Cheryl Guttman Krader, BS, Pharm

This article was reviewed by Joyce N. Mbekeani, MD, Moshe Szlechter, MD, and Matthew S. Wieder, MD.

Use of anxiety-screening questionnaires in patients needing intravitreal anti-VEGF injections may help to identify individuals at risk for elevated pain during the procedure, according to research presented at ARVO 2020.

The two-center, non-interventional, prospective study was designed to evaluate anxiety levels and sleep patterns as predictors of patient perceptions of pain following intravitreal injection. In a regression analysis that controlled for potential confounders, anxiety score measured with the General Anxiety Disorder-7 (GAD-7) questionnaire was the only variable examined that independently predicted pain. There were no statistically significant associations between intravitreal anti-VEGF injection pain and measured sleep parameters, age, gender, laterality, diagnosis, previous injections, or surgeon/site.

“Intravitreal anti-VEGF injections are the most commonly performed in-office intraocular procedure. Although generally well-tolerated, some patients experience pain, and because many patients undergo these treatments on a regular basis for treatment of a chronic condition, pain during the injection could result in poor adherence to future treatment,” said Matthew S. Wieder, MD.

“To identify strategies to combat the pain experienced by some patients, several studies have evaluated different techniques to decrease the pain, including changes in anesthesia and injection site," Wieder said. "The findings of our study support future research of modifications that target anxiety to help address pain perception of intravitreal anti-VEGF injections.”

Dr Wieder, resident, Department of Ophthalmology and Visual Sciences, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, presented the study for the Virtual ARVO meeting. 

Moshe Szlechter, MD, and Irene Rusu MD performed the injections. Dr Szlechter is a retina specialist at KLM Eye Care, Brooklyn, NY, and Dr Rusu is a retina specialist at Brooklyn Eye Center, Brooklyn, NY. Both are Assistant Professors of Ophthalmology and Visual Sciences at Albert Einstein College of Medicine, Bronx, NY.

Dr Szlechter explained the idea for the study occurred to him while he was lecturing in his community about ophthalmology procedures.

“I wound up speaking from the hip and said that I can predict based on a patient’s level of stress who will feel pain before I even administer the injection. I researched the idea after my lecture, and found no good data to support my assertion,” he said.

“It is interesting how a pre-existing psychological state influences a very physiological reaction. A patient's heightened anticipation and anxiety of future pain will actually make the procedure more painful.”

A standard technique was used at the two participating sites to control for potential confounding variables. Patients were given the GAD-7 (possible range 0-21) and Pittsburgh Sleep Quality Index (possible range 0-21) to complete prior to their injection. After the procedure, they were asked to rate the severity of pain after intravitreal injection as 0 to 10 with a visual analogue scale.

A total of 154 patients were recruited, of which 140 met the inclusion criteria for analysis. The total cohort was equally distributed between the two sites. The patients included in the analysis had a mean age of approximately 72 years and 56% were female. 

The two most common indications for the injections were wet age-related macular degeneration (40%) and diabetic macular edema (29%). Mean ± standard deviation scores were 4.9 ± 5.6 for the GAD-7, 6.3 ± 4.1 for the PSQI, and 3.69 ± 2.64 for pain. Mean ± standard deviation for overnight sleep was 6.7 ± 2.0 hours and was 7.6 ± 2.6 hours for sleep over 24 hours.

“Anxiety scores on the GAD-7 ranged from 0 to 21 and post-procedure pain scores ranged from 0 to 10, but most patients had low scores indicating mild to no anxiety and most experienced no or mild pain,” Dr Wieder said.

A statistically significant positive correlation was found between the GAD-7 score and pain (

For the sleep measures, both previous night’s sleep and sleep over the last 24 hours negatively correlated with pain, and there was a positive correlation between PSQI and pain scores (higher PSQI score indicates poorer sleep quality), although none of the correlations achieved statistical significance.

In the regression analysis that controlled for confounding variables, each point increase in the GAD-7 score predicted a 0.11-point increase in procedural pain score.

This article was adapted from a presentation at the 2020 virtual meeting of the Association for Research in Vision and Ophthalmology. None of the investigators has any relevant financial interest to declare.

