Efficacy of remote ischemic conditioning on blood pressure in essential hypertension in China (RICBP-EH): a randomised, controlled, parallel-group trial

Summary

Background

Inadequately controlled hypertension is a major global public health challenge. This study aimed to explore whether remote ischemic conditioning (RIC), a type of heart- and brain-protection treatment, could be used as an adjunctive therapy for people with poor blood pressure (BP) control.

Methods

This was a randomised, single-blinded, parallel-controlled trial conducted at a single centre in Changchun, China. Patients with clinically diagnosed essential hypertension and systolic blood pressure (SBP) ≥140 mm Hg, including those with SBP ≥140 mm Hg even after treatment or those who do not receive any treatment, were enrolled. Enrolled participants were randomly allocated (1:1) to either RIC or sham RIC for 7 days. Sitting BP was measured twice daily (morning: between 6:00 and 9:00; evening: between 18:00 and 21:00) from the day before treatment to the last day (8 days, 16 measurements). Blood pressure variability (BPV) was also calculated. The primary endpoint was the difference in average SBP during treatment (7 days, 14 measurements). Adverse events were recorded during the study period. The intention-to-treat analysis included all participants who were randomly assigned to a study group. This trial is registered with ClinicalTrials.gov, NCT05910242.

Findings

Between June 20, 2023, and March 6, 2024, 102 patients completed the study (n = 51 per group). In the intention-to-treat analysis, the average SBP during treatment was lower in the RIC group than the sham RIC group (143·3 ± 10·0 vs. 147·6 ± 6·3 mm Hg; baseline adjusted between-group difference: −4·8 mm Hg [95% CI, −6·9, −2·7 mm Hg]; P < 0·001). The trend of overall SBP (the daily average of morning and evening SBP) over time was significantly different between the two groups (F = 4·316, P < 0·001, group-by-time-interaction). The reduction degree of overall SBP at day 7 was larger in the RIC group than in the sham RIC group (−5·1 ± 8·1 vs. 2·0 ± 7·8 mm Hg; between-group difference: −7·2 mm Hg [95% CI, −10·3, −4·0 mm Hg]; P < 0·001). Additionally, no significant differences were observed in the number of adverse events between the two groups, and no major adverse events occurred.

Interpretation

Our findings suggest that RIC treatment can safely and effectively reduce BP in patients with essential hypertension who have SBP ≥140 mm Hg, regardless of whether antihypertensive drugs are applied or not. This finding provides a safe and effective antihypertensive strategy for treating essential hypertension in patients with poor BP control. However, further research is warranted to explore the mechanisms underlying the BP-lowering effects of RIC deeply.

Funding

National Natural Science Foundation of China, Science and Technology Department of Jilin Province, Jilin Provincial Key Laboratory, the Norman Bethune Health Science Center of Jilin University, the Talent Reserve Program of the First Hospital of Jilin University, and the Science and Technology Research Program of the Education Department of Jilin Province.

Research in context.

Evidence before this study

We searched PubMed for articles published, in any language, from database inception to July 10, 2025, using search terms (including but not limited to): “hypertension,” “blood pressure,” and “remote ischemic conditioning.” We also reviewed the references. Three case reports and one clinical trial were identified, and the results suggest that remote ischemic conditioning (RIC) has a blood pressure (BP)-lowering effect on patients with prehypertension or hypertension without antihypertensive drug use. However, there are still some patients whose BP remains uncontrolled despite taking antihypertensive medications, and the BP-lowering effect of RIC on this population remains unclear. We aimed to fill this knowledge gap.

Added value of this study

Compared with previous studies and to the best of our knowledge, our study is the first to include patients whose BP remains uncontrolled despite taking antihypertensive drugs. This randomised, single-blinded, parallel-controlled trial (NCT05910242) conducted at a single centre in Changchun, China showed that the average SBP during treatment was lower in the RIC group (n = 51) than the sham RIC group (n = 51) (143·3 ± 10·0 vs. 147·6 ± 6·3 mm Hg; baseline adjusted between-group difference: −4·8 mm Hg [95% CI, −6·9, −2·7 mm Hg]; P < 0·001). No significant differences in safety outcomes were noted between groups. These results address the knowledge gap we identified and validate the antihypertensive effect of RIC in a broader population, offering hope for its use as an adjunctive treatment to antihypertensive drugs.

Implications of all the available evidence

Our findings have significant clinical implications for patients who refuse to take antihypertensive medications, have poor drug responses, or exhibit drug intolerance. Given that our findings showed that RIC treatment can safely and effectively reduce BP in patients with essential hypertension who have SBP ≥140 mm Hg, regardless of whether antihypertensive drugs are applied or not, RIC could be a safe and effective antihypertensive strategy for treating essential hypertension in patients with poor BP control. However, further research is needed. Currently, we have initiated a multicentre clinical trial to investigate the long-term efficacy of RIC in patients with essential hypertension. Future studies should further explore the mechanisms underlying the BP-lowering effects of RIC.

