Recent practices at “stem cell clinics” in the United States have resulted in blinding complications for three patients who underwent bilateral intravitreal injection of adipose-derived stem cell injections for dry age-related macular degeneration, as recently published in the New England Journal of Medicine: patient’s vision went from 20/30 to no light perception and 20/200.
The “stem cell clinics” problem is that they provide unproven, unregulated, and costly ($50,000) treatment for a variety of disorders and raise high concern for patients.
By having studies listed on clinicaltrials.gov, “stem cell clinics” seemingly bolster their legitimacy to patients. clinicaltrials.gov website is simply a repository of clinical studies and does not judge the merits of the listed studies.
It is important to encourage patients to speak with a “trusted healthcare professional” prior to enrolling in a study. Exploring the difference between the positive stem cell research and the activities carried out at “stem cell clinics” is essential in preventing such catastrophic outcomes.
Further regulation of these “stem cell clinics” is also necessary to help prevent similar outcomes in the future.
“Implications of Stem Cell Clinics for Retina Patients and Clinical Trials” Retinal Physician, Volume 14, Issue: May 2017, page(s) 32,40: Ajay E. Kuriyan, MD, MS; Thomas Albini, MD; Harry W. Flynn, Jr., MD
“The Growing ‘Stem Cell Clinic’ Problem” American Journal of Ophthalmology, Volume 177, xix–xx: Ajay E. Kuriyan, MD, MS; Thomas Albini, MD; Harry W. Flynn, Jr., MD
Table 1. “Age-Related Macular Degeneration Clinical Trials With Oral Medications”
(Retinalphysician.com | April 2017)
Full Paper: Age-Related Macular Degeneration Clinical Trials With Oral Medications Table
Study: A Phase 2/3 Trial to Assess the Safety and Efficacy of Intravitreous Administration of Zimura (Anti-C5 Aptamer) in Subjects With Geographic Atrophy Secondary to Dry Age-Related Macular Degeneration
Purpose: To evaluate the safety and efficacy of intravitreous administration of Zimura when administered in subjects with geographic atrophy (GA) secondary to dry age-related macular degeneration
Design: Randomized, Safety/Efficacy, Parallel Assignment, Double Blind
Number of Patients: 300
Inclusion Criteria: Diagnosis of non-foveal GA secondary to dry AMD
Exclusion Criteria: Retinal atrophy involving the fovea; evidence of CNV; any prior treatment for AMD or any prior intravitreal treatment for any indication in either eye, except oral supplements of vitamins and minerals; any intraocular surgery or thermal laser within 3 months of trial entry; any prior thermal laser in the macular region, regardless of indication; any ocular or periocular infection in the 12 weeks prior to entry; previous therapeutic radiation in the region of the study eye; any sign of diabetic retinopathy in either eye
Full Paper: Retinal Physician Clinical Trial Update
Purpose: To characterize the first 10 years of intravitreal anti-vascular endothelial growth factor (VEGF) medication use for ophthalmic disease, including bevacizumab, ranibizumab, and aflibercept.
Design: A retrospective cohort study using administrative claims data from January 1, 2006 to December 31, 2015.
Subjects: Total of 124 835 patients 18 years of age or over in the United States.
Methods: OptumLabs Data Warehouse, which includes administrative claims data for over 100 million commercially insured and Medicare Advantage individuals, was used to identify patients receiving intravitreal anti-VEGF injections based on Current Procedural Terminology codes.
Main Outcome Measures: Total and annual numbers of intravitreal anti-VEGF injections, as well as injections per 1000 enrolled patients per general category of ophthalmic disease, overall and for each available medication.