Articles

Use of anxiety-screening questionnaires in patients needing intravitreal anti-VEGF injections may help to identify individuals at risk for elevated pain during the procedure, according to research presented at ARVO 2020. 

Improving patient comfort with intravitreal injections

This article was reviewed by Andrea Blitzer, MD, and Dimitra Skondra MD, PhD.

Reduction in the risk of developing age-related macular degeneration (AMD) may be another benefit of metformin for protecting against age-related diseases, according to a case-control study undertaken by a team of investigators at the University of Chicago.

Led by Dimitra Skondra, MD, PhD, associate professor, Department of Ophthalmology and Visual Science, the research analyzed 10 years of data from the IBM MarketScan Commercial and Medicare Supplemental databases. It found that the strongest effect occurred at low to moderate doses of metformin, was not restricted to patients with diabetes, but was not present among patients with diabetes who had diabetic retinopathy.

Andrea Blitzer, MD a member of Dr Skondra’s team and an ophthalmology resident at the University of Chicago, presented the findings on the virtual platform for ARVO 2020. 

Dr Blitzer said, “Further studies are needed to confirm the protective benefit that we identified for metformin and to investigate the underlying pathways. If our findings are confirmed in clinical trials, the research may lead to a novel therapeutic strategy for this blinding disease.”

Previous studies found that metformin reduced the incidence of diabetes mellitus, diabetes-related mortality, cardiovascular diseases, cancer, dementia, and all-cause mortality. It has also been reported to reduce the risk of glaucoma.

“Metformin targets mediators and pathways that affect inflammation, cell survival, stress defense, oxidative stress. All of these can play a role in health span and longevity, and a number of the pathways and mediators that are targets for metformin have also been implicated in the pathogenesis of AMD,” Dr Blitzer said.

“This led to Dr Skondra’s study investigating whether metformin decreases the risk of developing AMD using a big data approach.”

The cases and controls for the research were identified through a search of the MarketScan database for the years 2008 to 2017. The study looked at people 55 years of age or older who had newly diagnosed AMD.

A control subject was selected for each case from among a pool of 31 million patients and matched by age, comorbidities, and region of the US. The investigators were able to determine metformin usage based on claims data.

The study looked at a total of 312,404 cases that were then matched with controls. Compared with the controls, patients with AMD were more likely to smoke, to have hyperlipidemia, and to have diabetic retinopathy.

In a multivariate model adjusting for risk factors and other medications, the use of metformin significantly decreased the risk of being newly diagnosed with AMD within 2 years by 6%. With stratification by metformin dose, patients who had received low to moderate doses had the greatest risk reduction (9% and 10%, respectively).

Because metformin is primarily used as an antihyperglycemic drug, the investigators also analyzed the data to see if the potential protective effect of metformin on AMD development occurred only in the cohort of diabetic patients. They found that the protective effect was similar in the diabetic cohort as in the overall cohort, including with respect to dose dependency and the level of risk reduction.

Because cases were more likely than controls to have diabetic retinopathy, another analysis considered if the presence of this ocular complication of diabetes was an important factor for metformin’s risk reduction. The results showed that the benefit of metformin only occurred in the absence of diabetic retinopathy, the team reported.

Finally, a protective benefit of other antihyperglycemic medications and statins was investigated. In multivariate models, other diabetic medications seemed to have a mild protective effect as well, but metformin remained protective even in multivariate analysis adjusting for the effects of other medications

“Metformin is a well-tolerated and is the most commonly used oral medication to treat diabetes. The findings from our team may uncover a role for its use as a possible therapeutic intervention for AMD as well,” Dr Skondra said.

This article was adapted from a presentation at the 2020 virtual meeting of the Association for Research in Vision and Ophthalmology. Dr Skondra and Dr Blitzer have no relevant financial interests to report.

A large case-control study found that among adults aged 55 years and older, the use of metformin significantly decreased the risk of being newly diagnosed with age-related macular degeneration within 2 years. 

Antihyperglycemic drug associated with reduced risk of new onset AMD

This article was reviewed by William S. Gange, MD.

A retrospective study including a large patient sample shows that a small but significant proportion of individuals who are newly diagnosed with type 2 diabetes develop severe diabetic eye disease within 5 years. 

