Experience of intravitreal injections in a tertiary Hospital in Oman.

AIM: To find out statistical data regarding intravitreal injections in an outpatient department setup at a tertiary center in Oman.
DESIGN: Retrospective chart review.
METHODS: Data collection of patients who underwent intravitreal injections from November 2009 to May 2013 at Sultan Qaboos University Hospital.
RESULTS: Throughout a period of 42 months, a total of 711 intravitreal injections were performed. That included 214 patients (275 eyes). Around one-third of the eyes received two injections or more. The injected agents were bevacizumab (59.8%), ranibizumab (32.3%), triamcinolone (7.5%), and very few patients with endophthalmitis received intravitreal antibiotics and antifungal agents. The three most common indications for the injection therapy were diabetic macular edema (50.9%), choroidal neovascularization (24.3%), and retinal vein occlusive diseases (11.5%). Serious adverse events were rare, and they occurred as ocular (0.9% per patient) and systemic (3.3% per patient). There were 42 eyes received intravitreal triamcinolone, and 24% of them developed intraocular hypertension that required only medical treatment.
CONCLUSION: Different intravitreal agents are currently used to treat many ocular diseases. Currently, therapy with intravitreal agents is very popular, and it carries a promising outcome with more efficiency and safety.

Introduction

Invasive interventions to treat retina disorders are sometimes very essential to save the vision of many patients. The therapy with intravitreal injections has been used frequently in the last few years, especially after introducing antivascular endothelial growth factors (anti-VEGF). The first intravitreal injection was performed on 1911 by Ohm, who injected air into vitreous cavity as a treatment for retinal detachment.[1]

The first anti-VEGF, that was used intravitreally, was pegaptanib (macugen) which was approved by Food and Drug Administration (FDA) on 2004. After that, many other anti-VEGF agents were introduced, such as bevacizumab, ranibizumab, and aflibercept. Currently, the anti-VEGF agents are used worldwide to treat many retina disorders including exudative age-related macular degeneration (ARMD), diabetic macular edema, and retinal vein occlusions with macular edema. Those agents are also used by some retina specialists to treat other disorders such as central retinal serous chorioretinopathy,[234] parafoveal telangiectasia,[567] polypoidal choroidal vasculopathy,[891011] and previtrectomy in eyes with proliferative diabetic retinopathy.[12]

In our hospital, Sultan Qaboos University Hospital (SQUH) in Oman, the anti-VEGF agents were first introduced to treat medical retina diseases in the year 2009. Since then, this treatment has become very commonly used for different indications. The two intravitreal anti-VEGF agents that are used in SQUH are bevacizumab (avastin) and ranibizumab (Lucentis). Intravitreal steroids including preservative-free triamcinolone acetate (Triescence) are also used.

The aim of this study is to look at the experience in a tertiary hospital in Oman in the usage of intravitreal injections to treat different retinal disorders. Moreover, there are no similar published studies, so far, in Oman regarding this subject.

Methods

An approval from Ethics Committee Board of the institute was obtained to conduct this study. All patients who had intravitreal injection at the eye clinic of SQUH were enrolled. The covered period was from November 2009 to May 2013. Data of those patients were collected retrospectively through the electronic medical recording system. All cases who underwent intravitreal injection therapy in the eye clinic were included. Intravitreal injections that were performed in the main operation theater were not included in this study.

All injection procedures were performed in the minor operation room of the eye clinic. Each injection was done under aseptic technique. As a standard, every intravitreal injection procedure was done after instilling drops of anesthetic agents and povidone-iodine (5%). Eye speculum was also used in all procedures. The procedures were done either with topical or subconjunctival anesthesia. Postinjection antibiotic drops and eye patch for 2 h were applied in all patients. All patients received a course of topical antibiotic (moxifloxacin or ofloxacin eye drops) after the injection for a period of 1 week with a frequency of 4 times daily.

All agents that were used in the intravitreal injections were obtained from the hospital pharmacy on the same day of the procedure. Intravitreal bevacizumab and intravitreal antibiotics were prepared in the hospital pharmacy under strict sterile conditions.

