Publications by authors named "Ann Belmans"

60 Publications

Early high antibody-titre convalescent plasma for hospitalised COVID-19 patients: DAWn-plasma.

Eur Respir J 2021 Aug 26. Epub 2021 Aug 26.

Department of Intensive Care Medicine, University Hospitals Leuven, and Department of Cellular and Molecular Medicine, Laboratory of Intensive Care Medicine, KU Leuven, Leuven, Belgium.

Background: Several randomised clinical trials have studied convalescent plasma (CP) for COVID-19 using different protocols, with different SARS-CoV-2 neutralising-antibody-titres, at different time-points and severities of illness.

Methods: In the prospective multicentre DAWN-plasma trial, adult patients hospitalised with COVID-19 were randomised to 4 units of open-label convalescent plasma combined with standard of care (intervention group) or standard of care alone (control group). Plasma from donors with neutralising-antibody-titres (NT50) ≥1/320 was the product of choice for the study.

Results: Between May 2nd, 2020 and January 26th, 2021, 320 patients were randomised to convalescent plasma and 163 patients to the control group according to a 2:1 allocation scheme. A median volume of 884 mL convalescent plasma (IQR 806-906 mL) was administered, and 80.68% of the units came from donors with neutralising-antibody-titres (NT50) ≥1/320. Median time from onset of symptoms to randomisation was 7 days. The proportion of patients alive and free of mechanical ventilation on Day 15 was not different between both groups (convalescent plasma: 83.74% (n=267) control: 84.05% (n=137) - Odds ratio 0.99 (0.59-1.66) - p-value=0.9772). The intervention did not change the natural course of antibody titres. The number of serious or severe adverse events was similar in both study arms, and transfusion-related side effects were reported in 19/320 patients in the intervention group (5.94%).

Conclusions: Transfusion of 4 units of convalescent plasma with high neutralising-antibody-titres early in hospitalised COVID-19 patients did not result in a significant improvement of the clinical status, or a reduced mortality.
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http://dx.doi.org/10.1183/13993003.01724-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576805PMC
August 2021

Ninety-Day Follow-up Is Inadequate for Diagnosis of Fracture-related Infections in Patients with Open Fractures.

Clin Orthop Relat Res 2022 01;480(1):139-146

Department of Trauma Surgery, University Hospitals Leuven, Leuven, Belgium.

Background: Fracture-related infection (FRI) is a challenging complication in musculoskeletal trauma surgery and often complicates the management of open fractures. The CDC currently advocates a surveillance period of 90 days after fracture fixation, but it is unclear what duration of follow-up constitutes adequate surveillance for FRI. Inadequate follow-up will underestimate infections and, in clinical research, will make any interventions studied appear better than they really are, thereby resulting in misleading conclusions.

Questions/purposes: (1) What is the timing of FRI onset in patients with open fractures? (2) What is the proportion of FRIs captured when follow-up is limited to 90 days postoperatively versus when follow-up is extended to 1 year?

Methods: This is a secondary analysis of patient data from a previous retrospective cohort study that investigated whether the duration of perioperative antibiotic prophylaxis was independently associated with FRI in patients with open fractures. Of the 530 eligible patients in the source study, 3% (14) died. Of the remaining 516 patients, 97% (502) patients with 559 long-bone open fractures had 2 years of follow-up constituted the base cohort. Forty-seven fractures in 46 patients were complicated by FRI and were the focus of this secondary analysis. Medical records were reviewed in detail specifically for the current study. Seventy-eight percent (36 of 46) of patients were male, and the mean ± SD age was 42 ± 16 years. The most common mechanism of injury was a motor vehicle accident (63% [29 of 46] of patients), and the tibia was the most involved site (53% [25 of 47] of fractures). The median (interquartile range) time to debridement was 3.0 hours (IQR 2.0 to 4.0). FRIs developed in 3% (7 of 247) of Type I open fractures, 7% (11 of 164) of Type II, 17% (18 of 107) of Type IIIA, 29% (9 of 31) of Type IIIB, and 20% (2 of 10) of Type IIIC open fractures. Each clinic visit of each patient was reviewed, and data about the time of onset of any symptoms and signs suggesting or confirming an FRI, as reported by patients and/or determined by treating surgeons, were recorded. The proportions of FRIs with onset by specific time periods were determined. A Kaplan-Meier survival analysis was performed, and the FRI event rates with 95% confidence intervals were calculated.

Results: The median (IQR) time to the onset of FRI was 52 days (IQR 15 to 153). Follow-up of 90 days captured only 64% (30 of 47) of FRIs, whereas follow-up of 1 year captured 89% (42 of 47) of FRIs. The proportion of FRIs with onset within 1 year increased to 95% (42 of 44) in the presence of an already healed fracture.

Conclusion: Follow-up of 90 days after the management of an open long-bone fracture is inadequate for postoperative surveillance, especially for research purposes. Clinical research on interventions would report results appearing to be much better than they really are, potentially resulting in misleading conclusions. Follow-up of 1 year is preferable because most FRIs will develop before that time, especially when fracture union has occurred. A small percentage of patients may still develop infections beyond the first year after the management of an open fracture. The risk of missing these infections by not extending follow-up beyond 1 year must be balanced against the additional logistical burden. Future prospective multicenter studies and registries with long-term patient follow-up would help clarify this issue.Level of Evidence Level III, diagnostic study.
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http://dx.doi.org/10.1097/CORR.0000000000001911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673965PMC
January 2022

Tranexamic acid and bleeding in patients treated with non-vitamin K oral anticoagulants undergoing dental extraction: The EXTRACT-NOAC randomized clinical trial.

PLoS Med 2021 05 3;18(5):e1003601. Epub 2021 May 3.

Department of Cardiovascular Medicine, University Hospitals Leuven, Leuven, Belgium.

Background: Oral bleeding after dental extraction in patients on non-vitamin K oral anticoagulants (NOACs) is a frequent problem. We investigated whether 10% tranexamic acid (TXA) mouthwash decreases post-extraction bleeding in patients treated with NOACs.

Methods And Findings: The EXTRACT-NOAC study is a randomized, double-blind, placebo-controlled, multicenter, clinical trial. Patients were randomly assigned to 10% TXA or placebo mouthwash and were instructed to use the mouthwash once prior to dental extraction, and thereafter for 3 times a day for 3 days. The primary outcome was the number of patients with any post-extraction oral bleeding up to day 7. Secondary outcomes included periprocedural, early, and delayed bleeding, and the safety outcomes included all thrombotic events. The first patient was randomized on February 9, 2018 and the last patient on March 12, 2020. Of 222 randomized patients, 218 patients were included in the full analysis set, of which 106 patients were assigned to TXA (74.8 (±8.8) years; 81 men) and 112 to placebo (72.7 (±10.7) years; 64 men). Post-extraction bleeding occurred in 28 (26.4%) patients in the TXA group and in 32 (28.6%) patients in the placebo group (relative risk, 0.92; 95% confidence interval [CI], 0.60 to 1.42; P = 0.72). There were 46 bleeds in the TXA group and 85 bleeds in the placebo group (rate ratio, 0.57; 95% CI, 0.31 to 1.05; P = 0.07). TXA did not reduce the rate of periprocedural bleeding (bleeding score 4 ± 1.78 versus 4 ± 1.82, P = 0.80) and early bleeding (rate ratio, 0.76; 95% CI, 0.42 to 1.37). Delayed bleeding (rate ratio, 0.32; 95% CI, 0.12 to 0.89) and bleeding after multiple extractions (rate ratio, 0.40; 95% CI, 0.20 to 0.78) were lower in the TXA group. One patient in the placebo group had a transient ischemic attack while interrupting the NOAC therapy in preparation for the dental extraction. Two of the study limitations were the premature interruption of the trial following a futility analysis and the assessment of the patients' compliance that was based on self-reported information during follow-up.