According to the research, the risk for early development of this microvascular complication of diabetes is particularly high among patients with a history of renal disease, insulin use, A1c >9%, peripheral circulatory disease, neurologic disease, Black race, and advanced age at diagnosis.

“Currently, there are 30 million people with diabetes in the United States, and the number is expected to reach 40 million by 2030. As the population of diabetics continues to grow, screening all patients for diabetic eye disease at guideline-recommended intervals becomes a public health challenge,” said William S. Gange, MD, presenting the data at ARVO 2020.

“The findings of our study investigating risk factors for early development of severe diabetic eye disease can help to identify patients who are likely to benefit most from improved rates of screening,” Gange added.

Gange, resident USC Roski Eye Institute, Los Angeles, conducted the study with Brian Toy, MD, retina specialist and Assistant Professor of Clinical Ophthalmology, USC Roski Eye Institute, and faculty at the USC Schaeffer Center for Health Policy.

Employing a commercial claims database, they identified patients aged ≥18 years who were newly diagnosed with type 2 diabetes between 2007 and 2015 and who had at least 1 year of continuous enrollment preceding the diagnosis and a minimum of 2 years of continuing enrollment post-diagnosis.

Development of severe diabetic eye disease was identified by the presence of an ICD-9 or CPT code indicating a diagnosis of proliferative diabetic retinopathy, tractional retinal detachment, neovascular glaucoma, or blindness following the diagnosis of diabetes. Patients with any of these diagnoses prior to the initial diagnosis of diabetes were excluded.

The rate of development of the composite endpoint was analyzed at both 2 and 5 years post-diagnosis of diabetes. Patients included in the 5-year analysis had to have had at least 5 years of continuous enrollment after being diagnosed with diabetes.

For the 2-year risk analysis, 277,400 patients met the inclusion/exclusion criteria, of which approximately 4,000 (1.44%) developed severe diabetic eye disease by 2 years after their diabetes diagnosis. The 5-year analysis included approximately 71,000 patients, of which about 2,100 (2.91%) had developed severe diabetic eye disease.

“Proliferative diabetic retinopathy accounted for the majority of cases of severe diabetic eye disease, but a significant number of patients had developed blindness – 0.55% by 2 years and 1.18% by 5 years," Gange noted. "Tractional retinal detachment and neovascular glaucoma, however, were rare."

Comparisons between patients with and without severe diabetic eye disease showed a number of statistically significant differences between the two groups in demographic and clinical characteristics at 2 and 5 years. 

However, several of the differences dropped out in the regression model.

The finding that individuals who were younger at diagnosis were less likely than their advanced age counterparts to have developed severe diabetic eye disease may seem counterintuitive knowing that the risk for diabetic eye disease increases with time since diagnosis and that patients diagnosed with diabetes at a younger age will go on to develop significant amounts of diabetic eye disease. 

Gange explained, however, that the results of the study are understood by its design.

“Our study was based on longitudinal follow-up of patients that began at time of diagnosis," Gange said. "It is likely that patients who were older when diagnosed with diabetes had a longer duration of undiagnosed diabetes that would lead to higher rates of severe eye disease."

This article was adapted from Gange’s presentation at the 2020 virtual meeting of the Association for Research in Vision and Ophthalmology. Gange did not indicate any proprietary interests relevant to the subject matter.

An analysis using a large commercial claims database found that almost 3% of patients developed severe diabetic eye disease within 5 years of being diagnosed with type 2 diabetes. Clinical and demographic risk factors were also identified.

Identifying risk factors for severe diabetic eye disease

This article was reviewed by Sandeep N. Shah, MD

A post-hoc analysis of data from the DRCR Network Protocol V provides new insight on outcomes of eyes with center-involved diabetic macular edema (CI-DME) and good best-corrected visual acuity (BCVA) if treated with anti-VEGF therapy only if vision worsened. The research also identified features associated with a need for intervention.

 on Feb. 20, 2020 [Glassman AR, et al; DRCR Retina Network. 

. 2020;138(4):341-9] and presented at ARVO 2020 by Sandeep N. Shah, MD.

