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Abstract

Retinal vein occlusion is a common cause of vision loss due to a blockage of blood flow within the vasculature of the retina. Multiple therapeutic options, including vascular endothelial growth factor inhibitors and corticosteroids, exist to help ameliorate the complications of this condition. Still, unanswered questions about the most efficient treatment approach remain. Though pharmacists will likely not be involved in the hands-on administration of intravitreal medications, they can play a major role in ensuring patients receive appropriate, affordable care.

Introduction

Retinal vein occlusion (RVO) represents the second most common vascular cause for vision loss, following only diabetic retinopathy.1 The condition involves a blockage of blood flow within the retinal vasculature. The system of classification for this disorder involves three primary types based on the location of the occlusion. These include central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), and hemiretinal vein occlusion (HRVO). Retinal vein occlusion contributes to substantial resource utilization, accounting for 12% to 24% higher medical spending compared to similar patients without the disease.2 Historically, treatment was limited to surgical intervention alone, specifically for BRVO; however, recent advances in pharmacologic therapies have revolutionized the approach to management for this challenging condition.1

Pathophysiology

The central retinal vein carries blood from the retina. In the lamina cribrosa, a narrow mesh-like area near the entrance to the optic nerve, the central retinal vein and artery couple. Within this narrow passageway, the coupling of the vasculature may lead to venous constriction and subsequent impaired blood flow and thrombus formation, ultimately causing CRVO.3,4

Tributaries that feed the central vein can also become blocked causing BRVO. Similarly to CRVO, BRVO occurs at the site of arteriovenous crossings, often as a result of the arterial compression on a vein, which limits blood flow and may ultimately cause the formation of a clot.3 Depending on the location of the blockage, BRVO is considered major (affecting the branches of the central retinal vein) or macular (affecting the macular vein).5 Unlike CRVO, BRVO involves only a partial blockage of blood flow.1

A third classification of RVO includes HRVO. This less-common type of RVO is seen in about 20% of affected eyes and occurs secondary to an anatomic variation that leads to occlusion of one of two trunks of the central retinal vein.3,6

Retinal vein occlusion is also categorized as ischemic or non-ischemic based on the presence and extent of retinal ischemia. Though no widely accepted definition of these terms exist, this grouping is thought to have important prognostic implications.6

Epidemiology and Risk Factors

In 2015, it was estimated that more than 28 million individuals worldwide had RVO, equating to 0.77% of the world’s population.7 The vast majority of RVO cases are of the BRVO variety, which is about 6 times more common than CRVO.7-9 In more than 90% of cases, RVO occurs in one eye, as opposed to bilaterally.8 Approximately 10% of patients with a history of BRVO in one eye will develop BRVO in the other eye; while this occurs only in 1% of patients initially affected by CRVO unilaterally.5,10

One of the most important risk factors for the development of RVO is age. Less than 0.4% of individuals aged 55 and under experience RVO, while the prevalence rises to 4.6% in those at least 80 years of age.8 It is estimated that the risk of RVO development is approximately 1.6 times higher with each 10-year increase in age.7

Outside of age, the most significant risk factor for the development of RVO is systemic hypertension, which is estimated to nearly triple the risk of developing RVO.7 Other cardiovascular risk factors include a history of myocardial infarction or stroke, as well as elevated levels of total cholesterol.7 Elevated creatinine, a concomitant diagnosis of glaucoma or obstructive sleep apnea, a history of smoking, or use of contraceptives that increase thrombus formation risk also increase the chances of developing RVO.1,5,7 Finally, hypercoagulable states, including elevated homocysteine levels or factor V Leiden mutations, also raise patient risk.1 Homocysteine levels higher than the upper limit of normal are more commonly found in patients with CRVO than with BRVO.11

Diabetes mellitus has historically been reported as an additional risk factor, though a recent meta-analysis did not identify a correlation between diabetes diagnosis and risk of RVO development.7,10 It is thought that the relationship between RVO and diabetes mellitus is more related to the fact that cardiovascular abnormalities, as previously mentioned, increase the risk of both conditions.12

Case 1, Question 1 – JK is a 76-year-old female with a past medical history significant for hyperlipidemia, hypothyroidism, hypertension, and gout. She currently takes atorvastatin 10 mg once daily, levothyroxine 188 mcg once daily, lisinopril 20 mg once daily, and allopurinol 100 mg twice daily. Which risk factors for the development of retinal vein occlusion does this patient have?

Presentation and Prognosis

Most patients with RVO will present with painless, moderately-to-severely decreased visual acuity in one eye.1 Visual acuity is most commonly measured using either the Snellen or the Early Treatment in Diabetic Retinopathy Study (ETDRS) letter charts where changes are measured based on how many fewer letters patients can read after the onset of disease, or how many additional can be clearly seen secondary to an intervention.13

Visual acuity is typically less impaired with BRVO as compared to CRVO and the majority of these patients will experience improvement in their symptoms over time without intervention.8,14 Improvement in visual acuity changes without treatment secondary to BRVO is more likely in younger patients and in those who present with less impaired vision at baseline.14

While BRVO impacts patient wellbeing, CRVO reduces vision-related quality of life substantially more, especially when the disease affects both eyes.6,8 Without early treatment, prognosis is worse for CRVO patients than for those with BRVO. Whereas BRVO-induced visual acuity changes will improve over time without treatment in many cases, visual impairment secondary to CRVO actually worsens.15

