Ranibizumab in patients with dense cataract and proliferative diabetic retinopathy with rubeosis.

BACKGROUND: To evaluate the safety of ranibizumab as a surgical adjunct during cataract surgery in patients with proliferative diabetic retinopathy (PDR) with rubeosis, and to evaluate the efficacy and adverse effects of ranibizumab in treating PDR with rubeosis.
MATERIALS AND METHODS: Three intravitreal injections of 0.5 mg ranibizumab were administered on day-1, months-1 and -2 with cataract surgery 6-16 days after first injection. Retreatments with ranibizumab injections and pan-retinal photocoagulation (PRP) were given if recurrence or persistence of PDR was noted between months-3 and -11. Safety observation visits occurred at months-12, -18 and -24. Primary end points were incidence and severity of adverse events (AEs) that were related to both cataract surgery and treatment of PDR with rubeosis through month -12.
RESULTS: Of six patients screened, four (mean age 61.3 years) were enrolled. No AEs were noted with either cataract surgery or treatment of PDR. Neovascularization of iris (NVI) promptly regressed by 4 days after first ranibizumab injection, prior to cataract surgery in three of four patients (one had significantly regressed NVI by post-injection day-3 visit); NVI was not noted in any patient at 2 weeks after first ranibizumab injection. Recurrence of rubeosis or NVA after 3 monthly injections was not observed in any. At month-12, PDR was not present when assessed clinically and by fluorescein angiogram (FA). Only one patient developed neovascularization of disc and neovascularization elsewhere and required retreatments at months-5 and -9.
CONCLUSIONS: Multiple intravitreal injections of ranibizumab may be a safe, effective treatment adjunct for PDR and diabetes-related rubeosis.

Introduction

Diabetic retinopathy (DR) is a leading cause of vision loss in the working-age population in developed countries.[1] Recent research has established the role of vascular endothelial growth factor (VEGF) as a key mediator of retinal angiogenesis and vascular permeability in ocular neovascular conditions such as neovascular age-related macular degeneration (NV-AMD),[2] diabetic macular edema (DME),[3] and proliferative diabetic retinopathy (PDR).[4] Ranibizumab (Lucentis, Genentech, Inc., South San Francisco, CA) is a humanized monoclonal antibody antigen-binding fragment being used for the intravitreal treatment of NV-AMD,[5] and DME.[67] In this study, ranibizumab was used to inactivate or reduce VEGF levels in eyes to treat PDR with rubeosis iridis.

Pan-retinal photocoagulation (PRP) is the standard of care for PDR.[8] However, in the presence of a dense cataract, the view of the fundus may not be clear enough to perform adequate PRP. The current practice for eyes in which the laser cannot be done due to cataract, is to perform urgent cataract extraction followed by PRP. This approach can delay the PDR treatment for a few days. In addition, the view to the retina may be sub-optimal for a few weeks if surgery is complicated with hyphema in these rubeotic eyes, which can further delay the PRP treatment or mandate anterior chamber washout. Moreover, crystalline lens removal in eyes with PDR may accelerate the progression of the retinopathy and worsen the neovascularization of iris (NVI), probably by removing a barrier to the diffusion of angiogenic factors from the posterior to the anterior segment.[910]

We performed a pilot study in eyes with dense cataract and diabetes-related rubeosis (without tractional retinal detachment (TRD)) of treatment with ranibizumab intravitreal injections and subsequent cataract surgery a few days after the first injection. Our goal was to develop expedited treatment for eyes with diabetes-induced rubeosis iridis and cataract precluding PRP.

Materials and Methods

Study design

This study was an open-label, single-center, phase I trial with a 12-month treatment period (intervention phase) that included three monthly intravitreal injections of ranibizumab and cataract surgery after the first injection followed by a 12-month observation phase at months -12, -18 and -24. The study was approved by University of Medicine and Dentistry of New Jersey (UMDNJ) Institutional Review Board (IRB), conducted in accordance to the tenets of the Declaration of Helsinki, and was HIPAA-compliant. After written informed consent was obtained, enrolled patients received a loading intravitreal injection of 0.5 mg ranibizumab (day-0) followed by cataract surgery between days -6 and -16, and two additional monthly injections of ranibizumab (months -1 and -2). Follow-up visits were performed subsequently at months -3, -5, -7, -9 and -11. If neovascularization of iris (NVI), optic disc, and/or retina were present following three initial monthly ranibizumab injections at any follow-up visits, patients were retreated with intravitreal injection of ranibizumab and PRP (within 2 weeks of ranibizumab injection). Examinations including Early Treatment Diabetic Retinopathy Study (ETDRS) best corrected visual acuity (BCVA), intraocular pressure (IOP) measurement, ophthalmological examinations, slit-lamp photography, gonioscopy, color fundus photography, FA, and Stratus optical coherence tomography (OCT) were performed at all visits. An ultrasound was performed to rule out TRD and vitreous hemorrhage (VH) if adequate retinal examination could not be performed due to media opacity.

