**3.4 High-risk PDR with or without vision- impairing DME**

Eyes with high-risk PDR (i.e., ≥ ETDRS level 71) face the greatest risk of severe vision loss without intervention [4, 5]. Eyes with the most advanced forms of PDR have the largest relative benefit of RBZ compared with PRP when managing PDR. Also, RBZ was superior to PRP with respect to change in visual acuity over 2 years and prevention of vision-impairing CI-DME over 2 years, regardless of baseline characteristics [31]. On the other hand, combined therapy has shown benefits in the management of high-risk PDR.


Although anti-VEGF may be recommended as monotherapy in eyes with highrisk PDR, complete PRP within the effective period of anti- VEGF agents might be recommended. Advantages and disadvantages of treatment options should be considered, as well as the individual conditions of the patient.

### **3.5 Worsening PDR**

Worse baseline levels of DR severity (ETDRS scale) were associated with increased risk of worsening PDR (e.g., vitreous hemorrhage (VH), retinal detachment (RD), angle neovascularization (ANV), or neovascular glaucoma (NVG)), regardless of treatment with PRP or RBZ. There were generally fewer PDRworsening events (e.g., VH, RD, ANV, or NVG) in eyes treated with RBZ versus PRP for PDR. Through 2-year, the cumulative probability of worsening PDR was 42% for PRP versus 34% for RBZ. The 2-year cumulative probability of VH was 39% for the PRP group and 30% for the RBZ group. The 2-year cumulative probability of RD was low in each treatment group at 11% for the PRP group and 5% for the RBZ group [20]. The fact that worsening PDR events were at higher rates in the PRP group, suggests that at least during the first two years of follow-up:


As in the eyes with high-risk PDR, complete PRP within the effective period of anti- VEGF agents might be recommended. Advantages and disadvantages of treatment options should be considered, as well as the individual conditions of the patient.

#### **3.6 Vitrectomy for PDR**

Eyes in both groups (RBZ or PRP) had visual loss associated with VH, being more severe in the PRP group. The protocol required investigators to wait at least 8 weeks for a nonclearing VH before proceeding to vitrectomy (in the absence of known RD, iris NV, or ANV). VH was the primary indication for most PPV, 24 (80%) procedures in the PRP group and 6 (75%) procedures in the RBZ group. Endolaser or indirect ophthalmoscopic laser during PPV were applied in 80% of procedures in the PRP group and in all procedures in the RBZ group. Only 1 eye in the RBZ group received PRP independent of PPV. Possibly for convenience, the not masked investigators, decided to continue observing VH before proceeding to PPV in the RBZ group. The authors note that because VH, only 13% (7/52) in the RBZ group compared to 42% (29/69) in the PRP group underwent PPV at the end of 2 years. Therefore, because VH was the main indication for surgery in both groups, the reduced incidence of VH in the RBZ group and the potential difference in VH severity may explain the finding that eyes in the PRP group were more likely to undergo vitrectomy [20]. Although several studies do not support the hypothesis that anti-VEGF administered to an eye with PDR, with or without high-risk features (but without macular-threatening traction at baseline), causes tractional RD (TRD) more often than eyes with PRP [7, 28, 32], we must consider the possibility of additional PPV in these patients.

## **4. Discussion**

In clinical practice, treating PFC with one or more sessions may be sufficient to control PDR and no additional procedures are required. On the other hand, the cost of laser therapy is less expensive than anti-VEGF therapy and there is no risk of endophthalmitis or systemic adverse events [15]. The DRCR.net in a cost–benefit analysis regarding RBZ or PFC monotherapy for PDR, noted that it was more appropriate to start with PFC for patients with PDR without associated DME and RBZ for those with DME at the time of treatment detection [33]. Therefore, the relative benefits of treating PDR with anti-VEGF versus PFC could be considered in a patient presenting with DME, where anti-VEGF therapy is generally necessary, as long as the patient adheres to treatment and is able to access it. In Mexico, as in some countries, it is possible to adopt the algorithm suggested by the DRCR.net Protocol S; however, the circumstances of patients and environment could modify the scheme. Likewise, the advantages and disadvantages of treatment options should be considered, in addition to socioeconomic conditions, adherence to treatment, and access to "off-label" medications.

