Left atrial appendage occlusion vs novel oral anticoagulation for stroke prevention in atrial fibrillation: rationale and design of the multicenter randomized occlusion-AF trial.

BACKGROUND: The prevalence of atrial fibrillation (AF) is increasing globally, which is a major clinical and public health concern due to the 5-fold increased risk of stroke. Oral anticoagulation with novel oral anticoagulants (NOACs) is the current primary option for stroke prevention in patients with AF, although it increases the risk of major bleeding. Patients with prior ischemic cerebrovascular events are at particularly high risk of both recurrent ischemic events and major bleeding. Left atrial appendage occlusion (LAAO) provides an alternative option for stroke prevention in high-risk patients, however, with currently limited evidence. Thus, randomized trials comparing LAAO to NOACs are needed. OBJECTIVE: The Occlusion-AF trial is designed to assess whether LAAO is non-inferior to NOAC therapy for reduction of the combined endpoint of stroke, systemic embolism, major bleeding (Bleeding Academic Research Consortium ≥ 3) and all-cause mortality in patients with AF and a recent ischemic stroke or transient ischemic attack (TIA). METHODS AND ANALYSIS: Investigator-initiated multicenter, multinational, randomized open-label non-inferiority trial with blinded outcome evaluation (PROBE design). Patients with documented AF, and an ischemic stroke or TIA within 6 months will be eligible for enrollment. Major exclusion criteria are modified Rankin Scale > 3 at enrollment, glomerular filtration rate < 15 ml/min, and life-expectancy less than 2 years. A total of 750 patients will be randomized 1:1 to receive either a NOAC or LAAO using the Amplatzer Amulet (Abbott, MN, USA) or Watchman FLX (Boston Scientific, MN, USA) with subsequent life-long aspirin 75 mg daily. Follow-up will be based on in-office and telephone follow-up in combination with long-term follow-up (10 years) through national hospital discharge registries in the individual Nordic countries. The primary outcome will be a composite endpoint of stroke, systemic embolism, major bleeding (BARC ≥ 3) and all-cause mortality at 2-year follow-up. CONCLUSIONS: The Occlusion-AF trial is designed to compare LAAO to NOAC therapy for secondary stroke prevention in AF patients with a high risk of recurrent thromboembolic events, i.e. with previous ischemic stroke or TIA, and otherwise eligible for anticoagulation. The results are expected to contribute significantly to the understanding of the effects of LAAO compared to the standard contemporary pharmacological treatment in these patients.

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden.

Rational and design of the European randomized Optical Coherence Tomography Optimized Bifurcation Event Reduction Trial (OCTOBER).

Background: Percutaneous coronary intervention in complex bifurcation lesions is prone to suboptimal implantation results and is associated with increased risk of subsequent clinical events. Angiographic ambiguity is high during bifurcation stenting, but it is unknown if procedural guidance by intravascular optical coherence tomography (OCT) improves clinical outcome. Methods and Design: OCTOBER is a randomized, investigator-initiated, multicenter trial aimed to show superiority of OCT-guided stent implantation compared to standard angiographic-guided implantation in bifurcation lesions. The primary outcome measure is a 2-year composite end point of cardiac death, target lesion myocardial infarction, and ischemia-driven target lesion revascularization. The calculated sample size is 1,200 patients in total, and allocation is 1:1. Eligible patients have stable or unstable angina pectoris or stabilized non­ST elevation myocardial infarction, and a coronary bifurcation lesion with significant main vessel stenosis and more than 50 % stenosis in a side branch with a reference diameter ≥2.5mm. Treatment is performed by the provisional side branch stenting technique or 2-stent techniques, and the systematic OCT guiding protocol is aimed to evaluate (1) plaque preparation, (2) lesion length, (3) segmental reference sizes, (4) lesion coverage, (5) stent expansion, (6) malapposition, (7) wire positions, and (8) ostial results. Implications: A positive outcome of the OCTOBER trial may establish OCT as a routine tool for optimization of complex percutaneous coronary intervention, whereas a negative result would indicate that OCT remains a tool for ad hoc evaluation in selected cases.

