FEATURE ARTICLES

Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis

Ely, E. Wesley MD, MPH; Laterre, Pierre-François MD; Angus, Derek C. MD, MPH; Helterbrand, Jeffrey D. PhD; Levy, Howard MBBCh, PhD; Dhainaut, Jean-François MD, PhD; Vincent, Jean-Louis MD, PhD; Macias, William L. MD, PhD; Bernard, Gordon R. MD for the PROWESS Investigators

Author Information

From the Division of Allergy, Pulmonary and Critical Care Medicine and the Center for Health Services Research (EWE, GRB), Tennessee Valley Veteran’s Affairs Geriatric Research Education and Clinical Center (EWE), Vanderbilt University School of Medicine, Nashville, TN; Department of Critical Care and Emergency Medicine, Cliniques Universitaires St. Luc, Brussels, Belgium (PFL); Department of Critical Care Medicine, Clinical Research, Investigation and Systems Modeling of Acute Illness Laboratory, University of Pittsburgh School of Medicine, Pittsburgh, PA (DCA); Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (JDH, HL, WLM); Department of Intensive Care, Cochin Port-Royal University-Hospital, AP-HP, Paris V University, Paris, France (JFD); Department of Intensive Care, Erasme University Hospital, Free University of Brussels, Brussels, Belgium (JLV).

Dr. Ely is funded by the Paul Beeson Faculty Scholar Award for Study of Aging and the National Institute of Aging, grant AG01023-01A1.

Supported by Eli Lilly and Company. Drs. Ely, Laterre, Angus, Dhainaut, Vincent, and Bernard received institutional grant support and honorariums as consultants to Eli Lilly. Drs. Levy, Macias, and Helterbrand are employees and stockholders of Eli Lilly.

Address requests for reprints to: E. Wesley Ely, MD, Division of Allergy/Pulmonary/Critical Care Medicine, Tennessee Valley Veteran’s Affairs Geriatric Research Education and Clinical Center (GRECC), Vanderbilt University Medical Center for Health Services Research, 6th Floor Medical Center East 6109, Nashville, TN 37232-8300. E-mail: [email protected]

Drotrecogin alfa (activated) seems to be a major advance in our therapeutic armamentarium for patients with severe sepsis.

Critical Care Medicine 31(1):p 12-19, January 2003.

Abstract

Objective

To assess the effects of drotrecogin alfa (activated) therapy, a recombinant human activated protein C, across clinically relevant subpopulations in a randomized, phase 3, placebo-controlled study of patients with severe sepsis (recombinant human activated protein C worldwide evaluation in severe sepsis [PROWESS]).

Design

Univariate and multivariable analysis of prospectively defined subgroups from the PROWESS study.

Setting

A total of 164 medical centers in 11 countries.

Patients

A total of 1,690 patients with severe sepsis.

Measurements and Main Results

We report observed 28-day mortality rates for drotrecogin alfa (activated) and placebo patients for subgroups prospectively defined by demographic data, surgical status, type and site of infection, and clinical and biochemical measures of disease severity. We performed subgroup analyses to explore the consistency of the mortality benefit observed in the overall population and performed tests for both quantitative and qualitative interactions. To examine the magnitude of the treatment benefit with drotrecogin alfa (activated) across the underlying predicted risk of mortality spectrum, we used stepwise logistic regression on PROWESS placebo patients to generate a predicted risk of mortality model that simultaneously included many clinical and biochemical markers of mortality risk. Because drotrecogin alfa (activated) has anticoagulant properties, we also present analyses of bleeding and thrombotic events. Actual mortality rates were lower with drotrecogin alfa (activated) compared with placebo for nearly all prospectively defined subgroups. Both univariate and multivariable regression analyses showed a consistent relative risk reduction in 28-day mortality rates for drotrecogin alfa (activated). Larger absolute risk reductions were found with drotrecogin alfa (activated) in patients with a higher baseline predicted risk of mortality, and actual mortality rates were lower with drotrecogin alfa (activated) in all subgroups defined by disease severity measures where a ≥20% placebo mortality was observed. Although discriminatory power was limited by few observed events, the increased absolute risk of experiencing a serious bleeding event with treatment did not seem to vary according to the baseline predicted risk of mortality.

Conclusions

The administration of drotrecogin alfa (activated) to patients with severe sepsis was associated with a significant survival benefit that tended to increase with higher baseline likelihood of death. Current data suggest that the increased risk of bleeding does not vary according to likelihood of death.

Article Keywords

Keywords
drotrecogin alfa (activated), activated protein C, Xigris, severe sepsis, subgroups, Acute Physiology and Chronic Health Evaluation

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Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis