Neurorehabilitation and Neural Repair http://nnr.sagepub.com/
The Effects of Peroneal Nerve Functional Electrical Stimulation Versus Ankle-Foot Orthosis in Patients With Chronic Stroke: A Randomized Controlled Trial Francois Bethoux, Helen L. Rogers, Karen J. Nolan, Gary M. Abrams, Thiru M. Annaswamy, Murray Brandstater, Barbara Browne, Judith M. Burnfield, Wuwei Feng, Mitchell J. Freed, Carolyn Geis, Jason Greenberg, Mark Gudesblatt, Farha Ikramuddin, Arun Jayaraman, Steven A. Kautz, Helmi L. Lutsep, Sangeetha Madhavan, Jill Meilahn, William S. Pease, Noel Rao, Subramani Seetharama, Pramod Sethi, Margaret A. Turk, Roi Ann Wallis and Conrad Kufta Neurorehabil Neural Repair 2014 28: 688 originally published online 13 February 2014 DOI: 10.1177/1545968314521007 The online version of this article can be found at: http://nnr.sagepub.com/content/28/7/688
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NNRXXX10.1177/1545968314521007Neurorehabilitation and Neural RepairBethoux et al
Clinical Research Article
The Effects of Peroneal Nerve Functional Electrical Stimulation Versus Ankle-Foot Orthosis in Patients With Chronic Stroke: A Randomized Controlled Trial
Neurorehabilitation and Neural Repair 2014, Vol. 28(7) 688–697 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1545968314521007 nnr.sagepub.com
Francois Bethoux, MD1, Helen L. Rogers, PhD2, Karen J. Nolan, PhD3,4, Gary M. Abrams, MD5, Thiru M. Annaswamy, MD, MA6,7, Murray Brandstater, MD, PhD8, Barbara Browne, MD9, Judith M. Burnfield, PhD10, Wuwei Feng, MD, MS11, Mitchell J. Freed, MD12, Carolyn Geis, MD13, Jason Greenberg, MD14, Mark Gudesblatt, MD15, Farha Ikramuddin, MD16, Arun Jayaraman, PT, PhD17, Steven A. Kautz, PhD11,18, Helmi L. Lutsep, MD19, Sangeetha Madhavan, PhD20, Jill Meilahn, DO21, William S. Pease, MD22, Noel Rao, MD23, Subramani Seetharama, MD24, Pramod Sethi, MD25, Margaret A. Turk, MD26, Roi Ann Wallis, MD27, and Conrad Kufta, MD2
Abstract Background. Evidence supports peroneal nerve functional electrical stimulation (FES) as an effective alternative to ankle-foot orthoses (AFO) for treatment of foot drop poststroke, but few randomized controlled comparisons exist. Objective. To compare changes in gait and quality of life (QoL) between FES and an AFO in individuals with foot drop poststroke. Methods. In a multicenter randomized controlled trial (ClinicalTrials.gov #NCT01087957) with unblinded outcome assessments, 495 Medicare-eligible individuals at least 6 months poststroke wore FES or an AFO for 6 months. Primary endpoints: 10-Meter Walk Test (10MWT), a composite of the Mobility, Activities of Daily Living/Instrumental Activities of Daily Living, and Social Participation subscores on the Stroke Impact Scale (SIS), and device-related serious adverse event rate. Secondary endpoints: 6-Minute Walk Test, GaitRite Functional Ambulation Profile (FAP), Modified Emory Functional Ambulation Profile (mEFAP), Berg Balance Scale (BBS), Timed Up and Go, individual SIS domains, and Stroke-Specific Quality of Life measures. Multiply imputed intention-to-treat analyses were used with primary endpoints tested for noninferiority and secondary endpoints tested for superiority. Results. A total of 399 subjects completed the study. FES proved noninferior to the AFO for all primary endpoints. Both the FES and AFO groups improved significantly on the 10MWT. Within the FES group, significant improvements were found for SIS composite score, total mFEAP score, individual Floor and Obstacle course time scores of the mEFAP, FAP, and BBS, but again, no between-group differences were found. Conclusions. Use of FES is equivalent to the AFO. Further studies should examine whether FES enables better performance in tasks involving functional mobility, activities of daily living, and balance. Keywords functional electrical stimulation, stroke rehabilitation, foot drop, gait speed, quality of life, ankle-foot orthosis 1
17 Cleveland Clinic Foundation, Cleveland, OH, USA Rehabilitation Institute of Chicago, Chicago, IL, USA 18 Innovative Neurotronics, Austin, TX, USA Ralph H. Johnson VA Medical Center, Charleston, SC, USA 3 19 Kessler Foundation Research Center, West Orange, NJ, USA Oregon Health and Science University, Portland, OR, USA 4 20 Rutgers–New Jersey Medical School, Newark, NJ, USA University of Illinois at Chicago, Chicago, IL, USA 5 21 San Francisco VA Medical Center, San Francisco, CA, USA Marshfield Clinic Research Foundation, 1000 North Oak Avenue, 6 VA North Texas Health Care System, TX, USA Marshfield, WI, USA 54449 7 22 UT Southwestern Medical Center, Dallas, TX, USA The Ohio State University Wexner Medical Center, Columbus, OH, USA 8 23 Loma Linda University Medical Center, Loma Linda, CA, USA Marianjoy Rehabilitation Hospital, Wheaton, IL, USA 9 24 Magee Rehabilitation Hospital, Philadelphia, PA, USA Hartford Hospital, Hartford, CT, USA 10 25 Madonna Rehabilitation Hospital, Lincoln, NE, USA Guilford Neurologic Associates, Greensboro, NC, USA 11 26 Medical University of South Carolina, Charleston, SC, USA SUNY Upstate Medical University, Syracuse, NY, USA 12 27 Florida Hospital Neuroscience and Orthopedic Research Institute, West Los Angeles VA Medical Center, Los Angeles, CA, USA Orlando, FL, USA 13 Corresponding Author: Halifax Health Center for Neurosciences, Daytona Beach, FL, USA 14 Francois Bethoux, The Cleveland Clinic Foundation, Desk U10, 9500 Helen Hayes Hospital, West Haverstraw, New York, NY, USA 15 Euclid Avenue, Cleveland, OH 44195, USA. South Shore Neurologic Associates, Patchogue, NY, USA 16 Email: [email protected] University of Minnesota Fairview, Minneapolis, MN Downloaded from nnr.sagepub.com at TEXAS SOUTHERN UNIVERSITY on November 19, 2014 2
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Introduction Stroke represents a major public health problem, with an annual incidence of 795 000 cases in the United States1 and 15 million worldwide.2 Seventy-five percent of strokes occur in people aged 65 years or older.2 Stroke remains the fourth leading cause of death and the leading cause of serious, longterm disability in the United States.2 With more than 7 million stroke survivors,1 an estimated $34.3 billion was spend on direct and indirect cost of stroke-related care in 2008.3 Seventy percent of stroke survivors regain the ability to walk, but functional ambulation is limited in many because of residual spastic hemiparesis, and often requires the use of an assistive device for independent ambulation. Walking limitations have a continued and significant impact on functional performance and quality of life (QoL) for stroke survivors.4 An estimated 20% of all stroke survivors experience foot drop, a consequence of spastic hemiparesis from stroke.5 Foot drop, typically because of a combination of weakness of the ankle dorsiflexor muscles (agonists) and spasticity of the plantarflexor muscles (antagonists), results in a slower, less efficient gait and increases the risk of falls.6 The current standard of care for foot drop is the anklefoot orthosis (AFO). An AFO, usually made of polypropylene or carbon fiber, is a brace worn on the lower leg to hold the foot and ankle in the correct position. AFOs restrict the natural range of motion and flexibility of the ankle and foot resulting in limited walking ability on uneven terrains, and may be uncomfortable to wear.7 Functional electrical stimulation (FES), the use of neuromuscular electrical stimulation to activate muscles during functional tasks, is an alternative to the AFO. FES to the peroneal nerve provides active dorsiflexion during the swing phase of ambulation and can reduce foot drop by facilitating increased voluntary muscle activity,8 and improving the quality and symmetry of gait.9,10 There is strong support for FES both in clinical guidelines and in recently published literature. The Department of Veterans Affairs/Department of Defense (VA-DoD) and the American Heart Association (AHA)/American Stroke Association (ASA) both published clinical practice guidelines for stroke rehabilitation in 2010.3,11 The VA-DoD guidelines recommend the use of FES as an adjunctive treatment for motor relearning, at the acute and chronic phase (level B evidence).3 The AHA/ASA guidelines acknowledge published evidence showing improvement of gait with FES, when compared with or as a supplement to other rehabilitation modalities (neuroprosthetic effect).11 In several studies, peroneal nerve FES was associated with increased gait velocity,7,9,12,13 decreased energy expenditure with gait,7,12-14 and improved gait symmetry.9,10,15 Evidence in the literature primarily comes from nonrandomized, pre– post intervention studies with small sample sizes and short
follow-up periods. Few studies cover all dimensions of the International Classification of Functioning, Disability and Health (ICF). The recent publication of 3 larger randomized controlled trials (RCTs) comparing the use of FES to an AFO has added higher quality evidence to the literature.16-18 The purpose of this investigation was to measure the effects on gait performance and QoL of the WalkAide FES system (WA) compared with an AFO in individuals with foot drop secondary to hemiparetic stroke eligible for Medicare or Medicare Advantage benefits.
Methods Study design This study was an unblinded, parallel-group RCT of subjects with foot drop due to stroke conducted across 30 sites in the United States (Supplementary Table 1 [available online at http://nnr.sagepub.com/content/by/supplemental-data] provides detailed eligibility criteria). All subjects were consented and asked to sign an authorization to use and disclose information. Subjects meeting all inclusion and exclusion criteria were enrolled and randomized into 1 of 2 groups, WA or AFO, using a centralized computer-generated randomization scheme built into the electronic data capture system for this study. Subjects were followed for 6 months on measures of gait performance, functionality with activities of daily living, balance, and quality of life.
Clinical Evaluation and Measurement At screening, sites performed a medical history and a peripheral nerve stimulation test, collected demographic information, and completed the Mini Mental State Exam,19 Beck Depression Inventory,20 and a neurological evaluation to ensure inclusion and exclusion criteria were met. Subjects’ walking ability and gait speed were also assessed using a 10-Meter Walk Test (10MWT), during which subjects were allowed to use their usual assistive devices, but no physical assistance or external support/bracing was allowed. The 10MWT was used as an inclusion/exclusion criterion (subjects ambulating faster than 0.8 m/s were excluded), and as the initial (pre–device fitting) value in the primary endpoint analysis of change in gait velocity from screening to 6 months. Eligible subjects were randomized and scheduled for fitting of the study device within 2 weeks of randomization. Study devices were the WA (Innovative Neurotronics, Austin, TX) or an AFO. The WA is a battery-operated, single-channel electrical stimulator approved by the US Food and Drug Administration as treatment for foot drop. The device consists of a cuff worn around the proximal part of
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the lower leg, which holds the control module and surface electrodes. The WA uses a tilt sensor and accelerometer to trigger ankle dorsiflexion and control the timing and duration of peroneal nerve stimulation during the swing phase of gait. After initial fitting, programming, and patient education performed by a trained clinician, patients are able to use the WA to facilitate walking in daily activities. Fitting for the AFO was performed by a licensed orthotist; subjects coming in to the study with AFOs that met the standard of care were able to continue in their own orthosis. AFOs provided for subjects or AFOs fabricated as replacements were custom molded and either articulated or fixed at the ankle based on the professional opinion of the orthotist and clinical needs of the subject. Fitting for the WA was performed by a WA-certified orthotist or licensed physical therapist. After completing a 2-week progressive wearing schedule relevant to each device, subjects were instructed to wear their device on a full time basis (ie, for all walking activities throughout the day). Study measurements were performed at screening (without device), baseline (postfitting, with device) 1, 3 and 6 months (with device); the primary endpoint for data analysis was at 6 months (Supplementary Table 2 [available online at http://nnr.sagepub.com/content/by/supplementaldata] details measurement periodicity). For all walking performance tests, the subjects were instructed to use their usual assistive device (eg, cane, walker), and to use the same device at each visit. The primary endpoints for the trial were the following: gait velocity (10MWT),21 a composite score consisting of the sum of the Mobility, Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL) and Social Participation domain scores of the Stroke Impact Scale (SIS), and the device-related serious adverse event (SAE) rate. Secondary endpoints were the following: 6-Minute Walk Test (6MWT), GaitRite Functional Ambulation Profile (FAP), Modified Emory Functional Ambulation Profile (mEFAP), Berg Balance Scale (BBS), Timed Up and Go (TUG), Stroke-Specific Quality of Life (SSQoL), and individual SIS domain scores (Strength, Mobility, Communication, Emotion, Memory and Thinking, Social Participation, ADL/IADL, and Hand Function). Secondary measures were chosen in order to accurately assess general ambulation ability, performance in functional mobility tasks, dynamic balance, and parameters describing QoL and the impact of the disability from stroke. The chosen gait measures provide an assessment of walking endurance over longer distances (6MWT),22 gait quality (FAP),23 and ability to perform functional ambulation tasks (mEFAP).24 The measures chosen to assess balance, the BBS and TUG, are designed to test static and dynamic balance during functional tasks, including walking.25,26 Values for the TUG were extracted from the mEFAP battery. The impact of disability from stroke was assessed via the SIS
and the SSQoL, both of which provide a multidimensional assessment of the impact of stroke on physical function as well as stroke-related QoL.27,28 All the measures used have published reliability values, and standard instructions were used across all sites during data collection. All study personnel were trained to the administration of these tests, but actual interrater reliability was not assessed. All of the GaitRite walking trials were processed and analyzed by a central lab, and the instructions for walking on the mat were standardized.
