Remote blood pressure monitoring and behavioral intensification for stroke: A randomized controlled feasibility trial.

Measuring blood pressure (BP) at home and remote monitoring can improve the patient's adherence to BP control and vascular outcomes. This study evaluated the feasibility of a trial regarding the effects of an intensive mobile BP management strategy versus usual care in acute ischemic stroke patients. A feasibility-testing, randomized, open-labeled controlled trial was conducted. Remote BP measurement, data transmission, storage, and centralized monitoring system were organized through a Bluetooth-equipped sphygmomanometer paired to the participants' smartphones. Participants were randomized equally into intensive management (behavioral intensification to measure BP at home by texting, direct telephone call, or breakthrough visit) and control (usual care) groups. The primary feasibility outcomes were: 1) recruitment time for the pre-specified number of participants, 2) retention of participants, 3) frequency of breakthrough visit calls, 4) response to breakthrough visit call, and 5) proportions satisfying BP measurement criteria. Sixty participants were randomly assigned to the intensive management (n = 31) and control (n = 29) groups, of which 57 participants were included in the primary analysis with comparable baseline characteristics. Recruitment time from the first to the last participant was 350 days, and 95% of randomized participants completed the final visit (intensive, 94%; control, 98%). Eight breakthrough visit calls were made to 7 participants (23%), with complete and immediate responses within 3 ± 4 days. The median of half-day blocks fulfilling the BP measurement criteria per patient were 91% in the intensive group and 83% in the control group (difference, 12.2; 95% confidence interval, 2.2-22.2). No adverse events related to the trial procedures were reported. The intensive monitoring, including remote BP measurement, data transfer, and centralized monitoring system, engaged with behavioral intensification was feasible if the patients complied with the intervention. However, the device utilized would need further improvement prior to a large trial.

RCT Entities:   Population Interventions Outcomes

Introduction

Achieving and maintaining the target blood pressure (BP) in an individual would be one of the top priorities in preventing further vascular events after an ischemic stroke [1]. Sophisticated BP control is now feasible with various antihypertensive medications in the market, but there are still unanswered questions related to BP management.

Most of the current scientific reports are based on the office-measured BP, which is allegedly higher than home-measured BP [2]. Home-measured BP would be a better indicator reflecting the levels and fluctuations of BP in daily life, but scientific hurdles still exist including measurement, transfer, monitoring, and interpretation of remotely assessed BP, as well as subsequent pharmacological modifications. Medication adherence is vital to maintain adequate BP control, but amost half of the hypertensive patients discontinue recommended medications within a year [3]. Moreover, clinical questions regarding BP variability would be answered better through remote collection of frequent home BP measurements than standard office BP measurements.

BP control is the most important intervention for preventing further vascular events in stroke patients, but majority of them have a certain degree of cognitive decline and functional disabilities against actively engaging in traditional instructions [4, 5]. Therefore, they are practical candidates of remote BP collection and monitoring strategy and continuous behavioral motivation with tele-health interventions. Recently, there are many smartphone-based mobile healthcare devices commercially available with the development of communication technology. Many companies offer Food and Drug Administration-cleared or EC Medical-certified wireless BP monitors for tele-medicine or user convenience [6].

Until now, the tele-health strategy encompassing remote BP measurements and collection and behavioral interventions has been tested separately in various social and medical conditions [7-11]. However, self-monitoring alone did not contribute to better BP control and additional behavioral interventions were necessary [12]. In this context, we designed a phase-II feasibility-testing, randomized, open, clinical trial for South Korean ischemic stroke patients. This trial aimed to verify the real-world feasibility of 1) home BP measurements using a Bluetooth-equipped sphygmomanometer paired to a patient-owned smartphone and transferring them to a central sever, and 2) of behavioral interventions for improving BP measurement and control in daily life, and breakthrough calls for any danger signs regarding BP levels and measurements.

Methods

Study design and participants

This study was a multicenter, randomized, open-label, prospective, phase-II feasibility trial to investigate the feasibility and safety of remote BP measurement and transfer system, based on a Bluetooth-equipped sphygmomanometer with centralized monitoring, behavioral intervention, and an antihypertension medication algorithm. Local Institutional Review Boards of recruiting centers approved the trial (SNUBH IRB#, B-1604/343-001) and all the study participants provided written informed consent voluntarily. This trial is registered at clinicaltrials.gov (NCT03024476). The authors confirm that all ongoing and related trials for this intervention are registered. Trial registration was completed after the first trial participant was enrolled due to clerical errors. The trial protocol is accessible at protocol.io (dx.doi.org/10.17504/protocols.io.9nqh5dw). The first trial participant was enrolled on September 27, 2016 and the last participant completed the scheduled follow-up on December 7, 2017. The HEM-9200T, a Bluetooth-equipped sphygmomanometer used in the current trial, is a minor modification of the currently marketed HEM-7311 cleared to market under 510 (k) K133379 with minor button changes and additional Bluetooth Low Energy communication function.

