Survival and quality of life after early discharge in low-risk pulmonary embolism.

INTRODUCTION: Early discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes. METHODS: The multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism. RESULTS: The primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean±sd PEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of -9.1% (p<0.0001). Improvement was consistent across all PEmb-QoL dimensions. The EQ-5D-5L was 0.89±0.12 at 3 weeks after enrolment and improved to 0.91±0.12 at 3 months (p<0.0001). Female sex and cardiopulmonary disease were associated with poorer disease-specific and generic quality of life; older age was associated with faster worsening of generic quality of life. The ACTS burden score improved from 40.5±6.6 points at 3 weeks to 42.5±5.9 points at 3 months (p<0.0001). CONCLUSIONS: Our results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups.

Early discharge and home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban: an international multicentre single-arm clinical trial.

AIMS: To investigate the efficacy and safety of early transition from hospital to ambulatory treatment in low-risk acute PE, using the oral factor Xa inhibitor rivaroxaban. METHODS AND RESULTS: We conducted a prospective multicentre single-arm investigator initiated and academically sponsored management trial in patients with acute low-risk PE (EudraCT Identifier 2013-001657-28). Eligibility criteria included absence of (i) haemodynamic instability, (ii) right ventricular dysfunction or intracardiac thrombi, and (iii) serious comorbidities. Up to two nights of hospital stay were permitted. Rivaroxaban was given at the approved dose for PE for ≥3 months. The primary outcome was symptomatic recurrent venous thromboembolism (VTE) or PE-related death within 3 months of enrolment. An interim analysis was planned after the first 525 patients, with prespecified early termination of the study if the null hypothesis could be rejected at the level of α = 0.004 (<6 primary outcome events). From May 2014 through June 2018, consecutive patients were enrolled in seven countries. Of the 525 patients included in the interim analysis, three (0.6%; one-sided upper 99.6% confidence interval 2.1%) suffered symptomatic non-fatal VTE recurrence, a number sufficiently low to fulfil the condition for early termination of the trial. Major bleeding occurred in 6 (1.2%) of the 519 patients comprising the safety population. There were two cancer-related deaths (0.4%). CONCLUSION: Early discharge and home treatment with rivaroxaban is effective and safe in carefully selected patients with acute low-risk PE. The results of the present trial support the selection of appropriate patients for ambulatory treatment of PE.

Morbidity and mortality in patients with cardiovascular risk factors and obstructive sleep apnoea: results from the DIAST-CHF cohort.

STUDY OBJECTIVES: Aim of the study was to investigate the association between obstructive sleep apnoea (OSA) and cardiovascular morbidity and mortality in a cohort of patients with cardiovascular risk factors. METHODS: In this prospective study, 378 patients of the DIAST-CHF cohort were screened for OSA by home polygraphy. Inclusion criteria were risk factors for diastolic heart failure, such as hypertension, diabetes mellitus, atherosclerotic disease, or history of chronic heart failure. Patients were followed up after 1, 2, 5, 9 and 10 years for the occurrence of major adverse cardiac and cerebrovascular events (MACE and MACCE). RESULTS: 344 patients were included in the analysis, of which 60% were diagnosed with OSA (apnoea-hypopnoea index ≥5/h). Overall mortality was higher in the OSA group (14.9% vs. 5.9%; p = 0.007), but significance disappeared after adjustment for age and sex (hazard ratio (HR) 1.89, 95% confidence interval (CI) 0.86-4.16, p = 0.12). There was no significant difference in the occurrence of MACE or MACCE in patients with OSA compared to those without OSA (MACE: 31% vs. 30%; p = 0.61; MACCE: 32% vs. 30%; p = 0.53). CONCLUSION: We did not find evidence of an adverse effect of OSA on cardiovascular morbidity and mortality in a cohort of patients with cardiovascular risk factors.

Relevance of supraventricular runs detected after cerebral ischemia.

