Combined Treatment



Mário Guitana, MD
Lisbon Ophthalmologic Centre, Lisbon, Portugal.


Victor Ágoas, MD
Gama Pinto Ophthalmology Institute, Lisbon, Portugal.


Teresa Luísa Quintão, MD
Gama Pinto Ophthalmology Institute, Lisbon, Portugal.


José Henriques, MD
Gama Pinto Ophthalmology Institute, Lisbon, Portugal.



1. Introduction


Choroidal neovascularization in AMD has become a serious medical and social problem. One of the reasons for this is ageing of the population.

However, a better understanding of this disease and the emergence of new treatment options have been witnessed in recent years.

In clinical practice, combination treatments are a necessary measure when a disease is not well properly controlled with a single therapeutic modality. Using the gold standard therapy with anti-VEGF to control exsudative AMD is not enough because it does not structurally change the neovascular membrane, i.e., it does not result in its regression. Combined therapy is the logical step to counteract disease progression mechanisms which are self-supportive once initiated.

We combine agents that target angiogenesis-promoting cytokines with capillary occlusion therapies, such as photodynamic therapy (PDT) and PDT combined with an anti-VEGF and a corticoid, and as recent advance, using an anti-pericite therapeutic effect with the common goal to achieve a synergistic action, with improved outcomes, reduced retreatment frequency and more sustained effects(1,2). This additive effect allows patients to be treated with lower doses, entailing added value through increased tolerability and decreased costs(3)


2. Health economics in AMD treatment: efficacy versus efficiency and the importance of equity


2.1 Seeking efficacy and efficiency – resource saving

The efficacy of a given drug or technique is assessed when comparative studies of visual outcomes are performed.

If the observed outcomes are identical to those observed in previous studies it is concluded that no apparent advantages result from using the technique or drug in question.

However, if the number of treatment sessions decreases, a smaller number of medicine vials is used or patients visit the hospital less frequently, it is concluded that the efficiency of the drug or method is greater.

Drugs and methods that are equivalent in terms of efficacy may vary widely in terms of efficiency.

We are thus faced with efficiency gains and better use of resources – more patients are treated with the same budget!

This theoretical improvement in clinical efficiency has the advantage of reducing the number of treatment sessions, with a consequent decrease in the cost of drugs used to treat each patient.

Since each patient will make less visits to the hospital, the number of medical, nursing and technical staff hours required will decrease, the same occurring for equipment operation times and time spent at hospital premises(4).

It is referred in recent studies that the cost of drugs represents the greatest percentage of AMD treatment costs, as opposed to usual health cost distribution, where the largest percentage, of approximately 40%, corresponds to staff costs.

Calculated cost percentages for treatment with pegaptanib correspond to 17% for staff and 70% for the drug; for treatment with the ranibizumab protocol, 83% of costs are associated to the drug(5,6).


2.2 Combined treatments – visual outcomes and efficiency results

Although it has not been definitely proved (large multicentric, randomized, controlled studies are in course) that the visual outcomes of combined treatments, double or triple, are better than those observed for the gold standard treatment, consolidation of published studies referring a reduction in the number of retreatment sessions would be desirable.

However, improved treatment efficacy evidenced by better visual outcomes and an eventual reduction in the number of complications would also be desirable(7,8).

Calculated costs of 1 year of treatment per line of visual acuity were $84 for treatment with bevacizumab, following a regimen of treatment when necessary (PRN), and $766 for treatment with ranibizumab, following the gold standard protocol.

Combined treatment costs varied between $71 and $269(6). Due to their synergistic effect, combined treatments potentially lead to a decrease in the number of retreatment sessions, as well as sustained long-term visual benefits(1), with gains and better clinical efficiency.


3. Synergistic action and increased treatment effect

How can we explain the fact that a synergistic effect is theoretically achieved by using various mechanisms of action, sometimes more effective than the sum of their separate effects? (Fig.1)


3.1 Anti-VEGFs

The primary need to act on the key mechanism of the neovascularization  process – VEGF – is widely known.

By acting on this mechanism not only do we inhibit neovascularization but also act on oedema and the inflammatory mechanism, to a certain extent(9).