Subject Selection

Eligible subjects were aged ≥18 years with diabetes mellitus (DM), dense cataract, and PDR-induced rubeosis iridis, and had HgbA1C<12% measured within 60 days of baseline visit. Exclusion criteria included pregnancy or lactation, presence of TRD confirmed on ultrasound, history of cataract or/and glaucoma surgery, previous pars plana vitrectomy (PPV) in the study eye, active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in the study eye, use of intravitreal, peribulbar, or retrobulbar steroid within 3 months of screening in the study eye, history of treatment with intravitreal anti-VEGF within 60 days of screening in the study eye, concurrent use of systemic anti-VEGF agents, uncontrolled systemic conditions (i.e., hypertension, hypercholesterolemia, coronary artery disease, DM – HgbA1C ≥12%), having received any systemic experimental drug within 12 weeks prior to enrollment, and currently being treated for active systemic infection.

Outcome Measures

The primary end points of the study were incidence and severity of AEs that were cataract surgery related (for instance, hyphema and VH) and those that occurred during the treatment of PDR through month-12. Secondary end points of the study are summarized in Table 1.

Table 1

Secondary end points

Results

Patient demographics and baseline characteristics

Four patients were enrolled in this pilot study. Patient demographics and baseline characteristics are summarized in Table 2. Of note, patients 1 and 3 completed the intervention and observational years; patient 2 completed only the intervention phase because of the relocation of her residence, and patient 4 dropped out of the study 2 months after the third monthly ranibizumab injection.

Table 2

Patient demographics and baseline characteristics

Adverse Events

No adverse events (AEs) associated with either cataract surgery or treatment of PDR occurred in any of the four enrolled patients. Three patients were hospitalized due to their preexisting conditions and associated complications, namely diabetic foot ulcer, congestive heart failure (CHF), renal insufficiency, and gastritis [Table 3].

Table 3

Adverse events (AE) during the study

Proliferative Disease

Rubeosis iridis observed at baseline promptly resolved completely by the fourth day after the initial ranibizumab injection before cataract surgery in three of four patients. Rubeosis was markedly reduced in the fourth patient by this time and was totally resolved by the next visit at 2 weeks. Recurrence of rubeosis or NVA after three monthly ranibizumab injections was not observed during any follow-up visit for any patient. At month -12, PDR was not present as assessed clinically and by FA in all the three patients (1 lost to follow-up after month -3). One patient developed neovascularization of disc (NVD) at the month -5 follow-up visit and subsequently underwent both intravitreal ranibizumab injection and PRP. NVD regressed promptly and was not noted at the week -2 post-injection visit when PRP (parameters: 2402 shots with argon green laser; duration 200 ms; spot size 400 microns; power 200-300 mW) was performed at the slit lamp as per the study protocol. No PDR was noted at the month -7 visit; however, at the month -9 visit, NVD and neovascularization elsewhere (NVE) both were noted clinically and on FA. Combined treatment with intravitreal ranibizumab and additional PRP (parameters: 886 shots with argon green laser; duration 150 ms; spot size 400 microns; power 200-300 mW) 1 week later was performed, and regression of neovascularization was soon noted. No subsequent recurrence was noted in this patient during the course of the study.

Secondary Measurements

The results of all secondary end points are summarized in Table 1.

Case Reports

Case 1

A 63-year-old Hispanic male with a 2-year history of type 2 insulin-dependent DM. His medical history was significant for coronary heart disease, hypercholesterolemia, and hypertension. His DM had led to bilateral foot ulcers and left hallux amputation 3 months prior to enrollment. He was recruited into the study with NVI extending from 5.30 to 10 o’clock, a dense cataract, and PDR without traction retinal detachment on ultrasound. His NVI regressed 2 weeks after the first ranibizumab injection. No PDR was noted on retinal examination after the cataract surgery at the month -1 visit. However, NVD and NVE were noted at follow-up visits at months -5 and -9. (The detailed course of treatment has been described in the earlier section.) The ETDRS BCVA improved from 20/160 at baseline to 20/50 at month -2 and was 20/63 at month -12. The ocular examination remained stable after retreatment at month -9 with no recurrence of rubeosis through month -24.

