Surgical implantation of steroids with antiangiogenic characteristics for treating exudative macular degeneration
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The primary aim of this review is to investigate the effects of surgically implanted steroids with anti‐angiogenic properties in delaying visual loss in exudative macular degeneration. A secondary aim of this review is to compare the clinical outcomes and side effects of different surgically implanted anti‐angiogenic steroids. A third aim is to compare the intraocular drug delivery systems used for the administration of steroids in the treatment of exudative AMD in different clinical trials.
Background
Introduction
Age‐related macular degeneration (AMD) continues to be among the leading causes of blindness in the developed world. It is a degenerative disorder involving the central portion of the retina that is responsible for high‐resolution visual acuity. The two major types of AMD are classified based on specific abnormalities of the retinal pigment epithelium (RPE) and retina. The dry, or atrophic, form of AMD typically involves the RPE, choriocapillaris, and photoreceptors in the absence of serous or hemorrhagic leakage. The wet, or exudative, form includes choroidal neovascularization (CNV), leakage of blood and serum, and fibrovascular scarring. Because of the severity of disease found in the exudative form, it accounts for the majority of significant vision loss secondary to AMD (Ferris 1984). Treatment options for this disease are limited and there is a variety of therapies currently being investigated for exudative AMD. This review is concerned with the potential use of intravitreal anti‐angiogenic steroids for the treatment of exudative AMD.
Epidemiology
The World Health Organization (WHO) estimates that at least eight million individuals worldwide are severely visually impaired secondary to AMD (WHO 1997). It is estimated that in the United States 1.6 million people age 50 years and older have evidence of late AMD (Tielsch 2002). Large, population‐based studies worldwide have found varying prevalence rates of AMD, though they have consistently shown increased risk with age (Evans 2001). Accordingly, the Beaver Dam Eye Study found an increased incidence of age‐related maculopathy lesions with age (Klein 2002). With the growing aging population in the developed world, the number of people at risk for AMD is increasing.
Presentation and diagnosis
Individuals with atrophic AMD typically present with a slow and gradual deterioration in fine discriminate visual acuity, which may eventually lead to central vision loss. Exudative AMD is associated with a more rapid loss of vision. With CNV and leakage of fluid into the surrounding retina, central blurring or visual distortion occurs. Eventual scarring and extensive leakage can subsequently lead to more significant loss of vision.
Fundus examination of people with AMD reveals characteristic presentations that range from drusen and pigmentary changes in people with the atrophic form, to subretinal fluid or blood in the exudative form. In exudative AMD, fluorescein angiography is helpful in detecting subtle exudates associated with CNV. Based on fluorescein studies, CNV can be classified as classic or occult lesions. Classic lesions are characteristically well‐defined and have early hyperfluorescence, whereas occult lesions have late leakage or evidence of fibrovascular pigment epithelial detachment. Indocyanine green angiography is a similar study considered by some authors to be more sensitive in detecting areas of occult choroidal neovascularization (Stanga 2002). Another imaging study used in evaluating AMD is optical coherence tomography (OCT). This non‐invasive test images the retina using diagnostic laser interference patterns to reconstruct the macula area. This allows for quantitative measurements and detection of fluid accumulation.
Treatment options
The Macular Photocoagulation Studies (MPSG 1994) demonstrated a delay in vision loss after laser photocoagulation treatment for extrafoveal and juxtafoveal classic CNV secondary to AMD. Argon thermal laser photocoagulation of CNV is not an option for subfoveal CNV as it causes immediate loss of central vision due to damage to the overlying retina. Recurrence of CNV following thermal laser has been shown to occur within three years (MPSG 1994).
Photodynamic therapy (PDT) was developed as an alternative non‐thermal treatment for subfoveal CNV. In PDT, a photoreactive drug is used and activated with light to induce release of free radicals as the drug fills the proliferative neovascularization. The TAP Study Group demonstrated a reduced risk of visual loss for eyes with predominantly classic CNV after PDT treatment (Bressler 2001; TAP 1999). However, most participants receiving PDT need multiple treatments within the first year. Recent fluorescein angiographic guidelines for the evaluation and treatment of subfoveal CNV describe patients who are most likely to benefit from PDT with verteporfin. (TAP VIP 2003). A systematic review on PDT for AMD is also published on The Cochrane Library (Wormald 2002).
