Is Mindfulness-Based Stress Reduction Effective for People with Hypertension? A Systematic Review and Meta-Analysis of 30 Years of Evidence

Background: Hypertension is among the most important risk factors for cardiovascular diseases, which are considered high mortality risk medical conditions. To date, several studies have reported positive effects of mindfulness-based stress reduction (MBSR) interventions on physical and psychological well-being in other medical conditions, but no meta-analysis on MBSR programs for hypertension has been conducted. Objectives: The objective of this study was to determine the effectiveness of MBSR programs for hypertension. Methods: A systematic review and meta-analysis of randomized controlled trials examining the effects of MBSR on systolic and diastolic blood pressure (BP), anxiety, depression, and perceived stress in people with hypertension or pre-hypertension was conducted. The PubMed/MEDLINE and PsycINFO databases were searched in November 2020 to identify relevant studies. Results: Six studies were included. The comparison of MBSR versus control conditions on diastolic BP was associated with a statistically significant mean effect size favoring MBSR over control conditions (MD = −2.029; 95% confidence interval (CI): −3.676 to −0.383, p = 0.016, k = 6; 22 effect sizes overall), without evidence of heterogeneity (I2 = 0.000%). The comparison of MBSR versus control conditions on systolic BP was associated with a mean effect size which was statistically significant only at a marginal level (MD = −3.894; 95% CI: −7.736–0.053, p = 0.047, k = 6; 22 effect sizes overall), without evidence of high heterogeneity (I2 = 20.772%). The higher the proportion of participants on antihypertensive medications was, the larger the effects of MBSR were on systolic BP (B = −0.750, z = −2.73, p = 0.003). Conclusions: MBSR seems to be a promising intervention, particularly effective on the reduction of diastolic BP. More well-conducted trials are required.


Introduction
Cardiovascular disease refers to a class of disorders concerning heart and blood vessels which are considered as the primary cause of death in almost all countries by the World Health Organization (WHO) [1]. Hypertension, a long-term medical condition characterized by persistently elevated blood pressure (BP) in the arterial vessels, is a primary risk factor for cardiovascular disease, and, implicated in over 7.1 million deaths per year, it affects around 35% of the adult population worldwide [2,3]. The prevalence and control of hypertension respectively increases and decreases with advancing age [4]. Epidemiological data show that the prevalence, awareness, and control of hypertension differ across gender: it is well-established that men would have lower levels of hypertension The results showed that MBSR groups were associated with greater reductions in systolic and diastolic BP than control groups [51].

Rationale and Objectives
Overall, there is a shortage of research regarding MBSR interventions in people with hypertension. No study used meta-analytic techniques to summarize the existing evidence. In addition, the available review on this topic summarized the results from studies published in the 2012-2017 timeframe without meta-analytical methods, while the MBSR protocol was published for the first time in 1990 [52]; thus, it might be important to fill in the literature gap and to locate potentially additional studies that might be conducted and published before 2012 and after 2017.
Therefore, the primary objective of the present meta-analysis was to assess the effectiveness of MBSR programs on BP at post-treatment in people with hypertension compared to control conditions (wait-list conditions or treatment as usual, such as education groups about health behaviors, and other interventions based on stress reduction such as relaxation techniques). Since a significant level of heterogeneity was expected across the studies, we explored the potential moderator roles of age, gender, and concurrent antihypertensive drugs, as the literature data previously discussed suggest that hypertension control increases with antihypertensive drugs, it decreases with age, and it is lower amongst men [4][5][6][7]9].
Given the high rates of anxiety, depression, and stress symptoms associated with hypertension [30][31][32][33], as discussed before, a secondary objective of the present review was to summarize the evidence about the effects of MBSR on anxiety, depression, and perceived stress symptoms.

Method
The present systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines (PRISMA) [53].

