chronic heart failure ( chf ) is independently associated with several comorbid conditions , which in turn are also independent contributors to chf . from the clinical and research perspectives , chf and associated comorbidities similarly , randomized controlled trials ( rcts ) on chf often exclude all but the mildest forms of any comorbidity and enroll a restricted patient demographic , which may limit the generalizability of findings to the real world.1 this is problematic considering that comorbidities are common in chf , the presence of which may alter the pathophysiology and response to treatments.2 changes to chf guidelines reflect a growing awareness of these issues ; however , the efficacy of chf treatment in comorbid settings remains poorly understood . phase iv trials , which involve postmarketing surveillance of the uncontrolled treatment of a patient population , are needed to advance understanding of external validity.35 in this review , we have focused on patient demographics , diabetes mellitus ( dm ) , chronic renal failure ( crf ) , and atrial fibrillation in chf . pathophysiological variations in responses to treatments are seen for the following factors : doses ( eg , statin doses and asian patients ) , class of agents used ( eg , benefits of nitrates and hydralazine for chf in african american patients),6 or a particular agent within a class ( eg , the lack of effect of bucindolol in african american patients).7 specifically , in the case of beta - blockers ( bbs ) , there are intrinsic differences in pharmacology due to receptor selectivity , pharmacogenomics , and peripheral vasodilatory capacity . all these points have the potential to influence therapy for different groups of patients or those with a particular comorbidity . these points have been previously well discussed.810 the presence of common comorbidities , such as dm and crf , can affect the size of the treatment effect and , particularly in relation to crf , the size and safety of the dosing regime.11,12 these points may guide selection of one agent in a class over another or indicate the need for different treatment protocols . for these reasons , it is important that clinical demographics and comorbidities be representative , if not in the rct but in subsequent postmarketing tools , such as post hoc analyses , systematic reviews , and meta - analyses , or with actual surveillance during phase iv effectiveness and cost - effectiveness research . in this review , we examine the efficacy of bbs in chf patients with particular focus on hetergeneous demographic cohorts and comorbid conditions . rcts , as well as reviews / meta - analyses of rcts , which met the following criteria , were included : ( i ) head - to - head comparison of a bb with placebo , another bb , or another agent , irrespective of baseline therapy ; ( ii ) a minimum of 50 patients in total ; ( iii ) incidence of death as a reported end point ; ( iv ) incidence of cardiac and noncardiac events as reported end points ; ( v ) clinical follow - up of at least three months ; and ( vi ) peer - reviewed journal publications before december 1 , 2015 , indexed in medline . we searched for rcts in medline ( 19662015 ) , pubmed , embase , scopus , and cochrane databases , in addition to hand - searching the bibliographies of identified studies for additional references . we restricted our searches to english language , human studies , clinical trials , and controlled clinical trials . we used the keywords and medical subject headings  heart failure  and  chronic  or  congestive  and  beta - blockers  or  adrenergic beta - antagonists  . to the results of this core search , we added the additional keyword  clinical trials  as the first criterion . from the core search history , secondary searches were conducted , limiting studies to post hoc analyses , meta - analyses , and reviews , with the keywords  diabetes mellitus  ,  renal failure  ,  atrial fibrillation  , or we also searched using the individual bb names  bisoprolol  ,  bucindolol  ,  carvedilol  ,  metoprolol  , and nebivolol  in the secondary search . the first author performed the scan of articles by title and abstract and then analyzed each of the short - listed studies . we reviewed the methodological quality of the studies using standard criteria.13,14 the first author performed the data extraction , which included the following factors : age , sex , race , follow - up duration , new york heart association ( nyha ) class , left ventricular ejection fraction ( lvef ) , dm , crf , hypertension , ischemia , atrial fibrillation , and all - cause mortality . rcts , as well as reviews / meta - analyses of rcts , which met the following