Case 2

A 70-year-old Hispanic female with an 11-year history of insulin-dependent type 2 DM, an 11-year history of hypertension controlled with medications, and a 4-year history of chronic kidney disease and diabetic nephropathy. Rubeosis was noted to have resolved 4 days after the first injection. There was no recurrence of NVI or PDR seen during subsequent study visits. Notably, she was hospitalized at month -11 for bilateral pedal edema and dyspnea. She was treated for CHF exacerbation and pulmonary edema with intravenous steroids and diuretics, and also for an exacerbation of her pre-existing chronic kidney disease. The ETDRS BCVA improved from 20/400 at baseline to 20/63 at month -2, 20/25 at month 7, 20/23 at month -12.

Case 3

A 65-year-old Hispanic female with a 23-year history of noninsulin-dependent type 2 DM, hypercholesterolemia, and gastritis. Her ocular history included minimal VH in the left eye, and she was status post of PRP for PDR in both eyes. Her NVI responded promptly and was not noted at the visit 4 days after the first injection of ranibizumab. She completed her month -24 follow-up visit with no recurrence of PDR. Her course during the study was significant for a 2-day hospitalization for a flare-up of her preexisting gastritis 15 months after the last of three monthly ranibizumab injections. Her ETDRS BCVA improved from 20/200 at baseline to 20/80 at month -2 and 20/25 at months -7 and -12.

Case 4

A 43-year-old African American male with a history of DM, CHF, and hypertension treated with medications. He had received PRP for PDR in the past and also had a history of chronic open angle glaucoma. He completed study through the month -3 visit and subsequently withdrew from the study. NVI was resolved by the fourth day after the initial ranibizumab injection with no recurrence noted in subsequent visits. His ETDRS BCVA improved from 20/200 at baseline to 20/80 at month -2 and 20/100 at month -3.

Discussion

We report the results of a pilot study of multiple intravitreal injections of ranibizumab for the management of rubeosis iridis due to PDR in eyes with dense cataract that precluded PRP as the initial therapy for rubeosis. In this pilot study, multiple intravitreal injections of ranibizumab were well-tolerated in patients with rubeosis iridis, PDR, and cataract precluding PRP. No ocular or systemic AEs specifically related to the use of ranibizumab were observed. Ranibizumab, when used as a preoperative adjunct for cataract surgery, might minimize anterior segment bleeding during the surgery. It may also prevent delay in treatment for rubeosis and PDR in eyes where one may not be able to provide PRP unless cataract extraction is performed. Complete resolution of rubeosis iridis was achieved clinically in all eyes after the first ranibizumab injection. Regression of rubeosis was noted within 4 days after the injection in three of four cases and by the second week in the fourth subject. No retinal proliferative changes were identified in any eye after cataract extraction at the month -1 visit. One eye developed retinal neovascularization at months -5 and -9 (3 and 4 months after the last ranibizumab injection, respectively). Combined treatment with ranibizumab and PRP at months -5 and -9 were sufficient to achieve quiescence through the subsequent year of safety visits. All patients demonstrated regression of PDR as assessed clinically and by FA at month -12. Given the fact that cataract surgery may pose an increased risk of retinopathy progression, this clinical outcome may be noteworthy.

Anti-VEGF injections are being used by many ophthalmologists globally for the treatment of PDR; however, PRP is still considered the current standard of treatment for PDR. A few retrospective studies report regression of PDR with intravitreal anti-VEGF therapy without PRP,[11-14] however, no prospective long-term randomized study has been performed to compare intravitreal anti-VEGF with PRP in the treatment of PDR. The results of these retrospective case reports need to be validated. Our prospective pilot study was designed to evaluate the safety profile of three monthly injections of ranibizumab and the need of PRP treatment after three injections of ranibizumab in the treatment of PDR.

Some investigators have suggested that breakdown of the retinal-blood barrier in patients with PDR may increase systemic exposure to ranibizumab after intravitreal injection, thus causing increased risks, particularly that of nonocular hemorrhages and thromboembolic events.[1516] During the course of this study, two patients were treated for CHF. One underwent debridement for a diabetic foot ulcer. Two patients were treated for diabetic nephropathy, and one was treated for a gastritis flare-up. They were hospitalized due to these co-morbidities. During the study period, patient 1 further suffered a Methicillin-resistant Staphylococcus aureus (MRSA) foot infection and osteomyelitis during hospitalization. All of the co-morbidities occurred a long time after the preceding intravitreal ranibizumab injection [Table 3]. Due to the inherent nature of this uncontrolled, open-label pilot study and the complexity of intertwining co-morbidities, it is impossible to determine the role of ranibizumab may have played in these AEs.

In summary, the results of this study showed that multiple intravitreous injections of ranibizumab may be a safe, effective treatment adjunct for PDR and diabetes-induced rubeosis iridis. Intravitreal ranibizumab injection might permit more rapid treatment for patients with NVI and dense cataracts that prevent them from undergoing PRP, the standard therapy for PDR, until the cataract is removed and also may provide the potential benefit of reducing hemorrhagic ocular complications during cataract surgery.