Distance to invasive heart centre, performance of acute coronary angiography, and angioplasty and associated outcome in out-of-hospital cardiac arrest: a nationwide study.

AIMS: To evaluate whether the distance from the site of event to an invasive heart centre, acute coronary angiography (CAG)/percutaneous coronary intervention (PCI) and hospital-level of care (invasive heart centre vs. local hospital) is associated with survival in out-of-hospital cardiac arrest (OHCA) patients. METHODS AND RESULTS: Nationwide historical follow-up study of 41 186 unselected OHCA patients, in whom resuscitation was attempted between 2001 and 2013, identified through the Danish Cardiac Arrest Registry. We observed an increase in the proportion of patients receiving bystander CPR (18% in 2001, 60% in 2013, P < 0.001), achieving return of spontaneous circulation (ROSC) (10% in 2001, 29% in 2013, P < 0.001) and being admitted directly to an invasive centre (26% in 2001, 45% in 2013, P < 0.001). Simultaneously, 30-day survival rose from 5% in 2001 to 12% in 2013, P < 0.001. Among patients achieving ROSC, a larger proportion underwent acute CAG/PCI (5% in 2001, 27% in 2013, P < 0.001). The proportion of patients undergoing acute CAG/PCI annually in each region was defined as the CAG/PCI index. The following variables were associated with lower mortality in multivariable analyses: direct admission to invasive heart centre (HR 0.91, 95% CI: 0.89-0.93), CAG/PCI index (HR 0.33, 95% CI: 0.25-0.45), population density above 2000 per square kilometre (HR 0.94, 95% CI: 0.89-0.98), bystander CPR (HR 0.97, 95% CI: 0.95-0.99) and witnessed OHCA (HR 0.87, 95% CI: 0.85-0.89), whereas distance to the nearest invasive centre was not associated with survival. CONCLUSION: Admission to an invasive heart centre and regional performance of acute CAG/PCI were associated with improved survival in OHCA patients, whereas distance to the invasive centre was not. These results support a centralized strategy for immediate post-resuscitation care in OHCA patients.

Clinical course and prognosis of musculoskeletal pain in patients referred for physiotherapy: does pain site matter?

BACKGROUND: Danish patients with musculoskeletal disorders are commonly referred for primary care physiotherapy treatment but little is known about their general health status, pain diagnoses, clinical course and prognosis. The objectives of this study were to 1) describe the clinical course of patients with musculoskeletal disorders referred to physiotherapy, 2) identify predictors associated with a satisfactory outcome, and 3) determine the influence of the primary pain site diagnosis relative to those predictors. METHODS: This was a prospective cohort study of patients (n = 2,706) newly referred because of musculoskeletal pain to 30 physiotherapy practices from January 2012 to May 2012. Data were collected via a web-based questionnaire 1-2 days prior to the first physiotherapy consultation and at 6 weeks, 3 and 6 months, from clinical records (including primary musculoskeletal symptom diagnosis based on the ICPC-2 classification system), and from national registry data. The main outcome was the Patient Acceptable Symptom State. Potential predictors were analysed using backwards step-wise selection during longitudinal Generalised Estimating Equation regression modelling. To assess the influence of pain site on these associations, primary pain site diagnosis was added to the model. RESULTS: Of the patients included, 66% were female and the mean age was 48 (SD 15). The percentage of patients reporting their symptoms as acceptable was 32% at 6 weeks, 43% at 3 months and 52% at 6 months. A higher probability of satisfactory outcome was associated with place of residence, being retired, no compensation claim, less frequent pain, shorter duration of pain, lower levels of disability and fear avoidance, better mental health and being a non-smoker. Primary pain site diagnosis had little influence on these associations, and was not predictive of a satisfactory outcome. CONCLUSION: Only half of the patients rated their symptoms as acceptable at 6 months. Although satisfactory outcome was difficult to predict at an individual patient level, there were a number of prognostic factors that were associated with this outcome. These factors should be considered when developing generic prediction tools to assess the probability of satisfactory outcome in musculoskeletal physiotherapy patients, because the site of pain did not affect that prognostic association.

Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.

