Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock.

BACKGROUND: Cardiogenic shock is associated with substantial morbidity and mortality. Although inotropic support is a mainstay of medical therapy for cardiogenic shock, little evidence exists to guide the selection of inotropic agents in clinical practice. METHODS: We randomly assigned patients with cardiogenic shock to receive milrinone or dobutamine in a double-blind fashion. The primary outcome was a composite of in-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack or stroke diagnosed by a neurologist, or initiation of renal replacement therapy. Secondary outcomes included the individual components of the primary composite outcome. RESULTS: A total of 192 participants (96 in each group) were enrolled. The treatment groups did not differ significantly with respect to the primary outcome; a primary outcome event occurred in 47 participants (49%) in the milrinone group and in 52 participants (54%) in the dobutamine group (relative risk, 0.90; 95% confidence interval [CI], 0.69 to 1.19; P = 0.47). There were also no significant differences between the groups with respect to secondary outcomes, including in-hospital death (37% and 43% of the participants, respectively; relative risk, 0.85; 95% CI, 0.60 to 1.21), resuscitated cardiac arrest (7% and 9%; hazard ratio, 0.78; 95% CI, 0.29 to 2.07), receipt of mechanical circulatory support (12% and 15%; hazard ratio, 0.78; 95% CI, 0.36 to 1.71), or initiation of renal replacement therapy (22% and 17%; hazard ratio, 1.39; 95% CI, 0.73 to 2.67). CONCLUSIONS: In patients with cardiogenic shock, no significant difference between milrinone and dobutamine was found with respect to the primary composite outcome or important secondary outcomes. (Funded by the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario; ClinicalTrials.gov number, NCT03207165.).

A stepwise approach to coronary artery stenting in acute type A aortic dissection.

We present three cases of acute coronary obstruction postsurgical repair of type A aortic dissection, which were successfully treated with percutaneous coronary intervention. We describe a step-by-step approach to performing percutaneous coronary intervention in selective cases of coronary obstruction related to type A aortic dissection.

Inotrope versus placebo therapy in cardiogenic shock: Rationale and study design of the CAPITAL DOREMI2 trial.

BACKGROUND: Cardiogenic shock (CS) is a state of end-organ hypoperfusion related to cardiac dysfunction. Current guidelines recommend consideration of inotrope therapy in patients with CS, however no robust data support their use. The purpose of the CAPITAL DOREMI2 trial is to examine the efficacy and safety of inotrope therapy against placebo in the initial resuscitation of patients with CS. METHODS AND DESIGN: This is a multi-center, double-blind, randomized, placebo-controlled trial comparing single-agent inotrope therapy to placebo in patients with CS. A total of 346 participants with Society for Cardiovascular Angiography and Interventions class C or D CS will be randomized in a 1:1 fashion to inotrope or placebo therapy, which will be administered over a 12-hour period. After this period, participants will continue open-label therapies at the discretion of the treating team. The primary outcome is a composite of all-cause in-hospital death, and, as measured during the 12-hour intervention period, any of: sustained hypotension or high dose vasopressor requirements, lactate greater than 3.5 mmol/L at 6 hours or thereafter, need for mechanical circulatory support, arrhythmia leading to emergent electrical cardioversion, and resuscitated cardiac arrest. All participants will be followed for the duration of their hospitalization, and secondary outcomes will be assessed at the time of discharge. IMPLICATION: This trial will be the first to establish the safety and efficacy of inotrope therapy against placebo in a population of patients with CS and has the potential to alter the standard care provided to this group of patients.

Transcatheter mitral valve repair for inotrope dependent cardiogenic shock - Design and rationale of the CAPITAL MINOS trial.

BACKGROUND: Functional mitral regurgitation (MR) is an important clinical consideration in patients with heart failure. Transcatheter edge-to-edge repair (TEER) has emerged as a useful therapeutic tool for patients with chronic heart failure, however the role of TEER in patients with cardiogenic shock (CS) and MR has not yet been studied in a randomized trial. The Transcatheter Mitral Valve Repair for Inotrope Dependent Cardiogenic Shock (CAPITAL MINOS) trial was therefore designed to determine if TEER improves clinical outcomes in the CS population. METHODS AND DESIGN: The CAPITAL MINOS trial is an open-label, multi-center randomized clinical trial comparing TEER to medical therapy in patients with CS and MR. A total of 144 patients with Society for Cardiovascular Angiography and Interventions (SCAI) class C or D CS and at least 3+ MR will be randomized in a 1:1 ratio to TEER or medical therapy alone. The primary outcome will be a composite of in-hospital all-cause mortality, cardiac transplantation, implantation of durable left ventricular assist device, or discharge on palliative inotropic therapy. Patients will be followed for the duration of their index hospitalization for the primary outcome. Secondary outcomes include 6 month mortality. IMPLICATIONS: The CAPITAL MINOS trial will determine whether TEER improves outcomes in patients with CS and MR and will be an important step in optimizing treatment for this high-risk patient population.

