NatIonal Danish endocarditis stUdieS - Design and objectives of the NIDUS registry.

AIMS: The NatIonal Danish endocarditis stUdieS (NIDUS) registry aims to investigate the mechanisms contributing to the increasing incidence of infective endocarditis (IE) and to discover risk factors associated to the course, treatment and clinical outcomes of the disease. METHODS: The NIDUS registry was created to investigate a nationwide unselected group of patients hospitalized for IE. The National Danish healthcare registries have been queried for validated IE diagnosis codes (International Classification of Disease, 10th edition [ICD-10]: DI33, DI38, and DI398). Subsequently, a team of 28 healthcare professionals, including experts in endocarditis, will systematically review and evaluate all identified patient records using the modified Duke Criteria and the 2015 European Society of Cardiology modified diagnostic criteria. The registry will contain all cases with definite or possible IE found in primary data sources in Denmark between January 1, 2016, and December 31, 2021. We will gather individual patient data, such as clinical, microbiological, and echocardiographic characteristics, treatment regimens, and clinical outcomes. A digital data collection form will be used to the gathering of data. A sample of approximately 4,300 individual patients will be evaluated using primary data sources. CONCLUSIONS AND PERSPECTIVES: The NIDUS registry will be the first comprehensive nationwide IE registry, contributing critical knowledge about the course, treatment, and clinical outcomes of the disease. Additionally, it will significantly aid in identifying areas in which future research is needed.

Clinical implementation of partial oral treatment in infective endocarditis: the Danish POETry study.

BACKGROUND AND AIMS: In the Partial Oral Treatment of Endocarditis (POET) trial, stabilized patients with left-sided infective endocarditis (IE) were randomized to oral step-down antibiotic therapy (PO) or conventional continued intravenous antibiotic treatment (IV), showing non-inferiority after 6 months. In this study, the first guideline-driven clinical implementation of the oral step-down POET regimen was examined. METHODS: Patients with IE, caused by Staphylococcus aureus, Enterococcus faecalis, Streptococcus spp. or coagulase-negative staphylococci diagnosed between May 2019 and December 2020 were possible candidates for initiation of oral step-down antibiotic therapy, at the discretion of the treating physician. The composite primary outcome in patients finalizing antibiotic treatment consisted of embolic events, unplanned cardiac surgery, relapse of bacteraemia and all-cause mortality within 6 months. RESULTS: A total of 562 patients [median age 74 years (IQR, interquartile range, 65-80), 70% males] with IE were possible candidates; PO was given to 240 (43%) patients and IV to 322 (57%) patients. More patients in the IV group had IE caused by S. aureus, or had an intra-cardiac abscess, or a pacemaker and more were surgically treated. The primary outcome occurred in 30 (13%) patients in the PO group and in 59 (18%) patients in the IV group (P = .051); in the PO group, 20 (8%) patients died vs. 46 (14%) patients in the IV group (P = .024). PO-treated patients had a shorter median length of stay [PO 24 days (IQR 17-36) vs. IV 43 days (IQR 32-51), P < .001]. CONCLUSIONS: After clinical implementation of the POET regimen almost half of the possible candidates with IE received oral step-down antibiotic therapy. Patients in the IV group had more serious risk factors for negative outcomes. At 6-month follow-up, there was a numerically but not statistically significant difference towards a lower incidence of the primary outcome, a lower incidence of all-cause mortality and a reduced length of stay in the PO group. Due to the observational design of the study, the lower mortality may to some extent reflect selection bias and unmeasured confounding. Clinical implementation of PO regimens seemed feasible and safe.

Periodic Repolarization Dynamics Identifies ICD Responders in Nonischemic Cardiomyopathy: A DANISH Substudy.

