The Relevance of Arterial Blood Pressure in the Management of Glaucoma Progression: A Systematic Review

Abstract BACKGROUND Glaucoma is one of the leading causes of global blindness and is expected to co-occur more frequently with vascular morbidities in the upcoming years, as both are aging-related diseases. Yet, the pathogenesis of glaucoma is not entirely elucidated and the interplay between intraocular pressure, arterial blood pressure (BP) and ocular perfusion pressure is poorly understood. OBJECTIVES This systematic review aims to provide clinicians with the latest literature regarding the management of arterial BP in glaucoma patients. METHODS A systematic search was performed in Medline, Embase, Web of Science and Cochrane Library. Articles written in English assessing the influence of arterial BP and systemic antihypertensive treatment of glaucoma and its management were eligible for inclusion. Additional studies were identified by revising references included in selected articles. RESULTS 80 Articles were included in this systemic review. A bimodal relation between BP and glaucoma progression was found. Both high and low BP increase the risk of glaucoma. Glaucoma progression was, possibly via ocular perfusion pressure variation, strongly associated with nocturnal dipping and high variability in the BP over 24 h. CONCLUSIONS We concluded that systemic BP level associates with glaucomatous damage and provided recommendations for the management and study of arterial BP in glaucoma. Prospective clinical trials are needed to further support these recommendations.

2][3] The disease is characterized by structural and functional damage of the optic nerve head due to progressive loss of retinal ganglion cells and their axons. 4,5igh intraocular pressure (IOP) is a major risk factor for disease development and progression.][8][9][10] The rates of both glaucoma and high IOP are expected to co-occur more frequently as their rates keep rising parallel to the increasing life expectancy. 1,11To date, IOP is the only modifiable risk factor and therapeutic option in glaucoma.Nevertheless, some patients with normal or well-controlled IOP are still at risk for glaucomatous damage.The vascular paradigm suggests impaired systemic vascular function, thus compromising blood supply to the optic nerve head, as a risk factor for disease progression.
The interplay between IOP, blood pressure (BP), and ocular perfusion pressure (OPP) is poorly understood which limits the development of a universal consensus around these parameters in the management of glaucoma. 1,911][12][13][14] The role of BP in relation to glaucoma risk has been clarified by the use of 24-h ambulatory BP monitoring.Nocturnal hypotension is considered a potential systemic vascular risk factor for glaucoma.Moreover, abnormal circadian rhythms-such as an increased nighttime BP, an absence of nocturnal BP dipping, or an excessive nocturnal BP dip-have been associated with target-organ damage and increased cardiovascular risk. 1,2,13,15However, even with the cumulative evidence on dysregulations in BP, evidence-based clinical decision-making remains challenging due to conflicting evidence and the poor understanding of the complex interplay between glaucoma and BP.To address these challenges, we performed a systematic review of studies evaluating the role of BP and antihypertensive medication in glaucoma.

METHODS
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used as a guidance for this review. 16

Eligibility criteria
Articles that assessed the association between arterial BP and glaucoma were included.Other inclusion criteria were: (i) articles evaluating arterial BP in glaucoma patients, (ii) articles assessing the impact of BP on IOP and parameters of progression such as retinal nerve fiber layer changes, ganglion cell layer changes, visual field defects, and optic disc hemorrhages, and (iii) articles evaluating the impact of antihypertensive medication in glaucoma patients/on glaucoma progression.
We excluded articles that (i) already feature in meta-analyses in this review, (ii) articles that only reported on glaucoma prevalence in hypertensive cohorts.Other exclusion criteria were: (iii) a non-glaucoma population or animal studies, (iv) meeting abstracts and conference proceeding, and (v) articles written in other languages than English.

Search strategy
Articles were identified by searching Medline (via PubMed), Embase, Web of Science and Cochrane Library.The three concepts "glaucoma," "arterial blood pressure," and "management" and their synonyms were combined to search several electronic databases.The "carrot²" search results clustering engine' was used to broaden the concept "management."After reference import and deduplication selection based on title, abstract, and full text was executed respectively.The search was last performed on 28-07-2022 by researchers JVL and JVE and inconsistencies were solved by consensus.Replies on included articles were included to allow critical appreciation by the scientific community but are listed separately.Relevant articles found by scanning reference lists of included articles but published before 2015 were included only when they were cited in multiple included articles.

