Tadalafil for Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension in Patients With Heart Failure and Preserved Ejection Fraction: A Randomized Controlled Phase 3 Study.

BACKGROUND: We assessed the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension. METHODS: In the double-blind PASSION study (Phosphodiesterase-5 Inhibition in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-Capillary Pulmonary Hypertension), patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension were randomized 1:1 to receive tadalafil at a target dose of 40 mg or placebo. The primary end point was the time to the first composite event of adjudicated heart failure hospitalization or all-cause death. Secondary end points included all-cause mortality and improvements in New York Heart Association functional class or ≥10% improvement in 6-minute walking distance from baseline. RESULTS: Initially targeting 372 patients, the study was terminated early because of disruption in study medication supply. At that point, 125 patients had been randomized (placebo: 63; tadalafil: 62,). Combined primary end-point events occurred in 20 patients (32%) assigned to placebo and 17 patients (27%) assigned to tadalafil (hazard ratio, 1.02 [95% CI, 0.52-2.01]; P=0.95). There was a possible signal of higher all-cause mortality in the tadalafil group (hazard ratio, 5.10 [95% CI, 1.10-23.69]; P=0.04). No significant between-group differences were observed in other secondary end points. Serious adverse events occurred in 29 participants (48%) in the tadalafil group and 35 (56%) in the placebo group. CONCLUSIONS: The PASSION trial, terminated prematurely due to study medication supply disruption, does not support tadalafil use in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension, with potential safety concerns and no observed benefits in primary and secondary end points. REGISTRATION: URL: https://www.clinicaltrialsregister.eu/; Unique identifier: 2017-003688-37. URL: https://drks.de; Unique identifier: DRKS -DRKS00014595.

Real-world characteristics and use patterns of patients treated with vericiguat: A nationwide longitudinal cohort study in Germany.

PURPOSE: Vericiguat reduced clinical endpoints in patients experiencing worsening heart failure in clinical trials, but its implementation outside trials is unclear. METHODS: This retrospective analysis of longitudinally collected data was based on the IQVIA™ LRx database, which includes ~ 80% of the prescriptions of the 73 million people covered by the German statutory health insurance. RESULTS: Between September 2021 and December 2022, vericiguat was initiated in 2916 adult patients. Their mean age was 73 ± 13 years and 28% were women. While approximately 70% were uptitrated beyond 2.5 mg, only 36% reached 10 mg. Median time to up-titration from 2.5 mg to 5 mg was 17 (quartiles: 11-33) days, and from 2.5 to 10 mg 37 (25-64) days, respectively. In 87% of the patients, adherence to vericiguat was high as indicated by a medication possession ratio of  ≥ 80%, and 67% of the patients persistently used vericiguat during the first year. Women and older patients reached the maximal dose of 10 mg vericiguat less often and received other substance classes of guideline-recommended therapy (GDMT) less frequently. The proportion of patients receiving four pillars of GDMT increased from 29% before vericiguat initiation to 44% afterwards. CONCLUSION: In a real-world setting, despite higher age than in clinical trials, adherence and persistence of vericiguat appeared satisfactory across age categories. Initiation of vericiguat was associated with intensification of concomitant GDMT. Nevertheless, barriers to vericiguat up-titration and implementation of other GDMT, applying in particular to women and elderly patients, need to be investigated further.

Intensive heart rhythm monitoring to decrease ischemic stroke and systemic embolism-the Find-AF 2 study-rationale and design.

BACKGROUND: Atrial fibrillation (AF) is one of the most frequent causes of stroke. Several randomized trials have shown that prolonged monitoring increases the detection of AF, but the effect on reducing recurrent cardioembolism, ie, ischemic stroke and systemic embolism, remains unknown. We aim to evaluate whether a risk-adapted, intensified heart rhythm monitoring with consequent guideline conform treatment, which implies initiation of oral anticoagulation (OAC), leads to a reduction of recurrent cardioembolism. METHODS: Find-AF 2 is a randomized, controlled, open-label parallel multicenter trial with blinded endpoint assessment. 5,200 patients ≥ 60 years of age with symptomatic ischemic stroke within the last 30 days and without known AF will be included at 52 study centers with a specialized stroke unit in Germany. Patients without AF in an additional 24-hour Holter ECG after the qualifying event will be randomized in a 1:1 fashion to either enhanced, prolonged and intensified ECG-monitoring (intervention arm) or standard of care monitoring (control arm). In the intervention arm, patients with a high risk of underlying AF will receive continuous rhythm monitoring using an implantable cardiac monitor (ICM) whereas those without high risk of underlying AF will receive repeated 7-day Holter ECGs. The duration of rhythm monitoring within the control arm is up to the discretion of the participating centers and is allowed for up to 7 days. Patients will be followed for at least 24 months. The primary efficacy endpoint is the time until recurrent ischemic stroke or systemic embolism occur. CONCLUSIONS: The Find-AF 2 trial aims to demonstrate that enhanced, prolonged and intensified rhythm monitoring results in a more effective prevention of recurrent ischemic stroke and systemic embolism compared to usual care.

