Erland Erdmann

Thiazolidinedione therapy in type 2 diabetes is associated with an increased risk of heart failure, but this appears to lack long-term mortality consequences and may represent fluid retention rather than direct myocardial toxicity.

IASO-DCM trial tests if immunoadsorption with IgG substitution improves LVEF in DCM.

Effect of adaptive servo ventilation on central sleep apnea and sleep structure in systolic heart failure patients: polysomnography data from the SERVE‐HF major sub study

Heart rate of 77 bpm or higher at discharge was associated with an almost doubled mortality risk (p = 0.015), and a 5 bpm increase was associated with a 25% increase in mortality (p = 0.022).

FerreiraESC Heart Failure

Biomarkers in Patients with Heart Failure and Central Sleep Apnoea: Findings From the SERVE-HF Trial

AIMS: The Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients with Heart Failure trial investigated the effects of adaptive servo-ventilation (ASV) (vs. control) on outcomes of 1325 patients with heart failure and reduced ejection fraction (HFrEF) and central sleep apnoea (CSA). The primary outcome (a composite of all-cause death or unplanned HF hospitalization) did not differ between the two groups. However, all-cause and cardiovascular (CV) mortality were higher in the ASV group. Circulating biomarkers may help in better ascertain patients' risk, and this is the first study applying a large set of circulating biomarkers in patients with both HFrEF and CSA. METHODS AND RESULTS: Circulating protein-biomarkers (n = 276) ontologically involved in CV pathways, were studied in 749 (57% of the trial population) patients (biomarker substudy), to investigate their association with the study outcomes (primary outcome, CV death and all-cause death). The mean age was 69 ± 10 years, and > 90% were male. The groups (ASV vs. control and biomarker substudy vs. no biomarker) were well balanced. The "best" clinical prognostic model included male sex, systolic blood pressure < 120 mmHg, diabetes, loop diuretic, cardiac device, 6-min walking test distance, and N-terminal pro BNP as the strongest prognosticators. On top of the "best" clinical prognostic model, the biomarkers that significantly improved both the discrimination (c-index) and the net reclassification index (NRI) of the model were soluble suppression of tumorigenicity 2 for the primary outcome; neurogenic locus notch homolog protein 3 (Notch-3) for CV-death and all-cause death; and growth differentiation factor 15 (GDF-15) for all-cause death only. CONCLUSIONS: We studied 276 circulating biomarkers in patients with HFrEF and central sleep apnoea; of these biomarkers, three added significant prognostic information on top of the best clinical model: soluble suppression of tumorigenicity 2 (primary outcome), Notch-3 (CV and all-cause death), and GDF-15 (all-cause death).

Association of serious adverse events with Cheyne–Stokes respiration characteristics in patients with systolic heart failure and central sleep apnoea: A SERVE‐Heart Failure substudy analysis

BACKGROUND AND OBJECTIVE: Increases in Cheyne-Stokes respiration (CSR) cycle length (CL), lung-to-periphery circulation time (LPCT) and time to peak flow (TTPF) may reflect impaired cardiac function. This retrospective analysis used an automatic algorithm to evaluate baseline CSR-related features and then determined whether these could be used to identify patients with systolic heart failure (HF) who experienced serious adverse events in the Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure (SERVE-HF) substudy. METHODS: A total of 280 patients had overnight diagnostic polysomnography data available; an automated algorithm was applied to quantify CSR-related features. RESULTS: Median baseline CL, LPCT and TTPF were similar in the control (n = 152) and adaptive servo-ventilation (ASV, n = 156) groups. In both groups, CSR-related features were significantly longer in patients who did (n = 129) versus did not (n = 140) experience a primary endpoint event (all-cause death, life-saving cardiovascular intervention or unplanned hospitalization for worsening HF): CL, 61.1 versus 55.1 s (P = 0.002); LPCT, 36.5 versus 31.5 s (P < 0.001); TTPF, 15.20 versus 13.35 s (P < 0.001), respectively. This finding was independent of treatment allocation. CONCLUSION: Patients with systolic HF and central sleep apnoea who experienced serious adverse events had longer CSR CL, LPCT and TTPF. Future studies should examine an independent role for CSR-related features to enable risk stratification in systolic HF.

