Publications by authors named "Lars Videbæk"

63 Publications

Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction: A Substudy of the Empire HF Randomized Clinical Trial.

JAMA Cardiol 2021 Jan 6. Epub 2021 Jan 6.

Research Unit of Cardiology, Department of Cardiology, Odense University Hospital, Odense, Denmark.

Importance: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve outcomes in patients with heart failure and a reduced ejection fraction (HFrEF). The association with cardiac remodeling has not been investigated.

Objective: To investigate the outcome of the SGLT2i empagliflozin, compared with placebo, on cardiac remodeling in patients with HFrEF.

Design, Setting, And Participants: This exploratory post hoc analysis included participants with stable HFrEF and ejection fractions of 40% or less, who were randomly enrolled in an investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trial in Denmark. Enrollment commenced on June 29, 2017, and continued through September 10, 2019, with the last participant follow-up on December 20, 2019.

Interventions: Randomization (1:1) to empagliflozin (10 mg once daily) or matching placebo in addition to recommended heart failure therapy for 12 weeks.

Main Outcomes And Measures: Efficacy measures were changes from baseline to week 12 in left ventricular end-systolic and end-diastolic volume indexes, left atrial volume index, and left ventricular ejection fraction adjusted for age, sex, type 2 diabetes, and atrial fibrillation. Secondary efficacy measures included changes in left ventricular mass index, global longitudinal strain, and relative wall thickness.

Results: A total of 190 patients were randomized (95 each receiving empagliflozin and placebo), with a mean (SD) age of 64 (11) years; 162 were men (85.3%), 97 (51.1%) had ischemic HFrEF, 24 (12.6%) had type 2 diabetes, and the mean (SD) latest recorded left ventricular ejection fraction was 29% (8%). Of the 190, 186 completed the study. Empagliflozin significantly reduced left ventricular end-systolic volume index (-4.3 [95% CI, -8.5 to -0.1] mL/m2; P = .04), left ventricular end-diastolic volume index (-5.5 [95% CI, -10.6 to -0.4] mL/m2; P = .03), and left atrial volume index (-2.5 [95% CI, -4.8 to -0.1] mL/m2; P = .04) compared with placebo at 12 weeks' follow-up, with no change in left ventricular ejection fraction (1.2% [95% CI, -1.2% to 3.6%]; P = .32). These findings were consistent across subgroups. Of secondary efficacy measures, left ventricular mass index was significantly reduced by empagliflozin (-9.0 [95% CI, -17.2 to -0.8] g/m2; P = .03).

Conclusions And Relevance: In this small, randomized, short-term study, empagliflozin was associated with modest reductions in left ventricular and left atrial volumes with no association with ejection fraction. Effects beyond 12 weeks of SGLT2i use require further study.

Trial Registration: ClinicalTrials.gov Identifier: NCT03198585.
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http://dx.doi.org/10.1001/jamacardio.2020.6827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788505PMC
January 2021

Effect of Empagliflozin on Hemodynamics in Patients With Heart Failure and Reduced Ejection Fraction.

J Am Coll Cardiol 2020 12;76(23):2740-2751

Department of Cardiology, Odense University Hospital, Odense C, Denmark; Faculty of Health Sciences, University of Southern Denmark, Odense C, Denmark; Department of Cardiology, Copenhagen University, Hospital Rigshospitalet, Copenhagen, Denmark.

Background: Inhibition of the sodium-glucose cotransporter-2 (SGLT2i) improves outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but the mechanism by which they improve outcomes remains unclear.

Objectives: This study aimed to investigate the effects of sodium-glucose cotransporter-2 inhibitor empagliflozin on central hemodynamics in patients with HF and HFrEF.

Methods: This investigator-initiated, double-blinded, placebo-controlled, randomized trial enrolled 70 patients with HFrEF from March 6, 2018, to September 10, 2019. Patients were assigned to empagliflozin of 10 mg or matching placebo once daily on guideline-driven HF therapy for 12 weeks. The primary outcome was ratio of pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) at peak exercise after 12 weeks. Patients underwent right-heart catheterization at rest and during exercise at baseline and 12-week follow-up.

Results: Patients with HFrEF, mean age of 57 years, mean left-ventricular ejection fraction, 26%, and 12 (17%) with type 2 diabetes mellitus were randomized. There was no significant treatment effect on peak PCWP/CI (-0.13 mm Hg/l/min/m; 95% confidence interval: -1.60 to 1.34 mm Hg/l/min/m; p = 0.86). Considering hemodynamics over the full range of exercise loads, PCWP was significantly reduced (-2.40 mm Hg; 95% confidence interval: -3.96 to -0.84 mm Hg; p = 0.003), but not CI (-0.09 l/min/m; 95% confidence interval: -0.14 to 0.32 l/min/m; p = 0.448) by empagliflozin. This was consistent among patients with and without type 2 diabetes.

Conclusions: Among patients with stable HFrEF, empagliflozin for 12 weeks reduced PCWP compared with placebo. There was no significant improvement in neither CI nor PCWP/CI at rest or exercise.
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http://dx.doi.org/10.1016/j.jacc.2020.10.005DOI Listing
December 2020

Prevalence and prognostic association of ventricular arrhythmia in non-ischaemic heart failure patients: results from the DANISH trial.

Europace 2021 Apr;23(4):587-595

Department of Cardiology, Amager Hvidovre University Hospital, University of Copenhagen, Kettegaard Alle 30, 2650 Hvidovre, Denmark.

Aims: Improved risk stratification to identify non-ischaemic heart failure patients who will benefit from primary prophylactic implantable cardioverter-defibrillator (ICD) is needed. We examined the potential of ventricular arrhythmia to identify patients who could benefit from an ICD.

Methods And Results: A total of 850 non-ischaemic systolic heart failure patients with left ventricle ≤35% and elevated N-terminal pro-brain natriuretic peptides had a 24-h Holter monitor recording performed. We examined present non-sustained ventricular tachycardia (NSVT), defined as ≥3 consecutive premature ventricular contractions (PVCs) with a rate of ≥100/min, and number of PVCs per hour stratified into low (<30) and high burden (≥30) groups. Outcome measures were overall mortality, sudden cardiac death (SCD), and cardiovascular death (CVD). In total, 193 patients died, 49 from SCD and 125 from CVD. Non-sustained ventricular tachycardia (365 patients) was significantly associated with increased all-cause mortality [hazard ratio (HR) 1.47; 95% confidence interval (CI) 1.07-2.03; P = 0.02] and to CVD (HR 1.89; CI 1.25-2.87; P = 0.003). High burden PVC (352 patients) was associated with increased all-cause mortality (HR1.38; CI 1.00-1.90; P = 0.046) and with CVD (HR 1.78; CI 1.19-2.66; P = 0.005). There was no statistically significant association with SCD for neither NSVT nor PVC. In interaction analyses, neither NSVT (P = 0.56) nor high burden of PVC (P = 0.97) was associated with survival benefit from ICD implantation.

