INTRODUCTION — Visual impairment is a major health problem for older adults and has significant impact on functional status and quality of life. Visual impairment limits the ability to safely drive a car and is associated with increased rates of falls and hip fractures [1-3]. The growing number of older people in the population underscores the importance of this problem. (See "Approach to the evaluation of older drivers" and "Falls in older persons: Risk factors and patient evaluation".)
Age-related macular degeneration (AMD) is the leading cause of legal adult blindness and severe visual impairment in industrialized countries [4]. Other common causes of visual impairment in older adults are [5-7] (see "Cataract in adults" and "Open-angle glaucoma: Epidemiology, clinical presentation, and diagnosis" and "Diabetic retinopathy: Prevention and treatment"):
●Presbyopia
●Cataract
●Glaucoma
●Diabetic retinopathy
Treatment and prevention of AMD will be reviewed here. Treatment varies with the type of AMD: dry (atrophic or nonexudative) or wet (neovascular or exudative). These terms are defined elsewhere. (See "Age-related macular degeneration: Clinical presentation, etiology, and diagnosis", section on 'Definition and classification'.)
The etiology and diagnosis of AMD are discussed separately. (See "Age-related macular degeneration: Clinical presentation, etiology, and diagnosis".)
TREATMENT OF DRY AMD
Our approach
Smoking cessation — All patients should be encouraged to quit smoking or avoid initiating smoking due to the increased risk of progression to advanced age-related macular degeneration (AMD; ie, wet or severe dry AMD). We also recommend not vaping with nicotine-containing products, as nicotine may exacerbate neovascularization [8].
Blood pressure control — Multiple studies have found an association of hypertension and neovascular AMD. We therefore encourage monitoring and control of blood pressure in patients with dry or wet AMD [9].
Antioxidant vitamins and zinc — We suggest that patients with extensive intermediate-size drusen, at least one large drusen, or noncentral geographic atrophy in one or both eyes be treated with a daily oral eye vitamin supplement (eg, Ocuvite, PreserVision). Doses should be consistent with the Age-Related Eye Disease Study 2 (AREDS2) formulation (containing vitamin C 500 mg, vitamin E 400 international units, lutein 10 mg, zeaxanthin 2 mg, zinc 80 mg [as zinc oxide], and copper 2 mg [as cupric oxide]). The original AREDS formulation contained beta-carotene, which has been associated with an increased risk of lung cancer, particularly in smokers. Nonsmokers and others at low risk of lung cancer may use the original formulation, if available. Antioxidants have been hypothesized to prevent cellular damage in the retina by limiting the effects of free radicals produced in the process of light absorption [10]. (See "Vitamin supplementation in disease prevention", section on 'Cancer'.)
Patients with no AMD or mild or borderline AMD have not been shown to benefit from antioxidant and/or zinc supplementation within the limited timeframe studied; longer-duration studies are needed to fully answer this question.
●In the original AREDS trial, 3640 subjects (aged 55 to 80 years) were evaluated and designated to be in the following categories [11]:
•Category one – No AMD
•Category two – Mild or borderline dry AMD
•Category three – Moderate dry AMD
•Category four – Advanced dry AMD (geographic atrophy involving the macula) or wet AMD (choroidal neovascularization)
Participants were randomly assigned to one of four treatment groups: antioxidants (vitamin C 500 mg, vitamin E 400 international units, beta-carotene 15 mg); zinc (zinc oxide 80 mg and cupric oxide 2 mg); antioxidants plus zinc; or placebo. During an average follow-up of 6.3 years, the following findings were reported:
•Patients with no AMD (category one) or mild or borderline AMD (category two) did not benefit from antioxidant and/or zinc supplementation.
•Zinc plus antioxidants, compared with placebo, lowered the risk for progression to advanced AMD or visual acuity loss in the good eye (odds ratio [OR] 0.66, 95% CI 0.47-0.91) in patients with moderate and advanced AMD (categories three and four). Zinc alone was also associated with a lower risk of progression (OR 0.71, CI 0.52-0.99). Specifically, patients with extensive intermediate-size drusen, at least one large drusen, or noncentral geographic atrophy in one or both eyes benefited from treatment.
These findings suggest that patients with more extensive dry AMD may benefit from taking antioxidants and zinc at doses used in the AREDS trial. Eleven patients would need to be treated for seven years to prevent progression in one [11].
●The AREDS2 trial investigated whether adding additional antioxidants (the carotenoids lutein and zeaxanthin, and omega-3 fatty acids [docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)]) to the AREDS vitamin formulation would further decrease risk of AMD [12]. These additions did not reduce progression of early nonexudative AMD. Additionally, a systematic review of two randomized trials found that omega-3 fatty acid supplementation in patients with AMD did not decrease risk of progression to advanced AMD [13].
In a post hoc analysis of a subgroup of patients secondarily randomized to modified AREDS regimens that included substitution of lutein and zeaxanthin for beta-carotene, the substitution appeared to be effective for reducing the risk of progression to advanced AMD. Because more lung cancers were noted in the beta-carotene versus no beta-carotene group, the substitution of lutein and zeaxanthin for beta-carotene was recommended.
Follow-up — The type and frequency of follow-up depend on the severity of the AMD and risk of progression. Ophthalmology follow-up utilizes a number of modalities to monitor patients, including self-examination with Amsler grid, vision test with an eye chart, optical coherence tomography, or fundoscopic examination.
Unproven and ineffective therapies
Laser therapy — We do not recommend that patients with dry AMD be treated with laser therapy. Several studies have investigated the efficacy of laser therapy for prevention of progression in people with high-risk drusen. While early randomized trials suggested that laser therapy produced a small improvement in visual acuity [14-16], subsequent trials showed increased rates of choroidal neovascularization [17,18] or no benefit [19]. A systematic review of nine randomized trials found that laser photocoagulation of drusen led to drusen reduction but did not decrease the risk of choroidal neovascularization or loss of vision and did not appear to reduce the development of geographic atrophy acuity [20].