The inclusion criteria were 1) lesion-documented ischemic strokes, 2) age ≥19 years and admitted within 7 days after onset of symptoms, 3) mean systolic BP (SBP) ≥135 mm Hg for two consecutive days and >24 hours after onset of stroke, and 4) capability of using smartphones and a Bluetooth-equipped sphygmomanometer, and understanding trial instructions (Fig 1).

Fig 1

Study profile and subject disposition.

Major exclusion criteria were discharge to other facilities such as a nursing home or rehabilitation center, plans for endovascular interventions or vascular surgery within 3 months after stroke, or any known allergic reaction to olmesartan, amlodipine, or hydrochlorothiazide. Details are provided in S1 Appendix. Among the ischemic stroke patients admitted in the participating centers in the trial period, 4.4% participants were randomized in the current trial (range, 3.1–6.4%).

Randomization and trial procedures

Acute ischemic stroke patients with mean SBP ≥135 mm Hg during the two consecutive days, for >24 hours after onset of stroke, were screened for the trial. Trained research personnel instructed the patients for BP measurement, Bluetooth pairing between private smartphones and sphygmomanometer, and data transfer to the central server.

Screened patients were randomized at the time of discharge into the intensive management and control groups by a random number generator. Intensive management included behavioral intensification strategies such as 1) detailed instructions on regular measurement of BP (≥5 days in a week, ≥2 times a day in the morning and evening, altogether ≥10 times during a week), 2) a short-message service (SMS) through their smartphones to encourage BP measurements as recommended when the participants failed to abide by instructions, and 3) a telephone contact by a trained research personnel and/or a request for a breakthrough visit when the number of BP measurements were ≤6/week or ≥50% of SBP measurements exceeded the pre-defined target range of 110–135 mmHg. Physicians were instructed to follow a pre-specified olmesartan-based prescription algorithm in managing trial participants of the intensive management group (S2 Appendix) [13, 14].

The control group participants were also provided a Bluetooth-equipped sphygmomanometer and instructed to pair it with their smartphones for data transfer. However, behavioral intensification, telephone contacts, breakthrough visit calls, and prescription algorithm were not applied. Although antihypertensive prescription in this group was at the discretion of the responsible physician, olmesartan was the first recommended medication.

Study participants were asked to visit the study clinics at 30 days (± 10 days) and 90 days (±14 days) after randomization. Trial researchers checked BP measurement, connection and transfer status of sphygmomanometer, and adherence to antihypertensive medication. Participants who were requested for a breakthrough call had a specified check-up at each unplanned visit (Fig 2).

Fig 2

Overall trial design.

Measurement and transfer of home-measured BP

The trial organizer purchased a Bluetooth-equipped sphygmomanometer (HEM-9200T, Omron Healthcare, Co Ltd, Kyoto, Japan) and developed an Android application to establish a wireless connection between the smartphone and sphygmomanometer. The sphygmomanometer stored the BP measurements in the internal memory and automatically transferred the data to the in-house application installed on the paired smartphone. The application instantaneously transferred the BP data with date and time of measurements to the remote central server. Trial participants could see their BP data through the Android application and delete any erroneous values (Fig 3).

Fig 3

Remote BP measurement, data transmission, storage, and centralized BP monitoring system.

Trial personnel established and verified individual pairing between the trial participants’ smartphones and the provided sphygmomanometer, and the data transfer from the smartphone to the central server during the screening period. One participant was not randomized due to insecure pairing, possibly due to technical problems of the smartphone (manufacturer, TCL mobile Ltd). After randomization, central trial personnel surveyed all the data transfer to the central server through a central monitoring system and issued a breakthrough call in case of sustained failure of the data transfer, and requested a visit to the outpatient clinics on the next business day. All the participants were asked to bring back the sphygmomanometer during the regular clinic visit. At the breakthrough visit, pairing between the smartphone and sphygmomanometer was checked; if this was not possible, then the BP data were registered manually. When data transmission failure occurred in the control group, the stored BP measurements during the failure period were downloaded directly from the device.

