Microsoft Word - Mazarul Hassan 122 Original Article Randomised Controlled Trial to evaluate the effects of Intravitreal Bevacizumab adminis- tration on Visual Outcome in Diabetic Patients with Diabetic Macular Edema who Underwent Cataract Surgery Mazhar ul Hassan, P.S Mahar, Aziz ur Rehman, Nasir Bhattt, Asfandyar Asgahr, Ashraf Daud Pak J Ophthalmol 2010, Vol. 26 No. 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . See end of article for authors affiliations …..……………………….. Correspondence to: Mazhar ul Hasan Isra Postgraduate Institute of Ophthalmology Al-Ibrahim Eye Hospital Malir, Karachi Received for publication September 2009 …..……………………….. Purpose: To evaluate the efficacy of a single intravitreal Bevacizumab injection either immediately after cataract surgery or during cataract surgery for the management of postoperative decrease of vision in patients with DME. Material and Methods: Randomized, controlled, open-label, parallel group study of 60 eyes of 60 patients, having diabetic macular edema and lens opacity (of more than grade 3). The primary end-point was change in BCVA at 6 weeks compared with that at baseline using the Snellens acuity testing charts. Results: The mean changes in BCVA at 6 weeks compared with that at baseline were a worsening of visual acuity in the control group (no injection) and an improvement of visual acuity in the Bevacizumab group (p = 0.01). Conclusions: Intravitreal Bevacizumab after cataract surgery appears to be beneficial in preventing post- surgical visual loss in eyes with diabetic retinopathy by reducing the chance of macular thickening. any studies have revealed that visual outcome following cataract surgery in diabetic patients depends primarily on the status of macular edema1,2 or Macular ischemia due to diabetes). Previous reports have described many diabetic patients who developed severe maculopathy, following cataract surgery3. Since it is important to be able to predict long-term visual effects before cataract surgery is performed, surgeons need to have a better understanding of the natural course of diabetic macular edema in addition to diabetic retinopathy (DR) after cataract surgery. Diabetic macular edema has been shown to worsen after cataract surgery,4-6 although controversy remains as to the incidence of this worsening7,8. It has also been suggested that macular edema tends to show actual worsening in eyes afflicted with DR at the time of cataract surgery9. Distinguishing transient edema from substantial progression of maculopathy is impor- tant to the timing of treatment for the macular edema, including laser photocoagulation,10 vitrectomy,11 and triamcinolone injection12-14. H owever, until recently, there had been no quantitative study to examine the progression of diabetic macular edema after cataract surgery. A recent study described by Kim et al15 showed a short-term increase of macular thickness after cataract surgery. It has been suggested that 22% of diabetic patients develop increases in central retinal thickness after uncomplicated phaco-emulsification. The presence of CSME is a strong risk factor for subsequent macular thickening after surgery15. Even if the visual prognosis is improved by cataract surgery, macula edema remains a major risk factor for postoperative visual disturbance in diabetic patients. M 123 Treatment to lessen the risk of postoperative macular thickening in individuals with diabetes, laser photocoagulation remains the standard approach16. However, it is sometimes difficult to obtain the sufficient efficacy of laser treatment in the cases with dense cataract. Several other trials using intravitreal or sub-tenon’s triamcinolone acetonide17 and pars plana vitrectomy11 have been conducted, but no widely accepted technique has yet been established. Vascular endothelial growth factor (VEGF), is considered a key player in the progress of abnormal angiogenesis including DME18. Hypoxia induces VEGF gene transcription, and elevated levels of VEGF have been found in ocular fluid of patients with DME19. Bevacizumab is a humanized monoclonal antibody that inhibits all isoforms of