Introduction

Hypertension persists as the leading risk factor for cardiocerebrovascular disease worldwide, and is associated with 13·5% of deaths annually.¹ Lowering blood pressure (BP) is considered as an effective measure for preventing cardio-cerebrovascular events.² Although antihypertensive drugs and lifestyle changes are widely recommended, only 21% of the patients with hypertension worldwide achieve effective BP control.³ Unresponsiveness to antihypertensive drugs, significant side effects of combined medication, and patients' lack of attention to lifestyle changes, among others, may lead to poor BP control. Therefore, it is necessary to seek a novel and easily executable treatment to assist existing treatments in lowering BP.

Remote ischemic conditioning (RIC) represents a novel and non-invasive physical therapy that typically involves repetitive inflation-deflation of the distal limb to protect organs (eg, the heart, brain, and kidneys) through neural, humoral, and immune regulation.4, 5, 6, 7, 8, 9, 10 Theoretically, these mechanisms of action may facilitate the regulation of BP through multiple pathways. Preclinical studies have shown that RIC can reduce BP and ameliorate vascular remodelling by regulating inflammation in spontaneously hypertensive rats.^11,12 Some case reports have suggested that RIC may have a hypotensive effect in normotensive or prehypertensive individuals.^13,14 Recently, a clinical study showed that RIC can lower BP in patients with hypertension who were in the absence of antihypertensive medication.¹⁵ However, there is still a large proportion of patients who do not achieve adequate BP control despite medication use, and the antihypertensive effects of RIC in these patients remain uncertain.

We aimed to investigate the effects of RIC in patients with essential hypertension who were either untreated or still had systolic BP (SBP) ≥140 mm Hg despite antihypertensive medication use.

Methods

Study design and ethics

This RICBP-EH study (Efficacy of Remote Ischemic Conditioning on Blood Pressure in Essential Hypertension) enrolled 102 patients with essential hypertension at the First Hospital of Jilin University, Changchun, China, between June 20, 2023, and March 6, 2024, using a randomised, single-blinded, endpoint-blinded, parallel-controlled design. Patients were randomised to the RIC or sham RIC groups. Primary and secondary outcomes were assessed after the 7-day intervention.

The trial protocol was designed following CONSORT 2010 guidelines, approved by the Ethics Committee of the First Hospital of Jilin University (23K038), and was prospectively registered on ClinicalTrials.gov (NCT05910242). All patients provided written informed consent to participate and had the right to withdraw from the study at any time. This study adhered to the Declaration of Helsinki. The full protocol and statistical analysis plan can be found in Supplemental Materials.

Participants

The inclusion criteria were as follows: (1) age ≥18 years, male or female, (2) patients with clinically diagnosed essential hypertension and SBP ≥140 mm Hg, including those with SBP ≥140 mm Hg even after treatment or those who do not receive any treatment. The key exclusion criteria were secondary hypertension and office BP ≥ 180/110 mm Hg or 24-h average BP ≥ 170/100 mm Hg. The detailed inclusion and exclusion criteria are provided in Supplemental Materials. After meeting the inclusion and exclusion criteria, patients enter a baseline period. At this stage, the BP of patients will be reconfirmed (with three BP measurements in the morning and afternoon, respectively), ensuring that the SBP is above 140 mm Hg (Supplemental Figure S1).

Randomisation and masking

Eligible patients were randomly assigned to receive RIC or sham RIC in a 1:1 ratio according to a computer-generated block randomisation sequence (block sizes of 4, 6, and 8). The allocation sequences were stored in opaque envelopes. All patients were masked to the treatment assignment. The doctor who was responsible for the treatment assignment and conducting the RIC treatment opened the envelope and was instructed not to disclose to the patient whether they were receiving RIC or sham RIC. All outcome assessors who performed BP measurements and conducted the statistical analyses throughout the study were blinded to the randomisation assignment. The RIC and sham RIC devices were identical in appearance to ensure blinding.

Procedures

All the patients were treated with an automated device (BB-RIC-D5/LAPUL Medical Devices Co., Ltd., Beijing, China). The cuff was fixed on the left upper arm, and a pressure of 200 mm Hg was applied to the RIC group and 60 mm Hg to the sham RIC group. Each group protocol consisted of 5 min of ischemia followed by 5 min of reperfusion, repeated for four cycles twice daily for seven consecutive days. Additionally, patients were asked to maintain their usual lifestyle habits (including daily diet, sleep schedule, smoking, alcohol consumption, and exercise) throughout the study period. Among them, patients taking antihypertensive drugs were required to maintain their current regimen (including type, dosage, and frequency), while those not on antihypertensive therapy were instructed not to initiate any such treatment during the study period. If the BP of patients exceeded 180/110 mm Hg or symptoms related to hypertension occurred (such as dizziness, headache, tightness in the neck, palpitations, blurred vision, or nosebleeds, etc), it should be managed in accordance with the physician's clinical judgment.

