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. Randomized controlled trial of tissue plasminogen activator in proximal deep venous thrombosis. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. Usefulness of platelet glycoprotein IIb/IIIa inhibitors in coronary stenting for reconstruction of complex lesions: procedural and 30 day outcome. A prospective randomized double-blind trial of antithrombin III concentrate in the treatment of multiple-organ dysfunction syndrome during hematopoietic stem cell transplantation. High-dose antithrombin III treatment of severely injured patients: results of a prospective study. Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients undergoing colorectal surgery: results of the canadian colorectal DVT prophylaxis trial: a randomized, double-blind trial. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Heparin with and without graded compression stockings in the prevention of thromboembolic complications of major abdominal surgery: a randomized trial. Effect of local medical opinion leaders on quality of care for acute myocardial infarction: a randomized controlled trial. A prospective randomized comparison of the accuracy of computer-assisted versus GUSTO nomogram--directed heparin therapy.
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. To compare the efficacy and safety of recombinant human tissue-type plasminogen activator (rt-PA, supplied as Activase) with heparin alone or rt-PA plus heparin in the treatment of venographically documented proximal deep venous thrombosis (DVT) of the leg.
                Sixty-four patients underwent 65 randomizations to rt-PA alone (n = 36), rt-PA plus heparin (n = 17), or heparin alone (n = 12) in a prospective, multicenter, randomized, open-label trial, with efficacy assessed by a radiology panel unaware of treatment assignment. Patients randomly assigned to rt-PA received 0.05 mg/kg/hour for 24 hours via a peripheral vein, with a maximum dose of 150 mg. All patients then received heparin and warfarin for the remainder of the hospitalization. Follow-up venography was performed 24 to 36 hours after initiation of therapy.
                Complete or more than 50% lysis occurred in 10 (28%) patients treated with rt-PA, five (29%) patients with rt-PA plus heparin, and no patient treated with heparin. No lysis occurred in 16 (44%) patients treated with rt-PA plus heparin, and 10 (83%) patients who received heparin alone (p = 0.04). There was one major complication, a nonfatal intracranial hemorrhage in a patient who received rt-PA alone. At 7 to 10 days after initiation of treatment, the level of serum glutamic oxaloacetic transaminase nearly doubled among all patients, including those assigned to receive heparin alone.
                (1) rt-PA and rt-PA plus heparin cause more clot lysis than heparin alone; (2) the addition of heparin to rt-PA does not improve the lysis rate; (3) DVT treated with heparin is commonly associated with a rise in the transaminase level; (4) heparin does not increase the risk of bleeding from rt-PA therapy; and (5) alternative dosing regimens and modes of administration of rt-PA should be investigated to improve further its efficacy and safety in the treatment of acute DVT. When unfractionated heparin is used to treat acute venous thromboembolism, it is usually administered by intravenous infusion with coagulation monitoring, which requires hospitalization. However, subcutaneous administration of fixed-dose, weight-adjusted, unfractionated heparin may be suitable for inpatient and outpatient treatment of venous thromboembolism.
                To determine if fixed-dose, weight-adjusted, subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin for treatment of venous thromboembolism.
                Randomized, open-label, adjudicator-blinded, noninferiority trial of 708 patients aged 18 years or older with acute venous thromboembolism from 6 university-affiliated clinical centers in Canada and New Zealand conducted from September 1998 through February 2004. Of the randomized patients, 11 were subsequently excluded from the analysis of efficacy and 8 from the analysis of safety.
                Unfractionated heparin was administered subcutaneously as an initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours (n = 345). Low-molecular-weight heparin (dalteparin or enoxaparin) was administered subcutaneously at a dose of 100 IU/kg every 12 hours (n = 352). Both treatments could be administered out of hospital and both were overlapped with 3 months of warfarin therapy.
                Recurrent venous thromboembolism within 3 months and major bleeding within 10 days of randomization.
