The retina is a highly metabolic tissue and needs a constant high supply of oxygen. Insult to either choroidal or retinal vasculature can lead to a hypoxic state. Throughout the years, neovascularization has been seen to occur in areas neighboring such hypoxic areas. In 1989, this hypoxia-inducible and diffusible factor was discovered to be Vascular Endothelial Growth Factor (VEGF), initially coined as Vascular Permeability Factor (VPF). VEGF was found to be answerable for many types of retinopathies and the increased vascular permeability seen in them.
VEGF is a heparin-binding dimeric glycoprotein with di-sulfide-linked A and B subunits. VEGF has been found to be produced by many cell types in the retina including vascular endothelial cells, retinal pigment epithelium, pericytes, Muller cells, retinal neurons, and astrocytes. It is necessary for the survival of retinal cells; prenatally for proper embryological development of the retina as well as postnatally for preserving adult microvasculature, neuronal survival, and as a trophic factor for ocular tissues.
VEGF has a superfamily of cysteine knot proteins that includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF). VEGF-A further has 14 subtypes. The most important ones are the isoforms 121,145,165, 189, and 206. VEGF-A is mainly involved in angiogenesis, VEGF-B in embryonic angiogenesis, more precisely of myocardial tissues, VEGF-C in lymphangiogenesis, VEGF-D in the growth of lymphatic vasculature of the bronchioles, and PlGF in vasculogenesis, ischemic angiogenesis, wound healing, and carcinogenesis.
It is commonplace knowledge that antiVEGFs were initially approved for use to treat colorectal carcinoma. Anti-VEGFs have been used in Ophthalmology for a decade, initially off-label and now many of it being approved for use by the US Food and Drug administration for certain Ophthalmologic indications discussed below.
Mechanism of Action
When a disparity of supply vs. demand of oxygen occurs in the retina, Hypoxia-Inducible Factor-1 (HIF-1), a prominent regulator of oxygen homeostasis, is released. HIF-1 enables the expression of more than a hundred genes responsible for the production of erythropoietin, glycolytic enzymes, matrix metalloproteinases, and other angiogenic, mitogenic, and survival factors. HIF-1 when binds to its responsive elements, promotes the production of mainly VEGF, Stromal-derived factor-1 (SDF-1), and erythropoietin, all of which stimulate increased vascular permeability and endothelial cell proliferation.
VEGF is currently known as the main regulator of angiogenesis. They conduct their activities by activating three kinds of receptor tyrosine kinases VEGFR-1, VEGFR-2, and VEGFR-3. VEGFR-2 is mainly in charge of de novo vessel formation (vasculogenesis) as well as that from preexisting vessels (angiogenesis). Besides these, a cell surface glycoprotein, neuropilin-1 also behaves as an isoform-specific coreceptor for VEGF-A.
VEGFs exert their actions as such:
- They are the strongest endothelial mitogen.
- Express plasminogen activators in microvascular endothelial cells required for capillary formation.
- Express endothelial cell α1β1 and α2β1 integrins for migration.
- Increase expression of Intercellular adhesion molecule-1 (ICAM-1) on endothelial cells causing leukostasis causing the breakdown of the blood-retinal barrier.
- Increase the phosphorylation of the protein “occludin” that alters the tight junctions of the endothelial cells to leak the blood-retinal barrier.
Anti-VEGF agents prevent the above-listed actions leading to a decrease in the formation of abnormal blood vessels, leakage and collection of subretinal fluid, and hence preservation of vision.