Results

This study covered a period from November 2009 to May 2013 (42 months). A total of 711 injections were performed in a total of 214 patients at outpatient eye clinic of SQUH [Table 1].

Table 1

General data of the patients

Different intravitreal substances were used during those procedures [Figure 1]. The anti-VEGF agents (bevacizumab and ranibizumab) constituted around 92% of all injected substances. Patients who had injections in both eyes were 28.5% of total patients. These patients did not have the procedures in the same day, but at least 2 weeks apart in order to minimize the risk of systemic adverse events. Moreover, pathologies that had been treated in our patients are shown in Table 2. Around half of the patients, who required treatment with intravitreal injections, had diabetic macular edema. Although the total number of patients in our study was 214, few patients had been treated for more than one ocular condition. Hence, Table 2 shows that the total number of patients was 218 instead of 214. That was because three patients developed more than one ocular disorder in the same eye that required the injection therapy. Other disorders (6.9%) that are shown in Table 2 included central serous chorioretinopathy, parafoveal telangiectasia, polypoidal choroidal vasculopathy, endophthalmitis, previtrectomy in diabetic retinopathy, diabetic vitreous hemorrhage, and anterior ischemic optic neuropathy.

Figure 1

Substances that were used in the intra-vitreal injections

Table 2

Pathologies in the patients treated with intravitreal injections

A total of 53 patients (59 eyes) with choroidal neovascularization (CNV) were treated with anti-VEGF injections. The etiologies of CNV in those patents are listed in Table 3. The ARMD was the most common etiology for CNV.

Table 3

CNV with different etiologies

Intravitreal injections can be associated with adverse events. These events have ocular or systematic side effects. The common ocular side effects were not included in this review since they are very benign. Such benign side effects are subconjunctival hemorrhage and epithelial keratitis. Table 4 summarizes the serious adverse events (SAE) that occurred after the injections in our cohort of patients.

Table 4

Serious adverse events

Our results showed no incidence of postintravitreal injection endophthalmitis. Ocular adverse effects occurred only in two patients. One patient developed a retinal flap tear after a second ranibizumab injection to treat myopic CNV. That tear was treated with laser photocoagulation and did not progress further. The other patient developed vitreous hemorrhage after the first bevacizumab injections to treat diabetic macular edema. This patient was followed to observe the vitreous hemorrhage, which resolved spontaneously.

Intravitreal triamcinolone acetate injection was used in 39 patients (42 eyes). A total of 53 injections were performed in those eyes. Intraocular hypertension that required antiglaucoma treatment within 1 month after the injection occurred in 10 eyes (24%). However, none of the eyes required surgical intervention [Figure 2]. On the other hand, intraocular pressure was found to be constantly elevated after anti-VEGF injection in 4 eyes (1.6%) out of 249 eyes. Two of them were treated for Age-related macular degeneration (AMD) and two for retinal vein occlusion.

Figure 2

Optical coherent tomography of right eye for a patient with diabetic macular edema; (a) macular edema before treatment; (b) 1 month post triamcinolone acetate intravitreal injection revealed resolution of the edema

Systemic adverse events occurred in seven patients (3.3%). These included death, ischemic heart diseases, and cerebrovascular accidents (CVA). Table 5 summarizes those cases.

Table 5

Patients who develop adverse events after injections

Many patients in our study had lost their follow-up visits after the intravitreal injections. The total number of patients who lost the follow-up were 81 patients. Seven of them were referred back to their local hospitals, and out the nine patients who developed ocular and systemic adverse events, seven of them - including the deaths - did not show up after the events. The remaining 67 patients (31% of total patients of the study) failed to follow-up to our clinic due to unknown reasons.

Discussion

The trend for intravitreal therapy is increasing in the ophthalmology practice. It is used to treat different retinal disorders [Figure 3]. There are many studies and trials in literature describing clinical effects and benefits for these agents. The introduction of many safe agents that are injected intravitreally led to dramatic advances in treating many common retina disorders such as diabetic macular edema, ARMD, and retinal venous occlusions. In the era of laser therapy alone, the aim of treatment was mainly to stabilize vision and prevent moderate and severe visual loss. Currently, visual improvement is considered to be a primary goal in most of the clinical studies and trials of intravitreal therapy. Researchers are still going on either to discover new agents or to modify current agents to maximize their benefits and minimize the adverse events. In addition, some authors proposed that combined therapy including different agents and the laser is also beneficial especially to reduce the number of injections per patient who requires multiple injections.