Conclusion: Ventricular arrhythmia in non-ischaemic heart failure patients was associated with a worse prognosis but could not be used to stratify patients to ICD implantation.
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http://dx.doi.org/10.1093/europace/euaa341DOI Listing
April 2021

Atrial fibrillation is a marker of increased mortality risk in nonischemic heart failure-Results from the DANISH trial.

Am Heart J 2021 02 2;232:61-70. Epub 2020 Nov 2.

Department of Cardiology, Amager Hvidovre University Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Atrial fibrillation (AF) in heart failure (HF) patients has been associated with a worse outcome. Similarly, excessive supraventricular ectopic activity (ESVEA) has been linked to development of AF, stroke, and death. This study aimed to investigate AF and ESVEA's association with outcomes and effect of prophylactic implantable cardioverter defibrillator (ICD) implantation in nonischemic HF patients.

Methods: A total of 850 patients with nonischemic HF, left ventricle ejection fraction ≤35%, and elevated N-terminal pro-brain natriuretic peptides underwent 24 hours Holter recording. The presence of AF (≥30 seconds) and ESVEA (≥30 supraventricular ectopic complexes (SVEC) per hour or run of SVEC ≥20 beats) were registered. Outcomes were all-cause mortality, cardiovascular death (CVD), and sudden cardiac death (SCD).

Results: AF was identified in 188 patients (22%) and ESVEA in 84 patients (10%). After 4 years and 11 months of follow-up, a total of 193 patients (23%) had died. AF was associated with all-cause mortality (hazard ratio [HR] 1.44; confidence interval [CI] 1.04-1.99; P = .03) and CVD (HR 1.59; CI 1.07-2.36; P = .02). ESVEA was associated with all-cause mortality (HR 1.73; CI 1.16-2.57; P = .0073) and CVD (HR 1.76; CI 1.06-2.92; P = .03). Neither AF nor ESVEA was associated with SCD. ICD implantation was not associated with an improved prognosis for neither AF (P value for interaction = .17), nor ESVEA (P value for interaction = .68).

Conclusions: Both AF and ESVEA were associated with worsened prognosis in nonischemic HF. However, ICD implantation was not associated with an improved prognosis for either group.
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http://dx.doi.org/10.1016/j.ahj.2020.10.073DOI Listing
February 2021

Self-reported health status and the associated risk of mortality in heart failure: The DANISH trial.

J Psychosom Res 2020 Aug 17;137:110220. Epub 2020 Aug 17.

Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Cardiology, Zealand University Hospital, Roskilde, Denmark.

Objective: To examine the gradual association between self-reported health status and mortality in patients with heart failure (HF) as current research has focused on poor health status and increased risk of mortality.

Method: This is a substudy of the DANISH (Defibrillator Implantation in Patients with Nonischemic Systolic HF) trial in which 1116 patients were randomized to receive or not receive an implantable cardioverter-defibrillator. Health status was assessed by a single question of the Short-Form 36. Patients were classified as having excellent/very good, good, fair (reference) or poor health status. We assessed the association between health status and mortality using multivariable Cox proportional hazard models.

Results: Self-reported health status was completed by 943 (84%) patients at randomization with a median follow-up of 67 months and a health status distribution of; excellent/very good (n = 79, 8%), good (n = 369, 39%), fair (n = 409, 43%), and poor (n = 86, 9%). All-cause mortality (death events/ 100 person-years) occurred with gradual differences according to health status from excellent/ very good (2.14), good (3.74), fair (5.21) to poor health status (5.57). The gradual difference yielded a crude hazard ratio (HR) of 0.40, 95% CI 0.20-0.80 (adjusted HR 0.47 (95% CI 0.23-0.95) for excellent/ very good health status, HR 0.71, 95% CI 0.52-0.97 (adjusted HR 0.78 (95% CI 0.56-1.08) for good health status. Poor being worse than fair health status yielded a crude HR of 1.07, 95% CI 0.67-1.69.

Conclusion: Excellent/very good self-reported health status as assessed by a single question was associated with lower long-term mortality in patients with HF.
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http://dx.doi.org/10.1016/j.jpsychores.2020.110220DOI Listing
August 2020

Twelve weeks of treatment with empagliflozin in patients with heart failure and reduced ejection fraction: A double-blinded, randomized, and placebo-controlled trial.

Am Heart J 2020 10 17;228:47-56. Epub 2020 Jul 17.

Department of Cardiology, Herlev and Gentofte University Hospital, Borgmester Ib Juuls Vej 1, 2730 Herlev, Denmark; Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 København N, Denmark.

Aims: To investigate the effect of the sodium-glucose co-transporter-2 inhibitor empagliflozin on N-terminal pro-b-type natriuretic peptide (NT-proBNP) in patients with heart failure (HF) and reduced ejection fraction (HFrEF).

Methods And Results: Empire HF was an investigator-initiated, multi-center, double-blinded, placebo-controlled, randomized trial. Patients with mildly symptomatic HFrEF, mean (standard deviation (SD)) age 64 (11) years, 85% male, and mean left ventricular ejection fraction 29% (8), on recommended HF therapy were assigned to receive either empagliflozin 10 mg once daily or placebo for 12 weeks. The primary endpoint was the between-group difference in the change of NT-proBNP from baseline to 12 weeks. In total, 95 patients were assigned to empagliflozin and 95 to placebo. No significant difference in the change of NT-proBNP with empagliflozin versus placebo was observed [Empagliflozin: baseline, median (interquartile range (IQR)) 582 (304-1020) pg/mL, 12 weeks, 478 (281-961) pg/mL; Placebo: baseline, 605 (322-1070) pg/mL, 12 weeks, 520 (267-1075) pg/mL, adjusted ratio of change empagliflozin/placebo 0.98; 95% confidence interval (CI) 0.82-1.11, P = 0.7]. Further, no significant difference was observed in accelerometer-measured daily activity level [adjusted mean difference of change, empagliflozin versus placebo, -26.0 accelerometer counts; 95% CI -88.0 to 36.0, P = 0.4] or Kansas City Cardiomyopathy Questionnaire Overall Summary Score [adjusted mean difference of change, empagliflozin versus placebo 0.8; 95% CI -2.3 to 3.9, P = 0.6].

Conclusion: In low-risk patients with HFrEF with mild symptoms and on recommended HF therapy, empagliflozin did not change NT-proBNP after 12 weeks. Further, no change in daily activity level or health status was observed.
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http://dx.doi.org/10.1016/j.ahj.2020.07.011DOI Listing
October 2020

The impact of the glucagon-like peptide-1 receptor agonist liraglutide on natriuretic peptides in heart failure patients with reduced ejection fraction with and without type 2 diabetes.

Diabetes Obes Metab 2020 11 12;22(11):2141-2150. Epub 2020 Aug 12.

Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark.

Aim: To assess the effect of liraglutide, a glucagon-like peptide-1 receptor agonist, on urinary sodium excretion as well as on circulating adrenomedullin and copeptin levels in patients with type 2 diabetes (T2D).

Materials And Methods: In the LIVE study, patients (n = 241) with left ventricular ejection fraction ≤45% were randomized to liraglutide 1.8 mg daily or placebo for 24 weeks, and 30% had a concomitant diagnosis of T2D. Plasma levels of N-terminal brain-natriuretic-peptide (NT-proBNP) (a predefined secondary endpoint), midregional pro-atrial-natriuretic-peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM) and copeptin were measured at baseline and after 24 weeks in this substudy. The potential effect modification of T2D was assessed.