Conclusions: In patients on NOACs undergoing dental extraction, TXA does not seem to reduce the rate of periprocedural or early postoperative oral bleeding compared to placebo. TXA appears to reduce delayed bleeds and postoperative oral bleeding if multiple teeth are extracted.

Trial Registration: ClinicalTrials.gov NCT03413891 EudraCT; EudraCT number:2017-001426-17; EudraCT Public website: eudract.ema.europa.eu.
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http://dx.doi.org/10.1371/journal.pmed.1003601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128271PMC
May 2021

Endurance exercise and the risk of cardiovascular pathology in men: a comparison between lifelong and late-onset endurance training and a non-athletic lifestyle - rationale and design of the [email protected] study, a prospective cohort trial.

BMJ Open Sport Exerc Med 2021 16;7(2):e001048. Epub 2021 Apr 16.

Cardiovascular Sciences, KU Leuven University Hospitals Leuven, Leuven, Flanders, Belgium.

Introduction: Low and moderate endurance exercise is associated with better control of cardiovascular risk factors, a decreased risk of coronary artery disease and atrial fibrillation (AF). There is, however, a growing proportion of individuals regularly performing strenuous and prolonged endurance exercise in which the health benefits have been challenged. Higher doses of endurance exercise have been associated with a greater coronary atherosclerotic plaque burden, risk of AF and myocardial fibrosis (MF).

Methods And Analysis: [email protected] is a multicentre prospective cohort study aiming to assess the incidence of coronary atherosclerosis, AF and MF in lifelong endurance athletes compared to late-onset endurance athletes (initiation of regular endurance exercise after the age of 30 years) and healthy non-athletes.The primary endpoint is the incidence of mixed coronary plaques. Secondary endpoints include coronary calcium scores, coronary stenosis >50%, the prevalence of calcified and soft plaques and AF and MF presence. Tertiary endpoints include ventricular arrhythmias, left and right ventricular function at rest and during exercise, arterial stiffness and carotid artery intima media thickness.Two hundred male lifelong athletes, 200 late-onset athletes and 200 healthy non-athletes aged 45-70 will undergo comprehensive cardiovascular phenotyping using CT, coronary angiography, echocardiography, cardiac MRI, 12-lead ECG, exercise ECG and 24-hour Holter monitoring at baseline. Follow-up will include online tracking of sports activities, telephone calls to assess clinical events and a 7-day ECG recording after 1 year.

Ethics And Dissemination: Local ethics committees approved the [email protected] study. The trial was launched on 18 October 2018, recruitment is complete and inclusions are ongoing.

Trial Registration Number: NCT03711539.
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http://dx.doi.org/10.1136/bmjsem-2021-001048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055127PMC
April 2021

Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial.

EBioMedicine 2021 Apr 19;66:103288. Epub 2021 Mar 19.

Department of Cardiovascular Sciences and Clinical Department of Laboratory Medicine, KU Leuven, Belgium.

Background: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19.

Methods: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated.

Findings: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care.

Interpretation: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study.

Funding: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.
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http://dx.doi.org/10.1016/j.ebiom.2021.103288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979145PMC
April 2021

Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2-azithromycin trial.

Trials 2021 Feb 9;22(1):126. Epub 2021 Feb 9.

Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven, Leuven, Belgium.

Background: The rapid emergence and the high disease burden of the novel coronavirus SARS-CoV-2 have created a medical need for readily available drugs that can decrease viral replication or blunt the hyperinflammatory state leading to severe COVID-19 disease. Azithromycin is a macrolide antibiotic, known for its immunomodulatory properties. It has shown antiviral effect specifically against SARS-CoV-2 in vitro and acts on cytokine signaling pathways that have been implicated in COVID-19.

Methods: DAWn-AZITHRO is a randomized, open-label, phase 2 proof-of-concept, multicenter clinical trial, evaluating the safety and efficacy of azithromycin for treating hospitalized patients with COVID-19. It is part of a series of trials testing promising interventions for COVID-19, running in parallel and grouped under the name DAWn-studies. Patients hospitalized on dedicated COVID wards are eligible for study inclusion when they are symptomatic (i.e., clinical or radiological signs) and have been diagnosed with COVID-19 within the last 72 h through PCR (nasopharyngeal swab or bronchoalveolar lavage) or chest CT scan showing typical features of COVID-19 and without alternate diagnosis. Patients are block-randomized (9 patients) with a 2:1 allocation to receive azithromycin plus standard of care versus standard of care alone. Standard of care is mostly supportive, but may comprise hydroxychloroquine, up to the treating physician's discretion and depending on local policy and national health regulations. The treatment group receives azithromycin qd 500 mg during the first 5 consecutive days after inclusion. The trial will include 284 patients and recruits from 15 centers across Belgium. The primary outcome is time from admission (day 0) to life discharge or to sustained clinical improvement, defined as an improvement of two points on the WHO 7-category ordinal scale sustained for at least 3 days.

Discussion: The trial investigates the urgent and still unmet global need for drugs that may impact the disease course of COVID-19. It will either provide support or else justify the discouragement of the current widespread, uncontrolled use of azithromycin in patients with COVID-19. The analogous design of other parallel trials of the DAWN consortium will amplify the chance of identifying successful treatment strategies and allow comparison of treatment effects within an identical clinical context.

Trial Registration: EU Clinical trials register EudraCT Nb 2020-001614-38 . Registered on 22 April 2020.
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http://dx.doi.org/10.1186/s13063-021-05033-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871018PMC
February 2021

Patient satisfaction with intravenous regional anaesthesia or an axillary block for minor ambulatory hand surgery: A randomised controlled study.

Eur J Anaesthesiol 2020 10;37(10):847-856

From the Department of Anesthesiology, University Hospitals Leuven, Herestraat (AT, KV, MV de V, SR), I-Biostat, KU Leuven- University of Leuven, Kapucijnenvoer (AB), Department of Orthopedics, University Hospitals Leuven, Herestraat (ID) and Department of Cardiovascular Sciences, KU Leuven - University of Leuven, Herestraat, Leuven, Belgium (AT, MV de V, SR).

Background: Intravenous regional anesthesia (IVRA) and the axillary brachial plexus block are popular alternatives to general anaesthesia in ambulatory hand surgery. Although both have proven their effectiveness, patients' preferences have never been evaluated.

Objectives: We investigated patient satisfaction with both techniques and hypothesised that satisfaction after IVRA is noninferior compared with axillary brachial plexus block.

Design: A prospective, randomised controlled trial.

Setting: Ambulatory surgical day care centre, University Hospitals of Leuven, Belgium, from September 2016 to November 2017.

Patients: One hundred and twenty adults undergoing minor ambulatory hand surgery were included in this study.

Intervention: Patients received either IVRA with 300 mg lidocaine or an axillary block with 280 mg mepivacaine.

Main Outcome Measures: The primary endpoint was the evaluation of patient satisfaction using the 'Evaluation du Vécu de l'Anésthesie Locoregional' (EVAN-LR) questionnaire. Secondary outcomes included different procedural times, block quality, tourniquet discomfort, the incidence of block failure and postoperative nausea and vomiting (PONV), the severity of postoperative pain and the need for postoperative analgesics during the first 24 h.

