NEJM evidence最新文献

Morning Report is a time-honored tradition where physicians-in-training present cases to their colleagues and clinical experts to collaboratively examine an interesting patient presentation. The Morning Report section seeks to carry on this tradition by presenting a patient's chief concern and story, inviting the reader to develop a differential diagnosis and discover the diagnosis alongside the authors of the case. This report examines the story of a 50-year-old man who presented for evaluation of weakness on the left side of his body and difficulty speaking clearly. Using questions, physical examination, and testing, an illness script for the presentation emerges; the differential is refined until a diagnosis is made.

Background: Concerns persist regarding the cognitive safety of achieving very low levels of low-density lipoprotein (LDL) cholesterol. Although short-term studies are reassuring, the long-term cognitive effects of sustained exposure to very low LDL cholesterol levels through combined proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibition and statin therapy remain unknown.

Methods: This prospective study enrolled a subset of adults with atherosclerotic cardiovascular disease who had completed a neurocognitive substudy (EBBINGHAUS) of a placebo-controlled randomized trial of evolocumab (FOURIER) and were eligible for a long-term open-label extension. The objective of this current study was to assess the long-term effect of evolocumab on cognitive function. Cognitive function was assessed annually, and the primary end point was change from baseline in executive function within each group, measured using the spatial working memory strategy index score (range, 4-28), with lower scores indicating better performance.

Results: A total of 473 patients out of the 1974 patients in the parent EBBINGHAUS study were enrolled and additionally followed for a median of 5.1 years (maximum follow-up since original random assignment 7.2 years). The median age was 62 years; 70% were male, and 91% were White. At 12 weeks into the open-label extension period, median LDL cholesterol across the overall population was 35 mg/dl (interquartile range, 21-55 mg/dl). Treatment with evolocumab was not associated with a change in executive function during the open-label extension in either patients who were originally randomly assigned to and continued evolocumab (mean±standard deviation of 0.1±2.8, P=0.49) or patients originally randomly assigned to placebo who then started on evolocumab (-0.1±2.5, P=0.64). At the final study visit, executive function scores were similar between randomly assigned groups (17.5±3.7 and 17.3±3.7, respectively).

Conclusions: Exposure to very low levels of LDL cholesterol, achieved via PCSK9 inhibition and statin therapy, was not associated with cognitive impairment through long-term follow-up. Further studies are needed to assess the generalizability to adults at higher risk of dementia.

Background: Clinical guidelines have concluded that there are insufficient data to provide recommendations for the hemoglobin threshold for the use of red cell transfusion in patients with acute myocardial infarction (MI) and anemia. After the recent publication of the Myocardial Infarction and Transfusion (MINT) trial, we performed an individual patient-level data meta-analysis to evaluate the effect of restrictive versus liberal blood transfusion strategies.

Methods: We conducted searches in major databases. Eligible trials randomly assigned patients with MI and anemia to either a restrictive (i.e., transfusion threshold of 7-8 g/dl) or liberal (i.e., transfusion threshold of 10 g/dl) red cell transfusion strategy. We used individual patient data from each trial. The primary outcome was a composite of 30-day mortality or MI.

Results: We included 4311 patients from four trials. The primary outcome occurred in 334 patients (15.4%) in the restrictive strategy and 296 patients (13.8%) in the liberal strategy (relative risk [RR] 1.13, 95% confidence interval [CI], 0.97 to 1.30). Death at 30 days occurred in 9.3% of patients in the restrictive strategy and in 8.1% of patients in the liberal strategy (RR 1.15, 95% CI, 0.95 to 1.39). Cardiac death at 30 days occurred in 5.5% of patients in the restrictive strategy and in 3.7% of patients in the liberal strategy (RR 1.47, 95% CI, 1.11 to 1.94). Heart failure (RR 0.89, 95% CI, 0.70 to 1.13) was similar in the transfusion strategies. All-cause mortality at 6 months occurred in 20.5% of patients in the restrictive strategy compared with 19.1% of patients in the liberal strategy (hazard ratio 1.08, 95% CI, 1.05 to 1.11).

Conclusions: Pooling individual patient data from four trials did not find a definitive difference in our primary composite outcome of MI or death at 30 days. At 6 months, a restrictive transfusion strategy was associated with increased all-cause mortality. (Partially funded by a grant from the U.S. National Heart, Lung, and Blood Institute [R01HL171977].).

Background: Hemoglobin SC (HbSC) is a common sickle hemoglobinopathy that causes acute complications, chronic organ damage, and early death with no established disease-modifying treatment. In this trial, we examined the safety and efficacy of hydroxyurea treatment in patients with HbSC.

Methods: Prospective Identification of Variables as Outcomes for Treatment (PIVOT) was a double-blind, randomized, placebo-controlled, non-inferiority phase 2 trial in which we assigned children and adults with HbSC in Ghana to 12 months of hydroxyurea or placebo. The primary end point was hematologic dose-limiting toxicities (DLTs), including cytopenias or elevated hemoglobin levels during 12 months of blinded treatment. Clinical end points included vaso-occlusive pain events, acute chest syndrome, hospitalizations, transfusions, and malaria. Quality-of-life measures, organ function assessments, and rheological measurements were also collected.

