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Endogenous plasma activated protein C levels and the effect of enoxaparin and drotrecogin alfa (activated) on markers of coagulation activation and fibrinolysis in pulmonary embolism.

ABSTRACT: There are no published data on the status of endogenous activated protein C (APC) in pulmonary embolism (PE), and no data on the effect of drotrecogin alfa (activated) (DAA) given in addition to therapeutic dose enoxaparin.In this double-blind clinical trial, 47 patients with computed tomography (CT)-confirmed acute submassive PE treated with 1 mg/kg body weight of enoxaparin twice daily were randomized to groups receiving a 12-hour intravenous infusion of 6, 12, 18, or 24 ?g/kg/hour of DAA or a placebo. Blood samples were drawn before starting DAA infusion, after 4, 8 and 12 hours (at the end of the infusion period), and on treatment days 2, 3, 4, 5 and 6.Initial endogenous plasma activated protein C (APC) levels were 0.36 ± 0.48 ng/ml (<0.10 to 1.72 ng/ml) and remained in the same range in the placebo group. APC levels in patients treated with DAA were 13.67 ± 3.57 ng/ml, 32.71 ± 8.76 ng/ml, 36.13 ± 7.60 ng/ml, and 51.79 ± 15.84 ng/ml in patients treated with 6, 12, 18, and 24 ?g/kg/hour DAA, respectively. In patients with a D-dimer level >4 mg/L indicating a high level of acute fibrin formation and dissolution, DAA infusion resulted in a more rapid drop in soluble fibrin, D-dimer, and fibrinogen/fibrin degradation products (FDP) levels, compared to enoxaparin alone. There was a parallel decline of soluble fibrin, D-dimer, FDP, and plasmin-plasmin inhibitor complex (PPIC) in response to treatment with enoxaparin ± DAA, with no evidence of a systemic profibrinolytic effect of the treatment.In patients with acute submassive PE endogenous APC levels are low. DAA infusion enhances the inhibition of fibrin formation.ClinicalTrials.gov: NCT00191724.

SUBMITTER: Dempfle CE

PROVIDER: S-EPMC3222057 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Endogenous plasma activated protein C levels and the effect of enoxaparin and drotrecogin alfa (activated) on markers of coagulation activation and fibrinolysis in pulmonary embolism.

Dempfle Carl-Erik H CE Elmas Elif E Link Andreas A Suvajac Nenad N Liebe Volker V Janes Jonathan J Borggrefe Martin M

Critical care (London, England) 20110117 1

<h4>Introduction</h4>There are no published data on the status of endogenous activated protein C (APC) in pulmonary embolism (PE), and no data on the effect of drotrecogin alfa (activated) (DAA) given in addition to therapeutic dose enoxaparin.<h4>Methods</h4>In this double-blind clinical trial, 47 patients with computed tomography (CT)-confirmed acute submassive PE treated with 1 mg/kg body weight of enoxaparin twice daily were randomized to groups receiving a 12-hour intravenous infusion of 6, ...[more]

PMID: 21241489

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Project description:IntroductionIn March 2001, the results of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study were published, which indicated a 6.1% absolute reduction in 28-day mortality. Drotrecogin alfa (activated; DrotAA) was subsequently approved for use in patients with severe sepsis.MethodsIn December 2002, critical care units in England, Wales and Northern Ireland were invited to participate in an audit of DrotAA. Data for each infusion of DrotAA were linked to case mix and outcome data from a national audit. Use of DrotAA was described and a nonrandomized comparison of effectiveness was conducted.Results1,292 infusions of DrotAA were recorded in 112 units; 61% commenced during the first 24 hours in the unit. The majority (77%) of patients had three or more organs failing; lung (42%) and abdomen (40%) were the most common primary sites of infection. Crude hospital mortality was high (45%); at 28 days, only 18% had left acute hospital and 19% were still in the unit. For 30%, the full 96-hour infusion was not completed; 24% of infusions were interrupted; 8.1% experienced one or more serious adverse events, of which 77% were serious bleeding events. Of eight relative risks estimated from individually-matched (0.75 to 0.85) and propensity-matched (0.82 to 0.90) controls, seven were consistent with the results of PROWESS. Restricting the analysis to patients receiving DrotAA during the first 24 hours resulted in larger treatment effects (relative risks 0.62 to 0.81). For all matches, similar patterns were seen across subgroups. No effect of DrotAA was seen for two organs failing or lower severity scores, compared with a significant mortality reduction for three or more organs failing or higher severity scores.ConclusionUse of DrotAA was approximately one in 16 for admissions meeting the definition for severe sepsis and with two or more organs failing. Patients receiving DrotAA were younger and more severely ill but were less likely to have serious conditions in their past medical history. Nonrandomized estimates for the effectiveness of DrotAA were consistent with the findings of PROWESS. DrotAA appeared not to be effective in patients with less severe disease.

