2. Methods

This systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement (Page et al., 2021).

2.1 Search Strategy and RCT selection

The databases Medline (via Ovid), Embase (via Ovid), Cochrane Library, and Scopus were searched from inception to July 2021, using the search terms outlined in appendix 1. A further search on clinicaltrials.gov for additional completed clinical trials was undertaken in May 2022. All results were limited to English language and human studies using the available limit functions on each database. Inclusion criteria were published studies, randomized control trials (RCT), adults-only (≥18 years only), pharmacological intervention only. Studies were excluded if they were phase 1 trials, non-RCT/observational design, single-arm trials, participants <18, included animal data, in vitro trials, or had N<10 per arm and if the outcome or impact of the intervention was not clearly presented. The study protocol was not registered. However, the database PROSPERO was searched before starting the review to avoid duplication. Therapy with salt tablets was not treated as pharmacological therapy for the purpose of this review.

2.2 Study selection

Two independent investigators (D.J. and S.K.) performed the study selection. Titles and abstracts were screened for duplicates and eligibility. Among the relevant abstracts, full texts were assessed for eligibility.

2.3 Data extraction

Data extraction from the eligible studies was conducted by two independent investigators (D.J. and S.K.). Data were collected for the following domains: authors, journal, publication date, number of participants in experimental and control arms, patient disease group, study design, study duration, experimental medications and doses, control medication and doses, route, duration of follow up, age, sex, and the efficacy parameters as described by the authors not limiting to baseline BP, baseline postural BP drop, post-intervention BP and postural BP drop, symptom improvement.

2.4 Quality assessment

The included studies were quality assessed using the Risk of Bias (ROB) 2 tool from the Cochrane Collaboration (Sterne et al., 2019) for the standard domains including randomization, deviation of intended interventions, missing outcomes, measurement of the outcomes and selection of reported results. The assessment was conducted by two independent investigators (D.J. and S.K.) and any disagreements were resolved with consultation with a third author (F.M.). Studies with a high risk of bias in more than two domains were excluded (Figure 2).

2.5 Data synthesis and analysis

Excel was used to perform summary and descriptive statistics. Where a single study had multiple treatment arms of interest, the arms were assessed separately. Review Manager 5.4 (The Cochrane Collaboration, 2020) was utilized for the meta-analysis of the studies. We used a random-effects model with inverse-variance weighting and heterogeneity of the studies was assessed using the I2 statistic. Results are presented as the mean differences with 95% confidence intervals (CI) and displayed in forest plots.