Key Points
Question
Is aerobic exercise training an effective antihypertensive treatment in patients with resistant hypertension?
Findings
In this randomized clinical trial including 53 patients, a 12-week exercise training intervention promoted a clinically meaningful reduction in 24-hour and daytime ambulatory systolic and diastolic blood pressure.
Meaning
The findings show that aerobic exercise added to optimized medical therapy reduces blood pressure in patients with low responsiveness to drug treatment and has the potential to be incorporated in the standard care of these patients.
This randomized clinical trial evaluates whether an aerobic exercise training intervention reduces ambulatory blood pressure among patients with resistant hypertension.
Abstract
Importance
Limited evidence suggests exercise reduces blood pressure (BP) in individuals with resistant hypertension, a clinical population with low responsiveness to drug therapy.
Objective
To determine whether an aerobic exercise training intervention reduces ambulatory BP among patients with resistant hypertension.
Design, Settings, and Participants
The Exercise Training in the Treatment of Resistant Hypertension (EnRicH) trial is a prospective, 2-center, single-blinded randomized clinical trial performed at 2 hospital centers in Portugal from March 2017 to December 2019. A total of 60 patients with a diagnosis of resistant hypertension aged 40 to 75 years were prospectively enrolled and observed at the hospitals’ hypertension outpatient clinic.
Interventions
Patients were randomly assigned in a 1:1 ratio to a 12-week moderate-intensity aerobic exercise training program (exercise group) or a usual care control group. The exercise group performed three 40-minute supervised sessions per week in addition to usual care.
Main Outcomes and Measures
The powered primary efficacy measure was 24-hour ambulatory systolic BP change from baseline. Secondary outcomes included daytime and nighttime ambulatory BP, office BP, and cardiorespiratory fitness.
Results
A total of 53 patients completed the study, including 26 in the exercise group and 27 in the control group. Of these, 24 (45%) were women, and the mean (SD) age was 60.1 (8.7) years. Compared with the control group, among those in the exercise group, 24-hour ambulatory systolic BP was reduced by 7.1 mm Hg (95% CI, −12.8 to −1.4; P = .02). Additionally, 24-hour ambulatory diastolic BP (−5.1 mm Hg; 95% CI, −7.9 to −2.3; P = .001), daytime systolic BP (−8.4 mm Hg; 95% CI, −14.3 to −2.5; P = .006), and daytime diastolic BP (−5.7 mm Hg; 95% CI, −9.0 to −2.4; P = .001) were reduced in the exercise group compared with the control group. Office systolic BP (−10.0 mm Hg; 95% CI, −17.6 to −2.5; P = .01) and cardiorespiratory fitness (5.05 mL/kg per minute of oxygen consumption; 95% CI, 3.5 to 6.6; P < .001) also improved in the exercise group compared with the control group.
Conclusions and Relevance
A 12-week aerobic exercise program reduced 24-hour and daytime ambulatory BP as well as office systolic BP in patients with resistant hypertension. These findings provide clinicians with evidence to embrace moderate-intensity aerobic exercise as a standard coadjutant therapy targeting this patient population.
Trial Registration
ClinicalTrials.gov Identifier: NCT03090529
Introduction
Resistant hypertension persists as a clinical challenge, as it is a puzzling problem without a clear solution.1 The available treatment options to lower blood pressure (BP) in these patients, namely antihypertensive medications and kidney denervation, have had limited success,2,3,4 while permanent implant-based therapies await appropriate assessment.5 Despite the renewed clinical interest in kidney denervation,6,7,8 the invasive nature and health care costs of this procedure along with the increasing prevalence of hypertension clearly demonstrate the need for other effective treatment options, namely lifestyle strategies for the management of treatment-resistant hypertension.
Although exercise is recommended globally as a first-line approach for the treatment of hypertension,9,10 specific recommendations for those with treatment-resistant hypertension are lacking. Two trials11,12 provide preliminary evidence of the beneficial BP effects of exercise in individuals with treatment-resistant hypertension. However, uncertainty persists regarding the efficacy of exercise training for those with resistant hypertension because of limitations of these studies; they did not disclose the timing of the ambulatory BP assessments and important information regarding the exercise training program, so the exercise dose cannot be replicated.11 Furthermore, the exercise programs were very distinct in terms of exercise modality (treadmill exercise11 vs heated water–based exercise12) and intensity-monitoring strategies (target lactate concentrations11 vs perceived exertion12). The need for specialized personnel and infrastructures to conduct laboratory exercise assessments and deliver heated water–based exercise is challenging and further complicates replication in a clinical setting. The Exercise Training in the Treatment of Resistant Hypertension (EnRicH) randomized clinical trial was designed to overcome these methodological shortcomings by testing with a rigorous design if exercise training compared with usual care indeed reduces ambulatory BP among patients with resistant hypertension.
