|Year : 2018 | Volume
| Issue : 4 | Page : 144-152
The efficacy of adjunct therapy by intravitreal aflibercept and laser versus triamcinolone and laser in the treatment of diabetic macular edema: a 6-month study
Ashraf H Soliman
Department of Ophthalmology, Faculty of Medicine, Ain shams University, Ramses Street, Abbasia Square, Cairo, Egypt
|Date of Web Publication||13-Feb-2019|
Ashraf H Soliman
Department of Ophthalmology, Faculty of Medicine, Ain shams University, Ramses Street, Abbasia Square, Cairo 11517
Source of Support: None, Conflict of Interest: None
Aim The aim was to compare visual and central macular thickness (CMT) improvement and complications of adjunct intravitreal aflibercept (IAI) (2 mg) 0.05 ml followed by argon laser photocoagulation with adjunct intravitreal triamcinolone 4 mg/0.1 ml followed by argon laser photocoagulation in treating diabetic macular edema.
Patients and methods A total of 30 eyes of 26 patients with type II diabetes having visual loss owing to clinically significant macular oedema (CSME) and confirmed by fundus fluorescein angiography (FFA) and optical coherence tomography (OCT) were included. Patients were randomly assigned into two groups: group 1 was treated by IAI (0.05 ml) 2 mg/4 weeks (2q4) for a total of five doses, and group 2 by intravitreal triamcinolone acetonide 4 mg/0.1 ml. Best corrected visual acuity (BCVA) and clinical examination were done monthly. OCT was done at 2, 4, and 5 months. At 5 months, and CMT allowing, FFA was done and laser photocoagulation was performed on distinct leakers. OCT and FFA were done at 6 months, and results were compared between the two groups.
Results At 6 months, there was a statistically significant improvement (P<0.05) of CMT in the IAI group compared with IVTA group (P=0.04 and 0.469, respectively). The IVTA group showed an ill-sustained effect, where four cases required reinjection. BCVA for the IAI group continued to improve throughout the study period, with statistically significant values until the end point (P=0.033). IVTA group showed statistically significant improvement in BCVA at the 2-month and 4-month visits, but insignificant changes thereafter (P=0.76 at 6 months). These changes were similar to CMT. Overall, five (33%) eyes in the IVTA group had an increase in intraocular pressure (IOP), with the highest at 12th week, and were treated by topical timolol 0.5% bid. Moreover, one patient had a visually significant posterior subcapsular cataract, and phacoemulsification with intraocular lens (IOL) implantation was performed after the study. One case in each group developed self-limited vitreous hemorrhage, which resolved spontaneously.
Conclusion IAI/laser provides superior and more sustained anatomical CMT and BCVA results with fewer complications compared with the intravitreal triamcinolone/laser.
Keywords: argon laser photocoagulation, diabetic macular edema, intravitreal aflibercept, intravitreal triamcinolone
|How to cite this article:|
Soliman AH. The efficacy of adjunct therapy by intravitreal aflibercept and laser versus triamcinolone and laser in the treatment of diabetic macular edema: a 6-month study. J Egypt Ophthalmol Soc 2018;111:144-52
|How to cite this URL:|
Soliman AH. The efficacy of adjunct therapy by intravitreal aflibercept and laser versus triamcinolone and laser in the treatment of diabetic macular edema: a 6-month study. J Egypt Ophthalmol Soc [serial online] 2018 [cited 2019 Mar 26];111:144-52. Available from: http://www.jeos.eg.net/text.asp?2018/111/4/144/252178
| Introduction|| |
Diabetic retinopathy is one of the three major microvascular complications induced by diabetes mellitus. After twenty years of the disease, its incidence is virtually universal in type I diabetes mellitus (DM) and in nearly 80% of type II DM ,.
The most significant cause for deteriorated visual acuity in diabetic patients is diabetic macular edema (DME). A multitude of pathogenic factors have been implicated in its development, namely, the breakdown of the blood-retinal barrier, with leakage of intravascular fluid into the retinal tissue resulting in edema. This occurs owing to the formation of immature microvessels, which is fueled by the hypoxia-induced release of inflammatory mediators, vascular endothelial growth factors (VEGF A, B, C, and D), and placental growth factors from hypoxic retinal tissue .