Statin therapy — A pilot study found that high-dose atorvastatin (80 mg daily) was associated with regression of large soft drusen and vision improvement in 10 out of 23 patients with severe dry AMD. Confirmatory studies are needed to confirm the effectiveness of this treatment in dry AMD [21,22].
Rheopheresis — This procedure removes high molecular weight proteins from plasma, which results in the reduction of blood and plasma viscosity as well as erythrocyte and thrombocyte aggregation. Results from case series and a randomized trial suggest that therapeutic apheresis using double-filtration plasmapheresis in patients with severe dry AMD may be beneficial. The dry AMD treatment with Rheopheresis trial (ART) is a trial that treated dry AMD patients 10 times over a period of 17 weeks and found a significant improvement in vision compared with untreated controls [23]. Additional longer-term studies are warranted before we are able to recommend this treatment to our patients.
Stem cell therapy — A prospective study in nine patients with atrophic AMD (median age 77 years) found that subretinal transplantation of human embryonic stem cell-derived retinal epithelial cells improved visual acuity at 12 months in the treated eye compared with the untreated eye [24]. Systemic immunosuppression was given for 13 weeks, and adverse effects related to immunosuppression and cataracts, although the procedure was generally well-tolerated and patients were followed for up to three years. These findings support a proof-of-concept but are too preliminary to suggest a means of treatment.
TREATMENT OF WET AMD — Effective therapies for exudative or wet age-related macular degeneration (AMD) include intravitreous injection of a vascular endothelial growth factor (VEGF) inhibitor, photodynamic therapy (PDT), and supplementation with zinc and antioxidant vitamins. The decision about specific therapies must take into account the likelihood of visual recovery, which is better with smaller, more recent lesions, as well as the risks of the various therapies.
In general, our approach is as follows:
●For most patients with AMD and neovascularization, we recommend treatment with intravitreal bevacizumab, ranibizumab, or aflibercept. We no longer offer PDT to patients.
●We also suggest that patients with wet AMD in one or both eyes be treated with daily oral supplements consistent with the Age-Related Eye Disease Study 2 (AREDS2) formulation (containing vitamin C 500 mg, vitamin E 400 international units, lutein 10 mg, zeaxanthin 2 mg, zinc 80 mg [as zinc oxide], and copper 2 mg [as cupric oxide]). Alternatively, patients who are not smokers or former smokers may use the standard AREDS formulation, which contains beta-carotene rather than lutein or zeaxanthin. (See 'Antioxidant vitamins and zinc' above.)
The efficacy and adverse effects of these therapies are reviewed below. (See 'Efficacy of VEGF inhibitors and inhibitor-like drugs' below and 'Adverse effects of VEGF inhibitors' below.)
Blood pressure control — Multiple studies have found an association of hypertension and neovascular AMD. We therefore encourage monitoring and control of blood pressure in patients with dry or wet AMD [9].
VEGF inhibitors and inhibitor-like drugs — VEGF is a potent mitogen and vascular permeability factor that plays a pivotal role in neovascularization. Intravitreal injection of drugs that inhibit VEGF can limit progression of exudative AMD and stabilize, or reverse, visual loss [25]. (See "Age-related macular degeneration: Clinical presentation, etiology, and diagnosis", section on 'Pathogenesis'.)
A number of anti-VEGF molecules have been developed that can limit the destructive effects of choroidal neovascular membranes in patients with AMD. Long-term data from randomized trials are available for intravitreal ranibizumab [26], and data are available comparing bevacizumab with ranibizumab [27-29]. In a systematic review of 16 randomized trials (6347 participants) evaluating VEGF inhibitors, outcomes for bevacizumab and ranibizumab were similar and both improved visual acuity, as well as morphologic parameters, compared with placebo [25]. Another review concludes that intravitreal injection of ranibizumab every four weeks, bevacizumab (off-label) every four weeks, or aflibercept every eight weeks appear to have similar efficacy in the treatment of wet AMD [30]. In light of the significant difference in cost between bevacizumab and ranibizumab or aflibercept, off-label use of bevacizumab (requiring dose preparation for intravitreal injection) is increasingly being administered in the United States. In addition, brolucizumab is now approved for use in the United States, but we are awaiting additional clinical experience before recommending it.
Ranibizumab-nuna is a biosimilar to ranibizumab, approved by the US Food and Drug Administration (FDA) in 2021 [31]. Clinical data are limited. Other biosimilars for aflibercept and bevacizumab are also being tested for use in ophthalmology [32,33].
Delay in the initiation of VEGF therapy (greater than 21 weeks compared with less than 7 weeks) after first symptoms of wet AMD has been associated with poorer vision outcomes [34].
Long-term cardiovascular effects of these medications in the treatment of AMD are unknown [35]. Systemic levels are detectable after intravitreous injection of either ranibizumab or bevacizumab, which in theory might increase the risk of vascular events. Further studies are needed to determine if there is any increased risk, but clinicians should be aware of this concern when using VEGF inhibitors in patients who are at increased risk for hemorrhagic stroke or other serious bleeding or thrombotic events [36]. (See "Overview of angiogenesis inhibitors", section on 'Vascular endothelial growth factor' and 'Adverse effects of VEGF inhibitors' below.)