Results: Noninferiority of IVRA was shown for the median [IQR] total score on the EVAN-LR questionnaire, IVRA-group: 92 [87 to 96] vs. axillary brachial plexus block-group: 91[87 to 97]; Hodges--Lehmann estimator (95% confidence interval (CI)] for the shift: -0.25 (-2.60 to 2.20). Induction of anaesthesia and time to discharge, requiring partial recovery of the motor block, were significantly longer in the axillary brachial plexus block group. The IVRA-group had a lower block quality, a higher incidence of tourniquet-discomfort and higher median intra-operative and postoperative pain scores on day 0; 0 [0 to 2] vs. 0 [0 to 0] and 0.8 [0 to 1.8] vs. 0 [0 to 0.25], respectively, but no increase in the need for supplementary analgesics or conversion rate to general anaesthesia.

Conclusion: IVRA and axillary brachial plexus block result in comparably high patient satisfaction in ambulatory hand surgery.

Clinical Trial Registration: EudraCT 2016-002325-11.
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http://dx.doi.org/10.1097/EJA.0000000000001259DOI Listing
October 2020

The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial.

Eur Heart J 2020 10;41(38):3702-3710

Department of Medicine III, Goethe University of Frankfurt, Frankfurt, Germany.

Aims: Bone marrow-derived mononuclear cell (BM-MNC) therapy may improve myocardial recovery in patients following acute myocardial infarction (AMI), though existing trial results are inconsistent.

Methods And Results: Originally an open-label, multicentre Phase III trial, BAMI was designed to demonstrate the safety and efficacy of intracoronary infusion of BM-MNCs in reducing the time to all-cause mortality in patients with reduced left ventricular ejection fraction (LVEF, ≤45%) after primary angioplasty (PPCI) for ST-elevation AMI. Unexpectedly low recruitment means the trial no longer qualifies as a hypothesis-testing trial, but is instead an observational study with no definitive conclusions possible from statistical analysis. In total, 375 patients were recruited: 185 patients were randomized to the treatment arm (intracoronary infusion of BM-MNCs 2-8 days after PPCI) and 190 patients to the control arm (optimal medical therapy). All-cause mortality at 2 years was 3.26% [6 deaths; 95% confidence interval (CI): 1.48-7.12%] in the BM-MNC group and 3.82% (7 deaths; 95% CI: 1.84-7.84%) in the control group. Five patients (2.7%, 95% CI: 1.0-5.9%) in the BM-MNC group and 15 patients (8.1%, CI : 4.7-12.5%) in the control group were hospitalized for heart failure during 2 years of follow-up. Neither adverse events nor serious adverse events differed between the two groups. There were no patients hospitalized for stroke in the control group and 4 (2.2%) patients hospitalized for stroke in the BM-MNC group.

Conclusions: Although BAMI is the largest trial of autologous cell-based therapy in the treatment of AMI, unexpectedly low recruitment and event rates preclude any meaningful group comparisons and interpretation of the observed results.
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http://dx.doi.org/10.1093/eurheartj/ehaa651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666866PMC
October 2020

Optimum Blood Pressure in Patients With Shock After Acute Myocardial Infarction and Cardiac Arrest.

J Am Coll Cardiol 2020 08;76(7):812-824

Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Emergency Medicine and Services, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: In patients with shock after acute myocardial infarction (AMI), the optimal level of pharmacologic support is unknown. Whereas higher doses may increase myocardial oxygen consumption and induce arrhythmias, diastolic hypotension may reduce coronary perfusion and increase infarct size.

Objectives: This study aimed to determine the optimal mean arterial pressure (MAP) in patients with AMI and shock after cardiac arrest.

Methods: This study used patient-level pooled analysis of post-cardiac arrest patients with shock after AMI randomized in the Neuroprotect (Neuroprotective Goal Directed Hemodynamic Optimization in Post-cardiac Arrest Patients; NCT02541591) and COMACARE (Carbon Dioxide, Oxygen and Mean Arterial Pressure After Cardiac Arrest and Resuscitation; NCT02698917) trials who were randomized to MAP 65 mm Hg or MAP 80/85 to 100 mm Hg targets during the first 36 h after admission. The primary endpoint was the area under the 72-h high-sensitivity troponin-T curve.

Results: Of 235 patients originally randomized, 120 patients had AMI with shock. Patients assigned to the higher MAP target (n = 58) received higher doses of norepinephrine (p = 0.004) and dobutamine (p = 0.01) and reached higher MAPs (86 ± 9 mm Hg vs. 72 ± 10 mm Hg, p < 0.001). Whereas admission hemodynamics and angiographic findings were all well-balanced and revascularization was performed equally effective, the area under the 72-h high-sensitivity troponin-T curve was lower in patients assigned to the higher MAP target (median: 1.14 μg.72 h/l [interquartile range: 0.35 to 2.31 μg.72 h/l] vs. median: 1.56 μg.72 h/l [interquartile range: 0.61 to 4.72 μg. 72 h/l]; p = 0.04). Additional pharmacologic support did not increase the risk of a new cardiac arrest (p = 0.88) or atrial fibrillation (p = 0.94). Survival with good neurologic outcome at 180 days was not different between both groups (64% vs. 53%, odds ratio: 1.55; 95% confidence interval: 0.74 to 3.22).

Conclusions: In post-cardiac arrest patients with shock after AMI, targeting MAP between 80/85 and 100 mm Hg with additional use of inotropes and vasopressors was associated with smaller myocardial injury.
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http://dx.doi.org/10.1016/j.jacc.2020.06.043DOI Listing
August 2020

Impact of duration of perioperative antibiotic prophylaxis on development of fracture-related infection in open fractures.

Arch Orthop Trauma Surg 2021 Feb 14;141(2):235-243. Epub 2020 May 14.

Department of Trauma Surgery, University Hospitals Leuven, 3000, Leuven, Belgium.

Introduction: Infection is a common complication of open fractures potentially leading to nonunion, functional loss, and even amputation. Perioperative antibiotic prophylaxis (PAP) is standard practice for infection prevention in the management of open fractures. However, optimal duration of PAP remains controversial. The objectives were to assess whether PAP duration is independently associated with infection in open fractures and if administration of PAP beyond the commonly-recommended limit of 72 h has any effect on the infection rate.

Materials And Methods: Over a 14-year period from 2003 to 2017, 530 skeletally-mature patients with operatively-treated, non-pathologic, long-bone open fractures were treated at one institution. Twenty-eight patients were excluded because of death or loss to follow-up and the remaining 502 patients (with 559 open fractures) who completed a 24-month follow-up were included in this retrospective study. The outcome was fracture-related infection (FRI), defined by the criteria of a recent consensus definition. A logistic generalized estimating equations regression model was conducted, including PAP duration and variables selected by a least absolute shrinkage and selection operator (LASSO) method, to assess the association between PAP duration and FRI. Propensity score analysis using a 72-h cut-off was performed to further cope with confounding.

Results: PAP duration, adjusted for the LASSO selected predictors, was independently associated with FRI (OR: 1.11 [95%CI, 1.04-1.19] for every one-day increase in PAP duration, p = 0.003). PAP duration longer than 72 h did not significantly increase the odds for FRI compared to shorter durations (p = 0.06, analysis adjusted for propensity score).

Conclusions: This study found no evidence that administration of prophylactic antibiotics beyond 72 h in patients with long-bone open fractures is warranted. Analyses adjusted for known confounders even revealed a higher risk for FRI for longer PAP. However, this effect cannot necessarily be considered as causal and further research is needed.
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http://dx.doi.org/10.1007/s00402-020-03474-8DOI Listing
February 2021

Treatment failure and hospital readmissions in severe COPD exacerbations treated with azithromycin versus placebo - a post-hoc analysis of the BACE randomized controlled trial.