A cardiologist's guide to machine learning in cardiovascular disease prognosis prediction.

A modern-day physician is faced with a vast abundance of clinical and scientific data, by far surpassing the capabilities of the human mind. Until the last decade, advances in data availability have not been accompanied by analytical approaches. The advent of machine learning (ML) algorithms might improve the interpretation of complex data and should help to translate the near endless amount of data into clinical decision-making. ML has become part of our everyday practice and might even further change modern-day medicine. It is important to acknowledge the role of ML in prognosis prediction of cardiovascular disease. The present review aims on preparing the modern physician and researcher for the challenges that ML might bring, explaining basic concepts but also caveats that might arise when using these methods. Further, a brief overview of current established classical and emerging concepts of ML disease prediction in the fields of omics, imaging and basic science is presented.

Comparison of quantitative flow ratio with instantaneous wave-free ratio and resting full-cycle ratio during daily routine in the catheterization laboratory.

BACKGROUND: Quantitative flow ratio (QFR) is a novel, software-based method to evaluate the physiology of coronary lesions. The aim of this study was to compare QFR with the established invasive measurements of coronary blood flow using instantaneous wave-free ratio (iFR) or resting full-cycle ratio (RFR) in daily cathlab routine. METHODS: 102 patients with stable coronary artery disease and a coronary stenosis of 40%-90% were simultaneously assessed with QFR and iFR or RFR. QFR-computation was performed by two certified experts using the appropriate software (QAngio XA 3D 3.2). RESULTS: QFR showed a significant correlation (r = 0.75, p < 0.001) to iFR and RFR. The area under the receiver curve for all measurements was 0.93 (95% confidence interval, 0.87-0.98) for QFR compared to iFR or RFR. QFR based assessment required less time with a median of 501 s (IQR 421-659 s) compared to iFR or RFR which required a median of 734 s to obtain the result (IQR 512-967 s; p < 0.001). The median use of contrast medium was similar with 21 mL (IQR 16-30 mL) for the QFR-based and 22 mL (IQR 15-35 mL) for the iFR- or RFR-based diagnostic. QFR diagnostic required less radiation. The median dose area product for QFR was 307cGycm2 (IQR 151-429 cGycm2 ) compared to 599 cGycm2 (IQR 345-1082 cGycm2 ) for iFR or RFR, p < 0.001. CONCLUSION: QFR measurements of coronary artery blood flow correlate with iFR or RFR measurements and are associated with shorter procedure times and reduced radiation dose.

Higher troponin T serum concentrations in hospital patients without diagnosed cardiac diseases compared to a population-based cohort.

OBJECTIVES: Upper reference limits of high-sensitivity cardiac troponin T (hs-cTnT) are derived from healthy, population-based cohorts, and are frequently exceeded in hospitalized patients. In this study we aim to systematically examine the differences between in-hospital patients with no diagnosed cardiac diseases and a population-based cohort. METHODS: Retrospective analyses were performed in two independent cohorts. We included 5,652 participants of the prospective population-based LIFE cohort as well as 9,300 patients having been treated at our hospital between 2014 and 2021. In both cohorts, subjects with diagnosed or suspected cardiac diseases were excluded. We used Spearman's rank correlation for correlation analyses of hs-cTnT serum concentrations and age. Sex- and age-adjusted 99th percentiles for hs-cTnT in subjects with preserved renal function were obtained in both cohorts. RESULTS: In both cohorts, hs-cTnT serum concentrations positively correlated with age. Male sex was associated with higher hs-cTnT serum concentrations. Persons treated in hospital showed significantly higher hs-cTnT concentrations in females and males aged above 50. While in the population-based cohort only 99th percentile hs-cTnT results of females aged above 70 and males aged above 60 years exceeded the assay's upper reference limit, the 99th percentiles of in-hospital females over 40 years and males of all age groups exceeded this threshold. CONCLUSIONS: Besides age and sex, hospitalization per se is correlated with higher serum concentrations of hs-cTnT in most age groups. Our results indicate, that unconditionally applying current hs-cTnT cut-offs to inpatients might overestimate myocardial infarction and potentially lead to overdiagnosis.

