Phacoemulcification with Intravitreal Bevacizumab Injection in Patients with Cataract and Coexisting Diabetic Retinopathy: Prospective Randomized Study

Abstract

Objective:

To evaluate efficacy of intravitreal injection of bevacizumab at the time of cataract surgery on the postoperative progression of diabetic retinopathy (DR) and diabetic maculopathy.

Methods:

Patients were randomized to a standardized procedure of phacoemulsification with intraocular lens implantation alone (control group; 30 eyes) or to receive 1.25 mg intravitreal bevacizumab (0.05 mL of solution prepared from avastin, 100 mg/4 mL vial) at the end of surgery (IVB group; 27 eyes). Efficacy measures included best-corrected visual acuity (BCVA) testing, optical coherence tomography (OCT), and ophthalmoscopic examination at each postoperative visit during a 6-month follow-up.

Results:

There were no significant differences in central macular thickness (CMT), BCVA, or systemic condition between the control and IVB groups at baseline. Progression of diabetic maculopathy occurred in 15 eyes (50%) in the control group and 2 eyes (7.4%) in the intervention group (P=0.0008). There was no statistically significant difference in postoperative visual acuity between the 2 groups after 6 months (P=0.5). Five eyes in the control group and 1 eye in the intervention group progressed to neovascular glaucoma. Difference in mean postoperative CMT was not statistically significant between both groups (P=0.54).

Conclusions

: Intravitreal administration of 1.25 mg bevacizumab at the time of cataract surgery was safe and effective in preventing the progression of DR and diabetic maculopathy in patients with cataract and DR.

Introduction

Cataract is a major problem for diabetic patients because it decreases the vision, prevents adequate fundus examination, and interferes with the strategy of laser photocoagulation for diabetic retinopathy (DR). Diabetic patients have been reported to have higher prevalence of cataract and develop it at an earlier age than nondiabetics.^1,2

It is well established that after cataract surgery, patients with preexisting DR have a significant risk for progression of DR, diabetic maculopathy, and anterior segment neovascularization.^3–5 The risk of progression of retinopathy after cataract surgery is related to the severity at the time of surgery.^6–8 Patients with no retinopathy have an excellent prognosis,⁹ while those with retinopathy may have progression of DR and poor visual outcomes after surgery.

It has been well established that vascular endothelial growth factor (VEGF) plays a vital role in promoting neovascularization and increased vascular permeability in diabetic eyes. Levels of ocular VEGF are correlated with both the growth and permeability of new vessels.¹⁰ Furthermore, introduction of VEGF into normal primate eyes induces the same pathological processes as seen in DR, namely microaneurysm formation and increased vascular permeability. Also, studies have shown that vitreous samples from patients with diabetic macular edema (DME) contain elevated VEGF levels.¹¹ Based on these facts anti-VEGF agents like pegaptanib sodium and ranibizumab have been evaluated for DME in phase II randomized trials and a pilot study, respectively, with fairly promising results, especially for pegaptanib sodium.^12,13

Intravitreal bevacizumab is a new treatment modality that is currently being tried out for use in macular edema following central retinal vein occlusion, wet age-related macular degeneration, rubeosis iridis, proliferative diabetic retinopathy (PDR), and retinopathy of prematurity.^14–22 Although intravitreal use of bevacizumab is an off-label option, its use has risen exponentially over the last few years mainly due to its efficacy and economic considerations.²³

We performed a study to assess the safety and efficacy of intravitreal bevacizumab, an anti-VEGF agent, injected at the time of cataract surgery on the progression of DR in patients with cataract and DR.

Methods

Patients with DR with concurrent cataract were prospectively recruited between January and August 2009. Evaluation and management of all patients took place at Feiz Eye hospital.

Informed consent was obtained from all patients, and the study protocol was reviewed and approved by the Clinical Research Ethics Committee of the Iran University of Shahrekord. All patients were diagnosed with DR according to the Early Treatment Diabetic Retinopathy Study (ETDRS) criteria as well as concurrent significant cataract. Inclusion criteria were sight-limiting cataract in diabetic patients with poor fundus view precluding adequate monitoring and/or laser therapy with (1) the presence of clinically significant macular edema (CSME); (2) mild, moderate, severe, or very severe nonproliferative diabetic retinopathy (NPDR; any 2 features of NPDR as defined by the 4-2-1 rule) or PDR; or (3) a combination of 1 and 2.