Drugs
|
Anti VEGF |
Brand name |
Type |
Action |
Dose |
Vitreous half-life |
|
Pregatanib |
Macugen |
Aptamer |
Binds to VEGF 165 isomer |
0.3mg/0.05ml |
2.73 days |
|
Bevacizumab |
Avastin |
Humanized monoclonal antibody |
Forms protein complex by binding directly to VEGF |
1.25-2.5mg / 0.05ml |
4.9 days |
|
Ranibizumab |
Lucentis |
Monoclonal antibody fragment |
Stronger binding to VEGF-A ( 140 times more than Bevacizumab) Can penetrate internal limiting membrane and access the subretinal space |
0.5mg / 0.05ml |
9 days |
|
Aflibercept |
Eyelea |
Recombinant fusion protein |
Contains VEGF binding portions of the extracellular domains of VEGFR-1 and VEGFR-2, fused to the Fc portion of human immunoglobulin G |
2mg / 0.05ml |
3.63 days (rabbit) |
New Anti-VEGFs:
- Brolucizumab- humanized monoclonal single-chain variable fragment
- Sunitinib, Lapatinib, Sorafenib- tyrosine kinase inhibitors
- siRNA-Bevasiranib,, adPEDF- miscellaneous
Coadministration of Bevacizumab and Sunitinib has caused severe toxicity in the form of microangiopathic hemolytic anemia.
Half the adult dose is usually given for neonates in cases of Retinopathy of prematurity.
Indications
Posterior Segment
- Neovascular Age- Related Macular Degeneration
- Proliferative Diabetic Retinopathy
- Diabetic Macular Edema
- Central and branch retinal vein occlusion
- Neovascular glaucoma
- Retinopathy of prematurity
- Intraocular tumors
- Pigment Epithelial Detachment
- Myopic choroidal neovascularization
- Retinal vasculitis
- Coats disease
- Refractory post-surgical cystoid macular edema
- Chronic Central serous retinopathy
- Secondary Choroidal
Anterior Segment
- Pterygium
- Corneal neovascularization- usually prior to keratoplasty
- Iris neovascularization
- Trabeculectomy
Adverse Effects
Ocular
- Endophthalmitis
- Intraocular inflammation
- Raised intraocular pressure
- Rhegmatogenous retinal detachment
- Ocular hemorrhage- subconjunctival, choroidal, retinal
- Cataract
- Anterior ischemic optic neuropathy
- Retinal vein occlusion
- Retinal artery occlusion
- Ocular ischemic syndrome
- Cranial nerve palsy
Systemic
- Systemic hypertension
- Thromboembolism
- Myocardial Infarction
- Stroke
- Vomiting
- Epistaxis
- Leukopenia
- Neutropenia
- Alopecia
- Sensory neuropathy
- Proteinuria
- Gastrointestinal perforation (Seen with systemic administration)
- Acute decline in renal function(2),(3),(4)
Contraindications
- Ocular /periocular infections
- Fibrovascular proliferation in the macular region
- Recent thromboembolic event
- Known hypersensitivity to the drug
- Pregnancy and lactations
- Co-administration of live vaccines- decreased development of immunity
Procedure
- Explain the procedure to the patient and get their consent.
- Maintain sterility by administering anti-VEGF preferably in the operation theatre.
- Wash hands with 5% Povidine iodine.
- Wear sterile gowns and gloves.
- Use sterile drape over the affected eye after confirming the laterality.
- Use a speculum to spread the eyelids.
- Administer topical povidine iodine and topical antibiotics before administering the anti-VEGF.
- Usually, 30 gauge needles are used for injecting anti-VEGFs. Smaller, sharper needles have found to require less force for penetration and cause less reflux. A length between 0.5 and 0.62 inches is recommended.
- The patient is instructed to look away from the site of needle entry. Usually injection is given in the inferotemporal quadrant though any quadrant may be used.
- The injection is placed 3.5 mm posterior to the limbus for aphakic and pseudophakic patients and 4mm posterior to the limbus in phakic ones.
- Theoretically, pulling the conjunctiva over the injection site using forceps or sterile cotton swab creates a step-like entry path, decreasing the risk of entry of microorganisms.
- The needle is advanced towards the center of the eyeball and gently injected into the midvitreous cavity.
- As soon as the needle is removed, a sterile cotton swab is placed over the injection site to prevent reflux.
- The intraocular pressure and the central retinal artery perfusion are assessed.
