Independent Endpoint Committee Research Articles

Type 1 Myocardial Infarction in Patients With Acute Ischemic Stroke

Elevated values of high-sensitivity cardiac troponin (hs-cTn) are common in patients with acute ischemic stroke and are associated with poor prognosis. However, diagnostic and therapeutic implications in patients with ischemic stroke remain unclear. To identify factors indicative of myocardial infarction (MI) in patients with acute ischemic stroke and hs-cTn elevation. The primary hypothesis was that a dynamic change of hs-cTn values (>50% change) in patients with acute ischemic stroke indicates MI. This cross-sectional study was a prospective, observational study with blinded end-point assessment conducted across 26 sites in Germany. Patients were included if they had acute ischemic stroke within 72 hours and either (1) highly elevated hs-cTn values on admission (>52 ng/L) or (2) hs-cTn levels above the upper limit of normal and a greater than 20% change at repeated measurements. Patients were enrolled between August 2018 and October 2020 and had 1 year of follow-up. Statistical analysis was performed between April 2022 and August 2023. Standardized electrocardiography, echocardiography, and coronary angiography. Diagnosis of MI as adjudicated by an independent end-point committee based on the findings of electrocardiography, echocardiography, and coronary angiography. In total, 254 patients were included. End points were adjudicated in 247 patients (median [IQR] age, 75 [66-82] years; 117 were female [47%] and 130 male [53%]). MI was present in 126 of 247 patients (51%) and classified as type 1 MI in 50 patients (20%). Dynamic change in hs-cTn value was not associated with MI in univariable (32% vs 38%; χ2 P = .30) or adjusted comparison (odds ratio, 1.05; 95% CI, 0.31-3.33). The baseline absolute hs-cTn value was independently associated with type 1 MI. The best cutoffs for predicting type 1 MI were at hs-cTn values 5 to 10 times the upper limit normal. This study found that in patients with acute ischemic stroke, a dynamic change in hs-cTn values did not identify MI, underscoring that dynamic changes do not identify the underlying pathophysiological mechanism. In exploratory analyses, very high absolute hs-cTn values were associated with a diagnosis of type 1 MI. Further studies are needed how to best identify patients with stroke who should undergo coronary angiography.

Neuronal nets and logistic regression analysis provide improved prediction of infective endocarditis compared to the modified Duke Score: a post-hoc analysis of the prospective PRO-ENDOCARDITIS study

Abstract Introduction The modified Duke score is the currently recommended diagnostic algorithm in suspected infective endocarditis (IE). The categorization in major and minor criteria enables an easy clinical application, but may not optimally utilize individual patient's information. In contrast, detailed statistical evaluation of multiple characteristics using artificial intelligence and logistic regression report improved prediction of various cardiovascular diseases over conventional clinical strategies. We tested the hypothesis that neuronal nets and logistic regression analysis would provide improved prediction of IE as compared to the modified Duke score. Methods This post-hoc evaluation of the prospective observational PRO-ENDOCARDITIS study was conducted at the West German Heart and Vascular center between December 2017 and May 2019 and includes 261 patients. Duke criteria and clinical characteristics were prospectively collected. Transesophageal echocardiography (TEE) imaging was evaluated by a blinded cardiologist at a central core-lab. IE as primary endpoint was adjudicated by an independent clinical endpoint committee. The database was divided into a training (70%) and validation cohort (30%). We compared the value of the Duke score, neuronal nets and logistic regression analysis for prediction of the primary endpoint. Results The mean age was 60.1±16.1 years, 37.2% were female. In 47 cases, IE was present. The modified Duke score achieved an AUC of 0.863 in the training cohort and 0.913 within the validation cohort. The logistic regression and the neural net exceeded the predictive value in both cohorts (training cohort: 0.992 and 0.986; validation cohort: 0.964, 0.957; for logistic regression and neuronal nets, respectively, Figure 1). Without the use of TEE, the remaining Duke criteria only poorly predicted IE (training cohort: 0.771, 0.951 and 0.938; validation cohort: 0.835, 0.862 and 0.780, for the Duke score, logistic regression and neuronal nets, respectively). Discussion Logistic regression analysis and neuronal nets provide improved prediction of IE as compared to the clinically established modified Duke score. Further studies on larger databases are needed to confirm our results and provide algorithms for clinical routine. Funding Acknowledgement Type of funding sources: None.

Remnant cholesterol contributes to residual lipid risk after acute coronary syndromes

