MyVisionTest News Archive
Jan 15, 2012
How will the CATT results impact clinical practice?
The long-awaited primary outcome of the Comparison of Age-related Macular Degeneration Treatments Trial (CATT) study was that patients receiving either monthly Avastin (bevacizumab) or monthly Lucentis (ranibizumab) had equivalent visual acuity at 1 year.
For the majority of clinicians who already preferentially used Avastin for age-related macular degeneration (AMD), the data validate their choice of this much less expensive drug ($50) rather than the much more expensive Lucentis ($2000). Clinicians who made this choice did so despite quite modest clinical data for the safety and efficacy of Avastin compared to the robust level I data for Lucentis. Economic considerations likely influenced the selection of drug for individual patients.
The Trial in Context
The era of clinical pharmacotherapy for AMD is only slightly more than 10 years old. The US Food and Drug Administration (FDA) approved intravenous verteporfin (Visudyne) as a photosensitizer for photochemical light activation in 2000. Administered intravenously at 3-month intervals, it reduced the risk of significant vision loss compared to thermal laser photocoagulation or observation for predominantly classic AMD.
Pegaptanib sodium (Macugen), approved in December 2004 and administered intravitreally at 6-week intervals, also prevented severe vision loss and worked irrespective of the pattern of leakage on fluorescein angiography. Pegaptanib targeted a pathway in the underlying biology of AMD: the molecule is an aptamer that selectively binds the vascular endothelial growth factor (VEGF) 165 isoform. It was, however, better at preserving than improving vision. Only about 6% of patients gained 3 or more lines of vision.
In July 2005, the American Society of Retina Specialists heard presentations of the Systemic Avastin for the Treatment of Neovascular AMD (SANA) trial as well as case reports of intravitreal Avastin use supported by optical coherence tomography (OCT) documentation. MARINA, a placebo-controlled trial of Lucentis, and ANCHOR, a randomized comparison of Lucentis and photodynamic therapy, were published in 2006. Clinicians could obtain Avastin in 2005 and 2006 but were unable to use Lucentis until weeks after FDA approval in June 2006. With its easy availability, low cost, and suggested efficacy, intravitreal Avastin use for AMD expanded and multiple uncontrolled case series appeared in 2006 and 2007 with no obvious evidence of side effects or safety issues. After FDA approval of Lucentis in June 2006, many clinicians continued to use Avastin preferentially. Analysis of fee-for-service Medicare Part B claims data revealed that Avastin accounted for 58% and Lucentis for 41% (with pegaptanib sodium accounting for the other 1%) of intravitreal injections for AMD in 2008; Avastin was used in nearly two-thirds of individual AMD patients treated with an anti-VEGF agent.
Avastin is not a generic form of Lucentis; Lucentis and Avastin are different molecules produced in different cell culture systems. The two molecules have significant differences with potential implications for therapeutic action, pharmacokinetics, and possibly systemic safety and may also have implications for dosing interval.
Ranibizumab vs Bevacizumab and Fixed vs Variable Dosing
Importantly, CATT was a noninferiority trial. Primary outcome results were stated as showing that “there were equivalent mean changes in visual acuity averaged over the 1-year period” in all pairwise comparisons. The standard to establish noninferiority at 1 year was the loss or gain of 5 ETDRS letters. The Avastin-as-needed group lost more than the prespecified 5-letter difference, when compared to either Avastin-monthly (-5.7 letters) or Lucentis-monthly (-5.9) groups. This is potentially a concern.
For OCT, pairwise comparisons between Lucentis monthly and Avastin as needed at 1 year demonstrated that Lucentis showed a significantly greater decrease in thickness at the foveal center and the proportion of patients with no fluid on OCT. (see FIGURE) A stronger effect on leakage by Lucentis might eventually lead to actual differences in visual acuity outcomes; thus, the secondary outcomes of the 2-year data are important. However, at 1 year, there did not appear to be a significant correlation between amount of fluid, or the presence of fluid, and visual acuity outcomes.