Today, we know from several studies – CATT(10), SECURE(11), HORIZON(12), SEVEN YEAR update in ANCHOR/MARINA(13) – that antiangiogenic therapy does not cause neovascular network regression and that when therapy is discontinued mean visual acuity tends to return to baseline.

In fact, anti-VEGF therapy is effective at inhibiting tip cells because these are not protected by pericytes that envelop the already formed neovascular network(14).

Tip cells and tip cell membrane projections called filopodia,"the fingers that do the walking", "lead the way"(15) are crucial for neovascularization sprouting.

Tip cells produce PDGF-B, a growth factor which stimulates pericyte recruitment to line the neovascular network(16)

This means that angiogenesis progression does not depend solely on cell proliferation, but it also requires the formation of a pericytic reinforcement to stabilize the neovascular network.

This explains the anti-VEGF resistance described in the literature, because when therapy is discontinued the tip cells become active and grow again. Therefore, additional therapy is needed.


3.2 Synergistic action of corticoids

When steroids are added, a synergistic action is achieved, since steroids act on various levels of the inflammatory process and angiogenesis regulation.

The complexity and diversity of glucocorticoid (GC) receptors in human tissue is highlighted by evidence that up to 6,000 genes are expressed or suppressed within hours of GC exposure.

The enormous potential of using exogenous GC agents to downregulate processes involved in age-related macular degeneration must be balanced against a similar potential for counterproductive effects(8).

Steroids activate receptors that induce the synthesis of specific proteins from DNA.

Various mechanisms of action are proposed for steroids.

It is known that steroids act on local inflammatory mediators, stabilizing blood-retinal barrier function by increasing gap junction density and activity in capillary endothelial cells.

It is thought that triamcinolone decreases VEGF, which is a potent agent in increasing capillary permeability by increasing phosphorylation of proteins involved in tight intercellular junctions, such as occludin and Zonula Occludens-1 (ZO-1).

These agents also have an anti-inflammatory effect by inhibiting phospholipase A2, an enzyme that metabolizes cell membrane phospholipids to free arachidonic acid, which, in turn, originates thromboxane, leukotrienes and prostaglandins that cause vasodilatation, increased permeability and oedema.

They also have an angiostatic effect by promoting a decrease in extracellular matrix (ECM) turnover through inhibition of plasmin activation.

Plasmin activates matrix collagenases and metalloproteinases (MMP’s) that dissolve the capillary basement membrane and trigger angiogenesis, with endothelial cell differentiation, migration and proliferation (Fig. 2).

These agents also act on the interaction between ICAM-1 (Intercellular Adhesion Molecule-1) and leukocytes, inhibiting recruitment of the latter, thereby contributing to reduce the inflammatory component.

It is also thought steroids may act on SDF-1 (Stromal-cell Derived Factor-1), inhibiting its action (Fig. 3)(8,17).

Steroids also decrease the expression of Major Histocompatibility Complex Class II (MHC-II) molecules involved in the inflammatory process(18).

Therefore, we have scientific grounds supporting the combined action of treatment with corticoids(19,20) (Fig.4).


3.3 PDGF-B inhibition 

As we mentioned before, inhibiting PDGF-B facilitates the action of anti-VEGF therapies by inducing pericyte stripping, thereby allowing anatomical regression of the neovascular membrane.  


3.4 Associated FGF-2 inhibition and PEDF action

It is also possible to inhibit other factors, such as FGF-2, or induce PEDF locally, which has antiangiogenic effects that counteract the angiogenic effect of VEGF(15,16,17).


3.5 Acting on the structural level by damaging newly formed blood vessels – PDT

The actions already referred involve blocking or inhibiting neovascularization and inflammatory mediators.

However, it is also possible to act on a structural level, by damaging newly formed blood vessels.

This is achieved through cellular damage and death mediated by free radicals induced by the action of laser on a photosensitizing agent – verteporfin(18,19).

Standard fluence values of 50-J/cm² or lower fluence values of 25-J/cm² or 12-J/cm² are normally used in combined treatment.

Photodynamic therapy causes vascular occlusion but is associated to an inflammatory response that may be minimized by using corticoids and an anti-VEGF agent.

Both agents may also inhibit the angiogenic stimulus represented by a VEGF rebound effect following occlusion of new blood vessels(20).

