Academic Context and Problem Statement

Age-related macular degeneration (AMD) is one of the leading causes of vision loss in many high-income countries. Among its forms, neovascular AMD (also known as wet AMD) can be associated with submacular hemorrhage (SMH), a rare but severe condition. If untreated, SMH can lead to significant vision loss. Anti-vascular endothelial growth factor (anti-VEGF) therapy is the current mainstay treatment for neovascular AMD. However, evidence for its efficacy in treating SMH is limited. As such, researchers have sought to evaluate whether combining anti-VEGF therapy with intravitreal tissue plasminogen activator (tPA) or perfluoropropane (C3F8) gas could improve visual outcomes or promote the resolution of SMH.

Paper Source and Author Information

This study was conducted by a team of researchers from several UK institutions, including George S. P. Murphy, Azahir Saleh, Salma Ayis, among others. The participating institutions include King’s College Hospital, Sunderland Eye Infirmary, and Newcastle University, among others. The paper, titled “Tissue Plasminogen Activator or Perfluoropropane for Submacular Hemorrhage in Age-Related Macular Degeneration: A Factorial Randomized Clinical Trial,” was published online in JAMA Ophthalmology on October 17, 2024.

Study Design and Methods

Study Overview and Participants

This was a double-blind, placebo-controlled factorial randomized clinical trial designed to evaluate the safety and efficacy of tPA and C3F8 in treating SMH secondary to neovascular AMD. The trial enrolled 56 participants assessed within 14 days of SMH onset, with hemorrhages covering at least one disc area beneath the macula. Participants were randomly assigned to one of four treatment groups: sham injection, C3F8, tPA, or combined C3F8 + tPA. All participants received baseline intravitreal ranibizumab injections, followed by monthly as-needed injections of ranibizumab over 12 months.

Main Protocols and Statistical Analysis

The primary endpoint was best-corrected visual acuity (BCVA) at 3 months. Secondary outcomes included BCVA at 1 month and 12 months, the absorption of submacular hemorrhage, changes in retinal thickness, and other structural and functional metrics. Ocular imaging data were centrally analyzed using Scion Image software, and the Shapiro-Wilk test was used to evaluate data normality. Statistical analyses included analysis of variance (ANOVA), Kruskal-Wallis tests, and Bonferroni correction for multiple comparisons.

Key Findings

Primary Outcomes

By 3 months, participants in the tPA treatment groups (tPA and C3F8 + tPA) demonstrated significantly better average logMAR BCVA compared to those not receiving tPA (0.66 vs. 0.98; p = 0.02). However, there was no significant difference in BCVA between the C3F8 treatment groups and non-C3F8 groups (0.80 vs. 0.90; p = 0.43). These results suggest that tPA has a significant impact on improving visual acuity, whereas C3F8 does not show pronounced benefits.

Secondary Outcomes

At 1 month, the tPA groups also exhibited superior BCVA compared to non-tPA groups (0.78 vs. 1.03; p = 0.05). However, no significant difference was observed between C3F8 and non-C3F8 groups (0.80 vs. 1.01; p = 0.10). By 12 months, the BCVA advantage persisted for patients receiving tPA (0.60 vs. 0.97; p = 0.02), but not for those treated with C3F8 (0.81 vs. 0.87; p = 0.70).

Additionally, by 1 month, submacular hemorrhage was resolved in significantly more participants treated with tPA compared to those not receiving tPA (55.6% vs. 87.5%; p = 0.03). There was no significant difference between the C3F8 and non-C3F8 groups (73.3% vs. 74.1%; p = 0.62).

Safety Analysis

The safety profile was similar across all groups, with no significant differences in adverse events. Two patients in the tPA-treated groups experienced strokes; however, researchers attributed these events to pre-existing stroke risks rather than the tPA itself.

Conclusion and Implications

This study demonstrates that adding tPA to ranibizumab therapy can significantly improve visual outcomes for patients with SMH secondary to neovascular AMD. C3F8, in contrast, showed no significant impact on improving vision or hemorrhage absorption. These findings suggest that the visual improvements are primarily driven by tPA rather than C3F8, warranting further clinical trials focused on tPA’s efficacy in SMH treatment.

Research Highlights

1. Significant Effects of tPA: The study provides compelling evidence that tPA improves visual acuity and contributes to faster hemorrhage resolution.
2. Limited Role of C3F8: Unlike tPA, C3F8 did not demonstrate statistically significant benefits for treating SMH.
3. Acceptable Safety Profile: Across all intervention groups, the safety results were satisfactory, with no significant differences identified.

Broader Significance

This study contributes valuable insights into managing SMH secondary to neovascular AMD and introduces tPA as a promising adjunct therapy to anti-VEGF treatment. These findings pave the way for future trials to further validate tPA’s efficacy and explore its use with other anti-VEGF agents. Moreover, the study provides a foundation for designing larger-scale trials to confirm these preliminary findings.