criteria , were included : ( i ) head - to - head comparison of a bb with placebo , another bb , or another agent , irrespective of baseline therapy ; ( ii ) a minimum of 50 patients in total ; ( iii ) incidence of death as a reported end point ; ( iv ) incidence of cardiac and noncardiac events as reported end points ; ( v ) clinical follow - up of at least three months ; and ( vi ) peer - reviewed journal publications before december 1 , 2015 , indexed in medline . we searched for rcts in medline ( 19662015 ) , pubmed , embase , scopus , and cochrane databases , in addition to hand - searching the bibliographies of identified studies for additional references . we restricted our searches to english language , human studies , clinical trials , and controlled clinical trials . we used the keywords and medical subject headings  heart failure  and  chronic  or  congestive  and  beta - blockers  or  adrenergic beta - antagonists  . to the results of this core search , we added the additional keyword  clinical trials  as the first criterion . from the core search history , secondary searches were conducted , limiting studies to post hoc analyses , meta - analyses , and reviews , with the keywords  diabetes mellitus  ,  renal failure  ,  atrial fibrillation  , or we also searched using the individual bb names  bisoprolol  ,  bucindolol  ,  carvedilol  ,  metoprolol  , and nebivolol  in the secondary search . the first author performed the scan of articles by title and abstract and then analyzed each of the short - listed studies . we reviewed the methodological quality of the studies using standard criteria.13,14 the first author performed the data extraction , which included the following factors : age , sex , race , follow - up duration , new york heart association ( nyha ) class , left ventricular ejection fraction ( lvef ) , dm , crf , hypertension , ischemia , atrial fibrillation , and all - cause mortality . in total , 764 citations , four bb reviews,1518 and the references in the relevant articles were screened for rcts meeting the inclusion criteria . from among 50 articles , 38 articles were included1956 and 12 were excluded as not meeting the highlighted criteria.5768 additionally , 20 post hoc analyses , systematic reviews , and meta - analyses were identified in the secondary search and search of references ( table 1).6987 six bbs with varying cardiac specificity and extracardiac properties were tested in the studies identified . the majority of the studies compared bbs to placebo , with one larger study comparing two established bbs head to head . nearly all studies recruited chf cases ranging from mild to severe , with representation of the entire spectrum of illness within each study . in many cases , most studies addressed one or more of the following themes : the effects of bb with baseline heart failure ( hf ) either mild or severe ; safety , efficacy , and optimal methods for deriving clinical benefit ; utility in ischemic and nonischemic etiologies ; and benefits for older chf cohorts . the mean age of participants generally ranged between 50 years and 70 years , and no strict criteria were placed on excluding older participants . the seniors study , however , specifically enrolled patients older than 70 years of age , achieving a cohort mean age of 76  4.7 years.52 post hoc data were also provided by merit - hf.87 females were generally underrepresented , with only four studies enrolling at least one - third of female . seven studies described patient ethnicity , five of which predominantly enrolled caucasians . in the best study , 627 ( 23% ) of 2,708 patients were african american , 143 ( 6% ) hispanic , and 42 ( 2% ) listed as other . in this demographically diverse cohort , the study objectives were not achieved.25 a smaller study with the same agent , which did not disclose racial demography , however , demonstrated safety and efficacy.24 ischemic cardiomyopathy as etiology , coronary artery disease as comorbidity , and revascularization strategies were listed in 26 studies . in more than half the studies , at least 50% of participants had ischemic heart disease . more than two - thirds of trials reported hypertension as the etiology or a comorbidity of chf . eighteen trials listed concomitant diabetes . in most cases , the number of diabetics was between 18% and 40% . in the best trial , this study also provided greater details on the comorbidity , with 964 ( 35.5% ) of 2,708 participants diabetic , 398 ( 15% ) on insulin , and 313 ( 12% ) with end - organ complications . in a meta - analysis of seven trials , wherein 1,411 ( 25% ) of 5,757 participants had diabetes , bell et al showed evidence for benefit with