0. Moreover, the 3-genotype group construct that included β1389 Arg/Arg patients

had an interaction p value of 0.016, supporting the validity of subdividing the β1389 Gly carrier group by α2c polymorphism. In order to assess the relationship of adrenergic drive and outcomes, systemic venous plasma NE levels were measured at baseline and at months 3 and 12. Of the entire 2,392 patient cohort, 1,868 had baseline NE measured. Compared to patients who remained free of AF, patients who developed AF had higher baseline NE levels in the bucindolol group (581 ± 304 pg/ml vs. 514 ± 344 pg/ml, respectively, p = 0.009) and in the combined treatment groups (530 ± 231 pg/ml vs. 498 ± 326 pg/ml, respectively, p = 0.015). Bucindolol produced a significant reduction in NE levels at 3 months in patients who developed Dasatinib clinical trial Tyrosine Kinase Inhibitor Library price AF (by 129 ± 49 pg/ml, p = 0.0009 vs. placebo change) and in patients who remained free of AF (by 74 ± 12 pg/ml, p <0.0001 vs. placebo change), with no differences between the 2 groups (p = 0.23). Placebo-treated

patients exhibited increases in NE in both the new-onset AF subgroup (by 88 ± 46 pg/ml) and in patients who remained free of AF (by 21 ± 11 pg/ml, p = 0.29 vs. new-onset AF). Table 4 gives NE changes at 3 months within the pharmacogenetic subgroups, where it can be observed that there are similar degrees of NE lowering in the bucindolol β1389 Arg/Arg and Gly carrier genetic groups (respectively, 71 and 78 pg/ml and both p <0.010 vs. placebo change). Within the Gly carrier group, the α2c322–325 Del carrier subgroup has a large degree of bucindolol-associated NE reduction (by 164 pg/ml) as previously reported for the full 1,040, all rhythms

DNA substudy population (12), which is due to the exclusive presence of the α2c322–325 Del carrier genotype (14). The DNA substudy and the entire cohort parent populations were very similar in baseline characteristics, length of follow-up (2.0 vs. 2.1 years), overall event rates (respectively, 7.9% and 8.6%), and placebo event rates (respectively, 9.7% and 10.7%). Thus, there was no evidence that late entry of most in the DNA substudy relative to their randomization dates had any impact acetylcholine on the study population from the standpoint of development of new-onset AF. For new-onset AF, bucindolol demonstrated respective risk reductions of 41% (p = 0.0004) and 43% (p = 0.014) in the entire and DNA substudy cohorts of BEST. In placebo controlled HFREF trials, the effect of β-blockade on AF episodes by event duration has not been previously reported, and we evaluated effects on both paroxysmal and persistent AF. In the entire cohort the majority (68%) of AF episodes were >7 days duration or persistent, exhibiting a 38% reduction (p = 0.007) by bucindolol. Shorter or paroxysmal episodes of AF were not significantly reduced, although they had lower HRs than in the persistent group.