BACKGROUND:Delirium is a frequent complication in comatose Out-of-Hospital Cardiac Arrest (OHCA) survivors requiring postresuscitation intensive care and is associated with higher mortality and longer hospitalization. Despite this, there is no established pharmacologic strategy for delirium prevention in OHCA survivors. This trial aims to evaluate if prophylactic use of olanzapine in comatose OHCA patients can reduce delirium incidence, thereby leading to a shorter duration of hospitalization. METHODS:The Danish Out-of-Hospital Cardiac Arrest (DANOCHA) trial is an investigator-initiated, multicenter, randomized, controlled trial evaluating four postresuscitation interventions in adult patients resuscitated after OHCA including administration of prophylactic olanzapine compared with placebo. Comatose adult patients with OHCA of presumed cardiac cause and sustained return of spontaneous circulation (> 20 min) will be randomized 1:1 to receive either 10 mg of olanzapine or placebo immediately after inclusion in the trial and the two following evenings for a total of three doses. The primary outcome is days alive and out of the hospital within 30 days after admission. Analysis of primary outcome will be analyzed using the Wilcoxon rank-sum test. Results will be presented as medians with interquartile ranges and 95% confidence intervals for the median difference. Inclusion began in June 2023, and the study aims to include 1000 patients from five sites over an estimated time period of 3-4 years. The trial is registered at clinicaltrials.gov (identifier: NCT05895838) and euclinicaltrials.eu (2024-515997-28-00). PERSPECTIVES:Optimizing postresuscitation care through large-scale randomized trials is essential for improving outcomes of OHCA survivors. The findings from this part of the DANOHCA trial will provide evidence regarding the effects of prophylactic olanzapine in comatose OHCA survivors. TRIAL REGISTRATION:EudraCT no 2016-003265-26; EU CTIS no 2024-515997-28-00; ClinicalTrials.gov identifier NCT05895838.

AIM:The objectives were to: (i) compare symptoms of anxiety and depression between survivors and cohabiting spouses/partners, and (ii) investigate characteristics associated with higher scores of anxiety and depression in both parts, respectively. METHODS:This observational exploratory substudy used three-month follow-up data from the Blood Pressure and Oxygenation Targets after Cardiac Arrest (BOX)-trial, restricted to cohabiting survivor-partner dyads. Symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS-A anxiety, HADS-D depression). Paired comparisons were used to examine differences within the dyad, and multivariable linear regression models applied separately for survivors and spouses/partners to investigate associations between characteristics and symptom burden, reported as β with 95% confidence intervals (CI). RESULTS:Among 321 eligible OHCA survivors, 200 survivor-partner dyads were included. Median HADS-A scores were 4 (IQR 1-7) in survivors and 5 (IQR 1-8) in spouses/partners (p = 0.107). Median HADS-D scores were 1 (IQR 0-4) and 1 (IQR 0-3), respectively (p = 0.290). In adjusted regression analyses among survivors, higher age was associated with lower scores of HADS-A (β -0.065, 95% CI -0.125; -0.025; p = 0.012) and HADS-D (β -0.040, 95% CI -0.090; -0.00; p = 0.037). In sensitivity analyses, poorer self-rated health was associated with higher scores of HADS-A and HADS-D in both parts, and poorer survivor self-rated health was associated with higher scores of HADS-D among spouses/partners. CONCLUSION:Symptoms of anxiety and depression did not differ in survivors and their spouse/partners. Higher age was associated with lower scores of anxiety and depression among survivors, and poorer self-rated health with higher symptom-scores in both.

