Treatment of RVO With Intravitreal Macugen
JOHN A. WELLS, III, MD
Retinal vein occlusions (RVOs) are the most common retinal vascular disease encountered in daily clinical practice except for diabetic retinopathy.1 Branch retinal vein occlusions (BRVOs) and central retinal vein occlusions (CRVOs) share common risk factors but are believed to have slightly different pathogenetic mechanisms leading to venous obstruction. Both conditions are more common in patients over 50 and are associated with systemic vascular diseases, such as diabetes mellitus, hypertension, and cardiovascular disease in 50% to 70% of cases.1,2
In BRVO, the venous thrombosis occurs at the point of arteriovenous crossing and is believed to be due to mechanical constriction of the vein by arteriosclerosis within a confined space, the common adventitial sheath.2 In CRVO, the venous thrombosis occurs within the central retinal vein at the lamina cribrosa of the optic nerve head.3 Despite these different mechanisms, both BRVO and CRVO cause visual loss primarily because of associated cystoid macular edema (CME). Other causes of visual loss, such as vitreous hemorrhage, neovascular glaucoma, retinal detachment, and optic atrophy, are less common and are generally associated with more severe obstruction and retinal ischemia.
Macular grid laser treatment has been the mainstay of treatment of CME due to BRVO since the publication of the Branch Vein Occlusion Study (BVOS) in 1984. The BVOS demonstrated a clear benefit of grid laser treatment for eyes with vision of 20/40 or less secondary to macular edema from perfused BRVO.4 Unfortunately, the Central Vein Occlusion Study (CVOS) showed no benefit of macular grid laser treatment on CME due to CRVO.5 Additionally, not all BRVO eyes are good candidates for laser because it cannot be applied in eyes with dense intraretinal hemorrhage, and eyes with severe macular ischemia may actually do better without treatment. Accordingly, investigators have looked at other approaches to treat CME due to BRVO and CRVO, including laser-induced chorioretinal anastamosis, radial optic neurotomy, arteriovenous sheathotomy, and therapy with intravitreal steroids or anti-vascular endothelial growth factor (VEGF) agents such as pegaptanib sodium (Macugen, Eyetech/Pfizer), ranibizumab (Lucentis, Genentech), or bevacizumab (Avastin, Genentech).
|John A. Wells, III, MD, is a partner with the Palmetto Retina Center in Columbia, SC, and clinical associate professor of ophthalmology at the University of South Carolina in Columbia. Dr. Wells has received consulting fees, travel reimbursement, and honoraria from Pfizer and OSI. Dr. Wells can be reached at (803) 931-0077.|
There is strong scientific evidence that VEGF is the primary mediator of CME and neovascularization in both BRVO and CRVO.6-8 VEGF is not only a very potent stimulus for angiogenesis but is also one of the most potent mediators of vascular permeability. Therefore, the use of anti-VEGF agents as treatment of macular edema secondary to either CRVO or BRVO is an attractive option, particularly in CRVO where no proven, widely accepted therapy exists. A phase 2, randomized, placebo controlled, multicenter trial of intravitreous pegaptanib injections given every 6 weeks for CME due to CRVO has been completed and the results presented at the American Society of Retinal Specialists and American Academy of Ophthalmology meetings in 2006. At 30 weeks, after 5 consecutive intravitreous pegaptanib injections given at 6 week intervals over 24 weeks, patients treated with pegaptanib 1.0 mg (n=33) gained a mean of 9.9 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, patients treated with 0.3 mg (n=33) gained 7.1 ETDRS letters, and patients receiving sham injections (n=32) lost 3.2 letters. The difference between the 1.0-mg group and the sham group was statistically significant.9 This is the first randomized, controlled, clinical trial to demonstrate a positive treatment effect in patients with CME due to CRVO. Additionally, it is proof of the principle that inhibition of VEGF can improve vision and reduce CME in CRVO.
The other clinically available VEGF inhibitors, ranibizumab and bevacizumab, have been reported to reduce macular edema and improve visual acuity (VA) in a number of small, nonrandomized case series. The major difference between these drugs and pegaptanib is the selective VEGF165 inhibition of pegaptanib could theoretically be more advantageous in ischemic retinal disorders than the nonselective pan-VEGF inhibition of ranibizumab and bevacizumab. Pan-VEGF inhibition might theoretically block positive VEGF effects, such as neuroprotection, that might be important in ischemic retinal diseases.