Capillary occlusion induced by PDT leads to hypoperfusion of the treated area, a condition that is theoretically worsened by concomitant use of anti-VEGF agents that prevent recapillarization.

This effect has not been shown as negative; on the contrary, it appears that this recapillarization delay promotes neuronal recovery by decreasing oxygen and free radical concentrations(20).


3.6 Other sites of action – associated surgical therapy

We shall not elaborate on this treatment combination, as it will be referred in a chapter dedicated to surgery.


4. Main studies


4.1 Gold standard treatment

The efficacy and safety of combined treatments are evaluated in studies where drug combinations are compared with the gold standard treatment, which, according to the results of the MARINA(21) and ANCHOR(22) studies, consists of twelve consecutive monthly intravitreal injections of an antiangiogenic agent.

Use of this treatment regime led to outcomes of 90% in vision stabilization and approximately 30-40% of significant improvement after one year.


4.2 Combined treatments: double and triple treatments

Most combined treatments include reduced-fluence PDT  associated to an anti-VEGF agent. PDT, antiangiogenic agents and steroids are often used in triple treatments.

Combined therapy with PDT and anti-VEGF therapy seems to have a valid role, as suggested by the RADICAL(35)study results.

Dexamethasone seems to be preferable to triamcinolone since there is a decreased risk of ocular tension increase(31)

There are no precise guidelines on triple therapy indications, i.e. on dosage and type of drugs.

Some combined-treatment studies should be referred for their relevance, albeit in a summarized manner.


4.2.1 SUMMIT programme

This programme includes three large randomized clinical trials DENALI (USA),MONT BLANC (Europe)and EVEREST (Asia)– whose objective is to evaluate the efficacy and safety of combining PDT (Visudyne®) and ranibizumab, compared to monotherapy with this antiangiogenic agent, in patients with neovascular AMD and polypoidal disease (Everest).

Analysis results from the MONT BLANC(32) study at twelve months have shown no significant differences between the two groups, although the number of treatments required is slightly lower with the combined treatment. The DENALI(33) study had a similar result.The overall benefit for patients was a reduced frequency of Lucentis to at least three months during the study.

In the Everest study(34), in the patients with polypoidal vasculopathy, the combined treatment was more effective than monotherapy to promote regression of polypoid formations.


4.2.2 RADICAL  Phase 2 study  (Reduced Fluence VisudyneAnti-VEGF-Dexamethasone In Combination for AMD Lesions)

In this study, three Visudyne–Lucentis combination therapies were evaluated against Lucentis monotherapy.

Two-year, phase 2 final 24 months results(35) showed that the combination approach led to significantly fewer visits at which re-treatments were applied. Of the four treatment groups, the triple therapy half-fluence group had the fewest retreatment visits compared with Lucentis monotherapy.

Through 24 months, patients in the triple therapy half-fluence group had a mean of 4.2 retreatment visits compared with 8.9 for patients who received Lucentis monotherapy (P<.001).


4.2.3 LuceDex study

This study researched the role of dexamethasone in neovascular AMD treatment. This is a prospective, randomized clinical trial comparing two treatment groups, one treated with a combination of ranibizumab and dexamethasoneand the other undergoing ranibizumab monotherapy.

The LuceDex pilot study suggested a possible benefit of adding intravitreal dexamethasone to treatment of neovascular age-related macular degeneration with intravitreal ranibizumab. Choroidal neovascular membrane size decreased in Group 1 significantly compared with Group 2 (P < 0.05).A larger study is needed to further identify and define possible benefits of this combination therapy(36)


4.2.4 PDEX II study

This is a prospective, multicentric, randomized, non-inferiority study comparing the relative advantages of treatment with PDT in a reduced dose (reduced fluence), dexamethasone and ranibizumab versus monotherapy with ranibizumab(37)

Trial results were presented at the American Society of Retina Specialists meeting 2008, which compared combination therapy using reduced fluence PDT, intravitreal dexamethasone 500 mcg and intravitreal ranibizumab 0.5 mg, to monthly ranibizumab. Patients receiving the triple therapy needed fewer treatments than 12 per year.