OBJECTIVE: Prolonged ECG monitoring after stroke frequently reveals short paroxysmal atrial fibrillation (pAF) and supraventricular (SV) runs. The minimal duration of atrial fibrillation (AF) required to induce cardioembolism, the relevance of SV runs, and whether short pAF results from cerebral damage itself are currently being debated. We aimed to study the relevance of SV runs and short pAF detected by prolonged Holter ECG after cerebral ischemia during long-term follow-up. METHODS: Analysis is from the prospective Find-AF trial (ISRCTN46104198). We included patients with acute cerebral ischemia. Those without AF on admission received 7-day Holter ECG monitoring. We differentiated patients with AF on admission (AF-adm), with pAF (>30 seconds), with SV runs (>5 beats but <30 seconds in a 24-hour ECG interval), and without SV runs (controls). During follow-up, those with baseline pAF received another 7-day Holter ECG to examine AF persistence. RESULTS: A total of 254 of 281 initially included patients were analyzed (mean age 70.0 years, 45.3% female). Forty-three (16.9%) had AF-adm. A total of 211 received 7-day Holter ECG monitoring: 27 (12.8%) had pAF, 67 (31.8%) had SV runs, and 117 (55.5%) were controls. During a mean 3.7 years of follow-up, the SV runs group had more recurrent strokes (p = 0.04) and showed numerically more novel AF (12% vs 5%, p = 0.09) than the controls. Seventy-five percent of the patients with manifest pAF detected after cerebral ischemia still had AF during follow-up (50% paroxysmal, 50% persisting/permanent). CONCLUSIONS: Patients with cerebral ischemia and SV runs had more recurrent strokes and numerically more novel AF during follow-up and could benefit from further prolonged ECG monitoring. pAF detected after stroke is not a temporal phenomenon.

Association between Embolic Stroke Patterns, ESUS Etiology, and New Diagnosis of Atrial Fibrillation: A Secondary Data Analysis of the Find-AF Trial.

Background. Atrial fibrillation (AF) is an important cause of embolic stroke of undetermined source (ESUS). Imaging-patterns like multiple infarcts, simultaneous involvement of different circulations, infarcts of different ages, and isolated cortical infarcts are likely to indicate cardioembolic stroke. The aim of our study was to evaluate the association between embolic stroke patterns, ESUS, and the new diagnosis of AF. Methods. Stroke etiology and imaging characteristics from patients included in the Find-AF study were obtained. Embolic stroke patterns in CT- or MR-imaging were correlated with the diagnosis of ESUS as well as the short- (on baseline ECG and during 7-day Holter) and long-term (12-month follow-up) diagnosis of AF. Results. From 281 patients included in the Find-AF study, 127 (45.2%) patients with ischemic lesions detected in CT or MRI were included. 26 (20.5%) of these patients had ESUS. At least one embolic stroke pattern was detected in 67 (52.7%) patients. Embolic stroke patterns were not associated with ESUS (OR 1.57, 0.65-3.79, p = 0.317), the short-term (OR 0.64, 0.26-1.58, p = 0.327) or long-term diagnosis of AF (OR 0.72, 0.31-1.68, p = 0.448). Conclusions. This secondary data analysis of the Find-AF study could not provide evidence for an association between embolic stroke patterns, ESUS, and the new diagnosis of AF.

[GDF-15, MRproADM, CTproET1, and CTproAVP in patients with asymptomatic diastolic dysfunction]. / GDF-15, MRproADM, CTproET1 und CTproAVP bei Patienten mit asymptomatischer diastolischer Dysfunktion.