Exclusion criteria of the study were (1) previous ocular trauma and ocular surgery, (2) presence of significant media opacity other than cataract, for example, vitreous hemorrhage, (3) ocular diseases including uveitis, age-related macular retinopathy, and (4) intraoperative complications such as posterior capsular rupture. Patients with previous focal or grid laser photocoagulation for CSME were eligible, while those with previous panretinal laser photocoagulation for PDR were excluded.

Patients with a history of raised intraocular pressure (IOP) were not excluded from the study, but the IOP had to be controlled at <21 mmHg for at least 3 months prior to the enrollment.

A fundus examination with full pupil dilation was performed with a +90.0 diopter fundus lens before surgery and at each scheduled examination.

When the details of the fundus were obscured by the density of the cataract, retinopathy grading was based on the first postoperative day examination.

Grades of retinopathy were defined according to the Wisconsin Epidemiologic Study of Diabetic Retinopathy¹⁸ and CSME was classified based on the ETDRS.¹⁹

All of the phacoemulsification surgeries were performed by one experienced cataract surgeon. Patients were randomized to a standardized procedure of phacoemulsification with intraocular lens implantation alone (control group; 30 eyes) or to receive 1.25 mg intravitreal bevacizumab at the end of surgery (IVB group; 27 eyes).

Standard cataract extraction by phacoemulsification and intracapsular intraocular lens implantation was performed under topical anesthesia, using 2% lidocaine hydrochloride gel (Xylocaine; AstraZeneca) in an operation theater setting. At the end of the cataract surgery, in the IVB group, 1.25 mg of avastin (intravitreal) was injected at a site 3.5 mm posterior to the inferotemporal limbus using a 27 G needle.

Postoperatively, 1% prednisolone acetate eye drops with 0.5% ciprofloxacin eye drops were applied 4 times daily for 1 week, then tapering weekly over a 3-week period.

At baseline examination, best corrected visual acuity (BCVA), central macular thickness (CMT), and IOP were documented. The response to treatment was monitored functionally by BCVA assessment using ETDRS logMAR chart and anatomically by optical coherence tomography (OCT) macular thickness at weeks 1–4 and months 2–6 after surgery. Patients were also examined for potential corticosteroid-induced and surgery-related complications. Based on the clinical examination and OCT assessment, retinal laser photocoagulation was performed according to ETDRS guidelines. Focal or grid laser photocoagulation was performed for CSME and panretinal (scatter) laser photocoagulation, for patients with PDR.

Postoperative laser treatment was performed no sooner than 1 week after surgery. DR was graded as mild NPDR, moderate NPDR, severe NPDR, very severe NPDR, or PDR. CSME was classified according to the ETDRS.¹⁹ Progression of DR was based on assessment in a masked fashion by 2 retina specialists.

In both groups, DR was considered to have progressed when (1) a patient with preexisting DR developed a higher grade of retinopathy, with or without progression within the macula (eg, mild NPDR progressed to severe NPDR or higher grade), or (2) a patient with or without maculopathy developed CSME/increase in retinal thickening or hard exudation associated with retinal thickening from baseline levels.

The outcome measures include progression of postoperative DR and diabetic maculopathy during a 6-month follow-up, change in BCVA (Snellen converted to logMAR equivalent), changes in CMT determined by OCT, postoperative laser therapy, and progression to neovascular glaucoma (NVG).

Statistical analysis was performed using SPSS software v13.0. A 2-sample t-test was used to compare the means of the parametric data, and the chi-square test was used for categorical data.

Results

Of the 57 eyes (57 patients) recruited into the study, 30 did not receive intravitreal bevacizumab (control group) and 27 received an intravitreal bevacizumab injection (intervention group) at the end of surgery. Preoperative data were not statistically different between groups. The demographic, refractive, and visual data at the 6-month follow-up are listed in Table 1. No significant differences in blood pressure values nor long-term blood sugar were observed.

Table 1.

