Fig. 10.1
Laser scar. SD-OCT showing retinal pigmented epithelial loss and outer retinal disorganisation corresponding to conventional laser scar. (a–b) Different examples of conventional laser scars
Recently, endpoint management (Lavinsky et al. 2014) proposed that it can reduce collateral damage and can still be effective. The concept is to reduce the energy, so it is just not visible in colour photos, but mild changes appear in optical coherent topography (OCT). So far, there is no prospective randomised controlled trial to suggest that it is effective; however, there is a similar study to suggest that it might not be more effective than modified Early Treatment Diabetic Retinopathy Study (ETDRS) laser. The Diabetic Retinopathy Clinical Research Network (DRCR.net) (Fong et al. 2007) compared mild macular grid laser (MMG) with modified ETDRS laser treatment, citing the latter as the most commonly used method in performing laser for DME at the time of the study among the network investigators.
MMG burns are located over the entire posterior pole from 500 to 3000 microns from the centre of the macula, without burns within 500 microns of the optic disc. The burn intensity of the grid laser is barely visible (light grey); 200–300 burns in total are distributed evenly over the treatment area (approx. 2–3 burn widths apart). The MMG burns are lighter and more diffuse in nature and are distributed over the whole macula in both areas of thickened and unthickened retina. Microaneurysms are not directly photocoagulated. In contrast, the modified ETDRS laser comprised of treating only areas of thickened retina (and areas of retinal non-perfusion) and leaking microaneurysms. MMG did not show any superiority over modified ETDRS laser treatment. However, MMG did work in reducing oedema.
10.2.2 Subthreshold Micropulse Laser
The concept of micropulse laser is to deliver more energy to the RPE cells without the collateral damage to the neurosensory retina. Laser energy is delivered in pulses. For example, using a 5 % duty cycle at 200 ms duration, there is a very short active (ON) energy (0.1 ms) followed by a period of no (OFF) energy (1.9 ms). With each “burn” of 200 ms duration, there would be 100 of these short pulses. The OFF period allows the tissue to cool off, and hence more energy can be delivered to the targeted tissue (RPE) without heating the surrounding neurosensory retina.
We have published one of the first prospective randomised controlled trials to suggest that micropulse laser is as good as modified ETDRS treatment but with less scarring (Figueira et al. 2009) (Fig. 10.2).
Fig. 10.2
Micropulse treatment. (a) SD-OCT post-micropulse laser treatment without any visible laser scar. (b) Baseline SD-OCT with diabetic macular oedema
Vujosevic and colleagues (Vujosevic et al. 2010) confirmed our findings but also showed that retinal sensitivity is significantly better in patients treated with micropulse laser. Furthermore, not only were the laser scars not visible on clinical examination, fundus autofluorescence did not change in the micropulse diode laser group even after retreatment. Once we understand that micropulse laser works through activation of the RPE cells and it does not cause any visible collateral damage, it seems to make sense to remove the spacing between laser “burns”. This was confirmed in a prospective randomised controlled trial that high-density treatment is more effective (Lavinsky et al. 2011) than low density and modified ETDRS treatment.
10.3 Anti-VEGF Agents
Several pivotal trials have shown that anti-VEGF agents are superior to laser (Korobelinik et al. 2014; Nguyen et al. 2012). In a recent head to head comparison of three commonly used anti-VEGF agents, bevacizumab, ranibizumab and aflibercept (DRCR.net Protocol T) were able to improve visual acuity with 9.7 letters, 11.8 letters and 13.3 letters, respectively. When the vision was less than 69 letters (approximately 20/50) at baseline, the visual-acuity gain was 11.8 letters, 14.2 letters and 18.9 letters for bevacizumab, ranibizumab and aflibercept, respectively (P < 0.001 for aflibercept vs. bevacizumab, P = 0.003 for aflibercept vs. ranibizumab and P = 0.21 for ranibizumab vs. bevacizumab) (Wells et al. 2015).
Furthermore, the central subfield thickness on OCT decreased, on average by 101 ± 121 microns, 147 ± 134 microns and 169 ± 138 microns, with bevacizumab, ranibizumab and aflibercept, respectively. As it is a single study and also the treatment protocol was different from that recommended by the dosology of the approved drugs, it is unclear how the drug would compare with the recommended dosology. Furthermore, the dosage of ranibizumab was 0.3 mg, the approved dose in the USA for DME, rather than 0.5 mg commonly used for AMD and the approved dose for DME in most of the world. The latter might not be particularly meaningful as the head to head of 0.3 mg vs. 0.5 mg did not show any meaningful differences between the two dosages (Nguyen et al. 2012).
