Int Ophthalmol (2015) 35:73–79 DOI 10.1007/s10792-014-0019-5
ORIGINAL PAPER
The effect of combined treatment of bevacizumab and triamcinolone for diabetic macular edema refractory to previous intravitreal mono-injections ¨ mit Yolcu • Gu¨ngo¨r Sobaci U
Received: 15 December 2013 / Accepted: 14 November 2014 / Published online: 26 November 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract The purpose of this study is to evaluate the efficiency of combined treatment of bevacizumab and triamcinolone in refractory diffuse DME (DDME). Twenty-five pseudophakic eyes with DDME refractory to previous successive intravitreal bevacizumab (IVB, 1.25 and 2.5 mg/0.1 ml) and triamcinolone (IVT, 4 mg and 10 mg/0.1 ml) injections were included. The average number of injections was two (1–4). The mean best corrected visual acuity (BCVA) was 0.8 (0.3–1.5) logMAR before enrollment, 0.6 (0.0–1.5) logMAR at 6 months and 0.6 (0–1.8) logMAR at 12 months (p = 0.0001, p = 0.003). The median central macular thickness (CMT) of all the eyes was 575 (502–1049) lm at baseline, 370 (179–983) lm at 6 months, and 410 (198–929) lm at 12 months (p = 0.0001; p = 0.0001). At 6 months, the VA of 13 (52 %) patients was stabilized (± 0.2 logMAR of initial BCVA) and 12 (48 %) patients showed visual improvement ([0.2 logMAR). At 12 months, 10 (40 %) patients had stabilized vision, 13 (52 %) showed visual improvement and 2 (8 %)
This study was partly presented at the Retina Society Annual Meeting in Rome, September 21–25, 2011. ¨ . Yolcu (&) G. Sobaci U Department of Ophthalmology, GATA (Gulhane Military Medical Academy and Medical School), Ankara, Turkey e-mail: [email protected]
showed visual loss. At 6 months, 18 (72 %) patients showed anatomic stabilization (a decrease of 10 % to 50 % in initial CMT) and 7 (28 %) anatomical success (a decrease in CMT more than 50 % or B250 lm at final visit). At 12 months, 13 (52 %) patients showed anatomic stabilization, 10 (40 %) anatomic success, and 2 (8 %) anatomical failure (decrease in CMT less than 10 %). The combined application of IVB and triamcinolone may improve vision and decrease CMT in severe DDME cases refractory to previous monotherapies. Keywords Combined treatment Bevacizumab Triamcinolone Diabetic macular edema
Introduction Diabetic macular edema (DME) is the leading cause of visual loss in non-proliferative diabetic retinopathy (NPDR) patients [1]. The early treatment diabetic retinopathy study (ETDRS) established the standard for focal/grid laser treatment in clinically significant macular edema (CSME) by preventing 50 % of the patients from losing moderate degrees of vision [2]. Newer treatment options, namely intravitreal steroids and anti-VEGF agents, have been reported to give a chance of improvement rather than prevent visual loss in these patients [3–5]. There is an ongoing debate regarding the safety, efficiency, and economic concerns related to these intravitreal monotherapies, as
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they require frequent repetition to maintain the clinical effect [6]. There is still a selected group of patients with severe diffuse DME (DDME) refractory or resistant to intravitreal monotherapies. This study aimed to evaluate the effect of combined intravitreal bevacizumab (IVB) and intravitreal triamcinolone (IVT) on center-involving DDME, which was refractory to previous intravitreal monotherapies.