Importance: International resuscitation guidelines recommend targeted temperature management (TTM) at 33°C to 36°C in unconscious patients with out-of-hospital cardiac arrest for at least 24 hours, but the optimal duration of TTM is uncertain. Objective: To determine whether TTM at 33°C for 48 hours results in better neurologic outcomes compared with currently recommended, standard, 24-hour TTM. Design, Setting, and Participants: This was an international, investigator-initiated, blinded-outcome-assessor, parallel, pragmatic, multicenter, randomized clinical superiority trial in 10 intensive care units (ICUs) at 10 university hospitals in 6 European countries. Three hundred fifty-five adult, unconscious patients with out-of-hospital cardiac arrest were enrolled from February 16, 2013, to June 1, 2016, with final follow-up on December 27, 2016. Interventions: Patients were randomized to TTM (33 ± 1°C) for 48 hours (n = 176) or 24 hours (n = 179), followed by gradual rewarming of 0.5°C per hour until reaching 37°C. Main Outcomes and Measures: The primary outcome was 6-month neurologic outcome, with a Cerebral Performance Categories (CPC) score of 1 or 2 used to define favorable outcome. Secondary outcomes included 6-month mortality, including time to death, the occurrence of adverse events, and intensive care unit resource use. Results: In 355 patients who were randomized (mean age, 60 years; 295 [83%] men), 351 (99%) completed the trial. Of these patients, 69% (120/175) in the 48-hour group had a favorable outcome at 6 months compared with 64% (112/176) in the 24-hour group (difference, 4.9%; 95% CI, -5% to 14.8%; relative risk [RR], 1.08; 95% CI, 0.93-1.25; P = .33). Six-month mortality was 27% (48/175) in the 48-hour group and 34% (60/177) in the 24-hour group (difference, -6.5%; 95% CI, -16.1% to 3.1%; RR, 0.81; 95% CI, 0.59-1.11; P = .19). There was no significant difference in the time to mortality between the 48-hour group and the 24-hour group (hazard ratio, 0.79; 95% CI, 0.54-1.15; P = .22). Adverse events were more common in the 48-hour group (97%) than in the 24-hour group (91%) (difference, 5.6%; 95% CI, 0.6%-10.6%; RR, 1.06; 95% CI, 1.01-1.12; P = .04). The median length of intensive care unit stay (151 vs 117 hours; P < .001), but not hospital stay (11 vs 12 days; P = .50), was longer in the 48-hour group than in the 24-hour group. Conclusions and Relevance: In unconscious survivors from out-of-hospital cardiac arrest admitted to the ICU, targeted temperature management at 33°C for 48 hours did not significantly improve 6-month neurologic outcome compared with targeted temperature management at 33°C for 24 hours. However, the study may have had limited power to detect clinically important differences, and further research may be warranted. Trial Registration: clinicaltrials.gov Identifier: NCT01689077.

Use of Helicopters to Reduce Health Care System Delay in Patients With ST-Elevation Myocardial Infarction Admitted to an Invasive Center.

Timely reperfusion in ST-elevation myocardial infarction (STEMI) is essential. This study aimed to evaluate the reduction in system delay (time from emergency medical service [EMS] call to primary percutaneous coronary intervention [PPCI]) in patients with STEMI when using helicopter EMS (HEMS) rather than ground-based EMS (GEMS). This was a retrospective, nationwide cohort study of consecutive patients with STEMI treated with PPCI at 5 PPCI centers in Denmark. Polynomial spline curves were constructed to describe the association between system delay and distance to the PPCI center stratified by transportation mode. A total of 26,433 patients with STEMI were treated with PPCI between January 1, 1999, and December 31, 2016. In 16,436 patients field triaged directly to the PPCI center, the proportion treated within 120 minutes of the EMS call was 75% for those living 0 to 25 km from the PPCI center compared with 65% for all patients transported by GEMS (median transport distance 50 km [interquartile range 23 to 90]) and 64% for all patients transported by HEMS (median transport distance 119 km [interquartile range 99 to 142]). The estimated reduction in system delay owed to using HEMS rather than GEMS was 14, 16, 20, and 29 minutes for patients living 75, 100, 125, and 170 km from a PPCI center. In conclusion, this study confirmed that using HEMS ensures that most patients with STEMI, living up to 170 km from a PPCI center, can be treated within 120 minutes of their EMS call provided they are field triaged directly to the PPCI center.

