April 11, 2012 — A 2-year randomized controlled trial suggests that bevacizumab (Avastin, Genentech) is more effective than macular laser therapy in patients with diabetic macular edema. Ranjan Rajendram, MD, FRCOphth, from the Department of Medical Retina, Moorfields Eye Hospital, and the University College London Institute of Ophthalmology, London, United Kingdom, and colleagues reported the result of their trial in an article published online April 9 in the Archives of Ophthalmology.
The new article updates previously reported 1-year follow-up data from the same trial and provides further validation for an approach that many clinicians are already taking, Robert Frank, MD, PhD, a clinical correspondent for the American Academy of Ophthalmology, told Medscape Medical News.
"Many people are using bevacizumab, even though this is the only study out there that shows any benefits," said Dr. Frank, professor of ophthalmology and of anatomy/cell biology at Wayne State University School of Medicine in Detroit, Michigan. "I think it's an important study, though it's not yet definitive because there were only 80 patients, and you would usually like to have hundreds."
Macular laser therapy had been the mainstay of treatment for clinically significant diabetic macular edema since the 1980s. The procedure reduces the risk for moderate visual loss, but visual acuity improves (a 15-letter gain at 3 years) in less than 3% of patients, the researchers write.
More recently, preliminary evidence has emerged that intravitreal injections of antivascular endothelial growth factor (anti-VEGF) drugs are more effective, Dr. Frank said. Bevacizumab and the related drugs aflibercept (Eylea, Regeneron Pharmaceuticals) and ranibizumab (Lucentis, Genentech) are being used for this purpose.
To verify that bevacizumab is better than laser treatment, the researchers enlisted 80 patients with center-involving clinically significant macular edema.
The patients had best-corrected visual acuity in the study eye of 35 to 69 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 4 m (Snellen equivalent, ≥6/60 or ≤6/12), center-involving macular edema with central macular thickness on optical coherence tomography of at least 270 μm, at least 1 previous macular laser therapy, and no anti-VEGF treatment in the fellow eye in the previous 3 months.
The researchers randomly assigned the patients to receive either bevacizumab or laser therapy.
The patients receiving laser therapy received a 50-μm argon laser spot size (laser applied only >500 μm from the edge of the foveal avascular zone), with focal treatment aiming to cause mild blanching of the retinal pigment epithelium, and not darkening or whitening of microaneurysms. The researchers treated diffuse leakage or nonperfusion similarly in a grid pattern.
The patients receiving bevacizumab received an injection at baseline and at 6 and 12 weeks, and were reviewed at 18 weeks and then every 6 weeks until week 102 for the need of more injections. If the thinnest recorded central macular thickness was less than 270 μm at 18 weeks, then the researchers continued treatment only if they judged the macular thickness to be unstable.
If the central macular thickness of the patients receiving bevacizumab was greater than 270 μm at 18 weeks and at subsequent visits, then the researchers continued the bevacizumab injections until the patients had stable macular thickness. The researchers defined stable macular thickness as 3 consecutive visits with the thickness within 20 μm of the patient's thinnest recorded measurement.
Patients Fared Better With Bevacizumab Than With Laser Therapy
Overall, the patients receiving bevacizumab fared better than the patients receiving laser therapy. The mean ETDRS best-corrected visual acuity at 24 months in the bevacizumab group was 64.4 letters (±13.3 letters; range, 34 - 88 letters; Snellen equivalent, 20/50).
In the laser group, the mean best-corrected visual acuity at 24 months was 54.8 letters (±12.6 letters; range, 33 - 75 letters; Snellen equivalent, 20/80). The difference between the 2 groups was statistically significant (P = .005).
The patients receiving bevacizumab gained a mean of 8.6 (±9.1) letters, whereas the patients receiving laser therapy lost a mean of 0.5 (±10.6) letters.
The patients receiving bevacizumab reduced their central macular thickness a mean of 146 μm, whereas the laser patients reduced theirs 118 μm.
The patients receiving bevacizumab received a median of 13 treatments (interquartile range, 11 - 15 treatments) over the course of 24 months, whereas the patients receiving laser therapy had 4 treatments (interquartile range, 3 - 5 treatments).