VEGF20. It has been reported that intravitreal injection of bevacizumab yields promising results in various neovascular eye diseases, including age-related macular degeneration,21 central retinal vein occlusion,22 and DME23. Similar study was carried out by Lanzagorta et al24 who have shown improvement in the vision and decrease in the retinal thickening in the Bevacizumab group compared to control group. MATERIAL AND METHODS Study Design This trial was a randomized, controlled, open-label, parallel group study. Patients were recruited from the Al Ibraheem Eye Hospital between July 2008 and July 2009. The trial was conducted in conformance with the tenets of the Declaration of Helsinki. Approval was obtained from the Ethics Committee at the Al Ibraheem Eye Hospital, Karachi and each patient provided signed informed consent before study entry. Subject Selection Patients 20 years or older of either gender with type 1 or type 2 diabetes were eligible. All patients in the study underwent a complete ophthalmic examination, including best-corrected visual acuity (BCVA), slit- lamp biomicroscopy, funduscopy, applanation tonometry and fluorescein angiography (not more than a week old, other wise it was repeated) before recruitment, (because of the unavailability of optical coherence tomography in our institute we were unable to perform this test on all patients, only on few patients who were able to go to other centers for this test were performed); 60 patients with DME, who had significant lens opacity (more than grade 3 for any type of cataract: cortical, nuclear, or posterior sub capsular) by the Lens Opacities Classification System III were recruited for the study25. Other inclusion criteria were that DME had occurred 3 to 18 months earlier, macular edema involved the fovea, and best corrected visual acuity (BCVA) was 20/40 or worse. Exclusion criteria were a history of ocular surgery, inflammation and poor diabetic control, the presence of other ocular diseases, and intra-operative complications such as posterior capsule rupture and severe iris damage. Eyes with proliferative diabetic retinopathy, mixed maculopathy (ischemic and exudative) and also patients having DME due to Epi- retinal membrane or taut posterior hyaloid were also excluded. No patients had undergone photocoagu- lation of the treated eye within the previous 12 months, and none did so during follow-up. There was no previous intravitreal injection, including any VEGF inhibitors or steroid. Randomization and Masking Eyes were allocated to one of two groups (Bevacizumab or control). Neither subjects nor investigators were masked, but those who tested visual acuity, optometrists and statistical analyzers were masked as to treatment assignment of the eyes. Study Treatment The operative techniques included complete continuous curvilinear capsulorhexis and phacoemu- lsification through a 3.5-mm corneoscleral incision with intracapsular implantation of a foldable acrylic intraocular lens followed by a single intravitreal injection of bevacizumab. Bevacizumab was prepared by the institutional pharmacy as sterile filled and packed tuberculin syringes containing 0.05 ml (1.25 mg) bevacizumab, which was injected intra-vitrealy using a 30-gauge needle. Postoperatively, all patients received similar routine medication, including topical application of diclofenac sodium, an antibacterial agent, and 0.1% prednisolone 3 times daily for 3 months after surgery. Eyes in the control group received no injections. Outcome Measurements and Follow-up The primary end-point of the trial was a change in BCVA at 6 weeks follow-up, compared with that at baseline. BCVA was assessed by Snellen visual acuity chart. Similarly, resolution in macular edema in fluorescein angiography compared to baseline. 