Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined HF Population: The GENETIC-AF Trial. The purpose of this study was to compare the effectiveness of bucindolol with that of metoprolol succinate for the maintenance of sinus rhythm in a genetically defined heart failure (HF) population with atrial fibrillation (AF). Bucindolol is a beta-blocker whose unique pharmacologic properties provide greater benefit in HF patients with reduced ejection fraction (HFrEF) who have the beta-adrenergic receptor (ADRB1) Arg389Arg genotype. A total of 267 HFrEF patients with a left ventricular ejection fraction (LVEF) <0.50, symptomatic AF, and the ADRB1 Arg389Arg genotype were randomized 1:1 to receive bucindolol or metoprolol therapy and were up-titrated to target doses. The primary
A genotype-directed comparative effectiveness trial of Bucindolol and metoprolol succinate for prevention of symptomatic atrial fibrillation/atrial flutter in patients with heart failure: Rationale and design of the GENETIC-AF trial. Few therapies are available for the safe and effective treatment of atrial fibrillation (AF) in patients with heart failure. Bucindolol is a non-selective beta -blocker with mild vasodilator activity previously found to have accentuated antiarrhythmic effects and increased efficacy for preventing heart failure events in patients homozygous for the major allele of the ADRB1 Arg389Gly polymorphism (ADRB1 Arg389Arg genotype). The safety and efficacy of bucindolol for the prevention of AF or atrial flutter (AFL) in these patients has not been proven in randomized
Adrenergic receptor polymorphisms and prevention of ventricular arrhythmias with bucindolol in patients with chronic heart failure. β-blockers prevent cardiac arrhythmias in patients with chronic heart failure and reduced left ventricular ejection fraction, including ventricular tachycardia/ventricular fibrillation (VT/VF). We hypothesized that prevention of ventricular arrhythmias by the β -blocker/sympatholytic agent bucindolol is influenced by genetic variation in adrenergic receptors. From a substudy of the β-Blocker Evaluation of Survival Trial (n=1040), we identified those with the high functioning 389Arg versus the lower function 389Gly β(1) adrenergic receptor variant, and the loss of function α(2c)322-325 adrenergic receptor deletion versus the 322 to 325 wild-type (Wt)/deletion
Prevention of Atrial Fibrillation by Bucindolol Is Dependent on the Beta1389 Arg/Gly Adrenergic Receptor Polymorphism. This study assessed the impact of bucindolol, a beta-blocker/sympatholytic agent, on the development of atrial fibrillation (AF) in advanced chronic heart failure with reduced left ventricular ejection fraction (HFREF) patients enrolled in the BEST (Beta-Blocker Evaluation of Survival Trial). β-blockers have modest efficacy for AF prevention in HFREF patients. Bucindolol's effects on HF and ventricular arrhythmic endpoints are genetically modulated by β₁- and α(2c)-adrenergic receptor (AR) polymorphisms that can be used to subdivide HFREF populations into those with bucindolol effectiveness levels that are enhanced, unchanged, or lost. BEST enrolled 2,708 New York Heart
% reduction in mortality with bucindolol therapy, whereas Gly389 carriers did not derive a significant benefit.67 However, this association has not been replicated in additional studies or with other β-blockers.68Taking ancestry into account is extremely important in the assessment of pharmacogenomic effects. Genetic variation in the gene encoding G-protein receptor kinase 5, or GRK5 (GRK5), and β-blocker
Bucindolol, systolic blood pressure, and outcomes in systolic heart failure: a prespecified post hoc analysis of BEST. In the Beta-Blocker Evaluation of Survival Trial (BEST), systolic blood pressure (SBP) ≤ 120 mm Hg was an independent predictor of poor prognosis in ambulatory patients with chronic systolic heart failure (HF). Because SBP is an important predictor of response to β-blocker therapy, the BEST protocol prespecified a post hoc analysis to determine whether the effect of bucindolol varied by baseline SBP. In the BEST, 2706 patients with chronic systolic (left ventricular ejection fraction < 35%) HF and New York Heart Association class III (92%) or IV (8%) symptoms and receiving standard background therapy were randomized to receive either bucindolol (n = 1354) or placebo (n
Effect of bucindolol on heart failure outcomes and heart rate response in patients with reduced ejection fraction heart failure and atrial fibrillation. There is little evidence of beta-blocker treatment benefit in patients with heart failure and reduced left ventricular ejection fraction (HFREF) and atrial fibrillation (AF). We investigated the effects of bucindolol in HFREF patients with AF enrolled in the Beta-blocker Evaluation of Survival Trial (BEST). A post-hoc analysis of patients in BEST with and without AF was performed to estimate the effect of bucindolol on mortality and hospitalization. Patients were also evaluated for treatment effects on heart rate and the influence of beta1-adrenergic receptor position 389 (β(1)389) arginine (Arg) vs. glycine (Gly) genotypes. In the 303/2708