4.2.5 Cave study

In the multicenter CAVE study, reduced-fluence PDT plus bevacizumab plus triamcinolone therapy was compared with bevacizumab monotherapy, as well as with PDT plus bevacizumab dual therapy.Data from 103 patients were evaluated at one year. Mean retreatment rates were highest with bevacizumab monotherapy (4.57) and lowest with triple therapy (3.18)(38,39)

There were no significant between-group differences in mean VA gains. Interestingly, the greatest extension in treatment-free interval was with dual therapy, leading the investigators to conclude that addition of triamcinolone did not produce additional benefit(38,39)


4.2.6 Anti-Inflammatory treatment (Dexamethasone implant in combination with ranibizumab)

Six-month trial of 243 patients with CNV secondary to AMD, adjunctive therapy with the dexamethasone implant (Ozurdex) delayed the time to as-needed injections of 500 µg ranibizumab and reduced the need for repeated ranibizumab injections.

DEX Implant delayed the time to as-needed injection of ranibizumaband reduced the need for repeated ranibizumab treatment in patientswith CNV secondary to AMD.(40)


4.2.7 Anti-Inflammatory treatment. Pilot Study (Intravitreal ranibizumab and topical bromfenac)

This was a single-site, multiinvestigator, prospective, open-label, interventional, Phase II study of patients with new or recurrent exudative/neovascular age-related macular degeneration. Thirty eyes were enrolled consecutively and were randomized in a ratio of 2:1 to combination therapy with intravitreal ranibizumab and topical bromfenac, and ranibizumab alone.This pilot study(41) is the first to prospectively identify a biologic signal that may indicate combination therapy with an easily administered well-tolerated eyedrop and ranibizumab is efficacious for the treatment of neovascular age-related macular degeneration.


4.2.8 CABERNET study

The phase 3, multicenter, prospective, randomized CABERNET(42) (CNV secondary to AMD treated with beta radiation epiretinal therapy) study included a treatment arm of 302 patients receiving strontium-90 epimacular brachytherapy (NeoVista) and two mandatory Lucentis (ranibizumab,Genentech) injections, followed by as-needed injections. The control arm consisted of 155 patients receiving ranibizumab on a modified PIER protocol with 10 mandatory injections. The CABERNET study did not achieve its endpoint with a 10% non-inferiority margin. 


4.2.9 Combination therapy with low-dose transpupillary thermotherapy and intravitreal ranibizumab 

Treatment with low-dose TTT reduced the number or intravitreal injections of ranibizumab over 24 months. The results suggest that low-dose TTT can serve as an adjuvant in combination with intravitreal ranibizumab for neovascular AMD(43)


4.3 VIA study

The objective of this study is to determine whether a combination of a reduced dose of PDT and bevacizumab leads to a decrease in the number of treatment sessions required within a 6-month period, compared to monotherapy with bevacizumab(7)This randomized, double-blind, controlled clinical trial revealed that a combination of bevacizumab and 25-J/cm² or 12-J/cm² PDT led to a decrease of approximately 50% in the number of treatment sessions required within a 6-month period.

Favourable outcomes were also observed for visual acuity, although evaluation of this parameter was not the main objective of this study(7).


4.3.1 PDT combined with vitrectomy and dexamethasone

A combined pharmacosurgical intravitreal procedure was performed 24 to 36 hours after PDT, consisting of 23-gauge core vitrectomy and intravitreal substitution with BSS, dexamethasone and bevacizumab.The intravitreal retreatment rate was low (13/52) for this safe pharmaco-surgical regimen, corresponding to 25%(44)


4.4. Other promising forms of combined therapy

4.4.1FovistaTM (E1003, Ophthotech)

In pre-clinical models, combination of anti-PDGF and anti-VGEF successfully induced neovascular regression when administered in combination with anti-VEGF agents. (fig.5)(21).

Fovista is a 50 kD DNA anti-platelet-derived growth factor aptamer (directed against PDGF-B ,subunit B) that strongly binds to PDGF-B, and strips pericytes from mature neovascular vessel, leaving them more susceptible to treatment with an anti-VEGF agent.