124 Patients were evaluated at baseline and at 1, 3 and 6 weeks. BCVA, intraocular pressure (IOP), slit-lamp assessment and indirect ophthalmoscopic examination performed at each visit; fluorescein angiography was performed at baseline and 6 weeks follow-up. Sample Size 30 eyes (assuming a few dropouts) in each group were required to achieve a power of 80% based on an unpaired Student t test with a two-sided significance level of 0.05. Statistical Analysis Values are expressed as mean (SD). The significance of the differences between the intervention group and the control group data was assessed by the unpaired Student t test, and that between the pretreatment and post-treatment data within the same group was assessed by the paired Student t test. All statistical analyses were performed SPSS 17.0. A p value of less than 0.05 was considered to be statistically significant. RESULTS The study was performed at Al Ibrahim Eye Hospital, Karachi. During the study period, total 60 eyes of 60 patients were examined. All the patients fulfilled the inclusion and exclusion criteria. Out of 60 patients 32 (53.3%) were males and 28 (46.7%) were females (Table 1). Age range of patients was 45-83 years. Mean age of the patients was 58.3 years with standard deviation=7.35. Table 2 shows the distribution of Bevacizumab and control group. There were no significant differences between the groups (Bevacizumab and control) in age, gender and duration of DM, indicating that the baseline characteristics were well balanced. Also, there were no statistically significant differences in BCVA at the baseline. To evaluate postoperative changes we measured it at 1 day before and 1 and 6 weeks after cataract surgery. Preoperative visual acuity is shown in (Table 3). Postoperative visual acuity shows that there has been statistically significant difference between the Bevacizumab and control group (p<0.005). Most of the patients in Bevacizumab group had postoperative visual acuities above 6/18 with 27 out of 30 having either 6/12 or better compared to only 6 out of 30 in control group having 6/12 or better visual acuity. On the other hand none of the patients in Bevacizumab group had visual acuity lesser than 6/18 while control group has 11 patients having visual acuity lesser than 6/18 (Table 4, 5). Changes in DME between the two groups (on the basis of fluorescein angiography) is shown in figure 1. Table 1: Gender distribution Frequency n (%) Male 32 (53.3) Female 28 (46.7) Total 60 (100) Table 2: Control or bevacizumab group Frequency n (%) Bevacizumab group 30 (50) Control group 30 (50) Total 60 (100) Table 3: Preoperative vision Frequency n (%) 6/24 2 (3.3) 6/36 21 (35) 6/60 28 (46.7) Fc 8 (13.3) Hm 1 (1.7) Total 60 (100) Table 4: Post operative vision Frequency n (%) 6/6 20 (33.3) 6/9 13 (21.7) 6/12 8 (13.3) 6/18 8 (13.3) 6/24 5 (8.3) 6/36 2 (3.3) 6/60 4 (6.7) Total 60 (100) 125 Table 5: Post operative vision in control group vs bevacizumab group Visual acuity Bevacizumab Group (No. of patients) Control Group (No of patients) Total 6/6 18 2 20 6/9 9 4 13 6/12 2 6 8 6/18 1 7 8 6/24 -- 5 5 6/36 -- 2 2 6/60 -- 4 4 Total 30 30 60 0 5 10 15 20 25 Contr… Bevac… Decrease in DME Increase in EME No changes Fig. 1: (Changes in DME in both groups) DISCUSSION Many studies have revealed that intravitreal injection of bevacizumab is useful in the management of DME23,26. Similarly studies have shown that cataract surgery leads to noticeable thickening of retina, implying that operative invasion enhances retinal vascular permeability, because localized retinal edema is caused by focal leakage from microaneurysms and dilated capillary segments27. Many inflammatory mediators such as VEGF cause breakdown of the blood– retinal barrier28,29. Patel et al30 reported that VEGF levels in aqueous sample obtained from DM patients 1 day after surgery were approximately 10- fold higher than those of controls. Bevacizumab inhibits VEGF, which is a potent permeability factor implicated in cystoid macular edema (CME)29. Thus, we hypothesized that anti-VEGF therapy would help to prevent the development of macular edema after cataract surgery in DM patients. Similar work was carried out by Lanzagorta et al,24 who have shown improvement in the vision and decrease in the retinal thickening in the Bevacizumab group compared to control group. Recently, many studies have shown the clinical effect of intravitreal bevacizumab for pseudophakic CME31–33. Mason et al31 