Results: In the eligible subgroup of 231 patients with available biomarkers (115 randomized to liraglutide and 116 to placebo), MR-proANP decreased by 12% (P = .002) and NT-proBNP by 9% (P = .009) during liraglutide treatment compared with placebo at week 24. Interaction with T2D for the treatment effect of change in MR-proANP and NT-proBNP levels was P = .003 and P = .03, respectively. Consequently, in patients with T2D, liraglutide decreased MR-proANP by 27% (P < .001) and NT-proBNP by 25% (P = .02) compared with placebo, whereas no change was observed in patients without T2D. There was no effect of liraglutide on MR-proADM (P = .10) or copeptin (P = .52).

Conclusion: Liraglutide decreased the A- and B-type natriuretic peptides significantly in patients with heart failure with reduced ejection fraction (HFrEF) and concomitant T2D, suggesting a beneficial mechanism of liraglutide in T2D patients with HFrEF.
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http://dx.doi.org/10.1111/dom.14135DOI Listing
November 2020

Heart rate increases in liraglutide treated chronic heart failure patients: association with clinical parameters and adverse events.

Scand Cardiovasc J 2020 Oct 15;54(5):294-299. Epub 2020 Apr 15.

Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.

. Liraglutide, a glucagon-like peptide-1 agonist, is used for treatment of type 2 diabetes and has beneficial cardiovascular properties. However, treatment increases heart rate (HR) and possibly the risk of cardiovascular events in chronic heart failure (CHF) patients. We investigated potential associations between HR changes and clinical, laboratory and echocardiographic parameters and clinical events in liraglutide treated CHF patients. . This was a sub-study of the LIVE study. CHF patients ( = 241) with a left ventricular ejection fraction ≤45% were randomised to 1.8 mg liraglutide daily or placebo for 24 weeks. Electrocardiograms ( = 117) and readouts from cardiac implanted electronic devices ( = 20) were analysed for HR and arrhythmias. . In patients with sinus rhythm (SR), liraglutide increased HR by 8 ± 9 bpm (pulse measurements), 9 ± 9 bpm (ECG measurements) and 9 ± 6 bpm (device readouts) versus placebo (all <.005). Increases in HR correlated with liraglutide dose (=.01). HR remained unchanged in patients without SR. Serious cardiac adverse events were not associated with HR changes. . During 6 months of treatment, HR increased substantially in CHF patients with SR treated with liraglutide but was not associated with adverse events. The long-term clinical significance of increased HR in liraglutide treated CHF patients needs to be determined.
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http://dx.doi.org/10.1080/14017431.2020.1751873DOI Listing
October 2020

Postponement of Death by Pharmacological Heart Failure Treatment: A Meta-Analysis of Randomized Clinical Trials.

Am J Med 2020 06 13;133(6):e280-e289. Epub 2020 Mar 13.

Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.

Background: Outcome postponement has been proposed as an effect measure for preventive drug treatment. It describes the average delay of the investigated unwanted clinical event, achieved by taking medication. The objective was to estimate postponement of death for the following heart failure medications compared to placebo: beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), ARB added to ACE inhibitors, aldosterone antagonists, ivabradine, and renin antagonists.

Methods: We searched Medline and Embase from inception of databases until October 2017. Eligibility criteria were randomized placebo-controlled heart failure trials, including at least 1000 participants, with survival as a prespecified outcome and a minimum trial duration of 1 year. We calculated the outcome postponement by modeling the area between survival curves. This area was modeled on the basis of the hazard ratio or relative risk, the rate of mortality in the placebo group, and the trial duration. All results were standardized to a 3-year trial duration to ensure comparability between treatments.

Results: We identified 14 eligible trials, with a total of 52,014 patients. The results in terms of postponement of all-cause mortality was: beta-blockers 43.7 days (95% confidence interval [95% CI], 20.8-66.5), ACE inhibitors 41.0 days (95% CI, 18.8-63.3), and aldosterone-antagonists 41.3 days (95% CI, 14.3,68.4).

Conclusion: The modeled outcome postponement estimates reiterate beta-blockers, ACE inhibitors, and aldosterone antagonists as the mainstay of heart failure treatment. Furthermore, ivabradine or ARBs added to ACE inhibitors results in no statistically significant gain in survival.
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http://dx.doi.org/10.1016/j.amjmed.2019.11.015DOI Listing
June 2020

Quality of life and the associated risk of all-cause mortality in nonischemic heart failure.

Int J Cardiol 2020 04 4;305:92-98. Epub 2020 Feb 4.

Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Cardiology, Zealand University Hospital, Roskilde, Denmark.

Objectives: To examine the association between health-related quality of life (HRQoL) and mortality in patients with heart failure (HF).

Background: The potential association of HRQoL and mortality in patients with HF is unclear. We investigated this association in The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators (ICD) in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH).

Methods: In DANISH, a total of 1116 patients with non-ischemic systolic HF on guideline-recommended therapy were randomized to ICD therapy or usual clinical care. HRQoL was assessed at randomization using the disease-specific Minnesota Living with Heart Failure Questionnaire (MLHFQ, 0-105, high score indicating worse HRQoL). Multivariable Cox proportional hazard models were used to compare hazard ratios (HR) for all-cause mortality according to MLHFQ above or below 45, as recommended by a recent meta-analysis, to identify patients with poor HRQoL.

Results: HRQoL was completed by 935 (84%) patients at baseline with a median follow-up of 67 months (IQR 47-83). Patients with poor HRQoL (MLHFQ score > 45, median 60 (IQR 53-71),n = 350) had a higher incidence of all-cause mortality than patients with moderate/good HRQoL (MLHFQ ≤45, median 23 (IQR 13-33), n = 585), respectively 26% vs. 18% with an unadjusted HR of 1.57 (95% CI 1.19-2.08, p = .002), and an adjusted HR of 1.39 (95% CI 1.01-1.91, p = .04).

Conclusion: Poor HRQoL was associated with an increased risk of all-cause mortality after adjustment for traditional risk factors.

Clinical Trial Registration: https: //clinicaltrials.gov/ct2/show/NCT00542945(DANISH).
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http://dx.doi.org/10.1016/j.ijcard.2020.02.008DOI Listing
April 2020

Duration of Heart Failure and Effect of Defibrillator Implantation in Patients With Nonischemic Systolic Heart Failure.

Circ Heart Fail 2019 09 10;12(9):e006022. Epub 2019 Sep 10.

Faculty of Health and Medical Sciences (M.B.E., N.E.B., F.G., J.H.S., L.K., J.J.T.), University of Copenhagen, Denmark.

Background: Patients with nonischemic systolic heart failure (HF) have increased risk of sudden cardiac death (SCD) and death from progressive pump failure. Whether the risk of SCD changes over time is unknown. We seek here to investigate the relation between duration of HF, mode of death, and effect of implantable cardioverter-defibrillator implantation.