Ophthotech recently completed a prospective, randomized, controlled Phase 2b clinical trial of 449 patients with wet AMD, the largest phase 2 superiority study in retina. The results of this study were presented at the American Academy of Ophthalmology Annual Meeting last year (2012)

The goal of the study(45)was to assess the safety and efficacy of a combination of the anti-PDGF agent E10030 plus ranibizumab compared with ranibizumab monotherapy in patients with CNV secondary to AMD.

Patients were randomly assigned to 1 of 3 treatment groups: 0.3 mg E10030 plus ranibizumab 0.5 mg, 1.5 mg E10030 plus ranibizumab 0.5 mg, or ranibizumab 0.5 mg monotherapy. Both combination groups met their prespecified primary endpoint of superiority.

Patients receiving the combination of Fovista (1.5 mg) and Lucentis gained a mean of 10.6 letters of vision on the ETDRS standardized chart at 24 weeks, compared to 6.5 letters for patients receiving Lucentis monotherapy (p=0.019), representing a 62% additional benefit.  59% of patients showed 3-line gain (significant visual gain) at week 12, and 100% neovascular regression.

This is the first randomized prospective trial that demonstrated the combination chemotherapy for wet macular degeneration produced better visual results (statistically significant superior efficacy) than monotherapy with anti-VEGF agent(45,46)This study’s shortcoming was failing to compare the efficacy of combined treatment with that of monotherapy with the antiangiogenic agent(27).


4.4.2 VEGF Trap – aflibercept (EYLEA®)  -View 1 and 2 studies

Aflibercept, a VEGF Trap, is the product of a bioengineering process where extramembranous VEGFR-1 and 2 receptor fragments are fused with the IgG1 Fc fragment.

This recombinant protein is a composite decoy receptor based on VEGF receptors VEGFR-1 and VEGFR-2.

This fully soluble human VEGF-receptor fusion protein binds to all forms of VEGF-A, as well as the related placental growth factor (PlGF), constituting a specific, highly potent, long-acting blocker of these growth factors(47).

This VEGF Trap effectively suppresses tumor growth and vascularization in vivo, resulting in stunted and almost completely avascular tumours(48).

In two parallel Phase 3 studies(49,50), North American VIEW 1 and  the international VIEW 2 study, the primary endpoint was statistical non-inferiority in the proportion of patients who maintained (or improved) vision over 52 weeks compared to ranibizumab.

In the two studies, patients with the neovascular form of age-related macular degeneration all regimens of VEGF Trap-Eye, including VEGF Trap-Eye dosed every two months, successfully met the primary endpoint compared to the current standard of care, ranibizumab dosed every month.

In November 2011 EYLEA (aflibercept) gained FDA approval in the United States.The VEGF Trap may be used to treat choroidal neovascularization, alone or in combined treatment.


4.4.3 FGF-2 inhibition

RPE from CNV patients expresses angiogenic growth factors whose action is partly independent from VEGF.

In a study, Sthal concluded that anti-VEGF treatment (bevacizumab) inactivated all RPE-derived VEGF in a 3D collagen matrix culture of RPE isolated from surgically excised CNV-membranes (CNV-RPE) used to stimulate sprouting of endothelial cell (EC) spheroids, but was unable to fully inhibit EC sprouting induced by CNV-RPE.

Combined anti-VEGF/anti-FGF treatment inactivated both growth factors and reduced EC sprouting significantly.

In a comparison between the antiangiogenic effect of solitary anti-VEGF antibodies and combination treatment with anti-VEGF and anti-FGF-2 antibodies, greater inhibition was achieved for the latter.

Targeted combined therapy can be superior to solitary anti-VEGF therapy.

One possible candidate for combined therapy is FGF-2(51)


4.4.4 The balancing effect of PEDF and its delivery

In AMD, PEDF is significantly lower in RPE cells, the RPE basal lamina, Bruch’s membrane and choroidal stroma.

These data suggest the existence of a critical balance between PEDF and VEGF and the hypothesis that PEDF may be able to counteract the angiogenic potential of VEGF.

A decrease in PEDF may disrupt this balance and induce choroidal neovascularization (CNV) in AMD(52).

