Int Ophthalmol DOI 10.1007/s10792-013-9875-7
ORIGINAL PAPER
The effect of intravitreal bevacizumab injection before Ahmed valve implantation in patients with neovascular glaucoma Jung Youb Kang • Ki Yup Nam • Sang Joon Lee Seung Uk Lee
•
Received: 30 May 2013 / Accepted: 21 October 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract To evaluate the effect of intravitreal bevacizumab (IVB) before Ahmed valve implantation for treatment of neovascular glaucoma (NVG). This study is a retrospective, comparative, consecutive case series. The study group consisted of 27 eyes of 26 patients with NVG who underwent an Ahmed valve implantation. Thirteen eyes were treated with Ahmed valve implantation alone (control group), and 14 eyes were treated with a combination of preoperative IVB injection and Ahmed valve implantation (IVB group). Visual acuity, intraocular pressure (IOP), number of anti-glaucoma medications, surgical complications, and success rate were compared between the two groups. There were no significant differences in preoperative characteristics between the two groups. Visual acuity at 1, 2 weeks, and 1 month after surgery were significantly better in the IVB group (p = 0.038, 0.034, and 0.032, respectively). Hyphema associated with Ahmed valve implantation occurred significantly less in the IVB group (p = 0.016). On the other hand, the mean IOP and number of anti-glaucoma medications at all follow-up periods were similar between the J. Y. Kang K. Y. Nam S. J. Lee S. U. Lee (&) Department of Ophthalmology, College of Medicine, Kosin University, 34 Amnam-dong, Seo-gu, Busan 602-702, Republic of Korea e-mail: [email protected] S. J. Lee Department of Ophthalmology and Visual Science, Univeristy of Louisville, Louisville, KY, USA
two groups. Kaplan–Meier survival analysis showed the probability of success 6 months after surgery as 71.4 % in the IVB group and 84.6 % in the control group. No significant difference in success rate was found between the groups (p = 0.422). IVB before Ahmed valve implantation for treatment of NVG reduced the incidence of hyphema. In this retrospective study, IVB provided better visual outcome in the early postoperative periods but did not significantly improve mean IOP, number of anti-glaucoma medications, or success rate. Keywords Ahmed valve implantation Bevacizumab Neovascular glaucoma Refractory glaucoma
Introduction Refractory neovascular glaucoma (NVG) represents a surgical challenge to glaucoma specialists. In most patients with refractory NVG who have uncontrolled intraocular pressure (IOP) despite treatment (laser or glaucoma medication), surgical procedures such as trabeculectomy and aqueous shunting surgery have been performed. Neovascularization is highly correlated with ischemic retinal disorders including proliferative diabetic retinopathy, central retinal vein occlusion, and ocular ischemic syndrome [1]. Several mediators are involved in intraocular neovascularization. Vascular
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endothelial growth factor-A (VEGF-A), an endothelial cell-specific mitogen, is a key molecule among these mediators [2]. Bevacizumab (Avastin; Genentech, South San Francisco, CA, USA) is a recombinant antibody against VEGF-A approved for treatment of colorectal cancer [3]. Recently, bevacizumab has been widely applied for treatment of macular edema and neovascular age-related macular degeneration because of its marked reduction of neovascular activity and vascular permeability in ocular tissue [4, 5]. In addition, there have been several reports of bevacizumab being used for adjunctive treatment of patients with NVG. Intravitreal bevacizumab (IVB) injection has been reported to reduce iris rubeosis and IOP [6–11]. Patients with refractory NVG who have uncontrolled IOP may need urgent surgical intervention. Some NVG patients have already received IVB injections. In patients who did not receive IVB injections, preoperative bevacizumab injection is possible during preoperative preparation. Although many reports and studies have been published about IVB injections and its relationship to Ahmed implantation, there is little definitive evidence that preoperative bevacizumab is beneficial for Ahmed valve implantation. In this retrospective study, we compared the visual acuity, IOP, number of anti-glaucoma medications, success rate, and complications of Ahmed valve implantation with and without preoperative bevacizumab injection in patients with refractory NVG.
