This study follows the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) (26). The protocol for the systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (www.crd.york.ac.uk/PROSPERO/, CRD 42020213081 and registration date 09/10/2020). The Figure summarizes the study design.
Eligibility criteria
The PICOS framework was used for structuring the design of the study, research question and search as follows: Population (individuals aged ≥ 18 years diagnosed with pre-HTN or HTN); Intervention (one session of isometric resistance exercise or isometric handgrip training); Comparison (isometric resistance exercise or training versus [no exercise or training] control group); Outcome (SBP and DBP measurements by auscultation, oscillometry or 24-hour ambulatory BP monitoring); Study (RCTs).
Inclusion criteria for this review study include “prehypertension” and/or “hypertension” in the title and/or abstract used to describe the main characteristic of the study sample. The main body of the article must have a clear description of the study population (adults) and diagnosis of HTN: sustained high BP levels and/or use of antihypertensive drugs together with a medical history and/or skilled medical assessment. The criteria for “intervention” include a study with two or more arms, either isometric resistance exercise or training using handgrip as “comparator” versus a control group (no session of exercise or physical training, or receiving only primary care, usual care, care while on a waiting list etc.). For the purpose of conducting subgroup analyses, all exercise frequencies, intensities and times will be included. Only RCTs of prehypertensive or hypertensive individuals, defined in each RCT (overall, sustained high BP levels and/or use of antihypertensive drugs together with a medical history and/or skilled medical assessment), will be selected for the meta-analysis.
Inclusion and exclusion criteria
We will select all studies of individuals aged 18 or more with HTN measured using auscultation, oscillometry or 24-hour ambulatory BP monitoring (ABPM) involving isometric handgrip exercise or training as an intervention. Studies involving other interventions associated with exercise but with a clearly defined isometric resistance group and a control group (no exercise) will be fully reviewed for inclusion. Studies with participants taking antihypertensive medications will be eligible when medication was introduced either ≥ 4 weeks before the exercise/training intervention or during the intervention and data analysis.
Studies with individuals taking medication other than antihypertensive drugs or concomitant dietary (or supplement) interventions as well as review studies, studies with animal experimentation and studies that involve any condition other than pre-HTN or HTN will be excluded. Studies with similar characteristics published in different journals will be carefully reviewed and excluded if considered “duplicated publication.”
Search strategy
A prior search was conducted in the Medline database via PubMed to ascertain whether the research question of our review meets the FINER criteria (feasible, interesting, novel, ethical and relevant). A search strategy for RCTs was then developed to be undertaken by two independent reviewers (PCO and GW) in the databases recommended in the Cochrane Handbook for Systematic Reviews of Interventions (27): Medline, EMBASE (database of published European literature) and Cochrane databases (for access to trials that may not be indexed in MEDLINE and EMBASE). To broaden our search results, we will conduct searches for the Latin America literature through LILACS (Latin American and Caribbean Health Sciences Literature / Virtual Health Library [VHL]). Given that the intervention of interest may also be part of physical therapy rehabilitation programs, our searches will also be conducted in the Physiotherapy Evidence Database (PEDro, www.pedro.org.au). To minimize any publication bias, searches will also be undertaken on online gray literature including OpenGrey (www.opengrey.eu) and the Brazilian Coordination for the Improvement of Higher Education Personnel (CAPES) Bank of Theses and Dissertations (www.catalogodeteses.capes.gov.br). For unpublished ongoing trials, our searches will be undertaken in clinical trial registries: Brazilian Clinical Trials Registry (ReBEC, www.ensaiosclinicos.gov.br), Clinical Trial.gov (www.clinicaltrials.gov) and WHO International Clinical Trials Registry Platform (ICTRP, www.who.int/ictrp/en/). We will gather data through careful review of the articles retrieved and will contact authors by email to obtain any additional information as required. Articles in Portuguese, English and Spanish language with no date of publication limits will be eligible for inclusion. Upon completion of the review, we will undertake an additional search of all databases and registry platform to ensure the inclusion of the most recent studies.
The main search terms will include “hypertension,” “exercise,” “isometric exercise” and “blood pressure” (Table 1). The search terms for the study design (randomized clinical trial, RCT) will be entered in the databases MEDLINE (28) and EMBASE (29) for more accurate and sensitive searches (Table 1). The two study reviewers (PCO and GW) will work independently selecting the studies after an initial screening of titles and abstracts. When there will be no sufficient information in the abstract, the reviewers will retrieve and read the full text of the article. Any discrepancies will be resolved through a consensus discussion and, if necessary, any disagreements on the inclusion criteria will be resolved by a third reviewer (AML).