Abstract Background Increasing evidence indicates that cholesterol transported in triglyceride-rich lipoproteins (remnant cholesterol) is a causal risk factor for major adverse cardiovascular events (MACE) independent from other lipid fractions. To date, the relationship between remnant cholesterol (remnant-C) levels and cardiovascular (CV) outcomes after acute coronary syndromes (ACS) in patients with adequate low-density lipoprotein cholesterol (LDL-C) control is uncertain. Purpose This study evaluated the contribution of remnant-C to residual lipid risk after ACS. Methods Nested within 4'787 ACS patients in the prospective multicentre SPUM-ACS study (NCT0100070) we examined all patients presenting with LDL-C levels <100 mg/dl under lipid lowering therapy (n=756). Remnant-C was calculated as non-high-density lipoprotein cholesterol (non-HDL-C) minus calculated LDL-C using the Martin/Hopkins modified equation. The predefined primary outcome was a composite of CV death, myocardial infarction, and ischemia-driven revascularization at 12 months. Events were adjudicated by an independent external endpoint committee blinded to the lipid measurements. Multivariable-adjusted Cox models were fitted using smoothing splines for absolute remnant-C levels (continuous), log-transformed absolute remnant-C levels (continuous), remnant-C tertiles (categorical) and a prespecified cutoff (75th percentile) for high remnant-C (categorical). Bias-corrected bootstrapping was used for internal validation. Results Eighty-seven (11.5%) patients had an event, 14 (1.9%) patients withdrew consent, and 5 (0.7%) patients were lost to follow up at 12 months. In multivariable-adjusted analyses, remnant-C (hazard ratio [HR]: 1.63; 95% confidence interval [CI]: 1.04 to 2.74; per log2 increase; p=0.020), triglycerides (HR: 1.41; 95% CI: 1.04 to 1.96; per log2 increase; p=0.017), and low high-density lipoprotein (HDL)-C (HR: 0.56; 95% CI: 0.33 to 0.86; per log2 increase; p<0.040), but not LDL-C (HR: 1.41; 95% CI: 0.78 to 2.84; per log2 increase; p=0.272), were associated with MACE. High remnant-C was independently associated with elevated risk of MACE when adjusting for clinical and demographic factors including GRACE 2.0 risk estimates (HR: 2.43; 95% CI: 1.42 to 4.27; above vs. below 75th percentile; p<0.001; HR: 2.10; 95% CI: 1.09 to 4.70; tertile 3 vs. tertile 1; p=0.014). Conclusion In patients who develop ACS with LDL-C levels <100 mg/dl, levels of remnant-C and triglycerides, but not LDL-C, were associated with adverse CV outcomes independent of other risk factors. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Swiss National Science FoundationSwiss Heart Foundation

Neuronal nets and logistic regression analysis provide improved prediction of infective endocarditis compared to the modified Duke Score: a post-hoc analysis of the prospective PRO-ENDOCARDITIS study

Abstract Introduction The modified Duke score is the currently recommended diagnostic algorithm in suspected infective endocarditis (IE). The categorization in major and minor criteria enables an easy clinical application, but may not optimally utilize individual patient's information. In contrast, detailed statistical evaluation of multiple characteristics using artificial intelligence and logistic regression report improved prediction of various cardiovascular diseases over conventional clinical strategies. We tested the hypothesis that neuronal nets and logistic regression analysis would provide improved prediction of IE as compared to the modified Duke score. Methods This post-hoc evaluation of the prospective observational PRO-ENDOCARDITIS study was conducted at the West German Heart and Vascular center between December 2017 and May 2019 and includes 261 patients. Duke criteria and clinical characteristics were prospectively collected. Transesophageal echocardiography (TEE) imaging was evaluated by a blinded cardiologist at a central core-lab. IE as primary endpoint was adjudicated by an independent clinical endpoint committee. The database was divided into a training (70%) and validation cohort (30%). We compared the value of the Duke score, neuronal nets and logistic regression analysis for prediction of the primary endpoint. Results The mean age was 60.1±16.1 years, 37.2% were female. In 47 cases, IE was present. The modified Duke score achieved an AUC of 0.863 in the training cohort and 0.913 within the validation cohort. The logistic regression and the neural net exceeded the predictive value in both cohorts (training cohort: 0.992 and 0.986; validation cohort: 0.964, 0.957; for logistic regression and neuronal nets, respectively, Figure 1). Without the use of TEE, the remaining Duke criteria only poorly predicted IE (training cohort: 0.771, 0.951 and 0.938; validation cohort: 0.835, 0.862 and 0.780, for the Duke score, logistic regression and neuronal nets, respectively). Discussion Logistic regression analysis and neuronal nets provide improved prediction of IE as compared to the clinically established modified Duke score. Further studies on larger databases are needed to confirm our results and provide algorithms for clinical routine. Funding Acknowledgement Type of funding sources: None.

Discordant diagnostic criteria for pneumonia in COPD trials: a review.

Inhaled corticosteroids (ICS) have a class effect of increasing pneumonia risk in patients with COPD. However, pneumonia incidence varies widely across clinical trials of ICS use in COPD. This review clarifies methodological differences in defining and recording pneumonia events in these trials and discusses factors that could contribute to the varying pneumonia incidence. Literature searches and screening yielded 40 relevant references for inclusion. Methods used to capture pneumonia events in these studies included investigator-reported pneumonia adverse events, standardised list of signs or symptoms, radiographic confirmation of suspected cases and/or confirmation by an independent clinical end-point committee. In general, more stringent pneumonia diagnosis criteria led to lower reported pneumonia incidence rates. In addition, studies varied in design and population characteristics, including exacerbation history and lung function, factors that probably contribute to the varying pneumonia incidence. As such, cross-trial comparisons are problematic. A minimal set of standardised criteria for diagnosis and reporting of pneumonia should be used in COPD studies, as well as reporting of patients' pneumonia history at baseline, to allow comparison of pneumonia rates between trials. Currently, within-trial comparison of ICS-containing versus non-ICS-containing treatments is the appropriate method to assess the influence of ICS on pneumonia incidence.

