The incidence of intraocular pressure greater than 10 mm Hg from baseline at 36 months was highest in the 4-mg intravitreal triamcinolone acetonide (IVTA) group. SOC indicates standard of care.
eAppendix. SCORE Study Group Author Listing
Aref AA, Scott IU, Oden NL, Ip MS, Blodi BA, VanVeldhuisen PC, . Incidence, Risk Factors, and Timing of Elevated Intraocular Pressure After Intravitreal Triamcinolone Acetonide Injection for Macular Edema Secondary to Retinal Vein OcclusionSCORE Study Report 15. JAMA Ophthalmol. 2015;133(9):1022-1029. doi:10.1001/jamaophthalmol.2015.1823
Copyright 2015 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
The Standard of Care vs 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 provides guidance for clinical decision making and management of patients treated with IVTA.
To investigate the incidence, risk factors, and time course of IOP elevation in participants in the SCORE Study.
Design, Setting, and Participants
Secondary analysis conducted from August through December 2014 of a prospective, randomized clinical trial featuring an evaluable population conducted at 75 clinical sites. Six hundred eighty-two patients with macular edema secondary to retinal vein occlusion were enrolled in the study. The SCORE Study enrollment period ran from November 4, 2004, to February 29, 2008, with participant follow-up ending February 28, 2009.
Study participants were randomized to standard of care, 1 mg of IVTA, or 4 mg of IVTA therapy and followed up for a mean (SD) of 24.7 (10.3) months.
Main Outcomes and Measures
Intraocular pressure elevation greater than 10 mm Hg from baseline.
Kaplan-Meier incidences of IOP elevation greater than 10 mm Hg from baseline at 36 months were 0.02 (95% CI, 0.01-0.06), 0.09 (95% CI, 0.05-0.14), and 0.45 (95% CI, 0.38-0.53) in the standard of care, 1-mg IVTA, and 4-mg IVTA groups, respectively. The rates of IOP-related events were higher for the 4-mg IVTA group compared with the other groups (P ≤ .001 for main outcome measure). Younger age, 4-mg IVTA vs 1-mg IVTA treatment, and higher baseline IOP were found to confer greater risk for IOP-related events (P < .05 for all). The median number of days from time of first injection to IOP elevation greater than 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
Intravitreal triamcinolone acetonide injection therapy, in particular the 4-mg dose, is associated with an increased risk for IOP elevation. The risk factors for an IOP-related event include higher treatment dose, younger age, and higher baseline IOP. Intraocular pressure–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 the risks and benefits of IVTA therapy and also of the need for long-term follow-up of participants at risk for this complication.
clinicaltrials.gov Identifier: NCT00105027
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 the reduction of macular edema and visual rehabilitation.3,4 However, increased intraocular pressure (IOP) and subsequent glaucomatous optic neuropathy remain important potential complications associated with this treatment modality.5- 7 Owing to the retrospective nature of prior studies5- 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 was to determine the incidence, timing, and risk factors for IOP elevation among participants enrolled in the Standard of Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study.
The purpose of the current study was to determine the incidence, timing, and risk factors for intraocular pressure (IOP) elevation among participants enrolled in the Standard of Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study.
In the SCORE Study, intravitreal triamcinolone acetonide (IVTA) therapy was associated with an increased risk for IOP elevation.
The 4-mg IVTA dose, younger age, and higher baseline IOP are associated with increased risk for IOP-related events.
Intraocular pressure–related events may take several months from the time of first IVTA injection to occur.
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, Florida). 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 2 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.
Quiz Ref IDProspective 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 greater than or equal to 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 1 topical glaucoma medication, the most recent visual field finding 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) of 1 or 4 mg per 0.5 mL.
Intraocular pressure was measured at study visits at 4-month intervals after randomization and at safety visits 4 ± days and at 4 ± 1 weeks 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.
Age, sex, ethnicity, race, diabetes mellitus, systemic hypertension, coronary heart disease, retinal vein occlusion diagnosis (CRVO, BRVO, or hemiretinal vain occlusion), IOP, treatment group (1-mg IVTA, 4-mg IVTA, and SOC), pre-enrollment duration of macular edema, electronic Early Treatment Diabetic Retinopathy Study visual acuity letter score, central subfield and center point thickness based on optical coherence tomography, and areas of retinal hemorrhage and retinal thickness based on fundus photography were measured at baseline. Intraocular pressure and the need for IOP-lowering medications or glaucoma surgery were recorded at each study visit.