Sample Size Calculation The sample size needed to adequately power the study was estimated for each primary endpoint (gait speed, SIS composite score, and device-related SAE rate), and the largest estimate retained. Estimates were for a power of 80% to detect a difference between groups in gait speed of ≥0.1 m/s (2-sided t test, α = .025), a difference in SIS composite score of ≥15 points (2-sided t test, α = .025), and a difference in device-related SAE rate of no more than 3% (1-sided Blackwelder’s noninferiority test of difference in proportions, α = .05). The device-related SAE rate yielded the largest sample size estimate, 198 per group. This number was corrected for an estimated attrition rate of 20%, establishing the sample size estimate for this study at 495.
Statistical Analysis Study data were analyzed using per-protocol (completers) and intention-to-treat (ITT) analyses with missing data points calculated using multiple imputation. The results of the 2 analyses differed minimally; to preserve randomization and mitigate impact of bias resulting from subject dropout, the ITT analyses results are presented. To account for potential clustering at the site level, the ITT analysis on all endpoints were conducted on multiply imputed data via mixed-effect regression models in which the treatment arm was the fixed effect and the study center was the random effect. A noninferiority analysis was conducted at 6 months comparing the WA and AFO groups on the primary efficacy endpoints of gait velocity, the composite of the SIS Mobility, ADL/IADL and Social Participation domain scores, and the primary safety endpoint of the devicerelated SAE rates. The composite SIS score was chosen as a primary endpoint because selected domains accurately depict changes in functional ability, independence with ADLs, and community mobility. Moriello et al29 demonstrated that the majority of SIS domain items were linked to ICF domains. For the purposes of this study, this SIS composite score was considered most relevant and most likely to demonstrate changes in functional mobility
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Bethoux et al attributable to device use. SAEs were defined as serious device-related deteriorations in a subject’s health resulting in a life threatening illness, injury or a permanent impairment of body structure or function requiring inpatient hospitalization or prolongation of existing hospitalization, or resulting in medical or surgical intervention to prevent permanent impairment to a body structure or function. The noninferiority margin was considered met if the WA group demonstrated each of the following with 95% confidence: a change in gait velocity no more than 0.2 m/s below that of the AFO group (based on Perry’s classification of ambulation categories poststroke30), a change in SIS composite score no lower than 15 points below that of the AFO group (based on estimations of clinically meaningful change in SIS score27) and a device-related SAE rate no greater than 3% above that of the AFO group. If noninferiority was met, multiple secondary endpoints were scheduled for analysis at 6 months: 6 MWT distance, total and specific mEFAP task scores, GaitRite FAP score, ambulation category classification,30 BBS score, TUG time, specific SIS domain scores, and SSQoL score. Changes from baseline or percent change from baseline were tested using t tests or Blackwelder’s t or Z tests. A Bonferroni adjustment for multiple comparisons was performed setting the level of statistical significance at P = .001. The changes in ambulation category classification were demonstrated by a McNemar’s test.
Total number of subjects enrolled = 495 Subjects enrolled in WA arm = 242
Subjects enrolled in AFO arm = 253
Subjects exiting study: Reasons WA group
AFO group
Subjects deceased = 2
Subjects deceased = 2
Exited due to noncompliance with protocol = 25
Exited due to noncompliance with protocol = 13
(Including:intolerance to stimulation (3), inadequate dorsiflexion with stimulation (7), unsafe or unstable gait with device (8), and inability to independently use WA (2)).
Exited at subject request = 15
Exited at subject request = 18
(7 exited due to dissatisfaction with device)
(10 exited due to dissatisfaction with device)
Exited due to medical reasons = 7
Exited due to medical reasons = 4
Lost to Follow-up = 4
Lost to Follow-up = 3
Investigator withdrew other =2
Investigator withdrew other =1
Total number of subjects completing study = 399 (187 WA Arm, 212 AFO arm)
Figure 1. Participant flow diagram.
Abbreviations: WA, WalkAide functional electrical stimulation system; AFO, ankle-foot orthosis.
Results Subjects A total of 761 potential subjects were screened, of whom 266 failed to meet inclusion and exclusion criteria and 495 were enrolled at 30 rehabilitation centers nationwide between April 27, 2010 and April 26, 2012. A total of 399 subjects completed the study; 187 in the WA group and 212 in the AFO group. Figure 1 details participant flow through the study and sources of dropout. Table 1 outlines demographic information and screening measures for all subjects enrolled in the study. The only significant differences between groups initially were body mass index (BMI; P = .006) and gait speed (P = .05). Despite randomization procedures, gait speed in the WA group was slower than that of the AFO group by 0.04 m/s. Although this difference was statistically significant, it was not considered clinically significant, since it was not large enough to differentiate between ambulatory classification30; nor did it differ within the range of minimal clinically important differences (MCID) for gait speed established for the stroke population.31,32 The difference in BMI (which was lower in the WA group) was not sufficient to differentiate between BMI categories33 and was not considered clinically significant. These variables were therefore considered balanced in the analyses.
Primary Endpoints The results of the primary efficacy endpoints (gait velocity and SIS composite score) and primary safety endpoint (device-related SAE rate) analyses show the WA to be noninferior to the AFO (values presented in Table 2). No statistically significant between-group differences were observed for gait velocity or SIS composite score. Both WA and AFO groups demonstrated statistically significant improvement in gait velocity from screening to 6 months (P < .001). The between-group difference in mean change in gait velocity was 0.009 m/s (95% confidence interval [CI] = −0.04 to 0.06). Therefore, the WA group was not inferior to the AFO group because the lower CI margin (−0.04) was larger than the margin set for noninferiority (−0.2 m/s). The WA group demonstrated statistically significant improvement from baseline to 6 months on the SIS composite score (P = .05). The between-group difference in mean change in SIS composite score was 1.1 points (95% CI = −1.62 to −0.58). Noninferiority was met for the WA group since the lower CI margin (−1.62) is greater than the noninferiority margin set for this variable (−15 points). Only 2 device-related SAEs were reported in
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Table 1. Subject Demographics and Characteristics at Screening. Characteristics
WA Arm (n = 242)
AFO Arm (n = 253)
P Valuea
63.87 ± 11.33
64.30 ± 12.01
95 (39.26) 147 (60.74)
96 (37.94) 157 (62.06)
0 (0.00) 2 (0.83) 55 (22.73) 0 (0.00) 8 (3.31) 177 (73.14) 6.90 ± 6.43 0.449 ± 0.22 27.62 ± 2.44 7.98 ± 6.32 27.98 ± 4.93
2 (0.79) 3 (1.19) 55 (21.74) 1 (0.40) 5 (1.98) 187 (73.91) 6.86 ± 6.64 0.487 ± 0.21 27.49 ± 2.83 8.08 ± 6.58 29.21 ± 5.08
.681 .764 .560 .956 .050 .574 .864 .006
Age in years, mean ± SD Gender, n (%) Female Male Race, n (%) American Indian/Alaskan Asian Black/African American Hawaiian/Pacific Islander Other White (Caucasian) Time post onset of stroke in years, mean ± SD Gait speed at screening in m/s, mean ± SD Mini Mental Status Examination, mean ± SD Beck Depression Inventory, mean ± SD Body mass index in kg/m2, mean ± SD
Abbreviations: WA, WalkAide functional electrical stimulation system; AFO, ankle-foot orthosis. a P values in boldface indicate statistical significance.
