Treatment Strategies for Retinal Vascular Diseases

Retinal vascular diseases are a group of conditions characterized by abnormalities in retinal vasculature and/or blood chemistry.¹ These conditions can lead to significant vision loss if left untreated and are often caused by life-threatening comorbidities. Associated systemic findings require management by various health care providers, while ocular findings require medical and/or surgical intervention. This article reviews the treatment strategies for retinal vascular diseases, focusing on diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinal arterial occlusion (RAO).

DIABETIC RETINOPATHY

Management of DR requires a multidisciplinary approach, starting with optimal glycemic control. The Diabetic Control and Compliance Trial² and the United Kingdom Prospective Diabetes Study³ demonstrated that good glycemic control decreases the prevalence and progression of diabetes complications, including DR, in patients with either type 1 or 2 diabetes. Referral to a retina specialist must be considered in the presence of diabetic macular edema (DME), which can present at any stage of DR (Figure 1).

Another reason for referral to a retina specialist would be proliferative DR (PDR) diagnosed in the presence of any of the following: optic disc and/or retinal neovascularization, preretinal and/or vitreous hemorrhage, tractional retinal detachment (TRD), and neovascularization of the iris, which can lead to neovascular glaucoma (Figure 2).

Traditional Therapies

The safety and efficacy of laser procedures was established in the 1970s based on the results of the ETDRS⁴ and the Diabetic Retinopathy Study⁵; thus, focal photocoagulation and panretinal photocoagulation (PRP) became standard therapies. The Diabetic Retinopathy Vitrectomy Study⁶ confirmed that pars plana vitrectomy was an effective treatment for managing vitreous hemorrhage associated with PDR. In the early 2000s, the local delivery of corticosteroids was added to the armamentarium of treatment options for patients with DME who were nonresponsive to laser therapy⁷; intravitreal and periocular steroid injections are still used in particularly recalcitrant cases.⁸

In the mid 2000s, anti-angiogenics, particularly VEGF inhibitors, became the first-line therapy for DME.^9,10 The READ-2 study was the first landmark clinical trial to demonstrate the effectiveness of ranibizumab injection (Lucentis, Genentech) monotherapy for DME, resulting in FDA approval.^11,12 Since then, research groups such as the DRCR Retina Network (an independent collective of US retina specialists formerly known as The Diabetic Retinopathy Clinical Research Network) have conducted studies to demonstrate the clinical applications of anti-VEGF therapy for DME. As a result, agents such as aflibercept 2 mg (Eylea, Regeneron) were added to the list. Bevacizumab (Avastin, Genentech), an anti-VEGF agent approved by the FDA for the treatment of cancer, has been used off-label to manage DME for nearly 2 decades.¹³ In many cases, insurance payers require step-therapy starting with bevacizumab before trying other FDA-approved options.¹⁴ An intravitreal formulation of bevacizumab, bevacizumab-vikg (Lytenava Outlook Therapeutics), is also undergoing clinical trials for the treatment of DME.

Newer Drugs

Alternatives to the previously named drugs include various biosimilars. Two ranibizumab biosimilars (ranibizumab-nuna [Byooviz, Biogen] and ranibizumab-eqrn [Cimerli, Sandoz]), as well as two aflibercept biosimilars (aflibercept-jbvf [Yesafili, Biocon Biologics] and aflibercept-yszy [Opuviz, Samsung Bioepis]), have received FDA approval in recent years.^15,16

One important motivation for offering a variety of treatment options is to reduce the financial burden for the treatment of chronic diseases, such as DME.¹⁷ Other barriers to care include limited drug durability, injection fatigue reducing adherence to recommended follow-up, and practice sustainability to manage the increasing population of patients with retinal vascular disease. Aflibercept 8 mg (Eylea HD, Regeneron), a higher dose option compared with the original aflibercept 2 mg (Eylea, Regeneron), and faricimab (Vabysmo, Genentech), a biphasic anti-VEGF plus an angiopoietin-2 inhibitor, have each shown increased durability in clinical trials; after an initial three or four monthly loading doses, the treatment interval can in many patients be extended to every 8, 12, or 16 weeks.^18,19