Reproducibility of quantitative flow ratio: the QREP study.

BACKGROUND: Quantitative flow ratio (QFR) is a tool for physiological lesion assessment based on invasive coronary angiography. AIMS: We aimed to assess the reproducibility of QFR computed from the same angiograms as assessed by multiple observers from different, international sites. METHODS: We included 50 patients previously enrolled in dedicated QFR studies. QFR was computed twice, one month apart by five blinded observers. The main analysis was the coefficient of variation (CV) as a measure of intra- and inter-observer reproducibility. Key secondary analysis was the identification of clinical and procedural characteristics predicting reproducibility. RESULTS: The intra-observer CV ranged from 2.3% (1.5-2.8) to 10.2% (6.6-12.0) among the observers. The inter-observer CV was 9.4% (8.0-10.5). The QFR observer, low angiographic quality, and low fractional flow reserve (FFR) were independent predictors of a large absolute difference between repeated QFR measurements defined as a difference larger than the median difference (>0.03). CONCLUSIONS: The inter- and intra-observer reproducibility for QFR computed from the same angiograms ranged from high to poor among multiple observers from different sites with an average agreement of 0.01±0.08 for repeated measurements. The reproducibility was dependent on the observer, angiographic quality and the coronary artery stenosis severity as assessed by FFR.

Group-based exercise, individually supervised exercise and home-based exercise have similar clinical effects and cost-effectiveness in people with subacromial pain: a randomised trial.

QUESTION: What are the relative effects of group-based exercise, individual exercise and home-based exercise on clinical outcomes and costs in patients with subacromial pain? DESIGN: Multicentre, three-arm, randomised controlled trial with concealed allocation and intention-to-treat analysis. PARTICIPANTS: A total of 208 patients referred to municipal rehabilitation for management of subacromial pain in six municipalities in the Central Denmark Region. INTERVENTIONS: Patients were randomly allocated to group-based exercise rehabilitation (GE), individual exercise rehabilitation (IE) or home exercise rehabilitation (HE) for a period of 8 weeks. OUTCOME MEASURES: The primary outcome measure was the shortened version of the Disabilities of the Arm, Shoulder and Hand questionnaire (Quick-DASH). The secondary outcome measures included the EQ-5D-5L index, pain intensity, fear avoidance, psychological wellbeing, and the participant's perception of improvement and satisfaction. Healthcare and productivity costs were extracted from national health and social registers. RESULTS: There was no important between-group difference in Quick-DASH scores at 6 months: adjusted mean differences GE minus IE -2 (95% CI -9 to 5), GE minus HE -2 (95% CI -9 to 5) and HE minus IE 1 (95% CI -6 to 7). The estimates of the between-group differences were able to exclude any clinically important differences in the three regimens' effects on health benefits according to the EQ-5D-5L index and other secondary outcomes. The total average costs were highest for the IE group and lowest for the HE, but not statistically different across groups. CONCLUSION: In people with subacromial pain, group-based exercise, individually supervised exercise and home-based supervised exercise regimens have similar benefits. The home exercise intervention was associated with lowest costs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03055117.

Measles-mumps-rubella vaccine at 6 months of age, immunology, and childhood morbidity in a high-income setting: study protocol for a randomized controlled trial.

