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 .