CATT findings suggest Avastin not as good with more adverse reactions
MyVisionTest
Eye Institute is to be applauded for having sponsored this landmark
trial and for setting a new standard of transparency by submitting
most of the raw data on the Internet. Millions of people who cannot
afford Lucentis (ranibizumab) now have the benefit of a high level of
evidence as to the relative safety and efficacy of Avastin
(bevacizumab).
Most retinal ophthalmologists are using Avastin and an as-needed
treatment protocol. They have a vested interest in proving what they
have been doing is safe and effective. Some statements made in support
of Avastin and the as-needed protocol in the CATT report and echoed in
the accompanying editorial should therefore be carefully scrutinized.
The editorial statement that "the study was insufficiently powered to
identify differences in drug-related adverse effects" turned out not
to be correct. When dosing-regimen groups were combined, the
proportions of patients with serious systemic adverse events were
24.1% for Avastin and 19.0% for Lucentis (P = 0.04). After adjustment
for demographic features and coexisting illnesses at baseline, the
risk ratio for Avastin, as compared with Lucentis, was 1.29 (95%
confidence interval, 1.01 to 1.66; P = 0.04). Data from tables in the
supplemental appendix show that the life-threatening or disabling
events occurred in 3.51% of the combined Lucentis and 5.61% of the
combined Avastin groups (P = 0.04), 1.5% of who were being treated
with Lucentis and 2.5% of who were taking Avastin died.
The CATT report states that they found no significant difference
between the two drugs in venous thrombotic events. They report that
venous thrombotic events occurred infrequently (in approximately 1.0%
of patients), with the highest number 4, or 1.4% in the
Avastin-monthly group (P = 0.08 for all groups, P = 0.28 for the
Avastin groups vs. the Lucentis groups). This is consistent with the
magnitude of risk reported in the meta-analysis of the risk of venous
thromboembolism with the angiogenesis inhibitor Avastin in cancer
patients. In this study, the risk was not dose related. This suggests
that the risk of venous thrombosis is not dose sensitive and may
explain its occurrence with intravitreal Avastin which results in
substantially lower systemic dose than used in treating cancer
patients. On examining the tables in the supplemental appendix, if we
include retinal vein thrombosis, pulmonary embolus, deep vein
thrombosis and hepatic vein thrombosis then a venous thrombotic event
occurs in 0.15% of the Lucentis group and 1.15% of the Avastin group,
a highly significant difference (P < 0.02).
Attention has been drawn to the possible mechanism and the
significantly increased risk of gastrointestinal tract (GIT)
hemorrhage and ulceration associated with the use of Lucentis in
ANCHOR and of non-ocular hemorrhage in MARINA. The tables in the CATT
supplemental appendix show a greater proportion of Avastin patients
with anemia (2.35% vs. 1%, P < 0.03). This is a marker for GIT
bleeding in older patients; 1.85% of Avastin patients had either GIT
ulceration or hemorrhage compared with 0.7% of the Lucentis patients
(P < 0.03). Venous thrombosis is significantly more common in Avastin
patients than Lucentis patients. This has to be viewed in the light
that Lucentis may itself have a small but significant increase in GIT
hemorrhage and ulceration compared to controls.
This author disagrees with the statement in the editorial, "[The CATT
study] observed none of the expected adverse effects associated with
systemic anti-vascular endothelial growth factor (VEGF) therapy."
Clinical trials of intravenous Avastin in patients with cancer have
identified associations with arteriothrombotic events, venous
thrombotic events, gastrointestinal perforation and hemorrhage,
delayed wound healing, proteinuria, and hypertension and uncommonly
leukoencephalopathy. The expected increase in the anti-VEGF adverse
events - venous thrombosis, GIT hemorrhage and ulceration both were
highly statistically significant.
The increased risk of admission to hospital with infections may be
related to VEGF suppression; VEGF is involved in hematopoiesis,
leukocyte and monocyte migration and inflammation and its suppression
may impair immune defenses. VEGF may be more important for bacterial
than viral infections. An analysis of the supplementary tables showed
an increase in incidence of bacterial infections. There were
significantly more presumed bacterial infection adverse events
(89.7/100, 54.9/100, P < 0.01) in the Avastin versus the Lucentis
groups but there was no significant difference in the presumed viral
adverse events (17.2/100, 16.5/100, P = 0.37) or fungal infections
(1.6/100, 0.9/100, P = 0.14).
The results of this head to head comparison of these two drugs contain
some worrisome and important signals which should not be minimized or
ignored. It is of concern that the CATT report and the editorial fail
to warn of these apparent risks with using Avastin as opposed to
Lucentis and instead emphasizes its efficacy and promotes its
widespread use.
The anatomical data on efficacy, be it resolution of fluid on optical
coherence tomography (OCT) (P < 0.001) or cessation of leak on fundus
fluorescien angiography (FFA) (P < 0.001), all highly significantly
favor monthly Lucentis. The mean decrease in central retinal thickness
was greater in the Lucentis-monthly group (196 µm) than in the
other groups (152 to 168 µm, P = 0.03). Although a comparison of
monthly Lucentis versus as-needed Avastin was never the intention of
CATT and not withstanding it is a post hoc analysis, it is interesting
that they are significantly different (8.5, 5.9, P = 0.04). There were
3% more patients in the monthly Lucentis group that gained ≥3 lines
which would have been a significant difference if the group sizes were
larger (n = 805). The study, however, was insufficiently powered to
identify small differences, due in part to the high variability in
outcome. Nevertheless, if this was the patients better eye, then
gaining ≥3 lines equates to a substantially better quality of life
for one in 30 patients which may be a material consideration for a
patient making the choice between Lucentis and Avastin.
There is a 1.5 to 2 average letter loss at 12 months in the as-needed
regimen patients compared to the monthly. The curves are just starting
to separate and may move further apart in the 2-year data. Dye leakage
was absent more frequently in the monthly Lucentis patients; on
angiography in 58.8% of patients in the Lucentis-monthly group, 57.7%
in the Avastin-monthly group, 46.7% in the Lucentis-as-needed group,
and 41.0% in the Avastin-as-needed group (P < 0.001). In keeping with
this sign of activity the lesions were slightly larger at 12 months in
the two groups that were treated as needed (P = 0.047). It is hard to
justify calling these groups equivalent.
Has the profession used the prominent pulpit of the New England
Journal of Medicine to advance a message that was in its interest -
one that was ultimately incorrect?
Clin Experiment Ophthalmol. 2011 Aug;39(6):588-90
http://www.ncbi.nlm.nih.gov/pubmed/21631687
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