BACKGROUND: Identification of patients with nonischemic cardiomyopathy who may benefit from prophylactic implantation of a cardioverter-defibrillator. We hypothesized that periodic repolarization dynamics (PRD), a marker of repolarization instability associated with sympathetic activity, could be used to identify patients who will benefit from prophylactic implantable cardioverter defibrillator (ICD) implantation. METHODS: We performed a post hoc analysis of DANISH (Danish ICD Study in Patients With Dilated Cardiomyopathy), in which patients with nonischemic cardiomyopathy, left ventricular ejection fraction (LVEF) ≤35%, and elevated NT-proBNP (N-terminal probrain natriuretic peptides) were randomized to ICD implantation or control group. Patients were included in the PRD substudy if they had a 24-hour Holter monitor recording at baseline with technically acceptable ECG signals during the night hours (00:00-06:00). PRD was assessed using wavelet analysis according to previously validated methods. The primary end point was all-cause mortality. Cox regression models were adjusted for age, sex, NT-proBNP, estimated glomerular filtration rate, LVEF, atrial fibrillation, ventricular pacing, diabetes, cardiac resynchronization therapy, and mean heart rate. We proposed PRD ≥10 deg2 as an exploratory cut-off value for ICD implantation. RESULTS: A total of 748 of the 1116 patients in DANISH qualified for the PRD substudy. During a mean follow-up period of 5.1±2.0 years, 82 of 385 patients died in the ICD group and 85 of 363 patients died in the control group (P=0.40). In Cox regression analysis, PRD was independently associated with mortality (hazard ratio [HR], 1.28 [95% CI, 1.09-1.50] per SD increase; P=0.003). PRD was significantly associated with mortality in the control group (HR, 1.51 [95% CI, 1.25-1.81]; P<0.001) but not in the ICD group (HR, 1.04 [95% CI, 0.83-1.54]; P=0.71). There was a significant interaction between PRD and the effect of ICD implantation on mortality (P=0.008), with patients with higher PRD having greater benefit in terms of mortality reduction. ICD implantation was associated with an absolute mortality reduction of 17.5% in the 280 patients with PRD ≥10 deg2 (HR, 0.54 [95% CI, 0.34-0.84]; P=0.006; number needed to treat=6), but not in the 468 patients with PRD <10 deg2 (HR, 1.17 [95% CI, 0.77-1.78]; P=0.46; P for interaction=0.01). CONCLUSIONS: Increased PRD identified patients with nonischemic cardiomyopathy in whom prophylactic ICD implantation led to significant mortality reduction.

Attainment of Target Antibiotic Levels by Oral Treatment of Left-Sided Infective Endocarditis: A POET Substudy.

BACKGROUND: In the POET (Partial Oral Endocarditis Treatment) trial, oral step-down therapy was noninferior to full-length intravenous antibiotic administration. The aim of the present study was to perform pharmacokinetic/pharmacodynamic analyses for oral treatments of infective endocarditis to assess the probabilities of target attainment (PTAs). METHODS: Plasma concentrations of oral antibiotics were measured at day 1 and 5. Minimal inhibitory concentrations (MICs) were determined for the bacteria causing infective endocarditis (streptococci, staphylococci, or enterococci). Pharmacokinetic/pharmacodynamic targets were predefined according to literature using time above MIC or the ratio of area under the curve to MIC. Population pharmacokinetic modeling and pharmacokinetic/pharmacodynamic analyses were done for amoxicillin, dicloxacillin, linezolid, moxifloxacin, and rifampicin, and PTAs were calculated. RESULTS: A total of 236 patients participated in this POET substudy. For amoxicillin and linezolid, the PTAs were 88%-100%. For moxifloxacin and rifampicin, the PTAs were 71%-100%. Using a clinical breakpoint for staphylococci, the PTAs for dicloxacillin were 9%-17%.Seventy-four patients at day 1 and 65 patients at day 5 had available pharmacokinetic and MIC data for 2 oral antibiotics. Of those, 13 patients at day 1 and 14 patients at day 5 did only reach the target for 1 antibiotic. One patient did not reach target for any of the 2 antibiotics. CONCLUSIONS: For the individual orally administered antibiotic, the majority reached the target level. Patients with sub-target levels were compensated by the administration of 2 different antibiotics. The findings support the efficacy of oral step-down antibiotic treatment in patients with infective endocarditis.

