In 1993, the average retina subspecialist might have given 1 intravitreal injection during the course of a year. Today, that number is more likely to be 15 per day—“and many of us give 30 to 40 a day,” said Daniel F. Martin, MD, in his 2017 Jackson Memorial Lecture, titled “Intravitreal Therapy for Retinal Diseases: From CMV to CNV.”
Paradigm shift. During the past 25 years, “the greatest rate of growth in any procedure in all of medicine is CPT code 67028, Intravitreal injection of a pharmacological agent,” Dr. Martin said.
“In 1993, the total number of intravitreal injections paid for by fee-for-service Medicare was about 2,000,” he noted. “In 2016, this number had exploded to 3.3 million. And when one adds injections covered by Medicare Advantage programs, Medicaid, and commercial insurance programs, the estimated number of injections jumps to 7 million per year in the United States.” The worldwide estimate is over 20 million injections annually, he added.
From CMV retinitis to DME. For posterior segment diseases, this paradigm shift away from intravenous (IV) and oral therapy for a retinal disease to multiple repeated intravitreal injections began with the treatment of cytomegalovirus (CMV) retinitis. “What we do now, in all of our clinics? It started here,” Dr. Martin reminded the audience. CMV treatment took a leap forward first with the discovery that intravitreal injections of ganciclovir—unlike the IV drugs—were highly effective and, later, with the development of the ganciclovir implant.
The next shift in treatment patterns began at the Academy meeting in 2000, when P. Andrew Pearson, MD, reported that a different sustained-release implant, containing the steroid fluocinolone, led to complete resolution of diabetic macular edema (DME) in a small series of patients with severe, recalcitrant DME.
“Ophthalmologists immediately realized that they had the less-expensive version of fluocinolone—that is, triamcinolone—back home and started employing intravitreal injections of that drug without any clinical trial data to support its use,” Dr. Martin said, adding wryly, “retina people are fantastic at that.” Later, he noted, the treatment effect of intravitreal triamcinolone was confirmed in clinical trials.
Enter anti-VEGF drugs. In January 1999, Dr. Martin gave the first injection of an anti–vascular endothelial growth factor (anti-VEGF) drug. “David Wilson gave the second, and Julia Haller gave the third.” That drug, pegaptanib, was supplanted in 2005 when ranibizumab and bevacizumab emerged as effective treatments for wet age-related macular degeneration.
What we’ve learned about dosing. Dr. Martin outlined some lessons learned from the anti-VEGF era.
One of these is that “pro re nata [PRN] dosing results in excellent visual acuity [VA] outcomes—but 2 letters less gain than [with] monthly dosing. We’ve seen that time and again” in numerous clinical trials.
Considerations for choosing a regimen. Dr. Martin added that no predictive factors have emerged as to which patient will fall into that dosing group. “We have tortured the data, trying to make it confess. And it hasn’t.”
- Visual outcomes. “The most powerful predictor of VA outcomes is the visual acuity at week 12.”
- Subretinal hemorrhages. “These patients do very well with anti-VEGF injections alone.”
- Residual fluid. The presence of any residual fluid remaining after treatment “matters only if it’s intraretinal and in the center of the fovea.”
- Geographic atrophy (GA). At 2 years, GA is “more common in monthly-treated eyes than in PRN-treated eyes.”
Looking ahead. Will the number of injections ever decrease? “I don’t see this changing any time soon,” Dr. Martin said, thanks in part to an increase in the number of conditions that are expected to be treated with intravitreal drugs.
He noted that remaining challenges include the drop-off in VA gains between years 2 and 5 in AMD patients treated with anti-VEGF drugs. And, he concluded, “We still don’t have that sustained-release device that will allow us to treat our patients only 1 time a year. We all want that—the good news is that many people are working on that challenge.” —Jean Shaw
Financial disclosures. None.
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