Methods
Study Design and Settings
The EnRicH trial is a prospective, 2-center, single-blinded randomized clinical trial with a parallel 2-arm group performed in Portugal from March 2017 to December 2019. Patients were randomly assigned to a 12-week aerobic exercise training program plus usual care (exercise group) or to usual care (control group). The primary and secondary outcomes were assessed at baseline and after the 12-week intervention, which was conducted 48 hours after the last exercise session. All patients provided written informed consent. The study was approved by the Ethics Committee of the Centro Hospitalar do Baixo Vouga and registered on ClinicalTrials.gov. The trial protocol can be found in Supplement 1. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Participants
We prospectively enrolled patients with a diagnosis of resistant hypertension aged 40 to 75 years observed at the hospitals’ hypertension outpatient clinics.1 On initial screening, automated 24-hour ambulatory BP monitoring was performed, adherence to medications was documented by the 8-item Morisky Medication Adherence Scale, and the diagnosis of resistant hypertension was confirmed. Patients were required to have a mean systolic BP of 130 mm Hg or greater on 24-hour ambulatory BP monitoring and/or 135 mm Hg or greater during daytime hours while taking maximally tolerated doses of at least 3 antihypertensive agents, including a diuretic, or to have a controlled BP while taking 4 or more antihypertensive agents.1 Exclusion criteria are provided in the eMethods in Supplement 2. Medication adherence and the antihypertensive medication regimen remained unchanged throughout the study.
Randomization and Allocation
Computer-based stratified randomization was generated (1:1), with the strata defined by age (age 40 to 55 years, 56 to 65 years, and 66 to 75 years) and sex. Allocation was concealed in opaque envelopes until the beginning of the exercise or control intervention.
Outcomes
The primary efficacy end point was change in 24-hour ambulatory systolic BP from baseline to 3 months. Secondary outcomes included mean changes in all other BP variables, heart rate, body composition, cardiorespiratory fitness (maximum oxygen uptake; VO2 max), and adverse events (eg, hypertensive crisis, being hospitalized, or death by any cause), including adverse effects during or after the exercise sessions (eg, severe hypotension). A detailed description of the assessment procedures is provided in the eMethods in Supplement 2.
Study Treatment
Patients in the exercise group underwent a 12-week aerobic exercise training program composed of 3 supervised training sessions per week. Each session included a 10-minute warm-up, 40 minutes of aerobic exercise consisting of cycling and/or walking at 50% to 70% of VO2 max (11 to 14 on the Borg scale), and a 10-minute cooldown. Patients started with 20 minutes of exercise at 50% of VO2 max, and progression occurred weekly, alternating between a 5-minute increase in session duration and a 5% of VO2 max increase in intensity, until achieving 40 minutes at 70% of VO2 max, if tolerated. The control group received usual care, including advice on appropriate lifestyle behavior and optimal or best-tolerated drug treatment provided by their physicians.
Statistical Analysis
The EnRicH trial was powered for the primary outcome measure of 24-hour ambulatory systolic BP. Exploratory data analysis and Shapiro-Wilk tests were performed to determine the normality of the data distribution. Continuous variables are expressed as means with SDs or medians with interquartile ranges; mean differences are expressed with their 2-sided 95% CIs. Between-group differences at baseline and in the change from baseline to the end of the study were tested with unpaired t tests. Analysis of covariance was also used to adjust for baseline BP measurements. Paired t tests were performed for within-group comparisons from baseline to the end of the study. For categorical variables, counts and percentages are presented. Between-group comparisons at baseline in categorical variables were tested with the χ2 test. The level of significance was set as a 2-sided P value less than .05. All analyses were conducted with SPSS version 24.0 (SPSS Inc). The eMethods in Supplement 2 includes further statistical analysis details, including the sample size calculation.
