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The Debate on the Best Treatment for Large, Thick Submacular Hemorrhage in AMD

Op-Med is a collection of original articles contributed by Doximity members.

During the American Academy of Ophthalmology (AAO) 2020 debates, contrasting arguments were made for the treatment of large, thick submacular hemorrhage (SMH) in patients with exudative age-related macular degeneration (AMD). The options presented by Drs. Daniel Martin and Sophie Bakri included treating SMH using anti-vascular endothelial growth factor (anti-VEGF) monotherapy versus anti-VEGF in conjunction with displacement via vitrectomy and tissue plasminogen activator (tPA).  

Natural history studies prior to anti-VEGF treatment reported an average 3.5 lines loss in visual acuity in 3 years in patients with SMH from AMD [1]. In addition, we have learned from observational studies that having an underlying neovascular membrane etiology predicts worse visual outcomes [2]. Early submacular surgery case series involving evacuation of the clot demonstrated that some patients could achieve improved or stable visual acuity with anatomic reattachment, but patients with exudative AMD had poorer results and often had recurrent SMH [3, 4]. The Submacular Surgery Trial was unable to demonstrate a benefit to surgery in achieving stable or improved best corrected visual acuity in 2 years as compared to observation; in addition, 16% of patients developed retinal detachment [5]. However, today, surgery has evolved from evacuation to displacement using small gauge vitrectomy, wide angle viewing systems, 41 gauge for tiny retinotomies, and concurrent anti-VEGF therapy. 

Anti-VEGF monotherapy has been advocated as the sole treatment option for managing SMH. Shienbaum et al. reported that all AMD patients treated with anti-VEGF monotherapy for foveal involving SMH had either stable or improved vision [6]. Overall, there was an improvement in mean visual acuity from 20/300 to 20/125 and an improvement in mean central thickness on optical coherence tomography from 755 microns to 349 microns in a six month period. No patients had adverse outcomes or ocular complications. Altaweel et al. analyzed patients with exudative AMD enrolled in the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) [7]. In anti-VEGF monotherapy treated patients with large SMH (defined as hemorrhage greater than 50% of the lesion) compared to the rest of the patients enrolled in the trial, visual acuity and morphologic outcomes were equally improved. The CATT study investigators concluded that patients with large SMH from AMD can be managed similarly to those who have less or no blood.

Dr. Martin described his success in treating SMH with anti-VEGF monotherapy. He stressed that there was no clinical evidence from recent trials that SMH is toxic to the retina if persistent for more than 3 weeks. He emphasized that final visual acuity outcomes were determined by sub-RPE macular pathology, and that surgery had no beneficial effect on the hemorrhage below the RPE. Furthermore, patients with exudative AMD would be receiving anti-VEGF therapy anyway for their underlying condition, which would clear all SRH and most of the RPE hemorrhage. He emphasized the risks of surgery including retinal detachment, proliferative vitreoretinopathy, and cataract formation. Dr. Martin concluded that the standard of care should be anti-VEGF monotherapy for large, thick SMH. 

Despite the data reported in CATT, the trial excluded patients with poor visual acuity less than 20/320. Many patients with thick SMH have very poor vision and would not have been included in this trial. Thus, displacement of hemorrhage has been explored as an option in patients with very poor visual acuity. Vitrectomy with subretinal tPA has shown success in displacing subretinal hemorrhage and improvement in vision in some patients. Haupert et al. in 2001 was one of the first studies evaluating displacement of thick SMH using vitrectomy, subretinal tPA with a 36-gauge needle, fluid-air exchange, and prone positioning [8]. While this was a small study of 11 eyes, subretinal hemorrhage was successfully displaced in all 11 cases with final visual acuity improvement in majority of cases (8/11 cases with VA >20/400 at a mean of 6.5 months). Recurrent hemorrhage was a major complication. Chang et al. studied vitrectomy and subretinal tPA with and without anti-VEGF [9]. They reported that while vitrectomy, subretinal tPA, and tamponade could successfully displace thick SMH, there was a long term loss in visual acuity. However, adding anti-VEGF postoperatively could help maintain visual acuity gains after surgery [9]. 

Dr. Bakri emphasized that the majority of patients who develop thick SMH were those who had previously been treated with anti-VEGF. With SMH, anti-VEGF alone may not be able to penetrate the large, thick blood in order to reach the neovascular membrane nor promote resorption of the thick blood. She emphasized the animal studies that have shown that SMH can potentially damage the photoreceptors in 24 hours. The ideal surgical candidate is one who has medium to large hemorrhage, with a thickness greater than 500 microns, involving the subretinal fovea, and duration less than 14 days. Dr. Bakri states that patient selection is key. 

The audience vote: 58% preferred anti-VEGF monotherapy for large, thick SMH in neovascular AMD. The authors of this editorial agree with management of SMH using anti-VEGF monotherapy as the strategy of choice. 

References

1. Avery RL, Fekrat S, Hawkins BS, Bressler NM. Natural history of subfoveal subretinal hemorrhage in age-related macular degeneration. Retina. 1996;16(3):183-189.

2. Berrocal MH, Lewis ML, Flynn HW, Jr. Variations in the clinical course of submacular hemorrhage. Am J Ophthalmol. 1996;122(4):486-493.

3. Hanscom TA, Diddie KR. Early surgical drainage of macular subretinal hemorrhage. Arch Ophthalmol. 1987;105(12):1722-1723.

4. Wade EC, Flynn HW, Jr., Olsen KR, Blumenkranz MS, Nicholson DH. Subretinal hemorrhage management by pars plana vitrectomy and internal drainage. Arch Ophthalmol. 1990;108(7):973-978.

5. Bressler NM, Bressler SB, Childs AL, et al. Surgery for hemorrhagic choroidal neovascular lesions of age-related macular degeneration: ophthalmic findings: SST report no. 13. Ophthalmology. 2004;111(11):1993-2006.

6. Shienbaum G, Garcia Filho CA, Flynn HW, Jr., Nunes RP, Smiddy WE, Rosenfeld PJ. Management of submacular hemorrhage secondary to neovascular age-related macular degeneration with anti-vascular endothelial growth factor monotherapy. Am J Ophthalmol. 2013;155(6):1009-1013.

7. Altaweel MM, Daniel E, Martin DF, et al. Outcomes of eyes with lesions composed of >50% blood in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Ophthalmology. 2015;122(2):391-398.e395.

8. Haupert CL, McCuen BW, 2nd, Jaffe GJ, et al. Pars plana vitrectomy, subretinal injection of tissue plasminogen activator, and fluid-gas exchange for displacement of thick submacular hemorrhage in age-related macular degeneration. Am J Ophthalmol. 2001;131(2):208-215.

9. Chang W, Garg SJ, Maturi R, et al. Management of thick submacular hemorrhage with subretinal tissue plasminogen activator and pneumatic displacement for age-related macular degeneration. Am J Ophthalmol. 2014;157(6):1250-1257.

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