reported on 2 patients with persistent CME who had been effectively treated with bevacizumab, and both eyes showed noticeable improvement of VA. Similarly, another study, 25 cases of pseudophakic CME after cataract Surgery were investigated, and found a significant improvement in vision and a decrease in macular thickness32. However, unlike these studies, Spitzer et al33 reported that although 81% of patients showed significant improvement in central retinal thickening, visual outcome was not evidently improved. Therefore, the clinical effectiveness of intravitreal bevacizumab for pseudophakic CME remains controversial. These case series excluded diabetic patients, and there were several weeks (approximately 13 weeks) between the day of cataract surgery and intravitreal bevacizumab therapy. In contrast, we injected bevacizumab into the vitreous cavity on the same day as the cataract surgery, immediately after intraocular lens implantation. Our data suggested that the intravitreal injection of bevacizumab was effective in improving vision after cataract surgery in patients having diabetic macular edema. Based on our results, intravitreal injection of bevacizumab improved BCVA more effectively. The natural course of macular edema after cataract surgery can be self-limiting in some diabetic patients34. In fact, the increased retinal thickening at first month tended to show a decrease at third month. This incidence was consistent with the results of intravitreal triamcinolone for DME35,36. Among the new treatments, such as corticosteroid and anti-VEGF, drugs, laser photocoagulation remains the standard and the only treatment with proven efficacy in a large clinical trial10, 16. Even though we report the effectiveness of bevacizumab, the application of photocoagulation should be considered for the treatment of DME in most of cases with the exception of the dense cataract. The dose of bevacizumab evaluated in this study was 1.25 mg, which is that used most commonly in clinical practice21–26. However, because no dose- ranging studies were done, the ideal intravitreal concentration remains to be determined. Recurrence of 126 CME is a possibility and may require additional multiple injections of bevacizumab. Although there was no case of recurrent CME in our series, the long- term efficacy is also currently unknown. In the present study, the change in BCVA at 6 weeks compared with that at baseline (primary end- point) in the Bevacizumab group was statistically significantly less than that in the control group. One of the limitations of the study described herein is the use of an observation arm as control, rather than a sham injection, thereby making it impossible to ensure that the patient and investigators were masked with regard to treatment. However, this limitation was mitigated by ensuring that the technicians who performed the visual-acuity were masked. Other limitations of this study are that it was performed at a single centre, and that it involved individuals of only one race, factors that limit its generalizability. Although further investigation with a longer follow-up and a larger series of patients may be needed, anti-VEGF therapy may be a potent tool for the treatment of DME after cataract surgery. Bevacizumab contributed to the significant improvement of VA after cataract surgery at 6 weeks. Although a longer follow-up is needed, it is possible that intravitreal bevacizumab has the potential not only to prevent the progression of DME after cataract surgery, but also to improve its severity. Several reports have indicated that intravitreal or posterior sub-Tenon triamcinolone acetonide, or corticosteroid treatment, is also effective for reducing macula thickness in DME37–40. Shimura et al41 compared the effect of an intravitreal injection of bevacizumab with triamcinolone acetonide for DME, and found that the triamcinolone treatment yielded better results in terms of macular thickness reduction and improvement of VA41. However, they also found a significant postoperative increase of IOP in the triamcinolone injected eyes, whereas the bevacizumab-treated eyes