JDescription
Sickle cell retinopathy is a known complication of sickle cell disease. Sickle cell retinopathy is characterized by occlusion of the retinal vasculature resulting in ischemia and infarction of the retina and is classified into nonproliferative and proliferative subtypes. Patients with the latter subtype may experience serious vision impairments, including vision loss. Vascular endothelial growth factor inhibitors such as bevacizumab have been proposed as a treatment to improve visual function in patients with sickle cell retinopathy.

Summary of Evidence
For individuals with sickle cell retinopathy (SCR) who receive intravitreal bevacizumab, the evidence includes a single-center retrospective study, a case series, and multiple case reports. Relevant outcomes are symptoms, functional outcomes, change in disease status, morbid events, and treatment-related morbidity. Results of the retrospective study suggest that, in patients with undetached proliferative sickle retinopathy (PSR), intravitreal bevacizumab is better than other available treatment modalities (including laser photocoagulation and surgery) in terms of improving outcomes without resulting in complications. Case series and multiple case reports have described the use of intravitreal bevacizumab either as adjunctive therapy (used together with laser photocoagulation) or monotherapy to facilitate resolution of neovascularization and/or vitreous hemorrhage, and prevent recurrences. One case report described another application of bevacizumab as a presurgical adjunctive agent to decrease the risk of intraoperative bleeding and facilitate dissection of sea fan neovascular structures. No complications of bevacizumab use were reported in any studies except 1 case in which hyphema was observed in the treated eye. Despite generally favorable findings, the literature is limited overall. Future, well-designed studies are needed to further elucidate the role of intravitreal bevacizumab in the management of SCR. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with SCR who receive intravitreal vascular endothelial growth factor (VEGF) inhibitors other than bevacizumab, the evidence includes a single-center retrospective study and 1 case report. Relevant outcomes are symptoms, functional outcomes, change in disease status, morbid events, and treatment-related morbidity. In a retrospective study of patients with PSR, ranibizumab and aflibercept were used in cases of scarcity of bevacizumab. All 11 eyes treated with either ranibizumab or aflibercept demonstrated good outcomes; furthermore, eyes that did not initially respond to aflibercept responded when treatment was changed to bevacizumab, or vice versa. It is uncertain whether one VEGF inhibitor is superior to another. In addition, 1 case report described the successful use of intravitreal ranibizumab as an adjunct to laser photocoagulation in the management of PSR, with no observed adverse events. Future, well-designed studies are needed to further clarify the role of VEGF inhibitors other than bevacizumab in the management of SCR. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Background
Sickle Cell Retinopathy
Sickle cell disease (SCD) is an autosomal recessive genetic disorder caused by a point mutation in the beta (β) globin chain of the hemoglobin molecule, which decreases the ability of red blood cells to carry oxygen.¹ It is the most common inherited blood disorder, affecting an estimated 70,000 to 100,000 Americans.^1,2 In the United States, the disease is more common in individuals of African descent, including African Americans; Hispanic-Americans from Central and South America; and those of Middle Eastern, South Asian, and Mediterranean descent.² It is estimated that SCD occurs in approximately 1 out of every 365 and 16,300 Black/African American and Hispanic American births, respectively. There are several types of SCD, with the most common types being HbSS (homozygous disease), HbSC (heterozygous disease), and HbS/β-thalassemia (another heterozygous genotype). About 1 in 13 Black or African American babies are born with sickle cell trait (HbAS), an asymptomatic carrier state. Globally, the distribution of sickle hemoglobin overlaps mostly with areas affected by malaria; data have shown HbAS protects individuals against severe malaria.

Sickle cell retinopathy (SCR) is an ocular manifestation of the spectrum of SCD. In patients with SCD, local hypoxic conditions alter the shape of red blood cells into a rigid, sickle shape.³ These sickle-shaped red blood cells are less pliable than normal and become trapped in small blood vessels, including in various structures of the eye. Sickle cell retinopathy is therefore characterized by occlusion of the peripheral retinal vasculature, resulting in retinal ischemia. Depending on the absence or presence of vasoproliferative changes, SCR is stratified into nonproliferative and proliferative subtypes.

