Questioning the systemic safety of Avastin
MyVisionTest
(VEGF) agents have yielded dramatic improvements in the management of
a wide variety of neovascular ocular diseases including age-related
macular degeneration (AMD), diabetic retinopathy (DR), retinal vein
occlusion, and retinopathy of prematurity. These agents have thus
become one of the most commonly employed treatments, with 824,525
anti-VEGF intraocular injections given in 2008 in the United States.
There are currently 2 widely used agents: ranibizumab (Lucentis),
which is FDA-approved, and bevacizumab (Avastin), given off-label.
Despite its off-label status, a majority of the intravitreal anti-VEGF
injections given in the United States and around the world are for
Avastin, accounting for 58% of all injections in a US review of
Medicare fee-for-service Part B claims for neovascular AMD during
2008.
Two new studies add to the growing debate on the relative merits and
concerns on the use of Lucentis vs Avastin for the treatment of AMD.
The 1-year results of the CATT have for the first time demonstrated in
a randomized controlled trial that Avastin and Lucentis have somewhat
equivalent efficacy, with few differences in visual outcomes using
either a monthly injection schedule or treatment on an as-needed
basis. In terms of safety, the frequencies of arteriothrombotic and
venothrombotic events and mortality did not differ significantly
between the 2 compounds. However, the proportion of patients with
serious systemic adverse events was 24.1% for Avastin and 19.0% for
Lucentis (P = .04). After adjustment for demographic features and
coexisting illnesses at baseline, the risk of serious systemic adverse
events for Avastin was higher by 29% (P = .04), although no specific
organ system consistently accounted for the difference in adverse
events, with differences in rates greatest for infections and
gastrointestinal disorders. It should be re-emphasized, however, that
the CATT was not primarily designed or adequately powered to
conclusively detect differences in adverse event rates between these 2
agents.
Another recent study addressed systemic safety. In a retrospective
analysis of 146,942 Medicare case records, Curtis and associates
reported higher risks of stroke and all-cause mortality with
intravitreal injections of Avastin as compared to Lucentis for the
treatment of AMD. Further analysis of the Medicare claims database
presented at the 2011 ARVO annual meeting indicated an 11% higher risk
in all-cause mortality and 57% higher risk of hemorrhagic stroke with
Avastin, with no statistically significant differences in the risk of
either myocardial infarction or ischemic stroke.
The landmark Lucentis trials individually did not show a significant
increase in stroke risk. However, other studies suggest that patients
with a history of previous stroke may be at higher risk, as the
SUSTAIN study found that 10% of patients who had had an earlier stroke
suffered another stroke in the first 12 months. A meta-analysis of all
trials of anti-VEGF therapy for AMD up until 2008 also found that
Lucentis was linked to a significant increase in nonocular hemorrhage.
The study, however, was inconclusive for Avastin due to insufficient
data.
The main obstacle to obtaining good safety data for intraocular
Avastin is further highlighted in a recent randomized clinical trial
of Avastin vs laser for retinopathy of prematurity in 150 preterm
infants. The Bevacizumab Eliminates the Angiogenic Threat of
Retinopathy of Prematurity (BEAT-ROP) study on 150 preterm infants
suggested that intraocular injection of Avastin may be useful to treat
severe retinopathy of prematurity. This study, however, reported a
2-fold higher mortality rate with Avastin than laser (6.6% vs 2.6%),
with 4 of 5 deaths from respiratory failure. The authors of the study
suggested that a trial of 2800 infants would be needed to establish
systemic safety, a number that is clearly difficult to achieve.
In the absence of more convincing clinical trial data, the Medicare
claims data provide the best evidence to date in evaluating the safety
of anti-VEGF agents. In addition, there are 2 indirect but
increasingly compelling lines of evidence that may provide further
insights.
First, there is clear evidence of greater treatment-related mortality
with intravenous Avastin in cancer patients. A new meta-analysis of
treatment-related mortality with intravenous Avastin in cancer
patients by Ranpura and associates reported increased mortality with
intravenous Avastin. Compared with chemotherapy alone, the addition of
Avastin was associated with an increased risk of fatal adverse events,
with a relative risk of 1.46. The most common causes of mortality were
hemorrhage, neutropenia, and gastrointestinal tract perforation
(7.1%).
Second, it is becoming apparent that intraocular injections of Avastin
can significantly suppress systemic VEGF levels. Although the dose and
volume of delivery with intraocular injections (1.25 mg in 0.05 mL
typically) are much lower than the typical dose of 2.5 to 5 mg/kg/week
administered intravenously, there is accumulating evidence that
intraocular injections of Avastin can still suppress systemic VEGF
levels, in some cases by as much as intravenous injections. Clinical
studies have also found evidence of a fellow eye effect following
unilateral Avastin injections. For example, regression of retinal and
iris neovascularization secondary to diabetes mellitus in the injected
eye was associated with a subtle decrease in leakage of retinal and
iris neovascularization in the fellow uninjected eye in 1 study.
A satisfactory conclusion to the controversy surrounding Avastin
remains elusive despite the completion of the 1-year CATT results. In
the meantime, emerging data emphasize the need for heightened
surveillance for systemic adverse events with intraocular anti-VEGF
injections for different eye diseases. It is worth emphasizing again
that most elderly patients with AMD who might benefit from anti-VEGF
therapy are already at increased risk of cardiovascular and
cerebrovascular diseases.
Am J Ophthalmol. 2011 Sep;152(3):329-31
http://www.ncbi.nlm.nih.gov/pubmed/21855670
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