Disclosure:

The Surviving Sepsis Campaign has been underwritten in part by an unrestricted educational grant by Eli Lilly, Inc., the manufacturer of Drotrecogin Alfa (Activated). During the deliberations of the 2004 and 2008 Surviving Sepsis Campaign Guidelines Committees, there was no industry input into guidelines development and no industry presence at any of the meetings. In 2008, the Surviving Sepsis Campaign Guidelines Committee meetings were made possible by a grant from the Society of Critical Care Medicine. In both 2004 and 2008, the industry sponsors of educational grants to the Surviving Sepsis Campaign did not see the guidelines until the manuscript was peer reviewed and accepted for publication in final form.

Corresponding Bundle Element:

Drotrecogin Alfa (Activated) administered in accordance with a standardized ICU policy.

Related Measures

Drotrecogin Alfa (Activated) Administration

Background:

The 2008 Surviving Sepsis Campaign Guidelines suggest that adult patients with sepsis induced organ dysfunction associated with a clinical assessment of high risk of death, most of whom will have APACHE II ≥25 or multiple organ failure receive Drotrecogin Alfa (Activated), also known as recombinant activated protein C (rhAPC), if there are no contraindications. The Surviving Sepsis Campaign recommends that adult patients with severe sepsis and low risk of death, most of whom will have APACHE II <20 or one organ failure, do not receive rhAPC.

Mortality Benefit:

The first trial to assess the efficacy of rhAPC was the PROWESS trial. PROWESS was a phase 3, multinational, double-blind, placebo-controlled trial of rhAPC (24 μg·kg-1·hr-1 during 96 hrs) in patients with severe sepsis. The trial was powered to document a 15 percent reduction in the relative risk of 28-day all-cause mortality. [1] The trial was stopped early due to a statistically significant difference observed between the treatment and the placebo groups after the second interim analysis of 1,520 patients. PROWESS demonstrated a significant reduction in the 28-day all-cause mortality: absolute reduction of mortality, -6.1 percent (30.8 percent to 24.7 percent); relative risk reduction of mortality, 19.4 percent (95 percent confidence interval, 6.6-30.5; p=0.005); and a range of number needed to treat of 16 to 54.

Nevertheless, subsequent trials made interpretation of these results less straightforward. Please see Grading the Evidence below.

APACHE II Score:

In the PROWESS trial, patients were prospectively stratified, in part, by their baseline Acute Physiology and Chronic Health Evaluation (APACHE) II score. There are practical and methodologic limitations of the APACHE II score, which is not typically used to clinically manage individual patients. Nevertheless, The US Food and Drug Agency approved rhAPC for sepsis-induced organ dysfunction associated with high risk of death, such as APACHE II of > 25. In Europe, the European Agency for the Evaluation of Medicinal products approved rhAPC for the treatment of adult patients with two or more organ dysfunctions. The APACHE II score may be calculated courtesy of the French Society of Anesthesia and Intensive Care (see http://www.sfar.org/scores2/apache22.html).

Risk Assessment:

At present, risk assessment is best determined by bedside clinical evaluation and judgment. The use of a standardized policy in intensive care units for the administration of rhAPC may help to clarify decision making about when to apply rhAPC. See the Interim Drotrecogin Alfa (Activated) Administration Policy for a policy that may be used until your intensive care unit or hospital creates one.

Cost-Effectiveness:

Cost-effectiveness appears to be related to the severity of illness as calculated by APACHE II score.  The cost-effectiveness analysis of the PROWESS trial could document a $27,400 cost per quality-adjusted life-year when limited to patients with an APACHE II score of 24, whereas rhAPC was considered cost ineffective in patients with a lower risk of death. [2,3]

Exclusion Criteria:

Many patients were not included in trials establishing the efficacy of rhAPC in severe sepsis. Therefore, the effect of rhAPC is not documented in morbidly obese patients, those patients admitted to an intensive care unit in moribund state with an almost certain likelihood to die, in children, and in pregnant women. Patients with acute pancreatitis were not included in the PROWESS trial, nor were patients who required anticoagulation for a documented or suspected deep vein thrombosis or pulmonary embolism. In addition, hematologic diseases that could interfere with the anticoagulant effects of rhAPC (resistance to activated PC [Leyden mutation], hereditary deficiency of Protein C, Protein S, or antithrombin, known anticardiolipin antibody, lupus anticoagulant, and homocystinemia) were considered as exclusion criteria.