Longitudinal association between N-terminal B-type natriuretic peptide, anxiety and social support in patients with HFpEF: results from the multicentre randomized controlled Aldo-DHF trial.

BACKGROUND: Higher plasma levels of natriuretic peptides (NPs) have been associated with reduced anxiety in experimental research and a number of patient samples. As NP levels are elevated in heart failure patients, we investigate whether this elevation is related to anxiety in patients with heart failure with preserved ejection fraction (HFpEF). METHODS: Post-hoc regression and mediation analyses were conducted, using data of 422 patients with HFpEF from the randomized, placebo-controlled, double-blinded, two-armed, multicentre aldosterone in diastolic heart failure trial, testing associations and their mediators between the N-terminal B-type natriuretic peptide (NT-proBNP) and anxiety at baseline and over 12-month follow-up. Anxiety was measured by the Hospital Anxiety and Depression Scale (HADS), social support by the ENRICHD Social Support Inventory and physical functioning by the Short Form 36 Health Survey. RESULTS: The mean age of the study population was 66.8 ± 7.6 years, 47.6% were male and 86.0% had NYHA class II. NT-proBNP showed a weak negative correlation with HADS anxiety scores at baseline (r = - 0.087; p = 0.092), which was significant (r = - 0.165; p = 0.028) in men but not in women. NT-proBNP also tended to predict lower anxiety at 12-months in men. On the other hand, higher anxiety at baseline was associated with lower NT-proBNP scores 12 months later (r = - 0.116; p = 0.026). All associations lost significance in multivariate regression for age, perceived social support (ESSI), physical function (SF-36) and study arm. Mediation analyses revealed that social support acts as a full mediator for the link between NT-proBNP levels and anxiety. CONCLUSION: The mechanisms linking NT-proBNP to anxiety may be more complex than originally assumed. While effects of NT-proBNP on anxiety may be mediated by perceived social support, there may be an additional negative effect of anxiety on NT-proBNP. Future research should consider this possible bi-directionality of the association and assess the potential influence of gender, social support, oxytocin and vagal tone on the interaction of anxiety and natriuretic peptide levels. Trial Registration http://www.controlled-trials.com  (ISRCTN94726526) on 07/11/2006. Eudra-CT-number: 2006-002,605-31.

Chronic thromboembolic pulmonary hypertension and impairment after pulmonary embolism: the FOCUS study.

AIMS: To systematically assess late outcomes of acute pulmonary embolism (PE) and to investigate the clinical implications of post-PE impairment (PPEI) fulfilling prospectively defined criteria. METHODS AND RESULTS: A prospective multicentre observational cohort study was conducted in 17 large-volume centres across Germany. Adult consecutive patients with confirmed acute symptomatic PE were followed with a standardized assessment plan and pre-defined visits at 3, 12, and 24 months. The co-primary outcomes were (i) diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), and (ii) PPEI, a combination of persistent or worsening clinical, functional, biochemical, and imaging parameters during follow-up. A total of 1017 patients (45% women, median age 64 years) were included in the primary analysis. They were followed for a median duration of 732 days after PE diagnosis. The CTEPH was diagnosed in 16 (1.6%) patients, after a median of 129 days; the estimated 2-year cumulative incidence was 2.3% (1.2-4.4%). Overall, 880 patients were evaluable for PPEI; the 2-year cumulative incidence was 16.0% (95% confidence interval 12.8-20.8%). The PPEI helped to identify 15 of the 16 patients diagnosed with CTEPH during follow-up (hazard ratio for CTEPH vs. no CTEPH 393; 95% confidence interval 73-2119). Patients with PPEI had a higher risk of re-hospitalization and death as well as worse quality of life compared with those without PPEI. CONCLUSION: In this prospective study, the cumulative 2-year incidence of CTEPH was 2.3%, but PPEI diagnosed by standardized criteria was frequent. Our findings support systematic follow-up of patients after acute PE and may help to optimize guideline recommendations and algorithms for post-PE care.

Predictors of Atrial Fibrillation Development in Patients With Embolic Stroke of Undetermined Source: An Analysis of the RE-SPECT ESUS Trial.