Efficacy of VEGF inhibitors and inhibitor-like drugs
Ranibizumab — Ranibizumab is a recombinant humanized monoclonal antibody with specificity for VEGF [37,38]. Usual dosing of intravitreal ranibizumab for the treatment of wet AMD is 0.5 mg by intravitreal injection every month for three injections, with scheduled or variable treatment thereafter. In addition, an ocular implant has been FDA-approved in 2021 for treatment of patients with neovascular age-related macular degeneration who have responded to at least two intravitreal injections of a VEGF inhibitor. The implant is surgically inserted and removed (if necessary). Refill-exchange procedures occur approximately every six months [39]. The safety profile for the port delivery system reveals significantly greater risk of retinal detachment, endophthalmitis, and vitreous hemorrhage compared with monthly intravitreal injections [40]. In our opinion, the risk of this port delivery device at this time outweighs the benefit of a reduced treatment burden. Further studies are needed. (See 'Treatment schedules for VEGF inhibitors' below.)
Several randomized trials of patients with wet AMD have shown benefit [41-47]:
●The MARINA trial randomly assigned 716 patients with wet AMD to 24 monthly injections with ranibizumab 0.3 mg, ranibizumab 0.5 mg, or sham injection [41]. After one year, more patients treated with 0.3 mg or 0.5 mg ranibizumab lost fewer than 15 letters from baseline visual acuity (95 and 95 percent versus 62 percent with sham injection) and more patients treated with ranibizumab improved by at least 15 letters (25 and 34 percent versus 5 percent). There was also significant improvement in visual function in ranibizumab-treated patients, compared with a decline in sham-treated patients, as assessed by questionnaire at 12 months [42].
The benefits were maintained at two years and confirmed with findings of decreased leakage with fluorescein angiography and decreased fibrosis on optical coherence tomography (OCT) [43].
●The ANCHOR trial randomly assigned 423 patients with wet AMD to intravitreal ranibizumab (0.3 or 0.5 mg) or PDT with verteporfin [44]. After one year, more patients treated with 0.3 or 0.5 mg ranibizumab lost fewer than 15 letters of visual acuity (94 and 96 percent versus 64 percent with verteporfin) and more improved by at least 15 letters (36 and 40 percent versus 6 percent); outcomes were similar at two-year follow-up [45]. Predictors of response to ranibizumab were better baseline visual acuity, smaller choroidal neovascularization lesion size, and younger patient age [46].
Follow-up at seven years (mean 7.3 years, range 6.3 to 8.5 years) of patients who had participated in either the MARINA or ANCHOR trials found that 37 percent met the primary endpoint of 20/70 for best corrected visual acuity (BCVA), and 37 percent had a BCVA of 20/200 or worse [26]. Compared with baseline at study entry, visual acuity had declined by 15 or more letters for one-third, and one-half of eyes were stable. In the same cohort, progression of macular atrophy was detected in the majority of treated patients, and the extent of the atrophy was a major determinant of visual outcome at seven years following ranibizumab therapy (with initial dosing schedules more frequent than are now used) [48].
Bevacizumab — Bevacizumab and ranibizumab are closely-related antibodies. Ranibizumab is essentially an antibody fragment (Fab fragment) of bevacizumab with some modifications to the amino acid sequence that increase its binding of VEGF [49]. Bevacizumab is approved in the United States as an intravenous infusion for the systemic therapy of colorectal cancer. However, treatment with intravitreal bevacizumab for AMD is far less expensive than treatment with intravitreal ranibizumab (USD $50 compared with $1950 per injection) [50,51] and intravitreal bevacizumab is increasingly being administered as an off-label treatment in the United States [52].
Results from randomized trials comparing intravitreal bevacizumab and ranibizumab found no difference in visual acuity for the treatment of wet AMD [27,53]. In the Comparison of AMD Treatment Trial (CATT), 1185 patients with wet AMD were randomly assigned to one of four groups: intravitreal injections of bevacizumab (1.25 mg) or ranibizumab (0.5 mg), with either drug given either monthly or as needed [53]. At two-year follow-up, there was no difference in the primary outcome of mean change in visual acuity or in secondary outcomes, including visual acuity change of at least five letters; there was less gain in visual acuity with treatment as needed, compared with monthly. There were more serious adverse events with bevacizumab than ranibizumab (39.3 versus 31.7 percent), although mortality and atherothrombotic events were the same. A second trial with an analogous protocol, the IVAN, enrolled 610 patients and found that, for the primary outcome of best visual acuity at two years, bevacizumab was neither non-inferior nor inferior to ranibizumab [27]. There was no difference in mortality, atherothrombotic events, or hospital admission between the two drugs. A meta-analysis combining results from one-year data of the CATT trial and two-year data from the IVAN trial found that bevacizumab was non-inferior to ranibizumab for visual acuity [27]; additional randomized trials comparing the two drugs at two years also demonstrated non-inferiority for bevacizumab [28] or equivalent efficacy [54].
Aflibercept — Aflibercept is a recombinant fusion protein receptor that binds VEGF-A, VEGF-B, and placental growth factor (PLGF) and is FDA-approved for the treatment of wet AMD [55]. In two randomized trials of 2419 adult patients with wet AMD, intravitreal aflibercept (0.5 mg monthly, 2.0 mg monthly, or 2.0 mg every two months) was similarly effective in improving visual acuity at one and two years compared with intravitreal ranibizumab 0.5 mg monthly [56,57]. In addition, no differences at 24 months in the rate of development or growth of macular atrophy were seen in a comparison of 278 patients randomized to either ranibizumab or aflibercept [58].
Aflibercept has not been compared directly with bevacizumab, which is less costly. In a prospective study of 49 patients with AMD resistance to ranibizumab, aflibercept over 24 weeks improved BCVA by seven letters, though whether the improvement will be maintained over a longer period is unknown [59]. Aflibercept is less costly than ranibizumab and may allow for less frequent dosing (every two months).