A common symptom of RVO is macular edema. Macular edema occurs in RVO primarily due to excessive vascular endothelial growth factor (VEGF)-induced breakdown of the blood-retinal barrier, a barrier that typically restricts water flow into and out of the retina.16,17 Between 5% and 15% of patients with BRVO experience macular edema; however, about a quarter to a third of these cases are self-limiting.8 Macular edema is also a frequent complication of CRVO and requires early treatment.3 Improvement in symptoms is expected after the resolution of macular edema.14

Patients with CRVO are also more likely than BRVO patients to develop VEGF-mediated neovascularization and the formation of collateral vessels. While these alternative vascular pathways intend to redirect blood flow around the occlusion, their formation can lead to complications, such as neovascular glaucoma.1,3

As previously alluded to, the presence of ischemia is an important prognostic factor. Patients who experience non-ischemic visual acuity disturbances secondary to macular edema tend to fair better than those with ischemic disease, in which macular edema does not play a major role in decreasing visual acuity.1 Additionally, ischemic RVO increases the risk of neovascular glaucoma. This complication has been shown to occur in approximately one-fifth of patients with CRVO, but in up to 81% of patients with ischemic RVO.1

Treatment

Management of RVO begins with prompt identification and diagnosis of specific type (e.g., BRVO or CRVO), which will aid in making patient-specific treatment decisions. Treatment first involves targeting underlying modifiable risk factors as previously discussed. Lowering systolic blood pressure and elevated lipid levels and controlling diabetes mellitus lowers RVO risk.10 Further this has the added benefit of reducing the risk of myocardial infarction and stroke, which will further decrease RVO risk.

Beyond risk factor management, therapy for RVO involves VEGF inhibitors, intraocular corticosteroids, and several forms of medical intervention.10 Treatment should be individualized based on the type of RVO experienced and any resulting complications. There are no available therapies to specifically treat RVO; instead, treatment is focused on the adverse sequelae arising from the development of RVO.6 As such, medications and procedures targeting macular edema and neovascularization are the mainstays of therapy.

Though pharmacologic intervention is often used alongside medical procedures, a detailed discussion on the various non-pharmacological interventions for the treatment RVO, such as vitrectomy or panretinal photocoagulation and other forms of laser treatment, are beyond the scope of this activity.

Case 1, Question 2 – JK, our 76-year-old female patient from earlier, presents with significantly decreased visual acuity, but no eye pain. She is diagnosed by her ophthalmologist with a CRVO and associated macular edema. Which of the following is accurate about her prognosis and treatment plan?

A. The patient’s prognosis is likely better than if she presented with BRVO.
B. A wait-and-see approach would be the most appropriate for strategy for this patient.
C. Treatment with a VEGF inhibitor would reverse the occlusion and improve her vision.
D. The patient is more likely to develop neovascularization because of her CRVO diagnosis.

Vascular Endothelial Growth Factor Inhibitors

Five VEGF inhibitors – ranibizumab (Lucentis®), aflibercept (Eylea®), bevacizumab (Avastin®), brolucizumab (Beovu®), and pegaptanib (Macugen®) – are available on the market, though only ranibizumab and aflibercept are approved for use by the United States Food and Drug Administration (FDA) for the treatment of macular edema associated with RVO.18-20 Whereas bevacizumab is commonly used off-label for this condition, brolucizumab and pegaptanib are not currently used for this indication.10,12 That said, brolucizumab is currently in phase III studies for the treatment of patients with visual impairment due to macular edema secondary to BRVO and CRVO.21,22

Inhibitors of VEGF work in the eye by binding to two receptor tyrosine kinases, VEGFR1 and VEGFR2, which are the binding sites for VEGF-A. By inhibiting the binding site for VEGF-A, they work to reduce neovascularization and vascular leakage.18,19 Compared with bevacizumab, ranibizumab has a 100 to 140 times higher binding affinity for VEGF, while aflibercept is even greater.1

Ranibizumab

Ranibizumab is available as a 0.3 mg or 0.5 mg vial or prefilled syringe for intravitreal injection. Only the 0.5 mg strength is approved for the treatment of macular edema secondary to RVO.18 Beyond this indication, ranibizumab is also FDA-approved for use in neovascular (wet) age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy, and myopic choroidal neovascularization.18 For RVO, ranibizumab is to be dosed once monthly (approximately every 28 days).

The efficacy of ranibizumab for RVO-associated macular edema was established through two phase III prospective, randomized, placebo-controlled clinical trials (BRAVO and CRUISE). The aptly named BRAVO trial investigated the effectiveness and safety of ranibizumab 0.3 mg and 0.5 mg intraocular injections in patients with BRVO-associated macular edema.23 The study found that, in patients treated with the FDA-approved dose of 0.5 mg, visual acuity increased by an additional 11 letters compared to placebo. Additionally, more than double the number of patients achieved an improvement of at least 15 letters compared to placebo.

The CRUISE trial enrolled CVRO patients with resulting macular edema and was designed similarly to the BRAVO trial.24 The average difference in visual acuity gains between ranibizumab 0.5 mg and placebo were found to be a significant 14.1 letters from baseline at 6 months. While the difference in gains from placebo was similar between the BRAVO and CRUISE trial, it’s notable that the placebo group in the CRUISE trial experienced only a 0.8 letter gain from baseline as compared to a 7.3 letter gain from baseline in the BRAVO trial.23,24 This reemphasizes the earlier concept that visual acuity improves without treatment in patients with BRVO more substantially than can be expected with CRVO.