Association of annual volume and in-hospital outcomes of catheter-directed thrombolysis for pulmonary embolism.

OBJECTIVE: We sought to evaluate the association between the institutional volume of catheter-directed thrombolysis (CDT) for pulmonary embolism and in-hospital mortality. BACKGROUND: CDT is an increasingly utilized therapy in patients with intermediate/high-risk PE. However, data on the relationship between hospital volume and clinical outcomes remain limited. METHODS: Patients who underwent CDT between October 1, 2015, and March 31, 2021, were identified in the Vizient Clinical Database. The primary outcome was in-hospital mortality. Secondary outcome were major complications, length of stay, and cost. Hospitals were dichotomized into <8 and ≥ 8 cases/year following restricted cubic spline analysis. RESULTS: A total of 6741 CDT procedures at 171 hospitals were included with a median annual hospital volume of 4.1 cases (IQR = 1.9-8.3). A total of 44 hospitals (25.7%) were classified as high-volume ( ≥ 8 cases/year) and performed 60.9% of all CDT cases. CDT at high-volume centers was associated with lower in-hospital mortality (6.0% vs. 11.3%; p < 0.0001). Stroke and bleeding rates were similar, but pulmonary complications were more frequent at low-volume centers. CDT at high volume centers was associated with a significantly shorter length of stay and lower cost. The association between high CDT volume and in-hospital mortality persisted after adjustment for demographics (odds ratio [OR] = 0.49, [0.41-0.58]), demographics and risk factors (OR = 0.52 [0.44-0.62]), and demographics, risk factors, and troponin elevation (OR = 0.51 [0.40-0.66]). CONCLUSION: In a large contemporary cohort of patients undergoing CDT in the United States, low annual institutional volume of CDT was associated with higher in-hospital mortality.

Impact of intracoronary assessments on revascularization decisions: A contemporary evaluation.

OBJECTIVES: To investigate the real-world implementation of intracoronary assessment (ICA) techniques and evaluate their impact on clinical decisions regarding the management of coronary artery disease (CAD) in contemporary practice. BACKGROUND: Coronary angiogram is the gold standard used to diagnose vessel stenosis and guide percutaneous coronary intervention (PCI); however, it is limited by its two-dimensional imaging capabilities. ICA techniques like intravascular ultrasound and optical coherence tomography capture the vessel in three-dimensional images. Comparatively, fractional flow reserve provides information on the physiologic significance of coronary stenosis. Both techniques may improve PCI outcomes if they routinely change physician behavior. METHODS: Patients who underwent ICA between August 2015 and March 2020 were included in the study. The primary outcome was the clinical impact of ICA on physician clinical decision making of a stenotic vessel. The secondary outcome was the clinical changes that occurred following ICA. RESULTS: A total of 1135 patients were included in the study. Physiologic assessment (PA) and image assessment (IA) were performed in 61.4% and 38.6% respectively. Management plans were changed in 38.1% and 23.9% of patients who received PA and IA. Over half of the management change resulted in physicians deciding to not intervene on the stenotic vessel. One-year outcome of these decisions showed no significant increase in major adverse cardiac events (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.40-1.15; p = 0.15) or unplanned revascularization (HR, 0.78; 95% CI, 0.35-1.74; p = 0.55) suggesting reliance on PA/IA data did not increase risk. CONCLUSION: Selected ICA alters physician management of CAD in one-third of patients being evaluated for revascularization-typically leading to fewer interventions. All cause death is numerally lower in patients that received a change in management. However, the 1-year outcome of these altered decisions does not appear to be significantly different.

Transcatheter edge-to-edge repair in patients with mitral regurgitation and cardiogenic shock: a new therapeutic target.