Methods Patients We performed a retrospective chart review. Patients who underwent Ahmed valve implantation were consecutively recruited from January 2001 to December 2011 at the Gospel Hospital in Busan, Korea. Patients with intractable NVG who received Ahmed valve implantation because of high IOP (C22 mmHg) even after maximizing anti-glaucoma medications were included. Considering the pharmacokinetics of bevacizumab, patients who received IVB injection within 4 weeks of their Ahmed valve implantation were also included. Patients with other retinal diseases that did not cause NVG and patients with other
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glaucoma diseases (primary open-angle glaucoma, angle closure glaucoma, etc.) were excluded. Furthermore, patients that were lost to early follow-up (\6 months) were also excluded. The study cohort was divided into two groups—the preoperative IVB injection group (IVB group) and the Ahmed valve implantation without bevacizumab injection group (control group). Visual acuity, IOP, number of anti-glaucoma medications, success rate, and surgical complications were determined by chart review. Defining surgery as time zero, each patient was evaluated at 1 day, 1, 2 weeks, 1, 3, and 6 months after surgery. Visual acuity, IOP, complications, and number of antiglaucoma medications were investigated, assessed, and recorded at each visit. Surgical technique Between January 2001 and May 2007, Ahmed valve implantation was carried out without IVB (control group). After May 2007 when the use of bevacizumab began in our clinic, IVB before Ahmed valve implantation was initiated with patient consent in those who did not have contraindications to bevacizumab (IVB group). After topical anesthesia with 0.5 % proparacaine hydrochloride and disinfection with povidoneiodine, bevacizumab at a dosage of 1.25 mg/0.05 ml was injected using a 1-cc syringe with a 30-gauge (G) needle into the vitreous cavity through the pars plana at a position 3.5 mm posterior to the corneal limbus. Patients were then treated with topical 3 mg/ 1 ml gatifloxacin. Ahmed valve implantation was performed between 1 and 20 days after IVB. All the patients were treated with an identical surgical procedure performed by two surgeons (SDK and SJL). For Ahmed glaucoma valve implantation, a fornix-based conjunctival flap was created, and Tenon’s capsule was dissected. The tube of the Ahmed valve was irrigated with a balanced salt solution to prime the valve. The plate was secured to the sclera in the superotemporal quadrant 8–9 mm posterior to the surgical limbus. An entrance site into the anterior chamber was made with a 23-G needle. The tube of the valve was then passed through this 23-G needle track into the anterior chamber. The tube was anchored to the sclera. The conjunctival and Tenon’s capsule incisions were closed at the limbus.
Int Ophthalmol
Surgical outcomes
Statistical analysis
Visual acuity, IOP, number of anti-glaucoma medications, success rate, and surgical complications after Ahmed valve implantation were the primary outcomes of interest. We defined visual acuity as any improvement or deterioration from the preoperative visual acuity. A logarithm of the reciprocal of the decimal visual acuity was used to approximate the logarithm of the minimal angle of resolution (logMAR). Eyes without form vision were classified into one of four low-vision categories, which were assigned decimal equivalents as follows—counting finger = 0.005, hand motions = 0.0025, light perception = 0.00125, and no perception of light (NPL) = 0.0001 [12]. Surgical success and failure were defined before data analysis. Surgical success was defined as an IOP B21 mmHg with or without anti-glaucoma medication, and maintenance of visual acuity of light perception or better (except when preoperative visual acuity was NPL). Surgical failure was defined as an IOP C22 mmHg at two consecutive follow-up visits, or when additional glaucoma surgery was needed. Postoperative use of anti-glaucoma medication was not a criterion of success or failure.
All data were analyzed with the PASW Statistics 18 (SPSS Inc, Chicago, IL, USA). The success rate was analyzed using a log-rank test. Preoperative patient data, postoperative complications, postoperative change in visual acuity, IOP, and number of anti-glaucoma medications were compared between the two groups with the Fisher exact, Chi squared, and Mann–Whitney U tests. A p value of\0.05 was considered statistically significant.
Results Baseline characteristics A total of 27 eyes of 26 patients were included in the study. Fourteen eyes received Ahmed valve implantation with preoperative IVB injection (IVB group), and 13 eyes received only Ahmed valve implantation without preoperative IVB injection (control group). Table 1 shows the baseline characteristics of the two groups. There were no significant differences between the two groups in all categories, including preoperative visual acuity, preoperative IOP, and anti-glaucoma medication used before surgery.
Table 1 Baseline characteristics of the two study groups
IVB group (n = 14)
Control group (n = 13)
p*
0.72
Age (years), mean ± SD
54.8 ± 13.0
54.3 ± 10.8
Sex (male/female)
11/3
11/2
1.0
Eye (right/left) Etiology of NVG
7/7
7/6
0.85 0.53
12
9
Diabetes mellitus Central retinal vascular occlusion
1
2
Others
1
2
Phakia
6
7
Pseudophakia
8
3
Aphakia
0
3
Lens status
0.38
Earlier panretinal photocoagulation laser
11
8
0.68
Preoperative IOP (mmHg), mean ± SD
40.2 ± 11.3
44.7 ± 9.0
0.22
PRP panretinal photocoagulation
Number of preoperative anti-glaucoma medications, mean ± SD
2.2 ± 0.7
2.4 ± 0.9
0.62
* p value by Mann– Whitney test, Chi squared test, Fisher’s exact test
Preoperative visual acuity (logMAR), mean ± SD
2.81 ± 0.63
2.57 ± 1.03
0.93