Table 2. Primary Endpoint Analysis. Variable (Mean ± SE)
WA Initial
WA 6 Months
WA Change
WA Versus AFO AFO AFO Initial AFO 6 Months Change Noninferiority Test Inequality Test
10-Meter Walk 0.449 ± 0.014 0.635 ± 0.186** 0.487 ± 0.013 0.682 ± 0.020 0.195** Test (m/s) 0.022 Stroke Impact Scale 170.0 ± 2.7 175.0 ± 2.7 5.0* 168.8 ± 2.6 172.7 ± 2.8 3.9 (SIS) combination score (Mobility, ADL/IADL, and Social Participation Domains) SAEs 0 0 0 0 2 2
δ = −0.2 m/s; P < .0001 δ = −15 points; P < .0001
δ = −3% devicerelated SAE rate; P < .001
0.695 0.568
0.317
Abbreviations: WA = WalkAide functional electrical stimulation system; AFO, ankle-foot orthosis; SE, standard error; ADL/IADL, activities of daily living/instrumental activities of daily living; δ, noninferiority margin; SAE, serious adverse event. Within- and between-group analyses: *P < .05, **P < .001.
the AFO and none in the WA group; therefore, devicerelated SAE rates were not computed (Table 3 summarizes all AEs for the trial with a frequency ≥2%).
Secondary Endpoints: Walking Performance Multiple endpoints were measured to determine the impact of the WA and AFO on walking performance (values presented in Table 4); differences were determined to be significant if P ≤ .001 after Bonferroni correction. Significant within-group differences between baseline and 6 months were noted in the WA group for GaitRite FAP score
(P = .001), total mEFAP time (P < .001), and the mEFAP subtasks of Floor time (P = .001) and Obstacle Course time (P = .001). No significant between-group differences were found for these variables. To demonstrate the effects of changes in gait speed on functional ambulation, the subjects were grouped into functional ambulation categories30 by gait velocity (Supplementary Table 3 [available online at http://nnr.sagepub.com/content/by/supplemental-data] details subject categorization). A McNemar’s test showed statistically significant improvement in ambulation category between screening and 6 months for both groups (P < .001).
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Bethoux et al Table 3. Summary of Adverse Events. Serious AEs Relatedness Related to device Unrelated to device
Total (OR)
AFO (OR)
WA (OR)
2 (0.23) 41 (4.8)
2 (0.23) 16 (1.9)
0 (0.0) 25 (2.9)
Summary of AEs (Total AEs for Trial = 858; 436 in AFO Arm, 422 in WA Arm) Type of Eventa
Total (OR)
AFO (OR)
WA (OR)
Falls Other Pain in lower extremity or back Fatigue or muscle weakness Other medical conditions Skin irritation Muscle soreness
348 (41.0) 423 (49.4) 91 (10.6)
175 (20.4) 235 (27.4) 55 (6.4)
173 (20.2) 189 (22.0) 36 (4.2)
18 (2.1) 315 (36.7) 44 (5.1) 30 (3.5)
14 (1.6) 166 (19.3) 10 (1.2) 15 (1.75)
4 (0.5) 149 (17.4) 34 (3.9) 15 (1.75)
Abbreviations: AE, adverse event; OR, occurrence rate (in percentage) as compared with total number of AEs; WA = WalkAide functional electrical stimulation system; AFO, ankle-foot orthosis. a Events with a frequency ≥2% are reported.
Secondary Endpoints: Balance The impact of the WA and AFO on balance was measured using the BBS and TUG (Table 4). Statistically significant improvement on BBS score was noted for the WA group (P = .001). Neither the WA group nor AFO group exhibited statistically significant improvement in time to complete the TUG. No significant between groups differences were found for these variables.
Secondary Endpoints: Quality of Life The individual SIS domains and the SSQoL test were used as measures of QoL (Table 4). Neither group demonstrated any significant within group improvement for the individual domains of the SIS or for SSQoL score from baseline to 6-month follow-up. No significant between-group differences were found for these variables.
Discussion The results of this RCT confirm that the WA is noninferior to the standard of care AFO for each primary endpoint: (a) gait velocity, (b) SIS composite score, and (c) safety. The occurrence of device-related SAEs was extremely low (2 for AFO and none for WA group), demonstrating that both devices are safe and pose negligible risk to the user. Gait velocity is an important indication of function and level of disability,32 and the primary means of classifying ambulation status after stroke.34 Ambulation categories have also been linked to the impact of stroke on QoL.