PURPOSE OF REVIEW: Cardiogenic shock with significant mitral regurgitation portends a poor prognosis with limited therapeutic options. Herein, we review the available evidence regarding the patient characteristics, management, impact of transcatheter edge-to-edge repair (TEER) on hemodynamics, and clinical outcomes of patients with cardiogenic shock and mitral regurgitation. RECENT FINDINGS: Several observational studies and systematic reviews have demonstrated the feasibility and safety of TEER in cardiogenic shock complicated by degenerative or functional mitral regurgitation. Surgical interventions for mitral regurgitation remain limited owing to the risk profile of patients in cardiogenic shock. TEER has been studied in both degenerative and functional mitral regurgitation and remains feasible in the critically ill population. Moreover, TEER is associated with reduction in mitral regurgitation and improvement in-hospital and long-term mortality. SUMMARY: TEER remains a promising therapeutic option in cardiogenic shock complicated by significant mitral regurgitation, but additional research is required to identify patient and procedural characteristics, hemodynamic parameters, and the optimal time for intervention. Moreover, future randomized controlled trials are in progress to evaluate the potential benefit of TEER against medical management in cardiogenic shock and mitral regurgitation.

Dual antiplatelet therapy (PEGASUS) vs. dual pathway (COMPASS): a head-to-head in vitro comparison.

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is prescribed for 1-year after myocardial infarction. Two clinical strategies are considered at 1-year: continuation of DAPT or "Dual Pathway" (DP), using aspirin and rivaroxaban. No head-to-head comparative studies exist. In our in-vitro study, 24 samples of donor blood were treated with clinically proven concentrations of 5 antithrombotic regimens: aspirin, ticagrelor, rivaroxaban, DAPT, and DP. Thrombosis was analyzed using the Total Thrombus Analysis System (T-TAS) to measure both antiplatelet and anticoagulant effects. Flow cytometry was performed to quantify platelet activation. DAPT was the most potent antiplatelet regimen, delaying thrombus onset (p < .0001) and reducing thrombogenicity (p < .0001), relative to control. DP did not delay thrombus formation relative to aspirin alone (p = .69). DP was the most potent anticoagulant regimen, delaying thrombus onset (p < .0001) and reducing thrombogenicity (p < .0001), relative to control. DP showed synergistic antithrombotic effects by delaying thrombus onset (p < .0001) and reducing thrombogenicity (p = .0003), relative to rivaroxaban alone. Flow cytometry showed only DAPT (p = .0023) reduced platelet activation. DP treatment demonstrated synergistic antithrombotic effects over rivaroxaban alone, but no additional antiplatelet synergism over aspirin alone.

Inotropes, vasopressors, and mechanical circulatory support for treatment of cardiogenic shock complicating myocardial infarction: a systematic review and network meta-analysis.

PURPOSE: To compare the relative efficacy of supportive therapies (inotropes, vasopressors, and mechanical circulatory support [MCS]) for adult patients with cardiogenic shock complicating acute myocardial infarction. SOURCE: We conducted a systematic review and network meta-analysis and searched six databases from inception to December 2021 for randomized clinical trials (RCTs). We evaluated inotropes, vasopressors, and MCS in separate networks. Two reviewers performed screening, full-text review, and extraction. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework to rate the certainty in findings. The critical outcome of interest was 30-day all-cause mortality. PRINCIPAL FINDINGS: We included 17 RCTs. Among inotropes (seven RCTs, 1,145 patients), levosimendan probably reduces mortality compared with placebo (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.33 to 0.87; moderate certainty), but primarily in lower severity shock. Milrinone (OR, 0.52; 95% CI, 0.19 to 1.39; low certainty) and dobutamine (OR, 0.67, 95% CI, 0.30 to 1.49; low certainty) may have no effect on mortality compared with placebo. With regard to MCS (eight RCTs, 856 patients), there may be no effect on mortality with an intra-aortic balloon pump (IABP) (OR, 0.94; 95% CI, 0.69 to 1.28; low certainty) or percutaneous MCS (pMCS) (OR, 0.96; 95% CI, 0.47 to 1.98; low certainty), compared with a strategy involving no MCS. Intra-aortic balloon pump use was associated with less major bleeding compared with pMCS. We found only two RCTs evaluating vasopressors, yielding insufficient data for meta-analysis. CONCLUSION: The results of this systematic review and network meta-analysis indicate that levosimendan reduces mortality compared with placebo among patients with low severity cardiogenic shock. Intra-aortic balloon pump and pMCS had no effect on mortality compared with a strategy of no MCS, but pMCS was associated with higher rates of major bleeding. STUDY REGISTRATION: Center for Open Science ( https://osf.io/ky2gr ); registered 10 November 2020.