The HORIZON trial followed patients who completed the BRAVO or CRUISE trials and investigated outcomes for an additional 12 months.25 Patients were seen at least every 3 months and while patients with BRVO stayed relatively stable with less frequent monitoring, those with CRVO experienced a decline in vision without regular follow-up. The authors highlighted that therapy should be individualized after the initial 12 months of treatment.25

The idea of individualizing therapy was supported by the SHORE study, which compared ranibizumab monthly versus as needed after 7 monthly injections.26 Similar outcomes were seen between groups, despite patients in the “as needed” group receiving nearly half the number of injections. One small study further supported this concept, finding that only half of patients with BRVO required no additional therapy within 4 years, while a larger proportion of CRVO patients will likely need ongoing, long-term treatment.27

With regard to safety, nearly half of patients who receive ranibizumab experience conjunctival hemorrhage, while a smaller proportion experience eye pain, vitreous floaters, and intraocular pressure increases.18 Patients should have their intraocular pressure monitored before and 30 minutes after the injection. Additional warnings include a risk for endophthalmitis, which is an infection of the tissues or fluids inside the eyeball, and retinal detachment.18 No additional safety concerns arise with long-term use.25 Ranibizumab is contraindicated in patients with ocular or periocular infections and in those with known hypersensitivity to the drug or any of the medication’s excipients.18

Ranibizumab should be stored in the refrigerator, between 2° and 8° C (36° to 46° F), in the original carton until it is used. Both syringes and vials should be protected from light and must not be frozen.18

Currently there are no approved biosimilars for ranibizumab in the United States, though several are in development given that the market protection on ranibizumab expired in June 2020.28 The availability of these products is currently unknown and the indications for which the manufacturers of these products will seek approval is uncertain. That said, recent data supports one biosimilar’s use in RVO-associated macular edema.29

Aflibercept

Aflibercept gained FDA-approval for the treatment of RVO-associated macular edema in 2014.19 It shares many indications with ranibizumab, including neovascular (wet) AMD, DME, and diabetic retinopathy. For the indication of macular edema associated with RVO, aflibercept is to be dosed as 2 mg via intravitreal injection once every four weeks (approximately every 25 days).19 Given the increased binding affinity for VEGF, extended dosing intervals beyond monthly may be considered.30

Aflibercept was compared to placebo for macular edema associated with CRVO for up to 52 weeks in two phase III studies, COPERNICUS and GALILEO.31,32 A combined analysis of the trial data found that aflibercept improved visual acuity by an average of approximately 18 letters more than placebo compared to baseline at week 24.33 Further, the efficacy of aflibercept was maintained through 52 weeks using injections on an as needed basis, where the patients previously randomized to aflibercept received an average of 2.6 injections over 24 weeks.33

For BRVO, the VIBRANT study investigated the impact of aflibercept versus laser surgery for up to 52 weeks.34 This study found that at 6 months, patients who received monthly aflibercept had significantly improved visual acuity and significantly more patients achieved an improvement than the comparator group. The aflibercept group continued to experience statistically significantly better outcomes beyond 6 months, despite less frequent (every 8 weeks) injections. Moreover, approximately 80% of patients in the laser surgery group met the criteria to receive rescue aflibercept, while only 11% of patients treated with aflibercept were eligible for rescue laser treatment.34

The use of aflibercept in RVO was found to increase the risk of several adverse events compared to placebo. These include eye pain, conjunctival hemorrhage, an increase in intraocular pressure, corneal epithelium defects, vitreous floaters, ocular hyperemia, foreign body sensation in the eye, vitreous detachment, increased lacrimation, injection site pain, and the formation of cataracts. The product’s prescribing information suggests patients have their intraocular pressure monitored immediately after administration, though providers may find it prudent to monitor prior to the injection as well.19

Similar to ranibizumab, aflibercept is available in a pre-filled syringe or vial. Both should be refrigerated and kept between 2° and 8° C (36° to 46° F) prior to use. Care should be taken not to freeze the medication.19

Bevacizumab

Bevacizumab is FDA-approved for a variety of cancer types, but is routinely used off-label in practice for the treatment of macular edema associated with RVO.10,20 In 2015, bevacizumab was used about 1.5 times more frequently than both ranibizumab and aflibercept combined, despite not being FDA-approved for this indication.35 Two biosimilars are available for this product, including bevacizumab-AWWB (Mvasi®) and bevacizumab-BVZR (Zirabev®).36,37 While no data are available to support the use of biosimilar bevacizumab in RVO, their efficacy in this population is inferred based on the similarity to the reference product.

Bevacizumab is available in 100 mg/4 mL and 400 mg/16 mL vials. The standard dose of bevacizumab for RVO-associated macular edema is 1.25 mg, representing an injection volume of 0.05 mL. Bevacizumab, however, is only available in single-dose vials and does not contain preservatives, which adds to the complexity of partitioning small volume doses.1,20,36,37 Bevacizumab should be stored in the refrigerator until use.

The efficacy of bevacizumab was initially established in a 12-month study, which showed that, in patients with macular edema secondary to BRVO or CRVO for at least 3 months, bevacizumab improved visual acuity by approximately 16 letters on the ETDRS chart.38 Results were more pronounced in patients with BRVO than CRVO. These results prompted further study, which is described in more detail in the Comparative Efficacy Data section below.

