Discussion
This study demonstrates that increased retinal arteriolar oxygen saturation significantly contributes to being able to predict a higher treatment requirement for intravitreal aflibercept during the first year of DMO treatment in a PRN regimen.
In accordance with previous studies, retinal venular oxygen saturation found in this study was higher in patients with DMO as compared with previously measured reference values for healthy individuals and remained unchanged during anti-VEGF treatment.9 11 The lack of reduction in the pathologically increased venular oxygen saturation towards normal levels may seem counterintuitive given the beneficial effects of intravitreal aflibercept on both functional and anatomical outcomes. However, the applied method of retinal oximetry may be insensitive to regional changes in retinal blood flow and oxygen saturations in the macular area as the oxygen saturation was based on measurements on the four largest arterioles and venules passing through a protocol-defined area surrounding the optic disc. Furthermore, the oximeter does not provide any data on absolute oxygen delivery to the retinal tissue, but rather a snapshot of vascular oxygen saturations at a given blood flow. Additionally, the relative contribution to oxygen delivery of retinal and choroidal vasculature may vary and especially around the macular area.
Previous data have shown that while early haemodynamic changes in the diabetic retina involves arteriolar constriction and hypoperfusion, a change towards enhanced blood flow and arteriolar hyperperfusion is seen in later stages of DR. This is presumably due to loss of autoregulatory mechanisms and release of dilatory factors (eg, VEGF) from the hypoxic retina.13–16 Hence, altered arteriolar blood flow may explain the measured variation in retinal arteriolar oxygen saturation. Furthermore, it may at the same time explain the differences in treatment load as increased arteriolar oxygen saturation due to hyperperfusion may also reflect a worse degree of DMO. It must be emphasised that the associations between blood flow, oxygen saturation and disease severity and stage of progression are not fully understood.
One may expect that variation in the oxygen saturation in retinal arterioles would be limited by a ceiling effect as fully saturated blood is led towards the retinal tissue. However, the blood in retinal arterioles is desaturated by approximately 5%–10% immediately after passage through the optic disc even in healthy individuals. The reduction is thought to be due to countercurrent exchange between the central retinal arteriole and venule as a consequence of close proximity within the optic nerve and leaves room for arteriolar oxygen saturation to increase alongside an increase in retinal blood flow.6 11 17 18
While the oxygen saturation in retinal venules has previously been demonstrated to increase with increasing severity of DR, we did not find any association between venular oxygen saturation and need for intravitreal therapy in our study on patients with DMO.7 The increase in venular oxygen saturation with increasing severity of DR has previously been explained by lower oxygen consumption due to retinal ischaemia and shunting of blood.7 19 Hence, the venular oxygen saturation may be closer associated with ischaemic changes in the peripheral retina, whereas DMO is more closely associated with changes in flow and perfusion in the macular area.19
Our demonstration of retinal arteriolar oxygen saturation as a predictor of treatment response is supported by recently published data that increased retinal arteriolar oxygen saturation also predicts good functional outcome in regards of VA.9
HbA1c, blood pressure and duration of diabetes are well recognised systemic risk factors of DMO development and progression of disease.2 20 Furthermore, VA and foveal thickness prior to treatment have been associated with functional and anatomical outcome, respectively.21 Hence, these parameters were included in our multiple linear regression model, even though systemic factors have so far been unable to predict treatment load of anti-VEGF treatment.22 Accordingly, the systemic factors were all together only able to explain approximately 12% of the variation in need for intravitreal therapy if the ocular parameters were experimentally removed from our regression model. Thus, our results concur with previous reports and emphasise the importance of intraocular parameters as predictors of treatment response in advanced stages of disease. It must, however, be emphasised that oxygen saturation in retinal arterioles only explained approximately 19% of the variation in need for intravitreal therapy.
Due to the limited number of patients in this study, we decided to exclude smoking (pack-years) from the regression model. A previous study on healthy individuals has demonstrated that neither arteriolar nor venular oxygen saturation differ between patients categorised as either current smokers or non-smokers.11 Furthermore, we did not find any difference in the number of pack years between groups A and B in either retinal arterioles or venules. In contrast, we speculate that the ‘time from last cigarette’ could potentially influence oximetry measurements. Thus, the oxygen saturation in facial skin has been demonstrated to decrease immediately after cigarette smoking.23
We allowed that patients included in this study could previously have been subjected to both focal/grid laser photocoagulation and anti-VEGF therapy if performed more than 4 months prior to inclusion. In contrast to the previously demonstrated effect of panretinal photocoagulation on the oxygen saturation in retinal vessels, we do not expect focal/grid laser photocoagulation to course any detectable effect on retinal oximetry measurements due to the very limited amount of affected retinal tissue.24 25
Likewise, given that current available anti-VEGF agents have a half-life of approximately 7–10 days in humans and an estimated range of VEGF suppression between 26 and 69 days, we do not believe that anti-VEGF therapy administered more than 4 months prior to inclusion will have had any impact on the oxygen saturations measured in this study.26 However, data concerning this subject are lacking and the fact that we did not find any change in retinal oxygen saturations between BL and month 12 after both anti-VEGF therapy and focal/grid laser photocoagulation may in truth represent the best available evidence to substantiate our assumption.
This study is unique from most previously conducted studies by addressing predictors of treatment load of intravitreal therapy rather than predictors of functional and anatomical outcome. We believe that this is essential in regards to translation of results into clinical practice and individualised treatment plans as retinal oximetry may assist clinicians to identify patients who are expected to have the highest need for therapy. Furthermore, this study was strengthened by the prospective design and well-defined treatment algorithm.
A limitation to the study was the number of participants. However, sample size was calculated based on a predefined clinically meaningful difference given the relatively limited mean number of needed injections. Furthermore, the relatively short period of follow-up limits our study as our results do not provide data beyond 12 months of treatment. Given the nature of DMO and DMO treatment, long-term outcomes on retinal oximetry as a predictor of treatment load are warranted.
We also acknowledge that treatment algorithms for DMO vary greatly between clinical practices and hence, our results are so far limited to the specified PRN regimen. It is, thus, also unknown to what extend the adjunctive use of focal/grid laser photocoagulation has an impact on the ability to transfer our results to treatment regimens with aflibercept monotherapy. However, our results are approximately at the same level as previous anti-VEGF trials for DMO in regards to improvement in VA and CRT.27 Hence, we do not believe that the predictive value of retinal arteriolar oxygen saturation is unique to our population due to differences in response to treatment.
Also, the number of intravitreal injections between BL and month 12 in this study was fairly low as compared with the most previously conducted studies on anti-VEGF monotherapy for DMO.27 Hence, we speculate that the difference in need for therapy between groups (A and B) may be more pronounced in other treatment regimens with more frequent intravitreal injections. However, further studies with other treatment strategies, for example, intravitreal aflibercept with and without adjunctive focal/grid laser photocoagulation or treat and extend regimens are warranted to clarify the generalisability of our results.
In conclusion, retinal arteriolar oxygen saturation contributes significantly to predict the need for intravitreal aflibercept during the first year of DMO treatment. Hence, retinal oximetry may serve as a valuable non-invasive adjunctive to the already established procedures for retinal imaging in terms of individualised treatment plans.