Circadian Arterial Blood Pressure Variation and Glaucoma Progression: More Questions Than Answers?

To the Editor: We are delegates of the European Glaucoma Panel comprising young European glaucoma specialists, having recently discussed the article “Circadian Variation in Arterial Blood Pressure and Glaucomatous Optic Neuropathy—A Systematic Review and Meta-Analysis” by Bowe et al.¹

Glaucoma is characterized by progressive retinal ganglion cell loss commonly associated with elevated intraocular pressure. Lowering of intraocular pressure is therefore the mainstay of treatment; however, progression may occur despite significant reduction. Therefore additional risk factors such as vascular dysregulation and circadian blood pressure variation² have been considered as additional important mechanisms. The complex relationship between blood pressure and glaucoma progression continues to be debated, and we commend this recent review in bringing this discussion to the broad readership of your journal.

The authors rightly acknowledge some methodological limitations of their approach. We would like to highlight further significant issues, which limit both the internal and external validity of their conclusions.

The authors mention the lack of randomized controlled studies currently available. However, the primary data upon which their meta-analysis is based comprise only level IV evidence derived from retrospective cohort studies with a small total sample size (185 patients). The marked heterogeneity in data collection methods and outcomes (for both blood pressure and visual fields), variation in follow-up duration and poor quality of included studies would usually preclude the use of meta-analysis in this scenario, which therefore raises further doubt over the internal validity of the analysis.

We debated the external validity of this review in the context of our clinical practice. Optic nerve head perfusion is thought to impact all open angle glaucoma phenotypes, but patients with normal tension glaucoma may be more likely to have impaired regulation of ocular blood flow and demonstrate progression due to inadequate optic nerve head perfusion. Bowe et al. include studies examining patients with both primary open angle glaucoma and normal tension glaucoma. Accordingly, this significant subset of patients (which can account for 90% of glaucoma patients in countries such as Japan³) ought to have been analyzed separately in order to draw any meaningful conclusions into the clinical setting.

The wide distribution in age range of the patients analyzed by Bowe et al. is a further concern. Zhao et al. ⁴ recently identified a significant association between blood pressure and intraocular pressure that alters with age. Aging can therefore be regarded as an important confounding factor and ought to be adjusted for, casting further doubt on the clinical applicability of their conclusions.

Variability in the conduct and reporting of systematic reviews can limit their clinical impact. The PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)⁵ was therefore widely disseminated in 2009 to serve as the required benchmark for this process. Bowe et al. ¹ adhered to the older QUORUM (Quality of Reporting of Meta-Analyses) statement, but failed to address important issues relating to data collection, synthesis, and the evaluation of bias that are essential according to the PRISMA guidance.⁵

Bowe et al. provide a valuable contribution in highlighting the lack of high-quality evidence available studying the impact of circadian variations in blood pressure upon glaucoma progression, but we would also recommend great caution when interpreting the findings of their review. As a systematic review, there are important flaws in the methodology, and so it would be better regarded as a thorough narrative review that should raise awareness of the importance of blood pressure in glaucoma management, stimulate debate, and lead to future studies into this important issue.

DISCLOSURE

The European Glaucoma Panel is sponsored by Allergan but there is no conflict of interest with the content of the letter.