Lead Investigator: Nqoba Tsabedze, University of Witwatersrand
Title of Proposal Research: The efficacy of beta-blockers on morbidity and mortality endpoints in black hypertensive patients: A meta-analysis
Vivli Data Request: 8349
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Hypertension is considered the most common non-communicable disease globally. In 2015, it was estimated to affect 20.1% and 24.1% of women and men respectively, resulting in a global prevalence of approximately 22%. In Africa, the prevalence of hypertension has been estimated to be as high as 30%, yet blood pressure control is dismal, with awareness of diagnosis at 27%, and of these, 18% are treated, with only 7% controlled on treatment.
The majority of hypertensive patients will require pharmaceutical therapy and lifestyle interventions to achieve optimal blood pressure control. In the past three decades, five major medicine classes were routinely recommended for the treatment of hypertension. These included the angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, calcium channel blockers (CCBs), and the thiazide and thiazide-like diuretics.
Contemporary clinical guidelines on the management of uncomplicated essential hypertension have downgraded the indication of beta-blocker therapy, to be used only when cardiovascular conditions (coronary artery disease (CAD), Heart failure, Arrhythmias and in young women planning on pregnancy) dominate. This has been supported by evidence suggesting that beta blockers fail to reduce the central aortic pressure and hence are associated with increased stroke events. Despite the widespread awareness of the different efficacy of hypertensive therapy in the various races, this recommendation has been broadly applied to all racial groups.
A sub-analysis of the LIFE study found that the hazard ratio of Losartan compared to Atenolol in reducing the primary endpoint of the study (cardiovascular death, stroke, myocardial infarction) favored Atenolol in African patients [1.667 (95% CI 1.043-2.661)
Additionally, it is widely accepted that African patients are generally under-represented in the literature. “Although there are many possible combinations of blood pressure (BP)-lowering therapies, the best combination for the black population is still a subject of debate because no large randomized controlled trials have been conducted in this group to compare the efficacy of different combination therapies to address this issue.”
The second study does not include Beta-blockers as one of the three anti-hypertensive treatments but supports the notion that more studies are required looking specifically at the African population.
We are of the opinion that the exclusion of beta-blockers as a potential therapeutic option in black patients primarily comes from the lack of large randomized controlled trials (RCTs) investigating the efficacy of beta-blockers in treating hypertension in black patients. The majority of RCTs where evidence for beta-blocker therapy in hypertension arose were largely dominated by non-black populations. Thus, the lack of recommendation for beta-blocker therapy in black patients results from the lack of data rather than evidence against beta-blocker use in black patients.
We therefore hypothesise that a systematic review and a meta-analysis of pooled individual patient data of recent and old RCTs (with a focus on black patients), investigating the efficacy of new and old beta-blockers in the treatment of hypertension may reveal new insights into the role of beta-blockers in the treatment of hypertension in the black population. Furthermore, the role of new beta-blockers in the treatment of hypertension in all populations is still to be defined as there are currently no large RCTs investigating the efficacy of these new therapies.
Through our preliminary literature search, your research work has been identified as a possible source to retrieve the Individual patient data for inclusion in our systematic review and meta-analysis.
Statistical Analysis Plan
Quantitative analyses will be conducted according to standard Cochrane guidelines (Higgins, 2021).
Substantial differences in the underlying study designs, sampling methods, study drugs etc. are expected from the search results, which implies that variation between studies would not be attributed to sampling error only. Therefore, a random-effects model will be used in most cases to pool effect sizes, especially if substantial heterogeneity is detected among studies. Random effects will be weighted using the inverse variance method to calculate the pooled effect size. The DerSimonian-Laird estimator (DerSimonian and Laird, 1986) will be used to calculate the heterogeneity variance, 𝜏2.
Heterogeneity between studies will be evaluated using the I2 statistic to describe the percentage of between-study variability in effect estimates (for each outcome) attributable to true heterogeneity rather than chance (Higgins, 2003). Heterogeneity will be classified as follows:
- I2 ≤ 25%: low heterogeneity
- 25% < I2 < 75%: moderate heterogeneity
- I2 ≥ 75%: substantial heterogeneity
Based on these classifications, meta-analysis will be based on fixed-effect method, if I2 ≤ 25%, and random-effect methods will be used otherwise.