Quiz Ref IDKaplan-Meier analysis was performed to estimate the cumulative incidences of IOP elevation greater than 10 mm Hg from baseline, maximum rise greater than 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 here) on the risk for an IOP event. A stepwise 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 greater than 10 mm Hg from baseline according to the injection number was also examined as a post hoc exploratory analysis.
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 mean (SD) follow-up was 24.7 (10.3) months, with a mean (SD) of 3.2 (2.0) injections received among the IVTA participants.
Baseline characteristics of SCORE Study participants who experienced subsequent IOP elevation greater than 10 mm Hg from baseline (n = 103), maximum rise greater than 25 mm Hg (n = 116) or greater than 30 mm Hg (n = 55), or required medical (n = 134) and/or surgical IOP-lowering therapy (n = 6) are shown in Table 1.
The 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 greater than 10 mm Hg from baseline at 36 months were 0.02 (95% 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 < .001). Corresponding Kaplan-Meier curves for the outcome of IOP elevation greater than 10 mm Hg from baseline are depicted in the Figure. Differences were also noted for IOP greater than 25 mm Hg, IOP greater than 30 mm Hg, and requiring IOP-lowering medications, with the 4-mg IVTA group having the highest incidence of IOP elevation compared with the 1-mg IVTA and SOC groups (P < .001). 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.
Quiz Ref IDThe results of stepwise Cox regression analysis investigating the effect of baseline characteristics on the risk for IOP-related events are presented in Table 3. Younger age, 4-mg IVTA vs SOC, and 1-mg IVTA vs SOC were found to confer the greater risk for all IOP events, except glaucoma surgery to lower IOP. Higher baseline IOP conferred greater risk for all outcomes except IOP elevation greater than 10 mm Hg over baseline. Female sex was associated with a lower risk for IOP elevation greater than 10 mm Hg over baseline; smaller area of baseline retinal hemorrhage and lower screening visual acuity letter score were associated with a higher risk for IOP greater than 30 mm Hg during follow-up. No factors were associated with the need for glaucoma surgery.
Table 4 examines the relationship between the number of IVTA injections a participant received and IOP elevation greater than 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 greater than 10 mm Hg from baseline was 34.0 (n = 10) and 52.5 (n = 38) days among participants treated with 1-mg and 4-mg IVTA, respectively (data not shown; P = .62). The proportion with an IOP event after injection numbers 2 through 5 was similar to that of the first injection.
Prior epidemiologic studies have demonstrated an association between increased IOP and open-angle glaucoma.16,17 Interventional studies have supported the role of IOP reduction to decrease the risk for 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 greater than 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 the treatment of various posterior segment diseases, Vasconcelos-Santos and colleagues9 reported an incidence of IOP greater than or equal to 21 mm Hg of 32%, with a mean follow-up of 7.7 months. This compares with a 32% cumulative incidence of IOP greater than 25 mm Hg noted in the current study at 12 months. In a retrospective, observational case series, Smithen et al10 described a similar incidence of 40.4% for IOP greater than or equal to 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 greater than 25 mm Hg at 24 months after 4-mg IVTA injection in a large retrospective case series.