The early treatment diabetic retinopathy study (ETDRS) classification of clinically significant macular edema has set guidelines for us to know when to initiate treatment to achieve the highest levels of cure and future prophylaxis. The ETDRS guidelines state that clinically significant macular oedema (CSME) is diagnosed by one of three following scenarios: thickening of the retina at or within 500 μm of the center of the macula, hard exudates at or within 500 μm of the center of the macula with adjacent retinal thickening, or/and retinal thickening of one disc diameter or larger within one disc diameter of the center of the macula .
This gold standard CSME diagnosis, together with the improved understanding of the pathophysiology of VEGF, PIGF, and inflammatory mediators, has helped the evolution of the treatment strategies for diabetic maculopathy. These strategies are primarily focused on the obliteration of the hypoxic tissue and halting the production of inflammatory mediators (interleukins and cytokines) and endothelial growth factors ,.
The milestones in this evolution started with laser photocoagulation, which the ETDRS found to reduce risk of visual loss of 15 or more letters by half within one year. In addition to reducing the production of VEGF and other inflammatory mediators, it aids the retinal pigment epithelium in the active reabsorption of extravasated fluids into the intravascular compartment ,.
The development of intravitreal triamcinolone soon followed, making use of its well-known role in stopping the inflammatory cascade, inhibiting interleukin (IL)-6, IL-8, monocyte chemotactic protein-1, PDGF, and interferon-induced protein 10, leading to leukostasis, stabilization of the blood-retinal barrier, and the inhibition of platelet aggregation. It also leads to downregulation of VEGF receptors .
With evidence that intravitreal steroids produce significant ocular morbidity such as increased intraocular pressure (IOP) and cataracts, the search continued for a safer and equally potent treatment for DME, and so was the advent of the era of anti-VEGF .
The development of anti-VEGF started as a treatment for various tumors and expanded to cover any pathology associated with an increase of these factors, like DME, edema associated with vein occlusion, and neovascular age-related macular degeneration .
These small proteins have a pivot role in the control of angiogenesis, and five isomers have been isolated in humans: VEGF A, B, C, and D, and PIGF. Of these, VEGF A is the most important isomer in the development of ocular manifestations. Various generations of the drug have been developed, starting with pegabtanib sodium, bevacizumab, ranibizumab, and lastly aflibercept. Being mostly antibodies with Fc, Fab portions to VEGF, these drugs bind with VEGF molecules released from hypoxic tissues, creating a VEGF trap, and halting its angiogenic effect. Older drug forms such bevacizumab produce heterogenous multimeric immune complexes, which when cleared of the eye into the systemic circulation deposit in tissues, leading to undesirable effects like platelet aggregation and thromboembolic manifestations, and deposits in the kidney, leading to glomerular damage .
Aflibercept is a recombinant fusion protein produced from hamster ovary cells and weighs 115 kDa. Its advantage is that when fused with VEGF, it produces homogenous stable and inert complexes that do not deposit in the tissues, thus reducing the systemic adverse effects. In addition, it has a potent role in blocking placental growth factor PIGF, which adds to its effectiveness when compared with other anti-VEGF .
| Patients and methods|| |
A total of 30 eyes of 26 patients were included in this comparative study. It included patients with type II diabetes having visual loss owing to clinically significant macular edema as per the ETDRS criteria (retinal edema within 500 microns from the center of the fovea, hard exudates 500 microns from the center of the fovea associated with retinal edema, and retinal oedema of 1 disc diameter any part of which is within 1 disc diameter from the center of the fovea).
This was further confirmed by fundus fluorescein angiography (FFA) using the Topcon TRC-NW8F plus (Topcon Medical Systems Inc., Oakland, NJ, USA). Central macular thickness was measured using the Zeiss CIRRUS ™ 5000 (Carl Zeiss Meditec Inc., Dublin, CA, USA) optical coherence tomography (OCT). The diagnosis, prognosis, and treatment plans were explained to each patient, and a consent for the initiation of treatment was obtained.
Exclusion criteria included patients who have had previous intervention for DME whether injectable or optical intervention, uncontrolled diabetes followed by HBA1C every 6 weeks, proliferative retinopathy, and other associated ocular diseases (glaucoma, uveitis, etc.).
All cases were treated at Ain shams University Hospitals, and Al Mashreq Eye Hospitals, Cairo, Egypt.
