Association of Recent Use of Non-Vitamin K Antagonist Oral Anticoagulants With Intracranial Hemorrhage Among Patients With Acute Ischemic Stroke Treated With Alteplase.

Importance: Current guidelines recommend against use of intravenous alteplase in patients with acute ischemic stroke who are taking non-vitamin K antagonist oral anticoagulants (NOACs). Objective: To evaluate the safety and functional outcomes of intravenous alteplase among patients who were taking NOACs prior to stroke and compare outcomes with patients who were not taking long-term anticoagulants. Design, Setting, and Participants: A retrospective cohort study of 163 038 patients with acute ischemic stroke either taking NOACs or not taking anticoagulants prior to stroke and treated with intravenous alteplase within 4.5 hours of symptom onset at 1752 US hospitals participating in the Get With The Guidelines-Stroke program between April 2015 and March 2020, with complementary data from the Addressing Real-world Anticoagulant Management Issues in Stroke registry. Exposures: Prestroke treatment with NOACs within 7 days prior to alteplase treatment. Main Outcomes and Measures: The primary outcome was symptomatic intracranial hemorrhage occurring within 36 hours after intravenous alteplase administration. There were 4 secondary safety outcomes, including inpatient mortality, and 7 secondary functional outcomes assessed at hospital discharge, including the proportion of patients discharged home. Results: Of 163 038 patients treated with intravenous alteplase (median age, 70 [IQR, 59 to 81] years; 49.1% women), 2207 (1.4%) were taking NOACs and 160 831 (98.6%) were not taking anticoagulants prior to their stroke. Patients taking NOACs were older (median age, 75 [IQR, 64 to 82] years vs 70 [IQR, 58 to 81] years for those not taking anticoagulants), had a higher prevalence of cardiovascular comorbidities, and experienced more severe strokes (median National Institutes of Health Stroke Scale score, 10 [IQR, 5 to 17] vs 7 [IQR, 4 to 14]) (all standardized differences >10). The unadjusted rate of symptomatic intracranial hemorrhage was 3.7% (95% CI, 2.9% to 4.5%) for patients taking NOACs vs 3.2% (95% CI, 3.1% to 3.3%) for patients not taking anticoagulants. After adjusting for baseline clinical factors, the risk of symptomatic intracranial hemorrhage was not significantly different between groups (adjusted odds ratio [OR], 0.88 [95% CI, 0.70 to 1.10]; adjusted risk difference [RD], -0.51% [95% CI, -1.36% to 0.34%]). There were no significant differences in the secondary safety outcomes, including inpatient mortality (6.3% for patients taking NOACs vs 4.9% for patients not taking anticoagulants; adjusted OR, 0.84 [95% CI, 0.69 to 1.01]; adjusted RD, -1.20% [95% CI, -2.39% to -0%]). Of the secondary functional outcomes, 4 of 7 showed significant differences in favor of the NOAC group after adjustment, including the proportion of patients discharged home (45.9% vs 53.6% for patients not taking anticoagulants; adjusted OR, 1.17 [95% CI, 1.06 to 1.29]; adjusted RD, 3.84% [95% CI, 1.46% to 6.22%]). Conclusions and Relevance: Among patients with acute ischemic stroke treated with intravenous alteplase, use of NOACs within the preceding 7 days, compared with no use of anticoagulants, was not associated with a significantly increased risk of intracranial hemorrhage.

Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI.

BACKGROUND: In patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) with placement of stents, standard anticoagulation with a vitamin K antagonist plus dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor and aspirin reduces the risk of thrombosis and stroke but increases the risk of bleeding. The effectiveness and safety of anticoagulation with rivaroxaban plus either one or two antiplatelet agents are uncertain. METHODS: We randomly assigned 2124 participants with nonvalvular atrial fibrillation who had undergone PCI with stenting to receive, in a 1:1:1 ratio, low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months (group 1), very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months (group 2), or standard therapy with a dose-adjusted vitamin K antagonist (once daily) plus DAPT for 1, 6, or 12 months (group 3). The primary safety outcome was clinically significant bleeding (a composite of major bleeding or minor bleeding according to Thrombolysis in Myocardial Infarction [TIMI] criteria or bleeding requiring medical attention). RESULTS: The rates of clinically significant bleeding were lower in the two groups receiving rivaroxaban than in the group receiving standard therapy (16.8% in group 1, 18.0% in group 2, and 26.7% in group 3; hazard ratio for group 1 vs. group 3, 0.59; 95% confidence interval [CI], 0.47 to 0.76; P<0.001; hazard ratio for group 2 vs. group 3, 0.63; 95% CI, 0.50 to 0.80; P<0.001). The rates of death from cardiovascular causes, myocardial infarction, or stroke were similar in the three groups (Kaplan-Meier estimates, 6.5% in group 1, 5.6% in group 2, and 6.0% in group 3; P values for all comparisons were nonsignificant). CONCLUSIONS: In participants with atrial fibrillation undergoing PCI with placement of stents, the administration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a vitamin K antagonist plus DAPT for 1, 6, or 12 months. The three groups had similar efficacy rates, although the observed broad confidence intervals diminish the surety of any conclusions regarding efficacy. (Funded by Janssen Scientific Affairs and Bayer Pharmaceuticals; PIONEER AF-PCI ClinicalTrials.gov number, NCT01830543 .).

Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme.

OBJECTIVE: To characterise the pharmacokinetic-pharmacodynamic relationships for linezolid efficacy. DESIGN AND STUDY POPULATION: Retrospective nonblinded analysis of severely debilitated adult patients with numerous comorbid conditions and complicated infections enrolled under the manufacturer's compassionate use programme. METHODS: Patients received intravenous or oral linezolid 600 mg every 12 hours. Plasma concentrations were obtained and a multicompartmental pharmacokinetic model was fitted. Numerical integration of the fitted functions provided the area under the concentration-time curve over 24 hours (AUC), the ratio of AUC to minimum inhibitory concentration (AUC/MIC) and the percentage of time that plasma concentrations exceeded the MIC (%T>MIC). MAIN OUTCOME MEASURES: Modelled pharmacodynamic outcomes of efficacy included probabilities of eradication and clinical cure (multifactorial logistic regression, nonparametric tree-based modelling, nonlinear regression) and time to bacterial eradication (Kaplan-Meier and Cox proportional hazards regression). Factors considered included AUC/MIC, %T>MIC, site of infection, bacterial species and MIC, and other medical conditions. RESULTS: There were 288 cases evaluable by at least one of the efficacy outcomes. Both %T>MIC and AUC/MIC were highly correlated (Spearman r2 = 0.868). In our analyses, within specific infection sites, the probability of eradication and clinical cure appeared to be related to AUC/MIC (eradication: bacteraemia, skin and skin structure infection [SSSI], lower respiratory tract infection [LRTI], bone infection; clinical cure: bacteraemia, LRTI) and %T>MIC (eradication: bacteraemia, SSSI, LRTI; clinical cure: bacteraemia, LRTI). Time to bacterial eradication for bacteraemias appeared to be related to the AUC, %T>MIC and AUC/MIC. For most sites, AUC/MIC and %T>MIC models performed similarly. CONCLUSIONS: Higher success rates for linezolid may occur at AUC/MIC values of 80-120 for bacteraemia, LRTI and SSSI. Chance of success in bacteraemia, LRTI and SSSI also appear to be higher when concentrations remain above the MIC for the entire dosing interval.