Randomised feasibility trial into the effects of low-frequency electrical muscle stimulation in advanced heart failure patients

Objectives Low-frequency electrical muscle stimulation (LF-EMS) may have the potential to reduce breathlessness and increase exercise capacity in the chronic heart failure population who struggle to adhere to conventional exercise. The study’s aim was to establish if a randomised controlled trial of LF-EMS was feasible. Design and setting Double blind (participants, outcome assessors), randomised study in a secondary care outpatient cardiac rehabilitation programme. Participants Patients with severe heart failure (New York Heart Association class III–IV) having left ventricular ejection fraction <40% documented by echocardiography were eligible. Interventions Participants were randomised (remotely by computer) to 8 weeks (5×60 mins per week) of either LF-EMS intervention (4 Hz, continuous, n=30) or sham placebo (skin level stimulation only, n=30) of the quadriceps and hamstrings muscles. Participants used the LF-EMS straps at home and were supervised weekly Outcome measures Recruitment, adherence and tolerability to the intervention were measured during the trial as well as physiological outcomes (primary outcome: 6 min walk, secondary outcomes: quadriceps strength, quality of life and physical activity). Results Sixty of 171 eligible participants (35.08%) were recruited to the trial. 12 (20%) of the 60 patients (4 LF-EMS and 8 sham) withdrew. Forty-one patients (68.3%), adhered to the protocol for at least 70% of the sessions. The physiological measures indicated no significant differences between groups in 6 min walk distance(p=0.13) and quality of life (p=0.55) although both outcomes improved more with LF-EMS. Conclusion Patients with severe heart failure can be recruited to and tolerate LF-EMS studies. A larger randomised controlled trial (RCT) in the advanced heart failure population is technically feasible, although adherence to follow-up would be challenging. The preliminary improvements in exercise capacity and quality of life were minimal and this should be considered if planning a larger trial. Trial registration number ISRCTN16749049

1. Study population: It is necessary to specify the inclusion and exclusion criteria according to recent guidelines.
2. An important limitation is that heart failure diagnosis was not based on natriuretic peptides. 3. Authors should specify the associated comorbidities, echocardiographic findings and baseline natriuretic peptides in Table  1 4. Authors selected 60 symptomatic HFrEF (median age 66 years), overweight .1) with impaired functional capacity by cardiopulmonary exercise testing (CPX) due to shortness of breath or fatigue and NYHA III-IV. However, this is not congruent with the results showed in table 1 where the distance of 6-MWT is 237-337 m. Likewise, previous studies in obese subjects have shown that these individuals display per se a significant impairment of functional capacity. Authors should clarify how many patients exhibit NYHA class II-III -IV and the natriuretic peptides at inclusion. 5. There are important potential confounders that were not evaluated. For instance, there is scarce information about biomarkers. It appears, natriuretic peptides, sodium, renal function, iron deficiency inflammatory biomarkers were not tested in multivariate analysis. 6. The sample size is small (n=30 at each branch) with many dropouts and it should be stated as an important limitation. 7. The patients included have moderate reduction of exercise capacity and it should be stated. 8. Conclusion: Authors define their study population as a wellcharacterized cohort of patients with HFpEF. It should be modified. It is important to remark that an external validation of present findings to the whole spectrum of advanced HFrEF (NYHA III-IV) is questionable because the population included in this study exhibit greater functional capacity than observed in daily clinical practice. In the abstract (on page 2,line 34-35) the conclusion states that 'A larger RCT in the advanced heart failure population is therefore feasible.' I am not convinced as the text in the concluding line (on page 17, line 15) contradicts this. The conclusion of the abstract should reflect the findings which demonstrate that overall recruitment of 35% does not meet the recommended success criteria(page 5, line 143).

REVIEWER
The follow up at 20 weeks ( Fig 1, page 10) was poor and the authors may wish to expand on how they might improve this in a full RCT given that patients with NYHA III/IV have higher rates of morbidity and mortality. In this randomized study authors evaluated the feasibility and effectivity of LF-EMS in patients with heart failure with reduced left ventricular ejection fraction (HFpEF). Authors concluded this study was feasible however it did not show any improvement in functional or QoL in patients with advanced HFrEF. The hypothesis is pertinent and the protocol was meticulous. Authors should be congratulated. The main strength of this finding is that patients with advanced HFrEF can tolerate a home-based LF-EMS program. However, there are some issues that deserve to be commented/clarified.
Thank you, Dr Palau, for your comments on the manuscript. You have drawn our attention to some key issues that we can hopefully respond to in the revised manuscript and/or in the responses below: 1. Study population: It is necessary to specify the inclusion and exclusion criteria according to recent guidelines.
The recently updated ESC guidelines (2016)(2)  2. An important limitation is that heart failure diagnosis was not based on natriuretic peptides See below response 3. Authors should specify the associated comorbidities, echocardiographic findings and baseline natriuretic peptides in Table 1 The diagnosis of heart failure for participants included the use of NT Pro BNP and the cutoff value of >125 pg/ml was satisfied for all participants. We have amended the manuscript to include baseline BNP values considering the recent ESC guidelines which gives confirmation of the severity of our study population. As mentioned in response to the editorial comments, the majority of participants did not have ejection fraction measured by Simpsons biplane due to poor echogenicity and for many, persistent arrhythmia, I.e. fast AF. Instead, eyeball assessments of severe LV dysfunction were provided by an experienced echocardiographer and confirmed by the cardiologist in clinic. A note to this affect has been added to the results section (page 8, BNP at baseline has been included based on this recommendation and should strengthen our study. We have also added a comment in the discussion (page 16, line 373)regarding the high variability (caused by a few outliers) around 6mwt which may explain the higher than expected mean 6mwd at baseline. However, previous studies (3, 4) report <300m as prognostic cutoff in heart failure patients associated with an advanced disease state and so we don't feel that this detracts from our assertion that the study population were representative of the advanced heart failure population. 5. There are important potential confounders that were not evaluated. For instance, there is scarce information about biomarkers. It appears, natriuretic peptides, sodium, renal function, iron deficiency inflammatory biomarkers were not tested in multivariate analysis.
Sodium, creatinine, potassium urea and creatine kinase were measured alongside NT-pro BNP as a safety measure and as the results section states (page 11, line 292) there were no readings that were abnormal requiring any medical intervention. The authors accept that these biochemical markers may have confounded our results and have now added baseline NT pro BNP and creatinine levels for clarity (page 8, table 1). However, while it may be appropriate to include these markers in a larger RCT multivariate analysis, they were deemed outside the scope of this feasibility study.
6. The sample size is small (n=30 at each branch) with many dropouts and it should be stated as an important limitation.
We recognize that the study sample size is small and this is now stated as one of the limitations. Dropouts during the intervention were within the acceptable a priori criteria for retention, although we have inserted further suggestions for improving dropout in follow-up in the discussion section ( We have added a comment stating this to the discussion (page 16, line 373). See earlier response above 8. Conclusion: Authors define their study population as a well-characterized cohort of patients with HFpEF. It should be modified. It is important to remark that an external validation of present findings to the whole spectrum of advanced HFrEF (NYHA III-IV) is questionable because the population included in this study exhibit greater functional capacity than observed in daily clinical practice.
Whilst we accept that our baseline functional capacity was slightly higher than expected, we must reiterate that the patients were classified as eligible based on their clinical diagnosis using all clinical information available at the time by an experienced heart failure cardiologist.
In line with your comments however, we have modified the a sentence in the participants section(page 4, line 113) to make this point clear. Thank you for your review Dr Dalal. We are grateful for your comments and suggestions which we believe are fair and we hope the revised manuscript incorporates your advice.
In the abstract (on page 2,line 34-35) the conclusion states that 'A larger RCT in the advanced heart failure population is therefore feasible.' I am not convinced as the text in the concluding line (on page 17, line 15) contradicts this. The conclusion of the abstract should reflect the findings which demonstrate that overall recruitment of 35% does not meet the recommended success criteria(page 5, line 143).
We accept that our recruitment criterion was narrowly missed in the discussion section, but do not concede that this would completely prohibit a larger trial. However, we have reworded the conclusion of the abstract to mirror the main conclusion The follow up at 20 weeks (Fig 1, page 10) was poor and the authors may wish to expand on how they might improve this in a full RCT given that patients with NYHA III/IV have higher rates of morbidity and mortality.
We have added an extra section in the discussion (page 15, line 351) that makes suggestions regarding improving dropout. The discussion section (on page 15) begins by comparing the poor uptake of the intervention in the trial with poor uptake of CR in the UK. This is not a fair comparison as recruitment and retention in trials of CR are generally better than in the ordinary population. The authors may wish to refer to a recent study by Reeves et al 'A Novel Rehabilitation Intervention for Older Patients with Acute Decompensated Heart Failure-The REHAB-HF Pilot Study' JACC HF 2017) This pilot study also recruited patients with heart failure and multiple morbidities. It may prudent to refer to this study as there are several similarities in the participants and what can be learnt from a pilot RCT.
We accept the point that clinical trials generally have better retention than clinical practice due to extra resource and attention given to this. However, we believe that the uptake to an intervention such as this gives a valid indication of the potential demand for EMS in the heart failure population were it offered routinely.
Thank you for making us aware of the recent study by Reeves et al. We have referenced this paper (page 16, line 373) which we found helpful guiding these amendments. Nevertheless, it should be noted they excluded patients who they deemed at 'risk of 'non-adherence' unlike the pragmatic nature of our trial.
It would be useful to have some idea of the proposed sample size for a full RCT given that the authors state in the introduction that the findings of the pilot 'can be used for sample size calculations' (page 3, line 85) We previously included a sample size calculation and figure in an earlier draft of the manuscript. It was removed due to word and figure limit restrictions. We have reinstated a brief section (without the figure) on page 14 although the amended manuscript now exceeds the recommended word limit. We trust that this is acceptable to the editor?
The findings of this pilot RCT are of interest in informing future research that undertaking a full RCT would be challenging. The authors have acknowledged this but should make it clear in the abstract in light of the relatively minor improvements in their outcomes. Again, it would be worth looking at the effect sizes reported by Reeves et al ( see above) and how they have proceeded to a full RCT.
We have amended the abstract and conclusion of our study to reflect the finding that a larger RCT whilst possible, may not be worthwhile based on the minor improvements observed. The effect sizes from this study are modest in relation to the Reeves study although as mentioned earlier the patients in the Reeves trial were more carefully selected.

REVIEWER
Patricia Palau Hospital General Universitario de Castellón Spain REVIEW RETURNED 21-May-2017

GENERAL COMMENTS
The authors have not addressed most of the concerns I had with the previous submission. Furthermore, there are methodological issues that need to improve (inclusion criteria, exclusion criteria, functional class, echocardiographic findings, other comorbidities, etc.).