Mini Review on: Simple, Practical, and Evidence-Based - an Algorithm for The Diagnosis and Treatment of Iron Deficiency

Iron deficiency is a common comorbidity in chronic heart failure (CHF) with a negative impact on the outcome of the patient. Even without anaemia iron deficiency can cause decreased physical performance, poor quality of life, and increased mortality. Therefore it is important to diagnose and treat iron deficiency, especially in patients with CHF.

CowieEuropean Journal of Heart Failure

Adaptive Servo-Ventilationf for Central Sleep Apnoea in Systolic Heart Failure: Results of the Major Substudy of SERVE-HF

AIMS: The SERVE-HF trial investigated the impact of treating central sleep apnoea (CSA) with adaptive servo-ventilation (ASV) in patients with systolic heart failure. A preplanned substudy was conducted to provide insight into mechanistic changes underlying the observed effects of ASV, including assessment of changes in left ventricular function, ventricular remodelling, and cardiac, renal and inflammatory biomarkers. METHODS AND RESULTS: In a subset of the 1325 randomised patients, echocardiography, cardiac magnetic resonance imaging (cMRI) and biomarker analysis were performed at baseline, and 3 and 12 months. In secondary analyses, data for patients with baseline and 12-month values were evaluated; 312 patients participated in the substudy. The primary endpoint, change in echocardiographically determined left ventricular ejection fraction from baseline to 12 months, did not differ significantly between the ASV and the control groups. There were also no significant between-group differences for changes in left ventricular dimensions, wall thickness, diastolic function or right ventricular dimensions and ejection fraction (echocardiography), and on cMRI (in small patient numbers). Plasma N-terminal pro B-type natriuretic peptide concentration decreased in both groups, and values were similar at 12 months. There were no significant between-group differences in changes in cardiac, renal and systemic inflammation biomarkers. CONCLUSION: In patients with systolic heart failure and CSA, addition of ASV to guideline-based medical management had no statistically significant effect on cardiac structure and function, or on cardiac biomarkers, renal function and systemic inflammation over 12 months. The increased cardiovascular mortality reported in SERVE-HF may not be related to adverse remodelling or worsening heart failure.

Phenotyping of Sleep‐Disordered Breathing in Patients With Chronic Heart Failure With Reduced Ejection Fraction—the SchlaHF Registry

Background Different sleep‐disordered breathing ( SDB ) phenotypes, including coexisting obstructive and central sleep apnea ( OSA ‐ CSA ), have not yet been characterized in a large sample of patients with heart failure and reduced ejection fraction ( HF r EF ) receiving guideline‐based therapies. Therefore, the aim of the present study was to determine the proportion of OSA , CSA , and OSA ‐ CSA , as well as periodic breathing, in HF r EF patients with SDB . Methods and Results The German Schla HF registry enrolled patients with HF r EF receiving guideline‐based therapies, who underwent portable SDB monitoring. Polysomnography (n=2365) was performed in patients with suspected SDB . Type of SDB ( OSA , CSA , or OSA ‐ CSA ), the occurrence of periodic breathing (proportion of Cheyne‐Stokes respiration ≥20%), and blood gases were determined in 1557 HF r EF patients with confirmed SDB . OSA , OSA ‐ CSA , and CSA were found in 29%, 40%, and 31% of patients, respectively; 41% showed periodic breathing. Characteristics differed significantly among SDB groups and in those with versus without periodic breathing. There was a relationship between greater proportions of CSA and the presence of periodic breathing. Risk factors for having CSA rather than OSA were male sex, older age, presence of atrial fibrillation, lower ejection fraction, and lower awake carbon dioxide pressure ( pco 2 ). Periodic breathing was more likely in men, patients with atrial fibrillation, older patients, and as left ventricular ejection fraction and awake pco 2 decreased, and less likely as body mass index increased and minimum oxygen saturation decreased. Conclusions Schla HF data show that there is wide interindividual variability in the SDB phenotype of HF r EF patients, suggesting that individualized management is appropriate. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 01500759.