Results: Of the 243 enrolled patients (118 female), 212 eligible participants initiated blinded treatment at 20.0±5.0 mg/kg/day. DLTs occurred in more participants on hydroxyurea (33%) than the placebo (11%), with a difference of 22 percentage points (95% confidence interval [CI],11 to 34 percentage points), which exceeded the predefined 15 percentage point noninferiority margin. Elevated levels of hemoglobin occurred in 12 participants on hydroxyurea and 10 on the placebo. Hydroxyurea treatment was associated with 57.0 versus 149.6 vaso-occlusive pain events per 100 person-years (incidence rate ratio [IRR] 0.38; 95% CI, 0.28 to 0.52), and 12.9 versus 30.6 hospitalizations per 100 person-years (IRR 0.42; 95% CI, 0.22 to 0.81). A composite of acute sickle-related events occurred in 37 participants on hydroxyurea versus 69 participants on placebo (IRR 0.39; (95% CI, 0.26 to 0.59), a difference observed in both children and adults.

Conclusions: The PIVOT trial did not meet its primary end point. Hydroxyurea at 20 mg/kg in patients with HbSC was associated with more hematologic DLTs than placebo, but most were mild and transient. Hydroxyurea was associated with less vaso-occlusive pain and fewer sickle-related events in both children and adults; a new trial will need to be done to establish the efficacy of this approach. (Funded by Theravia; Pan-African Clinical Trials Registry number, PACTR 202108893981080).

Background: Fine particulate matter (PM_2.5) exposure is adversely linked to atherosclerotic cardiovascular disease (ASCVD). However, most studies focused on PM_2.5 mass rather than its chemical composition and specific sources. Particulate pollution sources can have distinct, cumulative, and potentially synergistic health impacts. We investigated the associations of source-specific PM_2.5 exposure with ASCVD mortality in the United States, considering the combined associations and regional variations.

Methods: We used data from the Centers for Medicare & Medicaid Services (including data from 65,838,403 participants) from 2000 to 2016. We estimated PM_2.5 exposure using machine-learning models and attributed components to five source categories. We used Poisson survival models to assess the associations with the source categories.

Results: Higher ASCVD mortality rate (rate ratio [95% confidence interval (CI)] per interquartile range increase) was associated with oil combustion (1.051 [1.049 to 1.052]), industrial pollution (1.054 [1.052 to 1.056]), coal and biomass burning (1.065 [1.062 to 1.067]), and motor vehicle pollution (1.044 [1.042 to 1.046]). These associations persisted even after limiting our sample to ZIP code-years with PM_2.5<9 μg/m³ - the current National Ambient Air Quality Standard. In these areas the observed rate ratio for a one-unit increase in PM_2.5 mass was 1.028 (95% CI, 1.026 to 1.029).

Conclusions: We found higher ASCVD mortality rate associated with PM_2.5, with differential effects across sources. These data highlight the importance of considering local population characteristics and exposure patterns when assessing health risks associated with PM_2.5.

Background: Cycle ergometry is a rehabilitation strategy used in the intensive care unit (ICU) which may help mitigate post-ICU impairments. We aimed to systematically review and summarize evidence examining the efficacy and safety of cycle ergometry in the ICU.

Methods: We included randomized controlled trials (RCTs) of critically ill adults with any diagnosis admitted to the ICU for >24 hours, comparing cycling interventions to control (no cycling). The primary outcome was physical function, using a hierarchical approach to standardize this outcome across trials. We performed random-effects meta-analyses and assessed the certainty of effect estimates using the Grading of Recommendations Assessment, Development, and Evaluation approach.

Results: We included 33 RCTs that enrolled 3274 patients. Cycling may improve physical function at ICU discharge (12 RCTs, 1291 patients, standardized mean difference [SMD], 0.33 [95% confidence interval (CI), 0.05 to 0.62], low certainty) and posthospital discharge (8 RCTs, 865 patients, SMD, 0.23, [95% CI, 0.04 to 0.42], low certainty). Cycling may decrease ICU length of stay (29 RCTs, 2575 patients, mean difference [MD], 1.06 days fewer [95% CI, 0.33 to 1.80 days fewer], low certainty) and probably decreases hospital length of stay (22 RCTs, 2060 patients, MD, 1.48 days fewer [95% CI, 0.47 to 2.49 days fewer], moderate certainty). Cycling may have no effect on ICU mortality (17 RCTs, 2039 patients, risk ratio, 12 fewer deaths per 1000 [95% CI, 43 fewer to 23 more], low certainty). The pooled rate of adverse events in the intervention group was 1% (11 RCTs, 4623 sessions, [95% CI, 0 to 2%], low certainty) and in the comparison group, 2% (6 RCTs, 3365 sessions, [95% CI, 0 to 5%], low certainty).

Conclusions: In this meta-analysis, we found that cycling with critically ill patients may improve physical function at ICU discharge and after hospital discharge, may reduce ICU length of stay, and probably reduces hospital length of stay, with no effect on other outcomes including mortality. We observed low to very low certainty of evidence for all but one outcome of interest. Adverse events were uncommon. (PROSPERO number, CRD 42018092132.).

AbstractDuring hospitalization, patients' blood pressure often varies substantially from their outpatient steady state and many patients experience marked fluctuations. Given a lack of guidelines for inpatient blood pressure management, treatment patterns vary and recent observational studies demonstrate intensive inpatient blood pressure treatment may be been associated with harm. This article reviews current knowledge in inpatient blood pressure management and proposes a randomized trial to compare clinical outcomes of more versus less restrictive blood pressure goals.