20 May 06

Drotrecogin plus heparin efficacious for adults with severe sepsis

Posted in rhAPC, Sepsis, Venous thromboembolism at 11:39 by Laci

Sepsis Late-Breaker: the EVBR Study

By Derek Angus, Frank Booth, Michael Matthay, Marcel Levi

SCCM 35th Critical Care Congress: Sepsis Late-Breaker. Presented Jan. 11, 2006. San Francisco

The Xigris and Prophylactic Heparin in Severe Sepsis (XPRESS) study was a phase 4 trial mandated by the FDA after subanalysis of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial suggested that heparin reduced the efficacy of drotrecogin.
The landmark PROWESS trial showed a significant decrease in mortality in severe sepsis with drotrecogin.

XPRESS was a multicenter, international study of approximately 1900 patients with severe sepsis who were receiving drotrecogin and at high risk for death. Patients were randomized to 1 of 3 treatment groups: mechanical thromboprophylaxis, unfractionated heparin, or low-molecular-weight heparin (enoxaparin) given in standard doses during the 96-hour drotrecogin infusion period.

Principal investigator Mitchell Levy, MD, FCCM, professor of medicine and director of the medical intensive care unit at Brown University in Providence, Rhode Island, delivered the findings. The primary end point was 28-day all-cause mortality. Secondary end points were any thrombotic event and safety and efficacy of the drug combination.

Twenty-eight-day mortality was unchanged in the 2 groups. Neither was the incidence of thrombotic events significantly different between the 2 groups, (drotrecogin plus heparin, 4.6% vs 5.1% in the control group. This was true both during the 96-hour infusion period and after 28 days of follow-up.
The primary end point of efficacy was similar between study and control groups of the study, with an absolute mortality rate of 31% across treatment groups after 28 days of follow-up. “In this high-risk group, that mortality rate is quite good,” Dr. Levy asserted.

“We are unable to conclude from this study whether drotrecogin plus heparin is any better than drotrecogin alone,” Dr. Levy noted. “This study was not designed to show that. What we can say is that physicians can safely add heparin without fear of a loss of efficacy with drotrecogin” in patients at high risk of deep vein thrombosis. Estimates show that approximately 85% to 90% of patients in intensive care units receive prophylactic heparin.
Because of the severity of their illness — often on mechanical ventilation and immobile — patients in this subgroup are also given heparin for thromboprophylaxis. “Heparin should be used in high-risk patients and PROWESS supports that,” Dr. Ely asserted.

Mark William, MD, associate medical director of the Xigris Product Team at Eli Lilly, told Mescape that “we can now reject the FDA hypothesis that adding heparin to [drotrecogin] reduces its efficacy…. What we found, though, was that if a patient was on heparin at the time [drotrecogin] was initiated, it was important for the patient to stay on it. Mortality was higher if heparin was stopped and restarted after [drotrecogin] was begun.”

Dr. Williams added that the combination of the 2 drugs did not result in a higher incidence of serious adverse effects, including bleeding, although the incidence of minor bleeding was increased in patients receiving dual therapy.

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