Localized injections limit the adverse events typically seen with intravenous administration, including myocardial infarction and stroke.1 Still, systemic adverse events may occur, and include cardiovascular abnormalities. One large retrospective case series identified that 0.6% of patients treated with intravitreal bevacizumab experienced systemic blood pressure elevations; 0.5% had cerebrovascular accidents; and 0.4% experienced myocardial infarctions.39

Corticosteroids

Intravitreal corticosteroids may also be used in the treatment of RVO. Currently only dexamethasone intravitreal implant (IVI) 0.7 mg, under the trade name Ozurdex®, is FDA-approved for the treatment of macular edema secondary to either CRVO or BRVO.40 Unlike the VEGF inhibitors, this agent should be stored at room temperature prior to administration.

Dexamethasone IVI was studied for both BRVO- and CRVO-associated macular edema in the GENEVA study.41 Regardless of the RVO type, it was found that a significantly greater percentage of those treated with dexamethasone IVI experienced at least a 15-letter improvement in visual acuity compared to placebo 3 months after administration. Additionally, the time to visual acuity improvement was significantly shorter for dexamethasone-treated patients as well.41

Despite the fact that the IVI is intended to release dexamethasone for up to 6 months,42 efficacy was not found to be enduring. Studies have shown no benefit of dexamethasone IVI compared to placebo at 6 and 12 months for BRVO patients.41,43 Additional strategies, such as retreatment up to every 4 months, use of two or more implants at a time, and combining therapy with other adjunctive therapies appears to ameliorate these effects to give patients a lasting response.42,44

The role of intravitreal corticosteroids is limited by adverse events. Dexamethasone IVI is associated with cataract formation, cataract progression, and intraocular pressure increases in approximately 20% of treated patients.45 Ocular hypertension and vitreous hemorrhage are also relatively common, occurring in nearly 4% of patients.45 Dexamethasone IVI is contraindicated patients with ocular or periocular infections, patients with glaucoma who have cup to disc ratios of greater than 0.8, those with a torn or ruptured posterior lens capsule, and individuals with known hypersensitivity to any component of the product.40

Dexamethasone IVI is supplied in a single-use plastic applicator that should be stored at room temperature. If the product is to be administered in the fellow eye, a separate applicator should be used. Following administration, patients should be monitored for intraocular pressure increases.40

Intravitreal triamcinolone and fluocinolone acetonide have also been studied for this indication. For macular edema in CRVO, triamcinolone significantly improved the likelihood that patients would gain at least 15 letters from baseline compared to standard of care;46 however the same was not found for BRVO.47 From a safety standpoint, approximately two months after triamcinolone administration, up to nearly 10% of patients experience rebound central retinal thickening, a finding that is associated with worsening visual outcomes.48

Fluocinolone acetonide IVI has also been shown to have some effect in CRVO. However, visual acuity improvements were inconsistent and use was complicated by cataract formation in all phakic eyes (eyes with their natural lenses).49,50 While triamcinolone for injection and fluocinolone acetonide IVI are FDA-approved for various ophthalmic conditions, neither is approved for use in the treatment of RVO.

Comparative Data

Given the effectiveness of the VEGF inhibitors and dexamethasone IVI compared to placebo, comparative data to determine relative effectiveness between these agents is of a high value. Fortunately, a large number of studies, systematic reviews, and meta-analyses are available to clarify the comparative effectiveness and safety of these medications.

Comparative Efficacy Data for BRVO-associated macular edema

Bevacizumab 1.25 mg for BRVO-associated macular edema was established in the MARVEL study, which was a randomized, double-blind, head-to-head study with ranibizumab 0.5 mg.51 The study found similar improvements in visual acuity at 6 months between the treatment groups when dosed every 4 weeks as needed.

Beyond this, numerous systematic reviews and meta-analyses sought to compare the efficacy of VEGF inhibitors. The efficacy of the VEGF inhibitors, bevacizumab, ranibizumab, and aflibercept, has consistently been found to be similar for BRVO.52,53 In addition, a similar number of injections is expected to be needed to maintain therapeutic benefits between ranibizumab and aflibercept.54

Anti-VEGF medications have also shown consistent benefit over intravitreal corticosteroid injections for BRVO. Compared with patients who received intravitreal corticosteroids, those treated with a VEGF inhibitor experienced greater mean visual acuity, a higher likelihood of at least a 15-letter improvement using the ETDRS chart, and improved quality of life at 6 and 12 months.52,55 Anti-VEGF medications were found to improve visual acuity by over 9 letters more on average compared to dexamethasone IVI in BRVO patients.52,55

Comparative Efficacy Data for CRVO-associated macular edema

Bevacizumab 1.25 mg every 4 weeks was compared to aflibercept 2 mg for the treatment of macular edema associated with CRVO and HRVO in the SCORE2 study.56 Bevacizumab was found to be non-inferior to aflibercept in improving visual acuity in this patient population.