Background Therapeutic options for BRAFV600-mutant melanoma in patients who progress on BRAF/MEK-inhibitors (BRAF/MEKi) and immune-checkpoint-inhibitor (ICI) therapy, are limited. We conducted a retrospective registry study to investigate post-ICI rechallenge with BRAF/MEKi, stratified by type of initial BRAF/MEKi therapy. Methods This retrospective study analysed patients from the EUMelaReg registry, who received adjuvant or first-line (1L) BRAF/MEKi in the advanced setting, followed by ICI therapy and were later retreated with BRAF/MEKi. Overall response rate (ORR) for rechallenge served as primary endpoint, disease-control rate (DCR), progression-free survival (PFS), and overall survival (OS) were further endpoints. A covariate-matched control group of patients who received BRAF/MEKi only after 1L ICI failure was selected for comparison. Results Among patients previously treated with adjuvant (n=42) or non-adjuvant (n=142) BRAF/MEKi, rechallenge after one interim ICI line resulted in ORRs of 26.2% and 30.3% and DCRs of 42.9% and 61.8%, respectively. Median PFS was 8.4 and 5.1 months, median OS 13.8 and 8.6 months, respectively. Overall, the rechallenge group had a 1-year OS of 43.2%, lower than the matched control (58.9%). The adjuvant subgroup was similar to control (55.4%), while the advanced subgroup showed notably poorer survival (39.9%). Subgroup analyses showed that both the pre-ICI response to BRAF/MEKi treatment and progressive disease prior to ICI were associated with outcome of the BRAF/MEKi rechallenge. Conclusion Rechallenge with BRAF/MEKi therapy under real-world conditions for advanced melanoma provides a valid treatment option. For patients who received their initial BRAF/MEKi therapy as adjuvant therapy there seems to be only limited impairment of outcomes.

BACKGROUND:Hemodynamic management after out-of-hospital cardiac arrest (OHCA) is critical, yet the impact of vasopressor-driven mean arterial pressure (MAP) targets on pulmonary circulation and right ventricular (RV) function remains unclear. METHODS:In this substudy of the randomized, double-blinded BOX trial, comatose OHCA survivors were allocated to low (63 mmHg) or high (77 mmHg) MAP targets. Pulmonary artery catheters (PAC) were used for serial hemodynamic assessment for 48 h after Intensive Care Unit admission. The primary endpoint was calculated pulmonary vascular resistance (PVR), secondary endpoints included pulmonary capillary wedge pressure (PCWP), pulmonary artery pulsatility index (PAPi), and RV cardiac power output (RV-CPO)-a measurement of RV pumping function. RESULTS:Among 730 included patients (median time randomization to PAC insertion 1.3 h), mPAP was consistently higher in the high-MAP group (mean difference 1.11-1.71 mmHg, 95% CI range 0.12-2.59). Calculated PVR was transiently lower in the high-MAP group during the first 24 h (mean difference -0.16 to -0.30, 95% CI range -0.31 to 0.11), before converging between groups. RV-CPO was lower in the low-MAP group throughout the observation period (mean difference 0.01-0.04 W [95% range 0.00-0.07], with the largest difference at 48 h. PCWP decreased in both groups but was significantly lower in the low-MAP group during the first 12 h (mean difference 1.06-1.40 mmHg, 95% CI range 0.25-2.38). CONCLUSIONS:In comatose OHCA survivors, targeting a higher MAP increased pulmonary artery pressures, PCWP, RV-CPO, heart rate, and cardiac output. The proportionally greater increase in cardiac output over pulmonary artery pressures resulted in a decreased calculated PVR. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT03141099. EDITORIAL COMMENT:In this secondary analysis of a subgroup in the BOX out of hospital cardiac arrest treatment trial for oxygen level targets, blood pressure treatment target levels, higher or lower were analyzed, including central circulatory outcomes, using a pulmonary artery catheter. The higher blood pressure target group had accompanying higher pulmonary artery pressures and cardiac output, with initially a small reduction in calculated pulmonary vascular resistance.

