Use of antithrombin III in critical patients. Treatment of severe preeclampsia with antithrombin concentrate: results of a prospective feasibility study. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. Do local opinion leaders augment hospital quality improvement efforts? A randomized trial to promote adherence to unstable angina guidelines. A double-blind and randomized placebo-controlled trial of low molecular weight heparin once daily to prevent deep-vein thrombosis in acute ischemic stroke. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma.
To evaluate the effect of the AT III concentrates upon the clinical evolution and hemostatic parameters.
                Prospective, open, randomized trial.
                Septic and multiple trauma patients admitted to our Intensive Care Unit.
                Levels of AT III below 70% were used as criteria to choose 36 patients, 20 of whom received treatment with AT III and 16 did not.
                AT III concentrates were administered at an initial dose of 60 U/kg followed by 10 U/kg every six hours.
                The administration of AT III neither contributes to alterations in haemostasis, nor the clinical evolution (evaluated according to Apache II score).
                The results suggest that the administration of AT III concentrates to critical patients with acquired low levels, but without manifest DIC, may not be justified; although further studies on a larger population are required to establish definite conclusions. The prospective feasibility study was designed to determine whether treatment with antithrombin (AT) concentrates could be used for patients with severe preeclampsia to provide clinical efficacy without the full systemic antihypertensive drug. Twenty-nine severe preeclamptic patients (24 to 36 weeks of gestation, gestosis index [GI] >/= 6 points) were randomized to receive AT (1500 U/day) or not. AT was given intravenously once daily for 7 consecutive days. Twenty-four hours of continuous infusion of 5000 U/day of unfractionated heparin was given simultaneously in both groups. There were no statistical differences in the clinical profiles of the two groups. Maternal symptoms were evaluated from the difference of GI before and after treatment, and fetal findings were evaluated from the changes of the biophysical profile score. Improvement was significantly greater in the AT group for both the GI ( P = 0.046) and the biophysical profile score ( P = 0.022). The improvement of coagulation parameters was also evaluated. The improvement of plasmin-plasmin inhibitor complex (PPIC), D-dimer levels, and platelet counts was observed in the AT group compared with the non-AT group. The coagulation index as a composite coagulation test parameter showed a significantly improvement in the AT group. No adverse events related to AT were observed. Given that AT plus heparin was significantly better than treatment with heparin alone for improvement of both GI and biophysical profile of infant, it is suggested that therapy with AT alone might be effective enough for severe preeclampsia. Activation of the coagulation system and depletion of endogenous anticoagulants are frequently found in patients with severe sepsis and septic shock. Diffuse microthrombus formation may induce organ dysfunction and lead to excess mortality in septic shock. Antithrombin III may provide protection from multiorgan failure and improve survival in severely ill patients.
                To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock.
                Double-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted from March 1997 through January 2000.
                A total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30 000 IU in total over 4 days) or a placebo (1% human albumin).
                All-cause mortality 28 days after initiation of study medication.
                Overall mortality at 28 days in the antithrombin III treatment group was 38.9% vs 38.7% in the placebo group (P =.94). Secondary end points, including mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin III and placebo groups. In the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n = 698), the 28-day mortality was nonsignificantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (P =.08). This trend became significant after 90 days (n = 686; 44.9% for antithrombin III group vs 52.5% for placebo group; P =.03). In patients receiving antithrombin III and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001).
                High-dose antithrombin III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin. The influence of an opinion leader intervention on adherence to Unstable Angina (UA) guidelines compared with a traditional quality improvement model was investigated.
                A group-randomized controlled trial with 2210 patients from 21 hospitals was designed. There were three intervention arms: (1) no intervention (NI); (2) a traditional Health Care Quality Improvement Program (HCQIP); and (3) a physician opinion leader in addition to the HCQIP model (OL). Quality indicators included: electrocardiogram within 20 minutes, antiplatelet therapy within 24 hours and at discharge, and heparin and beta-blockers during hospitalization. Hospitals could determine the specific indicators they wished to target. Potential cases of UA were identified from Medicare claims data. UA confirmation was determined by a clinical algorithm based on data abstracted from medical records. Data analyses included both hospital level analysis (analysis of variance) and patient level analysis (generalized linear models).
                The only statistically significant postintervention difference in percentage compliant was greater improvement for the OL group in the use of antiplatelet therapy at 24 hours in both hospital level (P = 0.01) and patient level analyses (P <0.05) compared with the HCQIP and NI groups. When analyses were confined to hospitals that targeted specific indicators, compared with the HCQIP hospitals, the OL hospitals showed significantly greater change in percentage compliant postintervention in both antiplatelet therapy during the first 24 hours (20.2% vs. -3.9%, P = 0.02) and heparin (31.0% vs.9.1%, P = 0.05).
                The influence of physician opinion leaders was unequivocally positive for only one of five quality indicators. To maximize adherence to best practices through physician opinion leaders, more research on how these physicians influence health care delivery in their organizations will be required. The effect of LMW heparin (Kabi 2165, Fragmin) was compared with placebo for the prevention of DVT in 103 patients with acute ischemic stroke using a prospective, double-blind, randomized trial design. Treatment was started within 72 hours, and LMW heparin was administered subcutaneously once daily according to body weight classes, which corresponded to about 55 to 65 Factor-Xa inhibitory U/kg, for 14 days, or until discharge from the hospital, if earlier. All patients underwent thrombosis surveillance with unilateral venography of the paretic limb. Evaluation of venography could be performed in 42 of 52 patients randomized to LMW heparin and in 50 of 51 patients randomized to placebo. The frequency of DVT was 15 of 42 patients or 36% (95% confidence interval 22 to 52%) in the LMW heparin group and 17 of 50 patients or 34% (21 to 49%) in the placebo group. The frequency of proximal thrombi was 5 of 42 (12%) and 8 of 50 (16%), respectively. There was one fatal pulmonary embolism in the placebo group. The mortality rate (28 days follow-up) was 5 of 52 in the LMW heparin group and 1 of 51 in the placebo group (p = 0.24). None of the deaths was related to treatment. No major hemorrhagic complications were observed. The mean Factor Xa inhibitory activity levels at peak concentration were 0.34 U/ml on day 2 and 0.42 U/ml on day 12 (p = 0.02). We conclude that LMW heparin in the dose range studied did not provide efficient prophylaxis against DVT in patients with acute ischemic stroke. There is continued debate as to whether a routine, early invasive strategy is superior to a conservative strategy for the management of unstable angina and myocardial infarction without ST-segment elevation.