BACKGROUND: The role of biomarkers in asymptomatic diastolic dysfunction (DD) has not been investigated so far. The aim of the study was to evaluate the clinical associations and the diagnostic property of different biomarkers in patients with asymptomatic DD. METHODS: Within a population based observational study, healthy participants (50-85 years) with an LVEF ≥ 50 % and no cardiovascular risk factor were prospectively identified. Patients were classified as having either DD (grade ≥ 1, n = 103) or no DD (CON: n = 85). All patients underwent physical examination including medical history, six-minute-walk-testing, QoL (SF-36), comprehensive echocardiography and blood sampling to measure routine values and specified biomarkers (NTproBNP, MRproANP, GDF-15, MRproADM, CTproET1, CTproAVP). RESULTS: In the DD-group plasma concentration of GDF-15 (p = 0,002), MRproADM (p < 0,001), and CTproAVP (p = 0,003) were significantly higher than in the CON-group. In contrast, NTproBNP (p = 0,390), MRproANP (p = 287), and CTproET1 (p = 0,393) did not differ. GDF-15, MRproADM and CTproAVP were significantly associated with the presence of DD. However, the significance of the seen associations was lost after multiple adjustments. NTproBNP, MRproANP, and MRproADM were significantly related to E / e' as a continuous measure of diastolic function. The significance of the seen associations was lost after multiple adjustments. In ROC analyses, none of the investigated biomarkers was able to relevantly improve the diagnosis of DD. CONCLUSION: In patients with asymptomatic DD plasma concentrations of GDF-15, MRproADM and CT-proAVP were significantly higher when compared with controls. In contrast, NTproBNP, MRproANP and CTproET1 did not differ. After adjustment for age, sex, BMI and renal function, no significant association between DD or E / e' and different biomarkers could be observed. Furthermore, none of the investigated biomarkers was able to substantially improve the diagnosis of DD.

Determinants of submaximal exercise capacity in patients at risk for heart failure with preserved ejection fraction-results from the DIAST-CHF study.

OBJECTIVES AND BACKGROUND: The aim of this study was to identify determinants of submaximal exercise capacity as measured by 6 min walking distance in patients at risk for heart failure with preserved ejection fraction (HFpEF). METHODS: A cross-sectional analysis from the prospective cohort programme Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure (DIAST-CHF) that included a total of 1937 patients (age, 50-85 years) with >1 risk factor (hypertension, atherosclerotic disease, diabetes mellitus, and obstructive sleep apnoea) was carried out. Besides comprehensive clinical phenotyping, standardized 6 min walk test and state-of-the-art echocardiography were performed, and blood samples for biomarker assessment were obtained. Patients with an ejection fraction <50% or without evaluable exercise test were excluded from this analysis. RESULTS: One thousand three hundred eighty-seven patients fulfilled all criteria for this analysis. In the univariate analysis, 6 min walk distance was inversely related to E/e' values (P < 0.001). In the multivariate analysis, 6 min walk distance decreased significantly with age, female sex, increasing body mass index, diabetes, chronic obstructive lung disease, and peripheral artery disease. However, the association of 6 min walk distance with resting parameters of diastolic function was significantly attenuated with multivariate regression. In contrast, mid-regional pro-adrenomedullin, mid-regional pro-atrial natriuretic peptide, and N-terminal pro-B-type natriuretic peptide were independently associated with submaximal exercise capacity when added to the base model (all P < 0.001). CONCLUSIONS: Classical risk factors for heart failure and neuroendocrine activation are independently associated with sub-maximal exercise capacity, while diastolic function parameters obtained at rest were not. This observation substantiates the role of co-morbidities as relevant contributors to the clinical picture of HFpEF and the limitation of resting indices of diastolic function for diagnosing HFpEF.

Finding atrial fibrillation in stroke patients: Randomized evaluation of enhanced and prolonged Holter monitoring--Find-AF(RANDOMISED) --rationale and design.

BACKGROUND: Detecting paroxysmal atrial fibrillation (AF) in patients with ischemic strokes presenting in sinus rhythm is challenging because episodes are often short, occur randomly, and are frequently asymptomatic. If AF is detected, recurrent thromboembolism can be prevented efficiently by oral anticoagulation. Numerous uncontrolled studies using various electrocardiogram (ECG) devices have established that prolonged ECG monitoring increases the yield of AF detection, but most established procedures are time-consuming and costly. The few randomized trials are mostly limited to cryptogenic strokes. The optimal method, duration, and patient selection remain unclear. Repeated prolonged continuous Holter ECG monitoring to detect paroxysmal AF within an unspecific stroke population may prove to be a widely applicable, effective secondary prevention strategy. STUDY DESIGN: Find-AFRANDOMISED is a randomized and controlled prospective multicenter trial. Four hundred patients 60 years or older with manifest (symptoms ≥24 hours or acute computed tomography/magnetic resonance imaging lesion) and acute (symptoms ≤7 days) ischemic strokes will be included at 4 certified stroke centers in Germany. Those with previously diagnosed AF/flutter, indications/contraindications for oral anticoagulation, or obvious causative blood vessel pathologies will be excluded. Patients will be randomized 1:1 to either enhanced and prolonged Holter ECG monitoring (10 days at baseline and after 3 and 6 months) or standard of care (≥24-hour continuous ECG monitoring, according to current stroke guidelines). All patients will be followed up for at least 12 months. OUTCOMES: The primary end point is newly detected AF (≥30 seconds) after 6 months, confirmed by an independent adjudication committee. We plan to complete recruitment in autumn 2014. First results can be expected by spring 2016.