Eligibility Criteria
To be eligible for this meta-analysis, studies were required to meet the following conditions, according to the PRISMA guidelines: (1) Participants: Studies were restricted to adult participants (age ≥ 18 years old) with either elevated BP (120-129/<80 mm Hg), or stage 1 (130-139/80-89 mm Hg) or stage 2 (≥140/90 mm Hg) hypertension. Participants were eligible if they were outpatients or inpatients, they were recruited from any setting, and they were undertaking antihypertensive drugs or they were unmedicated. Participants with comorbid psychiatric and/or medical conditions were not excluded.
(2) Intervention: Studies were included if they evaluated an MBSR intervention, based on the original program developed by Jon Kabat-Zinn [36], or a mindfulnessbased cognitive therapy (MBCT) developed by Segal, Williams, and Teasdale [54], or a mindfulness-based protocol adapted from these and maintaining a comparable format, e.g., eight group sessions of 2-4 h with the practice of mindfulness meditation as the key element.
(3) Comparator: Studies were eligible if they evaluated MBSR compared with either wait-list conditions, treatment as usual, such as education groups about health behaviors, or other interventions based on stress reduction such as relaxation techniques, but not including MBSR techniques/ingredients.
(4) Outcome measures: Studies were included if they assessed systolic and diastolic BP measured with at least two time points (i.e., at pre-and immediate post-test). Follow-up longer than immediate post-test were allowed. Different assessment modalities of BP were considered eligible: clinic and/or ambulatory BP, 24 h BP, day-time BP, and night-time BP. Studies were eligible if they used a variety of measurement devices such as automated oscillometric BP devices or manual sphygmomanometers.
In addition, studies were eligible if they assessed the effects of MBSR on anxiety, depression, and/or perceived stress symptoms. Studies were included if they assessed these outcomes by self-report measures and/or clinician-administered interviews, both with known psychometric properties (i.e., internal consistency values).
(5) Study design: Only randomized controlled trials (RCTs) were eligible. (6) Language: Studies published in English were included. (7) Publication timeframe: January 1990-November 2020. This timeframe was chosen because the MBSR protocol was developed and published for the first time in 1990 [16].
(8) Type of article: full-text published in peer-review journals.

Systematic Literature Search
Studies were identified by conducting an online systematic search of the electronic databases PubMed and PsycINFO through the following keywords: "MBSR OR mindfulness OR mind-body therapies AND hypertension OR prehypertension". We chose these two databases since this search strategy has been considered by some authors [55] to be associated with an optimal combination of databases for literature searches in systematic reviews, as PubMed and PsycINFO are focused on two key domains (medical literature and psychological literature, respectively) related to the research question of the review. The search was carried out by two independent reviewers from 27 to 30 November 2020. In addition, reference lists of the studies included in the meta-analysis were also examined.

Study Selection
Studies were screened against eligibility criteria by two reviewers working independently in two stages. During the first stage, studies were examined with regards to the eligibility criteria after reading the title and the abstract, respectively. During this stage, duplicates were removed. Subsequently, the authors met to compare their selections. Studies were not excluded if there was disagreement between the reviewers on inclusion or exclusion. During the second stage, two authors independently assessed the full text of the papers. At this stage, any disagreements about inclusion or exclusion of studies were discussed and resolved in meetings with another independent reviewer. A last stage consisted of the examination of the reference lists of the studies included in the review to identify studies which had not been located through the search based on the electronic databases.

Data Extraction and Coding
All the information was extracted from each included study and inserted into an Excel worksheet by a reviewer (R.C.). Another independent reviewer (i.e., not involved in the extraction of the data) (A.P.) checked the correctness of the data entered in the worksheet. After entering the data, any discrepancies were discussed in meetings between the two reviewers. The following information was extracted and coded from each study: (1) first author's surname, (2) publication date, (3) country, (4) inclusion and exclusion criteria, (5) study design, (5) control group, (6) assessment time points, (7) recruitment strategy, (8) treatment, (9) primary outcomes, (10) secondary outcomes, (11) total sample size, (12) diagnosis, (13) percentage of participants on antihypertensive agents, (14) mean age and standard deviation, (15) percentage of females, (16) percentage of participants with medical comorbidities, (17) pre-test and post-test mean BP score and the related standard deviations, and (18) findings related to systolic and diastolic BP, anxiety, depression, and stress between-group comparisons and changes.

