SCORE Study Report 15: Incidence, Risk Factors, and Timing of Elevated Intraocular Pressure after Intravitreal Triamcinolone Acetonide Injection for Macular Edema Secondary to Retinal Vein Occlusion

Abstract

Importance:

The Standard of Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study showed that intravitreal triamcinolone acetonide (IVTA) is effective at reducing macular edema and improving visual acuity in participants with retinal vein occlusion. Secondary analysis of the incidence, risk factors, and timing of intraocular pressure (IOP) elevation occurring after IVTA provide guidance for clinical decision-making and management of patients treated with IVTA.

Objective:

To investigate the incidence, risk factors, and time course of IOP elevation in participants in the SCORE Study.

Design, Setting, and Participants:

Prospective, randomized clinical trial conducted at 75 clinical sites. Six hundred eighty-two patients with macular edema secondary to retinal vein occlusion were enrolled in the study.

Intervention:

Study participants were randomized to standard of care (SOC), 1-mg IVTA, or 4-mg IVTA therapy and followed for 24.7 ± 10.3 (SD) months.

Main Outcome Measure:

IOP elevation > 10 mm Hg from baseline.

Results:

Kaplan-Meier incidences of IOP elevation > 10 mm Hg from baseline at 36 months were 0.02 (95% confidence interval [CI]: 0.01, 0.06), 0.09 (95% CI: 0.05, 0.14), and 0.45 (95% CI: 0.38, 0.53) in the SOC, 1-mg IVTA, and 4-mg IVTA groups, respectively. Rates of IOP-related events were higher for the 4-mg IVTA group compared with the other groups (P≤.0001 for main outcome measure). Younger age, 4-mg IVTA versus 1-mg IVTA treatment, and higher baseline IOP were found to confer greater risk of IOP-related events (P<.05 for all). The median number of days from time of first injection to IOP elevation > 10 mm Hg from baseline was 34.0 and 52.5 days in participants treated with 1-mg and 4-mg IVTA, respectively.

Conclusions and Relevance:

IVTA injection therapy, in particular the 4-mg dose, is associated with an increased risk of IOP elevation. Risk factors for an IOP-related event include higher treatment dose, younger age, and higher baseline IOP. IOP-related events may take several months from the time of first IVTA injection to occur. Clinicians should be mindful of these risk factors when assessing risk-benefit of IVTA therapy and also of the need for long-term follow-up of participants at risk for this complication.

Trial registration:

NCT00105027

INTRODUCTION

Macular edema associated with retinal vein occlusion is an important cause of visual morbidity.^1,2 Intravitreal triamcinolone acetonide (IVTA) is an effective therapeutic measure for reduction of macular edema and visual rehabilitation.^3,4 Unfortunately, increased intraocular pressure (IOP) and subsequent glaucomatous optic neuropathy remain important potential complications associated with this treatment modality.^5–7 Due to the retrospective nature of prior studies^5–12 investigating the clinical course of patients experiencing increased IOP in the setting of IVTA therapy, a wide range of incidence rates of this complication has been reported. The purpose of the current study is to determine the incidence, timing, and risk factors for IOP elevation among participants enrolled in the Standard of Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study.

METHODS

The SCORE Study design and methods, described in detail in previous SCORE Study reports, are summarized here in brief.^13–15 The protocol and consent forms for this randomized multicenter clinical study were approved by either a clinical site’s institutional review board or a centralized institutional review board (Jaeb Center for Health Research, Tampa, Fl). An independent data and safety monitoring committee, appointed by the National Eye Institute, provided data and safety monitoring oversight. The study adhered to the tenets of the Declaration of Helsinki. Written Health Insurance Portability and Accountability Act-compliant informed consents were obtained from all participants before screening for eligibility.