Study selection
The search of five electronic databases provided a total of 8,681 citations.After deduplication, 6,581 references remained.Of these, 6,276 were excluded based on title and 181 studies were excluded based on abstract, since these papers did not meet the inclusion criteria.Full texts of the remaining 124 papers were thoroughly examined.It appeared that 28 studies did not meet the previously described inclusion criteria.Seven additional citations were identified by searching reference lists of relevant papers.

Arterial hypertension
First, the relationship between hypertension and IOP is straightforward.It is hypothesized that high BP increases IOP by a dual mechanism.First high BP increases the blood flow and capillary perfusion pressure in the ciliary body leading to an increased production of aqueous humor.Second, high BP, decreases the aqueous outflow through an elevated episcleral venous pressure. 1,17enerally, for every 10 mm Hg increase in BP there is a ca.][19] Large-scale epidemiologic studies in the past aimed to explain the relationship between hypertension and glaucoma, with limited clinical implications.On the one hand, hypertension and increased blood flow leading to an increased OPP could compensate elevated IOP.On the other hand, among chronic hypertensive patients, progressive endothelial dysfunction through hypertensive microvascular damage compromises this positive effect on OPP resulting in suppressed endothelial vasoreactivity, hypoperfusion of the optic nerve head and progressive glaucomatous neurodegeneration.][29][30] However, most studies, including a recent meta-analyses of 16 studies, showed that hypertension is a risk factor for the development and progression of glaucoma (cfr.2][33][34][35][36][37][38][39][40][41][42] A 2020 meta-analysis concluded that (mostly office) hypertension, next to non-physiological BP dipping, was the most significant risk factor for primary open-angle glaucoma (POAG) among the evaluated systemic vascular factors. 7n accordance, a Nepalese study with 221 hypertensive POAG patients confirmed this finding.Patients with office hypertension, diabetes mellitus or the combination of both had a higher severity of POAG, with an odds ratio for severe visual field defects of 2.75, 4.72, and 19.9 (P = 0.001, P = 0.0031, and P = 0.0046); respectively.In this study, IOP did not differ between those with or without arterial hypertension. 43In 2015 a cross-sectional study found that higher systolic BP, diastolic BP and mean arterial pressure (MAP) were associated with thinner retinal nerve fiber layer thickness.They also observed a positive correlation between MAP and IOP.A study regarding normal-tension glaucoma (NTG) patients found that systemic hypertension was two times more frequently observed in NTG patients with arcuate scotomas.They hypothesized that the systemic vascular profile of the patient could predict the morphology of early scotoma in NTG. 45

Nocturnal hypotension
Systemic BP is a dynamic parameter that follows a normal circadian rhythm.During the night, BP physiologically decreases between 10% and 20% compared to the daytime BP level, this is categorized as normal dipping. 46However, in certain conditions, the nighttime BP either decreases too much (extreme dipping), does not sufficiently decrease (non-dipping), or even increases instead (reverse dipping).Studies indicated that people with an abnormal nocturnal dipping are at a higher risk of developing target-organ damage, including damage in the optic nerve head. 1,8The introduction of ambulatory BP monitoring enabled the continuous assessment of BP over a 24-h period, providing detailed insights into the relationship between glaucoma and low BP. 47,48Despite some discordance in literature, most studies concluded that nocturnal hypotension and extreme nocturnal BP dipping are risk factors for the development and progression of open-angle glaucoma (cfr.Table 2).0][51][52][53] In addition, nocturnal BP decrease seems to be accompanied by IOP increase (due to the supine resting position) resulting in reduced OPP at night.When extremes of both phenomena occur simultaneously, OPP drops substantially resulting in short-term ischemia of the optic nerve head and significant risk for glaucoma progression. 54Therefore, nighttime could be considered as a critical period for glaucoma patients. 8,14,19iven that the abovementioned cut-off values for nocturnal BP dipping, fall partly within the physiological range, 17 a deficient autoregulation mechanism is very likely.A study by Melgarejo et al. 50suggested that an increase in glaucoma risk is more likely to be due to the extreme dipping (dips > 20%) of nocturnal BP independently of the overall nocturnal BP level.6][57] One study reported that a diastolic OPP <35 mm Hg result in progression of glaucoma 2.3 times more likely. 5In a cross-sectional study including POAG and NTG patients, patients with nocturnal over dipping and diurnal systemic normotension (both treated and untreated) had more visual field loss (mean deviation = −16.6 dB, IQR: −18.9 to −2.7 dB) than patients with nocturnal over dipping and diurnal systemic hypertension (mean deviation = −3.9dB, IQR: −6.2 to −1.9 dB).They concluded that at the time of a 24-h ambulatory BP monitoring, nocturnal dipping patterns, and diurnal BP means should be analyzed in function of each other. 47Two other studies stated the importance of taking the cumulative nocturnal hypotension, the duration and magnitude of the nocturnal dip into account. 12,53wo study groups defined a comparable safety range for the nocturnal BP.Pillunat et al. 47 proposed the Dresden safety range for nocturnal MAP in POAG ranging between 65 and 90 mm Hg.Kwon et al. 12 defined optimal values of trough diastolic BP at night between 60 and 70 mm Hg.Patients with controlled IOP and a nocturnal BP within these safety ranges have slower progression rates than patients below this optimal value or might not be expected to progress at all.
In NTG patients, the association between nocturnal BP and glaucoma damage seems to offer particular insights.A Table 1 retrospective study from 2017 found that nocturnal dipping (average amount of nocturnal decrease of BP) and large variations in systolic BP accorded to higher incidence of paracentral scotoma in early NTG patients. 49In their prospective case-control study, Kwon et al. surmised an IOP-unrelated mechanism of progression.They concluded that nocturnal dipping exerts its effect on glaucomatous visual field progression through the occurrence of optic disc hemorrhages. 15This was supported by a retrospective study from 2020, that found a significant association between optic disc hemorrhages and fluctuations of diastolic BP and diurnal IOP on one side, and a greater probability of NTG disease progression on the other side. 58Miscellaneously, higher percentages nighttime diastolic BP dips and more severe glaucoma were reported in NTG patients with choroidal capillary drop-out on angiography-OCT. 59

