the protocol and results of the madit - crt study and the madit - crt long - term follow - up registry have been detailed in prior publications.1,4,7 in summary , 1820 patients with ischemic and nonischemic cardiomyopathy classified as having new york heart association ( nyha ) class i or ii symptoms with left ventricular ejection fraction 30% and qrs duration of at least 130  ms were randomly assigned to crt - d and icd - only treatment arms in a 3:2 ratio . all patients received optimal medical therapy for hf consisting of beta - blockers , angiotensin - converting enzyme inhibitors , angiotensin receptor blockers / angiotensin ii inhibitors , and statins . exclusion criteria included nyha class iii or iv symptoms , coronary artery bypass grafting surgery , percutaneous coronary intervention , or myocardial infarction within 90  days prior to enrollment ; second- or third - degree heart block ; atrial fibrillation 30  days prior to enrollment ; and comorbidities such as uremia ( blood urea nitrogen  > 70  mg / dl or creatinine > 3.0  mg / dl ) and liver failure . in the present study , we included only madit - crt patients with an lbbb ecg pattern at baseline because our previous data showed that the benefit of crt - d was restricted to lbbb patients only.3,4 accordingly , the present study population comprised 1281 lbbb patients , 70% of the total patient population of madit - crt . madit - crt was carried out from december 22 , 2004 , through june 22 , 2009 . following the publication of the primary results,1 a post - trial follow - up was conducted for all surviving study participants ( n=1691 ) until september 10 , 2010 ( phase i of the extended follow - up ) . after september 10 , 2010 , extended follow - up was conducted in 48 of 87 us centers that agreed to participate in the long - term follow - up registry requested by the us food and drug administration ( coordinated by the heart research follow - up program at the university of rochester medical center , rochester , ny ) and in 23 of 24 non - us centers as an investigator - initiated research project ( coordinated by the israeli association for cardiovascular trials at sheba medical center , ramat gan , israel ) . a total of 854 patients were involved , 407 in the us registry and 447 in the non - us registry . both phases of the post - trial follow - up were approved by the institutional review board of each participating center , and all patients provided written informed consent . post - trial clinical and adverse events were obtained at 6-month intervals during follow - up . patients with an lbbb and an implanted crt - d or an icd - only device were divided into 2 prespecified subgroups based on their sex , male or female . the primary end point of the current study was hf or death , whichever came first during long - term follow - up . secondary end points included long - term hf events and long - term all - cause mortality . three sex subgroups were prespecified : qrs < 150 versus 150  ms , ischemic or nonischemic etiology of heart disease , and age < 65 or > 65 years . the end points and the subgroups are the same as those used in the original study . the analyses were performed on an intention - to - treat basis using the initial treatment assignment in the study . the rate of crossover in the long - term follow - up study was reported previously : 9% from the icd to the crt - d arm and 5% from the crt - d to the icd arm.4 categorical data are presented as frequencies and percentages , and continuous variables are presented as meansd . baseline clinical characteristics were compared between sex subgroups using the  test or fisher s exact test for dichotomous variables and the wilcoxon signed - rank test for continuous variables . the cumulative probability of long - term hf or death , hf events , and all - cause mortality was displayed according to the kaplan  meier method by treatment arm within each sex subgroup , with comparisons of cumulative event rates by the log - rank test . multivariable cox proportional hazards regression analysis was used to assess the effect of crt - d to reduce the risk of long - term combined outcome of hf or death , hf alone , and long - term all - cause mortality . the cox model was further adjusted for relevant clinical covariates using best subset regression modeling ( age , creatinine 1.4  mg / dl , body mass index , ischemic etiology , hf hospitalization at month prior to enrollment , qrs 150  ms , coronary artery bypass grafting , left ventricular end - systolic volume  index at baseline , and black race ) . all statistical tests were 2-sided , and a p value of < 0.05 was considered statistically