The SCORE Study included two multicenter phase III randomized clinical trials that compared contemporaneous standard of care treatment with IVTA for the treatment of macular edema due to retinal vein occlusion, one among patients with branch retinal vein occlusion³ (BRVO) and the other among patients with central retinal vein occlusion⁴ (CRVO). Eyes were randomized to treatment with 1-mg IVTA, 4-mg IVTA, or standard of care (SOC). For BRVO, SOC was grid laser treatment for eyes without dense macular hemorrhage and deferral of laser until hemorrhage cleared sufficiently for laser to be administered in eyes with dense macular hemorrhage. For CRVO, SOC was observation.

Prospective participants underwent screening examinations within 21 days of randomization, which included IOP measurement by Goldmann applanation tonometry. Exclusion criteria included: 1) intravitreal corticosteroids within 6 months before randomization; 2) baseline IOP ≥ 25 mm Hg; 3) history of open-angle glaucoma; 4) history of steroid-induced IOP elevation requiring IOP-lowering treatment, and 5) evidence of pseudoexfoliation. Participants with a history of ocular hypertension were not excluded if the participant was using no more than one topical glaucoma medication, the most recent visual field was normal, and the optic nerve did not appear glaucomatous.

The IVTA formulation used in the SCORE Study was manufactured as a sterile, preservative-free, micronized triamcinolone acetonide injectable suspension (4-mg brand name Trivaris, Allergan, Inc, Irvine, CA) of 1 or 4 mg per 0.5 mL.

IOP was measured at study visits at 4-month intervals after randomization and at safety visits 4 days (±3 days) and at 4 weeks (± 1 week) after each injection. Treatment to lower IOP could be initiated at the discretion of the treating physician. Injections were repeated at 4-month intervals based on specific retreatment criteria, with allowance for deferral of injections based on reasons such as elevated IOP that required treatment.

Statistical Analysis

Age, gender, ethnicity, race, diabetes, systemic hypertension, coronary heart disease, retinal vein occlusion diagnosis (CRVO, BRVO or HRVO), IOP, treatment group (1-mg IVTA, 4-mg IVTA, and SOC), pre-enrollment duration of macular edema, electronic ETDRS visual acuity letter score, central subfield and center point thickness based on optical coherence tomography (OCT), and areas of retinal hemorrhage and retinal thickness based on fundus photography were measured at baseline. IOP and the need for IOP-lowering medications or glaucoma surgery were recorded at each study visit.

Kaplan-Meier analysis was performed to estimate the cumulative incidences of IOP elevation > 10 mm Hg from baseline, maximum rise > 25 mm Hg and > 30 mm Hg, and commencement of medical and/or surgical IOP-lowering therapy, with the log-rank test used to test for differences among treatment groups. These safety outcomes were defined a priori in the SCORE Study statistical analysis plan.

Participants with a diagnosis of neovascular glaucoma (n=22), SOC participants who received IVTA (n=28), those in an IVTA arm who did not receive an injection (n=1), and those without follow-up (n=15) were excluded from analyses. Eyes requiring IOP-lowering medication at baseline were excluded from analyses of commencement of IOP-lowering therapy. Day 4 visit data were excluded from the analyses as IOP elevation at this time was considered more likely the result of the injection and not steroid-related.

Cox regression analysis was performed as post hoc, exploratory analyses to investigate the effect of treatment assignment and baseline factors (noted above) on risk of an IOP event. A step-wise regression procedure alternating forward selection and backward elimination was used to identify predictors, keeping those factors significant at the 0.05 level. The proportion of participants who had IOP elevation > 10 mm Hg from baseline according to the injection number was also examined as a post hoc, exploratory analysis.

RESULTS

The SCORE Study enrolled 271 participants in the CRVO trial and 411 participants in the BRVO trial. After 66 exclusions, included in the analyses were 616 study participants (221 participants receiving 1-mg IVTA injection(s), 213 participants receiving 4-mg IVTA injection(s), and 182 SOC participants). The average follow-up was 24.7 ± 10.3 (SD) months, with an average of 3.2 ± 2.0 (SD) injections received among the IVTA participants.

Baseline characteristics of SCORE Study participants who experienced subsequent IOP elevation >10 mm Hg from baseline (n=103), maximum rise > 25 mm Hg (n=116) or > 30 mm Hg (n=55), or required medical (n=134) and/or surgical IOP-lowering therapy (n=6) are shown in Table 1.