Data extraction and management
After a complete search in each database, all articles retrieved will be exported as “.ris” or “.enib” files and imported into EndNote X9 arranged in folders by search platform, exclusion criteria and eligibility. All duplicates will be removed using EndNote X9 Find Duplicates command (Menu All references / References / Find duplicates). Our reviewers (PCO and GW) will use a search tool (Search, Title OR Abstract) to check for any remaining duplicates. In the next step, they will read the full text of all eligible studies. If they are considered relevant, the main data of the studies selected will be extracted and compiled in a pre-structured database in Excel 2010 for Windows: 1) study (authors, journal, year of publication, intervention, characteristics of exercise session or training); 2) participants (age, gender, body mass index [BMI], medical condition); and 3) methods (randomization, blinding) and outcome (sample size, mean and standard deviation at baseline and post-exercise session or training). For eligible studies with results presented in graphs, we will contact the authors by email to obtain this data or use GetDate Graph Digitizer 2.26 to extract the data. For studies evaluating BP at different time points, we will independently compare baseline measurements with results at each time point. Then our database will be formatted and imported into RStudio for data analyses.
Risk of bias
The risk of bias in RCTs will be assessed using Cochrane RoB 2 tool (www.riskofbias.info/) included in Cochrane Handbook (27, 30, 31). The assessment is based on a set of six domains of bias and judgement can be low, high or unclear risk of bias: randomization sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; and selective reporting. If participants are not blinded because blinding is not feasible for exercise intervention (one session of exercise or training), all studies will be classified as high risk of bias in the “blinding of participants and personnel" domain. No study will be excluded based on the risk of bias assessment. The risk of bias will be analyzed for the primary outcomes of interest in our review.
Risk of overall bias in systematic reviews
We will evaluate the strength of the evidence using the Grading of Recommendations Assessment, Development and Evaluation tool (GRADE; www.gradepro.org) (32). This tool evaluates confidence in estimates of paired effects as well as classifies treatment in a network meta-analysis: study design; methodological limitations (risk of bias); inconsistency; indirectness of evidence; imprecision; publication bias; magnitude of effect; dose-response gradient; and residual confounders (32).
Statistical analysis strategy
We will conduct separate analyses for the acute effect of isometric resistance exercise and the chronic effect of isometric handgrip training. All measures of effect will be presented as mean differences and their 95% confidence intervals (95% CIs) between exercise or training arms versus a (no exercise) control group. When data is reported in different units, the standardized mean difference will be used as it expresses the size of the intervention effect in each study relative to the variability observed in that study, together with their 95% CI. Mean differences or standardized mean differences will be pooled using a fixed- or random-effects model which is appropriate. A random-effects model will be used if studies do not have sufficient similarities to warrant a fixed-effects model and/or the data is reported in different units.
The summary estimate and confidence interval of the random effect refer to the center of the distribution of intervention effects, but do not describe the width of the distribution. Since the confidence interval from random effects refer to uncertainty in the location of the mean of systematically different effects in the studies, we will consider calculated values for a prediction interval (variation in treatment effects over different settings including what treatment effect is to be expected in future patients) (33) (Chart 1S, supplementary material).
Heterogeneity (percentage of the variability in effect estimates) will be assessed using the I2 statistic and Cochran Q test for each pairwise comparison (27, 34) (Chart 2S; supplementary material). If heterogeneity is found (p < 0.05) for potential effect modifiers, it will be tested using subgroup analysis or meta-regression (27). Potential confounders including age, gender, BMI, intervention duration (minutes OR weeks), exercise frequency per week, intervention intensity (low, moderate and high) will be assessed a priori.
A funnel plot will be constructed to assess publication bias if 10 or more studies are eligible to be included in the meta-analysis. All statistical tests will be two-tailed and the significance will be set at p < 0.05. Data modelizations will be performed with RStudio (version 1.3.959) using R package meta (version 3.6.1 for Windows) (https://www.r-project.org/). Chart 3S summarizes the main RStudio script (supplementary material) (database: META_ISOMETRICpas).