Brolucizumab — Brolucizumab, a single-chain antibody fragment that inhibits VEGF-A, has been approved by the FDA for the treatment of wet AMD [60]. It was found to be noninferior to aflibercept in visual function at week 48, with over 50 percent of eyes treated with brolucizumab being maintained on an every 12 weeks dosing schedule. However, safety concerns have been raised due to possible retinal vascular occlusions and inflammation-associated adverse events [61,62]. Therefore, we do not offer this drug to our patients with AMD at the present time.
Faricimab — Faricimab is a bispecific antibody that inhibits VEGF-A and angiopoeitin-2, approved by the FDA in 2022 for the treatment of wet AMD. The FDA approval for the treatment of wet AMD was based on the results of two randomized, double-masked, multicenter global studies [63]. In both studies, faricimab (with dosing up to every 16 weeks) was found to be noninferior to aflibercept (with dosing up to every eight weeks) and with comparable adverse events. Faricimab may offer patients a similar efficacy and adverse events profile with the possibility of significantly fewer needed injections.
Treatment schedules for VEGF inhibitors — The optimal frequency for injections of VEGF inhibitors is not known, although both the MARINA and ANCHOR trials evaluated monthly intravitreal injections. One commonly used schedule for ranibizumab and bevacizumab is monthly for three to six months, and then as needed determined by further assessment of disease activity. The schedule for aflibercept is to administer three doses (2 mg) at four-week intervals, followed by 2 mg every eight weeks [64].
Several trials have evaluated less frequent or individualized dosing for ranibizumab or bevacizumab. In the PIER trial, 184 patients with wet AMD were randomly assigned to intravitreal ranibizumab 0.3 mg, ranibizumab 0.5 mg, or sham injections monthly for three months and then quarterly with follow-up at 12 months [65]. Patients in both treatment groups had significantly less decline in visual acuity than sham (-1.6 and -0.2 letters versus -16.3 letters for control). However, treatment groups had some visual loss comparing visual acuity at 3 and 12 months, suggesting that some patients might have benefited from more frequent treatment. An observational study of patients treated with bevacizumab monthly for three months found that foveal thickening, which had improved during the course of treatment, worsened during the subsequent three months without treatment [66].
Several studies have shown that discontinuous (as-needed, guided by results of OCT) treatment with either ranibizumab or bevacizumab, compared with monthly injections, resulted in equivalent visual improvement but required fewer injections [67-71]. The CATT trial and a meta-analysis of the CATT and IVAN trials [27], however, showed a small reduction in vision compared with monthly treatment, although the difference was likely not clinically significant [53]. Additionally, the CATT trial found an increase in mortality in patients receiving discontinuous rather than monthly injections and raises safety concerns with intermittent dosing [27]. In a four-year follow-up of a cohort of patients (600 eyes) treated with variably dosed ranibizumab, one-fifth of patients whose treatment had been suspended because of inactive disease required resumption of therapy, indicating the need for ongoing indefinite close follow-up [72].
An alternate regimen to dosing as needed is a "treat-and-extend" regimen in which, after initial treatment and stabilization, the intervals for patient follow-up and treatment are adjusted based upon clinical findings. Intervals are extended two weeks if neovascular activity is not present and shortened by two weeks if either fluid or hemorrhage is seen; anti-VEGF treatment is administered at every visit, regardless of disease activity, so there is no prolonged lapse in treatment. Bevacizumab and ranibizumab are equally effective administered in a treat-and-extend regimen [73]. Several longitudinal cohort studies have demonstrated that "treat-and-extend" regimens can decrease the number of injections administered, and number of clinic visits per year compared with fixed-interval dosing while maintaining visual improvement comparable with other treatment regimens [74-77]. Reviews of real-world evidence find that treat-and-extend regimens are more likely to balance clinical outcomes and treat burden for patients with AMD compared with fixed dosing or pro re nata regimens [78,79].
Tachyphylaxis to VEGF inhibitors has been reported (affecting 2 percent in one series), and it is hypothesized that treatment schedules allowing intermittent rather than continuous cycles for injection might decrease the risk of tachyphylaxis [80].
In a multi-country retrospective study of response to VEGF inhibitors (mostly ranibizumab) in patients with AMD not participating in a randomized trial, visual acuity improved in the first three months following medication initiation [81]. However, initial improvement in visual acuity was not sustained, with subsequent decline correlating with the number of injections that patients received (an average of 5.0 in the first year and 2.2 in the second year).
Adverse effects of VEGF inhibitors — The short-term adverse effects (ocular and nonocular) of intravitreal ranibizumab and bevacizumab appear similar. Data on long-term adverse effects of the VEGF inhibitors are lacking.
In the randomized trials described above, ocular adverse effects included endophthalmitis (0.6 to 1.3 percent) and serious uveitis (1.3 percent) [43,45,82-84]. In a database study of 88,150 intravitreal injections for AMD, infectious endophthalmitis developed in 0.020 percent of procedures [85]. The risk did not increase with each successive injection, and there was no difference found between the types of anti-VEGF medications used. Noninfectious endophthalmitis developed in 0.012 percent of procedures. The incidence of noninfectious endophthalmitis was higher for bevacizumab compared with ranibizumab and aflibercept. Visual acuity loss of >2 lines 12 months after infectious and noninfectious endophthalmitis was 31 and 25 percent, respectively.
Increases in intraocular pressure (IOP) were also reported in randomized trials but were temporary, resolving within an hour of injection [86]. However, two small retrospective cohort studies showed an association between intravitreal anti-VEGF injections and increased risk for sustained IOP elevation (occurring in 11.6 versus 5.3 percent of VEGF treated and controls, respectively) [87,88]. Other ocular adverse effects that occurred more frequently than sham were: eye pain, floaters, punctate keratitis, cataracts, vitreous opacities, anterior chamber inflammation, vision disturbance, corneal edema, and ocular discharge. Data from industry-sponsored clinical trials of aflibercept have also demonstrated ocular adverse effects including eye pain, conjunctival hemorrhage, vitreous floaters, cataract formation, and elevated IOP [56].