Respir Res 2019 Oct 29;20(1):237. Epub 2019 Oct 29.

Laboratory of Respiratory Diseases, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Herestraat 49, O&NI, box 706, B-3000, Leuven, Belgium.

Background: In the BACE trial, a 3-month (3 m) intervention with azithromycin, initiated at the onset of an infectious COPD exacerbation requiring hospitalization, decreased the rate of a first treatment failure (TF); the composite of treatment intensification (TI), step-up in hospital care (SH) and mortality.

Objectives: (1) To investigate the intervention's effect on recurrent events, and (2) to identify clinical subgroups most likely to benefit, determined from the incidence rate of TF and hospital readmissions.

Methods: Enrolment criteria included the diagnosis of COPD, a smoking history of ≥10 pack-years and ≥ 1 exacerbation in the previous year. Rate ratio (RR) calculations, subgroup analyses and modelling of continuous variables using splines were based on a Poisson regression model, adjusted for exposure time.

Results: Azithromycin significantly reduced TF by 24% within 3 m (RR = 0.76, 95%CI:0.59;0.97, p = 0.031) through a 50% reduction in SH (RR = 0.50, 95%CI:0.30;0.81, p = 0.006), which comprised of a 53% reduction in hospital readmissions (RR = 0.47, 95%CI:0.27;0.80; p = 0.007). A significant interaction between the intervention, CRP and blood eosinophil count at hospital admission was found, with azithromycin significantly reducing hospital readmissions in patients with high CRP (> 50 mg/L, RR = 0.18, 95%CI:0.05;0.60, p = 0.005), or low blood eosinophil count (<300cells/μL, RR = 0.33, 95%CI:0.17;0.64, p = 0.001). No differences were observed in treatment response by age, FEV1, CRP or blood eosinophil count in continuous analyses.

Conclusions: This post-hoc analysis of the BACE trial shows that azithromycin initiated at the onset of an infectious COPD exacerbation requiring hospitalization reduces the incidence rate of TF within 3 m by preventing hospital readmissions. In patients with high CRP or low blood eosinophil count at admission this treatment effect was more pronounced, suggesting a potential role for these biomarkers in guiding azithromycin therapy.

Trial Registration: ClinicalTrials.gov number. NCT02135354 .
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http://dx.doi.org/10.1186/s12931-019-1208-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819655PMC
October 2019

High-sensitivity cardiac troponin release after conventional and minimally invasive cardiac surgery.

Anaesth Intensive Care 2019 May 5;47(3):255-266. Epub 2019 Jun 5.

1 Departments of Anaesthesia and Critical Care Medicine, OLV Hospital, Aalst, Belgium.

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http://dx.doi.org/10.1177/0310057X19845377DOI Listing
May 2019

Azithromycin during Acute Chronic Obstructive Pulmonary Disease Exacerbations Requiring Hospitalization (BACE). A Multicenter, Randomized, Double-Blind, Placebo-controlled Trial.

Am J Respir Crit Care Med 2019 10;200(7):857-868

Laboratory of Respiratory Diseases, Department of Chronic Diseases, Metabolism and Ageing.

Azithromycin prevents acute exacerbations of chronic obstructive pulmonary disease (AECOPDs); however, its value in the treatment of an AECOPD requiring hospitalization remains to be defined. We investigated whether a 3-month intervention with low-dose azithromycin could decrease treatment failure (TF) when initiated at hospital admission and added to standard care. In an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial, patients who had been hospitalized for an AECOPD and had a smoking history of ≥10 pack-years and one or more exacerbations in the previous year were randomized (1:1) within 48 hours of hospital admission to azithromycin or placebo. The study drug (500 mg/d for 3 d) was administered on top of a standardized acute treatment of systemic corticosteroids and antibiotics, and subsequently continued for 3 months (250 mg/2 d). The patients were followed for 6 months thereafter. Time-to-first-event analyses evaluated the TF rate within 3 months as a novel primary endpoint in the intention-to-treat population, with TF defined as the composite of treatment intensification with systemic corticosteroids and/or antibiotics, a step-up in hospital care or readmission for respiratory reasons, or all-cause mortality. A total of 301 patients were randomized to azithromycin ( = 147) or placebo ( = 154). The TF rate within 3 months was 49% in the azithromycin group and 60% in the placebo group (hazard ratio, 0.73; 95% confidence interval, 0.53-1.01;  = 0.0526). Treatment intensification, step-up in hospital care, and mortality rates within 3 months were 47% versus 60% ( = 0.0272), 13% versus 28% ( = 0.0024), and 2% versus 4% ( = 0.5075) in the azithromycin and placebo groups, respectively. Clinical benefits were lost 6 months after withdrawal. Three months of azithromycin for an infectious AECOPD requiring hospitalization may significantly reduce TF during the highest-risk period. Prolonged treatment seems to be necessary to maintain clinical benefits.
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http://dx.doi.org/10.1164/rccm.201901-0094OCDOI Listing
October 2019

Early goal-directed haemodynamic optimization of cerebral oxygenation in comatose survivors after cardiac arrest: the Neuroprotect post-cardiac arrest trial.

Eur Heart J 2019 06;40(22):1804-1814

Department of Cardiology, University Hospitals Leuven, Leuven, Belgium.

Aims: During the first 6-12 h of intensive care unit (ICU) stay, post-cardiac arrest (CA) patients treated with a mean arterial pressure (MAP) 65 mmHg target experience a drop of the cerebral oxygenation that may cause additional cerebral damage. Therefore, we investigated whether an early goal directed haemodynamic optimization strategy (EGDHO) (MAP 85-100 mmHg, SVO2 65-75%) is safe and could improve cerebral oxygenation, reduce anoxic brain damage, and improve outcome when compared with a MAP 65 mmHg strategy.

Methods And Results: A total of 112 out-of-hospital CA patients were randomly assigned to EGDHO or MAP 65 mmHg strategies during the first 36 h of ICU stay. The primary outcome was the extent of anoxic brain damage as quantified by the percentage of voxels below an apparent diffusion coefficient (ADC) score of 650.10-6 mm2/s on diffusion weighted magnetic resonance imaging (at day 5 ± 2 post-CA). Main secondary outcome was favourable neurological outcome (CPC score 1-2) at 180 days. In patients assigned to EGDHO, MAP (P < 0.001), and cerebral oxygenation during the first 12 h of ICU stay (P = 0.04) were higher. However, the percentage of voxels below an ADC score of 650.10-6 mm2/s did not differ between both groups [16% vs. 12%, odds ratio 1.37, 95% confidence interval (CI) 0.95-0.98; P = 0.09]. Also, the number of patients with favourable neurological outcome at 180 days was similar (40% vs. 38%, odds ratio 0.98, 95% CI 0.41-2.33; P = 0.96). The number of serious adverse events was lower in patients assigned to EGDHO (P = 0.02).

Conclusion: Targeting a higher MAP in post-CA patients was safe and improved cerebral oxygenation but did not improve the extent of anoxic brain damage or neurological outcome.
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http://dx.doi.org/10.1093/eurheartj/ehz120DOI Listing
June 2019

Clinical outcomes of heart-team-guided treatment decisions in high-risk patients with aortic valve stenosis in a health-economic context with limited resources for transcatheter valve therapies.

Acta Cardiol 2019 Dec 3;74(6):489-498. Epub 2018 Dec 3.