BACKGROUND: A proportion of patients with embolic stroke of undetermined source have silent atrial fibrillation (AF) or develop AF after the initial evaluation. Better understanding of the risk for development of AF is critical to implement optimal monitoring strategies with the goal of preventing recurrent stroke attributable to underlying AF. The RE-SPECT ESUS trial (Randomized, Double-Blind Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) provides an opportunity to assess predictors for developing AF and associated recurrent stroke. METHODS: RE-SPECT ESUS was a randomized, controlled trial (564 sites, 42 countries) assessing dabigatran versus aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. Of 5390 patients enrolled and followed for a median of 19 months, 403 (7.5%) were found to develop AF reported as an adverse event or using cardiac monitoring per standard clinical care. Univariable and multivariable regression analyses were performed to define predictors of AF. RESULTS: In the multivariable model, older age (odds ratio for 10-year increase, 1.99 [95% CI, 1.78-2.23]; P<0.001), hypertension (odds ratio, 1.36 [95% CI, 1.03-1.79]; P=0.0304), diabetes (odds ratio, 0.74 [95% CI, 0.56-0.96]; P=0.022), and body mass index (odds ratio for 5-U increase, 1.29 [95% CI, 1.16-1.43]; P<0.001) were independent predictors of AF during the study. In a sensitivity analysis restricted to 1117 patients with baseline NT-proBNP (N-terminal prohormone of brain natriuretic peptide) measurements, only older age and higher NT-proBNP were significant independent predictors of AF. Performance of several published predictive models was assessed, including HAVOC (AF risk score based on hypertension, age ≥75 years, valvular heart disease, peripheral vascular disease, obesity, congestive heart failure, and coronary artery disease) and CHA2DS2-VASc (stroke risk score based on congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, previous stroke, transient ischemic attack or thromboembolism [doubled], vascular disease, age 65 to 74 years, and sex category [female]) scores, and higher scores were associated with higher rates of developing AF. CONCLUSIONS: Besides age, the most important variable, several other factors, including hypertension, higher body mass index, and lack of diabetes, are independent predictors of AF after embolic stroke of undetermined source. When baseline NT-proBNP was available, only older age and elevation of this biomarker were predictive of subsequent AF. Understanding who is at higher risk of developing AF will assist in identifying patients who may benefit from more intense, long-term cardiac monitoring. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

Exercise Stress Real-Time Cardiac Magnetic Resonance Imaging for Noninvasive Characterization of Heart Failure With Preserved Ejection Fraction: The HFpEF-Stress Trial.

BACKGROUND: Right heart catheterization using exercise stress is the reference standard for the diagnosis of heart failure with preserved ejection fraction (HFpEF) but carries the risk of the invasive procedure. We hypothesized that real-time cardiac magnetic resonance (RT-CMR) exercise imaging with pathophysiologic data at excellent temporal and spatial resolution may represent a contemporary noninvasive alternative for diagnosing HFpEF. METHODS: The HFpEF-Stress trial (CMR Exercise Stress Testing in HFpEF; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621. URL: https://dzhk.de/; Unique identifier: DZHK-17) prospectively recruited 75 patients with echocardiographic signs of diastolic dysfunction and dyspnea on exertion (E/e'>8, New York Heart Association class ≥II) to undergo echocardiography, right heart catheterization, and RT-CMR at rest and during exercise stress. HFpEF was defined according to pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during exercise stress). RT-CMR functional assessments included time-volume curves for total and early (1/3) diastolic left ventricular filling, left atrial (LA) emptying, and left ventricular/LA long axis strain. RESULTS: Patients with HFpEF (n=34; median pulmonary capillary wedge pressure at rest, 13 mm Hg; at stress, 27 mm Hg) had higher E/e' (12.5 versus 9.15), NT-proBNP (N-terminal pro-B-type natriuretic peptide; 255 versus 75 ng/L), and LA volume index (43.8 versus 36.2 mL/m2) compared with patients with noncardiac dyspnea (n=34; rest, 8 mm Hg; stress, 18 mm Hg; P≤0.001 for all). Seven patients were excluded because of the presence of non-HFpEF cardiac disease causing dyspnea on imaging. There were no differences in RT-CMR left ventricular total and early diastolic filling at rest and during exercise stress (P≥0.164) between patients with HFpEF and noncardiac dyspnea. RT-CMR revealed significantly impaired LA total and early (P<0.001) diastolic emptying in patients with HFpEF during exercise stress. RT-CMR exercise stress LA long axis strain was independently associated with HFpEF (adjusted odds ratio, 0.657 [95% CI, 0.516-0.838]; P=0.001) after adjustment for clinical and imaging measures and emerged as the best predictor for HFpEF (area under the curve at rest 0.82 versus exercise stress 0.93; P=0.029). CONCLUSIONS: RT-CMR allows highly accurate identification of HFpEF during physiologic exercise and qualifies as a suitable noninvasive diagnostic alternative. These results will need to be confirmed in multicenter prospective research studies to establish widespread routine clinical use. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621. URL: https://dzhk.de/; Unique identifier: DZHK-17.

Comorbidities in heart failure with preserved ejection fraction.

