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.

Mental health sequelae in survivors of cardiogenic shock complicating myocardial infarction. A population-based cohort study.

PURPOSE: Cardiogenic shock secondary to acute myocardial infarction (AMI-CS) is associated with substantial short- and long-term morbidity and mortality. However, there are limited data on mental health sequelae that survivors experience following discharge. METHODS: We conducted a retrospective, population-based cohort study in Ontario, Canada of critically ill adult (≥ 18 years) survivors of AMI-CS, admitted to hospital between April 1, 2009 and March 31, 2019. We compared these patients to AMI survivors without shock. We captured outcome data using linked health administrative databases. The primary outcome was a new mental health diagnosis (a composite of mood, anxiety, or related disorders; schizophrenia/psychotic disorders; and other mental health disorders) following hospital discharge. We secondarily evaluated incidence of deliberate self-harm and death by suicide. We compared patients using overlap propensity score-weighted, cause-specific proportional hazard models. RESULTS: We included 7812 consecutive survivors of AMI-CS, from 135 centers. Mean age was 68.4 (standard deviation (SD) 12.2) years, and 70.3% were male. Median follow-up time was 767 days (interquartile range (IQR) 225-1682). Incidence of new mental health diagnosis among AMI-CS survivors was 109.6 per 1,000 person-years (95% confidence interval (CI) 105.4-113.9), compared with 103.8 per 1000 person-years (95% CI 102.5-105.2) among AMI survivors without shock. After propensity score adjustment, there was no difference in the risk of new mental health diagnoses following discharge [hazard ratio (HR) 0.99 (95% CI 0.94-1.03)]. Factors associated with new mental health diagnoses following AMI-CS included female sex, pre-existing mental health diagnoses, and discharge to a long-term hospital or rehabilitation institute. CONCLUSION: Survivors of AMI-CS experience substantial mental health morbidity following discharge. Risk of new mental health diagnoses was comparable between survivors of AMI with and without shock. Future research on interventions to mitigate psychiatric sequelae after AMI-CS is warranted.

Long-Term Outcomes of Cardiogenic Shock Complicating Myocardial Infarction.

BACKGROUND: Cardiogenic shock secondary to acute myocardial infarction (AMI-CS) is associated with substantial short-term mortality; however, there are limited data on long-term outcomes and trends. OBJECTIVES: This study sought to examine long-term outcomes of AMI-CS patients. METHODS: This was a population-based, retrospective cohort study in Ontario, Canada of critically ill adult patients with AMI-CS who were admitted to hospitals between April 1, 2009 and March 31, 2019. Outcome data were captured using linked health administrative databases. RESULTS: A total of 9,789 consecutive patients with AMI-CS from 135 centers were included. The mean age was 70.5 ± 12.3 years, and 67.7% were male. The incidence of AMI-CS was 8.2 per 100,000 person-years, and it increased over the study period. Critical care interventions were common, with 5,422 (55.4%) undergoing invasive mechanical ventilation, 1,425 (14.6%) undergoing renal replacement therapy, and 1,484 (15.2%) receiving mechanical circulatory support. A total of 2,961 patients (30.2%) died in the hospital, and 4,004 (40.9%) died by 1 year. Mortality at 5 years was 58.9%. Small improvements in short- and long-term mortality were seen over the study period. Among survivors to discharge, 2,870 (42.0%) required increased support in care from their preadmission baseline, 3,244 (47.5%) were readmitted to the hospital within 1 year, and 1,047 (15.3%) died within 1 year. The mean number of days at home in the year following discharge was 307.9 ± 109.6. CONCLUSIONS: Short- and long-term mortality among patients with AMI-CS is high, with minimal improvement over time. AMI-CS survivors experience significant morbidity, with high risks of readmission and death. Future studies should evaluate interventions to minimize postdischarge morbidity and mortality among AMI-CS survivors.

Inhaled anaesthesia compared with conventional sedation in post cardiac arrest patients undergoing temperature control: A systematic review and meta-analysis.

