(U.S.) Comparative Effectiveness Review: Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment: Comparative Effectiveness Update

open access

 Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
540 Gaither Road
Rockville, MD 20850
www.ahrq.gov

Future Research
Given the current state of evidence, unanswered questions, and balance of benefit and harms, how should future research be considered? Given the magnitude of relative mortality increase and underlying mortality rates in this patient population, it is clear that attempts to reduce
uncertainty in relative risk of mortality through clinical trials would require very large samples.
The confidence and credible intervals for the estimated relative increase in mortality span a range of values—the true relative increase in risk for adults could be higher or lower than 1.17 estimated here. Still these data do establish with sufficient certainty that mortality rates increase.
Questions are therefore raised regarding equipoise in pursuing some “true” relative risk in further clinical trials.
At the same time these agents will continue to be used for reasons beyond the scope of this review—for example, patient preference, availability of blood, possible emergence of infectious agents in the blood supply. It is therefore important to address whether there are patient subgroups with low risk of harm and how dosing practices influence harms. Unfortunately, these questions present complexities not addressed even in the most carefully designed trials. The
fundamental complexity concerns time-varying treatment and confounding—ESA dose is typically varied depending on the hemoglobin level achieved. It is well known that traditional analytical approaches fail to correctly estimate treatment effects under these conditions.139,204
Accordingly, it is unlikely that any future meta-analysis or systematic review will be able to inform these questions.
Still, there is a compelling rationale to examine observational data (e.g., carefully conducted registries) using methods appropriate to these questions—whether there is a subgroup and dosing strategy accompanied by some lower risk. A large registry with accurate and precise information on ESA dose (amount, frequency, duration, escalation), hemoglobin (baseline, and all recorded values preferably at times specified by protocol), stage of malignancy, treatment regimen and
response, and outcomes (including but not limited to thromboembolism, myocardial infarction, death including underlying and contributory causes) would provide the best opportunity to examine these questions. The Dosing and Outcomes Study of Erythropoiesis-Stimulating
Therapies (DOSE) is one example.205 While deriving conclusions from appropriate analytical methods—inverse probability weighting, G-methods, and marginal structural models—requires some assumptions for inference, they are approaches most able to address unanswered questions.
Lastly, we found many registered completed trials without clearly or readily identified results. The goals of trial registration fall short when results from completed trials are difficult to
identify. Investigators and trials registries must adopt effective procedures to assure timely reporting of results in registries.
In summary, a large collection of trials examining ESA use in patients undergoing cancer treatment provides evidence sufficient to conclude that hemoglobin levels are improved and transfusions avoided together with higher rates of thromboembolic events and mortality.
Whether there are subgroups at higher and lower risk of adverse events and mortality is unclear.
Future research to address the unanswered questions should be limited to examination of observational data collected during the course of usual patient care.