Department of Cardiovascular Medicine, University Hospitals Leuven, Leuven, Belgium.

Transcatheter aortic valve implantation (TAVI) is the preferred treatment modality for patients with severe aortic stenosis at high or prohibitive risk for surgical aortic valve replacement (SAVR). We aimed to evaluate real-world outcomes after treatment according to the decisions of the multidisciplinary heart team in a Belgian health-economic context. Four hundred and five high-risk patients referred to a tertiary centre between 1 March 2008 and 31 December 2015 were screened and planned to undergo SAVR, TAVI or medical treatment (MT). Patients undergoing SAVR had lower Society of Thoracic Surgeons scores and Euroscore-II when compared to TAVI or MT (median [IQR]: 6[4-8]; 7[5-10]; 8[6-13];  < .001 and 6[4-10]; 8[5-15]; 8[4-16];  = .006). At 1 year all-cause mortality was 14, 17 and 51% with SAVR, TAVI and MT, respectively ( < .001). Cardiovascular death and disabling stroke occurred in 9, 7 and 35% ( < .001) and 2, 2.7 and 1.7% ( = .91). According to Valve-Academic-Research-Consortium-II criteria, device success was 95 and 92% for TAVI and SAVR. The combined safety endpoint at 30 days favoured TAVI (22% vs. 47%) ( < .001). The combined efficacy endpoint at 1 year was comparable between groups (38 and 40%;  = .703). Finally, hospital stay was shorter with TAVI vs. SAVR (9[6-14] and 16[12-22] days;  < .001). Limited resources for transcatheter valve therapies in Belgium push a significant number of patients to SAVR, while TAVI in even higher risk patients translates into similar outcomes and shorter hospital stay. These findings underscore the need for broadening indications for TAVI, as well as readjustment of the budgetary allocations for hospitals in Belgium.
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http://dx.doi.org/10.1080/00015385.2018.1522461DOI Listing
December 2019

Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With ST-Segment Elevation Myocardial Infarction and Left Ventricular Dysfunction.

Circ Res 2018 08;123(5):579-589

Department of Cardiovascular Medicine, University Hospitals and KU Leuven, Belgium (J.B., A.B., P.C., S.J.).

Rationale: Allogeneic cardiac stem cells (AlloCSC-01) have shown protective, immunoregulatory, and regenerative properties with a robust safety profile in large animal models of heart disease.

Objective: To investigate the safety and feasibility of early administration of AlloCSC-01 in patients with ST-segment-elevation myocardial infarction.

Methods And Results: CAREMI (Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With STEMI and Left Ventricular Dysfunction) was a phase I/II multicenter, randomized, double-blind, placebo-controlled trial in patients with ST-segment-elevation myocardial infarction, left ventricular ejection fraction ≤45%, and infarct size ≥25% of left ventricular mass by cardiac magnetic resonance, who were randomized (2:1) to receive AlloCSC-01 or placebo through the intracoronary route at days 5 to 7. The primary end point was safety and included all-cause death and major adverse cardiac events at 30 days (all-cause death, reinfarction, hospitalization because of heart failure, sustained ventricular tachycardia, ventricular fibrillation, and stroke). Secondary safety end points included major adverse cardiac events at 6 and 12 months, adverse events, and immunologic surveillance. Secondary exploratory efficacy end points were changes in infarct size (percentage of left ventricular mass) and indices of ventricular remodeling by magnetic resonance at 12 months. Forty-nine patients were included (92% male, 55±11 years), 33 randomized to AlloCSC-01 and 16 to placebo. No deaths or major adverse cardiac events were reported at 12 months. One severe adverse events in each group was considered possibly related to study treatment (allergic dermatitis and rash). AlloCSC-01 elicited low levels of donor-specific antibodies in 2 patients. No immune-related adverse events were found, and no differences between groups were observed in magnetic resonance-based efficacy parameters at 12 months. The estimated treatment effect of AlloCSC-01 on the absolute change from baseline in infarct size was -2.3% (95% confidence interval, -6.5% to 1.9%).

Conclusions: AlloCSC-01 can be safely administered in ST-segment-elevation myocardial infarction patients with left ventricular dysfunction early after revascularization. Low immunogenicity and absence of immune-mediated events will facilitate adequately powered studies to demonstrate their clinical efficacy in this setting.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02439398.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.312823DOI Listing
August 2018

Nitric oxide for inhalation in ST-elevation myocardial infarction (NOMI): a multicentre, double-blind, randomized controlled trial.

Eur Heart J 2018 08;39(29):2717-2725

The Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.

Aims: Inhalation of nitric oxide (iNO) during myocardial ischaemia and after reperfusion confers cardioprotection in preclinical studies via enhanced cyclic guanosine monophosphate (cGMP) signalling. We tested whether iNO reduces reperfusion injury in patients with ST-elevation myocardial infarction (STEMI; NCT01398384).

Methods And Results: We randomized in a double-blind, placebo-controlled study 250 STEMI patients to inhale oxygen with (iNO) or without (CON) 80 parts-per-million NO for 4 h following percutaneous revascularization. Primary efficacy endpoint was infarct size as a fraction of left ventricular (LV) size (IS/LVmass), assessed by delayed enhancement contrast magnetic resonance imaging (MRI). Pre-specified subgroup analysis included thrombolysis-in-myocardial-infarction flow in the infarct-related artery, troponin T levels on admission, duration of symptoms, location of culprit lesion, and intra-arterial nitroglycerine (NTG) use. Secondary efficacy endpoints included IS relative to risk area (IS/AAR), myocardial salvage index, LV functional recovery, and clinical events at 4 and 12 months. In the overall population, IS/LVmass at 48-72 h was 18.0 ± 13.4% in iNO (n = 109) and 19.4 ± 15.4% in CON [n = 116, effect size -1.524%, 95% confidence interval (95% CI) -5.28, 2.24; P = 0.427]. Subgroup analysis indicated consistency across clinical confounders of IS but significant treatment interaction with NTG (P = 0.0093) resulting in smaller IS/LVmass after iNO in NTG-naïve patients (n = 140, P < 0.05). The secondary endpoint IS/AAR was 53 ± 26% with iNO vs. 60 ± 26% in CON (effect size -6.8%, 95% CI -14.8, 1.3, P = 0.09) corresponding to a myocardial salvage index of 47 ± 26% vs. 40 ± 26%, respectively, P = 0.09. Cine-MRI showed similar LV volumes at 48-72 h, with a tendency towards smaller increases in end-systolic and end-diastolic volumes at 4 months in iNO (P = 0.048 and P = 0.06, respectively, n = 197). Inhalation of nitric oxide was safe and significantly increased cGMP plasma levels during 4 h reperfusion. The Kaplan-Meier analysis for the composite of death, recurrent ischaemia, stroke, or rehospitalizations showed a tendency toward lower event rates with iNO at 4 months and 1 year (log-rank test P = 0.10 and P = 0.06, respectively).

Conclusions: Inhalation of NO at 80 ppm for 4 h in STEMI was safe but did not reduce infarct size relative to absolute LVmass at 48-72h. The observed functional recovery and clinical event rates at follow-up and possible interaction with nitroglycerine warrant further studies of iNO in STEMI.
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http://dx.doi.org/10.1093/eurheartj/ehy232DOI Listing
August 2018

Reversibility of severe mitral valve regurgitation after left ventricular assist device implantation: single-centre observations from a real-life population of patients.

Eur J Cardiothorac Surg 2018 06;53(6):1144-1150

Department of Cardiac Surgery, University of Leipzig, Leipzig Heart Center, Leipzig, Germany.