Randomization in the CATT trial was not only to drug, but also to dosing schedule. Roughly half of the patients randomized to each drug did not receive injections on a fixed monthly schedule but rather pro re nata (PRN; as needed) from month 2 onward based on clinical assessment, OCT findings, and fluorescein angiography if desired. Lucentis and Avastin yielded statistically similar visual acuity results when administered on the PRN dosing schedule as they did with the monthly schedule. With Lucentis, the PRN-treated eyes had 1.7 fewer letters of mean visual acuity score than eyes treated monthly at 1 year, but this difference was not statistically significant. With Avastin, there was also no statistical difference between visual acuity outcomes in monthly vs PRN dosing, but there were 2.6 fewer letters of mean visual acuity score with PRN Avastin than with monthly Lucentis at 52 weeks. Although this was not statistically significant, the comparison was felt to be “inconclusive” and a potential concern.
The figure charting the mean change in visual acuity score for monthly and PRN treatments shows the 4 groups fairly close together from baseline to 36 weeks. (see FIGURE) By 52 weeks, there appears to be a divergence between the 2 monthly groups and the 2 PRN groups, favoring the monthly treatment. Previous studies using various PRN regimens have suggested some flattening in the benefit of treatment over time. For now, PRN dosing seems feasible and worthy of further study.
The PRN dosing schedule resulted in 4 to 5 fewer injections over 1 year, a potentially huge economic benefit no matter which drug is used. The Avastin-as-needed group required a statistically greater number of injections than the Lucentis-as-needed group (7.7 vs 6.9) with an average per-patient cost of the study drug in the first year in the as-needed groups of $385 for Avastin vs $13,800 for Lucentis, with not all costs related to the drug. It is critical to note, however, that the CATT protocol required investigators to bring patients back to the office for examination at monthly intervals, regardless of whether they were assigned to the monthly or PRN arms of the study. This is different than the typical treat and extend regimen now in common use, in which both the evaluations and the treatments become less frequent if fluid is not present on the OCT. It is difficult to extrapolate outcomes comparable to the CATT study if eyes are not assessed every 4 weeks. Previous attempts to increase the intervals between Lucentis injections and physician visits to 3 months (PIER and EXCITE) resulted in the forfeiture of previous visual gains. Also, PRN treatment was given by the CATT investigators in slightly less than 75% of visits in which subsequent reading center assessment of the OCT indicated that an injection should have been given according to study protocol. Strict adherence to protocol might have led to different results.
Safety Concerns
Two secondary outcomes in the CATT trial were designated as safety issues: complications of treatment such as incidence of endophthalmitis, retinal detachment, cataract, or uveitis at 12 and 24 months; and the incidence of adverse events at 12 and 24 months. The 12-month safety data were reported with the 1-year primary outcome data.
Ocular adverse events were rare, occurring in less than 1% of patients. There were 2 cases of endophthalmitis among monthly Lucentis users and 4 cases of endophthalmitis among monthly Avastin users (P = .45), as well as 1 case of pseudoendophthalmitis in the monthly Lucentis group. Ophthalmologists used 1 of 3 povidone-iodine-based preinjection regimens, or a short course of topical antibiotics if allergic. Both drugs were supplied in glass vials wiped with alcohol prior to withdrawing medication according to a specific protocol. Half of the investigators used postinjection antibiotics. One in a hundred patients in the monthly injection groups were reported to have endophthalmitis. Because Lucentis is supplied in unit-dose packaging and the "off-label" use of Avastin requires aliquoting and storing in syringes, concerns have been raised about additional risk of infection. However, this additional risk seems small and is not really predictable or ascertainable from this study.
Assessment of the overall risk ratio for serious adverse events in both Avastin groups, after adjustment for demographic and baseline characteristics, was reported as 1.29 (95% confidence interval 1.01 to 1.66). This result was mainly attributable to hospitalizations for infections and to gastrointestinal disorders such as hemorrhaging, nausea, and vomiting. Other than bleeding, these are not expected systemic complications of VEGF inhibition. No significant changes in systemic diastolic or systolic blood pressure were reported.
