Surgery, Tissue Plasminogen Activator, Antiangiogenic Agents, and Age-Related Macular Degeneration Study: A Randomized Controlled Trial for Submacular Hemorrhage Secondary to Age-Related Macular Degeneration

Ophthalmology. 2023 Sep;130(9):947-957. doi: 10.1016/j.ophtha.2023.04.014. Epub 2023 Apr 22.


Purpose: To compare the efficacy and the safety of submacular hemorrhage (SMH) management using either surgical pars plana vitrectomy (PPV) or pneumatic displacement (PD) with tissue plasminogen activator (tPA) and vascular endothelial growth factor (VEGF) inhibitor added to each arm.

Design: Randomized, open-label, multicenter superiority study.

Participants: Ninety patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older with recent SMH (≤ 14 days) of more than 2 optic disc areas and predominantly overlying the retinal pigment epithelium.

Methods: Patients were assigned randomly to surgery (PPV, subretinal tPA [maximum, 0.5 ml/50 μg], and 20% sulfur hexafluoride [SF6] tamponade) or PD (0.05 ml intravitreal tPA [50 μg] and 0.3 ml intravitreal pure SF6). Both groups were asked to maintain a head upright position with the face forward at 45° for 3 days after intervention and received 0.5 mg intravitreal ranibizumab at the end of the intervention, at months 1 and 2, as the loading phase, and then on a pro re nata regimen during a 6-month follow-up.

Main outcome measures: The primary efficacy endpoint was mean best-corrected visual acuity (VA) change at month 3. The secondary endpoints were mean VA change at month 6, 25-item National Eye Institute Visual Function Questionnaire composite score value at months 3 and 6, number of anti-VEGF injections, and complications during the 6-month follow-up.

Results: Of the 90 patients randomized, 78 patients (86.7%) completed the 3-month efficacy endpoint visit. The mean VA change from baseline to month 3 in the surgery group (+16.8 letters [95% confidence interval (CI), 8.7-24.9 letters]) was not significantly superior to that in the PD group (+16.4 letters [95% CI, 7.1-25.7 letters]; adjusted difference β, 1.9 [-11.0; 14.9]; P = 0.767). Both groups achieved similar secondary outcomes at month 6. No unexpected ocular safety concerns were observed in either group.

Conclusions: Surgery did not yield superior visual gain nor additional benefit for SMH secondary to nAMD compared with PD at 3 months, with intravitreal anti-VEGF added to each arm. Both treatment strategies lead to a clinical improvement of VA without safety concerns for SMH over 6 months. Both design and results of the trial cannot be used to establish equivalence between treatments.

Financial disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Trial registration: NCT02557451.

Keywords: Age-related macular degeneration; Anti-VEGF agent; Hemorrhage; Pneumatic displacement; Vitrectomy; Vitreoretinal surgery.

Publication types

  • Randomized Controlled Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use
  • Fibrinolytic Agents / therapeutic use
  • Humans
  • Infant, Newborn
  • Intravitreal Injections
  • Macular Degeneration* / complications
  • Macular Degeneration* / drug therapy
  • Middle Aged
  • Ranibizumab / therapeutic use
  • Retinal Hemorrhage / drug therapy
  • Retinal Hemorrhage / etiology
  • Retinal Hemorrhage / surgery
  • Retinal Pigment Epithelium
  • Tissue Plasminogen Activator* / therapeutic use
  • Vascular Endothelial Growth Factor A


  • Tissue Plasminogen Activator
  • Angiogenesis Inhibitors
  • Fibrinolytic Agents
  • Vascular Endothelial Growth Factor A
  • Ranibizumab

Associated data