Production of leukotrienes by 5-lipoxygenase (5-LO) has been linked to unstable atherosclerotic plaques and cardiovascular events. VIA-2291 is a potent 5-LO inhibitor.
In a double-blinded study, 191 ...patients were randomly assigned 3 weeks after an acute coronary syndrome to receive 25, 50, or 100 mg VIA-2291 or placebo daily for 12 weeks. The primary study end point, whole blood stimulated leukotriene LTB4 at trough drug level, was reduced in all VIA-2291 groups (P<0.0001) in a dose-dependent fashion, with approximately 80% inhibition in >90% of patients in the 100-mg group. A significant reduction of urine leukotriene LTE4 was obtained in all dose groups. No serious adverse events were considered related to study drug. A subset of 93 patients who had undergone a 64-slice coronary CT examination at baseline continued on study medication for a total of 24 weeks and underwent a repeat scan. Five of these patients withdrew or were noncompliant and 28 had nonevaluable scans. Among the 60 remaining patients, new coronary plaques were observed in 5 of 18 (27.8%) placebo-treated patients and in 2 of 42 (4.8%) VIA-2291-treated patients (P=0.01). A reduction in noncalcified plaque volume at 24 weeks versus placebo was observed in VIA-2291-treated groups in the 34 of these 60 patients in whom this end point was analyzable (P<0.01).
VIA-2291 reduces leukotriene production at 12 weeks after an acute coronary syndrome. Preliminary data from the CT substudy suggest that such a reduction in leukotriene production may influence atherosclerosis; however, this requires confirmation in a larger study. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00358826.
Objectives
Emergency department (ED) visits for high blood pressure are increasing in frequency. We aimed to map those patients’ trajectory, from referral sources to the type of care received at the ...ED to anticipated actions for future high blood pressure concerns, and to better understand their reasons for consulting the ED for high blood pressure values.
Methods
Between 2018 and 2020, patients who presented to the Montreal Heart Institute’s ED for elevated blood pressure were recruited in a prospective observational study including a post hoc structured telephone interview and medical chart review. Five possible referral sources were predetermined. We provided proportions and 95% confidence intervals.
Results
A total of 100 patients were recruited (female: 59%, mean age: 69 ± 12). A majority (93%, 95% CI 88–98%) possessed a home blood pressure device, among which 46% (95% CI 36–56%) remembered receiving advice for its use. The main referral sources for high blood pressure to the ED were self-reference (53%, 95% CI 43–63%), advice of a lay person (19%, 95% CI 11–27%) or a nurse (13%, 95% CI 6–20%). Mainly, patients reported being concerned by concomitant symptoms or experiencing acute medical consequences (44%, 95% CI 34–54%), having followed the recommendation of a third party (33%, 95% CI 24–42%), or having concerns about their medication (6%, 95% CI 1–11%). Two weeks following their ED visits, consulting ED remained the main choice for future concerns about high blood pressure for 27% of participants. When specifically asked if they would return to the ED for elevated blood pressure, 73% (95% CI 64–83%) said yes.
Conclusions
Most patients who consulted the ED for elevated blood pressure values were self-referred. More can be done to promote blood pressure education, effective use of personal blood pressure devices, and recommendations for patients and health professionals when confronted with high blood pressure results.
Delirium and sedative-induced coma are described as incremental manifestations of cerebral dysfunction. Both may be associated with sedative or opiate doses and pharmacokinetic or pharmacogenetic ...variables, such as drug plasma levels (exposure), drug metabolism, and/or their transport across the blood-brain barrier.
To compare biological and drug treatment characteristics in patients with coma and/or delirium while in the ICU.
In 99 patients receiving IV fentanyl, midazolam, or both, we evaluated drug doses, covariates likely to influence drug effects (age, body mass index, and renal and hepatic dysfunction); delirium risk factors; concomitant administration of CYP3A and P-glycoprotein substrates/inhibitors; ABCB1, ABCG2, and CYP3A5 genetic polymorphisms; and fentanyl and midazolam plasma levels. Delirium and coma were evaluated daily. In patients with only coma (n=15), only delirium (n=7), and neither ever (n=14), we measured plasma levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-1RA, IL-6, IL-8, IL-10, IL-17,macrophage inflammatory protein-1β, and monocyte chemotactic protein-1.
Time to first coma was associated with fentanyl and midazolam doses (p=0.03 and p=0.01, respectively). The number of days in coma was associated with the number of days of coadministration of CYP3A inhibitors (r=0.30; p=0.006). Plasma levels of fentanyl were higher in patients with clinical coma (3.7±4.7 vs. 2.0±1.8 ng/mL, p=0.0001) as were midazolam plasma levels (1050±2232 vs. 168±249 ng/mL, p=0.0001). Delirium occurrence was unrelated to midazolam administration, cumulative doses, or serum levels. Days with delirium were associated with days of coadministration of P-glycoprotein inhibitor (r=0.35; p=0.0004). Delirious patients had higher levels of the inflammatory mediator IL-6 than comatose patients (129.3 vs. 35.0 pg/mL, p=0.05).
