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.

BACKGROUND: 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 trials. METHODS/DESIGN: The Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Metoprolol Succinate for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure (GENETIC-AF) trial is a multicenter, randomized, double-blinded "seamless" phase 2B/3 trial of bucindolol hydrochloride versus metoprolol succinate, for the prevention of symptomatic AF/AFL in patients with reduced ejection fraction heart failure (HFrEF). Patients with pre-existing HFrEF and recent history of symptomatic AF are eligible for enrollment and genotype screening, and if they are ADRB1 Arg389Arg, eligible for randomization. A total of approximately 200 patients will comprise the phase 2B component and if pre-trial assumptions are met, 620 patients will be randomized at approximately 135 sites to form the Phase 3 population. The primary endpoint is the time to recurrence of symptomatic AF/AFL or mortality over a 24-week follow-up period, and the trial will continue until 330 primary endpoints have occurred. CONCLUSIONS: GENETIC-AF is the first randomized trial of pharmacogenetic guided rhythm control, and will test the safety and efficacy of bucindolol compared with metoprolol succinate for the prevention of recurrent symptomatic AF/AFL in patients with HFrEF and an ADRB1 Arg389Arg genotype. (ClinicalTrials.govNCT01970501).

Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial.

Practice guidelines recommend dual antiplatelet therapy with aspirin and clopidogrel for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) regardless of in-hospital management strategy. Prasugrel-a thienopyridine adenosine diphosphate receptor antagonist that provides higher and less variable levels of platelet inhibition than clopidogrel-has demonstrated benefit when used to treat ACS patients undergoing percutaneous coronary intervention. However, the optimal approach to antiplatelet therapy for high-risk, medically managed NSTE ACS patients remains uncertain, as these patients have not been the focus of previous clinical trials of these therapies. TRILOGY ACS is a phase 3, randomized, double-blind trial enrolling approximately 10,300 NSTE ACS patients within 10 days of presentation with either unstable angina or NSTE myocardial infarction who are not intended to undergo revascularization procedures for their index event. Patients will be randomly allocated to prasugrel + aspirin versus clopidogrel + aspirin for a median duration of 18 months. A reduction in the maintenance dose of prasugrel for elderly patients (age >or=75 years) and those with body weight <60 kg is planned. The primary composite efficacy end point will be time to first occurrence of cardiovascular death, myocardial infarction, or stroke in patients aged <75 years. If the superiority of prasugrel is established in patients aged <75 years, the treatment arms will then be compared for all subjects (including those aged >or=75 years). TRILOGY ACS is the largest randomized clinical trial to date focusing exclusively on medically managed NSTE ACS patients and will provide important information regarding the optimal approach to oral antiplatelet therapy for this high-risk, understudied population.

The role of exercise in modulating the impact of an ultralow-fat diet on serum lipids and apolipoproteins in patients with or at risk for coronary artery disease.

BACKGROUND: Ultralow-fat diets are known to reduce high-density lipoprotein cholesterol (HDL-C) levels. In the setting of a multicomponent lifestyle intervention program, relationships between exercise variables and HDL-C levels were examined to determine whether exercise moderates this dietary effect on serum lipids and apolipoproteins. METHODS: We performed a 3-month, prospective, nonrandomized lifestyle intervention study (< or = 10% dietary fat; aerobic exercise [180 min/wk], group support, and yoga [60 min/day]) in 120 subjects with or at risk for coronary artery disease. RESULTS: After 3 months, dietary fat intake was reduced to 8.7% +/- 2.6% of total intake and the median weekly exercise time was 194 minutes. High-density lipoprotein cholesterol levels decreased by 8.3 +/- 11.3 mg/dL (P < .001), and triglyceride levels increased by 17.6 +/- 102.7 mg/dL (P = .026). A small dense low-density lipoprotein cholesterol (LDL-C) phenotype emerged indicated by a 13.8% LDL-C reduction accompanied by only a 2.3% reduction in apolipoprotein B levels (P = .064). Among subjects with exercise amounts less than those of the group median, HDL-C reductions were greater in those with more than (-13.5 +/- 16.0 mg/dL) versus less than (-2.5 +/- 7.5 mg/dL) the median reductions in fat intake (P = .026). Even among subjects who exercised > 194 min/wk, HDL-C was reduced compared with baseline (-7.4 +/- 7.9 mg/dL, P < .001). CONCLUSIONS: An ultralow-fat diet as a component of a comprehensive lifestyle intervention induces reductions in HDL-C and the emergence of a dyslipidemic lipid profile. Aerobic exercise only partially mitigates this effect.

Optimal healing environments for chronic cardiovascular disease.

A substantial increase in chronic cardiovascular disease is projected for the next several decades. This is attributable to an aging population and accelerated rates of obesity and diabetes. Despite technological advances that have improved survival for acute events, there is suboptimal translation of research knowledge for prevention and treatment of chronic cardiovascular illness. Beginning with a brief review of the demographics and pathogenesis of atherosclerotic cardiovascular disease, this paper discusses the obstacles and approaches to optimal care of patients with chronic cardiovascular disease. The novel concept of an optimal healing environment (OHE) is defined and explored as a model for integrative cardiac health care. Aspects generally underexamined in cardiac care such as intrapersonal/interpersonal characteristics of the health care provider and patient, mind/body/spirit wholeness and healing versus curing are discussed, as is the impact psychosocial factors may have on atherosclerosis and cardiovascular health. Information from research on the impact of an OHE might renew the healing mission in medicine, reveal new approaches for healing the heart and establish the importance of a heart-mind-body connection.

Achievement of heart health characteristics through participation in an intensive lifestyle change program (Coronary Artery Disease Reversal Study).

PURPOSE: Lifestyle habits and cardiovascular disease (CVD) risk factors are closely linked. Unfortunately, few individuals meet the goals for cardiovascular health that are recommended in public health initiatives. The purpose of this study was to determine the effect of an intensive lifestyle intervention program on the achievement of a group of recognized heart health characteristics as well as on the reduction of individual CVD risk factors. METHODS: Of 200 military healthcare beneficiaries with coronary artery disease or CVD risk factors (mean age = 61 years) who entered a 1-year, prospective, cohort, multicomponent lifestyle intervention study (lacto-ovo vegetarian diet, exercise, stress management, group support), 186 subjects enrolled and 144 participated for 1 year. RESULTS: At 3 months and 1 year compared with baseline, the proportion of subjects meeting 5 recognized heart health characteristics improved (P < .001): fiber intake >25 g/d (94% and 72% vs 35%); exercise > or =150 min/wk (79% and 58% vs 31%); low-density lipoprotein cholesterol <100 mg/dL (75% and 63% vs 46%); body mass index <25 kg/m (34% and 38% vs 23%); and blood pressure <140/90 mm Hg (84% and 83% vs 69%). At 1 year, more subjects (72% vs 32% at baseline), especially those with intervention adherence above (94%) versus below (58%) the study population median (P < .0005), achieved 3 or more of these characteristics. CONCLUSION: An intensive lifestyle intervention promotes achievement of important heart health characteristics that, if maintained, may substantially reduce CVD events.