Protocol V Sheds Light on Managing Mild Diabetic Macular Edema

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Medscape Ophthalmology Headlines / 2019-07-30

When it comes to the treatment of diabetic macular edema (DME), ophthalmologists have overwhelming evidence to guide their decision-making—but only up to a point.

DME consists of three clinical subcategories: center-involved DME (CI-DME) with visual acuity (VA) impairment, CI-DME with good vision, and non–CI-DME.[1] Out of these, the prospective data are only substantial and persuasive when it comes to supporting pharmacologic intravitreal treatment of CI-DME with VA impairment with either medications that inhibit vascular endothelial growth factor (VEGF)-A[2,3] or corticosteroids.[4,5] And, until now, the evidence guiding treatment of CI-DME with good VA in the modern era has been relatively scarce. Enter Protocol V, a multicenter, randomized clinical trial designed by the Diabetic Retinopathy Clinical Research Network to help provide guidance in the treatment of these patients.[6]



Investigators enrolled adults with type 1 or 2 diabetes at 91 sites in the United States and Canada. Study eyes had CI-DME (defined as central subfield thickening [CST] ≥ 305 microns in women and ≥ 320 microns in men) confirmed by optical coherence tomography on two different days within a 4-week window, with best-corrected visual acuity (BCVA) of 20/25 or better (at least 79 Early Treatment Diabetic Retinopathy Study [ETDRS] letters). Patients were excluded if they had undergone prior laser photocoagulation or intravitreal injection treatment for DME within the past 12 months.

As part of this study, 702 eyes were almost equally randomly assigned into three arms: observation, macular laser photocoagulation, or aflibercept. The primary outcome was a VA decrease of five or more letters from baseline at 2 years.

Eyes randomly assigned to receive aflibercept received one intravitreal injection at baseline and continued to receive injections at monthly follow-up visits if VA or CST was improving or worsening (defined as a VA change of five or more letters or ≥10% CST change) between either of the last two visits.

Eyes randomly assigned to the laser arm received macular laser at baseline, with retreatment at 13-week intervals if indicated.

The 2-year completion rate, excluding deaths, was 92%, and the median number of visits through 2 years was 18, 11, and 12 in the aflibercept, laser, and observation groups, respectively. The median number of injections through 2 years in the aflibercept group was eight. In the laser arm, 32% received additional macular laser during follow-up.

Investigators anticipated that more patients in the observation and laser arms may experience VA loss than in the aflibercept arm. Therefore, the trial design allowed eyes assigned to observation or laser to receive aflibercept if prespecified VA worsening criteria were met; specifically, aflibercept therapy was initiated if VA decreased from baseline by ≥ 10 ETDRS letters at one visit or by five to nine letters at two consecutive visits. Through 2 years, this endpoint was met in 34% and 25% of eyes in the observation and laser arms, respectively. Among those eyes that lost VA and initiated aflibercept treatment, the median number of injections before the 2-year endpoint was seven and nine in the laser and observation arms, respectively.

Despite 25%-34% of eyes in the laser and observation arms experiencing a clinically meaningful decrease in VA during the trial, at the 2-year time point the percentage of eyes with at least a five-letter VA decrease was 19%, 17% , and 16% in the observation, laser, and aflibercept groups, respectively, with no statistically significant differences between the groups.

The percentage of eyes with VA of 20/20 or better at 2 years was 66%, 71%, and 77% in the observation, laser, and aflibercept groups, respectively

Important Considerations Before Applying Clinically

Protocol V is an invaluable source of information and provides much-needed data to inform clinical discussions with patients who have CI-DME with good vision. Landmark phase 3 trials, such as VISTA/VIVID and RIDE/RISE, have demonstrated the overwhelming superiority of intravitreal anti-VEGF therapy for the management of CI-DME with VA loss, to the point that the decision to initiate treatment on a population basis in such clinical scenarios is now clear.[2,3,7] Comparatively, initiating therapy for CI-DME with good VA requires a more detailed consideration of the risk-benefit ratio on an individualized basis; data from Protocol V can be used to support observation, macular laser, or intravitreal anti-VEGF therapy.

On average, patients enrolled in Protocol V had good control of their diabetes and blood pressure. Furthermore, these patients were selected from clinical practices because of their willingness to attend frequent visits. Therefore, this population may not be representative of patients with diabetes in routine clinical care.

Another challenge in applying Protocol V’s data to clinical practice is that ETDRS BCVA was the sole driver of initiation of anti-VEGF therapy for eyes randomly assigned to observation or macular laser. ETDRS BCVA is a highly specific, rigorous, time-intensive method for determining VA. The majority of retina specialists do not perform this level of VA testing in routine clinical care. Worsening DME in the absence of VA loss was not a trigger in Protocol V for initiation of aflibercept therapy.

