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Systematic Review of Controlled Trials on Erythropoietin to Support Evidence-Based Guidelines

Systematic Review of Controlled Trials on Erythropoietin to Support Evidence-Based Guidelines

ABSTRACT: To support evidence-based clinical guidelines on erythropoietin use for anemia in oncology, we conducted systematic reviews of controlled trials on four patient groups. These were patients with treatment-related anemia; patients with disease-related anemia; patients transplanted with allogeneic hematopoietic stem cells; and those transplanted with autologous hematopoietic stem cells. Two reviewers followed a prospective protocol to select studies, abstract relevant outcomes, evaluate study quality, and conduct meta-analysis where data sufficed. For treatment-related anemia, meta-analysis of available evidence (22 trials; N = 1,927) demonstrated reduced odds of transfusion after erythropoietin, but higher-quality trials reported smaller odds reductions. In several trials, erythropoietin improved quality of life for groups with mean baseline hemoglobin < 10 g/dL. However, evidence was insufficient to determine whether initiating erythropoietin treatment earlier for newly anemic patients reduced the odds of transfusion or improved quality of life more than waiting until hemoglobin approached 10 g/dL. Limited evidence (6 trials; N = 693) suggested that erythropoietin decreased the risk of transfusion for patients with disease-related anemia. For those undergoing allotransplants, evidence (7 trials; N = 493) showed erythropoietin modestly decreased time to red cell engraftment and transfusions. Studies on erythropoietin after autologous transplants (6 trials; N = 321) did not support a beneficial effect of erythropoietin. [ONCOLOGY 16(Suppl 10):171-188, 2002]

In 1997, the Agency for
Care Policy and Research, now
known as the Agency for Healthcare Research and Quality (AHRQ), launched an
initiative to promote evidence-based practice in everyday care by establishing
12 Evidence-based Practice Centers. AHRQ establishes contracts with the
Evidence-based Practice Centers to develop evidence reports and technology
assessments on clinical topics that are common, expensive, and/or significant
for the Medicare and Medicaid populations. Through this program, AHRQ partners
with private and public organizations to improve the quality, effectiveness, and
appropriateness of clinical care by facilitating the translation of research
evidence into clinical practice.

Approach to Systematic Reviews

Program Overview

In 1998, the American Society of Hematology (ASH) and the
American Society of Clinical Oncology (ASCO) jointly nominated the topic
"Uses of Erythropoietin in Oncology" to AHRQ for an Evidence-based
Practice Center systematic review and evidence report. A panel appointed jointly
by ASH and ASCO intended to use the resulting evidence report to support
development of a clinical guideline for dissemination to their members. AHRQ
contracted with the Blue Cross and Blue Shield Association (BCBSA) Technology
Evaluation Center Evidence-based Practice Center to conduct the systematic
review and evidence report on erythropoietin.

Evidence-based Practice Centers develop evidence reports and
technology assessments based on rigorous, comprehensive syntheses and analyses
of relevant scientific literature, emphasizing explicit and detailed
documentation of methods, rationale, and assumptions. These scientific syntheses
may include meta-analyses and cost analyses. Each Evidence-based Practice Center
collaborates with other medical and research organizations so that a broad range
of experts is included in the development process. More detailed information on
the Evidence-based Practice Centers program, the topic nomination process, and
the list of centers is available at http://www.ahrq.gov/clinic/epcix/htm.[1]
Executive summaries and full copies of completed reports (with bibliographies
and evidence tables) are available at the same URL for viewing or complimentary
downloading. Complimentary single, printed copies also may be obtained from the
AHRQ Publications Clearinghouse (1-800-358-9295).

Systematic Review Methods

Protocols for systematic review are prospectively designed to
define study objectives and key questions; search strategy; patient populations
of interest; study selection criteria and methods to determine study
eligibility; outcomes of interest; data elements to be abstracted and
abstraction methods; and methods
to assess study quality. Usually, two independent reviewers complete
each step of the protocol. Reviewers individually evaluate studies against
selection criteria, abstract data separately, and compare their results after
each step. Disagreements are generally resolved by consensus
but may require resolution by a third reviewer.

A technical advisory group provides ongoing guidance on all
phases of each Evidence-based Practice Centers’ review. Six technical advisors
participated in the evidence report on use of erythropoietin in oncology
patients. ASCO and ASH each appointed two of the six advisors (including the
guideline panel co-chairs) and the Technology Evaluation Center Evidence-based
Practice Center staff recruited the remaining two.

Evidence-based Practice Centers reviews begin with a
comprehensive literature search that attempts to identify all publications of
relevant controlled trials. The search strategy for the review on erythropoietin
is described briefly in the Executive Summary posted on the AHRQ web site[1] and
more completely in the full evidence report.[2] The Medline, Cancerlit, and
Embase databases, last searched in December 1998, yielded 2,915 references. We
identified 28 additional reports by supplementary searches (eg, Current
Contents, bibliographies from manufacturers) through October 30, 1999, for a
total yield of 2,943 references.

