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Effect on Intraocular Pressure in PatientsReceiving Unilateral IntravitrealAnti-Vascular Endothelial Growth

Factor Injections

Quan V. Hoang, MD, PhD,1,2,3,4 Luis S. Mendonca, MD,1,2 Kara E. Della Torre, MD,1,2,4

Jesse J. Jung, MD,4 Angela J. Tsuang, MPH,4 K. Bailey Freund, MD1,2,3,4

Purpose: We assessed the frequency and predictive factors related to intraocular pressure (IOP) elevationin neovascular age-related macular degeneration (AMD) patients undergoing unilateral intravitreal ranibizumaband/or bevacizumab injections.

Design: Retrospective cohort study.Participants: Charts of 207 patients with neovascular AMD who presented to a single physician at a retinal

referral practice over a 6-month period were retrospectively reviewed.Methods: Data recorded included demographic information, clinical findings, total number of bevacizumaband ranibizumab injections received and IOP at each visit. Increases above baseline IOP of 5, 10, or 15mmHg on 2 consecutive visits while under treatment were noted.

Main Outcome Measures: The frequency of IOP elevation was compared between treated and untreatedeyes. In addition, among treated eyes, frequency and odds ratio of experiencing IOP elevation 5 mmHg abovebaseline on 2 consecutive visits was stratified by number of injections. For the main regression analysis, theoutcome variable was IOP elevation 5 mmHg on 2 consecutive visits and the main independent variable wastotal number of injections.

Results: On2 consecutive visits, 11.6% of treated versus 5.3% of untreated/control eyes experienced IOPelevation of 5 mmHg. The mean number of injections was higher in those with (24.4; 95% confidence interval[CI], 20.928.0; range, 9 39) than without IOP elevation of 5 mmHg (20.4; 95% CI, 18.921.8; range, 348) on2 consecutive visits. There was an increased odds ratio (5.75; 95% CI, 1.1927.8; P 0.03) of experiencingIOP elevation 5 mmHg on 2 consecutive visits in patients receiving 29 injections compared with 12

injections. Of the factors considered, only the total number of injections showed a statistically significantassociation with IOP elevation 5 mmHg above baseline on 2 consecutive visits in treated eyes (P 0.05).

Conclusions: A greater number of intravitreal anti-vasular endothelial growth factor injections is associatedwith an increased risk for IOP elevation 5 mmHg on 2 consecutive visits in eyes with neovascular AMDreceiving intravitreal ranbizumab and/or bevacizumab.

Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.Ophthalmology 2011;xx:xxx 2011 by the American Academy of Ophthalmology.

Intravitreal ranibizumab (Lucentis, Genentech, San Fran-cisco, CA) and bevacizumab (Avastin, Genentech) are anti-vascular endothelial growth factor (VEGF) agents used to

treat choroidal neovascularization and retinal vascular dis-orders.1,2 Rarely, ocular adverse events are reported thatinclude intraocular inflammation, retinal tears, vitreoushemorrhage, endophthalmitis, and lens changes.1,2 With theaddition of fluid into the vitreous cavity, it is not surprisingthat intraocular pressure (IOP) increases occur transientlyafter intravitreal injections.36 Elevations of IOP as a com-plication of anti-VEGF injections were not noted in theAnti-VEGF Antibody for the Treatment of PredominantlyClassic Choroidal Neovascularization in Age-Related Mac-ular Degeneration (ANCHOR) and Minimally Classic/Oc-cult Trial of the Anti-VEGF Antibody Ranibizumab in the

Treatment of Neovascular Age-Related Macular Degenera-tion (MARINA) trials1,2 or the VEGF Inhibition Study inOcular Neovascularization (VISION) trial,7,8 but recent re-

ports suggest sustained ocular hypertension (OHTN) canoccur after intravitreal ranibizumab or bevacizumab.912 Apost hoc analysis of data from the ANCHOR and MARINAtrials by Bakri et al showed a greater likelihood for prein-

jection IOP of6 mmHg from baseline and a preinjectionIOP of25 mmHg at 2 consecutive visits in eyes treatedwith intravitreal ranibizumab versus eyes receiving shaminjections over the 24-month follow-up period of thesestudies (Bakri SJ, Moshfeghi DM, Rundle A, et al. IOP ineyes treated with monthly ranibizumab: a post hoc analysisof data from the MARINA and ANCHOR trials. Paperpresented at: the American Academy of Ophthalmology

