INTRODUCTION: Drotrecogin alfa (activated; recombinant activated protein C) was shown to reduce 28-day all-cause mortality in patients with severe sepsis and to have an acceptable safety profile in 1690 patients studied in the F1K-MC-EVAD (PROWESS) trial. We analyzed all available data on the safety of treatment with drotrecogin alfa (activated) in 2786 adult patients with severe sepsis enrolled in all phase 2 and 3 clinical trials, and in an estimated 3991 patients receiving the drug in commercial use.
PATIENTS AND METHOD: Mortality and safety analyses were performed on all available data from adult severe sepsis patients enrolled in seven clinical trials as of 12 April 2002. Trial-specific safety data and spontaneously reported serious adverse events from commercial use were extracted from a pharmacovigilance database.
RESULTS: The 28-day mortality rate for all adult patients who received active treatment in all clinical trials was 25.3% (704/2786). Serious bleeding events during the infusion period and 28-day study period occurred in 2.8% (79/2786) and 5.3% (148/2786) of patients, respectively. Of bleeding events during the infusion period, 43% (34/79) were procedure-related. Fatal serious bleeding events during the infusion period occurred in 0.4% (12/2786) of cases. Intracranial hemorrhage (ICH) events during the infusion period and 28-day study period occurred in 0.6% (16/2786) and 1.1% (32/2786) of patients, respectively. Ten out of the 16 ICH events occurring during the study drug infusion period were associated with severe thrombocytopenia (<or= 30000/mm3) and/or meningitis. Serious bleeding and ICH events spontaneously reported from commercial use (n = 3991) occurred in 0.9% and 0.2% of patients, respectively.
CONCLUSION: Drotrecogin alfa (activated) significantly reduces mortality in severe sepsis. The efficacy and safety profiles of drotrecogin alfa (activated) have remained consistent over the conduct of multiple clinical trials. The most important serious adverse event associated with drotrecogin alfa (activated) treatment is bleeding. Additional clinical experience indicates that invasive procedures are associated with a substantial percentage of serious bleeding events, particularly those occurring at the start of infusion of the drug. Severe thrombocytopenia (for all serious bleeding events, including ICH) and meningitis (for ICH only) may be risk factors for serious bleeding. However, patients with severe thrombocytopenia and/or meningitis may be at greater risk for bleeding or ICH in the absence of drug therapy.
INTRODUCTION:
In the pivotal PROWESS trial, treatment with drotrecogin alfa (activated) [DrotAA] improved survival and had a favorable benefit-risk profile compared to placebo in adult patients with severe sepsis receiving standard supportive care. A global open-label trial of DrotAA in severe sepsis, ENHANCE, has recently been completed. Reported are 28-day mortality and safety-related observations during the study drug infusion period. Results are compared to PROWESS.METHODS:
Inclusion/exclusion criteria and the definition of serious adverse events (SAE) were virtually identical to PROWESS. SAE bleeding rates, including intracranial hemorrhage (ICH), during the study drug infusion period (4 days infusion + 1 day) was determined and all-cause mortality assessed at day 28.RESULTS:
There were 2378 adult patients enrolled at 400 sites in 25 countries.The majority of SAE bleeding events were adjudicated as being procedure related. The ICH rate during infusion was 0.6% (n=15) of which 5 (0.2%) were fatal. Meningitis or platelets < 40,000/mm3 were present in 5/15 (33%) and 4/15 (27%) of ICH cases, respectively. Meningitis and/or platelets <40,000/mm3 occurred in 8/15 (53%) patients. In comparison, placebo-treated and DrotAA-treated patients in PROWESS had ICH rates of 0% and 0.2% (n=2), of which both were fatal.CONCLUSIONS: Overall 28-day mortality was similar between ENHANCE and the DrotAA arm of PROWESS. The SAE bleeding rate was numerically greater in ENHANCE than in PROWESS with many events being considered procedure related. The ICH rate during infusion was 0.6%. Consistent with previous reports, meningitis and severe thrombocytopenia are potential risk factors. The favorable benefit-risk profile observed in the DrotAA treated subjects of PROWESS is reinforced by the data from Global ENHANCE.CLINICAL IMPLICATIONS:
Results of the Global ENHANCE trial provide further support for the favorable benefit-risk ratio observed in the PROWESS trial.
Global ENHANCE (DrotAA) (n = 2378)PROWESS (DrotAA) (n = 850)PROWESS (Placebo) (n = 840)28-Day mortality25.3% (n=600)24.7% (n=210)30.8% (n=259)SAE bleeding rate during infusion period3.8% (n=91)2.4% (n=20)1.0% (n=8)DISCLOSURE:
R. Beale, None. Eli Lilly and Company (Indianapolis, IN) provided support for this research.
PURPOSE:
Treatment with drotrecogin alfa (activated) [DrotAA] and standard supportive care in a phase 3 clinical trial conducted at 164 sites in 11 countries was found to be associated with a significant mortality reduction and favorable benefit-risk profile compared to placebo and standard supportive care in adult patients with severe sepsis (PROWESS; DrotAA n = 850; placebo n = 840). We now report baseline characteristics and mortality from a global, single-arm, open-label trial of DrotAA in adult patients with severe sepsis conducted at 400 sites in 25 countries (ENHANCE, n=2378).METHODS:
Inclusion and exclusion criteria were virtually identical to PROWESS. All-cause mortality was assessed at study day 28. Patients eligible for participation had known or suspected infection, 3 or 4 of the criteria defining the systemic inflammatory response syndrome, and 1 or more acute (<48 hr duration) organ dysfunctions. Patients at high risk for bleeding were excluded from participation.RESULTS:
VariableENHANCE (DrotAA) (N = 2378)PROWESS (DrotAA) (n = 850)PROWESS (Placebo) (n = 840)Baseline CharacteristicsAge (years; mean (SD))59 (17)60 (17)61(16)Males (%)585658APACHE II (mean (SD))22.0 (7.4)24.6 (7.6)25.0 (7.8)Acute Physiology Score (mean (SD))18.6 (7.1)20.2 (7.1)20.5 (7.1)Organ Dysfunctions (mean (SD))2.7 (1.1)2.4 (1.1)2.4 (1.1)≥2 Organ Dysfunctions (%)84.374.675.9≥3 Organ Dysfunctions (%)54.642.843.4Ventilator Support (%)82.073.377.6Vasopressor Support (%)73.771.875.528-Day MortalityOverall (%)25.324.730.8Only countries in both studies* (%)23.4 (n=1478)24.7 (n=814)31.7 (n=805)*Results for countries in common to both ENHANCE and PROWESSCONCLUSIONS: DrotAA patients in ENHANCE tended to have lower APACHE scores but more organ dysfunctions at baseline compared with placebo patients in PROWESS. Overall mortality was similar for DrotAA-treated patients in ENHANCE and PROWESS and lower than for patients receiving placebo. These data indicate that the treatment effect associated with DrotAA remains robust despite the increase in number of countries and investigative sites participating in clinical studies.CLINICAL IMPLICATIONS:
An increase in survival can be expected with the use of drotrecogin alfa (activated) in adult patients with severe sepsis.DISCLOSURE:
A.P. Wheeler, None. Eli Lilly and Company (Indianapolis, IN) provided support for this research.
