Exercise and Cognitive Retraining to Improve Cognition in Heart Failure.

The Feasibility of Exercise and Cognitive Retraining to Improve Memory, Attention and Concentration in Heart Failure.

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02151266

Acronym

EXCITE

Enrollment

Registered

2014-05-30

Start date

2013-07-31

Completion date

2017-12-30

Last updated

2021-01-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heart Failure

Keywords

Heart failure, Exercise, Cognitive training

Brief summary

Cognitive impairment (CI) is a prevalent problem in persons with HF heart failure (HF) and is associated with adverse clinical outcomes, higher mortality and poorer quality of life. Studies designed to attenuate or alleviate CI in persons with HF are limited, and evidenced based guidelines for screening and provision of care are practically nonexistent. Improvement in cognition has been reported following some therapies in HF and is thought to be the consequence of enhanced cerebral perfusion and oxygenation, suggesting that CI may be amenable to intervention in this population. Exercise is documented to increase cerebral perfusion and oxygenation by promoting neuroplasticity and neurogenesis, and, in turn, cognitive functioning. Brain derived neurotrophic factor (BDNF) is a key mechanism underlying the effect of exercise, but most studies of BDNF have not included individuals with CI or chronic illness populations, and its relationship to cognitive outcomes in HF is unknown. Cognitive retraining techniques, originally developed to treat traumatic brain injury, have also shown efficacy in broader neurologically-affected conditions and may provide added benefit to that of exercise. Animal studies suggest exercise and plasticity-based cognitive training could act synergistically through different neural mechanisms to have a more pronounced and positive impact on cognitive outcomes than either approach alone; but this has not been previously tested as an intervention to improve CI. The proposed feasibility study is designed to test the acceptability and limited efficacy of a combined exercise (Ex) and cognitive training (CT) program to improve CI in stable NYHA class II and III HF patients compared to either exercise alone or a no-intervention, attention-control group. Findings will be used to support the development of a future, large scale study to test the efficacy of this intervention to improve cognitive functioning, quality of life, and physiological markers of improved brain function in HF. In addition, we have an optional sub-study that participants may participate in order to further our understanding of biomarkers of inflammation and gen e expression before and after exercise.

Detailed description

Persons with heart failure (HF) have a four-fold greater likelihood of developing cognitive impairment (CI) than their age matched healthy counterparts, placing them at high risk for adverse clinical outcomes, poorer quality of life (QOL) and higher mortality. CI is a subtle but measurable deficit in one or multiple cognitive domains; it is a deficit greater than cognitive losses associated with normal aging. The few studies that have documented CI in HF are inconsistent. Few have used standard neuropsychological testing, and little is known about change in cognitive function over time in HF. Further, if CI is detected, there are currently no effective or evidenced-based guidelines to help restore or improve cognition in this population.Despite the aging population and projected rise of CI in HF, only 2 small intervention studies have been documented, indicating a critical need for further research in this area. The etiology of CI in HF is not fully understood, but several underlying mechanisms are consistently reported: reduced cerebral perfusion and oxygenation, brain structural changes (i.e., hippocampal damage, atrophy, loss of gray matter), and micro emboli.Clinical studies have shown that CI is improved after cardiac transplantation and is modifiable with standard therapies that improve cardiac output, oxygenation, fluid overload, and systemic and cerebral perfusion; these findings are inconsistent and anecdotal. The ability to positively influence cognitive function has important implications for patient adherence to a complex self-care regimen and the development of interventions that may partially reverse CI. Exercise improves clinical outcomes in HF by altering the deleterious peripheral and central mechanisms that contribute to HF exacerbations, worsen symptom severity, and lead to poor clinical outcomes. Less is known about the effect of exercise on cognitive function. Animal research has provided the most compelling evidence that exercise positively affects neuronal growth and the neural systems involved in learning and memory. Similar human findings have emerged; recent advances in neuroimaging support that participation in regular exercise leads to specific changes in brain structure and function. Exercise is also thought to enhance brain plasticity. BDNF appears to play a crucial role in this process: when BDNF levels increase following exercise, cognitive function improves. The association between exercise, BDNF and cognitive function has not been previously reported in HF. This feasibility study will clarify these important relationships and increase the potential for improving clinical outcomes in a future trial. Neurogenesis and neuroplasticity are means for the brain to recover from poor perfusion and oxygen deprivation such as that occurring in HF. Animal studies again provide the strongest evidence to date for using cognitive training (CT) to promote better cognitive functioning and provide a rationale for why a combined exercise and CT approach may be superior to monotherapy. Animal studies show that, like exercise, learning tasks and performing cognitively stimulating activities also increase BDNF levels and improve learning and memory. The effect of BDNF on brain function due to exercise however, is thought to be different from that occurring with CT. Exercise increases the proliferation and division of neuronal cells through BDNF, whereas CT appears to promote cell survival,suggesting a synergistic relationship may exist with greater benefit obtained when both are used together. The combination of exercise and plasticity-based CT has not been previously tested in HF or in other populations as an intervention for improving cognitive outcomes, but may be most optimal for targeting the underlying mechanisms for CI in HF. The proposed feasibility study is designed to test the acceptability, implementation and limited efficacy of a combined exercise (Ex) and cognitive training (CT) intervention in stable NYHA class II and III heart failure patients with cognitive impairment. A total of 60 participants will be randomized to one of three study arms: Ex/CT (N=20), Ex-alone (N=20), and attention control (N=20). The study aims are: Aim 1: To evaluate the feasibility of a 3-arm intervention (ExCT, Ex, AC) in heart failure patients with CI. Aim 1a. To test the acceptability and implementation of each study arm. Aim 2: To ascertain limited efficacy of the 3-arm intervention on changes in cognitive abilities Aim 3: To ascertain limited efficacy of the 3-arm intervention to improve cerebral oxygenation, physiological status, physical function and QOL.