INTRODUCTION: Patients admitted with return of spontaneous circulation (ROSC) following out of hospital cardiac arrest (OHCA) are often sedated to facilitate care. Volatile anaesthetics have been proposed as alternative sedatives because of their rapid offset. We performed a systematic review and meta-analysis comparing the use of volatile anaesthetics to conventional sedation in this population. MATERIALS: We searched four databases (MEDLINE, Embase, CENTRAL, and Scopus) from inception to January 6, 2022. We included randomized trials and observational studies evaluating patients admitted following ROSC. We pooled data and reported summary estimates using odds ratio (OR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, both with 95% confidence intervals (CIs). We assessed risk of bias using the Newcastle Ottawa Scale and certainty of evidence using GRADE methodology. RESULTS: Of 1,973 citations, we included three observational studies (n = 604 patients). Compared to conventional sedation, volatile agents had an uncertain effect on delirium (OR 0.96, 95% CI 0.68-1.37), survival to discharge (OR 0.66, 95% CI 0.17-2.61), and ICU length of stay (MD 1.59 days fewer, 95% CI 1.17-4.36, all very low certainty). Patients who received volatile anaesthetic underwent a shorter duration of mechanical ventilation (MD 37.32 hours shorter, 95% CI 7.74-66.90), however this was based on low-certainty evidence. No harms were described with use of volatile anesthetics. CONCLUSION: Volatile anaesthetics may be associated with a decreased duration of mechanical ventilation in patients admitted with ROSC however this is based on low-certainty evidence. Further data are needed to assess their role in this population.

Neurocognitive disorders amongst patients with congenital heart disease undergoing procedures in childhood.

BACKGROUND: Amongst children with congenital heart disease (CHD), earlier age of repair improves cardiovascular outcomes. The effects of early intervention on neurodevelopment remains unclear. We assessed the association between early life repair, cardiopulmonary bypass (CPB) and the incidence of neurocognitive disorders (NCD) amongst CHD patients. METHODS: We created two retrospective cohorts from the Quebec CHD Database; with data from 1988 to 2010. Complexity of reparative procedures for CHD lesions were used as the proxy of CPB exposure with more complex procedure means longer exposure to CPB. Study Population 1 included pediatric patients with a single reparative procedure and compared patients with complex (long CBP) versus isolated shunt (short CBP) lesions. To assess the effects of CPB alone in Study Population 2 we compared patients with isolated atrial septal defects (ASD) who had surgical (short CBP) versus percutaneous (no CBP) repairs. The primary endpoint for both cohorts was development of an NCD. RESULTS: In Study population 1, 1174 patients underwent complex surgical repair and 1620 had a shunt closure. The incidence of NCDs was 2.45/100 person-years in the complex surgery group, and 2.08/100 person-years in the shunt closure group. The following were associated with increased risk of developing a NCD: surgical complexity (Hazard Ratio [HR] = 1.20, 95% Confidence Interval [CI]: 1.01-1.42), younger age at intervention (AAI) (HR = 1.20, 95% CI: 1.16-1.25), male sex (HR = 1.91, 95% CI: 1.61-2.27), and later calendar year at intervention (HR = 1.06, 95% CI: 1.04-1.07). Study population 2 had 527 isolated ASD patients; 202 underwent surgical repair and 325 had percutaneous closure. The incidence of NCDs was not statistically different between groups. Male sex (HR = 1.77, 95% CI: 1.08-2.89) and younger AAI (HR = 1.15, 95% CI: 1.06-1.25) were associated with increased NCD risk. CONCLUSION: Increased surgical complexity, male sex and younger AAI were associated with increased risk of NCDs in pediatric CHD patients. Surveillance protocols should be considered to identify NCDs in CHD patients after cardiac intervention.

Risk of readmission after heart failure hospitalization in older adults with congenital heart disease.

BACKGROUND: Hospital readmissions are common in adults with congenital heart disease (CHD) with heart failure (HF). We sought to examine the temporal risk of readmissions, the prompting diagnoses and their determinants within one-year after a first HF hospitalization in older CHD patients. METHOD: We assembled a cohort from the Quebec CHD database of patients whose first-ever HF hospitalization occurred after age 40. Subjects were followed from the first HF discharge to the earliest of all-cause readmission, death, or one-year post-discharge. The Fine and Gray model was used to measure the weekly readmission risks. The one-year period was categorized into different stages based on readmission risks. A multinomial logistic regression model was adopted to identify the determinants of patients falling in different readmission stages. RESULTS: The one-year death-adjusted cumulative readmission risk was 48.8%. The absolute weekly risk of readmission was the highest at week 2, declined by 50% at week 8, and reached a plateau at week 27. Three phases-vigilance (1-8 weeks), transition (9-27 weeks), and plateau (28-52 weeks)-were identified, corresponding to high-risk, decreasing-risk, and stable-risk periods. Cardiovascular diseases accounted for 61.7%, 50.3%, and 43.2% of all readmissions during the three phases; systemic diseases accounted for 15.2%, 19.9%, and 31.2%. A history of past-12-month interventional procedures saw significantly decreased readmission risks. Longer hospital stays were associated with lower readmission risks at the vigilance phase only. CONCLUSION: Policy makers and caregivers should account for the change in risk over time, and phase-tailored strategies should be planned to effectively reduce readmissions.