When comparing the efficacy of anti-VEGF medications with corticosteroids in CRVO, no significant differences were found with regard to the proportion of patients gaining at least 15 letters at 12 months.57 Visual acuity was more likely to be improved at 6 months, however, in VEGF-treated patients compared to those receiving dexamethasone IVI.58

Comparative Safety Data

Rates of adverse events were similar between bevacizumab and other anti-VEGF therapies in clinical studies. No differences in safety were noted between bevacizumab and ranibizumab in the MARVEL study.51 In SCORE2, adverse events were rare in both the aflibercept and bevacizumab groups. However, a greater proportion of patients in the bevacizumab group experienced elevations in intraocular pressure and 1 patient treated with bevacizumab developed endophthalmitis compared to 0 in the aflibercept group.56

It is anticipated that local adverse events are similar across anti-VEGF medications when used as an intravitreal injection for RVO.59 Additionally, a large retrospective, claims-based cohort study found similar rates of acute myocardial infarction, acute cerebrovascular disease, major bleeding, and all-cause hospitalization between VEGF inhibitors.60 Finally, though all products are labeled with a warning for endophthalmitis, this complication is rare, affecting less than 0.2% of VEGF inhibitor-treated patients.61

Patients treated with anti-VEGF medications have a lower risk of developing cataracts and intraocular pressure increases compared to corticosteroid-treated patients.52,62 Still, overall rates of adverse events are similar between patients, suggesting that with appropriate patient selection and close monitoring, dexamethasone IVI may be a reasonable option.62

To summarize, VEGF inhibitors are similarly efficacious and safe when compared to one another. These findings are meaningful as this allows flexibility in medication selection within the anti-VEGF class depending on patient and provider preference, medication tolerance (e.g., the emergence of adverse events with one agent should preclude its use moving forward), and insurance coverage. Further, VEGF inhibitors are more effective than dexamethasone IVI, making them the preferred pharmacologic option for most patients. However, while dexamethasone IVI may increase intraocular pressure and cataract risk compared to VEGF inhibitors, it requires less frequent administration and may be an appropriate option for certain patients, particularly those who have concerns about receiving frequent intravitreal injections.62

Inadequate treatment response

A situation may arise during the course of a patient’s care in which it is determined that the patient is experiencing an inadequate therapeutic response to the current regimen. A meta-analysis found that patients with persistent RVO-associated macular edema despite ranibizumab or bevacizumab treatment did not experience improved visual acuity when switching to aflibercept.63 However, certain patient groups may benefit, such as those with non-ischemic CRVO.64 More research is needed to determine how patients respond after switching from one VEGF inhibitor to another.

Those patients failing therapy with a VEGF inhibitor may be considered for treatment with dexamethasone IVI. Data supports this course of action in both BRVO and CRVO, though more frequent administration of dexamethasone IVI should be considered for those with CRVO.65

Combination therapy including a VEGF inhibitor, dexamethasone IVI, and surgical intervention may also be considered, though limited data exist to support this approach. In patients who failed aflibercept or dexamethasone IVI monotherapy, a combination of the two agents can be effective for reducing macular edema.66 Combination VEGF inhibitor therapy, followed by laser or dexamethasone IVI may help reduce injection burden and improve outcomes.67 However, one-year results from a prospective, randomized study showed no additional benefit of adding macular laser to ranibizumab therapy.68

Another intervention that was studied was the use of bevacizumab monthly for three injections followed by dexamethasone IVI.69 Sequential therapy was found to be less effective for BRVO than dexamethasone IVI monotherapy but similarly effective for CRVO. A separate study, however, found synergistic benefit when combining these two agents, with almost 20% of patients not requiring retreatment after 6 months.70 Needless to say, questions remain about the ideal approach to combination therapy for the treatment of RVO complications.

Guideline Recommendations on Pharmacologic Therapy

Given the amount of primary literature on the topic, established guidelines can help pharmacists and other health care providers understand where each agent best fits in the treatment of RVO. Two sets of guidelines exist – the 2019 Preferred Practice Pattern from the American Academy of Ophthalmology (AAO) and the 2019 European Society of Retina Specialist (EURETINA) guidelines.10,12

The recommendations in these guidelines align nicely, suggesting general consensus on the approach to treatment. Prior to instituting pharmacologic intervention both guidelines emphasize risk reduction as the first line of therapy.10,12 With regard to treatment, VEGF inhibitors and corticosteroids are recommended for RVO-associated macular edema, while the former may also provide temporary aid for neovascularization in patients also treated with laser therapy.10

The guidelines suggest VEGF inhibitors as first line options for both BRVO and CRVO and that therapy should be individualized based on patient response. Corticosteroids should be considered in the setting of an inadequate response to anti-VEGF therapy or in patients who are unwilling to receiving monthly injections, though the latter will still require intraocular pressure monitoring 2 to 8 weeks after implantation.12 It is stressed that the risks of cataracts and glaucoma must be weighed when determining the role for intravitreal corticosteroids, including dexamethasone and triamcinolone.10

Role of the Pharmacist

While pharmacists may not necessarily be administering intravitreal injections to patients, they can still play a major role in the treatment of RVO. By assisting in the management of risk factors, aiding in patient identification and appropriate medication selection, and counseling patients on various aspects of their care, pharmacists can positively impact patient outcomes.

As mentioned, care for RVO begins by decreasing the risk of future occlusion. Those with RVO formation in one eye should be counseled on the risk of future RVO in the other eye. To reduce this risk, pharmacists can play an active role in helping mitigate RVO risk factors, including controlling systemic hypertension, diabetes mellitus, and elevated lipid levels. This can include recommending appropriate pharmacologic therapy for these conditions, counseling on the importance of medication adherence for prescribed agents, and discussing nonpharmacologic interventions, such as dietary and lifestyle changes.

Pharmacists can help ensure these agents are being appropriately prescribed for RVO. For example, given the availability of multiple doses of ranibizumab (0.3 mg and 0.5 mg), pharmacists can ensure the correct dose of 0.5 mg is used, since 0.3 mg is indicated only for DME.18 Storage is also an important consideration with these agents. Pharmacists should educate patients on proper storage if the patient will be taking the medication from the pharmacy to the provider’s office for administration.

Pharmacists can assist in the selection of appropriate therapy. Recommendations should be tailored to individual patients, considering the patient’s previous medication trials and insurance coverage. To that end, pharmacists may also play a role in helping aid patients afford their medications. Pharmacists can help by submitting prior authorization requests, by evaluating patient eligibility for copay assistance programs, and by identifying copay cards to help with high out-of-pocket costs.71-73

Pharmacists should also educate patients on expectations. Immediate resolution of visual disturbances is not realistic. Instead, patients should be educated that depending on their diagnosis (e.g., BRVO or CRVO), they have a greater chance of reverting to a near normal or may require ongoing therapy. Patients should also be counseled on adverse events they may experience and which symptoms to watch for. For example, patients treated with VEGF inhibitors should be counseled on the possibility of endophthalmitis. They should be informed that it may present as white or yellow discharge on or inside the eyelid, eye pain and redness, or sudden-onset photophobia.74 Given that patients will have impaired vision, pharmacists should also counsel on modifications to consider that can reduce the risk of injury, such as removing trip hazards and considering the addition of handrails around the home.

Case 2, Question 1 PH presents with new onset reduced visual acuity and is subsequently diagnosed with a CRVO with macular edema. He has a past medical history significant for uncontrolled hypertension. He does not have any insurance coverage at this time, as he recently lost his job. He recently stopped filling his antihypertensive medications due to cost. Choose and appropriate medication for the patient’s CRVO diagnosis. Also suggest an appropriate dosing regimen.

Case 2, Question 2 Based on your selection of a pharmacologic option for PH in Case 2, Question 1, which counseling points should you include about the medication selected?

Conclusion

Retinal vein occlusion is a common vascular disorder that can lead to devastating consequences for patients. Beyond the economic burden, patients may experience lasting reduced visual acuity and diminished quality of life. Despite few pharmacologic options and a wealth of research on the topic, there remain some unanswered questions about the best treatment approach. Pharmacists can play a role in controlling underlying risk factors, ensuring appropriate treatment, and helping patients afford costly medications. As more data emerge and the role of the pharmacist in RVO continues to develop, it is the hope that treatment efficiency and outcomes will continue to improve.