The 30 eyes were randomly assigned 1 : 1 into two groups. The first group was treated by intravitreal aflibercept (IAI) (0.05 ml) 2 mg/4weeks (2q4) for a total of five doses, and the second by intravitreal triamcinolone acetonide 4 mg/0.1 ml. Injections were performed under completely aseptic conditions in an operating theater by a highly skilled ophthalmic surgeon.
The patients were seen first day postoperatively for any signs of complications (hemorrhage, increased IOP, and inadvertent lens injury).
Patients were followed up by clinical assessment (best corrected visual acuity (BCVA) and ophthalmological examination) on a monthly basis, and imaged by OCT at 2, 4, and 5 months. At the 5-month mark, FFA was done, and, central macular thickness (CMT) allowing, argon laser photocoagulation was performed according to the pattern of leakage (spot size 50 μm, duration 0.05 s). Patients were imaged again at 6 months, and results were compared between the two groups regarding the BCVA and CMT, and the rate of complications.
| Results|| |
The study comprised 30 eyes of 26 patients from October 2017 to September 2018. Overall, 62% were female and 38% males. Age group ranged from 38 to 66 years, with a mean age of 45.6 years.
We randomly divided the patients into two groups and followed up at 2, 4, and 5 months by clinical assessment and OCT. At the 5-month mark, when CMT was low enough by OCT, FFA was performed, and argon laser session (spot size 50 μm) was performed to eyes whose CMT was low enough, with distinct leakage sites (focal). After that, the patients were imaged at the 6-month end point by FFA and OCT to assess the final outcomes.
BCVA was measured and recorded in every visit, using the decimal system. These can be seen in [Table 1] and [Figure 1],[Figure 2],[Figure 3],[Figure 4].
|Table 1 The results in BCVA, and a significant improvement in both groups, which was more significant and improved throughout the study in the intravitreal aflibercept group (group 1), whereas there was a shorter lived response in the IVTA group|
Click here to view
|Figure 3 The difference in the mean between the two groups in terms of baseline BCVA. The difference was statistically insignificant between the two groups (P>0.05).|
Click here to view
|Figure 4 A line chart showing the difference in BCVA response between the two groups, with a continuing improvement in the intravitreal aflibercept group until the study end point (four lines), and an initial improvement in the IVTA group, followed by a plateau at the 4-month mark (2.4 lines).|
Click here to view
Central macular thickness changes
Difference in the baseline CMT between the two groups was statistically insignificant. The IAI group showed a consistent improvement in the CMT throughout the follow-up, being statistically significant at the second month, fourth month, and sixth month visit. At the end of the study period, only two of the 15 eyes showed a mild increase in CMT from an initial improvement.
In the IVTA group, there was an improvement in CMT, being statistically significant at the second and fourth month visits, but levelling off and becoming insignificant thereafter. At the end of the study, seven patients showed a relapse of the condition, and a noticeable increase in CMT. This was found to be nearly four times that of the IAI group. A total of four patients required reinjection between 2 and 4 months of initial treatment. This is more clearly explained in [Table 2] and [Figure 5].
|Table 2 The CMT results throughout the study, with a statistically significant difference between the two groups at the 5-month and 6-month follow-up (marked by an Asterix)|
Click here to view
|Figure 5 Line chart showing the difference between the two groups; the decrease (improvement) is more obvious and consistent in the intravitreal aflibercept group as compared with the IVTA group.|
Click here to view
Incidence of complications
In the IAI group, one patient developed limited vitreous hemorrhage that subsided spontaneously within 4 weeks. Two patients showed an increase in CMT at the end of the follow-up period, after an initial improvement. No other systemic or ocular complicated ensued.
However, the IVTA group showed a few ocular complications. A total of five (33%) patients developed increased intraocular pressure, which was highest at the 12th week, and this was treated by timolol 0.5% bid. In three cases, the condition subsided by the sixth month of the injection, whereas in two cases, the condition took longer time to resolve (average 10 months), but no perimetric or retinal nerve fiber layer changes in the OCT were recorded. One patient developed limited vitreous hemorrhage, which was absorbed by the sixth week.
A total of four (26.6%) patients required reinjection of triamcinolone at the second and fourth month follow-up.
One patient developed a rapidly progressive posterior subcapsular cataract, becoming visually significant by the sixth month, and a phacoemulsification with intraocular lens (IOL) implantation was performed after the study follow-up period.
Overall, seven patients showed an increase in CMT (relapse) at the end of the follow-up period.