carvedilol in all groups , specifically , a reduction in relative risk ( rr ) of 28% ( 95% confidence interval [ ci ] : 3%46% ; p = 0.03 ] in diabetics.69 haas et al compared four different bbs from six studies and noted similar prognostic benefits for treated diabetics ( rr : 0.84 ; 95% ci : 0.730.96 ; p = 0.011 ) ; however , the magnitude of benefit was less compared to that in nondiabetics , ( rr : 0.72 ; 95% ci : 0.650.79 ; p < 0.001).70 finally , post hoc analyses in merit - hf showed a 76% higher risk of hospitalizations for hf ; however , a mortality benefit from metoprolol was only seen when the data were pooled with those from the cibis ii and copernicus trials , due to the small sample size.71,72 renal function and renal impairment were presented in a limited number of studies , mostly presenting data as mean serum creatinine . in the cibis iii trial , 182 ( 18% ) of 1,010 of participants were reported as having a history of renal disease . mol / l , and estimated glomerular filtration rate ( egfr ) was not detailed . post hoc analysis of the seniors trial showed that egfr was strongly associated with outcomes and that nebivolol was equally efficacious across low- , middle- , or high - egfr ( < 55.5 , 55.572.8 , or > 72.8 ml / min/1.73 m ) tertiles . in the low egfr group to the high , the primary outcome ( all - cause mortality or cardiovascular hospitalization ) was reported in 282 ( 40% ) of 704 patients ( hazard ratio [ hr ] : 0.81 ; 95% ci : 0.641.03 ; p = 0.087 ) , 218/704 ( 31% ) patients ( hr : 0.83 ; 95% ci : 0.631.08 ; p = 0.164 ) , and 202/704 ( 29% ) patients ( hr : 0.93 ; 95% ci : 0.701.22 ; p = 0.597 ) . there were higher rates of drug discontinuation due to bradycardia in the moderate - egfr group.54 in a post hoc analysis of cibis ii trial , 849/2,647 ( 32% ) participants who had egfr < 60 ml / min were more likely to die or be hospitalized ( rr : 0.66 ; 95% ci : 0.50.88 ) . treatment withdrawals were higher , as was mortality , with reducing renal function , more so the 63/2,584 patients with egfr < 30 ml / min , with hr = 0.59 ( 95% ci : 0.301.18 ) , compared to 0.68 ( 95% ci : 0.560.83 ) for patients with egfr > 30 ml / min.73 in a post hoc analysis of merit - hf , 493/3,965 ( 12% ) were identified with low egfr < 45 ml / min , 976/3,965 ( 25% ) had moderate egfr 4560 ml / min , and 2,496/3,965 ( 63% ) had high egfr . metoprolol had differing efficacy levels against placebo across egfr tertiles , whereby the mortality and hf hospitalization risk were the greatest in the low - egfr group ( hr : 0.44 ; 95% ci : 0.310.63 ; p = 0.0001 ) compared to the high - egfr group ( hr : 0.75 ; 95% ci : 0.620.92 ; p = 0.05).74 finally , in an eight - trial meta - analysis , badve et al reported findings that also supported the benefit of bbs in terms of reducing risk of all - cause ( rr : 0.72 ; 95% ci : 0.640.80 ) and cardiovascular mortality ( rr : 0.66 ; 95% ci : 0.490.89 ) , but with increased risk of bradycardia ( rr : 4.92 ; 95% ci : 3.207.55 ) and hypotension ( rr : 5.08 ; 95% ci : 3.487.41).75 atrial fibrillation was reported in 10 studies , with rates of approximately 10%20% of participants . with an older cohort , in the seniors and eneca trials , between 25% and 35% had atrial fibrillation at baseline.59,60 kotecha et al extracted individual patient data from 10 rcts , where 3,066/18,254 ( 17% ) had atrial fibrillation at baseline . crude mortality rates were higher with atrial fibrillation ( 633/3,064 ; 21% ) compared to 2,237/13,945 ( 16% ) for sinus rhythm after mean follow - up of 1.5 years ( sd : 1.1 years ) . bb treatment did not lead to a significant mortality benefit in atrial fibrillation ( rr : 0.97 ; 95% ci : 0.831.14 ; p = 0.73 ) as with sinus rhythm ( rr : 0.73 ; 95% ci : 0.670.80 ; p < 0.01 ) . the authors also did not find benefit across subgroups of age , sex , lvef , nyha class , heart rate , and baseline medical therapy.76 in an older meta - analysis , benefits of bb in preventing atrial fibrillation were highlighted77 ; however , in known atrial fibrillation and hf , a four study meta - analysis,78 and a post hoc analysis from cibis ii22 supported the findings of kotecha et al for heart rates , mcalister et al performed a meta - analysis that showed that for every 5 beats / min reduction , there was a concomitant 18% reduction ( 95% ci : 6%29% ) in risk of death.79 six bbs with varying cardiac specificity and extracardiac properties were tested in the studies identified . the majority of the studies compared bbs to placebo , with one larger study comparing two established bbs head to head . nearly all studies recruited chf cases ranging from mild to severe , with representation of the entire