BACKGROUND: Measles is a highly contagious and serious infection. Before the introduction of vaccination, measles caused yearly epidemics putting vulnerable children at risk of brain damage and death. Despite safe and cost-effective vaccines, measles remains a leading cause of death in children globally. Due to insufficient vaccine coverage and low levels of in utero transferred antibodies from vaccinated mothers, outbreaks of measles in Denmark and other high-income countries are observed at increasing frequency. The current vaccine was introduced in Denmark in 1987 as a one-shot measles-mumps-rubella vaccine at 15 months, a timing chosen to avoid inhibition of the infant's immune response by maternal antibodies. One generation later, the MMR vaccinated mothers have lower antibody levels compared to the naturally infected, and their infants are already susceptible at 6 months of age or earlier, thus increasing the risk of epidemics. METHODS: The Danish MMR trial is a double-blind randomized clinical trial recruiting between March 2019 and December 2021 with last patient last visit in February 2022. Altogether N = 6500 infants aged 6 months will be randomly assigned to intramuscular vaccination with routine MMR (M-M-R VaxPro) or placebo (solvent only). According to the Danish Childhood vaccination program, all infants will receive a routine MMR vaccination at 15 months of age. At randomization, 1 month later, and 1 month after routine MMR vaccination at 15 months of age, a blood sample is drawn from app. 10% (N = 600) of the population. Additionally, hair, saliva, and urine are sampled at randomization. The co-primary study outcomes are immunogenicity 1 month after MMR vaccination at 6 months of age assessed as plaque-reduction neutralization test, and incidence of infectious disease hospitalizations from randomization to 12 months of age. Six weeks post randomization, all participants are interviewed regarding adverse events. TRIAL REGISTRATION: The trial is registered in the EU Clinical Trials Registry. EudraCT registration number: 2016-001901-18 . Registered on 14 February 2017.

A multicentre, randomized, controlled open-label trial to compare an Accelerated Rule-Out protocol using combined prehospital copeptin and in-hospital high sensitive troponin with standard rule-out in patients suspected of acute Myocardial Infarction - the AROMI trial.

BACKGROUND: Suspicion of acute myocardial infarction (AMI) is among the most common reasons for admission to hospital in Denmark. Owing to this suspicion, an estimated 50,000 patients are admitted every year. Only 15-20% are finally diagnosed with AMI, whereas 40% are discharged after rule-out of AMI and without initiation of any treatment or need for further admission. In patients discharged after rule-out, the current diagnostic protocol, using consecutive troponin measurements, results in an average length of stay (LOS) of 8-12 h. This leads to overcrowding in both the emergency departments and coronary care units. Measuring copeptin and high-sensitivity cardiac troponin (hs-cTn) upon hospital arrival has shown potential for early rule-out of AMI. However, the diagnostic performance may be improved by accelerating the copeptin measurement of blood sampled already in the pre-hospital phase. Additional evidence on LOS reduction and safety of the rule-out strategy in a large cohort of all-comers is needed. METHODS/DESIGN: The rule-out potential is being evaluated in a randomized controlled trial including 4800 patients admitted to hospital for suspicion of AMI. Patients are randomized to either standard rule-out (consecutive troponin measurements) or accelerated rule-out (copeptin measured in a blood sample acquired before hospital admission, combined with troponin measured in the first blood sample upon admission). DISCUSSION: Sampling blood for copeptin analysis already in the pre-hospital phase and combining this with a later hs-cTn measurement may be the optimal timing for achieving the best diagnostic performance in an AMI rule-out protocol/strategy. Moreover, we are directly comparing pre-hospital and in-hospital blood sample results to address this issue of timing, and we also are comparing single-marker strategies with dual-marker strategies. If the combination of copeptin and hs-cTn is confirmed to rule out AMI safely, implementation of this fast rule-out protocol could optimize patient flow, reduce health care expenses and enable allocation of resources to patients with confirmed illness. In future, when point-of-care analyses of copeptin and hs-cTn are available, hospitalization of the large proportion of patients with symptoms raising suspicion of AMI could potentially be avoided. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02666326 . Registered on January 24, 2016.

Randomized comparison of sirolimus eluting, and biolimus eluting bioresorbable polymer stents: the SORT-OUT VII optical coherence tomography study.