Coma is associated with fentanyl and midazolam exposure; delirium is unrelated to midazolam and may be linked to inflammatory status. These data suggest that iatrogenic coma and delirium are not mechanistically linked.
Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to ...investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission.
The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants.
Trial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0–61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio OR 0·79, 95·1% CI 0·61–1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57–0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001).
In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended.
The Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.
The use of 2 internal thoracic artery (ITA) grafts increases survival 10 years after coronary artery bypass grafting (CABG) compared with single ITA grafting. Statin treatment was also shown to ...decrease development and progression of saphenous vein graft atherosclerosis. This study examined the effect of statin treatment on long-term survival after CABG.
Operative, survival, and pharmacologic data of 6655 patients who underwent CABG with ITAs between 1995 and 2007 in our institution were obtained.
Patients with bilateral ITA grafts had an average 10-year-survival rate of 83% +/- 2% compared with 67% +/-1% in patients with single ITA grafts (p = 0.0001). Statin treatment caused a significant decrease in the long-term risk of death among patients who underwent single ITA grafting (hazard ratio HR, 0.735, p = 0.0001). However, statin treatment had no effect on the risk of long-term death among patients who underwent bilateral ITA grafting (HR, 1.053; p = 0.7806).
Statin treatment initiated early after grafting improved long-term survival in patients with a single ITA graft but not in those with bilateral ITA grafts. Survival of statin-treated patients with single ITA grafts was similar to bilateral ITA patients.
ICU delirium is common and adverse. The Intensive Care Delirium Screening Checklist (ICDSC) score ranges from 0 to 8, with a score of 4 or higher indicating clinical delirium. We investigated whether ...lower (subsyndromal) values affect outcome.
600 patients were evaluated with the ICDSC every 8Symbol: see texth.
Of 558 assessed patients 537 noncomatose patients were divided into three groups: no delirium (score = 0; n = 169, 31.5%), subsyndromal delirium (score = 1-3; n = 179, 33.3%), and clinical delirium (score >or=4; n = 189, 35.2%). ICU mortality rates were 2.4%, 10.6%, and 15.9% in these three groups, respectively. Post-ICU mortality was significantly greater in the clinical delirium vs. no delirium groups (hazard ratio = 1.67) after adjusting for age, APACHE II score, and medication-induced coma. Relative ICU length of stay was: no delirium < subsyndromal delirium < clinical delirium and hospital LOS: no delirium < subsyndromal delirium approximately clinical delirium. Patients with no delirium were more likely to be discharged home and less likely to need convalescence or long-term care than those with subsyndromal delirium or clinical delirium. ICDSC score increments higher than 4/8 were not associated with a change in mortality or LOS.
Clinical delirium is common, important and adverse in the critically ill. A graded diagnostic scale permits detection of a category of subsyndromal delirium which occurs in many ICU patients, and which is associated with adverse outcome.
This study aims to describe the outcomes after heart transplantation using a bridge-to-bridge strategy with a sequence of extracorporeal membrane oxygenation (ECMO) support followed by temporary ...total artificial heart implantation (TAH-t).
A retrospective, multicenter analysis of 54 patients who underwent TAH-t implantation following an ECMO for cardiogenic shock was performed (ECMO-TAH-t group). A control group of 163 patients who underwent TAH-t implantation as a direct bridge to transplantation (TAH-t group) was used to assess this strategy's impact on outcomes.
Fifty-four patients, averaging 47 ± 13 year old, underwent implantation of a TAH-t after 5.3 ± 3.4 days of ECMO perfusion for cardiogenic shock. In the ECMO-TAH-t group, 20 patients (20/54%; 37%) died after TAH-t implantation and 57 patients (57/163%; 35%) died in the TAH-t group (Gray test; P = .49). The top 3 causes of death of patients on TAH-t support were multisystem organ failure (40%), sepsis (20%), and neurologic events (20%). Overall, 32 patients (32/54%; 59%) underwent heart transplantation in the ECMO-TAH-t group compared with 106 patients (106/163%, 65%) in the TAH-t group (P = .44). No significant difference in survival was observed at 6 months, 1 year, and 3 years after heart transplant (ECMO-TAH-t group: 94%, 87%, and 80% vs 87%, 83%, and 76% in the TAH-t group, respectively). Deterioration of liver function (bilirubin, aspartate transaminase, and alanine aminotransferase levels on TAH-t) was associated with increased mortality before heart transplant in both groups.