spectrum of illness within each study . in many cases , most studies addressed one or more of the following themes : the effects of bb with baseline heart failure ( hf ) either mild or severe ; safety , efficacy , and optimal methods for deriving clinical benefit ; utility in ischemic and nonischemic etiologies ; and benefits for older chf cohorts . the mean age of participants generally ranged between 50 years and 70 years , and no strict criteria were placed on excluding older participants . the seniors study , however , specifically enrolled patients older than 70 years of age , achieving a cohort mean age of 76  4.7 years.52 post hoc data were also provided by merit - hf.87 females were generally underrepresented , with only four studies enrolling at least one - third of female . seven studies described patient ethnicity , five of which predominantly enrolled caucasians . in the best study , 627 ( 23% ) of 2,708 patients were african american , 143 ( 6% ) hispanic , and 42 ( 2% ) listed as other . in this demographically diverse cohort , the study objectives were not achieved.25 a smaller study with the same agent , which did not disclose racial demography , however , demonstrated safety and efficacy.24 ischemic cardiomyopathy as etiology , coronary artery disease as comorbidity , and revascularization strategies were listed in 26 studies . in more than half the studies , at least 50% of participants had ischemic heart disease . more than two - thirds of trials reported hypertension as the etiology or a comorbidity of chf . the number of diabetics was between 18% and 40% . in the best trial , 36% of participants were diabetic . this study also provided greater details on the comorbidity , with 964 ( 35.5% ) of 2,708 participants diabetic , 398 ( 15% ) on insulin , and 313 ( 12% ) with end - organ complications . in a meta - analysis of seven trials , wherein 1,411 ( 25% ) of 5,757 participants had diabetes , bell et al showed evidence for benefit with carvedilol in all groups , specifically , a reduction in relative risk ( rr ) of 28% ( 95% confidence interval [ ci ] : 3%46% ; p = 0.03 ] in diabetics.69 haas et al compared four different bbs from six studies and noted similar prognostic benefits for treated diabetics ( rr : 0.84 ; 95% ci : 0.730.96 ; p = 0.011 ) ; however , the magnitude of benefit was less compared to that in nondiabetics , ( rr : 0.72 ; 95% ci : 0.650.79 ; p < 0.001).70 finally , post hoc analyses in merit - hf showed a 76% higher risk of hospitalizations for hf ; however , a mortality benefit from metoprolol was only seen when the data were pooled with those from the cibis ii and copernicus trials , due to the small sample size.71,72 renal function and renal impairment were presented in a limited number of studies , mostly presenting data as mean serum creatinine . in the cibis iii trial , 182 ( 18% ) of 1,010 of participants were reported as having a history of renal disease . mol / l , and estimated glomerular filtration rate ( egfr ) was not detailed . post hoc analysis of the seniors trial showed that egfr was strongly associated with outcomes and that nebivolol was equally efficacious across low- , middle- , or high - egfr ( < 55.5 , 55.572.8 , or > 72.8 ml / min/1.73 m ) tertiles . in the low egfr group to the high , the primary outcome ( all - cause mortality or cardiovascular hospitalization ) was reported in 282 ( 40% ) of 704 patients ( hazard ratio [ hr ] : 0.81 ; 95% ci : 0.641.03 ; p = 0.087 ) , 218/704 ( 31% ) patients ( hr : 0.83 ; 95% ci : 0.631.08 ; p = 0.164 ) , and 202/704 ( 29% ) patients ( hr : 0.93 ; 95% ci : 0.701.22 ; p = 0.597 ) . there were higher rates of drug discontinuation due to bradycardia in the moderate - egfr group.54 in a post hoc analysis of cibis ii trial , 849/2,647 ( 32% ) participants who had egfr < 60 ml / min were more likely to die or be hospitalized ( rr : 0.66 ; 95% ci : 0.50.88 ) . treatment withdrawals were higher , as was mortality , with reducing renal function , more so the 63/2,584 patients with egfr < 30 ml / min , with hr = 0.59 ( 95% ci : 0.301.18 ) , compared to 0.68 ( 95% ci : 0.560.83 ) for patients with egfr > 30 ml / min.73 in a post hoc analysis of merit - hf , 493/3,965 ( 12% ) were identified with low egfr < 45 ml / min , 976/3,965 ( 25% ) had moderate egfr 4560 ml / min , and 2,496/3,965 ( 63% ) had high egfr . metoprolol had differing efficacy levels against placebo across egfr tertiles , whereby the mortality and hf hospitalization risk were the greatest in the low - egfr group ( hr : 0.44 ; 95% ci : 0.310.63 ; p = 0.0001 ) compared to the high - egfr group ( hr : 0.75 ; 95% ci : 0.620.92 ; p = 0.05).74 finally , in an eight - trial meta - analysis , badve et al reported findings that also supported the benefit of bbs in terms of reducing risk of all - cause ( rr : 0.72 ; 95% ci : 0.640.80 ) and cardiovascular mortality ( rr : 0.66 ; 95% ci : 0.490.89 ) , but with increased risk of bradycardia ( rr : 4.92 ; 95% ci : 3.207.55 ) and hypotension ( rr : 5.08 ; 95% ci : 3.487.41).75 atrial fibrillation was reported in 10 studies , with rates of approximately 10%20% of participants . with an older cohort , in the seniors and eneca trials , between 25% and 35% had atrial fibrillation at baseline.59,60 kotecha et al extracted individual patient data from 10 rcts , where 3,066/18,254 ( 17% ) had atrial fibrillation at baseline . crude mortality rates were higher with atrial fibrillation ( 633/3,064 ; 21% ) compared to 2,237/13,945 ( 16% ) for sinus rhythm after mean follow - up of 1.5 years ( sd : 1.1 years ) . bb treatment did not lead to a significant mortality benefit in atrial fibrillation ( rr : 0.97 ; 95% ci : 0.831.14 ; p = 0.73 ) as with sinus rhythm ( rr : 0.73 ; 95% ci : 0.670.80 ; p < 0.01 ) . the authors also did not find benefit across subgroups of age , sex , lvef , nyha class , heart rate , and baseline medical therapy.76 in an older meta - analysis , benefits of bb in preventing atrial fibrillation were highlighted77 ; however , in known atrial fibrillation and hf , a four study meta - analysis,78 and a post hoc analysis from cibis ii22 supported the findings of kotecha et al for heart rates , mcalister et al performed a meta - analysis that showed that for every 5 beats / min reduction , there was a concomitant 18% reduction ( 95% ci : 6%29% ) in risk of death.79 eighteen trials listed concomitant diabetes . in most cases , the number of diabetics was between 18% and 40% . in the best trial , this study also provided greater details on the comorbidity , with 964 ( 35.5% ) of 2,708 participants diabetic , 398 ( 15% ) on insulin , and 313 ( 12% ) with end - organ complications . in a meta - analysis of seven trials , wherein 1,411 ( 25% ) of 5,757 participants had diabetes , bell et al showed evidence for benefit with carvedilol in all groups , specifically , a reduction in relative risk ( rr ) of 28% ( 95% confidence interval [ ci ] : 3%46% ; p = 0.03 ] in diabetics.69 haas et al compared four different bbs from six studies and noted similar prognostic benefits for treated diabetics ( rr : 0.84 ; 95% ci : 0.730.96 ; p = 0.011 ) ; however , the magnitude of benefit was less compared to that in nondiabetics , ( rr : 0.72 ; 95% ci : 0.650.79 ; p < 0.001).70 finally , post hoc analyses in merit - hf showed a 76% higher risk of hospitalizations for hf ; however , a mortality benefit from metoprolol was only seen when the data were pooled with those from the cibis ii and copernicus trials , due to the small sample size.71,72 renal function and renal impairment were presented in a limited number of studies , mostly presenting data as mean serum creatinine . in the cibis iii trial , 182 ( 18% ) of 1,010 of participants mean serum creatinine was 101 mol / l , and estimated glomerular filtration rate ( egfr ) was not detailed . post hoc analysis of the seniors trial showed that egfr was strongly associated with outcomes and that nebivolol was equally efficacious across low- , middle- , or high - egfr ( < 55.5 , 55.572.8 , or > 72.8 ml / min/1.73 m ) tertiles . in the low egfr group to the high , the primary outcome ( all - cause mortality or cardiovascular hospitalization ) was reported in 282 ( 40% ) of 704 patients ( hazard ratio [ hr ] : 0.81 ; 95% ci : 0.641.03 ; p = 0.087 ) , 218/704 ( 31% ) patients ( hr : 0.83 ; 95% ci : 0.631.08 ; p = 0.164 ) , and 202/704 ( 29% ) patients ( hr : 0.93 ; 95% ci : 0.701.22 ; p = 0.597 ) . there were higher rates of drug discontinuation due to bradycardia in the moderate - egfr group.54 in a post hoc analysis of cibis ii trial , 849/2,647 ( 32% ) participants who had egfr < 60 ml / min were more likely to die or be hospitalized ( rr : 0.66 ; 95% ci : 0.50.88 ) . treatment withdrawals were higher , as was mortality , with reducing renal function , more so the 63/2,584 patients with egfr < 30 ml / min , with hr = 0.59 ( 95% ci : 0.301.18 ) , compared to 0.68 ( 95% ci : 0.560.83 ) for patients with egfr > 30 ml / min.73 in a post hoc analysis of merit - hf , 493/3,965 ( 12% ) were identified with low egfr < 45 ml / min , 976/3,965 ( 25% ) had moderate egfr 4560 ml / min , and 2,496/3,965 ( 63% ) had high egfr . metoprolol had differing efficacy levels against placebo across egfr tertiles , whereby the mortality and hf hospitalization risk were the greatest in the low - egfr group ( hr : 0.44 ; 95% ci : 0.310.63 ; p = 0.0001 ) compared to the