Intravenous beta-blockers in ST-segment elevation myocardial infarction: A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: The role of intravenous (IV) beta-blockers in conjunction with percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) remains unclear. We therefore conducted a meta-analysis to assess their role in the acute phase of STEMI. METHODS: We systematically searched the Cochrane Libraries, Medline, and EMBASE for RCTs comparing IV beta-blockers with inactive controls in STEMI patients undergoing PCI. The primary outcome was left ventricular ejection fraction (LVEF). Pooling was performed using DerSimonian and Laird random-effects models. RESULTS: Four RCTs (n=1149) were included in our meta-analysis. All RCTs only enrolled patients with confirmed STEMI with symptoms lasting <6 or <12hours, and presenting in Killip Class 1 or 2. Mean age ranged across trials from 58.5-62.5years. Most patients were male (range: 74.8%-86.3%). Data suggest that IV beta-blockers may improve LVEF at 0-2weeks (weighted mean difference [WMD]: 1.9%; 95% confidence interval [CI]: -0.7%, 4.5%) and 4-6weeks (WMD: 1.4%; 95% CI: -3.1%, 5.9%) post-infarct, reaching statistical significance at 24weeks (WMD: 2.6%; 95% CI: 0.6%, 4.6%). Rates of ventricular arrhythmia (risk ratio [RR]: 0.65; 95% CI: 0.33, 1.29), any arrhythmia (RR: 0.67; 95% CI: 0.36, 1.27), and cardiogenic shock (RR: 0.77; 95% CI: 0.31, 1.95) during index hospitalization were numerically lower with IV beta-blockers, but 95% CIs were wide. CONCLUSIONS: In STEMI patients presenting in Killip Class 1 or 2, IV beta-blockers in conjunction with PCI are associated with improved LVEF at 24weeks relative to PCI alone.

Varenicline and Adverse Cardiovascular Events: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Varenicline is an efficacious smoking-cessation drug. However, previous meta-analyses provide conflicting results regarding its cardiovascular safety. The publication of several new randomized controlled trials (RCTs) provides an opportunity to reassess this potential adverse drug reaction. METHODS AND RESULTS: We searched MEDLINE, EMBASE, and the Cochrane Library for RCTs that compare varenicline with placebo for smoking cessation. RCTs reporting cardiovascular serious adverse events and/or all-cause mortality during the treatment period or within 30 days of treatment discontinuation were eligible for inclusion. Relative risks (RRs) with 95% CIs were generated by using DerSimonian-Laird random-effects models. Thirty-eight RCTs met our inclusion criteria (N=12 706). Events were rare in both varenicline (57/7213) and placebo (43/5493) arms. No difference was observed for cardiovascular serious adverse events when comparing varenicline with placebo (RR 1.03, 95% CI 0.72-1.49). Similar findings were obtained when examining cardiovascular (RR 1.04, 95% CI 0.57-1.89) and noncardiovascular patients (RR 1.03, 95% CI 0.64-1.64). Deaths were rare in both varenicline (11/7213) and placebo (9/5493) arms. Although 95% CIs were wide, pooling of all-cause mortality found no difference between groups (RR 0.88, 95% CI 0.50-1.52), including when stratified by participants with (RR 1.24, 95% CI 0.40-3.83) and without (RR 0.77, 95% CI 0.40-1.48) cardiovascular disease. CONCLUSIONS: We found no evidence that varenicline increases the rate of cardiovascular serious adverse events. Results were similar among those with and without cardiovascular disease. Given varenicline's efficacy as a smoking cessation drug and the long-term cardiovascular benefits of cessation, it should continue to be prescribed for smoking cessation.