showed no significant change. Because one of the most important side effects of triamcinolone treatment is elevation of the IOP, bevacizumab may be beneficial for patients who are known steroid responders and who are unresponsive to non-steroidal anti- inflammatory drugs. In our small case series, there was not significant increase of IOP postoperatively, and no eyes showed infection and other severe ocular complications. However, a larger number of cases are needed to verify the safety of bevacizumab treatment. In summary intravitreal bevacizumab immedi- ately after phacoemulsification or during the cataract surgery prevents exacerbation of the macular edema seen in many diabetic patients undergoing cataract surgery. Results of our study show that patients who have diabetic macular edema before undergoing the cataract surgery, should receive an intravitreal injection of bevacizumab either during the cataract surgery or immediately after it, to improve visual outcome after cataract surgery and to prevent decrease in vision due to increase in macular edema after cataract surgery. Author’s affiliation Dr. Mazhar ul Hassan Assistant Professor Isra Postgraduate institute of Ophthalmology Al – Ibrahim Eye Hospital, Malir, Karachi Prof. P.S Mahar Isra Postgraduate Institute of Ophthalmology Al – Ibrahim Eye Hospital, Malir, Karachi Dr. Aziz ur Rehman Isra Postgraduate Institute of Ophthalmology Al – Ibrahim Eye Hospital, Malir, Karachi Dr.Nasir Bhattt Isra Postgraduate Institute of Ophthalmology Al – Ibrahim Eye Hospital, Malir, Karachi Dr. Asfandyar Asgahr Isra Postgraduate Institute of Ophthalmology Al – Ibrahim Eye Hospital, Malir, Karachi Dr. Ashraf Daud Isra Postgraduate Institute of Ophthalmology Al – Ibrahim Eye Hospital, Malir, Karachi REFERENCE 1. Joussen AM, Smyth N, Niessen C. Pathophysiology of diabetic macular edema. Dev Ophthalmol. 2007; 39: 1–12. 2. Zaczek A, Olivestedt G, Zetterstrom C. Visual outcome after phacoemulsification and IOL implantation in diabetic patients. Br J Ophthalmol. 1999; 83: 1036–41. 3. Benson WE, Brown GC, Tasman W, et al. Extracapsular cataract extraction with placement of a posterior chamber lens in patients with diabetic retinopathy. Ophthalmology. 1993; 100: 730–8. 4. Dowler JGF, Sehmi KS, Hykin PG, et al. The natural history of macular edema cataract surgery in diabetes. Ophthalmology. 1999; 106: 663–8. 5. Dowler JGF, Hykin PG, Hamilton AMP. Phacoemulsification versus extracapsular cataract extraction in patients with diabetes. Ophthalmology. 2000; 107: 457–62. 6. Funatsu H, Yamashita H, Noma H, et al. Prediction of macular edema exacerbation after phacoemulsification in patients with nonproliferative diabetic retinopathy. J Cataract Refract Surg. 2002; 28: 1355–63. 7. Early Treatment Diabetic Retinopathy Study Research Group. Results after lens extraction in patients with diabetic 127 retinopathy: Early Treatment Diabetic Retinopathy Study report number 25. Arch Ophthalmol. 1999; 117: 1600–6. 8. Squirrell D, Bhola R, Bush J, et al. A prospective, case controlled study of the natural history of diabetic retinopathy and maculopathy after uncomplicated phacoemulsification cataract surgery in patients with type 2 diabetes. Br J Ophthalmol. 2002; 86: 565–571. 9. Henricsson M, Heijl A, Janzon L. Diabetic retinopathy before and after cataract surgery. Br J Ophthalmol. 1996; 80: 789–93. 10. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985; 103: 1796–1806. 11. Tachi N, Ogino N. Vitrectomy for diffuse macular edema in cases of diabetic retinopathy. Am J Ophthalmol. 1996; 122: 258- 60. 12. Jonas JB, Sofker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am J Ophthalmol. 2001; 132: 425–7. 13. Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002; 109: 920–7. 14. Jonas JB, Kreissig I, Sofker A, et al. Intravitreal injection of triamcinolone for diffuse diabetic macular edema. Arch Ophthalmol. 2003; 121: 57–61. 15. Kim SJ, Equi R, Bressler NM. Analysis of macular edema after cataract surgery in patients with diabetes using optical coherence tomography. Ophthalmology. 2007; 114: 881–9. 16. Writing Committee for the Diabetic Retinopathy Clinical Research Network. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol. 2007; 125: 469–80. 17. Conway MD, Canakis C, Livir-Rallatos C, et al. Intravitreal triamcinolone acetonide for refractory chronic pseudophakic cystoid macular edema. J Cataract Refract Surg. 2003; 29: 27–33. 18. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004; 25: 581–611. 19. Funatsu H, Yamashita H, Nakamura S, et al. Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor are related to diabetic macula edema. Ophthalmology. 2006; 113: 294–301. 20. Ferrara N, Hillan KJ, Gerber HP, et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004; 3: 391–400. 21. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006; 113: 363–72. 22. Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina. 2006; 26: 279– 84. 23. Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, et al. Pan- American Collaborative Retina Study Group. Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: results from the Pan-American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology. 2007; 114: 743– 50. 24. Lanzagorta-aresti A, Palacios-Pozo E, Menezo Rozalen JL, et al. Prevention of vision loss after cataract surgery in diabetic macular edema with intravitreal bevacizumab: a pilot study. Retina. 2009. 29: 530-5. 25. Chylack LT Jr, Wolfe JK, Singer DM, et al. Longitudinal Study of Cataract Study Group. The Lens Opacities Classification System III. Arch Ophthalmol. 1993; 111: 831-6. 26. Diabetic Retinopathy Clinical Research Network. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology. 2007; 114: 1860-7. 27. Cunha-Vaz JG. Studies on the pathophysiology of diabetic retinopathy: the blood-retinal barrier in diabetes. Diabetes. 1983; 32: 20-7. 28. Stern AL, Taylor DM, Dalburg LA, et al. Pseudophakic cystoid maculopathy: a study of 50 cases. Ophthalmology. 1981; 88: 942– 6. 29. Qaum T, Xu Q, Joussen AM, et al. VEGF-initiated bloodretinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci. 2001; 42: 2408–13. 30. Patel JI, Hykin PG, Cree IA. Diabetic cataract removal: postoperative progression of maculopathy-growth factor and clinical analysis. Br J Ophthalmol. 2006; 90: 697–701. 31. Mason JO III, Albert MA Jr, Vail R. Intravitreal bevacizumab (Avastin) for refractory pseudophakic cystoid macular edema. Retina. 2006; 26: 356–7. 32. Arevalo JF, Garcia-Amaris RA, Roca JA, et al. Pan-American Collaborative Retina Study Group. Primary intravitreal bevacizumab for the management of pseudophakic cystoid macular edema: pilot study of the Pan-American Collaborative Retina Study Group. J Cataract Refract Surg. 2007; 33: 2098-105. 33. Spitzer MS, Ziemssen F, Yoeruek E, et al. Efficacy of intravitreal bevacizumab in treating postoperative pseudophakic cystoid macular edema. J Cataract Refract Surg. 2008; 34: 70–5. 34. Kim SJ, Equi R, Bressler NM. Analysis of macular edema after cataract surgery in patients with diabetes using optical coherence tomography. Ophthalmology. 2007; 114: 881-9. 35. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008; 115: 1447–59. 36. Diabetic Retinopathy Clinical Research Network. Randomized trial of peribulbar triamcinolone acetonide with and without focal photocoagulation for mild diabetic macular edema: a pilot study. Ophthalmology. 2007; 114: 1190–6. 37. Jonas JB, Kreissig I, Söfker A, et al. Intravitreal injection of triamcinolone for diffuse diabetic macular edema.Arch Ophthalmol. 2003; 121: 57–61. 38. Sutter FK, Simpson JM, Gillies MC. Intravitreal triamcinolone for diabetic macular edema that persists after laser treatment:three-month efficacy and safety results of a prospective, randomized, double-masked, placebo-controlled clinical trial. Ophthalmology. 2004; 111: 2044–9. 39. Massin P, Audren F, Haouchine B, et al. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology. 2004; 111: 218–24. 40. Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002; 109: 920–7. 41. Shimura M, Nakazawa T, Yasuda K, et al. Comparative therapy evaluation of intravitreal bevacizumab and triamcinolone acetonide on persistent diffuse diabetic macular edema. Am J Ophthalmol. 2008; 145: 854–61.