Venous and arterial thromboembolism in severe sepsis.

The burden of thromboembolism (TE) in severe sepsis is largely unknown. We assessed the prevalence of venous and arterial TE in patients with severe sepsis over a four-week period. We performed a retrospective analysis of a pooled database of three randomized, placebo-controlled trials of two novel pharmacological agents for the treatment of severe sepsis, drotrecogin alfa (activated) (DrotAA) and secretory phospholipase A2 inhibitor (sPLA(2)I). The study was conducted at intensive care units of the participating institutions. A total of 2,649 patients with known or suspected infection and sepsis-associated acute organ dysfunction were enrolled in the three trials and were assigned to treatment groups (DrotAA=850; sPLA2I=578; placebo=1221). The database was queried for venous and arterial TE, using investigator reports of serious adverse events. Eighty-four of 2,649 patients (3.2%; 95% confidence interval, 2.5% to 3.9%) developed at least one thromboembolic event over 28 days. Nearly three-quarters of episodes were atheroembolic (n=62); 25% involved the deep venous system (n=25). Ischemic stroke (n=30) and venous thromboembolism (n=25) each occurred in about 1% of patients. Ischemic stroke and acute coronary syndrome had a higher peak incidence during the first five days compared to venous TE onset, which was more constant over the 28-day period. Subgroup analysis by pooled treatment groups yielded TE rates of 2.0% (DrotAA), 3.5% (placebo), and 4.0% (sPLA2I), respectively. Clinically manifest TE occurred in about 3% of severe sepsis patients treated in the intensive care unit over a 28-day period. Arterial TE may be more common than previously recognized. More accurate estimates of TE prevalence and relationship to sepsis await future studies.

Treatment of heparin-induced thrombocytopenia with drotrecogin alfa (activated).

A patient was administered drotrecogin alfa (activated) in addition to the standard of care for presumed severe sepsis and circulatory shock. Heparin-induced thrombocytopenia (HIT) and hepatic and splenic thromboses complicated her clinical course. Because drotrecogin alfa (activated) treatment is associated with improvement in thrombotic manifestations and thrombocytopenia, it was continued as the sole antithrombotic agent after the HIT became apparent. This approach was chosen despite the patient's severe hepatic and renal dysfunction, which made the use of direct thrombin inhibitors unfavorable. She survived with a reasonable outcome and salvage of her limbs. Although this case suggests a potential role of drotrecogin alfa (activated) in the management of HIT, systematic evaluation of its efficacy in this situation is warranted.

Platelet glycoprotein IIb/IIIa antagonists: lessons learned from clinical trials and future directions.

Platelets play an important role in the pathophysiology of acute myocardial infarction, unstable angina, and ischemic stroke. The expression of the glycoprotein IIb/IIIa (alphaIIb/beta3 integrin) receptor on the surface of activated platelets constitutes the common pathway for platelet aggregation. Glycoprotein IIb/IIIa has low affinity for its soluble ligands (fibrinogen and von Willebrand factor) in resting platelets. In the setting of vascular injury, platelet activation occurs after binding of the glycoprotein Ib-IX-V receptor to von Willebrand factor in the extracellular matrix (at high shear rate) and binding of soluble agonists to specific platelet membrane receptors. The ensuing inside-out signaling increases several-fold the affinity and avidity of alphaIIb/beta3 for its ligands. High affinity ligand binding to alphaIIb/beta3 triggers outside-in signaling, causing microskeletal contraction and platelet retraction. The signaling pathways for inside-out and outside-in signaling are incompletely understood. Glycoprotein IIb/IIIa antagonists were developed under the premise that these agents would abrogate platelet aggregation while preserving platelet monolayer deposition at sites of injury. A number of parenteral and oral agents have been developed and evaluated in clinical trials. Three of them are approved in the United States and other countries: abciximab (ReoPro; the Fab fragment of a chimeric human-mouse antibody), eptifibatide (Integrelin; a cyclic heptapeptide), and tirofiban (Aggrastat; a tyrosine-derived nonpeptide molecule). The greatest clinical impact of these parenteral agents (used in conjunction with aspirin and heparin) has been in the prevention of ischemic complications after percutaneous coronary intervention. In contrast, oral agents have yielded disappointing results in the secondary prevention of acute coronary syndromes, and none of them are approved at present. Eptifibatide and tirofiban are specific for alphaIIb/beta3, whereas abciximab also exhibits cross-reactivity with the alphavbeta3 and alphaMbeta2 integrins. Although alphaIIb/beta3 is unique to platelets and megakaryocytes, alphavbeta3 is more widely distributed and mediates several functions, including endothelial cell migration, monocyte adhesion, angiogenesis, and inhibition of apoptosis. alphaMbeta2 mediates leukocyte-platelet interactions. In the percutaneous coronary intervention trials, abciximab has been more efficacious than the other parenteral agents, perhaps because of cross-reactivity with these other integrins, the pharmacodynamic profile of abciximab, or other effects. Other documented effects of abciximab include acute dethrombosis, reduction of thrombin generation, and improved flow in the coronary microcirculation after percutaneous coronary intervention. Abciximab is presently under evaluation in the treatment of acute ischemic stroke. Promising data have been obtained in experimental models of tumor angiogenesis and sickle cell anemia.

Measuring outcomes as a function of baseline severity of ischemic stroke.

BACKGROUND: The spectrum of neurological impairments following acute ischemic stroke is broad. The initial stroke severity predicts responses to treatment and outcomes after ischemic stroke. While clinical trials are using baseline severity as an enrollment criterion or a stratified variable, adjustment of outcome measures as a function of initial impairments has not been done. METHODS: We developed a responder analysis that defines favorable outcomes at 90 days as influenced by the baseline National Institutes of Health Stroke Scale (NIHSS). Favorable outcome was defined as a modified Rankin Scale (mRS) score of 0 if the baseline NIHSS score was <8, mRS score of 0-1 if the NIHSS score was 8-14, and mRS score of 0-2 if the NIHSS score was >14. The concept stemmed from the data of two European rtPA trials. The analysis is a predefined secondary endpoint in a trial testing abciximab. We also used the analysis to reexamine the Trial of Org 10172 in Acute Stroke Treatment data. RESULTS: The responder analysis did not change the overall results of any of the 3 previous trials, but it did give information about differences in responses among subgroups of patients. Evidence about the potential utility of tPA for treatment of patients with mild stroke appeared from the analysis of the second European trial of rtPA. The analysis also provided a hint of efficacy of abciximab. CONCLUSIONS: The responder analysis appears to be a potentially useful way to evaluate outcomes of patients enrolled in clinical trials in stroke. The results of the analysis have clinical relevance and can further explain differences in responses to therapies. In addition, the analysis allows for improved comparisons of results among clinical trials.