Effects of intensive blood pressure treatment on orthostatic hypertension: individual level meta-analysis

Dear Editor

We read with interest the individual participant data meta-analysis by Jones et al. (BMJ 2025;388:e080507) examining the effects of intensive blood pressure (BP) treatment on orthostatic hypertension. While the study provides valuable insights into a poorly understood clinical phenomenon, several methodological and conceptual limitations warrant discussion.

First, the merging of trials with fundamentally different designs-goal-directed BP trials and placebo-controlled trials introduces significant heterogeneity. The pathophysiological mechanisms and treatment effects in placebo-controlled trials (e.g., initiating therapy in untreated patients) differ markedly from goal-directed trials (e.g., intensifying therapy in partially treated patients). Pooling these may obscure critical distinctions, as evidenced by the moderate heterogeneity (I²=38%) and divergent effect sizes between trial types (OR 0.95 for goal trials vs. 0.87 for placebo trials). Prior work emphasizes that such heterogeneity undermines the validity of pooled estimates unless rigorously addressed through stratified analyses or meta-regression.¹

Second, the definition of orthostatic hypertension remains contentious. The study uses a ≥20/10 mmHg rise in systolic/diastolic BP upon standing, but recent consensus guidelines propose combining this threshold with standing systolic BP ≥140 mmHg to improve specificity.² Notably, only 1.9% of participants met the latter criterion at baseline, suggesting most cases identified by the authors represent transient BP fluctuations rather than sustained orthostatic hypertension. This discrepancy risks conflating physiological variability with pathological phenotypes, limiting clinical applicability.

Third, the analysis lacks long-term clinical outcome data. While the study reports reduced odds of orthostatic hypertension with intensive treatment, the clinical significance of this finding remains unclear. Orthostatic hypertension has been linked to cardiovascular events and mortality in observational studies,³ but whether treatment-mediated reductions in orthostatic hypertension translate to lower risks of these outcomes requires validation. Without such data, the implications for practice remain speculative.

Fourth, subgroup analyses-particularly the larger treatment effect in non-Black individuals and those without diabetes-raise concerns about residual confounding. These subgroups may differ systematically in comorbidities, medication adherence, or autonomic function, none of which were adequately adjusted for. Post hoc subgroup analyses in meta-analyses are prone to false-positive findings due to multiple testing, as highlighted by recent methodological critiques.⁴

Finally, the absence of patient-reported outcomes (e.g., dizziness, falls) represents a critical gap. Orthostatic hypertension is often asymptomatic, but its clinical relevance hinges on symptom burden and quality of life. Excluding these endpoints prevents a balanced assessment of treatment risks and benefits, contrary to evolving standards for patient-centered outcomes research.⁵

In conclusion, while this meta-analysis advances our understanding of orthostatic hypertension, future studies should adopt standardized definitions, prioritize clinical outcomes, and incorporate patient-reported measures.

References
1. Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual participant data: rationale, conduct, and reporting. BMJ 2010;340:c221.
2. Ricci F, Fedorowski A, Radico F, et al. Diagnostic criteria for orthostatic hypertension: A consensus statement. J Hypertens 2022;40(5):811-8.
3. Frewen J, Savva GM, Boyle G, et al. Orthostatic hypotension and orthostatic hypertension predict incident dementia among older adults: The Irish Longitudinal Study on Ageing. J Alzheimers Dis 2021;81(2):603-13.
4. Sun X, Briel M, Walter SD, et al. Credibility of claims of subgroup effects in randomised controlled trials: systematic review. BMJ 2010;340:c117.
5. Basch E, Deal AM, Dueck AC, et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. JAMA 2017;318(2):197-8.