Risk Factors for Macula Subretinal Haemorrhage in Patients with Neovascular AMD
Macular subretinal haemorrhage is a dreaded complication of neovascular age related macula degeneration (AMD), with a poor visual prognosis. The risk of macula haemorrhage is high in patients with neovascular AMD not treated with anti-VEGF injections, with a rate of 74% for predominately classic neovascular membrane (ANCHOR trial) and 57% for minimally classic and occult membrane (MARINA trial) over 18 months. There are now several studies looking at the risk of macula subretinal haemorrhage in patients with neovascular AMD treated with anti-VEGF injections.
Anti-VEGF is effective in reducing the risk of macula subretinal haemorrhage
The data from both MARINA and ANCHOR studies showed that monthly anti-VEGF injections are effective in significantly reducing the risk of macula subretinal haemorrhage in patients with neovascular AMD. The risk of haemorrhage in patients treated with ranibizumab is 21% in the ANCHOR trial and 22% in the MARINA trial over 18 months, a significant improvement from the rate quoted above. However, the data in the PIERS study showed that when ranibizumab is given only every 12 weeks, the protective effect on macula subretinal haemorrhage is lost . This confirms that suppression of the macula neovascular activity is key to preventing macula subretinal haemorrhages.
Further evidence comes from a recent publication reporting an increased rate of macula subretinal haemorrhage when injection therapy is interrupted by the COVID-19 pandemic. For the patients whom unfortunately suffered from a macula subretinal haemorrhage in this study, the interval between the appearance of large macula subretinal haemorrhage and the last intravitreal anti-VEGF injection was significantly longer than the usual interval between 2 intravitreal anti-VEGF injections.
Another recent study looks at the risk of macula subretinal haemorrhage and the intravitreal anti-VEGF injection dosing interval. They reported no association between macula subretinal haemorrhage with prolonged dosing intervals or recent interval extension, and postulated that other factors may result in these haemorrhages in patients already adequately treated with anti-VEGF injections.
Anti-coagulation, hypertension and macula subretinal haemorrhages
In patients with neovascular AMD who have never been treated with anti-VEGF injections, there has been an association between anti-coagulation and macula subretinal haemorrhages (here and here). However, in patients treated with anti-VEGF injections, anti-coagulation does not have an association with macula subretinal haemorrhage. This finding is confirmed in 2 different studies, including a smaller study, and CATT, a large randomised controlled trial looking at the effectiveness for both ranibizumab and bevacizumab (avastin) for neovascular AMD.
A number of studies confirmed hypertension is a risk factor for large macula subretinal haemorrhage, for both untreated and anti-VEGF treated patients with neovascular AMD (here, here and here).
Clinical implications
The prevalence of anti-coagulation use in patients with neovascular AMD is between 49% and 61% (Matsunaga et al., 2021), and many of these patients are concerned that the anti-coagulation will make them more susceptible to macula subretinal haemorrhage. Based on the evidence available, as long as the macula neovascular activity is well suppressed by anti-VEGF injections, anti-coagulation is not associated with an increased risk of macula subretinal haemorrhage. In general, it is safe for these patients while on anti-VEGF injections or deemed quiescent without treatment, to continue with anti-coagulation. The only exception would be neovascular AMD patients with one eye already lost with massive subretinal haemorrhage, where a more careful discussion of risks and benefits is required.
Blood pressure needs to be well optimised in all patients with neovascular AMD to minimise the risk of macula subretinal haemorrhages.