Progressive Elaboration Framework of Mortality in Treated and Controlled Hypertension: A Pooled Analysis of Contributing Factors to Silent or Uncontrollable Fatal Syndromes
Conditions: Hypertension, Morality, Death, Pre-Eclampsia, Cardiovascular Diseases, Stroke, Renal Disease, Artery Stenosis, Arterial Aneurysm, Arterial Rupture, Maternal Death
Sponsor: DejthidaNathaphong

Study Protocol and Statistical Analysis Plan
Title: Progressive Elaboration Framework of Mortality in Treated and Controlled Hypertension: An
Observational Study of Pooled Literature and Clinical Data of Contributing Factors to Silent or
Uncontrollable Fatal Syndromes
NCT Number: [To be added after PRS registration]
Document Date: 20 September 2025
1. Study Overview
This pooled analysis aims to investigate and synthesize mortality outcomes among individuals with
treated and well-controlled hypertension by analyzing available literature and clinical trial data.
Despite blood pressure control, a substantial proportion of patients suffer fatal outcomes such as
cardiovascular or unexplained death. Understanding the risk factors or underlying mechanisms is
essential to guide future research, treatment optimization, and risk stratification.
2. Objectives
To identify and quantify the proportion of deaths in clinical studies among patients with controlled
hypertension.
To explore potential contributing factors leading to mortality despite well-controlled BP, including
comorbidities, pharmacotherapy, age, and control variability.
To evaluate mortality by subtype: cardiovascular, cerebrovascular, renal, or all-cause.
To generate hypotheses and construct frameworks for future interventional or mechanistic studies.
To explain the end-point without cost, budget or effectiveness associated
3. Study Design
Study Design Type: Observational pooled literature review with meta-analytical approach.
Study Sources: Peer-reviewed articles, published clinical trials (RCTs or open-label), prospective
and retrospective cohort studies.
Study type to included:
Interventional studies: RCTs, open-label trials, pragmatic trials.
Non-interventional studies: cohort, case-control, prospective/retrospective observational studies.
Systematic reviews and meta-analyses (if containing extractable arm-level or subgroup-level death
data).
Post-hoc or pooled analyses from published trials if mortality is clearly reported in a controlled arm
that original study does not report outcomes (Detailed in population)
Inclusion Criteria:
Participants with hypertension under treatment.
Confirmed blood pressure control

Mortality outcome explicitly reported
Includes at least one group/arm/cohort labeled or described as “controlled hypertension” with fatal
outcomes recorded.
Population of participants recruit to inclusion criteria for analysis
Human participants of any age group (including neonatal, pediatric, adult, and elderly populations).
Participants with treated and controlled hypertension as defined by the original study authors — not
limited to a specific BP threshold (i.e., SBP <140 mmHg or <130 mmHg not required).
Both primary and secondary hypertension types are eligible (e.g., essential, renovascular,
endocrine).
All of study include: Explicitly reports death, mortality, or fatal outcome in the context of controlled
hypertension, regardless of initial BP value or class of treatment or duration of therapy or
Exclusion Criteria:
Studies not reporting mortality.
Case reports, reviews without primary mortality data.
Animal or in-vitro studies.
Studies focused solely on pulmonary hypertension, glaucoma, or portal hypertension.
Post-hoc, secondary, or sub-analysis reports without baseline data and insufficient raw mortality
data.
Cost associated and effectiveness study
Editorials, letters, or opinion papers with no extractable data
4. Statistical Analysis Plan
4.1 Data Extraction
Extracted variables: author, year, study design, number of deaths (per group), mean SBP/DBP,
treatment details, follow-up time, comorbidities, event timing, subgroup classification.
Data managed using Zotero, Rayyan, and SRDR+ and COvidence export to STATA
4.2 Outcomes
Primary: All-cause vascular mortality in patients with controlled hypertension meaning
Cardiovascular mortality (Cardiac-related death in controlled hypertension patients),
cerebrovascular death(Stroke-related fatal outcomes in BP-controlled patients), renal
occlusion/rupture/failure causing death (Mortality from renal failure in treated, controlled
hypertensives), life-threatening vascular rupture, Major Adverse Cardiovascular Death
Secondary:
Sudden death define death suddenly with autopsy or complete CPR during collapse of cardiac or
respiratory or brain arrested

End-organ failure leading to death define vascular abnormality causing failure of organ leading
death with evidence by imaging, laboratory investigation or autopsy confirmation
ICU death define systemic arterial hypertension is the main reason for admission at critical care unit
report death
Maternal associated hypertension death define from record from healthcare provider confirm
pregnancy with or without antenatal care define mortality outcomes of hypertension during
pregnancy both from gynecologic organ failure or systemic organ failure
Hypertension associated death in the young define mortality outcomes that clear defined high blood
pressure of that age and declared mortality cause during or after any type of treatment
4.3 Analysis Methods
Meta-analysis of proportions and risk ratios (RR) using DerSimonian and Laird random-effects
model.
Meta-regression (logistic or Poisson depending on format) for exploring associations (e.g., age,
sex, baseline comorbidity, drug class).
Sensitivity analysis excluding high-bias studies or small samples (<100).
Heterogeneity: Assessed using I² statistic and Cochrane Q.
Publication bias: Funnel plots and Egger’s test.
Software: R (metafor, meta, dmetar), Stata (metan, metareg), Python for transformation.
5. Data Management and Ethics
Public domain published data only; no individual patient data used.
No IRB or informed consent required.
All data will be kept in secure cloud-based repositories (Zotero, Google Drive, GitHub repo for R
code)
6. Timeline
Literature screening: July–October 2025
Data extraction: September–December 2025
Analysis: January 2026
Manuscript submission: April 2026
7. Limitations
Variability in BP target definition and control verification.
Incomplete reporting or subgroup data across included studies.
Residual confounding due to observational nature.
8. Expected Outputs

High-quality pooled estimates for mortality outcomes.
Identification of research gaps and clinical predictors.
Protocol transparency for ClinicalTrials.gov posting and PROSPERO (ID: [To be added])
registration.
Prepared by: Boat Dejthida (Principal Investigator)
End of Document