shown to correlate with mortality reduction over a mid - term follow - up in sr patients .
we recently described significant long - term improvements in left ventricular ef and left ventricular reversal of maladaptive remodelling in af patients treated with the combined crt and avj approach . in af patients with preserved avj conduction ,
no consistent correlation has been reported until now between reverse remodelling and mortality reduction after crt in af patients .
the present study may be considered an extension of the previous one and aimed to evaluate , in a much larger patient cohort , whether the effect of the combined avj ablation and crt strategy may also translate into favourable long - term survival of hf patients with permanent af .
to our knowledge , this is the first study comparing outcomes among patients treated with crt , between those in sr and those with af , and , even more importantly , among patients with af , based on whether or not these patients underwent avj ablation .
the dramatic difference in mortality rate observed between af - drugs and af - abl could support the view that avj ablation may be strongly recommended to achieve effective crt in af patients .
however , our data should be confirmed by prospective randomized trials , possibly comparing in these patients vvir - icd and rate control vs. crt - d+avj ablation . despite a 20% prevalence of af among hf patients treated with crt , randomized controlled crt trials
therefore , there are virtually no data investigating the effects of crt on survival in hf patients with permanent af .
both ventricular conduction delay and af are associated with a poor prognosis in hf patients .
small studies have shown beneficial effects of crt also in patients with hf and af , with an improvement in nyha class , exercise capacity , and quality of life . in the present study
, the multivariable analysis did not detect any significant differences in overall , cardiac , and hf long - term mortality rates between patients in sr and in permanent af .
our recent contribution described similar long - term improvements in left ventricular ef and left ventricular reversal of maladaptive remodelling between sr and af patients treated with crt . in this study , mean left ventricular ef increase at 1 year was of 6.5% absolute units in both the sr group and the af group , with a concomitant decrease in the left ventricular end - systolic volume of 20% in the sr patients compared with 15% in the af group .
these results are consistent with the similar mortality rates that we observed in our patients with either sr or af .
it is important to point out that studies reporting benefits of crt in permanent af included patients with either a low ventricular rate or a previously ablated avj .
this situation is , however , not frequent in clinical practice and many patients with af have a high ventricular rate ( at least during exertion ) despite concomitant treatment with negative chronotropic af - drugs ( e.g. beta - blockers , digitalis , amiodarone ) .
moreover , the activation of rate - smoothing features such as vrr or trigger mode may effectively regularize heart rate , whereas forcing faster heart rates may become deleterious .
hence , avj ablation may be the only procedure allowing a  complete heart rate control in these patients .
such a procedure offers the advantage of obtaining a regular ventricular rhythm and , probably more importantly , ensures effective crt through pure and constant biventricular pacing .
achievement of a regular ventricular rhythm through avj ablation has been associated with an improvement in global cardiac mechanics .
avj ablation may therefore find an elective indication in hf patients treated with crt , as it should allow greater benefits compared with those observed in the general population in which the  ablate and pace strategy is conventionally used to obtain a more regular and slower heart rhythm .
another possible explanation for the impressive effects on survival obtained as a result of avj ablation may be related to the fact that , after avj ablation , most patients suspended both digoxin and amiodarone : data derived from randomized trials suggest that digoxin and amiodarone may have a negative impact on morbidity and mortality in hf patients .
recently published data have suggested that in hf patients with af , crt confers long - term improvements of ef , end - systolic volume , nyha class , and exercise capacity only in patients who undergo avj ablation .
such extensive improvements in ef and in left ventricular geometry have already been correlated to favourable prognosis in hf patients in sr .
the previous findings advocating that avj ablation optimizes crt delivery thus yielding a significant reverse remodelling effect are consistent with what has been described in the present study . the analysis of the different death modes , stratified on the propensity of a patient being ablated , given its presenting characteristics , allowed to elucidate the role of avj ablation in patients with permanent af treated with crt .
overall , cardiac and hf deaths were significantly lower in af patients who underwent avj ablation compared with those who were not ablated .
this survival benefit was mainly due to the protective effect of avj ablation on deaths for hf .
af patients who underwent avj ablation had a nine - fold lower hf mortality compared with non - ablated af patients .
kaplan - meier analysis revealed that the time pattern of survival for hf becomes apparent after 4 months of crt ; this time point , shortly after avj ablation , corresponds to the same period when the reverse remodelling process becomes manifest in the avj - abl population .
taken together , these findings suggest , as previously described in sr patients , that the reverse remodelling effect produced by crt may translate to a lower incidence of hf death in the avj - abl group .
no clear statement may be made regarding possible effects on mortality from sudden cardiac death in af patients treated with crt , due to the low number of sudden death events that occurred in our patient cohort and due to the significant difference in patients receiving icd back - up between the two groups .