Sequential bridging from ECMO to TAH-t followed by heart transplantation is a viable option for a group of highly selected patients.
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•A predictive model for COVID-19 hospitalization or death was developed.•This model was based on 7 risk factors for COVID-19.•This model identified high-risk subjects who could benefit from ...colchicine therapy.
A predictive model for hospitalization due to COVID-19 or death was developed in the placebo group (N=2,084) from a large clinical trial of colchicine in COVID-19 patients (N = 4,159).
The 7 variables retained in the predictive model were age, gender, body-mass index, history of respiratory disease, use of diabetes drugs, use of anticoagulants, and use of oral steroids at the time of randomization. An optimal threshold value identified from the predictive model was used to classify high-risk patients (those with a predicted probability above the optimal threshold) and low-risk patients (those with a predicted probability below the optimal threshold). The number needed to treat to prevent 1 hospitalization or death with colchicine treatment decreased from 71 in the whole study population (N = 4,159) to 29 in the high-risk subgroup (N=1,692).
This model could serve to identify high-risk subjects who will particularly benefit from early colchicine therapy.
We sought to assess the outcomes after heart transplantation (HT) of patients supported with a temporary total artificial heart (t-TAH) as a bridge to transplantation in high-volume centers.
A ...retrospective analysis of 217 consecutive patients who underwent t-TAH (SynCardia Systems, Tucson, Arizona) implantation between January 2014 and May 2019 in 6 high-volume North American centers was performed. End points included survival and adverse events after t-TAH and HT.
The mean age of patients was 49 ± 12 years, and heart failure etiologies were non-ischemic dilated cardiomyopathy (36%), ischemic (25%), restrictive (12%), and cardiac graft failure (9%). A total of 101 (48%) patients had Interagency Registry for Mechanically Assisted Circulatory Support patient profile 1, and 65 (31%) had Interagency Registry for Mechanically Assisted Circulatory Support patient profile 2. At the end of the study period, 138 of 217 (63.5%) patients had undergone HT, and 75 (34.5%) patients died before HT. The mean time between t-TAH implantation and HT averaged 181 ± 179 days (range: 0-849) and the mean follow-up after HT was 35 ± 25 months. The overall survival in the entire cohort was 75%, 64%, and 58% at 1, 2, and 5 years, respectively. Post-transplant survival was 88%, 84%, 79%, and 74% at 6 months, 1 year, 2 years, and 5 years, respectively. Among the 32 patients (23%) who died after HT, the main causes of death were chronic allograft vasculopathy (25%), multiorgan failure (21.8%), sepsis (15.6%), and stroke (9%).
In this multicenter study, almost two thirds of patients implanted with a t-TAH could be transplanted. The overall and post-transplantation survival after t-TAH was satisfactory in these critically ill patients.
Background/Objectives
Chronic kidney disease (CKD) is a risk factor for long‐term survival in cardiac surgery. The Cockcroft‐Gault, Modification of Diet in Renal Disease (MDRD) study, CKD ...Epidemiology Collaboration (CKD‐EPI), revised Lund‐Malmö (LM), and full age spectrum equations are used to estimate glomerular filtration rates (eGFR), but each have advantages and disadvantages. Our objective was to determine which equation better predicts long‐term survival.
Methods
Data on 1492 consecutive patients who underwent isolated off‐pump coronary artery bypass surgery between September 1996 and December 2008 were prospectively collected. Preoperative and postoperative eGFR were calculated using the five equations and compared using Cox regression analyses and time‐dependent receiver operating characteristic (ROC) curves at 10 years.
Results
In a Cox regression model after correction for significant predictors of long‐term mortality, adjusted hazard ratios (HR) for one standard deviation increase in preoperative eGFR were 0.661 (P < .0001), 0.844 (P = .0166), 0.787 (P = .0002), 0.746 (P < .0001), and 0.717 (P < .0001) for the CG, MDRD, CKD‐EPI, LM, and FAS equations, respectively. The areas under the time‐dependent ROC curve at 10 years also showed that the CG formula has a better predictive value. Postoperative eGFR at discharge were also significant predictors of long‐term mortality (HR = 0.603, P < .0001; HR = 0.725, P < .0001; HR = 0.688, P < .0001; HR = 0.673, P < .0001; HR = 0.632, P < .0001 for the CG, MDRD, CKD‐EPI, LM, and FAS equations, respectively).
Conclusions
The CG formula was shown to better predict survival in cardiac surgery, though the FAS equation has a comparable prognostic value. Additionally, postoperative eGFR at discharge also predicted long‐term survival.
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