Results from a phase I clinical trial of intravitreal administration of an IE4-deleted adenoviral vector expressinghuman pigment epithelium-derived factor (AdPEDF.11) suggest that antiangiogenic activity may be sustained for several months after single intravitreal injection of AdPEDF.11 doses greater than 10(9) PU.

This study provides evidence that adenoviral vector-mediated ocular gene transfer is a viable approach in the treatment of ocular disorders, suggesting that further studies of the efficacy of AdPEDF.11 in the treatment of patients with neovascular AMD, as well as promising combined treatments, should be performed(53).


4.4.5 Ranibizumab and Sorafenib

In two cases of recurrent exudative AMD in which intravitreal ranibizumab was used in combination with oral sorafenib, a tyrosine kinase inhibitor, improvements were observed in optical coherence tomography(54),indicating this might also be a promising combination treatment.


4.4.6 Hydroxymethylglutaryl-coenzyme A reductase inhibitors, ACE inhibitors, trimethazine and third-generation beta-blockers

Statins have been referred as hypolipidemic, anti-inflammatory and antioxidant agents, improving endothelial function by increasing nitric oxide synthesis and release.

Therefore, they might influence AMD pathogenesis.

In fact, some studies refer a favourable effect on AMD, suggesting a role for these substances in combined treatment(55).

A recent article refers treatment with ACE-inhibitors and/or AR blockers, combined with a statin, aspirin and third-generation beta-adrenergic receptor blockers or trimethazine can be used with some advantage in certain forms of AMD(56).


5. Considerations

The FOCUS study(57) was one of the first multicentric studies performed using combined treatment with PDT (Visudyne®) and ranibizumab (Lucentis®), comparing its therapeutic efficacy with that of PDT monotherapy.

This study’s shortcoming was failing to compare the efficacy of combined treatment with that of monotherapy with the antiangiogenic agent.(57)

Although it is not a correct practice to compare results of two different studies, visual outcomes in this study (considering the combined treatment arm) were inferior to the outcomes observed for monotherapy with the antiangiogenic agent in the ANCHOR study.

Most combined treatment studies performed were either non-controlled studies or only monotherapy with PDT was used in the control group. This is the case of the FOCUS study.

An important question is to determine whether combining anti-VEGF agents with PDT results in a real increase in treatment efficacy regarding the primary endpoint, visual acuity, in addition to reducing the number of retreatment sessions required to stabilize vision.

The final 24-month results from Phase IIRADICAL studyshowed that Visudyne®–Lucentis® combination therapy significantly decreased the number of retreatment visits required over two years, while patients' vision outcome was maintained within one line with an acceptable safety profile, compared with Lucentis®alone(35)

As already known, although PIER(58) and PRONTO(59)study results reveal that the number of injections required to stabilize vision corresponds to an average of 6 injections/year, it is also true that the visual outcomes observed in these studies were not as good as those observed in the MARINA and ANCHOR studies.

However, as already referred, if the number of treatment sessions and anti-VEGF vials required decreases and if patients make fewer visits to the hospital, we have a significant gain in efficiency, even in the absence of comparative gains in visual acuity (i.e., the same efficacy), as well as better use of resources – a larger number of patients treated with the same budget.


6.The future of combined treatment

Only time will tell, whether double and triple treatments, will display similar efficacy results as the gold standard treatment.

In most combined studies, notably the DENALI, MONT BLANC, RADICAL, LuceDex, CAVE, and VIA studies, the number of re-treatments needed was lower than with monotherapy.

It is known that some patients respond better to monotherapy, while others respond better to combined treatment; this is very likely due to individual patient and disease characteristics.

In the near future, development of non-anti-VEGF treatments with neuroprotective, antifibrotic and anti-inflammatory actions may contribute to the increased efficacy of new combined treatments.

Subtenon injection of long acting cortisones (anecortave) in combination with other procedures, namely anti-VEGF agents, should be studied(60).

Despite having been abandoned in monotherapy, these agents might prove useful in the combined treatment of AMD(61).

Intensive research is currently in course regarding alternative actions on crucial neovascularization cascade steps and mechanisms that trigger this process (signalling), since these have the potential to become alternative strategies for the combined treatment of AMD. Emerging therapies will be described in a separate chapter. It shall be referred that the complexity of signalling pathways supports the concept of combined therapy as a way of achieving more adequate control of biological functions in general and neovascularization in particular(62,63).