Rifampicin reduces plasma concentration of linezolid in patients with infective endocarditis.

BACKGROUND: Linezolid in combination with rifampicin has been used in treatment of infective endocarditis especially for patients infected with staphylococci. OBJECTIVES: Because rifampicin has been reported to reduce the plasma concentration of linezolid, the present study aimed to characterize the population pharmacokinetics of linezolid for the purpose of quantifying an effect of rifampicin cotreatment. In addition, the possibility of compensation by dosage adjustments was evaluated. PATIENTS AND METHODS: Pharmacokinetic measurements were performed in 62 patients treated with linezolid for left-sided infective endocarditis in the Partial Oral Endocarditis Treatment (POET) trial. Fifteen patients were cotreated with rifampicin. A total of 437 linezolid plasma concentrations were obtained. The pharmacokinetic data were adequately described by a one-compartment model with first-order absorption and first-order elimination. RESULTS: We demonstrated a substantial increase of linezolid clearance by 150% (95% CI: 78%-251%), when combined with rifampicin. The final model was evaluated by goodness-of-fit plots showing an acceptable fit, and a visual predictive check validated the model. Model-based dosing simulations showed that rifampicin cotreatment decreased the PTA of linezolid from 94.3% to 34.9% and from 52.7% to 3.5% for MICs of 2 mg/L and 4 mg/L, respectively. CONCLUSIONS: A substantial interaction between linezolid and rifampicin was detected in patients with infective endocarditis, and the interaction was stronger than previously reported. Model-based simulations showed that increasing the linezolid dose might compensate without increasing the risk of adverse effects to the same degree.

High JAK2V617F variant allele frequency is associated with coronary artery but not aortic valve calcifications in patients with Philadelphia-negative myeloproliferative neoplasms.

BACKGROUND: Patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) have a higher burden of cardiac calcifications compared to the general population. It is not known whether the JAK2V617F mutation is associated with increased cardiac calcification. AIM: To investigate if a higher JAK2V617F variant allele frequency (VAF) is associated with severe coronary atherosclerosis and the presence of aortic valve calcification (AVC). METHODS: Patients with MPNs were examined by cardiac computer tomography to establish coronary artery calcium score (CACS) and AVC score. The first VAF after diagnosis was registered. Severe coronary atherosclerosis was defined as a CACS >400 and AVC was defined as an AVC score >0. RESULTS: Among 161 patients, 137 were JAK2V617F mutation-positive, with a median VAF of 26% (interquartile range 12%-52%). A VAF in the upper quartile range was associated with a CACS >400 [odds ratio (OR) 15.96, 95% confidence interval [CI] 2.13-119.53, p = .0070], after adjustment for cardiovascular risk factors and MPN subtype. An association was not found for the presence of AVC (OR 2.30, 95% CI 0.47-11.33, p = 0.31). CONCLUSION: In patients with MPNs, there is a significant association between having a VAF in the upper quartile (>52%), and severe coronary atherosclerosis, defined as a CACS >400. The presence of AVC is not associated with VAF.

Streptococcal species as a prognostic factor for mortality in patients with streptococcal bloodstream infections.