Table 1.

Baseline and Demographic Characteristics of Participants who Experienced an IOP-Related Event in The SCORE Study.

		Maximum IOP During Follow-up
	All participants	>25 mm Hg	>30 mm Hg	>10 mm Hg from baseline	IOP-lowering Medication	Glaucoma surgery
Mean age ±SD (range)	67.0 ± 11.5 (27.0, 94.0)	65.2 ± 11.7 (32.0, 90.0)	63.1 ± 13.2 (32.0, 90.0)	63.3 ± 12.5 (27.0, 90.0)	65.2 ± 11.6 (32.0, 90.0)	62.7 ± 5.54 (55.0, 68.0)
Mean baseline IOP ±SD (range)	15.2 ± 3.07 (8.00, 24.0)	16.6 ± 2.82 (10.0, 23.0)	16.8 ± 3.02 (12.0, 23.0)	15.3 ± 2.85 (10.0, 23.0)	16.2 ± 2.94 (10.0, 23.0)	17.2 ± 2.93 (12.0, 20.0)
Female Gender, N (%)	301 (48%)	44 (38%)	21 (38%)	36 (35%)	55 (41%)	2 (33%)
White, N (%)	562 (90%)	99 (85%)	48 (87%)	88 (85%)	116 (87%)	6 (100%)
Not Hispanic or Latino, N (%)	568 (91%)	107 (92%)	50 (91%)	92 (89%)	123 (92%)	4 (67%)
Systemic Hypertension, N (%)	449 (71%)	78 (67%)	37 (67%)	71 (69%)	90 (67%)	5 (83%)
Diabetes Mellitus, N (%)	106 (17%)	16 (14%)	8 (15%)	18 (17%)	20 (15%)	1 (17%)
BRVO, N (%)	328 (52%)	56 (48%)	24 (44%)	55 (53%)	67 (50%)	2 (33%)
CRVO, N (%)	243 (39%)	48 (41%)	24 (44%)	38 (37%)	54 (40%)	3 (50%)
HRVO, N (%)	56 (9%)	12 (10%)	7 (13%)	10 (10%)	13 (10%)	1 (17%)
1-mg IVTA, N (%)	221 (35%)	21 (18%)	4 (7%)	16 (16%)	34 (25%)	0 (0%)
4-mg IVTA, N (%)	213 (34%)	86 (74%)	49 (89%)	83 (81%)	90 (67%)	5 (83%)
Standard of care, N (%)	193 (31%)	9 (8%)	2 (4%)	4 (4%)	10 (7%)	1 (17%)
Sample size	627	116	55	103	134	6

IOP, Intraocular pressure (mm Hg); IVTA, Intravitreal triamcinolone; SD, standard deviation; IOP Med, commencement of intraocular-pressure lowering medication.

Results of Kaplan-Meier analysis estimating the cumulative incidence of IOP-related events by treatment assignment at 12, 24, and 36 months are shown in Table 2. The cumulative incidences of IOP elevation > 10 mm Hg from baseline at 36 months were 0.02 (95% confidence interval [CI]: 0.01, 0.06), 0.09 (95% CI: 0.05, 0.14), and 0.45 (95% CI: 0.38, 0.53) in the SOC, 1-mg IVTA, and 4-mg IVTA assignment groups, respectively (p< 0.0001). Corresponding Kaplan-Meier curves for the outcome of IOP elevation > 10 mm Hg from baseline are depicted in Figure 1. Differences were also noted for IOP > 25 mm Hg, IOP > 30 mm Hg, and requiring IOP-lowering medications, with the 4-mg IVTA group having the highest incidence of IOP elevation compared with 1-mg IVTA and SOC (P<0.0001). Note that few participants in the SOC group required initiation of IOP-lowering therapy during follow-up. Glaucoma surgical interventions were rare in these participants, but highest in the 4-mg IVTA group.

Table 2.

Cumulative Incidences of Intraocular Pressure-Related Event in the SCORE Study.