“Protocol V randomized adults with type 1 or 2 diabetes who had CI-DME and Snellen equivalent BCVA of 20/25 or better to initial management with aflibercept, focal/grid laser, or observation with aflibercept given in the laser and observation groups if VA decreased from baseline. At 2 years, there was no difference in VA loss between the three study arms, and mean VA was 20/20 in all groups. Based on these results, many clinicians and patients might choose initial observation for eyes with CI-DME and good VA, withholding anti-VEGF treatment unless VA worsens,” said Shah, Principal Investigator for Protocol V at the Retina Vitreous Center, Oklahoma City, OK.

“Overall, the data from Protocol V show that some patients will do quite well if managed with observation, and that using the DRCR Retina Network protocol-defined approach combining BCVA and OCT-measured central subfield thickness (CST) is an effective strategy for determining when to initiate anti-VEGF treatment," Shah added. "Knowing risk factors that predispose to the need for anti-VEGF therapy helps in deciding follow-up intervals and patient education.”

In Protocol V, a total of 236 eyes were randomized to initial management with observation. Per the protocol, patients were to be followed initially after 2 months. Anti-VEGF treatment was initiated if VA worsened by ≥10 letters or more from baseline at any visit or if there was a loss of 5 to 9 letters at two consecutive visits.

The schedule for ongoing follow-up of eyes that did not have worsening of VA was determined based on findings of the OCT. If the CST worsened, defined by an increase of at least 10% from the last visit or an increase to >400 microns, the follow-up interval was reduced to a minimum of 1 month.

However, the maximum follow-up interval was extended to every 4 months for eyes that did not have a worsening of CST.

During the 2 years of follow-up in the observation group, 19% of eyes experienced a BCVA loss of 10 or more letters at least once and 39% experienced a 5- to 9-letter loss at least once. At the next follow-up visit, however, only 32% of eyes had a sustained VA loss and began aflibercept, whereas 46% of these eyes never went on to need aflibercept during the 2 years of the trial.

“These data show how important the role of repeatability of VA change is in an overall treatment regimen,” Shah said.

At the end of the 2-year follow-up, 66% of eyes did not require anti-VEGF treatment with aflibercept and 31% of those eyes had spontaneous resolution of DME with a median VA of 20/20. Within the subgroup of eyes that received anti-VEGF treatment per study criteria, VA was still good at 2 years (median 20/25) and 70% did not lose ≥1 line of VA.

The analysis of factors associated with receipt of aflibercept showed greater baseline CST, having advanced diabetic retinopathy, and need for treatment of DME in the fellow eye increased the likelihood for intervention. Eyes with baseline CST ≥300 µm were approximately twofold more likely to go on to anti-VEGF treatment than eyes with less macular thickening. 

The impact of diabetic retinopathy severity was analyzed with eyes classified using the ETDRS grading system. It found that eyes with a DRSS level ≥47 (moderately severe nonproliferative diabetic retinopathy and above) were 2.22 times more likely than eyes with a DRSS level ≤43 (moderate NPDR and below) to need aflibercept treatment. 

A need for DME treatment in the fellow eye within 4 months of randomization increased the likelihood that a patient would receive aflibercept in the study eye by 2.55-fold.

“However, even in these three higher risk groups, only about 50% of the eyes received anti-VEGF treatment. Therefore, although clinicians and patients should understand treatment expectations when they are in the higher risk groups, many of these eyes still will not need treatment,” said Adam R. Glassman, MS, lead author of the 

 paper and Director, DRCR.net Coordinating Center, Jaeb Center for Health Research, Tampa, FL.

Discussing the limitations of the report, Shah identified the post-hoc nature of the analysis and that it did not evaluate the laser group, which required fewer injections than the aflibercept group. 

In addition, some of the associations identified may have been due to chance considering that multiple characteristics were evaluated. 

Finally, the treatment decisions were guided by VA measurements obtained with the E-ETDRS testing protocol refraction, which may differ from the approach used in clinical settings.

Shah and Glassman have no relevant financial interests to disclose.

A new analysis from the DRCR Network Protocol V showed that many patients with center-involved diabetic macular edema and good vision do not require treatment for visual acuity loss. 

Author | Cheryl Guttman Krader, BS, Pharm

Articles

Improving patient comfort with intravitreal injections

Antihyperglycemic drug associated with reduced risk of new onset AMD

Identifying risk factors for severe diabetic eye disease

New Protocol V findings offer guidance for managing DME