36 Age-related macular degeneration

Background

Definition

Age-related macular degeneration (AMD) is defined as degeneration of the macula that occurs after 50 years of age and which cannot be attributed to an obvious systemic or ocular cause. There are two types of AMD – geographic atrophy and neovascular AMD. In geographic atrophy the retinal pigment epithelium atrophies with secondary loss of the photoreceptors. In neovascular AMD new vessels grow from the choroidal circulation through Bruchs membrane and into the retinal pigment epithelium. Choroidal new vessels are commonly defined as “classic” or “occult”. Classic neovascularisation is seen as well-defined leakage observed early during fluorescein angiography. Occult neovascularisation presents as ill-defined fluorescence. It is thought that these two angiographic patterns reflect the different extent to which the vessels have penetrated the retinal pigment epithelium, occult vessels lying underneath the retinal pigment epithelium.

AMD is associated with “drusen”, which are yellow spots clinically observable on the retina. Drusen and pigmentary abnormalities are commonly seen in older people, not all of whom will go on to develop visually impairing age-related macular degeneration. People with large, ill-defined “soft” drusen are more likely to develop age-related macular degeneration. A classification system has been proposed to enable comparison between different studies.1

Incidence/prevalence

Age-related macular degeneration is the most important cause of visual loss in most industrialised countries, accounting for approximately half of all registrations for blindness and partial sight.2 Pooled analysis of the major population-based studies of AMD shows that the prevalence of geographic atrophy in at least one eye increases from 0·7/1000 at ages 55 to 59 to 106/1000 at ages 90 and over.3 Neovascular AMD increases from 0·3/1000 at ages 55 to 59 to 113/1000 at ages 90 and over.

The Beaver Dam Eye Study estimated that the five-year incidence of AMD increased from 0·4% in the 55–64 age-group to 5·4% in the 75 and over age-group. The overall incidence in the Beaver Dam Study (ages 43 and over) was 0·9%.4

Aetiology

Most of the aetiological studies on AMD have been conducted in white populations in North America, Europe and Australia. These studies have been both population based and hospital based. The main risk factor for development of AMD is age. People aged 90 years and above are over 50 times more likely to have AMD causing visual impairment compared to those aged 55–59.5 Genetic predisposition is the next most important aetiological factor. People with a sibling who has the disease are 20 times more likely to develop the disease compared to those who do not have a sibling with the disease.6 The only other risk factor that has been demonstrated consistently in observational studies to be associated with AMD is cigarette smoking. People who smoke are two to three times more likely to develop AMD. A variety of other factors have been studied, including cardiovascular disease and its risk factors, dietary levels of antioxidant micronutrients, lifetime light exposure and oestrogens in women. Inconsistent results have been found.

Prognosis

Large drusen and retinal pigment epithelial hyperpigmentation are significant risk factors for developing neovascular AMD. It has been estimated that approximately 12% of people with bilateral soft drusen will develop either unilateral or bilateral neovascular AMD within 10 years, 4% will develop bilateral disease and 2·5% will become legally blind.7 In one cohort, 26% of people with neovascular AMD in one eye developed neovascular disease in their fellow eye within five years.8 Almost half of these were legally blind by five years. Approximately half of eyes with geographic atrophy and good visual acuity will experience significant visual loss (doubling of visual angle) within two years.9

Overview of interventions

Treatments for age-related macular degeneration can be divided into the following categories: first, interventions designed to treat choroidal neovascular membranes and, second, interventions designed to slow down the progression of the disease more generally. In addition, there have been attempts to relocate the retina physically in order to restore vision after the retina has been damaged by AMD.

Box 36.1 Approaches to treatment of AMD

Treatment of choroidal neovascular membranes

•Laser treatment

–thermal laser photocoagulation,* laser treatment combined with photoreactive drugs (photodynamic therapy)*

•Radiation treatment

–external beam using photon or proton beams*

–brachytherapy

•Heat treatment (transpupillary thermotherapy)

•Treatments with antiangiogenic drugs

–interferon*

–thalidomide

–steroids

•Physical removal of the new vessels

–submacular surgery with or without injection of fibrinolytic agent*

Treatments designed to halt the progression of AMD

•Antioxidant vitamin and mineral supplements*

•Laser treatment of drusen at risk of progression to advanced AMD*

Treatments designed to improve the choroidal circulation

•Membrane differential filtration*

•Pentoxifylline*

•Heparin*

•Lipotriad*

Relocation of the retina

Box 36.1 shows the approaches that have been taken to treat AMD. The interventions marked with an asterisk are ones for which randomised controlled trials are available and are therefore considered in this review.