			Cumulative Incidence (95% Confidence Limits)
IOP Event	Treatment Assignment	Total No.	12-month	24-month	36-month	Log-rank p-value
IOP > 25 mm Hg	SOC	182	0.02 (0.01, 0.06)	0.03 (0.02, 0.08)	0.08 (0.04, 0.16)	<.0001
	1-mg IVTA	221	0.07 (0.05, 0.12)	0.10 (0.06, 0.15)	0.12 (0.08, 0.19)
	4-mg IVTA	213	0.32 (0.26, 0.38)	0.43 (0.36, 0.51)	0.47 (0.39, 0.55)
IOP > 30 mm Hg	SOC	182	0.01 (0.00, 0.04)	0.01 (0.01, 0.05)	0.01 (0.01, 0.05)	<.0001
	1-mg IVTA	221	0.01 (0.00, 0.04)	0.02 (0.01, 0.06)	0.02 (0.01, 0.06)
	4-mg IVTA	213	0.18 (0.13, 0.24)	0.23 (0.18, 0.30)	0.27 (0.20, 0.34)
IOP > 10 mm Hg from baseline	SOC	182	0.01 (0.01, 0.04)	0.02 (0.01, 0.06)	0.02 (0.01, 0.06)	<.0001
	1-mg IVTA	221	0.06 (0.03, 0.10)	0.08 (0.05, 0.12)	0.09 (0.05, 0.14)
	4-mg IVTA	213	0.29 (0.24, 0.36)	0.41 (0.34, 0.48)	0.45 (0.38, 0.53)
IOP-lowering Medication	SOC	169	0.04 (0.02, 0.08)	0.05 (0.03, 0.10)	0.09 (0.04, 0.18)	<.0001
	1-mg IVTA	215	0.11 (0.07, 0.16)	0.16 (0.11, 0.22)	0.19 (0.14, 0.26)
	4-mg IVTA	206	0.38 (0.32, 0.45)	0.45 (0.38, 0.52)	0.48 (0.40, 0.56)
Glaucoma Surgical Intervention	SOC	182	0.00 (0.00, 0.00)	0.00 (0.00, 0.00)	0.02 (0.00, 0.12)	0.0271
	1-mg IVTA	221	0.00 (0.00, 0.00)	0.00 (0.00, 0.00)	0.00 (0.00, 0.00)
	4-mg IVTA	213	0.00 (0.00, 0.03)	0.02 (0.01, 0.05)	0.04 (0.02, 0.10)

IOP, Intraocular pressure (mm Hg); IVTA, Intravitreal triamcinolone; SOC, Standard of Care

Figure 1.

Kaplan-Meier analysis depicting IOP elevation > 10 mm Hg above baseline according to treatment group. The incidence of IOP > 10 mm Hg from baseline at 36 months was highest in the 4-mg IVTA group.

Results of stepwise Cox regression analysis investigating the effect of baseline characteristics on risk of IOP-related events are presented in Table 3. Younger age, 4-mg IVTA versus SOC, and 1-mg IVTA versus SOC were found to confer greater risk for all IOP events, except for glaucoma surgery to lower IOP. Higher baseline IOP conferred greater risk for all outcomes except IOP elevation > 10 mm Hg over baseline. Female gender was associated with a lower risk of IOP elevation > 10 mm Hg over baseline; smaller area of baseline retinal hemorrhage and lower screening visual acuity letter score were associated with a higher risk of IOP > 30 mm Hg during follow-up. No factors were associated with need for glaucoma surgery.

Table 3.