Because there still is no satisfactory treatment for exudative AMD, there is growing interest in novel medical therapies targeting CNV secondary to AMD. Clinical and basic science research has directed attention to angiogenesis as a key target for the medical treatment of CNV. Several anti‐angiogenic agents are being investigated for their potential benefit in treating exudative AMD and other pathologic neovascularization of ocular tissues (see Table 1). Inflammatory processes have also been shown to play a significant role in the pathogenesis of AMD and development of CNV (Penfold 2001). Given these potential pharmacologic targets for inducing regression of CNV, steroids are being investigated for their potential anti‐inflammatory and anti‐angiogenic effects.
Penfold et al reviewed laboratory evidence demonstrating that intravitreal corticosteroids mediate anti‐inflammatory responses by inducing the resorption of exudate and down‐regulating inflammatory stimuli (Penfold 2001). Angiostatic steroids are a separate class of steroids that mediate specific anti‐angiogenic activity independent of steroid hormone activity. Angiostatic steroids have been shown to inhibit neovascularization in intraocular tumors in animals (BenEzra 1997; Clark 1999; Penn 2001). These steroids are believed to inhibit angiogenesis by increasing the synthesis of plasminogen activator inhibitor, which subsequently inhibits plasmin generation, a process essential to the invasion of new vessels (Blei 1993).
The clinical use of steroids for the treatment of exudative AMD will necessitate an effective and practical method of administering these agents into the eye. Intravitreal injections are used for administering drugs for posterior segment diseases in efforts to minimize unwanted systemic effects and to produce effective concentrations locally. More recently, various intraocular drug delivery systems have been developed for longer‐term administration of pharmacologic agents (Kurz 2002). With sustained‐release gancyclovir implants being used in the treatment of CMV retinitis (Musch 1997), intraocular drug delivery devices for chronic corticosteroid treatment are also being examined (Jaffe 2000). Surgically implanted degradable polymer microspheres are also being tested as a way to administer anti‐angiogenic agents for the treatment of choroidal and retinal diseases (Carrasquillo 2003; Yasukawa 1999).
Rationale for systematic review
With the support of laboratory evidence and advances in drug delivery systems, intravitreal steroids are currently being examined for the treatment of neovascular AMD in the clinical setting. However, the classes of steroids, dosages, and drug delivery systems being used vary between clinical studies. The diversity in methodology warrants a review of these trials to help draw meaningful conclusions about the effectiveness and relevance of steroids in the future management of exudative AMD.
Objectives
The primary aim of this review is to investigate the effects of surgically implanted steroids with anti‐angiogenic properties in delaying visual loss in exudative macular degeneration. A secondary aim of this review is to compare the clinical outcomes and side effects of different surgically implanted anti‐angiogenic steroids. A third aim is to compare the intraocular drug delivery systems used for the administration of steroids in the treatment of exudative AMD in different clinical trials.
Methods
Criteria for considering studies for this review
Types of studies
This review will include randomized controlled trials (RCTs).
Types of participants
We will include trials in which participants were diagnosed with neovascular macular degeneration as defined by study investigators.
Types of interventions
We will include trials in which surgical implantation (device, suspension, or micro‐sphere) of a steroid with anti‐angiogenic characteristics is compared to another treatment, placebo, or no treatment.
Types of outcome measures
Primary outcome
The primary outcome for this review will be loss of visual acuity measured at 12 months or more, but no more than 24 months. Depending on the data presented in the trial reports, we will examine the proportion of people with loss of three or more lines of logMAR visual acuity (equivalent to a doubling of the visual angle).
Secondary outcomes
The secondary outcomes for this review will be as follows.
1) Contrast sensitivity measured at 12 months using standardized charts and analyzed using log contrast sensitivity values.
2) Size and characteristics of lesion as determined by flourescein angiography.
3) Retinal thickness and parameters as measured by OCT at 12 months.
4) Quality of life measures as assessed by any validated measurement scales will be reported for included trials.
