Journal Club 17th April 2020
Special Thanks to Ali Makateb MD for Presentation
Special Thanks to Kaveh Fadakar M.D for Presentation .
Special Thanks to Ali Makateb MD for Presentation
Special Thanks to Kaveh Fadakar M.D for Presentation .
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Current treatment plans can be formulated based on three pieces of information: the location of the PCV complex, the baseline vision, and the response to previous therapy. Options available are photodynamic therapy (PDT), anti-VEGF therapy, combination of PDT and anti-VEGF, and laser photocoagulation.
The results of the EVEREST clinical trial highlighted a higher rate of polyp closure with PDT alone or when combined with ranibizumab. They found a greater polyp regression with PDT combined with ranibizumab (77.8%), followed by PDT alone (71.4%) and less closure with ranibizumab alone (28.6%).
The EVEREST-II and PLANET evaluated anti-VEGF and combination therapy. EVEREST II compared ranibizumab with combination of ranibizumab and PDT at baseline and PLANET, aflibercept with or without rescue PDT available after 3 months. Both studies showed a significant gain in visual acuity in the anti-VEGF monotherapy arm at 1 year. Polyp closure rates were 34.7% (EVEREST-II) and 38.9% (PLANET). The mean of injections was 7.3 for (EVEREST-II) and 8.1 (PLANET).
A recently published analysis of the Japanese cohort of EVEREST II study over 12 months confirmed the same conclusion as in the 24–month study. The best available evidence suggests that combination therapy resulted in improved vision and achieved a higher rate of complete polyp regression with a lower number of anti-VEGF injections when compared with monotherapy.
Our recommendations based on available study data to include PDT as art of treatment are based on the following:
2.Anti-VEGF alone can reduce serosanguinous complications in PCV.
PCV has a less reliable response to anti-VEGF therapy than exudative AMD. Aqueous humor of eyes with PCV contains high levels of VEGF when compared to controls but less than in eyes with exudative AMD. In Asia, PDT has been the first-line therapy for PCV while in the USA, anti-VEGF is often first-line treatment for serosanguinous maculopathy.
Few retrospective studies with bevacizumab showed a low rate of polyp closure (21%).
Characteristics associated with better vision outcome such as smaller lesion, absence of PED at baseline, and no CNV recurrences.
The PEARL 1 study, a prospective, open-label clinical trial of monthly intravitreal ranibizumab injections (IRI) in 13 eyes showed statistically significant improvement in visual acuity and decrease in central foveal thickness (CFT) at 1 year. This study found a decreased volume of the PCV complexes in 38%, but an increase in 31% after 1 year. When a higher dose of IRI was used (2.0 mg) in 19 eyes in the PEARL 2 study , there was a better response in polyp regression at 6 months (78.9% decreased polyps vs 21.1% stable), similar to EVEREST study results in the PDT subgroups.
EVEREST II showed that combination therapy resulted in superior visual and angiographic outcomes at the same time reducing the need for repeat injections during the first year of treatment.
In the LAPTOP study, a prospective, multicenter randomized clinical trial comparing PDT with IRI showed a superior visual acuity in the IRI arm. Recently, long-term visual acuity results in 29 eyes with PCV based on the first-choice treatment, either PDT or IVR concluding that the better VA in the initial IRI group compared with the PDT group at 2 years was retained at the 5-year follow-up.
The EPIC study was a 6-month prospective open-label investigator-sponsored trial in 21 eyes that evaluated the treatment results of intravitreal aflibercept injections (IAI) for PCV with hemorrhage and exudation in eyes previously treated with ranibizumab and bevacizumab. At 6 months, vision was stable or improved in 19/21 eyes (91%). Subretinal fluid resolved in 72% of the eyes, and subretinal hemorrhage resolved in 75%. The polyps regressed in 67% of the eyes and the BNV decreased in one eye only but was stable in all other eyes. The retinal pigment epithelial detachment (PED) improved in 87% of the eyes.
The 96-week multicenter randomized clinical trial PLANET study compared IAI monotherapy with IAI with rescue PDT. They all received initially monthly IAI for 3 months. Vision and/or functional outcomes were achieved in more than 85% of participants who were treated with IAI only, and no signs of leakage from polypoidal lesions in more than 80%. The potential benefit of adding PDT could not be determined unfortunately since only fewer than 15% met the criteria of a suboptimal response to receive PDT.
Currently, there is no evidence that adding PDT to aflibercept can give any additional benefit to the patient. If aflibercept is used, fixed dosing should be planned and patient prepared.
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. 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.
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, 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
reference of image : here