Multivariate Cox Regression Analysis for Risk of IOP-Related Events in SCORE Study

IOP Event		IOP > 25 mm Hg		IOP > 30 mm Hg		IOP > 10 mm Hg over baseline		IOP-lowering Medications
		N=588		N=588		N=588		N=564
Baseline Characteristic		Hazard Ratio	P-value	Hazard Ratio	P-value	Hazard Ratio	P-Value	P-value	Hazard Ratio
Age (per 1 year increase in age)		0.98 (0.96,0.99)	0.0099	0.96 (0.94–0.98)	0.0011	0.96 (0.95,0.98)	<0.0001	0.98 (0.96,0.99)	0.0039
Treatment assignment	1-mg IVTA	2.38 (1.05,5.39)	<0.0001	1.24 (0.21,7.36)	<0.0001	3.19 (1.06,9.66)	<0.0001	3.20 (1.53,6.67)	<0.0001
	4-mg IVTA	14.32 (6.93,29.59)		27.25 (6.65,111.73)		24.48 (9.00,66.62)		12.17 (6.12,24.18)
Baseline IOP (per 1 mm Hg increase)		1.20 (1.13,1.28)	<0.0001	1.21 (1.11,1.37)	<0.0001			1.14 (1.08,1.20)	<0.0001
Female						0.60 (0.40,0.91)	0.0155
Baseline retinal hemorrhage based on fundus photography (per 1 disc area increase)				0.86 (0.77,0.96)	0.0081
Screening visual acuity letter score (per 1 increase in score)				0.98 (0.96,0.99)	0.0103

Table 4 examines the relationship between the number of IVTA injections a participant received and IOP elevation > 10 mm Hg from baseline. After the first injection, 5% of the 1-mg IVTA participants had an event compared with 18% of the 4-mg IVTA participants. The median number of days from time of first injection to IOP elevation > 10 mm Hg from baseline was 34.0 (n=10) and 52.5 days (n=38) among participants treated with 1-mg and 4-mg IVTA, respectively (data not shown, p=0.62). The proportion with an IOP event after injection number 2 through 5 was similar to that of the first injection.

Table 4.

Proportion of Participants with a Change from BL in IOP > 10 mmHg Event after an Injection, but Prior to Subsequent Injection

	1-mg IVTA Treatment Group				4-mg IVTA Treatment Group
Injection Number	Number of Participants with an Injection	Number of Participants with an IOP Event	Proportion	Number of New Cases	Number of Participants with an Injection	Number of Participants with an IOP Event	Proportion	Number of New Cases
1	221	10	0.05	10	213	38	0.18	38
2	173	3	0.02	1	166	32	0.19	22
3	124	6	0.05	3	104	24	0.23	16
4	86	3	0.03	1	71	9	0.13	2
5	54	1	0.02	0	43	7	0.16	5
6	40	0	0.00	0	19	1	0.05	0
7	21	1	0.05	1	12	0	0.00	0
8	10	0	0.00	0	7	0	0.00	0
9	4	0	0.00	0	4	0	0.00	0

DISCUSSION

Prior epidemiologic studies demonstrate an association between increased IOP and open-angle glaucoma.^16,17 Interventional studies have supported the role of IOP reduction to decrease the risk of development and progression of the disease.^18–20 Elevated IOP is an important, treatable risk factor for the development of glaucomatous optic neuropathy.

Clinically significant IOP increases occurred with relatively high incidence in SCORE Study participants treated with IVTA injections. In 4-mg IVTA participants, the 36-month cumulative incidence of IOP elevation > 10 mm Hg over baseline was 45%, with a 36-month incidence of 48% for participants requiring IOP-lowering medication.

Precise mechanisms of steroid-induced IOP rise may include downregulation of trabecular matrix metalloproteinase activity,²¹ increased myocilin production,²² and/or decreased trabecular phagocytic activity.^23,24 These biochemical events result in increased resistance to aqueous outflow at the level of the trabecular meshwork and may be initiated by steroids administered by any route.²⁵ Despite the widespread use of anti-vascular endothelial growth factor therapy, IVTA injections may occasionally be indicated for the treatment of macular edema associated with a range of posterior segment diseases including retinal vein occlusion, diabetic macular edema, and uveitis.²⁶

The incidences of IOP elevation in the SCORE Study are consistent with the literature. In a study of participants receiving 4-mg IVTA for treatment of various posterior segment diseases, Vasconecelos-Santos and colleagues⁹ reported an incidence of IOP ≥ 21 mm Hg of 32% with a mean follow-up of 7.7 months. This compares to a 32% cumulative incidence of IOP > 25 mm Hg noted in the current study at 12-months. In a retrospective, observational case series, Smithen et al¹⁰ describe a similar incidence of 40.4% for IOP ≥ 24 mm Hg with a mean follow-up of 9.3 months. Roth et al⁷ described a somewhat lower incidence of 28.2% for IOP > 25 mm Hg at 24 months after 4-mg IVTA injection in a large retrospective case series.