Careful scrutiny of the data in the Supplementary Appendix for raw percentages of probable cardiac or neurologic events does not show a difference between groups that appears clinically important. Fifteen of 599 people (2.5%) in the Lucentis groups and 15 of 586 (2.6%) in the Avastin groups were noted to have had cardiac arrest, cardiorespiratory arrest, coronary artery occlusion, myocardial infarction, cerebellar infarction, cerebral hemorrhage, or cerebrovascular accident by week 52. This is somewhat higher than the 2.1% rate of thromboembolic events (17 of 874 patients) reported in the Lucentis package insert for the 1-year pooled data from the PIER, and MARINA, and ANCHOR studies. Statistical analysis would require uniform definitions and adjustment for baseline characteristics and length of follow-up, which exceed what a cursory look can reveal. However, it appears that the most feared risks, and those most often discussed with patients, are not different between the 2 drugs. Other caveats regarding safety are that the age and particular comorbidities of patients with age-related macular degeneration may not extrapolate to other diseases such as diabetic macular edema or myopic degeneration. If fellow eyes of CATT participants were also treated with anti-VEGF agents, then the systemic toxicity information comparing drugs is difficult to interpret. Information is not given regarding the doses, drugs, or frequency of anti-VEGF agents used to treat fellow eyes.
The FDA approved Lucentis as safe for use in the treatment of age-related macular degeneration on the basis of multiple level I randomized controlled clinical trials. A systematic review in 2010 included 13 prospective randomized controlled trials of Avastin with a total of 591 patients (range 13–102) and short follow-up that were not felt to meet quality standards for phase III trials. Subsequently the randomized ABC trial compared 65 bevacizumab patients to 66 standard-of-care patients; the numbers were deemed too small to reliably assess safety data. The CATT trial reports the largest number of Avastin recipients to date in a level I study of sufficient quality to provide evidence for the safety of intravitreal Avastin in the treatment of wet age-related macular degeneration and corroborates the safety outcomes of Lucentis in prior studies.
The Future
A clinician treating a patient with exudative AMD after release of the CATT results should feel equally justified using either Lucentis or Avastin. The physician may be slightly less comfortable choosing between either fixed or variable dosing, because of the tiny red flag with visual acuity in the PRN Avastin group and the lack of adherence of investigators to a strict protocol of PRN treatment that further differs from the commonly used "treat and extend." It remains unknown whether the statistically significant greater decrease in central retinal thickness seen in the Lucentis groups will be maintained and whether that will translate into a meaningful effect on visual acuity at 2 years. Similarly, it remains unknown whether the systemic side effects in the Avastin groups will coalesce into a meaningful pattern that indicates this larger and slower-moving molecule, delivered in relatively small ophthalmic doses, is less safe than the FDA-approved Lucentis.
Importantly, it may be even more dramatic to watch what happens to clinical patterns of use of VEGF Trap-eye. Cost has clearly driven the use of Avastin over Lucentis in clinical practice as well as a general familiarity with Avastin by the time Lucentis became commercially available. Reducing the frequency of examinations and injections may well prove to be a cost advantage over Lucentis, but Avastin treatment will likely still cost less than the VEGF Trap-eye, a molecule that will initially be unfamiliar to most clinicians. Now that level I evidence exists regarding safety and efficacy for Avastin, it is intriguing to imagine how clinical usage might shift if there were 3 highly effective drugs: 1 that required half the number of injections, 1 that was significantly less expensive, and 1 that was the familiar reference drug, Lucentis.
The CATT leadership, clinical centers, and the patients who participated are to be congratulated for capturing objective data clinicians can use to guide the selection of pharmacotherapy for exudative AMD. Importantly, we await the 2-year data, especially with regard to mean visual acuity outcomes in relation to retinal thickness, comparisons of monthly vs PRN treatment regimens, and safety outcomes. Even if advantages of Lucentis over Avastin are eventually confirmed, the 40-fold price differential of Lucentis over Avastin will likely remain. We are hopeful that the results of the CATT trial, coupled with competition from newer agents, will provide physicians with more cost-effective means for treating AMD patients.
Read more...