BACKGROUND:Encorafenib is a BRAF inhibitor with a pharmacodynamic profile distinct from that of dabrafenib, including a longer dissociation half-life that may enable more sustained BRAF inhibition. It has been hypothesized that this could translate into superior clinical efficacy. We aimed to determine whether encorafenib plus binimetinib is superior to dabrafenib plus trametinib in terms of clinical activity and outcomes. METHODS:Patients were identified through the Danish Metastatic Melanoma Database, a national registry collecting prospective data on systemic treatments. We retrospectively retrieved baseline, treatment, and outcome data for patients with metastatic BRAF-mutant melanoma treated with encorafenib plus binimetinib or dabrafenib plus trametinib from 2017 to 2024. Both unmatched and propensity score-matched analyses were conducted to mitigate potential confounding. RESULTS:A total of 751 patients were included (422 dabrafenib plus trametinib, 329 encorafenib plus binimetinib). Baseline characteristics were balanced between groups. In the unmatched cohort, no statistically differences were observed between dabrafenib plus trametinib and encorafenib plus binimetinib in progression-free survival (PFS; median = 7.9 vs 8.0 months; hazard ratio [HR] = 0.99, P = .90), overall survival (median = 15.5 vs 15.4 months; HR = 0.91, P = .30), or melanoma-specific survival (median = 16.2 vs 15.7 months; HR = 0.94, P = .50). Propensity score-matched analyses confirmed these findings (PFS: HR = 1.05, P = .60; overall survival: HR = 0.922, P = .41; melanoma-specific survival: HR = 0.97, P = .74). Post hoc power analysis for detecting a 3-month survival difference was adequate for PFS (97.5%) but limited for overall survival (56.3%) and melanoma-specific survival (52.1%). CONCLUSIONS:We found no evidence that encorafenib plus binimetinib is superior to dabrafenib plus trametinib in metastatic melanoma. These findings suggest that the choice between these combinations should be guided by tolerability profiles and economic considerations rather than efficacy.

BACKGROUND:Adjuvant anti-PD-1 therapy improves recurrence-free survival in resected stage III melanoma, but its impact on survival remains uncertain. OBJECTIVE:To evaluate the association of adjuvant anti-PD-1 therapy with overall survival (OS) and melanoma-specific mortality (MSM) in patients with stage III melanoma. METHODS:Five-year OS and MSM were compared between stage III melanoma patients diagnosed before (pre-cohort: June 2016-May 2018, n = 450) and after (post-cohort: January 2019-December 2020, n = 552) implementation of adjuvant anti-PD-1 in Denmark. Post-cohort patients receiving adjuvant anti-PD-1 were propensity score-matched to pre-cohort patients. RESULTS:Median follow-up exceeded 5 years in both cohorts. At the population level, no difference in 5-year OS or MSM was demonstrated between the total cohorts. In the post-cohort, 297 patients (53.8%) received adjuvant anti-PD-1. After matching (n = 279 per group), adjuvant anti-PD-1 was associated with higher 5-year OS (80.3% vs. 71.7%; HR 0.67, 95% CI 0.47-0.95; p = 0.022). 5-year MSM estimates were inconclusive (16.6% vs. 20.8%, HR 0.77, 95% CI 0.52-1.14; p = 0.24). Among matched patients with occult nodal disease, results were also inconclusive (OS HR 0.70, 95% CI 0.46-1.06). Sensitivity power analyses indicated that only large effects were detectable given the available events. CONCLUSIONS:We were unable to demonstrate an improved survival at the population level after adjuvant anti-PD-1 introduction, but matched analysis showed higher OS in treated patients. However, uncertainty in disease-specific outcomes and limited power preclude firm conclusions. Mature trial data are essential for defining the role of adjuvant therapy alongside emerging neoadjuvant strategies. Until then, carefully individualized adjuvant treatment decisions are of particular importance.