Question

In people with choroidal neovascularisation (CNV) lesions associated with AMD does thermal laser photocoagulation reduce the risk of vision loss?

The evidence

The aim of thermal laser photocoagulation of CNV lesions is to seal off the new vessels and prevent them from leaking and/or growing larger.

We found 11 randomised controlled trials that have evaluated thermal laser photocoagulation – MPS-SMDS,10 COSG-AMD,11 MPS-AMDS K,12 Mestres et al. (1993),13 MMSG,14 Yassur et al. (1982),15 MPS-subfoveal recurrent,16 MPS-subfoveal new,17 Coscas et al. (1991),18 Bressler et al. (1996)19 and Arnold et al. (1997).20 All the trials were parallel group studies. Two trials enrolled two eyes from some of the patients but did not adjust for this in the analysis. However, the number of people with two eyes enrolled was small and this was unlikely to have affected the results. None of the studies were double-blind studies, that is, in all the studies, either the patient or the outcome assessment was unmasked to treatment group. In five of the studies, all other quality parameters were considered to be adequate.10–12,16,17 In none of the other trials was concealment of the randomisation schedule adequately described.

Participants in these studies were aged 50 years or over and had some visual acuity reduction associated with AMD. Most studies specified a lower limit for visual acuity ranging between 20/320 and 20/100. All studies recruited men and women and nine studies reported the numbers of men and women. The percentage of women ranged from 49% to 76%. Almost all studies excluded people who had had previous laser photocoagulation or other eye/systemic disease incompatible with the study. One study (MPSsubfoveal recurrent) examined treatment of new vessels after previous laser photocoagulation.

Participants were selected into the different studies according to the location of the CNV relative to the foveal avascular zone (FAZ). Extrafoveal CNV was defined where the border of the lesion was more than 200 microns from the centre of the FAZ. Juxtafoveal CNV was defined 1–199 microns from the centre of the FAZ and subfoveal CNV occurred directly under the centre of the FAZ. In most studies, the CNV was classic and generally well defined. Three studies examined poorly demarcated/occult subfoveal

CNV.18–20

The type of intervention differed according to the location and type of CNV. Argon green or blue-green laser was developed first and evaluated for the treatment of extrafoveal CNV. Krypton red laser was thought to have advantages for treating CNV close to the fovea because the red wavelength was not absorbed by xanthophyll in the inner retina. Two studies used dye red laser or a combination of the krypton/ argon/yellow dye as chosen by the treating clinician. Poorly demarcated subfoveal CNV was treated with perifoveal and scatter laser photocoagulation.

Most studies compared laser photocoagulation with no treatment. Two studies compared different types of laser,11,13 while two studies compared argon and krypton lasers against no treatment.16,17

In general, the primary outcome was visual acuity. This was usually presented as change in visual acuity from

baseline to a defined follow up time, usually between 12 and 36 months. In most studies, logMAR charts were used (ETDRS or Bailey-Lovie) and the proportion of people experiencing a doubling of the visual angle (three or more lines lost) or quadrupling of the visual angle (six or more lines lost) could be estimated from the report. Secondary outcomes were more variable but included contrast sensitivity, reading speed and progression of the disease.

The results of the studies are presented in Table 36.1. MPS-SMDS found that laser photocoagulation of classic CNV located more than 200 microns from the FAZ was effective with a relative risk of 0·32 (95% CI 0·18–0·57) and number needed to treat (NNT) of 3·3 (2·3–5·7).

