In this issue of the Journal, Drs. Jahr and Williams report an exploration of data from an earlier clinical trial conducted by Biopure Corp. that had been reported in 2008.1 This phase III trial tested a bovine hemoglobin-based oxygen carrier (HBOC) (HemoPure) as a safe replacement of erythrocyte transfusion in an elective orthopedic surgical population. Neither this product nor several similar ones have been licensed by the FDA for clinical use in the United States, although it is in limited clinical use in the Republic of South Africa and the Russian Federation. It has also been used in an “expanded access” program in the United States in individual patients suffering critically severe anemia that threatens their survival, when blood is not an option.2–4
What have the authors found by digging deep into the data from a past clinical trial of an HBOC that is not currently licensed by the FDA?
BACKGROUND: WHY HBOC'S?
Blood is a vitally important, precious, and rare national resource. It is widely used in medicine and surgery to remedy many life-threatening conditions, as both erythrocyte transfusion and blood products and components. The use of transfusions has increased in the decades after WW II, and the demands have increased by the introduction of new surgical procedures in aging populations. The continuity of the supply has been constrained by periodic shortages of specific blood types and the short shelf life in banked blood. Because of the tragic events of the AIDS and associated hepatitis crises in the 1970s and 1980s, the blood supply was perceived to be “tainted” and its safety was threatened. A search for an alternative was begun. A report by the Naval Research Advisory Committee recommended an intensive search for an alternative as an important priority.5 The alternative for blood transfusion was a solution of hemoglobin removed from the erythrocyte which was pasteurized and purified to remove contaminating micro-organisms and stromal fragments, thereby making it safe. The hemoglobin also had to be extensively modified to satisfy additional criteria.6,7 Eight different hemoglobin preparations were developed and subjected to rigorous testing by commercial companies and the US Army, culminating in phase III clinical trials in which the safety and the ability of the product to effectively replace transfusion was tested.8 Unfortunately, all the tested products failed to achieve FDA licensure because of both safety and efficacy concerns.7,9 The reasons for the failure of the products are varied and may involve flaws in the products and in the execution of the trials.3,7,10
Regardless of the clinical failures, much new knowledge has been gained both about the hemoglobin molecule itself and its behavior in the circulation.6 One unfavorable property of free hemoglobin is its propensity to scavenge nitric oxide (NO), the important vasodilator signal, and thereby interfere with normal vasoregulation.7 A common finding in the HBOC clinical trials was the higher incidence of adverse outcomes in the HBOC treated than in the transfused cohorts. Many subjects in the trials were elderly suffering from a variety of chronic inflammatory conditions that are characterized by endothelial dysfunction11 manifesting in impaired release of NO and impaired vasodilation. In such subjects, the introduction of free hemoglobin, by its scavenging NO, may result in an adverse synergy.12 Any unbalanced distribution of conditions characterized by endothelial dysfunction may introduce bias to increase the probability of adverse outcomes in the HBOC-treated population. Unpublished review of adverse outcomes and comorbidities in the trial by Hemosol found a gross maldistribution of diabetic subjects between HBOC and transfusion recipients.
WHAT MAIN LESSONS HAVE DRS. JAHR AND WILLIAMS LEARNED FROM THE EXPLORATION OF AN HBOC TRIAL?
Adequacy of treatment of the anemia by the HBOC
The HBOC treatment in the trial demonstrated significant transfusion avoidance. Sixty per cent of HBOC-treated subjects avoided transfusion, whereas 40% of subjects required transfusion, in addition to the HBOC. This suggests that the HBOC cohort comprised 2 distinct populations presumably differentiated by their severity of blood loss resulting in continuing anemia.
As noted by the authors, a substantial dilutional effect was evident in that the 32.5 g total hemoglobin mass, in a single unit of HemoPure diluted in a plasma volume 5-fold to 6-fold (2500 to 3500 mL), failed to offset the erythrocytic hemoglobin lost in a similar volume and failed to reach the transfusion threshold, in the face of continuing blood loss. Thus, bleeding subjects required repeated infusion of the HBOC. Because blood loss continued, the infusions would “chase,” but fail to reach, the transfusion threshold. The rapid loss of free hemoglobin from the circulation (plasma t1/2 = 24 hours or less) also contributed this “chasing” the threshold. The original trial design may not have anticipated this possible flaw. Hence, it may have resulted in excessive volume replacement without sufficient treatment of the anemia. The process would only be stopped by controlling blood loss or by administering transfusion.
It could be argued, and noted by the authors, that in a future study conducted under the currently prevailing acceptance of lower hemoglobin triggers in the range of 7–9 g/dL.13–17 One 250 mL unit of HBOC containing 13 g/dL hemoglobin could be used more effectively to treat blood loss.
