Interferon alfa therapy for age‐related macular degeneration
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The aim of this review is to investigate interferon alfa as a treatment modality for neovascular age‐related macular degeneration.
Background
Introduction
Age‐related macular degeneration (AMD) is a progressive and degenerative disease of the retina that occurs with increasing frequency with age. There are two major types of AMD: non‐neovascular, or atrophic, and neovascular AMD. The non‐neovascular type is characterized by drusen (yellow spots under the retina), pigmentary changes (re‐distribution of melanin within the retinal pigment epithelial (RPE) cells under the retina and migration of melanin into the retina), and geographic atrophy (loss of the RPE and choriocapillaris).
This review is concerned with neovascular AMD. The hallmark of this type of AMD is choroidal neovascularization (CNV). Choroidal neovascularization is the process by which a vascular membrane, which originates in the choroid, grows under and through the RPE and Bruch's membrane to spread beneath the retina. These vessels may leak and bleed causing exudative or hemorrhagic retinal detachments, or both. The process usually evolves into a fibrous scar, which replaces the outer layers of the retina, the RPE and the choriocapillaris. The scarred retina has a greatly diminished visual function.
Epidemiology
Age‐related macular degeneration increases in prevalence from 0% among people younger than 55 years old to 18.5% among those 85 years or older (O'Shea 1998). It is the leading cause of irreversible vision loss in the elderly (Ghafour 1983; Hyman 1987; Leibowitz 1980; Tielsch 1994). While the non‐neovascular type is much more common, it is the neovascular type that is responsible for the most serious loss of vision. Neovascular AMD occurs in only 10% of people with AMD, yet 80% of those with severe visual loss (less than 20/200 Snellen acuity) have the neovascular form (Leibowitz 1980).
In the Beaver Dam Eye Study, the 10‐year incidence of neovascular AMD was 1.4% in those 43 to 86 years of age but increased to 4.1% in people over 75 years of age (Klein 2002). These findings were slightly lower in the Blue Mountain Eye Study (Mitchell 1995). In the Beaver Dam Study, the prevalence of neovascular AMD was 1.2% but also increased with age. The prevalence data are similar in other large population studies from the United States, Australia, and the Netherlands (Leibowitz 1980; Mitchell 1995; Vingerling 1995).
Neovascular AMD is rarely seen in black patients attending specialty eye clinics (Gregor 1978; Chumbley 1977), however large population studies such as the National Health and Nutrition Examination Survey (NHANES III) could not detect differences between the black and white groups because of the low prevalence (Klein 1995). Most studies support the notion that family history is a risk factor for AMD (Piguet 1993; Seddon 1997; Silvestri 1994) but there is no evidence that socio‐economic aspects are related (EDCCSG 1992; Goldberg 1988; Klein 1994). There are no studies to consistently show that modifiable factors such as lipid levels, light exposure, or alcohol intake put people at greater risk in developing AMD. One notable exception is smoking (Klein 1996; Mitchell 2002; Paetkau 1978). Hypertension (AREDS 2000; Hyman 1983) and increased body index mass (AREDS 2000; Schaumberg 2001) may have some association as well. High doses of vitamins C and E, beta‐carotene, and zinc may provide a modest protective effect against the progression of AMD in patients with extensive drusen or fellow eyes with neovascular AMD (AREDS 2001). With the aging population, more cases of this blinding disease would be expected in the future.
Presentation and diagnosis
Neovascular age‐related macular degeneration usually affects one eye at a time. The symptoms of AMD are metamorphopsia (distortions while looking at objects), scotomata (missing spots) and blurry vision. Individuals with AMD may be unaware of the change in their vision or may note difficulty with normal activities such as reading and writing, watching television, driving and recognizing faces. If AMD affects only one eye, visual loss may go undetected until monocular testing at routine eye examinations or by chance occlusion of the better eye. Frequently, people are unaware that their disturbed binocular vision is caused by changes in only one eye.