Am J Ophthalmol. 2011 Oct;152(4):509-14
Tags: Lucentis, Avastin, dosing strategy, adverse drug effects, CATT
The long-awaited primary outcome of the Comparison of Age-related Macular Degeneration Treatments Trial (CATT) study was that patients receiving either monthly Avastin (bevacizumab) or monthly Lucentis (ranibizumab) had equivalent visual acuity at 1 year. For the majority of clinicians who already preferentially used Avastin for age-related macular degeneration (AMD), the data validate their choice of this much less expensive drug ($50) rather than the much more expensive Lucentis ($2000). Clinicians who made this choice did so despite quite modest clinical data for the safety and efficacy of Avastin compared to the robust level I data for Lucentis. Economic considerations likely influenced the selection of drug for individual patients.
The era of clinical pharmacotherapy for AMD is only slightly more than 10 years old. The US Food and Drug Administration (FDA) approved intravenous verteporfin (Visudyne) as a photosensitizer for photochemical light activation in 2000. Administered intravenously at 3-month intervals, it reduced the risk of significant vision loss compared to thermal laser photocoagulation or observation for predominantly classic AMD.
Pegaptanib sodium (Macugen), approved in December 2004 and administered intravitreally at 6-week intervals, also prevented severe vision loss and worked irrespective of the pattern of leakage on fluorescein angiography. Pegaptanib targeted a pathway in the underlying biology of AMD: the molecule is an aptamer that selectively binds the vascular endothelial growth factor (VEGF) 165 isoform. It was, however, better at preserving than improving vision. Only about 6% of patients gained 3 or more lines of vision.
In July 2005, the American Society of Retina Specialists heard presentations of the Systemic Avastin for the Treatment of Neovascular AMD (SANA) trial as well as case reports of intravitreal Avastin use supported by optical coherence tomography (OCT) documentation. MARINA, a placebo-controlled trial of Lucentis, and ANCHOR, a randomized comparison of Lucentis and photodynamic therapy, were published in 2006. Clinicians could obtain Avastin in 2005 and 2006 but were unable to use Lucentis until weeks after FDA approval in June 2006. With its easy availability, low cost, and suggested efficacy, intravitreal Avastin use for AMD expanded and multiple uncontrolled case series appeared in 2006 and 2007 with no obvious evidence of side effects or safety issues. After FDA approval of Lucentis in June 2006, many clinicians continued to use Avastin preferentially. Analysis of fee-for-service Medicare Part B claims data revealed that Avastin accounted for 58% and Lucentis for 41% (with pegaptanib sodium accounting for the other 1%) of intravitreal injections for AMD in 2008; Avastin was used in nearly two-thirds of individual AMD patients treated with an anti-VEGF agent.
Avastin is not a generic form of Lucentis; Lucentis and Avastin are different molecules produced in different cell culture systems. The two molecules have significant differences with potential implications for therapeutic action, pharmacokinetics, and possibly systemic safety and may also have implications for dosing interval.
Ranibizumab vs Bevacizumab and Fixed vs Variable Dosing
Importantly, CATT was a noninferiority trial. Primary outcome results were stated as showing that “there were equivalent mean changes in visual acuity averaged over the 1-year period” in all pairwise comparisons. The standard to establish noninferiority at 1 year was the loss or gain of 5 ETDRS letters. The Avastin-as-needed group lost more than the prespecified 5-letter difference, when compared to either Avastin-monthly (-5.7 letters) or Lucentis-monthly (-5.9) groups. This is potentially a concern.