Chronic heart failure is one of the most common causes of hospitalization and death in industrialized countries. Demographic changes with an aging population are expected to further increase the prevalence of chronic heart failure. The associated increase in comorbidities in patients with chronic heart failure leads to a less favorable prognosis for survival. A selection of the major comorbidities discussed in this review-along with prevalence, impact on prognosis, treatment approaches, and current study status-include atrial fibrillation, arterial hypertension, coronary artery disease, coronary microvascular dysfunction, renal dysfunction, type 2 diabetes, sleep apnea, reduced lymphatic reserve, and the effects on oxygen utilization and physical activity. The complex clinical picture of heart failure with preserved ejection fraction (HFpEF) remains challenging in the nearly absence of evidence-based therapy. Except for comorbidity-specific guidelines, no HFpEF-specific treatment of comorbidities can be recommended at this time. Optimized care is becoming increasingly relevant to reducing hospitalizations through a seamless inpatient and outpatient care structure. Current treatment is focused on symptom relief and management of associated comorbidities. Therefore, prevention through early minimization of risk factors currently remains the best approach.

Catheter ablation for atrial fibrillation: impact on mortality, morbidity, quality of life, and implications for the future.

Despite the advances in technologies and techniques in the field of catheter ablation for cardiac arrhythmias, it is estimated that the prevalence of atrial fibrillation (AF) will further increase in the nearest future. The latest trials have proven the beneficial effect on mortality after pulmonary vein isolation in patients with impaired left ventricular function, while no such effect has been seen in patients without left ventricular dysfunction. This raises the question of whether catheter ablation for AF is still suited for the latter patient cohort or whether the endpoint of mortality is not adequate enough. Not only does pulmonary vein isolation reduce the burden of atrial fibrillation, but it also somehow alters the patients' perception of it in the case of recurrence. Independent of the presence of ventricular dysfunction, patients experience a relief of AF-related symptoms, which is accompanied by an increase in quality of life based on the available patient-reported outcome measures, despite AF recurrence. Trials that are currently recruiting patients seek to unveil the accountable circumstances for these remaining uncertainties and help expand our understanding of a procedure that has been routinely performed for two decades.

Use of the HAVOC Score to Identify Patients at Highest Risk of Developing Atrial Fibrillation.

BACKGROUND: Recent studies using insertable cardiac monitors (ICMs) show a high incidence of atrial fibrillation (AF). Further identifying subsets of patients who could benefit most from ICMs is desirable. We evaluated whether the HAVOC risk score which predicts AF in patients with cryptogenic stroke also predicts AF detection by ICMs in those without recent stroke. METHODS: Participants were included from the prospective, industry-sponsored REVEAL AF study assessing AF incidence in patients with CHADS2 scores ≥3 or =2 with 1 or more additional AF risk factors, who had ICM data and were not receiving anti-arrhythmic drugs. Ischemic stroke occurring less than 1 year prior to enrollment or documented AF were exclusion criteria. AF was defined as an adjudicated ICM-detected episode ≥6 min in duration. HAVOC scores were calculated by assigning 4 points for congestive heart failure, 2 points for each of hypertension, age ≥75 years, valvular disease, and coronary artery disease, and 1 point for each of peripheral vascular disease and obesity (body mass index >30). Scores classified risk as low (0-4), intermediate (5-9), or high (10-14); corresponding AF detection rates were compared using the log-rank test. AF incidence rates in patients with and without a history of remote stroke at baseline were also compared. RESULTS: Among 391 participants, the mean age was 71.5 ± 9.8 years and 186 (47.6%) were women. In total, 130 (33.2%) developed AF over 18 months. Stratification by HAVOC risk score was: 95 (24%) low, 241 (62%) intermediate, and 55 (14%) high. At 18 months, AF incidence in patients with low HAVOC scores (19.5%) was lower than in those with intermediate (32.1%) or high (34.2%) scores. AF incidence was similar among those with (n = 78) versus without (n = 313) remote stroke (27.3% vs. 29.8%; median time from stroke to ICM insertion was 4.2 [2.2-8.2] years). CONCLUSIONS: The HAVOC risk score identified a subset of individuals at greatest risk of developing AF, while AF incidence rates were similar among those with and without remote stroke. The use of the HAVOC score could help identify those at greatest likelihood of manifesting AF during long-term monitoring.

Effect of Sacubitril/Valsartan vs Standard Medical Therapies on Plasma NT-proBNP Concentration and Submaximal Exercise Capacity in Patients With Heart Failure and Preserved Ejection Fraction: The PARALLAX Randomized Clinical Trial.