Definitions of trial endpoints and criteria for success

As a phase-II trial, the primary feasibility endpoints of the current trial were as follows: 1) recruitment time of the pre-specified number of participants, 2) retention of included participants, 3) frequency of breakthrough visit calls, 4) number of patients responding to the breakthrough visit calls, and 5) proportion of patients fulfilling the criteria of BP measurement. Criteria for success are provided in Table 2 with the results of the primary endpoints. Secondary feasibility/efficacy endpoints were as follows: 1) average proportion of out-of-range (OOR) measurements, 2) weighted average proportion of OOR measurements (two-fold weights for consecutive OOR values), 3) vascular events including recurrent stroke, myocardial infarction, and any cause of death. Secondary safety endpoints included: 1) dizziness, fall, orthostatic hypotension, or any low BP-related events, 2) other adverse events potentially related to high or low BP, and 3) mortality (S3 Appendix).

Table 2

Results of primary endpoints and criteria for success of feasibility.

Primary endpoints	Intensive management group (n, 31)	Control group (n, 29)	Difference (95% CI)	Success criteria 1	Decision for success
Recruitment time to prespecified number of subjects (days)	328	340	N/A	10 months	Fail
Retention of included participants (n, %)	29 (94%)	28 (97%)	-3.00% (-14.21, 8.21)	90%	Pass
Total number of frequency of calls for breakthrough visit (n) 2	8	N/A		20	Pass
Breakthrough visit response (n, %)	8 (100%)	N/A		95%	Pass
Days between calls and visit (day)	2 [0, 3]			3 days	Pass
Compliance to BP measurements (n, %)	31 (100%)	26 (90%)	10.34% (-1.36, 22.05)	90%	Pass
Duration of transmission failure per subject (day) 3	0 [0, 0]	0 [0, 1]	-4.53 (-9.72, 0.66)	3 days	Pass
Percentage of half-day blocks satisfying BP measurement criteria per patient 4	91% [76, 97]	83% [65, 90]	12.22 (2.2, 22.24)	80%	Pass

Values presented as median [interquartile range], frequencies (percentages), or number.

1 Pass if the estimate exceeds the success criteria

2 Eight breakthrough visit calls were issued to 7 subjects (23%).

3 Mean ± SD, 0.7 ± 2.2 (intensive) versus 5.2 ± 13.5 (control)

4 P = 0.02 by Mann-Whiteney's U-test

Sample size

The sample size for the trial was based on feasibility considerations, because this trial focused primarily on determining feasibility of the main future trial. We aimed to recruit 60 patients who were randomized into two group (n = 30 per group). This number is within the recommended sample size for pilot or feasibility trials [15, 16].

Statistical analyses

Feasibility or efficacy outcomes were evaluated using the intention-to-treat (ITT) as well as per-protocol (PP) analysis sets, and safety endpoints were examined using the safety analysis population. Demographics and baseline characteristics are presented by groups and are reported as mean (± standard deviation [SD]) or median (interquartile range) for continuous variables and count (percentage) for categorical variables. Feasibility or efficacy outcomes collected only from the intensive management group were summarized as numbers and percentages with 95% confidence intervals (CI). Mixed model for repeated measures analysis was performed to examine changes in mean SBP or diastolic BP (DBP) measurements across follow-up weeks after randomization. In this analysis, a center effect was adjusted as a random factor. Due to a non-significant interaction between the study group and elapsed weeks from randomization, a test for equality as well as linear trend of mean SBP or DBP variables across weeks were performed for all participants (S2 Table).

All the statistical analyses were performed using the SAS 9.4 (SAS Institute, Cary, NC, USA) with a two-sided test, and statistical significance set at alpha = 0.05.

Results

Sixty ischemic stroke patients hospitalized in the three participating centers were randomly assigned to the intensive management group (n = 31; 52%) and the control group (n = 29; 48%). Three participants withdrew their consent during follow-up. One participant from the control group violated the exclusion criteria after randomization and was included in the ITT dataset, but removed from the PP analysis. Primary feasibility endpoints were collected for 57 participants (29 from the intensive management group and 28 from the control group).

The two groups were comparable for demographics, vascular risk factors, and stroke characteristics (Table 1). Hypertension was diagnosed in 46 participants (21 [68%] and 25 [86%] in the intensive management group and control group, respectively), and antihypertensive medication before the index stroke was prescribed in 27 participants (12 [39%] and 15 [52%] in the intensive management group and control group, respectively).

Table 1

Characteristics of the patients at baseline.