Cardiovascular effects of these medications in the treatment of AMD are uncertain [35,89]. In the SAILOR study of intravitreal ranibizumab for wet AMD, stroke occurred in more patients treated with 0.5 mg compared with 0.3 mg of ranibizumab (1.2 versus 0.3 percent, respectively) [90]. In subsequent pooled analysis of five trials, the risk for stroke was not significantly increased for patients treated with ranibizumab 0.3 mg versus control (odds ratio [OR] 1.2, 95% CI 0.4-4.4) [91]. Patients treated with ranibizumab 0.5 mg versus control had a slightly increased risk for stroke (OR 2.2, 95% CI 0.8-7.1) that was not statistically significant. However, the stroke rate in both groups was lower than anticipated, and the clinical significance of the dose-related difference is uncertain.
There are few studies comparing adverse effects among the VEGF inhibitors. In one randomized trial of 1208 patients comparing intravitreal bevacizumab and ranibizumab injections, the rate of serious adverse effects was significantly higher with bevacizumab than with ranibizumab (24 versus 19 percent), mostly due to hospitalizations for infections (eg, pneumonia and urinary tract infections) and gastrointestinal disorders (eg, bleeding and nausea and vomiting) [92]. Rates of stroke, myocardial infarction, and mortality were similar in both groups. It is inconclusive whether the greater rate of serious adverse effects of bevacizumab is clinically significant and a reflection of a true difference in risk.
Further studies are needed to determine if there is any increased risk of stroke, but clinicians should be aware of this concern when using VEGF inhibitors in patients who are at increased risk for stroke [36].
Safety in patients taking anticoagulants or antiplatelet drugs — The bleeding risk of intravitreal injections in patients taking anticoagulants seems minimal, and anticoagulation should not need to be discontinued prior to injection. There were no reported hemorrhagic complications in several series of patients taking anticoagulant or antiplatelet medications who received intravitreal injections of VEGF inhibitors [93,94].
Antioxidant vitamins and zinc — We suggest treatment with supplements in these daily doses: vitamin C 500 mg, vitamin E 400 international units, lutein 10 mg, zeaxanthin 2 mg, zinc 80 mg (as zinc oxide), and copper 2 mg (as cupric oxide). Beta-carotene 15 mg may be used in lieu of lutein and zeaxanthin in nonsmokers. Individual components of vitamins and zinc vary based on a given multivitamin preparation. Information on dietary supplements is available from the NIH (NIH Dietary Supplement Label Database).
In a 2017 meta-analysis, antioxidant multivitamins reduced the likelihood of progression to late AMD (OR 0.72, 95% CI 0.58-0.90; three trials; moderate-quality evidence) [95]. Included in this systematic review were the AREDS and AREDS2 studies, which represented most of the evidence presented [11,12]. The AREDS trial found a statistically significant benefit of antioxidants (vitamins C and E and beta-carotene) plus zinc supplementation on progression of early AMD in one eye in patients with wet AMD or vision loss due to dry AMD in the other eye [11]. Subsequently, the AREDS2 trial found that substitution of lutein and zeaxanthin for beta-carotene and using a lower zinc dose did not affect the treatment benefit [12]. Beta-carotene has been associated with an increased risk for lung cancer and possibly to an increased risk of coronary heart disease, particularly in smokers [96]. (See 'Antioxidant vitamins and zinc' above.)
Preliminary findings suggest that certain risk alleles for AMD (CHF and ARMS2) may influence preferential response to zinc or antioxidant vitamins [97]. However, further confirmation will be needed to determine the role for genotyping to guide therapy. A statement from the American Academy of Ophthalmology recommends that until tailoring management strategy to genotype results has been shown to provide benefit in published clinical trials, genotyping should be confined to patients participating in research trials [98]. (See "Age-related macular degeneration: Clinical presentation, etiology, and diagnosis", section on 'Genetic factors'.)
Photodynamic therapy — PDT involves intravenous injection of the photosensitizing dye verteporfin just prior to treatment with a photo-activating laser applied through the eye with a specific contact lens. The activated dye forms reactive free radicals that damage the vascular endothelium and result in thrombosis of the neovascular tissue that retains dye more avidly than normal vessels. However, these vessels often reopen [99,100]. As an example, 33 percent of 108 eyes in one study showed evidence of recurrent choroidal neovascularization at 18 months following a course of PDT [101]. Retreatment with PDT is safe [102,103].
The role for PDT has decreased with the increasing use of anti-VEGF therapy. We suggest PDT (with or without intravitreal bevacizumab, aflibercept, or ranibizumab) for patients who fail to respond to initial anti-VEGF therapies.
Prior to anti-VEGF treatments, PDT was primarily indicated in patients with a subfoveal neovascular membrane, in whom treatment with a conventional laser was contraindicated because of the iatrogenic scotoma. An analysis of two randomized trials (609 patients) and a subsequent systematic review of three trials (1022 patients) found that, compared with placebo, PDT was associated with a lower rate of vision loss at one year [99,104]. Vision remained relatively stable over three years of follow-up [102].
Thermal laser photocoagulation — With the availability of newer pharmacologic therapies and the risk of scotoma and vision loss with photocoagulation, laser photocoagulation for choroidal neovascularization is rarely recommended [105]. Thermal laser photocoagulation uses a relatively high intensity of thermal laser energy to coagulate the abnormal choroidal neovascular membrane. An adverse consequence of this treatment is focal damage to the overlying retina with the formation of a permanent blind spot. Thus, if used, this treatment should be limited to very small lesions outside of the central macula.