Methods And Results: We examined the risk of all-cause death and SCD according to the duration of HF among patients with nonischemic systolic HF enrolled in the DANISH (Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality). In all, 1116 patients were included. Patients were divided according to quartiles of HF duration (≤8, 9≤18, 19≤65, and ≥66 months). Patients with the longest duration of HF were older, more often men, had more comorbidity, and more often received a cardiac resynchronization therapy device. Doubling of HF duration was an independent predictor of both all-cause mortality (hazard ratio [HR], 1.27; 95% CI, 1.17-1.38; P<0.0001), and SCD (HR, 1.29; 95% CI, 1.11-1.50; P=0.0007). The proportion of deaths caused by SCD was not different between HF quartiles (P=0.91), and the effect of implantable cardioverter-defibrillator implantation on all-cause mortality was not modified by the duration of HF (P=0.59).

Conclusions: Duration of HF predicted both all-cause mortality and risk of SCD independently of other risk indicators. However, the proportion of death caused by SCD did not change with longer duration of HF, and the effect of implantable cardioverter-defibrillator was not modified by the duration of HF.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00542945.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006022DOI Listing
September 2019

Association between left ventricular diastolic function and right ventricular function and morphology in asymptomatic aortic stenosis.

PLoS One 2019 30;14(7):e0215364. Epub 2019 Jul 30.

Department of Cardiology Odense University Hospital, Odense, Denmark.

Background: Aortic stenosis (AS) is a progressive disease in which left ventricular (LV) diastolic dysfunction is common. However, the association between diastolic dysfunction and right ventricular (RV) loading conditions and function has not been investigated in asymptomatic AS patients.

Methods And Findings: A total of 41 patients underwent right heart catheterization and simultaneous echocardiography at rest and during maximal supine exercise, stratified according to resting diastolic function. Cardiac chamber size and morphology was assessed using cardiac magnetic resonance imaging (cMRI). RV stroke work index, pulmonary artery (PA) compliance, PA elastance, PA pulsatility index, and right atrial pressure (RAP) were calculated at rest and maximal exercise. Ten patients (24%) had normal LV filling pattern, 20 patients (49%) had grade 1, and 11 patients (27%) had grade 2 diastolic dysfunction. Compared to patients with normal diastolic filling pattern, patients with diastolic dysfunction had lower RV end-diastolic volume (66 ± 11 ml/m2 vs. 79 ± 15 ml/m2, p = 0.02) and end-systolic volume (25 ± 7 ml/m2 vs. 32 ± 9 ml/m2, p = 0.04). An increase in mean RAP to ≥15 mmHg following exercise was not seen in patients with normal LV filling, compared to 4 patients (20%) with mild and 7 patients (63%) with moderate diastolic dysfunction (p = 0.003). PA pressure and PA elastance was increased in grade 2 diastolic dysfunction and correlated with RV volume and maximal oxygen consumption (r = -0.71, p < 0.001).

Conclusions: Moderate diastolic dysfunction is associated with increased RV afterload (elastance), which is compensated at rest, but is associated with increased RAP and inversely related to maximal oxygen consumption during maximal exercise.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215364PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667115PMC
February 2020

The effect of implantable cardioverter-defibrillator in patients with diabetes and non-ischaemic systolic heart failure.

Europace 2019 Aug;21(8):1203-1210

Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, Denmark.

Aims: Implantable cardioverter-defibrillator (ICD) implantation reduce the risk of sudden cardiac death, but not all-cause death in patients with non-ischaemic systolic heart failure (HF). Whether co-existence of diabetes affects ICD treatment effects is unclear.

Methods And Results: We examined the effect of ICD implantation on risk of all-cause death, cardiovascular death, and sudden cardiac death (SCD) according to diabetes status at baseline in the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischaemic Systolic Heart Failure on Mortality (DANISH) trial. Outcomes were analysed by use of cumulative incidence curves and Cox regressions models. Of the 1116 patients enrolled, 211 (19%) had diabetes at baseline. Patients with diabetes were more obese, had worse kidney function and more were in New York Heart Association Class III/IV. The risk of device infections and other complications in the ICD group was similar among patients with and without diabetes (6.1% vs. 4.6% P = 0.54). Irrespective of treatment group, diabetes was associated with higher risk of all-cause death, cardiovascular death, and SCD. The treatment effect of ICD in patients with diabetes vs. patients without diabetes was hazard ratio (HR) = 0.92 (0.57-1.50) vs. HR = 0.85 (0.63-1.13); Pinteraction = 0.60 for all-cause mortality, HR = 0.99 (0.58-1.70) vs. HR = 0.70 (0.48-1.01); Pinteraction = 0.25 for cardiovascular death, and HR = 0.81 (0.35-1.88) vs. HR = 0.40 (0.22-0.76); Pinteraction = 0.16 for sudden cardiac death.

Conclusion: Among patients with non-ischaemic systolic HF, diabetes was associated with higher incidence of all-cause mortality, primarily driven by cardiovascular mortality including SCD. Treatment effect of ICD therapy was not significantly modified by diabetes which might be due to lack of power.
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http://dx.doi.org/10.1093/europace/euz114DOI Listing
August 2019

Risk Models for Prediction of Implantable Cardioverter-Defibrillator Benefit: Insights From the DANISH Trial.

JACC Heart Fail 2019 08 10;7(8):717-724. Epub 2019 Jul 10.

Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.

Objectives: This study aims to identify patients with nonischemic heart failure who are more likely to benefit from implantable cardioverter-defibrillator (ICD) implantation by use of established risk prediction models.

Background: It has been debated whether an ICD for primary prevention reduces mortality in patients with nonischemic heart failure.

Methods: The Seattle Heart Failure Model (SHFM) predicts all-cause mortality whereas the Seattle Proportional Risk Model (SPRM) predicts the proportion of sudden cardiac death (SCD) versus nonsudden death, with a higher score indicating a greater proportion of SCD. We report the effect of ICD implantation on all-cause mortality and SCD, according to median SPRM and SHFM scores in all 1,116 patients enrolled in the DANISH (Danish study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on mortality) trial.

Results: Among patients with an SPRM score above the median (n = 558), ICD implantation reduced all-cause mortality (hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.43 to 0.94), whereas patients with lower SPRM scores (n = 558) had no effect (HR: 1.08; 95% CI: 0.78 to 1.49, p for interaction = 0.04). The corresponding numbers for SHFM score above and below the median were HR: 0.84; 95% CI: 0.62 to 1.13 and HR: 0.82; 95% CI: 0.53 to 1.28, respectively (p for interaction = 0.980). In 177 patients with upper SPRM/upper SHFM, ICD implantation reduced all-cause mortality (HR: 0.45; 95% CI: 0.25 to 0.80) when compared to 381 patients with lower SPRM/upper SHFM (HR: 1.09; 95% CI: 0.76 to 1.55) (p for interaction <0.001).

Conclusions: Nonischemic heart failure patients with high predicted relative likelihood of SCD, as estimated by higher SPRM score, seemed to benefit from ICD implantation. (DANISH [Danish ICD Study in Patients With Ditaled Cardiomyopathy]; NCT00542945).
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http://dx.doi.org/10.1016/j.jchf.2019.03.019DOI Listing
August 2019

Association between Type D personality and outcomes in patients with non-ischemic heart failure.

Qual Life Res 2019 Nov 10;28(11):2901-2908. Epub 2019 Jul 10.

Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Purpose: The "distressed" (Type D) personality trait has been reported to be over-represented in patients with heart failure (HF) compared to the background population and may provide prognostic information for mortality. We examined the association between Type D personality and outcomes in the DANISH trial (The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators in Patients with Non-ischemic Systolic Heart Failure on Mortality).

Methods: The DANISH trial included a total of 1116 patients with non-ischemic HF on guideline-recommended therapy. Type D personality was assessed with the Type D Scale (DS14) at baseline and investigated through follow-up accordingly. Multivariable Cox proportional hazard models were used to compare hazard ratios (HR) of cardiovascular and all-cause mortality.

Results: Type D personality assessment was completed by 873 (78%) patients at baseline and Type D personality was found in 120 (14%) patients. The median follow-up was 67 months (interquartile range [IQR] 48-83). Among patients with versus without Type D personality, 22% versus 19% died from all-cause yielding similar incidence rates of 4.62 (95% CI 3.14-6.87) versus 3.95 (95% CI 3.37-4.66) per 100 person-years. The adjusted risk of all-cause mortality was not significantly different in patients with versus without Type D personality with an adjusted HR of 1.31 (95% CI 0.84-2.03, p = 0.23) with similar results for cardiovascular death (HR 1.46 (95% CI 0.88-2.44, p = 0.15).

Conclusion: Type D personality was not significantly associated with increased risk of all-cause mortality or cardiovascular death in patients with non-ischemic HF.
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http://dx.doi.org/10.1007/s11136-019-02241-6DOI Listing
November 2019

Empagliflozin in heart failure patients with reduced ejection fraction: a randomized clinical trial (Empire HF).

Trials 2019 Jun 21;20(1):374. Epub 2019 Jun 21.

Department of Cardiology, Herlev-Gentofte Hospital, Herlev Ringvej 75, 2730, Herlev, DK, Denmark.

Background: Data from recent cardiovascular outcome trials in patients with type 2 diabetes (T2D) suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors can prevent development of heart failure (HF) and prolong life in patients without HF. Ongoing event-driven trials are investigating whether the same effect is present in patients with well-defined HF. The mechanism behind the effect of SGLT2 inhibitors in patients with T2D and the potential effect in patients with overt HF is presently unknown.

Methods: This is a randomized, double-blinded, placebo-controlled, parallel group, clinical trial including HF patients with reduced left ventricular ejection fraction (HFrEF) with an ejection fraction ≤ 40% on optimal therapy recruited from specialized HF clinics in Denmark. The primary aim is to investigate the effect of the SGLT2 inhibitor empagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP). Secondary endpoints include cardiac biomarkers, function and hemodynamics, metabolic and renal parameters, daily activity level, and quality of life. Patients are assigned 1:1 to 90 days treatment with empagliflozin 10 mg daily or placebo. Patients with T2D are required to be on recommended doses of anti-glycemic therapy with a hemoglobin A1c (HbA1c) of 6.5-10.0% (48-86 mmol/mol). To show a between-group difference in the change of NT-proBNP of 30%, a total of 189 patients will be included.

Discussion: The Empire HF trial will elucidate the effects and modes of action of empagliflozin in HFrEF patients with and without T2D and provide important mechanistic data which will complement ongoing event-driven trials.

Trial Registration: Clinicaltrialsregister.eu, EudraCT Number 2017-001341-27 . Registered on 29 May 2017. ClinicalTrials.gov, NCT03198585 . Registered on 26 June 2017.
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http://dx.doi.org/10.1186/s13063-019-3474-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588901PMC
June 2019

End-systolic wall stress in aortic stenosis: comparing symptomatic and asymptomatic patients.

Open Heart 2019;6(1):e001021. Epub 2019 Apr 9.

Cardiology, Odense University Hospital, Odense, Denmark.

Aims: In aortic stenosis (AS), there is poor association between symptoms and conventional markers of AS severity or left ventricular (LV) systolic function. This may reflect that symptoms arise from LV diastolic dysfunction or that aortic valve area (AVA) and transvalvular gradient do not reflect afterload. We aimed to study the impact of afterload (end-systolic wall stress [ESWS]) on the presence of symptoms in AS and to test whether symptoms are related to increased ESWS or LV remodelling.

Methods And Results: In a prospective study, ESWS was estimated by measuring LV wall thickness from MRI and estimated LV end systolic pressure from echocardiographic mean gradient and systolic blood pressure in 78 patients with severe AS scheduled for aortic valve replacement and 91 patients with asymptomatic severe AS. Symptomatic patients had lower indexed AVA (0.40±0.11 vs 0.45±0.09 cm/m, p=0.009). They had undergone more extensive remodelling (MRI LV mass index [LVMi]: 85±24 vs 69±17 g/m, p<0.0001), had higher tricuspid regurgitant gradient (24±8 mm Hg vs 19 ± 7 mm Hg, p=0.0001) and poorer global longitudinal strain (-15.6±3.8 vs -19.9±3.2%, p<0.0001). ESWS was higher among symptomatic patients (96±51 vs 76±25 kdynes/cm, p=0.003). Multivariate logistic regression identified echocardiographic relative wall thickness, tricuspid gradient, mitral deceleration time, early diastolic strain rate, MRI LVMi, MRI LV end-diastolic volume index and ESWS as independently associated with being symptomatic.

Conclusion: ESWS can be estimated from multimodality imaging combining MRI and echocardiography. It is correlated with LV remodelling and neurohormonal activation and is independently associated with symptomatic status in AS.
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http://dx.doi.org/10.1136/openhrt-2019-001021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519411PMC
April 2019

Long-Term Risk of Heart Failure in Breast Cancer Patients After Adjuvant Chemotherapy With or Without Trastuzumab.

JACC Heart Fail 2019 03;7(3):217-224

Department of Cardiology, Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.

Objectives: This study sought to evaluate the long-term risk of developing heart failure (HF) in patients receiving trastuzumab therapy.

Background: Trastuzumab has improved the prognosis in patients with HER2-positive breast cancer, but it can induce left ventricular dysfunction with reduced ejection fraction or HF during treatment. The long-term risk of HF is less well described.

Methods: In a nationwide Danish retrospective cohort study, 9,901 patients scheduled for adjuvant treatment for early-stage breast cancer were identified in the Danish Breast Cancer Cooperative Group database. Of these, 8,812 patients (25% HER2-positive; 51.7 ± 8.5 years of age) received chemotherapy including anthracycline; and if they were HER2 positive, trastuzumab was added. The primary endpoint was a diagnosis of HF assessed before and after 18 months in a landmark analysis to distinguish short- and long-term risks.