Adverse Effects of Treatment with rhAPC:

Bleeding is the most frequent and serious adverse event that may be induced by rhAPC treatment, and patients at high risk of serious bleeding events should not be treated with rhAPC. [1] The risk of bleeding events should be carefully weighed at the time of the initial clinical evaluation of severely septic patients. Clinicians should consider needed surgeries and/or invasive procedures. Intracranial bleeding is the most severe bleeding event observed in clinical studies of rhAPC. The main risk factor for intracranial bleeding was severe thrombocytopenia andmeningeal infection. Patients with a baseline platelet count of < 30,000/mm3 should not receive rhAPC; previous platelet transfusion should likely not be used to allow rhAPC treatment; platelet count should be carefully monitored by short-time sequential measurements during treatment to anticipate the platelets decrease; platelet transfusion should be used to maintain platelet count at > 30,000/mm3.

Grading the Evidence: [See Ranking the Evidence]

The Grade 1 recommendations below are based on strong evidence for care based on a number of qualitative considerations, while Grade 2 suggestions are weaker recommendations for care. “B” level evidence generally derives from randomized control trials with certain limitations or very well-done observational or cohort studies. “C” level evidence reflects well-done observational or cohort studies with controls. “D” level evidence generally reflects case series data or expert opinion.

• The 2008 Surviving Sepsis Campaign Guidelines suggests that adult patients with sepsis induced organ dysfunction associated with a clinical assessment of high risk of death, most of whom will have APACHE II ≥25 or multiple organ failure, receive rhAPC if there are no contraindications (Evidence Grade 2B, except for patients within 30 days of surgery where it is Grade 2C). Relative contraindications should also be considered in decision making.

• The Surviving Sepsis Campaign recommends that adult patients with severe sepsis and low risk of death, most of whom will have APACHE II <20 or one organ failure, do not receive rhAPC (Grade 1A).          

Rationale: The evidence concerning use of rhAPC in adults is primarily based on two randomized controlled trials (RCTs): PROWESS (1,690 adult patients, stopped early for efficacy) [1], and ADDRESS (stopped early for futility). [4] Additional safety information comes from an open-label observational study called ENHANCE. [5] The ENHANCE trial also suggested early administration of rhAPC was associated with better outcomes.

PROWESS involved 1,690 patients and documented 6.1 percent in absolute total mortality reduction with a relative risk reduction (RRR) of 19.4 percent (95 percent CI, 6.6-30.5, p=0.005), with a number needed to treat (NNT) of 16. [1] Controversy associated with the results focused on a number of subgroup analyses. Subgroup analyses have the potential to mislead due to the absence of an intent to treat, sampling bias, and selection error. [6] The analyses suggested increasing absolute and relative risk reduction with greater risk of death using both higher APACHE II scores and greater number of organ failures. [7] In Europe, this led to drug approval for patients with high risk of death (such as APACHE II ≥25) and more than one organ failure.

The ADDRESS trial involved 2,613 patients judged to have a low risk of death at the time of enrollment. Twenty-eight-day mortality from all causes was 17 percent on placebo vs. 18.5 percent on APC, relative risk (RR) 1.08 (95 percent CI, 0.92-1.28). [4] Again, debate focused on subgroup analyses; analyses restricted to small subgroups of patients with APACHE II score over 25, or more than one organ failure which failed to show benefit. However, these patient groups also had a lower mortality than in PROWESS. 