Characteristics of the Study Population

	Group without avastin injection	Group with avastin injection
Number of patients	30	27
Male/female (m:f)	17/13	14/13
Mean age (years)	62.3±14	61.5±12.7
Preoperative BCVA	0.11±0.06	0.10±0.05
Macular thickness	315±71.9	310.92±72.4
Type of DM
IDDM	10	8
NIDDM	20	19
Duration of DM (years)	16.5	15.5
Duration of hypertension (years)	6.4	6.00

BCVA, best-corrected visual acuity; DM, diabetes mellitus; IDDM, insulin-dependent diabetes mellitus; NIDDM, non-insulin-dependent diabetes mellitus.

The mean age of the patients was 68.5 years (range 60–75 years). All eyes had DR at baseline ranging from mild to severe as defined by ETDRS criteria (Table 2). The mean preoperative BCVA was 1.00±0.60 logMAR units, which is an Approximate Snellen Equivalent of 6/60. The mean baseline CMT was 379±105 μm and the mean baseline IOP was 14.6±3.0 mmHg. There were no intraoperative (or perioperative) complications. All eyes completed 6 months of follow-up.

Table 2.

Preoperative Diabetic Retinopathy and Maculopathy

Characteristic	Control	Intervention
Retinopathy
Mild NPDR	5	3
Moderate NPDR	11	2
Severe NPDR	10	14
Very severe NPDR	3	7
PDR	1	1
Maculopathy/CSME
Not present	13	14
Present	17	13

NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; CSME, clinically significant macular edema.

At baseline, a VA of 1.00±0.06 logMAR in group 1 and 1.00±0.05 logMAR in group 2 (P=0.60) was measured. Table 3 shows the mean postoperative BCVA over the 6-month follow-up. The mean BCVA improved to a maximum of 0.56±0.26 in control group 1-month postoperative and 0.43±0.15 in the IVB group.

Table 3.

Postoperative Visual Acuity

Postoperative period (months)	Without avastin injection	With avastin injection	P value
1	0.56±0.26	0.43±0.15	0.01
3	0.57±0.23	0.48±0.25	0.09
6	0.59±0.12	0.51±0.13	0.5

The final mean BCVA at 6 months in control group and case group was 0.59±0.12 and 0.51±0.13, respectively. The improvement of BCVA was statistically significant 1 month after surgery in both groups (P=0.01) but was not statistically significant 6 months (P=0.5) postoperatively.

The mean CMT at baseline measured by OCT was 291±71.9 μm (range=200–410) in group 1 and 302±73 μm (range=210–430) in group 2. At the 3-month control visit the patients in group 1 had a mean central retinal thickness (CRT) of 317±72 μm (range=226–436), as did those of group 2 mean CRT of 312±72 μm (range=227–435). Statistical analysis showed no significant difference between both groups concerning CRT at baseline and 6 months (Table 4).

Table 4.

Postoperative Macular Thickness

Postoperative period (months)	Without avastin injection	With avastin injection	P value
1	315±72	310±72	0.3
3	317.8±72	312±75	0.4
6	356±70	313±78	0.5

Tables 5 and 6 show the progression of DR and diabetic maculopathy after surgery. DR progressed in 40% of eyes in the control group and 11% of eyes in the intervention group; the difference between groups was statistically significant (P=0.0009, chi-square test). Progression of diabetic maculopathy occurred in 50% of eyes in the control group and 7.4% of eyes in the intervention group; the difference between groups was statistically significant (P=0.0008, chi-square test).

Table 5.

Change in Diabetic Retinopathy After Cataract Surgery

		Control			Avastin
Group		Eyes	No change	Progression	Eyes	No change	Progression
Preop. retinopathy	Mild NPDR	5	3	2	3	3	0
	Moderate NPD	11	8	3	2	2	0
	Severe NPDR	10	4	6	14	12	2
	Very severe NPDR	3	2	1	7	6	1
	PDR	1	1	0	1	1	0

Table 6.