The diagnosis of AMD can be made clinically and with the help of imaging such as angiography. At the onset of symptoms, fundus examination often reveals subretinal exudation of fluid, lipid, or blood. Fluorescein angiography may be necessary to detect subtle exudation in some patients with a recent change in vision. Choroidal neovascularization has several characteristic patterns on fluorescein angiography. Classic CNV is defined as a well‐demarcated area with early hyperfluorescence and increasing fluorescein leakage on late frames of the angiogram. Occult CNV occurs in two different patterns: fibrovascular pigment epithelial detachment (PED) and late leakage of an undetermined source.
Two other tests may aid in studying patients with neovascular AMD: indocyanine green angiography images the choroidal circulation better than fluorescein and may show 'hot' spots under the RPE that are amenable to treatment. Optical coherence tomography (OCT), a noninvasive imaging modality, shows cross‐sectional images of the retina, RPE, and choroid. Recent papers define the characteristic appearance of the different stages of the disease process on OCT (Ting 2002; Van Kerckhoven 2001).
Treatment options
There is currently no cure for neovascular AMD. Therapy options are based on angiographic pathology appearance, whether the AMD includes classic or occult lesions. Treatments most frequently used for neovascular AMD include argon green laser photocoagulation and photodynamic therapy (PDT). However, laser photocoagulation used to obliterate neovascularization causes full thickness retinal burns and, in the case of subfoveal lesions, leads to immediate vision loss. Lesions that are treated with thermal laser need to be well‐defined extrafoveal or juxtafoveal membranes to avoid producing a central scotoma. Only a small percentage of patients with exudative neovascular AMD fit the criteria for argon laser treatment and those that can undergo laser treatment experience a 50% recurrence rate after the laser (MPSG 1991).
Photodynamic therapy was designed to treat CNV without damaging the overlying retina. This more selective treatment is advantageous for subfoveal lesions. In PDT, a photosensitizing drug is injected intravenously and preferentially adheres to the CNV. Focusing a non‐thermal laser light on the patient's CNV activates the dye. The highlighted CNV vessels are preferentially occluded when treated with the appropriate laser dose without permanent damage to the adjacent choroid and retina. Currently, PDT with verteporfin (Visudyne) has been approved by the Food and Drugs Association (FDA) in the US to treat classic subfoveal CNV. However, only approximately one third of all patients with neovascular AMD are classic. More than 90% of these patients require retreatment after three months and most need multiple treatments during the first year (TAP 1999). A Cochrane review of PDT is published in The Cochrane Library (Wormald 2003).
Antiangiogenic therapy is a new approach to the treatment of neovascular AMD. Angiogenesis is a complex process that results in new blood vessel formation. This process requires interactions between different factors that can be either stimulatory or inhibitory. These factors have been identified in CNV formation in animal models and human tissue (Aiello 1994; Kvanta 1996; Lopez 1996). Antiangiogenic treatments work by either blocking stimulatory factors or promoting the inhibitory ones. One of the potential antiangiogenic treatments includes interferon therapy. Interferon functions as an antiangiogenic agent by inhibiting the migration and proliferation of vascular endothelial cells (Brouty‐Boye 1980). Interferon alfa has been shown to inhibit iris neovascularization in animal models (Miller 1993). It has also been used in the treatment of hepatitis, solid tumors, and hematologic malignancies in humans (Baron 1991). Antiangiogenesis therapy modalities provide a promising means of treating the potentially devastating problem of AMD.
Objectives
The aim of this review is to investigate interferon alfa as a treatment modality for neovascular age‐related macular degeneration.
Methods
Criteria for considering studies for this review
Types of studies
This review will include randomized controlled trials.
Types of participants
We will include trials in which participants were people with neovascular age‐related macular degeneration as defined by study investigators.
Types of interventions
We will include studies in which interferon alfa treatment is compared to another treatment, placebo, or no treatment.
Types of outcome measures
Primary outcomes
The primary outcome for this review will be best corrected visual acuity at one year follow‐up.
Secondary outcomes
Secondary outcomes that will be measured if reported will include the following.