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IOP The preoperative mean IOP was 40.2 ± 11.3 mmHg in the IVB group and 44.7 ± 9.0 mmHg in the control group (p = 0.22 by Mann–Whitney test). Compared to preoperative IOP, the two groups showed a statistically significant IOP decrease at all postoperative time points (p \ 0.05 by Wilcoxon signed-rank test). The differences in mean IOP between the two groups were not statistically significant at any followup period (Fig. 1). Number of anti-glaucoma medications The mean number of medications was 2.2 ± 0.7 in the IVB group and 2.4 ± 0.9 in the control group (p = 0.62 by Mann–Whitney test). Compared with the preoperative number of medications, both groups showed a statistically significant difference in the number of medications at all postoperative time points (p \ 0.05 by Mann–Whitney test). At each time point, however, the difference between the mean number of medications in the two groups was not statistically significant (Fig. 2). Surgical complications A comparison of surgical complications between the IVB group and the control group is shown in Table 2. Hyphema was the most frequent complication, and it occurred only in the control group (p = 0.02). As for the other complications, there were relatively small differences between the two groups, and the differences were not significant. None of the patients had systemic complications related to IVB, such as
Fig. 2 Mean number of anti-glaucoma medications after Ahmed valve implantation in eyes with or without preoperative bevacizumab injection. There was no significant difference between the two groups at any time point
Table 2 Complications in the two groups Complications
IVB group (n = 14)
Control group (n = 13)
p**
0.47
Early postoperative complications Hypotony
1
2
Hyphema
0
5
0.02*
Flat anterior chamber requiring anterior chamber reformation
1
0
0.47
Bleb leak requiring resuture
2
0
0.26
Outflow tract obstruction
2
1
0.26
Choroidal detachment
0
1
0.48
Late postoperative complications Hypotony
0
2
0.22
Implant exposure
2
0
0.26
Evisceration
1
0
0.52
Endophthalmitis
0
0
N/A
Hypotony maculopathy Pthisis
0 0
0 0
N/A N/A
N/A not available * p \ 0.05 ** p value by Fisher’s exact test
anaphylactic shock, severe elevation in blood pressure, cerebrovascular accident, or myocardial infarction during the follow-up period. The probability of success Fig. 1 Mean IOP after Ahmed valve implantation in eyes with or without preoperative bevacizumab injection. The mean IOP decreased in the two groups at all time points compared with preoperative IOP. The mean IOP of the two groups was not statistically significantly different at any follow-up period
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A comparison of the Kaplan–Meier survival curve analysis between the two groups is presented in Fig. 3. The probability of success 6 months after surgery was
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Compared to preoperative data, IVB before Ahmed valve implantation provided a better visual outcome at all postoperative time points (p \ 0.05 by Wilcoxon signed-rank test). Conversely, the control group did not show statistically significant changes in visual acuity at any postoperative time point.
Discussion
Fig. 3 Kaplan–Meier survival curves of surgical outcomes after Ahmed valve implantation for eyes in the IVB group (dotted line) and the control group (solid line). The log-rank test revealed no significant difference in the survival time between the two groups. IVB intravitreal bevacizumab
71.4 % in the IVB group and 84.6 % in the control group. The log-rank test revealed no significant difference in the survival time between the two groups (p = 0.42) (Fig. 3). Visual acuity The preoperative mean visual acuity was logMAR 2.81 ± 0.63 in the IVB group and logMAR 2.57 ± 1.03 in the control group. There was no statistical difference between the two groups (p = 0.93 by Mann–Whitney test). At 1, 2 weeks, and 1 month after surgery, the mean visual acuity of the two groups showed statistically significant differences (Fig. 4).
Fig. 4 Mean visual acuity after Ahmed valve implantation in eyes with or without preoperative bevacizumab injection. *A statistically significant difference in visual acuity between the two groups at 1, 2 weeks, and 1 month
This study evaluated the effects of IVB before Ahmed valve implantation for NVG caused by ischemic retinal diseases. The IOP-reducing effect of bevacizumab injection in eyes with NVG has been demonstrated in some case reports [13–15]. Recent studies have also reported that intraoperative or preoperative IVB injection may contribute to the lowering of IOP after surgery [16, 17]. Yazandi et al. [8] postulated a ‘reversible anatomic closure’ for angle closure of the neovascular membrane. Adjunctive bevacizumab injection for refractory NVG may affect the reversible part of the synechial angle, and this may produce further IOP reduction after Ahmed valve implantation. Unlike these studies, our study showed slightly better IOP reduction in the control group, but there were no significant differences between the two groups in mean IOP at all follow-up periods. To evaluate the IOP-reducing effect of adjunctive bevacizumab injection on refractory NVG, more studies are needed. As shown in Table 2, there are several complications associated with Ahmed valve implantation. Among these complications, hyphema was the most common in the early postoperative period of our study. Hyphema may cause visual disturbance after surgery. Our data revealed that IVB before Ahmed valve implantation reduced hyphema associated with surgery. This reduction may have been caused by regression of new vessels. Previous studies have shown that IVB causes immediate regression of iris and angle neovascularization [18]. In a recent study, neovascular regression was demonstrated by histopathological analysis [19]. Regression of neovascularization before Ahmed valve implantation is beneficial for preventing hyphema in patients with NVG. An earlier study reported that preoperative IVB injection before Ahmed valve implantation improves the success rate [20]. Recent studies are inconclusive about the benefits of combining IVB with this