	Intensive management group (n, 31)	Control group (n, 29)
Male sex: n (%)	19 (61%)	20 (69%)
Age (yeas): Mean (SD)	60 ± 12	56 ± 10
Vascular risk factors: n (%)
Hypertension	21 (68%)	25 (86%)
Antihypertensive medication before stroke	12 (39%)	15 (52%)
Diabetes mellitus	5 (16%)	9 (31%)
Hyperlipidemia	6 (19%)	5 (17%)
Smoking	12 (39%)	11 (38%)
Atrial fibrillation	2 (6%)	4 (14%)
Stroke information
Stroke mechanism (TOAST): n(%)
Large artery atherosclerosis	15 (48%)	9 (31%)
Small vessel occlusion	8 (26%)	13 (45%)
Cardioembolism	2 (6%)	4 (14%)
Other determined etiology	2 (6%)	0 (0%)
Undetermined etiology	4 (13%)	3 (10%)
Baseline NIHSS score	1 [0, 4]	2 [1, 2]
Prestroke dependency (mRS score ≥1)	2 (6%)	2 (7%)

Primary feasibility endpoints of the trial

Results of primary feasibility endpoints and their success criteria are presented in Table 2. Recruitment time from inclusion of the first trial participant to the final one was 350 days (S1 Fig). Among the randomized participants, 95% completed the final visit at 3 months after randomization (intensive group, n = 29 [94%]; control group, n = 28 [97%]. Eight breakthrough calls were requested to 7 participants (23%) in the intensive management group. Breakthrough calls were issued because of BP measurement transmission failure (n = 1.13%), elevated BP levels (n = 6.75%), and BP lower than the target range (n = 1.13%). Intervals from the breakthrough calls to visits were median 2 days (maximum 11 days). Results of the PP analyses are provided in the S2 Table.

The mean durations (±SD) of BP collection were 84.2 ± 20.0 days for the intensive management group and 88.7 ± 13.9 days for the control group. Transmission failure was observed in 5 participants (16%) of the intensive group and 8 (28%) of the control group, for mean (± SD) 0.7 ± 2.2 days in the intensive group and 5.2 ± 13.5 in the control group. The median (interquartile range) of blocks per patient that satisfied the criteria of BP measurements was 91% (76, 97) in the intensive group and 83% (65, 90) in the control group (difference, 12.2%; 95% CI, 2.2–22.2; P = 0.02 using Mann-Whitney's U-test; S1 Table). Mean BP levels were similar in both the groups over the trial period, irrespective of the ITT and PP population (Fig 4; S3 Table).

Fig 4

BP measurements during trial period.

Of all the primary endpoints, only the recruitment time for the pre-specified number of patients failed to reach the success criteria for feasibility. The intensive management group passed the success criterion with respect to compliance of BP measurement, duration of transmission per participant, and proportions of half-day blocks per patient fulfilling the criteria of BP measurements, but the control group did not (S4 Appendix).

Secondary feasibility and safety endpoints of the trial

The proportion of outliers, defined as a proportion of measurements being OOR for SBP values, was comparable between the two groups (intensive group, 0.4 ± 0.2%; control group, 0.4 ± 0.2%). Weighted proportion of SBP outliers was also similar (intensive group, 0.7 ± 0.3%; control group, 0.7 ± 0.4%). The occurrence of outliers above or below the recommended SBP range was not different (S5 Appendix) and rates of vascular events were comparable (Table 3).

Table 3

Secondary outcomes of the trial.

	Intensive management group (n, 31)	Control group (n, 29)	Differences (95% CI)
Secondary efficacy endpoints
Average proportion of OOR measurements (%)	41 ± 17	43 ± 19	-1.76 (-10.92, 7.41)
Weighted average proportion of OOR measurements	66 ± 33	67 ± 35	-0.58 (-18.06, 16.9)
Vascular events
Recurrent stroke	2 (6%)	1 (3%)	3.00% (-46.38, 52.38)
Myocardial infarction	0	0
All kinds of death	0	0
Secondary safety endpoint†
Any adverse event	4 (13%)	5 (17%)	-4.34% (-50.98, 42.31)
Serious adverse event	3 (10%)	3 (10%)	-0.67% (-48.70, 47.36)
Mortality	0	0

Values presented as means ± standard deviations, frequencies (percentages), or medians [interquartile ranges].

Adverse events during the clinical trial were detected in 4 (13%) and 5 participants (17%) of the intensive management and control groups, respectively. In the intensive management group, no event related to the trial procedures was documented. In the control group, possible associations were suspected in one case of headache and one case of edema, but both of them were mild and the participants continued to participate in the trial. Serious adverse events were reported in 3 participants (10%) in the intensive group and 3 participants (10%) in the control group, but no relationship with the trial procedures was established (S4 Table). No participant was withdrawn from the trial due to occurrence of adverse events, and no mortality was reported.

Prescribed antihypertensive medications were well tolerated and compliance with the recommended algorithm was acceptable (S5 Table). Data on individual BP measurements are provided in S2 Fig.

