Recombinant human activated protein C sentenced to the death of a thousand cuts?

I n this issue of Critical Care Medicine, Dr. Laterre and colleagues (1) present longer term follow-up data to the clinical trial of recombinant human activated protein C (rhAPC) in severe septic patients with lower severity of illness (ADDRESS) (2). There was no statistically significant difference in outcomes between subjects in the treatment and placebo groups. The report provides reassurance that there is no late effect of rhAPC. With data available for approximately 90% of subjects, the overall 1-yr mortality rate was 34.1%. Because most deaths occurred within 90 days, this is a reasonable mortality landmark for determining a benefit in clinical trials of severe sepsis. Although this study adds to a multitude of studies regarding rhAPC, we seem no closer to a consensus about the drug. PROWESS included patients with severe sepsis and an a priori plan for a primary analysis stratified by a variety of clinical factors (3). Presumably, this would guide subsequent studies, should there be no overall effect. However, there was a mortality benefit for the whole cohort (absolute risk reduction, 6.1%; 95% confidence interval [CI], 1.9–10.3%). After analyzing subgroups, regulatory bodies concluded that the sickest patients benefited the most, and rhAPC was approved for those at a high risk for death. Statistically, an Acute Physiology and Chronic Health Evaluation (APACHE) II score 25 provided the best discrimination of those likely to benefit (absolute risk reduction, 12.8%; 95% CI, 6.2–19.4%) (4). ADDRESS was designed to answer the question about lower-risk patients for whom rhAPC was not already indicated (2). This study was stopped early because of a projected lack of effect. Among ADDRESS patients with an APACHE II score 25 (12% of those enrolled), those treated with rhAPC had numerically higher mortality than those assigned to placebo (absolute risk increase, 4.8%; 95% CI, 4.9% decrease to 14.2% increase). This raised questions about PROWESS’ conclusions, despite the clear differences in studies, as shown by the dissimilarity in mortality among placebo patients (APACHE II 25: PROWESS 43.7%, ADDRESS 24.7%; APACHE II 25: PROWESS 19.0%, ADDRESS 16.0%). The sequence in which we received data produced some of the uncertainty about rhAPC. PROWESS demonstrated a benefit, but only for half of the subjects. Then, ADDRESS showed no effect. We tend to simplify these results as contradictory: one was positive, and one was negative. If the sequence was changed, would the same conclusions have been reached? If PROWESS was without overall effect but the subgroup at highest risk showed a benefit, there would have been a second study examining only those at a higher risk. If that study demonstrated rhAPC was beneficial, we would have reached a consensus that rhAPC should be used for severe septic patients at a high risk for death. Instead, rhAPC has become contentious (5–8). Given the heterogeneity of severe sepsis, it would be surprising if any single agent were uniformly effective. We certainly would not expect a single chemotherapeutic agent to be useful in all cancers. If a single drug were to be successful, it would have to address pathways common to the majority of patients. Alternatively, it may work only in a subgroup of patients with the targeted derangement. rhAPC may fit such a description. Considering the acceptance of other therapies without definitive mechanisms of action (e.g., lower tidal volume ventilation [9]), it is peculiar that similar uncertainty causes a reluctance to use rhAPC. The increased risk of bleeding is important when considering rhAPC use. This is a complex issue because we cannot confidently predict who will benefit from treatment and who will bleed. We must determine the net effect for the entire study population and imperfectly extrapolate this as a probability of benefit for an individual patient. When rhAPC is given, there is no immediate feedback that a clinician made the correct decision. When thrombolytics are administered for acute myocardial infarction, chest pain resolves and the electrocardiogram normalizes. With rhAPC, the patient lives, dies, or bleeds. The clinician only credits rhAPC with bleeding. This favors an omission bias–omitting action with a net benefit to avoid the possibility of harm (10, 11). Another rhAPC study is planned to “help clinicians better identify severe sepsis patients at high risk of death who are more likely to benefit (12). ” Although it may not be intended as a “tie-breaking” study, some might view it as such. Dichotomizing studies as either positive or negative contributes to the confusion about rhAPC. PROWESS and ADDRESS did not demonstrate opposite results of equal magnitude. Among high-risk patients, PROWESS had very convincing results for a benefit and ADDRESS was too underpowered to show anything definitive. If we combine the high-risk patients from ADDRESS and PROWESS, the composite absolute risk reduction is 7.8% (95% CI, 2.3–13.3%; p .006). However, because both studies were halted before target enrollment, it is difficult to determine the influence that early stopping had on the common estimate of effect. The upcoming study should be designed with consideration of prior results. Early stopping should be discouraged. Suppose 500 subjects are randomized and the outcomes are identical to the high-risk group in ADDRESS. Enrollment in this study could be halted because of a trend toward harm with p . 23 and without definitive results. If we then combine data from all three studies, there is a composite 3.9% absolute risk reduction (95% CI, 0.6% risk increase to 8.4% risk reduction) *See also p. 1457.