Aims: To show non-inferiority of the 67- or 87 µm thick, sirolimus-eluting Orsiro drug eluting stent (DES) to the 122 µm thick, biolimus-eluting Nobori DES regarding size of vessel lumen outside the stent at 13-month follow-up. Methods and results: This study was a substudy to the SORT-OUT VII trial, a prospective, 1:1-randomized, comparison of the two stents in patients with stable coronary artery disease or acute coronary syndrome. Optical coherence tomography was acquired after percutaneous coronary intervention and at 13-month follow-up. The substudy was powered to access non-inferiority (Δ = 0.60 mm2) of the Orsiro DES to the Nobori DES for the primary endpoint of mean extra stent lumen (ESL) i.e. vessel lumen outside the stent at 13-month follow-up. We randomized 124 patients to Orsiro (n = 60) or Nobori (n = 64). Due to a difference in the one-sided 95%-confidence interval of 0.26 mm2, but increased to 0.82 mm2 after appropriate log-transformation, it could not be rejected that Orsiro exceeded the non-inferiority limit. Testing for superiority, Orsiro had a significantly larger mean ESL at follow-up (Orsiro: 0.11 mm2 [0.02;0.30] mm2, Nobori: 0.03 mm2 [0.00;0.17] mm2, P = 0.04). Stent strut coverage was, Orsiro: 97.6 % [93.8;99.4]%, and Nobori: 96.3 % [90.5;98,6]% (P = 0.13). Conclusion: Orsiro DES had a significantly larger mean ESL at follow-up and it could not be excluded that Orsiro exceeded the limit for non-inferiority. Nobori DES had a more heterogeneous distribution of neointima but stent strut coverage did not differ significantly between the two stents.

A 45-SNP genetic risk score is increased in early-onset coronary artery disease but independent of familial disease clustering.

BACKGROUND AND AIMS: Common genetic risk variants may contribute to the heritability of early-onset coronary artery disease (CAD). We aimed to investigate the association of a genetic risk score (GRS) with age upon CAD-onset and to test the association between the GRS, familial clustering, and CAD severity in early-onset CAD. METHODS: 134 early-onset CAD patients (<40 years), 446 late-onset CAD patients (male >55 years/female >65 years), and 89 healthy controls were genotyped for 45 CAD-associated SNPs and a GRS was created. In early-onset CAD patients, family pedigrees with information on 1585 1st and 2nd degree relatives were used to calculate a stratified log-rank family score (SLFS) as a measure of familial clustering. RESULTS: Early-onset patients had a higher mean GRS than late-onset CAD patients (p = 0.02) and healthy controls (p < 0.0001). In the adjusted model, a GRS increase of one SD was associated with 1.2 years (95% CI 0.1-2.2) earlier onset. The GRS was not associated with the SLFS in the regression model (p = 0.41) and did not differ between SLFS tertiles (p = 0.98). The SLFS predicted the number of affected coronary vessels (OR [95% CI] per SD increase in SLFS: 2.0 [1.4-3.0]), whereas the association between the GRS and CAD severity was not statistically significant (OR [95% CI] per SD increase in GRS: 1.3 [0.9-1.9]). CONCLUSIONS: The GRS was increased in early-onset CAD patients, but not associated with the SLFS, suggesting that these common genetic variants are of minor importance in familial clustering of early-onset CAD. Furthermore, family pedigree analysis may predict CAD severity more precisely than common variants.

Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)-a multicentre, double-blind, randomised, placebo-controlled trial.

AIMS: To determine the effect of the glucagon-like peptide-1 analogue liraglutide on left ventricular function in chronic heart failure patients with and without type 2 diabetes. METHODS AND RESULTS: LIVE was an investigator-initiated, randomised, double-blinded, placebo-controlled multicentre trial. Patients (n = 241) with reduced left ventricular ejection fraction (LVEF ≤45%) were recruited (February 2012 to August 2015). Patients were clinically stable and on optimal heart failure treatment. Intervention was liraglutide 1.8 mg once daily or matching placebo for 24 weeks. The LVEF was similar at baseline in the liraglutide and the placebo group (33.7 ± 7.6% vs. 35.4 ± 9.4%). Change in LVEF did not differ between the liraglutide and the placebo group; mean difference (95% confidence interval) was -0.8% (-2.1, 0.5; P = 0.24). Heart rate increased with liraglutide [mean difference: 7 b.p.m. (5, 9), P < 0.0001]. Serious cardiac events were seen in 12 (10%) patients treated with liraglutide compared with 3 (3%) patients in the placebo group (P = 0.04). CONCLUSION: Liraglutide did not affect left ventricular systolic function compared with placebo in stable chronic heart failure patients with and without diabetes. Treatment with liraglutide was associated with an increase in heart rate and more serious cardiac adverse events, and this raises some concern with respect to the use of liraglutide in patients with chronic heart failure and reduced left ventricular function. More data on the safety of liraglutide in different subgroups of heart failure patients are needed.