Reliable connection between the sphygmomanometer and the central system

Unexpected and unexplained technical failures occasionally occurred during the trial period. One participant was removed from the trial before randomization due to the unrecoverable failure in establishing Bluetooth pairing. After randomization, following incidences were reported and BP measurements had to be manually registered: unpaired device after Android operating system upgrade (n = 1), permanent failure in pairing of the sphygmomanometer and smartphones (n = 6), and intermittent unpairing but spontaneous recovery (n = 12). The sphygmomanometer was not portable and participants who travelled frequently had to record their BP manually. The trial participants were recommended to be the sole users of the Bluetooth-equipped sphygmomanometer, but there was no way to guarantee that.

Discussion

For the current phase-II feasibility trial, we developed a wireless BP measurement, transmission, storage, and monitoring system using a Bluetooth-equipped sphygmomanometer paired to the participants’ smartphones. Ischemic stroke patients were randomized into the intensive management and control groups to test whether this system with the behavioral intensification strategy for BP measurement and control was feasible in the real-world clinical practice. Therefore, we have documented that the inclusion and retention of trial participants proceeded as expected and the response rate of breakthrough visit calls was complete. The Bluetooth-based wireless BP collection system faced mechanical failure frequently and required centralized monitoring and technical interventions. Behavioral intensification, including SMS and telephone calls, increased the frequency of BP measurements. However, we did not document any improvement in BP control in the intensive management group as compared to the control group.

We have proved the feasibility and safety of the wireless BP measurements, transmission, storage, and monitoring system based on a Bluetooth-equipped sphygmomanometer with behavioral intensification in ischemic stroke patients. Among the ischemic stroke admissions in the trial period, 4.4% patients were randomized in the current trial. Elevated BP levels are associated with increased risk of recurrent ischemic events in stroke patients [17]. Stricter control of hypertension can be started by increasing the frequency of BP measurements [18], and recently published guidelines recommend home BP monitoring and modification of antihypertensive medications accordingly [2]. Ischemic stroke patients with limited access to home BP monitoring, due to physical and cognitive disability, need additional attention in the provision of technical support [19, 20] for the application of our trial results. We used a pre-specified prescription algorithm of BP-lowering medication based on olmesartan, which was well tolerated. Additionally, BP control could be a feasible and practical area of tele-medicine [21]. With an emergent back-up system, such as breakthrough visit calls, Bluetooth-based data transfer and centralized monitoring system could work even for other health systems and disease entities.

Securing reliable connection for data transmission and storage between the trial participants and central server is a key component of the tele-health system [22]. The trial investigators tried to build a readily applicable technical system to collect, transfer, and store remotely measured BP data, and thereby adapted the Bluetooth technology that is prevalent and mature in the market [23, 24]. However, we experienced unexpected technical obstacles during the clinical trial, mostly due to improper functioning of the smartphone in conveying BP data to the central server. The smartphone application experienced one major upgrade and 72 minor modifications during the trial period. Future trials need to consider the instability of such a system, and try and establish a direct connection between the sphygmomanometer and data storage system via technology [25].

We issued breakthrough visit calls to trial participants in cases of data transmission failure and sustained BP outliers. Those calls received immediate and complete responses, suggesting that traditional medical interface would be a helpful back-up tool even in the era of tele-medicine. In this trial, there was no evidence regarding the effect of pre-specified BP-lowering medication algorithm, which could be due to the shorter trial duration. No adverse events related to this algorithm were reported.

The objective of the current trial was to prove the feasibility of remote BP collection/monitoring system and behavioral intensification strategy; hence, it was not adequately powered to document differences in BP control or clinical outcomes. The duration of our trial was limited to 90 days. We could not show any difference in BP control between the two groups. Since we utilized smartphones and Bluetooth-equipped sphygmomanometers, trial participants would have been younger, intellectual, and with milder stroke severity. Although we had randomized the participants, the control group may have been motivated to measure their BP more frequently. Providing a sphygmomanometer itself may have worked as a behavioral stimulus. We had to exclude severe stroke patients who were likely to need long-term care facilities. We cannot entirely exclude a chance of sharing the sphygmomanometer among family members although we explicitly discouraged that. The non-portability of BP monitors could discourage potential participants and manual recording of BP at home could be prone to errors. For future clinical trials, adoption of a user identification technology should be considered [26]. The trial comprised of ethnic and cultural Korean population, and the behavioral intervention and smartphone technology may not be applicable to other countries [27].

Several practical points are worthy of discussion for future trials or researches. Future implementation of a similar remote system should comply with the local regulations regarding security of data storage and transmission. The data server in this trial was physically separate from the hospital information system. Smartphones are widely used, but the elderly usually face difficulties in using and manipulating smartphones. Interfaces between smartphones and wireless healthcare devices, including BP monitors, could be difficult for them. To overcome the issue of technological illiteracy, a consumer-friendly user interface design such as iHealth Labs could be helpful.

Conclusion

This phase-II randomized clinical trial proved the feasibility and safety of the intensive monitoring system, comprising of wireless home BP measurement, transfer, storage, and monitoring system and behavioral intervention, to improve BP measurement and control in acute ischemic stroke patients. However, technical considerations are important to establish secure connection for BP data transmission dependent on a smartphone. We also documented that the tele-medicine system still requires human interface to overcome technical failures and sustain behavioral changes for motivation. The tele-health system, as applied in the current trial, has not been perfected to the point that it did not require intense monitoring and adjustment by humans. Therefore, although the feasibility of the tele-health system in BP control of stroke patients has been documented and even if patients complied with the intervention, the system itself would certainly need to be perfected before any larger scale trials are considered.

CONSORT 2010 checklist of information to include when reporting a pilot or feasibility trial*.

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CONSORT 2010 checklist of information to include when reporting a pilot or feasibility randomized trial in a journal or conference abstract.

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Detailed selection criteria.

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Suggested prescription algorithm of blood pressure-lowering medication.

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Details of trial endpoints: Half-day blocks and weighted average proportion of blood pressure measurement outliers.

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Details on failure to reach success criteria for feasibility.

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Blood pressure measurement outliers.

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Recruitment time to pre-specified number of participants by recruiting center.

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Individual blood pressure plot.

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Anonymized dataset and data dictionary.

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Proportion of patients fulfilling the criteria of blood pressure measurement.

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Primary and secondary outcomes of the trial from per-protocol population.

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Average blood pressure measurements during the trial.

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Adverse events.

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Compliance of study drugs.

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22 Oct 2019

PONE-D-19-21291

Remote Blood Pressure Monitoring And Behavioral Intensification for Stroke: A Randomized Controlled Feasibility Trial

PLOS ONE

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have reported an excellent method for the remote BP measurement in ischemic stroke patients and demonstrated that it is feasible and safe. The study and its design is appropriate and the results have been well analysed.

The following minor suggestions are provided to make the manuscript more appealing for the readers.

1. The authors should add a relevant recent ref. for smartphone based mobile healthcare devices in the introduction.

Vashist, S. K., & Luong, J. H. T. (2019). Commercially Available Smartphone-Based Personalized Mobile Healthcare Technologies. In Point-of-Care Technologies Enabling Next-Generation Healthcare Monitoring and Management (pp. 81-115). Springer, Cham.

2. The authors should menton about the regulatory status of the Bluetooth-equipped sphygmomanometer (HEM-9200T, Omron Healthcare, Co Ltd, Kyoto, Japan) whether it is FDA and/or CE certified. Do the authors know whether the device has been checked for its equivalence to a clinically-validated predicate device for BP measurement?

3. If there are any limitations of the approach or the mobile healthcare technology involved, these need to be clearly reported in discussion. The most critical is the interface of the commercial mobile healthcare devices to the regulatory healthcare information systems (HIS) being used in healthcare. The second is the security of the data.

4. Some companies such as iHealth have developed dedicated softwares such as iHealth Pro in which they can integrate data from several mobile healthcare devices used by patients directly into a single software that can be easily viewed by doctor and easy to integrate with HIS. The authors should comment on this and discuss it in the discussion section.

5. The most significant advantage of mobile healthcare is the significantly reduced healthcare monitoring and management costs and more compliance expected from the patients together with their comfort and reduced time spent in clinics for follow ups. It would be useful if authors can comment on this imp aspect.

Reviewer #2: Authors present a report of a feasibility trial testing an intervention comprising of remote BP monitoring and behavioral intensification involving 60 ischemic stroke survivors. This report is well written and presents the data in a coherent manner. I wonder why it took a bit of time to reach sample size in reasonable time from 3 study sites.

Figure 4, week 15 systolic BP bar plot for the intensive group does not have confidence intervals showing in the figure.

No other comments

Reviewer #3: This study tested the feasibility of a trial for effects of a mobile BP management strategy vs. “usual care” for patients with acute ischemic stroke. Sixty participants were assigned randomly to intensive management or control groups. Five primary feasibility outcomes were examined, with 57 participants included in the primary analysis.

The authors are to be commended for presenting an exhaustive review of the trial findings; the study was obviously very well planned, and conducted and documented with great care. While the writing could benefit from careful review by a native English speaker to correct a number of minor grammatical errors, overall the results are clearly presented, and they are presented in an impressive amount of detail.

I do have some comments and suggestions that I believe would improve this manuscript; these are primarily related to the way certain aspects of the study are reported and the conclusions that have been reached.

1. The authors are actually varying two things in this study: (1) the monitoring system with or without fairly intensive support and (2) prescribed vs discretionary hypertension treatment. While the “control” group is receiving “usual care” in terms of being treated at the discretion of their physician, I am assuming that being given home monitoring equipment is not “usual” for ischemic stroke patients, so “usual care” isn’t really correct. This should be made more clear. Had a difference in BP management been observed, I’m not sure if the authors would have been able to differentiate the effects of intense monitoring from effects of differences in BP treatment. The authors should explain/justify why the treatment strategies were different for the two groups. This was either their decision, or they had no choice. Either way, this should be explained/justified.

2. Recruiting took a very long time, and did not meet the authors’ "success criteria." Since a larger trial would require an even larger cohort, it would be helpful if the authors discussed why they felt this was a problem and what they think might be done about it. The authors state that only 4.4% of patients with ischemic stroke during the time of the study were randomized, but the screening figure only gives information on those who were actually screened. Was the problem the fact that the eligibility criteria ruled out the majority of stroke patients, perhaps due to lack of technical ability? What percentage of the other 95.6% were actually eligible? How many eligible patients were approached and declined? How many would have been eligible except for a lack of technical skill? This information will be valuable in planning future recruiting efforts.

3. The authors state in the Results that “Unexpected and unexplained technical failures infrequently occurred during the trial period” but in the Discussion say “The Bluetooth-based wireless BP collection system faced mechanical failure not infrequently and required centralized monitoring and technical interventions.” Is the statement in the Results section incorrect?

4. It is not clear to me what happened if there was transmission failure in the control group. (Intervention group received breakthrough calls, but not the control group). The paragraph on technical failures does not differentiate by group; how were technical problems dealt with in the control group? Does this account for the difference in duration of transmission failure per subject/day (Table 2)?

5. It seems like the issue of non-portability is another limitation that should be discussed, as it could discourage potential subjects from wanting to participate. Having to record things manually while away from home would be prone to error.

6. I feel that the authors have focused the discussion section largely on their conclusion that they have proved feasibility; however, I wonder whether feasibility has really been proven. Based on the evidence presented, the authors have overstated the conclusions (i.e., proven feasibility) of conducting such a study on a larger scale. As the authors themselves state, “securing reliable connection…would be a key component. However, we have experienced unexpected technical obstacles…the smartphone application experienced one major upgrade and 72 minor modifications. Future trials need to consider the instability of such system.” This does not sound like a system that is “ready for prime time.” A more appropriate conclusion would be that, as designed, the system has not been perfected to the point that it did not require intense monitoring and adjustment. Therefore, the system itself would certainly need to be perfected before any larger scale trials could be considered. The authors conclude that BP control in the intensive management group did not improve over that in the control group. However, the performance from a technical standpoint WAS improved by intensive management. While the conclusion of “no difference” between intense and no management may be true for BP control, isn’t the more important point that intense management was needed to make the system work accurately at all? In the interest of performing future trials, I think that it would have been much more helpful if the discussion were focused on what didn’t work, and why, and how to fix it, rather than emphasizing the positive features of the trial and concluding that feasibility had been proven. There is a lot of valuable and important information here, but I don't think the authors have presented it in the most accurate or helpful light.

Minor comments:

• While the individual BP plots are beautiful and impressive, they really aren’t needed here, and take the focus away from the more important problems the investigators faced.

• The authors describe response to breakthrough times as “immediate”; however, in 4/7 cases, the response was delayed by 3 or more days, which in a short trial, could result in a sizeable loss of data. Again, be more realistic here; it is more helpful to look at the individual data and discuss where problems existed and why, than to make a judgment based on median delay which is indeed short.

• The percentage of half-day blocks reported for the intensive management group in Table 2 has a 95% confidence interval of 60% to 112%. This strongly implies that the data are not normally distributed and should not be summarized with a mean and sd or compared to a mean “success criteria.” A more meaningful standard would be to set the success criteria at or above a certain percentile (75th? 90th?), and evaluate the data with non-parametrics.

• This is also the case for duration of transmission failures. Please use non-parametric standards.

Overall, this is a very nice piece of work. Obviously a lot of time was spent summarizing a great deal of data quite beautifully. I think the study is very interesting, but I do feel like the authors failed in the discussion to really address the more interesting and more important aspects of their trial in sufficient detail. There were definitely some major problems in terms of feasibility, and the discussion would be much more valuable to future researchers (and realistic) if the authors addressed these. Information on why something ISN'T feasible is just as important (if not more so) than a (questionable) conclusion that it is.