For OCT, pairwise comparisons between Lucentis monthly and Avastin as needed at 1 year demonstrated that Lucentis showed a significantly greater decrease in thickness at the foveal center and the proportion of patients with no fluid on OCT. (see FIGURE) A stronger effect on leakage by Lucentis might eventually lead to actual differences in visual acuity outcomes; thus, the secondary outcomes of the 2-year data are important. However, at 1 year, there did not appear to be a significant correlation between amount of fluid, or the presence of fluid, and visual acuity outcomes. Randomization in the CATT trial was not only to drug, but also to dosing schedule. Roughly half of the patients randomized to each drug did not receive injections on a fixed monthly schedule but rather pro re nata (PRN; as needed) from month 2 onward based on clinical assessment, OCT findings, and fluorescein angiography if desired. Lucentis and Avastin yielded statistically similar visual acuity results when administered on the PRN dosing schedule as they did with the monthly schedule. With Lucentis, the PRN-treated eyes had 1.7 fewer letters of mean visual acuity score than eyes treated monthly at 1 year, but this difference was not statistically significant. With Avastin, there was also no statistical difference between visual acuity outcomes in monthly vs PRN dosing, but there were 2.6 fewer letters of mean visual acuity score with PRN Avastin than with monthly Lucentis at 52 weeks. Although this was not statistically significant, the comparison was felt to be “inconclusive” and a potential concern.
The figure charting the mean change in visual acuity score for monthly and PRN treatments shows the 4 groups fairly close together from baseline to 36 weeks. (see FIGURE) By 52 weeks, there appears to be a divergence between the 2 monthly groups and the 2 PRN groups, favoring the monthly treatment. Previous studies using various PRN regimens have suggested some flattening in the benefit of treatment over time. For now, PRN dosing seems feasible and worthy of further study.
The PRN dosing schedule resulted in 4 to 5 fewer injections over 1 year, a potentially huge economic benefit no matter which drug is used. The Avastin-as-needed group required a statistically greater number of injections than the Lucentis-as-needed group (7.7 vs 6.9) with an average per-patient cost of the study drug in the first year in the as-needed groups of $385 for Avastin vs $13,800 for Lucentis, with not all costs related to the drug. It is critical to note, however, that the CATT protocol required investigators to bring patients back to the office for examination at monthly intervals, regardless of whether they were assigned to the monthly or PRN arms of the study. This is different than the typical treat and extend regimen now in common use, in which both the evaluations and the treatments become less frequent if fluid is not present on the OCT. It is difficult to extrapolate outcomes comparable to the CATT study if eyes are not assessed every 4 weeks. Previous attempts to increase the intervals between Lucentis injections and physician visits to 3 months (PIER and EXCITE) resulted in the forfeiture of previous visual gains. Also, PRN treatment was given by the CATT investigators in slightly less than 75% of visits in which subsequent reading center assessment of the OCT indicated that an injection should have been given according to study protocol. Strict adherence to protocol might have led to different results.
Safety Concerns
Two secondary outcomes in the CATT trial were designated as safety issues: complications of treatment such as incidence of endophthalmitis, retinal detachment, cataract, or uveitis at 12 and 24 months; and the incidence of adverse events at 12 and 24 months. The 12-month safety data were reported with the 1-year primary outcome data.Ocular adverse events were rare, occurring in less than 1% of patients. There were 2 cases of endophthalmitis among monthly Lucentis users and 4 cases of endophthalmitis among monthly Avastin users (P = .45), as well as 1 case of pseudoendophthalmitis in the monthly Lucentis group. Ophthalmologists used 1 of 3 povidone-iodine-based preinjection regimens, or a short course of topical antibiotics if allergic. Both drugs were supplied in glass vials wiped with alcohol prior to withdrawing medication according to a specific protocol. Half of the investigators used postinjection antibiotics. One in a hundred patients in the monthly injection groups were reported to have endophthalmitis. Because Lucentis is supplied in unit-dose packaging and the "off-label" use of Avastin requires aliquoting and storing in syringes, concerns have been raised about additional risk of infection. However, this additional risk seems small and is not really predictable or ascertainable from this study.
Assessment of the overall risk ratio for serious adverse events in both Avastin groups, after adjustment for demographic and baseline characteristics, was reported as 1.29 (95% confidence interval 1.01 to 1.66). This result was mainly attributable to hospitalizations for infections and to gastrointestinal disorders such as hemorrhaging, nausea, and vomiting. Other than bleeding, these are not expected systemic complications of VEGF inhibition. No significant changes in systemic diastolic or systolic blood pressure were reported.