Postoperative Progression of Diabetic Retinopathy and Diabetic Maculopathy

	Group
Progression	Control	Intervention	P value
Diabetic retinopathy
No progression	18	24	0.000
Progression	12	3
Maculopathy
No progression	15	25	0.000
Progression	15	2

Laser photocoagulation was performed in 50% of eyes in the control group and 44.4% eyes in the intervention group; the difference was not statistically significant (P=0.43, chi-square test). Postoperative progression to NVG occurred in 5 eyes in the control group and in 1 eye in the intervention group. We did not observe any adverse events that could be related to the injection itself or the medication used.

Discussion

It has been reported that the VEGF, induced by ocular hypoxia, is an important factor in the development of abnormal angiogenesis and macular edema.¹⁰

Bevacizumab is an anti-VEGF agent that is approved for the treatment of disseminated colorectal cancer but is not licensed for intraocular use. However, bevacizumab appears to show efficacy similar to that of ranibizumab, for the treatment of DME and PDR.^24–26

Therefore anti-VEGF therapy might be expected to show a dramatic reduction of DME. Bevacizumab has indeed attracted interest due to its low cost, but also due to its proven efficacy. Further, its systemic safety has been shown, but indeed only in cancer studies. Systemic safety has not been approved in the context of intraocular use.^26,27

We conformed to the widely used concentration of the drug (1.25 mg/0.05 mL bevacizumab) in this study. This study demonstrated a marked reduction of macular edema 1 week after intravitreal anti-VEGF therapy.

However, recurrence of macular edema occurred within 4 weeks. A retinal penetration study revealed the absence of bevacizumab 4 weeks after the injection,²⁸ which may suggest the limited effect of bevacizumab on suppression of VEGF activity.

Whether cataract surgery itself increases the risk of progression of DR is still controversial. Some authors observed increased risks^7,29–31 whereas others reported no difference,^6,32–37 and postulated that the retinopathy progression may simply represent the natural history of the disease.^32,34,38

Previously, some reports confirmed the usefulness of bevacizumab, a humanized monoclonal antibody that inhibits all isoforms of VEGF, in the prevention of macular thickening after phacoemulcification.^39–41

In our study, the rate of retinopathy progression was 40% in eyes that did not receive intravitreal bevacizumab (control group) and 11% in eyes that did receive intravitreal bevacizumab (intervention group) at 6 months after cataract surgery with IOL implantation. These results are similar to that found by Cheema et al.⁴²

The rate of retinopathy progression after cataract surgery has been reported to be influenced by variables such as age,^33,43 race, severity of preoperative DR,^6,9,44 duration of diabetes,⁶ levels of HbA1c,^6,45 poor glycemic control, duration of diabetes mellitus (DM), renal function, hypertension, insulin treatment, surgeon inexperience, posterior capsule disruption,⁴⁶ and postoperative inflammation.⁴²

Jaffe et al.⁷ report a rate of DR progression of >70% after extracapsular cataract surgery. The reported rate of progression of DR following phacoemulcification in the general diabetic population ranges between 20% and 34%.^9,34,37,47

In our study, the rate of retinopathy progression in the control group is similar to that reported by Chatterjee et al.⁴⁸ in British Afro-Caribbean diabetic patients undergoing phacoemulcification and Cheema et al. in Arab diabetic patients.⁴²

We found that this progression was more evident particularly in patients without avastin injection (40% of eyes with DR compared with 11% eyes of with avastin injection) with a statistically significant rate of occurrence.

Whatever the etiology, the retinal capillaries appear to react with a pathological response to the surgery, resulting in disruption of the blood-retinal barrier and/or occlusion of the capillaries. The clinical correlates of these events are transudation and macular edema and/or induction of retinal ischemia leading to neovascularization.³⁰ In previous studies, the progression of retinopathy occurred at the rate of 42% in 70 eyes,⁶ 13% in 91 eyes,³⁶ and 21% in 47 eyes.⁹

Pollack et al.⁴⁴ reported that CSME was observed in 50% of eyes with DR in 6 weeks after surgery. Many studies have revealed that intravitreal injection of bevacizumab is useful in the management of DME.^23,24,49

In this study, CSME occurred in 50.0% of eyes in control group and in 7.4% of eyes in the IVB group. However, the maculopathy progression rate was significantly lower in the intervention group than in the control group in our study over the 6-month follow-up. These results are similar to that found by Cheema et al.⁴²