Clinical Use of Coronary CTA-Derived FFR for Decision-Making in Stable CAD.

OBJECTIVES: The goal of this study was to assess the real-world clinical utility of fractional flow reserve (FFR) derived from coronary computed tomography angiography (FFRCT) for decision-making in patients with stable coronary artery disease (CAD). BACKGROUND: FFRCT has shown promising results in identifying lesion-specific ischemia. The real-world feasibility and influence on the diagnostic work-up of FFRCT testing in patients suspected of having CAD are unknown. METHODS: We reviewed the complete diagnostic work-up of nonemergent patients referred for coronary computed tomography angiography over a 12-month period at Aarhus University Hospital, Denmark, including all patients with new-onset chest pain with no known CAD and with intermediate-range coronary lesions (lumen reduction, 30% to 70%) referred for FFRCT. The study evaluated the consequences on downstream diagnostic testing, the agreement between FFRCT and invasively measured FFR or instantaneous wave-free ratio (iFR), and the short-term clinical outcome after FFRCT testing. RESULTS: Among 1,248 patients referred for computed tomography angiography, 189 patients (mean age 59 years; 59% male) were referred for FFRCT, with a conclusive FFRCT result obtained in 185 (98%). FFRCT was ≤0.80 in 31% of patients and 10% of vessels. After FFRCT testing, invasive angiography was performed in 29%, with FFR measured in 19% and iFR in 1% of patients (with a tendency toward declining FFR-iFR guidance during the study period). FFRCT ≤0.80 correctly classified 73% (27 of 37) of patients and 70% (37 of 53) of vessels using FFR ≤0.80 or iFR ≤0.90 as the reference standard. In patients with FFRCT >0.80 being deferred from invasive coronary angiography, no adverse cardiac events occurred during a median follow-up period of 12 (range 6 to 18 months) months. CONCLUSIONS: FFRCT testing is feasible in real-world symptomatic patients with intermediate-range stenosis determined by coronary computed tomography angiography. Implementation of FFRCT for clinical decision-making may influence the downstream diagnostic workflow of patients. Patients with an FFRCT value >0.80 being deferred from invasive coronary angiography have a favorable short-term prognosis.

A statistical analysis protocol for the time-differentiated target temperature management after out-of-hospital cardiac arrest (TTH48) clinical trial.

BACKGROUND: The TTH48 trial aims to determine whether prolonged duration (48 hours) of targeted temperature management (TTM) at 33 (±1) °C results in better neurological outcomes compared to standard duration (24 hours) after six months in comatose out-of-hospital cardiac arrest (OHCA) patients. METHODS: TTH48 is an investigator-initiated, multicentre, assessor-blinded, randomised, controlled superiority trial of 24 and 48 hours of TTM at 33 (±1) ° C performed in 355 comatose OHCA patients aged 18 to 80 years who were admitted to ten intensive care units (ICUs) in six Northern European countries. The primary outcome of the study is the Cerebral Performance Category (CPC) score observed at six months after cardiac arrest. CPC scores of 1 and 2 are defined as good neurological outcomes, and CPC scores of 3, 4 and 5 are defined as poor neurological outcomes. The secondary outcomes are as follows: mortality within six months after cardiac arrest, CPC at hospital discharge, Glasgow Coma Scale (GCS) score on day 4, length of stay in ICU and at hospital and the presence of any adverse events such as cerebral, circulatory, respiratory, gastrointestinal, renal, metabolic measures, infection or bleeding. With the planned sample size, we have 80% power to detect a 15% improvement in good neurological outcomes at a two-sided statistical significance level of 5%. DISCUSSION: We present a detailed statistical analysis protocol (SAP) that specifies how primary and secondary outcomes should be evaluated. We also predetermine covariates for adjusted analyses and pre-specify sub-groups for sensitivity analyses. This pre-planned SAP will reduce analysis bias and add validity to the findings of this trial on the effect of length of TTM on important clinical outcomes after cardiac arrest. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01689077 , 17 September 2012.