Objectives: This study evaluates the impact of untreated preoperative severe mitral valve regurgitation (MR) on outcomes after left ventricular assist device (LVAD) implantation.

Methods: Of the 234 patients who received LVAD therapy in our centre during a 6-year period, we selected those who had echocardiographic images of good quality and excluded those who underwent mitral valve replacement prior to or mitral valve repair during LVAD placement. The 128 patients selected were divided into 2 groups: Group A with severe MR (n = 65) and Group B with none to moderate MR (n = 63, 28 with moderate MR). We evaluated transthoracic echocardiography preoperatively [15 (7-28) days before LVAD implantation; median (interquartile range)] and postoperatively up to the last available follow-up [501 (283-848) days after LVAD]. We collected mortality, complications and clinical status indicators of the patient cohort.

Results: We observed a significant decrease in the severity of MR after LVAD implantation (severe MR 51% pre- vs 6% post-LVAD implantation, P < 0.001). There was no difference between groups in terms of right heart failure, rate of urgent heart transplantation, pump thrombosis or ventricular arrhythmias. There was no difference in 1-year survival and 3-year survival (87.7% vs 88.4% and 71.8% vs 66.6% for Groups A and B, respectively, P = 0.97).

Conclusions: Preoperative severe MR resolves in the majority of patients early on after LVAD implantation and is not associated with worse clinical outcomes or intermediate-term survival.
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http://dx.doi.org/10.1093/ejcts/ezx476DOI Listing
June 2018

The association of volumetric response and long-term survival after cardiac resynchronization therapy.

Eur Heart J Cardiovasc Imaging 2017 Oct;18(10):1109-1117

Department of Cardiovascular Diseases, University Hospital Gasthuisberg, Catholic University Leuven, Herestraat 49, 3000 Leuven, Belgium.

Aims: Clinical experience indicates that limited or no reverse left ventricular (LV) remodelling may not necessarily imply non-response to cardiac resynchronization therapy (CRT). We investigated the association of the extent of LV remodelling, mechanical dyssynchrony, and survival in patients undergoing CRT.

Methods And Results: In 356 CRT candidates, three blinded readers visually assessed the presence of mechanical dyssynchrony (either apical rocking and/or septal flash) before device implantation and also its correction by CRT 12 ± 3 months post-implantation. To assess LV reverse remodelling, end-systolic volumes (ESV) were measured at the same time points. Patients were divided into four subgroups: no LV remodelling (ESV change 0 ± 5%), mild LV reverse remodelling (ESV reduction 5-15%), significant LV reverse remodelling (ESV reduction ≥15%), and LV volume expansion (ESV increase ≥5%). Patients were followed for all-cause mortality during the median follow-up of 36 months. Patients with LV remodelling as in the above defined groups showed 58, 54, and 84% reduction in all-cause mortality compared to patients with volume expansion. In multivariable analysis, LVESV change remained independently associated with survival, with an 8% reduction in mortality for every 10% decrease in LVESV (P = 0.0039), but an optimal cut-off point could not be established. In comparison, patients with corrected mechanical dyssynchrony showed 71% reduction in all-cause mortality (P < 0.001).

Conclusion: Volumetric response assessed at 1-year after CRT is strongly associated with long-term mortality. However, an optimal cut-off cannot be established. The association of the correction of mechanical dyssynchrony with survival was stronger than that of any volumetric cut-off.
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http://dx.doi.org/10.1093/ehjci/jex188DOI Listing
October 2017

The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: rationale and design of the BAMI trial.

Eur J Heart Fail 2017 11 25;19(11):1545-1550. Epub 2017 Sep 25.

Johann-Wolfgang-Goethe University, Frankfurt, Germany.

Over the past 13 years bone marrow-derived mononuclear cells (BM-MNCs) have been widely investigated for clinical efficacy in patients following acute myocardial infarction (AMI). These early phase II trials have used various surrogate markers to judge efficacy and, although promising, the results have been inconsistent. The phase III BAMI trial has therefore been designed to demonstrate that intracoronary infusion of BM-MNCs is safe and will significantly reduce the time to first occurrence of all-cause death in patients with reduced left ventricular ejection fraction after successful reperfusion for ST-elevation AMI (powered with the aim of detecting a 25% reduction in all-cause mortality). This is a multinational, multicentre, randomized, open-label, controlled, parallel-group phase III study aiming to enrol approximately 3000 patients in 11 European countries with at least 17 sites. Eligible patients who have impaired left ventricular ejection (≤45%) following successful reperfusion for AMI will be randomized to treatment or control group in a 1:1 ratio. The treatment group will receive intracoronary infusion of BM-MNCs 2-8 days after successful reperfusion for AMI added on top of optimal standard of care. The control group will receive optimal standard of care. The primary endpoint is time from randomization to all-cause death. The BAMI trial is pivotal and the largest trial to date of BM-MNCs in patients with impaired left ventricular function following AMI. The aim of the trial is to provide a definitive answer as to whether BM-MNCs reduce all-cause mortality in this group of patients.
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http://dx.doi.org/10.1002/ejhf.829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607485PMC
November 2017

Mean arterial pressure of 65 mm Hg versus 85-100 mm Hg in comatose survivors after cardiac arrest: Rationale and study design of the Neuroprotect post-cardiac arrest trial.

Am Heart J 2017 Sep 23;191:91-98. Epub 2017 Jun 23.

Department of Cardiology, University Hospitals Leuven, Leuven, Belgium.

Background: Post-cardiac arrest (CA) patients admitted to the intensive care unit (ICU) have a poor prognosis, with estimated survival rates of around 30%-50%. On admission, these patients have a large cerebral penumbra at risk for additional damage in case of suboptimal brain oxygenation during their stay in the ICU. The aim of the Neuroprotect post-CA trial is to investigate whether forcing mean arterial blood pressure (MAP) and mixed venous oxygen saturation (SVO) in a specific range (MAP 85-100 mm Hg, SVO 65%-75%) with additional pharmacological support (goal-directed hemodynamic optimization) may better salvage the penumbra, reduce cerebral ischemia, and improve functional outcome when compared with current standard of care (MAP 65 mm Hg).

Design: The Neuroprotect post-CA trial (NCT02541591) is a multicenter, randomized, parallel-group, open-label, assessor-blinded, monitored, and investigator-driven clinical trial. The trial will be conducted in 2 tertiary care hospitals in Belgium (UZ Leuven and ZOL-Genk). A total of 112 eligible patients will be randomly assigned in a 1:1 ratio to goal-directed hemodynamic optimization or standard care strategy by an interactive voice response system. Patients will be stratified according to the presence of an initial shockable rhythm. Adult patients (≥18 years) resuscitated from out-of-hospital CA of a presumed cardiac cause who are unconscious upon hospital admission are eligible for inclusion. Patients can be included irrespective of their presenting heart rhythm but need to have a sustained return of spontaneous circulation. Trial interventions will take 36 hours starting from ICU admission. The primary outcome is the extent of cerebral ischemia as quantified by the apparent diffusion coefficient on diffusion-weighted magnetic resonance imaging to be performed at day 4-5 post-CA. Secondary outcomes include surrogate biomarkers of brain injury (neuron specific enolase) at day 1-5, neuropsychological and functional testing at hospital discharge, a Short Form-36 health questionnaire at 180 days, and outcome as assessed with cerebral performance category scores at ICU discharge and at 180 days.