Materials and methods The patients in this study were recruited from those who were being followed up in the retina section of our center between January 2010 and February 2012. The complete medical record of each patient was scanned and all the patients selected for the study were pseudophakos. Informed consent for the study was obtained from all the study participants. The study adhered to the tenets of the Declaration of Helsinki. All patients had NPDR with chronic DDME (more than a six-month history of visual acuity decrease) which was center-involving (location of CSME) and OCT-based central macular thickness (CMT) of 500 lm or more (Spectralis, Heidelberg Engineering, Heidelberg, Germany). Baseline best corrected visual acuities (BCVAs) were in the range of logMAR 0.3–1.5 (Snellen equivalent of 20/40 to 20/630). One eye from each patient was selected, and if both eyes were eligible for the study, the eye with the greater macula thickness was used. Patients were excluded if they had a CMT value of less than 500 lm, associated ocular and/or systemic conditions affecting systemic status (recent history of medication or surgery in patients with cardiovascular and cerebrovascular events) or visual outcome including those who had undergone cataract surgery within 6 months of enrollment, any focal/grid laser and panretinal photocoagulation (PRP) performed within the previous 6 months, amblyopia, glaucoma [except cases with intraocular pressure (IOP) increase from previous IVT but normal pressure with topical medications], vitreoretinal surgery at any time, vitreomacular traction, vitreoretinal interface abnormalities including epiretinal membrane, ischemic maculopathy (foveal avascular zone(FAZ) [800 lm) hypertension, diabetic nephropathy, and higher glycated hemoglobin ([8 %) and pregnancy. All the patients in this study who were accepted as refractory to mono-injections, had received at least
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two mono-injections of Bevacizumab (Altuzan, Roche, F.Hoffman-Roche Ltd, Basel, Switzerland) including normal doses (1.25 mg/0.05 ml) and higher doses (2.5 mg/0.1 ml), successively and triamcinolone (Kenacort-A, Deva Holding, Istanbul) at normal (4.0 mg/0.1 ml) and higher doses (10 mg/0.1 ml) successively before the enrollment. IVB had been injected at four- to six-week intervals and IVT at 10- to 12-week intervals. From these resistant cases, only those with a CMT value of 500 lm or more were enrolled to elucidate the role of combined treatment in this study. The combined IVB/IVT treatment regimen was administered at three-month intervals. All the procedures in this study complied with the general guidelines for preparation of the drugs and administration of intravitreal injections [7]. Combined injection was not repeated if DDME was refractory or had anatomical failure (defined as CMT decrease of less than 10 % or increase in baseline CMT) to the previous injection. Combined injections were deferred when anatomical success (CMT value of less than 250 lm, and/or 50 % decrease in baseline CMT) and/or functional success (BCVA improvement of 0.3 logMAR) were obtained [8]. Macular focal/ modified grid laser was applied only to those with anatomical and functional stabilization (decrease in CMT of less than 50 % and increase in BCVA of less than 0.3 logMAR) could be achieved [9]. All OCTbased CMT measurements were made by the same examiner at the same time of day (9 a.m.–12 p.m.) on each visit. In addition, baseline fluorescein angiography (FA) was applied to all patients to identify leaking microaneurisms and to search for ischemic maculopathy in eyes which experienced unexplained visual loss during the follow-up period. To prepare the combined injection, a vial of 10 mg of triamcinolone (40 mg in 1 ml) was placed on a flat surface at a 45° angle with the top uppermost for at least 2 h. Before the injection, eyes were softened with manual eye compression, then gently removing the supernatant (0.8 ml) [10], 0.05 ml of the remaining slurry was loaded into a 1-ml, 27-G needle syringe, and after adding 0.05 ml (1.25 mg) of bevacizumab into the syringe, the solution was injected through the pars plana, 3.5–4.0 mm behind the limbus [11]. Corneal paracentesis was performed immediately if central retinal artery pulsation observed by indirect ophthalmoscope was lost after the intravitreal injection. IOP measurements were taken throughout 3 h
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and on the first day after the injection. Regular OCT measurements were repeated at each visit. A median of three successive CMT measurements was calculated on each visit. The primary outcome measurement was to achieve anatomical success. Regarding relative change in CMT from baseline CMT, the anatomical outcomes at 12 months were categorized into three groups of anatomical stabilization, anatomical success, and anatomical failure [8]. Using ± 0.2 logMAR difference from the baseline BCVA, final VAs were categorized in three groups of visual (functional) stabilization (final BCVA within ± 0.2 logMAR of baseline BCVA), visual gain ([0.2 decrease of logMAR BCVA from baseline), and visual loss ([0.2 increase of logMAR BCVA from baseline) [8]. Relevant data, including the number of injections, and associated adverse events, were included in the secondary outcome measures. Statistical analyses were made using SPSS 18.0. Non-parametric tests (Chi-squared/Fisher’s exact, and Spearman correlation tests) were used as appropriate. A p value of \0.05 was considered statistically significant in all the analyses.