Goldberg classified SCR into 5 stages (Table 1) according to the pathophysiological progression of the disease and examination findings that are associated with each stage.⁴ Stages I to II represent nonproliferative SCR while stages III to V represent proliferative SCR.⁵ Vitreous hemorrhage (stage IV) and retinal detachment (stage V) are the most common causes of vision loss in patients with SCR, a condition that is typically asymptomatic until such complications occur.⁶

Proliferative sickle retinopathy (PSR) affects up to 40% and 20% of patients with HbSC and HbSS, respectively.⁷ The incidence of vision loss in patients with HbSS and HbSC affected by PSR has been reported as 31 per 1000 eyes compared with 1.4 per 1000 eyes in patients with nonproliferative disease.

Table 1. Goldberg Classification of Sickle Cell Retinopathy

Stage	Description
I	Peripheral arteriolar occlusion
II	Arteriovenous anastomosis at the retinal border
III	Peripheral neovascularization with fibrous proliferation (sea fan)
IV	Vitreous hemorrhage1
V	Tractional retinal detachment

¹ Commonly a result of bleeding from the neovascularization.

Screening and Diagnosis
Regular retinal exams are important for the early-stage diagnosis of SCR.⁸ Several imaging modalities are used in the screening and diagnostic testing of SCR.⁹ Fluorescein angiography is used to reveal abnormal blood vessels (particularly sea fan-shaped vessels) in the retina, and areas without blood flow. Spectral-domain optical coherence tomography is used to identify areas of retinal thinning, and optical coherence tomography angiography can reveal abnormalities in the retinal microvasculature in both proliferative and nonproliferative SCR.⁷

Management
Treatment protocols for SCR are not standardized; however, they share the common goal to reduce and prevent complications of ischemia, infarction, and subsequent neovascularization.⁶ Specifically, the aim of treatment is to prevent progression to SCR stages IV and V, which are associated with vision loss.⁷

Observation only (i.e., no intervention) may be indicated for small, asymptomatic, sea fan neovascular lesions or lesions shown to autoinfarct (spontaneously regress) with decreased vascularization.⁹ However, treatment may be necessary for rapidly growing and vascularized proliferative lesions. Although there is no evidence-based, widely-accepted treatment algorithm, laser photocoagula­tion is the current mainstay of treatment for PSR.⁷ Laser photocoagula­tion of large, ischemic areas can prevent the release of proangiogenic factors that promote the proliferation of new, abnormal blood vessels.⁹ However, evidence in favor of laser anticoagulation is not very strong.⁵ A 2022 systematic review concluded that no studies have conclusively demonstrated that laser photocoagulation induces regression of PSR or prevents new occurrences when compared to observation.¹⁰ Surgical management for SCR is reserved for vitreous hemorrhage that is bilateral, non-clearing, or in a monocular patient; or retinal detachment.^7,5 Vitrectomy is a common surgical procedure for clearing vitreous hemorrhage and facilitating retinal reattachment.

In recent years, there have been many advances in systemic therapies for SCD. Systemic therapies (e.g., red blood cell exchange transfusions, hydroxyurea, voxelotor, crizanlizumab, gene therapies) may have a role in prophylactic management of SCR.^9,5, These therapies reduce total sickle hemoglobin red cells and promote adequate blood flow and tissue perfusion; however, it is unknown how they may influence the development and progression of SCR.⁷ While health outcomes and mortality rates have improved in the past few decades due to better diagnosis and treatments for SCD, disease management is still based on limited clinical information in adults.² Further research is needed on evidence-based management approaches, particularly those that improve quality of life, increase longevity, and mitigate complications such as SCR. Allogeneic stem-cell therapy from human leukocyte antigen-matched donors remains the only known cure for SCD, although studies on gene therapy have been promising.¹¹

Vascular Endothelial Growth Factor Inhibitors
The pathophysiology of SCR, though complex and multifactorial, is considered to be mediated through vascular endothelial growth factor (VEGF).¹ In response to the hypoxia induced by vascular occlusion, hypoxia-inducible factor 1 (HIF-1) stimulates angiogenesis through the production and release of proangiogenic growth factors such as VEGF, leading to retinal neovascularization. Immunohistochemical studies have found that HIF-1 and VEGF are expressed in the inner retina of eyes with untreated PSR, while in control eyes, HIF-1 is not expressed and VEGF is only weakly expressed. Since elevated VEGF has been implicated in SCR, VEGF inhibitors may have a role in the management of the condition. Intravitreal VEGF inhibitors have been shown to be effective in several other retinal vascular diseases and are considered to be an emerging therapy for SCR.^12,7 Multiple articles describe the off-label use of anti-VEGF therapy by intravitreal injection for treatment of SCR.^8,13

Regulatory Status
In 2004, bevacizumab (Avastin^®) was first approved by the U.S. Food and Drug Administration (FDA) for treatment of metastatic colorectal cancer. Bevacizumab has since been FDA-approved for treatment of various other cancers.