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operation. Ma et al. [17] reported that intraoperative IVB injection does not seem to improve surgical outcomes after Ahmed valve implantation in NVG. Takihara et al. [16] reported that IVB before trabeculectomy with mitomycin C does not significantly improve surgical outcomes over longer periods in NVG. Takihara postulated that the lack of the improved probability of success might be related to the transient nature of IVB. The pharmacokinetics of bevacizumab in rabbit vitreous suggest that most of the bevacizumab in the aqueous humor is eliminated within 1 month [21]. The effect of neovascular regression persists for 8–10 weeks after IVB [22]; then, iris rubeosis in eyes with IVB returns within 6 months after treatment [23]. In our data, there were no significant differences in the probability of success between the IVB group and the control group at 6 months after Ahmed valve implantation. It is speculated that elimination of the anti-angiogenic effect of IVB might cause the recurrence of neovascularization. The improved probability of success might be achieved by repeat IVB after Ahmed valve implantation. Our data showed statistically significant differences in visual outcomes at early periods (1, 2 weeks, and 1 month) between the IVB and control groups. These differences may be related to the reduction in hyphema. Hyphema would affect visual acuity in the control group until it completely resorbed. Our data also showed that IVB before Ahmed valve implantation provides better visual outcomes at all postoperative time points. There are several possible explanations. First, reduced hyphema by preoperative IVB may have made the surgical procedure easier to perform. Uncomplicated surgery can lead to reduction in operation time and unnecessary manipulation. Thus, a less challenging operation can lead to good surgical results even if it cannot improve the surgical rate. Second, reduced hyphema would have enabled early onset of panretinal photocoagulation (PRP). Early PRP after surgery may stabilize the retina in NVG. Finally, preoperative IVB might have caused a visual-sparing effect due to relief of macular edema. This study had several limitations. First, selection bias was an inevitable factor due to its retrospective nature. To address this bias, we compared the surgical outcomes before the use of bevacizumab with those after the use of bevacizumab. Differences in when Ahmed valve implantation was performed could also
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cause bias due to differences in the surgical procedure; however, the two surgeons did not alter any of the surgical procedures. Additionally, we found no significant differences in the preoperative characteristics that could be a potential prognostic factor between two groups. Therefore, comparison with eyes before the use of bevacizumab provided significant information about the benefits and the limitations of IVB with Ahmed valve implantation for NVG treatment. Second, a 6 month follow-up period may be insufficient to obtain the significant effect of preoperative IVB injection. However, the number of patients with long-term follow-up ([6 months) were too small to obtain statistical results. Another limitation of this study is that we did not strictly standardize IVB protocol. There were various intervals between IVB injection and Ahmed valve implantation (1–20 days). Furthermore, although repeated anti-VEGF injections are a generally accepted dosing scheme, these results may not reflect actual clinical practice. However, there was no necessity for additional bevacizumab injections because none of patients showed recurrence of neovascularization on iris or retinal edema. Further prospective and randomized studies with long-term follow-up and multiple injections would more clearly reveal the effect of intravitreal anti-VEGF on Ahmed valve glaucoma implantation in patients with NVG. In conclusion, IVB before Ahmed valve implantation reduced hyphema. In this study, IVB provided better visual outcomes at early postoperative periods but did not significantly improve the mean IOP, number of anti-glaucoma medications, or success rate. Prospective studies with longer follow-up periods are warranted.
References 1. Brown GC, Magargal LE, Schachat A, Shah H (1984) Neovascular glaucoma. Etiologic considerations. Ophthalmology 91:315–320 2. Funatsu H, Yamashita H, Sakata K et al (2005) Vitreous levels of vascular endothelial growth factors and intracellular adhesion molecule 1 are related to diabetic macular edema. Ophthalmology 112:908–916 3. Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342 4. Rosenfeld PJ, Fung AE, Puliafito CA (2005) Optical coherence tomography findings after intravitreal injection
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of bevacizumab (Avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging 36:336–339 Avery RL, Pieramici DJ, Rabena MD et al (2006) Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 113:363–372 Beutel J, Peters S, Luke M et al (2010) Bevacizumab as adjuvant for neovascular glaucoma. Acta Ophthalmol 88:103–109 Sothornwit N (2008) Intravitreal bevacizumab for Ahmed glaucoma valve implantation in neovascular glaucoma: a case report. J Med Assoc Thai 91:162–165 Yazdani S, Hendi K, Pakaravan M et al (2007) Intravitreal bevacizumab (Avastin) injection for neovascular glaucoma. J Glaucoma 16:437–439 Yazdani S, Hendi K, Pakaravan M et al (2009) Intravitreal bevacizumab injection for neovascular glaucoma: a randomized controlled trial. J Glaucoma 18:632–637 Kahook MY, Schuman JS, Noecker RJ (2006) Intravitreal bevacizumab in a patient with neovascular glaucoma. Ophthalmic Surg Lasers Imaging 37:144–146 Moraczewski AL, Lee RK, Palmberg PF et al (2009) Outcomes of treatment of neovascular glaucoma with intravitreal bevacizumab. Br J Ophthalmol 93:589–593 Sidoti PA, Dunphy TR, Baerveldt G et al (1995) Experience with the Baeveldt glaucoma implant in treating neovascular glaucoma. Ophthalmology 102:1107–1118 Gheith ME, Siam GA, de Barros DS et al (2007) Role of intravitreal bevacizumab in neovascular glaucoma. J Ocul Pharmacol Ther 23:487–491 Btioglu F, Astam N, Ozmert E (2008) Rapid improvement of retinal and iris neovascularization after a single intravitreal bevacizumab injection in a patient with central retinal
