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PROSPERO International prospective register of systematic reviews
Comparative systemic safety of bevacizumab and ranibizumab for neovascular agerelated macular degeneration: a systematic review and meta-analysis
Vittorio Bertele’, Annalisa Campomori, Usha Chakravarthy, Roberto D’Amico, Kay Dickersin, Jennifer Evans, Laurent Kodjikian,
Koren Kwag, Kristina Lindsley, Yoon Loke, Ersilia Lucenteforte, Maureen Maguire, Daniel Martin, Lorenzo Moja, Alessandro
Mugelli, Barney Reeves, Chris Rogers, Christine Schmucker, Manju Subramanian, Gianni Virgili
Citation
Vittorio Bertele’, Annalisa Campomori, Usha Chakravarthy, Roberto D’Amico, Kay Dickersin, Jennifer Evans,
Laurent Kodjikian, Koren Kwag, Kristina Lindsley, Yoon Loke, Ersilia Lucenteforte, Maureen Maguire, Daniel
Martin, Lorenzo Moja, Alessandro Mugelli, Barney Reeves, Chris Rogers, Christine Schmucker, Manju
Subramanian, Gianni Virgili. Comparative systemic safety of bevacizumab and ranibizumab for neovascular agerelated macular degeneration: a systematic review and meta-analysis. PROSPERO 2014:CRD42014009586 Available
from http://www.crd.york.ac.uk/PROSPERO_REBRANDING/display_record.asp?ID=CRD42014009586
Review question(s)
To assess the effects of bevacizumab compared with ranibizumab on serious systemic adverse events (SSAEs) and
mortality in patients with neovascular age-related macular degeneration (AMD).
Searches
We will systematically search EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials
(CENTRAL). We will hand search the reference lists of relevant studies to find additional publications. We will also
search clinical trials registers, including the metaRegister of Controlled Trials (mRCT), ClinicalTrials.gov, and the
WHO International Clinical Trials Registry Platform (ICTRP) to identify ongoing studies, or studies that have been
completed, but not published. We will also contact investigators to seek information on unpublished safety data.
Finally, we will use the Google search engine to locate additional information about studies not reported in the
medical literature, but available online. We will use terms such as the principal investigator’s name and the study
name or acronym. All data will comply with personal data protection rules.
Types of study to be included
Head-to-head randomized controlled trials (RCTs) directly comparing the safety of bevacizumab and ranibizumab in
patients with neovascular AMD, irrespective of the language or publication status.
Condition or domain being studied
Neovascular AMD (also called wet AMD).
Neovascular AMD is a progressive, degenerative disease of the retina in which blood vessels grow aberrantly behind
the retina under the macula. Without treatment, its natural course will result in a fibrous scar that greatly diminishes
central visual capacity.
Participants/ population
Patients affected by neovascular AMD will be included.
Intervention(s), exposure(s)
Vascular endothelial growth factor (VEGF) is a cytokine that promotes vascular leakage and growth. Accordingly,
VEGF inhibitors such as bevacizumab (brand name Avastin; Genentech/Roche, South San Francisco, CA) and
ranibizumab (brand name Lucentis; Genentech/Roche, South San Francisco, CA) are used intravitreally to block the
abnormal growth of blood vessels (i.e., choroidal neovascularization [CNV]) involved in neovascular AMD as well as
in other eye disorders (e.g., macular edema due to diabetic retinopathy). As VEGF is overexpressed in some tumors,
this class of drugs is also used in cancer treatment (e.g., colorectal cancer).
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Bevacizumab is approved by drug regulatory authorities for intravenous use as a cancer therapy, but not approved for
intravitreal use in the treatment of CNV in AMD. However, it is widely used off-label for this indication. The dosage
of bevacizumab most commonly recommended by ophthalmologists for intravitreal injection is 1.25 mg. However,
we will consider studies irrespective of the dosage administered or treatment regimen (i.e., bevacizumab can either be
injected once a month [continuous regimen] or as needed [discontinuous regimen]). Studies will be included
irrespective of the type of regimen, length of treatment, or duration of follow-up.
Comparator(s)/ control
We will include head-to-head RCTs comparing intravitreal bevacizumab (intervention) and ranibizumab
(comparator). The approved dosage of ranibizumab as indicated in the “Summary of Product Characteristics” is 0.5
mg. However, we will include studies irrespective of the applied dosage or schedule.
Outcome(s)
Primary outcomes
We will assess the following systemic outcomes:
(1) All-cause mortality and
(2) All SSAEs.
We will be inclusive when selecting SSAEs. For this reason, we will not define them a priori, but will accept the
definition adopted by study authors. Our assumption is that, in most RCTs, serious adverse events might be
differently defined, but usually relate to medical occurrences that: result in death, are life threatening, require hospital
admission or prolongation of hospital stay, cause persistent or significant disability/incapacity, or are medically
important events or reactions.
If the information in published study reports and in unpublished supporting documents (e.g., meeting abstracts or
presentations) is inadequate to assess the extent of SSAEs, we will contact the study authors for clarification.
For the primary analysis, we will combine outcomes collected at the maximum follow-up reported, since this
corresponds to the maximal cumulative drug dosage.
Secondary outcomes
(1) Myocardial infarction: fatal and/or non-fatal myocardial infarction.
(2) Stroke: fatal and/or non-fatal stroke.
(3) Arteriothrombotic event: any composite outcome that considered at least two of the following events: a)
myocardial infarction, b) stroke, c) angina and ischemic heart disease, d) thrombosis, and e) death from
cardiovascular diseases.