1 2011 by the American Academy of Ophthalmology ISSN 0161-6420/11/$see front matterPublished by Elsevier Inc. doi:10.1016/j.ophtha.2011.08.011


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(AAO) Annual Meeting, October 17, 2010; Chicago, IL). Inaddition, in a large-scale study of sustained OHTN afterintravitreal anti-VEGF treatment by Good et al,9 it wasnoted that patients with pre-existing glaucoma had higherrates of IOP elevation (33%) versus those without pre-existing glaucoma (3.1%). A recent series from our groupreported 25 eyes of 23 patients that experienced sustainedIOP elevations, of which 3 eyes (12%) required laser

treatment and 5 eyes (20%) required trabeculectomy.13Herein we assess the frequency and possible predictive

factors related to IOP elevation of5, 10, or15 mmHgover baseline IOP on 2 consecutive visits in neovascularage-related macular degeneration (AMD) patients undergo-ing unilateral intravitreal anti-VEGF injections, comparingthe treated eye versus the contralateral, untreated eye toserve as a control.

Methods

Institutional review board approval was obtained for this Health

Insurance Portability and Accountability Act-compliant, retrospec-tive cohort study, and all research adhered to the tenets of theDeclaration of Helsinki. We retrospectively reviewed the charts ofa consecutive series of 207 neovascular AMD patients who wereseen between February 1, 2010 and July 31, 2010, by a singlephysician (K.B.F.) at 2 offices of the Vitreous Retina MaculaConsultants of New York, who were followed for 9 weeks, andhad been unilaterally treated along their course with 3 intravit-real injections of ranibizumab (0.5 mg/0.05 ml) and/or bevaci-zumab (1.25 mg/0.05 ml). Patients with a baseline diagnosis ofglaucoma were excluded if their baseline IOP (defined as thepreinjection IOP on the day of their initial injection of ranibizumabor bevacizumab in either eye) was 21 and therefore deemed notwell-controlled.

All injections were performed under topical anesthesia. Before

injection, the eye was treated with antibiotic drops, topical propa-racaine hydrochloride (0.5%), and topical 5% povidone-iodinesolution. Injections were performed 3.5 to 4.0 mm posterior to thelimbus with either a 32-gauge needle (ranibizumab 0.5 mg/0.05ml) or a 31-gauge needle (bevacizumab 1.25 mg/0.05 ml). Noparacenteses or IOP measurements were performed immediatelyafter injection. After the procedure, patients were instructed to useantibiotic drops 4 times daily for 2 days. Subsequent visits andinjections occurred based on a treat-and-extend dosing regimenas described previously, whereby maintenance therapy was givenwhile attempting to increase the interval between treatments.14

Data recorded for each patient included basic demographicinformation, clinical examination findings, and total number ofbevacizumab and ranibizumab injections received (Table 1). Bi-lateral IOP measurements before the instillation of dilating agentswere recorded on the day of first treatment and at each subsequentoffice visit. All IOP measurements were performed using Gold-mann applanation tonometry by certified ophthalmic technicianswho were not masked to previous IOP measurements. The fre-quency of eyes experiencing an increase in IOP above baseline of5, 10, or 15 mmHg on 2 consecutive visits were noted(Table 2). Initiation of a new IOP-lowering drop, laser trabeculo-plasty, or filtration surgery during a time in which the patient wasactively receiving intravitreal injections was also noted.

The 207 patients were divided into approximately 4 equallysized groups (ranging from 4857 eyes per group; Table 3). Thenumber of injections received in groups I, II, III and IV, was 312,1321, 2228, and 29 total injections, respectively. The fre-

quency and odds ratio (OR; Table 3) of experiencing IOP elevationof 5 mmHg above baseline on 2 consecutive visits werecalculated. For the main regression analysis, the dependent, out-come variable was the absence or presence of IOP elevation of5mmHg above baseline on 2 consecutive visits. The main inde-pendent variable was the total number of injections, defined as thesum of bevacizumab and ranibizumab injections received in agiven eye. The association between the outcome variable and eachpossible confounder in question was assessed individually by theFisher exact test, chi square test, or unpaired Student t test (Table4). Analysis was performed using Stata 11 software (StataCorp,

College Station, TX). Significance was accepted at P

0.05.

