Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression

Kalil, André C.; LaRosa, Steven P.

doi:10.1016/s1473-3099(12)70157-3

Cited by 71 publications

(40 citation statements)

References 42 publications

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“…A subsequent retrospective multicenter cohort study of patients with septic shock, early use of APC was associated with 6.1% absolute reduction in 30 d mortality [38] . Another metaanalysis by Kalil et al [39] , noted a significant reduction in hospital mortality (18%), and increased bleeding rate (5.4%) with the real life use of APC compared with controls.…”

Section: Protein Cmentioning

confidence: 97%

Anticoagulant modulation of inflammation in severe sepsis

Allen

Sawheny

Kinasewitz

2015

WJCCM

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Inflammation and coagulation are so tightly linked that the cytokine storm which accompanies the development of sepsis initiates thrombin activation and the development of an intravascular coagulopathy. This review examines the interaction between the inflammatory and coagulation cascades, as well as the role of endogenous anticoagulants in regulating this interaction and dampening the activity of both pathways. Clinical trials attempting to improve outcomes in patients with severe sepsis by inhibiting thrombin generation with heparin and or endogenous anticoagulants are reviewed. In general, these trials have failed to demonstrate that anticoagulant therapy is associated with improvement in mortality or morbidity. While it is possible that selective patients who are severely ill with a high expected mortality may be shown to benefit from such therapy, at the present time none of these anticoagulants are neither approved nor can they be recommended for the treatment of sepsis.

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Section: Protein Cmentioning

confidence: 97%

Anticoagulant modulation of inflammation in severe sepsis

Allen

Sawheny

Kinasewitz

2015

WJCCM

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“…Clinical studies showed that recombinant wt-APC therapy increases risk for serious bleeding, [98][99][100] implying that APC mutants that have reduced anticoagulant activity but retain normal cell-signaling actions should enable APC therapies with reduced risk of bleeding complications. Preclinical studies of the signaling-selective APC mutants 5A-APC, 3K3A-APC, APC-2Cys, and K193E-APC, and of an anticoagulant-selective APC mutant, E149A-APC, have proved invaluable to clarify which of APC's 2 broad types of actions, namely anticoagulant or cytoprotective, is more important or essential for reducing injury in preclinical injury models (Table 2).…”

Section: Apc Variants: Preclinical Studiesmentioning

confidence: 99%

“…100,112 The PROWESS-SHOCK trial required by the European Medicines Agency was completed in 2011 and failed to show benefit for wt-APC for severe adult sepsis, 113 resulting in withdrawal of the drug from the market. Nonetheless, controversy is notable, and an extensive meta-analysis and metaregression of effectiveness and safety of wt-APC for sepsis covering .40 000 patients concluded that real-life use of wt-APC was more in line with the PROWESS trial than the PROWESS-SHOCK trial (see Kalil and LaRosa 99 and Christiaans et al 100 ). What are the lessons to be learned from clinical data from sepsis trials, including data for wt-APC?…”

Section: Apc: Translation To Clinical Therapiesmentioning

confidence: 99%

Activated protein C: biased for translation

Griffin

Zloković

Mosnier

2015

Blood

226

320

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The homeostatic blood protease, activated protein C (APC), can function as (1) an antithrombotic on the basis of inactivation of clotting factors Va and VIIIa; (2) a cytoprotective on the basis of endothelial barrier stabilization and anti-inflammatory and antiapoptotic actions; and (3) a regenerative on the basis of stimulation of neurogenesis, angiogenesis, and wound healing. Pharmacologic therapies using recombinant human and murine APCs indicate that APC provides effective acute or chronic therapies for a strikingly diverse range of preclinical injury models. APC reduces the damage caused by the following: ischemia/reperfusion in brain, heart, and kidney; pulmonary, kidney, and gastrointestinal inflammation; sepsis; Ebola virus; diabetes; and total lethal body radiation. For these beneficial effects, APC alters cell signaling networks and gene expression profiles by activating protease-activated receptors 1 and 3. APC’s activation of these G protein–coupled receptors differs completely from thrombin’s activation mechanism due to biased signaling via either G proteins or β-arrestin-2. To reduce APC-associated bleeding risk, APC variants were engineered to lack >90% anticoagulant activity but retain normal cell signaling. Such a neuroprotective variant, 3K3A-APC (Lys191-193Ala), has advanced to clinical trials for ischemic stroke. A rich data set of preclinical knowledge provides a solid foundation for potential translation of APC variants to future novel therapies.

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“…A meta-analysis reported by Kalil et al [18] in 2012 confirmed these results, with an 18% decrease in relative risk of mortality. Subsequently, however, two studies, performed by Annane et al [19] and Ranieri et al [20], respectively, showed that drotrecogin alfa (activated) provided no benefit in critically patients with septic shock and increased the severity of their illness.…”

Section: Drotrecogin Alfa (Activated)mentioning

confidence: 72%

Management of Infections in Critically Ill Patients

Hranjec

Sawyer

2014

Surgical Infections

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Background: Critically ill patients have an increased risk of developing infections and infectious complications, sometimes followed by death. Despite a substantial investment of resources in outcomes improvement, optimum treatment for such patients remains unclear for practicing intensivists. Methods: We conducted a review that highlights the most recent developments in the prevention, diagnosis, and management of infection and the evaluation of its outcomes. The review examines the prevention of infection, such as through daily bathing with chlorhexidine and the addition of probiotics to treatment regimens, and questions the previous standards of care, including the monitoring of gastric residuals and treatment of severely ill patients with drotrecogin alfa (activated). It also discusses novel approaches to the treatment of severely ill infected patients with extra-corporeal membrane oxygenation and the earlier normalization of body temperature. Results: The development of new antibiotics continues at a slow pace, with the likelihood that alternative approaches to the management of infection, including changes in the quality of patient care, are producing needed improvements. Conclusions: Clinical outcomes of infection are improving slowly as medical teams strive for better patient care. Lack of reimbursement is unnecessary as a punitive approach to infectious diseases.

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Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression

Cited by 71 publications

References 42 publications

Anticoagulant modulation of inflammation in severe sepsis

Anticoagulant modulation of inflammation in severe sepsis

Activated protein C: biased for translation

Management of Infections in Critically Ill Patients

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