Results The study comprised 25 eyes of 25 patients with a mean age of 66.72 ± 2.13 years. The patient demographics are given in Table 1. Overall, a median of 4 (1–12) IVB, and 3 (2–8) IVT injections had been administered before enrollment in the study. IVT had been selected as the first treatment option in 7 (28 %) cases and IVB in 18 (72 %) (not shown in the table). Table 1 Patient demographics in the study Age, years, Mean ± SD (Range)
66.72 ± 2.13 (47–85)
Gender, n (male/female)
7 (28 %)/18 (72 %)
DM durations, months, (Range)
20 (5–42)
Duration of DDME, months, Mean ± SD
36.4 ± 12.4
Diabetes medication Oral anti-diabetic drugs, n
9 (36 %)
Insulin, n HT, n
16 (64 %) 12 (48 %)
Renal disease, n
2 (8 %)
Heart disease, n
4 (16 %)
Throughout the 12-month follow-up period, the mean number of injections was 2.16 ± 1.07 (1–4). Twenty-one (84 %) eyes had PRP for at least 6 months before the study and eight (32 %) eyes required additional peripheral laser treatment during the follow-up period. Grid/focal laser was also applied to 18 of 25 eyes (72 %) after the combined treatment. HbA1C levels were maintained at below 8 % with insulin for all patients (100 %), and no additional medical or surgical intervention for diabetic systemic complications was required during the follow-up period. Mean BCVA was logMAR 0.8 (0.3–1.5) before the enrollment, logMAR 0.6 (0.0–1.5) at 6 months, and logMAR 0.6 (0–1.8) at 12 months (p = 0.0001, p = 0.003 respectively, Wilcoxon) (Fig. 1). During the follow-up, the median CMT of the cases measured by Heidelberg Spectralis OCTTM were 575 (502–1049) lm before the combined injection, 370 (179–983) lm at 6 months and 410 (198–929) lm at 12 months (p = 0.0001; p = 0.0001, respectively, Wilcoxon) (Fig. 2). There was no statistically significant difference between the BCVA and CMT measurements at 6 and 12 months (p = 0.87; p = 0.54, respectively, Wilcoxon). At 6 months, 13 (52 %) patients had stabilized vision (according to baseline BCVA to remain in the range of ± 0.2 logMAR) and 12 (48 %) patients showed visual improvement (C0.2 logMAR). At 12 months, 10 (40 %) patients had stabilized vision, 13 (52 %) patients showed visual improvement, and two (8 %) had visual loss. At 6 months, 18 (72 %) patients had anatomic stabilization (CMT less than 50 % of the initial value) and seven (28 %) patients achieved anatomical success (a reduction in baseline CMT more than 50 % or 250 microns or lower CMT). At 12 months, 13 (52 %) patients had anatomic stabilization, 10 (40 %) patients, anatomic success, and two (8 %) patients had anatomical failure. There was a moderate correlation between the changes in logMAR BCVA and the changes in CMT values at 6 months(r = 0.53, p = 0.31, Spearman test) and at 12 months(r = 0.42, p = 0.16, Pearson test). The mean IOP (18.32 ± 1.54 mmHg) was higher at 12 months compared to baseline IOP (16.12 ± 3 mmHg) (p = 0.003, t test), but was still within normal limits. No additional glaucoma medication was required. Corneal paracentesis was safely
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Fig. 1 Change in BCVA at 12 months *Friedman test, **Wilcoxon test
Fig. 2 Change in CMT at 12 months *Friedman test **Wilcoxon test
applied within 3 min of the post-injection period in 6 (11 %) eyes (not shown in the table). Nine (12 %) patients with increased IOP ([10 mmHg from
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baseline) requiring glaucoma medication before enrollment in this study were kept under control with topical medications (dorzolamide hydrochloride-
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timolol maleate ophthalmic solution, CosoptTM) during the follow-up period. Two of these cases required additional medication (Brimonidine tartrate ophthalmic solution, Alphagan-PTM) after enrollment. None required glaucoma surgery and no additional complication occurred.
Discussion The results of this study have shown that combined treatment of IVB plus IVT might have some beneficial effect in the treatment of severe DME refractory to previous intravitreal monotherapies. There was a moderate correlation of functional outcomes with anatomical outcomes in this study. A significant therapeutic effect from monotherapies with IVT and anti-VEGF agents on DME has been shown in different clinical trials [12–15]. However, anatomical and functional success rates or correlations between them have not been maintained in long-term followups [12–15]. Tsilimbaris et al. showed that the primary use of a combination of IVB and triamcinolone in cases with DME may respond favorably [16]. Others have reported that combined treatment had no more effect than monotherapy [15, 17]. The combined treatment in the current study was administered to a selected group of patients with NPDR, associated with severe DDME and refractory to previous successive intravitreal monotherapies. The current study differs from previous studies in that both therapeutic agents, IVB and IVT were attempted in both traditional and clinically permissible high doses before the study. This combined treatment protocol provided stabilization of visual acuity in 10 (40 %) eyes and improvement in 13 (52 %) eyes at the end of 12 months. This treatment regimen also decreased CMT effectively below 400 lm which provided the opportunity of performing macular laser to 18 of 25 eyes (72 %). The preference of either IVB or IVT as a first line treatment before enrollment did not affect these results significantly (not shown in the results section). In respect of the results of the 12-month follow-up period of the cases, it can be stated that the combination of these intravitreal drugs may not pose an additional risk of future complications in this population. Better functional and anatomical outcomes in this study population might also be related to the patient demographics including HbA1C levels,