Project description:IntroductionPrevious cost-effectiveness analyses (CEA) reported that Drotrecogin alfa (DrotAA) is cost-effective based on a Phase III clinical trial (PROWESS). There is little evidence on whether DrotAA is cost-effective in routine clinical practice. We assessed whether DrotAA is cost-effective in routine practice for adult patients with severe sepsis and multiple organ systems failing.MethodsThis CEA used data from a prospective cohort study that compared DrotAA versus no DrotAA (control) for severe sepsis patients with multiple organ systems failing admitted to critical care units in England, Wales, and Northern Ireland. The cohort study used case-mix and mortality data from a national audit, linked with a separate audit of DrotAA infusions. Re-admissions to critical care and corresponding mortality were recorded for four years. Patients receiving DrotAA (n = 1,076) were matched to controls (n = 1,650) with a propensity score (Pscore), and Genetic Matching (GenMatch). The CEA projected long-term survival to report lifetime incremental costs per quality-adjusted life year (QALY) overall, and for subgroups with two or three to five organ systems failing at baseline.ResultsThe incremental costs per QALY for DrotAA were £30,000 overall, and £16,000 for the subgroups with three to five organ systems failing. For patients with two organ systems failing, DrotAA resulted in an average loss of one QALY at an incremental cost of £15,000. When the subgroup with two organ systems was restricted to patients receiving DrotAA within 24 hours, DrotAA led to a gain of 1.2 QALYs at a cost per QALY of £11,000. The results were robust to other assumptions including the approach taken to projecting long-term outcomes.ConclusionsDrotAA is cost-effective in routine practice for severe sepsis patients with three to five organ systems failing. For patients with two organ systems failing, this study could not provide unequivocal evidence on the cost-effectiveness of DrotAA.

Project description:IntroductionSince the launch of drotrecogin alfa activated (DrotAA), institutions and individual countries have published data on its use in clinical practice, based on audit or registry data. These studies were limited in size and geographic locale and included patients with greater disease severity and higher mortality than those in clinical trials. The purpose of this study was to compare baseline characteristics and clinical outcomes (using appropriate statistical adjustments) of patients treated or not treated with DrotAA from the international PROGRESS (Promoting Global Research Excellence in Severe Sepsis) cohort study of severe sepsis.MethodsPROGRESS was a global, non-interventional, multi-center, prospective, observational study of patients having a diagnosis of severe sepsis treated in intensive care units at a participating institution. All treatment modalities were as per standard of care at the participating institutions. Baseline characteristics and hospital mortality were analyzed and regression techniques used to develop propensity and outcome models adjusted for baseline imbalances between groups.ResultsOverall, 14,543 patients from 37 countries were enrolled and 12,492 had complete data for analysis. Germany was the highest enrolling country (1,810; 14.5%) and the US had the most DrotAA patients (206, 23.3%); 882 (7%) overall received DrotAA therapy. DrotAA-treated patients were younger (median age 58 vs. 61 years), had greater organ dysfunction (cardiovascular: 90% vs. 74%; respiratory: 90% vs. 81%; renal: 60% vs. 45%; metabolic: 63% versus 42%; 3 or more organ dysfunctions: 84% vs. 67%) and had a higher median APACHE II score (26 vs. 23, all with P < 0.001). Although in-hospital mortality was similar for DrotAA and non-DrotAA-treated patients (49.6% vs. 49.7%, respectively), after adjusting for imbalances, patients receiving DrotAA had a 28% (0.60 to 0.86, 95% Confidence Intervals) reduction in the odds of death and a relative risk reduction of 17% (P = 0.0003).ConclusionsIn the PROGRESS registry, DrotAA-treated patients were younger, more severely ill, and had fewer co-morbidities than patients not treated with DrotAA. After adjustment for group differences, a significant reduction in the odds of death was observed for patients that received DrotAA compared with those that did not.

Project description:Ultrasound-facilitated and catheter-directed low-dose fibrinolysis (EKOS) has shown favorable hemodynamic and safety outcomes in intermediate- to high-risk pulmonary embolism (PE) cases. This prospective single-arm monocentric study assessed the effects of using a delivery catheter for fibrinolysis as a novel approach for acute intermediate- to high-risk patients on pulmonary artery hemodynamics PE. Forty-five patients (41 intermediate-high and 4 high risk) with computer tomography (CT)-confirmed PE underwent EKOS therapy. By protocol, a total of 6 mg of tissue-plasminogen activator (t-PA) was administered over 6 h in the pulmonary artery (unilateral 6 mg or bilateral 12 mg). Unfractionated heparin was provided periprocedurally. The primary safety outcome was death, as well as major and minor bleeding within 48 of procedure initiation and at 90 days. The primary effectiveness outcomes were: 1. to assess the difference in pulmonary artery pressure from baseline to 6 h post-treatment as a primary precise surrogate marker, and 2. to determine the echocardiographic RV/LV ratio from baseline to 48 h and at 90 days post-delivery. Pulmonary artery pressure decreased by 15/6/10 mmHg (p < 0.001). The mean RV/LV ratio decreased from 1.2 ± 0.85 at baseline to 0.85 ± 0.12 at 48 and to 0.76 ± 0.13 at 90 days (p < 0.001). Five patients (11%) died within 90 days of therapy. Pulmonary artery hemodynamics were assessed using a delivery catheter for fibrinolysis, which is reproducible for identifying PE at risk of adverse outcomes. The results matched the right heart catheter results in EKOS and Heparin arm of Ultima trial, thereby confirming the validity of this potential diagnostic tool to assess therapy effectiveness and thereby reduce additional procedure-related complications, hospital residency, and economics. These results stress the importance of having an interdisciplinary team involved in the management of PE to evaluate the quality of life of these patients and this protocol shortens ICU admission to 6 h.

Dataset Information

Endogenous plasma activated protein C levels and the effect of enoxaparin and drotrecogin alfa (activated) on markers of coagulation activation and fibrinolysis in pulmonary embolism.

Publications

Endogenous plasma activated protein C levels and the effect of enoxaparin and drotrecogin alfa (activated) on markers of coagulation activation and fibrinolysis in pulmonary embolism.

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