Results: Median follow-up was 5.4 years (interquartile range [IQR]: 4.1 to 6.8 years). In the trastuzumab group, 60 patients had HF by 9 years versus 51 in the group who were treated with chemotherapy alone, corresponding to incidence rates per 1,000 patient years of 5.3 (95% confidence interval [CI]: 4.1 to 6.8) versus 1.4 (95% CI: 1.1 to 1.8), respectively. The cumulative incidence of HF was higher in the trastuzumab group at both the short- and long-term (p < 0.01), yielding adjusted hazard ratios of 8.7 (95% CI: 4.6 to 16.5; p < 0.01) for early HF and 1.9 (95% CI: 1.2 to 3.3; p = 0.01) for late HF associated with trastuzumab treatment.

Conclusions: Trastuzumab treatment is associated with a 2-fold increased risk of late HF compared with chemotherapy treatment alone.
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http://dx.doi.org/10.1016/j.jchf.2018.09.001DOI Listing
March 2019

The impact of implantable cardioverter-defibrillator implantation on health-related quality of life in the DANISH trial.

Europace 2019 Jun;21(6):900-908

Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark.

Aim: The Danish Study to Assess the Efficacy of Implantable Cardioverter-Defibrillators (ICD) in Patients with Non-ischaemic Systolic Heart Failure (HF) on Mortality (DANISH) found no overall effect on all-cause mortality. The effect of ICD implantation on health-related quality of life (HRQoL) remains to be established as previous trials have demonstrated conflicting results. We investigated the impact of ICD implantation on HRQoL in patients with non-ischaemic systolic HF, a prespecified secondary endpoint in DANISH.

Methods And Results: In DANISH, a total of 1116 patients with non-ischaemic systolic HF were randomly assigned (1:1) to ICD implantation or usual clinical care (control). Patients completed disease-specific HRQoL as assessed by Minnesota Living with Heart Failure Questionnaire (MLHFQ; 0-105, high indicating worse). Changes in HRQoL 8 months after randomization were assessed with a mixed-effects model. At randomization, MLHFQ was completed by 935 (84%) patients (n = 472 in the ICD group and n = 463 in the control group) and was reassessed in 274 (58%) and 292 (63%) patients, respectively after 8 months for the primary analysis. Patients in the ICD group vs. the control group had similar improvements in MLHFQ after 8 months [least square mean -7.0 vs. -4.2 (P = 0.13)]. A clinically relevant improvement (decrease ≥5) in the MLHFQ overall score at 8 months was observed in 151 patients in the ICD group and 148 patients in the control group [55% vs. 51%, respectively (P = 0.25)].

Conclusion: Implantable cardioverter-defibrillator implantation in patients with non-ischaemic systolic HF did not significantly alter HRQoL compared with patients randomized to usual clinical care.
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http://dx.doi.org/10.1093/europace/euz018DOI Listing
June 2019

Effect of family nursing therapeutic conversations on health-related quality of life, self-care and depression among outpatients with heart failure: A randomized multi-centre trial.

Patient Educ Couns 2018 08 7;101(8):1385-1393. Epub 2018 Mar 7.

COHERE, Department of Business and Economics, University of Southern Denmark, Odense, Denmark.

Objective: To evaluate the short-term (3 months) effects of family nursing therapeutic conversations (FNTC) on health-related quality of life, self-care and depression in outpatients with Heart failure (HF).

Methods: A randomised multi-centre trial was conducted in three Danish HF clinics. The control group (n = 167) received usual care, and the intervention group (n = 180) received FNTCs as supplement to usual care. Primary outcome was clinically significant changes (6 points) in Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score between groups. Secondary outcomes were changes in self-care behaviour and depression scores. Data were assessed before first consultation and repeated after three months.

Results: No statistically significant difference was found in the change of KCCQ, self-care and depression scores between the groups. KCCQ scores of patients in the FNTC group changed clinically significant in seven domains, compared to one domain in the control group, with the highest improvement in self-efficacy, social limitation and symptom burden.

Conclusion: FNTC was not superior to standard care of patients with HF regarding health-related quality of life, self-care and depression.

Implication For Practice: Addressing the impact of the disease on the family, might improve self-efficacy, social limitation and symptom burden in patients with heart failure.
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http://dx.doi.org/10.1016/j.pec.2018.03.006DOI Listing
August 2018

[Management of cardiovascular complications secondary to medical treatment of cancer].

Ugeskr Laeger 2018 Feb;180(7)

As the prognoses of both heart and cancer patients have improved along with a longer life expectancy in the general population, the prevalence of both heart- and cancer diseases is increasing. Thus, a larger proportion of cancer patients will have cardiovascular co-morbidity and an increased risk of cardiovascular complications during and after cancer treatment. In this article, the current knowledge on the prevention, monitoring and treatment of cardiotoxicity induced by medical anti-cancer treatment with focus on anthracyclines, trastuzumab and 5-fluorouracil is described.
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February 2018

Relation of Left Atrial Size, Cardiac Morphology, and Clinical Outcome in Asymptomatic Aortic Stenosis.

Am J Cardiol 2017 Nov 16;120(10):1877-1883. Epub 2017 Aug 16.

Department of Cardiology, Odense University Hospital, 5000 C Odense, Denmark.

Left atrial (LA) dilation in asymptomatic severe aortic stenosis (AS) may be an indicator of advanced disease. We aimed to investigate the association between LA volume index and left ventricular (LV) morphology assessed with cardiac magnetic resonance imaging (cMRI), and to assess the association with cardiac events. Ninety-two asymptomatic patients with aortic valve area <1 cm, aortic peak jet velocity >3.5 m/s, and ejection fraction ≥50% were prospectively enrolled and divided according to echocardiographic-derived LA volume index  <35 ml/m. Patients underwent echocardiography, cMRI, exercise testing, and were followed for the composite end point of death, readmission, or aortic valve replacement. Aortic valve area index was similar (0.45 ± 0.08 cm/m vs 0.45 ± 0.09 cm/m, p = 0.85) in patients with a dilated and normal LA. On cMRI patients with dilated LA were characterized by higher LV mass index (73 ± 17 g/m vs 66 ± 16 g/m, p = 0.03), increased right ventricle (70 ± 14 ml/m vs 63 ± 12 ml/m, p = 0.01) and LV end-diastolic volume index (84 ± 18 ml/m vs 77 ± 16 ml/m, p = 0.05), and higher brain natriuretic peptide. Late enhancement pattern was similar. During follow-up 20 events were recorded in patients with LA dilation compared with 8 in patients with normal LA (adjusted hazard ratio 2.77, 95% confidence interval 1.19 to 6.46, p = 0.02); also B-type natriuretic peptide  >125 pg/ml was associated with adverse outcome (adjusted hazard ratio 3.63, 95% confidence interval interval 1.28 to 10.32, p = 0.02). LA dilation is associated with LV remodeling and provides prognostic information in severe asymptomatic AS.
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http://dx.doi.org/10.1016/j.amjcard.2017.07.101DOI Listing
November 2017

Age and Outcomes of Primary Prevention Implantable Cardioverter-Defibrillators in Patients With Nonischemic Systolic Heart Failure.

Circulation 2017 Nov 6;136(19):1772-1780. Epub 2017 Sep 6.

