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Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial.

ABSTRACT: Gene transfer has rarely been tested in randomized clinical trials.To evaluate the safety and efficacy of intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) in heart failure.A randomized, double-blind, placebo-controlled, phase 2 clinical trial was conducted in US medical centers (randomization occurred from July 19, 2010, to October 30, 2014). Participants 18 to 80 years with symptomatic heart failure (ischemic and nonischemic) and an ejection fraction (EF) of 40% or less were screened; 86 individuals were enrolled, and 56 were randomized. Data analysis was of the intention-to-treat population. Participants underwent exercise testing and measurement of left ventricular EF (echocardiography) and then cardiac catheterization, where left ventricular pressure development (+dP/dt) and decline (-dP/dt) were recorded. Participants were randomized (3:1 ratio) to receive 1 of 5 doses of intracoronary Ad5.hAC6 or placebo. Participants underwent a second catheterization 4 weeks later for measurement of dP/dt. Exercise testing and EF were assessed 4 and 12 weeks after randomization.Intracoronary administration of Ad5.hAC6 (3.2?×?109 to 1012 virus particles) or placebo.Primary end points included exercise duration and EF before and 4 and 12 weeks after randomization and peak rates of +dP/dt and -dP/dt before and 4 weeks after randomization. Fourteen placebo participants were compared (intention to treat) with 24 Ad5.hAC6 participants receiving the highest 2 doses (D4?+?5).Fifty-six individuals were randomized and monitored for up to 1 year. Forty-two participants (75%) received Ad5.hAC6 (mean [SE] age, 63 [1] years; EF, 30% [1%]), and 14 individuals (25%) received placebo (age, 62 [1] years; EF, 30% [2%]). Exercise duration showed no significant group differences (4 weeks, P?=?.27; 12 weeks, P?=?.47, respectively). The D4?+?5 participants had increased EF at 4 weeks (+6.0 [1.7] EF units; n?=?21; P?

SUBMITTER: Hammond HK

PROVIDER: S-EPMC5535743 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial.

Hammond H Kirk HK Penny William F WF Traverse Jay H JH Henry Timothy D TD Watkins Matthew W MW Yancy Clyde W CW Sweis Ranya N RN Adler Eric D ED Patel Amit N AN Murray David R DR Ross Robert S RS Bhargava Valmik V Maisel Alan A Barnard Denise D DD Lai N Chin NC Dalton Nancy D ND Lee Martin L ML Narayan Sanjiv M SM Blanchard Daniel G DG Gao Mei Hua MH

JAMA cardiology 20160501 2

<h4>Importance</h4>Gene transfer has rarely been tested in randomized clinical trials.<h4>Objective</h4>To evaluate the safety and efficacy of intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) in heart failure.<h4>Design, setting, and participants</h4>A randomized, double-blind, placebo-controlled, phase 2 clinical trial was conducted in US medical centers (randomization occurred from July 19, 2010, to October 30, 2014). Participants 18 to 80 years with symptomatic he ...[more]

PMID: 27437887

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Project description:BackgroundAdvanced heart failure (HF) is characterized by high morbidity and mortality. Conventional therapy may not sufficiently reduce patient suffering and maximize quality of life.ObjectivesThe authors investigated whether an interdisciplinary palliative care intervention in addition to evidence-based HF care improves certain outcomes.MethodsThe authors randomized 150 patients with advanced HF between August 15, 2012, and June 25, 2015, to usual care (UC) (n = 75) or UC plus a palliative care intervention (UC + PAL) (n = 75) at a single center. Primary endpoints were 2 quality-of-life measurements, the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary and the Functional Assessment of Chronic Illness Therapy-Palliative Care scale (FACIT-Pal), assessed at 6 months. Secondary endpoints included assessments of depression and anxiety (measured via the Hospital Anxiety and Depression Scale [HADS]), spiritual well-being (measured via the FACIT-Spiritual Well-Being scale [FACIT-Sp]), hospitalizations, and mortality.ResultsPatients randomized to UC + PAL versus UC alone had clinically significant incremental improvement in KCCQ and FACIT-Pal scores from randomization to 6 months (KCCQ difference = 9.49 points, 95% confidence interval [CI]: 0.94 to 18.05, p = 0.030; FACIT-Pal difference = 11.77 points, 95% CI: 0.84 to 22.71, p = 0.035). Depression improved in UC + PAL patients (HADS-depression difference = -1.94 points; p = 0.020) versus UC-alone patients, with similar findings for anxiety (HADS-anxiety difference = -1.83 points; p = 0.048). Spiritual well-being was improved in UC + PAL versus UC-alone patients (FACIT-Sp difference = 3.98 points; p = 0.027). Randomization to UC + PAL did not affect rehospitalization or mortality.ConclusionsAn interdisciplinary palliative care intervention in advanced HF patients showed consistently greater benefits in quality of life, anxiety, depression, and spiritual well-being compared with UC alone. (Palliative Care in Heart Failure [PAL-HF]; NCT01589601).

Project description:Preliminary evidence suggests that meditative exercise may have benefits for patients with chronic systolic heart failure (HF); this has not been rigorously tested in a large clinical sample. We sought to investigate whether tai chi, as an adjunct to standard care, improves functional capacity and quality of life in patients with HF.A single-blind, multisite, parallel-group, randomized controlled trial evaluated 100 outpatients with systolic HF (New York Heart Association class I-III, left ventricular ejection fraction ?40%) who were recruited between May 1, 2005, and September 30, 2008. A group-based 12-week tai chi exercise program (n = 50) or time-matched education (n = 50, control group) was conducted. Outcome measures included exercise capacity (6- minute walk test and peak oxygen uptake) and disease-specific quality of life (Minnesota Living With Heart Failure Questionnaire).Mean (SD) age of patients was 67 (11) years; baseline values were left ventricular ejection fraction, 29% (8%) and peak oxygen uptake, 13.5 mL/kg/min; the median New York Heart Association class of HF was class II. At completion of the study, there were no significant differences in change in 6-minute walk distance and peak oxygen uptake (median change [first quartile, third quartile], 35 [-2, 51] vs 2 [-7, 54] meters, P = .95; and 1.1 [-1.1, 1.5] vs -0.5 [-1.2, 1.8] mL/kg/min, P = .81) when comparing tai chi and control groups; however, patients in the tai chi group had greater improvements in quality of life (Minnesota Living With Heart Failure Questionnaire, -19 [-23, -3] vs 1 [-16, 3], P = .02). Improvements with tai chi were also seen in exercise self-efficacy (Cardiac Exercise Self-efficacy Instrument, 0.1 [0.1, 0.6] vs -0.3 [-0.5, 0.2], P < .001) and mood (Profile of Mood States total mood disturbance, -6 [-17, 1] vs -1 [-13, 10], P = .01).Tai chi exercise may improve quality of life, mood, and exercise self-efficacy in patients with HF. Trial Registration clinicaltrials.gov Identifier: NCT00110227.

Dataset Information

Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial.

Publications

Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial.

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