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vein occlusion and neovascular glaucoma. Int Ophthalmol 28:59–61 Vatavuk Z, Bencic G, Mandic Z (2007) Intravitreal bevacizumab for neovascular glaucoma following central retinal artery occlusion. Eur J Ophthalmol 17:269–271 Takihara Y, Inatani M, Kawaji T et al (2011) Combined intravitreal bevacizumab and trabeculectomy with mitomycin C versus trabeculectomy with mitomycin C alone for neovascular glaucoma. J Glaucoma 20:196–201 Ma KT, Yang JY, Kim JH et al (2012) Surgical results of Ahmed valve implantation with intraoperative bevacizumab injection in patients with neovascular glaucoma. J Glaucoma 21:331–336 Iliev ME, Dommig D, Wolf-Shnurrbursch U et al (2006) Intravitreal bevacizumab (Avastin) in the treatment of neovascular glaucoma. Am J Ophthalmol 142:1054–1056 Yoshida N, Hisatomi T, Ikeda Y et al (2011) Intravitreal bevacizumab treatment for neovascular glaucoma: histopathological analysis of trabeculectomy specimens. Graefes Arch Clin Exp Ophthalmol 249:1547–1552 Eid TM, Radwan A, el-Manawy W et al (2009) Intravitreal bevacizumab and aqueous shunting surgery for neovascular glaucoma: safety and efficacy. Can J Ophthalmol 44:451–456 Bakri SJ, Snyder MR, Reid JM et al (2007) Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 114:855–859 Silva Paula J, Jorge R, Alves Costa R et al (2006) Short-term results of intravitreal bevacizumab (Avastin) on anterior segment neovascularization in neovascular glaucoma. Acta Ophthalmol Scand 84:5556–5557 Wakabayashi T, Oshima Y, Sakaguchi H et al (2008) Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal diseases in 41 consecutive cases. Ophthalmology 115:1571–1580
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ORIGINAL PAPER
The effect of intravitreal bevacizumab injection before Ahmed valve implantation in patients with neovascular glaucoma Jung Youb Kang • Ki Yup Nam • Sang Joon Lee Seung Uk Lee
•
Received: 30 May 2013 / Accepted: 21 October 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract To evaluate the effect of intravitreal bevacizumab (IVB) before Ahmed valve implantation for treatment of neovascular glaucoma (NVG). This study is a retrospective, comparative, consecutive case series. The study group consisted of 27 eyes of 26 patients with NVG who underwent an Ahmed valve implantation. Thirteen eyes were treated with Ahmed valve implantation alone (control group), and 14 eyes were treated with a combination of preoperative IVB injection and Ahmed valve implantation (IVB group). Visual acuity, intraocular pressure (IOP), number of anti-glaucoma medications, surgical complications, and success rate were compared between the two groups. There were no significant differences in preoperative characteristics between the two groups. Visual acuity at 1, 2 weeks, and 1 month after surgery were significantly better in the IVB group (p = 0.038, 0.034, and 0.032, respectively). Hyphema associated with Ahmed valve implantation occurred significantly less in the IVB group (p = 0.016). On the other hand, the mean IOP and number of anti-glaucoma medications at all follow-up periods were similar between the J. Y. Kang K. Y. Nam S. J. Lee S. U. Lee (&) Department of Ophthalmology, College of Medicine, Kosin University, 34 Amnam-dong, Seo-gu, Busan 602-702, Republic of Korea e-mail: [email protected] S. J. Lee Department of Ophthalmology and Visual Science, Univeristy of Louisville, Louisville, KY, USA
two groups. Kaplan–Meier survival analysis showed the probability of success 6 months after surgery as 71.4 % in the IVB group and 84.6 % in the control group. No significant difference in success rate was found between the groups (p = 0.422). IVB before Ahmed valve implantation for treatment of NVG reduced the incidence of hyphema. In this retrospective study, IVB provided better visual outcome in the early postoperative periods but did not significantly improve mean IOP, number of anti-glaucoma medications, or success rate. Keywords Ahmed valve implantation Bevacizumab Neovascular glaucoma Refractory glaucoma
Introduction Refractory neovascular glaucoma (NVG) represents a surgical challenge to glaucoma specialists. In most patients with refractory NVG who have uncontrolled intraocular pressure (IOP) despite treatment (laser or glaucoma medication), surgical procedures such as trabeculectomy and aqueous shunting surgery have been performed. Neovascularization is highly correlated with ischemic retinal disorders including proliferative diabetic retinopathy, central retinal vein occlusion, and ocular ischemic syndrome [1]. Several mediators are involved in intraocular neovascularization. Vascular
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endothelial growth factor-A (VEGF-A), an endothelial cell-specific mitogen, is a key molecule among these mediators [2]. Bevacizumab (Avastin; Genentech, South San Francisco, CA, USA) is a recombinant antibody against VEGF-A approved for treatment of colorectal cancer [3]. Recently, bevacizumab has been widely applied for treatment of macular edema and neovascular age-related macular degeneration because of its marked reduction of neovascular activity and vascular permeability in ocular tissue [4, 5]. In addition, there have been several reports of bevacizumab being used for adjunctive treatment of patients with NVG. Intravitreal bevacizumab (IVB) injection has been reported to reduce iris rubeosis and IOP [6–11]. Patients with refractory NVG who have uncontrolled IOP may need urgent surgical intervention. Some NVG patients have already received IVB injections. In patients who did not receive IVB injections, preoperative bevacizumab injection is possible during preoperative preparation. Although many reports and studies have been published about IVB injections and its relationship to Ahmed implantation, there is little definitive evidence that preoperative bevacizumab is beneficial for Ahmed valve implantation. In this retrospective study, we compared the visual acuity, IOP, number of anti-glaucoma medications, success rate, and complications of Ahmed valve implantation with and without preoperative bevacizumab injection in patients with refractory NVG.