Daytime hypotension
A 2020 retrospective cohort study found that minimum daytime systolic BP and diastolic BP could be, similar to nocturnal dipping or nocturnal hypotension, a potential risk factor for structural glaucomatous progression.Patients with a minimum systolic BP ≤107 mm Hg showed more peripapillary retinal nerve fiber layer thinning (P < 0.001) and patients with a minimum diastolic BP ≤63 mm Hg had more progression of macular ganglion cell-inner plexiform layer thinning (P < 0.001). 60These findings reinforce the importance of maintaining a minimal daytime BP level instead of an overall mean threshold level.Jammal et al. 54 report a significant faster rate of RNFL loss in glaucoma patients with lower mean BP, systolic BP or diastolic BP with and without antihypertensive treatment after correction for age, gender, race, glaucoma diagnosis, CCT, follow-up time, and baseline RNFL thickness in the Duke Glaucoma Registry.

Abnormal BP variability over 24-h
Ambulatory BP monitoring permits the quantification of reading-to-reading BP variability over 24-h.In the hypertension and cardiovascular fields, high variability in the 24-h BP increases the risk of cardiovascular diseases independently of the average 24-h BP level. 61High variability in the BP suggests impaired autonomous central nervous system mechanisms to maintain a constant BP level, which is the case in patients with diabetes, obesity, or previous cardiovascular diseases.Increased BP variability would not be regulated in eyes with glaucomatous damage as their autoregulatory mechanisms to maintain the ocular blood flow and supply would be impaired.Therefore, beyond the absolute level and nocturnal hypotension, it is hypothesized that high variability in the BP over 24-h could increase the risk of glaucoma damage by impaired OPP related to abnormal changes in the systemic BP.
Compared to the cumulative evidence on nocturnal hypotension, few studies have addressed the potential role of 24-h BP variability and glaucoma risk.In 237 patients with NTG, Lee et al. 52 documented that patients with nocturnal BP dipping greater than 20% had significantly increased reading-to-reading daytime BP variability and OPP (defined as by Bill et al. 62 ) compared to normal dippers or non-dippers.Moreover, an increased daytime MAP or OPP variability predicted the progression of visual field defects.Similar findings have been replicated in case-control studies of patients with NTG, 58,63 with additional documentation of fluctuations in the diastolic OPP related to the progression of glaucoma damage. 58In a study including 93  is independent of the 24-h MAP average level. 64Even more, high 24-h MAP variability related to higher glaucoma progression. 65rom a pathophysiological perspective, it is hypothesized that drops in the BP due to high variability is what leads to impaired OPP.Apart from nocturnal hypotension, the quantification of 24-h BP variability relies on indexes such as standard deviation, coefficient of variation, or variability independent of the mean.Each of these indexes gives an absolute number usually reported in publications with the symbol "±."This refers to how far apart data points (e.g., BP recordings) are from the center of the distribution (e.g., 24-h BP average).The extrapolation of this definition to the pathophysiology of glaucoma suggests that the association between variability and glaucoma needs to be addressed.In this regard, the Leuven research group conducted a study to test the hypothesis that the association between high 24-h MAP variability and glaucoma risk was driven by sporadic drops in the MAP rather than peaks. 66To test this hypothesis, they equitably quantified the five largest drops and peaks in the MAP over 24 h (n = 94 and n = 96).Dips rather than peaks in the 24-h MAP related to open-angle glaucoma damage.This could be explained by the fact that patients with normal but highly variable BP are more likely to reach lower OPP repeatedly, and secondly, because patients with high BP exhibit higher BP variability, being more likely to excessively drop in BP, reducing OPP.][33][34][35][36][37][38][39][40][41][42][43] Antihypertensive medication should therefore aim to stabilize BP variability, avoiding extreme dips in the BP, while ensuring nocturnal BP is normal.This in turn should decrease the risk of glaucoma associated with sporadic or constant low BP.