(4) Serious hemorrhage, as defined in each study, including, but not limited to, cerebral, pulmonary and
gastrointestinal hemorrhage. These are usually defined as a hemorrhage that is associated with anemia, transfusion,
hemostatic intervention, hospitalization, or fatal bleeding.
(5) Serious neutropenia, as defined in each study. These are usually defined as neutropenia of grade 3 and 4
associated with sepsis and life-threatening infections.
(6) Gastrointestinal perforation.
(7) Serious infection as defined by each study, including, but not limited to, pneumonia, lung abscess, and pyothorax.
These are usually defined as an infection associated with the use of intravenous antibiotic, hospitalization, intubation,
or death.
(8) Treatment-related drug discontinuations.
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(9) SSAE classified according to the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Classes
(version 17.0), including: benign, malignant, or unspecified neoplasms; cardiovascular disorders; gastrointestinal
disorders; general disorders and administration site conditions; infections and infestations; nervous system disorders;
and respiratory, thoracic and mediastinal disorders.
(10) Serious adverse events previously associated with drugs affecting the vascular endothelial growth factor (VEGF)
pathway (i.e., arteriothrombotic events, systemic hemorrhage, congestive heart failure, venous thrombotic events,
hypertension, and vascular death).
Data extraction, (selection and coding)
Two investigators will independently screen the titles and abstracts of the identified studies. The full texts of
potentially eligible studies will be retrieved and independently assessed using the predefined inclusion criteria.
Discrepancies will be resolved through discussion and, when necessary, by consulting a third investigator. Two
investigators will independently extract the following data about each study: publication data; study acronym and
identifier, first author’s surname, geographical location of study, and year of publication; study design; number of
participants and population characteristics; intervention and comparator , including drug, dosage, and administration;
methods used for recording SSAEs (e.g., whether they were based on patient report, review of medical records, or
both); and SSAEs.
Risk of bias (quality) assessment
The risk for bias in each included study will be assessed according to the criteria outlined in the Cochrane Handbook
for Systematic Reviews of Interventions, which addresses the following key domains: sequence generation, allocation
concealment, blinding of participants and personnel, incomplete outcome data, selective outcome reporting, and other
sources of bias.
If the information in published study reports is inadequate to assess methodological quality, we will contact the study
authors for clarification. Since this is a rapid systematic review, if the authors do not respond within one week, we
will classify the study according to the information available.
Strategy for data synthesis
We will use the risk ratio (RR) to measure the association between anti-VEGF treatment and outcomes.
Individual participants will serve as the unit of analysis. Since repeated SSAEs can occur in the same participant, we
will consider the number of individuals with SSAE(s), rather than the number of SSAEs.
We will present the cumulative estimates as follows. We will use a random effects Mantel-Haenszel method, which is
more robust when pooling sparse data. For each meta-analysis, we will report the chi-squared p-value and the Isquared value with 95% confidence intervals (CI). However, we anticipate that a limited number of RCTs in each
pairwise comparison, whether it is due to the paucity of studies in the field or to incomplete reporting, will prevent the
formal assessment of statistical heterogeneity and publication bias. All p-values will be two-tailed. For all tests,
except for heterogeneity, a probability level lower than 0.05 will be considered statistically significant. We will not
formally adjust for multiplicity of comparisons, but will consider this problem when interpreting the analyses.
Analysis of subgroups or subsets
A pre-specified subgroup analysis will be performed to explore differences in studies that have adopted different
doses and treatment regimen. We cannot anticipate the designation of low dose versus high doses, and this might be
relatively arbitrary. As a secondary analysis, we will combine SSAE data at the one-year follow-up as most of the
drug dose is delivered within the first treatment year with the exception of continuous regimens that are rarely used in
practice. We will also perform a sensitivity analysis excluding unpublished data.
Dissemination plans
Release of findings in scientific medical journals. Reports will also be made available to the Italian national and
regional authorities and, upon request, to any stakeholder of any country that may be interested.
Contact details for further information
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Lorenzo Moja
Via Pascal 36
Milan, Italy 20133
[email protected]
Organisational affiliation of the review
Italian Cochrane Centre
http://www.cochrane.it
Review team
Vittorio Bertele’,
Annalisa Campomori,
Usha Chakravarthy,
Roberto D’Amico,
Kay Dickersin,
Jennifer Evans,
Laurent Kodjikian,
Koren Kwag,
Kristina Lindsley,
Yoon Loke,
Ersilia Lucenteforte,
Maureen Maguire,
Daniel Martin,
Lorenzo Moja,
Alessandro Mugelli,
Barney Reeves,
Chris Rogers,
Christine Schmucker,
Manju Subramanian,
Gianni Virgili,
Anticipated or actual start date
26 March 2014
Anticipated completion date
26 May 2014
Funding sources/sponsors
Azienda USL, Modena, Italy
Conflicts of interest
None known
Language
English
Country
Italy
Subject index terms status
Subject indexing assigned by CRD
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Subject index terms
Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Humans; Macular Degeneration
Stage of review
Ongoing
Date of registration in PROSPERO
02 May 2014
Date of publication of this revision
06 May 2014
DOI
10.15124/CRD42014009586
Stage of review at time of this submission
Preliminary searches
Piloting of the study selection process
Formal screening of search results against eligibility criteria
Data extraction
Risk of bias (quality) assessment
Data analysis
Started
Completed
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
No
No
No
PROSPERO
International prospective register of systematic reviews
The information in this record has been provided by the named contact for this review. CRD has accepted this information in good
faith and registered the review in PROSPERO. CRD bears no responsibility or liability for the content of this registration record,
any associated files or external websites.
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