From Department of Cardiology, Rigshospitalet, University of Copenhagen, Denmark (M.B.E., F.G., R.V., C.H., J.H.S., D.E.H., S.P., L.K., J.J.T.); Department of Cardiology, Aarhus University Hospital, Denmark (J.C.N., H.E.); Department of Cardiology, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark (J.H., N.E.B.); Department of Cardiology, Odense University Hospital, Denmark (L.V., A.B.); Department of Health, Science and Technology (E.K., A.M.T., C.T.-P.) and Clinical Institute (N.E.B.), Aalborg University, Denmark; Department of Cardiology and Epidemiology/Biostatistics, Aalborg University Hospital, Denmark (E.K., A.M.T., C.T.-P.); Analysis Group Inc, Boston, MA (J.S.); Department of Cardiology, Zealand University Hospital, Roskilde, Denmark (L.L.O.); Frederiksberg Heart Clinic, Denmark (P.H.); Department of Cardiology, Lillebaelt Hospital, Vejle, Denmark (F.H.S.); Department of Cardiology, Odense University Hospital, Svendborg, Denmark (K.E.); and Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark (J.J.T.).

Background: The DANISH study (Danish Study to Assess the Efficacy of ICDs [Implantable Cardioverter Defibrillators] in Patients With Non-Ischemic Systolic Heart Failure on Mortality) did not demonstrate an overall effect on all-cause mortality with ICD implantation. However, the prespecified subgroup analysis suggested a possible age-dependent association between ICD implantation and mortality with survival benefit seen only in the youngest patients. The nature of this relationship between age and outcome of a primary prevention ICD in patients with nonischemic systolic heart failure warrants further investigation.

Methods: All 1116 patients from the DANISH study were included in this prespecified subgroup analysis. We assessed the relationship between ICD implantation and mortality by age, and an optimal age cutoff was estimated nonparametrically with selection impact curves. Modes of death were divided into sudden cardiac death and nonsudden death and compared between patients younger and older than this age cutoff with the use of χ analysis.

Results: Median age of the study population was 63 years (range, 21-84 years). There was a linearly decreasing relationship between ICD and mortality with age (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.003-1.06; =0.03). An optimal age cutoff for ICD implantation was present at ≤70 years. There was an association between reduced all-cause mortality and ICD in patients ≤70 years of age (HR, 0.70; 95% CI, 0.51-0.96; =0.03) but not in patients >70 years of age (HR, 1.05; 95% CI, 0.68-1.62; =0.84). For patients ≤70 years old, the sudden cardiac death rate was 1.8 (95% CI, 1.3-2.5) and nonsudden death rate was 2.7 (95% CI, 2.1-3.5) events per 100 patient-years, whereas for patients >70 years old, the sudden cardiac death rate was 1.6 (95% CI, 0.8-3.2) and nonsudden death rate was 5.4 (95% CI, 3.7-7.8) events per 100 patient-years. This difference in modes of death between the 2 age groups was statistically significant (=0.01).

Conclusions: In patients with systolic heart failure not caused by ischemic heart disease, the association between the ICD and survival decreased linearly with increasing age. In this study population, an age cutoff for ICD implantation at ≤70 years yielded the highest survival for the population as a whole.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00542945.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028829DOI Listing
November 2017

Risk of heart disease in relation to radiotherapy and chemotherapy with anthracyclines among 19,464 breast cancer patients in Denmark, 1977-2005.

Radiother Oncol 2017 05 30;123(2):299-305. Epub 2017 Mar 30.

Department of Oncology, Odense University Hospital, Denmark; Institute of Clinical Research, University of Southern Denmark, Denmark. Electronic address:

Background And Purpose: The risk of heart disease subsequent to breast cancer radiotherapy was examined with particular focus on women receiving anthracycline-containing chemotherapy.

Material And Methods: Women diagnosed with early-stage breast cancer in Denmark, 1977-2005, were identified from the register of the Danish Breast Cancer Cooperative Group, as was information on cancer-directed treatment. Information on heart disease was sought from the Danish National Patient and Cause of Death Registries. Incidence rate ratios were estimated comparing left-sided with right-sided cancer (IRR, LvR), stratified by calendar year, age, and time since breast cancer radiotherapy.

Results: Among 19,464 women receiving radiotherapy, the IRR, LvR, was 1.11 (95% CI 1.03-1.20, p=0.005) for all heart disease and among those also receiving anthracyclines the IRR, LvR, was 1.32 (95% CI 1.02-1.70, p=0.03). This risk was highest if the treatment was given before the age of 50years (IRR, LvR, 1.44, (95% CI 1.04-2.01) but there was no significant trend with age or time since treatment.

Conclusions: Radiotherapy for left-sided breast cancer is associated with a higher risk of heart disease than for right-sided with the largest increases seen in women who also received anthracycline-containing chemotherapy.
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http://dx.doi.org/10.1016/j.radonc.2017.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446317PMC
May 2017

Association Between Left Atrial Dilatation and Invasive Hemodynamics at Rest and During Exercise in Asymptomatic Aortic Stenosis.

Circ Cardiovasc Imaging 2016 Oct;9(10)

From the Department of Cardiology, Odense University Hospital, Denmark (N.L.C., J.S.D., R.C.-S., R.B., E.V.S., L.V., J.E.M.); Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense (K.J.), and Department of Cardiology, Lillebaelt Hospital, Vejle, Denmark (F.H.S.).

Background: Transition from an asymptomatic to symptomatic state in severe aortic stenosis is often difficult to assess. Identification of a morphological sign of increased hemodynamic load may be important in asymptomatic aortic stenosis to identify patients at risk.

Methods And Results: Thirty-nine patients with asymptomatic severe aortic stenosis (aortic valve area <1 cm, peak jet velocity >3.5 m/s) underwent exercise testing with simultaneous invasive hemodynamic monitoring and Doppler echocardiography. Cardiac index, pulmonary artery pressure, and pulmonary capillary wedge pressure (PCWP) were recorded. Patients were followed up for the composite end point of death, unplanned hospitalization, or aortic valve replacement. Patients were stratified into 2 groups according to left atrial (LA) volume index ≥35 mL/m. In 25 patients (64%) LA volume index was ≥35 mL/m. Aortic valve area was similar between groups (0.81±0.15 versus 0.84±0.18 cm; P=0.58). PCWP was higher at rest and during exercise in patients with LA volume index ≥35 mL/m (P<0.01), despite similar cardiac index. At rest, PCWP was <12 mm Hg in 11 patients (44%) with LA dilatation, whereas PCWP was <25 mm Hg in 1 patient (4%) with exercise. LA volume index and E/e' predicted exercise PCWP>30 mm Hg with areas under the receiver operating curve of 0.75 and 0.84, respectively. During follow-up, 14 cardiac events were recorded. LA volume was associated with a hazard ratio of 1.90 (95% confidence interval, 0.92-4.15).

Conclusions: LA size reflects hemodynamic burden in patients with asymptomatic severe aortic stenosis. Quantitative measurements of LA and diastolic function are associated with left ventricular filling pressures with exercise and could be used to identify asymptomatic patients with increased hemodynamic burden.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02395107.
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http://dx.doi.org/10.1161/CIRCIMAGING.116.005156DOI Listing
October 2016

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.

Eur J Heart Fail 2017 01 28;19(1):69-77. Epub 2016 Oct 28.