high - egfr group ( hr : 0.75 ; 95% ci : 0.620.92 ; p = 0.05).74 finally , in an eight - trial meta - analysis , badve et al reported findings that also supported the benefit of bbs in terms of reducing risk of all - cause ( rr : 0.72 ; 95% ci : 0.640.80 ) and cardiovascular mortality ( rr : 0.66 ; 95% ci : 0.490.89 ) , but with increased risk of bradycardia ( rr : 4.92 ; 95% ci : 3.207.55 ) and hypotension ( rr : 5.08 ; 95% ci : 3.487.41).75 atrial fibrillation was reported in 10 studies , with rates of approximately 10%20% of participants . with an older cohort , in the seniors and eneca trials , between 25% and 35% had atrial fibrillation at baseline.59,60 kotecha et al extracted individual patient data from 10 rcts , where 3,066/18,254 ( 17% ) had atrial fibrillation at baseline . crude mortality rates were higher with atrial fibrillation ( 633/3,064 ; 21% ) compared to 2,237/13,945 ( 16% ) for sinus rhythm after mean follow - up of 1.5 years ( sd : 1.1 years ) . bb treatment did not lead to a significant mortality benefit in atrial fibrillation ( rr : 0.97 ; 95% ci : 0.831.14 ; p = 0.73 ) as with sinus rhythm ( rr : 0.73 ; 95% ci : 0.670.80 ; p < 0.01 ) . the authors also did not find benefit across subgroups of age , sex , lvef , nyha class , heart rate , and baseline medical therapy.76 in an older meta - analysis , benefits of bb in preventing atrial fibrillation were highlighted77 ; however , in known atrial fibrillation and hf , a four study meta - analysis,78 and a post hoc analysis from cibis ii22 supported the findings of kotecha et al for heart rates , mcalister et al performed a meta - analysis that showed that for every 5 beats / min reduction , there was a concomitant 18% reduction ( 95% ci : 6%29% ) in risk of death.79 post hoc analyses , systematic reviews , and meta - analyses are postmarketing tools that help refine or make sense of the collective evidence . all the small and large rcts using bbs in chf have answered the question of safety and efficacy very well . studies have set out to enroll cohorts with a good spectrum of illness severity , as detailed in the nyha class and mean lvef . to control for confounders , studies may have controlled the heterogeneity of the other demographic and comorbid variables . guidelines are shaped around the findings of large rcts , and appear to suggest that findings from these homogeneous studies apply equally to heterogeneous  real - world  patients . this may , in fact , be the case , although examples are presenting that a broader perspective may be needed . post hoc analysis from merit - hf and pooling of results with cibis ii and copernicus show similar survival in women and men.80,81 the best trial , with greater participant heterogeneity , showed significant differences in baseline clinical and laboratory characteristics , such as younger age , black race , higher nonischemic etiology , higher heart rate and left bundle branch block , and lower plasma noradrenaline levels , where the prognostic predictive variables also varied in magnitude between females and males.82 in another post hoc analysis using the best study population , the authors achieved conformity with the cibis - ii and merit - hf trials , including matching of the racial demographics , and were able to show that bucindolol treatment was associated with significantly lower mortality , raising the possibility of subgroup differences in responses to bbs.15 possible explanations include difference in disease pathophysiology , different baseline noradrenaline levels , functional polymorphisms of -adrenergic receptors , or more advanced disease at baseline , ie , higher risk . however , for carvedilol , in the uschf trials , 217/1,004 african american patients and a further 121 from the copernicus trial showed significant mortality benefits.7,83 the african american heart failure trial ( aheft ) has highlighted the benefits of vasodilatory therapy in this group.88 whether bbs as a class or intrinsic differences between agents have effects on diverse communities must be the focus of future phase iv research.89,90 bb therapy is underutilized for both hf and diabetes , as well as the latter s complication such as nephropathy , despite evidence of sympathetic system overactivity , partly due to historical concerns of tolerability , adverse hemodynamic and metabolic effects , and lack of selectivity of bbs . heterogeneity within the same class of bbs perhaps poses the greatest challenge in its use . arguably , vasodilating bbs such as carvedilol and nebivolol offer the opportunity to study whether theoretical benefits translate to real - world improvements in metabolic profiles and renal function as they reduce