Importance: There is limited evidence on the benefits of sacubitril/valsartan vs broader renin angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute walk distance, and quality of life in patients with heart failure and mildly reduced or preserved left ventricular ejection fraction (LVEF >40%). Objective: To evaluate the effect of sacubitril/valsartan on N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, 6-minute walk distance, and quality of life vs background medication-based individualized comparators in patients with chronic heart failure and LVEF of more than 40%. Design, Setting, and Participants: A 24-week, randomized, double-blind, parallel group clinical trial (August 2017-October 2019). Of 4632 patients screened at 396 centers in 32 countries, 2572 patients with heart failure, LVEF of more than 40%, elevated NT-proBNP levels, structural heart disease, and reduced quality of life were enrolled (last follow-up, October 28, 2019). Interventions: Patients were randomized 1:1 either to sacubitril/valsartan (n = 1286) or to background medication-based individualized comparator (n = 1286), ie, enalapril, valsartan, or placebo stratified by prior use of a renin angiotensin system inhibitor. Main Outcomes and Measures: Primary end points were change from baseline in plasma NT-proBNP level at week 12 and in the 6-minute walk distance at week 24. Secondary end points were change from baseline in quality of life measures and New York Heart Association (NYHA) class at 24 weeks. Results: Among 2572 randomized patients (mean age, 72.6 years [SD, 8.5 years]; 1301 women [50.7%]), 2240 (87.1%) completed the trial. At baseline, the median NT-proBNP levels were 786 pg/mL in the sacubitril/valsartan group and 760 pg/mL in the comparator group. After 12 weeks, patients in the sacubitril/valsartan group (adjusted geometric mean ratio to baseline, 0.82 pg/mL) had a significantly greater reduction in NT-proBNP levels than did those in the comparator group (adjusted geometric mean ratio to baseline, 0.98 pg/mL) with an adjusted geometric mean ratio of 0.84 (95% CI, 0.80 to 0.88; P < .001). At week 24, there was no significant between-group difference in median change from baseline in the 6-minute walk distance with an increase of 9.7 m vs 12.2 m (adjusted mean difference, -2.5 m; 95% CI, -8.5 to 3.5; P = .42). There was no significant between-group difference in the mean change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (12.3 vs 11.8; mean difference, 0.52; 95% CI, -0.93 to 1.97) or improvement in NYHA class (23.6% vs 24.0% of patients; adjusted odds ratio, 0.98; 95% CI, 0.81 to 1.18). The most frequent adverse events in the sacubitril/valsartan group vs the comparator group were hypotension (14.1% vs 5.5%), albuminuria (12.3% vs 7.6%), and hyperkalemia (11.6% vs 10.9%). Conclusions and Relevance: Among patients with heart failure and left ventricular ejection factor of higher than 40%, sacubitril/valsartan treatment compared with standard renin angiotensin system inhibitor treatment or placebo resulted in a significantly greater decrease in plasma N-terminal pro-brain natriuretic peptide levels at 12 weeks but did not significantly improve 6-minute walk distance at 24 weeks. Further research is warranted to evaluate potential clinical benefits of sacubitril/valsartan in these patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03066804.

[The importance of health-related quality of life at baseline in predicting event-free survival in patients with a cardiovascular risk profile]. / Die Bedeutung gesundheitsbezogener Lebensqualität für die Vorhersage des ereignisfreien Überlebens bei Patienten mit kardiovaskulärem Risikoprofil.

The importance of health-related quality of life at baseline in predicting event-free survival in patients with a cardiovascular risk profile Background: Manifest heart failure impairs all dimensions of health-related quality of life (HRQOL). However, the role of HRQOL in patients with risk factors for the development of heart failure with preserved ejection fraction (HFpEF) is only poorly understood. Objective: In this post-hoc analysis of the DIAST-CHF observational study, we tested the hypothesis whether a lower HRQOL at baseline is prognostically associated with an increase in cardiovascular events during follow-up in elderly patients with a cardiovascular risk profile. Methods: The DIAST-CHF observational study enrolled 1.937 patients aged 50 to 85 years with at least one risk factor for the development of HFpEF. HRQOL was assessed using the German version of the Short-Form-36 (SF-36) Health Survey. Results: Patients with comorbid chronic diseases, including manifest heart failure, coronary artery disease, atrial fibrillation, diabetes mellitus and depression, rated their health status (Self-rated health, SRH) significantly worse than those without comorbidities. Older age, higher body-mass index and elevated serum amino-terminal pro-brain natriuretic peptide (NTproBNP) concentration as well as lower left ventricular ejection fraction (LVEF) and impaired 6-minute walk test showed significant relationships to SRH. Kaplan-Meier analyses and Cox regression models using quartiles of either SF-36 subscales "Physical Component Summary" (PCS) or SRH groups demonstrated significant differences in event-free survival (all-cause death or cardiovascular hospitalization), whereas no difference in event-free survival was observed among the quartiles of the SF-36 subscale "Mental Component Summary" (MCS). Conclusion: In patients with risk factors for the development of HFpEF, HRQOL questionnaires are suitable instruments for risk stratification if they capture physical impairments, rather than psychological limitations of quality of life.