Steno Diabetes Center, Gentofte, Denmark.

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.
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http://dx.doi.org/10.1002/ejhf.657DOI Listing
January 2017

Risk of pacemaker or implantable cardioverter defibrillator after radiotherapy for early-stage breast cancer in Denmark, 1982-2005.

Radiother Oncol 2017 01 15;122(1):60-65. Epub 2016 Sep 15.

Department of Oncology, Odense University Hospital, Denmark; Institute of Clinical Research, University of Southern Denmark, Denmark.

Background And Purpose: To examine the risk of cardiac conduction abnormalities or severe ventricular arrhythmias requiring implantation of a cardiac implantable electronic device (CIED), either a pacemaker or an implantable cardioverter-defibrillator, subsequent to breast cancer (BC) radiotherapy (RT).

Material And Methods: All women treated for early-stage BC in Denmark from 1982 to 2005 were identified from the Danish Breast Cancer Cooperative Group. By record linkage to the Danish Pacemaker and ICD Registry information was retrieved on CIED implants subsequent to RT. Standardized incidence ratios (SIR) of CIED implantation were estimated for women receiving RT and compared to women not receiving RT for BC. Uni- and multivariate Poisson regression models were used to estimate incidence rate ratios (IRR) among irradiated women compared to non-irradiated.

Results: Of 44,423 BC patients, 179 had a CIED implanted among 18,251 women who received RT, and 401 had a CIED in 26,172 who did not receive RT. The unadjusted IRR was 1.09 (0.91-1.30 95% CI) for CIED implants among women receiving RT compared to non-irradiated women and the IRR was 1.13 (0.93-1.38 95% CI) when adjustments were made.

Conclusions: BC RT as practiced in Denmark in 1982-2005 did not increase the risk of CIED implants. This indicates that RT for BC does not increase the risk of severe ventricular arrhythmias or cardiac conduction abnormalities.
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http://dx.doi.org/10.1016/j.radonc.2016.08.024DOI Listing
January 2017

Rationale, design, and baseline characteristics of the DANish randomized, controlled, multicenter study to assess the efficacy of Implantable cardioverter defibrillators in patients with non-ischemic Systolic Heart failure on mortality (DANISH).

Am Heart J 2016 Sep 4;179:136-41. Epub 2016 Jul 4.

Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: The effect of an implantable cardioverter defibrillator (ICD) in patients with symptomatic systolic heart failure (HF) caused by coronary artery disease is well documented. However, the effect of primary prophylactic ICDs in patients with systolic HF not due to coronary artery disease is much weaker. In addition, HF management has improved, since the landmark ICD trials and a large proportion of patients now receive cardiac resynchronization therapy (CRT) where the effect of ICD treatment is unknown.

Methods: In the DANISH study, 1,116 patients with symptomatic systolic HF not caused by coronary artery disease have been randomized to receive an ICD or not, in addition to contemporary standard therapy. The primary outcome of the trial is time to all-cause death. Follow-up will continue until June 2016 with a median follow-up period of 5 years. Baseline characteristics show that enrolled patients are treated according to current guidelines. At baseline, 97% of patients received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 92% received a β-blocker, 58% a mineralocorticoid receptor antagonist, and 58% were scheduled to receive CRT. Median age was 63 years (range, 21-84 years) at baseline, and 28% were women.

Conclusion: DANISH will provide pertinent information about the effect on all-cause mortality of a primary prophylactic ICD in patients with symptomatic systolic HF not caused by coronary artery disease on contemporary standard therapy including CRT.
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http://dx.doi.org/10.1016/j.ahj.2016.06.016DOI Listing
September 2016

Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure.

N Engl J Med 2016 09 27;375(13):1221-30. Epub 2016 Aug 27.

From the Department of Cardiology, Rigshospitalet (L.K., J.J.T., F.G., R.V., C.H., J.H.S., D.E.H., S.P.), and the Department of Cardiology, Bispebjerg Hospital (J.J.T.), University of Copenhagen, Copenhagen; the Department of Cardiology, Aarhus University Hospital, Aarhus (J.C.N., H.E.); the Department of Cardiology, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup (J.H., N.E.B.); the Department of Cardiology, Odense University Hospital, Odense (L.V., A.B.); the Department of Cardiology, Aalborg University Hospital (E.K., A.M.T., C.T.-P.), and the Clinical Institute, Aalborg University (N.E.B.), Aalborg; the Department of Cardiology, Zealand University Hospital, Roskilde (G.J.); Frederiksberg Heart Clinic, Frederiksberg (P.H.); the Department of Cardiology, Lillebaelt Hospital, Vejle (F.H.S.); and the Department of Cardiology, Odense University Hospital, Svendborg (K.E.) - all in Denmark.

Background: The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT).

Methods: In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death.

Results: After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29).

Conclusions: In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).
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http://dx.doi.org/10.1056/NEJMoa1608029DOI Listing
September 2016

Prehospital lung ultrasound for the diagnosis of cardiogenic pulmonary oedema: a pilot study.

Scand J Trauma Resusc Emerg Med 2016 Aug 2;24:96. Epub 2016 Aug 2.

Mobile Emergency Care Unit, Odense University Hospital, Odense, Denmark.

Background: An improved prehospital diagnostic accuracy of cardiogenic pulmonary oedema could potentially improve initial treatment, triage, and outcome. A pilot study was conducted to assess the feasibility, time-use, and diagnostic accuracy of prehospital lung ultrasound (PLUS) for the diagnosis of cardiogenic pulmonary oedema.

Methods: A prospective observational study was conducted in a prehospital setting. Patients were included if the physician based prehospital mobile emergency care unit was activated and one or more of the following two were present: respiratory rate >30/min., oxygen saturation <90 %. Exclusion criteria were: age <18 years, permanent mental disability or PLUS causing a delay in life-saving treatment or transportation. Following clinical assessment PLUS was performed and presence or absence of interstitial syndrome was registered. Audit by three physicians using predefined diagnostic criteria for cardiogenic pulmonary oedema was used as gold standard.

Results: A total of 40 patients were included in the study. Feasibility of PLUS was 100 % and median time used was 3 min. The gold standard diagnosed 18 (45.0 %) patients with cardiogenic pulmonary oedema. The diagnostic accuracy of PLUS for the diagnosis of cardiogenic pulmonary oedema was: sensitivity 94.4 % (95 % confidence interval (CI) 72.7-99.9 %), specificity 77.3 % (95 % CI 54.6-92.2 %), positive predictive value 77.3 % (95 % CI 54.6-92.2 %), negative predictive value 94.4 % (95 % CI 72.7-99.9 %).

Discussion: The sensitivity of PLUS is high, making it a potential tool for ruling-out cardiogenic pulmonary. The observed specificity was lower than what has been described in previous studies.

Conclusions: Performed, as part of a physician based prehospital emergency service, PLUS seems fast and highly feasible in patients with respiratory failure. Due to its diagnostic accuracy, PLUS may have potential as a prehospital tool, especially to rule out cardiogenic pulmonary oedema.
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http://dx.doi.org/10.1186/s13049-016-0288-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970268PMC
August 2016