7. Practical aspects

Combined therapies have long been used in the treatment of oncological and numerous other systemic diseases.

In neovascular AMD, the objective of combined treatments acting upon different stages of the physiopathological process or the signalling pathway that triggers its mechanisms of action is to achieve synergistic action; therefore, an increased treatment effect and/or a decrease in the number of retreatment sessions required to stabilize vision are to be expected, as well as a more prolonged effect, smaller doses and increased drug tolerance(1).

Treatment of this disease focuses on three main targets(1).

1. Neovascularization.

2. The angiogenic process.

3. The inflammatory, cicatricial and exudative process.

In clinical practice, the following therapies are currently used in combined treatment:

1 – Photodynamic therapy with verteporfin, with standard, low or very low fluence.

2 – Antiangiogenic agents ranibizumab 0.5mg (Lucentis®), bevacizumab 1.25mg (Avastin®); pegaptanib 0.3mg (Macugen®) and VEGF Trap – aflibercept 2 mg  (EYLEA®)

3 – Anti-inflammatory treatment with intravitreal dexamethasone or triamcinolone, with or without core vitrectomy to allow injection of a greater volume of an anti-VEGF (0.5mg/0.5ml) and dexamethasone (0.5mg/0.5ml) solution.

Based on efficacy in terms of visual acuity and considering the level of clinical evidence for the studies performed, it is possible to conclude that no level I evidence exists to recommend combined treatment instead of monotherapy.

However, recently,the large (449 patients) randomized, controlled Phase IIb study assessed efficacy and safety of Fovista in combination with Lucentis. To achieve a 62% relative visual benefit over anti- VEGF monotherapy is extraordinary.  If the results of this large phase 2b trial are confirmed in a phase 3 trial, this combination therapy modality has the potential to change our treatment model for patients with exsudative AMD.(45,46)

If both clinical efficacy and efficiency (smaller number of treatment sessions required; longer absence of active disease between treatments; smaller drug, staff and structural costs; smaller doses/increased tolerance) criteria are considered, combined treatment based on anti-VEGF agents should be favoured in most forms of exudative AMD, as early as possible, as suggested also by several studies with levels of evidence II-1 and II-2 and numerous studies with levels of evidence II-3 and III.

Clinical criteria and the doctor’s experience should also weight significantly in deciding whether or not to opt for combined treatment.


7.1 Particular cases of AMD

Due to their poor response to monotherapy, cases of Retinal Angiomatous Proliferation (RAP) and Polypoid Choroidal Vasculopathy should be primary candidates for anti-VEGF-based combined treatment. In the Everest Study,verteporfin PDT combined with ranibizumab 0.5 mg or alone was superior to ranibizumab monotherapy in achieving complete regression of polyps in this 6-month study in patients with symptomatic macular polypoidal choroidal vasculopathy(34)


7.2 Improved healthcare and increased equity

If combined treatments are proved to lead to better outcomes (greater VA line gains) or more sustained gains, as referred in most studies, the superior clinical efficacy of this treatment approach will be established.

Although the costs of two or three different treatments need to be considered when calculating combined treatment costs, costs per patient will be reduced if fewer overall resources are used.

This is a more efficient strategy, as well as a principle to follow in health economics: to manage scarce resources so that health investments may benefit more patients, instead of necessarily making expense cuts.

It is also about increasing equity – increasing the number of patients benefiting from treatment(1).


Levels of clinical evidence

Level I– At least one well-designed study – randomized, controlled studies.

Level II-1– High-quality, non-randomized, controlled studies.

Level II-2– Studies with a control group involving more than one research centre or group.

Level II-3– Studies with no control group; series studies, with or without intervention.

Level III– Opinion of respected authorities, based on clinical experience, descriptive studies or specialised committee reports.



ACE- angiotensin converting enzyme

AR- angiotensin receptor

ICAM-1- Intercellular Adhesion Molecule-1

SDF-1-CRXR4 Axis– Stromal-Derived Factor-1 and its CRXR-4 receptor

PEDF- Pigment Epithelium-Derived Factor

VEGF- Vascular Endothelial Growth Factor


Last revision: October 2013