Stent Retrievers for the Treatment of Acute Ischemic Stroke: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

IMPORTANCE: Stent retrievers are a promising alternative for the treatment of acute ischemic stroke (AIS). Several recently completed clinical trials have examined the use of stent retrievers with intravenous recombinant tissue plasminogen activator (rtPA) compared with rtPA alone. OBJECTIVE: To conduct a systematic review and meta-analysis of randomized clinical trials to quantify the benefits and risks of using stent retrievers in addition to rtPA for the treatment of AIS. DATA SOURCES: The MEDLINE, EMBASE, and Cochrane Library of Clinical Trials databases were searched from inception to July 2015 for the keywords stent*, retriev*, Solitaire, Trevo, Revive, and stroke. Trial registries were also searched. A total of 326 publications were identified and 213 potentially relevant records were screened. STUDY SELECTION: Randomized clinical trials that examined stent retrievers with rtPA vs rtPA alone were included in the meta-analysis. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted study data and performed quality assessment using the Cochrane Risk of Bias Tool. DerSimonian and Laird random-effects models were used to estimate relative risks (RRs), risk differences (RDs), and numbers needed to treat. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients achieving functional independence (defined as a score of 0-2 on the modified Rankin Scale, with 0 indicating no disability and 6 indicating death) at 90 days. Risks of all-cause mortality, intracranial hemorrhage, and parenchymal hematoma at 90 days were also assessed. RESULTS: Five randomized clinical trials met our inclusion criteria (n = 1287 patients). Patients randomized to stent-retriever therapy with rtPA had significantly improved rates of functional independence at 90 days compared with those randomized to rtPA alone (RR, 1.72; 95% CI, 1.48-1.99; RD, 0.19; 95% CI, 0.13-0.25). When data were pooled across trials, the effect of stent-retriever therapy on all-cause mortality at 90 days was inconclusive (RR, 0.82; 95% CI, 0.60-1.11; RD, -0.04; 95% CI, -0.08 to 0.1). There were similarly no detectable differences in the risks of intracranial hemorrhage (RR, 1.15; 95% CI, 0.67-1.97; RD, 0.00; 95% CI, -0.02 to 0.03) or parenchymal hematoma (RR, 1.18; 95% CI, 0.71-1.94; RD, 0.01; 95% CI, -0.01 to 0.04), although the 95% CIs were wide. Fixed-effects sensitivity analyses produced similar results for all outcomes. CONCLUSIONS AND RELEVANCE: The use of stent retrievers in conjunction with rtPA vs rtPA alone is associated with significant improvement of functional independence 90 days after AIS.

Pharmacological management strategies for stroke prevention following transcatheter aortic valve replacement: A systematic review.

BACKGROUND: The most appropriate pharmacological treatment for stroke prevention after transcatheter aortic valve replacement (TAVR) is unclear. We performed a systematic review of randomized controlled trials (RCTs) and observational studies examining the effect of various pharmacological treatment regimens on rates of stroke, bleeding, and death after TAVR. METHODS: We searched Cochrane Library, Embase, and Medline for RCTs and observational studies comparing ≥2 antithrombotic regimens in TAVR patients. Included antithrombotic regimens were defined as one or more antiplatelet agents (aspirin, clopidogrel, prasugrel, or ticagrelor) and/or anticoagulants (vitamin K antagonists or novel oral anticoagulants). RESULTS: Eight studies (2 RCTs and 6 observational studies) met our inclusion criteria (n=1598). Rates of major stroke ranged from 0% to 5.6% with no detected differences between treatment arms. All-cause mortality ranged from 5% to 15%, and no differences in mortality were detected between therapies. A consistent pattern of reduction in major or life-threatening bleeding was found with a single antiplatelet therapy (SAPT) compared to dual antiplatelet therapy (DAPT). However, this difference only reached statistical significance in a single cohort study (risk ratio 0.24; 95% confidence interval 0.12, 0.46). No differences between anticoagulant therapies were detected for any endpoint. Overall, studies were underpowered to detect differences between treatment groups. CONCLUSION: Similar rates of stroke, bleeding, and mortality were found among most studies. A trend towards reduced rates of major or life-threatening bleeding when comparing SAPT to DAPT was found. Numbers of events were small, highlighting the need for larger studies on which to base pharmacological recommendations post-TAVR.