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Reviewer #1: No

Reviewer #2: Yes: Dr. Fred Stephen Sarfo

Reviewer #3: No

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4 Dec 2019

Respond to reviewers is prepared as a PDF format.

Submitted filename: BOSS Trial_PLoS One_17_Response to Reviewers.pdf

Click here for additional data file.

27 Dec 2019

PONE-D-19-21291R1

Remote Blood Pressure Monitoring And Behavioral Intensification for Stroke: A Randomized Controlled Feasibility Trial

PLOS ONE

Dear Dr Kim,

Thank you for submitting your revised manuscript to PLOS ONE and for your careful attention to the reviewer comments. After careful consideration, we feel that it has merit but still does not fully meet PLOS ONE’s publication criteria as it currently stands. Specifically, I think Reviewer 3 makes a valid point about overstating your conclusion in both the abstract and main paper and you may think about using their suggested wording instead. The phrasing and grammar of the text would also benefit from attention and you may wish to get a native English speaker to revise it. Therefore, we invite you to submit a revised version of the manuscript that addresses these points. ​

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: N/A

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: (No Response)

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have addressed all the review comments. The revised draft can be accepted for publication.

Reviewer #3: I thank the authors for their careful consideration of my comments and the manner in which they have been addressed. This is a small point, but I still feel that the conclusion as stated in the abstract and discussion (and conclusion) should be tempered to reflect that the authors have not proven feasibility with the tested system, as it is "not feasible" to give patients a device that requires so much maintenance. Perhaps a more cautious conclusion would be that intensive monitoring in itself was feasible, insofar as patients complied with the intervention, but that the device utilized would need to be improved prior to a larger trial.

Also, the paper still needs some work grammatically.

**********

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Reviewer #1: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

29 Jan 2020

January 29th, 2019

Dear reviewers and editorial staffs of PLoS One;

We would like to thank the reviewers and editor for their positive evaluation and obliging suggestion on our manuscript. We provide responses to the reviewers’ comments below. Responses will follow the verbatim of reviewers’ comments (blue color). Additionally, we modified several sentences to make our point clearer. All the changes were specified in the marked version of our draft.

Reviewer #3;

I thank the authors for their careful consideration of my comments and the manner in which they have been addressed. This is a small point, but I still feel that the conclusion as stated in the abstract and discussion (and conclusion) should be tempered to reflect that the authors have not proven feasibility with the tested system, as it is "not feasible" to give patients a device that requires so much maintenance. Perhaps a more cautious conclusion would be that intensive monitoring in itself was feasible, insofar as patients complied with the intervention, but that the device utilized would need to be improved prior to a larger trial.

Also, the paper still needs some work grammatically.

Editorial staffs;

Specifically, I think Reviewer 3 makes a valid point about overstating your conclusion in both the abstract and main paper and you may think about using their suggested wording instead. The phrasing and grammar of the text would also benefit from attention and you may wish to get a native English speaker to revise it. Therefore, we invite you to submit a revised version of the manuscript that addresses these points.

We appreciate the reviewer #3's considerate suggestion on the conclusion and perspectives of our study results. After contemplation and along with the editor's advices, we concluded both abstract and main text with your wording.

Conclusion section of the abstract;

The intensive monitoring, including remote BP measurement, data transfer, and centralized monitoring system, engaged with behavioral intensification was feasible if the patients complied with the intervention. However, the device utilized would need further improvement prior to a large trial.

Conclusion section of the main text;

This phase-II randomized clinical trial proved the feasibility and safety of the intensive monitoring system, comprising of wireless home BP measurement, transfer, storage, and monitoring system and behavioral intervention, to improve BP measurement and control in acute ischemic stroke patients. However, technical considerations are important to establish secure connection for BP data transmission dependent on a smartphone. We also documented that the tele-medicine system still requires human interface to overcome technical failures and sustain behavioral changes for motivation. The tele-health system, as applied in the current trial, has not been perfected to the point that it did not require intense monitoring and adjustment by humans. Therefore, although the feasibility of the tele-health system in BP control of stroke patients has been documented and even if patients complied with the intervention, the system itself would certainly need to be perfected before any larger scale trials are considered.

Submitted filename: BOSS Trial_PLoS One_27_Response to Reviewers.pdf

Click here for additional data file.

10 Feb 2020

Remote Blood Pressure Monitoring And Behavioral Intensification for Stroke: A Randomized Controlled Feasibility Trial

PONE-D-19-21291R2

Dear Dr. Kim,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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Antony Bayer

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

25 Feb 2020

PONE-D-19-21291R2

Remote Blood Pressure Monitoring And Behavioral Intensification for Stroke: A Randomized Controlled Feasibility Trial

Dear Dr. Kim:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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PLOS ONE