To illustrate the effect of pegaptanib inhibition of VEGF165 in RVOs, representative cases of CRVO and BRVO will be presented.
CRVO: CASE #1
A 76-year-old white female had sudden onset of painless vision loss in her right eye in August 2004. Her past ocular history was significant for adult-onset diabetes and hypertension. Her medications included glipizide (Glucotrol, Pfizer) and insulin for her diabetes, and nifedipine, lisinopril, and atenolol (Tenormin, AstraZeneca) for her hypertension. She had no previous history of any ocular disease.
On ocular examination, her corrected vision was 20/80 OD (61 ETDRS letters) and 20/20 OS (83 letters). Intraocular pressure (IOP) was 14 mm Hg OD and 16 mm Hg OS. There was no afferent papillary defect. Slit lamp exam showed bilateral mild nuclear sclerotic cataracts. There was no rubeosis in either eye. Dilated fundus examination showed a classic non-ischemic CRVO with CME in the right eye and a normal fundus in the left eye. Fluorescein angiography (FA) showed typical delayed arteriovenous transit in the right eye consistent with CRVO with late petalloid CME in the right eye. An optical coherence tomography (OCT)3 examination gave a central retinal thickness of 398 +/-19 μm and a total volume of 8.86 mm3 (Figure 1).
Initial injection of pegaptanib 0.3 mg was given intravitreally in the right eye on Oct. 4, 2004. At the 3-day follow-up exam, VA in the right eye had improved to 20/30 and repeat OCT3 central retinal thickness (CRT) was 196 +/-17 μm, an improvement of 202 μm in 72 hours. The total volume was 8.38 mm3, with residual nasal edema noted (Figure 2).
Figure 1. This OCT map shows CME with a center point thickness of 398 μm. VA is 20/80.
Figure 2. OCT map obtained 72 hours after initial treatment with pegaptanib shows a marked reduction in macular edema with the center point thickness now measuring 196 μm. VA is now 20/30.
The patient continued to receive regular injections of pegaptanib sodium 0.3 mg every 6 weeks for a total of 5 injections. At the week 12 visit, after 2 injections, VA was 20/25 (79 ETDRS letters) and the OCT measured CRT remained 198 +/-4 μm, with further reduction in the total volume to 7.43 mm3. FA showed the CME to be resolving. At week 30, after 5 injections, the vision had declined to 20/63 (61 ETDRS letters), but OCT demonstrated recurrent foveal thickening to 307 +/-18 μm due to vitreofoveal traction. FA at this visit showed no CME, and no treatment was given. At the week 54 visit, vitreofoveal traction had spontaneously resolved and the vision had recovered to 20/32 (76 letters). The OCT-measured CRT was 221 +/-7 μm, with a total volume of 7.32 mm3 (Figure 3).
Figure 3. OCT examination obtained 1 year after therapy began and 30 weeks after the last injection of pegaptanib. The OCT showed a center point thickness of 221 μm with a normal macular contour.
At the week-54 visit, the patient's right eye had improved 15 ETDRS letters and CRT had declined 177 μm from baseline. The Table (available online at http://www.retinalphysician.com/rvo_table/) summarizes the vision and OCT findings at each of these time points.
The interesting facts of this case are:
► Visual acuity and OCT-measured retinal thickness obtained 3 days after the first injection showed marked VA improvement and reduction in CME, indicating a rapid effect of VEGF165 inhibition on CME in CRVO.
► This improvement was maintained until week 30, when focal vitreofoveal traction developed and vision dropped to 20/63. Without treatment, this traction spontaneously separated, vision recovered to a good level, and OCT-measured retinal thickness recovered as well.
► The resolution of CME was sustained for 30 weeks after the last pegaptanib injection. This likely means that collateral venous outflow developed during pegaptanib therapy and normalization of central venous pressure prevented recurrence of macular edema when therapy ceased.