Methods Patients We performed a retrospective chart review. Patients who underwent Ahmed valve implantation were consecutively recruited from January 2001 to December 2011 at the Gospel Hospital in Busan, Korea. Patients with intractable NVG who received Ahmed valve implantation because of high IOP (C22 mmHg) even after maximizing anti-glaucoma medications were included. Considering the pharmacokinetics of bevacizumab, patients who received IVB injection within 4 weeks of their Ahmed valve implantation were also included. Patients with other retinal diseases that did not cause NVG and patients with other
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glaucoma diseases (primary open-angle glaucoma, angle closure glaucoma, etc.) were excluded. Furthermore, patients that were lost to early follow-up (\6 months) were also excluded. The study cohort was divided into two groups—the preoperative IVB injection group (IVB group) and the Ahmed valve implantation without bevacizumab injection group (control group). Visual acuity, IOP, number of anti-glaucoma medications, success rate, and surgical complications were determined by chart review. Defining surgery as time zero, each patient was evaluated at 1 day, 1, 2 weeks, 1, 3, and 6 months after surgery. Visual acuity, IOP, complications, and number of antiglaucoma medications were investigated, assessed, and recorded at each visit. Surgical technique Between January 2001 and May 2007, Ahmed valve implantation was carried out without IVB (control group). After May 2007 when the use of bevacizumab began in our clinic, IVB before Ahmed valve implantation was initiated with patient consent in those who did not have contraindications to bevacizumab (IVB group). After topical anesthesia with 0.5 % proparacaine hydrochloride and disinfection with povidoneiodine, bevacizumab at a dosage of 1.25 mg/0.05 ml was injected using a 1-cc syringe with a 30-gauge (G) needle into the vitreous cavity through the pars plana at a position 3.5 mm posterior to the corneal limbus. Patients were then treated with topical 3 mg/ 1 ml gatifloxacin. Ahmed valve implantation was performed between 1 and 20 days after IVB. All the patients were treated with an identical surgical procedure performed by two surgeons (SDK and SJL). For Ahmed glaucoma valve implantation, a fornix-based conjunctival flap was created, and Tenon’s capsule was dissected. The tube of the Ahmed valve was irrigated with a balanced salt solution to prime the valve. The plate was secured to the sclera in the superotemporal quadrant 8–9 mm posterior to the surgical limbus. An entrance site into the anterior chamber was made with a 23-G needle. The tube of the valve was then passed through this 23-G needle track into the anterior chamber. The tube was anchored to the sclera. The conjunctival and Tenon’s capsule incisions were closed at the limbus.
Int Ophthalmol
Surgical outcomes
Statistical analysis
Visual acuity, IOP, number of anti-glaucoma medications, success rate, and surgical complications after Ahmed valve implantation were the primary outcomes of interest. We defined visual acuity as any improvement or deterioration from the preoperative visual acuity. A logarithm of the reciprocal of the decimal visual acuity was used to approximate the logarithm of the minimal angle of resolution (logMAR). Eyes without form vision were classified into one of four low-vision categories, which were assigned decimal equivalents as follows—counting finger = 0.005, hand motions = 0.0025, light perception = 0.00125, and no perception of light (NPL) = 0.0001 [12]. Surgical success and failure were defined before data analysis. Surgical success was defined as an IOP B21 mmHg with or without anti-glaucoma medication, and maintenance of visual acuity of light perception or better (except when preoperative visual acuity was NPL). Surgical failure was defined as an IOP C22 mmHg at two consecutive follow-up visits, or when additional glaucoma surgery was needed. Postoperative use of anti-glaucoma medication was not a criterion of success or failure.
All data were analyzed with the PASW Statistics 18 (SPSS Inc, Chicago, IL, USA). The success rate was analyzed using a log-rank test. Preoperative patient data, postoperative complications, postoperative change in visual acuity, IOP, and number of anti-glaucoma medications were compared between the two groups with the Fisher exact, Chi squared, and Mann–Whitney U tests. A p value of\0.05 was considered statistically significant.