Results

A total of 207 patients were included in this study. The meanpatient age at the initiation of treatment was 79 years; 35% weremale, and 56% of eyes were phakic at the time of initial ranibi-zumab or bevacizumab injection (see Table 1 for other baselinedemographic information). Mean number of total injections was20.8 (range, 348). Mean follow-up time was 148.6 weeks (range,9.7274). On 2 consecutive visits, 11.6% of treated versus 5.3%of untreated/control eyes experienced IOP elevation of5 mmHg

Table 1. Baseline Demographic and Clinical Characteristics ofPatients Studied

Characteristic Value

Patients (n) 207Laterality 110 OD (53.1%)

Age at first anti-VEGF injectionMean 79Range 5097

Male 72 (34.8%)With hypertension 126 (60.9%)

With diabetes mellitus 25 (12.1%)With glaucoma family history 21 (10.1%)With history of PDT 51 (24.6%)Eyes that received pegaptanib 15 (7.2%)

Eyes that received bevacizumab 67 (32.4%)Eyes that received ranibizumab 200 (96.6%)With personal history of glaucoma 28 (13.5%)Phakic at time of first injection 115 (55.6%)

Phakic at time of last injection 88 (42.5%)With PCIOL 114 (55.1%)With ACIOL 5 (2.4%)Aphakic 1 (0.48%)

Status after YAG capsulotomy 8 (3.9%)

Received intravitreal steroid injections 29 (14.0%)Status after peripheral iridotomy 21 (10.1%)With pseudoexfoliative material on lens capsule 1 (0.48%)

With prior noncataract ocular surgery 4 (1.9%)Injections (n)

Mean 20.8Range 348Median 21

ACIOL anterior chamber intraocular lens implant; OD right eye;PCIOL posterior chamber intraocular lens implant; PDT photody-namic therapy; VEGF vascular endothelial growth factor; YAG yttrium-aluminum-garnet laser.Baseline demographic and clinical characteristics of patients included inthe study were assessed. All intravitreal steroid injections composed of

triamcinolone acetonide.

Ophthalmology Volume xx, Number x, Month 2011

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(P 0.02). Among those with IOP elevation 5 mmHg on 2consecutive visits, the mean total number of injections performedwas 24.4 (95% confidence interval [CI], 20.928.0; range, 939),during a mean follow-up of 183.0 weeks (95% CI, 157.2208.8;

range, 48.1260.0). Those without IOP elevation

5 mmHg on2 consecutive visits had fewer injections (20.4; 95% CI, 18.921.8; range, 348) and mean follow-up (144.1 weeks; 95% CI,133.2154.9; range, 9.7274.0).

The OR (Table 3) of experiencing IOP elevation5 mmHg on2 consecutive visits was stratified by the number of injectionsreceived into groups I, II, III, and IV. The data indicated that foreyes with a total of29 injections, the odds of developing IOPelevation 5 mmHg on 2 consecutive visits is 5.75 times (95%CI, 1.192.78; P 0.03) as large as those receiving 12 injec-tions. The data weakly indicated that for eyes with a total of 13 to21 injections, the odds of developing IOP elevation 5 mmHg on2 consecutive visits is 3.76 times (95% CI, 0.75718.6; P 0.11) greater than those receiving 12 injections. There was nosignificant difference when comparing group III with group II

(P 0.30) or group IV with group II (P 0.41), but there was amarginal difference when comparing group IV to group III (P 0.08).

There was a positive correlation between the number of intra-vitreal anti-VEGF injections and the risk of experiencing IOPelevation5 mmHg above baseline IOP on 2 consecutive visits,implying that the number of injections is a predictor of elevation inIOP. Specifically, of the factors considered (Table 4), only the total

number of injections (OR, 1.5; P 0.05; univariate analysis)showed an association with IOP elevation.