The current study identified higher baseline IOP as an independent risk factor for IOP greater than 25 mm Hg after IVTA injection. Participants experiencing an IOP greater than 25 mm Hg had a mean (SD) baseline IOP of 16.6 (2.84) mm Hg compared with 14.93 (3.03) mm Hg among those without an IOP greater than 25 mm Hg (data not shown; P < .001 based on t test). Prior studies6,9,10 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 greater than or equal to 15 mm Hg experienced an IOP elevation after IVTA compared with 22.7% of those with baseline IOP less than 15 mm Hg (P < .01). When interpreting higher baseline IOP as a risk factor for postinjection 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 for steroid-related IOP rise in our study, consistent with studies by Shukla et al27 and Roth et al.7 Although younger participants in the study conducted by Vasconcelos-Santos and colleagues9 had an increased risk for IOP rise compared with older participants, this did not reach statistical significance. In that study, 50% of participants younger than age 40 years experienced steroid-related IOP rise compared with 31.3% of participants older than 40 years of age (P = .60). Shukla and colleagues27 found that IOP rise occurred in 45% of participants younger than 45 years vs 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 dose 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 owing to variable concentrations injected through a small-gauge needle.31 The current analysis is unique in prospectively comparing 2 different dosages of IVTA with SOC therapy with regard to IOP-related events. Participants treated with 4-mg IVTA had significantly higher risk for IOP greater than 25 mm Hg compared with SOC (hazard ratio, 14.32), and 1-mg IVTA had a much smaller increase in risk over SOC (hazard ratio, 2.38) (P < .001 for a treatment group effect). This represents a clinically important finding as treating practitioners may wish to consider a lower IVTA dose 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 greater than 10 mm Hg over baseline in the current study was 34.0 days (range, 21 to 598 days) and 52.5 days (range, 26 to 135 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 greater than or equal to 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 individuals with glaucoma and ocular hypertension were found to experience these events relatively sooner.7 Another possibility for differences noted in the time to onset of an IOP-related event in this study was the use of a micronized, nondispersive triamcinolone formulation (Trivaris; Allergan Inc) 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), which may have delayed the time to onset of an IOP rise. However, in a study32 investigating differences in pharmacokinetics and pharmacodynamics among 4 distinct formulations of triamcinolone acetonide, the preserved formulation (Kenalog; Bristol-Meyers Squibb) was found to have longer vitreous visibility and durability than 3 nonpreserved formulations, including Trivaris.
There was no relationship between the number of 1-mg IVTA or 4-mg IVTA injections a participant received and having an IOP elevation greater than 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 for 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 2 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.
The 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 owing to variable concentrations injected via a small-gauge needle. The current study used a preservative-free, micronized triamcinolone acetonide injectable suspension (4-mg Trivaris), 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 greater than 25 mm Hg, or 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.
Quiz Ref IDThe limitations of the present study included 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 used a triamcinolone acetonide formulation (Trivaris) 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), 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 study 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.
Corresponding Author: Paul C. VanVeldhuisen, PhD, The EMMES Corporation, 401 N Washington St, Ste 700, Rockville, MD 20850 (email@example.com).
Submitted for Publication: December 3, 2014; final revision received April 14, 2015; accepted April 23, 2015.
Published Online: June 18, 2015. doi:10.1001/jamaophthalmol.2015.1823.
Author Contributions: Drs Oden and VanVeldhuisen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Aref, Scott, VanVeldhuisen.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Aref, Scott, Oden, VanVeldhuisen.
Critical revision of the manuscript for important intellectual content: Aref, Scott, Ip, Blodi, VanVeldhuisen.
Statistical analysis: Oden, Ip, VanVeldhuisen.
Obtained funding: Blodi, VanVeldhuisen.
Administrative, technical, or material support: Aref, VanVeldhuisen.
Study supervision: Aref, Blodi, VanVeldhuisen.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Ip reported receiving personal fees from Alimera and Thrombogenics. Dr VanVeldhuisen reported receiving grants and nonfinancial support from Allergan Inc. No other disclosures were reported.
Funding/Support: The SCORE Study was funded by the National Eye Institute (National Institutes of Health, Department of Health and Human Services) grants 5U10EY014351, 5U10EY014352, and 5U10EY014404. Financial support was also provided in part by Allergan Inc through donation of investigational drug and partial funding of site monitoring visits and secondary data analyses. Dr Aref is supported by National Institutes of Health Core Grant EY001792 and an unrestricted grant from Research to Prevent Blindness in preparation of this article. Drs Scott and VanVeldhuisen have received grant support from the National Eye Institute.
Role of the Funder/Sponsor: Neither Allergan Inc nor Research to Prevent Blindness played any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Because the trial was funded by the National Eye Institute/National Institutes of Health under a cooperative agreement, a National Eye Institute program director participated in SCORE Study committees and assisted but did not direct study leadership in the design, implementation, and execution of the SCORE Study.
Group Information: The SCORE Study Investigator Group members are listed in the eAppendix in the Supplement.