PURPOSE: Streptococcal bloodstream infections (BSIs) are common, yet prognostic factors are poorly investigated. We aimed to investigate the mortality according to streptococcal species and seasonal variation. METHODS: Patients with streptococcal BSIs from 2008 to 2017 in the Capital Region of Denmark were investigated, and data were crosslinked with nationwide registers for the identification of comorbidities. A multivariable logistic regression analysis was performed to assess mortality according to streptococcal species and season of infection. RESULTS: Among 6095 patients with a streptococcal BSI (mean age 68.1 years), the 30-day mortality was 16.1% and the one-year mortality was 31.5%. With S. pneumoniae as a reference, S. vestibularis was associated with a higher adjusted mortality both within 30 days (odds ratio (OR) 2.89 [95% confidence interval (CI) 1.20-6.95]) and one year (OR 4.09 [95% CI 1.70-9.48]). One-year mortality was also higher in S. thermophilus, S. constellatus, S. parasanguinis, S. salivarius, S. anginosus, and S. mitis/oralis. However, S. mutans was associated with a lower one-year mortality OR 0.44 [95% CI 0.20-0.97], while S. gallolyticus was associated with both a lower 30-day (OR 0.42 [95% CI 0.26-0.67]) and one-year mortality (OR 0.66 [95% CI 0.48-0.93]). Furthermore, with infection in the summer as a reference, patients infected in the winter and autumn had a higher association with 30-day mortality. CONCLUSIONS: The mortality in patients with streptococcal BSI was associated with streptococcal species. Further, patients with streptococcal BSIs infected in the autumn and winter had a higher risk of death within 30 days, compared with patients infected in the summer.

Recurrence of bacteremia and infective endocarditis according to bacterial species of index endocarditis episode.

PURPOSE: In patients surviving infective endocarditis (IE) recurrence of bacteremia or IE is feared. However, knowledge is sparse on the incidence and risk factors for the recurrence of bacteremia or IE. METHODS: Using Danish nationwide registries (2010-2020), we identified patients with first-time IE which were categorized by bacterial species (Staphylococcus aureus, Enterococcus spp., Streptococcus spp., coagulase-negative staphylococci [CoNS], 'Other' microbiological etiology). Recurrence of bacteremia (including IE episodes) or IE with the same bacterial species was estimated at 12 months and 5 years, considering death as a competing risk. Cox regression models were used to compute adjusted hazard ratios of the recurrence of bacteremia or IE. RESULTS: We identified 4086 patients with IE; 1374 (33.6%) with S. aureus, 813 (19.9%) with Enterococcus spp., 1366 (33.4%) with Streptococcus spp., 284 (7.0%) with CoNS, and 249 (6.1%) with 'Other'. The overall 12-month incidence of recurrent bacteremia with the same bacterial species was 4.8% and 2.6% with an accompanying IE diagnosis, while this was 7.7% and 4.0%, respectively, with 5 years of follow-up. S. aureus, Enterococcus spp., CoNS, chronic renal failure, and liver disease were associated with an increased rate of recurrent bacteremia or IE with the same bacterial species. CONCLUSION: Recurrent bacteremia with the same bacterial species within 12 months, occurred in almost 5% and 2.6% for recurrent IE. S. aureus, Enterococcus spp., and CoNS were associated with recurrent infections with the same bacterial species.

Streptococcal infective endocarditis: clinical features and outcomes according to species.

PURPOSE: Infective endocarditis (IE) is frequently caused by streptococcal species, yet clinical features and mortality are poorly investigated. Our aim was to examine patients with streptococcal IE to describe clinical features and outcomes according to streptococcal species. METHODS: From 2002 to 2012, we investigated patients with IE admitted to two tertiary Danish heart centres. Adult patients with left-sided streptococcal IE were included. Adjusted multivariable logistic regression analyses were performed, to assess the association between streptococcal species and heart valve surgery or 1-year mortality. RESULTS: Among 915 patients with IE, 284 (31%) patients with streptococcal IE were included [mean age 63.5 years (SD 14.1), 69% men]. The most frequent species were S. mitis/oralis (21%) and S. gallolyticus (17%). Fever (86%) and heart murmur (81%) were common symptoms, while dyspnoea was observed in 46%. Further, 18% of all cases were complicated by a cardiac abscess/pseudoaneurysm and 25% by an embolic event. Heart valve surgery during admission was performed in 55% of all patients, and S. gallolyticus (OR 0.28 [95% CI 0.11-0.69]) was associated with less surgery compared with S. mitis/oralis. In-hospital mortality was 7% and 1-year mortality 15%, without any difference between species. CONCLUSION: S. mitis/oralis and S. gallolyticus were the most frequent streptococcal species causing IE. Further, S. gallolyticus IE was associated with less heart valve surgery during admission compared with S. mitis/oralis IE. Being aware of specific symptoms, clinical findings, and complications related to different streptococcal species, may help the clinicians in expecting different outcomes.

New methods for quantification of amoxicillin and clindamycin in human plasma using HPLC with UV detection.

OBJECTIVES: We aimed to develop simple and rapid HPLC methods for determination of amoxicillin and clindamycin in human plasma. METHODS: Plasma samples were pretreated by direct deproteinization with acetonitrile and the analytical separation took place on a reverse phase Poroshell 120 EC-C18 column (2.7 µm, 2.1 × 100 mm) with a gradient of acetonitrile. UV detection at 229 nm for amoxicillin and 204 nm for clindamycin was used for determination of the antibiotics in plasma. RESULTS: The calibration curves were linear over the concentration ranges of 1-100 mg/L for amoxicillin and 1-15 mg/L for clindamycin with a correlation coefficient of ≥0.98. Intra-assay precisions were all ≤15% and the accuracies were within ±15%. The limit of quantification (LOQ) was found to be 0.5 mg/L for amoxicillin and 1 mg/L for clindamycin with inter-assay imprecision coefficient of variances (CVs) of 18.7% and 15.6%, respectively. The present HPLC methods were successfully applied on spike-in samples and on plasma samples collected 4-6 and 3.5-5.5 h after oral antibiotic administration of 500 mg of amoxicillin and 600 mg of clindamycin, respectively. CONCLUSIONS: We have developed HPLC methods with UV detection for quantification of amoxicillin and clindamycin in human plasma. The methods are fast, simple and suitable for use in routine settings and clinical studies.

Prevalence of Infective Endocarditis in Streptococcal Bloodstream Infections Is Dependent on Streptococcal Species.

BACKGROUND: Streptococci frequently cause infective endocarditis (IE), yet the prevalence of IE in patients with bloodstream infections (BSIs) caused by different streptococcal species is unknown. We aimed to investigate the prevalence of IE at species level in patients with streptococcal BSIs. METHODS: We investigated all patients with streptococcal BSIs, from 2008 to 2017, in the Capital Region of Denmark. Data were crosslinked with Danish nationwide registries for identification of concomitant hospitalization with IE. In a multivariable logistic regression analysis, we investigated the risk of IE according to streptococcal species adjusted for age, sex, ≥3 positive blood culture bottles, native valve disease, prosthetic valve, previous IE, and cardiac device. RESULTS: Among 6506 cases with streptococcal BSIs (mean age 68.1 years [SD 16.2], 52.8% men) the IE prevalence was 7.1% (95% CI, 6.5-7.8). The lowest IE prevalence was found with Streptococcus pneumoniae (S pneumoniae) 1.2% (0.8-1.6) and Spyogenes 1.9% (0.9-3.3). An intermediary IE prevalence was found with Sanginosus 4.8% (3.0-7.3), Ssalivarius 5.8% (2.9-10.1), and Sagalactiae 9.1% (6.6-12.1). The highest IE prevalence was found with Smitis/oralis 19.4% (15.6-23.5), Sgallolyticus (formerly Sbovis) 30.2% (24.3-36.7), Ssanguinis 34.6% (26.6-43.3), Sgordonii 44.2% (34.0-54.8), and Smutans 47.9% (33.3-62.8). In multivariable analysis using S pneumoniae as reference, all species except S pyogenes were associated with significantly higher IE risk, with the highest risk found with S gallolyticus odds ratio (OR) 31.0 (18.8-51.1), S mitis/oralis OR 31.6 (19.8-50.5), S sanguinis OR 59.1 (32.6-107), S gordonii OR 80.8 (43.9-149), and S mutans OR 81.3 (37.6-176). CONCLUSIONS: The prevalence of IE in streptococcal BSIs is species dependent with S mutans, S gordonii, S sanguinis, S gallolyticus, and S mitis/oralis having the highest IE prevalence and the highest associated IE risk after adjusting for IE risk factors.

Outcome of Dialysis-Requiring Acute Kidney Injury in Patients With Infective Endocarditis: A Nationwide Study.