Although there is a relationship between CST (amount of DME) and VA,[8] it is an imperfect one, and the field of retina research would benefit from a more comprehensive understanding of imaging biomarkers and how they can be used to guide therapy for each patient

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Photodynamic Therapy ( PDT ) in Central Serous Chorioretinopathy (CSC)

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PDT first requires the intravenous administration of a photosensitizer, followed by the administration of nonthermal red light into the affected eye. After light is absorbed by the photosensitizer, it is transformed to its excited state. Oxygen, highly reactive, short-lived singlet oxygen, and reactive oxygen radicals are generated, causing local photo-oxidative damage because of its short life time. This damage is induced by an effect on nucleic acid, enzymes, and cellular membranes, and is caused by both cellular and vascular, and immunological mechanisms. For the effect to be induced, the three most important parameters to be taken into account are the characteristics of the photosensitizer, the involved tissue, and treatment parameters. Aside from preference of verteporfin to accumulate in areas of abnormal neovascularization, verteporfin also appears to accumulate in the choroidal vasculature. For CSC, PDT is thought to lead to short-term hypoperfusion of the choriocapillaris and to longterm remodeling of choroidal vasculature, resulting in a reduction of leakage of fluid to under the retina. The latter mechanism is of special interest in the treatment of CSC, because the disease primarily affects the choroidal circulation, resulting in areas of choroidal vascular hyperpermeability that might finally result in the accumulation of subretinal fluid (SRF).

PS = Photosensitizer

Before performing PDT, the pupil of the treated eye requires dilation, for instance with 1.0% tropicamide and 2.5% phenylephrine. Subsequently, an intravenous infusion of verteporfin is administered over a period of 10 minutes.

For half-dose PDT, 3mg/m2 verteporfin is used, while 6mg/m2 is given for PDT with using half the standard fluence (half-fluence PDT), half the standard treatment time (half-time), or nonreduced standard (full) settings. Fifteen minutes after the start of the infusion, an anesthetic eye drop is given (oxybuprocaine 0.4% or equivalent), a contact lens (a Volk PDT lens) is positioned on the eye that requires treatment, and the aiming beam of the laser is focused on the treatment area. The magnification factor should be considered in the settings of the PDT machine. For indocyanine green angiography (ICGA)-guided PDT, the area of treatment is chosen based on the hyperfluorescent areas on mid-phase ICGA (approximately 10–15minutes) that often roughly corresponds to the areas with SRF on optical coherence tomography (OCT), as well as the areas of leakage on the midphase fluorescein angiogram (FA; approximately 3minutes). The area of the aiming beam corresponds to the area of the subsequent laser spot area. The spot size can be defined based on the diameter of the hyperfluorescent area on ICGA. In cases with separated multifocal areas of active SRF leakage, multiple treatment spots can be applied to the additional areas immediately after the first treatment, taking care that the macular area should be treated first after verteporfin infusion.

Although most studies have performed ICGA-guided PDT, aiming to treat the underlying—supposedly primarily abnormal—choroid/choriocapillaris, some authors also have described good results with PDT guided by hyperfluorescent leaking (hot spot) areas on FA. As choroidal abnormalities on ICGA often are more extensive than areas of leakage on FA, a potential risk in FA-guided PDT is under-treatment because smaller treatment spots tend to be used. It has been advocated to keep the edge of a treatment spot at least 200μm away from the optic disc rim, to prevent potential damaging effects of PDT to the optic disc, but evidence suggests that this is not necessary. In half-dose PDT, the treatment is performed with standard fluency (50 J/cm2 ; can be reduced to 25 J/cm2 in a half-fluence treatment protocol), a PDT laser wavelength of 689 nm, and a standard treatment duration of 83 seconds (can be reduced to 42seconds in a half-time treatment protocol). Treatment must be performed at 15 minutes after the start of the verteporfin infusion to maximize the localization of the effect of treatment to the choroid and minimize possible damage to the adjacent retinal structures.

No studies regarding the recommended minimum time period between ICGA and PDT treatment have been conducted yet.

Although the exact number is not known, it is suggested that 15%–50% of patients with acute CSC might experience one or more recurrences or persistent SRF within the first year after onset of symptoms. Because PDT has been shown to be effective in acute CSC, it is now often used in cases with persistent SRF for more than 3 months. A recent study by Mohabati et al. showed that acute CSC cases that received early PDT treatment had a significantly lower number of SRF recurrences during long-term follow-up (4% recurrences in PDT-treated patients versus 24% recurrences in untreated patients), and similar findings previously were reported by Ozkaya et al. (Mohabati et al., under review).

In summary, there is strong evidence that PDT with reduced settings in acute CSC is effective in resolving SRF and improving vision, and early PDT also could reduce the number of recurrences. Long-term follow-up studies in chronic CSC (cCSC) cases that underwent PDT treatment have proven that PDT is a safe intervention. It might be expected that this is also true for PDT in acute CSC.

In 2018, the results of the PLACE trial—the first large prospective multicenter randomized controlled treatment trial for cCSC—were published. In this European investigator initiated study by Van Dijk et al., ICGA-guided half-dose PDT was compared to ICGA-guided high-density subthreshold micropulse laser treatment. The results clearly showed superiority of half-dose PDT over micropulse laser treatment. With regard to the primary end point of complete resolution of SRF, 67% of cases achieved complete resolution after half-dose PDT at final follow-up as compared to 29% of patients who received micropulse laser in the PLACE trial.

reference :

Editors: Jay Chhablani

eBook ISBN: 9780128173015

Paperback ISBN: 9780128168004

Imprint: Academic Press

Published Date: 19th March 2019