Nevertheless, the treatment protocol used in Protocol T was pragmatic and can be easily implemented. The study drugs were injected into the study eyes at baseline and then every 4 weeks unless visual acuity was 20/20 or better with a central subfield thickness below the eligibility threshold, and there was no improvement or worsening in response to the past two injections. Improvement was considered to be an increase in the visual-acuity letter score of five or more (approximately 1 Snellen line) or a decrease in the central subfield thickness of 10 % or more; worsening was considered to be a decrease in the visual-acuity letter score of five or more or an increase in the central subfield thickness of 10 % or more.
Starting at the 24-week visit, irrespective of visual acuity and central subfield thickness, an injection was withheld if there was no improvement or worsening after two consecutive injections, but treatment was reinitiated if the visual-acuity letter score or the central subfield thickness worsened.
Laser photocoagulation therapy (focal, grid or both) was initiated at or after the 24-week visit for persistent diabetic macular oedema, defined on the basis of protocol-specified criteria. Treatment for diabetic macular oedema other than the randomly assigned anti-VEGF agent or laser therapy was permitted if a study eye met the criteria for treatment failure.
10.3.1 Subgroup Analysis Based on Baseline OCT
As mentioned previously, anti-VEGF agents were superior to laser treatment overall; however, anti-VEGF agents are not suitable for everyone. In some cases, it is due to the cost of the drug, in others the frequency of the follow up or the concern over the associated adverse events of the treatment. Hence, it may be useful to consider whether in some circumstances, laser might be an alternative.
Based on the RESTORE study (Mitchell et al. 2011), using time-domain OCT, if the central subfield thickness (CST) is less than 300 microns, there were no significant differences in efficacy between laser and ranibizumab treatment groups. Bearing in mind, if using most spectral-domain (SD) OCT, the value should be near 340–350 microns, as most SD-OCT measured a CST about 40–50 microns more. Furthermore, even for those between 300 and 400 microns on time-domain OCT (i.e. 340–440 microns in SD-OCT), the visual gain was about seven letters compared with four letters. It is statistically significant but might be less clinically meaningful. In particular, in clinical settings, the number of injections tends to be lower than in clinical trials.
10.3.2 Patterns of Anti-VEGF Responses
Undoubtedly the overall results of anti-VEGF are good; however, as noted in Protocol T, there is a big variation in OCT responses. For instance, even in the aflibercept group, which showed the best response, the average reduction of retinal thickness was 169 ± 138 microns; the variation is almost as big as the average reduction. Furthermore, if one is looking at the bevacizumab group (probably the most commonly used anti-VEGF worldwide), the average reduction of retinal thickness was 101 ± 121 microns; the variation is larger than the reduction. This suggests a big variation in individual responses.
In DRCR.net Protocol I, one of the earlier studies, DRCR.net analysed 37 baseline demographic, systemic, ocular, OCT, and fundus photographic variables that were assessed for association with change in visual acuity or OCT between baseline and 1 year. After adjusting for baseline visual acuity, a larger visual-acuity treatment benefit was associated with younger age (P < 0.001), less severe diabetic retinopathy on clinical exam (P = 0.003), and the absence of surface wrinkling retinopathy (P < 0.001). CST evolution during the first treatment year also predicted better vision outcomes (P < 0.001). After adjusting for baseline CST, lipid was associated with more favourable OCT improvement (P = 0.004) (Bressler et al. 2012).
CST evolution can be summarised into four groups as shown in Table 10.1 (Bressler et al. 2012). One could argue that about two thirds of the patients have early response and good vision gain, confirming the first-line role of anti-VEGF agents. The late responders may be treated with anti-VEGF if there were no other treatments available. However, with steroid approved for DME, it is reasonable to wait for the late responders to respond, or one should consider changing therapy earlier. Finally about a quarter of the patients did not respond anatomically, and the vision gain was no different from the laser monotherapy arm. It is important to identify this group of patients earlier and offer alternative therapies or surgery (Figs. 10.3, 10.4, 10.5 and 10.6).
Table 10.1
Central subfield thickness evolution in DRCR.net Protocol I ranibizumab-treated patients
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