Risk of Bias in Individual Studies
Risk of bias in individual studies was assessed by using the risk of bias assessment tool developed by the Cochrane Collaboration [56]. A reviewer assessed risk of bias independently, then another reviewer evaluated the judgements assigned by the first one, and each discrepancy was discussed and resolved. Each study was judged on six methodological domains considering how certain methodological characteristics might have impacted the results (random sequence generation, appropriate randomization, allocation concealment, treatment allocation, blinding of outcome assessors, blinding of participants and personnel). According to the guidelines provided by Higgins and Green [56], each domain was rated as high, low, or unclear. Risk of bias was classified as low if it was regarded as low by the two independent reviewers for all the domains, as unclear if it was regarded as low or unclear for all the domains, and as high if it was regarded as high for one or more domains.

Meta-Analysis
A random-effect meta-analysis was carried out. The effect sizes for meta-analyses were calculated as differences in means (MD) [57], i.e., the mean of all the differences between all sample means, using sample sizes, mean scores, and standard deviations (SD). The use of a MD effect-size index allowed a change in BP to be detected through the same unit of measurement across the studies. Effect sizes were calculated by comparing MBSR conditions versus a combined condition which resulted from the combination of the effect sizes derived from both no-intervention (i.e., wait lists) and active control conditions (i.e., progressive muscle relaxation and health education). Negative effect sizes suggested that MBSR was superior as compared with controls. MD indices were chosen since BP was assessed through the same measurement unit (i.e., mm Hg) across the included studies. Heterogeneity between the studies was calculated using the I 2 index, which represents a measure of between-study heterogeneity in percentage attributable to variability rather than chance [58]. A value approximating zero indicates homogeneity, whereas values of 0-25%, 25-50%, and 50-100% represent low, acceptable, and high heterogeneity, respectively [58]. The likelihood of publication bias was estimated through the Egger's test, which is an unweighted regression analysis based on the precision of each study as the independent variable and the effect size divided by its standard error as the dependent variable [59]. A non-statistically significant result of the t-test for the null hypothesis of an intercept equal to zero allows us to discard publication bias [59]. In addition, in order to verify the likelihood that the findings are subjected to publication bias, the funnel plot [60] was inspected.
Multivariate meta-regressions were carried out investigating the effects of gender (coded as the percentage of females), age (coded as the mean age in the study), and anti-hypertensive medications (coded as the percentage of participants on this type of medications).
All the analyses were performed with a 95% confidence interval (CI). The metaanalysis was carried out through the Comprehensive Meta-Analysis software version 3.0 and summarized in the forest plots.

Study Selection
Initially, the research returned a total number of 32 articles. The total number of articles after duplicates were removed was 30. From this initial pool, we excluded 5 articles, screened based on English language and type of publication, and the remaining 25 full texts were analyzed more closely. After applying eligibility criteria, 19 articles were excluded from the final review. The final number of articles enrolled in this study was 6. Figure 1 presents the PRISMA flow chart depicting the study selection process.

Study Characteristics
An overview of the characteristics of the study samples, selection criteria, outcome measures, and main results related to BP, anxiety, depression, and perceived stress symptoms are shown in Table 1.

Participant and Setting Characteristics
All except one of the studies included patients recruited at private clinics and hospitals [61][62][63]65,66]. One study [69] included adults recruited from a senior housing facility. Five studies [61][62][63]65,66] included both genders, whereas one study [69] included only men. Two studies [61,66] included unmedicated patients with grade-1 hypertension, one study [62] included unmedicated stage-1 hypertension, and one study [63] included cardiac patients (coronary artery disease, mitral valve replacement, other cardiovascular diseases) referred to a specialized cardiac clinic-all the participants received antihypertensive drugs (i.e., angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, calcium channel blockers, and diuretics). One study [69] included older adults aged 62 years or older recruited from a senior housing facility (13 with hypertension, stage I and II, 4 with pre-hypertension, 3 normotensive), and the type of medication was not specified. One study [63] included patients with a diagnosis of coronary heart disease who had been hospitalized or had had symptoms of heart disease within the last 1 year.

