Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. METHODS: In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. FINDINGS: Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55-0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55-1·53; p=0·76). INTERPRETATION: Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication [corrected]. FUNDING: Boehringer Ingelheim and Canadian Institutes of Health Research.

Normalization of blood clotting characteristics using prothrombin complex concentrate, fibrinogen and FXIII in an albumin based fluid: experimental studies in thromboelastometry.

BACKGROUND: Colloid fluids supplemented with adequate combinations of coagulation factor concentrates with the capability to restore coagulation could be a desirable future treatment component in massive transfusion. METHODS: Starting from a coagulation factor and blood cell-free albumin solution we added Prothrombin Complex Concentrate, Fibrinogen Concentrate and Factor XIII in different combinations and concentrations to analyze their properties to restore thromboelastometry parameters without the use of plasma. Further analysis under the presence of platelets was performed for comparability to whole blood conditions. RESULTS: Albumin solutions enriched with Fibrinogen Concentrate, Factor XIII and Prothrombin Complex Concentrate at optimized concentrations show restoring coagulation potential. Prothrombin Complex Concentrate showed sufficient thrombin formation for inducing fibrinogen polymerization. The combination of Prothrombin Complex Concentrate and Fibrinogen Concentrate led to the formation of a stable in vitro fibrin clot. Fibrinogen and Factor XIII showed excellent capacity to improve fibrin clot firmness expressed as Amplitude at 10 min and Maximal Clot Firmness. Fibrinogen alone, or in combination with Factor XIII, was able to restore normal Amplitude at 10 min and Maximal Clot Firmness values. In the presence of platelets, the thromboelastometry surrogate parameter for thrombin generation (Clotting Time) improves and normalizes when compared to whole blood. CONCLUSIONS: Combinations of coagulation factor concentrates suspended in albumin solutions can restore thromboelastometry parameters in the absence of plasma. This kind of artificial colloid fluids with coagulation-restoring characteristics might offer new treatment alternatives for massive transfusion. TRIAL REGISTRATION: Study registered at the institutional ethic committee "Institut de Recerca, Hospital Santa Creu i Sant Pau, with protocol number IIBSP-CFC-2013-165.

Association of preoperative glucose concentration with myocardial injury and death after non-cardiac surgery (GlucoVISION): a prospective cohort study.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) is the most common perioperative cardiovascular complication and is independently associated with 30-day mortality. We aimed to assess the association between preoperative glucose concentration and postoperative MINS and mortality. METHODS: The VISION study is a prospective cohort study done at 12 centres in eight countries. Patients aged 45 years or older who required at least one overnight hospital admission for non-cardiac surgery were enrolled from Aug 6, 2007, to Jan 11, 2011. In the GlucoVISION analysis, we assessed the relations between preoperative casual or fasting glucose concentration and MINS within 3 days after surgery using logistic regression, and 30-day mortality using Cox proportional regression, in people with and without diabetes. FINDINGS: 11 954 patients were included in this analysis, of whom 2809 (23%) had diabetes. Within the first three postoperative days, MINS occurred in 813 (7%) patients. 249 (2%) patients died by day 30. More patients with diabetes had MINS (odds ratio [OR] 1·98 [95% CI 1·70-2·30]; p<0·0001), and died (OR 1·41 [1·08-1·86]; p=0·016) than did patients without diabetes. Casual glucose concentrations were associated with MINS in all patients (adjusted OR 1·06 [1·04-1·09] per 1 mmol/L increment in glucose; p=0·0003), and with death in patients without diabetes (adjusted hazard ratio [HR] 1·13 [95% CI 1·05-1·23] per mmol/L; p=0·002). We noted a progressive relation between unadjusted fasting glucose concentration and both MINS (OR 1·14 [1·08-1·20] per mmol/L; p<0·0001), driven by the effect in the subgroup without previous diabetes (pinteraction=0·025), and 30-day mortality (HR 1·10 [1·02-1·19] per mmol/L; p=0·013). For patients without diabetes, casual glucose of more than 6·86 mmol/L and fasting glucose of more than 6·41 mmol/L predicted MINS (OR 1·71 [1·36-2·15]; p<0·0001, and OR 2·71 [1·85-3·98]; p<0·0001, respectively). For patients with diabetes, only casual glucose concentration more than 7·92 mmol/L predicted MINS (OR 1·47 [1·10-1·96]; p=0·0096). INTERPRETATION: Preoperative glucose concentration, particularly casual glucose concentration, predicts risk for postoperative cardiovascular outcomes, especially in patients without diabetes. FUNDING: Full funding sources listed at the end of the paper (see Acknowledgments).