WoehrleEuropean Respiratory Journal

Adaptive servo ventilation for central sleep apnoea in heart failure: SERVE-HF on-treatment analysis

This on-treatment analysis was conducted to facilitate understanding of mechanisms underlying the increased risk of all-cause and cardiovascular mortality in heart failure patients with reduced ejection fraction and predominant central sleep apnoea randomised to adaptive servo ventilation versus the control group in the SERVE-HF trial. Time-dependent on-treatment analyses were conducted (unadjusted and adjusted for predictive covariates). A comprehensive, time-dependent model was developed to correct for asymmetric selection effects (to minimise bias). The comprehensive model showed increased cardiovascular death hazard ratios during adaptive servo ventilation usage periods, slightly lower than those in the SERVE-HF intention-to-treat analysis. Self-selection bias was evident. Patients randomised to adaptive servo ventilation who crossed over to the control group were at higher risk of cardiovascular death than controls, while control patients with crossover to adaptive servo ventilation showed a trend towards lower risk of cardiovascular death than patients randomised to adaptive servo ventilation. Cardiovascular risk did not increase as nightly adaptive servo ventilation usage increased. On-treatment analysis showed similar results to the SERVE-HF intention-to-treat analysis, with an increased risk of cardiovascular death in heart failure with reduced ejection fraction patients with predominant central sleep apnoea treated with adaptive servo ventilation. Bias is inevitable and needs to be taken into account in any kind of on-treatment analysis in positive airway pressure studies.

CowieNew England Journal of Medicine

Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure

CowieCardiac failure review

Sleep-disordered Breathing in Heart Failure – Current State of the Art

Sleep-disordered breathing (SDB), either obstructive sleep apnoea (OSA) or central sleep apnoea (CSA)/Cheyne-Stokes respiration (CSR) and often a combination of the two, is highly prevalent in patients with heart failure (HF), is associated with reduced functional capacity and quality of life, and has a negative prognostic impact. European HF guidelines identify that sleep apnoea is of concern in patients with HF. Continuous positive airway pressure is the treatment of choice for OSA, and adaptive servoventilation (ASV) appears to be the most consistently effective therapy for CSA/CSR while also being able to treat concomitant obstructive events. There is a growing body of evidence that treating SDB in patients with HF, particularly using ASV for CSA/CSR, improves functional outcomes such as HF symptoms, cardiac function, cardiac disease markers, exercise tolerance and quality of life. However, conflicting results have been reported on 'hard' outcomes such as mortality and healthcare utilisation, and the influence of effectively treating SDB, including CSA/CSR, remains to be determined in randomised clinical trials. Two such trials (SERVE-HF and ADVENT-HF) in chronic stable HF and another in post-acute decompensated HF (CAT-HF) are currently underway.

WoehrleBMC Cardiovascular Disorders

Determining the prevalence and predictors of sleep disordered breathing in patients with chronic heart failure: rationale and design of the SCHLA-HF registry

BACKGROUND: The objective of the SCHLA-HF registry is to investigate the prevalence of sleep-disordered breathing (SDB) in patients with chronic heart failure with reduced left ventricular systolic function (HF-REF) and to determine predictors of SDB in such patients. METHODS: Cardiologists in private practices and in hospitals in Germany are asked to document patients with HF-REF into the prospective SCHLA-HF registry if they meet predefined inclusion and exclusion criteria. Screening was started in October 2007 and enrolment was completed at the end of May 2013. After enrolment in the registry, patients are screened for SDB. SDB screening is mainly undertaken using the validated 2-channel ApneaLink™ device (nasal flow and pulse oximetry; ResMed Ltd., Sydney, Australia). Patients with a significant number of apneas and hypopneas per hour recording time (AHI ≥15/h) and/or clinical symptoms suspicious of SDB will be referred to a cooperating sleep clinic for an attended in-lab polysomnography with certified scoring where the definite diagnosis and, if applicable, the differentiation between obstructive and central sleep apnea will be made. Suggested treatment will be documented. DISCUSSION: Registries play an important role in facilitating advances in the understanding and management of cardiovascular disease. The SCHLA-HF registry will provide consistent data on a large group of patients with HF-REF that will help to answer questions on the prevalence, risk factors, gender differences and stability of SDB in these patients by cross-sectional analyses. Further insight into the development of SDB will be gained by extension of the registry to include longitudinal data.