significant . the protocol and results of the madit - crt study and the madit - crt long - term follow - up registry have been detailed in prior publications.1,4,7 in summary , 1820 patients with ischemic and nonischemic cardiomyopathy classified as having new york heart association ( nyha ) class i or ii symptoms with left ventricular ejection fraction 30% and qrs duration of at least 130  ms were randomly assigned to crt - d and icd - only treatment arms in a 3:2 ratio . all patients received optimal medical therapy for hf consisting of beta - blockers , angiotensin - converting enzyme inhibitors , angiotensin receptor blockers / angiotensin ii inhibitors , and statins . exclusion criteria included nyha class iii or iv symptoms , coronary artery bypass grafting surgery , percutaneous coronary intervention , or myocardial infarction within 90  days prior to enrollment ; second- or third - degree heart block ; atrial fibrillation 30  days prior to enrollment ; and comorbidities such as uremia ( blood urea nitrogen  > 70  mg / dl or creatinine > 3.0  mg / dl ) and liver failure . in the present study , we included only madit - crt patients with an lbbb ecg pattern at baseline because our previous data showed that the benefit of crt - d was restricted to lbbb patients only.3,4 accordingly , the present study population comprised 1281 lbbb patients , 70% of the total patient population of madit - crt . madit - crt was carried out from december 22 , 2004 , through june 22 , 2009 . following the publication of the primary results,1 a post - trial follow - up was conducted for all surviving study participants ( n=1691 ) until september 10 , 2010 ( phase i of the extended follow - up ) . after september 10 , 2010 , extended follow - up was conducted in 48 of 87 us centers that agreed to participate in the long - term follow - up registry requested by the us food and drug administration ( coordinated by the heart research follow - up program at the university of rochester medical center , rochester , ny ) and in 23 of 24 non - us centers as an investigator - initiated research project ( coordinated by the israeli association for cardiovascular trials at sheba medical center , ramat gan , israel ) . a total of 854 patients were involved , 407 in the us registry and 447 in the non - us registry . both phases of the post - trial follow - up were approved by the institutional review board of each participating center , and all patients provided written informed consent . post - trial clinical and adverse events were obtained at 6-month intervals during follow - up . patients with an lbbb and an implanted crt - d or an icd - only device were divided into 2 prespecified subgroups based on their sex , male or female . the primary end point of the current study was hf or death , whichever came first during long - term follow - up . secondary end points included long - term hf events and long - term all - cause mortality . three sex subgroups were prespecified : qrs < 150 versus 150  ms , ischemic or nonischemic etiology of heart disease , and age < 65 or > 65 years . the end points and the subgroups are the same as those used in the original study . the analyses were performed on an intention - to - treat basis using the initial treatment assignment in the study . the rate of crossover in the long - term follow - up study was reported previously : 9% from the icd to the crt - d arm and 5% from the crt - d to the icd arm.4 categorical data are presented as frequencies and percentages , and continuous variables are presented as meansd . baseline clinical characteristics were compared between sex subgroups using the  test or fisher s exact test for dichotomous variables and the wilcoxon signed - rank test for continuous variables . the cumulative probability of long - term hf or death , hf events , and all - cause mortality was displayed according to the kaplan  meier method by treatment arm within each sex subgroup , with comparisons of cumulative event rates by the log - rank test . multivariable cox proportional hazards regression analysis was used to assess the effect of crt - d to reduce the risk of long - term combined outcome of hf or death , hf alone , and long - term all - cause mortality . the cox model was further adjusted for relevant clinical covariates using best subset regression modeling ( age , creatinine 1.4  mg / dl , body mass index , ischemic etiology , hf hospitalization at month prior to enrollment , qrs 150  ms , coronary artery bypass grafting , left ventricular end - systolic volume  index at baseline , and black race ) . all statistical tests were 2-sided , and a p value of < 0.05 was