Schmid et al34 showed that individuals who transition from one ambulation category to another exhibited meaningful changes in SIS domain scores. MCIDs for gait speed have been reported in the stroke population and range from 0.1 m/s31 to 0.16 m/s.32 Both the WA and AFO groups in this study showed increases in gait speed above the established MCID (0.186 and 0.195 m/s, respectively). The results of this study show increases in gait speed slightly above those noted in the literature. The percentage changes in gait speed were 41.4% for the WA and 40.0% for the AFO group. Hausdorff and Ring9 studied the effects of peroneal nerve FES in 24 subjects with chronic hemiparesis and noted a change in gait speed from baseline to 8 weeks of 34%. Studies by Stein et al7,12 looking at a population of subjects with nonprogressive (cardiovascular accident) and progressive (multiple sclerosis) disorders reported percent increases in gait speed with FES ranging from 32% at 6 months12 to 37.8% at 11 months.7 The changes observed in this study are also slightly above those of Kluding et al17 who found a change in gait speed of 0.14 m/s in the FES group and 0.15 m/s in the AFO group. The Perry ambulation categories use gait speed to classify ambulation status from physiologic to full community ambulation, with categories separated by a maximum change of 0.2 m/s.30 The mean gait speed of both groups fell within the category of most-limited community ambulation at screening. The change in both groups (~0.2 m/s) was sufficient to move these means into the least-limited community ambulation category, representing a significant improvement in community mobility and function. These results indicate that the WA is equivalent to the AFO in
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33.1 −96.0 −12.0 −8.7 −16.0 −42.6 −16.7 5.8 2.6 2.2 3.2 −0.2 −0.6 0.3 0.4 2.7 2.1 2.4 4.5
.002
The Effects of Peroneal Nerve Functional Electrical Stimulation Versus Ankle-Foot Orthosis in Patients With Chronic Stroke: A Randomized Controlled Trial Francois Bethoux, Helen L. Rogers, Karen J. Nolan, Gary M. Abrams, Thiru M. Annaswamy, Murray Brandstater, Barbara Browne, Judith M. Burnfield, Wuwei Feng, Mitchell J. Freed, Carolyn Geis, Jason Greenberg, Mark Gudesblatt, Farha Ikramuddin, Arun Jayaraman, Steven A. Kautz, Helmi L. Lutsep, Sangeetha Madhavan, Jill Meilahn, William S. Pease, Noel Rao, Subramani Seetharama, Pramod Sethi, Margaret A. Turk, Roi Ann Wallis and Conrad Kufta Neurorehabil Neural Repair 2014 28: 688 originally published online 13 February 2014 DOI: 10.1177/1545968314521007 The online version of this article can be found at: http://nnr.sagepub.com/content/28/7/688
Published by: http://www.sagepublications.com
On behalf of:
American Society of Neurorehabilitation
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2014
NNRXXX10.1177/1545968314521007Neurorehabilitation and Neural RepairBethoux et al
Clinical Research Article
The Effects of Peroneal Nerve Functional Electrical Stimulation Versus Ankle-Foot Orthosis in Patients With Chronic Stroke: A Randomized Controlled Trial
Neurorehabilitation and Neural Repair 2014, Vol. 28(7) 688–697 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1545968314521007 nnr.sagepub.com
Francois Bethoux, MD1, Helen L. Rogers, PhD2, Karen J. Nolan, PhD3,4, Gary M. Abrams, MD5, Thiru M. Annaswamy, MD, MA6,7, Murray Brandstater, MD, PhD8, Barbara Browne, MD9, Judith M. Burnfield, PhD10, Wuwei Feng, MD, MS11, Mitchell J. Freed, MD12, Carolyn Geis, MD13, Jason Greenberg, MD14, Mark Gudesblatt, MD15, Farha Ikramuddin, MD16, Arun Jayaraman, PT, PhD17, Steven A. Kautz, PhD11,18, Helmi L. Lutsep, MD19, Sangeetha Madhavan, PhD20, Jill Meilahn, DO21, William S. Pease, MD22, Noel Rao, MD23, Subramani Seetharama, MD24, Pramod Sethi, MD25, Margaret A. Turk, MD26, Roi Ann Wallis, MD27, and Conrad Kufta, MD2
Abstract Background. Evidence supports peroneal nerve functional electrical stimulation (FES) as an effective alternative to ankle-foot orthoses (AFO) for treatment of foot drop poststroke, but few randomized controlled comparisons exist. Objective. To compare changes in gait and quality of life (QoL) between FES and an AFO in individuals with foot drop poststroke. Methods. In a multicenter randomized controlled trial (ClinicalTrials.gov #NCT01087957) with unblinded outcome assessments, 495 Medicare-eligible individuals at least 6 months poststroke wore FES or an AFO for 6 months. Primary endpoints: 10-Meter Walk Test (10MWT), a composite of the Mobility, Activities of Daily Living/Instrumental Activities of Daily Living, and Social Participation subscores on the Stroke Impact Scale (SIS), and device-related serious adverse event rate. Secondary endpoints: 6-Minute Walk Test, GaitRite Functional Ambulation Profile (FAP), Modified Emory Functional Ambulation Profile (mEFAP), Berg Balance Scale (BBS), Timed Up and Go, individual SIS domains, and Stroke-Specific Quality of Life measures. Multiply imputed intention-to-treat analyses were used with primary endpoints tested for noninferiority and secondary endpoints tested for superiority. Results. A total of 399 subjects completed the study. FES proved noninferior to the AFO for all primary endpoints. Both the FES and AFO groups improved significantly on the 10MWT. Within the FES group, significant improvements were found for SIS composite score, total mFEAP score, individual Floor and Obstacle course time scores of the mEFAP, FAP, and BBS, but again, no between-group differences were found. Conclusions. Use of FES is equivalent to the AFO. Further studies should examine whether FES enables better performance in tasks involving functional mobility, activities of daily living, and balance. Keywords functional electrical stimulation, stroke rehabilitation, foot drop, gait speed, quality of life, ankle-foot orthosis 1
17 Cleveland Clinic Foundation, Cleveland, OH, USA Rehabilitation Institute of Chicago, Chicago, IL, USA 18 Innovative Neurotronics, Austin, TX, USA Ralph H. Johnson VA Medical Center, Charleston, SC, USA 3 19 Kessler Foundation Research Center, West Orange, NJ, USA Oregon Health and Science University, Portland, OR, USA 4 20 Rutgers–New Jersey Medical School, Newark, NJ, USA University of Illinois at Chicago, Chicago, IL, USA 5 21 San Francisco VA Medical Center, San Francisco, CA, USA Marshfield Clinic Research Foundation, 1000 North Oak Avenue, 6 VA North Texas Health Care System, TX, USA Marshfield, WI, USA 54449 7 22 UT Southwestern Medical Center, Dallas, TX, USA The Ohio State University Wexner Medical Center, Columbus, OH, USA 8 23 Loma Linda University Medical Center, Loma Linda, CA, USA Marianjoy Rehabilitation Hospital, Wheaton, IL, USA 9 24 Magee Rehabilitation Hospital, Philadelphia, PA, USA Hartford Hospital, Hartford, CT, USA 10 25 Madonna Rehabilitation Hospital, Lincoln, NE, USA Guilford Neurologic Associates, Greensboro, NC, USA 11 26 Medical University of South Carolina, Charleston, SC, USA SUNY Upstate Medical University, Syracuse, NY, USA 12 27 Florida Hospital Neuroscience and Orthopedic Research Institute, West Los Angeles VA Medical Center, Los Angeles, CA, USA Orlando, FL, USA 13 Corresponding Author: Halifax Health Center for Neurosciences, Daytona Beach, FL, USA 14 Francois Bethoux, The Cleveland Clinic Foundation, Desk U10, 9500 Helen Hayes Hospital, West Haverstraw, New York, NY, USA 15 Euclid Avenue, Cleveland, OH 44195, USA. South Shore Neurologic Associates, Patchogue, NY, USA 16 Email: [email protected] University of Minnesota Fairview, Minneapolis, MN Downloaded from nnr.sagepub.com at TEXAS SOUTHERN UNIVERSITY on November 19, 2014 2