- Postoperatively, topical antibiotics are prescribed.
Combination Therapy
- Photodynamic therapy
- Intravitreal steroids (usually Triamcinolone and Dexamethasone)
- Triple Therapy ( Bevacizumab, Verteperforin and Triamcinolone
- Radiation
- Anti PDGF
Preferred Practice pattern
- The Royal College of Ophthalmologists recommends using both visual functions as defined by visual acuity and morphological patterns by optical coherence tomography (anatomical outlook) and/or fluorescein angiography (physiologic outlook) to aid in the initiation, follow up and halting treatment using anti-VEGFs.
- The visual acuity monitoring depends on the baseline visual acuity at presentation to evaluate if the therapy is working. A better initial visual acuity usually means a better visual prognosis.
- The treatment is to be given only such that permanent destruction of the neural and supporting cells hasn’t occurred yet. To guide this, it’s useful to know that morphological changes usually precede vision loss.
- Careful monitoring of the fellow eye on each visit.
- There are multiple ways of administering the antiVEGFs and each can be tailored according to the patient’s condition, choices as well as the doctor’s judgment. Each case is generally started with three initiation or loading doses- each at an interval of a month each.
- After that, the patient can be kept on either consistent dosing at definite intervals like one monthly for Ranibizumab and two monthly for Aflibercept.
- Another approach is a more flexible PRN dosing based on monitoring the patient’s functional and morphological condition.
- Yet another used approach is to “treat and extend” aiming for a dry retina. Using this, OCT and FA are usually repeated every 8-12 weeks and compared with the baseline to evaluate the disease activity. If the lesion is equivalent or increasing, the treatment is continued; if regression has occurred, the interval between each dose may be prolonged or even stopped completely.
- A response is usually considered good if there is an increase in visual gain by 5 or more letters and a reduction of the subretinal/intraretinal fluid leading to more than 75% decreases in the central retinal thickness. A poor response, if the visual gain is less than 4 letters from the baseline and less than 25% decrease in the central retinal thickness. Non-changing parameters are considered as non-responsive patients.
- In case of poor or non-responders, we can try and see the effect of another antiVEGFs than that initially administered and check for a response. There are some patients who show only partial response with some anti VEGFs but do better with others.
- If the patient is still not improving or degrading, one of the above mentioned combination therapies or a surgical approach can be employed.
Milestone Trials
Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD ( MARINA, 2006)- Among AMD patients with minimally classic and occult choroidal neovascularization, Ranibizumab was seen to improve visual acuity and prevent loss of vision in such patients.
Anti-VEGF Antibody for the Treatment of PredominantlyClassic Choroidal Neovascularization in Age-Related Macular Degeneration trail(ANCHOR, 2009) –Ranibizumab was found to be more effective than verteperforin photodynamic therapy in AMD patients with classic CNV.
Study of the Efficacy and Safety of Ranibizumab Injection in Patients with Macular Edema Secondary to Branch Retinal Vein Occlusion (BRAVO, 2010)-In patients with macular edema secondary to branch retinal vein occlusion, Ranibizumab was observed to aid in quick visual improvement in the following six months.
Study of the Efficacy and Safety of Ranibizumab Injection in Patients With Macular Edema Secondary to Central Retinal Vein Occlusion (CRUISE,2010) - Ranibizumab was also noted to hasten the visual recovery in the subsequent six months in patients with macular edema secondary to central retinal vein occlusion.
Diabetic Retinopathy Clinical Research Network, Protocol T (DRCR T, 2016) - Among patients with central diabetic macular edema with vision worse than 20/50, Aflibercept was found to have the most efficacy compared to Bevacizumab (in years 1 and 2) and Ranibizumab (year 1). Only half the number of injections were required in the second year as compared to the first year.
Bevacizumab Eliminates the Angiogenic Threat for Retinopathy of Prematurity (BEAT-ROP, 2010) – Bevacizumab was seen to decrease the recurrence of stage 3 zone 1 ROP but not zone 2.