Results Baseline characteristics A total of 27 eyes of 26 patients were included in the study. Fourteen eyes received Ahmed valve implantation with preoperative IVB injection (IVB group), and 13 eyes received only Ahmed valve implantation without preoperative IVB injection (control group). Table 1 shows the baseline characteristics of the two groups. There were no significant differences between the two groups in all categories, including preoperative visual acuity, preoperative IOP, and anti-glaucoma medication used before surgery.
Table 1 Baseline characteristics of the two study groups
IVB group (n = 14)
Control group (n = 13)
p*
0.72
Age (years), mean ± SD
54.8 ± 13.0
54.3 ± 10.8
Sex (male/female)
11/3
11/2
1.0
Eye (right/left) Etiology of NVG
7/7
7/6
0.85 0.53
12
9
Diabetes mellitus Central retinal vascular occlusion
1
2
Others
1
2
Phakia
6
7
Pseudophakia
8
3
Aphakia
0
3
Lens status
0.38
Earlier panretinal photocoagulation laser
11
8
0.68
Preoperative IOP (mmHg), mean ± SD
40.2 ± 11.3
44.7 ± 9.0
0.22
PRP panretinal photocoagulation
Number of preoperative anti-glaucoma medications, mean ± SD
2.2 ± 0.7
2.4 ± 0.9
0.62
* p value by Mann– Whitney test, Chi squared test, Fisher’s exact test
Preoperative visual acuity (logMAR), mean ± SD
2.81 ± 0.63
2.57 ± 1.03
0.93
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IOP The preoperative mean IOP was 40.2 ± 11.3 mmHg in the IVB group and 44.7 ± 9.0 mmHg in the control group (p = 0.22 by Mann–Whitney test). Compared to preoperative IOP, the two groups showed a statistically significant IOP decrease at all postoperative time points (p \ 0.05 by Wilcoxon signed-rank test). The differences in mean IOP between the two groups were not statistically significant at any followup period (Fig. 1). Number of anti-glaucoma medications The mean number of medications was 2.2 ± 0.7 in the IVB group and 2.4 ± 0.9 in the control group (p = 0.62 by Mann–Whitney test). Compared with the preoperative number of medications, both groups showed a statistically significant difference in the number of medications at all postoperative time points (p \ 0.05 by Mann–Whitney test). At each time point, however, the difference between the mean number of medications in the two groups was not statistically significant (Fig. 2). Surgical complications A comparison of surgical complications between the IVB group and the control group is shown in Table 2. Hyphema was the most frequent complication, and it occurred only in the control group (p = 0.02). As for the other complications, there were relatively small differences between the two groups, and the differences were not significant. None of the patients had systemic complications related to IVB, such as
Fig. 2 Mean number of anti-glaucoma medications after Ahmed valve implantation in eyes with or without preoperative bevacizumab injection. There was no significant difference between the two groups at any time point
Table 2 Complications in the two groups Complications
IVB group (n = 14)
Control group (n = 13)
p**
0.47
Early postoperative complications Hypotony
1
2
Hyphema
0
5
0.02*
Flat anterior chamber requiring anterior chamber reformation
1
0
0.47
Bleb leak requiring resuture
2
0
0.26
Outflow tract obstruction
2
1
0.26
Choroidal detachment
0
1
0.48
Late postoperative complications Hypotony
0
2
0.22
Implant exposure
2
0
0.26
Evisceration
1
0
0.52
Endophthalmitis
0
0
N/A
Hypotony maculopathy Pthisis
0 0
0 0
N/A N/A
N/A not available * p \ 0.05 ** p value by Fisher’s exact test
anaphylactic shock, severe elevation in blood pressure, cerebrovascular accident, or myocardial infarction during the follow-up period. The probability of success Fig. 1 Mean IOP after Ahmed valve implantation in eyes with or without preoperative bevacizumab injection. The mean IOP decreased in the two groups at all time points compared with preoperative IOP. The mean IOP of the two groups was not statistically significantly different at any follow-up period
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A comparison of the Kaplan–Meier survival curve analysis between the two groups is presented in Fig. 3. The probability of success 6 months after surgery was
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Compared to preoperative data, IVB before Ahmed valve implantation provided a better visual outcome at all postoperative time points (p \ 0.05 by Wilcoxon signed-rank test). Conversely, the control group did not show statistically significant changes in visual acuity at any postoperative time point.
Discussion
Fig. 3 Kaplan–Meier survival curves of surgical outcomes after Ahmed valve implantation for eyes in the IVB group (dotted line) and the control group (solid line). The log-rank test revealed no significant difference in the survival time between the two groups. IVB intravitreal bevacizumab
71.4 % in the IVB group and 84.6 % in the control group. The log-rank test revealed no significant difference in the survival time between the two groups (p = 0.42) (Fig. 3). Visual acuity The preoperative mean visual acuity was logMAR 2.81 ± 0.63 in the IVB group and logMAR 2.57 ± 1.03 in the control group. There was no statistical difference between the two groups (p = 0.93 by Mann–Whitney test). At 1, 2 weeks, and 1 month after surgery, the mean visual acuity of the two groups showed statistically significant differences (Fig. 4).