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Introduction Stroke represents a major public health problem, with an annual incidence of 795 000 cases in the United States1 and 15 million worldwide.2 Seventy-five percent of strokes occur in people aged 65 years or older.2 Stroke remains the fourth leading cause of death and the leading cause of serious, longterm disability in the United States.2 With more than 7 million stroke survivors,1 an estimated $34.3 billion was spend on direct and indirect cost of stroke-related care in 2008.3 Seventy percent of stroke survivors regain the ability to walk, but functional ambulation is limited in many because of residual spastic hemiparesis, and often requires the use of an assistive device for independent ambulation. Walking limitations have a continued and significant impact on functional performance and quality of life (QoL) for stroke survivors.4 An estimated 20% of all stroke survivors experience foot drop, a consequence of spastic hemiparesis from stroke.5 Foot drop, typically because of a combination of weakness of the ankle dorsiflexor muscles (agonists) and spasticity of the plantarflexor muscles (antagonists), results in a slower, less efficient gait and increases the risk of falls.6 The current standard of care for foot drop is the anklefoot orthosis (AFO). An AFO, usually made of polypropylene or carbon fiber, is a brace worn on the lower leg to hold the foot and ankle in the correct position. AFOs restrict the natural range of motion and flexibility of the ankle and foot resulting in limited walking ability on uneven terrains, and may be uncomfortable to wear.7 Functional electrical stimulation (FES), the use of neuromuscular electrical stimulation to activate muscles during functional tasks, is an alternative to the AFO. FES to the peroneal nerve provides active dorsiflexion during the swing phase of ambulation and can reduce foot drop by facilitating increased voluntary muscle activity,8 and improving the quality and symmetry of gait.9,10 There is strong support for FES both in clinical guidelines and in recently published literature. The Department of Veterans Affairs/Department of Defense (VA-DoD) and the American Heart Association (AHA)/American Stroke Association (ASA) both published clinical practice guidelines for stroke rehabilitation in 2010.3,11 The VA-DoD guidelines recommend the use of FES as an adjunctive treatment for motor relearning, at the acute and chronic phase (level B evidence).3 The AHA/ASA guidelines acknowledge published evidence showing improvement of gait with FES, when compared with or as a supplement to other rehabilitation modalities (neuroprosthetic effect).11 In several studies, peroneal nerve FES was associated with increased gait velocity,7,9,12,13 decreased energy expenditure with gait,7,12-14 and improved gait symmetry.9,10,15 Evidence in the literature primarily comes from nonrandomized, pre– post intervention studies with small sample sizes and short
follow-up periods. Few studies cover all dimensions of the International Classification of Functioning, Disability and Health (ICF). The recent publication of 3 larger randomized controlled trials (RCTs) comparing the use of FES to an AFO has added higher quality evidence to the literature.16-18 The purpose of this investigation was to measure the effects on gait performance and QoL of the WalkAide FES system (WA) compared with an AFO in individuals with foot drop secondary to hemiparetic stroke eligible for Medicare or Medicare Advantage benefits.
Methods Study design This study was an unblinded, parallel-group RCT of subjects with foot drop due to stroke conducted across 30 sites in the United States (Supplementary Table 1 [available online at http://nnr.sagepub.com/content/by/supplemental-data] provides detailed eligibility criteria). All subjects were consented and asked to sign an authorization to use and disclose information. Subjects meeting all inclusion and exclusion criteria were enrolled and randomized into 1 of 2 groups, WA or AFO, using a centralized computer-generated randomization scheme built into the electronic data capture system for this study. Subjects were followed for 6 months on measures of gait performance, functionality with activities of daily living, balance, and quality of life.
Clinical Evaluation and Measurement At screening, sites performed a medical history and a peripheral nerve stimulation test, collected demographic information, and completed the Mini Mental State Exam,19 Beck Depression Inventory,20 and a neurological evaluation to ensure inclusion and exclusion criteria were met. Subjects’ walking ability and gait speed were also assessed using a 10-Meter Walk Test (10MWT), during which subjects were allowed to use their usual assistive devices, but no physical assistance or external support/bracing was allowed. The 10MWT was used as an inclusion/exclusion criterion (subjects ambulating faster than 0.8 m/s were excluded), and as the initial (pre–device fitting) value in the primary endpoint analysis of change in gait velocity from screening to 6 months. Eligible subjects were randomized and scheduled for fitting of the study device within 2 weeks of randomization. Study devices were the WA (Innovative Neurotronics, Austin, TX) or an AFO. The WA is a battery-operated, single-channel electrical stimulator approved by the US Food and Drug Administration as treatment for foot drop. The device consists of a cuff worn around the proximal part of
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the lower leg, which holds the control module and surface electrodes. The WA uses a tilt sensor and accelerometer to trigger ankle dorsiflexion and control the timing and duration of peroneal nerve stimulation during the swing phase of gait. After initial fitting, programming, and patient education performed by a trained clinician, patients are able to use the WA to facilitate walking in daily activities. Fitting for the AFO was performed by a licensed orthotist; subjects coming in to the study with AFOs that met the standard of care were able to continue in their own orthosis. AFOs provided for subjects or AFOs fabricated as replacements were custom molded and either articulated or fixed at the ankle based on the professional opinion of the orthotist and clinical needs of the subject. Fitting for the WA was performed by a WA-certified orthotist or licensed physical therapist. After completing a 2-week progressive wearing schedule relevant to each device, subjects were instructed to wear their device on a full time basis (ie, for all walking activities throughout the day). Study measurements were performed at screening (without device), baseline (postfitting, with device) 1, 3 and 6 months (with device); the primary endpoint for data analysis was at 6 months (Supplementary Table 2 [available online at http://nnr.sagepub.com/content/by/supplementaldata] details measurement periodicity). For all walking performance tests, the subjects were instructed to use their usual assistive device (eg, cane, walker), and to use the same device at each visit. The primary endpoints for the trial were the following: gait velocity (10MWT),21 a composite score consisting of the sum of the Mobility, Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL) and Social Participation domain scores of the Stroke Impact Scale (SIS), and the device-related serious adverse event (SAE) rate. Secondary endpoints were the following: 6-Minute Walk Test (6MWT), GaitRite Functional Ambulation Profile (FAP), Modified Emory Functional Ambulation Profile (mEFAP), Berg Balance Scale (BBS), Timed Up and Go (TUG), Stroke-Specific Quality of Life (SSQoL), and individual SIS domain scores (Strength, Mobility, Communication, Emotion, Memory and Thinking, Social Participation, ADL/IADL, and Hand Function). Secondary measures were chosen in order to accurately assess general ambulation ability, performance in functional mobility tasks, dynamic balance, and parameters describing QoL and the impact of the disability from stroke. The chosen gait measures provide an assessment of walking endurance over longer distances (6MWT),22 gait quality (FAP),23 and ability to perform functional ambulation tasks (mEFAP).24 The measures chosen to assess balance, the BBS and TUG, are designed to test static and dynamic balance during functional tasks, including walking.25,26 Values for the TUG were extracted from the mEFAP battery. The impact of disability from stroke was assessed via the SIS
and the SSQoL, both of which provide a multidimensional assessment of the impact of stroke on physical function as well as stroke-related QoL.27,28 All the measures used have published reliability values, and standard instructions were used across all sites during data collection. All study personnel were trained to the administration of these tests, but actual interrater reliability was not assessed. All of the GaitRite walking trials were processed and analyzed by a central lab, and the instructions for walking on the mat were standardized.