Conclusions: The Neuroprotect post-CA trial will investigate whether a more aggressive hemodynamic strategy to obtain a MAP 85-100 mm Hg and SVO 65%-75% reduces brain ischemia and improves outcome when compared with standard treatment (MAP 65 mm Hg) in comatose post-CA survivors.
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http://dx.doi.org/10.1016/j.ahj.2017.06.010DOI Listing
September 2017

Optical Coherence Tomography Findings in Patients With Coronary Stent Thrombosis: A Report of the PRESTIGE Consortium (Prevention of Late Stent Thrombosis by an Interdisciplinary Global European Effort).

Circulation 2017 Sep 18;136(11):1007-1021. Epub 2017 Jul 18.

From Department of Cardiology, University Hospitals Leuven and Department of Cardiovascular Sciences, KU Leuven, Belgium (T.A., D.D.C., W.D.); Deutsches Herzzentrum München, Technische Universität München, Germany (M.J., E.X., T.T., A.K., R.A.B.); Department of Cardiology, St. Antonius Hospital, Nieuwegein, The Netherlands (T.C.G., J.M.t.B.); Department of Cardiovascular Sciences, University of Leicester & Leicester NIHR Cardiovascular Biomedical Research Unit, Glenfield Hospital, United Kingdom (N.M., A.H. Goodall, A.H. Gershlick); Hospital Universitario de La Princesa, Madrid, Spain (F.A., J.C.); Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy (K.K., V.S., G.G.); Département de Cardiologie, AP-HP, DHU FIRE, U-1148 INSERM, Hôpital Bichat, Paris, France (L.J.F.); Universitäts- Herzzentrum Freiburg-Bad Krozingen, Germany (F.-J.N.); Department of Cardiology, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (T.H.); Antwerp Cardiovascular Institute, ZNA Middelheim, Belgium (I.B.); Department of Cardiology, ICRC, St. Anne University Hospital, Masaryk University, Brno, Czech Republic (O.H.); Department of Biostatstics (I-BioStat), KU Leuven - University of Leuven & Universiteit Hasselt, Belgium (A.B.); Medizinische Klinik und Poliklinik I, Ludwig-Maximilians-Universität, Munich, Germany (S.M.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (S.M., A.K., M.J., R.A.B.).

Background: Stent thrombosis (ST) is a serious complication following coronary stenting. Intravascular optical coherence tomography (OCT) may provide insights into mechanistic processes leading to ST. We performed a prospective, multicenter study to evaluate OCT findings in patients with ST.

Methods: Consecutive patients presenting with ST were prospectively enrolled in a registry by using a centralized telephone registration system. After angiographic confirmation of ST, OCT imaging of the culprit vessel was performed with frequency domain OCT. Clinical data were collected according to a standardized protocol. OCT acquisitions were analyzed at a core laboratory. Dominant and contributing findings were adjudicated by an imaging adjudication committee.

Results: Two hundred thirty-one patients presenting with ST underwent OCT imaging; 14 (6.1%) had image quality precluding further analysis. Of the remaining patients, 62 (28.6%) and 155 (71.4%) presented with early and late/very late ST, respectively. The underlying stent type was a new-generation drug-eluting stent in 50.3%. Mean reference vessel diameter was 2.9±0.6 mm and mean reference vessel area was 6.8±2.6 mm. Stent underexpansion (stent expansion index <0.8) was observed in 44.4% of patients. The predicted average probability (95% confidence interval) that any frame had uncovered (or thrombus-covered) struts was 99.3% (96.1-99.9), 96.6% (92.4-98.5), 34.3% (15.0-60.7), and 9.6% (6.2-14.5) and malapposed struts was 21.8% (8.4-45.6), 8.5% (4.6-15.3), 6.7% (2.5-16.3), and 2.0% (1.2-3.3) for acute, subacute, late, and very late ST, respectively. The most common dominant finding adjudicated for acute ST was uncovered struts (66.7% of cases); for subacute ST, the most common dominant finding was uncovered struts (61.7%) and underexpansion (25.5%); for late ST, the most common dominant finding was uncovered struts (33.3%) and severe restenosis (19.1%); and for very late ST, the most common dominant finding was neoatherosclerosis (31.3%) and uncovered struts (20.2%). In patients presenting very late ST, uncovered stent struts were a common dominant finding in drug-eluting stents, and neoatherosclerosis was a common dominant finding in bare metal stents.

Conclusions: In patients with ST, uncovered and malapposed struts were frequently observed with the incidence of both decreasing with longer time intervals between stent implantation and presentation. The most frequent dominant observation varied according to time intervals from index stenting: uncovered struts and underexpansion in acute/subacute ST and neoatherosclerosis and uncovered struts in late/very late ST.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.026788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598909PMC
September 2017

Introducing ICD-resistant mortality as an end point to evaluate the clinical efficacy of an implantable cardioverter-defibrillator in ischaemic cardiomyopathy.

Acta Cardiol 2018 Feb 7;73(1):19-27. Epub 2017 Jul 7.

a Department of Cardiovascular Sciences , University of Leuven , Leuven , Belgium.

Objective: A new end point called ICD-resistant mortality was evaluated to assess the clinical efficacy of ICD implantations.

Methods And Results: In 302 ICD patients with ischaemic cardiomyopathy, we investigated which clinical parameters predicted useful ICD implantations using cumulative incidence competing risk analysis. Implantation was deemed clinically useful when the ICD provided appropriate therapy and the patient survived implantation by 1 year and the first shock by 30 days. ICD-resistant mortality (ICDRM) was defined as death within 30 days after the first shock, within 1 year of implantation or without previous appropriate ICD therapy. After 5 years, ICDRM occurred in 23% of implantations, while 36% were clinically useful. After multivariable analysis, ICDRM was associated with LVEF <35% (HR: 2.63; p = .005), beta-blocker dose <50% (HR: 2.0; p = .01) and anterior or diffuse infarct location (HR: 3.61; p = .001 and HR: 2.89; p = .02). Useful ICD implantations were associated with beta-blocker dose <50% (HR: 1.64; p = .02) and non-anterior infarct location (HR: 3.22 vs anterior and 1.59 vs diffuse; combined p<.001).

Conclusions: Five years after implantation, an ICD could be classified as useful in 1 out of 3, while ICDRM occurred in one out of four patients. At 10 years, up to 80% of implantations could be categorized. Lower LVEF was related with significantly higher incidence of ICDRM. Anterior infarcts were associated with more ICDRM and less useful implantations than non-anterior infarcts. Future risk stratification for ICD should focus more on the discrimination between arrhythmic risk, probably preventable by ICDs and ICD-resistant mortality risk.
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http://dx.doi.org/10.1080/00015385.2017.1322776DOI Listing
February 2018

Optical coherence tomography findings: insights from the "randomised multicentre trial investigating angiographic outcomes of hybrid sirolimus-eluting stents with biodegradable polymer compared with everolimus-eluting stents with durable polymer in chronic total occlusions" (PRISON IV) trial.

EuroIntervention 2017 Aug 4;13(5):e522-e530. Epub 2017 Aug 4.

Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands.

Aims: The PRISON IV trial investigated the next-generation sirolimus-eluting stent (SES) with ultra-thin struts and biodegradable polymer against the second-generation everolimus-eluting stent (EES) with thin struts and durable polymer in patients with successfully recanalised chronic total occlusions (CTO). In this study, we examined the secondary optical coherence tomography endpoints.

