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 Surviving Sepsis Campaign Guidelines Committee, there was no industry input into guidelines development and no industry presence at any of the meetings. Industry awareness or comment on the recommendations was not allowed. The sponsors of the educational grants did not see the recommendations 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:
Drotrecogin Alfa (Activated), a.k.a. recombinant activated protein C (rhAPC), is recommended in patients at high risk of death (APACHE II of > 25, sepsis-induced multiple organ failure, septic shock, or sepsis-induced acute respiratory distress syndrome) and no absolute contraindication related to bleeding risk or relative contraindication that outweighs the potential benefit of rhAPC. In Europe, rhAPC is indicated for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care.
The inflammatory response in severe sepsis is integrally linked to pro-coagulant activity and endothelial activation. The inflammatory response in sepsis is pro-coagulant in the early stages. In a large, multicenter, randomized, controlled trial, the PROWESS trial (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) rhAPC, an endogenous anticoagulant with anti-inflammatory properties, has been shown to improve survival in patients with sepsis-induced organ dysfunction. [1]
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 is essential to avoid capricious and unscientific decision-making about applying rhAPC. See Interim Drotrecogin Alfa (Activated) Administration Policy for a policy that may be used until your intensive care unit or hospital may adopt one.
Given the uncertainty of risk assessment and the potential for rapid deterioration of patients with severe sepsis and septic shock, once a patient has been identified as at high-risk of death, treatment should begin as soon as possible. Further inclusion and exclusion criteria are discussed 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. 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 the European community, 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). There are practical and methodologic limitations of the APACHE II score, which was not designed and is not used to manage individual patients usually.
Nevertheless, the observed mortality difference between the treatment and the placebo groups seemed limited to the patient population with the higher risk of death, assessed by a baseline APACHE II score of 24 or by two or more organ dysfunctions. [1,2,3] As a whole, the trial and subgroup analysis were consistent with a significant reduction of mortality in the more severely ill patients. In addition, the subsequent analysis of long-term survival after the 1-yr survey revealed that the reduction of mortality was most evident in patients at high risk of death as assessed by the APACHE II score, with a significant increase in median survival of 13 months (71 days vs. 430 days, p = .0005). [4,5]
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. [6,7]
PROWESS Exclusion Criteria:
For safety and evident reasons in a phase 3 study, many patients could not be included in the PROWESS trial. Therefore, the effect of rhAPC is not documented in patients affected by a morbid obesity, admitted in intensive care unit in moribund state and almost certain likelihood to die, in children, and in pregnant women. Due to the possibility of misleading inclusion criteria, patients with acute pancreatitis were not included in the trial. This was also the case for 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 PC, PS, or antithrombin, known anticardiolipin antibody, lupus anticoagulant, and homocystinemia) were considered as non-inclusion criteria.
PROWESS Trial Results:
The PROWESS trial was a phase 3, multinational, double-blind, placebo-controlled trial evaluating 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. The trial 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 = .005); and range of number needed to treat, 16–54. Subsequent analysis of the long-term efficacy could document a significant reduction of in-hospital mortality (29.4 percent vs. 34.6 percent in the placebo group) without an increase in hospital length of stay. [4,5]
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. Bleeding was the most frequent adverse event observed in the PROWESS trial. [1,2,8] As a whole, the incidence of bleeding events was 24.9 percent in the rhAPC group vs. 17.7 percent in the placebo group (p < .001).
The risk of bleeding events should be carefully weighed by the initial clinical and biological evaluation of the patient or according to the anticipated therapeutic modalities, with special reference to surgery and invasive procedures, frequently needed in severely ill patients. Although rarely observed, intracranial bleeding is the most severe bleeding event that could be observed in clinical studies. In the PROWESS trial and subsequent open studies, the main risk factors of intracranial bleeding were a severe thrombocytopenia and a meningeal infection.
The following practical recommendations should be observed to reduce the risk of bleeding events:
- In patients at risk requiring planned surgery or invasive procedures, rhAPC should not be administered until 12 hours after surgery or a major invasive procedure.
- Thanks to the short half-life of the molecule, cessation of infusion should restore the previous level of hemostasis within 2 hours. [9,10] Thus, the treatment should be stopped 2 hrs before any surgical procedure. For less invasive procedures, the infusion should be stopped 2 hours before and could be restarted 2 hours after.
- Patients with severe thrombocytopenia seem to carry a special risk of severe bleeding events. The general risk of bleeding induced by a thrombocytopenia of < 30,000/mm3 and the lack of effect of rhAPC on platelet count support the following recommendations:
- 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.
Administration in Overt DIC:
Patients with DIC should be considered for urgent treatment with rhAPC provided that the risk of bleeding events seems acceptable. Based on expert opinion, an increase in adverse bleeding events is unlikely except in severe consumption coagulopathy (platelets < 30,000/mm3; fibrinogen < 1,000/mm3; prothrombin time < 30 percent). Platelets count should be carefully monitored in DIC treated patients because rhAPC has no documented effect on thrombocytopenia.
Interactions with Heparin and Warfarin:
There are recent biological data supporting the possibility of a heparin–rhAPC interaction. The observed relative risk reduction in 28-day all-cause mortality for the rhAPC treatment group in PROWESS compared with the placebo group was greatest for patients not exposed to heparin (39.91 percent) vs. patients exposed to heparin (11.31 percent). The observed 28-day all-cause mortality was not different in the rhAPC group between the patients who were exposed and those not exposed to heparin (24.92 percent vs. 24.07 percent). As a whole, the results of the PROWESS trial raise the possibility that heparin might reduce the efficacy of rhAPC. [1,11,12]
In addition, due to the effect of all anti–vitamin K compounds on PC and PS liver synthesis, patients recently treated by warfarin (within 7 days) should not receive rhAPC. However, the results of the PROWESS trial were unable to document a link between the occurrence of bleeding events and the increase in APTT, prothrombin time, or the international normalized ratio level.
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