RéSUMé: OBJECTIF: Comparer l'efficacité relative des thérapies de soutien (inotropes, vasopresseurs et assistance circulatoire mécanique [ACM]) chez les patients adultes atteints d'un choc cardiogénique compliquant un infarctus aigu du myocarde. SOURCES: Nous avons réalisé une revue systématique et une méta-analyse en réseau et effectué des recherches dans six bases de données depuis leur création jusqu'à décembre 2021 pour en tirer les études randomisées contrôlées (ERC). Nous avons évalué les inotropes, les vasopresseurs et les ACM dans des réseaux distincts. Deux réviseurs ont effectué la recherche, l'évaluation du texte intégral et l'extraction. Nous avons utilisé le système de notation GRADE (Grading of Recommendations Assessment, Development, and Evaluation) pour évaluer la certitude des résultats. Le critère d'évaluation d'intérêt était la mortalité toutes causes confondues à 30 jours. CONSTATATIONS PRINCIPALES: Nous avons inclus 17 ERC. Parmi les inotropes (sept ERC, 1145 patients), le lévosimendan a probablement réduit la mortalité par rapport au placebo (rapport de cotes [RC], 0,53; intervalle de confiance [IC] à 95 %, 0,33 à 0,87; certitude modérée), mais principalement en cas de choc de sévérité moindre. La milrinone (RC, 0,52; IC 95 %, 0,19 à 1,39; certitude faible) et la dobutamine (RC, 0,67, IC 95 %, 0,30 à 1,49; certitude faible) pourraient n'avoir aucun effet sur la mortalité par rapport au placebo. En ce qui concerne l'ACM (huit ERC, 856 patients), il pourrait n'y avoir aucun effet sur la mortalité avec un ballon intra-aortique (IABP) (RC, 0,94; IC 95 %, 0,69 à 1,28; certitude faible) ou un ACM percutané (ACMp) (RC, 0,96; IC 95 %, 0,47 à 1,98; certitude faible), par rapport à une stratégie sans ACM. L'utilisation d'un ballon intra-aortique était associée à moins de saignements majeurs par rapport à une ACMp. Nous n'avons trouvé que deux ERC évaluant les vasopresseurs, ce qui n'a pas fourni suffisamment de données pour la méta-analyse. CONCLUSION: Les résultats de cette revue systématique et de la méta-analyse en réseau indiquent que le lévosimendan réduit la mortalité par rapport au placebo chez les patients présentant un choc cardiogénique de faible gravité. Le ballon intra-aortique et l'ACMp n'ont eu aucun effet sur la mortalité par rapport à une stratégie sans ACM, mais l'ACMp était associée à des taux plus élevés de saignements majeurs. ENREGISTREMENT DE L'éTUDE: Center for Open Science ( https://osf.io/ky2gr ); enregistrée le 10 novembre 2020.

Acute kidney injury after radial or femoral artery access in ST-segment elevation myocardial infarction: AKI-SAFARI.

BACKGROUND: Acute kidney injury (AKI) complicating primary percutaneous coronary intervention (PCI) is an independent predictor of short- and long-term outcomes in patients presenting with ST-elevation myocardial infarction (STEMI). Prior studies suggest a lower incidence of AKI in patients undergoing PCI through radial artery compared to femoral artery access; however, no randomized clinical trials have specifically investigated this question in patients presenting with STEMI. METHODS: To determine whether radial access (RA) is associated with a reduced frequency of AKI following primary PCI, we performed a substudy of the SAFARI-STEMI trial. The SAFARI-STEMI trial was an open-label, multicenter trial, which randomized patients presenting with STEMI to RA or femoral access (FA), between July 2011 and December 2018. The primary outcome of this post hoc analysis was the incidence of AKI, defined as an absolute (>0.5 mg/dL) or relative (>25%) increase in serum creatinine from baseline. RESULTS: In total 2,285 (99.3%) of the patients enrolled in SAFARI-STEMI were included in the analysis-1,132 RA and 1,153 FA. AKI occurred in 243 (21.5%) RA patients and 226 (19.6%) FA patients (RR: 0.91, 95% CI: 0.78-1.07, P = .27). An absolute increase in serum creatinine >0.5 mg/dL was seen in 49 (4.3%) radial and 52 (4.5%) femoral patients (RR: 1.04, 95% CI: 0.71-1.53, P = .83). AKI was lower in both groups when the KDIGO definition was applied (RA 11.9% vs FA 10.8%; RR: 0.90, 95% CI: 0.72-1.13, P = .38). CONCLUSIONS: Among STEMI patients enrolled in the SAFARI-STEMI trial, there was no association between catheterization access site and AKI, irrespective of the definition applied. These results challenge the independent association between catheterization access site and AKI noted in prior investigations.