BACKGROUND:The microaxial flow pump (mAFP) has demonstrated improved outcomes in selected patients with ST-segment elevation acute myocardial infarction and cardiogenic shock (STEMI-CS). However, its use has been associated with bleeding events. OBJECTIVES:The authors analyzed bleeding in the international multicenter randomized DanGer Shock (Danish German Shock) trial. METHODS:A total of 355 patients with ST-segment elevation acute myocardial infarction and cardiogenic shock were randomized to either mAFP (n = 179) or standard care alone (n = 176). Bleeding events were classified according to Bleeding Academic Research Consortium (BARC) type 3-5. RESULTS:In the mAFP group, 47 patients (26.3% [95% CI: 20.3%-33.2%]) experienced BARC type 3-5 bleeding, compared with 27 (15.3% [95% CI: 10.7%-21.4%]) in the standard care group; P < 0.001. Median follow-up was 121 days (Q1-Q3: 3-180 days). Among the 210 patients treated with any mechanical circulatory support (MCS), 2 of 74 bleeding events (2.7%) occurred in the cath lab, 35 (47.3%) while on MCS, and 37 (50.0%) after the MCS was removed. Bleeding increased with complexity of MCS: OR for BARC 3-5 bleeding with mAFP was 4.94 (95% CI: 2.30-10.65); P < 0.001, with venoarterial extracorporeal membrane oxygenation (VA-ECMO) 8.06 (95% CI: 2.81-23.09); P < 0.001, and with combined mAFP+VA-ECMO 27.40 (95% CI: 9.82-76.43); P < 0.001, no device as reference. Multivariable logistic regression identified use of mAFP, renal replacement therapy, and escalation to VA-ECMO as predictors of BARC type 3-5 bleeding. CONCLUSIONS:Patients randomized to mAFP experienced more bleeding than the standard care group. Bleeding was associated with the complexity of MCS, with one-half of the bleeding events occurring after device removal. (Danish Cardiogenic Shock Trial [DanShock]; NCT01633502).

BACKGROUND:Post-cardiac arrest care for patients resuscitated from out-of-hospital cardiac arrest (OHCA) includes multiple pharmacological and physiological interventions, yet optimal strategies to reduce post-cardiac arrest syndrome-related morbidity and mortality remain uncertain. The DANOHCA (Danish Out-of-Hospital Cardiac Arrest) trial evaluates four such interventions-high-dose dexamethasone, prophylactic olanzapine, elevated backrest position, and early wakeup-in a factorial trial framework. This manuscript presents the complete statistical analysis plan for analyses common to all four DANOHCA interventions. METHODS:DANOHCA is an investigator-initiated, multicenter, randomized, 2 × 2 × 2 × 2 factorial clinical trial enrolling comatose adult OHCA patients with a presumed cardiac etiology who achieve sustained return of spontaneous circulation, with randomization within 180 min of return of spontaneous circulation. Participants are co-randomized to Dexamethasone versus placebo, olanzapine versus placebo, backrest elevation at 35° versus 5°, and early (≤ 6 h) versus late (28-36 h) wakeup, with pharmacological interventions blinded and physiological interventions open-label. This statistical analysis plan specifies the primary and secondary outcomes, covariate adjustment, handling of missing data, assessments of interactions between interventions, and assumption checks, with all primary analyses conducted according to the intention-to-treat principle. The analysis plan is finalized prior to completion of randomization. RESULTS:The primary outcomes are 90-day all-cause mortality for the dexamethasone and backrest interventions, and days alive outside hospital within 30 days for the olanzapine and early wakeup interventions, with common secondary and tertiary endpoints including mortality at later time points, neurological function, health-related quality of life, organ function, and safety outcomes. Mixed-effects regression models, Cox regression, stratified nonparametric tests, and prespecified sensitivity analyses will be applied to minimize bias and quantify intervention effects, including their associated uncertainties. CONCLUSION:This predefined statistical analysis plan provides a detailed, transparent framework for the primary analyses and reporting of the DANOHCA trial. TRIAL REGISTRATION:Clinical Trials Information System (CTIS): 2024-515997-28-00.