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treatment naı¨ve status in respect of grid/focal laser treatment before the enrollment, and the inclusion of non-ischemic cases. On the other hand, there is uncertainty of the risk of cataract formation due to the study design (all had pseudophakic eyes). It was also noted that in some patients, FA was needed but there was no evidence of macular ischemia due to this treatment regimen. In literature, the combination of photo laser coagulation, intravitreal steroids or VEGF-inhibitors, or both, has shown early compelling evidence that some patients may benefit from less re-treatment compared to monotherapy [6]. As indicated in the RESTORE study, combined treatment was followed by grid/focal laser in this study [18]. Although the visual outcomes in the 18 eyes to which grid laser could be added to the combined treatment did not show any significant difference, the small number of cases with short-term follow-up in this study prevents any judgement about the additive effect of grid/focal laser in this study. In a study by Hauser et al., a 4 mg dose of IVT was shown to be no more effective than 1 or 2 mg in eyes with cystic DME [19]. Therefore, in future studies it may be reasonable to investigate the effect of 2 mg instead of 10 mg IVT, in combined treatment as suggested by Folgosa et al. [20]. The current study suggests that the combination of IVB and IVT may still be a valid treatment option in refractory severe DDME. This beneficial effect might be due to substantial activation of well-known antiinflammatory/antiangiogenic pathways [21–23]. Repeated intravitreal high-dosage injections of 20 mg IVT have been shown to be safe, and no tachyphylaxis has been detected in a comparative study [24]. The beneficial effect of combined treatment in this study might also be related to the prevention of tachyphylaxis shown in IVB injections [25]. Systemic control of the patients in the current study was strictly maintained before and during the study period. Therefore, positive beneficial effect of this combination cannot be attributed to decrease of systemic/local risk factors in this study period. Recent studies have suggested that ranibizumab should be considered as the first treatment option in DDME [26, 27]. Although other studies comparing bevacizumab to ranibizumab are not conclusive, head to-head comparison is needed in this regard [28]. Therefore, there is a possibility that the use of ranibizumab instead of bevacizumab might alter the results obtained in this study.
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Limitations to this study include that the study design did not permit any conclusions on the safety concerns of IVB and IVT. In addition, the relatively short follow-up time, numbers, and patient selection (pseudophakos) created some bias in the results. To prevent bias on the therapeutic effect of intravitreal agents, only those who had no macular focal/grid during the follow-up were included. Currently wellknown adverse effects including cataracts and glaucoma from IVT injections cannot be disregarded in this context. It was observed that IOP changes could be manageable in these pseudophakic eyes and no other safety concern emerged from these patients. The retrospective design of the study created bias especially on the treatment strategy selected. In addition, the definition of a refractory case was based mainly on OCT-based criteria. Strict criteria were used for inclusion and exclusion and well-known measures for evaluating the outcomes in the selected group of patients to prevent bias. Combined IVB plus IVT injection was found to be a plausible option in the management of chronic DDME in cases unsuitable for laser treatment and refractory to the current intravitreal monotherapies. Further prospective, controlled clinical studies on larger patient populations are required to confirm the efficacy of IVB plus IVT injections applied to severe DDME, refractory or resistant to previous intravitreal monotherapies. Conflict of interest None of the authors have any conflict of interest with the submission.
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Int Ophthalmol (2015) 35:73–79 5. Yilmaz T, Cordero-Coma M, Gallagher MJ, Teasley LA (2011) Systematic review of intravitreal bevacizumab injection for treatment of primary diabetic macular oedema. Acta Ophthalmol 89:709–717 6. Koss MJ, Naser H, Sener A, Ackermann H, Al-Sarireh F, Singh P et al (2012) Combination therapy in diabetic macular oedema and retinal vein occlusion—past and present. Acta Ophthalmol 90:580–589 7. Jaissle GB, Szurman P, Bartz-Schmidt KU (2005) [Recommendation for the implementation of intravitreal injections—statement of the German Retina Society, the German Society of Ophthalmology (DOG) and the German Professional Association of Ophthalmologists (BVA)]. Klinische Monatsblatter fur Augenheilkunde. 