Sex-specific in-hospital outcomes of transcatheter aortic valve replacement with third generation transcatheter heart valves.

BACKGROUND: Sex-based differences in transcatheter aortic valve replacement (TAVR) outcomes have been previously documented. However, whether these differences persist with contemporary third generation transcatheter heart valves (THVs) is unknown. METHODS: We utilized Vizient's clinical database/resource manager (CDB/RM™) to identify patients who underwent TAVR between January 1, 2018 and March 31, 2020 to compare in-hospital outcomes between males and females. The primary endpoint was in-hospital mortality. Secondary endpoints included key in-hospital complications, length of stay, discharge disposition, and cost. Unadjusted, propensity-score matched and risk-adjusted analyses of outcomes were performed. RESULTS: During the study period, 44,280 patients (24,842 males, 19,438 females) underwent TAVR. The primary endpoint of in-hospital mortality was higher in females than in males (1.6 vs. 1.1% p < .001) in unadjusted analysis and persisted following propensity matching (1.6 vs. 0.9%, p < .001) and multivariable logistic regression with various risk-adjustment models. In the most comprehensive model adjusting for age, race, and clinical comorbidities, female sex was associated with 34% greater odds of in-hospital death (95% CI 20-50%, p < .001). Unadjusted and risk-adjusted rates of post-TAVR stroke, vascular complication, and blood transfusion were higher in females. Moreover, females demonstrated longer hospitalizations, higher costs and reduced rates of independent discharge home. CONCLUSION: Sex-based differences in TAVR in-hospital outcomes persist in contemporary practice with third generation transcatheter heart valves. Further research is needed to assess the reasons for these observed disparities and to identify effective mitigation strategies.

Revisiting the Evidence for Dipyridamole in Reducing Restenosis: A Systematic Review and Meta-analysis.

ABSTRACT: Atherosclerosis remains a leading cause of morbidity and mortality, with revascularization remaining a cornerstone of management. Conventional revascularization modalities remain challenged by target vessel reocclusion-an event driven by mechanical, thrombotic, and proliferative processes. Despite considerable advancements, restenosis remains the focus of ongoing research. Adjunctive agents, including dipyridamole, offer a multitude of effects that may improve vascular homeostasis. We sought to quantify the potential therapeutic impact of dipyridamole on vascular occlusion. We performed a literature search (EMBASE and MEDLINE) examining studies that encompassed 3 areas: (1) one of the designated medical therapies applied in (2) the setting of a vascular intervention with (3) an outcome including vascular occlusion rates and/or quantification of neointimal proliferation/restenosis. The primary outcome was vascular occlusion rates. The secondary outcome was the degree of restenosis by neointimal quantification. Both human and animal studies were included in this translational analysis. There were 6,839 articles screened, from which 73 studies were included, encompassing 16,146 vessels followed up for a mean of 327.3 days (range 7-3650 days). Preclinical studies demonstrate that dipyridamole results in reduced vascular occlusion rates {24.9% vs. 48.8%, risk ratio 0.53 [95% confidence interval (CI) 0.40-0.70], I2 = 39%, P < 0.00001}, owing to diminished neointimal proliferation [standardized mean differences -1.13 (95% CI -1.74 to -0.53), I2 = 91%, P = 0.0002]. Clinical studies similarly demonstrated reduced occlusion rates with dipyridamole therapy [23.5% vs. 31.0%, risk ratio 0.77 (95% CI 0.67-0.88), I2 = 84%, P < 0.0001]. Dipyridamole may improve post-intervention vascular patency and mitigate restenosis. Dedicated studies are warranted to delineate its role as an adjunctive agent after revascularization.

Impact of baseline beta-blocker use on inotrope response and clinical outcomes in cardiogenic shock: a subgroup analysis of the DOREMI trial.