Sample Size Calculation The sample size needed to adequately power the study was estimated for each primary endpoint (gait speed, SIS composite score, and device-related SAE rate), and the largest estimate retained. Estimates were for a power of 80% to detect a difference between groups in gait speed of ≥0.1 m/s (2-sided t test, α = .025), a difference in SIS composite score of ≥15 points (2-sided t test, α = .025), and a difference in device-related SAE rate of no more than 3% (1-sided Blackwelder’s noninferiority test of difference in proportions, α = .05). The device-related SAE rate yielded the largest sample size estimate, 198 per group. This number was corrected for an estimated attrition rate of 20%, establishing the sample size estimate for this study at 495.
Statistical Analysis Study data were analyzed using per-protocol (completers) and intention-to-treat (ITT) analyses with missing data points calculated using multiple imputation. The results of the 2 analyses differed minimally; to preserve randomization and mitigate impact of bias resulting from subject dropout, the ITT analyses results are presented. To account for potential clustering at the site level, the ITT analysis on all endpoints were conducted on multiply imputed data via mixed-effect regression models in which the treatment arm was the fixed effect and the study center was the random effect. A noninferiority analysis was conducted at 6 months comparing the WA and AFO groups on the primary efficacy endpoints of gait velocity, the composite of the SIS Mobility, ADL/IADL and Social Participation domain scores, and the primary safety endpoint of the devicerelated SAE rates. The composite SIS score was chosen as a primary endpoint because selected domains accurately depict changes in functional ability, independence with ADLs, and community mobility. Moriello et al29 demonstrated that the majority of SIS domain items were linked to ICF domains. For the purposes of this study, this SIS composite score was considered most relevant and most likely to demonstrate changes in functional mobility
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Bethoux et al attributable to device use. SAEs were defined as serious device-related deteriorations in a subject’s health resulting in a life threatening illness, injury or a permanent impairment of body structure or function requiring inpatient hospitalization or prolongation of existing hospitalization, or resulting in medical or surgical intervention to prevent permanent impairment to a body structure or function. The noninferiority margin was considered met if the WA group demonstrated each of the following with 95% confidence: a change in gait velocity no more than 0.2 m/s below that of the AFO group (based on Perry’s classification of ambulation categories poststroke30), a change in SIS composite score no lower than 15 points below that of the AFO group (based on estimations of clinically meaningful change in SIS score27) and a device-related SAE rate no greater than 3% above that of the AFO group. If noninferiority was met, multiple secondary endpoints were scheduled for analysis at 6 months: 6 MWT distance, total and specific mEFAP task scores, GaitRite FAP score, ambulation category classification,30 BBS score, TUG time, specific SIS domain scores, and SSQoL score. Changes from baseline or percent change from baseline were tested using t tests or Blackwelder’s t or Z tests. A Bonferroni adjustment for multiple comparisons was performed setting the level of statistical significance at P = .001. The changes in ambulation category classification were demonstrated by a McNemar’s test.
Total number of subjects enrolled = 495 Subjects enrolled in WA arm = 242
Subjects enrolled in AFO arm = 253
Subjects exiting study: Reasons WA group
AFO group
Subjects deceased = 2
Subjects deceased = 2
Exited due to noncompliance with protocol = 25
Exited due to noncompliance with protocol = 13
(Including:intolerance to stimulation (3), inadequate dorsiflexion with stimulation (7), unsafe or unstable gait with device (8), and inability to independently use WA (2)).
Exited at subject request = 15
Exited at subject request = 18
(7 exited due to dissatisfaction with device)
(10 exited due to dissatisfaction with device)
Exited due to medical reasons = 7
Exited due to medical reasons = 4
Lost to Follow-up = 4
Lost to Follow-up = 3
Investigator withdrew other =2
Investigator withdrew other =1
Total number of subjects completing study = 399 (187 WA Arm, 212 AFO arm)
Figure 1. Participant flow diagram.
Abbreviations: WA, WalkAide functional electrical stimulation system; AFO, ankle-foot orthosis.
Results Subjects A total of 761 potential subjects were screened, of whom 266 failed to meet inclusion and exclusion criteria and 495 were enrolled at 30 rehabilitation centers nationwide between April 27, 2010 and April 26, 2012. A total of 399 subjects completed the study; 187 in the WA group and 212 in the AFO group. Figure 1 details participant flow through the study and sources of dropout. Table 1 outlines demographic information and screening measures for all subjects enrolled in the study. The only significant differences between groups initially were body mass index (BMI; P = .006) and gait speed (P = .05). Despite randomization procedures, gait speed in the WA group was slower than that of the AFO group by 0.04 m/s. Although this difference was statistically significant, it was not considered clinically significant, since it was not large enough to differentiate between ambulatory classification30; nor did it differ within the range of minimal clinically important differences (MCID) for gait speed established for the stroke population.31,32 The difference in BMI (which was lower in the WA group) was not sufficient to differentiate between BMI categories33 and was not considered clinically significant. These variables were therefore considered balanced in the analyses.
Primary Endpoints The results of the primary efficacy endpoints (gait velocity and SIS composite score) and primary safety endpoint (device-related SAE rate) analyses show the WA to be noninferior to the AFO (values presented in Table 2). No statistically significant between-group differences were observed for gait velocity or SIS composite score. Both WA and AFO groups demonstrated statistically significant improvement in gait velocity from screening to 6 months (P < .001). The between-group difference in mean change in gait velocity was 0.009 m/s (95% confidence interval [CI] = −0.04 to 0.06). Therefore, the WA group was not inferior to the AFO group because the lower CI margin (−0.04) was larger than the margin set for noninferiority (−0.2 m/s). The WA group demonstrated statistically significant improvement from baseline to 6 months on the SIS composite score (P = .05). The between-group difference in mean change in SIS composite score was 1.1 points (95% CI = −1.62 to −0.58). Noninferiority was met for the WA group since the lower CI margin (−1.62) is greater than the noninferiority margin set for this variable (−15 points). Only 2 device-related SAEs were reported in
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Table 1. Subject Demographics and Characteristics at Screening. Characteristics
WA Arm (n = 242)
AFO Arm (n = 253)
P Valuea
63.87 ± 11.33
64.30 ± 12.01
95 (39.26) 147 (60.74)
96 (37.94) 157 (62.06)
0 (0.00) 2 (0.83) 55 (22.73) 0 (0.00) 8 (3.31) 177 (73.14) 6.90 ± 6.43 0.449 ± 0.22 27.62 ± 2.44 7.98 ± 6.32 27.98 ± 4.93
2 (0.79) 3 (1.19) 55 (21.74) 1 (0.40) 5 (1.98) 187 (73.91) 6.86 ± 6.64 0.487 ± 0.21 27.49 ± 2.83 8.08 ± 6.58 29.21 ± 5.08
.681 .764 .560 .956 .050 .574 .864 .006
Age in years, mean ± SD Gender, n (%) Female Male Race, n (%) American Indian/Alaskan Asian Black/African American Hawaiian/Pacific Islander Other White (Caucasian) Time post onset of stroke in years, mean ± SD Gait speed at screening in m/s, mean ± SD Mini Mental Status Examination, mean ± SD Beck Depression Inventory, mean ± SD Body mass index in kg/m2, mean ± SD
Abbreviations: WA, WalkAide functional electrical stimulation system; AFO, ankle-foot orthosis. a P values in boldface indicate statistical significance.