Results: There were 959 945 anti-VEGF injections among 124 835 patients from 2006 to 2015. Among all injections, 64.6% were of bevacizumab, 22.0% ranibizumab, and 13.4% aflibercept; 62.7% were performed to treat age-related macular degeneration (AMD), 16.1% to treat diabetic retinal diseases (including 0.9% of all injections that were for proliferative diabetic retinopathy), 8.3% to treat retinal vein occlusions, and 12.9% for all other uses. Use of bevacizumab and ranibizumab for AMD plateaued as of 2011/2012 and decreased thereafter (in 2006, 58.8 and 35.3 injections/1000 AMD patients, respectively; in 2015, 294.4 and 100.7 injections/1000), whereas use of aflibercept increased (1.1 injections/1000 AMD patients in 2011 to 183.0 injections/1000 in 2015). Bevacizumab use increased each year for diabetic retinal disease (2.4 injections/1000 patients with diabetic retinal disease in 2009 to 13.6 per 1000 in 2015) while that of ranibizumab initially increased significantly and then declined after 2014 (0.1 in 2009 to 4.0 in 2015). Aflibercept use increased each year in patients with diabetic etinal diseases and retinal vein occlusions (both >0.1 per 1000 retinal vein occlusion patients in 2011, 5.6 and 140.2 in 2015).
Conclusions: Intravitreal injections of anti-VEGF medications increased annually from 2006 to 2015. Bevacizumab was the most common medication used, despite its lacking U.S. Food and Drug Administration approval to treat ophthalmic disease, and AMD was the most common condition treated. Ranibizumab use declined after 2014 while both the absolute and relative use of bevacizumab and aflibercept increased. Ophthalmology 2017;124:352-358 ª 2016 by the American Academy of Ophthalmology
Full Paper: Trends of Anti-Vascular Endothelial Growth Factor Use in Ophthalmology Among Privately Insured and Medicare Advantage Patients
Since Kelly and Wendel introduced the victrectomy technique to reattach the macular hole (MH),1 considerable advances in surgical treatment have been achieved. As a consequence, MH has now become a surgically treatable disease with standardized techniques incorporating vitrectomy, induction of posterior vitreous detachment, internal limiting membrane (ILM) peeling, and gas tamponade.2 Although there was a debate on ILM peeling in the past, ILM peeling has been established to improve surgical success rates.3–6 In addition, retinal ILM peeling has been facilitated by staining dye such as indocyanine green.7,8
The rationale for ILM peeling is that MH can occur and enlarge owing to contraction of perifoveal vitreous and cellular constituents with myofibroblastic differentiation on the surface of the ILM.2,9 Although ILM has no inherent contractile properties, it does act as a scaffold for contractile tissue to exert tangential traction on fovea. Several studies using optical coherence tomography (OCT) have reported the dynamic sealing process after MH surgery.10–13 Foveal tissue elongation and macular migration have been noted following ILM peeling after surgery for MH and diabetic macular edema.14–17 In addition, there is a significant correlation between these morphologic changes and visual function such as metamorphopsia.14
Although ILM peeling has become a widely accepted surgical technique since the introduction of MH surgery, the optimal extent of ILM peeling is not known and the anatomic and functional outcomes according to peeling extent have not been investigated. The purpose of this study was to investigate the influence of the extent of ILM peeling on anatomic and functional outcomes of MH surgery.
Full Paper: Extent of Internal Limiting Membrane Peeling and its Impact on Macular Hole Surgery Outcomes: A Randomized Trial
Arecent Diabetic Retinopathy Clinical Research Network (DRCR.net) comparative effectiveness trial found that for patients with diabetic macular edema (DME) and approximate Snellen equivalent baseline visual acuity (VA) of 20/50 or worse aflibercept produced greater mean VA gains at 1 year than bevacizumab or ranibizumab. In contrast, no difference in mean VA improvement was identified for patients with baseline VAs of 20/32 to 20/40.1
These agents also vary substantially in cost. O nthe basis of 2015 wholesale acquisition costs, aflibercept (2.0 mg) costs $1850,2 ranibizumab (0.3mg) costs $1170,2 and bevacizumab repackaged at compounding pharmacies into syringes for ophthalmologic use containing 1.25mg of bevacizumab costs approximately $6 0per dose.3 Considering that these medicines may be given 9 to 11 times in the first year of treatment1 and, on average, 17 times during 5 years,4 total costs can be substantial. In 2010, when these intravitreous agents were being used predominantly for age-related macular degeneration, ophthalmologic use of anti–vascular endothelial growth factor (VEGF)therapy cost approximately $2 billion or one-sixth of the entire Medicare Part B drug budget.3 In 2013, Medicare Part B expenditures for aflibercept and ranibizumab alone totaled $2.5 billion.5 Given these costs, the DRCR.net investigators believed it was important to analyze the relative cost-effectiveness of treating DME using each agent.