BACKGROUND: Cardiogenic shock (CS) is associated with significant morbidity and mortality. The impact of beta-blocker (BB) use on patients who develop CS remains unknown. We sought to evaluate the clinical outcomes and hemodynamic response profiles in patients treated with BB in the 24 h prior to the development of CS. METHODS: Patients with CS enrolled in the DObutamine compaREd to MIlrinone trial were analyzed. The primary outcome was a composite of all-cause mortality, resuscitated cardiac arrest, need for cardiac transplant or mechanical circulatory support, non-fatal myocardial infarction, transient ischemic attack or stroke, or initiation of renal replacement therapy. Secondary outcomes included the individual components of the primary composite and hemodynamic response profiles derived from pulmonary artery catheters. RESULTS: Among 192 participants, 93 patients (48%) had received BB therapy. The primary outcome occurred in 47 patients (51%) in the BB group and in 52 (53%) in the no BB group (RR 0.96; 95% CI 0.73-1.27; P = 0.78) throughout the in-hospital period. There were fewer early deaths in the BB group (RR 0.41; 95% CI 0.18-0.95; P = 0.03). There were no differences in other individual components of the primary outcome or in hemodynamic response between the two groups throughout the remainder of the hospitalization. CONCLUSIONS: BB therapy in the 24 h preceding the development of CS did not negatively influence clinical outcomes or hemodynamic parameters. On the contrary, BB use was associated with fewer deaths in the early resuscitation period, suggesting a paradoxically protective effect in patients with CS. Trial registration ClinicalTrials.gov Identifier: NCT03207165.

Impact of sex on outcomes after percutaneous repair of functional mitral valve regurgitation.

BACKGROUND: The role of percutaneous repair of functional mitral regurgitation (MR) is evolving. Left ventricle remodeling is known to be different between men and women; however, outcomes following percutaneous repair of functional MR have not considered the impact of sex. METHODS: Between 2012 and 2018, 175 patients underwent percutaneous repair of functional MR with the Mitra Clip NT/NTR (Abbott) at our institution. Patients were assessed in a dedicated clinic with a follow-up that averaged 0.7 ± 1.2 years and extended to 5.7 years. RESULTS: Men had a larger body surface area than women (p < .001), and were more likely than women to have diabetes preoperatively (p = .02). There were no deaths or instances of single leaflet detachment. Immediate postprocedure MR was ≤2+ in 158 (90%) with a mean trans-mitral valve repair gradient of 3.4 ± 1.0 and 3.5 ± 2.1 mmHg, respectively for women and men (p = .8). One- and 2-year freedom from MR ≥3+ was 86.0 ± 3.5% and 77.6 ± 5.1%, respectively. After adjusting for differences between male and female patients, women were more likely to have recurrent MR ≥3+ (hazard ratio, 4.7; 95% confidence interval, 1.2-18.4; p = .03). Upon adjusted analysis, there was also no association between gender and survival (p = .2). One- and 2-year survival was 69.8 ± 4.3% and 54.3 ± 5.5%, respectively. CONCLUSION: Women are more likely to have recurrent severe MR after percutaneous repair of functional MR. The mechanism for this remains undetermined.

Effect of Moderate vs Mild Therapeutic Hypothermia on Mortality and Neurologic Outcomes in Comatose Survivors of Out-of-Hospital Cardiac Arrest: The CAPITAL CHILL Randomized Clinical Trial.

