The treatment of diabetic macular edema (DME) has become one of the most challenging management issues faced by ophthalmologists in daily practice. This is partly due to the multifactorial nature of DME, progression of the disease and the clinical capacity needed to administer intravitreal injections. In recent years, the treatment options for DME have expanded to include intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents and steroids, and most recently, the use of intravitreal implants. In determining clinically relevant endpoints for clinical studies of these treatments, it is important to consider the patient’s journey and experience with a treatment over a specific time-period rather than isolated outcomes at a pre-specified time-point. Area under the curve (AUC) is an ideal tool for data analysis particularly when it comes to sustained release therapies such as dexamethasone (Ozurdex®, Allergan Inc., California, US) and intravitreal fluocinolone acetonide implant (0.2μg/day FAc implant; Iluvien®, Alimera Sciences Inc., Georgia, US). Unlike single time-point outcomes, AUC analysis provides the average letters gained per day over the entire treatment period, providing a better measure of long-term effectiveness. A recent analysis using the AUC approach highlights the significant visual acuity benefit resulting from the 0.2μg/day fluocinolone acetonide (FAc) implant during the FAME (Fluocinolone Acetonide for Macular Edema) trials. A step-by-step instruction is included in this article that allows statistical analysis of the AUC data from both functional and anatomical outcomes, using a free software tool to further facilitate the use of this technique for future investigators.
Diabetic macular edema, intravitreal implants, ILUVIEN
Sepehr Bahadorani has nothing to declare in relation to this article. Michael Singer would like to disclose consultant speaker research for Allergan, consultant speaker research for Genentech, speaker research for Regeneron and consultant research for Alimera Sciences.
The authors would like to acknowledge the help from Aron Trevino, who confirmed the accuracy of the AUC R code. Medical writing support was provided by Katrina Mountfort and James Gilbart at Touch Medical Media, supported by Alimera Sciences.
Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.
March 07, 2017 Accepted:
March 22, 2017
Michael A Singer, 9157 Huebner Road, San Antonio, TX 78240, US. E: firstname.lastname@example.org
The publication of this article was supported by Alimera Sciences, who was given the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the authors’ discretion.
Supplementary Information 1
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Vascular exposure to hyperglycemia over extended periods, destroys the retinal endothelial cell tight junctions and leads to the development of macular edema with consequent visual loss.1 Indeed, diabetic macular edema (DME) is the most common cause of visual impairment in diabetic patients.2 At the same time, considering that the incidence of diabetes is on the rise, it becomes prudent to effectively address DME. According to the World Health Organization (WHO) study, the global incidence of diabetes has risen from 108 million in 1980 to 422 million in 2014 and attributes to 2.6% of global blindness.3 These estimates are expected to rise further due to the increasing prevalence of diabetes, ageing of the population and the increasing life expectancy of those with diabetes.
Until recently, the standard of care for DME was laser photocoagulation, which slows progression of vision loss but rarely results in improvement of vision, even after 3 years of treatment. According to the Early Treatment of Diabetic Retinopathy Study (ETDRS), laser treatment of clinically significant macular edema (CSME) decreases the risk of moderate vision impairment (15 letters) by half over 3 years.4 Nonetheless, the introduction of intravitreal pharmacologic agents, namely the anti-vascular endothelial growth factor (VEGF) agents and corticosteroids, has changed the prognosis of DME from stabilization of vision to improvement.
Pathogenesis and treatment
The pathogenesis of DME is attributed to the destruction of endothelial cell tight junctions but more specifically, it is thought that, as a consequence of non-perfusion and hypoxia in diabetic retinopathy, production of VEGF and other inflammatory cytokines attributes to the distortion of vascular barriers The endothelial cells and their tight junctions act as a barrier to maintain the water and protein balance between the intravascular and extravascular compartments. Nevertheless, VEGF and other inflammatory cytokines disrupt this barrier function by altering the structure of the cytoskeleton and/or by affecting the expression of adhesive proteins at endothelial junctions.5–7 Therefore, not surprisingly, DME treatments target the direct intravitreal injection of steroids and anti-VEGF agents. Current intravitreal treatments include short acting options such as intravitreal triamcinolone,8 Ozurdex(R) (Allergan Inc., Irvine, CA, US), a dexamethasone implant,9 anti- VEGF agents including ranibizumab,12–14 bevacizumab,15 pegaptanib,16 and aflibercept,17 and longer-acting options such as Iluvien (Alimera Sciences Inc., Alpharetta, GA, US) which releases 0.2 μg/day fluocinolone acetonide (FAc) for 36 months.10,11
Bevacizumab (Avastin®, Genentech, San Francisco, CA, US) is a full-length humanized monoclonal antibody that binds to all the isoforms of VEGF.18,19 According to the BOLT (Bevacizumab Or Laser Therapy) trial, in patients with CSME and treated with bevacizumab, mean best corrected visual acuity (BCVA) was significantly higher (64.4±13.3; mean ± standard deviation [SD] ETDRS letters) than patients treated with laser (54.8±12.6 ETDRS letters). This study showed that the bevacizumab arm gained a median of 9 ETDRS letters in comparison to 2.5 letters in laser treatment group (p=0.005).15 Additionally, the Diabetic Retinopathy Clinical Research (DRCR) study reveals a more robust reduction of central subfield thickness (CST) in the bevacizumab arm compared to the laser arm.20