Randomised comparison of manual compression and FemoSeal™ vascular closure device for closure after femoral artery access coronary angiography: the CLOSure dEvices Used in everyday Practice (CLOSE-UP) study.

AIMS: To compare in a randomised trial the safety and efficacy of the FemoSeal vascular closure device (VCD) versus manual compression (MC) after femoral access coronary angiography (CAG). METHODS AND RESULTS: In 13 months, 1,014 patients were included and 1,001 patients entered analysis. Median [interquartile range] closure time was 8.0 [6-10] minutes after MC versus 1.0 [1-1] minute (p<0.0001) for the FemoSeal VCD. Bed rest for one hour after the closure procedure was recommended in both groups. The primary endpoint of incidence of large groin haematoma was 6.7% in the MC group vs. 2.2% (p=0.002) in the FemoSeal group. The combined endpoint of 14-day adverse vascular events occurred in 1.0% in the MC group vs. 0.6% in the FemoSeal VCD group (p=0.7). Manual compression (OR 3.3, 95% CI: 1.5-7.2, p=0.002), female gender (OR 2.1, 95% CI: 1.1-3.9, p=0.018), and multiple punctures (OR 10.5, 95% CI: 3.2-34.3, p=0.001) were identified as independent predictors of adverse events and large haematomas. CONCLUSIONS: Closure of femoral access after coronary angiography by the FemoSeal vascular closure device was safe, faster, and associated with significantly fewer in-hospital large haematomas as compared to closure by manual compression.

Improving motivation and goal setting for return to work in a population on sick leave: a controlled study.

AIM: Limited knowledge precludes evidence-based interventions targeting return to work among employees on sick leave. The objective of this study was to examine the vocational effect of an intervention focused on motivation, goal setting, and planning of return to work. DESIGN AND METHODS: A total of 2,795 people, across 6 municipalities, on sick leave for at least 21 days received a questionnaire; 1,256 with a self-assessed poor prognosis for fast return to work were eligible for the study. An examination by a specialist in social medicine, followed by additional counselling by a social worker, was offered to 510 residents in two municipalities and accepted by 264 (52%). The goal was to enhance motivation, goal setting, and planning of return to work. Residents in the remaining municipalities (n=746) received the standard case management offered by the municipalities; 845 (67%) persons completed a follow-up questionnaire gathering data on general health and employment status. The duration of the sick leave was analysed by Cox regression, and the chance of being gainfully employed was analysed by logistic regression analysis, both adjusted for several covariates. RESULTS: The intervention neither shortened sick leave periods nor increased the likelihood of gainful employment after one year (OR 0.76; 95% CI 0.45-1.28). CONCLUSIONS: A low-cost counselling programme addressing motivation, goal setting, and planning of return to work did not improve vocational outcomes or reduce the duration of sick leave.

Eating disorder that was diagnosed before pregnancy and pregnancy outcome.

OBJECTIVE: The purpose of this study was to determine the association of an eating disorder that was diagnosed before pregnancy and a preterm delivery and/or the delivery of a low-birth-weight or small-for-gestational-age infant. STUDY DESIGN: This was a register-based follow-up study. We included 302 women who were hospitalized with an eating disorder before pregnancy who were delivered of 504 children and 900 control subjects who were delivered of 1552 children. The association of eating disorders, birth weight, and gestational age was assessed by bivariate and multivariate analyses. RESULTS: The risk of a low-birth-weight infant was twice as high in women with a previous eating disorder compared with women with no such disorder (odds ratio, 2.2; 95% CI, 1.4-3.2). The risk of preterm delivery and a small-for-gestational-age infant was increased to 70% and 80% (odds ratio, 1.7 [95% CI, 1.1-2.6]; odds ratio, 1.8 [95% CI, 1.3-2.4]), respectively. CONCLUSION: Women who were hospitalized for an eating disorder that was diagnosed before pregnancy were at increased risk of impaired pregnancy outcome.