The current study identifies higher baseline IOP as an independent risk factor for IOP > 25 mm Hg after IVTA injection. Participants experiencing an IOP > 25 mm Hg had a mean baseline IOP of 16.6 ± 2.84 (SD) mm Hg compared to 14.93 ± 3.03 (SD) mm Hg among those without an IOP > 25 mm Hg (data not shown; p<0.0001 based on t-test). Prior studies^6,9,10 also identified higher baseline IOP as a risk factor for steroid-related IOP elevation. In a retrospective case series, Smithen et al¹⁰ found that 60% of nonglaucomatous patients with baseline IOP ≥ 15 mm Hg experienced an IOP elevation after IVTA compared with 22.7% of those with baseline IOP < 15 mm Hg (P<.01). When interpreting higher baseline IOP as a risk factor for post-injection IOP elevation to a predefined level, it is important to note that this may relate to less of a steroid-related IOP increase, but rather to the higher baseline IOP enabling the threshold to be reached more easily. Further, the predefined threshold levels of 25 mm Hg and 30 mm Hg used in this study and throughout the literature are arbitrary in nature. Elevations to these respective IOP levels may be tolerated to different degrees among various individuals.

Younger age was associated with an increased risk of steroid-related IOP rise in our study consistent with studies by Shukla et al²⁷ and Roth et al.⁷ Although younger subjects in the study performed by Vasconcelos-Santos and colleagues⁹ had an increased risk of IOP rise compared to older subjects, this did not reach statistical significance. In that study, 50% of participants younger than age 40 experienced steroid-related IOP rise compared to 31.3% of participants older than 40 years of age (P=0.604). Shukla and colleagues²⁷ found that IOP rise occurred in 45% of subjects ≤ 45 years versus 21% of older patients (P=.006). The reason for the increased risk among younger patients is not clear. Shukla et al²⁷ postulated that higher endogenous cortisol levels in younger individuals may lead to greater susceptibility to an IOP-related event with further exposure to therapeutic steroids. Another possibility is that younger age allows for increased gene expression of the trabecular meshwork proteins responsible for decreased outflow facility. Indeed, steroid-response ocular hypertension has been found to occur with relatively high frequency in the pediatric population.²⁸

The dosage administered in a single IVTA injection may range from 1 to 25 mg.^29,30 Dosages up to 4 mg are more typical, although the actual dose administered may vary due to variable concentrations injected through a small gauge needle.³¹ The current analysis is unique in prospectively comparing two different dosages of IVTA with standard of care therapy with regard to IOP-related events. Participants treated with 4-mg IVTA had significantly higher risk of IOP > 25 mm Hg compared with SOC (HR=14.32), and 1-mg IVTA had a much smaller increase in risk over SOC (HR=2.38) (p<0.0001 for a treatment group effect). This represents a clinically important finding as treating practitioners may wish to consider a lower IVTA dosage in patients with other risk factors for an IOP-related event. This was the recommendation in the primary SCORE Study reports.^3,4

