Do more anti-VEGF injections lead to better clinical outcomes?

Michael Larson, MDThe appropriate use of agents that inhibit vascular endothelial growth factor (VEGF) can bring significant improvements to both short-term and long-term visual acuity for patients with neovascular AMD.

The limiting factor for clinical improvement may be as simple as too few injections.

“You can do a very good job of administering anti-VEGF therapy tailored to the individual patient’s needs while limiting expenses and exposure to risks by avoiding unnecessary injections,” said Michael Larsen, MD, DMSc, professor of clinical ophthalmology at the Rigshospitalet and the University of Copenhagen, Denmark.

“It is a demanding task though, because if you give an average of four injections per year, it will be too little to provide patients something that approaches the quality of results that has been demonstrated in controlled clinical trials,” he said. “You have to give closer to seven or eight injections and you have to time it right.”

Dr. Larsen explored real world results of anti-VEGF treatment for wet AMD and found that most patients require seven to eight anti-VEGF injections annually and about 10 office visits to assess clinical status.

Treatment patterns vary

Treatment patterns vary

Clinical treatment patterns vary dramatically from country to country and from region to region within countries, Dr. Larsen continued.

The frequency of examination, assessment, and treatment depend on a variety of elements, including practice setting, local regulations, reimbursement requirements, patient factors, and other components.

Under-treatment is common and patients who receive too few treatments have poorer clinical outcomes.

The CATT study clearly showed that anti-VEFG injections of ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech) improved and maintained best-corrected visual acuity (BCVA).

There was somewhat better improvement using on-label administration, a mean of 22.9 injections per year, compared to a mean of 13.4 injections per year on PRN schedules, but the differences were small.

During monthly visits, patients on both on-label and PRN regimens showed very good maintenance of vision gained during the first few months over the remainder of the 2-year study period.

Other retrospective studies showed similar results.

A 2.6-year review of ranibizumab PRN showed an initial improvement of 8.4 letters with maintenance of improvement on a mean of 8.6 injections per year.

A review of fixed-interval anti-VEGF dosing found a mean improvement of 14 letters after five years of treatment with 10.5 injections per year.

Results from LUMINOUS Study

Results from the LUMINOUS Study showed the other end of the treatment spectrum.

After a mean of 4.3 to 5.7 injections over 12 months, visual acuity had largely returned to baseline for about 3,500 patients in Germany, the Netherlands, Belgium, and Sweden.

“The one positive thing I can say about those who continue to give a relatively low number of treatments on average is that even if patients do not have much improvement in visual acuity, they will have avoided the natural history of losing 24 letters over two years,” Dr. Larsen explained.

“We have to remember that many young ophthalmologists have never seen the spontaneous course of wet AMD.”

“For patients who start out at 20/20 visual acuity, after the first year of wet AMD, they will have lost their driver’s license. After the second year, they will have lost the ability to read without telescopic lenses or devices such as an iPad,” he added. “Even inadequate treatment can slow the decline in visual loss, even if patients do not get much of a gain in visual acuity.”

Retrospective studies also show that as many as 1/3 of patients may lose 15 letters or more due to geographic atrophy and fibrosis.

The loss is more severe in cases with classic lesion components and under-treatment.

Frequent treatment definitely cannot prevent the loss of 15 or more letters, but continuing loss of acuity is much less likely for patients who receive an adequate number of injections.

Frequent office visits

Frequent office visits

The key to effective PRN treatment is frequent office visits to assess the patient’s condition.

Visits every four to six weeks particularly can be helpful in practice settings where an anti-VEGF injection can be given on the spot as needed. Problems begin to arise when patients must schedule a separate return visit for an injection.

A study published in Acta Ophthalmologica in 2015 found that patients who routinely were administered injections on the same day as the need-to-treat was identified gained 5.8 letters over the first three months. Before same-day injections became the norm, patients were injected on average two weeks after the need-to-inject was identified and they gained only 1.5 letters after the same 90-day period.

An unexpected repeat visit for treatment is a bother for patients, Dr. Larsen noted.

Taxis and public transportation may make it possible for patients to come back in a few days or weeks in urban areas, but it is problematic in rural areas where patients may have to rely on family members or friends for transportation to and from medical visits.

“Even when family and friends offer to assist, patients may shy away because they see it as an imposition,” he added. “When that happens, we see that people cannot come to the doctor every month, so they end up going every three months and treatment suffers.”

Michael Larsen, MD

e. MICLAR01@regionh.dk

This article was adapted from Dr. Larsen’s presentation, “Long-term Anti-VEGF Monotherapy: Do Patients Improve?,” at the 2015 American Academy of Ophthalmology meeting.