Systemic antihypertensive medication
Studies investigating the role of antihypertensive medication in glaucoma are often not corrected for the presence or severity of existing hypertension and yield contradictory conclusions (cfr.Table 3). 17,67he Thessaloniki Eye Study reported that iatrogenic DBP <90 mm Hg leads to increased cupping and decreased rim area compared to spontaneous DBP <90 mm Hg. 68 Hence, some postulate that the (over)treatment of hypertension, rather than the disease itself, is a significant modifier of glaucoma. 11,56Aggressive decrease in the BP due to antihypertensive treatment could potentially lead to low DBP and consequently low OPP. 56,57,69,70Thus, when treating systemic hypertension, an increase in glaucoma risk could exist if OPP decreases. 11Some studies found a correlation between progression and the number of antihypertensive agents 54,67 whereas another did not. 71Ocular blood flow could potentially be improved in hypertensive patients with drug-induced low nocturnal BP by adapting their medical regime. 57,72For instance, changing the time of medication intake from the evening to morning. 4,73n the other hand it is also believed that undertreatment of hypertension may influence the disease progression of hypertensive glaucoma patients and that some antihypertensive drugs may have protective effects on glaucoma development. 1,14A Danish registry database study reported that antihypertensive medication seems to delay glaucoma onset but not necessarily reduce the immediate risk thereof.They also found a greater protective effect proportional to the cumulative number of different antihypertensive drugs. 69he effect of systemic antihypertensive medication on glaucoma risk can be either IOP-or non-IOP related. 3,74It has been established that systemic β-blockers, especially non-selective types, have a lowering effect on IOP.However, in the Gütenberg Health Study, Höhn et al. could not detect a significant trend of lower IOP (selective BB: −0.12 mm Hg; non-selective BB: −0.7 mm Hg) in non-glaucoma subjects.This finding was attributed to a long-term "drift" effect. 74egarding calcium channel blockers (CCB), mixed findings have also been reported.On one hand, it has been suggested that CCB delay visual field deterioration (possibly due to a neuroprotective effect). 3,14,75Hu et al. 76 documented that nimodipine benefits patients with NTG by increasing the macular capillary vessel density evaluated on OCT-angiography.On the other hand, studies have found that CCB increase the risk of POAG after controlling for systemic hypertension (OR 1.70 P = 0.03). 34Zheng et al. found that CCB, especially amlodipine, were the most significant drug class to be associated with a 26% risk increase of POAG (having had at least one glaucoma procedure) (OR 1.26, 95% CI: 1.18-1.35).No dose-response relationship was identified.β-blocker use was associated with a 23% lesser incidence of POAG (OR 0.77; 95% CI: 0.72-0.83).No association between POAG and the use of loop diuretics or angiotensinconverting enzyme (ACE) inhibitors could be established. 42A more recent study underlines the relative higher accordance between CCB and filtration surgery in POAG compared to thiazides.Other drugs investigated in this study, such as angiotensin-II receptor blockers (ARB), had no significant association with POAG progression. 77aution must be made since these findings often do not correct for the existence of concomitant hypertension.
A retrospective study investigating a cohort from the Groningen Longitudinal Glaucoma study observed a good and highly significant interaction between age and angiotensin-II receptor blockers in relation to glaucoma progression.This suggests a higher benefit of ARB on glaucoma progression in elderly individuals.A significant association between ACE inhibitors, ARB and lower suspect POAG was also reported. 70On the other hand, a large cross-sectional population-based study in a multi-ethnic Asian population found that patients using antihypertensive medication, particularly ACE inhibitors and diuretics, had significantly thinner retinal nerve fiber layers and ganglion cell-inner plexiform layers. 67ynergistic or antagonistic effects of certain antihypertensive agents with certain topical glaucoma therapies have been considered.The addition of a topical β-blocker may not induce a significant reduction in IOP if the patient has already been prescribed an oral β-blocker.Moreover, all drug combinations could increase the risk for adverse effects. 3A long-term case-control study investigating how systemic antihypertensive medications influence the change in IOP after initiating prostaglandin drop therapy did not find a significant impact of antihypertensive medication on the IOP-reduction after topical prostaglandin initiation. 73