An IOP-related event after IVTA injection may take several weeks to months to occur. The median time from injection to IOP elevation > 10 mm Hg over baseline in the current study was 34.0 days (range, 21 to 598 days) and 53.5 days (range, 26 to 135 days) days in the 1-mg and 4-mg treatment groups, respectively. Importantly, the current analysis excluded all patients with a previous diagnosis of glaucoma and/or baseline IOP ≥ 25 mm Hg. Prior studies investigating this outcome did not exclude such patients and, therefore, time to IOP rise was found to be of shorter duration as glaucomatous and ocular hypertensive individuals were found to experience these events relatively sooner.⁷ Another possibility for differences noted in time to onset of an IOP-related event in this study is the use of a micronized, nondispersive triamcinolone formulation (Trivaris, Allergan Inc., Irvine, CA) as opposed to preserved formulations used in most prior studies. The triamcinolone formulation used in this study is suspended in a proprietary hydrogel (Hyladur, Allergan Inc., Irvine, CA), which may have delayed the time to onset of an IOP rise. However, in a study³² investigating differences in pharmacokinetics and pharmacodynamics among four distinct formulations of triamcinolone acetonide, the preserved formulation (Kenalog, Brystol-Meyers-Squibb, Princeton, NJ) was found to have longer vitreous visibility and durability than three non-preserved formulations, including Trivaris.

There was no relationship between the number of 1-mg IVTA or 4-mg IVTA injections a participant receives and having an IOP elevation > 10 mm Hg above baseline (Table 4). Investigating this relationship between the number of injections and IOP elevation is complex. Although we may expect a greater number of injections to be associated with a higher risk of IOP events, it is possible there may be an opposite effect, in that IOP events after a first injection may cause the physician to hold off on subsequent injections; therefore, fewer injections may be associated with a higher number of IOP events. Thus, it may be that multiple IVTA injections drive IOP events, but that IOP events impact the physician’s behavior for subsequent IVTA treatment. These two opposing factors likely impact the interpretation of data presented in Table 4. Further, it is not clear whether multiple events are distinct events, or whether an IOP event after a second injection is a continuation of an event after the first injection.

Strengths of the present study include prospectively gathered data from a large number of participants enrolled at various clinical sites and presenting at defined intervals after intervention. Although risk factors for steroid-related IOP-rise have been studied previously, prior investigations were largely retrospective in nature with irregular follow-up intervals.²⁴ Further, the intended IVTA dose in retrospective studies may have varied from the actual dose delivered during intravitreal injection due to variable concentrations injected via a small gauge needle. The current study utilized a preservative-free, micronized triamcinolone acetonide injectable suspension (4-mg brand name Trivaris, Allergan, Inc, Irvine, CA), allowing for greater consistency of injection concentration. The present study included only eyes with a baseline diagnosis of macular edema associated with retinal vein occlusion. Prior studies included a range of posterior segment pathologies, including uveitic diseases, which may have varied in their independent contribution to an IOP-related event. The current analysis excluded participants with a baseline diagnosis of glaucoma, IOP > 25 mm Hg, or prior history of steroid-related IOP rise. These prospectively defined exclusion criteria were not followed in prior studies and may have confounded the incidence, risk, and timing data.

Limitations of the present study include a lack of structural and functional measures of optic nerve health in individuals experiencing an IOP-related event. Such data would allow for an assessment of the risk and progression of glaucomatous optic neuropathy associated with IVTA therapy. Additionally, our study did not include predefined criteria for initiating IOP-lowering therapy, which was left to the discretion of treating clinicians. The present study utilized a triamcinolone acetonide formulation (Trivaris, Allergan Inc., Irvine, CA) that is not commercially available and, therefore, not used in routine clinical practice. The unique pharmacokinetics and pharmacodynamics of this agent, which is suspended in a proprietary hydrogel (Hyladur, Allergan Inc., Irvine, CA), may have impacted the results. However, prior studies using different triamcinolone formulations have reported similar risk factors, suggesting that the active ingredient, triamcinolone acetonide, plays the greatest role in IOP-related events. Because the goal of the paper had many exploratory aspects, no adjustments for multiple testing were performed. Results of these analyses need to be interpreted in light of the lack of statistical adjustments.

This study demonstrates a higher incidence of IOP-related events occurring after 4-mg IVTA therapy compared with the 1-mg dose and no injection of steroid, for macular edema associated retinal vein occlusion. Younger patients with higher baseline IOPs require vigilant long-term follow-up by the treating clinician as IOP events may take several months to occur and the incidence of such an event increases over time. Particularly, for high-risk patients, a lower dosage of IVTA should be considered, but close follow-up is still warranted.