Full Paper: Cost-effectiveness of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema Treatment
Age-Related Macular Degeneration (AMD) is one of the leading causes of visual impairment in individuals over the age of 55 years in developed countries.1 The neovascular form of AMD, with vascular endothelial growth factor (VEGF) as one of the key factors, causes severe and irreversible vision loss, frequently resulting in legal blindness.2,3 In recent years, VEGF inhibition by anti-VEGF antibodies has significantly improved visual outcomes in patients with neovascular AMD. However, in many patients with neovascular AMD anti-VEGF needs to be continuously administered over many years to persistently suppress disease activity and maintain visual function.
The need for long-term treatment with anti-VEGF agents has also become evident in the extension studies, where long-term outcomes 7-8 years after initiation of intensive ranibizumab therapy suggest that many patients require long-term treatment with anti-VEGF agents.4 However, despite the beneficial effect of anti-VEGF therapy, long-term side effects are not clarified yet and are a matter of ongoing controversy. There is evidence that repeated long-term anti-VEGF treatment may accelerate atrophy of different ocular tissues. Retinal pigment epithelium atrophy,5 as well as scleral thinning, has been reported.6 In the last years, several studies have investigated the effect of intravitreal anti-VEGF injections on the peripapillary retinal nerve fiber layer (RNFL). There exists some controversy regarding the effect of anti-VEGF agents on retinal ganglion cells (RGCs). In mice, some reports suggest severe damage to RGCs after local treatment with VEGF binding agents,7 while another report did not find any changes within the retinal ganglion cell layer (RGCL) after VEGF receptor blockade in mice.8 Because most studies have analyzed peripapillary optical coherence tomography (OCT) scans, these reports have focused on RNFL change after antiVEGF treatment. However, several studies focusing on glaucoma patients have shown that RGCL thickness changes may be a more sensitive marker for global and regional visual field sensitivities.9,10
In the present study, we investigated RNFL and RGCL changes in the macular area in eyes receiving long-term intravitreal anti-VEGF treatment for neovascular AMD using spectral-domain optical coherence tomography (Spectralis SDOCT; Heidelberg Engineering, Heidelberg, Germany) and automated segmentation of macular scans.
Full Paper: Retinal Ganglion Cell Layer Change in Patients Treated With Anti–Vascular Endothelial Growth Factor for Neovascular Age-related Macular Degeneration
A 59-year-old patient with bilateral worsening diabetic macular edema received intravitreal injection of aflibercept (Eylea; Regeneron, Tarrytown, NY) to the left eye only. On 1-month follow-up, there was noted bilateral improvement of visual acuity and diabetic macular edema on spectral-domain optical coherence tomography imaging, reflecting bilateral effect of unilateral treatment with aflibercept.