The results of studies treating classic CNV closer to the FAZ were more equivocal. In the MPS-AMDS K study,12

58% of the no treatment group experienced a loss of six or more lines of visual acuity 36 months after randomisation compared to 49% of the group treated with krypton red laser. This gives a relative risk of 0·85 (CI 0·70–1·04) corresponding to a number needed to treat (NNT) of 11·7. However, this result does not exclude a harmful effect of treatment. The authors concluded that treatment was to be recommended because of a trend in visual acuity improvement in the treated group (P = 0·02) and a subgroup analysis (unclear whether defined a priori) showing a larger effect in people without hypertension. A similar effect size was seen in MMSG,14 which included people with juxtafoveal and extrafoveal CNV. Pooling the results of these two trials using a fixed effects model gives a pooled relative risk of 0·85 (CI 0·72–0·99) for loss of vision (two or more/six or more lines) at 24 or 36 months. Calculating an NNT based on the pooled risk difference gives an estimate of 10 people to be treated (CI 5·3–100) for one person to benefit.

Three studies have examined thermal laser photocoagulation of classic CNV directly below the FAZ. The MPS studies examined subfoveal new vessels and subfoveal vessels developing after previous laser photocoagulation.16,17 In both studies they demonstrated a benefit of treatment with NNTs of 6·1 (CI 3·6–20·6) and 5·1 (CI 2·8–26·9), respectively for six or more lines of visual acuity lost at 24 months follow up. The pooled relative risk from these trials is 0·47 (CI 0·31–0·71). Yassur et al.15 demonstrated a similar effect size but the length of follow up was unclear.

In two studies of macular scatter (grid) laser photocoagulation of poorly defined subfoveal CNV, little benefit of treatment was detected. Bressler et al.19 found a relative risk of 0·93 (CI 0·48–1·78) and Arnold et al.20 found a relative risk of 1·36 (CI 0·84–2·18) for loss of six or more lines of visual acuity at 24 and 60 months, respectively. In contrast, Coscas et al.18 found that perifoveal treatment of

poorly demarcated subfoveal CNV was effective with a relative risk of 0·68 (CI 0·53–0·88) and NNT of 4 (CI 2·4–10·4). However, the study group for this study included participants with well-defined, presumably classic, subfoveal CNV.

There was no evidence to suggest that either argon green or krypton red laser was more effective.11,16,17

Comment

Overall, it is likely that laser photocoagulation of classic CNV is an effective treatment when compared to no treatment. However, the size of the treatment effect is not well estimated to date. There has been only one trial randomising 224 people with extrafoveal CNV. It is a little surprising that trials of the treatment of subfoveal CNV

(new vessels and recurrent vessels) indicate a more favourable result than trials of juxtafoveal CNV. There is little evidence that laser photocoagulation is effective for occult CNV. Two trials of macular scatter (grid) photocoagulation for occult subfoveal CNV did not demonstrate any benefit. One trial of perifoveal photocoagulation demonstrated an effect for classic and occult subfoveal CNV, but this was a poorer quality study and has not been repeated.

Question

In people with CNV lesions associated with AMD does photodynamic therapy reduce the risk of vision loss?

The evidence

Photodynamic therapy aims to treat the CNV without affecting the retina. Photoreactive chemicals are injected into the blood and irradiated with light as they pass through the CNV. The light activates the chemicals, causing them to emit free radicals that destroy the new vessel.

There has been one Cochrane review of photodynamic therapy.21 This includes one published parallel group randomised trial (TAP Study – 609 participants).22 This was a high-quality study with adequate allocation concealment, reasonable attempts to mask participants and outcome assessment and one eye only enrolled for each participant. Rates of follow up were high. The majority of the participants were white (98%) with a mean age of 75 years.

People with vision 20/40 to 20/200 were included and CNV lesions were less than 5400 microns in diameter and had to have a classic component. People with previous treatment or other significant eye or systemic disease were excluded.

Fisher’s exact

Tabel 36.1 Thermal laser photocoagulation

group RR CI95% sided)-(2

group

(months)

a lostacuity

randomisedNo.