Measurement of BP

In our study, BP was measured using an electronic sphygmomanometer, which is practical for patients undergoing antihypertensive therapy.¹⁶ It is simple to use and suitable for repeated daily assessments, which help monitor daily BP changes in patients during treatment. We provided electronic sphygmomanometers (Omron 711, Japan) to prospective patients and professional physicians or nurses used these instruments to measure their BP. In both groups, BP was measured every morning between 6:00 and 9:00 (before breakfast and washing) and every evening between 18:00 and 21:00 (eating and bathing were not allowed ≥1 h before measurement).¹⁷ The same sphygmomanometers and BP measurement personnel were maintained during the study period. To ensure high data quality and patients' adherence to the measurement schedule, we repeatedly emphasised the correct measurement methods and time points before and during the study.

BP measurements were started the day before RIC and continued until the end of RIC for eight consecutive days. Tea, alcohol, smoking, strenuous exercise, and urine holding were not allowed 30 min before BP measurement. BP was recorded at 1 min intervals using an electronic sphygmomanometer three consecutive times after 5 min of seated rest. The cuff was placed on the right arm and maintained at the heart level during each measurement. When the difference between the first two measurements was ≤5 mm Hg, the average of the first two measurements was adopted as the final result, and when the difference between the first two measurements was>5 mm Hg, the average of the last two measurements was adopted as the final result. The overall BP was defined as the daily average morning and evening BP. During treatment, BP was measured at 30 min after RIC or sham RIC on the right arm (the opposite arm that was receiving RIC treatment).

Calculation of BPV

The BP variability (BPV) was calculated as follows (Table 1): The morning−evening variability was calculated as the standard deviation (SD) of the difference between daily morning and evening BP over 7 days (SD of seven morning−evening BP). Similarly, day-by-day variability was calculated as the SD of the overall BP for seven consecutive days (SD of seven day-by-day overall BP).^17,18

Table 1.

Calculation formula for BPV.

Variables	Formulas
Morning-evening BPV	$\sqrt{\frac{1}{n-1}\sum _{i=1}^n{\left(\left(M_i-E_i\right)-\overline{\left(M-E\right)}\right)}^2}$
Day-by-day BPV	$\sqrt{\frac{1}{n-1}\sum _{i=1}^n{\left(O_i-\overline{O}\right)}^2}$

Where M represents the morning BP, E represents the evening BP, and O represents the overall BP (the daily average of the morning and evening BP). i represents the day of treatment; n represents the total number of treatment days, and in this study was 7 days.

BPV, blood pressure variability.

Outcomes

The primary efficacy outcome was the average SBP during treatment (7 days, 14 measurements). The secondary efficacy outcomes included the average diastolic BP (DBP) during treatment, trend of overall SBP/DBP over time, degree of reduction in overall SBP/DBP at day 7, and BPV during treatment.

Safety outcomes are adverse events during RIC treatment (eg, hypertensive emergency, hypotension, cardiocerebrovascular disease, dizziness, nausea, palpitations, pain in arm, skin ecchymosis, and allergic dermatitis associated with RIC pressure treatment). The complete outcomes are detailed in Supplemental Materials.

Statistical analysis

Based on our previous studies, the SBP of the sham RIC group was estimated to be 150 mm Hg. RIC was expected to reduce SBP by 10 mm Hg. Assuming α = 0·05, power = 0·8, SD = 17, and a 1:1 ratio of patients between the two groups, the estimated sample size of each group was calculated to be 46 patients. Considering a 10% loss to follow-up, we estimated that 51 patients were required per group, totalling 102 patients.

Data management and statistical analyses were conducted in SPSS software version 26·0 (IBM Corp., Armonk, NY, USA), and data plotting was conducted in GraphPad Prism software version 9·0 (GraphPad Software, LLC, San Diego, CA, USA). Categorical variables were presented as counts (percentages) and compared between two groups using the χ² test or Fisher's precision probability test. Continuous variables were tested for normal distribution using the Shapiro–Wilk method. Normally distributed variables were presented as mean ± SD and compared using the unpaired t test. Non-normally distributed variables were presented as medians (interquartile ranges) and compared using the Mann–Whitney U test.