                Recurrent venous thromboembolism occurred in 13 patients in the unfractionated heparin group (3.8%) compared with 12 patients in the low-molecular-weight heparin group (3.4%; absolute difference, 0.4%; 95% confidence interval, -2.6% to 3.3%). Major bleeding during the first 10 days of treatment occurred in 4 patients in the unfractionated heparin group (1.1%) compared with 5 patients in the low-molecular-weight heparin group (1.4%; absolute difference, -0.3%; 95% confidence interval, -2.3% to 1.7%). Treatment was administered entirely out of hospital in 72% of the unfractionated heparin group and 68% of the low-molecular-weight heparin group.
                Fixed-dose subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin in patients with acute venous thromboembolism and is suitable for outpatient treatment.
                clinicaltrials.gov Identifier: NCT00182403. Intracoronary stent implantation during percutaneous transluminal coronary angioplasty (PTCA) has shown favorable results, reducing acute complications associated with PTCA, such as coronary artery dissection and abrupt or threatened vessel closure. However, treatment of lesions with a complex morphology and diffuse disease, requiring long or multiple coronary stents, is still associated with a poorer outcome. We investigated the hypothesis that abciximab might lead to a different outcome in patients with complex coronary lesions, which require long or multiple stent implantation.
                One hundred and six patients were randomized to receive either a combination of abciximab (bolus and 12 hour infusion) and weight-adjusted low-dose heparin or weight-adjusted heparin alone and followed up to 30 days.
                The procedural success rate was 100% in both groups of patients. In the control group a composite rate of major adverse events such as any death irrespective of cause, Q wave or non-Q wave myocardial infarction, acute or subacute stent thrombosis and urgent revascularization of 15.3% was shown at 30-day follow-up. The use of abciximab reduced the composite adverse event rate to 3.7% (76% absolute reduction, p < 0.05).
                The use of abciximab during high risk stenting is safe and reduces the risk of cardiac events at 30-day follow-up as compared to standard treatment with heparin. A longer follow-up period is warranted to confirm the beneficial effects observed at 30 days with abciximab in this setting. Many of the complications of high-dose therapy with hematopoietic stem cells are caused by or lead to the multiple-organ dysfunction syndrome (MODS). In hematopoietic stem cell transplantation (HSCT), acquired antithrombin III (ATIII) deficiency is independently associated with MODS to the exclusion of transplant type, preparative regimen, and bacteremia. In experimental settings, replacement of ATIII can ameliorate the severity of MODS that develops in response to a variety of pathologic stimuli, suggesting that ATIII supplementation might improve the clinical course of MODS in patients undergoing HSCT. We performed a study to determine if ATIII can improve the morbidity of MODS in HSCT. Forty-nine patients undergoing HSCT, who developed pulmonary dysfunction (oxygen saturation of <90%), central nervous system dysfunction (drop of >4 points in the mini-mental status exam), or hepatic dysfunction (bilirubin >34 micromol/L [2.0 mg%], weight gain of >5% over baseline, and abdominal pain, possibly of hepatic origin) with a concomitant ATIII activity of <84% were double-blind randomized to receive ATIII concentrate, 70 units/kg within 24 hours of recognition of initial organ dysfunction followed by 50 units/kg 8, 16, 48, and 72 hours later, or albumin placebo. The group randomized to ATIII had a lower severity-of-illness score (15.7 +/- 19.2 vs. 28.6 +/- 25.2, p = 0.03), shorter duration of hospitalization (14.9 +/- 16.7 vs. 25.7 /- 17.9 days, p = 0.03), and lower hospital charges ($138,700 +/- $23,500 vs. $206,400 +/- $34,000). ATIII concentrate was associated with improved morbidity of MODS in patients undergoing HSCT when given early in the evolution of the syndrome. Antithrombin III (AT III) treatment has been shown to reduce disseminated intravascular coagulation and to inhibit thrombin, which plays a central role in the activation of platelets and other inflammatory systems in conditions with severe inflammation. The objective of this study was to evaluate the influence of early and high-dose administration of AT III to patients with severe multiple injuries on the inflammatory response and outcome.
                In a placebo-controlled, double-blind study, 40 consecutive patients with Injury Severity Scores of 29 or greater who met the inclusion criteria were randomized to receive either AT III or placebo within 360 minutes after trauma. Twenty patients were administered AT III for a period of 4 days, aiming to achieve AT III concentrations of 140% of normal.