VEGF inhibitors with adjuvant therapy — Two techniques that cause vascular occlusion to the target tissue have been investigated as adjuvant treatment to be used in combination with VEGF inhibition. Transpupillary thermotherapy (TTT) delivers a waveform near the infrared spectrum through the pupil to the target tissue. At low doses (136 mW/mm), the surrounding neurosensory retina is not damaged. PDT is described above. (See 'Photodynamic therapy' above.)
In a randomized trial, combined ranibizumab and verteporfin PDT was more effective than PDT alone [106]. The combination of PDT with bevacizumab has been effective in case series, with randomized trials underway [107-109]. Studies conflict on whether intravitreal triamcinolone in combination with PDT provides added benefit [110-113].
In a randomized trial with a sham procedure as control, 100 patients were assigned to receive quarterly low-dose TTT or sham TTT for two years [114]. Patients in the TTT group required fewer treatments with ranibizumab compared with those in the sham group (mean 8.0 versus 6.3 over two years). There was no difference in corrected visual acuity or lesion area between groups.
Surgery — Three procedures have been tried, with varying success, for AMD: subretinal tissue plasminogen activator (tPA) injection with pneumatic displacement of blood, submacular surgery, and macular translocation surgery.
●The simplest and most effective surgery for large submacular hemorrhages involves subretinal injection of tPA and pneumatic displacement of the hemorrhage into the inferior retina [115].
●Submacular surgery involves the removal of abnormal subretinal neovascularization and large submacular hemorrhages, if present. Clinical trials have been largely disappointing, showing lack of benefit and high rates of retinal detachment [116-118]. There may be a role for submacular surgery, however, in patients with large peripapillary membranes [119].
●Macular translocation surgery is experimental and involves moving the macula to a less diseased area of the retina in patients with subfoveal choroidal neovascularization [120,121]. The advent of effective pharmacologic therapy has limited the use of this surgical modality to patients with large submacular hemorrhages, or patients unresponsive to VEGF inhibitors [122]. The surgical risks are substantial (retinal detachment, proliferative vitreoretinopathy, diplopia) [123].
Radiation therapy — External beam radiation therapy has been studied in patients with AMD. A meta-analysis of randomized, controlled trials concluded that there was no consistent evidence of benefit [124]. The long-term safety of radiation therapy is unknown.
VISUAL AIDS — Patients who have age-related macular degeneration (AMD) may benefit from referral to low vision specialists and visual rehabilitation programs, as well as the use of a variety of visual aids for increasing reading ability and mobility. Tablet computers such as the iPad that allow for easy enlargement of the text and backlighting with excellent contrast of the letters are often helpful. In our experience, the success of visual aids is directly correlated with the motivation of the patient. An implantable telescope lens was approved by the US Food and Drug Administration (FDA) in 2010 for use in patients who have not yet had cataract surgery and have macular pathology [125]. Besides the high cost of the device and significant risks associated with its implantation, it offers benefit to a select number of patients with visual disability.
PREVENTION — Healthy lifestyle habits may be helpful in preventing age-related macular degeneration (AMD).
Diet — The relationship between diet and the risk of AMD has been evaluated in a number of observational studies (see "Healthy diet in adults"):
●Healthy diets, particularly those high in carotenoids, lutein, zeaxanthin, and zinc, have been associated with decreased risk of AMD, although results are not consistent in all studies [126-132].
●Adherence to a Mediterranean diet in the Age-Related Eye Disease Study (AREDS) study, which included 2525 participants, was associated with a reduction in the risk of progression to advanced AMD over a 13-year follow-up, although this effect may have been modified by genetic susceptibility; dietary adherence did not impact progression in patients homozygous for the CFH Y402H allele. [133].
In a prospective cohort study of nearly 5000 participants, greater adherence to a Mediterranean diet was associated with a 41 percent reduced risk of incident advanced AMD, compared with lower adherence (hazard ratio [HR] 0.59, 95% CI 0.37-0.95) over a mean follow-up of 9.9 years [134].
●Greater fish intake as well as omega-3 and omega-6 polyunsaturated fatty acids are associated with a decreased risk of AMD [135-140].
Nutritional and vitamin supplements — Based on the available evidence, antioxidant vitamins do not appear to be effective in preventing AMD.
A 2017 meta-analysis found no effect on the development of AMD with vitamin E supplementation (risk ratio [RR] 0.97, 95% CI 0.90-1.06; four trials; high-quality evidence), beta-carotene (RR 1.00, 95% CI 0.88-1.14; two trials; high-quality evidence), and vitamin C (RR 0.96, 95% CI 0.79-1.18; one study; high-quality evidence) [141]. Use of multivitamins was associated with slight increased risk of AMD (RR 1.21, 95% CI 1.02-1.43; moderate-quality evidence). An earlier meta-analysis reported similar findings with vitamin A, vitamin C, vitamin E, zinc, lutein, zeaxanthin, alpha carotene, beta carotene, beta cryptoxanthin, and lycopene [142].
Vitamin B preparations may have some efficacy in preventing AMD. In a randomized trial evaluating B vitamins, 5205 women at increased risk for cardiovascular disease without AMD at baseline were randomly assigned to B vitamins (folic acid 2.5 mg/day, pyridoxine 50 mg/day, and cyanocobalamin 1 mg/day) or placebo [143]. Women in the treatment arm had a reduced risk of developing AMD compared with the placebo group. At an average of 7.3 years follow-up, 55 women in the treatment group and 82 in the placebo group developed evidence of AMD (RR 0.66, 95% CI 0.47-0.93). This effect was demonstrable by two years. If these results are confirmed in other populations, vitamin B preparations may be a helpful intervention in the prevention of AMD.