All primary and secondary analyses were conducted on the intention-to-treat (ITT) population, and safety analyses were performed on the safety population. For the ITT population, randomly missing efficacy endpoint were filled using multiple imputations based on five imputations. Non-normally distributed data (such as BPV) were logarithmically transformed into normal data. The primary and secondary outcomes were also performed in the per-protocol (PP) population for a sensitivity analysis. The PP population consisted of patients who met all inclusion criteria, fully received the specified treatment, and completed BP measurements. Analysis of covariance (ANCOVA) was used to evaluate differences in BP, heart rate (HR), and BPV between the two groups during treatment, with baseline BP or HR measurements serving as covariates. Repeated-measures ANOVA was applied to analyse the differences in the trend of BP over time between the two groups (group-by-time interaction). The unpaired t test was used to compare the differences between groups at baseline and the differences in the degree of BP reduction from baseline to the end of treatment (day 7), and ANCOVA was used to adjust baseline BP measurements.

Homogeneity of the treatment effect for the primary outcome was assessed through subgroup analyses on prespecified subgroups: age (<50 years or ≥50 years), sex (male or female), and antihypertensive drugs, using a multiple linear regression model with treatment, subgroup variables, and their interaction terms as independent variables. A post hoc subgroup analysis of diabetes (yes/no), smoking (yes/no), and obesity (yes/no) were additionally performed as an investigator-initiated exploratory analysis. The P value of the interaction term indicated the homogeneity of treatment effects. More details on statistical analysis of subgroups are available in the Supplemental Materials. 2-sided P values < 0·05 were considered significant.

Role of the funding source

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Results

Baseline characteristics

Between June 20, 2023, and March 6, 2024, 656 patients underwent an eligibility review, of which 102 eligible patients were randomised to the RIC and sham RIC groups and were included in the ITT analysis. No crossover was observed between the two groups. Due to nine patients receiving less than 10 complete cycles of treatment (four and five in the RIC and sham RIC groups, respectively), 93 patients completed the study according to the protocol and were included in the PP analysis. The screening process is illustrated (Fig. 1).

Fig. 1.

Flow diagram of screening and enrolment of patients with essential hypertension. ITT, intention-to-treat; PP, per protocol; RIC, remote ischemic conditioning.

The RIC and sham RIC groups had similar baseline characteristics (Table 2). ITT population analysis showed that the mean age of the 102 patients was 54·9 ± 12·7 years, and 54 (52·9%) were male. The characteristics of patients in the PP analysis set were presented in Supplemental Table S1.

Table 2.

Baseline demographic and clinical characteristics of the ITT population.

Variables	RIC group (n = 51)	Sham RIC group (n = 51)
Age, y	53·1 ± 13·6	56·7 ± 11·6
Male, n (%)	27 (52·9)	27 (52·9)
Height, m	1·7 ± 0·1	1·7 ± 0·1
Weight, median (IQR), kg	70·0 (63·0–80·0)	71·0 (60·0–81·0)
Body mass index, median (IQR), kg/m2	26·0 (22·9–29·3)	25·3 (24·0–28·4)
Living habits, n (%)
Smoking	14 (27·5)	15 (29·4)
Alcohol drinking	14 (27·5)	14 (27·5)
Regular exercise	7 (13·7)	9 (17·6)
Medication, n (%)
Antihypertensive drugs	40 (78·4)	41 (80·4)
ACE inhibitor/angiotensin receptor blocker	16 (31·4)	18 (35·3)
β-Blockers	1 (2·0)	4 (7·8)
Calcium channel blockers	21 (41·2)	21 (41·2)
Diuretics	2 (3·9)	5 (9·8)
Others	10 (19·6)	10 (19·6)
Diabetes, n (%)	8 (15·7)	10 (19·6)
Heart disease, n (%)	6 (11·8)	8 (15·7)
Stroke, n (%)	2 (3·9)	4 (7·8)
Hyperlipidemia, n (%)	10 (19·6)	13 (25·5)
Family history of hypertension, n (%)	14 (27·5)	17 (33·3)
Overall BP, mm Hg
SBP	148·5 ± 8·1	148·0 ± 8·6
DBP	92·1 ± 7·4	89·9 ± 9·7
Morning BP, mm Hg
SBP	146·6 ± 10·9	146·6 ± 9·4
DBP	91·7 ± 9·0	89·6 ± 9·5
Evening BP, mm Hg
SBP	150·4 ± 8·6	149·4 ± 11·1
DBP	92·5 ± 7·6	90·2 ± 11·0
Overall heart rate, bpm	75·8 ± 10·6	77·0 ± 9·3
Morning heart rate, bpm	74·9 ± 11·3	76·5 ± 10·2
Evening heart rate, bpm	76·6 ± 11·2	77·4 ± 10·0

Regular exercise is defined as at least 30 min of moderate dynamic aerobic exercise (eg, walking, jogging, cycling, or swimming) on 5–7 days weekly.