Results
Participants
From the 94 patients who met the enrollment criteria, 60 patients agreed to participate. Seven terminated the study prematurely; thus, 53 patients completed the follow-up assessments and were included in the analysis (Figure 1). Of these, 24 (45%) were women, and the mean (SD) age was 60.1 (8.7) years. Patients’ characteristics are shown in the Table.
Figure 1. Flow Diagram Depicting the Study Design.
Table. Baseline Demographic and Clinical Characteristics.
| Characteristic | Mean (SD) | P value | |
|---|---|---|---|
| Exercise group (n = 26) | Control group (n = 27) | ||
| Age, y | 59.3 (8.2) | 60.8 (9.2) | .53 |
| Male, No. (%) | 14 (54) | 15 (56) | .90 |
| Weight, kg | 81.5 (14.7) | 83.0 (15.6) | .70 |
| Body mass indexa | 29.8 (4.9) | 30.4 (5.0) | .64 |
| Fat mass, % | 34.3 (8.0) | 35.0 (9.6) | .80 |
| Medical history, No. (%) | |||
| Currently smoking | 5 (19) | 3 (11) | .41 |
| Diabetes | 3 (12) | 6 (22) | .30 |
| Hyperlipidemia | 20 (77) | 21 (78) | .94 |
| Family history of hypertension | 17 (65) | 15 (56) | .47 |
| Obesity | 11 (42) | 14 (52) | .49 |
| Overweight | 12 (46) | 10 (37) | .50 |
| Stroke | 3 (12) | 1 (4) | .28 |
| Transient ischemic attack | 1 (4) | 2 (7) | .58 |
| Myocardial infarction | 3 (12) | 4 (15) | .73 |
| Medication, No. (%) | |||
| Antihypertensive drugs, mean (SD), No. | 4.6 (0.9) | 4.7 (0.6) | .66 |
| Controlled BP on ≥4 drugs | 14 (54) | 14 (52) | .88 |
| Diuretics | 26 (100) | 27 (100) | NA |
| ACE inhibitors/angiotensin receptor antagonists | 26 (100) | 26 (96) | .32 |
| Calcium channel blockers | 26 (100) | 26 (96) | .32 |
| β-Blockers | 16 (62) | 16 (59) | .87 |
| Centrally acting sympatholytic agent | 8 (31) | 13 (48) | .20 |
| Direct-acting vasodilators | 26 (100) | 27 (100) | NA |
| Aldosterone antagonist | 10 (39) | 11 (41) | .87 |
| Antiplatelet drug | 4 (15) | 7 (26) | .34 |
| Hypoglycemic drug | 3 (12) | 6 (22) | .30 |
| Lipid-lowering drugs | 20 (77) | 21 (78) | .94 |
| Lipid, metabolic, and urinary parameters | |||
| Fasting glucose, mg/dL | 114.0 (41.7) | 105.5 (17.5) | .34 |
| Total cholesterol, mg/dL | 174.8 (36.5) | 183.7 (52.2) | .49 |
| HDL cholesterol, mg/dL | 48.9 (12.9) | 49.8 (15.3) | .84 |
| LDL cholesterol, mg/dL | 102.4 (30.1) | 108.9 (39.9) | .53 |
| Triglycerides, mg/dL | 117.4 (49.4) | 126.2 (79.9) | .64 |
| Hemoglobin A1c, % | 5.8 (1.1) | 5.8 (0.5) | .88 |
| Urinary sodium excretion, mmol/24 h | 168.2 (69.5) | 166.2 (48.7) | .91 |
| Urinary potassium excretion, mmol/24 h | 80.4 (25.8) | 71.8 (24.6) | .24 |
| Microalbuminuria, median (IQR), mg/24 h | 14.6 (6.9-19.2) | 14.5 (10.5-115.2) | .53 |
| BP, mm Hg | |||
| 24-h | |||
| Systolic BP | 127.4 (12.2) | 126.1 (17.2) | .75 |
| Diastolic BP | 75.6 (7.8) | 73.3 (10.2) | .37 |
| Mean BP | 92.9 (8.0) | 90.8 (11.6) | .46 |
| Daytime | |||
| Systolic BP | 133.0 (12.3) | 131.9 (18.0) | .81 |
| Diastolic BP | 79.4 (8.1) | 77.3 (10.5) | .42 |
| Mean BP | 97.2 (8.0) | 95.4 (12.0) | .52 |
| Nighttime | |||
| Systolic BP | 115.0 (15.0) | 115.4 (16.5) | .93 |
| Diastolic BP | 67.3 (9.4) | 66.2 (9.6) | .69 |
| Mean BP | 83.1 (10.3) | 82.7 (11.1) | .89 |
| Office | |||
| Systolic BP | 140.7 (16.6) | 141.1 (15.3) | .94 |
| Diastolic BP | 84.3 (8.8) | 84.4 (10.0) | .96 |
| Mean BP | 103.0 (10.1) | 103.2 (10.9) | .95 |
| Cardiorespiratory fitness, mL/kg per min of oxygen consumption | 34.8 (5.6) | 32.4 (6.8) | .20 |
Abbreviations: ACE, angiotensin-converting enzyme; BP, blood pressure; HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein; NA, not applicable.