BACKGROUND: Infective endocarditis (IE) may be complicated by acute kidney injury, yet data on the use of dialysis and subsequent reversibility are sparse. METHODS: Using Danish nationwide registries, we identified patients with first-time IE from 2000 to 2017. Dialysis-naïve patients were grouped into: those with and those without dialysis during admission with IE. Continuation of dialysis was followed 1 year postdischarge. Multivariable adjusted Cox proportional hazard analysis was used to examine 1-year mortality for patients surviving IE according to use of dialysis. RESULTS: We included 7307 patients with IE; 416 patients (5.7%) initiated dialysis treatment during admission with IE and these were younger, had more comorbidities and more often underwent cardiac valve surgery compared with nondialysis patients (47.4% vs 20.9%). In patients with both cardiac valve surgery and dialysis treatment (n = 197), 153 (77.7%) initiated dialysis on or after the date of surgery. The in-hospital mortality was 40.4% and 19.0% for patients with and without dialysis, respectively (P < .0001). Of those who started dialysis and survived hospitalization, 21.6% continued dialysis treatment within 1 year after discharge. In multivariable adjusted analysis, dialysis during admission with IE was associated with an increased 1-year mortality from IE discharge, hazard ratio = 1.64 (95% confidence interval, 1.21-2.23). CONCLUSION: In dialysis-naïve patients with IE, approximately 1 in 20 patients initiated dialysis treatment during admission with IE. Dialysis identified a high-risk group with an in-hospital mortality of 40% and an approximate 20% risk of continued dialysis. Those with dialysis during admission with IE showed worse long-term outcomes than those without.

Dabigatran and the Risk of Staphylococcus aureus Bacteremia: A Nationwide Cohort Study.

BACKGROUND: Treatment with dabigatran, an oral direct thrombin inhibitor, reduces the virulence of Staphylococcus aureus in in vitro and in vivo models. However, it remains to be determined whether dabigatran reduces the risk of S. aureus infections in humans. We investigated the incidence rate of S. aureus bacteremia (SAB) in patients with atrial fibrillation treated with the direct thrombin inhibitor dabigatran compared with patients treated with the factor Xa-inhibitors rivaroxaban, apixaban, and edoxaban. METHODS: In this observational cohort study, 112 537 patients with atrial fibrillation who initiated treatment with direct oral anticoagulants (August 2011-December 2017) were identified from Danish nationwide registries. The incidence rates of SAB in patients treated with dabigatran versus patients treated with the factor Xa-inhibitors were examined by multivariable Cox regression accounting for time-dynamic changes in exposure status during follow-up. RESULTS: A total of 112 537 patients were included. During a median follow-up of 2.0 years, 186 patients in the dabigatran group and 356 patients in the factor Xa-inhibitor group were admitted with SAB. The crude incidence rate of SAB was lower in the dabigatran group compared with the factor Xa-inhibitor group (22.8 [95% confidence interval [CI], 19.7-26.3] and 33.8 [95% CI, 30.5-37.6] events per 10 000 person-years, respectively). In adjusted analyses, dabigatran was associated with a significantly lower incidence rate of SAB compared with factor Xa-inhibitors (incidence rate ratio, .76; 95% CI, .63-.93). CONCLUSIONS: Treatment with dabigatran was associated with a significantly lower incidence rate of SAB compared with treatment with factor Xa-inhibitors.

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

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.

The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT).

OBJECTIVES: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT). METHODS: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years. RESULTS: As of May 2020, 296 patients have been randomized at 20 centers in Denmark. CONCLUSION: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

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

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.

Proposal for the use of echocardiography in bloodstream infections due to different streptococcal species.