Searching for Atrial Fibrillation Poststroke: A White Paper of the AF-SCREEN International Collaboration.

Cardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non-vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non-vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated.

Brain Natriuretic Peptide and Discovery of Atrial Fibrillation After Stroke: A Subanalysis of the Find-AFRANDOMISED Trial.

Background and Purpose- Diagnosing paroxysmal atrial fibrillation (pAF) can be challenging after acute ischemic stroke. Enhanced and prolonged Holter-ECG monitoring (EPM) improves the detection rate but is not feasible for all patients. We hypothesized that brain natriuretic peptide (BNP) may help to identify patients with stroke at high risk for pAF to select patients for EPM more effectively. Methods- Patients with acute cerebral ischemia ≥60 years presenting in sinus rhythm and without history of AF were included into a prospective, randomized multicenter study to receive either EPM (3× 10-day Holter-ECG) or usual stroke care diagnostic work-up. BNP plasma levels were measured on randomization and 3 months thereafter. Levels were compared between patients with and without pAF detected by means of EPM or usual care. Furthermore, the number needed to screen for EPM depending on BNP cut offs was calculated. Results- A total of 398 patients were analyzed. In 373 patients (93.7%), BNP was measured at baseline and in 275 patients (69.1%) after 3 months. pAF was found in 27 patients by means of EPM and in 9 patients by means of usual care (P=0.002). Median BNP was higher in patients with pAF as compared to patients without AF in both study arms at baseline (57.8 versus 28.3 pg/mL in the EPM arm, P=0.0003; 46.2 versus 27.7 pg/mL, P=0.28 in the control arm) and after 3 months (74.9 versus 31.3 pg/mL, P=0.012 in the EPM arm, 99.3 versus 26.3 pg/mL, P=0.02 in the control arm). Applying a cut off of 100 pg/mL, the number needed to screen was reduced from 18 by usual care to 3 by EPM. Conclusions- BNP measured early after ischemic stroke identifies a subgroup of patients with stroke at increased risk for AF, in whom EPM is particularly efficacious. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01855035.

Rhythm monitoring strategies in patients at high risk for atrial fibrillation and stroke: A comparative analysis from the REVEAL AF study.

BACKGROUND: Reducing atrial fibrillation (AF)-related stroke requires timely AF diagnosis, but the optimal monitoring strategy is unknown. OBJECTIVE: We used insertable cardiac monitor (ICM) data from the REVEAL AF study to compare AF detection rates by various short-term continuous monitoring (STM) strategies. METHODS AND RESULTS: Patients without known AF, but with CHADS2 scores ≥3 (or = 2 with ≥1 additional AF risk factor) received an ICM for AF detection. One-time STM strategies were assessed by computing AF incidence at 1, 2, 7, 14, and 30 days post-ICM insertion. Repeated STM strategies (quarterly 24-hour, 48-hour, 7-day, or monthly 24-hour monitoring) were modeled by randomly selecting day(s) within a 30-day window around each nominal evaluation date over a 1-year period (simulated 10,000 times). Endpoints included AF ≥6 minutes, AF ≥1 hour, and daily AF burden ≥1 and ≥ 5.5 hours. The impact of compliance on AF detection was evaluated using daily compliance rates of 85%, 75%, 65% and 55% during follow-up months 1-3, 4-6, 7-9, and 9-12, respectively. Based on data from 385 patients (71.5 ±â€¯9.9 years; CHADS2 score 3.0 ±â€¯1.0) the incidence of AF ≥6 minutes via ICM at 12 months was 27.1% (95% CI, 22.5-31.5%). This exceeded the range of estimated rates from all modeled one-time and repeated STM strategies (0.8% for 24-hour Holter monitoring to 10.6% for quarterly 7-day monitoring). Findings were similar for all AF endpoints. Modeled non-compliance reduced AF detection by 4.5% to 22.9%. CONCLUSIONS: Most AF episodes detected via ICMs would go undetected via conventional STM strategies, thus preventing optimal prophylaxis for adverse consequences.

Efficacy of team-based collaborative care for distressed patients in secondary prevention of chronic coronary heart disease (TEACH): study protocol of a multicenter randomized controlled trial.