Background Randomised trials recently showed that sequencing of first-line (1L) immune checkpoint inhibitor (ICI) and second-line (2L) BRAF-MEK-inhibitor (BRAF/MEKi) combination therapy provides better clinical outcomes in BRAFV600-mutated, irresectable/metastatic melanoma than the inverse sequence. However, efficacy benchmark data for 2L BRAF/MEKi are limited as the combination was developed for 1L use, lacking estimates for the impact of prior ICI. Methods This retrospectively study analysed 2,343 patients from the EUMelaReg registry with BRAFV600-mutated melanoma who received BRAF/MEKi either as 2L after failing 1L ICI (n=654) or as 1L treatment (n=1,689). Patients with prior adjuvant ICI or BRAF/MEKi were excluded. Prognostic imbalances between the two groups were adjusted using 1:1 inverse propensity score matching. Key efficacy outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and time on treatment (TOT). Results Patients in the 2L cohort achieved outcomes from start of treatment at least equivalent to the matched 1L BRAF/MEKi cohort. Kaplan-Meier estimates demonstrated longer median PFS (8.4 vs 7.7 months; p=0.01) and longer median TOT (7.8 vs 6.2 months; p=0.002) for patients treated with 2L BRAF/MEKi compared to 1L. Median OS from start of 2L (17.2 months) or 1L (16.0 months) BRAF/MEKi was similar (p=0.73) despite inherent bias from differing index dates. ORR among both groups (56.4% vs 53.5%; p=0.32) was equal. Conclusion This study further supports the recommended sequencing of ICI as 1L and BRAF/MEKi as 2L therapy for patients with BRAFV600-mutated melanoma. It shows that prior failure of ICI does not compromise the efficacy of BRAF/MEKi treatment.

BACKGROUND:Microaxial flow pump (mAFP) use in selected patients with ST-segment-elevation myocardial infarction complicated by cardiogenic shock improves survival. The present study aimed to assess the influence of delay from first symptoms to randomization on the benefit of an mAFP in patients with ST-segment-elevation myocardial infarction complicated by cardiogenic shock. METHODS:This was a secondary analysis of the international, multicenter, randomized, open-labeled DanGer Shock trial (Danish-German Cardiogenic Shock). A total of 345 of 355 patients with ST-segment-elevation myocardial infarction and cardiogenic shock were enrolled in this substudy. Patients were stratified into quartiles according to delay from first symptoms to randomization to either an mAFP or standard care alone. The end point was death from any cause at 180 days for treatment with an mAFP versus standard of care, according to time from onset of symptoms to randomization obtained by logistic regression analysis. RESULTS:Mortality at 180 days increased across quartiles of time from onset of symptoms to randomization: Q1 (0-140 minutes), 36%; Q2 (141-248 minutes), 53%; Q3 (249-650 minutes), 59%; and Q4 (> 651 minutes), 62%, respectively (log-rank P=0.002). However, those with longer delays were also older and more often women. Median age rose from 66 years (interquartile range, 57-73) in the earliest quartile to 71 years (interquartile range, 62-79) in the latest quartile (P=0.005), and the proportion of women increased from 15% to 34%, respectively. Combining the 3 lowest quartiles for the time from onset of symptoms to randomization, the mAFP treatment was associated with an odds ratio of 0.51 (95% CI, 0.31-0.84), whereas the odds ratio for the highest quartile was 0.92 (95% CI, 0.38-2.22; P for interaction = 0.26). CONCLUSIONS:In patients with ST-segment-elevation myocardial infarction complicated with cardiogenic shock, treatment with an mAFP was associated with reduced all-cause mortality, but the treatment benefit appeared to weaken with prolonged time from the onset of symptoms to randomization. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01633502.

Nivolumab plus ipilimumab has demonstrated activity after anti-PD-1 failure in advanced melanoma, but its effectiveness in later lines and as rechallenge remains unclear. We aimed to characterize outcomes of nivolumab/ipilimumab administered in the third line or beyond. Using the Danish Metastatic Melanoma Database (DAMMED), we identified patients with metastatic melanoma (excluding uveal melanoma) treated with nivolumab/ipilimumab after at least two prior lines of therapy, including adjuvant treatment, between 2017 and 2024. Baseline characteristics, prior treatments, and clinical outcomes were collected. Seventy-three patients were included (median age 57.8 years), of whom 47.9% had brain metastases. Most had progressed on anti-PD-1-based therapy (93.2%); 32.9% had prior exposure to anti-CTLA-4, and 84.9% had received BRAF/MEK inhibitors. Nivolumab/ipilimumab was administered as third-line therapy in 71.2%. After a median follow-up of 27.6 months, the overall response rate was 23.3% (12.5% with prior anti-CTLA-4 exposure vs. 28.6% without). Median duration of response was 19.4 months (95% CI, 14.5-NR). Median PFS was 2.7 months (95% CI, 2.4-5.7) and median OS was 9.6 months (95% CI, 6.5-20.1). In conclusion, in heavily pretreated melanoma, nivolumab/ipilimumab induces durable responses in a minority of patients, with reduced efficacy after prior anti-CTLA-4 exposure.

