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N Engl J Med ; 386(21): 1986-1997, 2022 05 26.
Article in English | MEDLINE | ID: covidwho-1864788


BACKGROUND: Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. METHODS: We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025. RESULTS: A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, -2.6 percentage points; 95% CI, -3.8 to -1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, -1.1 to 1.7; one-sided P = 0.04 for noninferiority). CONCLUSIONS: Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established. (Funded by the Canadian Institutes of Health Research and others; POISE-3 number, NCT03505723.).

Antifibrinolytic Agents , Tranexamic Acid , Antifibrinolytic Agents/adverse effects , Antifibrinolytic Agents/therapeutic use , Canada , Hemorrhage/etiology , Hemorrhage/prevention & control , Humans , Surgical Procedures, Operative , Thrombosis/chemically induced , Thrombosis/drug therapy , Tranexamic Acid/adverse effects , Tranexamic Acid/therapeutic use
PLoS One ; 17(2): e0262264, 2022.
Article in English | MEDLINE | ID: covidwho-1793544


We estimated excess mortality in Medicare recipients in the United States with probable and confirmed Covid-19 infections in the general community and amongst residents of long-term care (LTC) facilities. We considered 28,389,098 Medicare and dual-eligible recipients from one year before February 29, 2020 through September 30, 2020, with mortality followed through November 30th, 2020. Probable and confirmed Covid-19 diagnoses, presumably mostly symptomatic, were determined from ICD-10 codes. We developed a Risk Stratification Index (RSI) mortality model which was applied prospectively to establish baseline mortality risk. Excess deaths attributable to Covid-19 were estimated by comparing actual-to-expected deaths based on historical (2017-2019) comparisons and in closely matched concurrent (2020) cohorts with and without Covid-19. Overall, 677,100 (2.4%) beneficiaries had confirmed Covid-19 and 2,917,604 (10.3%) had probable Covid-19. A total of 472,329 confirmed cases were community living and 204,771 were in LTC. Mortality following a probable or confirmed diagnosis in the community increased from an expected incidence of about 4.0% to actual incidence of 7.5%. In long-term care facilities, the corresponding increase was from 20.3% to 24.6%. The absolute increase was therefore similar at 3-4% in the community and in LTC residents. The percentage increase was far greater in the community (89.5%) than among patients in chronic care facilities (21.1%) who had higher baseline risk of mortality. The LTC population without probable or confirmed Covid-19 diagnoses experienced 38,932 excess deaths (34.8%) compared to historical estimates. Limitations in access to Covid-19 testing and disease under-reporting in LTC patients probably were important factors, although social isolation and disruption in usual care presumably also contributed. Remarkably, there were 31,360 (5.4%) fewer deaths than expected in community dwellers without probable or confirmed Covid-19 diagnoses. Disruptions to the healthcare system and avoided medical care were thus apparently offset by other factors, representing overall benefit. The Covid-19 pandemic had marked effects on mortality, but the effects were highly context-dependent.

COVID-19/mortality , Medicare/trends , Aged , Aged, 80 and over , COVID-19/economics , Female , Humans , Incidence , Insurance Benefits/trends , Long-Term Care/trends , Male , Mortality , Risk Factors , SARS-CoV-2/pathogenicity , Skilled Nursing Facilities/trends , United States
Crit Care Med ; 49(10): 1684-1693, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1452742


OBJECTIVES: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. DESIGN: A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process. PARTICIPANTS: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. MEASUREMENTS AND MAIN RESULTS: The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. CONCLUSIONS: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

Hypnotics and Sedatives/pharmacokinetics , Hypnotics and Sedatives/therapeutic use , Congresses as Topic , Consensus , Delphi Technique , District of Columbia , Humans , Hypnotics and Sedatives/pharmacology , Respiration, Artificial/instrumentation , Respiration, Artificial/methods , Time Factors