considered statistically significant . among 1281 study patients , there were 394 women ( 31% ) and 887 men . women more often had nonischemic etiology of cardiomyopathy and properties of more severe hf including higher frequency of prior hf hospitalizations and higher left ventricular end - systolic volume at baseline , whereas men had higher frequency of previous coronary artery bypass grafting revascularization and conduction and rhythm disturbances including atrial arrhythmias , longer pr and qrs intervals , and higher blood urea nitrogen and creatinine levels . women were more likely prescribed digitalis and beta - blockers , whereas men were more likely prescribed statins . clinical and echocardiographic characteristics of men and women with left bundle - branch block values are meansd and number ( percentage ) . ace indicates angiotensin - converting enzyme ; arb , angiotensin receptor blocker ; bmi , body mass index ; bsa , body surface area ; bun , blood urea nitrogen ; cabg , coronary artery bypass grafting ; crt - d , cardiac resynchronization therapy with defibrillator ; hf , heart failure ; lav , left atrial volume ; lvedv , left ventricular end - diastolic volume ; lvef , left ventricular ejection fraction ; lvesv , left ventricular end - systolic volume ; nyha , new york heart association . meier survival analysis ( figure1a and 1b ) showed significant reduction in all - cause mortality events in the composite outcome of hf or death ( figure2a and 2b ) and in hf alone ( figure  s1a and s1b ) in men and women with lbbb treated with crt - d versus an icd only . cumulative probability of death by treatment arm in women ( a ) and men ( b ) . crt - d indicates cardiac resynchronization therapy with defibrillator ; icd , implantable cardioverter - defibrillator . cumulative probability of hf or death by treatment arm in women ( a ) and men ( b ) . crt - d indicates cardiac resynchronization therapy with defibrillator ; hf , heart failure ; icd , implantable cardioverter - defibrillator . multivariable analysis ( table2 ) showed that women with crt - d versus icd only had significantly greater risk reduction in hf or death ( hazard ratio [ hr ] 0.29 , p<0.001 , versus hr 0.59 , p<0.001 ) and hf alone ( hr 0.23 , p<0.001 , versus hr 0.50 , p<0.001 ) than men , with a significant sex - by - treatment interaction ( p=0.003 for hf or death and p=0.008 for hf only ) . both women and men had significant mortality benefits with crt - d versus icd only ( women : hr 0.49 , p=0.038 ; men : hr 0.70 , p=0.032 ; interaction p=0.365 ) . multivariable models to assess treatment effect by sex of crt - d versus icd alone on all - cause mortality , hf only , and hf or death crt - d indicates cardiac resynchronization therapy with defibrillator ; hf , heart failure ; hr , hazard ratio ; icd , implantable cardioverter - defibrillator . adjusted for treatment arm , age , creatinine 1.4 , body mass index , ischemic etiology , congestive hf hospitalization at month prior to enrollment , qrs 150  ms , coronary artery bypass grafting , left ventricular end - systolic volume index at baseline , black race , sex , and sex - by - treatment interaction . as shown in the univariate analysis ( figure3 ) , women with crt - d had significant risk reduction in hf or death with both qrs < 150  and 150  ms compared with icd only , whereas men showed significant benefit only from crt - d with qrs 150  ms . for both subgroups , women had greater reduction of hf or death with crt - d versus an icd only than men , with significant sex - by - treatment interaction ( p<0.05 for both ) . forest plot shows risk of heart failure or death event by sex according to treatment group in subgroups of patients . crt - d indicates cardiac resynchronization therapy with defibrillator ; hr , hazard ratio ; icd , implantable cardioverter - defibrillator ; lbbb , left bundle - branch block . treatment with crt - d was associated with a greater reduction in the end point of hf alone and in the combined end point of hf or death in women compared with men . there was a significant mortality reduction in men with qrs < 150  ms , but it was less prominent in those with qrs 150  ms ( table3 ) . multivariable models to assess the treatment effect by sex and qrs duration of crt - d versus icd alone on all - cause mortality , hf only , and hf or death crt - d indicates cardiac resynchronization therapy with defibrillator ; hf , heart failure ; hr , hazard ratio ; icd , implantable cardioverter - defibrillator . adjusted for treatment arm , age , creatinine 1.4 , body mass index , ischemic etiology , congestive hf hospitalization at month prior to enrollment , coronary artery bypass grafting , left ventricular end - systolic volume index at baseline , black race , sex , and sex - by - treatment interaction . we further assessed other possible prespecified subgroup differences in the long - term benefit of crt - d for the end point of hf or death between men and women with lbbb ( figure3 ) . this analysis showed that the incremental long - term benefit of crt - d was more pronounced and statistically significant among patients with nonischemic cardiomyopathy and among younger patients , whereas among patients with ischemic cardiomyopathy and in older patients ( aged 65  years ) , there was no statistically significant difference between men and women in the long - term benefit of crt - d ( figure3 ) . kaplan  meier survival analysis ( figure1a and 1b ) showed significant reduction in all - cause mortality events in the composite outcome of hf or death ( figure2a and 2b ) and in hf alone ( figure  s1a and s1b ) in men and women with lbbb treated with crt - d versus an icd only . cumulative probability of death by treatment arm in women ( a ) and men ( b ) . crt - d indicates cardiac resynchronization therapy with defibrillator ; icd , implantable cardioverter - defibrillator . cumulative probability of hf or death by treatment arm in women ( a ) and men ( b ) . crt - d indicates cardiac resynchronization therapy with defibrillator ; hf , heart failure ; icd , implantable cardioverter - defibrillator . multivariable analysis ( table2 ) showed that women with crt - d versus icd only had significantly greater risk reduction in hf or death ( hazard ratio [ hr ] 0.29 , p<0.001 , versus hr 0.59 , p<0.001 ) and hf alone ( hr 0.23 , p<0.001 , versus hr 0.50 , p<0.001 ) than men , with a significant sex - by - treatment interaction ( p=0.003 for hf or death and p=0.008 for hf only ) . both women and men had significant mortality benefits with crt - d versus icd only ( women : hr 0.49 , p=0.038 ; men : hr 0.70 , p=0.032 ; interaction p=0.365 ) . multivariable models to assess treatment effect by sex of crt - d versus icd alone on all - cause mortality , hf only , and hf or death crt - d indicates cardiac resynchronization therapy with defibrillator ; hf , heart failure ; hr , hazard ratio ; icd , implantable cardioverter - defibrillator . adjusted for treatment arm , age , creatinine 1.4 , body mass index , ischemic etiology , congestive hf hospitalization at month prior to enrollment , qrs 150  ms , coronary artery bypass grafting , left ventricular end - systolic volume index at baseline , black race , sex , and sex - by - treatment interaction . as shown in the univariate analysis ( figure3 ) , women with crt - d had significant risk reduction in hf or death with both qrs < 150  and 150  ms compared with icd only , whereas men showed significant benefit only from crt - d with qrs 150  ms . for both subgroups , women had greater reduction of hf or death with crt - d versus an icd only than men , with significant sex - by - treatment interaction ( p<0.05 for both ) . forest plot shows risk of heart failure or death event by sex according to treatment group in subgroups of patients . crt - d indicates cardiac resynchronization therapy with defibrillator ; hr , hazard ratio ; icd , implantable cardioverter - defibrillator ; lbbb , left bundle - branch block . treatment with crt - d was associated with a greater reduction in the end point of hf alone and in the combined end point of hf or death in women compared with men . there was a significant mortality reduction in men with qrs < 150  ms , but it was less prominent in those with qrs 150  ms ( table3 ) . multivariable models to assess the treatment effect by sex and qrs duration of crt - d versus icd alone on all - cause mortality , hf only , and hf or death crt - d indicates cardiac resynchronization therapy with defibrillator ; hf , heart failure ; hr , hazard ratio ; icd , implantable cardioverter - defibrillator . adjusted for treatment arm , age , creatinine 1.4 , body mass index , ischemic etiology , congestive hf hospitalization at month prior to enrollment , coronary artery bypass grafting , left ventricular end - systolic volume index at baseline , black race , sex , and sex - by - treatment interaction . we further assessed other possible prespecified subgroup differences in the long - term benefit of crt - d for the end point of hf or death between men and women with lbbb ( figure3 ) . this analysis showed that the incremental long - term benefit of crt - d was more pronounced and statistically significant among patients with nonischemic cardiomyopathy and among younger patients , whereas among patients