Physical activity — Physical activity appears to have a protective effect. In a meta-analysis of observational studies in White populations, higher levels of physical activity were associated with lower likelihood of developing early AMD (OR 0.92, 95% CI 0.86-0.98; eight studies, >38,000 patients) and late AMD (OR 0.59, 95% CI 0.49-0.72; seven studies, >28,000 patients) [144].
Smoking — Smoking increases the risk of developing dry and wet AMD. The association of smoking and AMD is discussed elsewhere. (See "Age-related macular degeneration: Clinical presentation, etiology, and diagnosis", section on 'Risk factors'.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Age-related macular degeneration (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Treatment of age-related macular degeneration (AMD) varies with the type (see 'Treatment of dry AMD' above and 'Treatment of wet AMD' above):
•Dry AMD (atrophic or nonexudative):
-We suggest that patients with extensive intermediate size drusen, at least one large drusen, or noncentral geographic atrophy in one or both eyes be treated with a daily oral eye vitamin supplement (Grade 2B). These should be consistent with the Age-Related Eye Disease Study 2 (AREDS2) formulation (containing vitamin C 500 mg, vitamin E 400 international units, lutein 10 mg, zeaxanthin 2 mg, zinc 80 mg [as zinc oxide], and copper 2 mg [as cupric oxide]). Alternatively, patients who are not smokers or former smokers may use the standard AREDS formulation, which contains beta-carotene rather than lutein or zeaxanthin. (See 'Antioxidant vitamins and zinc' above.)
-Patients may also wish to consider entering clinical trials of therapy aimed at slowing progression of AMD. In the United States, information regarding available trials is available at the government’s clinical trials database.
-Smoking may increase the risk of progression to advanced AMD. Thus, patients with AMD should be encouraged to quit smoking. (See 'Smoking' above and "Overview of smoking cessation management in adults".)
•Wet AMD (neovascular or exudative):
-For most patients with AMD and neovascularization, we recommend treatment with an intravitreal vascular endothelial growth factor (VEGF) inhibitor (eg, bevacizumab, ranibizumab, aflibercept) (Grade 1B). (See 'VEGF inhibitors and inhibitor-like drugs' above and 'Photodynamic therapy' above.)
-We also suggest that patients with wet AMD in one or both eyes be treated with daily oral supplements (Grade 2B). These should be consistent with the AREDS2 formulation (containing vitamin C 500 mg, vitamin E 400 international units, lutein 10 mg, zeaxanthin 2 mg, zinc 80 mg [as zinc oxide], and copper 2 mg [as cupric oxide]). Alternatively, patients who are not smokers or former smokers may use the standard AREDS formulation, which contains beta-carotene rather than lutein or zeaxanthin. (See 'Antioxidant vitamins and zinc' above.)
●Counseling patients to quit smoking is important part of preventing AMD and also may reduce the risk of other smoking-related disorders. (See 'Smoking' above and "Overview of smoking cessation management in adults".)
●We encourage monitoring and control of blood pressure in patients with wet or dry AMD.
●The available evidence does not support the use of antioxidants to prevent or delay the onset of AMD in unaffected individuals. However, given other apparent health benefits, we encourage a diet that includes fruits, green leafy vegetables, fish, and nuts. We also encourage physical activity. (See 'Prevention' above.)
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41 : Ranibizumab for neovascular age-related macular degeneration.
42 : Improved vision-related function after ranibizumab treatment of neovascular age-related macular degeneration: results of a randomized clinical trial.
43 : Angiographic and optical coherence tomographic results of the MARINA study of ranibizumab in neovascular age-related macular degeneration.
44 : Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
45 : Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study.
46 : Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results.
47 : Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2.
48 : Macular atrophy progression and 7-year vision outcomes in subjects from the ANCHOR, MARINA, and HORIZON studies: the SEVEN-UP study.
49 : The price of sight--ranibizumab, bevacizumab, and the treatment of macular degeneration.
50 : Intravitreal avastin: the low cost alternative to lucentis?
51 : Trials that matter: two faces of progress in the treatment of age-related macular degeneration.
52 : Pharmacotherapy for neovascular age-related macular degeneration: an analysis of the 100% 2008 medicare fee-for-service part B claims file.
53 : Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results.
54 : Ranibizumab or Bevacizumab for Neovascular Age-Related Macular Degeneration According to the Lucentis Compared to Avastin Study Treat-and-Extend Protocol: Two-Year Results.
55 : Ranibizumab or Bevacizumab for Neovascular Age-Related Macular Degeneration According to the Lucentis Compared to Avastin Study Treat-and-Extend Protocol: Two-Year Results.
56 : Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration.
57 : Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies.
58 : Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies.
59 : Intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration.
60 : HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration.
61 : HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration.
62 : Safety Outcomes of Brolucizumab in Neovascular Age-Related Macular Degeneration: Results From the IRIS Registry and Komodo Healthcare Map.
63 : Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials.
64 : Aflibercept (eylea) for age-related macular degeneration.
65 : Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1.
66 : Treatment of neovascular age-related macular degeneration with intravitreal bevacizumab: efficacy of three consecutive monthly injections.
67 : Anti-VEGF agents in the treatment of neovascular age-related macular degeneration: applying clinical trial results to the treatment of everyday patients.
68 : A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study.
69 : Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: the second year of a prospective study.
70 : Fixed-interval versus OCT-guided variable dosing of intravitreal bevacizumab in the management of neovascular age-related macular degeneration: a 12-month randomized prospective study.
71 : Outcomes with As-Needed Ranibizumab after Initial Monthly Therapy: Long-Term Outcomes of the Phase III RIDE and RISE Trials.
72 : A 4-year longitudinal study of 555 patients treated with ranibizumab for neovascular age-related macular degeneration.
73 : Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol.
