How will the CATT results impact clical practice?
MyVisionTest
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.
Am J Ophthalmol. 2011 Oct;152(4):509-14
http://www.ncbi.nlm.nih.gov/pubmed/21961847
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