ACE, angiotensin-converting enzyme; BP, blood pressure; DBP, diastolic blood pressure; IQR: interquartile range; ITT, intention-to-treat; SBP, systolic blood pressure.

Efficacy outcomes

Between-group differences in the average BP during the treatment

Table 3 and Supplemental Figure S2 show the average BP of the ITT population during treatment. The average SBP during treatment was significantly lower in the RIC group than in sham RIC group (143·3 ± 10·0 vs. 147·6 ± 6·3 mm Hg; baseline adjusted between-group difference: −4·8 mm Hg [95% CI, −6·9, −2·7 mm Hg]; P < 0·001).

Table 3.

Difference in average BP between the two groups during the treatment in the ITT population.

Efficacy outcome	RIC group (n = 51)	Sham RIC group (n = 51)	Difference (95% CI)a	P valuea	Difference (95% CI)b	P valueb
	Day 1–7	Day 1–7
Overall BP, mm Hg
SBP	143·3 ± 10·0	147·6 ± 6·3	−4·8 (−6·9, −2·7)	<0·001‡	−4·8 (−7·0, −2·7)	<0·001‡
DBP	89·2 ± 7·7	89·9 ± 8·3	−2·4 (−4·0, −0·7)	0·006†	−2·5 (−4·2, −0·8)	0·004†
Morning BP, mm Hg
SBP	142·3 ± 9·8	147·2 ± 8·0	−5·0 (−7·2, −2·6)	<0·001‡	−4·8 (−7·1, −2·5)	<0·001‡
DBP	89·2 ± 8·0	89·4 ± 8·4	−1·8 (−3·7–0·1)	0·069	−1·8 (−3·6, 0·1)	0·060
Evening BP, mm Hg
SBP	144·3 ± 10·7	148·1 ± 6·1	−4·4 (−7·2, −1·7)	0·002†	−4·4 (−7·2, −1·6)	0·002†
DBP	89·2 ± 7·8	90·3 ± 8·8	−2·5 (−4·7, −0·4)	0·023∗	−2·8 (−4·9, −0·7)	0·011∗
Overall heart rate, bpm	76·0 ± 9·2	78·4 ± 8·4	−1·5 (−3·4, 0·4)	0·129	−1·7 (−3·7, 0·3)	0·097
Morning heart rate, bpm	75·3 ± 9·6	77·6 ± 8·5	−1·2 (−3·3, 0·9)	0·270	−1·2 (−3·4, 1·0)	0·277
Evening heart rate, bpm	76·8 ± 9·6	79·2 ± 8·7	−2·0 (−4·4, 0·5)	0·115	−2·4 (−4·9, −0·1)	0·058

The negative differences in the changes between the groups indicate a benefit for the RIC group.

BP, blood pressure; CI, confidence interval; DBP, diastolic blood pressure; ITT, intention-to-treat; RIC, remote ischemic conditioning; SBP, systolic blood pressure.

∗P < 0.05; †P < 0.01; ‡P < 0.001.

^aDifferences (95% CI) and P values from the ANCOVA model (adjusted baseline BP or heart rate).

^bDifferences (95% CI) and P values from the ANCOVA model (adjusted baseline BP or heart rate, age, sex).

Similarly, the average DBP during treatment was significantly lower in the RIC group than in sham RIC group (89·2 ± 7·7 vs. 89·9 ± 8·3 mm Hg; baseline adjusted between-group difference: −2·4 mm Hg [95% CI, −4·0, −0·7 mm Hg]; P = 0·006). The PP analysis observed similar results (Supplemental Table S2).

Between-group differences in the trend of overall BP over time

Table 4 and Fig. 2 show the trends of BP over time in the ITT population. There was a significant difference in the trend of overall SBP over time between the groups, and we observed a trend toward decreased overall SBP in the RIC group (F = 4·316, P < 0·001, group-by-time interaction).

Table 4.

Difference in the trend of BP over time between the two groups in the ITT population.

Efficacy outcome	Group		Time		Group-by-time interaction
	F	P value	F	P value	F	P value
Overall BP
SBP	5·513	0·021	3·691	0·002	4·316	<0·001‡
DBP	0·031	0·861	2·719	0·014	3·078	0·006†
Morning BP
SBP	5·527	0·021	0·903	0·352	1·030	0·318
DBP	0·002	0·963	3·236	0·004	2·612	0·017∗
Evening BP
SBP	3·836	0·053	3·336	0·003	1·905	0·077
DBP	0·150	0·700	1·751	0·108	1·642	0·134

The P value of group-by-time interaction (<0·05) indicates that there was a significant difference in BP changes over time between the RIC and sham RIC groups.