Discussion

Elevations of IOP were not noted to be a complication ofranibizumab injections in the ANCHOR and MARINA trialsas determined by mean monthly preinjection measurementsduring the 2-year follow-up.1,2 In the VISION trial,7,8 therewas no evidence of increased mean preinjection IOP over 2years after the injection of intravitreal pegaptanib every 6weeks. Mean values for IOP returned to preinjection levels by1 week after injections. In contrast, post hoc analysis of datafrom the ANCHOR and MARINA trials by Bakri et al showeda greater likelihood for preinjection IOP of6 mmHg frombaseline and a preinjection IOP of25 mmHg at 2 consec-utive visits in eyes treated with ranibizumab 0.3 mg (5.4%) or0.5 mg (4.5%) versus eyes receiving sham injections (1.3%)over the 24-month follow-up period of these studies. In addi-tion, 11.4% of all ranibizumab-treated patients experienced1OHTN/glaucoma-related event in the study eye compared with6.4% of sham/photodynamic therapy control patients over 24months (P 0.008; Bakri SJ, Moshfeghi DM, Rundle A, et al.IOP in eyes treated with monthly ranibizumab: a post hoc

Table 2. Frequency of Eyes Meeting Criteria for Intraocular Pressure (IOP) Elevation on 2 Consecutive Visits in Treated Eyes andContralateral, Untreated Eyes in Patients Receiving Unilateral Ranibizumab and/or Bevacizumab Therapy

Group Criteria (on 2 Consecutive Visits) Total Eyes (n)Untreated Eyes Meeting

Criteria, n (%)Treated Eyes Meeting

Criteria, n (%) P

A 5 mmHg increase from baseline IOP 207 11 (5.3) 24 (11.6) 0.02*

B 10 mmHg increase from baseline IOP 207 1 (0.5) 10 (4.8) 0.01*C 15 mmHg increase from baseline IOP 207 0 (0.0) 4 (1.9) 0.06D Started on IOP-lowering intervention 207 3 (1.4) 13 (6.3) 0.01*

Analysis was performed on 207 patients who received bevacizumab and/or ranibizumab injections in only 1 eye. The number (and percent) of patientswho met the criteria listed in the second column on 2 consecutive visits were compared between the contralateral, treatment-nave eye (untreated;fourth column) and the eye that received bevacizumab or ranbizumab injections (treated; fifth column). The Fisher exact test and chi square test wereused to compare the untreated and treated eyes (6th column). The Fisher exact test was used over chi square if a cell value was 5.Baseline IOP was defined as the IOP measured in the respective eye on the day of initial injection of bevacizumab or ranibizumab in the treated eye.*P0.05.

Table 3. Frequency and Odds Ratio (OR) of Intraocular Pressure (IOP) Elevation5 mmHg above Baseline on 2 ConsecutiveVisits Stratified by Number of Total Injections Received

Group

Injections

(n) Total Eyes (n) IOP Elevation>

5 mmHg, n (%) OR (95% CI) versus Group IP

I 12 48 2 eyes (4.2) II 1321 57 8 eyes (14) 3.76 (0.75718.6) 0.11III 2228 52 4 eyes (7.7) 1.92 (0.33511.0) 0.47IV 29 50 10 eyes (20) 5.75 (1.1927.8) 0.03*

CI confidence interval.The 207 patients were divided into approximately 4 equally sized groups (third column). The number of total intravitreal injections of bevacizumab orranibizumab received in groups I, II, III, and IV, was 312, 1321, 2228, and 29 total injections, respectively (second column). The frequency of eyeswith IOP elevation of5 mmHg above baseline IOP was calculated (chi-square; P 0.10). The ORs were calculated comparing each group to groupI, and the P values are reported in the 6th column. There was no significant difference found when comparing group III with group II (P 0.30) or groupIV with group II (P 0.41), but there was a marginal difference when comparing group IV with group III ( P 0.08).*P0.05.

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analysis of data from the MARINA and ANCHOR trials.Paper presented at: AAO Annual Meeting, October 17, 2010;Chicago, IL).

