MONTREAL — Recombinant human activated protein C can be a lifesaver for some of the sickest patients with community-acquired pneumonia, Gary E. Garber, M.D., said at an international conference on community-acquired pneumonia.

Yet despite evidence that the coagulation inhibitor reduces mortality in patients with severe sepsis and community-acquired pneumonia (CAP) as their infection source, clinicians have been slow to embrace activated protein C—or drotrecogin alfa (Xigris)—as an adjunctive therapy for this well-defined patient population, said Dr. Garber, head of the division of infectious diseases at the University of Ottawa and the Ottawa Hospital.

In the landmark 2001 Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, activated protein C (APC) reduced mortality from severe sepsis by nearly 20% among the 850 patients who received the drug, compared with the 840 patients given the placebo (N. Engl. J. Med. 2001;344:699–709). The findings led to FDA approval of the drug for adult patients who have a high risk of death due to severe sepsis associated with acute organ dysfunction.

In a retrospective analysis of the investigation, Dr. Garber and his colleagues determined that more than 35% of the study participants had CAP as their infection source, and of these, 26% had Streptococcus pneumoniae identified as the pathogen (Crit. Care Med. 2005;33:952–61).

Those CAP patients treated with APC had a 28% relative reduction in mortality, compared with those who received placebo. In patients with confirmed S. pneumoniae infections, “mortality fell from an absolute mortality of 32.9% to 20% with APC treatment,” representing about a 40% relative reduction in mortality, he said.

The drug also had a significant effect on morbidity: Treated patients experienced faster resolution of cardiovascular and respiratory dysfunction and had more vasopressor- and ventilator-free days alive, compared with placebo patients, Dr. Garber said.

Because of its anticoagulant properties, APC is associated with an increased risk of serious bleeding, especially for patients with a preexisting risk for bleeding, such as those with central nervous system lesions or severe thrombocytopenia. This risk is one of the psychological barriers to wider usage of the drug, he noted.

In the PROWESS trial, 3.5% of the treated patients experienced bleeding-related complications, compared with 2% of patients on placebo. In both the treatment and placebo groups, the bleeding was usually related to an invasive procedure. However, Dr. Garber pointed out that “bleeding is a major risk associated with severe sepsis. If monitored, it is easily managed and is not a contraindication to using APC.”

The drug is contraindicated in situations in which bleeding cannot be easily monitored; in patients with intracranial trauma or increased intracranial pressure; and in those who have had a recent epidural catheter, he said.

“In reality, when weighed against the benefit of keeping these patients alive, the slightly increased bleeding risk becomes less relevant,” Dr. Garber said at the conference, which was sponsored by the International Society of Chemotherapy. Uncertainties about patient selection and drug cost are also barriers to clinician acceptance of APC, although neither concern is scientifically supported, he said.

“It is not that difficult to determine which patients should be treated with APC. Patients with pneumonia and systemic inflammation clearly benefit,” he said, alluding to the retrospective PROWESS analysis; these data indicated that levels of interleukin-6—a strong negative prognostic marker in sepsis—dropped rapidly with APC treatment in septic CAP patients.

Specifically, “patients admitted to the [intensive care unit] with community-acquired pneumonia who require ventilatory and inotropic support will likely benefit from adjunctive treatment,” Dr. Garber said. “These patients are at high risk of death, and experience tells us that the relative benefit of APC increases with increased mortality [risk] and severity of underlying coagulopathy and inflammation.”

In terms of cost, a therapeutic course of APC in prototypic CAP patients with severe sepsis is more than twice that of tissue plasminogen activator (TPA), but it can save 6 out of every 100 lives, compared with 1 in 1,000 for TPA. “Instead of debating the role of APC in severe sepsis, we should be asking why TPA is the standard of care,” he said.

Other obstacles to acceptance of APC include a poor understanding of and lack of standardized treatment protocols for sepsis, particularly severe sepsis, the condition for which the drug is approved, Dr. Garber hypothesized. He has served as an advisor for the drug's manufacturer, Eli Lilly & Co.

Perceived barriers notwithstanding, “in well-defined patient populations like CAP in the intensive care unit, APC should, without question, become a regular part of our treatment strategies,” he said.

Toward this end, clinicians need to be better educated ion the management of severe sepsis in community-acquired pneumonia, Dr. Garber said.

Activated Protein C Seen as Underused in Sepsis, Pneumonia