this observational study has several limitations , being a non - randomized study ; to consider , however , our cohort of 1285 patients with a median follow - up of 34 months represents one of the largest series evaluating the effects of crt reported so far .
it may have been useful to have an af control group not treated with crt , but the data are derived from a pre - defined crt registry of consecutively implanted patients .
also , outcome may have been biased by patients selection and changes in both pharmacological and non - pharmacological therapies over the study period .
unfortunately , only two of the four centres rigorously collected follow - up echocardiographic data . for this reason ,
the observations of the present study were interpreted and integrated with the findings of the previous contribution .
the limits posed by the differences in the baseline characteristics between the study groups were mitigated by the statistical analysis which considered possible confounding effects of centre , gender , age , aetiology , qrs duration , functional nyha class , baseline left ventricular ef , and device type in the fitted models .
moreover , to avoid over - fitting , confounding was addressed by adjusting the cox models by the quintiles of the ps .
given the longitudinal , observational design of the study , even these adjusted models may not guarantee complete suppression of some confounders , hence the need for confirmatory randomized studies .
although the af group was numerically inferior to the sr group , the subdivision of af patients in avj - abl and af - drugs resulted in two numerically balanced groups with similar baseline characteristics .
finally , the declining number of patients over the follow - up may represent a limitation , but this is the case of any observational cohort study .
all the available patients were included and only few patients were either lost to follow - up or had incomplete outcome data ; the latter were excluded from the study .
despite a 20% prevalence of af among hf patients treated with crt , randomized controlled crt trials have generally included only patients in sr . therefore , there are virtually no data investigating the effects of crt on survival in hf patients with permanent af .
both ventricular conduction delay and af are associated with a poor prognosis in hf patients .
small studies have shown beneficial effects of crt also in patients with hf and af , with an improvement in nyha class , exercise capacity , and quality of life . in the present study
, the multivariable analysis did not detect any significant differences in overall , cardiac , and hf long - term mortality rates between patients in sr and in permanent af .
our recent contribution described similar long - term improvements in left ventricular ef and left ventricular reversal of maladaptive remodelling between sr and af patients treated with crt . in this study , mean left ventricular ef increase at 1 year was of 6.5% absolute units in both the sr group and the af group , with a concomitant decrease in the left ventricular end - systolic volume of 20% in the sr patients compared with 15% in the af group .
these results are consistent with the similar mortality rates that we observed in our patients with either sr or af .
it is important to point out that studies reporting benefits of crt in permanent af included patients with either a low ventricular rate or a previously ablated avj .
this situation is , however , not frequent in clinical practice and many patients with af have a high ventricular rate ( at least during exertion ) despite concomitant treatment with negative chronotropic af - drugs ( e.g. beta - blockers , digitalis , amiodarone ) .
moreover , the activation of rate - smoothing features such as vrr or trigger mode may effectively regularize heart rate , whereas forcing faster heart rates may become deleterious .
hence , avj ablation may be the only procedure allowing a  complete heart rate control in these patients .
such a procedure offers the advantage of obtaining a regular ventricular rhythm and , probably more importantly , ensures effective crt through pure and constant biventricular pacing .
achievement of a regular ventricular rhythm through avj ablation has been associated with an improvement in global cardiac mechanics .
avj ablation may therefore find an elective indication in hf patients treated with crt , as it should allow greater benefits compared with those observed in the general population in which the  ablate and pace strategy is conventionally used to obtain a more regular and slower heart rhythm .
another possible explanation for the impressive effects on survival obtained as a result of avj ablation may be related to the fact that , after avj ablation , most patients suspended both digoxin and amiodarone : data derived from randomized trials suggest that digoxin and amiodarone may have a negative impact on morbidity and mortality in hf patients .
recently published data have suggested that in hf patients with af , crt confers long - term improvements of ef , end - systolic volume , nyha class , and exercise capacity only in patients who undergo avj ablation .
such extensive improvements in ef and in left ventricular geometry have already been correlated to favourable prognosis in hf patients in sr .
the previous findings advocating that avj ablation optimizes crt delivery thus yielding a significant reverse remodelling effect are consistent with what has been described in the present study .
the analysis of the different death modes , stratified on the propensity of a patient being ablated , given its presenting characteristics , allowed to elucidate the role of avj ablation in patients with permanent af treated with crt .
overall , cardiac and hf deaths were significantly lower in af patients who underwent avj ablation compared with those who were not ablated .
this survival benefit was mainly due to the protective effect of avj ablation on deaths for hf .
af patients who underwent avj ablation had a nine - fold lower hf mortality compared with non - ablated af patients .
kaplan - meier analysis revealed that the time pattern of survival for hf becomes apparent after 4 months of crt ; this time point , shortly after avj ablation , corresponds to the same period when the reverse remodelling process becomes manifest in the avj - abl population .