The Hemoglobin deficit
This concept is a useful descriptive addition by combining the magnitude and duration of the intensity of the hypoxic threat to the normal functioning of the organs dependent of adequate oxygen delivery. The authors calculated an average 3-fold difference in “hemoglobin deficit” between HBOC-treated and transfused subjects, illustrating the flaw noted above. If adverse outcomes (AEs and SAEs) were causally related to the magnitude of the hemoglobin deficit, the adverse outcomes would be more frequent in the HBOC-treated cohort. Although this possibility was not explored in detail, the data in a Table showed comparison of the proportion of patients experiencing AEs and SAEs in the 2 treatment arms. Contrary to expectations, there was no similar difference in the proportion of subjects experiencing AEs and SAEs between treatment arms. The frequency of adverse outcomes, however, was not explored. This could be interpreted that a specific exacerbation of adverse outcomes by HBOC treatment per se is less likely. Further support for this proposition is found in the application of logistic modeling and proportional hazards analysis to examine for specific predictors of only cardiac adverse events. Hemoglobin deficit, age, and history of cardiac disease were significant predictors of cardiac adverse outcomes, but HBOC treatment was not.
Mortality has been extensively used in clinical trials as a safety signal. In the 2008 trial, 10 and 6 deaths were recorded in the HBOC and transfusion-treated cohorts, respectively. Although blinded review of the events found no causal relationship to treatment, the difference in mortality rates is still notable. Furthermore, HBOC-treated patients older than 80 years experienced 5 of the 10 deaths as opposed to only 1 of the 5 deaths in the transfusion arm. It may be possible that more of the oldest subjects with endothelial dysfunction may be more prone to HBOC-associated adverse outcomes.12 Only an extensive review of the distribution of comorbidities could shed light on such possibilities.
The infusion of large volumes of crystalloid may dilute clotting factors to an extent that may be manifested in impaired coagulation and excessive blood loss. However, no compelling evidence of a coagulopathy caused by HBOC was found by the authors because only 4 and 3 subjects received multiple units of blood components or blood products in the 2 cohorts. The authors concluded coagulopathy was not a major complication in a significant proportion of either HBOC-treated or transfusion-treated subjects.
SUMMARY OF THE AUTHORS′ CONCLUSIONS
The principal conclusion offered is that the BioPure product is safe for periodic replacement of transfusion, in total volumes up to 2500 mL with a caveat. HBOC treatment per se does not seem to contribute significantly to a cardiac adverse outcome “base,” but the authors expressed concern about patients with cardiac disease and those older than 80 years. The product is a feasible “oxygen bridge to transfusion.”
The concept of hemoglobin deficit is a useful addition to the analysis of clinical trial data on blood loss and anemia treatment and may be helpful in identifying undertreatment of anemia. The application of logistic regression and proportional hazards analysis has revealed “hidden” correlations.
DISCUSSION AND CONCLUSIONS
The authors have done a service to the HBOC community by performing a deep dive into a data set from an “older” clinical trial that had been deemed to have failed. Yet, they demonstrated that the bovine HBOC product, produced by BioPure Corp., can be successfully used, under specific circumstances, to avoid transfusion in a high proportion of subjects undergoing elective orthopedic surgical procedures that commonly consume a significant proportion of the blood supply.18 This is important in view of the current practice of deliberately reducing or avoiding transfusion exposure14,16,19 by accepting lower transfusion triggers to reduce the probability of transfusion reactions,16,20,21 of adverse outcomes more commonly occurring in transfused persons,22,23 and of the immune-modulating effects of transfusion and their sequelae.24,25 The use of the product is qualified as a matter of caution, in that patients with cardiac disease26 and those older than 80 years who may experience more frequent adverse outcomes should not be exposed to these products unless it is unavoidable.
The limitation because of the dilutional effects has become of lesser significance because the transfusion thresholds are lowered by evidence accumulating of its safety.14,16,27 The limitations inherent in the relatively low hemoglobin content of this product are no longer seen as a disadvantage because substantially lower transfusion thresholds of 7–9 g/dL are largely accepted as the evidence-based practice17,19,24,28 and superior outcomes achieved by the practice of patient blood management.29–34
The bovine product is being used successfully in the treatment of critically severe anemia in the expanded access program when blood is not an option. This is an important therapeutic modality in patients who cannot or will not accept transfusion.35 Military planners are still searching for universal usable oxygen carriers for in-the-field resuscitation.36
Despite the failure of the HBOC products tested in the early 2000s, the search for a safe and efficacious HBOC is continuing today,7,37 and newer applications are also being proposed.3,8
Blood is a rare national resource. Its safety and availability are of vital concern. Over the years, transfusion practice has been evolving. As the population ages and the demand for blood and its components are increasing, efforts to conserve the supply are being implemented by ongoing critical evaluation of its use. Continuing efforts to assure its safety are met by increasing resource allocation. Continuing evaluation of blood and transfusion use is necessary because the supply is diminishing by a shrinking all-volunteer donor base. The procurement of a safe and expedient alternative to erythrocyte transfusion is an objective with obvious benefits.
Similar explorations of the past “failed” trials would be a welcome addition to our knowledge of why and how the trials failed, to help design better trials in the future.
[Disclosure: The author was an executive of Hemosol Corp. He has no interest in any commercial enterprise in the field. At the time of this writing, a war is raging in Eastern Europe; this work is dedicated to those whose blood is being shed.]
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