Importance: Comatose survivors of out-of-hospital cardiac arrest experience high rates of death and severe neurologic injury. Current guidelines recommend targeted temperature management at 32 °C to 36 °C for 24 hours. However, small studies suggest a potential benefit of targeting lower body temperatures. Objective: To determine whether moderate hypothermia (31 °C), compared with mild hypothermia (34 °C), improves clinical outcomes in comatose survivors of out-of-hospital cardiac arrest. Design, Setting, and Participants: Single-center, double-blind, randomized, clinical superiority trial carried out in a tertiary cardiac care center in eastern Ontario, Canada. A total of 389 patients with out-of-hospital cardiac arrest were enrolled between August 4, 2013, and March 20, 2020, with final follow-up on October 15, 2020. Interventions: Patients were randomly assigned to temperature management with a target body temperature of 31 °C (n = 193) or 34 °C (n = 196) for a period of 24 hours. Main Outcomes and Measures: The primary outcome was all-cause mortality or poor neurologic outcome at 180 days. Neurologic outcome was assessed using the Disability Rating Scale, with poor neurologic outcome defined as a score greater than 5 (range, 0-29, with 29 being the worst outcome [vegetative state]). There were 19 secondary outcomes, including mortality at 180 days and length of stay in the intensive care unit. Results: Among 367 patients included in the primary analysis (mean age, 61 years; 69 women [19%]), 366 (99.7%) completed the trial. The primary outcome occurred in 89 of 184 patients (48.4%) in the 31 °C group and in 83 of 183 patients (45.4%) in the 34 °C group (risk difference, 3.0% [95% CI, 7.2%-13.2%]; relative risk, 1.07 [95% CI, 0.86-1.33]; P = .56). Of the 19 secondary outcomes, 18 were not statistically significant. Mortality at 180 days was 43.5% and 41.0% in patients treated with a target temperature of 31 °C and 34 °C, respectively (P = .63). The median length of stay in the intensive care unit was longer in the 31 °C group (10 vs 7 days; P = .004). Among adverse events in the 31 °C group vs the 34 °C group, deep vein thrombosis occurred in 11.4% vs 10.9% and thrombus in the inferior vena cava occurred in 3.8% and 7.7%, respectively. Conclusions and Relevance: In comatose survivors of out-of-hospital cardiac arrest, a target temperature of 31 °C did not significantly reduce the rate of death or poor neurologic outcome at 180 days compared with a target temperature of 34 °C. However, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02011568.

Journal Initiatives to Enhance Preclinical Research: Analyses of Stroke, Nature Medicine, Science Translational Medicine.

Background and Purpose- Preclinical research using animals often informs clinical trials. However, its value is dependent on its scientific validity and reproducibility, which are, in turn, dependent on rigorous study design and reporting. In 2011, Stroke introduced a Basic Science Checklist to enhance the reporting and methodology of its preclinical studies. Except for Nature and Science journals, few others have implemented similar initiatives. We sought to estimate the impact of these journal interventions on the quality of their published reports. Methods- All articles published in Stroke, Nature Medicine, and Science Translational Medicine over 9 to 18 years and in 2 control journals without analogous interventions over a corresponding 11.5 years were reviewed to identify reports of experiments in nonhuman mammals with proposed clinical relevance. The effect of journal interventions on the reporting and use of key study design elements was estimated via interrupted time-series analyses. Results- Of 33 009 articles screened, 4162 studies met inclusion criteria. In the 3.5 to 12 years preceding each journal's intervention, the proportions of studies reporting and using key study design elements were stable except for blinding in Stroke and randomization in Science Translational Medicine, which were both increasing. Post-intervention, abrupt and often marked increases were seen in the reporting of randomization status (level change: +17% to +44%, P≤0.005), blinding (level change: +20% to +40%, P≤0.008), and sample size estimation (level change: 0% to +40%, P≤0.002 in 2 journals). Significant but more modest improvements in the use of these study design elements were also observed. These improvements were not seen in control journals. Conclusions- Journal interventions such as Stroke's author submission checklist can meaningfully improve the quality of published preclinical research and should be considered to enhance study transparency and design. However, such interventions are alone insufficient to fully address widespread shortcomings in preclinical research practices.

Standards and Methodological Rigor in Pulmonary Arterial Hypertension Preclinical and Translational Research.

Despite advances in our understanding of the pathophysiology and the management of pulmonary arterial hypertension (PAH), significant therapeutic gaps remain for this devastating disease. Yet, few innovative therapies beyond the traditional pathways of endothelial dysfunction have reached clinical trial phases in PAH. Although there are inherent limitations of the currently available models of PAH, the leaky pipeline of innovative therapies relates, in part, to flawed preclinical research methodology, including lack of rigour in trial design, incomplete invasive hemodynamic assessment, and lack of careful translational studies that replicate randomized controlled trials in humans with attention to adverse effects and benefits. Rigorous methodology should include the use of prespecified eligibility criteria, sample sizes that permit valid statistical analysis, randomization, blinded assessment of standardized outcomes, and transparent reporting of results. Better design and implementation of preclinical studies can minimize inherent flaws in the models of PAH, reduce the risk of bias, and enhance external validity and our ability to distinguish truly promising therapies form many false-positive or overstated leads. Ideally, preclinical studies should use advanced imaging, study several preclinical pulmonary hypertension models, or correlate rodent and human findings and consider the fate of the right ventricle, which is the major determinant of prognosis in human PAH. Although these principles are widely endorsed, empirical evidence suggests that such rigor is often lacking in pulmonary hypertension preclinical research. The present article discusses the pitfalls in the design of preclinical pulmonary hypertension trials and discusses opportunities to create preclinical trials with improved predictive value in guiding early-phase drug development in patients with PAH, which will need support not only from researchers, peer reviewers, and editors but also from academic institutions, funding agencies, and animal ethics authorities.