References

  1. MacDonald D. The ABCs of RVO: a review of retinal venous occlusion. Clin Exp Optom. 2014;97:311-323.
  2. Fekrat S, Shea AM, Hammill BG, et al. Resource use and costs of branch and central retinal vein occlusion in the elderly. CurrMedResOpin. 2010;26(1):223-230.
  3. Keren S, Loewenstein A, Coscas G. Pathogenesis, prevention, diagnosis and management of retinal vein occlusion. World J Ophthalmol. 2014;4(4):92-112.
  4. Williamson TH. A "throttle" mechanism in the central retinal vein in the region of the lamina cribrosa. Br J Ophthalmol. 2007;91(9):1190-1193.
  5. Cochran ML, Mahabadi N, Czyz CN. Branch retinal vein occlusion. [Updated 2020 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020. Accessed at: https://www.ncbi.nlm.nih.gov/books/NBK535370/
  6. Khayat M, Williams M, Lois N. Ischemic retinal vein occlusion: characterizing the more severe spectrum of retinal vein occlusion. Surv Ophthalmol. 2018;63(6):816-850.
  7. Song P, Xu Y, Zha M, et al. Global epidemiology of retinal vein occlusion: a systematic review and meta-analysis of prevalence, incidence, and risk factors. J Glob Health. 2019;9(1):010427.
  8. Laouri M, Chen E, Looman M, Gallagher M. The burden of disease of retinal vein occlusion: review of the literature. Eye (Lond). 2011;25(8):981-988.
  9. Zhou JQ, Xu L, Wang S, et al. The 10-year incidence and risk factors of retinal vein occlusion: the Beijing eye study. Ophthalmology. 2013;120(4):803-808.
  10. Flaxel CJ, Adelman RA, Bailey ST, et al. Retinal vein occlusions preferred practice pattern. Ophthalmology. 2020;127(2):P288-P320.
  11. Cho BJ, Bae SH, Park SM, et al. Comparison of systemic conditions at diagnosis between central retain vein occlusion and branch retinal vein occlusion. PLoS One. 2019;14(8):e0220880.
  12. Schmidt-Erfurth U, Garcia-Arumi J, Gerendas BS, et al. Guidelines for the management of retinal vein occlusion by the European Society of Retina Specialists (EURETINA). Ophthalmologica. 2019;242(3):123-162.
  13. Shamir RR, Friedman Y, Joskowicz L, et al. Comparison of Snelle and Early Treatment Diabetic Retinopathy Study charts using a computer simulation. Int J Ophthalmol. 2016;9(1):119-123.
  14. Hayreh SS, Zimmerman MB. Branch retinal vein occlusion: natural history of visual outcome. JAMA Ophthalmol. 2014;132(1):13-22.
  15. McIntosh RL, Rogers SL, Lim L, et al. Natural history of central retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2010;117(6):1113-1123.
  16. Nishinaka A, Inoue Y, Fuma S, et al. Pathophysiological role of VEGF on retinal edema and nonperfused areas in mouse eyes with retinal vein occlusion. Invest Ophthalmol Vis Sci. 2018;59(11):4701-4713.
  17. Soubrane G, Coscas G. Pathogenesis of serous detachment of the retina and pigment epithelium. In: Retina. 5th ed. Ed: Hinton DR. Saunders; 2013:618-623.
  18. Lucentis [package insert]. South San Francisco, CA: Genentech; 2018.
  19. Eylea [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; 2019.
  20. Avastin [package insert]. South San Francisco, CA: Genentech; 2020.
  21. gov. Assessing the efficacy and safety of brolucizumab versus aflibercept in patients with visual impairment due to macular edema secondary to branch retinal vein occlusion (RAPTOR). Accessed at: https://www.clinicaltrials.gov/ct2/show/NCT03802630. Updated November 2, 2020. Accessed November 13, 2020.
  22. gov. Assessing the efficacy and safety of brolucizumab versus aflibercept in patients with visual impairment due to macular edema secondary to central retinal vein occlusion (RAVEN). Accessed at: https://www.clinicaltrials.gov/ct2/show/NCT03810313. Updated September 14, 2020. Accessed November 13, 2020.
  23. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1102-1112.
  24. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1124-1133.
  25. Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular edema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012;119(4):802-809.
  26. Campochiaro PA, Wykoff CC, Singer M, et al. Monthly versus as-needed ranibizumab injections in patients with retinal vein occlusion: the SHORE study. Ophthalmology. 2014;121(12):2432-2442.
  27. Campochiaro PA, Sophie R, Pearlman J, et al. Long-term outcomes in patients with retinal vein occlusion treated with ranibizumab: the RETAIN study. Ophthalmology. 2014;121(1):209-219.
  28. Mehr S. Who are the key Lucentis biosimilar players to watch? Biosimilars Review & Report. 2020. Available at: https://biosimilarsrr.com/2020/01/16/who-are-the-key-lucentis-biosimilar-players-to-watch/ Accessed November 13, 2020.
  29. Sharma S, RE-ENACT 2 Study Investigators Group, Khan M, Chaturvedi A. A multicenter, retrospective study (RE-ENACT 2) on Razumab™ (world's first biosimilar ranibizumab) in retinal vein occlusion. Ophthalmol Ther. 2020;9(3):625-639.
  30. Casselholm de Salles M, Amrén U, Kvanta A, Epstein DL. Injection frequency of aflibercept versus ranibizumab in a treat-and-extend regimen for central retinal vein occlusion: a randomized clinical trial. Retina. 2019;39(7):1370-1376.
  31. Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am JOphthalmol. 2013;155(3):429–437.
  32. Korobelnik JF, Holz FG, Roider J, et al. Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: one-year results of the phase 3 GALILEO study. Ophthalmology. 2014;121(1):202-208.
  33. Pielen A, Clark WL, Boyer DS, et al. Integrated results from the COPERNICUS and GALILEO studies. Clin Ophthalmol. 2017;11:1533-1540.
  34. Clark WL, Boyer DS, Heier JS, et al. Intravitreal aflibercept for macular edema following branch retinal vein occlusion: 52-week results of the VIBRANT study. Ophthalmology. 2016;123(2):330-336.
  35. Parikh R, Ross JS, Sangaralingham LR, et al. Trends of anti-vascular endothelial growth factor use in ophthalmology among privately insured and Medicare advantage patients. Ophthalmology. 2017;124(3):352-358.
  36. Mvasi [package insert]. Thousand Oaks, CA: Amgen Inc.; 2019.
  37. Zirabev [package insert]. New York, NY: Pfizer Inc.; 2019.
  38. Prager F, Michels S, Kriechbaum K, et al. Intravitreal bevacizumab (Avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of a prospective clinical trial. Br J Ophthalmol. 2009;93(4):452-456.
  39. Wu L, Martínez-Castellanos MA, Quiroz-Mercado H, et al. Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol. 2008;246(1):81-87.
  40. Ozurdex [package insert]. Madison, NJ: Allergan USA, Inc.; 2020.
  41. Haller JA, Bandello F, Belfort R Jr, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117(6):1134-1146.