PURPOSE:Among responders to PD-1/PD-L1 blockade, it remains unclear whether tumour type and traditional baseline patient and tumour characteristics provide additional prognostic information for progression risk beyond response depth. METHODS:In this nationwide, population-based cohort study, we identified adults with metastatic melanoma (MM), renal cell carcinoma (RCC), or non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 monotherapy or dual checkpoint blockade. Analyses were restricted to responders by investigator-assessed RECIST (complete or partial response) with outcomes administratively censored at 5 years. Prespecified baseline and on-treatment variables were evaluated for associations with progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier and Cox models and assessed for consistency across tumour types. RESULTS:Among 2127 responders, PFS trajectories within response depth categories (complete response and partial response) were highly similar across MM, RCC, and NSCLC. Prespecified variables with prognostic value in the overall population, including performance status and treatment line, provided limited additional prognostic information once response depth was known. Depth of response (complete vs partial) was the strongest independent factor associated with progression risk within each tumour cohort. CONCLUSIONS:Among patients with MM, RCC, or NSCLC who achieved an objective response to PD-1/PD-L1 blockade, tumour type and traditional baseline prognostic factors provided limited additional stratification of progression risk once response depth was known. These findings suggest that, within the tumour types studied, response durability is primarily associated with response depth rather than other known clinical features, supporting prospective evaluation of response-guided follow-up strategies and interventions designed to deepen responses.

INTRODUCTION:The therapeutic benefit of sentinel node biopsy (SNB) for melanoma patients remains controversial. We aimed to evaluate the association between SNB and survival outcomes in a nationwide population-based Danish cohort. MATERIALS AND METHODS:This retrospective cohort study included patients diagnosed with cutaneous melanoma between 2010 and 2017 who were candidates for SNB according to contemporary national guidelines. Augmented inverse probability of treatment weighting (AIPTW) was used to estimate standardized absolute risks and risk differences (RD) for 5-year overall survival, melanoma-specific mortality, other-cause mortality, and recurrence outcomes under two hypothetical strategies: all patients undergoing SNB versus no patients undergoing SNB. RESULTS:Of 6952 eligible patients, 5679 (81.7%) underwent SNB. After AIPTW, the standardized 5-year overall survival was higher under the SNB strategy (82.5% vs 73.7%, RD -8.8 pp, 95% CI -12.0; -5.6), whereas there was no clear difference in melanoma-specific mortality between strategies (9.0% vs 9.8%, RD -0.8 pp, 95% CI -3.0; 1.5). Other-cause mortality was lower under the SNB strategy (8.5% vs 16.8%, RD -8.3 pp, 95% CI -11.1; -5.5). No difference was found for standardized 5-year risk of any recurrence (19.0% vs 18.9%; RD 0.1 pp, 95% CI -3.2; 3.4), nor for distant recurrence. Regional nodal recurrence was lower under the SNB strategy (4.6% vs 8.5%, RD -3.9 pp, 95% CI -6.3; -1.5). CONCLUSION:Since SNB cannot plausibly influence other-cause mortality, our findings indicate residual confounding despite robust adjusted analyses. Observational data such as ours cannot reliably determine whether SNB confers a therapeutic effect.