New-onset atrial fibrillation and associated outcomes and resource use among critically ill adults-a multicenter retrospective cohort study.

BACKGROUND: New-onset atrial fibrillation (NOAF) is commonly encountered in critically ill adults. Evidence evaluating the association between NOAF and patient-important outcomes in this population is conflicting. Furthermore, little is known regarding the association between NOAF and resource use or hospital costs. METHODS: Retrospective analysis (2011-2016) of a prospectively collected registry from two Canadian hospitals of consecutive ICU patients aged ≥ 18 years. We excluded patients with a known history of AF prior to hospital admission. Any occurrence of atrial fibrillation (AF) was prospectively recorded by bedside nurses. The primary outcome was hospital mortality, and we used multivariable logistic regression to adjust for confounders. We used a generalized linear model to evaluate contributors to total cost. RESULTS: We included 15,014 patients, and 1541 (10.3%) had NOAF during their ICU admission. While NOAF was not associated with increased odds of hospital death among the entire cohort (adjusted odds ratio [aOR] 1.02 [95% confidence interval [CI] 0.97-1.08]), an interaction was noted between NOAF and sepsis, and the presence of both was associated with higher odds of hospital mortality (aOR 1.28 [95% CI 1.09-1.36]) than either alone. Patients with NOAF had higher total costs (cost ratio [CR] 1.09 [95% CI 1.02-1.20]). Among patients with NOAF, treatment with a rhythm-control strategy was associated with higher costs (CR 1.24 [95% CI 1.07-1.40]). CONCLUSIONS: While NOAF was not associated with death or requiring discharge to long-term care among critically ill patients, it was associated with increased length of stay in ICU and increased total costs.

Optimizing the Early Resuscitation After Out-of-Hospital Cardiac Arrest.

Resuscitation after out-of-hospital cardiac arrest can be one of the most challenging scenarios in acute-care medicine. The devastating effects of postcardiac arrest syndrome carry a substantial morbidity and mortality that persist long after return of spontaneous circulation. Management of these patients requires the clinician to simultaneously address multiple emergent priorities including the resuscitation of the patient and the efficient diagnosis and management of the underlying etiology. This review provides a concise evidence-based overview of the core concepts involved in the early postcardiac arrest resuscitation. It will highlight the components of an effective management strategy including addressing hemodynamic, oxygenation, and ventilation goals as well as carefully considering cardiac catheterization and targeted temperature management. An organized approach is paramount to providing effective care to patients in this vulnerable time period.

Evaluation of an in vitro coronary stent thrombosis model for preclinical assessment.

Stent thrombosis remains an infrequent but significant complication following percutaneous coronary intervention. Preclinical models to rapidly screen and validate therapeutic compounds for efficacy are lacking. Herein, we describe a reproducible, high throughput and cost-effective method to evaluate candidate therapeutics and devices for either treatment or propensity to develop stent thrombosis in an in vitro bench-top model. Increasing degree of stent malapposition (0.00 mm, 0.10 mm, 0.25 mm and 0.50 mm) was associated with increasing thrombosis and luminal area occlusion (4.1 ± 0.5%, 6.3 ± 0.5%, 19.7 ± 4.5%, and 92.6 ± 7.4%, p < 0.0001, respectively). Differences in stent design in the form of bare-metal, drug-eluting, and bioresorbable vascular scaffolds demonstrated differences in stent thrombus burden (14.7 ± 3.8% vs. 20.5 ± 3.1% vs. 86.8 ± 5.3%, p < 0.01, respectively). Finally, thrombus burden was significantly reduced when healthy blood samples were incubated with Heparin, ASA/Ticagrelor (DAPT), and Heparin+DAPT compared to control (DMSO) at 4.1 ± 0.6%, 6.9 ± 1.7%, 4.5 ± 1.2%, and 12.1 ± 1.8%, respectively (p < 0.01). The reported model produces high throughput reproducible thrombosis results across a spectrum of antithrombotic agents, stent design, and degrees of apposition. Importantly, performance recapitulates clinical observations of antiplatelet/antithrombotic regimens as well as device and deployment characteristics. Accordingly, this model may serve as a screening tool for candidate therapies in preclinical evaluation.