Control

Intervention

Study

Well-demarcated classic subfoveal CNV (directly under centre of foveal avascular zone)

67 0·48 0·33–0·71 <0·001

32

* Unclear

c 123

RED-K treatmentNo

.,al etYassur

15 1982

K-RED, krypton red; A, Argon; A-G, Argon green; A-BG, argon blue-green; RR, relative risk

statednot waschart (1991).al

etCoscas Snellen;used (1997).al

etArnold andMMSG used:were Lovie/EDTRS)-(Bailey chartslogMAR studiesmost

In a

fovealof zoneavascular

centrefrom

microns100–1500 b

trial;the nonein theof wastrials takenthis accountinto

moreenrolled onethan pereye inperson

trialsThese c

demarcated-well wellas

Includes d

*Deterioration: moving to a worse visual acuity group: three groups defined at beginning of study: 6/9–6/18; 6/21–6/60; < 6/60

Verteporfin 6 mg/m2 of body surface area) was compared to placebo (5% dextrose in water) administered via intravenous infusion of 30 ml over 10 minutes. This was followed after 15 minutes by application of 83 seconds of laser light at 689 nm delivered as 50 joules/cm2 at an intensity of 600 mW/cm2 using a spot size with a diameter 1000 microns larger than the greatest linear dimension of the CNV lesion.

Visual acuity was the main outcome. It was measured using the ETDRS chart, and two outcomes – loss of three or more lines of visual acuity and loss of six or more lines of visual acuity – were examined at 12 and 24 months.

The trial found that photodynamic therapy was effective in preventing visual loss. At 24 months, the relative risk of losing six or more lines of visual acuity was 0·61 (CI 0·45–0·81) with an NNT of 8·3 (CI 5·3–20). Subgroup analyses, specified a priori, suggested that the benefits of treatment may be confined to people with no signs of occult CNV.

The VIP study from the same group (not yet incorporated into the Cochrane review) enrolled patients with subfoveal occult CNV. The study was of a similar design to the TAP Study. At two years, 55% of the treatment group compared with 68% of the control group lost at least three lines of visual acuity (P = 0·032). Twenty-nine per cent of the treated group compared to 47% of the control group lost at least six lines of acuity (P = 0·004).

Photodynamic therapy in people with classic and occult choroidal neovascularisation due to AMD is effective in reducing the risk of visual loss.

Comment

Trials to date have been funded by the manufacturer. Further independent evidence is required.

Question

In people with CNV lesions associated with AMD does radiation therapy reduce the risk of vision loss?

The evidence

Ionising radiation inhibits vascular endothelial cell proliferation in vitro. It is thought that the retina can withstand cumulative doses up to 25 Gy without significant harm. The aim of radiation therapy is to slow down or prevent the progression of CNV without damaging the retina. The biological effect of radiation therapy depends on the dose per fraction, the number of fractions and the time between fractions. There have been two methods proposed for

delivering the dose – external beam radiotherapy and brachytherapy. There are no reported trials for the latter, but the trials of external beam radiotherapy are summarised below.

Table 36.2 shows out details of the five randomised controlled trials that have evaluated external beam radiotherapy – Bergink et al. (1998),23 Kobayashi and Kobayashi (2002),24 RAD Study (1999),25 Marcus et al. (2001)26 and Char et al. 1999.27 All the trials were parallel group studies. In one trial23 it was not clear if one or both eyes had been enrolled in the trial. Two of the studies made efforts to mask patients and outcome assessors to treatment group using “sham irradiation”.25,26 The role of sham treatment in keeping the patients unaware of their treatment was demonstrated by Marcus et al.26

The average age of participants in these studies ranged between 72 and 76 years. The proportion of women ranged from 48% to 64%. Some studies specified an upper limit for visual acuity of 20/40,27 20/5024 or 20/20023; the others specified a lower limit of 20/32026 or 20/400.25 There was little consistency on exclusions, although eligibility for laser photocoagulation, previous treatment for CNV, other eye disease and other systemic disease were considered in some studies. All studies enrolled participants with subfoveal CNV. In Bergink et al.23 and RAD Study25 this was further described as classic or occult. It must be assumed that in the absence of any clear statement, patients with classic or occult CNV were enrolled in the other studies.

The dose of radiation used differed in all the studies. Bergink et al.23 used the highest dose with 24 Gy delivered in four fractions. Char et al.27 delivered the lowest dose with one fraction of 7·5 Gy. Follow up ranged from 12 to 24 months. In Char27 follow up ranged from seven to 32 months. The results of the studies are presented in Table 36.2.