74 : Treatment outcomes after 3 years in neovascular age-related macular degeneration using a treat-and-extend regimen.
75 : Two-year outcomes of "treat and extend" intravitreal therapy for neovascular age-related macular degeneration.
76 : Prospective Trial of Treat-and-Extend versus Monthly Dosing for Neovascular Age-Related Macular Degeneration: TREX-AMD 1-Year Results.
77 : Treat-and-Extend versus Monthly Regimen in Neovascular Age-Related Macular Degeneration: Results with Ranibizumab from the TREND Study.
78 : Treat and extend versus pro re nata regimens of ranibizumab and aflibercept in neovascular age-related macular degeneration: a comparative study.
79 : A systematic review of as needed versus treat and extend ranibizumab or bevacizumab treatment regimens for neovascular age-related macular degeneration.
80 : Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab.
81 : Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration.
82 : Pegaptanib for neovascular age-related macular degeneration.
83 : Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study.
84 : Postinjection endophthalmitis in the comparison of age-related macular degeneration treatments trials (CATT).
85 : Incidence and Outcomes of Infectious and Noninfectious Endophthalmitis after Intravitreal Injections for Age-Related Macular Degeneration.
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87 : Sustained elevated intraocular pressures after intravitreal injection of bevacizumab, ranibizumab, and pegaptanib.
88 : Effect on intraocular pressure in patients receiving unilateral intravitreal anti-vascular endothelial growth factor injections.
89 : Adverse events with intravitreal injection of vascular endothelial growth factor inhibitors: nested case-control study.
90 : Adverse events with intravitreal injection of vascular endothelial growth factor inhibitors: nested case-control study.
91 : Cerebrovascular accidents in patients treated for choroidal neovascularization with ranibizumab in randomized controlled trials.
92 : Ranibizumab and bevacizumab for neovascular age-related macular degeneration.
93 : Medical consequences of stopping anticoagulant therapy before intraocular surgery or intravitreal injections.
94 : Incidence of hemorrhagic complications after intravitreal bevacizumab (avastin) or ranibizumab (lucentis) injections on systemically anticoagulated patients.
95 : Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.
96 : Drugs for preventing lung cancer in healthy people.
97 : CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration.
98 : Recommendations for genetic testing of inherited eye diseases: report of the American Academy of Ophthalmology task force on genetic testing.
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104 : Photodynamic therapy for neovascular age-related macular degeneration.
105 : Laser photocoagulation for neovascular age-related macular degeneration.
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107 : Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age-related macular degeneration.
108 : Intravitreal bevacizumab (Avastin) in combination with verteporfin photodynamic therapy for choroidal neovascularization associated with age-related macular degeneration (IBeVe Study).
109 : Verteporfin photodynamic therapy combined with intravitreal bevacizumab for neovascular age-related macular degeneration.
110 : Periocular triamcinolone and photodynamic therapy for subfoveal choroidal neovascularization in age-related macular degeneration.
111 : Triamcinolone acetonide as adjunctive treatment to verteporfin in neovascular age-related macular degeneration: a prospective randomized trial.
112 : Combination of photodynamic therapy and intraocular triamcinolone for exudative age-related macular degeneration and long-term chorioretinal macular atrophy.
113 : A retrospective analysis of triple combination therapy with intravitreal bevacizumab, posterior sub-tenon's triamcinolone acetonide, and low-fluence verteporfin photodynamic therapy in patients with neovascular age-related macular degeneration.
114 : Combination therapy with low-dose transpupillary thermotherapy and intravitreal ranibizumab for neovascular age-related macular degeneration: a 24-month prospective randomised clinical study.
115 : Management of thick submacular hemorrhage with subretinal tissue plasminogen activator and pneumatic displacement for age-related macular degeneration.
116 : Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: ophthalmic findings: SST report no. 11.
117 : Surgery for hemorrhagic choroidal neovascular lesions of age-related macular degeneration: ophthalmic findings: SST report no. 13.
118 : Submacular surgery for choroidal neovascularisation secondary to age-related macular degeneration.
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120 : Long-term results of submacular surgery combined with macular translocation of the retinal pigment epithelium in neovascular age-related macular degeneration.
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123 : Macular translocation for neovascular age-related macular degeneration.
124 : Radiotherapy for neovascular age-related macular degeneration.
125 : Radiotherapy for neovascular age-related macular degeneration.
126 : Healthy lifestyles related to subsequent prevalence of age-related macular degeneration.
127 : Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group.
128 : Dietary intake of antioxidants and risk of age-related macular degeneration.
129 : Intake of key micronutrients and food groups in patients with late-stage age-related macular degeneration compared with age-sex-matched controls.
130 : Prospective study of intake of fruits, vegetables, vitamins, and carotenoids and risk of age-related maculopathy.
131 : Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study.
132 : The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22.
133 : Adherence to a Mediterranean diet, genetic susceptibility, and progression to advanced macular degeneration: a prospective cohort study.
134 : Mediterranean Diet and Incidence of Advanced Age-Related Macular Degeneration: The EYE-RISK Consortium.
135 : Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration.
136 : Progression of age-related macular degeneration: association with dietary fat, transunsaturated fat, nuts, and fish intake.
137 : Dietary fatty acids and the 5-year incidence of age-related maculopathy.
138 : Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis.
139 : Dietaryω-3 fatty acid and fish intake and incident age-related macular degeneration in women.
140 : The relationship of dietary omega-3 long-chain polyunsaturated fatty acid intake with incident age-related macular degeneration: AREDS report no. 23.
141 : Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration.
142 : Dietary antioxidants and primary prevention of age related macular degeneration: systematic review and meta-analysis.
143 : Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study.
144 : Physical Activity and Age-related Macular Degeneration: A Systematic Literature Review and Meta-analysis.