Combination Therapy

Beyond management of DME, many patients require treatment for the proliferative component of DR. Intravitreal anti-VEGF injections have become a first-line therapy for severe NPDR, as well as PDR. Together, the post-hoc assessment of data from the RIDE and RISE trials for DME, the DRCR Protocol S, and the PANORAMA study have shown a notable reversal of DR severity with intravitreal anti-VEGF therapy, reinforcing anti-VEGF therapy as a practical option for monotherapy or in conjunction with PRP for the treatment of severe NPDR and PDR.^20-23 For patients with vitreous hemorrhage, TRD, and/or neovascular glaucoma, a combination approach of intravitreal injections, laser, and surgical intervention (ie, pars plana vitrectomy) can be used.^24,25 Patients with neovascular glaucoma may additionally require surgery and long-term management.²⁶

Novel Delivery Methods

Ongoing clinical trials are investigating the efficacy of other modalities to improve drug bioavailability and durability with the goal of reducing injection burden and improving overall outcomes. This includes the ranibizumab injection 100 mg/mL ocular implant (Susvimo, Genentech), which is administered via a single injection into the subretinal or suprachoroidal space and delivers anti-VEGF therapy.^27,28

Patients with DR must be educated that theirs is a chronic and complex disease requiring careful, methodical, and long-term care.

RETINAL VEIN OCCLUSION

RVO, classified as either CRVO or BRVO (Figure 3) and can lead to retinal hemorrhages, edema, and ischemia. RVO is the second most common retinal vascular disease,²⁹ and its effects are similar to those of DR. Management strategies are also similar, including addressing any underlying conditions such as hypertension, diabetes, and hypercoagulability and reducing risk factors such as smoking and sleep apnea.

In the 1990s, the standard treatment of RVOs was macular grid and PRP,^30-32 but this was found to offer limited benefit. PRP is, however, a viable option for treating the neovascular component of RVO. Intravitreal steroids were studied and used in the mid-2000s and are still used in recalcitrant cases or if nonresponsive to anti-VEGF therapy.³³ Use of the dexamethasone intravitreal implant 0.7 mg (Ozurdex, AbbVie) is now a common treatment approach, particularly in refractory cases of macular edema.^34,35

Anti-VEGF agents have gained favor as a first-line therapy for macular edema associated with RVO, as well as in combination with PRP for neovascularization (Figure 4). Several studies have confirmed the safety and efficacy of these same agents used in the treatment of DR,^36-43 although usually fewer injections are needed to manage these patients.^44,45 In advanced RVO cases in which the patient has developed vitreous hemorrhage, TRD, and neovascular glaucoma, the same management approach may be taken as described previously for PDR.

RETINAL ARTERY OCCLUSION

Central RAO and branch RAO usually result from the embolic blockage of a retinal artery, leading to sudden vision loss. The risks for RAO are similar to those associated with heart attack and stroke (eg, diabetes and systemic hypertension).^46,47 Therefore, the management of RAO requires both immediate intervention and long-term prevention. Other significant etiologic or associated comorbidities, such as giant cell arteritis, must be ruled out to prevent other potentially catastrophic outcomes.⁴⁸

From a systemic standpoint, RAO requires immediate medical attention to prevent other sequelae, as the patient may be at risk of a stroke.⁴⁹ Therefore, patients with RAO should be immediately referred to a stroke prevention center or an emergency department.

Several treatments, such as ocular massage, hyperbaric oxygen therapy, anterior chamber paracentesis, carbogen inhalation, and acetazolamide infusion, have been suggested to dislodge the embolus and restore retinal perfusion; however, the efficacy of these interventions is debated, and their use is not universally endorsed.⁴⁶ Long-term systemic management of underlying conditions, including hypertension, diabetes, and hyperlipidemia, is essential to reduce similar events or other comorbidities. Antithrombotic therapy, such as aspirin or anticoagulants, may be indicated to prevent further embolic events.

NOT SURPRISINGLY, COMANAGEMENT IS CRUCIAL

The treatment of retinal vascular disease is complicated, requiring a comprehensive approach tailored to the specific condition. DR, RVO, and RAO each present unique challenges, but advances in medical and surgical therapies have significantly improved visual outcomes for patients with these conditions. Ongoing research and development of novel therapeutic agents and techniques continues to improve our ability to manage these complex conditions effectively. Collaboration among optometrists, ophthalmologists, and other health care professionals is essential to optimize treatment strategies and improve patient care.