222:390–395. Empfehlung fur die Durchfuhrung von intravitrealen Injektionen— Stellungnahme der Retinologischen Gesellschaft, der Deutschen Ophthalmologischen Gesellschaft (DOG) und des Berufsverbands der Augenarzte Deutschland (BVA) 8. Sobaci G, Ozge G, Erdurman C, Durukan HA, Bayraktar ZM (2012) Comparison of grid laser, intravitreal triamcinolone, and intravitreal bevacizumab in the treatment of diffuse diabetic macular edema. Ophthalmol J Int Ophtalmol (Int J Ophthalmol) (Zeitschrift fur Augenheilkunde) 227:95–99 9. Fong DS, Strauber SF, Aiello LP, Beck RW, Callanan DG, Danis RP et al (2007) Comparison of the modified early treatment diabetic retinopathy study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol 125:469–480 10. Kosobucki BR, Freeman WR, Cheng L (2006) Photographic estimation of the duration of high dose intravitreal triamcinolone in the vitrectomised eye. Br J Ophthalmol 90:705–708 11. Cheng L, Banker AS, Martin M, Kozak I, Freeman WR (2009) Triamcinolone acetonide concentration of aqueous humor after decanted 20-mg intravitreal injection. Ophthalmology 116:1356–1359 12. Arevalo JF, Sanchez JG, Fromow-Guerra J, Wu L, Berrocal MH, Farah ME et al (2009) Comparison of two doses of primary intravitreal bevacizumab (Avastin) for diffuse diabetic macular edema: results from the Pan-American Collaborative Retina Study Group (PACORES) at 12-month follow-up. Graefe’s Arch Clin Experim Ophthalmol (Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie) 247:735–743 13. Goyal S, Lavalley M, Subramanian ML (2011) Meta-analysis and review on the effect of bevacizumab in diabetic macular edema. Graefe’s Arch Clin Experim Ophthalmol (Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie) 249:15–27 14. Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO et al (2011) The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 118:615–625 15. Soheilian M, Ramezani A, Obudi A, Bijanzadeh B, Salehipour M, Yaseri M et al (2009) Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology 116:1142–1150 16. Tsilimbaris MK, Pandeleondidis V, Panagiototglou T, Arvanitaki V, Fragiskou S, Eleftheriadou M et al (2009)
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ORIGINAL PAPER
The effect of combined treatment of bevacizumab and triamcinolone for diabetic macular edema refractory to previous intravitreal mono-injections ¨ mit Yolcu • Gu¨ngo¨r Sobaci U
Received: 15 December 2013 / Accepted: 14 November 2014 / Published online: 26 November 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract The purpose of this study is to evaluate the efficiency of combined treatment of bevacizumab and triamcinolone in refractory diffuse DME (DDME). Twenty-five pseudophakic eyes with DDME refractory to previous successive intravitreal bevacizumab (IVB, 1.25 and 2.5 mg/0.1 ml) and triamcinolone (IVT, 4 mg and 10 mg/0.1 ml) injections were included. The average number of injections was two (1–4). The mean best corrected visual acuity (BCVA) was 0.8 (0.3–1.5) logMAR before enrollment, 0.6 (0.0–1.5) logMAR at 6 months and 0.6 (0–1.8) logMAR at 12 months (p = 0.0001, p = 0.003). The median central macular thickness (CMT) of all the eyes was 575 (502–1049) lm at baseline, 370 (179–983) lm at 6 months, and 410 (198–929) lm at 12 months (p = 0.0001; p = 0.0001). At 6 months, the VA of 13 (52 %) patients was stabilized (± 0.2 logMAR of initial BCVA) and 12 (48 %) patients showed visual improvement ([0.2 logMAR). At 12 months, 10 (40 %) patients had stabilized vision, 13 (52 %) showed visual improvement and 2 (8 %)
This study was partly presented at the Retina Society Annual Meeting in Rome, September 21–25, 2011. ¨ . Yolcu (&) G. Sobaci U Department of Ophthalmology, GATA (Gulhane Military Medical Academy and Medical School), Ankara, Turkey e-mail: [email protected]
showed visual loss. At 6 months, 18 (72 %) patients showed anatomic stabilization (a decrease of 10 % to 50 % in initial CMT) and 7 (28 %) anatomical success (a decrease in CMT more than 50 % or B250 lm at final visit). At 12 months, 13 (52 %) patients showed anatomic stabilization, 10 (40 %) anatomic success, and 2 (8 %) anatomical failure (decrease in CMT less than 10 %). The combined application of IVB and triamcinolone may improve vision and decrease CMT in severe DDME cases refractory to previous monotherapies. Keywords Combined treatment Bevacizumab Triamcinolone Diabetic macular edema
Introduction Diabetic macular edema (DME) is the leading cause of visual loss in non-proliferative diabetic retinopathy (NPDR) patients [1]. The early treatment diabetic retinopathy study (ETDRS) established the standard for focal/grid laser treatment in clinically significant macular edema (CSME) by preventing 50 % of the patients from losing moderate degrees of vision [2]. Newer treatment options, namely intravitreal steroids and anti-VEGF agents, have been reported to give a chance of improvement rather than prevent visual loss in these patients [3–5]. There is an ongoing debate regarding the safety, efficiency, and economic concerns related to these intravitreal monotherapies, as
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they require frequent repetition to maintain the clinical effect [6]. There is still a selected group of patients with severe diffuse DME (DDME) refractory or resistant to intravitreal monotherapies. This study aimed to evaluate the effect of combined intravitreal bevacizumab (IVB) and intravitreal triamcinolone (IVT) on center-involving DDME, which was refractory to previous intravitreal monotherapies.