BACKGROUND: Coronary heart disease (CHD) is the leading cause of death and years of life lost worldwide. While effective treatments are available for both acute and chronic disease stages there are unmet needs for effective interventions to support patients in health behaviors required for secondary prevention. Psychosocial distress is a common comorbidity in patients with CHD and associated with substantially reduced health-related quality of life (HRQoL), poor health behavior, and low treatment adherence. METHODS: In a confirmatory, randomized, controlled, two-arm parallel group, multicenter behavioral intervention trial we will randomize 440 distressed CHD patients with at least one insufficiently controlled cardiac risk factor to either their physicians' usual care (UC) or UC plus 12-months of blended collaborative care (TeamCare = TC). Trained nurse care managers (NCM) will proactively support patients to identify individual sources of distress and risk behaviors, establish a stepwise treatment plan to improve self-help and healthy behavior, and actively monitor adherence and progress. Additional e-health resources are available to patients and their families. Intervention fidelity is ensured by a treatment manual, an electronic patient registry, and a specialist team regularly supervising NCM via videoconferences and recommending protocol and guideline-compliant treatment adjustments as indicated. Recommendations will be shared with patients and their physicians who remain in charge of patients' care. Since HRQoL is a recommended outcome by both, several guidelines and patient preference we chose a ≥ 50% improvement over baseline on the HeartQoL questionnaire at 12 months as primary outcome. Our primary hypothesis is that significantly more patients receiving TC will meet the primary outcome criterion compared to the UC group. Secondary hypotheses will evaluate improvements in risk factors, psychosocial variables, health care utilization, and durability of intervention effects over 18-30 months of follow-up. DISCUSSION: TEACH is the first study of a blended collaborative care intervention simultaneously addressing distress and medical CHD risk factors conducted in cardiac patients in a European health care setting. If proven effective, its results can improve long-term chronic care of this vulnerable patient group and may be adapted for patients with other chronic conditions. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00020824, registered on 4 June, 2020; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00020824.

NfL (Neurofilament Light Chain) Levels as a Predictive Marker for Long-Term Outcome After Ischemic Stroke.

Background and Purpose- Ischemic stroke causes major disability as a consequence of neuronal loss and recurrent ischemic events. Biomarkers predicting tissue damage or stroke recurrence might be useful to guide an individualized stroke therapy. NfL (neurofilament light chain) is a promising biomarker that might be used for this purpose. Methods- We used individual data of patients with an acute ischemic stroke and clinical long term follow-up. Serum NfL (sNfL) was quantified within 24 hours after admission and after 1 year and compared with other biomarkers (GDF15 [growth differentiation factor 15], S100, NT-proBNP [N-terminal pro-B-type natriuretic peptide], ANP [atrial natriuretic peptide], and FABP [fatty acid-binding protein]). The primary end point was functional outcome after 90 days and cerebrovascular events and death (combined cardiovascular end point) within 36 months of follow-up. Results- Two hundred eleven patients (mean age, 68.7 years; SD, ±12.6; 41.2% women) with median clinical severity on the National Institutes of Health Stroke Scale (NIHSS) score of 3 (interquartile range, 1-5) and long-term follow-up with a median of 41.8 months (interquartile range, 40.0-44.5) were prospectively included. We observed a significant correlation between sNfL and NIHSS at hospital admission (r=0.234; P<0.001). sNfL levels increased with the grade of age-related white matter changes (P<0.001) and were able to predict unfavorable clinical outcome (modified Rankin Scale score, ≥2) 90 days after stroke (odds ratio [OR], 1.562; 95% CI, 1.003-2.433; P=0.048) together with NIHSS (OR, 1.303; 95% CI, 1.164-1.458; P<0.001) and age-related white matter change rating (severe; OR, 3.326; 95% CI, 1.186-9.326; P=0.022). Similarly, sNfL was valuable for the prediction of the combined cardiovascular end point (OR, 2.002; 95% CI, 1.213-3.302; P=0.007), besides NIHSS (OR, 1.110; 95% CI, 1.000-1.232; P=0.049), diabetes mellitus (OR, 2.942; 95% CI, 1.306-6.630; P=0.005), and age-related white matter change rating (severe; OR, 4.816; 95% CI, 1.206-19.229; P=0.026) after multivariate regression analysis. Kaplan-Meier analysis revealed significantly more combined cardiovascular end points (18 [14.1%] versus 38 [45.8%], log-rank test P<0.001) during long-term follow-up in patients with elevated sNfL levels. Conclusions- sNFL is a valuable biomarker for functional independence 90 days after ischemic stroke and predicts cardiovascular long-term outcome. Clinical Trial Registration- URL: http://www.isrctn.com. Unique identifier: ISRCTN 46104198.