BP, blood pressure; DBP, diastolic blood pressure; ITT, intention-to-treat; SBP, systolic blood pressure.

∗P < 0.05; †P < 0.01; ‡P < 0.001.

Fig. 2.

Trends of BP over time in the ITT population. Panels A, C, and E display the trend of overall, morning, and evening systolic blood pressure over time, respectively. Panels B, D, and F display the trend of overall, morning, and evening diastolic blood pressure over time, respectively. Error bars represent 95% CI. P was used for the interaction effect of group and days based on repeated-measures ANOVA. DBP, diastolic blood pressure; ITT, intention-to-treat; RIC, remote ischemic conditioning; SBP, systolic blood pressure.

The trend of overall DBP over time was also significantly different between the groups, and a decreasing trend was observed in the RIC group (F = 3·078, P = 0·006, group-by-time interaction). The PP analysis observed similar results (Supplemental Table S3).

Between-group differences in the degree of reduction in overall BP at day 7

Table 5 and Supplementary Figure S3 show the reduction degree of overall BP at day 7 in the ITT population. At day 7, overall SBP changed from 148·5 ± 8·1 mm Hg (baseline) to 143·4 ± 11·2 mm Hg in RIC group and from 148·0 ± 8·6 mm Hg (baseline) to 150·0 ± 7·1 mm Hg in the sham-RIC group, the net difference between groups was −7·2 mm Hg (95% CI, −10·3, −4·0; P < 0·001). Additionally, the proportion of patients with overall SBP <140 mmHg in the RIC group at day 7 was higher than that in the sham RIC group, with a difference of 37·2% (43·1 vs. 5·9; 95% CI, 22·1, 52·3; P < 0·001).

Table 5.

BP at baseline and day 7 of treatment in the ITT population.

Efficacy outcome	RIC group (n = 51)			Sham-RIC group (n = 51)			Unadjusteda	P valuea	Adjustedb	P valueb
	Baseline	Day 7	Change	Baseline	Day 7	Change	Between group difference in change (95% CI)		Between group difference in change (95% CI)
Overall BP, mm Hg
SBP	148·5 ± 8·1	143·4 ± 11·2	−5·1 ± 8·1	148·0 ± 8·6	150·0 ± 7·1	2·0 ± 7·8	−7·2 (−10·3, −4·0)	<0·001‡	−7·0 (−9·9, −4·0)	<0·001‡
DBP	92·1 ± 7·4	89·3 ± 8·7	−2·8 ± 5·6	89·9 ± 9·7	90·5 ± 8·8	0·7 ± 6·8	−3·4 (−5·9, −1·0)	0·007†	−2·9 (−5·2, −0·6)	0·016∗
Morning BP, mm Hg
SBP	146·6 ± 10·9	142·1 ± 12·5	−4·5 ± 9·0	146·6 ± 9·4	149·6 ± 9·3	3·0 ± 9·0	−7·5 (−11·0, −3·9)	<0·001‡	−7·5 (−10·8, −4·1)	<0·001‡
DBP	91·7 ± 9·0	89·0 ± 9·2	−2·7 ± 7·2	89·6 ± 9·5	90·9 ± 9·2	1·4 ± 8·2	−4·1 (−7·1, −1·0)	0·009†	−3·3 (−6·1, −0·5)	0·020∗
Evening BP, mm Hg
SBP	150·4 ± 8·6	144·6 ± 11·4	−5·8 ± 11·4	149·4 ± 11·1	150·4 ± 8·4	1·0 ± 10·9	−6·8 (−11·2, −2·5)	0·003†	−6·2 (−9·8, −2·5)	0·001†
DBP	92·5 ± 7·6	89·6 ± 9·4	−2·9 ± 7·4	90·2 ± 11·0	90·1 ± 9·7	−0·1 ± 8·2	−2·8 (−5·9, 0·3)	0·075	−2·0 (−4·7, 0·8)	0·160
Participants with overall SBP < 140 mm Hg at day 7, n (%)
	22 (43·1)			3 (5·9)			37·2 (22·1, 52·3)	<0·001‡	/	/
Heart rate, bpm
Overall	75·8 ± 10·6	77·3 ± 10·1	1·5 ± 8·7	77·0 ± 9·3	78·4 ± 8·6	1·4 ± 6·8	0·1 (−3·0, 3·2)	0·949	−0·3 (−3·1, 2·4)	0·803
Morning	74·9 ± 11·3	75·5 ± 10·9	0·6 ± 9·9	76·5 ± 10·2	76·9 ± 9·5	0·4 ± 8·4	0·3 (−3·3, 3·9)	0·885	−0·4 (−3·6, 2·8)	0·793
Evening	76·6 ± 11·2	79·1 ± 11·2	2·4 ± 10·5	77·4 ± 10·0	79·9 ± 9·1	2·5 ± 8·9	−0·1 (−3·9, 3·7)	0·974	−0·4 (−3·7, 2·9)	0·809

The negative differences in the changes between the groups indicate a benefit for the RIC group.

