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Safety issues concerning intravitreous VEGF inhibition

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Selectively inhibiting the vascular endothelial growth factor (VEGF) has proven to be an efficacious treatment for age-related macular degeneration; however, ophthalmologists may have concerns about safety.

With pegaptanib sodium (Macugen, Pfizer), there is no evidence of systemic toxicities. To decrease the risk of adverse events, proper procedures should be followed for the intravitreous injection of pegaptanib for wet AMD.

Safety profile

Because pegaptanib specifically targets VEGF₁₆₅ in the eye, the pathologic VEGF isoform, the likelihood for systemic adverse events is low.

In the VISION trial of pegaptanib,¹ there was no evidence of systemic adverse events attributable to the study drug. Rather, most of the adverse events associated with pegaptanib were ocular and were related to the intravitreal injection procedure.

A literature review by Jager et al² identified studies evaluating intravitreous injection for ocular disease. The review covered 14,866 injections in 4,382 eyes.

The prevalence of endophthalmitis, including cases of pseudoendophthalmitis, was 0.3% per injection and 0.9% per eye. The researchers concluded the risk of serious adverse events after intravitreous injection was low, but cautioned that ophthalmologists should pay careful attention to injection technique and should monitor patients postinjection.

The overall rate of adverse events in the VISION trial¹ was similar between pegaptanib and usual care at both the 1- and 2-year endpoints: 19% vs. 15% and 17% vs. 19%, respectively.^1,3

Discontinuation for adverse events was low at 1% for both pegaptanib and usual care at year 1 and rates of 4% with pegaptanib and 2% with usual care at year 2. Mortality was also low, with a 2% rate in both treatment groups at year 1 and a 1% rate in both groups at year 2.

Second year of treatment

Data on patients who received a second year of treatment confirmed the favorable safety profile of pegaptanib in patients with wet AMD.⁴ In the first year, 1,190 patients received at least one study treatment. Treatment was 0.3 mg, 1 mg or 3 mg of pegaptanib or a sham injection. There were more than 7,500 intravitreous injections of pegaptanib.

In the second year, 425 patients continued the same treatment as in year 1 and received at least one study treatment in year 2. There were more than 2,600 intravitreous injections of pegaptanib in the second year.

As in earlier reports of the VISION trial, the most common adverse events were transient and mild to moderate.

The researchers noted that common ocular adverse events were reported in a higher proportion of eyes that received sham injections rather than active treatment, suggesting that the events were related to the injection preparation procedure and not to the injection itself.

Serious adverse events in year 1 include endophthalmitis, with a rate of 0.16%/injection; retinal detachment, with a rate of 0.08%/injection; and traumatic cataract, with a rate of 0.07%/injection. Most cases of endophthalmitis during year 1 were caused by violations of the injection preparation protocol.

Among patients who continued pegaptanib in year 2, there were no new reports of endophthalmitis or traumatic cataract. The rate of retinal detachment was 0.15%/injection in year 2.

During both years of the study, the researchers did not see a correlation between pegaptanib and adverse events seen with systemic, nonselective VEGF inhibitors such as hypertension, thromboembolic events, and serious hemorrhagic events.

Figure. The rate of endophthalmitis following intravitreous injections of pegaptanib was comparable to the rate observed with other common ophthalmic surgical procedures.1

Endophthalmitis

Endophthalmitis is a potentially serious adverse effect of intravitreous injections of which ophthalmologists should be aware. Consequently, the pegaptanib label carries a warning that drugs delivered by intravitreous injections have been associated with endophthalmitis.⁵

Twelve patients (1.3%) in the VISION study¹ developed endophthalmitis in the first year of treatment for an endophthalmitis rate of 1.3% per patient and 0.16% per injection.

The researchers noted that the rate was similar to that identified by Jager et al² in their review of intravitreous injections and comparable to the rate, per procedure, of endophthalmitis associated with other routinely performed ophthalmic surgeries such as cataract surgery (0.4%), glaucoma surgery (0.2%), vitrectomy (0.03%) and corneal transplantation (0.08%) (Figure).

In eight of the 12 patients, the infection was associated with protocol violations, most commonly, the absence of an eyelid speculum. Two thirds of endophthalmitis patients in the VISION study had a positive culture result with coagulase-negative Staphylococcus epidermiditis as the most common isolate.

With appropriate treatment, only 1 of the 12 patients experienced severe vision loss; thus, endophthalmitis accounted for severe vision loss in only 0.1% of the study patients during the first year of the study.

The VISION researchers emphasized that to achieve maximum benefit with pegaptanib, ophthalmologists must follow appropriate aseptic techniques carefully, which include the use of broad-spectrum antibiotic drops and povidone iodine, as well as sterile gloves, drape and speculum. Ophthalmologists must also educate patients about possible symptoms of endophthalmitis and monitor patients closely after each injection.

References

1. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.
2. Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a comprehensive review. Retina. 2004;24:676-698.
3. Meiler WF, et al. The VISION Study: Safety of a second year of Macugen treatment for neovascular MAD. Presented at the American Society of Retina Specialists Meeting. July 16-20, 2005. Montreal.
4. The VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group. Pegaptanib sodium, an anti-VEGF aptamer, for neovascular age-related macular degeneration: safety results of the 2 prospective, multicenter, controlled clinical trials. Ophthalmology. 2006: In press.
5. Pegaptanib [prescribing information]. Available at http://www.emea.europa.eu/humandocs/Humans/EPAR/macugen/macugen.htm. Last accessed Oct. 5, 2006.