Activated Protein C for Severe Sepsis and A Low Risk of Death
Abstract & Commentary
By Stephen W. Crawford, MD, Professor, Pulmonary Medicine, Naval Medical Center, San Diego, CA, is Associate Editor for Critical Care Alert.
Dr. Crawford is a consultant for Cubist Pharmaceuticals, and is on the speaker’s bureau for Ortho Biotech.
Synopsis: A randomized, multi-center trial demonstrated no survival advantage for adults with severe sepsis with only single-organ failure or APACHE II scores less than 25 who were treated with activated protein C.
Source: Abraham E, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005;353:1332-1341.
In 2001, the PROWESS trial of 1690 patients with severe sepsis1 demonstrated that a 96-hour infusion of activated protein C, or drotrecogin alfa (activated) (DrotAA, Xigris®) at 24 g/kg/h decreased mortality at 28 days from 30.8% to 24.4% (P = 0.005). This impact of activated protein C was most notable among those patients with APACHE II scores in the third and fourth quartiles—that is, the sickest patients saw the greatest benefit. On this basis, the FDA approved Xigris® for administration in severe sepsis and multi-organ failure or an APACHE II score greater than 25. In addition, the FDA required a study among patients with severe sepsis and a low risk of death. The ADDRESS Study Group recently reported the results of this second, FDA-mandated study.
This double-blinded, placebo-controlled, randomized, multi-center trial examined patients with severe sepsis who had either single-organ failure or an APACHE II score < 25. They enrolled 2640 patients and examined 28-day mortality as the primary end-point. The inclusion/exclusion criteria were very similar to the original PROWESS trial, except that those patients whom the investigators thought had a high likelihood of dying were excluded. The study was terminated early because of a low likelihood of detecting a statistically significant improvement in outcome in the treated group. There were no statistically significant differences in 28-day mortality (17.0% in placebo vs 18.5% in the DrotAA group) or in-hospital mortality (20.5% in placebo vs 20.6% in DrotAA group). Seventy-seven percent of deaths were sepsis-related. Notably, the rate of serious bleeding was more frequent among patients receiving DrotAA (2.4% vs 1.2% during infusion, and 3.9% vs 2.2% during the 28-day study period).
Subgroup analyses yielded interesting information. Among the 321 patients with APACHE II scores ≥ 25, there was no significant difference in 28-day mortality between DrotAA and placebo (29.5% vs 24.7%). Notably, in the subgroup of patients who had surgery within 30 days and single organ failure (314 patients in the placebo and 321 in the DrotAA group), there were significantly higher mortality and bleeding events in the DrotAA group.
Commentary
The answer is in: The glass is half full. As a therapeutic nihilist, I am always glad to see a study that confirms scenarios where I do not have to pull out another infusion, especially a relatively expensive medication such as Xigris®. This large, multiple-institution, multiple-country study is convincing evidence that activated protein C does not improve survival for adult patients with sepsis and a "low" risk of dying. Personally, if I had an estimated 20% in-hospital mortality risk, I would not consider it "low"! Also, this study confirms again the increased risk of serious bleeding associated with this agent—approximately double that of the placebo groups. On the basis of this study, activated protein C should not be given to adults with severe sepsis and a only single-organ failure or an APACHE II score < 25.
I am happy to have this information. However, there are elements of this study that I find very disconcerting. First, if the improved outcome in severely ill sepsis patients is the effect of protein C on the coagulation cascade, why is it not protective or effective in patients with fewer organ failures? Is this mechanism of action correct?
Secondly, why did activated protein C not improve the mortality rates in the subgroup with APACHE II scores ≥ 25 in the present study? Among these 321 patients in the ADDRESS trial the 28-day mortality was actually worse than in the placebo group (29.5 % vs 24.7%). PROWESS had demonstrated a 6.1% absolute reduction in mortality at 28 days (from 30.8% to 24.7%) among their 1690 patients. The authors seem to do some hand waving to explain away the lack of effect. They note that the study was not powered to detect a difference. However, even the trend is in the wrong direction. They observe that the 95% confidence intervals for the specific subgroups in the two studies overlap, albeit just barely. Additionally, they point out that the mean APACHE II score for the PROWESS study was 33.1 compared to 28.1 for the subgroup in the ADDRESS trial, and the mortality rates for the placebo group in PROWESS was 43.7% compared to 24.7% in ADDRESS. They suggest that the patients enrolled in PROWESS were substantially sicker than in ADDRESS.
I am left with conflicting conclusions about this ADDRESS trial. Firstly, I am confident that we should not administer activated protein C to adults with severe sepsis who have single-organ failure or APACHE II scores less than 25. However, I am unsure how sick my patient has to be before I do give the drug.
It is quite possible that activated protein C actually is effective in the sickest of the severe sepsis patients. However, it is also possible that advances in adjunctive therapy for severe sepsis have significantly improved the outcomes and that a marginal benefit of activated protein C is no longer apparent. That is, the improved mortality rates seen in ADDRESS compared to PROWESS may be less accounted for the degree of illness of the populations than by an overall improvement in the care of these patients over time.
On the basis of theses studies, I am more convinced that early recognition of the systemic inflammatory response syndrome, prompt antibiotic administration, aggressive fluid resuscitation, ventilatory support, renal replacement therapy, proper patient positioning and stress-dose corticosteroid support are critical to the outcome of adults with severe sepsis. I am less convinced of the role of activated protein C. I will continue to use it in patients who I think are so ill that they have nothing to lose. On second thought, is the glass half empty?
Reference
- Bernard GR, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699-709.
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