Intervention Characteristics
Three studies [61][62][63] applied MBSR, in accordance with the original program of Jon Kabat-Zinn. Two studies [65,66] applied MBCT. One study [69] applied an 8-week mindfulness-based program, designed to teach mindfulness meditation and to develop social and emotional skills. All studies also included daily home practice. All but one study [61][62][63][66][67][68][69] reported information on who led the MBSR group: one psychologist [65], two therapists [62], one therapist [61], one psychiatrist [66], and one instructor [69], all trained in MBSR protocol. One study [65] did not report information about the instructor's background. All but one study [61][62][63]66,69] reported daily home practice of 15 to 45 min-one study [66] did not specify the length of home meditation practice. Control groups differed widely between studies. Two studies [62,63] used a wait list, one study [61] applied progressive muscle relaxation, one study [69] a social support group, one study [46] a health education session about cardiovascular disease and its management, and one study [66] 8 weekly health education sessions.

Outcome Measures BP Measures
Diastolic and systolic BP were assessed as outcome measures in all studies using two different measurement methods: clinic BP and ambulatory BP. Both methods differed widely from one study to another. All studies assessed clinic BP: three studies used an automated oscillometric BP device [61,62,69], two studies used a manual sphygmomanometer [63,65], and one study [62] used only the ambulatory BP measure. Two studies [61,66] measured both clinic and ambulatory BP, although one study [61] did not report results on ambulatory BP.

Risk of Bias in Individual Studies
Three studies [62,65,69] were classified as at high-risk of bias, two studies [61,66] were judged as at unclear risk of bias, and one study [63] was considered as at low-risk of bias. An overview of the risk of bias assessments is provided in Table 2.    Subsequently, when the studies associated with a high risk of bias were removed through a sensitivity analysis [57,59,61], the comparison of MBSR versus control conditions on diastolic BP was associated with a statistically significant mean effect size favoring MBSR over control conditions (MD = −3.057; 95% CI: −4.030 to −2.084, p = 0.000, k = 3; 8 effect sizes), without evidence of heterogeneity (I 2 = 0.00%). Egger's test did not result statistically significant, suggesting absence of publication bias (intercept = −0.305, t (1) = 0.494, 1-tailed p-value = 0.353, 2-tailed p-value = 0.707).

Moderator Analyses
Two moderator analyses were carried out separately by multivariate meta-regressions, where mean age, the percentage of females, and the percentage of participants on antihypertensive medications were entered as predictors.
Mean An overview of the analyses carried out in the meta-analysis is presented in Table 3.

Discussion
Hypertension is among the most important risk factors for cardiovascular diseases, a primary cause of death worldwide. The NICE guidelines [7] highlight an important role of stress in the development of this medical problem. MBSR represents an effective strategy for the management of a variety of psychological and medical conditions. A quantitative summary of the available evidence about its effectiveness for people with hypertension has not been conducted yet.
The present study is the first work using meta-analytical techniques to pool the evidence about the effectiveness of MBSR programs for hypertension. We identified 6 studies, one more study than the most recent review [52], on this topic. The present findings suggest that MBSR is a promising strategy for people with hypertension. Specifically, we found that the effects of MBSR programs were associated with significant mean effect sizes on both diastolic and systolic BP, without evidence of high heterogeneity and publication bias. MBSR resulted more effective than different control conditions, including wait lists, health education, and relaxation groups. This result appears interesting as both systolic and diastolic BP have been considered independent predictors of adverse cardiovascular outcomes [71,72]. Overall, the effects of MBSR on BP are consistent with the data from studies that found a reduction in BP following participation in MBSR programs in other clinical populations, such as patients with cancer, patients with hypertension taking part in transcendental meditation and yoga programs, and in non-clinical populations such as healthcare workers [44][45][46][47][48].
Moderator analyses were not able to identify significant predictors of the effects on diastolic BP, since gender, age, and concurrent antihypertensive medications were not related to the effect sizes on this outcome. However, for systolic BP, we found that the higher the proportion of participants on antihypertensive medications was, the larger the effects of MBSR were, suggesting that the benefits of MBSR might be optimal in combination with antihypertensive drugs. However, since the studies did not randomly assign participants to antihypertensive drugs or antihypertensive drugs + MBSR conditions through an additive design, this conclusion is preliminary and needs further empirical support by future studies aimed to evaluate the superiority of the combination of antihypertensive drugs and MBSR over antihypertensive drugs alone. The lack of moderator effects of age and gender suggests that the extent to which MBSR programs are effective in the management of BP might not differ across age cohorts and gender. Specifically, the fact that age was not a moderator of the effects of MBSR is in contrast with evidence from a previous systematic review [51], where meditation played a noticeable role in decreasing the BP of subjects older than 60 years of age. The lack of moderator effects of age and gender seems to be particularly relevant for clinical practice since older people and men tend to have lower hypertension awareness and control than younger ones and women, respectively [4][5][6]; thus, it seems to be in contrast with the clinical expectation that older people and men would have a less positive response to MBSR on BP.
In the present review, evidence from two studies suggested that MBSR programs were more effective than control conditions on reducing anxiety and depression symptoms, as suggested by self-report measures. In addition, data from three studies showed that MBSR programs were associated with significantly higher changes in perceived stress symptoms. These results are in line with previous evidence from systematic reviews which showed that MBSR interventions are capable to reduce anxious and depressive symptoms and stress levels in chronic diseases such as heart failure [73,74]. Unfortunately, due to the small number of studies, we were not able to pool the data on anxiety, depression, and perceived stress through meta-analyses.
In conclusion, the present meta-analytic study suggests that MBSR might be a useful strategy aimed to increase the individual's capacity to manage both diastolic and systolic BP in people with different stages of hypertension. Therefore, MBSR programs might be a valid adjuvant in both the treatment and prevention of hypertension. This appears particularly relevant in times of the COVID-19 pandemic, where most of the constraints on the population relate to physical activity and lifestyle changes [75].