Transient increases in IOP are not uncommon with theaddition of fluid into the vitreous cavity. There have beenseveral published reports demonstrating short-term, tran-sient increases in IOP after intravitreal anti-VEGF agents,which were shown to return to 25 mmHg within 30 to 60minutes without IOP-lowering therapy.36 These studiessuggested increases in IOP tend to be higher in phakicpatients,3 and eyes with a history of glaucoma were thoughtto take longer to return to baseline IOP.4 No predictivevalue was found for baseline IOP, age, sex, refractive error,

or previous intravitreal injections in determining postinjec-tion IOP. In addition, intravitreal steroids are known tocause sustained increases in IOP, which occurs in approxi-mately 38.3% of eyes receiving intravitreal triamcinoloneacetonide.15 Before the widespread use of intravitreal anti-VEGF therapy, Jager et al15 reported that sustained OHTNoccurred in 2.4% of eyes receiving intravitreal injections ofany chemical, excluding triamcinolone acetonide, with themajority occurring in eyes receiving intravitreal fomivirsenfor cytomegalovirus retinitis.

There have been several recent reports of sustainedOHTN occurring in eyes receiving intravitreal ranibizumab

or bevacizumab. Bakri et al reported 4 eyes of 4 patients thatexperienced delayed and sustained OHTN after 1 or 2intravitreal ranibizumab injections for treatment of choroi-dal neovascularization secondary to neovascular AMD inpatients without a history of glaucoma or OHTN.10 How-ever, all of these patients had received prior injections ofintravitreal pegaptanib, bevacizumab, or triamcinolone.10

Kahook et al11 reported 6 cases of sustained elevation inIOP after single or multiple (up to 10) intravitreal bevaci-zumab injections for treatment of choroidal neovasculariza-tion in various diseases. Three of these 6 patients had nohistory of glaucoma or suspected glaucoma. Adelman et al12

reported 4 cases (out of 116 patients; 3.45%) of OHTN after

multiple intravitreal injections (range, 319; mean, 13.3) ofbevacizumab and/or ranibizumab in patients with neovas-cular AMD, none of whom had a history of glaucoma,OHTN, or optic nerve changes suspicious for glaucoma. Alarge-scale study that examined the rate of persistent IOPchanges with anti-VEGF injections and showed 13 of 215eyes (6%) injected with bevacizumab and/or ranibizumabhad sustained elevation in IOP after a median of 9 injec-tions.9 Patients with pre-existing glaucoma had higher prev-alence of IOP elevation (33% vs 3.1% in those withoutpre-existing glaucoma). Although there was a difference inthe incidence of sustained IOP elevation in bevacizumab-

Table 4. Association between Clinical Factors and Experiencing Intraocular Pressure (IOP) Elevation5 mmHg Above Baseline on2 Consecutive Visits

Clinical FactorP value, 2/

Fisher or t test Odds Ratio 95% Confidence IntervalP Value,

Univariate

Older age at first anti-VEGF injection 0.79 0.994 0.9481.04 0.78

Sex (male) 0.77 1.14 0.4742.76 0.77History of hypertension 0.86 1.08 0.4492.60 0.86History of diabetes mellitus 0.09*

Positive glaucoma family history 0.28 1.95 0.5986.38 0.27History of PDT 0.29 1.63 0.6524.06 0.30Pegaptanib injections, (n) 0.94 0.939 0.7711.27 0.94History of pegaptanib injection 0.39 2.04 0.5317.81 0.30Bevacizumab injections, (n) 0.44 1.02 0.9661.08 0.44

Total no. of anti-VEGF injections (continuous variable) 0.06* 1.04 0.9981.09 0.06*Total no. of anti-VEGF injections (categorical variable) 0.07* 1.50 0.9952.26 0.05*Greater mean interval between injections 0.51 1.03 0.9371.13 0.52Personal history of glaucoma 0.54 1.33 0.4174.21 0.63

Phakic at time of first injection 0.11 0.475 0.1881.20 0.12Phakic at time of last injection 0.73 0.858 0.3652.02 0.73PCIOL 0.92 0.959 0.4082.25 0.92ACIOL 0.55 1.95 0.20818.2 0.56Aphakia

Status after YAG capsulotomy 0.23 2.68 0.51014.1 0.24

History of intravitreal steroid 0.10* 2.32 0.8346.44 0.11Intravitreal steroid injections, (n) 0.95 0.994 0.8291.19 0.95History of IOP elevation soon after intravitreal steroid injection

History of peripheral iridotomy 0.72 1.31 0.3564.82 0.68Pseudoexfoliative material on lens capsule Prior noncataract ocular surgery