insulin resistance and do not adversely interfere with blood glucose control.77,91 haas et al noted that 24.6% of diabetic subjects from six studies using bisoprolol , metoprolol , and carvedilol ( anzhfrcg , best , cibis - ii , copernicus , merit - hf , and uschfsg ) appeared to derive benefits from bb therapy , although the magnitude of benefit was less than that achieved in non - dm subjects.78 in the merit - hf study , diabetics had a 76% higher risk of hospitalization , and this risk was significantly reduced with metoprolol , although considering the small sample size , a mortality benefit was not shown.22,79 however , with carvedilol , a seven - study meta - analysis , wherein 25% of 5,757 patients had diabetes , showed similar survival benefits between the different subclasses.80 in the comet study , which compared carvedilol and metoprolol , the diabetics , who comprised 24% of the patients , did not reach statistical significance.79,86 published rcts have not conclusively addressed the question of whether a bb class is superior in chf with comorbid dm , and this remains an area for phase iv trials . autonomous sympathetic overactivity and susceptibility to iatrogenic peripheral vasoconstriction are several considerations in cardiorenal syndrome . in the latter , first - generation bbs , such as propranolol , which modulate at both 1 and 2 receptors , pose the greatest risk to renal function by reducing cardiac output , and unopposed activation of 1-induced reflex increased sympathetic activity and peripheral resistance.92 even second - generation bbs such as metoprolol with smaller affinity for 2 receptors can increase renal vascular resistance , although not conclusively shown to alter renal function.93 similar to diabetics , higher grades of renal impairment were a limiting factor for enrollment.12 data from merit - hf and cibis - ii trials showed equal efficacy in reducing mortality and hospitalization with egfr < 45 ml / min and > 60 ml / min for metoprolol and across all strata for bisoprolol , although , numerically , all - cause mortality did not improve with egfr < 60 ml / min.84,85 third - generation or vasodilatory bbs , however , increase cardiac output and renal blood flow while reducing renal vascular resistance . post hoc analysis from seniors , trialling the vasodilatory bb nebivolol demonstrated that the relative benefits were similar in patients with and without renal impairment , perhaps highlighting a greater benefit in absolute terms.2,54 pooled data of 4,217 patients from the capricorn and copernicus trials showed significantly improved outcomes for patients with egfr between 45 ml / min and 60 ml / min , but not with egfr < 45 ml / min.85 however , in a trial with 114 hemodialysis - dependent patients , there was a statistically significant mortality benefit with carvedilol treatment.42 there is uniformity in the consensus that all grades of renal impairment require bb therapy ; however , the optimal agent when faced with metabolic and cardiorenal syndromes awaits dedicated research . even more importantly , in the acute decompensated heart failure national registry ( adhere ) database , 63.6% of admitted patients were classified as having at least moderate renal impairment , which in turn predicted other comorbid risks,12 flagging this area as needing greater focus . the question of rate has a clear consensus , whereby lower rates do translate to better outcomes.79 the dose or the agents are vehicles in delivering this target ; however , as all trials have used the maximal tolerated dose as a study criterion , this still remains the target in clinical settings . the main pharmacological therapies that are used in maintaining sinus rhythm are either contraindicated as with flecainide , not proven with sotalol , or have long - term toxicity concerns with amiodarone . between 10% and 35% of trial participants have comorbid atrial fibrillation , whereby the most recent 10-study meta - analysis could not demonstrate an outcome benefit with bbs.76 interestingly , in seven studies with 11,952 patients , bbs significantly reduced the incidence of atrial fibrillation from 39 to 28 per 1,000 patient - years , a 27% reduction of the rr ( 95% ci : 1438 ; p < 0.001).77 using a strategy of catheter ablation restored and maintained sinus rhythm , with concomitant improvement of cardiac function , cardiac dimensions and quality of life.94,95 a randomized study of 1,376 patients , which excluded persistent atrial fibrillation and used cardioversion with amiodarone , sotalol , or dofetilide to maintain sinus rhythm , did not show significantly different results relative to the rate - controlled arm.96 the finding from