The procedures appeared to be equally safe. At 24 months, the mean foveal avascular zone of 1000 μm or more in greatest linear dimension was 736 μm (±208 μm) in the bevacizumab group and 661 μm (±231 μm) in the laser group, a difference that was not statistically significant (P = .44).
The patients receiving bevacizumab experienced 27 adverse events, 22 of which were related to the injections. A few patients in both groups experienced transient vision loss. One patient in the bevacizumab group had high intraocular pressure and was subsequently treated for ocular hypertension.
Three patients in the laser group had serious ocular adverse events: 1 vitreous hemorrhage (in the nonstudy eye); 1 loss of greater than 30 ETDRS letters, which followed a fall and loss of consciousness; and 1 vitreomacular traction with macular edema, which was successfully treated with a vitrectomy and delamination.
There were no cases of endophthalmitis, intraocular inflammation, or retinal detachment in the bevacizumab group.
"In conclusion, this investigator-initiated single-center study provides evidence for the longer-term use of bevacizumab," the authors write. "This finding will be reassuring to physicians charged with delivery of this relatively new treatment."
Head-to-Head Drug Comparison on the Horizon
Dr. Frank said he was looking forward to further trials that would compare the drug therapies head to head. Excluding physicians fees, bevacizumab costs only $50 per injection, whereas ranibizumab costs $1950 and aflibercept $1850. Dr. Frank added that a single laser treatment costs about $750.
Bevacizumab is less expensive than the competing drugs because it has mostly been used systemically in much larger quantities as a cancer treatment, he said. Typically, however, it has been repackaged by pharmacies, rather than sold specifically for intravitreal injection, and clinicians should be wary of nonsterile repackaging, he warned.
In addition, Dr. Frank said laser remains a useful treatment in patients with macular edema if the center is not involved, but appears threatened by the disease.
The researchers point out that the benefits of laser therapy may not be "fully realized" until at least the second year, so a combination therapy approach should be considered.
This work was supported by grants from Moorfields Special Trustees and the National Institute for Health Research UK to the Biomedical Research Centre for Ophthalmology based at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology. The authors and Dr. Frank have disclosed no relevant financial relationships.
The new article updates previously reported 1-year follow-up data from the same trial and provides further validation for an approach that many clinicians are already taking, Robert Frank, MD, PhD, a clinical correspondent for the American Academy of Ophthalmology, told Medscape Medical News.
"Many people are using bevacizumab, even though this is the only study out there that shows any benefits," said Dr. Frank, professor of ophthalmology and of anatomy/cell biology at Wayne State University School of Medicine in Detroit, Michigan. "I think it's an important study, though it's not yet definitive because there were only 80 patients, and you would usually like to have hundreds."
Macular laser therapy had been the mainstay of treatment for clinically significant diabetic macular edema since the 1980s. The procedure reduces the risk for moderate visual loss, but visual acuity improves (a 15-letter gain at 3 years) in less than 3% of patients, the researchers write.
More recently, preliminary evidence has emerged that intravitreal injections of antivascular endothelial growth factor (anti-VEGF) drugs are more effective, Dr. Frank said. Bevacizumab and the related drugs aflibercept (Eylea, Regeneron Pharmaceuticals) and ranibizumab (Lucentis, Genentech) are being used for this purpose.
To verify that bevacizumab is better than laser treatment, the researchers enlisted 80 patients with center-involving clinically significant macular edema.
The patients had best-corrected visual acuity in the study eye of 35 to 69 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 4 m (Snellen equivalent, ≥6/60 or ≤6/12), center-involving macular edema with central macular thickness on optical coherence tomography of at least 270 μm, at least 1 previous macular laser therapy, and no anti-VEGF treatment in the fellow eye in the previous 3 months.
The researchers randomly assigned the patients to receive either bevacizumab or laser therapy.
The patients receiving laser therapy received a 50-μm argon laser spot size (laser applied only >500 μm from the edge of the foveal avascular zone), with focal treatment aiming to cause mild blanching of the retinal pigment epithelium, and not darkening or whitening of microaneurysms. The researchers treated diffuse leakage or nonperfusion similarly in a grid pattern.