The RAD Study,25 which was the highest quality study, found little evidence of an effect of 16 Gy of radiation delivered in eight fractions on visual acuity loss to due CNV (relative risk 0·97, CI 0·73–1·28). Similarly Marcus et al.,26 which was the only other study to use sham irradiation in the control group, found little effect of 14 Gy delivered in seven fractions (relative risk 1·23, CI 0·56–2·68). Bergink et al.23 and Kobayashi and Kobayashi24 used higher doses of radiation and found more evidence of a protective effect of radiation. In Kobayashi and Kobayashi,24 results of analysis of mean logMAR scores were highly statistically significant in favour of treatment. However, these studies were not double masked. The study using the lowest dose27 found the strongest effect, but this was not statistically significant and may be subject to several biases due to the study design.

Comment

Overall there is little evidence that low-dose radiation therapy (less than 20 Gy) is effective in preventing visual

Subfoveal CNV

12 32 52 0·63 0·36–1·10 0·141

3 +

68

4 6 No treatment

24

.,al et*Bergink

23 1998

24 22 43 0·52 0·27–1·01 0·062

6 +

treatmentNo 101

2

10

20

24 andKobayashi 2000Kobayashi,

12 51 53 0·97 0·73–1·28 0·883

3 +

8 2 Sham irradiation 205

16

25 1999Study,

RAD

loss due to subfoveal CNV. Of the published studies to date, higher quality studies have been less likely to demonstrate treatment effects. High-quality trials of higher doses of radiation (20 to less than 25 Gy) need to be undertaken using sham irradiation as a control group.

Question

In people with CNV lesions associated with AMD does interferon alfa-2a reduce the risk of vision loss?

The evidence

Interferon alfa-2a has antiangiogenic properties, which is why it has been proposed as a treatment for CNV associated with AMD.

Table 36.3 sets out details of the three randomised controlled trials that have evaluated subcutaneous interferon alfa-2a – Engler et al. (1994),28 Poliner et al. (1993)29 and PTMDSG (1997).30 All the trials were parallel group studies. In two of the trials28,29 it was not clear whether one or two eyes were enrolled in the trial and/or whether the analysis of the eyes was conducted appropriately.

The average age of participants in these studies was 73 years28,30 and 77 years.29 The proportion of women ranged from 40% to 61%. All three studies specified a lower limit of visual acuity for inclusion in the study of 20/200,29 20/32030 or 20/400.28 Exclusion criteria included other eye disease, other systemic disease and previous treatment. PTMDSG specified that the lesion should be less than 12 disc areas (Macular Photocoagulation Study definitions).30

All three studies used a dose of 3 million international units (IU) of interferon injected subcutaneously. PTMDSG also examined doses of 1·5 million IU and 6 million IU.30 Dose frequencies were similar in the three studies with Engler et al.28 and PTMDSG30 using a schedule of three injections per week and Poliner et al.29 using a schedule of alternate days. The length of treatment varied, with PTMDSG treating for 12 months and the other studies for two months.

PTMDSG, which was the highest quality study, found little evidence that 12-month treatment with interferon alfa-2a is effective in preventing visual loss due to CNV associated with AMD.30 Follow up at 12 months showed that 50% of the treatment group compared with 38% of the control group had lost three or more lines of visual acuity

(relative risk 1·30, CI 0·99–1·71). This result is approaching statistical significance in the direction of harm of treatment with one person harmed for every nine persons treated (NNH = 8·7). There was no apparent dose–response effect.

The other two studies were small. Engler et al.28 enrolled 43 patients and treated them with 3 million IU of

interferon. They found a highly beneficial effect of treatment with a relative risk of 0·22 (CI 0·06–0·88). It is difficult to explain why this finding should be so different from that of PTMDSG – there are no obvious differences between the studies other than the duration of treatment (2 months v 12 months). PTMDSG was a better quality and considerably larger study.

Comment

Overall there is little evidence that interferon alfa-2a (3 million IU subcutaneously) is effective in preventing visual loss due to subfoveal CNV when used over a 12-month period. Different doses and different treatment schedules could usefully be studied.

Question

In people with CNV lesions associated with AMD does submacular surgery reduce the risk of vision loss?

The evidence

“Submacular surgery” refers to the surgical removal of CNV lesions along with associated scar tissue and blood.

We found no trials reporting a comparison of submacular surgery versus no treatment. One trial31 did not find a difference when a fibrinolytic agent (tissue plasminogen activator) was used during submacular surgery and compared to balanced salt solution. Although this was a high-quality study it was small (80 patients randomised) and therefore modest differences in effect cannot be ruled out.

