The Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial is the only phase III study that has evaluated the efficacy and safety of rh-APC (drotrecogin alfa [activated]; Xigris, Eli Lilly Inc., Indianapolis, IN) in patients with severe sepsis. The PROWESS trial was a prospective, randomized, double-blind, placebo-controlled, multicenter study involving 164 medical centers in 16 countries. The primary study end point was the effect of drotrecogin alfa (activated) on 28-day, all-cause mortality. Secondary end points included a pharmacokinetic analysis of the drug, an evaluation of the impact of drotrecogin alfa on organ function, and a comprehensive safety analysis.
To be enrolled in PROWESS, patients had to have severe sepsis based on a modified version of the ACCP-SCCM 1992 guidelines. Patients were required to have a documented or suspected infection, have at least three SIRS criteria, and have evidence of at least one acute (< 24 hrs) organ dysfunction. Specifically, the PROWESS inclusion criteria were as follows:
Patient was known or suspected to have infection with at least one of the following:
White blood cells present in a sterile site
Radiographic evidence of pneumonia plus purulent sputum
High risk for infection (e.g., ascending cholangitis)
Modified SIRS criteria:
Patient had at least three of the following four criteria:
Temperature of 38°C or higher, or 36°C or lower.
Heart rate of at least 90 beats/minute (unless drug- or disease-induced alteration).
Respiratory rate of at least 20 breaths/ minute or partial pressure of oxygen (PaCO2) of 32 mm Hg or less, or mechanical ventilation.
White cell count of 12 x 103/mm3 or greater, or 4 x 103/mm3 or less, or greater than 10% immature neutrophils.
Organ or system dysfunction:
Patient had at least one of the following five criteria:
Cardiovascular: systolic blood pressure of 90 mm Hg or less, or mean arterial pressure of 70 mm Hg or less for at least 1 hour, despite adequate fluid resuscitation, adequate intravascular volume, or use of vasopressors.
Renal: urine output less than 0.5 ml/kg/hour for 1 hour despite adequate fluid resuscitation.
Respiratory: ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO2:FIO2) of 250 or less if other organ dysfunction, or 200 or less if the lung was the only dysfunctional organ.
Rhematologic: platelet count of 80 x 103/mm3 or less, or a decrease by 50% in the preceding 3 days.
Unexplained metabolic acidosis: pH of 7.30 or less, or base deficit of at least 5 mmol/L with lactate more than 1.5 times above the upper limit of normal.
The investigators also chose explicit exclusion criteria, specifically targeting those patients who might not be evaluable (e.g., futile prognosis) or at increased risk for experiencing drotrecogin alfa-induced bleeding (e.g., hemorrhagic stroke, major trauma, thrombocytopenia, and recent thrombolytic, antiplatelet, or anticoagulant therapy). The complete list of exclusion criteria was as follows:
Patient was pregnant or breast-feeding.
Patient was younger than 18 years or weighed more than 135 kg.
Platelet count was less than 30 x 103/mm3.
Patient had a known hypercoagulable condition:
Hereditary protein C, protein S, or antithrombin III deficiency.
Anticardiolipin or antiphospholipid antibody.
Recent or highly suspected pulmonary embolism or deep venous thrombosis (within 3 mo).
Patient had a condition that increased the risk of bleeding:
Surgery with general or spinal anesthesia within 12 hours.
Potential need for surgery during the infusion.
Active postoperative bleeding.
Severe head trauma.
Intracranial surgery or stroke within 3 months.
Arteriovenous malformation, cerebral aneurysm, or mass lesion in the central nervous system.
Congenital bleeding diatheses.
Gastrointestinal bleeding within 6 weeks (except if corrected by surgery).
Trauma with increased risk of bleeding.
Futility -- patient was not expected to survive more than 28 days; advance directive, moribund state with imminent death.
Patient was positive for the human immuno-deficiency virus with CD4+ count of 50/mm3 or less.
Patient had chronic renal failure requiring dialysis (acute renal failure permitted).
Patient underwent transplantation -- bone marrow, liver, pancreas, lung, or small bowel (kidney transplant permitted).
Patient had portosystemic hypertension, jaundice, cirrhosis, or chronic ascites.
Patient had acute pancreatitis without a source for infection.
Patient had participated in another investigational study within 30 days.
Patient was receiving any of the following drugs or regimens:
Unfractionated heparin within 8 hours before the infusion (prophylactic heparin up to 15,000 U/day was permitted).
Low-molecular-weight heparin within 12 hours (prophylactic doses permitted).
Warfarin within 7 days before the infusion, and if the prothrombin time exceeded the upper limit of normal.
Acetylsalicylic acid more than 650 mg/day within 3 days before the study.
Thrombolytic therapy within 3 days before the study (catheter clearance doses permitted).
Glycoprotein IIb-IIIa antagonists within 7 days before the study.
Antithrombin III with dose greater than 10,000 U within 12 hours before the study.
Protein C within 24 hours of the study.
With use of a block randomization strategy, patients were randomly assigned to receive an infusion of either drotrecogin alfa (24 µg/kg/hr for 96 hrs) or placebo. Drotrecogin alfa therapy was initiated no later than 24 hours after all the study criteria were fulfilled. Patients were monitored for 28 days after the initiation of the study drug, or until they expired. All outcomes were analyzed by using an intention-to-treat approach.
After the second interim analysis (1690 patients), study enrollment was suspended after a statistically significant mortality benefit was observed. At 28 days, 24.7% of the patients who received drotrecogin alfa died compared with 30.8% of patients who received placebo (absolute risk reduction of 6.1%, relative risk reduction of 19.4%, p=0.005). A number-needed-to-treat analysis suggests that one life could be saved for every 16 patients treated with drotrecogin alfa.
