SAN DIEGO – Findings from studies recently completed or nearing completion should help better inform clinicians about the use of an anticoagulation strategy for patients with sepsis, Dr. Steven P. LaRosa said at the annual congress of the Society of Critical Care Medicine.
Dr. Steven P. LaRosa
"There are multiple reasons why one would think that an anticoagulant drug may be effective in sepsis," said Dr. LaRosa, director of the Ocean State Clinical Coordinating Center at Rhode Island Hospital, Providence. "Cytokine release can cause the elaboration of tissue factor and the activation of the coagulation system, resulting in fibrin formation. Endogenous anticoagulants such as antithrombin and activated protein C [APC] are rapidly consumed and depleted, losing another homeostatic mechanism. Fibrinolysis is impaired through the activation of plasminogen activator inhibitor-1."
The APC drotrecogin alfa (activated) (Xigris) has been approved for severe sepsis since 2001, but its effectiveness is in question, Dr. LaRosa said. Subgroup analysis from the randomized, placebo-controlled, phase III clinical trial of Xigris versus placebo found that patients with vasopressor-dependent shock and one sign of organ hypoperfusion had a greater than 7% absolute reduction in mortality with Xigris use (Intensive Care Med. 2008;34:1935-47). This supported findings from an earlier human endotoxin challenge model of APC (Shock 2004;21:222-9). In that model, "the only real effect we saw with APC was maintenance of blood pressure in the volunteers who received APC compared with placebo," said Dr. LaRosa, who is also assistant professor of medicine at Brown University’s Alpert Medical School in Providence.
These developments led to the PROWESS-SHOCK trial, a confirmatory study that is enrolling patients with septic shock who require vasopressors despite adequate fluid resuscitation and who have associated hypoperfusion. The study was initially sized at 1,500 patients, Dr. LaRosa said, "but the size had to be increased because of a low aggregate mortality. The trial is expected to end sometime in the summer of 2011."
A study presented at a poster session by Dr. LaRosa and Dr. Andre Kalil of the same center examined all of the observational cohort studies that have been done since the approval of Xigris for sepsis. Combined, the studies enrolled more than 42,000 patients. "We saw a 17% relative risk reduction with APC, which was highly statistically significant," Dr. LaRosa reported. "So while we’re waiting for the randomized, controlled confirmatory trial, I think the observational trials do give us some assistance in deciding on the use of the drug."
Another anticoagulation strategy for sepsis patients involves the use of recombinant soluble thrombomodulin (ART-123). Manufactured by Artisan Pharma and currently available for use in Japan, ART-123 "is a thrombin scavenger and an activator of APC," Dr. LaRosa said. "It also blocks high-mobility group protein B1’s binding to the receptor for advanced glycation endoproducts, and it has multiple effects of inhibiting the complement cascade."
In a phase II, placebo-controlled trial, 234 patients received ART-123 0.06 mg/kg over 30 minutes once daily or heparin 8 U/kg per hour for 24 hours (J. Thromb. Haemost. 2007;5:31-41). They were treated for 6 days. "These were all-comers with disseminated intravascular coagulation [DIC] due to malignancy or infection," Dr. LaRosa said. "The treatment effect resided in patients with infection-induced DIC, such that they had a greater than 6% absolute reduction in mortality."
This led to a larger phase II study that enrolled 750 patients. The trial was completed in April 2010, but the results are not yet available, Dr. LaRosa said.
Another molecule starting to be targeted clinically in humans with sepsis is vascular endothelial growth factor (VEGF). This molecule "clearly increases vascular dilation and permeability, induces the expression of cell adhesion molecules, and upregulates tissue factor RNA," Dr. LaRosa said. "High levels of VEGF in humans with sepsis correlate with increased vascular permeability, poor outcome, and disease severity."
In February 2010 a multicenter trial of bevacizumab (Avastin) was launched in 20 patients with septic shock. Bevacizumab is a humanized monoclonal antibody directed against VEGF. "This drug binds to VEGF and impairs angiogenesis," he said. "It’s approved for use in breast, lung, and colon cancer. It has a long half-life, and its chief side effect is hypertension."
The patients received placebo or bevacizumab IV 10 mg/kg over the course of 90 minutes. "The estimated completion date was January 2011, so the results are not yet available," he said.
P2Y12 ADP-receptor antagonists may also play a role in the future of care for sepsis patients. A placebo-controlled, healthy human endotoxin challenge model with prasugrel was launched in November 2009 to examine coagulation activation and platelet-leukocyte interactions, Dr. LaRosa said. The trial was to be completed in June 2010, but its results have not yet been reported.