Autoregulation
In healthy eyes, retinal blood flow is autoregulated and a relatively constant blood flow is maintained despite changes in the local metabolic environment and changes in OPP. 19,22,44Constant perfusion can be assured within the range of approximately 20 mm Hg around the patients usual MAP. 53When OPP falls out of this range, autoregulation fails.Some glaucoma patients have impaired autoregulation of ocular blood flow (cfr.Table 4).In these patients, ocular blood flow instability may predispose the optic disc structures to ischemia-reperfusion damage.It has been documented that both tails of the arterial BP distribution relates with impaired autoregulatory mechanism in the eyes to maintain an adequate blood flow and supply. 78As previously mentioned, hypertensive glaucoma patients also have, microvascular damage which further disrupts autoregulation mechanisms and increases susceptibility to glaucoma progression.Studies reporting nocturnal hypotension and increased variability of BP and OPP as risk factors for glaucoma also supported that functional vascular dysregulation could be involved in the pathogenesis of glaucoma. 13,22,24,49,79,80This hypothesis may also explain why lowering IOP beyond a critical value is sufficient to restore OBF in certain patients, but may be inadequate as a treatment in patients with significant autoregulatory dysfunction. 14ome glaucoma patients also present with features of a more generalized vascular dysfunction.Lindemann et al. 79 found a higher occurrence of impaired autonomic cardiovascular dysregulation in NTG.The Lifelines Cohort Study found that low heart rate variability, a measurement for autonomic modulation of the heart, was associated with glaucoma. 81Binggeli et al. used nailfold capillaroscopy with cold provocation to examine the relation between BP and vascular dysregulation in glaucoma patients.Their study revealed that patients with vascular dysregulation have on average lower systolic and diastolic BP.Both vascular dysregulation and low BP are core elements of Flammer syndrome, of which the prevalence is higher in NTG. 82ocatürk et al. assessed the BP charts of healthy patients and glaucoma patients.They noted that the systolic and diastolic BP graphs of glaucoma patients seemed blunted compared to those of healthy patients, especially in the early morning.This suggests that early morning blunted sympathetic activity may play a role in the pathophysiology of glaucoma. 83nother study investigated the autonomic regulation to carbohydrate ingestion and postural change in 19 NTG, 18 POAG and 36 control patients, age and gender matched.They concluded that both NTG and POAG manifest some systemic autonomic dysregulation, but that the characteristics of the dysregulation may differ between the two subtypes. 84