Relative risk reduction of death was numerically lower in the subgroup of patients with recent surgery (n=502) in the PROWESS trial (30.7 percent placebo vs. 27.8 percent APC) [7] when compared to the overall study population (30.8 percent placebo vs. 24.7 percent APC). [1] In the ADDRESS trial, patients with recent surgery and single organ dysfunction who received APC had significantly higher 28-day mortality rates (20.7 percent vs. 14.1 percent, p=0.03, n=635). [4]

Serious adverse events did not differ in the studies [1,4,5] with the exception of serious bleeding, which occurred more often in the patients treated with APC: PROWESS, 2 percent vs. 3.5 percent (p=0.06) [1]; ADDRESS, 2.2 percent vs. 3.9 percent (p<0.01) [4]; and ENHANCE, 6.5 percent (open label). [5] 

Intracranial hemorrhage (ICH) occurred in the PROWESS trial in 0.1 percent (placebo) and 0.2 percent (APC) (n.s.) [1]; in the ADDRESS trial 0.4 percent (placebo) vs. 0.5 percent (APC) (n.s.) [4]; and in the ENHANCE trial 1.5 percent. [5] Registry studies of rhAPC report higher bleeding rates than randomized controlled trials, suggesting that the risk of bleeding in actual practice may be greater than reported in PROWESS and ADDRESS. [8,9]

The two RCTs in adult patients were methodologically strong, precise, and provide direct evidence regarding death rates. The conclusions are limited, however, by inconsistency that is not adequately resolved by subgroup analyses (thus the designation of moderate quality evidence). Results, however, consistently fail to show benefit for the subgroup of patients at lower risk of death, and consistently show increases in serious bleeding. The RCT in pediatric severe sepsis failed to show benefit and has no important limitations. Thus, for low risk and pediatric patients, the 2008 Surviving Sepsis Campaign Guidelines rate the evidence as high quality. 

For adult use there is probable mortality reduction in patients with clinical assessment of high risk of death, most of whom will have APACHE II >25 or multiple organ failure. There is likely no benefit in patients with low risk of death, most of whom will have APACHE II <20 or single organ dysfunction. The effects in patients with more than one organ failure who have APACHE II <25 are unclear, and in that circumstance one may use clinical assessment of the risk of death and number of organ failures to support a treatment decision. There is a certain increased risk of bleeding with administration of rhAPC, which may be higher in surgical patients and in the context of invasive procedures. Decision on utilization depends upon assessing likelihood of mortality reduction versus increases in-bleeding and cost. 

A European Regulatory mandated randomized controlled trial of rhAPC vs. placebo in patients with septic shock is now ongoing. [10]

References:

1. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. New England Journal of Medicine. 2001;344:699–709.
2. Manns BJ, Lee H, Doig CJ, et al. An economic evaluation of activated protein C treatment for severe sepsis. New England Journal of Medicine. 2002;347:993–999.
3. Angus DC, Linde-Zwirbie WT, Clermont G, et al. Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Critical Care Medicine. 2003;31:1–11.

4. Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M, Rea-Neto A, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. New England Journal of Medicine. 2005; 353:1332-1341.

5. Vincent JL, Bernard GR, Beale R, et al. Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: Further evidence for survival and safety and implications for early treatment. Critical Care Medicine. 2005;33:2266-2277.

6. Oxman AD, Guyatt GH. A consumer's guide to subgroup analyses. Annals of Internal Medicine. 1992;116:78-84.

7. Ely EW, Laterre PF, Angus DC, Helterbrand JD, Levy H, Dhainaut JF, Vincent JL, Macias WL, Bernard GR. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Critical Care Medicine. 2003;31:12-19.

8. Kanji S, Perreault MM, Chant C, et al. Evaluating the use of Drotrecogin alfa activated in adult severe sepsis: A Canadian multicenter observational study. Intensive Care Medicine. 2007;33:517-523.

9. Bertolini G, Rossi C, Anghileri A, et al. Use of Drotrecogin alfa (activated) in Italian intensive care units: The results of a nationwide survey. Intensive Care Medicine. 2007;33:426-434.

10. European Medicines Agency (EMEA). Committee for Medicinal Products for Human Use February 2007 Plenary Meeting Monthly Report. EMEA/85096/2007. London, 2 March 2007. Available at: www.emea.europa.eu/pdfs/human/press/pr/8509607en.pdf.

Content adapted extensively from:

• Dellinger, RP, Levy, MM, Carlet, JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Critical Care Medicine. 2008;36(1):296-327.
• Fourrier F. Recombinant human activated protein C in the treatment of severe sepsis: An evidence-based review. Critical Care Medicine. 2004;32(Suppl.):S534–S541.