Materials and methods The patients in this study were recruited from those who were being followed up in the retina section of our center between January 2010 and February 2012. The complete medical record of each patient was scanned and all the patients selected for the study were pseudophakos. Informed consent for the study was obtained from all the study participants. The study adhered to the tenets of the Declaration of Helsinki. All patients had NPDR with chronic DDME (more than a six-month history of visual acuity decrease) which was center-involving (location of CSME) and OCT-based central macular thickness (CMT) of 500 lm or more (Spectralis, Heidelberg Engineering, Heidelberg, Germany). Baseline best corrected visual acuities (BCVAs) were in the range of logMAR 0.3–1.5 (Snellen equivalent of 20/40 to 20/630). One eye from each patient was selected, and if both eyes were eligible for the study, the eye with the greater macula thickness was used. Patients were excluded if they had a CMT value of less than 500 lm, associated ocular and/or systemic conditions affecting systemic status (recent history of medication or surgery in patients with cardiovascular and cerebrovascular events) or visual outcome including those who had undergone cataract surgery within 6 months of enrollment, any focal/grid laser and panretinal photocoagulation (PRP) performed within the previous 6 months, amblyopia, glaucoma [except cases with intraocular pressure (IOP) increase from previous IVT but normal pressure with topical medications], vitreoretinal surgery at any time, vitreomacular traction, vitreoretinal interface abnormalities including epiretinal membrane, ischemic maculopathy (foveal avascular zone(FAZ) [800 lm) hypertension, diabetic nephropathy, and higher glycated hemoglobin ([8 %) and pregnancy. All the patients in this study who were accepted as refractory to mono-injections, had received at least
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two mono-injections of Bevacizumab (Altuzan, Roche, F.Hoffman-Roche Ltd, Basel, Switzerland) including normal doses (1.25 mg/0.05 ml) and higher doses (2.5 mg/0.1 ml), successively and triamcinolone (Kenacort-A, Deva Holding, Istanbul) at normal (4.0 mg/0.1 ml) and higher doses (10 mg/0.1 ml) successively before the enrollment. IVB had been injected at four- to six-week intervals and IVT at 10- to 12-week intervals. From these resistant cases, only those with a CMT value of 500 lm or more were enrolled to elucidate the role of combined treatment in this study. The combined IVB/IVT treatment regimen was administered at three-month intervals. All the procedures in this study complied with the general guidelines for preparation of the drugs and administration of intravitreal injections [7]. Combined injection was not repeated if DDME was refractory or had anatomical failure (defined as CMT decrease of less than 10 % or increase in baseline CMT) to the previous injection. Combined injections were deferred when anatomical success (CMT value of less than 250 lm, and/or 50 % decrease in baseline CMT) and/or functional success (BCVA improvement of 0.3 logMAR) were obtained [8]. Macular focal/ modified grid laser was applied only to those with anatomical and functional stabilization (decrease in CMT of less than 50 % and increase in BCVA of less than 0.3 logMAR) could be achieved [9]. All OCTbased CMT measurements were made by the same examiner at the same time of day (9 a.m.–12 p.m.) on each visit. In addition, baseline fluorescein angiography (FA) was applied to all patients to identify leaking microaneurisms and to search for ischemic maculopathy in eyes which experienced unexplained visual loss during the follow-up period. To prepare the combined injection, a vial of 10 mg of triamcinolone (40 mg in 1 ml) was placed on a flat surface at a 45° angle with the top uppermost for at least 2 h. Before the injection, eyes were softened with manual eye compression, then gently removing the supernatant (0.8 ml) [10], 0.05 ml of the remaining slurry was loaded into a 1-ml, 27-G needle syringe, and after adding 0.05 ml (1.25 mg) of bevacizumab into the syringe, the solution was injected through the pars plana, 3.5–4.0 mm behind the limbus [11]. Corneal paracentesis was performed immediately if central retinal artery pulsation observed by indirect ophthalmoscope was lost after the intravitreal injection. IOP measurements were taken throughout 3 h
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and on the first day after the injection. Regular OCT measurements were repeated at each visit. A median of three successive CMT measurements was calculated on each visit. The primary outcome measurement was to achieve anatomical success. Regarding relative change in CMT from baseline CMT, the anatomical outcomes at 12 months were categorized into three groups of anatomical stabilization, anatomical success, and anatomical failure [8]. Using ± 0.2 logMAR difference from the baseline BCVA, final VAs were categorized in three groups of visual (functional) stabilization (final BCVA within ± 0.2 logMAR of baseline BCVA), visual gain ([0.2 decrease of logMAR BCVA from baseline), and visual loss ([0.2 increase of logMAR BCVA from baseline) [8]. Relevant data, including the number of injections, and associated adverse events, were included in the secondary outcome measures. Statistical analyses were made using SPSS 18.0. Non-parametric tests (Chi-squared/Fisher’s exact, and Spearman correlation tests) were used as appropriate. A p value of \0.05 was considered statistically significant in all the analyses.