Methods And Results: The main PRISON IV trial randomised 330 patients to either SES or EES. At nine months, 281 (85%) patients underwent repeat angiography. Of these, 60 consecutive patients received optical coherence tomography divided over both stent groups. The mean number of struts analysed was 750±337 and 633±358 in SES and EES patients, respectively (p=0.07). The minimal lumen area, minimal stent area, maximal neointima area and neointimal thickness were comparable between the groups (4.8±2.1 and 4.4±1.5 mm2; 5.3±1.8 and 5.3±1.4 mm2; 2.5±2.0 and 2.2±1.5 mm2; 0.7±1.7 and 0.4±0.2 mm). The percentage of uncovered struts was higher with EES (6.2±7.5% and 11.9±13.4%, p=0.04), whereas the percentage of malapposed struts and mean number of coronary evaginations were significantly higher with SES (2.9±4.0% and 1.2±2.4%, p=0.02; 18.5±17.7 and 5.3±3.1, p=0.004).

Conclusions: The optical coherence tomography findings of this substudy demonstrated improved strut coverage with ultra-thin strut SES with bioresorbable polymer compared to thin-strut EES with durable polymer in CTO. On the other hand, SES showed a higher rate of stent strut malappositon and coronary evaginations. The clinical relevance of these findings remains to be demonstrated.
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http://dx.doi.org/10.4244/EIJ-D-17-00261DOI Listing
August 2017

The CECARI Study: Everolimus (Certican®) Initiation and Calcineurin Inhibitor Withdrawal in Maintenance Heart Transplant Recipients with Renal Insufficiency: A Multicenter, Randomized Trial.

J Transplant 2017 20;2017:6347138. Epub 2017 Feb 20.

Department of Cardiology, University Hospitals Leuven, 3000 Leuven, Belgium.

In this 3-year, open-label, multicenter study, 57 maintenance heart transplant recipients (>1 year after transplant) with renal insufficiency (eGFR 30-60 mL/min/1.73 m) were randomized to start everolimus with CNI withdrawal ( = 29) or continue their current CNI-based immunosuppression ( = 28). The primary endpoint, change in measured glomerular filtration rate (mGFR) from baseline to year 3, did not differ significantly between both groups (+7.0 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, = 0.18). In the on-treatment analysis, the difference did reach statistical significance (+9.4 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, = 0.047). The composite safety endpoint of all-cause mortality, major adverse cardiovascular events, or treated acute rejection was not different between groups. Nonfatal adverse events occurred in 96.6% of patients in the everolimus group and 57.1% in the CNI group ( < 0.001). Ten patients (34.5%) in the everolimus group discontinued the study drug during follow-up due to adverse events. The poor adherence to the everolimus therapy might have masked a potential benefit of CNI withdrawal on renal function.
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http://dx.doi.org/10.1155/2017/6347138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337890PMC
February 2017

Reduction of the dose of radiotherapy to the elective neck in head and neck squamous cell carcinoma; a randomized clinical trial. Effect on late toxicity and tumor control.

Radiother Oncol 2017 02 12;122(2):171-177. Epub 2016 Aug 12.

Department of Radiation Oncology, KU Leuven - University of Leuven, University Hospitals Leuven, Belgium.

Background And Purpose: A multi-center prospective randomized clinical trial has been performed investigating whether a reduction of the dose to the elective nodal sites in head and neck cancer delivered by intensity modulated radiotherapy (IMRT) would result in a reduction of late side effects without compromising tumor control.

Materials And Methods: Two hundred patients were included. The prescription dose to the elective nodal volumes was a normalized iso-effective dose in 2Gy fractions (NID) of 50Gy in the standard arm and of 40Gy in the experimental arm. Late toxicity was scored at 6, 12, 18 and 24months using the RTOG scoring system.

Results: We observed a trend toward less dysphagia at 6months in the experimental arm, however this was not confirmed after longitudinal analysis. Regarding moderate salivary gland toxicity we observed lower incidence of salivary gland toxicity ⩾grade 1, at 6 (p=0.01) and 18months (p=0.03). After two years of follow up, we did not observe significant differences in estimated local failure rate (14.1% in the 40Gy arm vs 14.4% in the 50Gy arm), estimated regional failure rate (13.0% vs 5.5% in the 40 and the 50Gy arm respectively), estimated metastatic recurrence (13.4% vs 18.5% in the 40 and the 50Gy arm respectively), estimated disease-free survival (57.9% vs 65.3% in the 40 and the 50Gy arm respectively) nor estimated overall survival (72.0% vs 73.2% in the 40 and the 50Gy arm respectively).

Conclusions: In our study population there was no statistically significant difference regarding survival and estimated recurrence rates between both arms of this study. We found a trend toward less dysphagia at 6months (however not significant after longitudinal analysis) and found a significant reduction of any salivary gland toxicity at 6 and 18months in the 40Gy arm.
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http://dx.doi.org/10.1016/j.radonc.2016.08.009DOI Listing
February 2017

Functional performance and quality of life in high-risk comorbid patients undergoing transcatheter aortic valve implantation for symptomatic aortic valve stenosis.

Eur Heart J Qual Care Clin Outcomes 2016 Jul;2(3):184-192

Department of Cardiovascular Medicine, University Hospitals Leuven, Herestraat 49, Leuven, Belgium.

Aims: We assessed the impact of transcatheter aortic valve implantation (TAVI) on functional performance and quality of life (QoL) in a high-risk patient population with multiple comorbidities.

Methods And Results: Between January 2009 and December 2014, 145 high-risk patients (EuroSCORE II 7.3% [4.9; 14.9]) with severe symptomatic aortic valve stenosis (AS) underwent TAVI in a single centre. We prospectively evaluated New York Heart Association (NYHA) functional class, 6-minute walking distance (6MWD), and QoL using the validated Dutch version of the EuroQol-5D (EQ-5D) descriptive assessment and a visual analogue scale (EQ-VAS) at baseline, 30 days, as well as 6, 12, and 24 months after TAVI. All patients were eligible for analysis. New York Heart Association functional class improved significantly at 30-day, 6-, 12-, and 24-month follow-up (P < 0.001 for all). The absolute 6MWD improved significantly at 30 days (+19.3 ± 8.2 m; P= 0.0499) and at 6 months (+23.3 ± 8.1 m; P = 0.0194). A favourable trend was maintained at 12 months (+17.1 ± 8.8 m; P = 0.1879), whereas at 24 months 6MWD was similar to baseline values. No significant change in the descriptive assessment of QoL (EQ5D) was observed, whereas the EQ-VAS showed a significant improvement in QoL up to 24 months (P < 0.0180 for all time-points).

Conclusion: In high-risk comorbid patients with symptomatic AS, TAVI results in a significant but temporary improvement of functional performance when assessed with objective measures of 6MWD but not of EQ-5D. Moreover, TAVI has a significant and sustained impact on subjective well-being and exercise capacity assessed with the EQ-VAS and NYHA score.
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http://dx.doi.org/10.1093/ehjqcco/qcw001DOI Listing
July 2016

Histamine Receptor H1-Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome.

Gastroenterology 2016 Apr 2;150(4):875-87.e9. Epub 2016 Jan 2.

Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium. Electronic address:

Background & Aims: Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial.

Methods: By using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects. The sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n = 28) or placebo (n = 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis. The primary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension.

Results: TRPV1 responses of submucosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their pre-incubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidazole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P = .024), and reduced abdominal pain scores (ebastine 39 ± 23 vs placebo 62 ± 22; P = .0004).

Conclusions: In studies of rectal biopsy specimens from patients, we found that HRH1-mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS. ClinicalTrials.gov no: NCT01144832.
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http://dx.doi.org/10.1053/j.gastro.2015.12.034DOI Listing
April 2016
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