Associations of methylarginines and homoarginine with diastolic dysfunction and cardiovascular risk factors in patients with preserved left ventricular ejection fraction.

BACKGROUND: Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and homoarginine are considered to modulate nitric oxide synthesis. We evaluated whether ADMA, SDMA, and homoarginine are associated with diastolic dysfunction. METHODS AND RESULTS: We investigated primary care patients at cardiovascular risk with preserved left ventricular ejection fraction from the multicenter DIAST-CHF study. We measured serum concentrations of ADMA, SDMA, and homoarginine and performed standardized echocardiographic examinations. Among 1,396 patients (mean age 65.3 ± 8.3 y, 54.6% women), diastolic dysfunction was ruled out in 261 patients (18.7%). Mild and moderate/severe grades of diastolic dysfunction were present in 900 (64.5%) and 235 (16.8%) study participants, respectively. After adjustments for cardiovascular risk factors, ADMA and SDMA were positively and homoarginine negatively associated with N-terminal pro-B-type natriuretic peptide and midregional pro-adrenomedullin (P < .05 for all). Lower homoarginine levels were associated with diastolic dysfunction, and higher ADMA and SDMA levels were associated with the severity of diastolic dysfunction (P < .05 for all). CONCLUSIONS: Higher levels of ADMA and SDMA and lower levels of homoarginine are associated with an adverse cardiovascular risk profile and diastolic dysfunction. Further studies should clarify the potential of these amino acid derivatives for the therapy of cardiovascular diseases.

Differential interaction of clinical characteristics with key functional parameters in heart failure with preserved ejection fraction--results of the Aldo-DHF trial.

BACKGROUND: To investigate the interaction of clinical characteristics with disease characterising parameters in heart failure with preserved ejection fraction (HFpEF). Methods and results In the multicenter, randomized, placebo-controlled, double-blinded, Aldo-DHF trial investigating the effects of spironolactone on exercise capacity (peakVO2) and diastolic function (E/e') n=422 patients with HFpEF (age 67 ± 8 years, 52% females, LVEF 67 ± 8%) were included. After multiple adjustment, higher age was significantly related to reduced peakVO2, and to increased E/e', NT-proBNP, LAVI as well as LVMI (all p<0.05). Female gender (p<0.001), CAD (p=0.002), BMI (p<0.001), sleep apnoea (p=0.02), and chronotropic incompetence (CI, p=0.002) were related to lower peakVO2 values. Higher pulse pressure (p=0.04), lower heart rates (p=0.03), CI (p=0.03) and beta-blocker treatment (p=0.001) were associated with higher E/e'. BMI correlated inversely (p=0.03), whereas atrial fibrillation (p<0.001), lower haemoglobin levels (p<0.001), CI (p=0.02), and beta-blocker treatment (p<0.001) were associated with higher NT-proBNP. After multiple adjustment for demographic and clinical variables peakVO2 was not significantly associated with E/e' (r=+0.01, p=0.87), logNT-proBNP (r=0.09, p=0.08), LAVI (r=+0.03, p=0.55), and LVMI (r=+0.05, p=0.37). The associations of E/e' with logNT-proBNP (r=0.21, p<0.001), LAVI (r=+0.29, p<0.001) and LVMI (r=0.09, p=0.06) were detectable also after multiple adjustment. CONCLUSIONS: Demographic and clinical characteristics differentially interact with exercise capacity, resting left ventricular filling index, neurohumoral activation, and left atrial and ventricular remodelling in HFpEF. Exercise intolerance in HFpEF is multi-factorial and therapeutic approaches addressing exercise capacity should therefore not only aim to improve single pathological mechanisms. REGISTRATION: ISRCTN94726526 (http://www.controlled-trials.com), Eudra-CT-number 2006-002605-31.