No systemic adverse effects were noted for IVTA group.
| Discussion|| |
This study dealt with clinically significant DME, and compared two treatment regimens of adjunct therapy (IAI and laser versus triamcinolone acetonide with laser) to prove which one was more potent and had sustained effect in the control of the condition. The study has proved that IAI 2 mg every four weeks for five injections followed by laser had a stronger control of the condition as compared with intravitreal triamcinolone with laser. The best0corrected visual acuity results were also in favor of the IAI group versus the IVTA, where there was an improvement of four lines as compared with 2.4 lines, respectively.
Concerning the frequency of the drug administration, the dosage regimen of IAI seems to decrease the CMT more consistently, and hence renders the eyes more ready for laser photocoagulation therapy if and when needed. This was not the case in the IVTA group, where a single injection did not render the CMT low enough for laser treatment in four eyes, and they required reinjection to achieve a decrease in CMT.
Our results are in agreement with a consensus study carried out by Avitabile and team, who researched the current treatment profile for aflibercept and found the 5-month initial loading dose to be effective in improving the visual and anatomical functions of the retina, with long-lasting effects, and they even recommended it to be the standard therapy for DME. They also concluded that after the loading dose, any retreatments should only be given as needed. In our study, we used laser photocoagulation to provide the patient with more stable and longer lasting results ,.
In another study conducted by Wells and coauthors, they compared aflibercept with other anti-VEGF and found a significant improvement of visual acuity in eyes treated with aflibercept, with patients’ BCVA improving 3.5 lines more than initial BCVA. These results were very comparable to ours, where our patients improved four lines at the end of the 6-month follow-up .
In a 24-week pilot study conducted by Andrade and colleagues, six injections of aflibercept were found to be very effective in improving visual acuity (P<0.05) and CMT. In addition, they also noted that no ocular or systemic adverse reactions had occurred, and these results were in agreement to ours, despite that in the current study aflibercept was only injected five times .
The results of another study by Mitchell and team found similar results to our aflibercept group. They proved IAI was effective in reducing CMT and delaying the progression of diabetic retinopathy .
One of our patient’s OCT results can be seen in [Figure 6], comparing the baseline with the end point CMT changes in OCT, which were found comparable to many studies.
|Figure 6 Baseline (left) and final outcome at 6 months (right) images of a patient treated by intravitreal aflibercept 2q4 five injections (intravitreal aflibercept group 1). There is an obvious improvement of the central macular thickness and a corresponding improvement in BCVA.|
Click here to view
Concerning the IVTA group, this study’s results were similar to those found by Beck et al.  and team, who discovered that although IVTA reduces CMT and improves BCVA, these effects do not last long and need adjunct laser photocoagulation, or reinjection. They also stated that IVTA injection also comes with potential ocular complications, namely, cataract and increased intraocular pressure .
Regarding the finding of increased intraocular pressure in the cases treated by IVTA, our results were similar to those found by Storey et al. , in which they recorded increase IOP in 13.2% of cases (14 eyes out of 106) that received 2 mg/0.1 ml. Our five (33%) cases developed a higher rate of the IOP increase probably owing to the higher dose used (4 mg/0.1 ml) .
As for the effect of triamcinolone acetonide (IVTA) which we found to be short lived and of a considerable degree of relapse, our results were found to similar to those published by Jeon and Lee , where they found that the increase in BCVA to be significant at the first and second months (P<0.05), but improvement was short lived, where it was not sustained by the third month of follow-up. This pattern is nearly congruent to our visual result pattern. As for the CMT, they showed an initial 11% improvement in that parameter, which also did not last long .
Another study conducted by Patelli et al.  was done to describe the improvement of CMT and visual acuity over time in patients with DME after intravitreal injection of triamcinolone acetonide (IVTA), they found visual acuity improved quickly, peaking at 2 weeks, after which it remained stable for 3 months and then decreased. These were very similar to our study results .
In a study conducted by Gillies , IVTA produced a statistically significant long-term improvement of BCVA, but it was also associated with steroid-induced glaucoma and cataract. In the second year of their research, at least one reinjection was needed in 69% of cases to maintain these results. This long-term stability of vision was not noted in our study.
| Conclusion|| |
Both aflibercept and triamcinolone lead to a statistically significant decrease in central macular thickness and improvement of best-corrected visual acuity in patients with DME. These effects were significantly stronger and longer lasting in aflibercept as compared with triamcinolone, which showed a more short-term effect. Intravitreal triamcinolone does have its documented ocular complications, namely, increased IOP and cataract formation. Therefore, aflibercept is a more potent and a safer drug to use in the treatment of DME.