these , albeit relatively small , trials showing discrepancies in outcomes between the strategies , compared to the larger study , does again raise the question of external validity and application of results . again , population - level posttrial studies must be used to monitor or even trial such strategies when there are no controls on the patients . in summation , post hoc analysis has provided some insights into the interaction between bb treatments in hf for race and comorbid conditions . the results suggest that the rr reduction could be greater for those with more advanced disease compared to those on placebo . the results , however , do not provide any pathophysiological insights into the potential mechanism of benefit . they also do not provide insight into the additional benefits of using a particular class of bb with a theoretical benefit against a particular comorbidity , eg , vasodilatory bb in diabetics or renal impairment . what can be done ? while there are robust postmarketing publications in the form of post hoc analyses , clinical reviews , or meta - analyses , actual postmarketing surveillance or phase iv trials on effectiveness and cost - effectiveness appear to be less well conducted . would be using the prospective database from treating centers that would collect data from all treated patients . the more difficult part would be finding a method that allows these findings to sit alongside rcts and thus be factored into guidelines relevant for a more global hf community and patient demography . a consistent process  from establishing safety and efficacy , to evaluating morbidity and mortality outcomes and posttrial subgroup or pooled analysis  has been established in the comparison of bb or placebo for systolic hf . gaps exist in the recruitment of more heterogeneous patient cohorts , showing features such as ethinic diversity , comorbid conditions of diabetes , renal impairment , or sicker patients . with the need to remove confounders and maintain strong internal and external validity in trial design , the potential for phase iv studies future researchers and drug companies should continue to focus on delivering all levels of randomized controlled studies . research groups or institutes and health systems should give greater emphasis on building robust phase iv studies to better understand the safety , efficacy , and cost - effectiveness of proven therapies initially used in a controlled group , at the population level . clinical guidelines should similarly reflect potential problems with data from a homogeneous cohort for what is now a more global population being treated .
backgroundbeta - blockers ( bbs ) are the mainstay prognostic medication for all stages of chronic heart failure ( chf ) . 
 there are many classes of bbs , each of which has varying levels of evidence to support its efficacy in chf 
 . however , most chf patients have one or more comorbid conditions such as diabetes , renal impairment , and/or atrial fibrillation . 
 patient enrollment to randomized controlled trials ( rcts ) often excludes those with certain comorbidities , particularly if the symptoms are severe . 
 consequently , the extent to which evidence drawn from rcts is generalizable to chf patients has not been well described . 
 clinical guidelines also underrepresent this point by providing generic advice for all patients . 
 the aim of this review is to examine the evidence to support the use of bbs in chf patients with common comorbid conditions.methodswe searched medline , pubmed , and the reference lists of reviews for rcts , post hoc analyses , systematic reviews , and meta - analyses that report on use of bbs in chf along with patient demographics and comorbidities.resultsin total , 38 studies from 28 rcts were identified , which provided data on six bbs against placebo or head to head with another bb agent in ischemic and nonischemic cardiomyopathies . 
 several studies explored bbs in older patients . 
 female patients and non - caucasian race were underrepresented in trials . 
 end points were cardiovascular hospitalization and mortality . 
 comorbid diabetes , renal impairment , or atrial fibrillation was detailed ; however , no reference to disease spectrum or management goals as a focus could be seen in any of the studies . in this sense , enrollment may have limited more severe grades of these comorbidities.conclusionsrcts provide authoritative information for a spectrum of chf presentations that support guidelines . rcts may provide inadequate information for more heterogeneous chf patient cohorts . greater phase iv research may be needed to fill this gap and inform guidelines for a more global patient population .