Fig. 4 Mean visual acuity after Ahmed valve implantation in eyes with or without preoperative bevacizumab injection. *A statistically significant difference in visual acuity between the two groups at 1, 2 weeks, and 1 month
This study evaluated the effects of IVB before Ahmed valve implantation for NVG caused by ischemic retinal diseases. The IOP-reducing effect of bevacizumab injection in eyes with NVG has been demonstrated in some case reports [13–15]. Recent studies have also reported that intraoperative or preoperative IVB injection may contribute to the lowering of IOP after surgery [16, 17]. Yazandi et al. [8] postulated a ‘reversible anatomic closure’ for angle closure of the neovascular membrane. Adjunctive bevacizumab injection for refractory NVG may affect the reversible part of the synechial angle, and this may produce further IOP reduction after Ahmed valve implantation. Unlike these studies, our study showed slightly better IOP reduction in the control group, but there were no significant differences between the two groups in mean IOP at all follow-up periods. To evaluate the IOP-reducing effect of adjunctive bevacizumab injection on refractory NVG, more studies are needed. As shown in Table 2, there are several complications associated with Ahmed valve implantation. Among these complications, hyphema was the most common in the early postoperative period of our study. Hyphema may cause visual disturbance after surgery. Our data revealed that IVB before Ahmed valve implantation reduced hyphema associated with surgery. This reduction may have been caused by regression of new vessels. Previous studies have shown that IVB causes immediate regression of iris and angle neovascularization [18]. In a recent study, neovascular regression was demonstrated by histopathological analysis [19]. Regression of neovascularization before Ahmed valve implantation is beneficial for preventing hyphema in patients with NVG. An earlier study reported that preoperative IVB injection before Ahmed valve implantation improves the success rate [20]. Recent studies are inconclusive about the benefits of combining IVB with this
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operation. Ma et al. [17] reported that intraoperative IVB injection does not seem to improve surgical outcomes after Ahmed valve implantation in NVG. Takihara et al. [16] reported that IVB before trabeculectomy with mitomycin C does not significantly improve surgical outcomes over longer periods in NVG. Takihara postulated that the lack of the improved probability of success might be related to the transient nature of IVB. The pharmacokinetics of bevacizumab in rabbit vitreous suggest that most of the bevacizumab in the aqueous humor is eliminated within 1 month [21]. The effect of neovascular regression persists for 8–10 weeks after IVB [22]; then, iris rubeosis in eyes with IVB returns within 6 months after treatment [23]. In our data, there were no significant differences in the probability of success between the IVB group and the control group at 6 months after Ahmed valve implantation. It is speculated that elimination of the anti-angiogenic effect of IVB might cause the recurrence of neovascularization. The improved probability of success might be achieved by repeat IVB after Ahmed valve implantation. Our data showed statistically significant differences in visual outcomes at early periods (1, 2 weeks, and 1 month) between the IVB and control groups. These differences may be related to the reduction in hyphema. Hyphema would affect visual acuity in the control group until it completely resorbed. Our data also showed that IVB before Ahmed valve implantation provides better visual outcomes at all postoperative time points. There are several possible explanations. First, reduced hyphema by preoperative IVB may have made the surgical procedure easier to perform. Uncomplicated surgery can lead to reduction in operation time and unnecessary manipulation. Thus, a less challenging operation can lead to good surgical results even if it cannot improve the surgical rate. Second, reduced hyphema would have enabled early onset of panretinal photocoagulation (PRP). Early PRP after surgery may stabilize the retina in NVG. Finally, preoperative IVB might have caused a visual-sparing effect due to relief of macular edema. This study had several limitations. First, selection bias was an inevitable factor due to its retrospective nature. To address this bias, we compared the surgical outcomes before the use of bevacizumab with those after the use of bevacizumab. Differences in when Ahmed valve implantation was performed could also
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cause bias due to differences in the surgical procedure; however, the two surgeons did not alter any of the surgical procedures. Additionally, we found no significant differences in the preoperative characteristics that could be a potential prognostic factor between two groups. Therefore, comparison with eyes before the use of bevacizumab provided significant information about the benefits and the limitations of IVB with Ahmed valve implantation for NVG treatment. Second, a 6 month follow-up period may be insufficient to obtain the significant effect of preoperative IVB injection. However, the number of patients with long-term follow-up ([6 months) were too small to obtain statistical results. Another limitation of this study is that we did not strictly standardize IVB protocol. There were various intervals between IVB injection and Ahmed valve implantation (1–20 days). Furthermore, although repeated anti-VEGF injections are a generally accepted dosing scheme, these results may not reflect actual clinical practice. However, there was no necessity for additional bevacizumab injections because none of patients showed recurrence of neovascularization on iris or retinal edema. Further prospective and randomized studies with long-term follow-up and multiple injections would more clearly reveal the effect of intravitreal anti-VEGF on Ahmed valve glaucoma implantation in patients with NVG. In conclusion, IVB before Ahmed valve implantation reduced hyphema. In this study, IVB provided better visual outcomes at early postoperative periods but did not significantly improve the mean IOP, number of anti-glaucoma medications, or success rate. Prospective studies with longer follow-up periods are warranted.
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