Results The study comprised 25 eyes of 25 patients with a mean age of 66.72 ± 2.13 years. The patient demographics are given in Table 1. Overall, a median of 4 (1–12) IVB, and 3 (2–8) IVT injections had been administered before enrollment in the study. IVT had been selected as the first treatment option in 7 (28 %) cases and IVB in 18 (72 %) (not shown in the table). Table 1 Patient demographics in the study Age, years, Mean ± SD (Range)
66.72 ± 2.13 (47–85)
Gender, n (male/female)
7 (28 %)/18 (72 %)
DM durations, months, (Range)
20 (5–42)
Duration of DDME, months, Mean ± SD
36.4 ± 12.4
Diabetes medication Oral anti-diabetic drugs, n
9 (36 %)
Insulin, n HT, n
16 (64 %) 12 (48 %)
Renal disease, n
2 (8 %)
Heart disease, n
4 (16 %)
Throughout the 12-month follow-up period, the mean number of injections was 2.16 ± 1.07 (1–4). Twenty-one (84 %) eyes had PRP for at least 6 months before the study and eight (32 %) eyes required additional peripheral laser treatment during the follow-up period. Grid/focal laser was also applied to 18 of 25 eyes (72 %) after the combined treatment. HbA1C levels were maintained at below 8 % with insulin for all patients (100 %), and no additional medical or surgical intervention for diabetic systemic complications was required during the follow-up period. Mean BCVA was logMAR 0.8 (0.3–1.5) before the enrollment, logMAR 0.6 (0.0–1.5) at 6 months, and logMAR 0.6 (0–1.8) at 12 months (p = 0.0001, p = 0.003 respectively, Wilcoxon) (Fig. 1). During the follow-up, the median CMT of the cases measured by Heidelberg Spectralis OCTTM were 575 (502–1049) lm before the combined injection, 370 (179–983) lm at 6 months and 410 (198–929) lm at 12 months (p = 0.0001; p = 0.0001, respectively, Wilcoxon) (Fig. 2). There was no statistically significant difference between the BCVA and CMT measurements at 6 and 12 months (p = 0.87; p = 0.54, respectively, Wilcoxon). At 6 months, 13 (52 %) patients had stabilized vision (according to baseline BCVA to remain in the range of ± 0.2 logMAR) and 12 (48 %) patients showed visual improvement (C0.2 logMAR). At 12 months, 10 (40 %) patients had stabilized vision, 13 (52 %) patients showed visual improvement, and two (8 %) had visual loss. At 6 months, 18 (72 %) patients had anatomic stabilization (CMT less than 50 % of the initial value) and seven (28 %) patients achieved anatomical success (a reduction in baseline CMT more than 50 % or 250 microns or lower CMT). At 12 months, 13 (52 %) patients had anatomic stabilization, 10 (40 %) patients, anatomic success, and two (8 %) patients had anatomical failure. There was a moderate correlation between the changes in logMAR BCVA and the changes in CMT values at 6 months(r = 0.53, p = 0.31, Spearman test) and at 12 months(r = 0.42, p = 0.16, Pearson test). The mean IOP (18.32 ± 1.54 mmHg) was higher at 12 months compared to baseline IOP (16.12 ± 3 mmHg) (p = 0.003, t test), but was still within normal limits. No additional glaucoma medication was required. Corneal paracentesis was safely
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Fig. 1 Change in BCVA at 12 months *Friedman test, **Wilcoxon test
Fig. 2 Change in CMT at 12 months *Friedman test **Wilcoxon test
applied within 3 min of the post-injection period in 6 (11 %) eyes (not shown in the table). Nine (12 %) patients with increased IOP ([10 mmHg from
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baseline) requiring glaucoma medication before enrollment in this study were kept under control with topical medications (dorzolamide hydrochloride-
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timolol maleate ophthalmic solution, CosoptTM) during the follow-up period. Two of these cases required additional medication (Brimonidine tartrate ophthalmic solution, Alphagan-PTM) after enrollment. None required glaucoma surgery and no additional complication occurred.