BACKGROUND:The inflammatory response to whole-body ischemia, as seen in comatose survivors after out-of-hospital cardiac arrest (OHCA), is associated with increased morbidity and mortality. Early high-dose dexamethasone may dampen the inflammatory response, which may diminish secondary brain damage and other organ injury and decrease mortality. The aim is to evaluate the effect of high-dose dexamethasone in post-resuscitation care. METHODS:The Danish Out-of-Hospital Cardiac Arrest (DANOHCA) trial is an investigator-initiated, multicenter, randomized, controlled trial evaluating four post-resuscitation interventions in adult patients resuscitated after OHCA including blinded early administration of high-dose dexamethasone compared with placebo (isotonic saline). Adult OHCA patients with presumed cardiac etiology and sustained return of spontaneous circulation will be randomized 1:1 to receive 20 mg of dexamethasone or placebo immediately after inclusion in the trial and repeated the following two mornings for a total of three doses. The primary outcome is all-cause mortality within 90 days using a log-binomial regression analysis to estimate the relative risk of death from any cause between randomization and Day 90. Enrollment began in June 2023, with the aim to include 1000 patients at five sites in 3-4 years. The trial is registered at clinicaltrials.gov (identifier: NCT05895838) and euclinicaltrials.eu (2024-515997-28-00). PERSPECTIVES:It is of paramount importance to optimize post-resuscitation care through large-scale randomized trials. Global ischemia-reperfusion-induced inflammatory response with resulting organ failures represents a possible target for interventions after OHCA. This part of the DANOHCA trial will provide new evidence on the impact of high-dose dexamethasone in survivors of OHCA. TRIAL REGISTRATION:Clinical Trials Information System (CTIS): 2024-515997-28-00.

BACKGROUND:Survivors of out-of-hospital cardiac arrest (OHCA) who remain comatose after return of spontaneous circulation are routinely sedated and mechanically ventilated during early post-resuscitation care. Although prolonged sedation has traditionally been considered necessary, contemporary normothermia-based temperature control allows earlier wake-up call. The optimal timing of an early wake-up call remains unknown and may influence overall mortality, neurological recovery, duration of mechanical ventilation, and length of hospital stay. METHODS:The Danish Out-of-Hospital Cardiac Arrest (DANOHCA) trial (clinicaltrials.gov identifier: NCT05895838; and euclinicaltrials.eu, identifier: 2024-515,997-28-00) is an investigator-initiated, multicenter, randomized clinical trial using a 2 × 2 × 2 × 2 factorial design evaluating four interventions in patients resuscitated from OHCA. The present protocol describes the comparison of an early versus late wake-up call strategy. Adult patients (≥ 18 years) with presumed cardiac-cause of OHCA, sustained return of spontaneous circulation, and persistent unconsciousness on intensive care unit admission are randomized 1:1 to early wake-up call (≤ 6 h after randomization) or late wake-up call (28-36 h after randomization). Wake-up call includes interruption of sedation, assessment of neurology, and may be followed by extubation if predefined neurological and respiratory criteria are fulfilled. The primary endpoint is days alive and out of hospital within 30 days after randomization. Analyses will follow a modified intention-to-treat principle. PERSPECTIVES:Optimizing post-resuscitation care remains a cornerstone in managing comatose cardiac arrest survivors and improving outcomes. We hypothesize that sedation for 28-36 h leads to more days alive outside of the hospital in 30 days compared to sedation for ≤ 6 h. TRIAL REGISTRATION:EudraCT number: 2016-003265-26; EU CTIS no 2024-515997-28-00; ClinicalTrials.gov identifier: NCT05895838.

