NASHVILLE, TENN--Drotrecogin alfa (activated)—a recombinant form of human activated protein C—has been shown to improve survival in patients with sepsis.[1]

In fact, enrollment in a phase III clinical trial of drotrecogin alfa (activated) was discontinued because an interim analysis found the drug to be clearly effective. It reduced the relative and absolute risks of death during the trial by 19.4% and 6.1%, respectively, in patients with severe sepsis.

There are approximately 750,000 cases of sepsis in the United States each year; at least 225,000 of them are fatal. Until now, however, none of the many drugs that have been investigated for use in sepsis patients have proved effective in lowering mortality.

"I would be greatly surprised if the FDA [Food and Drug Administration] does not approve this therapy," commented Steven M. Opal, MD, one of the study's Data and Safety Review Board members, in an interview with PULMONARY REVIEWS. "If the therapy is approved, I anticipate that it will be routinely used," said Dr. Opal, a Professor of Medicine in the Infectious Disease Division of Brown University School of Medicine in Providence, Rhode Island.

Because of the study's clinical implications, the results of the trial were released before their scheduled March 8 publication in the New England Journal of Medicine and are available on that journal's Web site.[1] Study results were also presented at the recent annual meeting of the Society of Critical Care Medicine, held in San Francisco.

A RECOMBINANT HUMAN PROTEIN

Activated protein C is best known for its role in the coagulation cascade--it encourages fibrinolysis--but it also appears to have important anti-inflammatory effects. In patients with severe sepsis, endogenous activated protein C levels are often deficient because of complex interactions among inflammatory cytokines, thrombomodulin, and other mediators. The deficiency in endogenous activated protein C levels is believed to contribute to the coagulopathy and excessive inflammation that characterize sepsis.

Drotrecogin alfa (activated) counteracts this deficiency, but it may do more as well. In the new study, mortality was decreased in the patients with normal baseline protein C levels, as well as in those with reduced levels, leading the researchers to postulate that the effect of drotrecogin alfa (activated) goes beyond simple replacement of activated protein C. This suggests, they say, that it may not be necessary to ascertain activated protein C levels to identify the patients with sepsis who would benefit from this therapy.

PERFORMED WELL IN PRIOR TRIALS

The drug protected against lethal Escherichia coli sepsis in a baboon model[2] and reduced levels of plasma D-dimer and serum interleukin (IL) 6-- markers of coagulopathy and inflammation, respectively--in a subsequent phase II trial of patients with severe sepsis.[3] This evidence was sufficient to justify the phase III trial, which was randomized, double-blinded, and placebo-controlled, and was conducted at 164 centers in 11 countries.

Enrollment occurred from July 1998 through June 2000. Patients were eligible if they had a known or suspected infection and met the following criteria within a 24-hour period:

• Three or more signs of systemic inflammation.

• Sepsis-induced dysfunction of at least one organ or system that had lasted no more than 24 hours.

Therapy consisted of drotrecogin alfa (activated) (24 µg/kg/h) or placebo for 96 hours. The infusions were stopped an hour before percutaneous procedures or major surgery and resumed one hour and 12 hours later, respectively, if there were no bleeding complications. Follow-up lasted 28 days after the start of therapy or until death.

For the primary statistical analysis, the patient groups were stratified according to baseline APACHE II score, age, and protein C level. The relative and absolute mortality rates were then calculated. Survival was also assessed in separate subgroup analyses of various baseline characteristics, including infection site, number of dysfunctional organs or systems, and presence or absence of protein C deficiency.

The study protocol did not require a standardized approach to the provision of other interventions, such as antibiotics, fluids, vasopressors, or ventilatory support.

COULD THIS BE A FUTURE STANDARD OF CARE?

The study population included 1,690 patients, 850 in the drotrecogin alfa (activated) group and 840 in the placebo group. At baseline, the two groups were similar in terms of demographics, disease severity, and indicators of inflammation and coagulopathy. They also had comparable rates and types of infection.

In both groups, the lungs and abdomen were the most common infection sites. About one third of patients in both groups had positive blood cultures, about one quarter had gram-positive infections, and one fifth had gram-negative infections.

Most of the patients had at least two dysfunctional organs or systems. Protein C deficiency was detected in almost 88% of the patients in whom such levels were measured. Virtually all patients had elevated D-dimer and IL-6 levels.

The vast majority of both groups got at least 90% of their assigned therapy. Mortality at 28 days was 24.7% in the drotrecogin alfa (activated) group and 30.8% in the placebo group--a significant difference. The efficacy of drotrecogin alfa (activated) was consistent regardless of the infection site, number of organ or system failures, or baseline protein C level.

BLEEDING MORE COMMON IN THE TREATMENT GROUP

The proportion of patients who had at least one serious adverse event was similar in both groups--approximately 12%. However, serious bleeding was significantly more common in the patients given drotrecogin alfa (activated) than in those who had been given placebo (3.5% vs 2.0%).

The difference in the rate of serious bleeding occurred only during the 96-hour infusion period; furthermore, only patients with an identifiable predisposition to bleeding, such as traumatic injury or gastro-intestinal ulceration, appeared to be affected. Coadministration of heparin had no effect on the bleeding rate.

No patients developed neutralizing antibodies to activated protein C. The incidence of thrombotic events was similarly low in both groups.

"[Drotrecogin alfa (activated)] will probably become a standard of care for severe sepsis not too far in the future,unless we see a peculiar toxicity or something else unexpected that did not appear in the clinical trials," speculated Dr. Opal, who is also the Director of the Infection Control Service at Memorial Hospital of Rhode Island in Pawtucket.

--Timothy Begany

References
1. Bernard GR, Vincent J-L, Laterre P-F, et al, for the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group. Efficacy and safety of recombinant human activated protein C for severe sepsis. Available at: http://www.nejm.com/content/bernard/1.asp. Accessed February 26, 2001.

2. Taylor FB Jr, Chang A, Esmon CT, et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest. 1987;79:918-925.

3. Hartman DL, Bernard GR, Helterbrand JD, et al. Recombinant human activated protein C (rhAPC) improves coagulation abnormalities associated with severe sepsis. Intensive Care Med. 1998;24(suppl 1):S77.

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