The association between demographic or clinical characteristics and IOP elevation5 mmHg above baseline on 2 consecutive visits were assessed. TheFisher exact test and chi square test were used when comparing 2 categorical variables. The Fisher exact test was used over chi squared if a cell value was5. A 2-sample Student t test was used when comparing a categorical variable against a continuous variable., univariate regression could not be performed; ACIOL anterior chamber intraocular lens implant; PCIOL posterior chamber intraocular lensimplant; PDT photodynamic therapy; VEGF vascular endothelial growth factor; YAG yttrium-aluminum-garnet laser.*P0.10.


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treated eyes (9.9%; 10 of 101 patients) versus ranibizumabeyes (3.1%; 3 of 96 patients), the power of the differencewas only 0.037 at the 0.05 level. Choi et al16 reported aseries of 5 of 127 patients (5.5%) who experienced sus-tained IOP elevation (25 mmHg on 2 separate visits or asingle IOP 25 mmHg that required glaucoma medicationor surgery) after receiving intravitreal ranibizumab, bevaci-zumab, or pegaptinib.16 A recent series from our group at

the Vitreous Retina Macula Consultants of New York re-ported 25 eyes of 23 patients that experienced sustained IOPelevations to levels of 25 to 58 mmHg (mean, 35.8). Nota-bly, of these 25 eyes, 23 (92%) required pharmacologic IOPreduction, 3 (12%) required laser treatment, and 5 (20%)required trabeculectomy.13

There have been several theories regarding possiblemechanisms of how intravitreal anti-VEGF injections couldlead to sustained IOP elevation, including a pharmacologiceffect of VEGF blockade, an inflammatory mechanism/trabeculitis, impaired outflow owing to protein aggregates/silicone droplet debris, and damage to outflow pathwaysdue to the repeated trauma and/or IOP spikes associated

with the injection procedure. Specifically, Good et al9

re-ported 33% of 21 patients in a glaucoma subgroup experi-enced sustained elevated IOP after fewer injections. Thiswas attributed to a likely pre-existent compromise in aque-ous humor outflow facility.9 Adelman et al12 proposed anti-VEGF injections may decrease trabecular meshwork func-tion, either mechanically or physiologically, but Kernt etal17 reported no in vivo toxicity to the trabecular meshworkwith standard concentrations of bevacizumab.17 Also, anincrease in concentration of aqueous humor protein hasbeen associated with elevated IOP in uveitis.1,2,18 It hasbeen suggested that an immunologic reaction may be in-duced by anti-VEGF agents, resulting in inflammation andsubsequent IOP elevation.19 In this model, bevacizumabwould be more likely to result in sustained elevation in IOPthan ranibizumab because it would be more proinflamma-tory because of its Fc portion and longer serum and vitrealhalf-life related to its larger size. Good et al9 noted adifference in rates of sustained IOP elevation between 2different study centers and suggested this may be due todifferences in the way pharmacies and clinics prepare, ship,and store prefilled bevacizumab syringes or different injec-tion techniques. In addition, it has been suggested that adisruption of the anterior hyaloid or zonules may allowaccess for high-molecular-weight proteins to enter the an-terior chamber and result in OHTN. Multiple doses of theseproteins may mechanically or physiologically disrupt the

normal aqueous humor outflow.12 Other investigators havetheorized that silicone oil used to lubricate the componentsof syringes, or the accumulation of protein aggregates mayplay a role in these sustained IOP elevations.20,21

The present study examined the long-term effect of in-travitreal injections of anti-VEGF agents on IOP. We founda significant positive correlation between the number ofinjections and the probability of experiencing IOP elevation5 mmHg above baseline IOP on 2 consecutive visits.We may have underestimated the risk of IOP elevation,because we omitted criteria D (Table 2). This omissionexcluded patients who were initiated on IOP-lowering treat-

ment by their glaucoma specialist or comprehensive oph-thalmologist after a single, markedly elevated IOP readingand who, as a result, may not have met our criteria for IOPelevation (Table 2). Specifically, our data suggested anincreased OR (5.75) of experiencing IOP elevation 5mmHg on 2 consecutive visits among patients receiving29 intravitreal ranibizumab and/or bevacizumab injec-tions compared with those who received 12 injections.

