May 01, 2020
Ocular complications rank among the most debilitating health consequences for adults with diabetes mellitus. One complication, diabetic macular edema (DME), is a leading cause of vision loss in working age adults. DME has historically been treated with macular laser photocoagulation and local corticosteroid injection. In recent years, however, intravitreal anti-vascular endothelial growth factor (VEGF) pharmacotherapy has emerged as a new standard of care for the treatment of patients with decreased vision secondary to center-involving DME.
"We have strong clinical trial evidence supporting the efficacy of pharmacological management with intravitreal anti-VEGF agents," says Andrew J. Barkmeier, M.D., with Ophthalmology at Mayo Clinic in Rochester, Minnesota. "Meta-analysis of these trials, however, remains underpowered to evaluate for potentially significant differences in systemic serious adverse event rates after treatment."
To address the evidence gap, Dr. Barkmeier and fellow researchers retrospectively assessed the relative rates of systemic serious adverse events (SAE) after DME treatment with intravitreal anti-VEGF pharmacotherapy, macular laser photocoagulation, and injection of corticosteroid medications, using a large national administrative claims database of commercially insured adults. Results were published in Ophthalmology in 2019.
VEGF as therapeutic target
"VEGF is a critical growth factor in angiogenesis and acts on vascular endothelia, abnormally increasing retinal vascular permeability. This makes it an attractive therapeutic target," says Dr. Barkmeier. "However, intravenous anti-VEGF therapy has been associated with serious systemic complications and increased mortality in patients with cancer. Given that association, there is concern that intravitreal injection of anti-VEGF medications may also pose a systemic risk."
From the OptumLabs database, researchers identified patients who were privately insured or enrolled with Medicare Advantage, age 18 years or older, and treated with anti-VEGF for DME between Jan. 1, 2006, and Dec. 31, 2015 — as well as control patients receiving macular laser or intravitreal corticosteroid injections for DME. Patients had a minimum of one year of medical coverage before initial treatment.
Of the patients receiving treatment for DME during the study period, 23,348 met criteria for inclusion in the analysis. Of that cohort:
- 9,219 patients were initially treated with intravitreal anti-VEGF pharmacotherapy
- 13,365 patients were initially treated with macular laser photocoagulation
- 764 patients received intravitreal corticosteroid as initial DME management
Overall, patients in the study received 24,685 anti-VEGF injections, 20,574 macular laser photocoagulation procedures and 981 intravitreal corticosteroid injections within six months of their initial treatment for DME, or before being censored due to receiving an alternative treatment.
"Baseline characteristics between the groups were similar, although a smaller proportion of patients receiving initial macular laser photocoagulation were age 65 years or older, compared with the anti-VEGF or corticosteroid groups," says Dr. Barkmeier. "Anti-VEGF pharmacotherapy was more frequently used as initial DME treatment in the latter years of the study."
In the anti-VEGF and macular laser groups, respectively:
- 5.5% and 4.3% of patients had a history of a myocardial infarction
- 12.9% and 11.3% had prior cerebrovascular disease
- 23.0% and 16.4% had moderate or severe renal disease
Comparison of systemic risk
Primary systemic SAE outcome measures identified by the research team included myocardial infarction, cerebrovascular disease, major bleeding and all-cause hospitalization occurring within six months of initial DME treatment. Researchers then compared the rate of these outcomes after anti-VEGF pharmacotherapy versus the rate after macular laser photocoagulation or intravitreal corticosteroid treatment.
Researchers found no difference in the risk of cerebrovascular disease (HR 0.96 [95% CI, 0.65-1.41], p = 0.83), major bleeding (HR 1.23 [95% CI, 0.76-1.99], p = 0.41), or myocardial infarction (HR 1.03 [95% CI, 0.73-1.44], p = 0.88) between patients receiving anti-VEGF pharmacotherapy and patients treated with macular laser photocoagulation. Similarly, there were no differences in the risk of primary systemic SAE outcomes compared to patients receiving intravitreal corticosteroid pharmacotherapy. Subgroup analyses of patients at potentially elevated systemic risk revealed similar findings. Patients who received anti-VEGF pharmacotherapy did, however, have an increased rate of all-cause hospital admission compared with those receiving initial macular laser photocoagulation (HR 1.17 [95% CI, 1.05-1.30], p = 0.01).
Overall, this study offers further evidence of a relatively safe systemic risk profile for intravitreal anti-VEGF pharmacotherapy. "We identified no increased risk of stroke, major bleeding or myocardial infarction after initiation of intravitreal anti-VEGF treatment for DME," says Dr. Barkmeier. "Although the potential difference in all-cause hospitalization may merit further investigation, it is increasingly evident that these medications are well-tolerated systemically when delivered as intravitreal pharmacotherapy for sight-threatening retinal disease, including in the real-world treatment of DME."
For more information
Maloney MH, et al. Risk of systemic adverse events associated with intravitreal anti-VEGF therapy for diabetic macular edema in routine clinical practice. Ophthalmology. 2019;126:1007.