In 2006, ranibizumab (Lucentis^®) was first approved by the U.S. FDA for treatment of neovascular (wet) age-related macular degeneration. Ranibizumab has since been FDA-approved for treatment of macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization.

In 2011, aflibercept (Eylea^®) was first approved by the U.S. FDA for treatment of neovascular (wet) age-related macular degeneration. Aflibercept has hence been FDA-approved for treatment of macular edema following retinal vein occlusion, diabetic macular edema, and diabetic retinopathy.

No vascular endothelial growth factor inhibitors (including bevacizumab, ranibizumab, and aflibercept) are currently FDA-approved for treatment of sickle cell retinopathy.

Policy
Intravitreal use of bevacizumab is investigational/unproven therefore considered NOT MEDICALLY NECESSARY for the treatment of individuals with sickle cell retinopathy.

Intravitreal use of vascular endothelial growth factor inhibitors other than bevacizumab is investigational/unproven therefore considered NOT MEDICALLY NECESSARY for the treatment of individuals with sickle cell retinopathy.

Policy Guidelines
This policy addresses the use of vascular endothelial growth factor inhibitors for treatment of sickle cell retinopathy and does not address other ophthalmic conditions.

Coding
See the Codes table for details.

Benefit Application
BlueCard^®/National Account Issues
State or federal mandates (e.g., Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Bevacizumab for Sickle Cell Retinopathy
Clinical Context and Therapy Purpose
The purpose of intravitreal bevacizumab in patients with sickle cell retinopathy (SCR) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with SCR.

Interventions
The therapy being considered is intravitreal bevacizumab injection.

Comparators
The following therapies are currently being used in the management of SCR: observation, laser photocoagulation (mainstay of treatment), and vitreoretinal surgery (e.g., vitrectomy).

Outcomes
The general outcomes of interest are symptoms, functional outcomes, change in disease status, morbid events, and treatment-related morbidity. Visual acuity (VA) is a commonly used outcome measure in studies of various retinal diseases, including sickle cell retinopathy (Table 2).

Follow-up in the available literature ranges from 27 days to 7 years. Optimal duration of follow-up is unknown, but longer follow-up is of interest to monitor sustained safety (e.g., absence of adverse effects) and efficacy (e.g., lack of progression of SCR).

Table 2. Health Outcome Measures Relevant to Sickle Cell Retinopathy

Outcome	Measure (Units)	Description	Clinically Meaningful Difference
Visual acuity	ETDRS test charts (logMAR)	Measures central visual function; 0.1 logMAR = 5 ETDRS letters or 1 line; lower logMAR signifies better visual acuity	10 – 15 ETDRS letters (1 – 2 lines)14,15

ETDRS: Early Treatment of Diabetic Retinopathy Study; logMAR: logarithm of the minimum angle of resolution. 

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Retrospective Studies
Obeng et al. (2022) conducted a retrospective analytical study using records of patients who underwent vascular endothelial growth factor (VEGF) inhibitor therapy and other treatments for proliferative sickle retinopathy (PSR) at a hospital in Ghana.¹⁶ Tables 3 and 4 summarize characteristics and results of the study. A total of 80 eyes (40 patients) were identified. Mean patient age was 31.7 ± 9.3 years (range, 26 – 56) and the mean follow-up period was 6 ± 1 years (range, 5 – 7). Of the 80 eyes, 72 were treated with a VEGF inhibitor (bevacizumab; or ranibizumab or aflibercept if bevacizumab was not available) as initial treatment (n = 30 eyes), after laser photocoagulation (n = 40 eyes), or autoinfarction (n = 2 eyes); and 8 were treated with retinal surgery. Of the 72 eyes treated with a VEGF inhibitor, 70 and 2 eyes had improvement and maintenance of final VA, respectively, while all 8 eyes that underwent surgery had worsening of final VA. All 30 eyes that received VEGF inhibitor therapy as initial treatment were without complications. All 40 eyes that were previously treated with laser photocoagulation developed recurrent new vessels (fresh elevated sea fans and vitreous hemorrhage); this complication was corrected with VEGF inhibitor therapy. The 2 eyes treated with autoinfarction became completely blind; similarly, all 8 eyes that underwent vitreoretinal surgery experienced complications that resulted in blindness at the last follow-up visit. The authors concluded that VEGF inhibitor therapy is better than other available modalities for management of undetached PSR. Study limitations include single-center focus and variable follow-up durations.