SI conversion factors: To convert glucose to millimoles per liter, multiply by 0.0555; cholesterol to millimoles per liter, multiply by 0.0259; and triglycerides to millimoles per liter, multiply by 0.0113.
Calculated as weight in kilograms divided by height in meters squared.
BP Effects of Exercise Training
The change in 24-hour ambulatory systolic BP was significantly different between groups by −7.1 mm Hg (95% CI, −12.8 to −1.4; P = .02), with a mean (SD) change of −6.2 (12.2) mm Hg in the exercise arm vs 0.9 (8.1) mm Hg in the control arm (Figure 2; eTable 1 in Supplement 2). Similarly, 24-hour ambulatory diastolic BP was significantly reduced in the exercise arm compared with the control arm (−5.1 mm Hg; 95% CI, −7.9 to −2.3; P = .001) (Figure 2; eTable 1 in Supplement 2).
Figure 2. Changes in Ambulatory and Office Blood Pressure (BP).
Change from baseline to the end of treatment in 24-hour and daytime ambulatory BP as well as office systolic and diastolic BP in the exercise and control groups. Significant changes from baseline to the end of the intervention in 24-hour, daytime, and office systolic and diastolic BP were observed in the exercise group compared with the control group. There was a significant between-group difference in favor of the exercise group for 24-hour and daytime ambulatory systolic and diastolic BP and for office systolic BP. Error bars indicate standard deviations.
Daytime ambulatory systolic BP (−8.4 mm Hg; 95% CI, −14.3 to −2.5; P = .006) and diastolic BP (−5.7 mm Hg; 95% CI, −9.0 to −2.4; P = .001) as well as office systolic BP (−10.0 mm Hg; 95% CI, −17.6 to −2.5; P = .01) were also significantly reduced in the exercise arm compared with the control arm (Figure 2; eTable 1 in Supplement 2). Mean BP changes are provided in eFigure 1 in Supplement 2. There were no differences in nighttime ambulatory BP and office diastolic BP between groups (eFigure 2 and eTable 1 in Supplement 2). Individual BP changes from baseline to the end of the exercise and control interventions are provided in eFigure 3 in Supplement 2.
Cardiorespiratory Fitness and Other Clinical Effects of Exercise Training
Individuals in the exercise arm improved cardiorespiratory fitness by 14% (mean [SD] change of 4.7 [3.1] mL/kg per minute of oxygen consumption; P < .001), while it remained unchanged in those in the control arm (eTable 2 in Supplement 2), resulting in a between-group difference of 5.05 mL/kg per minute of oxygen consumption (95% CI, 3.5 to 6.6; P < .001). There was also a significant between-group difference in the change in heart rate (24-hour and daytime) in favor of the exercise arm (eTable 2 in Supplement 2). There were no between-group differences in body composition (eTable 2 in Supplement 2) or biochemical or urinary parameters (eTable 3 in Supplement 2).
Safety and Compliance
Patients in the exercise arm attended a mean (SD) of 98.8% (3.2%) of the 36 total exercise sessions (median adherence rate, 100%; minimum, 89%). There were no major adverse events or complications registered during the study. Two patients reported dizziness after 2 of the exercise sessions, and 2 patients reported musculoskeletal complaints (knee and hip soreness) in the first weeks of the exercise intervention.