Adverse effects
We will categorize adverse effects as ocular or systemic. We plan to report and describe all adverse effects observed including, but not limited to, those listed below. We will enumerate adverse event data from each trial included, recognizing that reliable evidence of rare events is unlikely to emerge from RCTs alone. We will not attempt to summarize observational studies examining rare events associated with steroid use for neovascular macular degeneration.
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Ocular: retinal detachment; hemorrhage; infection; cataract; steroid‐induced rise in intraocular pressure and steroid‐induced glaucoma; papillary abnormalities; rubeosis; pigment epithelial detachment; loss of vision; photopsia; ptosis; anterior chamber inflammation; corneal abrasion; pain; foreign body sensation; chemosis and subconjuctival hemorrhage; lid edema; dry eye; vitreous prolapse; vitreous floaters; intraocular air; tearing.
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Systemic: cardiovascular; neurological; respiratory; genitourinary; kidney; joint; fatigue; headache.
Search methods for identification of studies
Electronic searches
Trials will be identified from the Cochrane Central Register of Controlled Trials ‐ CENTRAL (which contains the Cochrane Eyes and Vision Group trials register) on The Cochrane Library, MEDLINE, EMBASE and LILACS. There will be no language or date restrictions in the electronic search for trials.
The following strategy will be used to search CENTRAL on The Cochrane Library:
#1 MACULAR DEGENERATION explode tree 1 (MeSH)
#2 RETINAL DEGENERATION explode tree 1 (MeSH)
#3 RETINAL NEOVASCULARIZATION single term (MeSH)
#4 CHOROIDAL NEOVASCULARIZATION single term (MeSH)
#5 MACULA LUTEA explode tree 1 (MeSH)
#6 MACULA* next LUTEA*
#7 ((MACUL* or RETINA* or CHOROID*:TI) and (DEGENER* or NEOVASC*:TI))
#8 ((MACUL* or RETINA* or CHOROID*:AB) and (DEGENER* or NEOVASC*:AB))
#9 (#7 or #8)
#10 MACULOPATH*:TI
#11 MACULOPATH*:AB
#12 (#10 or #11)
#13 (#1 or #2 or #3 or #4 or #5 or #6 or #9 or #12)
#14 ANGIOGENESIS INHIBITORS single term (MeSH)
#15 INTERFERON‐ALPHA explode tree 1 (MeSH)
#16 TRIAMCINOLONE explode tree 1 (MeSH)
#17 INTEGRINS explode tree 1 (MeSH)
#18 THALIDOMIDE single term (MeSH)
#19 SOMATOSTATIN single term (MeSH)
#20 ANTINEOPLASTIC AGENTS explode tree 1 (MeSH)
#21 ENDOTHELIAL GROWTH FACTORS single term (MeSH)
#22 HORMONE ANTAGONISTS explode tree 1 (MeSH)
#23 PLASMINOGEN INACTIVATORS explode tree 1 (MeSH)
#24 DEXAMETHASONE explode tree 1 (MeSH)
#25 (#14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24)
#26 ANGIOGEN*:TI
#27 ANGIOGEN*:AB
#28 INTERFERON:TI
#29 INTERFERON:AB
#30 (ANTI‐VEGF or (ANTI next VEGF))
#31 (TRIAMCINOLON* or DEXAMETHASON*:TI)
#32 (TRIAMCINOLON* or DEXAMETHASON*:AB)
#33 (ANGIOSTATIN* or SOMASTATIN* or LANREOTIDE*:TI)
#34 (ANGIOSTATIN* or SOMASTATIN* or LANREOTIDE*:AB)
#35 AGM‐1470
#36 (THALIDOMIDE or ANECORTAVE or FUMAGILLIN)
#37 (RHUFAB* or PEGAPTANIB or PEGYLATED or KENELOG)
#38 (ENDOTHELIAL:TI next GROW*:TI next FACTOR*:TI)
#39 (ENDOTHELIAL:AB next GROW*:AB next FACTOR*:AB)
#40 (HORMONE*:TI next ANTAGONIST*:TI)
#41 (HORMONE*:AB next ANTAGONIST*:AB)
#42 (PLASMINOGEN*:AB next INACTIVAT*:AB)
#43 (PLASMINOGEN*:TI next INACTIVAT*:TI)