Partial oral antibiotic treatment for bacterial brain abscess: an open-label randomized non-inferiority trial (ORAL)

BackgroundThe advised standard treatment for bacterial brain abscess following surgery is 6 to 8 weeks of intravenous (IV) antibiotic treatment, but an early switch to oral antibiotic treatment has been suggested to be equally effective.MethodsThis investigator-initiated, international, multi-center, parallel group, open-label, randomized (1:1 allocation) controlled trial will examine if oral treatment after 2 weeks of IV antibiotic therapy is non-inferior to standard 6–8 weeks of IV antibiotics for bacterial brain abscess in adults (≥ 18 years of age). The study will be conducted at hospitals across Denmark, the Netherlands, France, Australia, and Sweden. Exclusion criteria are severe immunocompromise or impaired gastro-intestinal absorption, pregnancy, device-related brain abscesses, and brain abscess caused by nocardia, tuberculosis, or Pseudomonas spp. The primary objective is a composite endpoint at 6 months after randomization consisting of all-cause mortality, intraventricular rupture of brain abscess, unplanned re-aspiration or excision of brain abscess, relapse, or recurrence. The primary endpoint will be adjudicated by an independent blinded endpoint committee. Secondary outcomes include extended Glasgow Outcome Scale scores and all-cause mortality at end of treatment as well as 3, 6, and 12 months since randomization, completion of assigned treatment, IV catheter associated complications, durations of admission and antibiotic treatment, severe adverse events, quality of life scores, and cognitive evaluations. The planned sample size is 450 patients for a one-sided alpha of 0.025 and a power of 90% to exclude a difference in favor of standard treatment of more than 10%. Date of initiation of first study center was November 3, 2020, with active recruitment for 3 years and follow-up for 1 year of all patients.DiscussionThe results of this study may guide future recommendations for treatment of bacterial brain abscess. If early transition to oral antibiotics proves non-inferior to standard IV treatment, this will provide considerable health and costs benefits.Trial registrationClinicalTrials.gov NCT04140903, first registered 28.10.2019. EudraCT number: 2019-002845-39, first registered 03.07.2019

Sex-specific differences in total ischemic time coincide with similar cardiovascular outcome in patients with acute coronary syndrome: a Swiss multicentre cohort study

Abstract Background Previous studies showed prolonged patient and system delay in female patients with acute coronary syndromes (ACS) which is thought to be a major driver of discrepancies in their cardiovascular (CV) outcomes. Indeed, timely management is particularly important in patients with ST-segment elevation myocardial infarction (STEMI), as increased total ischemic time augments infarct size and relates to poor CV survival. However, contemporary evidence on sex-specific differences in ACS management and discrepancies in outcomes is limited and controversial. Purpose We sought to systematically investigate whether a sex-gap in symptom-to-door (STD), door-to-balloon (DTB)/door-to-PCI (DTP) time exists in a prospective ACS cohort and if such differences translate into different rates of major adverse cardiovascular events (MACE) at one year. Methods From 2009 to 2019, 4'930 ACS patients with a main diagnosis of NSTEMI (43.3%), STEMI (53.3%) or unstable angina (3.4%) were enrolled in the multicentre, prospective SPUM-ACS study of which 4'671 completed follow-up at one year. STD, DTB and DTP time was analyzed. The primary endpoint, a composite measure of all-cause death, nonfatal myocardial infarction, nonfatal stroke and ischemia-driven revascularization, was adjudicated by an independent clinical endpoint committee. Kaplan-Meier and multivariate-adjusted Cox proportional hazard regression models were used for time-to-event analyses. Results A total of 1'019 (20.7%) women and 3'911 (79.3%) men with a main diagnosis of ACS were included in the study. At presentation, women were older (69.6±12.0 vs. 62.2±12.1 years, P<0.001), more likely to have impaired renal function (median, 81.2 vs. 89.2 ml/min/1.73m2, P<0.001) and a history of hypertension (63.9% vs. 54.3%, P<0.001). STD time was significantly higher in female STEMI (median, 3.2 vs. 2.5 hours, P<0.001) and NSTEMI patients (median, 7.0 vs. 5.0 hours, P=0.015). Importantly, DTB time did not differ between sexes in STEMI patients (1.0 vs. 1.0 hour, P=0.430). Similarly, DTP time of female NSTEMI patients was comparable to males (4.3 vs. 4.4 hours, P=0.855). In the entire cohort, female ACS patients did not show a higher occurrence of the primary endpoint at one year (crude HR 0.86, 95% CI 0.72–1.04; adjusted HR 0.83, 95% CI, 0.66–1.05). In a multivariate-adjusted subgroup analysis, neither female STEMI (adjusted HR 0.82, 95% CI 0.59–1.15) nor NSTEMI patients (adjusted HR 0.87, 95% CI 0.61–1.24) showed higher hazards for the primary endpoint compared to male patients. Conclusions Women with a main diagnosis of STEMI show considerably higher prehospital delay, thus prolonged total ischemic time which is mainly driven by increased STD time. Intriguingly, this does not translate into higher rates of MACE compared to men at one year. Women with ACS may particularly benefit from measures aimed at reducing prehospital delay, as this may further improve long-term prognosis after the acute event. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Swiss National Science Foundation - SNFFoundation for Cardiovascular Research - Zurich Heart House