Discussion The results of this study have shown that combined treatment of IVB plus IVT might have some beneficial effect in the treatment of severe DME refractory to previous intravitreal monotherapies. There was a moderate correlation of functional outcomes with anatomical outcomes in this study. A significant therapeutic effect from monotherapies with IVT and anti-VEGF agents on DME has been shown in different clinical trials [12–15]. However, anatomical and functional success rates or correlations between them have not been maintained in long-term followups [12–15]. Tsilimbaris et al. showed that the primary use of a combination of IVB and triamcinolone in cases with DME may respond favorably [16]. Others have reported that combined treatment had no more effect than monotherapy [15, 17]. The combined treatment in the current study was administered to a selected group of patients with NPDR, associated with severe DDME and refractory to previous successive intravitreal monotherapies. The current study differs from previous studies in that both therapeutic agents, IVB and IVT were attempted in both traditional and clinically permissible high doses before the study. This combined treatment protocol provided stabilization of visual acuity in 10 (40 %) eyes and improvement in 13 (52 %) eyes at the end of 12 months. This treatment regimen also decreased CMT effectively below 400 lm which provided the opportunity of performing macular laser to 18 of 25 eyes (72 %). The preference of either IVB or IVT as a first line treatment before enrollment did not affect these results significantly (not shown in the results section). In respect of the results of the 12-month follow-up period of the cases, it can be stated that the combination of these intravitreal drugs may not pose an additional risk of future complications in this population. Better functional and anatomical outcomes in this study population might also be related to the patient demographics including HbA1C levels,
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treatment naı¨ve status in respect of grid/focal laser treatment before the enrollment, and the inclusion of non-ischemic cases. On the other hand, there is uncertainty of the risk of cataract formation due to the study design (all had pseudophakic eyes). It was also noted that in some patients, FA was needed but there was no evidence of macular ischemia due to this treatment regimen. In literature, the combination of photo laser coagulation, intravitreal steroids or VEGF-inhibitors, or both, has shown early compelling evidence that some patients may benefit from less re-treatment compared to monotherapy [6]. As indicated in the RESTORE study, combined treatment was followed by grid/focal laser in this study [18]. Although the visual outcomes in the 18 eyes to which grid laser could be added to the combined treatment did not show any significant difference, the small number of cases with short-term follow-up in this study prevents any judgement about the additive effect of grid/focal laser in this study. In a study by Hauser et al., a 4 mg dose of IVT was shown to be no more effective than 1 or 2 mg in eyes with cystic DME [19]. Therefore, in future studies it may be reasonable to investigate the effect of 2 mg instead of 10 mg IVT, in combined treatment as suggested by Folgosa et al. [20]. The current study suggests that the combination of IVB and IVT may still be a valid treatment option in refractory severe DDME. This beneficial effect might be due to substantial activation of well-known antiinflammatory/antiangiogenic pathways [21–23]. Repeated intravitreal high-dosage injections of 20 mg IVT have been shown to be safe, and no tachyphylaxis has been detected in a comparative study [24]. The beneficial effect of combined treatment in this study might also be related to the prevention of tachyphylaxis shown in IVB injections [25]. Systemic control of the patients in the current study was strictly maintained before and during the study period. Therefore, positive beneficial effect of this combination cannot be attributed to decrease of systemic/local risk factors in this study period. Recent studies have suggested that ranibizumab should be considered as the first treatment option in DDME [26, 27]. Although other studies comparing bevacizumab to ranibizumab are not conclusive, head to-head comparison is needed in this regard [28]. Therefore, there is a possibility that the use of ranibizumab instead of bevacizumab might alter the results obtained in this study.
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Limitations to this study include that the study design did not permit any conclusions on the safety concerns of IVB and IVT. In addition, the relatively short follow-up time, numbers, and patient selection (pseudophakos) created some bias in the results. To prevent bias on the therapeutic effect of intravitreal agents, only those who had no macular focal/grid during the follow-up were included. Currently wellknown adverse effects including cataracts and glaucoma from IVT injections cannot be disregarded in this context. It was observed that IOP changes could be manageable in these pseudophakic eyes and no other safety concern emerged from these patients. The retrospective design of the study created bias especially on the treatment strategy selected. In addition, the definition of a refractory case was based mainly on OCT-based criteria. Strict criteria were used for inclusion and exclusion and well-known measures for evaluating the outcomes in the selected group of patients to prevent bias. Combined IVB plus IVT injection was found to be a plausible option in the management of chronic DDME in cases unsuitable for laser treatment and refractory to the current intravitreal monotherapies. Further prospective, controlled clinical studies on larger patient populations are required to confirm the efficacy of IVB plus IVT injections applied to severe DDME, refractory or resistant to previous intravitreal monotherapies. Conflict of interest None of the authors have any conflict of interest with the submission.
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