A large multi-centre trial, SSTS, is ongoing in the USA. Submacular surgery is being compared to thermal laser photocoagulation. The results of the pilot study have been published.32 Until the results of SSTS are available there is not enough evidence on the effects of submacular surgery to recommend its use.

Question

In people with early AMD or AMD, does supplementation with antioxidant vitamin and/or mineral supplements reduce the risk of vision loss?

The evidence

The retina is subject to the combined effects of light and oxygen leading to the development of harmful free radicals. Antioxidant vitamin and mineral supplementation aims to protect the retina from the effects of free radicals,

11 50 0·22 0·06–0·88 0·008

2

2 +

43

2 Placebo

3 3 per week

.,al et*Engler

28 1994

thereby slowing down the progression of AMD and vision loss.

There has been one Cochrane review of the effects of antioxidant vitamin and mineral supplementation in people with AMD.33 Seven trials that randomised 4119 people were included in the review. The majority of people (88%) were enrolled in one trial (AREDS).34 This was a highquality study that had an average of six years of supplementation and follow up. There were three intervention groups: antioxidants (vitamin C 500 mg, vitamin E 400 IU, beta-carotene 15 mg), zinc (80 mg zinc oxide) and antioxidants plus zinc. People supplemented daily with antioxidants and/or zinc were less likely to lose 15 or more letters of visual acuity (equivalent to a doubling of the visual angle) (odds ratio 0·79, 99% CI 0·60–1·04), when compared to people taking placebo. This effect was seen more strongly in people with moderate to severe disease (OR 0·73, 99% CI 0·54–0·99). The other trials included in the review were small and their results inconsistent.

Comment

AREDS was a large high-quality study. It is likely that its results are relevant to people similar to those enrolled in the study, that is a relatively well-nourished subgroup of the American population. Further trials in populations with different nutritional status are required.

Question

In people with drusen likely to progress to advanced AMD, does thermal laser photocoagulation reduce the risk of vision loss?

The evidence

Thermal laser photocoagulation can induce drusen to disappear, even if the drusen are not treated directly. The exact mechanism behind this is unknown. The rationale behind laser treatment of drusen is that reducing the burden of drusen may decrease the likelihood of progression to AMD.

Table 36.4 sets out details of the trials that have evaluated laser treatment of drusen – CNVPT,35 Olk et al. (1999),36 Figueroa and Regeuras (1997),37 Little et al. (1997)38 and Frenneson and Nilsson (1995).39 Two types of studies have been done. Where people with both eyes affected by drusen at risk of developing into AMD have been enrolled these studies are called “bilateral drusen studies”. People with exudative AMD in one eye and drusen in the other have been enrolled in “fellow eye studies”. The usual study design in bilateral drusen studies is to enrol both eyes in the study and then randomly assign one eye to treatment. In the

fellow eye studies, only the eye with drusen and not exudative AMD is enrolled in the study and participants randomly assigned to treatment or no treatment. CNVPT35 and Olk et al.36 reported bilateral drusen and fellow eye studies. Figueroa and Regeuras37 enrolled both bilateral drusen and fellow eye patients. The latter were not randomised but all treated with laser. They are not included in Table 36.4. Frennesson enrolled both types of patient but did not present the results separately.

Bilateral drusen studies present particular problems in analysis. They are essentially matched pair studies. The matching has to be taken into account in the analysis. Although trialists may use appropriate statistical tests, reporting of these data in a form that enables the reader to calculate relevant effect measures, such as relative risk and NNT, is very rarely done. Figueroa and Regeuras37 and Olk et al.36 did not analyse eyes appropriately. None of the trials were “double masked” and none described generation of the allocation sequence.

The average age of participants in these studies ranged from 69 to 75 years and the proportion of women ranged from 59% to 67%. Most studies specified a lower limit for visual acuity in the study eye. This limit ranged from 20/25 to 20/63. Olk et al.36 CNVPT35 and Little et al.38 specified a minimum number of large drusen for inclusion in the study (5, 10 and 20, respectively). Exclusion criteria were not consistently applied but included previous eye treatment and other systemic and ocular diseases.