Cost-effectiveness of 7-day-Holter monitoring alone or in combination with transthoracic echocardiography in patients with cerebral ischemia.

BACKGROUND AND PURPOSE: Prolonged Holter monitoring of patients with cerebral ischemia increases the detection rate of paroxysmal atrial fibrillation (PAF); this leads to improved antithrombotic regimens aimed at preventing recurrent ischemic strokes. The aim of this study was to compare a 7-day-Holter monitoring (7-d-Holter) alone or in combination with prior selection via transthoracic echocardiography (TTE) to a standard 24-h-Holter using a cost-utility analysis. METHODS: Lifetime cost, quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER) were estimated for a cohort of patients with acute cerebral ischemia and no contraindication to oral anticoagulation. A Markov model was developed to simulate the long-term course and progression of cerebral ischemia considering the different diagnostic algorithms (24-h-Holter, 7-d-Holter, 7-d-Holter after preselection by TTE). Clinical data for these algorithms were derived from the prospective observational Find-AF study (ISRCTN 46104198). RESULTS: Predicted lifelong discounted costs were 33,837 for patients diagnosed by the 7-d-Holter and 33,852 by the standard 24-h-Holter. Cumulated QALYs were 3.868 for the 7-d-Holter compared to 3.844 for the 24-h-Holter. The 7-d-Holter dominated the 24-h-Holter in the base-case scenario and remained cost-effective in extensive sensitivity analysis of key input parameter with a maximum of 8,354 /QALY gained. Preselecting patients for the 7-d-Holter had no positive effect on the cost-effectiveness. CONCLUSIONS: A 7-d-Holter to detect PAF in patients with cerebral ischemia is cost-effective. It increases the detection which leads to improved antithrombotic regimens; therefore, it avoids recurrent strokes, saves future costs, and decreases quality of life impairment. Preselecting patients by TTE does not improve cost-effectiveness.

Excessive supraventricular ectopic activity is indicative of paroxysmal atrial fibrillation in patients with cerebral ischemia.

BACKGROUND: Detecting paroxysmal atrial fibrillation (PAF) in patients with cerebral ischemia is challenging. Frequent premature atrial complexes (PAC/h) and the longest supraventricular run on 24-h-Holter (SV-run(24 h)), summarised as excessive supraventricular ectopic activity (ESVEA), may help selecting patients for extended ECG-monitoring, especially in combination with echocardiographic marker LAVI/a' (left atrial volume index/late diastolic tissue Doppler velocity). METHODS: Retrospective analysis from the prospective monocentric observational trial Find-AF (ISRCTN-46104198). Patients with acute stroke or TIA were enrolled at the University Hospital Göttingen, Germany. Those with sinus rhythm at presentation received 7-day Holter-monitoring. ESVEA was quantified in one 24-hour interval free from PAF. Echocardiographic parameters were assessed prospectively. RESULTS: PAF was detected in 23/208 patients (11.1%). The median was 4 [IQR 1; 22] for PAC/h and 5 [IQR 0; 9] for SV-run(24 h). PAF was more prevalent in patients with ESVEA: 19.6% vs. 2.8% for PAC/h >4 vs. ≤ 4 (p<0.001); 17.0% vs. 4.9% for SV-run(24 h >5) vs. ≤ 5 beats (p = 0.003). Patients with PAF showed more supraventricular ectopic activity: 29 PAC/h [IQR 9; 143] vs. 4 PAC/h [1]; [14] and longest SV-run(24 h = 10) [5]; [21] vs. 0 [0; 8] beats (both p<0.001). Both markers discriminated between the PAF- and the Non-PAF-group (area under receiver-operator-characteristics-curve 0.763 [95% CI 0.667; 0.858] and 0.716 [0.600; 0.832]). In multivariate analyses log(PAC/h) and log(SV-run(24 h)) were independently indicative of PAF. In Patients with PAC/h ≤ 4 and normal LAVI/a' PAF was excluded, whereas those with PAC/h >4 and abnormal LAVI/a' showed high PAF-rates. CONCLUSIONS: ESVEA discriminated PAF from non-PAF beyond clinical factors including LAVI/a' in patients with cerebral ischemia. Normal LAVI/a'+PAC/h ≤ 4 ruled out PAF, while prevalence was high in those with abnormal LAVI/a'+PAC/h >4.