taken together , these findings suggest , as previously described in sr patients , that the reverse remodelling effect produced by crt may translate to a lower incidence of hf death in the avj - abl group . no clear statement may be made regarding possible effects on mortality from sudden cardiac death in af patients treated with crt , due to the low number of sudden death events that occurred in our patient cohort and due to the significant difference in patients receiving icd back - up between the two groups .
this observational study has several limitations , being a non - randomized study ; to consider , however , our cohort of 1285 patients with a median follow - up of 34 months represents one of the largest series evaluating the effects of crt reported so far .
it may have been useful to have an af control group not treated with crt , but the data are derived from a pre - defined crt registry of consecutively implanted patients .
also , outcome may have been biased by patients selection and changes in both pharmacological and non - pharmacological therapies over the study period .
one limitation may be the lack of a  direct correlation between remodelling effect and mortality data .
unfortunately , only two of the four centres rigorously collected follow - up echocardiographic data . for this reason ,
the observations of the present study were interpreted and integrated with the findings of the previous contribution .
the limits posed by the differences in the baseline characteristics between the study groups were mitigated by the statistical analysis which considered possible confounding effects of centre , gender , age , aetiology , qrs duration , functional nyha class , baseline left ventricular ef , and device type in the fitted models .
moreover , to avoid over - fitting , confounding was addressed by adjusting the cox models by the quintiles of the ps .
given the longitudinal , observational design of the study , even these adjusted models may not guarantee complete suppression of some confounders , hence the need for confirmatory randomized studies . although the af group was numerically inferior to the sr group ,
the subdivision of af patients in avj - abl and af - drugs resulted in two numerically balanced groups with similar baseline characteristics .
finally , the declining number of patients over the follow - up may represent a limitation , but this is the case of any observational cohort study .
all the available patients were included and only few patients were either lost to follow - up or had incomplete outcome data ; the latter were excluded from the study .
in our large multicentre series , the long - term overall survival of drug refractory hf patients with permanent af and left ventricular conduction delay treated with crt was similar to that of sr patients .
however , in hf patients with permanent af , avj ablation in addition to crt appears to improve long - term overall mortality compared with crt alone , primarily by reducing hf death .
avj ablation seems to be a fundamental adjunct to ensure adequate crt delivery and thus reducing mortality in patients with permanent af .
funding to pay the open access publication charges for this article was provided by mt tedeschi , irccs istituto clinico humanitas , clinical research department , rozzano ( mi ) , italy .
 aimsto investigate the effects of cardiac resynchronization therapy ( crt ) on survival in heart failure ( hf ) patients with permanent atrial fibrillation ( af ) and the role of atrio - ventricular junction ( avj ) ablation in these patients.methods and resultsdata from 1285 consecutive patients implanted with crt devices are presented : 1042 patients were in sinus rhythm ( sr ) and 243 ( 19% ) in af . 
 rate control in af was achieved by either ablating the avj in 118 patients ( avj - abl ) or prescribing negative chronotropic drugs ( af - drugs ) . compared with sr , 
 patients with af were significantly older , more likely to be non - ischaemic , with higher ejection fraction , shorter qrs duration , and less often received icd back - up . during a median follow - up of 34 months , 170/1042 patients in sr and 39/243 in af died ( mortality : 8.4 and 8.9 per 100 person - year , respectively ) . 
 adjusted hazard ratios were similar for all - cause and cardiac mortality [ 0.9 ( 0.571.42 ) , p = 0.64 and 1.00 ( 0.601.66 ) p = 0.99 , respectively ] . among af patients , 
 only 11/118 avj - abl patients died vs. 28/125 af - drugs patients ( mortality : 4.3 and 15.2 per 100 person - year , respectively , p < 0.001 ) . 
 adjusted hazard ratios of avj - abl vs. af - drugs was 0.26 [ 95% confidence interval ( ci ) 0.090.73 , p = 0.010 ] for all - cause mortality , 0.31 ( 95% ci 0.100.99 , p = 0.048 ) for cardiac mortality , and 0.15 ( 95% ci 0.030.70 , p = 0.016 ) for hf mortality.conclusionpatients with hf and af treated with crt have similar mortality compared with patients in sr . in af , 
 avj ablation in addition to crt significantly improves overall survival compared with crt alone , primarily by reducing hf death . 
Introduction
Methods
Design
Patients
Adjudicated classification of deaths
Device implantation and programming
Statistical analysis
Results
Long-term survival stratified according to baseline rhythm
Long-term survival of atrial fibrillation patients stratified according to atrio-ventricular junction ablation
Discussion
Effects of cardiac resynchronization therapy in heart failure patients with permanent atrial fibrillation compared with sinus rhythm
Importance of atrio-ventricular junction ablation in patients with permanent atrial fibrillation
Study limitations
Conclusions
Funding