with ischemic cardiomyopathy and in older patients ( aged 65  years ) , there was no statistically significant difference between men and women in the long - term benefit of crt - d ( figure3 ) . in this madit - crt long - term follow - up substudy , we extended the knowledge regarding the sex first , we showed that although only women with crt - d in the trial experience gained a benefit for hf or death and hf alone with qrs duration > 150 or < 150  ms , in the long term , both sexes gained hf or death , hf alone , and mortality risk reductions regardless of qrs duration . second , women had more pronounced benefit with crt - d in hf or death and hf alone , and this effect was consistent regardless of qrs duration . third , men with qrs < 150  ms compared with men with qrs 150  ms derived less pronounced benefit from crt - d with reduction in hf or death and hf alone , but they had significantly lower long - term mortality . optimizing patient selection for crt is an ongoing challenge . guidelines8,9 emphasize the use of left ventricular ejection fraction 35% , lbbb morphology , and qrs duration 150  ms as major clinical variables for selection criteria with crt in mild hf patients . there are conflicting data for crt outcome regarding the importance of qrs duration versus qrs morphology . cleland et  al10 suggested that qrs duration is more important for crt outcomes than qrs morphology ; however , they enrolled patients with mild to severe hf in their study , and the study had different control arms ( icd or optimal medical therapy ) . bryant et  al11 showed in a meta - analysis that only patients with qrs > 150  ms benefit from crt , but they did not address qrs morphology in their analysis , which also included both randomized and nonrandomized studies of patients with mild to severe hf . defibrillation for ambulatory heart failure trial ( raft ) study investigators showed that lbbb morphology was more important than qrs duration , and qrs duration did not significantly predict outcomes in the multivariable analysis.12 zusterzeel et  al13 performed a patient - level meta - analysis combining data from recent randomized trials available at the us food and drug administration and showed that only patients with lbbb morphology benefited from crt . they also found that women had better outcomes with crt with shorter qrs duration ( 130 to 149  ms ) , whereas men had no such benefit . it should be noted that zusterzeel et  al did not investigate long - term crt outcomes by sex . in our study , we emphasized the current knowledge of crt - d results by sex and qrs duration , and with a long patient follow - up , we can confirm that both men and women with mild hf and lbbb morphology derived impressive benefit with crt - d , regardless of qrs duration ; in particular , women had a pronounced benefit . importantly , we could show that men and women with lbbb and qrs < 150 or > 150  ms benefited from crt - d with long - term cardiac resynchronization . our data show that in mild hf patients with depressed left ventricular ejection fraction , lbbb configuration is the most important factor for predicting effectiveness of crt - d therapy , whereas qrs duration is of less importance . it has been suggested that women have shorter qrs duration than men in the absence of any conduction disturbance.14,15 in our study , women had significantly shorter baseline qrs durations , but they gained even greater clinical benefit from crt - d than men , suggesting that women may have more dyssynchrony , at shorter qrs durations , that leads to better response with crt - d . this is in alignment with a previous retrospective study6 restricted to nyha class iii or iv patients with lbbb and nonischemic cardiomyopathy showing that men experienced echocardiographic volume reductions with crt only at qrs duration > 150  ms , whereas women had an echocardiographic response both > 150 and < 150  ms . in this study , however , data on outcomes of hf and mortality were not provided . another study evaluating registry data5 compared mortality risk with crt among patients with nyha class iii by qrs morphology and duration . they showed that women with lbbb had greater mortality reductions than men and that longer qrs durations were correlated with better outcome in both women and men ; however , it should be noted that no control group was available to appreciate the magnitude of effect of qrs duration on outcomes , and the follow - up in this study was relatively short ( median of 2.9  years ) . in the present study , we confirmed these results on sex - specific long - term outcomes with crt - d , and we emphasized that women with