Prophilaxis effect of intravitreal ranibizumab in DR evaluated by Udaondo et al. reported that 1 month after surgery the incidence of CSME in the control group was 25.92% and in the treatment group was 3.70% and at 3 months it was 22.22% and 3.70%, respectively.⁵⁰

In this study, the indication for surgery in all patients was for visual improvement or when the density of lens opacity was severe enough to prevent retinal assessment. This poses a challenge in management of this group of patients since diabetic maculopathy and retinopathy are reasons for poor visual outcome following cataract surgery in diabetics.^51–53 In fact, cataract surgery ought to be performed earlier among diabetics compared with their nondiabetic counterparts to ensure timely assessment of the retina.⁴ Every effort was made to perform laser therapy before cataract surgery as it is well-known that DME can progress after such surgery.

In this study serial OCT examinations were performed rather than fluorescein angiography after surgery because OCT is a more sensitive means of detecting macular topographic changes.⁵⁴ Although patients in the intervention group had a significantly lower incidence of progression of maculopathy, the CMT and average macular thickness were not statistically significantly different between groups at any postoperative time point.

Significant improvement in the mean BCVA was seen in first month after operation, but 6 months after surgery this difference was no longer statistically significant. In conclusion, intraoperative IVB treatment during cataract surgery in patients with DR is effective in preventing complications of DR in the short-term. However, this beneficial effect does not appear to continue in the long-term. These results are similar to other studies' results.^39,42,55

Adequate panretinal laser photocoagulation is essential if there is severe peripheral retinal ischemia or early retinal neovascularization. This photocoagulation should be applied preoperatively. If this is not possible, it can be done in the early postoperative period.⁵⁶ Pollack et al.⁴⁴ reported that preoperative laser treatment may stabilize the retinopathy but does not prevent all postoperative progression. This was reflected in the finding that there was no difference between groups in mean visual acuity after 6 months.

Laser photocoagulation for CSME and PDR was performed in both groups during the study period based on ETDRS criterion. Although progression of postoperative DR and maculopathy occurred more frequently in the control group, there was no statistical difference in the rate of laser therapy between groups.

This was a reflection of the presence of untreated preoperative retinopathy and maculopathy in both groups in the early postoperative assessment rather than of a progression of diabetic changes.

Laser therapy was performed promptly, especially for CSME, which may explain why both groups had similar visual acuity and CMT during the 6-month follow-up period. However, it has also been observed that after laser photocoagulation for CSME, visual acuity may not improve for a considerable time and OCT may not show any significant change in macular thickness values.⁵⁷

Five eyes in the control group progressed to NVG during the follow-up; 1 eye in the intervention group progressed to NVG.

Our results also show that bevacizumab was well tolerated and no systemic adverse events were noticed during the study. Ocular tolerance was also high and no ocular inflammation was noted.

Various case reports⁵⁸ and studies^24,59 show the effectiveness of anti-VEGF therapy on retinal neovascularization in patients with DM. Some studies^60,61 document the usefulness of nonspecific antiangiogenic therapy, such as triamcinolone acetonide, injected into the vitreous at the completion of cataract surgery in cases of diabetic maculopathy. Other studies^62–67 report beneficial effects of bevacizumab as an adjuvant or a primary treatment in cases of DR and maculopathy. Combining the 2 procedures of cataract surgery and intravitreal injection of bevacizumab reduces the potential risk for 2 intraocular episodes to a single episode.

Our preliminary study provides evidence that inhibition of VEGF associated with both pathological ocular neovascularization and increased retinal vascular permeability in DR may produce a clinically meaningful and statistically significant benefit in the treatment of DME.

In conclusion, preliminary data from this study indicate that diabetic patients with DR who undergo combined phacoemulsification and intravitreal injection of 1.25 mg bevacizumab were associated with statistically significant reduction of progression of DR and maculopathy at 6 months postoperatively with no significant adverse events.

However, large randomized controlled trials are recommended to realize the full potential of this therapy in diabetic patients having cataract surgery for delineating the relative contributions of cataract removal and CMT reduction to visual acuity improvement.

Footnotes

Author Disclosure Statement

Authors do not have any financial interest in the subject matter of this article.

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