It is generally known that the pathogenesis and progression of DR involves changes in the vitreous structure and its relationship with the vitreoretinal interface [34–40]. A study whose objective was to evaluate the costs and usefulness of early PPV compared to PFC and intravitreal RBZ in PDR patients without DME, using a "decision analysis" based on the results of DRCR.net Protocol S at 2 years of treatment for each scenario, concluded that PPV as a treatment strategy demonstrates a similar cost utility to treatment with PFC and a more favorable cost utility compared to short-term intravitreal RBZ therapy [41]. This advantage over anti-VEGF is continuing when lifetime costs are considered. The safety of anti-VEGFs compared to primary PPV (without anti-VEGF) for persistent VH is being evaluated in the Protocol AB.

Currently, the PANORAMA study [42], a double-masked, randomized phase 3 trial, the objective of which is to evaluate the efficacy and safety of intravitreal injection of AFB compared to sham therapy in improving moderate-to-severe NPDR in the absence of CI-DME, demonstrate at week 24 that AFB improved the severity of DR in patients with moderately severe to severe NPDR and suggests that anti-VEGF can reverse disease progression in these patients.

In turn, there is interest if steroid therapy in the treatment of DME can delay the progression or even improve DR. Corticosteroids inhibit the inflammatory processes involved in DME, including the production of pro-inflammatory mediators, increased levels of VEGF, and the loss of endothelial tension-binding proteins [43, 44]. There are clinical trials that have shown some benefit of intravitreal

*Treatment Algorithm in Proliferative Diabetic Retinopathy - From Protocols to the Real World DOI: http://dx.doi.org/10.5772/intechopen.99843*

#### **Figure 1.**

*Treatment flow-chart in different presenting PDR scenarios. DME: Diabetic macular edema; DNCVH: Dense non-clearing vitreous hemorrhage; CI-DME: Center-involving diabetic macular edema. NCI-DME: Noncenter-involving diabetic macular edema; NV: New vessels; PDR: Proliferative diabetic retinopathy; PFC: Panretinal photocoagulation; TRD: Tractional retinal detachment threatening or involving macula; PPV: Pars plana vitrectomy. <sup>1</sup> If starting anti-VEGF for DME, PFC can be deferred since the same anti-VEGF may control both DME and PDR. <sup>2</sup> Consider factors such as risk of non-compliance, treatment cost, and treatment burden. <sup>3</sup> Cases with TRD should not receive only anti-VEGF therapy due to increased traction progression risk. <sup>4</sup> Anti-VEGF injection can be applied a few days before PPV is performed to decrease intraoperative and postoperative VH.*

steroids in the progression of DR [12, 45]. The "DR-Pro-Dex" study provides the first long-term evidence that the dexamethasone implant has the potential to not only delay the progression of DR and PDR but may also improve the severity of DR in 24 months [46]. On the other hand, the results of the "TRADITION" study conclude that the implantation of dexamethasone at the end of a PPV in patients with TRD improves the severity of PDR and reduces the detachment rates [47].

In the case of DME, the little or no response of the anti-VEGF used and its relationship with persistent peripheral retinal ischemia require modifications in treatment. Alternatives should be considered such as: switching from anti-VEGF, intravitreal dexamethasone implant, additional PFC (peripheral retina), PPV or combining treatments. Although anti-VEGF monotherapy achieves stabilization of NV in PDR, adding PFC could result in a lower frequency of intravitreal applications, resulting in lower risks and costs for the patient.

In **Figure 1**, a flow-chart of treatment modalities for different presenting PDR scenarios is shown.

#### **5. Conclusion**

In general, the objective to achieve success in the treatment of PDR and DME is the inhibition of VEGF and pro-inflammatory factors, a condition that seems to be obtained more efficiently with pharmacological therapy in relation to retinal ablation. Currently the indications for laser, intravitreal drug therapy (anti-VEGF's and anti-inflammatory steroids) and PPV are increasingly clear. Based on the results previously mentioned, anti-VEGF therapy appears to be emerging as first-line therapy in PDR, as is currently suggested in the treatment of DME. Treatment regimens in patients with severe NPDR with or without DME, may be indifferent to those currently suggested in PDR patients with or without DME; including that early PPV is an alternative to prevent retinal complications of diabetic microvascular disease. This chapter suggests a treatment algorithm for PDR in different settings; however, we must not forget that both DME and PDR are different manifestations of DR and therefore must be assessed individually. Treatment decisions can be different for each manifestation and can be modified depending on its behavior. Several protocols are currently being developed to more accurately understand the behavior of PDR and DME in different settings and to provide a more solid foundation for an effective and timely treatment scheme.