IAI/laser provides superior and more sustained anatomical (CMT) and BCVA results with fewer complications compared with the intravitreal triamcinolone/laser. The positive effects of aflibercept seem to be more durable than those of intravitreal triamcinolone acetonide. Although the IVTA combined with laser provides a good response in cases of diffuse DME, and is more economic, it does have the major adverse effects of increased intraocular pressure and posterior subcapsular cataracts. Laser therapy is recommended when edema becomes focal as seen on FFA by the help of the intravitreal drugs to maintain a more sustained improvement of BCVA and retinal thickness parameters.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interesting.
| References|| |
Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984; 102:527–532.
Liew G, Michaelides M, Bunce C. A comparison of the causes of blindness certifications in England and Wales in working age adults (16–64 years), 1999–2000 with 2009–2010. BMJ Open 2014; 4:e004015.
Antcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy. Semin Ophthalmol 1999; 14:223–232.
Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographs − an extension of the modified Airlie House classification. ETDRS Report Number 10. Ophthalmology 1991; 98:786–806.
Funatsu H, Yamashita H, Noma H, Mimura T, Yamashita T, Hori S. Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. Am J Ophthalmol 2002; 133:70–77.
Virgili G, Parravano M, Menchini F, Brunetti M. Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for diabetic macular oedema. Cochrane Database Syst Rev 2012; 12:CD007419.
Stefansson E. The therapeutic effects of retinal laser treatment and vitrectomy. A theory based on oxygen and vascular physiology. Acta Ophthalmol Scand 2001; 79:435–440.
Miura Y, Klettner A, Roider J. VEGF antagonists decrease barrier function of retinal pigment epithelium in vitro: possible participation of intracellular glutathione. Invest Ophthalmol Vis Sci 2010; 51:4848–4855.
Sohn HJ, Han DH, Kim IT, Oh IK, Kim HK, Lee DY, Nam DH. Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus bevacizumab for diabetic macular edema. Am J Ophthalmol 2011; 152:686–694.
Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR et al.
Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010; 117:1064–1077.
Grant MB, Afzal A, Spoerri P, Pan H, Shaw LC, Mames RN. The role of growth factors in the pathogenesis of diabetic retinopathy. Expert Opin Investig Drugs 2004; 13:1275–1293.
Andrade Gcde, Dias JR, Maia A, Farah ME, Meyer CH, Rodrigues EB. Intravitreal injections of ZIV-aflibercept for diabetic macular edema: a pilot study. Retina 2016; 36:1640–1645.
Avitabile T, Azzolini C, Bandello F, Boscia F, De Falco S, Fornasari D et al.
Aflibercept in the treatment of diabetic macular edema: a review and consensus paper. Eur J Ophthalmol 2017; 27:627–639.
Wells JA, Glassman AR, Ayala AR. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology 2016; 123:1351–1359.
Mitchell P, McAllister I, Larsen M, Staurenghi G, Korobelnik JF, Boyer DS et al.
Evaluating the impact of intravitreal aflibercept on diabetic retinopathy progression in the VIVID-DME and VISTA-DME. Stud Ophthalmol Retina 2018; 2:988–996.
Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, Glassman AR et al.
Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009; 127:245–251.
Storey P, Obeid A, Pancholy M, Goodman J, Borka D, Su D, Regillo C et al.
Ocular hypertension after intravitreal injection of 2 mg triamcinolone. Retina 2018; doi:10.1097/IAE.0000000000002361. [Epub ahead of print]
Jeon S, Lee WK. Effect of intravitreal triamcinolone in diabetic macular edema unresponsive to intravitreal bevacizumab. Retina 2014; 34:1606–1611.
Patelli F, Fasolino G, Radice P, Russo S, Zumbo G, Di Tizio F, Frisone G. Time course of changes in retinal thickness and visual acuity after intravitreal triamicinolone acetonide for diffuse diabetic macular edema with and without previous macular laser treatment. Retina 2005; 25:840–845.
Gillies MC, McAllister IL, Zhu M, Wong W, Louis D, Arnold JJ, Wong TY. Intravitreal triamcinolone prior to laser treatment of diabetic macular edema: 24-month results of a randomized controlled trial. Ophthalmology 2011; 118:866–872.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]