#44 (#26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43)
#45 #13 and (#25 or #44)
The following strategy will be used to search MEDLINE on SilverPlatter:
#1 "MACULAR‐DEGENERATION"/ all subheadings
#2 "RETINAL‐DEGENERATION"/ all subheadings
#3 "RETINAL‐NEOVASCULARIZATION"/ all subheadings
#4 "CHOROIDAL‐NEOVASCULARIZATION"/ all subheadings
#5 explode "MACULA‐LUTEA"/ all subheadings
#6 (MACUL* or RETINA* or CHOROID*) near (DEGENER* or NEOVASC*) in TI,AB
#7 MACULOPATH* in TI,AB
#8 (MACULA* near3 LUTEA) in TI,AB
#9 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8)
#10 "ANGIOGENESIS‐INHIBITORS"/ all subheadings
#11 "ANGIOGENESIS‐FACTOR"/ all subheadings
#12 "INTERFERON‐ALPHA"/ all subheadings
#13 explode "TRIAMCINOLONE"/ all subheadings
#14 explode "INTEGRINS"/ all subheadings
#15 "THALIDOMIDE"/ all subheadings
#16 "SOMATOSTATIN"/ all subheadings
#17 explode "ANTINEOPLASTIC‐AGENTS"/ all subheadings
#18 "ENDOTHELIAL‐GROWTH‐FACTORS"/ all subheadings
#19 explode "HORMONE‐ANTAGONISTS"/ all subheadings
#20 explode "PLASMINOGEN‐INACTIVATORS"/ all subheadings
#21 explode "DEXAMETHASONE"/ all subheadings
#22 (#10 or #11 or #12 or 13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21)
#21 ANGIOGEN*
#22 INTERFERON*
#23 ANTI‐VEGF* or "ANTI VEGF"
#24 TRIAMCINOLON* or DEXAMETHASON*
#25 ANGIOSTATIN*
#26 SOMASTATIN* or LANREOTIDE
#27 AGM‐1470 or "AGM 1470"
#28 THALIDOMIDE or ANECORTAVE or FUMAGILLIN
#29 RHU?FAB* or PEGAPTANIB or PEGYLATED or KENELOG
#30 (ENDOTHELIAL near GROWTH near FACTOR*)
#31 HORMONE* near3 ANTAGONIST*
#32 PLASMINGEN near3 INACTIVAT*
#33 (#21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32) in TI,AB
#34 #9 and (#22 or #33)
The following strategy will be used to search EMBASE on SilverPlatter:
#1 explode "RETINA‐MACULA‐DEGENERATION"/ all subheadings
#2 "RETINA‐DEGENERATION"/ all subheadings
#3 "SUBRETINAL‐NEOVASCULARIZATION"/ all subheadings
#4 ((MACUL* or RETINA* or CHOROID*) near (DEGENER* or NEOVASC*)) in TI,AB
#5 MACULOPATH* in TI,AB
#6 (MACULA* near3 LUTEA) in TI,AB
#7 (#1 or #2 or #3 or #4 or #5 or #6)
#8 explode "ANGIOGENESIS‐INHIBITOR"/ all subheadings
#9 "ANGIOGENIC‐FACTOR"/ all subheadings
#10 "ANGIOGENESIS"/ all subheadings
#11 explode "INTERFERON"/ all subheadings
#12 "TRIAMCINOLONE"/ all subheadings
#13 "INTEGRIN"/ all subheadings
#14 "SOMATOSTATIN"/ all subheadings
#15 "THALIDOMIDE"/ all subheadings
#16 "ANTINEOPLASTIC‐AGENT"/ all subheadings
#17 "ENDOTHELIAL‐CELL‐GROWTH‐FACTOR"/ all subheadings
#18 explode "HORMONE‐ANTAGONIST"/ all subheadings
#19 explode "PLASMINOGEN‐ACTIVATOR‐INHIBITOR"/ all subheadings
#20 "DEXAMETHASONE"/ all subheadings
#21 (#8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20)
#22 ANGIOGEN*
#23 INTERFERON*
#24 ANTI‐VEGF* or "ANTI VEGF"
#25 TRIAMCINOLON* or DEXAMETHASON*
#26 ANGIOSTATIN*
#27 SOMASTATIN* or LANREOTIDE
#28 AGM‐1470 or "AGM 1470"
#29 THALIDOMIDE or ANECORTAVE or FUMAGILLIN
#30 RHU?FAB* or PEGAPTANIB or PEGYLATED or KENELOG
#31 (ENDOTHELIAL near GROWTH near FACTOR*)
#32 HORMONE* near3 ANTAGONIST*
#33 (PLASMINGEN near ACTIVAT* near INHIBIT*)
#34 (#22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33) in TI,AB
#35 #7 and (#21 or #34)
LILACS will be searched using the terms (MACUL$ or RETINA$ or CHOROID$) in combination with (DEGENER* or NEOVASC$) or MACULOPATHY or MACULA LUTEA.