Next, studies are selected for data abstraction using
criteria specified in the protocol. The primary study selection criteria for the
erythropoietin review required that studies be designed as controlled trials
comparing the outcomes of managing anemia with and without erythropoietin in a
patient population relevant to one of four clinical settings. These were (1)
anemia due primarily to cancer therapy; (2) anemia due primarily to a
malignancy; (3) high-dose myeloablative therapy followed by an allogeneic
transplant of hematopoietic stem cells from peripheral blood or bone marrow; and
(4) high-dose myeloablative therapy followed by an autologous transplant of
hematopoietic stem cells. We defined the setting as anemia primarily due to
cancer therapy if trials limited enrollment to patients undergoing concurrent
chemotherapy or radiation therapy with conventional nonmyeloablative doses. We
defined the setting as anemia primarily due to malignancy if some enrolled
patients did not receive concurrent chemotherapy or radiation therapy while on
study.[2] Trials were excluded if there were < 10 similarly treated evaluable
patients in each arm.

In the available trials, erythropoietin treatment (with
transfusion used as necessary) was always compared with red blood cell (RBC)
transfusion alone; no trials compared erythropoietin to any other alternative.
All randomized controlled trials relevant to any of the four clinical settings
were included. Studies that used nonrandomized concurrent or historical controls
were included if the reviewers could determine that similar patients were
included in the treatment and control groups. Nonrandomized trials were
considered to be of lesser quality than randomized controlled trials. Outcomes
of interest included

  • Magnitude
    of change in hemoglobin (Hgb) levels.
  • Percentage
    of patients who met criteria for a hematologic response as defined in each study’s
  • Percentage
    of patients who were transfused.
  • Number
    of RBC units transfused per patient normalized to a 4-week period.
  • Quality
    of life.
  • Symptoms
    of anemia (besides fatigue or other components measured by quality-of-life
  • Adverse
    effects of treatment.

The systematic review addressed the following key questions
separately for each clinical setting:

1. Effects of
Erythropoietin Treatment
—What were the
relative effects on outcomes of managing anemia with erythropoietin compared
with transfusion alone? In settings other than stem-cell transplants, what were
the relative effects of erythropoietin treatment when different Hgb thresholds
were used to initiate erythropoietin treatment?

2. Variations in
Erythropoietin Regimens
—In the included
studies, did variations in the erythropoietin treatment regimen (such as dose,
frequency, duration, route) affect the outcomes of treatment? Were these
variations likely to confound interpretation of the evidence on the relative
effects of erythropoietin treatment according to the alternative Hgb thresholds
for initiating treatment?

3. Identification of Patient Response—Were there populations
or subgroups of patients more or less likely to benefit from erythropoietin
treatment? Were there laboratory measurements that either predicted or permitted
early identification of patients whose anemia responded to erythropoietin?

4. Data on Adverse Effects—What
were the incidence and severity of adverse effects associated with the use of
erythropoietin and how did these compare with the adverse effects of

Data abstraction for adverse events also was limited to
controlled trials so that effects of erythropoietin could be distinguished from
effects of disease progression or concurrent therapies for the underlying

To supplement the systematic review, we conducted a
literature-based meta-analysis of the effect of erythropoietin on the odds of
transfusion for patients with anemia or at risk of anemia due primarily to
cancer therapy. A random effects model was used to calculate the combined odds
ratio of transfusion for the 12 randomized controlled trials that reported
numbers or percentages of patients transfused, with or without erythropoietin
administered subcutaneously, for treatment-related anemia. The odds ratio
expresses the relative likelihood that erythropoietin-treated patients will be
transfused compared with the likelihood for controls. Published data were
insufficient for literature-based meta-analysis of other outcomes, or of odds of
transfusion in other clinical settings.

Sensitivity analysis compared results of higher-quality
trials to those of lesser-quality trials. A trial was classified as higher
quality when it was randomized and double-blinded and met our criteria
concerning limits on the number of subjects excluded from the analysis of
results. We required that < 10% of subjects within each study arm were
excluded from the analysis and that the ratio of exclusions from each arm was
less than 2:1; or, alternatively, that results were reported as an
intention-to-treat analysis.

External Review

AHRQ requires that Evidence-based Practice Center reports
undergo extensive review by external experts and representatives of stakeholder
organizations. Early in each project, these individuals review and provide input
to modify the study protocol. Later, they review and comment on the report’s
initial draft. However, each Evidence-based Practice Center has ultimate
responsibility for the final draft of its reports, subject to AHRQ review.

For the erythropoietin report,[2] the BCBSA Technology
Evaluation Center Medical Advisory Panel, which includes nationally recognized
experts in technology assessment and hematology/oncology, reviewed a preliminary
analysis of the evidence base. Additionally, 20 external reviewers critiqued the
study protocol and draft report, and revisions were made based on their
comments. Eight reviewers were invited by Technology Evaluation Center based on
their expertise in medical oncology, hematology, transfusion medicine,
quality-of-life and systematic review methodology. One reviewer directed another
AHRQ Evidence-based Practice Center and is a medical oncologist. Ten reviewers
were appointed by professional organizations other than ASCO or ASH and by
patient advocacy groups. These reviewers included clinical and research
specialists involved in the treatment of cancer and/or management of
cancer-related anemia and patient advocacy representatives. One external
reviewer was from the technical staff of Ortho Biotech, Inc. Lists of the
Technology Evaluation Center Medical Advisory Panel members, external reviewers,
and technical advisors are included in the evidence report’s appendices.[2]


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