Age-dependent yield of screening for undetected atrial fibrillation in stroke patients: the Find-AF study.

Diagnosis of paroxysmal atrial fibrillation (AF) in stroke patients is challenging, but highly clinically relevant. The percentage of stroke patients with permanent AF increases with age, but limited data are available for the age-dependent yield of paroxysmal AF by Holter monitoring. Patients with acute cerebral ischemia were included into the prospective observational Find-AF study. Patients free from AF at presentation received 7 day Holter monitoring. We calculated the percentage of otherwise undetected paroxysmal AF and the number needed to screen for age groups under 60 years, and in 5 year clusters from the age of 60 up to 85 and older. 272 patients were included, 43 (15.8 %) had AF at admission, 33 patients with paroxysmal AF were identified by 7 day Holter (n = 29) or medical history (n = 4).The yield of 7 day Holter ECG clearly increased with older age (p = 0.004): <60 years: 5 %, 60-64 years: 5 %, 65-69 years: 7 %, 70-74 years: 11 %, 75-79 years: 13 %, 80-84 years: 25 %, ≥ 85 years: 39 %. The number needed to screen (NNS) to find one patient with paroxysmal AF decreased with age: ≤ 60 years: 18, 60-64 years: 20, 65-69 years: 14, 70-74 years: 9, 75-79 years: 8, 80-84 years: 4, ≥ 85 years: 3, respectively. In patients <65 years, all AF cases were detected by Holter ECG. The percentage of paroxysmal AF in stroke patients increases with age. The 7 day Holter ECG is most efficient in elderly patients.

Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial.

IMPORTANCE: Diastolic heart failure (ie, heart failure with preserved ejection fraction) is a common condition without established therapy, and aldosterone stimulation may contribute to its progression. OBJECTIVE: To assess the efficacy and safety of long-term aldosterone receptor blockade in heart failure with preserved ejection fraction. The primary objective was to determine whether spironolactone is superior to placebo in improving diastolic function and maximal exercise capacity in patients with heart failure with preserved ejection fraction. DESIGN AND SETTING: The Aldo-DHF trial, a multicenter, prospective, randomized, double-blind, placebo-controlled trial conducted between March 2007 and April 2012 at 10 sites in Germany and Austria that included 422 ambulatory patients (mean age, 67 [SD, 8] years; 52% female) with chronic New York Heart Association class II or III heart failure, preserved left ventricular ejection fraction of 50% or greater, and evidence of diastolic dysfunction. INTERVENTION: Patients were randomly assigned to receive 25 mg of spironolactone once daily (n=213) or matching placebo (n=209) with 12 months of follow-up. MAIN OUTCOME MEASURES: The equally ranked co-primary end points were changes in diastolic function (E/e') on echocardiography and maximal exercise capacity (peak VO2) on cardiopulmonary exercise testing, both measured at 12 months. RESULTS: Diastolic function (E/e') decreased from 12.7 (SD, 3.6) to 12.1 (SD, 3.7) with spironolactone and increased from 12.8 (SD, 4.4) to 13.6 (SD, 4.3) with placebo (adjusted mean difference, -1.5; 95% CI, -2.0 to -0.9; P < .001). Peak VO2 did not significantly change with spironolactone vs placebo (from 16.3 [SD, 3.6] mL/min/kg to 16.8 [SD, 4.6] mL/min/kg and from 16.4 [SD, 3.5] mL/min/kg to 16.9 [SD, 4.4] mL/min/kg, respectively; adjusted mean difference, +0.1 mL/min/kg; 95% CI, -0.6 to +0.8 mL/min/kg; P = .81). Spironolactone induced reverse remodeling (left ventricular mass index declined; difference, -6 g/m2; 95% CI, -10 to-1 g/m2; P = .009) and improved neuroendocrine activation (N-terminal pro-brain-type natriuretic peptide geometric mean ratio, 0.86; 95% CI, 0.75-0.99; P = .03) but did not improve heart failure symptoms or quality of life and slightly reduced 6-minute walking distance (-15 m; 95% CI, -27 to -2 m; P = .03). Spironolactone also modestly increased serum potassium levels (+0.2 mmol/L; 95% CI, +0.1 to +0.3; P < .001) and decreased estimated glomerular filtration rate (-5 mL/min/1.73 m2; 95% CI, -8 to -3 mL/min/1.73 m2; P < .001) without affecting hospitalizations. CONCLUSIONS AND RELEVANCE: In this randomized controlled trial, long-term aldosterone receptor blockade improved left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms, or quality of life in patients with heart failure with preserved ejection fraction. Whether the improved left ventricular function observed in the Aldo-DHF trial is of clinical significance requires further investigation in larger populations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN94726526; Eudra-CT No: 2006-002605-31.