Manual searches
We will search the bibliographies of included trials for details of further relevant trials.
We will handsearch the abstracts of the following conference proceedings.
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Association of Research in Vision and Ophthalmology, Fort Lauderdale, April 25‐29, 2004
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American Society of Retinal Specialists, New York City, August 16‐21, 2003
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Ocular Imaging 2004, Bascom Palmer Eye Institute, Palm Beach, FL, December 5‐6, 2003
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American Academy of Ophthalmology Meeting, Retinal Subspecialty Meeting, Anaheim, CA, November 15, 2003
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Angiogenisis, Bascom Palmer Eye Institute, Coral Gables, FL, January 5, 2005
We will contact the following individuals and organizations.
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Alcon Laboratories, Inc., Fort Worth, TX
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Doheny Eye Institute, Los Angeles, CA
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Weng Tao, MD, PhD, Neurotech USA, Neurotech USA, Inc., Lincoln, RI
Data collection and analysis
Assessment of search results
Two reviewers independently will assess the titles and abstracts resulting from electronic searches. We will obtain full copies of all potentially or definitely relevant articles. Two reviewers will assess each article to ensure they meet the inclusion criteria. Only those articles meeting the inclusion criteria will be assessed for quality. We will contact authors to clarify details as necessary to make a complete assessment of the relevance of each study.
Assessment of methodological quality
Two reviewers will assess the methodological quality of the studies that meet the inclusion criteria. Reviewers will not be masked to any trial details during the assessment. We will consider four parameters of quality when assessing articles: allocation concealment and method of allocation to treatment; masking of providers and recipients of care; masking of outcome assessment; completeness of follow up. Both reviewers will independently grade each parameter of trial quality: A ‐ adequate; B ‐ unclear; C ‐ Inadequate. Disagreements between reviewers will be resolved by discussion. We will contact trial authors for clarification of any parameter graded B. We will perform a sensitivity analysis of trials scoring C and describe the results.
Data collection
Two reviewers independently will extract data using a form developed by the Cochrane Eyes and Vision Group. One reviewer will enter data into RevMan and a second reviewer will re‐enter the data using the double data‐entry facility to check for errors and inconsistencies.
Data synthesis
Before combining trial data, we will assess heterogeneity using a standard chi square test and the I square test. If substantial heterogeneity is present (e.g. I square > 50%) we will not pool the results but will present a descriptive summary of results. If there are sufficient trials, we will investigate the heterogeneity by examining study characteristics including: patient age, visual acuity, lesion size and composition, drug delivery system, type and dose of steroid used. We will combine data using a random effects model unless there are fewer than three studies in which case we will use a fixed effect model.
It is expected that most of the outcome measures will be in binary format e.g. loss of visual acuity of three lines or more. We will summarize the results of studies using the odds ratio, unless the event rate is common in which case we will use the risk ratio. For continuous data, such as contrast sensitivity, we will report the weighted mean difference.
Sensitivity analysis
Sensitivity analysis will be conducted to examine how strongly related our review results are to decisions and assumptions that have been made during the review. We will repeat the analysis after excluding studies of lower methodological quality (i.e. graded C on any parameter), unpublished data, and industry‐funded studies.