AIMS:In STEMI-related cardiogenic shock, left ventricular unloading with a micro-axial flow pump (mAFP) improved survival in the Danish German (DanGer) Shock trial, though some patients in both groups required escalation to higher volume temporary mechanical circulatory support systems (tMCS). This study aims to investigate tMCS escalation strategies and outcome in non-comatose patients with STEMI-related cardiogenic shock. METHODS AND RESULTS:In this post hoc analysis of the DanGer Shock trial, patients in both study groups were stratified as escalated vs. not escalated to treatments other than a percutaneously implanted mAFP (Impella CP®). Logistic regression models were fitted to investigate the differential association of baseline markers with the likelihood of an escalation in patients randomized to mAFP vs. standard of care, adjusted for age and country. The 180-day all-cause mortality risk for the four groups was evaluated using the Kaplan-Meier method. Of the 355 patients included in the DanGer Shock trial, 60 underwent tMCS escalation, 25/179 (14%) allocated to the mAFP group, and 35/176 (20%) allocated to the control group (adjusted odds ratio 0.52, 95% confidence interval 0.30-0.91). Median time from randomization to escalation was 12 h (2.7-66.5) in the mAFP arm vs. 0.7 h (IQR: 0.4-2.7) in the standard of care arm (P < 0.001). A higher baseline lactate predicted an escalation in the standard of care arm (odds ratio 1.80, 95% confidence interval 1.14-3.13), but not in the mAFP arm (odds ratio 0.57, 95% confidence interval 0.29-1.15, interaction-P < 0.01). Mortality was significantly higher in patients who underwent tMCS escalation (71.7% vs. 48.1%, P < 0.01) and highest in escalated patients from the standard of care arm (80.0%). Interestingly, those escalated in the mAFP arm had a comparable mortality risk to the non-escalated patients in the standard of care group (60.0% vs. 53.2%). CONCLUSION:In the DanGer Shock trial of STEMI-related cardiogenic shock, escalation to tMCS occurred in almost 1/5 patients, was more likely in the control group, and was associated with a higher mortality risk. Even with early escalation (<1 h), patients escalated from the control group had the highest mortality, underscoring the need for future trials to define optimal escalation strategies.

BACKGROUND:Three cardiogenic shock (CS) phenotypes have been proposed and validated in various datasets: noncongested (phenotype I), cardiorenal (phenotype II), and cardiometabolic CS (phenotype III). The DanGer Shock trial demonstrated a mortality benefit of microaxial flow pump (mAFP) use in myocardial infarction-related CS. In this post-hoc analysis, we aimed to assess the trajectories and outcomes of these phenotypes in the DanGer Shock population. METHODS:Patients randomized to the DanGer Shock trial were retrospectively assigned to 1 of 3 CS phenotypes at admission. Missing values for phenotyping were imputed using multiple random forest imputation. Outcomes were 180-day mortality and the trajectories of key clinical, laboratory and hemodynamic parameters first 72 hours within phenotypes, stratified by allocation to mAFP or standard of care. RESULTS:Of 355 adult patients in the trial, 145 (41%), 38 (11%), and 172 (48%) patients were in the noncongested, cardiorenal, and cardiometabolic phenotypes, respectively. The 180-day mortality was greater in cardiometabolic (69%) compared with the noncongested (33%) and cardiorenal CS (47%) groups. Clinical metabolic and hemodynamic trajectories and their treatment response differed between phenotypes. mAFP use was associated with lower mortality in noncongested CS (odds ratio, 0.51 [0.28-0.91], P = .02). The odds of mortality were 0.81 [0.57-1.16] (P = .25) in cardiometabolic and 0.91 [0.35-2.34] (P = .84) in cardiorenal CS (P for interaction: .43). CONCLUSION:In this post-hoc analysis of the DanGer Shock trial, predefined CS phenotypes showed distinct outcomes, with the noncongested phenotype faring best and the cardiometabolic the worst. The greatest apparent benefit of mAFP was observed in noncongested CS. These findings are hypothesis-generating and warrant confirmation in prospective studies. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov unique identifier: NCT01633502. Condensed Abstract In this DanGer Shock post-hoc analysis, study participants were retrospectively assigned to 1 of 3 cardiogenic shock (CS) phenotypes: noncongested, cardiorenal, or cardiometabolic CS. In total, 41%, 11%, and 48% of all 355 patients were in these phenotypes, respectively. The 180-day mortality was greater in the cardiometabolic (69%) compared with the noncongested (33%) and cardiorenal CS (47%) groups. mAFP use was associated with lower mortality in the noncongested and numerically in the cardiometabolic, but not in cardiorenal CS group. In summary, CS phenotypes showed distinct outcomes, with the noncongested phenotype faring best and the cardiometabolic faring the worst. The greatest apparent benefit of mAFP was observed in noncongested CS.