Careful scrutiny of the data in the Supplementary Appendix for raw percentages of probable cardiac or neurologic events does not show a difference between groups that appears clinically important. Fifteen of 599 people (2.5%) in the Lucentis groups and 15 of 586 (2.6%) in the Avastin groups were noted to have had cardiac arrest, cardiorespiratory arrest, coronary artery occlusion, myocardial infarction, cerebellar infarction, cerebral hemorrhage, or cerebrovascular accident by week 52. This is somewhat higher than the 2.1% rate of thromboembolic events (17 of 874 patients) reported in the Lucentis package insert for the 1-year pooled data from the PIER, and MARINA, and ANCHOR studies. Statistical analysis would require uniform definitions and adjustment for baseline characteristics and length of follow-up, which exceed what a cursory look can reveal. However, it appears that the most feared risks, and those most often discussed with patients, are not different between the 2 drugs. Other caveats regarding safety are that the age and particular comorbidities of patients with age-related macular degeneration may not extrapolate to other diseases such as diabetic macular edema or myopic degeneration. If fellow eyes of CATT participants were also treated with anti-VEGF agents, then the systemic toxicity information comparing drugs is difficult to interpret. Information is not given regarding the doses, drugs, or frequency of anti-VEGF agents used to treat fellow eyes.
The FDA approved Lucentis as safe for use in the treatment of age-related macular degeneration on the basis of multiple level I randomized controlled clinical trials. A systematic review in 2010 included 13 prospective randomized controlled trials of Avastin with a total of 591 patients (range 13–102) and short follow-up that were not felt to meet quality standards for phase III trials. Subsequently the randomized ABC trial compared 65 bevacizumab patients to 66 standard-of-care patients; the numbers were deemed too small to reliably assess safety data. The CATT trial reports the largest number of Avastin recipients to date in a level I study of sufficient quality to provide evidence for the safety of intravitreal Avastin in the treatment of wet age-related macular degeneration and corroborates the safety outcomes of Lucentis in prior studies.
The Future
A clinician treating a patient with exudative AMD after release of the CATT results should feel equally justified using either Lucentis or Avastin. The physician may be slightly less comfortable choosing between either fixed or variable dosing, because of the tiny red flag with visual acuity in the PRN Avastin group and the lack of adherence of investigators to a strict protocol of PRN treatment that further differs from the commonly used "treat and extend." It remains unknown whether the statistically significant greater decrease in central retinal thickness seen in the Lucentis groups will be maintained and whether that will translate into a meaningful effect on visual acuity at 2 years. Similarly, it remains unknown whether the systemic side effects in the Avastin groups will coalesce into a meaningful pattern that indicates this larger and slower-moving molecule, delivered in relatively small ophthalmic doses, is less safe than the FDA-approved Lucentis.
Importantly, it may be even more dramatic to watch what happens to clinical patterns of use of VEGF Trap-eye. Cost has clearly driven the use of Avastin over Lucentis in clinical practice as well as a general familiarity with Avastin by the time Lucentis became commercially available. Reducing the frequency of examinations and injections may well prove to be a cost advantage over Lucentis, but Avastin treatment will likely still cost less than the VEGF Trap-eye, a molecule that will initially be unfamiliar to most clinicians. Now that level I evidence exists regarding safety and efficacy for Avastin, it is intriguing to imagine how clinical usage might shift if there were 3 highly effective drugs: 1 that required half the number of injections, 1 that was significantly less expensive, and 1 that was the familiar reference drug, Lucentis.
The CATT leadership, clinical centers, and the patients who participated are to be congratulated for capturing objective data clinicians can use to guide the selection of pharmacotherapy for exudative AMD. Importantly, we await the 2-year data, especially with regard to mean visual acuity outcomes in relation to retinal thickness, comparisons of monthly vs PRN treatment regimens, and safety outcomes. Even if advantages of Lucentis over Avastin are eventually confirmed, the 40-fold price differential of Lucentis over Avastin will likely remain. We are hopeful that the results of the CATT trial, coupled with competition from newer agents, will provide physicians with more cost-effective means for treating AMD patients.
Read more...
Am J Ophthalmol. 2011 Oct;152(4):509-14