                The AT III and placebo groups were comparable with respect to Injury Severity Score, age, incidence of blood pressure less than 80 mm Hg on admission, initial base deficit, and start of the test drug. The patients in the AT III group received a total of about 20,000 IU during the first 4 days. AT III levels of 130 to 140% could be achieved by this regimen, whereas in the control group the AT III concentration averaged about 70%. In the AT III group prothrombin tended to be elevated and prothrombin fragment F1+2 as well as thrombin-AT III complex tended to be lower on the first day. No differences between groups, however, could be observed with respect to partial thromboplastin time, prothrombin time, platelets, plasminogen activator inhibitor I, soluble tumor necrosis factor receptor II, neutrophil elastase, interleukin (IL)-1 receptor antagonist, IL-6, and IL-8. Mortality (15 vs. 5%), incidence of respiratory failure (55 vs. 55%), duration of mechanical ventilation (13 vs. 12 days), and length of stay in the surgical intensive care unit (19 vs. 21 days) were also similar in both treatment groups. The duration of organ failure, however, was shorter in the patients receiving AT III.
                The early and high-dose administration of AT III to patients with severe blunt trauma appears not to attenuate the posttraumatic inflammatory response or to significantly improve outcome. To compare the effectiveness and safety of low-dose unfractionated heparin and a low-molecular-weight heparin as prophylaxis against venous thromboembolism after colorectal surgery.
                In a multicenter, double-blind trial, patients undergoing resection of part or all of the colon or rectum were randomized to receive, by subcutaneous injection, either calcium heparin 5,000 units every 8 hours or enoxaparin 40 mg once daily (plus two additional saline injections). Deep vein thrombosis was assessed by routine bilateral contrast venography performed between postoperative day 5 and 9, or earlier if clinically suspected.
                Nine hundred thirty-six randomized patients completed the protocol and had an adequate outcome assessment. The venous thromboembolism rates were the same in both groups. There were no deaths from pulmonary embolism or bleeding complications. Although the proportion of all bleeding events in the enoxaparin group was significantly greater than in the low-dose heparin group, the rates of major bleeding and reoperation for bleeding were not significantly different.
                Both heparin 5,000 units subcutaneously every 8 hours and enoxaparin 40 mg subcutaneously once daily provide highly effective and safe prophylaxis for patients undergoing colorectal surgery. However, given the current differences in cost, prophylaxis with low-dose heparin remains the preferred method at present. Septic shock is frequently complicated by a syndrome of disseminated intravascular coagulation (DIC). Numerous uncontrolled clinical studies have reported that antithrombin III (ATIII) substitution might prevent DIC and death in septic shock.
                We conducted a randomized double-blind placebo-controlled trial in patients with a documented septic shock and DIC. The patients received either a placebo or ATIII (90 to 120 IU/kg in loading dose, then 90 to 120 IU/kg/d during 4 days). Administration of fresh frozen plasma, platelets, and fibrinogen concentrates was restricted to patients with hemorrhages and severe decreases in prothrombin time, platelet count, and fibrinogen levels.
                Thirty-five patients entered the study (18 placebo, 17 ATIII). Both groups were well balanced for all demographic, hemodynamic, and biologic data. Three patients were excluded before the treatment allocation code was broken. In the ATIII group, ATIII levels were rapidly corrected and remained over normal levels until day 10; sequential protein C and protein S levels were not modified. The duration of DIC was significantly reduced: in the ATIII group, 64 percent of patients were cured of DIC at day 2, and 71 percent were cured at the end of treatment vs in the placebo group, 11 percent (p < 0.01) and 33 percent (p < 0.05), respectively. In the 32 included patients, the mortality in ICU was reduced by 44 percent in the ATIII group (p = 0.22, NS). Care loads and transfusion requirements were not different. No side effect was observed.