Table 3. Summary of Key Retrospective Study Characteristics

Study	Study Type	Country	Dates	Participants	Treatment 1	Treatment 2	Follow-Up
Obeng et al. (2022)16	Retrospective analytical study (1 hospital)	Ghana	2013 – 2020	N = 40 patients (80 eyes) who received treatment for PSR; eyes without TRD and dense VH received VEGF inhibitor therapy, and eyes with dense TRD and dense VH received surgery	Intravitreal bevacizumab (or ranibizumab or aflibercept if bevacizumab not available); total number of injections ranged from 3 – 6 depending on the severity of PSR; n = 72 eyes	Vitreoretinal surgery; n = 8 eyes	Mean follow-up of 6 ± 1 years (range, 5 – 7)

PSR: proliferative sickle retinopathy; TRD: tractional retinal detachment; VEGF: vascular endothelial growth factor; VH: vitreous hemorrhage.

Table 4. Summary of Key Retrospective Study Results

Study	No. of Eyes in Analysis	Quality of Post-treatment VA vs. Pretreatment VA	Mean Difference between Final Post-treatment and Pretreatment VA, logMAR units	No. of Eyes with Complication from Intervention
Obeng et al. (2022)16	80
VEGF inhibitor therapy	72	70 eyes had improvement; 2 eyes had maintenance	0.50 ± 1.0	0 eyes (initial treatment with VEGF inhibitor); 40 eyes (previously treated with laser photocoagulation); 2 eyes (previously treated with autoinfarction)
Vitreoretinal surgery	8	8 eyes had worsening	NR	8
p-value			< .005

logMAR: logarithm of the minimum angle of resolution; NR: not reported; VA: visual acuity; VEGF: vascular endothelial growth factor.

Case Series/Reports
A case series and several case reports evaluating the use of bevacizumab for sickle cell retinopathy have been published.

Cai et al. (2018) reported a case series of 5 patients (5 eyes) treated with intravitreal bevacizumab monotherapy for stage III or IV SCR.¹ Patient age ranged from 33 to 47 years. One patient was treated for new peripheral sea fan neovascularization and 4 were treated for recurrent vitreous hemorrhage. Tables 5 and 6 summarize the characteristics and results of the study. In patients treated for vitreous hemorrhage, improvement in VA was seen as early as 2 weeks after treatment. All patients showed at least partial regression of the peripheral sea fan neovascularization and decreased leakage on fluorescein angiography. Two cases had recurrent vitreous hemorrhage in the follow-up period after the initial injection, of which 1 did not recur until after 13 months. All patients tolerated the injections well; no complications were reported. Study limitations include the retrospective nature of data, variable follow-up periods, and small sample size.

Moshiri et al. (2013) reported the case of a 37-year-old patient with SCR who presented with painless vision loss in the right eye of 5 days’ duration.¹⁷ Visual acuity measured hand motions in the right eye. Dilated ophthalmoscopy showed temporal retinal detachment, associated with an area of active sea fan retinal neovascularization and resultant retinal tears. Intravitreal bevacizumab was administered as a presurgical intervention 3 days before the surgical procedure (which included vitrectomy) for tractional retinal detachment. After the presurgical bevacizumab injection, the retinal neovascularization associated with retinal detachment and the resultant retinal tears appeared more fibrotic and less vascular than before the injection. Surgery was completed without difficulty and with minimal bleeding, which was considered to be atypical in the experience of the surgeons. One month after surgery, The VA was 20/50 and the retina remained attached; no bleeding was observed during the postoperative recovery period.