BACKGROUND: Infective endocarditis (IE) is diagnosed in 7-8% of streptococcal bloodstream infections (BSIs), yet it is unclear when to perform transthoracic (TTE) and transoesophageal echocardiography (TOE) according to different streptococcal species. The aim of this sub-study was to propose a flowchart for the use of echocardiography in streptococcal BSIs. METHODS: In a population-based setup, we investigated all patients admitted with streptococcal BSIs and crosslinked data with nationwide registries to identify comorbidities and concomitant hospitalization with IE. Streptococcal species were divided in four groups based on the crude risk of being diagnosed with IE (low-risk < 3%, moderate-risk 3-10%, high-risk 10-30% and very high-risk > 30%). Based on number of positive blood culture (BC) bottles and IE risk factors (prosthetic valve, previous IE, native valve disease, and cardiac device), we further stratified cases according to probability of concomitant IE diagnosis to create a flowchart suggesting TTE plus TOE (IE > 10%), TTE (IE 3-10%), or "wait & see" (IE < 3%). RESULTS: We included 6393 cases with streptococcal BSIs (mean age 68.1 years [SD 16.2], 52.8% men). BSIs with low-risk streptococci (S. pneumoniae, S. pyogenes, S. intermedius) are not initially recommended echocardiography, unless they have ≥3 positive BC bottles and an IE risk factor. Moderate-risk streptococci (S. agalactiae, S. anginosus, S. constellatus, S. dysgalactiae, S. salivarius, S. thermophilus) are guided to "wait & see" strategy if they neither have a risk factor nor ≥3 positive BC bottles, while a TTE is recommended if they have either ≥3 positive BC bottles or a risk factor. Further, a TTE and TOE are recommended if they present with both. High-risk streptococci (S. mitis/oralis, S. parasanguinis, G. adiacens) are directed to a TTE if they neither have a risk factor nor ≥3 positive BC bottles, but to TTE and TOE if they have either ≥3 positive BC bottles or a risk factor. Very high-risk streptococci (S. gordonii, S. gallolyticus, S. mutans, S. sanguinis) are guided directly to TTE and TOE due to a high baseline IE prevalence. CONCLUSION: In addition to the clinical picture, this flowchart based on streptococcal species, number of positive blood culture bottles, and risk factors, can help guide the use of echocardiography in streptococcal bloodstream infections. Since echocardiography results are not available the findings should be confirmed prospectively with the use of systematic echocardiography.

Temporal changes in cardiovascular disease and infections in dialysis across a 22-year period: a nationwide study.

BACKGROUND: Cardiovascular diseases (CVD) and infections are recognized as serious complications in patients with end stage kidney disease. However, little is known about the change over time in incidence of these complications. This study aimed to investigate temporal changes in CVD and infective diseases across more than two decades in chronic dialysis patients. METHODS: All patients that initiated peritoneal dialysis (PD) or hemodialysis (HD) between 1996 and 2017 were identified and followed until outcome (CVD, pneumonia, infective endocarditis (IE) or sepsis), recovery of kidney function, end of dialysis treatment, death or end of study (December 31st, 2017). The calendar time was divided into 5 periods with period 1 (1996-2000) being the reference period. Adjusted rate ratios were assessed using Poisson regression. RESULTS: In 4285 patients with PD (63.7% males) the median age increased across the calendar periods from 65 [57-73] in 1996-2000 to 69 [55-76] in 2014-2017, (p <  0.0001). In 9952 patients with HD (69.2% males), the overall median age was 71 [61-78] without any changes over time. Among PD, an overall non-significant decreasing trend in rate ratios (RR) of CVD was found, (p = 0,071). RR of pneumonia increased significantly throughout the calendar with an almost two-fold increase of the RR in 2014-2017 (RR 1.71; 95% CI 1.46-2.0), (p <  0.001), as compared to the reference period. The RR of IE decreased significantly until 2009 (RR 0.43; 95% CI 0.21-0.87), followed by a return to the reference level in 2010-2013 (RR 0.87; 95% CI 0.47-1.60 and 2014-2017 (RR 1.1; 95% CI 0.59-2.04). A highly significant (p <  0.001) increase in sepsis was revealed across the calendar periods with an almost 5-fold increase in 2014-2017 (RR 4.69 95% CI 3.69-5.96). In HD, the RR of CVD decreased significantly (p <  0.001) from 2006 to 2017 (RR 0.85; 95% CI 0.79-0.92). Compared to the reference period, the RR for pneumonia was high during all calendar periods (p <  0.05). The RR of IE was initially unchanged (p = 0.4) but increased in 2010-2013 (RR 2.02; 95% CI 1.43-2.85) and 2014-2017 (RR 3.39; 95% CI 2.42-4.75). No significant changes in sepsis were seen. CONCLUSION: Across the two last decades the RR of CVD has shown a decreasing trend in HD and PD patients, while RR of pneumonia increased significantly, both in PD and in HD. Temporal trends of IE in HD, and particularly of sepsis in PD were upwards across the last decades.