DISCUSSION
This systematic review provides an up-to-date evaluation of the interplay between systemic BP and glaucoma progression.Although there is some discordance, there appears to exist a bimodal, U-shaped relation between BP and glaucoma progression. 20,57Both low and high BP relate to lower RNFL and ganglion cell thickness, especially in the absence of adequate autoregulation on both sides. 78Low BP, whether intrinsic or drug-induced, leads to low OPP and, in the absence of sufficient autoregulation, possibly to ischemia of the optic nerve head.High BP is associated with higher IOP, higher BP variability and microvascular disease which in turn leads to lower perfusion.66]85 Recent evidence indicated that an increased reading-to-reading variability and drops in MAP over 24-h related to progression visual field defects in patients with POAG, 85 especially during the daytime. 65The relation between antihypertensive treatment and glaucoma-in studies often uncorrected for the presence or severity of hypertension-is insufficiently understood, mostly given the bias of existing refractory hypertension.Lastly, the correlation of glaucoma with nocturnal BP dipping has been established and systemic hypotension should be ruled out in case of glaucomatous progression, especially in patients with normal or well-controlled IOP. 4 A simple, non-invasive method such as 24-h ABPM proves to be a valuable tool in BP assessment. 14,37,83Intensive BP treatment Table 3 and the time of antihypertensive drug intake could increase the effect of nocturnal dipping depending on the patients susceptibility. 86If nocturnal hypotension is detected, change in pharmacological treatment might be considered.Although morning intake would theoretically reduce the risk of nocturnal dipping, the Hygia and MAPEC trials point to a more pronounced reduction of cardiovascular mortality associated with nighttime dosing. 4,73,87he clinical implementation of the findings of the SPRINT trial, STEP trial and the most recent guidelines concerning the treatment of systemic hypertension may have a key role in the management of glaucoma the coming years. 11,88,89The trial demonstrated that treating arterial hypertension to a target of less than 120 mm Hg reduced cardiovascular events and the overall risk of death in all hypertensive patients. 88Following those findings, the 2017 ACA/AHA hypertension guidelines redefined office hypertension as a systolic BP of 130 mm Hg or higher or DBP of 80 mm Hg or higher. 90These stricter targets broaden the group of patients needing antihypertensive treatment and will increase the number of patients with coexisting systemic hypertension and glaucoma.In this group, glaucomatous progression due to medication-induced hypotension is likely to become more frequent, despite well-controlled IOPs, causing a clinical dilemma between cardiologists and ophthalmologists.Although reducing cardiovascular mortality takes precedence over preserving vision, the impact of visual impairment on psychosocial well-being and quality of life should also be considered.A balance between quality adjusted life years, disability-adjusted life years, and years of life lost must be considered when evaluating patients with glaucoma and concomitant hypertension.A hypothetical approach could give priority to the independent increase of diastolic BP, given some-olderstudies pointing to systolic BP as only modifier of cardiovascular risk and the proven importance of diastolic BP in glaucoma. 91,92ecently some additional evidence regarding the choice of antihypertensive in association with glaucoma risk has been published.A retrospective study on antihypertensive use in 31,170 glaucoma vs. non-glaucoma participants with arterial hypertension did not show higher incidence of glaucoma in the groups on single diuretics, ACE inhibitors or β-blockers, but did show higher odds ratios in the groups on ARB monotherapy, CCB monotherapy, and various combination treatments. 93Additionally, a study on glaucoma entries in the UK biobank (n = 427,480) led to the conclusion that CCB treatment is associated with a 1.39 odds ratio (P = 0.001) on having glaucoma. 94The deleterious effect of CCB on glaucoma incidence was in line with two other recent meta-analyses. 95,96A possible causal mechanism of this CCB effect is that impairment of autoregulation might result in no further pharmaceutical dilation in affected zones and that dilation of other-more healthy-capillary beds shunt away blood to unaffected areas. 96,97Previously, CCBs (more specifically nifedipine) and ACE inhibitors have been argued beneficial in the discussion around endothelial dysfunction and Flammer syndrome.This highlights the necessity to adjust for vascular comorbidity as these drugs might be used in patient groups that are prone to glaucoma due to a vascular cause. 98This also prompts the idea for studies designed to further quantify autoregulation and retinal vascular response before and after start of antihypertensive medication including the different classes of CCBs.
Regarding β-blockers, one meta-analysis also points to a decreased glaucoma incidence (OR 0.83 [0.75-0.92]).However, only in one of the included studies, adjustment for covariates as BMI, smoking status, age, gender, and incident hypertension was executed.In this study, the lower OR for β-blockers and glaucoma incidence was barely significant (0.91 [0.83-0.99]). 95,99garding ACE inhibitors, only two studies provided evidence against its use.Chong et al. 67 found that ACE inhibitors (and diuretics) were associated with more RNFL and GCL thinning after adjustment of covariates.Langman et al. 100 report higher incidence of POAG in this group both in current as past intake, which brings the authors to point towards uncontrolled hypertension rather than the class of medication as culprit.
Taken together the authors speculate that as first line treatment for hypertension in glaucoma patients thiazides and/or to a lesser extent ACE inhibitors or β-blockers, depending on concomitant comorbidities as heart failure, lung or kidney disease, could be considered (rather than CCBs).However, validation studies are needed to support such clinical recommendations.
Ophthalmologists do not commonly treat hypertension and professionals who do, haven't established preferred practice patterns on the management of arterial BP in their glaucoma patients. 17he importance of arterial BP in glaucoma management has also not yet been addressed in recent studies or most guidelines on the diagnosis and treatment of arterial hypertension. 101Glaucoma featured for the first time in the new hypertension guideline released in 2023 by the European Society of Hypertension.Most of our recommendations below are in line with this guideline. 102Of note, the recommendation puts β-blockers forward as mainstay treatment in hypertensive patients with glaucoma, based on one study and an possible IOP-lowering effect. 42,103,104][107] Therefore, this recommendation may be reconsidered in a future update of the Hypertension Guidelines.
Further studies investigating BP targets and their impact on glaucoma incidence and progression are needed.Additional sub-analyses studying the effect of antihypertensive drugs on glaucoma incidence and progression also merit to be investigated more.
Limitations of this review are methodological in nature and inherent to the represented research.Only papers in English were included, OPP and BP parameters are heterogeneously reported, and a lot of studies do not adjust for continuous BP levels, or even the mere presence of arterial hypertension, nor other covariates.
Based on our systemic literature review, we propose some clinical recommendations for the management of glaucoma patients with concomitant systemic hypertension, summarized in Figure 1, and some research recommendations for future studies on this topic.-In case of nocturnal (over-)dippers, morning dosing of antihypertensive medication could be considered (taking into account the pros and cons as discussed above).-Up till now there is insufficient evidence to justify decrease of antihypertensive medication in case of merely nocturnal over-dipping.-Currently available evidence suggests that CCB may not be recommended as first line treatment in patients with both glaucoma and arterial hypertension.Instead, thiazides and/or to a lesser extent ACE inhibitors might be more suitable.β-blockers might also be potentially beneficial in glaucoma.However, additional evidence is needed to support such clinical recommendations.

