Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT0437258

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Tissue Necrosis and Necrotizing Fasciitis After Intramuscular Administration of Diclofenac

OBJECTIVE: To report 6 cases of severe local reactions associated with intramuscular injection of diclofenac

Endotracheal and upper airways suctioning: changes in newborns’ physiological parameters Aspiración del tubo endotraqueal y de las vías aéreas superiores: alteraciones en los parámetros fisiológicos en recién nacidos Aspiração do tubo orotraqueal e de vias aéreas superiores: alterações nos parâmetros fisiológicos em recém-nascidos

This study investigated which physiological parameters change when endotracheal and upper airway suctioning is performed immediately before, immediately after and five minutes after this procedure is performed in newborns hospitalized in a Neonatal Intensive Care Unit (NICU). This is a quantitative and longitudinal study, before and after type, performed in the NICU of a public institution in the city of Fortaleza, CE, Brazil. The sample was composed of 104 newborns using oxigenotherapy and who needed endotracheal and upper airway suctioning. The results showed significant alterations in respiratory and heart rates (p<0.05) in neonates using Oxyhood and nasal CPAP while the pulse significantly changed (p<0.05) in newborns placed in oxyhood, using nasal CPAP and Mechanical Ventilation; oxygen saturation was the only parameter that did not alter significantly. We propose that nurses develop non-pharmacological interventions to reduce potential alterations caused in newborns’ physiological parameters due to this procedure.<br>Se objetivó investigar cuales son los parámetros fisiológicos que se alteran en la ejecución de la aspiración del tubo endotraqueal (TOT) y de las vías aéreas superiores (VAS), comparándolos inmediatamente antes, inmediatamente después y cinco minutos después de la realización del referido procedimiento. Se trata de un estudio cuantitativo, longitudinal, del tipo antes y después, realizado en una Unidad de Terapia Intensiva Neonatal (UTIN) de una institución pública en Fortaleza, CE, Brasil. La muestra constó de 104 recién nacidos que usaban oxigenoterapia, y que necesitaron de aspiración del tubo endotraqueal y de las vías aéreas superiores. Los resultados mostraron, alteraciones significativas (p<0,05) en las frecuencias respiratorias (FR) y cardíaca (FC) de los recién nacidos en uso de Oxi-Hood y CPAP nasal, y también del pulso (p<0,05) para los recién nacidos en Oxi-Hood, CPAP nasal y Ventilación Mecánica (VM), siendo la saturación de oxígeno (SpO2), el único parámetro que no fue estadísticamente significativo. Se propone a los enfermeros desarrollar intervenciones no farmacológicas para reducir posibles alteraciones de los parámetros fisiológicos de los recién nacidos provenientes de este procedimiento.<br>Objetivou-se investigar quais são os parâmetros fisiológicos que se alteram na execução da aspiração do tubo orotraqueal (TOT) e das vias aéreas superiores (VAS), comparando-os imediatamente antes, imediatamente depois e cinco minutos após a realização do referido procedimento. Trata-se de estudo quantitativo, longitudinal, do tipo antes e depois, realizado em Unidade de Terapia Intensiva Neonatal (Utin) de uma instituição pública em Fortaleza, CE, Brasil. A amostra constou de 104 recém-nascidos em uso de oxigenoterapia, e que necessitaram de aspiração do tubo orotraqueal e das vias aéreas superiores. Os resultados mostraram alterações significativas (p<0,05) nas frequências respiratória (FR) e cardíaca (FC) dos recém-nascidos, em uso de tenda de oxigênio (Oxi-Hood) e pressão contínua das vias aéreas (CPAP nasal), e também de pulso (p<0,05) para os recém-nascidos em Oxi-Hood, CPAP nasal e ventilação mecânica (VM), sendo a saturação de oxigênio (SpO2) o único parâmetro que não foi estatisticamente significante. Propõe-se aos profissionais enfermeiros o desenvolvimento de intervenções não farmacológicas para reduzir possíveis alterações dos parâmetros fisiológicos dos recém-nascidos, decorrentes desse procedimento