At baseline, treatment and control groups were found to be similar with respect to demographics, severity of illness, and time from detection of first organ dysfunction to start of the drug infusion. Approximately 75% of patients had at least two dysfunctional organ systems at the time of enrollment. Eighty percent of patients were admitted to the ICU from home with the diagnosis of severe sepsis. The lung (54%) and abdomen (20%) were the most common sites of infection. Thirty-three percent of patients had a suspected infection without a positive culture. Of the 67% of patients with a positive culture, only 50% had documented bacteremia (33% of the total population). The prevalence rates of gram-positive and gram-negative infections were similar between treatment and placebo groups.
Baseline D-dimer concentrations (4.15-4.22 µg/ml, normal range 0-0.39 µg/ml) and serum IL-6 concentrations (484-497 pg/ml, normal range 0.38-10.09 pg/ml) were elevated across the study population and found to be equal between groups. Plasma D-dimer and IL-6 concentrations declined more rapidly in the drotrecogin alfa-treated group and were lower than baseline values in the first week after the start of therapy. This highlights drotrecogin alfa's potent antithrombotic and antiinflammatory effects.[48,49] Plasma protein C activity was depressed (48% of normal) in approximately 80% of patients at baseline and increased to an average of 74% of normal by day 4 after the start of therapy. Prothrombin time and activated partial thromboplastin time (aPTT) were also monitored during the infusion. Prothrombin time decreased over the duration of the infusion in a similar fashion in each group (from 18.5 to 16.1 sec in the drotrecogin alfa group vs from 18.1 to 15.5 sec in the placebo group, p>0.05). After an initial aPTT increase in the drotrecogin alfa group, aPTT declined more rapidly and to a greater extent in the placebo group (from 42 to 36 sec in the placebo group vs from 43 to 42 sec in the drotrecogin alfa-treated group, p<0.05).[48,49]
The mortality benefit did not differ between groups when patients were stratified by age, gender, severity of illness (acute physiology and chronic healthy evaluation [APACHE] II score), presence of various disease states (i.e., hypertension, liver disease, chronic obstructive pulmonary disease, malignancy, recent trauma, or surgery), baseline protein C activity, or baseline antithrombin and IL-6 concentrations.[50,51,52] Although no mortality benefit was observed with drotrecogin alfa when patients were stratified according to a history of myocardial infarction, this is likely the result of a statistical type I error because very few patients (267 patients) had this clinical history. When patients were stratified according to the number of dysfunctioning organ systems, no mortality benefit was observed in those patients with only one failing organ at enrollment. The reduction in mortality with drotrecogin alfa seems to increase relative to the number of organs that are failing. Absolute risk reductions in mortality for the patients with one, two, three, four, and five failing organs were 1.7%, 5.3%, 8.2%, 7.9%, and 21%, respectively. Note that PROWESS was not powered to evaluate these outcomes; thus, any conclusions are speculative and require confirmation through additional research.
Drotrecogin alfa has the potential, through its anticoagulant and thrombolytic activity, to induce bleeding complications. In the PROWESS trial, over the 28-day study period, more patients receiving drotrecogin alfa experienced serious bleeding (3.5%) than did patients receiving placebo (2.0%, p=0.06). This suggests that one of every 67 patients treated with drotrecogin alfa will experience a serious bleeding event. During the 96-hour infusion period, the prevalence of serious bleeding events was significantly greater in the drotrecogin alfa group than in the placebo group (2.4% vs 1.0%, p=0.024). Patients at the highest risk for bleeding complications (e.g., gastrointestinal ulceration, aPTT > 120 sec, international normalized ratio > 3, traumatic injury, or platelet count < 30 x 103/mm3) accounted for the majority of patients who experienced a bleeding event. Four fatal bleeding complications were observed in the drotrecogin alfa group, with each of these events occurring during the 96-hour infusion period. Only one patient in the placebo group experienced a fatal bleeding complication 6 days after the infusion. It is important to emphasize that serious bleeding still occurred during the PROWESS study despite the careful exclusion of patients with risk factors for bleeding.
A theoretical concern is that the mortality benefits of drotrecogin alfa may be associated with a morbidity penalty. Survivors of severe sepsis may have a compromised functional status and a subsequently prolonged ICU stay. A number of functionality and morbidity assessments were completed as part of the PROWESS study. The Therapeutic Intervention Scoring System (TISS) score (a measure of intensity of ICU care), the Sepsis-Related Organ Function Assessment (SOFA) score (a measure of organ dysfunction), and the Activities of Daily Living (ADL) score (a measure of functional status) were found to be equal between survivors in the drotrecogin alfa group and those in the placebo group. In fact, the numbers of vasopressor-free days (20.1 vs 18.8, p=0.014) and ventilator-free days (14.3 vs 13.2, p=0.049) were greater in the patients who received drotrecogin alfa therapy (Table 1).
The results of the PROWESS trial dramatically have changed the way many critical care practitioners view the pathogenesis and treatment of sepsis and MODS. The important relationship among inflammation, coagulation, and fibrinolysis in the patient with severe sepsis is now much more clearly defined. In comparison to previous phase III trials investigating new therapies for severe sepsis, the PROWESS trial is the first large, well-constructed study to demonstrate a significant mortality benefit.[9,55,56]
Pharmacotherapy. 2001;21(11) © 2001 Centers for Disease Control and Prevention (CDC)
Cite this: Recombinant Human Activated Protein C, Drotrecogin Alfa (Activated): A Novel Therapy for Severe Sepsis - Medscape - Nov 01, 2001.