Two types of laser photocoagulation were used. CNVPT35 and Olk et al.36 applied the laser in a scatter or grid pattern. Figueroa and Regeuras37 and Little et al.38 applied the laser directly at the drusen. Frennesson39 used a mixture of these techniques. The number of laser burns used ranged from 20 in CNVPT35 to 132 (range 23 to 516) in Little et al.38 Olk et al.36 compared visible and invisible (subthreshold) burns.

Although all the studies reported a significant reduction in the number of drusen, prevention of visual loss was not demonstrated convincingly in any of the studies. In a posthoc subgroup analysis in the CNVPT study, it was found that laser-treated eyes with 50% or more drusen reduction at one year were less likely to lose vision.35 However, the overall results for the trial did not indicate any overall benefit of scatter/grid laser photocoagulation of eyes with drusen in preventing vision loss.

Olk et al.’s36 was a pilot study for planning a larger multicentre randomised controlled trial. In an analysis that ignored the matched pairs they found a significant improvement in vision in treated eyes. However, this was not statistically significant when the bilateral drusen and fellow eye studies were separated and analysed appropriately.

Figueroa and Regeuras,37 Little et al.38 and Frennesson and Nilsson39 were small studies that would be unlikely to detect anything other than large treatment effects.

Tabel 36.4 Laser treatment of drusen

Comment

There is little evidence to support the use of prophylactic laser treatment of drusen in the prevention of AMD. Published studies to date do not answer this question adequately – in general, they have been small and at risk of bias. In addition, specific issues as to the analysis of matched pair data have not always been addressed. The results of ongoing trials are awaited.

Question

In people with AMD do treatments aiming to improve the choroidal circulation reduce the risk of vision loss?

The evidence

A number of treatments have been studied whose overall aim is to improve some (often undetermined) aspects of the microcirculation with the aim of halting the progression of AMD. The studies are listed below in chronological order.

●Brunner et al. (2000)40 – membrane differential filtration

●Kruger (1998)41 – oral pentoxifylline

●Lebuisson et al. (1986)42 – ginkgo biloba extract

●Brown (1974)43 – lipotriad

●Zahn (1968)44 – heparin

●Havener and Sheets (1958)45 – heparin.

The trials of heparin44,45 and lipotriad43 were done before trial methodology was well established in ophthalmology. They were small, at risk of bias and, as the treatments considered are not currently debated, they are not considered further here.

The trial on Ginkgo biloba extract42 has been included in a Cochrane review.46 However, it was the only trial available and, as only 20 patients were randomised and it was not masked, it does not contribute to the evidence and is not considered further.

The trial on pentoxifylline41 demonstrated that a 3-month course of oral pentoxifylline treatment increased choroidal but not retinal blood flow. Further trials are needed to establish whether it prevents visual loss over a longer period.

Brunner et al.40 randomised 40 patients in a trial of membrane differential filtration, which aims to improve the microcirculation by removing high molecular weight proteins and lipoproteins from the blood. The treatment group was treated five times over a period of 21 weeks. The study was small and did not follow up the participants for a long enough period. There was a marginal improvement in visual acuity in the treated group compared to the control group but this was small and, as the study was unmasked, could well be attributable to bias.

Comment

None of the treatments aimed to improve the microcirculation have been demonstrated to be effective in preventing visual loss in AMD. Studies have been small and poor quality. Some of these treatments suffer from lack of a credible biological hypothesis, and some of them may involve considerable inconvenience and potential risk to patients (membrane differential filtration).

Implications for research

Although many different interventions have been proposed for the treatment of AMD, few have been evaluated sufficiently thoroughly to provide meaningful estimates of risks and benefits either for people with AMD or for ophthalmologists. Large, well-designed randomised controlled trials of interventions for AMD are required. Small trials are to be discouraged. The research community needs to focus on using common outcome measures that are relevant to patients.

Implications for practice

Treatment of neovascular AMD with photodynamic therapy and laser photocoagulation will slow down the progression of the disease, provided treatment is started early enough. The implications of photodynamic therapy for screening, healthcare provision and costs have not been explored fully. Other treatments should not be provided outside the remit of randomised controlled trials to evaluate their effectiveness.

References

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Ophthalmology 1997;104:7–21.

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