Interventions

BEHAVIORALExercise and Cognitive retraining

Walking 5 times per week at moderate intensity; cognitive retraining one-hour 2 times per week.

BEHAVIORALExercise Only

BEHAVIORALStretching and Flexibility

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

SUPPORTIVE_CARE

Masking

SINGLE (Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

40 Years to 75 Years

Healthy volunteers

Inclusion criteria

men and women between the ages of 40 and 75; English speaking; live independently within a 60 mile radius of Atlanta; meet education corrected cut-offs on the MMSE indicating cognitive impairment (score of 20 for 8-9 yrs of schooling; 22 for 10-12 yrs of schooling; 23 for \>12 yrs) have a computer with internet connection; documented medical diagnosis of NYHA class II or III systolic. Left ventricular ejection fraction (LVEF) ≥ 10% that is documented within the last year by echocardiogram, cardiac catheterization ventriculography or radionuclide ventriculography; Receiving medication therapy for HF according to American College of Cardiology (ACC) American Heart recommendation guidelines for at least 8 weeks prior to study enrollment. \-

Exclusion criteria

NYHA class I or IV; change in HF therapy within 8 weeks; worsening HF symptoms within last 5 days; unstable angina; renal insufficiency (serum creatinine \> 3.o mg/dL); fixed rate pacemaker; uncontrolled hypertension; not involved in any structured exercise program or exercising 3 or more times per week for a minimum of 30 minutes and; not hospitalized within the last 30-days; not diagnosed with any neurological disorder that may interfere with cognitive function; Beck Depression Inventory II (BDI-II) score greater than 25; any disorder interfering with exercise participation. \-

Design outcomes

Primary

Measure	Time frame	Description
Visual Memory Score Change	Baseline, 3 months, 6 months	Visual memory will be assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RBANS figure recall requires the participant to remember a recent figure and redraw it from memory. The range of possible scores is 0-20. Scores are averaged, and then converted to z score. Z-scores are used when neurocognitive test scores use different measurement scales, e.g., time to completion and number correct. This allows to report performance in a straightforward manner, with low and high scores reflecting poor and good performance consistently across different types of tests, and to provide interpretation of a person's performance in comparison to a group. For interpretive purposes, a z-score has a mean of 0 and a standard deviation of 1. This means that an individual who has a z-score of 1.5 is performing one and a half standard deviations above the group to which he/she is compared.
Change in Working Memory Score	Baseline, 3 months, 6 months	Digit Span Forward (0-16), Digit Span Backwards (0-16), Digit Span Sequencing (0-16) and Letter Number Sequencing (0-48) sections from the Wechsler Adult Intelligence Scale - Fourth Edition are used to assess Working Memory. The range of possible scores for each section are in parentheses. The Digit Span subtest require the repetition of verbally presented series of numbers that increase in length; trials include the repeating of numbers in forward, backward, and numerical order. The Letter-Number sequencing test requires the repeating strings of letters and numbers in numerical and then in alphabetical order. Color Trails Test (CTT) Part 2, participants rapidly connect numbered circles in sequence while alternating between pink and yellow circles. Higher scores reflect better outcome. Scores reflect number correct and are averaged for total correct Working Memory score; are then converted to Z-score.
Change in Reaction Time	Baseline, 3 months, 6 months	Scores are automatically calculated via the scoring software embedded within the CalCap and are standardized based on age and education level norms. Normative data are stratified by both age (20-34, 35-44, 45+) and education (\< 16 years, 16 years, \> 16 years). Lower scores reflect slower reaction time and higher scores reflect faster reaction time. Scores are automatically converted to age/education based standard scores and are reported as a T-score. T-scores (as Z-scores) are used when neurocognitive test scores use different measurement scales, e.g., time to completion and number correct. This allows to report performance in a straightforward manner, with low and high scores reflecting poor and good performance consistently across different types of tests, and to provide interpretation of a person's performance in comparison to a group.
Verbal Memory Score Change	Baseline, 3 months, 6 months	List Learning (0-40), List Recall (0-10), and List Recognition (0-20) sections from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) are used to assess Verbal memory.The range of scores for each section are in parentheses. Higher scores reflect better verbal memory. Scores are averaged for a total Verbal memory score, then converted to Z-score. Z-scores are used when neurocognitive test scores use different measurement scales, e.g., time to completion and number correct. This allows to report performance in a straightforward manner, with low and high scores reflecting poor and good performance consistently across different types of tests, and to provide interpretation of a person's performance in comparison to a group. For interpretive purposes, a z-score has a mean of 0 and a standard deviation of 1. This means that an individual who has a z-score of 1.5 is performing one and a half standard deviations above the group to which he/she is compared.
Change in Processing Speed/Attention Score	Baseline, 3 months, 6 months	RBANS coding (0-89) Color Trails 1 (timed test, 1-5 minutes) measures attention. The length of time to complete each part is recorded; lower raw scores reflect better processing speed and attention. Lower raw scores reflect better processing speed and attention. Scores are averaged for a total score, then converted to Z scores. Z-scores are used when neurocognitive test scores use different measurement scales, e.g., time to completion and number correct. This allows to report performance in a straightforward manner, with low and high scores reflecting poor and good performance consistently across different types of tests, and to provide interpretation of a person's performance in comparison to a group. For interpretive purposes, a z-score has a mean of 0 and a standard deviation of 1. This means that an individual who has a z-score of 1.5 is performing one and a half standard deviations above the group to which he/she is compared.