(1) Contrast sensitivity or any other validated measures of visual function as available in the studies.
(2) Assessment of choroidal neovascularization regression by fluorescein angiography or optical coherence tomography (OCT). This may include resolution of subretinal or intraretinal fluid by OCT evaluation.
(3) Any ocular/systemic effects as reported in the trials.
(4) Quality of life measures ‐ as assessed by any validated measurement scales.
(5) Economic data ‐ comparative cost analysis will be performed if data are available.
(6) Financial interest of authors will be analyzed in the final review if data are available.
Follow‐up
We will include trials in which participants are followed for at least one year (52 weeks).
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 (Latin American and Caribbean Literature on Health Sciences). There will be no date or language restrictions.
The following strategy will be used to search CENTRAL on The Cochrane Library:
#1 MACULAR DEGENERATION
#2 RETINAL DEGENERATION
#3 NEOVASCULARIZATION PATHOLOGIC
#4 (macula* near degener*)
#5 (macula* near neovasc*)
#6 (retina* near degener*)
#7 (retina* near neovasc*)
#8 (choroid* near degener*)
#9 (choroid* near neovasc*)
#10 maculopath*
#11(#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10)
#12 INTERFERON‐ALPHA
#13 INTERFERON ALFA‐2A
#14 INTERFERON ALFA‐2B
#15 INTERFERON ALFA‐2C
#16 interferon*
#17 (#12 or #13 or #14 or #15 or #16)
#18 (#11 and #17)
The following strategy will be used to search MEDLINE on SilverPlatter:
#1 explode "MACULAR‐DEGENERATION"/ all subheadings
#2 explode "NEOVASCULARIZATION,‐PATHOLOGIC"/ all subheadings
#3 explode "MACULA‐LUTEA"/ all subheadings
#4 (#1 or #2 or #3)
#5 ((macula* or retina* or choroid*) near (degener* or neovasc*)) in TI,AB
#6 maculopath* in TI,AB
#7 (macula* near lutea) in TI,AB
#8 (#5 or #6 or #7)
#9 (#4 or #8)
#10 explode "INTERFERON‐ALPHA"/ all subheadings
#11 "INTERFERON‐ALFA‐2A"/ all subheadings
#12 "INTERFERON‐ALFA‐2B"/ all subheadings
#13 "INTERFERON‐ALFA‐2C"/ all subheadings
#14 RECOMBINANT‐PROTEINS"/ all subheadings
#15 #14 and (PY=1989‐1989)
#16 "INTERFERON‐TYPE‐I,‐RECOMBINANT"/ ALL SUBHEADINGS
#17 #16 and (PY=1989‐1999)
#18 "INTERFERON‐TYPE‐I"/ all subheadings
#19 #18 and (PY=1983‐1991)
#20 interferon* in TI,AB
#21 (#10 or #11 or #12 or #13 or #15 or #17 or #19 or #20)
#22 (#9 and #21)
To identify randomized controlled trials, this search will be combined with the Cochrane Highly Sensitive Search Strategy phases one and two as contained in the Cochrane Reviewers' Handbook (Alderson 2004).
The following strategy wlll 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 (#1 or #2 or #3)
#5 ((macula* or retina* or choroid*) near (degener* or neovasc*) in TI,AB)
#6 maculopath* in TI,AB
#7 (macula* near lutea) in TI,AB
#8 (#5 or #6 or #7)
#9 (#4 or #8)
#10 explode "INTERFERON"/ all subheadings
#11 interferon* in TI,AB
#12 (#10 or #11)
#13 (#9 and #12)
To identify randomized controlled trials, this search will be combined with the following search:
#1 "RANDOMIZED‐CONTROLLED‐TRIAL"/ all subheadings
#2 "RANDOMIZATION"/ all subheadings
#3 "CONTROLLED‐STUDY"/ all subheadings
#4 "MULTICENTER‐STUDY"/ all subheadings
#5 "PHASE‐3‐CLINICAL‐TRIAL"/ all subheadings
#6 "PHASE‐4‐CLINICAL‐TRIAL"/ all subheadings
#7 "DOUBLE‐BLIND‐PROCEDURE"/ all subheadings
#8 "SINGLE‐BLIND‐PROCEDURE"/ all subheadings
#9 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8)
#10 (random* or cross?over* or factorial* or placebo* or volunteer*) in TI,AB
#11 (singl* or doubl* or trebl* or tripl*) near (blind* or mask*) in TI,AB
#12 (#9 or #10 or #11)
#13 HUMAN in DER
#14 (ANIMAL or NONHUMAN) in DER
#15 (#13 and #14)
#16 (#14 not #15)
#17 (#12 not #16)
LILACS will be searched using the terms (macul$ or retina$ or choroid$) in combination with (degener* or neovasc$) or maculopath$ or macula lutea.