Ranibizumab (Lucentis®, Genentech, San Francisco, CA, US) is a humanized, affinity-matured, monoclonal antibody Fab fragment that binds to all isoforms of human VEGF-A.18 Unlike the full-length antibodies (e.g., bevacizumab), ranibizumab’s lack of the Fc region makes the medication more permeable to retinal pigment epithelium (RPE) layers and thus, theoretically, ranibizumab is more effective than bevacizumab in reaching the choroidal neovascularization beneath the RPE layer.21 Nevertheless, considering these structural differences, the half-life of ranibizumab is markedly shorter than bevacizumab and the medication clears more quickly from systemic circulation following an intravitreal injection with half-lives of 2 hours and 20 days, respectively.22–25
The READ-2 study (Ranibizumab for Edema of the mAcula in Diabetes) was a pioneering work that demonstrated a significantly better BCVA outcome for DME patients following ranibizumab (0.5 mg) injection compared to laser treatment: A BCVA gain of 7.24 letters in the ranibizumab arm compared to a loss of 0.43 letters in the laser arm at month 6.26 Later studies continued to support the effectiveness of ranibizumab in treatment of DME as well as its superiority over laser treatment. According to the RESTORE study, in comparison to laser treatment alone, ranibizumab (0.5 mg) monotherapy over a 12 months period results in a significantly greater proportion of DME patients with a BCVA letter score ≥15.14 The RESOLVE study also shows that, in comparison to sham and after a 12-month period, three monthly intravitreal injections of ranibizumab (0.3 or 0.5 mg) significantly improved the BCVA from baseline by 10.3±9.1 letters. Also, in the ranibizumab group, there was a significant reduction in central retinal thickness (194.2±135.1 μm) compared to the sham group (48.4±153.4 μm).13 RIDE and RISE are identical phase III studies that compared the efficacy and safety of sham and ranibizumab injections in patients with DME. In RIDE the proportion of patients gaining ≥15 ETDRS letters in BCVA from baseline at month 24, were as follows: 19.2% (sham or cross over to 0.5 mg), 36.8% (0.3 mg), and 40.2% (0.5 mg). On the same note, the RIDE study shows a 22.0% (sham/0.5 mg), 51.2% (0.3 mg), and 41.6% (0.5 mg) improvements in BCVA.12
Pegaptanib (Macugen®, Gilead Sciences Inc., San Dimas, CA, US) is another anti-angiogenic antibody that specifically binds and blocks the activity of extracellular VEGF-A165 isoform, which is the most potent and abundant form of VEGF.27 This treatment is administered as monthly or bimonthly intravitreous injections. The combined analysis of multiple trials demonstrated a lower loss of visual acuity at 12 months in patients treated with pegaptanib (0.3 mg: 70% of patients; 1.0 mg: 71% of patients; 3.0 mg: 65% of patients) treatment compared to the sham injection group (55%).28
Aflibercept (Eylea®, Regeneron Pharmaceutical, Tarrytown, NY, US) is a recombinant fusion protein that contains portions of human VEGF receptor fused to the Fc domain of human immunoglobulin G (IgG)1 antibody.29 The DA VINCI study demonstrates that aflibercept injection is more effective than the laser at improving BCVA as well as CST at week 52: aflibercept arm with BCVA gain of 9.7 to 12 letters and CST reduction of 165.4 to 227.4 μm compared to laser arm with BCVA loss of 1.3 and CST reduction of 58.4 μm.17 Likewise, results of two parallel studies, VIVID and VISTA, depict superiority of aflibercept arm a gain in visual acuity compared to the laser arm in patients with DME. letters for ranibizumab.. The mean BCVA gain from baseline to week 148 following treatment with aflibercept or laser was 10.4–10.5 and 1.4 letters in VISTA and 10.3–11.7 and 1.6 letters in VIVID, respectively.30 Finally, the DRCR study shows that at 2 years, mean visual acuity improvement are 12.8 letters for aflibercept, 10.0 letters for bevacizumab and 12.3 for ranibizumab.31
Inflammation is an important mechanism of DME development and thus, when anti-VEGF agents yield suboptimal results or systemic vascular disorders limit their use, or clinical capacity is limited, steroids become the mainstay of treatment. Intravitreal triamcinolone acetonide has been shown to effectively reduce macular edema in the short term13 but is limited by a short duration of action and the need for repeated injections and visits. In addition, intraocular pressure (IOP) rises of >10 mm Hg (18% for 1 mg; 33% for 4 mg) as well as an increased need for cataract surgery (46% for 1 mg; 83% for 4 mg) are adverse reactions that discourage most clinicians from using triamcinolone as a preferred agent for first-line treatment of DME.32
The dexamethasone intravitreal implant (0.7 mg), also known as Dexamethasone Posterior Segment Drug Delivery System (Ozurdex), consists of micronized dexamethasone in a biodegradable copolymer of polylactic-co-glycolic acid which releases dexamethasone into the vitreous over a period up to 6 months as shown in male monkey studies.33 The implant is inserted into the vitreous with a 22-gauge needle,34 with the goal of reducing the frequency of intravitreal injections. Multiple studies show that the dexamethasone intravitreal implant is an effective means of improving BCVA and reducing macular edema in patients with DME.35–37
The adverse reactions of the dexamethasone implant include the need for IOP lowering medications to manage ocular hypertension (41.5% for dexamethasone versus 9.1% for sham) and cataract progression (67.9% for dexamethasone versus 20.4% for sham).38
Fluocinolone acetonide implant
Recently, a new generation of a non-biodegradable, long term intravitreal implant, 0.2 μg/day FAc, has become available. The implant is inserted into the vitreous with a 25-gauge needle. The implant contains 0.19 mg of FAc and releases the drug at a rate of 0.2 μg of FAc per day over a period of 36 months.10,39 This formulation potentially means fewer injections, visits and improved management of patients.40
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