Figure 3

Different agents used intravitreally to treat different disorders. tPA: Tissue plasminogen activator, CNV: Choroidal neovascularization, VMT: Vitreo-macular traction, MH: Macular hole

In our study, the three common indications that required intravitreal injections were: Diabetic macular edema (50.9%), CNV (24.3%), and retinal vein occlusions (11.5%). This conclusion is similar to what was found by a study conducted in eight Latin American Institutions, including 1173 patients.[13]

Different intravitreal substances were used in our institute. However, 99.6% of all substances were bevacizumab (59.8%), ranibizumab (32.3%), and triamcinolone acetate (7.5%). One study was conducted at Bascom Palmer Eye Institute included 10,142 injections over a period of 2½ years (June 2007 to January 2010) revealed that bevacizumab was used in 72.12% of all injections, followed by triamcinolone acetate (with and without preservatives) in 18.2%, and ranibizumab in 9.67%.[14] The low cost of bevacizumab, which is an off-labeled substance for intraocular use, over the ranibizumab, which is FDA-approved therapy for many retinal disorders, is the most likely reason for the popular use of bevacizumab over other anti-VEGF agents. Triamcinolone acetate is not considered as a first-line treatment by many retina specialists mainly due to the risk of development of cataract and ocular hypertension.

Serious adverse effects after intraocular injections are very rare in clinical practice. They can be classified as ocular or systemic. They can be also classified according to their effects on vision as minor (sight-nonthreatening) or major (sight-threatening). The most common minor complication is subconjunctival hemorrhage. This can occur in around 64% of eyes.[13] In our patients, this was not registered consistently since the majority of patients were re-assessed after 1 month from the injection, by the time any subconjunctival hemorrhage is usually resolved. SAE are reported in many studies in literature. Ocular SAE occurred in two. However, they did not have any further consequences in long-term follow-up visits. We did not record any cases with endophthalmitis, uveitis, or retinal detachment. In one large comprehensive review study, the following incidences were found: Endophthalmitis (0.2% per injection), retinal detachment (0.9% per injection), retinal breaks (0.3% per injection), and uveitis (6.3% per injection).[1]

Systemic adverse events after intravitreal injections can occur particularly after using anti-VEGF. However, these events are reported in patients with comorbid conditions, such as diabetes mellitus and hypertension, without receiving anti-VEGF intravitreal injections. The association between the anti-VEGF intravitreal injections and the systemic adverse events is not proven and still under investigations. Indirect evidence was revealed by few studies, and that was by measuring the VEGF after anti-VEGF injections.[151617] Those studies showed that the level of VEGF was reduced significantly after the intravitreal injections of anti-VEGF. Vascular thrombotic events are the likely adverse events after anti-VEGF injections, and occasionally they can be fatal. These events include CVA, myocardial infarctions, gastrointestinal (GI) bleeding, and others. Many studies suggested that anti-VEGF intravitreal injections are responsible for postinjection thromboembolic (TE) events.[13181920] The rates of some systemic adverse events were found in many studies as follow total death (0.4–5.7%); nonfatal myocardial infarction (0.4–1.4%); nonfatal CVA (0.5–1.4%); GI bleeding (2.2–9%).[132021] In our patients, as summarized in Table 5, seven patients were reported to have systemic events after anti-VEGF injections. Those events seem that they are related to TE pathophysiology. However, many of the patients developed the event after many months from the last injection of anti-VEGF. Hence, the direct relationship between the anti-VEGF and development of the adverse event is still ambiguous. We know that these patients have multiple comorbid conditions like diabetes mellitus and blood hypertension, which themselves are strongly associated with the development of TE events. A time frame from the time of anti-VEGF injections and the development of TE events is not yet clear. The anti-VEGF substances may induce changes such as inhibition of new vasculogenesis in many organs and hence will result in the development of TE events. However, the duration of this process is unknown and needs further elaboration by future researchers.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.