BP, blood pressure; CI, confidence interval; DBP, diastolic blood pressure; ITT, intention-to-treat; SBP, systolic blood pressure.

∗P < 0.05; †P < 0.01; ‡P < 0.001.

^aDifferences (95% CI) and P values from unpaired t test.

^bDifferences (95% CI) and P values from the ANCOVA model (adjusted baseline BP or heart rate).

Overall DBP was also changed from 92·1 ± 7·4 mm Hg (baseline) to 89·3 ± 8·7 mm Hg in RIC group and from 89·9 ± 9·7 mm Hg (baseline) to 90·5 ± 8·8 mm Hg in the sham-RIC group, the net difference between groups was −3·4 mmHg (95% CI, −5·9, −1·0; P = 0·007). The PP analysis observed similar results (Supplemental Table S4).

Between-group differences in BPV during the treatment

Compared with the sham RIC group, there was no significant difference in the overall BPV during the treatment period and in the last 2 days of treatment in the RIC group (Supplemental Table S5). Intra-group analysis of RIC showed that day-by-day systolic BPV (SBPV) significantly decreased in the later phase of treatment compared with the early phase (0·4 ± 0·4 vs. 0·6 ± 0·3, P = 0·008), and there were no significant differences in other BPV indicators within the group (Supplemental Table S6).

Safety outcomes

All randomised patients who received at least one RIC treatment were included in the safety analysis (Table 6). No significant adverse events or complications were recorded during the study period. Two patients in the RIC group experienced pain during the compression process, and three patients developed skin ecchymosis after multiple compressions. No adverse events were observed in the sham RIC group. The occurrence of adverse events did not differ between the two groups.

Table 6.

Safety outcomes.

RIC related adverse events	RIC group (n = 51)	Sham-RIC group (n = 51)	P value
Hypertensive emergency	0 (0)	0 (0)	/
Hypotension	0 (0)	0 (0)	/
Cardiocerebrovascular diseases	0 (0)	0 (0)	/
Dizziness	0 (0)	0 (0)	/
Nausea	0 (0)	0 (0)	/
Palpitations	0 (0)	0 (0)	/
Pain in arm	2 (3·9)	0 (0)	0·475
Skin ecchymosis	3 (5·9)	0 (0)	0·241
Allergic dermatitis	0 (0)	0 (0)	/

Hypertensive emergency is defined as severe elevations in overall BP (>180/120 mm Hg) associated with evidence of new or worsening target organ damage. Hypotension is defined as overall BP < 100/60 mm Hg. Numerical rating scale ≥1 was defined as pain. RIC, remote ischemic conditioning.

Subgroup analyses

There were no significant interactions between subgroups and treatment effects except for the obesity subgroup (P value for interaction, 0·022, Supplemental Figure S4).

Discussion

This randomised, single-blinded, endpoint-blinded, parallel-controlled trial showed that RIC significantly reduced BP in patients with essential hypertension who have suboptimal BP control, regardless of whether antihypertensive drugs were applied. BP showed a significant downward trend throughout the treatment period. No major adverse events occurred during treatment, and no significant differences were observed in the incidence of intervention-related safety outcomes between the two groups.

Recently, some researchers conducted preliminary explorations of the impact of RIC on BP. Medias conducted a series of studies on himself (normotensive/prehypertensive) and discovered that RIC may lower BP.^13,14,19,20 This finding was further supported by Tong et al., who found that RIC may lower BP in patients with prehypertension.²¹ Guo et al. demonstrated that without antihypertensive drug use, RIC compression on both upper arms can reduce 24-h average BP by 3·6/2·7 mm Hg in patients with mild hypertension, thereby expanding the potential application of RIC to patients with mild hypertension.¹⁵ However, none of the above studies included patients with essential hypertension whose SBP remained ≥140 mm Hg after taking antihypertensive drugs. Our findings addressed these gaps, validated the antihypertensive effect of RIC in a broader population range, and strengthened the conclusion that RIC could lower BP in patients with essential hypertension, regardless of whether antihypertensive drugs are administered.