Prognostic value of right ventricular echocardiographic measures in patients with heart failure with reduced ejection fraction.

PURPOSE: Right ventricular (RV) dysfunction is associated with poor outcome in patients with heart failure. In order to better predict mortality in this patient group we wanted to compare the prognostic value of conventional and advanced RV echocardiographic measures. METHODS: Echocardiographic examinations were retrieved from 701 patients. End point was all-cause mortality and follow-up 100%. RV parameters were measured offline in accordance with current guidelines. Speckle tracking was derived using the algorithm originally designed for the left ventricle. RESULTS: During follow-up (median: 39 months) 118 patients (16.8%) died. RV global longitudinal strain (GLS) and RV free wall strain (FWS) remained associated with mortality after multivariable adjustment independent of Tricuspid annular plane systolic excursion (TAPSE) (RV GLS: HR 1.07, 95%CI 1.02-1.13, p = 0.010, per 1% decrease) (RV FWS: HR 1.05, 95%CI 1.01-1.09, p = 0.010, per 1% decrease). This seemed to be caused by significant associations in men. All RV estimates provided prognostic information incremental to established risk factors and significantly increased C-statistics. CONCLUSIONS: RV GLS and FWS were associated with mortality in HFrEF patients after multivariable adjustment independent of TAPSE. TAPSE, however, remained as the strongest prognosticator in women. More research is needed to identify whether speckle tracking could be superior to conventional RV measures in identifying HFrEF patients with poor outcome.

Hemodynamic monitoring by intracardiac impedance measured by cardiac resynchronization defibrillators: Evaluation in a controlled clinical setting (BIO.Detect HF II study).

BACKGROUND: In patients with cardiac resynchronization therapy defibrillators (CRT-Ds), intracardiac impedance measured by dedicated CRT-D software may be used to monitor hemodynamic changes. We investigated the relationship of hemodynamic parameters assessed by intracardiac impedance and by echocardiography in a controlled clinical setting. METHODS: The study enrolled 68 patients (mean age, 66 ± 9 years; 74% males) at 12 investigational sites. The patients had an indication for CRT-D implantation, New York Heart Association class II/III symptoms, left ventricular ejection fraction 15%-35%, and a QRS duration ≥150 ms. Two months after a CRT-D implantation, hemodynamic changes were provoked by overdrive pacing. Intracardiac impedance was recorded at rest and at four pacing rates ranging from 10 to 40 beats/min above the resting rate. In parallel, echocardiography measurements were performed. We hypothesized that a mean intra-individual correlation coefficient (rmean) between stroke impedance (difference between end-systolic and end-diastolic intracardiac impedance) measured by CRT-D and the aortic velocity time integral (i.e., stroke volume) determined by echocardiography would be significantly larger than 0.65. RESULTS: The hypothesis was evaluated in 40 patients with complete data sets. The rmean was 0.797, with a lower confidence interval bound of 0.709. The study hypothesis was met (p = 0.007). A stepwise reduction of stroke impedance and stroke volume was observed with increasing heart rate. CONCLUSIONS: Intracardiac impedance measured by implanted CRT-Ds correlated well with the aortic velocity time integral (stroke volume) determined by echocardiography. The impedance measurements bear potential and are readily available technically, not requiring implantation of additional material beyond standard CRT-D system.