Crystal Structures of a Stabilized β1-Adrenoceptor Bound to the Biased Agonists Bucindolol and Carvedilol The β(1)-adrenoceptor (β(1)AR) is the site of action of beta blockers used in the treatment of cardiac-related illnesses. Two beta blockers, carvedilol and bucindolol, show distinctive activities compared to other beta blockers and have been proposed as treatments tailored to the Arg/Gly389 (8.56) polymorphism of the human β(1)AR. Both carvedilol and bucindolol are classified as biased agonists, because they stimulate G protein-independent signaling, while acting as either inverse or partial agonists of the G protein pathway. We have determined the crystal structures of a thermostabilized avian β(1)AR mutant bound to bucindolol and to carvedilol at 3.2 and 2.3 Å resolution, respectively
to achieve target dose in the GENETIC-AF trial. Patients randomized to metoprolol (n = 125) or bucindolol (n = 131) entering 24-week efficacy follow-up and receiving study medication were evaluated. Bradycardia was defined as an electrocardiogram (ECG) heart rate (HR) <60 beats per minute (bpm) and severe bradycardia <50 bpm. Mean HR in sinus rhythm (SR) was 62.6 ± 12.5 bpm for metoprolol and 68.3 ± 11.1 bpm for bucindolol ( < .0001), but in AF HRs were not different (87.5 bpm vs 89.7 bpm, respectively). Episodes per patient for bucindolol vs metoprolol were 0.82 vs 2.08 ( < .001) for bradycardia and 0.24 vs 0.57 for severe bradycardia ( < .001), with 98.9% of the episodes occurring in SR. Patients experiencing bradycardia had a 4.15-fold higher prevalence of study medication dose reduction ( <.0001
. The mean age of included patients ranged from 49 to 76 years; the proportion of men ranged from 54 to 90%. The proportion of patients with ischaemic heart failure ranged from 29% to 89% (where reported). Baseline left ventricular ejection fraction ranged from 17% to 36% (..
of ACEinhibitors, ARBs, and MRAs.69-Blockers such as bisoprolol, metoprolol CR/XL, andcarvedilol reduce mortality in patients with HF-REF on ACEinhibitors.70-73However, bucindolol did not reduce mortal-ity.74-Blocker should be initiated in stable patients althoughit can also be initiated with caution in patients with recentdecompensation.75Diuretics relieve dyspnea and edema effectively
. In the BEST trial, we used Cox regression analysis to examine the effect of bucindolol on the current standard composite of cardiovascular death or heart failure hospitalization (CVD/HFH) compared with the original primary mortality endpoint and the expanded composite that included emergency department (ED) visits. We also undertook an analysis of recurrent events primarily using the Lin, Wei, Ying , and Yang model. Overall, 448 (33%) patients on placebo and 411 (30%) patients on bucindolol died (hazard ratio [HR]: 0.90; 95% confidence interval [CI]: 0.78 to 1.02; p = 0.11). A total of 730 (54%) patients experienced CVD/HFH on placebo and 624 (46%) on bucindolol (HR: 0.80; 95% CI: 0.72 to 0.89; p < 0.001). Adding ED visits increased these numbers to 768 (57%) and 668 (49%), respectively (HR: 0.81; 95
, including heart failure hospitalization or the composite of all-cause mortality and heart failure hospitalization, yielded similar results. LVEF change ≥5 U was associated with a modest increase in discrimination when added to traditional predictors and was predictive of outcomes in both the bucindolol and placebo treatment groups. LVEF change as a predictor of outcomes was affected by sex and race
reported. In the randomized controlled Beta-blocker Evaluation of Survival Trial (BEST; 1995-1999), of the 2707 (bucindolol=1353; placebo=1354) patients with heart failure and left ventricular ejection fraction ≤35%, 918 received care at VA hospitals, of which 98% (n=898) were male. Of the 1789 receiving care at non-VA hospitals, 68% (n=1216) were male. Our analyses were restricted to these 2114 male
Racial differences in mortality in patients with advanced systolic heart failure: potential role of right ventricular ejection fraction. In Beta-Blocker Evaluation of Survival Trial (BEST) bucindolol significantly reduced mortality among Caucasians with systolic heart failure (HF) but not among African Americans. Whether this differential effect can be explained by racial differences in baseline . The higher risk of death among African Americans in BEST may in part be due to their lower RVEF which may in part explain the lack of response to bucindolol among these patients. Future studies need to examine the role of low RVEF on the effect of beta-blockers in patients with systolic HF.
reduced RVEF varies by the receipt of beta-blockers. In the Beta-Blocker Evaluation of Survival Trial (BEST), 2708 patients with chronic advanced HF and left ventricular ejection fraction < 35%, receiving standard background therapy with renin-angiotensin inhibition, digoxin, and diuretics, were randomized to receive bucindolol or placebo. Of these 2008 had data on baseline RVEF, and 14% (146/1017 ) and 13% (125/991) of the patients receiving bucindolol and placebo respectively had RVEF < 20%. Among patients in the placebo group, all-cause mortality occurred in 33% and 43% of patients with RVEF ≥ 20% and < 20% respectively (unadjusted hazard ratios {HR}, 1.33; 95% confidence intervals {CI}, 0.99-1.78; p = 0.055 and adjusted HR, 0.99; 95% CI, 0.71-1.37; p = 0.934). Among those receiving bucindolol