High plasma levels of soluble LOX-1 portends poor survival in acute coronary syndromes beyond GRACE 2.0: a multicentre prospective cohort study

Abstract Background While inflammatory states and dyslipidemias confer a dismal prognosis following myocardial ischaemia, the role of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) which sits at the confluence of these conditions remains elusive. Given soluble LOX-1' (sLOX-1) pivotal role in inflammatory processes underlying atherosclerotic plaque progression, we sought to study its prognostic utility on the risk of adverse events in acute coronary syndromes (ACS). Purpose Hence, we aimed to investigate whether sLOX-1 is an independent predictor of all-cause death at one year beyond traditional and emerging risk factors for poor survival following ACS. Methods 2678 ACS patients were recruited in the prospective, multicentre SPUM-ACS trial, of which 2525 completed follow-up at one year. Major adverse cardiovascular events, including death from any cause, were adjudicated by an independent clinical endpoint committee. By employing high-sensitive enzyme-linked immunosorbent assay, sLOX-1 was assessed in the plasma at the time of presentation in ACS and age-matched chronic coronary syndrome (CCS) patients. Kaplan-Meier survival analysis and Cox proportional hazard regression models, adjusted for baseline variables and the GRACE 2.0 score, were used to study the predictive utility of sLOX-1. Results At the time of presentation, ACS patients, specifically those with ST-segment elevation ACS, had significantly elevated sLOX-1 levels as compared to patients with CCS (median, 35.40 vs. 2.00 pg/ml, P<0.0001). Patients in the upper sLOX-1 tertile were at heightened risk for both death from any cause (crude HR 1.785, 95% CI 1.083–2.941, P<0.05; adjusted HR 2.035, 95% CI 1.176–3.519, P<0.05) and CV death (crude HR 2.447, 95% CI 1.285–4.663, P<0.01; adjusted HR 2.383, 95% CI 1.206–4.710, P<0.05) compared to those in the first tertile. Importantly, sLOX-1 remained an independent predictor of all-cause death after adjustment for known risk factors of adverse outcome and the GRACE 2.0 score (adjusted + GRACE 2.0 HR 1.896, 95% CI 1.034–3.476, P<0.05). Conclusions Plasma sLOX-1 is elevated in ACS patients and predicts poor survival independent of both traditional and emerging risk factors and provides prognostic information beyond GRACE 2.0. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Swiss National Science FoundationFoundation for Cardiovascular Research - Zurich Heart House

Sex-specific temporal trends in the incidence of atrial fibrillation in a large Norwegian population-based study 1986–2014

Abstract Background Due to population aging, increasing prevalence of obesity and enhanced detection, the prevalence of atrial fibrillation (AF) worldwide is increasing steadily. Considerable sex differences in the epidemiology of AF such as lower prevalence and later onset in women compared to men have been reported. However, little is known about sex-specific temporal trends in AF incidence within the general population. Purpose To explore sex-specific age-adjusted secular trends in the incidence of AF in a general population from Norway between 1986 and 2014. Methods A total of 16,865 men and 15,413 women aged 20 years or older and without AF were enrolled in a longitudinal population study between 1986 and 2008 and followed up for incident AF to the end of 2014. Follow-up was from the date of attendance to the date of AF, emigration or death, whichever came first. All AF cases were validated by an independent endpoint committee using hospital and death records. AF incidence rates were calculated for each calendar year by dividing the number of AF cases per year by the corresponding person-time at risk. To allow for non-linear time trends, calendar year was fitted using fractional polynomials. Poisson regression was used to estimate calendar year-specific AF incidence rates adjusted for age. All analyses were stratified by sex. Results A total of 911 AF events in women and 1,139 AF events in men occurred over 324,090 person-years and 294,531 person-years of follow-up, respectively. During the study period AF incidence rates in men were at least double that in women (Figure). Age-adjusted AF incidence rates in women increased from 1986, peaked at 0.87 per 1000 person-years in 1998 and then decreased slightly towards 2014. In men AF incidence rates increased up to 2.18 per 1000 person-years in 2005 and then steeply decreased. Conclusion(s) AF incidence rates decreased in both women and men towards the end of the study period. The decrease was more profound in men compared to that in women. One possible explanation is more pronounced reduction in incidence and better treatment of myocardial infarction in men compared to women given that the aetiology of AF in men is mainly ischemic heart disease-related. However, further epidemiological analyses should be undertaken to identify explanatory factors. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): University Hospital of North Norway, Northern Norway Regional Health Authority

Myocardial Infarction Can Be Safely Excluded by High-sensitivity Troponin I Testing 3 Hours After Emergency Department Presentation.