High-sensitivity troponin assay improves prediction of cardiovascular risk in patients with cerebral ischaemia.

BACKGROUND AND PURPOSE: Clinical scores are recommended for predicting cardiovascular risk in patients with cerebral ischaemia to inform secondary prevention. Blood biomarkers may improve prediction beyond clinical scores. METHODS: Within the observational Find-AF trial (ISRCTN46104198), 197 patients >18 years of age with cerebral ischaemia and without atrial fibrillation had blood sampled at baseline. The predictive value of five biomarkers for a combined vascular endpoint (acute coronary syndrome, stroke, cardiovascular death) and all-cause mortality was determined, alone and in addition to the Essen Stroke Risk Score (ESRS), Stroke Prognostic Instrument 2 (SPI-2) and National Institutes of Health Stroke Scale (NIH-SS). RESULTS: There were 23 vascular events (11.7%) and 13 deaths (6.6%) to 1 year follow-up. In multivariate analyses of all markers, only high-sensitivity troponin T (hsTropT) remained independently predictive for vascular events (p=0.045) and all-cause mortality (p=0.004). hsTropT was higher in patients with a vascular event (median 12.7 ng/ml vs 5.1 ng/ml), and patients with hsTropT above the median of 6.15 ng/ml had vascular events more frequently (HR 3.86, p=0.008). For prediction of vascular events as well as all-cause mortality, hsTropT significantly improved multivariate Cox regression models with ESRS, SPI-2 or NIH-SS. The c-statistic increased non-significantly from 0.695 (ESRS) or 0.710 (hsTropT) to 0.747 (ESRS+hsTropT) and from 0.699 (SPI-2) to 0.763 (SPI-2+hsTropT). No patient with a low-risk ESRS and an hsTropT below the median had a vascular event or died. CONCLUSIONS: hsTropT predicts vascular events and all-cause mortality in patients with acute cerebral ischaemia and improves prediction beyond established clinical scores.

Impact of obstructive sleep apnoea on diastolic function.

We investigated whether obstructive sleep apnoea (OSA) independently affects diastolic function in a primary care cohort of patients with cardiovascular risk factors. 378 study participants with risk factors for diastolic dysfunction were prospectively included and a polygraphy was performed in all patients. Diastolic dysfunction was assessed by comprehensive echocardiography including tissue Doppler. Sleep apnoea was classified according to apnoea/hypopnoea index (AHI) as none (AHI <5 events·h(-1)), mild (AHI ≤5 to <15 events·h(-1)) or moderate-to-severe (AHI ≥15 events·h(-1)). Patients with central sleep apnoea (n=14) and patients with previously diagnosed sleep apnoea (n=12) were excluded. In the remaining 352 subjects, 21.6% had an AHI ≥15 events·h(-1). The prevalence of diastolic dysfunction increased with the severity of sleep apnoea from 44.8% (none) to 56.8% (mild) to 69.7% (moderate-to-severe sleep apnoea) (p=0.002). The degree of diastolic dysfunction also increased with sleep apnoea severity (p=0.004). In univariate regression analysis, age, desaturation index, AHI, cardiac frequency, angiotensin receptor 1 antagonist therapy, body mass index (BMI) and left ventricular mass were associated with diastolic dysfunction. In multivariate regression analysis, only age, BMI, AHI and cardiac frequency were independently associated with diastolic dysfunction. Moderate-to-severe OSA is independently associated with diastolic dysfunction in patients with classical risk factors for diastolic dysfunction.