The frequency of IOP elevation 5 mmHg on 2 consec-utive visits in patients receiving 12 injections was 4.2%,which was similar to that found in the untreated control eyesof these unilaterally injected patients (5.3%). The frequencyof IOP elevation 5 mmHg on 2 consecutive visits inpatients receiving 29 injections was much higher (20%;10 of 50 eyes). Further analysis of the untreated, contralat-eral control eyes in this subset of the 50 patients thatreceived 29 injections (Table 3; group IV) revealed thatthe frequency of IOP elevation 5 mmHg above baselineon 2 consecutive visits was 10% (5 of 50 eyes). Thissubset of 50 patients had 36.27.1 visits (mean standarddeviation) over 21530.2 weeks. This further supports the

notion that developing IOP elevation 5 mmHg abovebaseline on 2 consecutive visits is not merely a reflectionof the number of IOP measurements/clinic visits.

Of the factors considered, only the total number of injec-tions showed a statistically significant association with havingIOP elevation related to intravitreal anti-VEGF treatment forneovascular AMD. The following clinical factors were notfound to be associated with experiencing IOP elevation 5mmHg on 2 consecutive visits: Age at first anti-VEGFinjection, sex, personal history of hypertension, family historyof glaucoma, personal history of glaucoma, history of IOPelevation soon after intravitreal steroid injection, history ofphotodynamic therapy, history of pegaptanib intravitreal injec-tion, mean interval between injections, number of intravitrealsteroid injections, history of peripheral iridotomy, personalhistory of diabetes mellitus (P 0.09), history of intravitrealsteroid injection (OR, 2.32; 95% CI, 0.8346.44; P 0.11;univariate analysis), and phakic status at the time of initialinjection (OR, 0.475; 95% CI, 0.188 1.20; P 0.12). Of note,our study was not adequately powered to compare the likeli-hood of experiencing IOP elevation 5 mmHg on 2 con-secutive visits in patients who were injected with bevacizumabversus ranibizumab and may not have had a sufficient samplesize to reach significance for the following: evidence of pseu-doexfoliative material, prior posterior capsule capsulotomy,prior noncataract ocular surgery, and presence of an anteriorchamber intraocular lens or aphakia. Although there was not an

association of a personal history of glaucoma with experienc-ing IOP elevation 5 mmHg on 2 consecutive visits, con-trary to the report from Good et al,9 it should be noted that ourexclusion criteria omitted 3 patients with pre-existing glau-coma with poorly controlled IOP at baseline. Lens status(phakia vs pseudophakia) at the time of last injection was notfound to be associated with IOP elevation 5 mmHg on 2consecutive visits, which does not support the hypothesis thatprotein aggregates or silicone microdroplets play an etiologicrole in IOP elevation.20,21

In summary, our results suggest that a greater number ofinjections may increase the risk for IOP elevation 5

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mmHg on 2 consecutive visits in eyes with neovascularAMD receiving intravitreal anti-VEGF therapy. We recom-mend routine monitoring of preinjection IOP in all patientsreceiving intravitreal anti-VEGF therapy.

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Footnotes and Financial Disclosures

Originally received: February 16, 2011.

Final revision: August 2, 2011.

Accepted: August 3, 2011.

Available online: . Manuscript no. 2011-261.

1 Vitreous Retina Macula Consultants of New York, New York, New

York.

2 LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and

Throat Institute, New York, New York.

3 Edward S. Harkness Eye Institute, Columbia University College of Phy-

sicians and Surgeons, New York, New York.

4 Department of Ophthalmology, New York University Medical Center,

New York, New York.

Financial Disclosure(s):

The authors have made the following disclosures:

K. Bailey Freund Consultant, Research Support Genentech; Consultant

Alcon; Consultant Regeneron; Consultant Alimera.Supported by the LuEsther T. Mertz Retinal Research Center, Manhat-

tan Eye, Ear, and Throat Institute, and The Macula Foundation Inc. The

funding organizations had no role in the design or conduct of this

research.

Correspondence:

K. Bailey Freund, MD, 460 Park Avenue, Fifth Floor, New York, NY

10022. E-mail: [email protected]


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