                Mortality was reduced by 44 percent in this trial, but the difference did not reach the statistical significance. Circulating protein C and protein S levels were not modified by ATIII supplementation. High doses of ATIII concentrates significantly improved sepsis-induced DIC during septic shock. The trend toward improved survival suggests further randomized studies. One hundred and seventy-six patients scheduled for elective major abdominal surgery were randomized to two prophylactic regimens to prevent postoperative thromboembolism. All patients were screened with the 125I-labelled fibrinogen uptake test, and thromboembolism was verified by ascending phlebography and/or perfusion/ventilation lung scintigraphy. In the group of patients receiving low-dose heparin treatment (5000 units twice daily subcutaneously) 12 per cent developed thromboembolic complications. In the other group, where low-dose heparin treatment was supplemented with graded compression stockings only 2 per cent developed thromboembolism. It is concluded that the combination of low-dose heparin and the use of graded compression stockings is superior to heparin alone in preventing thromboembolism following major abdominal surgery. The effectiveness of recruiting local medical opinion leaders to improve quality of care is poorly understood.
                To evaluate a guideline-implementation intervention of clinician education by local opinion leaders and performance feedback to (1) increase use of lifesaving drugs (aspirin and thrombolytics in eligible elderly patients, beta-blockers in all eligible patients) for acute myocardial infarction (AMI), and (2) decrease use of a potentially harmful therapy (prophylactic lidocaine).
                Randomized controlled trial with hospital as the unit of randomization, intervention, and analysis.
                Thirty-seven community hospitals in Minnesota.
                All patients with AMI admitted to study hospitals over 10 months before (1992-1993, N=2409) or after (1995-1996, N=2938) the intervention.
                Using a validated survey, we identified opinion leaders at 20 experimental hospitals who influenced peers through small and large group discussions, informal consultations, and revisions of protocols and clinical pathways. They focused on (1) evidence (drug efficacy), (2) comparative performance, and (3) barriers to change. Control hospitals received mailed performance feedback.
                Hospital-specific changes before and after the intervention in the proportion of eligible patients receiving each study drug.
                Among experimental hospitals, the median change in the proportion of eligible elderly patients receiving aspirin was +0.13 (17% increase from 0.77 at baseline), compared with a change of -0.03 at control hospitals (P=.04). For beta-blockers, the respective changes were +0.31 (63% increase from 0.49 at baseline) vs +0.18 (30% increase from baseline) for controls (P=.02). Lidocaine use declined by about 50% in both groups. The intervention did not increase thrombolysis in the elderly (from 0.73 at baseline), but nearly two thirds of eligible nonrecipients were older than 85 years, had severe comorbidities, or presented after at least 6 hours.
                Working with opinion leaders and providing performance feedback can accelerate adoption of some beneficial AMI therapies (eg, aspirin, beta-blockers). Secular changes in knowledge and hospital protocols may extinguish outdated practices (eg, prophylactic lidocaine). However, it is more difficult to increase use of effective but riskier treatments (eg, thrombolysis) for frail elderly patients. Failure to adequately anticoagulate the blood of patients receiving recombinant tissue plasminogen activator (TPA) leads to greater rates of rethrombosis. In a multicentered, randomized trial in 51 patients we compared the ability to achieve and maintain therapeutic anticoagulation by use of computer-assisted heparin therapy or the GUSTO (Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries) heparin nomogram guidelines in patients with myocardial infarction treated with recombinant TPA. Heparin therapy was initiated with either computer-generated starting doses or GUSTO guideline starting doses. Activated partial thromboplastin times were measured every 6 to 8 hours for the first 24 hours. The therapeutic range used in this trial was 1.5 to 2.5 times the patient's baseline activated partial thromboplastin time (APTT). Ninety-four percent of the APTT ratios in the computer group were equal to or greater than 1.5 in the first 24 hours compared with 78% in the GUSTO group (p < 0.009). No significant difference in bleeding was found (7.7% for GUSTO; 4.2% for computer). Incremental time-dependent changes in heparin dose were found (day 1, 1110 +/- 243 units/hr, APTT ratio = 2.5 +/- 1.4; day 3, 1380 +/- 374 units/hr, APTT ratio, 1.9 +/- 0.4). Computer-assisted heparin therapy TPA results in superior anticoagulation accuracy compared with the GUSTO guidelines. In addition, the pharmacodynamic response to heparin changes in the 2 to 3 days after administration of TPA, leading to greater heparin requirements.
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.