Afelimomab-another therapeutic option in sepsis therapy?

T imes are changing. Since the beginning of the new millennium, skepticism has moved to optimism in sepsis research. The PROWESS study (1) was just one in a series of publications demonstrating that improvement in sepsis therapy is possible. Low-dose corticosteroids and early goal-directed strategies are other new strategies to reduce mortality rate in septic patients (2–4). In the current issue of Critical Care Medicine, Dr. Panacek and colleagues (5) report on the results of the MONARCS trial. Does this trial fit in the series of the “positive” ones? The authors conclude that treatment with the murine monoclonal antibody to human tumor necrosis factor (TNF)afelimomab is safe and reduces mortality rate in septic patients with elevated interleukin (IL)-6 levels. From the point of view of the study protocol, the MONARCS trial was successful. Focusing on patients with positive IL-6 tests, in this trial the primary study population consisted of high mortality risk patients (47.6% mortality rate in patients with IL-6 levels 1000 ng/mL vs. 28.6% in patients with negative IL-6 tests). The importance of this selection gets clear when looking on the numbers more closely: Compared with the mortality reduction achieved in the PROWESS trial, the effect in the MONARCS trial is smaller. Although one might be skeptical about the statistical model used for the adjustment of differences between control and experimental group, even the uncorrected absolute risk reduction is still 4%; in other words, the number needed to treat is 25. However, the relative risk reduction is much smaller in the MONARCS than in the PROWESS trial (11.9% vs. 19.8%). It has been demonstrated for protein C therapy that the relative risk reduction is independent of the preexisting mortality risk (6). If we assume the same to be true for afelimomab treatment, we can calculate that the number needed to treat in a population with a preexisting mortality risk of 30.8% would increase to approximately 39 (compared with approximately 16 for protein C treatment in patients with the same underlying mortality risk). This simple mathematical consideration underlines that the effectiveness of afelimomab therapy is smaller than other new interventions in sepsis therapy. Possibly more important, it demonstrates that careful selection of patients is essential. Wrong or less strict patient selection may be one of the reasons why previous sepsis trials and especially previous trials on anti-TNF-directed therapies failed. Conversely, this also has an important impact on daily praxis. The decision of which patients on the intensive care unit should receive the new treatment is critical. This aspect has been addressed by many hospitals and intensive care units when giving strict guidelines for the use of innovative (but expensive) therapies. The low rate of patients with positive blood cultures has raised doubts about the representativeness of the patients included in the MONARCS trial. In addition, it remains unclear whether in daily praxis screening for septic patients with elevated IL-6 levels is practicable and would result in a comparable risk population. The decision whether to give afelimomab is facilitated by the fact that the clinical evaluation committee of the MONARCS trial did not find clinically relevant differences of afelimomab effectiveness between subgroups, including those with varying concomitant medications. The absolute risk reduction in the subgroup of patients receiving concomitant anti-coagulation was still 5% and in the subgroup of patients receiving concomitant corticosteroids 5.3%—both in favor of afelimomab (E. A. Panacek, personal communication, 2004). A series of trials on different anti-TNF-directed therapies have been undertaken. Combining the results of those studies using monoclonal antibodies against TNF(7–13, 5), a slight but significant improvement in mortality rate can be detected (odds ratio, 0.89; confidence interval, 0.80–0.98; Fig. 1). However, calculating the effect size of trials on afelimomab treatment only, the difference between treatment and control group marginally fails to reach statistical significance (odds ratio, 0.86; confidence interval, 0.75–1.0). Clinicians will have to decide whether the rather small improvement in survival is worth the risks. Although adverse events and serious adverse events were not more common in the afelimomab group, the human anti-mouse antibody formation in one fifth of the patients may have relevant implication for future therapeutic options in these patients. In context of the increasing discussion on registration of clinical trials and publication bias (14), the 4-yr delay between the end of the trial and submission for publication is remarkable—and regrettable. In January 2004, a secondary analysis on the adequacy of antibiotic treatment was published (15). Now, after the main