Manual searches
We will search the reference lists of the studies included in the review for information about further trials. We will not be handsearching journals or conference proceedings for this review.
Data collection and analysis
Selection of trials
Both reviewers will independently evaluate the titles and abstracts resulting from the electronic searches. We will assess the resulting abstracts for those meeting the inclusion criteria and full article copies will be obtained for those that do. We will then appropriately select any trial that fulfills the stated criteria. We will contact authors to clarify any details necessary to make a complete assessment of the relevance of the study.
Assessment of methodological quality
Both reviewers will assess the sources of systematic bias in trials according to methods set out in section 6 of the Cochrane Reviewers' Handbook (Alderson 2004). The following parameters will be considered: method of allocation concealment (selection bias), masking of participants and researchers (performance bias), masking of outcome (detection bias), rates of follow up and compliance as well as analysis of all patients after randomization (attrition bias). Each of the parameters will be graded as (A) Adequate or Yes, (B) Unclear or Not Reported, or (C) Inadequate or No. Agreement between reviewers will be documented. We will contact the authors of trials categorized as B for additional information. If the authors do not respond, we will assign a grade to the trial based on the available information.
Extraction of study characteristics
We will extract study characteristics and report them in a table format. We will describe each study in terms of methods, participants, interventions, and outcomes. Additional details will be recorded in a separate category titled 'Notes'.
Data collection
Both reviewers will independently extract the data using a form developed by the Cochrane Eyes and Vision Group. Any discrepancies will be discussed and documented. One reviewer will enter the data into Review Manager and the second reviewer will check the entered data for any errors or inconsistencies. We will extract the data from each study that are pertinent to the outcomes outlined for the review. Our goal will be to extract similar data from each study in our review. If necessary we will transform outcome data to achieve consistency of results. We will resolve any discrepancies by discussion. We will contact the authors for more information if data are missing or difficult to interpret from a paper.
Data synthesis
The primary outcome for this review will be best corrected visual acuity. We will assess the proportion of people in treatment and control groups with three or more lines of vision loss on a LogMAR chart (equivalent to a doubling of the visual angle). We will use the measure of visual acuity loss reported that corresponds most closely to a doubling of the visual angle for studies that have not used the ETDRS or equivalent LogMAR chart. Depending on data available in trial reports, we may also consider visual acuity, or change in visual acuity, as a continuous measure.
As people have two eyes but interferon is administered systemically we will take care to ensure that data for the person will be extracted from the trials (for example binocular acuity or visual acuity in one selected study eye). If data are presented for eyes and not people we may be able to use these data (via the general inverse variance method) provided there is enough information in the trial reports to enable us to take into account the lack of independence between eyes.
Before combining the data, we will assess heterogeneity by examining the characteristics of the study. We will also use the forest plots of results of the studies and examine the I squared statistic for inconsistency and chi square test for statistical heterogeneity. If heterogeneity is detected among the results of the included studies, we will present the results as descriptive data. We anticipate that the proportion of people in the control group progressing to outcome (loss of vision) will be high (> 10%). For this reason we will use the relative risk as our effect measure. Continuous data will be summarized using a weighted mean difference.
Sensitivity analysis
Sensitivity analyses 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.