The primary outcome of our study was the average SBP (14 measurements) during the 7-day treatment period, which reflects the overall antihypertensive effect of RIC during the treatment period. Compared with sham RIC, RIC reduced SBP and DBP by 7·2 mm Hg and 3·4 mm Hg at day 7, respectively. These findings have important clinical significance for patients who refuse to take or require a combination of antihypertensive drugs. RIC is expected to lower or even normalise BP without increasing antihypertensive drug use. Additionally, though no direct comparison has been made, its antihypertensive effect is similar to that of existing non-pharmacological treatments, such as exercise (SBP reduced by 7·1 mm Hg, DBP reduced by 5·1 mm Hg),²² dietary control (SBP reduced by 10 mm Hg, DBP reduced by 3·8 mm Hg),²³ and renal denervation (SBP reduced by 7·4 mm Hg, DBP reduced by 4·1 mm Hg).²⁴ Furthermore, RIC also has significant protective effects on the heart, brain, and kidneys.^5,10,25 Therefore, it could be that RIC makes patients with these systemic diseases more suitable candidates for RIC-based antihypertensive treatment.

Previous studies did not observe an immediate decrease in BP following a single session of RIC treatment.²⁶ This indicates that the BP-lowering effect of RIC is not so rapid. The main mechanism by which RIC lowers BP may be related to two aspects. First, RIC can increase the level of vasodilator nitric oxide.²⁷ However, the release and increase of nitric oxide take time, so the RIC treatment will not immediately produce a BP-lowering effect. Second, RIC can effectively inhibit the excessive excitement of the sympathetic nerve.²⁸ However, the time course of the RIC's inhibition of the sympathetic nerve remains unclear, this may also take some time. Besides, the BP-lowering effect of RIC might also be related to the cumulative physiological mechanism of RIC. In this study, we observed that the BP of the RIC group showed a downward trend over time. This also proves the above speculation.

Recent studies have shown that BPV is a predictor of cardiovascular and cerebrovascular risks independent of BP levels. The effects of certain antihypertensive drugs on BPV may be associated with stroke risk. For example, amlodipine reduces BPV, which may be related to its reduced stroke risk, whereas atenolol increases BPV, which may be related to increased stroke risk.²⁹ Therefore, BP-lowering treatments should ideally reduce BP levels and variability simultaneously. Studies on the effects of RIC on BPV are limited. Our previous study in healthy adults found that RIC may stabilise the circadian rhythm of mean arterial pressure³⁰; this finding suggests that RIC could potentially exert an impact on BPV. This is the first study to evaluate the effects of RIC on BPV in patients with essential hypertension. The results showed that although there was no significant difference in BPV (including “morning−evening” and “day-by-day” variability) between the two groups during the treatment period (days 1–7), it was found that day-by-day SBPV significantly decreased in the later stage of treatment compared with the early stage within the RIC group, suggesting that RIC has a role in stabilising BPV during lowering BP levels. Given the lack of significant difference in the incidence of adverse events between the two groups, RIC provides patients with a safe and effective non-pharmacological intervention option.

However, this study had some limitations. First, its small size and single-centre design may have introduced bias; therefore, larger, multicentre studies are needed to validate the findings. Second, the treatment duration and BP monitoring times were relatively short, with only 7 days of observation, and the lack of long-term follow-up makes it impossible to assess the occurrence of cardiovascular and cerebrovascular events. It is not yet clear whether long-term intervention has an impact on BP and BPV, and whether it has long-term clinical benefits. Currently, our team is conducting a large-scale multicentre study on the impact of RIC on essential hypertension (NCT: 03945305), which may help answer these questions. Thirdly, the baseline physical activity levels of the participants were not collected in this study. For a large population of hypertension patients, physical activity may be more clinically relevant than regular exercise/structured exercise.³¹ In our multicentre study, we will use wrist-worn accelerometers or other devices to obtain physical activity levels. Additionally, the specific mechanism involved in the BP-lowering effect of RIC requires further research, and more work is needed to fully understand the impact of RIC on BP and BPV, thereby providing a more solid theoretical basis for the treatment of hypertension with RIC.

In conclusion, RIC treatment can safely and effectively reduce BP in essential hypertension patients who have SBP ≥140 mmHg, regardless of whether antihypertensive drugs are applied or not. This finding provides a safe and effective antihypertensive strategy for treating essential hypertension in patients with poor BP control.

Contributors

W-JY, YQ, RA, YY, and Z-NG participated in the design of the study and the development of the protocol. W-JY, S-JW, and J-XR participated in patient data collection. PZ did the statistical analysis. W-JY wrote the first draft of the manuscript with input from YY, Z-NG. W-JY, PZ, YY, and Z-NG accessed and verified the underlying data. All authors agreed on the content of the manuscript, reviewed drafts, and approved the final version.

Data sharing statement

The data supporting the findings of this study are available from the corresponding author upon a reasonable request.

Declaration of interests

We declare no competing interests.