  42. Dugel PU, Capone A Jr, Singer MA, et al. Two or more dexamethasone intravitreal implants in treatment-naïve patients with macular edema due to retinal vein occlusion: subgroup analysis of a retrospective chart review study. BMC Ophthalmol. 2015;15:118.
  43. Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118(12):2453-2460.
  44. Yoon YH, Kim JW, Lee JY, et al. Dexamethasone intravitreal implant for early treatment and retreatment of macular edema related to branch retinal vein occlusion: the multicenter COBALT study. Ophthalmologica. 2018;240(2):81-89.
  45. Tufail A, Lightman S, Kamal A, et al. Post-marketing surveillance study of the safety of dexamethasone intravitreal implant in patients with retinal vein occlusion or noninfectious posterior segment uveitis. Clin Ophthalmol. 2018;12:2519-2534.
  46. Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9):1101-1114.
  47. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular Edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127(9):1115-1128.
  48. Dikmetas O, Kuehlewein L, Gelisken F. Rebound phenomenon after intravitreal injection of triamcinolone acetonide for macular edema. Ophthalmologica. 2020.
  49. Ramchandran RS, Fekrat S, Stinnett SS, Jaffe GJ. Fluocinolone acetonide sustained drug delivery device for chronic central retinal vein occlusion: 12-month results. Am J Ophthalmol. 2008;146(2):285-291.
  50. Jain N, Stinnett SS, Jaffe GJ. Prospective study of a fluocinolone acetonide implant for chronic macular edema from central retinal vein occlusion: thirty-six-month results. Ophthalmology. 2012;119(1):132-137.
  51. Narayanan R, Panchal B, Das T, et al. A randomised, double-masked, controlled study of the efficacy and safety of intravitreal bevacizumab versus ranibizumab in the treatment of macular oedema due to branch retinal vein occlusion: MARVEL report no. 1. Br J Ophthalmol. 2015;99(7):954-959.
  52. Shalchi Z, Mahroo O, Bunce C, Mitry D. Anti-vascular endothelial growth factor for macular oedema secondary to branch retinal vein occlusion. Cochrane Database Syst Rev. 2020;7(7):CD009510.
  53. Spooner K, Hong T, Fraser-Bell S, Chang AA. Current outcomes of anti-VEGF therapy in the treatment of macular oedema secondary to branch retinal vein occlusions: a meta-analysis. Ophthalmologica. 2019;242(3):163-177.
  54. Pichi F, Elbarky AM, Elhamaky TR. Outcome of "treat and monitor" regimen of aflibercept and ranibizumab in mcular edema secondary to non-ischemic branch retinal vein occlusion. Int Ophthalmol. 2019;39(1):145-153.
  55. Gao L, Zhou L, Tian C, et al. Intravitreal dexamethasone implants versus intravitreal anti-VEGF treatment in treating patients with retinal vein occlusion: a meta-analysis. BMC Ophthalmol. 2019;19(1):8.
  56. Scott IU, VanVeldhuisen PC, Ip MS, et al. Effect of bevacizumab vs aflibercept on visual acuity among patients with macular edema due to central retinal vein occlusion: the SCORE2 randomized clinical trial. JAMA. 2017;317(20):2072-2087.
  57. Qian T, Zhao M, Wan Y, et la. Comparison of the efficacy and safety of drug therapies for macular edema secondary to central retinal vein occlusion. BMJ Open. 2018;8(12):e022700.
  58. Ford JA, Shyangdan D, Uthman OA, et al. Drug treatment of macular oedema secondary to central retinal vein occlusion: a network meta-analysis. BMJ Open. 2014;4(7):e005292.
  59. Deonandan R, Jones S. Anti-vascular endothelial growth factor drugs for the treatment of retinal conditions: a review of the safety [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2017.
  60. Maloney MH, Payne SR, Herrin J, et al. Risk of systemic adverse events after intravitreal bevacizumab, ranibizumab, and aflibercept in routine clinical practice. Ophthalmology. 2020:S0161-6420(20)30782-X.
  61. Xu K, Chin EK, Bennett SR, et al. Endophthalmitis after intravitreal injection of vascular endothelial growth factor inhibitors: management and visual outcomes. Ophthalmology. 2018;125(8):1279-1286.
  62. Ming S, Xie K, Yang M, et al. Comparison of intravitreal dexamethasone implant and anti-VEGF drugs in the treatment of retinal vein occlusion-induced oedema: a meta-analysis and systematic review. BMJ Open. 2020;10(6):e032128.
  63. Spooner K, Hong T, Bahrami B, Chang A. A meta-analysis of patients with treatment-resistant macular oedema secondary to retinal vein occlusions following switching to aflibercept. Acta Ophthalmol. 2019;97(1):15-23.
  64. Khurana RN, Chang LK, Bansal AS, et al. Aflibercept for previously treated macular edema associated with central retinal vein occlusions: 1-year results of the NEWTON study. Ophthalmol Retina. 2018;2(2):128-133.
  65. Georgalas L, Tservakis I, Kiskira EE, et al. Efficacy and safety of dexamethasone intravitreal implant in patients with retinal vein occlusion resistant to anti-VEGF therapy: a 12-month prospective study. Cutan Ocul Toxicol. 2019;38(4):330-337.
  66. Giuffrè C, Cicinelli MV, Marchese A, et al. Simultaneous intravitreal dexamethasone and aflibercept for refractory macular edema secondary to retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol. 2020;258(4):787-793.
  67. Horner F, Lip PL, Mushtaq B, et al. Combination therapy for macular oedema in retinal vein occlusions: 3-year results from a real-world clinical practice. Clin Ophthalmol. 2020;14:955-965.
  68. Song S, Yu X, Zhang P, et al. Combination of ranibizumab with macular laser for macular edema secondary to branch retinal vein occlusion: one-year results from a randomized controlled double-blind trial. BMC Ophthalmol. 2020;20(1):241.
  69. Mayer WJ, Remy M, Wolf A, et al. Comparison of intravitreal bevacizumab upload followed by a dexamethasone implant versus dexamethasone implant monotherapy for retinal vein occlusion with macular edema. Ophthalmologica. 2012;228(2):110-116.
  70. Singer MA, Bell DJ, Woods P, et al. Effect of combination therapy with bevacizumab and dexamethasone intravitreal implant in patients with retinal vein occlusion. Retina. 2012;32(7):1289-1294.
  71. Lucentis Access Solutions. Accessed at: https://www.genentech-access.com/hcp/brands/lucentis.html. Accessed November 19, 2020.
  72. Eylea patient assistance program. Accessed at: https://hcp.eylea.us/eylea4u/patient-support/patient-assistance-program. Accessed November 19, 2020.
  73. Allergan patient assistance program. Accessed at: https://www.abbvie.com/patients/patient-assistance/allergan-patient-assistance-program.html. Accessed November 19, 2020.
  74. American Society of Retina Specialists. Endophthalmitis. 2016. Accessed at: https://www.asrs.org/patients/retinal-diseases/29/endophthalmitis. Accessed November 19, 2020.