Secondary

Measure	Time frame	Description
Functional Capacity	Baseline, 3 months, 6 months	Functional capacity will be assessed by six-minute walk across all 3 arms of the study.

Other

Measure	Time frame	Description
Peak V02	Baseline and 3 months	To evaluate change in cardio-respiratory fitness Peak V02 was assessed at baseline and 3 months using a motorized treadmill test across 3 arms of the study

Countries

United States

Participant flow

Participants by arm

Arm	Count
Exercise and Cognitive Retraining Aerobic exercise; Computerized cognitive retraining program; Heart failure education; Home visits; telephone follow-up. Exercise and Cognitive retraining: Walking 5 times per week at moderate intensity; cognitive retraining one-hour 2 times per week.	19
Exercise Only Each participant will be provided with an individualized target heart rate (THR)zone based on treadmill results. Under the supervision of a research nurse, participants will begin the walking sessions at 60% of THR and increase to 70% by week 5. Participants will walk a minimum of 5 times per week for a duration of 30 minutes. Exercise Only	29
Stretching and Flexibility Stretching and flexibility movements; heart failure education; home visits; telephone follow-up. Stretching and Flexibility	21
Total	69

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Did NOT receive intervention	3	6	2
Overall Study	Lost to Follow-up	1	4	1
Overall Study	Not able to exercise	4	5	4

Baseline characteristics

Characteristic	Exercise and Cognitive Retraining	Total	Stretching and Flexibility	Exercise Only
Age, Continuous	59 years STANDARD_DEVIATION 11	61 years STANDARD_DEVIATION 10	63 years STANDARD_DEVIATION 9	60 years STANDARD_DEVIATION 10
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	13 Participants	38 Participants	9 Participants	16 Participants
Race (NIH/OMB) More than one race	2 Participants	4 Participants	1 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	4 Participants	27 Participants	11 Participants	12 Participants
Region of Enrollment United States	19 participants	69 participants	21 participants	29 participants
Sex: Female, Male Female	12 Participants	37 Participants	8 Participants	17 Participants
Sex: Female, Male Male	7 Participants	32 Participants	13 Participants	12 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 19	0 / 29	0 / 21
other Total, other adverse events	0 / 19	0 / 29	0 / 21
serious Total, serious adverse events	0 / 19	0 / 29	0 / 21

Outcome results

Primary

Change in Processing Speed/Attention Score

RBANS coding (0-89) Color Trails 1 (timed test, 1-5 minutes) measures attention. The length of time to complete each part is recorded; lower raw scores reflect better processing speed and attention. Lower raw scores reflect better processing speed and attention. Scores are averaged for a total score, then converted to Z scores. Z-scores are used when neurocognitive test scores use different measurement scales, e.g., time to completion and number correct. This allows to report performance in a straightforward manner, with low and high scores reflecting poor and good performance consistently across different types of tests, and to provide interpretation of a person's performance in comparison to a group. For interpretive purposes, a z-score has a mean of 0 and a standard deviation of 1. This means that an individual who has a z-score of 1.5 is performing one and a half standard deviations above the group to which he/she is compared.