BackgroundThe accuracy and speed by which acute myocardial infarction (AMI) is excluded are an important determinant of emergency department (ED) length of stay and resource utilization. While high‐sensitivity troponin I (hsTnI) >99th percentile (upper reference level [URL]) represents a “rule‐in” cutpoint, our purpose was to evaluate the ability of the Beckman Coulter hsTnI assay, using various level‐of‐quantification (LoQ) cutpoints, to rule out AMI within 3 hours of ED presentation in suspected acute coronary syndrome (ACS) patients.MethodsThis multicenter evaluation enrolled adults with >5 minutes of ACS symptoms and an electrocardiogram obtained per standard care. Exclusions were ST‐segment elevation or chronic hemodialysis. After informed consent was obtained, blood samples were collected in heparin at ED admission (baseline), ≥1 to 3, ≥3 to 6, and ≥6 to 9 hours postadmission. Samples were processed and stored at –20°C within 1 hour and were tested at three independent clinical laboratories on an immunoassay system (DxI 800, Beckman Coulter). Analytic cutpoints were the URL of 17.9 ng/L and two LoQ cutpoints, defined as the 10 and 20% coefficient of variation (5.6 and 2.3 ng/L, respectively). A criterion standard MI diagnosis was adjudicated by an independent endpoint committee, blinded to hsTnI, and using the universal definition of MI.ResultsOf 1,049 patients meeting the entry criteria, and with baseline and 1‐ to 3‐hour hsTnI results, 117 (11.2%) had an adjudicated final diagnosis of AMI. AMI patients were typically older, with more cardiovascular risk factors. Median (IQR) presentation time was 4 (1.6–16.0) hours after symptom onset, although AMI patients presented ~0.5 hour earlier than non‐AMI. Enrollment and first blood draw occurred at a mean of ~1 hour after arrival. To evaluate the assay's rule‐out performance, patients with any hsTnI > URL were considered high risk and were excluded. The remaining population (n = 829) was divided into four LoQ relative categories: both hsTnI < LoQ (Lo‐Lo cohort); first hsTnI < LoQ and 2nd > LoQ (Lo‐Hi cohort); first > LoQ and second < LoQ (Hi‐Lo cohort); or both > LoQ (Hi‐Hi cohort). In patients with any hsTnI result <20% CV LoQ (Groups 1–3), n = 231 (23.9% ruled out), AMI negative predictive value (NPV) was 100% (95% confidence interval [CI] = 98.9% to 100%). In patients with any hsTnI below the 10% LoQ, n = 611 (58% rule out), AMI NPV was 100% (95% CI = 99.5% to 100%). Of the Hi‐Hi cohort (i.e., no hsTnI below the 10% LoQ, but both < URL), there were four AMI patients, NPV was 98.2% (95% CI = 95.4% to 99.3%), and sensitivity was 96.6.ConclusionsPatients presenting >3 hours after the onset of suspected ACS symptoms, with at least two Beckman Coulter Access hsTnI < URL and at least one of which is below either the 10 or the 20% LoQ, had a 100% NPV for AMI. Two hsTnI values 1 to 3 hours apart with both < URL, but also >LoQ had inadequate sensitivity and NPV.

Short or Long Antibiotic Regimes in Orthopaedics (SOLARIO): a randomised controlled open-label non-inferiority trial of duration of systemic antibiotics in adults with orthopaedic infection treated operatively with local antibiotic therapy

BackgroundOrthopaedic infections, such as osteomyelitis, diabetic foot infection and prosthetic joint infection, are most commonly treated by a combination of surgical debridement and a prolonged course of systemic antibiotics, usually for at least 4–6 weeks. Use of local antibiotics, implanted directly into the site of infection at the time of surgery, may improve antibiotic delivery and allow us to shorten the duration of systemic antibiotic therapy, thereby limiting the frequency of side effects, cost and selection pressure for antimicrobial resistance.MethodsSOLARIO is a multicentre open-label randomised controlled non-inferiority trial comparing short and long systemic antibiotic therapy alongside local antibiotic therapy. Adult patients with orthopaedic infection, who have given informed consent, will be eligible to participate in the study provided that no micro-organisms identified from deep tissue samples are resistant to locally implanted antibiotics. Participants will be randomised in a 1:1 ratio to receive either a short course (≤ 7 days) or currently recommended long course (≥ 4 weeks) of systemic antibiotics. The primary outcome will be treatment failure by 12 months after surgery, as ascertained by an independent Endpoint Committee blinded to treatment allocation. An absolute non-inferiority margin of 10% will be used for both per-protocol and intention-to-treat populations. Secondary outcomes will include probable and definite treatment failure, serious adverse events, treatment side effects, quality of life scores and cost analysis.DiscussionThis study aims to assess a treatment strategy that may enable the reduction of systemic antibiotic use for patients with orthopaedic infection. If this strategy is non-inferior, this will be to the advantage of patients and contribute to antimicrobial stewardship.Trial registrationClinicaltrials.gov, NCT03806166. Registered on 11 November 2019.

Randomised controlled trial of gradual antipsychotic reduction and discontinuation in people with schizophrenia and related disorders: the RADAR trial (Research into Antipsychotic Discontinuation and Reduction)

IntroductionAntipsychotic medication is effective in reducing acute symptoms of psychosis, but it has a range of potentially serious and debilitating adverse effects and is often disliked by patients. It is...