Limitations and Future Directions
The small number of studies is a strong shortcoming of this review and the present results should be considered preliminary. The evidence related to a statistical significance for systolic BP with a p-value at a marginal significance level (p = 0.047) might be due to insufficient power, which did not allow us to detect a significant effect. Another limitation concerns the fact that only three studies assessed the effects of MBSR at follow-up and this prevented the evaluation of the effects long-term. In addition, we pooled data from studies using different control conditions. Sensitivity analyses that distinguished the comparisons based upon wait lists from those based upon active control conditions (i.e., health education or relaxation groups) did not detect significant mean effect sizes because they were probably underpowered.
Moreover, it should be considered that two out of the six studies were judged at high risk of methodological bias. This issue was handled through a sensitivity analysis that excluded such studies and found a significant mean effect size for diastolic but not for systolic BP. Overall, these limitations suggest the need for further research based upon larger and good-quality trials using long-term follow-up assessments.
Another aspect that should be investigated is the role of moderators. The present moderator analyses were not able to identify significant moderators of the effect sizes on diastolic BP. It would be interesting to explore further variables, for example the potential role of comorbid psychiatric disorders. Unfortunately, none of the included studies reported these data to allow us to perform this analysis. In addition, it would be useful to investigate whether a greater reduction in BP associated with MBSR protocols can predict a lower risk of cardiovascular failure or stroke in the long term.
More research is needed about the effects of MBSR on psychological outcomes including anxiety, depression, and perceived stress, since in our review, only three studies assessed perceived stress and two assessed anxiety and depression symptoms, respectively. It would be interesting to examine whether MBSR can have some effects on psychological variables which generally have a key role in the management and prognosis of hypertension, such as quality of life, health-related locus of control, and self-management skills [76][77][78].
Another relevant aspect to be investigated in the future is whether MBSR can be combined with other psychological interventions aimed to improve health status in hypertension, such as lifestyle interventions that promote an optimal level of physical activity [79]. It is also not clear which mindfulness facets were responsible for the reduction in BP levels or also in anxious-depressive and stress symptoms. It might be that the nonjudgement facet plays a role in this since it has already been found to be the strongest predictor of anxious-depressive symptoms in cross-sectional studies amongst all mindfulness facets [80,81]. However, in our search, we did not identify process-based studies; therefore, the psychological processes through which MBSR might work for people with hypertension remain still unexplored and future dismantling trials [82] are required to investigate this key point.

Conclusions
This is the first meta-analysis which summarized the available evidence about the effectiveness of MBSR programs on BP for people at different stages of hypertension. In six studies, MBSR produced higher changes than control conditions on both diastolic and systolic BP, even if changes on systolic BP were only at a marginal significance level. In studies with a higher proportion of participants on antihypertensive medications, the effects of MBSR on systolic BP were larger. In conclusion, MBSR programs seem to be a promising intervention for people with hypertension, particularly effective on the reduction of diastolic BP.