Depending on the outcome being reported the results will be presented as either relative risk (for dichotomous outcomes) or Standardised Mead Differences (SMDs) along with Hedges g (for continuous outcomes). Associated 95% CIs will be reported for all point estimates.
Bias will be assessed using the Risk of Bias tool v2.0 (RoB 2) for meta-analyses (Sterne, 2019). In addition, the AMSTAR 2 tool will also be used to assess the bias of any non-randomised studies that may form part of the extracted data, such as, systematic reviews (Shea et al., 2017).
Subgroup analyses
Subgroup analyses will be performed as part of a sensitivity analysis to assess the robustness of the results.The following subgroup analyses are planned for the primary outcome:
- 2nd and 3rd generation beta-blockers vs all other interventions
- 2nd and 3rd generation beta-blockers vs placebo
- 2nd and 3rd generation beta-blockers vs calcium channel blockers
- 2nd and 3rd generation beta-blockers vs ACE inhibitors
- 2nd and 3rd generation beta-blockers vs angiotensin receptor blockers
- 2nd and 3rd generation beta-blockers vs all non-beta-blocker interventions
- 2nd and 3rd generation beta-blockers vs 1st generation beta-blockers
The following subgroup analyses are planned for the secondary outcomes:
- 2nd and 3rd generation beta-blockers vs all other interventions
- 2nd and 3rd generation beta-blockers vs placebo
- 2nd and 3rd generation beta-blockers vs calcium channel blockers
- 2nd and 3rd generation beta-blockers vs ACE inhibitors
- 2nd and 3rd generation beta-blockers vs angiotensin receptor blockers
- 2nd and 3rd generation beta-blockers vs all non-beta-blocker interventions
- 2nd and 3rd generation beta-blockers vs 1st generation beta-blockers
Sub-group analysis, in addition to sensitivity analysis, will be conducted using meta-regression if more than ten (k >10) studies are included in the meta-analysis. The sparsity of cardiovascular events aggregated to the black population in existing RCTs is a hurdle which we anticipate. Therefore, One-step individual level meta-analysis, if possible, will be preferred if (k <10) less than ten studies are included. In this scenario, mixed effects regression analysis will be utilized as it allows both between participant and between study variation. Joint modelling of time-to-event and longitudinal data may be considered if appropriate time-to-event individual-level data is acquired.
Analysis will be conducted in R version 4.2.1. The lme4, meta and tidyverse packages will be used for the analysis.
Requested Studies:
A Randomized, Double-Blind, Multi-Center Study Comparing the Effects of Carvedilol Modified Release Formulation (COREG MR) and Atenolol in Combination With and Compared to an Angiotensin Converting Enzyme Inhibitor (Lisinopril) on Left Ventricular Mass Regression in Hypertensive Patients With Left Ventricular Hypertrophy (LVH).
Data Contributor: GlaxoSmithKline
Study ID: NCT00108082
Sponsor ID: COR100216
A Randomized, Double-blind, Positive-Controlled, Multicenter Study Comparing the Efficacy of Carvedilol Phosphate Modified Release Formulation (COREG MR) and Metoprolol Succinate Extended Release (TOPROL-XL) on the Reduction of Microalbuminuria in Patients With Hypertension and Microalbuminuria
Data Contributor: GlaxoSmithKline
Study ID: NCT00123903
Sponsor ID: COR103560
A Randomized, Double-Blind, Multi-Center Study Comparing the Effects of Carvedilol Phosphate Modified Release Formulation (COREG- MR) With Metoprolol Succinate (TOPROL XL) on the Lipid Profile in Normolipidemic, or Mildly Dyslipidemic Hypertensive Patients
Data Contributor: GlaxoSmithKline
Study ID: NCT00273052
Sponsor ID: COR103561
A Randomized, Double-Blind, Multicenter Study Comparing the Effects of Administration of Modified Release COREG or Placebo on Blood Pressure in Essential Hypertension Patients
Data Contributor: GlaxoSmithKline
Study ID: 105517/367
Sponsor ID: 105517/367
Summary of Results:
The extensive delay in the last two datasets has resulted in us not being able to include the datasets in the research project.
One dataset received is empty, as in the dataset has been released but the study was abandoned (which we only realized upon receiving it). The study has continued without the Vivli.org datasets.