Contemporary Antithrombotic Treatment in Patients with Non-valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: Rationale and Design of the Greek AntiPlatElet Atrial Fibrillation (GRAPE-AF) Registry

Approximately 5 to 7% of patients undergoing percutaneous coronary intervention (PCI) for the treatment of coronary artery disease require chronic oral anticoagulation (OAC) on top of aspirin and a P2Y12 receptor antagonist, mainly due to non-valvular atrial fibrillation (AF). The advent of non-vitamin K antagonist oral anticoagulants (NOACs) increased treatment options, while there is cumulative evidence that dual combination of a NOAC and a P2Y12 receptor antagonist attenuates risk of bleeding, compared to traditional triple therapy, consisting of a vitamin K antagonist (VKA), aspirin, and a P2Y12 receptor antagonist, without significantly compromising efficacy. Greek AntiPlatElet Atrial Fibrillation (GRAPE-AF, NCT 03362788) is an observational, nationwide study of non-valvular AF patients undergoing PCI, planning to enroll over 1-year period > 500 participants in 25 tertiary and non-tertiary PCI centers in Greece. Key data to be collected pre-discharge include demographics, detailed past medical history, and antithrombotic and concomitant treatment. Patients will be followed up at 1, 6, and 12months post hospital discharge. Αt each follow-up visit, data on antithrombotic treatment, ischemic, bleeding, and adverse events will be collected. Study's primary endpoint is clinically significant bleeding (Bleeding Academic Research Consortium, BARC ≥ 2) at 12months, between VKAs and NOACs-treated patients, analyzed using Cox proportional hazards models, by an intention-to-treat principle. An independent endpoint committee will adjudicate all clinical events. This study aims at providing "real-world" information on current antithrombotic treatment patterns and clinical outcome of patients with non-valvular AF undergoing PCI.

Daily remote monitoring of implantable cardioverter-defibrillators: insights from the pooled patient-level data from three randomized controlled trials (IN-TIME, ECOST, TRUST).

AimsRemote monitoring of implantable cardioverter-defibrillators may improve clinical outcome. A recent meta-analysis of three randomized controlled trials (TRUST, ECOST, IN-TIME) using a specific remote monitoring system with daily transmissions [Biotronik Home Monitoring (HM)] demonstrated improved survival. We performed a patient-level analysis to verify this result with appropriate time-to-event statistics and to investigate further clinical endpoints.Methods and resultsIndividual data of the TRUST, ECOST, and IN-TIME patients were pooled to calculate absolute risks of endpoints at 1-year follow-up for HM vs. conventional follow-up. All-cause mortality analysis involved all three trials (2405 patients). Other endpoints involved two trials, ECOST and IN-TIME (1078 patients), in which an independent blinded endpoint committee adjudicated the underlying causes of hospitalizations and deaths. The absolute risk of death at 1 year was reduced by 1.9% in the HM group (95% CI: 0.1–3.8%; P = 0.037), equivalent to a risk ratio of 0.62. Also the combined endpoint of all-cause mortality or hospitalization for worsening heart failure (WHF) was significantly reduced (by 5.6%; P = 0.007; risk ratio 0.64). The composite endpoint of all-cause mortality or cardiovascular (CV) hospitalization tended to be reduced by a similar degree (4.1%; P = 0.13; risk ratio 0.85) but without statistical significance.ConclusionIn a pooled analysis of the three trials, HM reduced all-cause mortality and the composite endpoint of all-cause mortality or WHF hospitalization. The similar magnitudes of absolute risk reductions for WHF and CV endpoints suggest that the benefit of HM is driven by the prevention of heart failure exacerbation.

Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial

Ixmyelocel-T is an expanded, multicellular therapy produced from a patient's own bone marrow by selectively expanding two key types of bone marrow mononuclear cells: CD90+ mesenchymal stem cells and CD45+ CD14+ auto-fluorescent+ activated macrophages. Early phase clinical trials suggest that intramyocardial delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and quality-of-life outcomes in patients with heart failure due to ischaemic dilated cardiomyopathy. We aimed to assess the safety and efficacy of catheter-based transendocardial injection of ixmyelocel-T cell therapy in patients with heart failure and reduced ejection fractions. In this randomised, double-blind, placebo-controlled phase 2B trial (ixCELL-DCM), patients from 31 sites in North America with New York Heart Association class III or IV symptomatic heart failure due to ischaemic dilated cardiomyopathy, who had left ventricular ejection fraction 35% or less, an automatic implantable cardioverter defibrillator, and who were ineligible for revascularisation procedures were randomly assigned (1:1) to receive ixmyelocel-T or placebo at the time of bone marrow aspiration and followed for 12 months. Randomisation was done through an interactive (voice/web) response system. The pharmacist, treating physician, and coordinator at each site were unblinded, but the the follow-up team was completely blinded. The primary endpoint was a composite of all-cause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated heart failure based on the blinded adjudication of an independent clinical endpoint committee. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01670981. Between April 2, 2013, and Jan 28, 2015, 126 participants were randomly assigned to receive either ixmyelocel-T (n=66) or placebo (n=60). 114 (90%) patients comprised the modified intention-to-treat population and 109 (87%) patients were included in the per-protocol primary efficacy analysis (58 in the ixmyelocel-T group and 51 in the placebo group). The primary efficacy endpoint was observed in 47 patients: 50 events in 25 (49%) of 51 patients in the placebo group and 38 events in 22 (38%) of 58 patients in the ixmyelocel-T group, which represents a 37% reduction in cardiac events compared with placebo (risk ratio 0·63 [95% CI 0·42-0·97]; p=0·0344). 41 (75%) of 51 participants in the placebo group had serious adverse events versus 31 (53%) of 58 in the ixmyelocel-T group (p=0·0197). To the best of our knowledge, ixCELL-DCM is the largest cell therapy study done in patients with heart failure so far. The transendocardial delivery of ixmyelocel-T in patients with heart failure and reduced ejection fraction due to ischaemic dilated cardiomyopathy resulted in a significant reduction in adjudicated clinical cardiac events compared with placebo leading to improved patient outcomes. Vericel Corporation.