The patients receiving bevacizumab received an injection at baseline and at 6 and 12 weeks, and were reviewed at 18 weeks and then every 6 weeks until week 102 for the need of more injections. If the thinnest recorded central macular thickness was less than 270 μm at 18 weeks, then the researchers continued treatment only if they judged the macular thickness to be unstable.
If the central macular thickness of the patients receiving bevacizumab was greater than 270 μm at 18 weeks and at subsequent visits, then the researchers continued the bevacizumab injections until the patients had stable macular thickness. The researchers defined stable macular thickness as 3 consecutive visits with the thickness within 20 μm of the patient's thinnest recorded measurement.
Patients Fared Better With Bevacizumab Than With Laser Therapy
Overall, the patients receiving bevacizumab fared better than the patients receiving laser therapy. The mean ETDRS best-corrected visual acuity at 24 months in the bevacizumab group was 64.4 letters (±13.3 letters; range, 34 - 88 letters; Snellen equivalent, 20/50).
In the laser group, the mean best-corrected visual acuity at 24 months was 54.8 letters (±12.6 letters; range, 33 - 75 letters; Snellen equivalent, 20/80). The difference between the 2 groups was statistically significant (P = .005).
The patients receiving bevacizumab gained a mean of 8.6 (±9.1) letters, whereas the patients receiving laser therapy lost a mean of 0.5 (±10.6) letters.
The patients receiving bevacizumab reduced their central macular thickness a mean of 146 μm, whereas the laser patients reduced theirs 118 μm.
The patients receiving bevacizumab received a median of 13 treatments (interquartile range, 11 - 15 treatments) over the course of 24 months, whereas the patients receiving laser therapy had 4 treatments (interquartile range, 3 - 5 treatments).
The procedures appeared to be equally safe. At 24 months, the mean foveal avascular zone of 1000 μm or more in greatest linear dimension was 736 μm (±208 μm) in the bevacizumab group and 661 μm (±231 μm) in the laser group, a difference that was not statistically significant (P = .44).
The patients receiving bevacizumab experienced 27 adverse events, 22 of which were related to the injections. A few patients in both groups experienced transient vision loss. One patient in the bevacizumab group had high intraocular pressure and was subsequently treated for ocular hypertension.
Three patients in the laser group had serious ocular adverse events: 1 vitreous hemorrhage (in the nonstudy eye); 1 loss of greater than 30 ETDRS letters, which followed a fall and loss of consciousness; and 1 vitreomacular traction with macular edema, which was successfully treated with a vitrectomy and delamination.
There were no cases of endophthalmitis, intraocular inflammation, or retinal detachment in the bevacizumab group.
"In conclusion, this investigator-initiated single-center study provides evidence for the longer-term use of bevacizumab," the authors write. "This finding will be reassuring to physicians charged with delivery of this relatively new treatment."
Head-to-Head Drug Comparison on the Horizon
Dr. Frank said he was looking forward to further trials that would compare the drug therapies head to head. Excluding physicians fees, bevacizumab costs only $50 per injection, whereas ranibizumab costs $1950 and aflibercept $1850. Dr. Frank added that a single laser treatment costs about $750.
Bevacizumab is less expensive than the competing drugs because it has mostly been used systemically in much larger quantities as a cancer treatment, he said. Typically, however, it has been repackaged by pharmacies, rather than sold specifically for intravitreal injection, and clinicians should be wary of nonsterile repackaging, he warned.
In addition, Dr. Frank said laser remains a useful treatment in patients with macular edema if the center is not involved, but appears threatened by the disease.
The researchers point out that the benefits of laser therapy may not be "fully realized" until at least the second year, so a combination therapy approach should be considered.
This work was supported by grants from Moorfields Special Trustees and the National Institute for Health Research UK to the Biomedical Research Centre for Ophthalmology based at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology. The authors and Dr. Frank have disclosed no relevant financial relationships.
I hope the heat does not cause more damage
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