                We enrolled 2220 patients with unstable angina and myocardial infarction without ST-segment elevation who had electrocardiographic evidence of changes in the ST segment or T wave, elevated levels of cardiac markers, a history of coronary artery disease, or all three findings. All patients were treated with aspirin, heparin, and the glycoprotein IIb/IIIa inhibitor tirofiban. They were randomly assigned to an early invasive strategy, which included routine catheterization within 4 to 48 hours and revascularization as appropriate, or to a more conservative (selectively invasive) strategy, in which catheterization was performed only if the patient had objective evidence of recurrent ischemia or an abnormal stress test. The primary end point was a composite of death, nonfatal myocardial infarction, and rehospitalization for an acute coronary syndrome at six months.
                At six months, the rate of the primary end point was 15.9 percent with use of the early invasive strategy and 19.4 percent with use of the conservative strategy (odds ratio, 0.78; 95 percent confidence interval, 0.62 to 0.97; P=0.025). The rate of death or nonfatal myocardial infarction at six months was similarly reduced (7.3 percent vs. 9.5 percent; odds ratio, 0.74; 95 percent confidence interval, 0.54 to 1.00; P<0.05).
                In patients with unstable angina and myocardial infarction without ST-segment elevation who were treated with the glycoprotein IIb/IIIa inhibitor tirofiban, the use of an early invasive strategy significantly reduced the incidence of major cardiac events. These data support a policy involving broader use of the early inhibition of glycoprotein IIb/IIIa in combination with an early invasive strategy in such patients. To address whether all medically fit patients with curatively resected stage II colon cancer should be offered adjuvant chemotherapy as part of routine clinical practice, to identify patients with poor prognosis characteristics, and to describe strategies for oncologists to use to discuss adjuvant chemotherapy in practice.
                An American Society of Clinical Oncology Panel, in collaboration with the Cancer Care Ontario Practice Guideline Initiative, reviewed pertinent information from the literature through May 2003.
                A literature-based meta-analysis found no evidence of a statistically significant survival benefit of adjuvant chemotherapy for stage II patients. Recommendations The routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer is not recommended. However, there are populations of patients with stage II disease that could be considered for adjuvant therapy, including patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology.
                Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease. The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. Patients with stage II disease should be encouraged to participate in randomized trials. To evaluate the safety and potential efficacy of antithrombin III (AT III) in reducing mortality in patients with severe sepsis.
                Prospective, randomized, placebo-controlled, double-blind, phase II, multicenter, multinational clinical trial.
                Seven academic medical center intensive care units (ICU) in Belgium, Denmark, the Netherlands, Norway and Sweden.
                42 patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III or placebo.
                Patients received either an intravenous loading dose of 3000 IU AT III followed by a maintenance dose of 1500 IU every 12 h for 5 days or equivalent amounts of placebo.
                All patients were evaluated for safety and for 30-day all-cause mortality.
                The administration of AT III was safe and well-tolerated. It was followed by a 39 % reduction in 30-day all-cause mortality (NS). The reduction in mortality was accompanied by a considerably shorter stay in the ICU. Patients treated with AT III exhibited a better performance in overall severity of illness and organ failure scores (Acute Physiology and Chronic Health Evaluation II, multiple organ failure, organ system failure), which was noticeable soon after initiation of treatment. Patients treated with AT III demonstrated a better resolution of pre-existing organ failures and a lower incidence of new organ failures during the observation period. A meta-analysis comprising this and two other double-blind, placebo-controlled trials with AT III with a total of 122 patients suffering from severe sepsis confirms the positive trend. The results of the meta-analysis demonstrate a 22.9 % reduction in 30-day all-cause mortality in patients treated with AT III. Although still too small to be confirmative, the meta-analysis clearly points to the fact that a sufficiently powered phase III trial is warranted to prove whether AT III has a beneficial role in the treatment of severe sepsis. About half the patients treated with curative resection for colorectal cancer do not survive long-term. Adjuvant chemotherapy given during and after surgery may prevent hepatic metastases and improve patient survival. In patients with colorectal cancer, we have done a multicentre, randomised controlled trial comparing five-year survival after intraportal infusion of fluorouracil (1 g per day) plus heparin (10,000 U per day) (130 patients) or heparin alone (123) during curative resection and for 7 days thereafter, or after resection alone (145). There was no reduction in liver metastasis or increased overall survival advantage in either active-treatment arm of the study. However, patients who had stage III, Dukes' C (lymph-node-positive) tumours resected and were treated with fluorouracil plus heparin had a significant (p less than 0.03) survival advantage of about 16% compared with surgery-only controls. Further study of intraportal infusion of chemotherapeutic agent as adjuvant treatment to surgery in patients with colorectal cancer appears worthwhile.
AT III cannot be recommended for critically ill patients based on the available evidence. A randomized controlled trial of AT III, without adjuvant heparin, with prespecified inclusion criteria and good bias protection is needed.