Babalola (2010) reported the case of a 25-year-old patient with SCR who presented with progressive loss of vision in the left eye of 3 months’ duration.¹⁸ Visual acuity was 6/5 in the right eye, and counting fingers on the temporal field in the left eye. The right eye had sea fan (with leakage confirmed by fluorescein angiography) and the left eye had dense vitreous hemorrhage. Intravitreal bevacizumab (1.25 mg) was administered into both eyes while laser therapy was applied only to the right eye. On day 1 (day after injection), no fresh hemorrhage was seen in either eye and the old vitreous hemorrhage in the left eye remained unchanged. On day 5, a crescentic hyphema was seen in the left eye, with red cells in the anterior segment; there was no change in the sea fans in the right eye. The author commented that it is unclear if or how bevacizumab increased the likelihood of the hyphema. By day 12, hyphema size increased to 30%. A paracentesis was performed the next day with no recurrence of hyphema; however, the vitreous hemorrhage in the left eye remained unchanged. By day 26, the sea fan in the right eye resolved, but there was still no change in the vitreous hemorrhage. A repeat fluorescein angiogram on day 27 confirmed the absence of leaks from the sea fan neovascular lesions.

Shaikh (2008) described the case of a 32-year-old patient with SCR who presented with vitreous hemorrhage in the right eye of 2 weeks' duration.¹⁹ At presentation, the VA was 20/25 in the right eye and 20/20 in the left eye; active sea fan neovascularization was noted in the right eye. Vitreous hemorrhage precluded adequate use of laser photocoagulation. In the next week, the VA in the right eye decreased to 20/40. Patient consented to receive intravitreal bevacizumab (1.25 mg). At 2-weeks postinjection, the VA improved to 20/25 and vitreous hemorrhage appeared close to resolution. At 4-week follow-up, the VA further improved to 20/20, the vitreous hemorrhage resolved fully, and angiography showed no areas of active neovascularization. At 6-week follow-up, no recurrent hemorrhage or neovascularization was noted. Authors concluded that intravitreal bevacizumab may have a role in the primary and/or adjunct therapy of SCR.

Siqueira et al. (2006) reported the case of a 36-year-old patient with PSR who presented with decreased vision in the right eye of 3 months' duration.²⁰ Examination found a VA of 20/60 in the right eye and 20/20 in the left eye, retinal neovascularization in both eyes, and vitreous hemorrhage in the right eye. The patient was offered laser photocoagulation in the left eye and vitrectomy with endophotocoagulation in the right eye; vitreous hemorrhage precluded the use of laser photocoagulation in the right eye. The patient declined vitrectomy and consented to receive intravitreal bevacizumab (1.5 mg/0.06 mL) in the right eye. At 1-week follow-up, the VA was still 20/60 in the right eye but fluorescein angiography showed decreased leakage from the neovascularization. At 4-week follow-up, the VA was 20/20 in both eyes and fluorescein angiography showed regression of the retinal neovascularization; no adverse events were observed. The authors suggested that intravitreal bevacizumab could be used as an adjunct to laser photocoagulation in the management of PSR and may preclude vitrectomy for some patients.

Table 5. Summary of Key Case Series Characteristics

Study	Country	Participants	Treatment	Follow-Up
Cai et al. (2018)1	U.S.	N = 5 patients (5 eyes) with PSR	Intravitreal bevacizumab	8 months (range, 5 – 11)

PSR: proliferative sickle retinopathy; US: United States.

Table 6. Summary of Key Case Series Results

Study	Treatment	No. of Injections	Preinjection VA	Postinjection VA
Cai et al. (2018)1	Intravitreal bevacizumab	Range, 1 – 3	Range, 20/20 to count fingers	Range, 20/16 to 20/25

VA: visual acuity.

Section Summary: Bevacizumab for Sickle Cell Retinopathy
The evidence on intravitreal bevacizumab for SCR is limited overall. Results of a recent retrospective study suggest that, in patients with undetached PSR, intravitreal bevacizumab is better than other available treatment modalities (including laser photocoagulation and surgery) in terms of improving outcomes without resulting in complications. Case series and multiple case reports have described the use of intravitreal bevacizumab either as adjunctive therapy (used together with laser photocoagulation) or monotherapy to facilitate resolution of neovascularization and/or vitreous hemorrhage, and prevent recurrences. The studies indicate that bevacizumab may have a role in cases where the posterior eye segment view does not permit adequate application of laser, or where sea fan neovascularization remains vascularized despite prior laser treatment; bevacizumab may preclude the need for vitreoretinal surgery in these cases. One case report described a different application of bevacizumab as a presurgical adjunctive agent to decrease the risk of intraoperative bleeding and facilitate dissection of sea fan neovascular structures. No complications of bevacizumab use were reported in any studies except 1 case in which hyphema was observed in the treated eye; this eye had resolution of sea fan neovascularization but not vitreous hemorrhage. Despite generally favorable findings, several questions remain about disease stage to initiate treatment given that most patients treated with bevacizumab had stage III or IV SCR, optimal frequency and interval of treatment, optimal duration of follow-up, and adverse events related to therapy. Randomized controlled clinical trials would be preferred to further elucidate the role of intravitreal bevacizumab in the management of SCR.