lbbb derived significantly greater mortality or hf reduction with crt - d compared with icd only than men . interestingly , in our study , women aged < 65  years had greater benefit from crt - d versus an icd than men , but the groups had similar results with age > 65  years . we speculate that this difference in outcomes may be related to other significant comorbidities in the older women that may result in competing modes of death or worsening of hf mortality . several baseline differences between men and women may have contributed to the differences in long - term outcomes in our study . men were more likely to have higher creatinine levels , ischemic cardiomyopathy , and prior atrial tachyarrhythmias , characteristics that are related to worse prognosis in hf . first , women had different baseline clinical characteristics than men ; however , our findings were consistent after adjustment for these covariates and across subgroups . second , when assessing outcomes in men and women with qrs < 150  ms , we may have had limited statistical power because of the relatively smaller number of patients with qrs < 150  ms in our study and the lower event rate in these subgroups . third , madit - crt was not originally designed to assess reduction of mortality alone with crt - d ; therefore , it may not be adequately powered for the end point of mortality , especially when evaluating subgroups . nevertheless , this study is one of the largest randomized controlled crt - d trials in patients with mild hf using a control group of icd patients that has such long - term follow - up . in addition , we had a relatively large proportion of women , almost one - third of the total patient population , and that is much higher than most other clinical trials . in this madit - crt long - term follow - up study , we showed that in patients with lbbb configuration , both men and women gained sustained reductions in hf or death , hf alone , and mortality with crt - d therapy regardless of qrs duration . women had more pronounced benefit in outcomes for hf or death and hf alone compared with men . consequently , we believe that clinical decisions regarding crt - d use should be based on qrs morphology rather than qrs duration . the madit - crt trial was sponsored by an unrestricted research grant from boston scientific corporation to the university of rochester , rochester , ny , and to the israeli association for cardiovascular trials . drs moss , goldenberg , zareba , klein , kutyifa and solomon are receiving grant support from boston scientific . figure  s1 . cumulative probability of heart failure by treatment arm in women ( a ) and men ( b ) .
backgroundprevious studies have shown conflicting results regarding the benefit of cardiac resynchronization therapy ( crt ) by sex and qrs duration.methods and resultsin the multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy ( madit - crt ) , we evaluated long - term clinical outcome of heart failure ( hf ) or death , death , and hf alone by sex and qrs duration ( dichotomized at 150  ms ) in left bundle - branch block patients with crt with defibrillator backup ( crt - d ) versus implantable cardioverter - defibrillator ( icd ) only . 
 there were 394 women ( 31% ) and 887 men with left bundle - branch block . during the median follow - up of 5.6 years , women derived greater clinical benefit from crt - d compared with implantable cardioverter - defibrillator only , with a significant 71% reduction in hf or death ( hazard ratio [ hr ] 0.29 , p<0.001 ) and a 77% reduction in hf alone ( hr 0.23 , p<0.001 ) compared with men , who had a 41% reduction in hf or death ( hr 0.59 , p<0.001 ) and a 50% reduction in hf alone ( hr 0.50 , p<0.001 ) ( all sex - by - treatment interaction p<0.05 ) . 
 men and women had similar reduction in long - term mortality with crt - d versus implantable cardioverter - defibrillator only ( men : hr 0.70 , p=0.03 ; women : hr 0.59 , p=0.04 ) . 
 the incremental benefit of crt - d in women for hf or death and hf alone was consistent with qrs < 150 or > 150  ms.conclusionsduring long - term follow - up of mild hf patients with left ventricular dysfunction and wide qrs , both women and men with left bundle - branch block derived sustained benefit from crt - d versus implantable cardioverter - defibrillator only , with significant reduction in hf or death , hf alone , and all - cause mortality regardless of qrs duration . 
 there is an incremental benefit with crt - d in women for the end points of hf or death and hf alone.clinical trial registrationurl : https://clinicaltrials.gov/. unique identifiers : nct00180271 , nct01294449 , and nct02060110 .