Natriuretic peptides for the detection of paroxysmal atrial fibrillation in patients with cerebral ischemia--the Find-AF study.

BACKGROUND AND PURPOSE: Diagnosis of paroxysmal atrial fibrillation (AF) can be challenging, but it is highly relevant in patients presenting with sinus rhythm and acute cerebral ischemia. We aimed to evaluate prospectively whether natriuretic peptide levels and kinetics identify patients with paroxysmal AF. METHODS: Patients with acute cerebral ischemia were included into the prospective observational Find-AF study. N-terminal pro brain-type natriuretic peptide (NT-proBNP), brain-type natriuretic peptide (BNP) and N-terminal pro atrial-type natriuretic peptide (NT-proANP) plasma levels were measured on admission, after 6 and 24 hours. Patients free from AF at presentation received 7 day Holter monitoring. We prospectively hypothesized that patients presenting in sinus rhythm with NT-proBNP>median were more likely to have paroxysmal AF than patients with NT-proBNPmedian (239 pg/ml), 17.9% had paroxysmal AF in contrast to 7.4% with NT-proBNP<239 pg/ml (p = 0.025). The ratio of early (0 h) to late (24 h) plasma levels of NT-proBNP showed no difference between both groups. For the detection of paroxysmal atrial fibrillation, BNP, NT-proBNP and NT-proANP at admission had an area under the curve in ROC analysis of 0.747 (0.663-0.831), 0.638 (0.531-0.744) and 0.663 (0.566-0.761), respectively. In multivariate analysis, BNP was the only biomarker to be independently predictive for paroxysmal atrial fibrillation. CONCLUSIONS: BNP is independently predictive of paroxysmal AF detected by prolonged ECG monitoring in patients with cerebral ischemia and may be used to effectively select patients for prolonged Holter monitoring.

Growth-differentiation factor-15 and functional outcome after acute ischemic stroke.

Blood biomarkers may improve the performance in predicting early stroke outcome beyond well-established clinical factors. We investigated the value of growth-differentiation factor-15 (GDF-15) to predict functional outcome after 90 days in a prospectively collected patient cohort with symptoms of acute ischemic stroke. Two hundred eighty-one patients with symptoms of acute ischemic stroke were prospectively investigated. Serial blood samples for GDF-15 analysis were obtained after the admission of the patient, after 6 and 24 h. Primary outcome was the dichotomized modified ranking scale (MRS) 90 days after the initial clinical event. Within the final study population (264 patients, mean age 70.3 ± 12.7 years, 55.3% male), National Institutes of Health Stroke Scale (NIH-SS) [odds ratio (OR) 1.269, 95% confidence interval (CI) 1.141-1.412, p < 0.001] and initial GDF-15 levels (OR 1.029, 95% CI 1.007-1.053, p = 0.011) were independently associated with a MRS ≥ 2 after day 90 after multiple regression analysis. Growth-differentiation factor-15 levels increase with higher NIH-SS-tertiles (p = 0.005). Receiver-operator characteristic curves demonstrated a discriminatory accuracy to predict unfavourable stroke outcome of 0.629 (95% CI 0.558-0.699), 0.753 (95% CI 0.693-812) and 0.774 (95% CI 0.717-0.832) for GDF-15, NIH-SS and the combination of these variables. The additional use of GDF-15 to NIH-SS ameliorates the model with a net reclassification index of 0.044 (p = 0.541) and integrated discrimination improvement of 0.034 (p = 0.443). Growth-differentiation factor-15 as an acute stroke biomarker independently predicts unfavourable functional 90 day stroke outcome. Discriminatory value in addition to NIH-SS is only modestly distinct.