Observational follow‐up of the PROactive study: a 6‐year update

AIMS: The PROactive study investigated pioglitazone for secondary prevention of macrovascular events in type 2 diabetes mellitus. Pioglitazone showed a 10% (non-significant) relative risk (RR) reduction for the primary composite endpoint and a significant 16% reduction for the main secondary endpoint (death, myocardial infarction, stroke) after a mean 34.5 months. There was no difference in cumulative malignancy incidence, but an imbalance in bladder malignancies (pioglitazone 14, placebo 5). We present a pre-specified 6-year interim analysis of a 10-year observational follow-up. METHODS: Any patient completing PROactive was eligible. No study treatments were provided. A Cox proportional hazard model compared non-adjudicated macrovascular events (same endpoints as PROactive excluding acute coronary syndrome) based on original randomization. Malignancies were compared using conventional RR ratios. RESULTS: Of 5238 randomized patients, 3599 (74%) entered the follow-up. For the follow-up (mean 5.8 years) or combined double-blind and follow-up periods (≤9.5 years, mean 8.7), there were no statistically significant differences in primary or main secondary endpoints. For the combined period, a similar percentage of patients had any diagnosed malignancy (RR = 1.05, 95% CI [0.89, 1.24]) or bladder malignancy (RR = 1.06, 95% CI [0.59, 1.89]) in the pioglitazone and placebo groups. There were fewer cases of bladder malignancy with pioglitazone (15 [0.6%] vs. 19 [0.7%] for placebo) for the combined period when events diagnosed in the first 365 days were excluded, and fewer cases for the follow-up period alone (10 [0.5%] vs. 17 [1.0%] for placebo). Further analyses of pioglitazone use (including use during follow-up) found no significant difference in bladder malignancies between any and no pioglitazone use for the combined period. CONCLUSIONS: These data suggest that improved macrovascular outcomes seen with pioglitazone subside without continued pioglitazone treatment. The double-blind period bladder cancer imbalance did not persist in follow-up.

CowieEuropean Journal of Heart Failure

Rationale and Design of the SERVE-HF Study: Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnoea with Adaptive Servo-Ventilation in Patients with Chronic Heart Failure

Ischemic Preconditioning for Prevention of Contrast Medium–Induced Nephropathy

Background— Contrast medium–induced acute kidney injury is associated with substantial morbidity and mortality. The underlying mechanism has been attributed in part to ischemic kidney injury. The aim of this randomized, double-blind, sham-controlled trial was to assess the impact of remote ischemic preconditioning on contrast medium–induced acute kidney injury. Methods and Results— Patients with impaired renal function (serum creatinine >1.4 mg/dL or estimated glomerular filtration rate <60 mL · min −1 · 1.73 m −2 ) undergoing elective coronary angiography were randomized in a 1:1 ratio to standard care with (n=50) or without ischemic preconditioning (n=50; intermittent arm ischemia through 4 cycles of 5-minute inflation and 5-minute deflation of a blood pressure cuff). Overall, both study groups were at high risk of developing contrast medium–induced acute kidney injury according to the Mehran risk score. The primary end point was the incidence of contrast medium–induced kidney injury, defined as an increase in serum creatinine ≥25% or ≥0.5 mg/dL above baseline at 48 hours after contrast medium exposure. Contrast medium–induced acute kidney injury occurred in 26 patients (26%), 20 (40%) in the control group and 6 (12%) in the remote ischemic preconditioning group (odds ratio, 0.21; 95% confidence interval, 0.07–0.57; P =0.002). No major adverse events were related to remote ischemic preconditioning. Conclusions— Remote ischemic preconditioning before contrast medium use prevents contrast medium–induced acute kidney injury in high-risk patients. Our findings merit a larger trial to establish the effect of remote ischemic preconditioning on clinical outcomes. Clinical Trial Registration— URL: http://www.germanctr.de . Unique identifier: U1111-1118-8098.

GheorghiadeEuropean Journal of Heart Failure

Cinaciguat reduced PCWP at 8 h compared with placebo in COMPOSE 1 (n=12) with no relevant change in cardiac index, and showed no meaningful difference in dyspnoea in COMPOSE EARLY (n=62).