Discussion
The EnRicH trial showed 12 weeks of moderate-intensity aerobic exercise training decreased the powered primary efficacy end point of 24-hour systolic BP in patients with resistant hypertension by 7.1 mm Hg compared with usual care. Daytime BP (systolic, −8.4 mm Hg; diastolic, −5.7 mm Hg), 24-hour diastolic BP (−5.1 mm Hg), and office systolic BP (−10.0 mm Hg) were also significantly reduced after exercise training compared with usual care. The magnitude of these differences in BP are clinically meaningful and associated with lower risk of cardiovascular morbidity and mortality in adults with hypertension.13
From a clinical perspective, these results are encouraging because the exercise prescription tested in the EnRicH trial is easily reproducible and has the potential to be applied on a larger scale in a setting more representative of clinical practice for which integrating drug treatment and exercise training are recommended. Our results confirm that aerobic exercise training, which is already recommended as first-line treatment for hypertension, should be extended to those with resistance to pharmacological treatment. The exercise intervention resulted in a reduction in 24-hour ambulatory BP comparable with the reduction observed in successful kidney denervation clinical trials. For instance, the SPYRAL HTN-ON MED trial7 reported a decrease of 7.4 mm Hg for systolic BP and 4.2 mm Hg for diastolic BP at 6 months after kidney denervation compared with sham control.
From a public health perspective, the results of the EnRicH trial are quite promising. There is mounting evidence the reduction of systolic BP is linearly associated with a lower risk of cardiovascular morbidity and mortality in adults with hypertension.13 For instance, a reduction in systolic BP of 10 mm Hg or diastolic BP of 4 mm Hg is associated with approximately 30% lower risk of stroke and approximately 20% lower risk of myocardial infarction.14 Altogether, the results of the EnRicH trial reaffirm the safety and efficacy of exercise training reported in previous trials among those with hypertension15 and improve our understanding in the context of treatment-resistant hypertension.
Limitations
Limitations of the EnRicH trial should be acknowledged. On average, our sample consisted of patients with baseline biochemical parameters near or at the recommended levels, which limits the generalizability of our findings to patients with a more adverse cardiometabolic profile. Also, the EnRicH trial was not powered to detect potential effects in subgroups of interest (eg, men compared with women). Additionally, results of the EnRicH trial are specific to aerobic exercise and may not be generalizable to other types of exercise (eg, resistance exercise).
Conclusions
In conclusion, the EnRicH trial showed a significant reduction in systolic and diastolic BP in patients with resistant hypertension after a 12-week moderate-intensity aerobic exercise program, both under ambulatory conditions and in the office. In this study, when added to optimized medical therapy, aerobic exercise reduced BP to clinically meaningful levels in a patient population with a low responsiveness to drug treatment and has the potential to be incorporated into the standard care of these patients.
Trial protocol and statistical analysis plan.
eMethods.
eTable 1. Ambulatory and office blood pressure measurements at baseline and after the 12-week exercise program.
eTable 2. Changes in body composition, cardiorespiratory fitness, and heart rate.
eTable 3. Changes in lipid, metabolic, and urinary parameters.
eFigure 1. Change from baseline to the end of treatment in 24-hour and daytime ambulatory mean blood pressure in both study groups.
eFigure 2. Change from baseline to the end of treatment in nighttime ambulatory systolic and diastolic blood pressure in both study groups.
eFigure 3. Individual change in 24-hour ambulatory systolic blood pressure, daytime ambulatory systolic blood pressure, and office systolic blood pressure from baseline to the end of the 12-week intervention in both study groups.
eReferences.
Data sharing statement.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol and statistical analysis plan.
eMethods.
eTable 1. Ambulatory and office blood pressure measurements at baseline and after the 12-week exercise program.
eTable 2. Changes in body composition, cardiorespiratory fitness, and heart rate.
eTable 3. Changes in lipid, metabolic, and urinary parameters.
eFigure 1. Change from baseline to the end of treatment in 24-hour and daytime ambulatory mean blood pressure in both study groups.
eFigure 2. Change from baseline to the end of treatment in nighttime ambulatory systolic and diastolic blood pressure in both study groups.
eFigure 3. Individual change in 24-hour ambulatory systolic blood pressure, daytime ambulatory systolic blood pressure, and office systolic blood pressure from baseline to the end of the 12-week intervention in both study groups.
eReferences.
Data sharing statement.