Other Vascular Endothelial Growth Factor Inhibitors for Sickle Cell Retinopathy
Clinical Context and Therapy Purpose
The purpose of intravitreal VEGF inhibitors other than bevacizumab in patients with SCR is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with SCR.

Interventions
The therapy being considered is intravitreal VEGF inhibitors other than bevacizumab.

Comparators
The following therapies are currently being used in the management of SCR: observation, laser photocoagulation (mainstay of treatment), and vitreoretinal surgery (e.g., vitrectomy).

Outcomes
The general outcomes of interest are symptoms, functional outcomes, change in disease status, morbid events, and treatment-related morbidity. Visual acuity is a commonly used outcome measure in studies of various retinal diseases, including sickle cell retinopathy.

Follow-up in the available literature ranges from 9 months to 7 years. Optimal duration of follow-up is unknown but longer follow-up is of interest to monitor sustained safety (e.g., absence of adverse effects) and efficacy (e.g., lack of progression of SCR).

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Retrospective Studies
In the retrospective study by Obeng et al. (2022), discussed in the previous section, ranibizumab and aflibercept were used in cases of scarcity of bevacizumab.¹⁶ Five eyes treated with ranibizumab and 6 eyes treated with aflibercept demonstrated good outcomes; specific outcomes were not reported separately for each VEGF inhibitor. In 1 eye that did not respond after the third injection with bevacizumab, new vessels regressed after treatment was changed to aflibercept. Similarly, 2 eyes that did not respond well to initial treatment with aflibercept responded after treatment was changed to bevacizumab. Study investigators noted that it is therefore not established whether one VEGF inhibitor is superior to another.

Case Reports
Mitropoulos et al. (2014) reported the case of a 27-year-old patient with SCR who presented with blurred vision and floaters in the right eye of 3 days’ duration with no improvement.²¹ Examination found a VA of 6/18 in the right eye and 6/6 in the left eye, and vitreous hemorrhage in the right eye. A fluorescein angiography confirmed leakage from the sea fan neovascularization in the right eye, with ischemia in the periphery. Patient received intravitreal ranibizumab (0.5 mg) injection in the right eye. One week postinjection, the VA was 6/9 in the right eye, the vitreous hemorrhage improved, and retinal neovascularization regressed. At 4-week follow-up, the VA was 6/6 in both eyes, the vitreous hemorrhage was totally absorbed, and retinal neovascularization further regressed. Laser photocoagulation was also applied to ischemic areas in the right eye. No recurrence of the neovascularization was noted at 3 months. At 9-month follow-up, the VA remained stable at 6/6 in both eyes, with no observed adverse events. Authors suggested that intravitreal ranibizumab could be used as an adjunct to laser photocoagulation in the management of PSR and may preclude vitrectomy for vitreous hemorrhage in some patients.

Section Summary: Other Vascular Endothelial Growth Factor inhibitors for Sickle Cell Retinopathy
Evidence on the use of other VEGF inhibitors for treatment of SCR is limited. In a retrospective study of patients with PSR, ranibizumab and aflibercept were used in cases of scarcity of bevacizumab. All 11 eyes treated with either ranibizumab or aflibercept demonstrated good outcomes; furthermore, eyes that did not initially respond to aflibercept responded when treatment was changed to bevacizumab, or vice versa. Study authors commented that it is therefore uncertain whether one VEGF inhibitor is superior to another. In addition, 1 case report described the successful use of intravitreal ranibizumab as an adjunct to laser photocoagulation in the management of PSR, with no observed adverse events. As is the case for bevacizumab, several questions remain regarding optimal dosing, frequency, and interval of treatment; long-term efficacy and safety; and exact place in therapy. Future, well-designed studies are needed to further clarify the role of VEGF inhibitors other than bevacizumab in the management of SCR.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Currently, there are no evidence-based guidelines for screening for sickle cell retinopathy (SCR). Expert consensus recommendations for patients with sickle cell disease (SCD) include referral to an ophthalmologist for a dilated eye examination to evaluate for retinopathy beginning at age 10 years, and rescreening at 1- to 2-year intervals for individuals with a normal dilated retinal examination.²² Strong recommendations for ophthalmic complications of SCD include: "Refer children and adults with vitreoretinal complications of proliferative sickle retinopathy (PSR) refractory to medical treatment for evaluation and possible vitrectomy" and "refer persons of all ages with PSR to an ophthalmologist for evaluation and possible laser photocoagulation therapy." No statements are made regarding use of vascular endothelial growth factor inhibitors.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in January 2023 did not identify any ongoing or unpublished trials that would likely influence this review.