Full Paper: Reduction of Diabetic Macular Edema in the Untreated Fellow Eye Following Intravitreal Injection of Aflibercept
Macular hole surgery was first described in 1991 by Kelly and Wendel1 and Wendel et al.2 Randomized controlled studies subsequently demonstrated the superiority of surgery over conservative management. These studies used perfluoropropane (C3F8) gas as a tamponade agent, rather than the originally described sulfur hexafluoride (SF6), and advised 2 weeks of face-down positioning (FDP).3-5 The surgical technique has been refined over the past 2 decades.6 Recent studies have demonstrated the additional benefit of internal limiting membrane (ILM) peeling at the time of surgery, and hole closure rates in most recent series are greater than 90%.7-10
There remains broad variability in clinical practice and management of this condition, with no consensus regarding the best surgical approach, particularly regarding the choice of intravitreal tamponade and duration of FDP.11-13 Many investigators have reported good results without FDP.14-25 Various mechanisms of action of the gas tamponade are postulated in macular hole surgery,26 with all assuming that bubble-fovea contact is relevant. Therefore, it would seem intuitive that a larger, longer-acting bubble combined with FDP should be beneficial because this would both facilitate and prolong this apposition. However, there is optical coherence tomography evidence that hole closure occurs very early in the postoperative period, often within the first 24 hours.27-29 As such, longer-acting gases and prolonged (or indeed any) FDP may be unnecessary.
By using a noninferiority study design applied to a large prospective (nonrandomized) registry-based cohort, we aimed to observe whether withholding FDP was noninferior to FDP (of any duration) and whether SF6 gas was noninferior to longer-acting gas tamponades. The present article presents the anatomic outcomes.
Full Paper: The Effect of Postoperative Face-Down Positioning and of Long- versus Short-Acting Gas in Macular Hole Surgery
There is a subset of eyes with neovascular age-related macular degeneration (AMD) that have persistent exudation despite fixed-interval intravitreous anti–vascular endothelial growth factor (VEGF) injections.
To evaluate the effect of topical dorzolamide hydrochloride–timolol maleate on anatomic and functional outcomes in eyes with neovascular AMD and incomplete response to anti-VEGF therapy.
Design, Setting, and Participants
An exploratory, prospective single-arm interventional study at a tertiary referral academic private practice. Patients with neovascular AMD and persistent macular edema despite fixed-interval intravitreous anti-VEGF therapy were enrolled. Baseline spectral-domain optical coherence tomography and clinical data, including visual acuity and intraocular pressure, were obtained at enrollment and from one visit before enrollment. The study was performed at the Retina Service of Wills Eye Hospital and the offices of Mid Atlantic Retina from February 1, 2015, through September 30, 2015. Patients were followed up for at least 2 visits after enrollment. Central subfield thickness, maximum subretinal fluid height, and maximum pigment epithelial detachment height from spectral-domain optical coherence tomography were recorded at each visit. INTERVENTIONS Enrolled eyes received a regimen of topical dorzolamide-timolol twice daily and continued to receive the same intravitreous anti-VEGF therapy at the same interval as received before enrollment for the duration of the study.
Main Outcomes and Measures
Change in central subfield thicknesswas the primary outcome measure. Changes in maximum subretinal fluid height, maximum pigment epithelial detachment height, and visual acuity were the secondary outcome measures.
Ten patients (10 eyes) completed the study. The mean age of the patients was 78.2 years (age range, 65-91 years), and 6 were male. Eight eyes received intravitreous aflibercept, and 2 eyes received intravitreous ranibizumab. All study eyes had been receiving long-term anti-VEGF therapy with the same medication before study enrollment for a mean of 21.9 injections. The mean central subfield thickness decreased from 419.7 μmat enrollment to 334.1 μm at the final visit (P = .01). The mean maximum subretinal fluid height decreased from 126.6 μmat enrollment to 49.5 μm at the final visit (P = .02). The mean maximum pigment epithelial detachment height decreased from 277.4 μmat enrollment to 239.9 μmat the final visit (P = .12). The mean logMAR visual acuity were 0.54 at enrollment and 0.48 at the final visit (P = .60).
Conclusions and Relevance
These data suggest that topical dorzolamide-timolol may reduce central subfield thickness and subretinal fluid in eyes with persistent exudation despite consistent, fixed-interval intravitreous anti-VEGF treatment for neovascular AMD.
Full Paper: Topical Dorzolamide-Timolol With Intravitreous Anti–Vascular Endothelial Growth Factor for Neovascular Age-Related Macular Degeneration