Research recommendations
-Future research might benefit from BP data being presented continuously, and when categorized, being presented by different cut-off values to enable comparison. 10866]85 This patient exhibits all mentioned risk factors for glaucoma progression except overall nocturnal MAP that is still in the Dresden safety range. 47These overlays could visually aid the clinician in evaluating 24-h ABPMs.ABPM, ambulatory blood pressure measurement; DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure.

-
If a patient presents with glaucomatous progression despite normal or well-controlled IOP, 24-h ABPM is useful to rule out nocturnal systemic hypotension or high BP variability.-In glaucoma patients with concomitant systemic hypertension a low threshold to perform a 24-h ABPM is justified.-Antihypertensive adjustment should be based on 24-h ABPM.Repeated 24-h ABPM is recommended after medication changes.-Diagnosed nocturnal (over-)dipping or high BP variability in a glaucoma patient should prompt a collaborative treatment strategy between the treating physician and ophthalmologist.-In case of high daytime BP fluctuation, high (to normal) BP and relatively absent nocturnal dipping, intensification of the antihypertensive treatment could lower BP variability.

Figure 1 .
Figure 1.Figure of a simplified, individual example of a 24-h ABPM with overlay of recommended BP levels.The recommendations are based on the cited references that are also mentioned in the manuscript text, where the daytime upper limits are derived from the ACA/AHA hypertension guidelines.90This includes the daytime systolic optimum between 107 and 130 mm Hg,60 the daytime diastolic optimum between 63 and 80 mm Hg,60 the nocturnal MAP Dresden safety range between 65 and 90 mm Hg47 and the nocturnal diastolic optimum between 60 and 70 mm Hg.12 High BP variability features in this review as glaucoma progression risk factor, however clear cut-off values have not been put forward yet.50,[64][65][66]85 Thi patient exhibits all mentioned risk factors for glaucoma progression except overall nocturnal MAP that is still in the Dresden safety range.47These overlays could visually aid the clinician in evaluating 24-h ABPMs.ABPM, ambulatory blood pressure measurement; DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. 44

Table 1 : Arterial hypertension Type of study Study population Patients Eyes Men/women Country/ Ethnicity Age Hypertension Antihypertensives Conclusion Significance level
Dielemans et al. 33

Table 2 :
Nocturnal dipping and hypotension