References

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2. Centers for Disease Control and Prevention (CDC). Sickle Cell Disease. August 18, 2022. https://www.cdc.gov/ncbddd/sicklecell/facts.html. Accessed January 4, 2023.
3. American Academy of Ophthalmology, Shah VA, Sambhara D, Bracha P, et al. Sickle Cell Retinopathy. December 18, 2022. https://eyewiki.aao.org/Sickle_Cell_Retinopathy#cite_note-3. Accessed January 9, 2023.
4. Goldberg MF. Classification and pathogenesis of proliferative sickle retinopathy. Am J Ophthalmol. Mar 1971; 71(3): 649-65. PMID 5546311
5. Abdalla Elsayed MEA, Mura M, Al Dhibi H, et al. Sickle cell retinopathy. A focused review. Graefes Arch Clin Exp Ophthalmol. Jul 2019; 257(7): 1353-1364. PMID 30895451
6. Belin PJ, Lee AC, Greaves G, et al. The use of bevacizumab in pediatric retinal and choroidal disease: A review. Eur J Ophthalmol. May 2019; 29(3): 338-347. PMID 30757919
7. American Academy of Ophthalmology, Akhter M, Latting MW, Scott AW. Management of Proliferative Sickle Cell Retinopathy. October 2018. https://www.aao.org/eyenet/article/proliferative-sickle-cell-retinopathy. Accessed January 10, 2023.
8. Menaa F, Khan BA, Uzair B, et al. Sickle cell retinopathy: improving care with a multidisciplinary approach. J Multidiscip Healthc. 2017; 10: 335-346. PMID 28919773
9. American Society of Retina Specialists. Retina Health Series - Sickle Cell Retinopathy. 2020. https://www.asrs.org/patients/retinal-diseases/41/sickle-cell-retinopathy. Accessed January 10, 2023.
10. Myint KT, Sahoo S, Thein AW, et al. Laser therapy for retinopathy in sickle cell disease. Cochrane Database Syst Rev. Dec 12 2022; 12(12): CD010790. PMID 36508693
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12. Campochiaro PA, Aiello LP, Rosenfeld PJ. Anti-Vascular Endothelial Growth Factor Agents in the Treatment of Retinal Disease: From Bench to Bedside. Ophthalmology. Oct 2016; 123(10S): S78-S88. PMID 27664289
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Coding Section

Codes	Number	Description
CPT	N/A
HCPCS	C9257	Injection, bevacizumab, 0.25 mg
	J0177 (effective 04/01/2024)	Injection, afilbercept hd, 1 mg
	J0178	Injection, aflibercept, 1 mg
	J0179	Injection, brolucizumab-dbll, 1 mg
	J2777	Injection, faricimab-svoa, 0.1 mg
	J2778	Injection, ranibizumab, 0.1 mg
	J9035	Injection, bevacizumab, 10 mg
	Q5107	Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg
	Q5118	Injection, bevacizumab-bvzr, biosimilar, (Zirabev), 10 mg
	Q5124	Injection, ranibizumab-nuna, biosimilar, (byooviz), 0.1 mg
	Q5126	Injection, bevacizumab-maly, biosimilar, (alymsys), 10 mg
ICD10 CM	D57.00-D57.819	Sickle Cell disease code range
	H36	Retinal disorders in diseases classified elsewhere (code first underlying disease)
ICD10 PCS		Inpatient Codes do not apply to Outpatient Procedures
Type of Service	Ophthalmology
Place Of Service	Outpatient/Professional

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2023 Forward     

04/15/2024	Adding HCPCS code J0177 effective 04/01/2024. No other changes made.
04/11/2023	New Policy