Cardiovascular safety of albiglutide in the Harmony programme: a meta-analysis

Albiglutide is a glucagon-like peptide-1 receptor agonist, a new class of drugs used to treat type 2 diabetes. We did a prospective meta-analysis of the cardiovascular safety of albiglutide as stipulated by the US Food and Drug Administration recommendations for the assessment of new treatments for diabetes. We did a meta-analysis of eight phase 3 trials and one phase 2b trial in which patients were randomly assigned to albiglutide, placebo, or active comparators (glimepiride, insulin glargine, insulin lispro, liraglutide, pioglitazone, or sitagliptin). The safety population included 5107 patients, of whom 2524 took albiglutide (4870 person-years) and 2583 took comparators (5213 person-years). Possible major cardiovascular events were recorded prospectively and adjudicated by an independent endpoint committee masked to treatment allocation. The primary endpoint was a composite of first occurrence of major adverse cardiovascular events (ie, cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) or hospital admission for unstable angina. Secondary endpoints were major adverse cardiovascular events alone, all-cause mortality, silent myocardial infarction, hospital admission for heart failure, chest pain, other angina, and subdural or extradural haemorrhage. The occurrence of all other adverse events classified by the investigators as cardiovascular events were documented, but these were not adjudicated. The primary endpoint was not significantly different between albiglutide and all comparators (58 events vs 58 events; hazard ratio [HR] 1·00, 95% CI 0·68-1·49, p=0·0019 for non-inferiority). Major adverse cardiovascular event alone was also not significantly different (52 events vs 53; HR, 0·99; 95% CI, 0·65-1·49). When albiglutide was compared separately with placebo or active comparators, we noted no significant differences. We detected no significant differences in the other secondary endpoints. More patients had atrial fibrillation or atrial flutter in the albiglutide group (35 [1·4%] of 2524 patients; 8·6 events per 1000 patient-years) than in the all-comparators group (16 [0·6%] of 2583 patients; 3·4 events per 1000 patient-years). Cardiovascular events were not significantly more likely to occur with albiglutide than with all comparators. Because the upper bound of the 95% CI for major adverse cardiovascular event plus hospital admission for unstable angina was greater than 1·3, a dedicated study with a cardiovascular endpoint is underway to confirm the safety of albiglutide. GlaxoSmithKline.

Air quality, stroke, and coronary events: results of the Heinz Nixdorf Recall Study from the Ruhr Region.

Studies have shown that air pollution is associated with cardiopulmonary mortality, but there has been less research of the possible effect of air pollution on stroke and non-fatal coronary events. The Heinz Nixdorf Recall (HNR) study addressed the question of the effect of long-term air pollution on stroke and coronary events. Ambient acoustic noise was also considered as a risk factor. The HNR study, initiated in 2000, is a prospective, population-based cohort study in the Ruhr region of Germany. Long-term exposure to fine-particle dust (PM10, PM2.5 and PM(2.5abs) [carbon black content]) and traffic noise at the subjects' home addresses were determined using land-use regression and dispersion models, respectively. Strokes and coronary events were ascertained from patient records by an independent end-point committee on the basis of predefined study criteria. The adjusted hazard ratio (HR) was calculated using Cox regression analysis for an increase in concentration from the 5th to the 95th percentile for each exposure. Data from 4433 subjects were evaluated. The incidence of stroke was 2.03 per 1000 person-years (PY), and that of coronary events was 3.87 per 1000 PY. The highest hazard ratios for stroke were seen for PM10 (HR 2.61, 95% confidence interval [CI] 1.13-6.00) and PM2.5 (HR 3.20, 95% CI 1.26-8.09). The highest hazard ratios for coronary events were found for PM10 (HR 1.07, 95% CI 0.56-2.04) and for PM(2.5abs) (HR 1.37, 95% CI 0.80-2.36). Long-term exposure to fine-particle dust is associated with a higher risk of stroke, regardless of the subject's exposure to noise at his or her home address. The results for coronary events are less clear, but still suggest increased risk.

Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial

SummaryBackgroundStenting is an alternative to endarterectomy for treatment of carotid artery stenosis, but long-term efficacy is uncertain. We report long-term data from the randomised International Carotid Stenting Study comparison of these treatments.MethodsPatients with symptomatic carotid stenosis were randomly assigned 1:1 to open treatment with stenting or endarterectomy at 50 centres worldwide. Randomisation was computer generated centrally and allocated by telephone call or fax. Major outcomes were assessed by an independent endpoint committee unaware of treatment assignment. The primary endpoint was fatal or disabling stroke in any territory after randomisation to the end of follow-up. Analysis was by intention to treat ([ITT] all patients) and per protocol from 31 days after treatment (all patients in whom assigned treatment was completed). Functional ability was rated with the modified Rankin scale. This study is registered, number ISRCTN25337470.Findings1713 patients were assigned to stenting (n=855) or endarterectomy (n=858) and followed up for a median of 4·2 years (IQR 3·0–5·2, maximum 10·0). Three patients withdrew immediately and, therefore, the ITT population comprised 1710 patients. The number of fatal or disabling strokes (52 vs 49) and cumulative 5-year risk did not differ significantly between the stenting and endarterectomy groups (6·4% vs 6·5%; hazard ratio [HR] 1·06, 95% CI 0·72–1·57, p=0·77). Any stroke was more frequent in the stenting group than in the endarterectomy group (119 vs 72 events; ITT population, 5-year cumulative risk 15·2% vs 9·4%, HR 1·71, 95% CI 1·28–2·30, p<0·001; per-protocol population, 5-year cumulative risk 8·9% vs 5·8%, 1·53, 1·02–2·31, p=0·04), but were mainly non-disabling strokes. The distribution of modified Rankin scale scores at 1 year, 5 years, or final follow-up did not differ significantly between treatment groups.InterpretationLong-term functional outcome and risk of fatal or disabling stroke are similar for stenting and endarterectomy for symptomatic carotid stenosis.FundingMedical Research Council, Stroke Association, Sanofi-Synthélabo, European Union.

Anemia is a predictor of graft loss but not cardiovascular events and all‐cause mortality in renal transplant recipients: follow‐up data from the ALERT study

It is well established that post-transplantation anemia (PTA) in renal transplant recipients (RTRs) is associated with reduced graft survival. However, there is an uncertainty of the effect of PTA on cardiovascular events and all-cause mortality. We examined prospectively in a large cohort of erythropoietin-naive patients the effects of PTA on cardiovascular morbidity, patient survival, and graft survival. A prospective cohort study of RTRs (n = 2102) included in the ALERT study. Cox regression models were used to evaluate the impact of PTA on study endpoints: first occurrence of a major adverse cardiac event, all-cause death, and the incidence of death-censored graft loss. Mean follow-up was 6.7 yr. All endpoints were adjudicated by an independent endpoint committee. Twenty-nine percent of women and 30% of men were anemic. Hemoglobin levels were not associated with any effect on cardiovascular morbidity and mortality (HR 0.97 [0.90-1.05] per g/dL, p = 0.48) or all-cause death (HR 0.96 [0.90-1.03] per g/dL, p = 0.24) after extensive multivariate adjustments for clinical and demographic factors. Hemoglobin levels were negatively associated with graft loss (HR 0.86 [0.80-0.92] per g/dL, p < 0.001). PTA was not associated with an increased incidence of cardiovascular morbidity and mortality or all-cause mortality.

Abstract TMP103: Combined Results of Two Phase 3 Studies of PA32540, an Antiplatelet Therapy of Enteric-Coated Aspirin and Immediate-Release Omeprazole, in Patients with Previous Cerebrovascular Disease

Introduction: Antiplatelet therapy with aspirin is a mainstay for secondary prevention of ischemic strokes and other vascular events. Yet, many patients do not take aspirin or discontinue it due to gastrointestinal (GI) side effects. Proton pump inhibitors are often co-prescribed to those who develop aspirin-related dyspepsia or who are at risk for GI complications. We investigated a new aspirin formulation (PA32540), which is a coordinated-delivery tablet of immediate-release (IR) omeprazole (40 mg) and enteric-coated (EC) aspirin (325 mg), in an effort to improve co-prescription compliance, reduce GI side effects, and improve overall antiplatelet therapy efficacy. Methods: Two phase 3 double-blind multicenter studies included a subset of subjects with ≥ 1 transient ischemic attack or ischemic stroke who were prescribed aspirin at 325 mg once daily for ≥ 3 months for secondary prevention of cardiovascular (CV) events. All subjects were randomly assigned to once-daily treatment with PA32540 or 325 mg EC aspirin. Use of coumadin was excluded. Endoscopic assessments for gastric or duodenal ulcers were performed at screening and at 1, 3, and 6 months. Major adverse cardiovascular events (MACE) were adjudicated by an independent blinded endpoint committee. Results: Baseline characteristics and rates of discontinuation are shown in Table 1. The rate of gastroduodenal ulcers and discontinuations due to upper GI events were significantly lower following administration of PA32540 vs EC aspirin alone over 6 months. No difference in MACE was identified. Conclusion: In patients with previous cerebrovascular disease, PA32540 was associated with a significantly lower rate of endoscopic gastroduodenal ulcers, a higher rate of treatment continuation, and no increase in the number of MACE, compared with aspirin alone. These findings support the use of a single tablet prescription of omeprazole and aspirin for improving the overall efficacy of antiplatelet therapy.