► Pegaptanib is not associated with the common side effects of elevated IOP and cataract that are seen with intravitreal steroids in treatment of CRVO.
BRVO CASE #2
A 73-year-old white female presented in November 2005 with recent onset of painless blurring of vision in her right eye. Initial evaluation revealed VA of 20/60 OD and 20/40 OS with a superotemporal BRVO in the right eye with dense intraretinal hemorrhage precluding laser therapy. Five weeks later there was sufficient clearing of intraretinal hemorrhage to allow macular grid laser treatment. Pre-laser her vision had declined to counting fingers in the right eye and OCT examination showed a CRT of 366 μm with thickening of the upper and temporal inner subfields to greater than 400 μm. Four and a half months later the vision was 20/200 OD (29 ETDRS letters) and OCT examination showed a CRT of 487 +/-69 μm and a total volume of 10.95 mm3 with severe superior and temporal edema (Figure 4). There was intraretinal hemorrhage still involving the inferior aspect of the edematous macula. After discussion of treatment options, the patient elected to receive intravitreal pegaptanib injection every 6 weeks for a total of 3 injections and then every 6 weeks thereafter if vision loss or persistent CME warranted additional therapy.
The first injection of pegaptanib 0.3 mg was given in April 2006. At week 18, after 3 injections, vision in the right eye had improved to 20/100 (51 ETDRS letters or 22-letter improvement, over 4 lines better than baseline). Additionally the OCT-measured CRT had declined to 154 +/-9 μm with some residual superotemporal edema. Treatment was withheld at this visit, and when the patient returned at week 24, the vision had declined to 20/160 (40 letters) and the central retinal thickness measured 499 +/-27 μm. Pegaptanib was reinstituted, and after 3 further treatments the vision had improved to 20/125 (56 letters or a 27-letter improvement from baseline). The OCT-measured central retinal thickness 1 week after the seventh injection was 132 +/-7 μm with some trace residual edema (Figure 5). Therapy is ongoing.
Figure 4. OCT map of the right eye showing a superotemporal BRVO with severe CME prior to pegaptanib treatment. VA is 20/200 (29 ETDRS letters) and the center point thickness is 487 μm.
The key conclusions from this case:
► VEGF inhibition with intravitreal pegaptanib injections reduces macular edema and improves vision in BRVO in reproducible fashion, even after discontinuing initial therapy.
► This validates the principle of VEGF165 inhibition as treatment of macular edema due to BRVO.
► One can infer that VEGF inhibition might be useful in cases of BRVO where laser is not possible (eg, in cases with dense intraretinal hemorrhage) or in cases where laser may not be indicated (eg, in ischemic macular BRVO).
These cases illustrate the potential effectiveness of selective VEGF165 inhibition in the treatment of CME due to CRVO and BRVO. The results of the unpublished phase 2 randomized trial of pegaptanib in CRVO represent a breakthrough in that this is the first randomized trial in CRVO that has shown a statistically significant benefit of treatment on vision vs untreated controls. Numerous reports also exist in the literature of nonrandomized case series of treatment of CRVO and BRVO with intravitreal bevacizumab and ranibizumab. These reports uniformly report improvement in vision and CME. Whether these nonselective VEGF inhibitors are better than pegaptanib in treatment of RVO and whether the toxicity of nonselective VEGF inhibition is greater will have to await the results of randomized trials of these agents, planned for the near future. Additionally, randomized trials of intraocular steroids for treatment of CRVO and BRVO have begun. Whether the incidence of cataract and steroid-induced glaucoma with steroid therapy will make it less attractive compared to VEGF inhibitors remains to be seen as the results of these randomized trials become known. In the meantime, VEGF inhibition with pegaptanib is a promising therapy that could be considered in CRVO, where no other proven therapy exists, and in BRVO, where retinal ischemia or intraretinal hemorrhage precludes laser therapy. RP
Figure 5. At week 43, after 7 pegaptanib injections, vision had improved 27 ETDRS letters or over 5 lines with a marked reduction in the center point thickness to 132 μm.
Author disclaimer: These are individual cases from my clinical practice treated within the context of clinical trials of pegaptanib sodium. No treatment recommendation for the use of pegaptanib in daily clinical practice is implied.
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