Table 2. Primary Endpoint Analysis. Variable (Mean ± SE)
WA Initial
WA 6 Months
WA Change
WA Versus AFO AFO AFO Initial AFO 6 Months Change Noninferiority Test Inequality Test
10-Meter Walk 0.449 ± 0.014 0.635 ± 0.186** 0.487 ± 0.013 0.682 ± 0.020 0.195** Test (m/s) 0.022 Stroke Impact Scale 170.0 ± 2.7 175.0 ± 2.7 5.0* 168.8 ± 2.6 172.7 ± 2.8 3.9 (SIS) combination score (Mobility, ADL/IADL, and Social Participation Domains) SAEs 0 0 0 0 2 2
δ = −0.2 m/s; P < .0001 δ = −15 points; P < .0001
δ = −3% devicerelated SAE rate; P < .001
0.695 0.568
0.317
Abbreviations: WA = WalkAide functional electrical stimulation system; AFO, ankle-foot orthosis; SE, standard error; ADL/IADL, activities of daily living/instrumental activities of daily living; δ, noninferiority margin; SAE, serious adverse event. Within- and between-group analyses: *P < .05, **P < .001.
the AFO and none in the WA group; therefore, devicerelated SAE rates were not computed (Table 3 summarizes all AEs for the trial with a frequency ≥2%).
Secondary Endpoints: Walking Performance Multiple endpoints were measured to determine the impact of the WA and AFO on walking performance (values presented in Table 4); differences were determined to be significant if P ≤ .001 after Bonferroni correction. Significant within-group differences between baseline and 6 months were noted in the WA group for GaitRite FAP score
(P = .001), total mEFAP time (P < .001), and the mEFAP subtasks of Floor time (P = .001) and Obstacle Course time (P = .001). No significant between-group differences were found for these variables. To demonstrate the effects of changes in gait speed on functional ambulation, the subjects were grouped into functional ambulation categories30 by gait velocity (Supplementary Table 3 [available online at http://nnr.sagepub.com/content/by/supplemental-data] details subject categorization). A McNemar’s test showed statistically significant improvement in ambulation category between screening and 6 months for both groups (P < .001).
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Bethoux et al Table 3. Summary of Adverse Events. Serious AEs Relatedness Related to device Unrelated to device
Total (OR)
AFO (OR)
WA (OR)
2 (0.23) 41 (4.8)
2 (0.23) 16 (1.9)
0 (0.0) 25 (2.9)
Summary of AEs (Total AEs for Trial = 858; 436 in AFO Arm, 422 in WA Arm) Type of Eventa
Total (OR)
AFO (OR)
WA (OR)
Falls Other Pain in lower extremity or back Fatigue or muscle weakness Other medical conditions Skin irritation Muscle soreness
348 (41.0) 423 (49.4) 91 (10.6)
175 (20.4) 235 (27.4) 55 (6.4)
173 (20.2) 189 (22.0) 36 (4.2)
18 (2.1) 315 (36.7) 44 (5.1) 30 (3.5)
14 (1.6) 166 (19.3) 10 (1.2) 15 (1.75)
4 (0.5) 149 (17.4) 34 (3.9) 15 (1.75)
Abbreviations: AE, adverse event; OR, occurrence rate (in percentage) as compared with total number of AEs; WA = WalkAide functional electrical stimulation system; AFO, ankle-foot orthosis. a Events with a frequency ≥2% are reported.
Secondary Endpoints: Balance The impact of the WA and AFO on balance was measured using the BBS and TUG (Table 4). Statistically significant improvement on BBS score was noted for the WA group (P = .001). Neither the WA group nor AFO group exhibited statistically significant improvement in time to complete the TUG. No significant between groups differences were found for these variables.
Secondary Endpoints: Quality of Life The individual SIS domains and the SSQoL test were used as measures of QoL (Table 4). Neither group demonstrated any significant within group improvement for the individual domains of the SIS or for SSQoL score from baseline to 6-month follow-up. No significant between-group differences were found for these variables.
Discussion The results of this RCT confirm that the WA is noninferior to the standard of care AFO for each primary endpoint: (a) gait velocity, (b) SIS composite score, and (c) safety. The occurrence of device-related SAEs was extremely low (2 for AFO and none for WA group), demonstrating that both devices are safe and pose negligible risk to the user. Gait velocity is an important indication of function and level of disability,32 and the primary means of classifying ambulation status after stroke.34 Ambulation categories have also been linked to the impact of stroke on QoL.
Schmid et al34 showed that individuals who transition from one ambulation category to another exhibited meaningful changes in SIS domain scores. MCIDs for gait speed have been reported in the stroke population and range from 0.1 m/s31 to 0.16 m/s.32 Both the WA and AFO groups in this study showed increases in gait speed above the established MCID (0.186 and 0.195 m/s, respectively). The results of this study show increases in gait speed slightly above those noted in the literature. The percentage changes in gait speed were 41.4% for the WA and 40.0% for the AFO group. Hausdorff and Ring9 studied the effects of peroneal nerve FES in 24 subjects with chronic hemiparesis and noted a change in gait speed from baseline to 8 weeks of 34%. Studies by Stein et al7,12 looking at a population of subjects with nonprogressive (cardiovascular accident) and progressive (multiple sclerosis) disorders reported percent increases in gait speed with FES ranging from 32% at 6 months12 to 37.8% at 11 months.7 The changes observed in this study are also slightly above those of Kluding et al17 who found a change in gait speed of 0.14 m/s in the FES group and 0.15 m/s in the AFO group. The Perry ambulation categories use gait speed to classify ambulation status from physiologic to full community ambulation, with categories separated by a maximum change of 0.2 m/s.30 The mean gait speed of both groups fell within the category of most-limited community ambulation at screening. The change in both groups (~0.2 m/s) was sufficient to move these means into the least-limited community ambulation category, representing a significant improvement in community mobility and function. These results indicate that the WA is equivalent to the AFO in
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33.1 −96.0 −12.0 −8.7 −16.0 −42.6 −16.7 5.8 2.6 2.2 3.2 −0.2 −0.6 0.3 0.4 2.7 2.1 2.4 4.5
.002
