Although it is often under-recognised, α1-antitrypsin deficiency (AATD) represents one of the most common genetic respiratory disorders worldwide. Since the publication of studies in the late 1980s, ...which demonstrated that plasma-derived augmentation therapy with intravenous α1-antitrypsin (AAT) can reverse the biochemical deficiencies in serum and lung fluid that characterise emphysema, augmentation therapy has become the cornerstone of patient management. This article, with a focus on experience gained in clinical practice in Germany, provides an overview of some of the research highlights and clinical experience gained in the use of augmentation therapy for AATD during the past 25 years, and briefly discusses the potential role of AAT augmentation therapy in lung transplant recipients. Additionally, the goals of AAT augmentation therapy will be discussed, namely to delay the progression of emphysema, reduce the frequency of exacerbations and improve health-related quality of life. Beyond pulmonary disease, there is recent growing evidence to indicate that AATD could also play a role in rare disorders such as panniculitis, granulomatosis with polyangiitis and ulcerative colitis.
Central sleep apnea is associated with poor prognosis and death in patients with heart failure. Adaptive servo-ventilation is a therapy that uses a noninvasive ventilator to treat central sleep apnea ...by delivering servo-controlled inspiratory pressure support on top of expiratory positive airway pressure. We investigated the effects of adaptive servo-ventilation in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea.
We randomly assigned 1325 patients with a left ventricular ejection fraction of 45% or less, an apnea-hypopnea index (AHI) of 15 or more events (occurrences of apnea or hypopnea) per hour, and a predominance of central events to receive guideline-based medical treatment with adaptive servo-ventilation or guideline-based medical treatment alone (control). The primary end point in the time-to-event analysis was the first event of death from any cause, lifesaving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening heart failure.
In the adaptive servo-ventilation group, the mean AHI at 12 months was 6.6 events per hour. The incidence of the primary end point did not differ significantly between the adaptive servo-ventilation group and the control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval CI, 0.97 to 1.31; P=0.10). All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=0.01; and hazard ratio for cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=0.006).
Adaptive servo-ventilation had no significant effect on the primary end point in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea, but all-cause and cardiovascular mortality were both increased with this therapy. (Funded by ResMed and others; SERVE-HF ClinicalTrials.gov number, NCT00733343.).
Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an ...open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT.
Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007.
Between March 1, 2006, and Oct 13, 2010, 140 patients from RAPID-RCT entered RAPID-OLE: 76 from the early-start group and 64 from the delayed-start group. Between day 1 and month 24 (RAPID-RCT), the rate of lung density loss in RAPID-OLE patients was lower in the early-start group (-1·51 g/L per year SE 0·25 at total lung capacity TLC; -1·55 g/L per year 0·24 at TLC plus functional residual capacity FRC; and -1·60 g/L per year 0·26 at FRC) than in the delayed-start group (-2·26 g/L per year 0·27 at TLC; -2·16 g/L per year 0·26 at TLC plus FRC, and -2·05 g/L per year 0·28 at FRC). Between months 24 and 48, the rate of lung density loss was reduced in delayed-start patients (from -2·26 g/L per year to -1·26 g/L per year), but no significant difference was seen in the rate in early-start patients during this time period (-1·51 g/L per year to -1·63 g/L per year), thus in early-start patients the efficacy was sustained to month 48.
RAPID-OLE supports the continued efficacy of A1PI in slowing disease progression during 4 years of treatment. Lost lung density was never recovered, highlighting the importance of early intervention with A1PI treatment.
CSL Behring.
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.
A large randomised treatment trial (SERVE-HF) showed that treatment of central sleep apnoea with adaptive servoventilation in patients with heart failure and reduced ejection fraction (HFREF) ...increased mortality, although the analysis of the composite primary endpoint (time to first event of death from any cause, life-saving cardiovascular intervention, or unplanned hospital admission for worsening heart failure) was neutral. This secondary multistate modelling analysis of SERVE-HF data investigated associations between adaptive servoventilation and individual components of the primary endpoint to try to better understand the mechanisms underlying the observed increased mortality.
In SERVE-HF, participants were randomly assigned to receive either optimum medical treatment for heart failure alone (control group), or in combination with adaptive servoventilation. We analysed individual components of the primary SERVE-HF endpoint separately in a multistate model, with and without three covariates suggested for effect modification (implantable cardioverter defibrillator at baseline, left ventricular ejection fraction LVEF, and proportion of Cheyne-Stokes Respiration CSR). The SERVE-HF study is registered with ClinicalTrials.gov, number NCT00733343.
Univariate analysis showed an increased risk of both cardiovascular death without previous hospital admission (hazard ratio HR 2·59, 95% CI 1·54-4·37, p<0·001) and cardiovascular death after a life-saving event (1·57, 1·01-2·44, p=0·045) in the group receiving adaptive servoventilation versus the control group. Adjusted analysis showed that the increased risk attributed to adaptive servoventilation of cardiovascular death without previous hospital admission for worsening heart failure varied with LVEF and that the risk attributed to adaptive servoventilation of hospital admission for worsening heart failure varied with LVEF and CSR. In patients with LVEF less than or equal to 30%, use of adaptive servoventilation markedly increased the risk of cardiovascular death without previous hospital admission (HR 5·21, 95% CI 2·11-12·89, p=0·026).
Adaptive servoventilation is associated with an increased risk of cardiovascular death in patients with heart failure and reduced ejection fraction (LVEF ≤45%) treated for predominant central sleep apnoea. This multistate modelling analysis shows that this risk is increased for cardiovascular death in patients not previously admitted to hospital, presumably due to sudden death, and in patients with poor left ventricular function.
ResMed.
Background
ApneaLink is a novel single-channel screening device for sleep apnea detection which is based on pressure-transduced measurement of oronasal airflow, summarised as respiratory disturbance ...index per hour of recording time (RDI
ApneaLink
). We tested ApneaLink's diagnostic performance in a patient population with high prevalence of sleep apnea.
Methods
ApneaLink was applied simultaneously with in-laboratory polysomnography (PSG) (
n
= 102, 24 female, age 54.7 years) and sequentially with PSG in the unattended home setting (
n
= 131, 37 female, age 59.1 years). Predictive values were computed for apnea-defining thresholds of apnea–hypopnea index (AHI) ≥ 5/h, ≥10/h, ≥15/h. Night-to-night variability (NNV) was assessed over three consecutive nights (
n
= 55, 10 female, age 48.9 years).
Results
RDI
ApneaLink
correlated well with apnea–hypopnea index on PSG (PSG
AHI
) on simultaneous (
r
= 0.98, bias −0.7) and unattended home application (
r
= 0.95, bias −0.6). Predictive values were highest at AHI ≥ 10/h (in-laboratory: sensitivity 91.1%, specificity 87.5%, LR+ (positive likelihood ratio) 7.4, LR− 0.1; home: sensitivity 80%, specificity 85.5%, LR+5.5, LR− 0.2). NNV was low
.
Conclusion
ApneaLink is an accurate screening tool for sleep apnea in a population with high prevalence of the disorder.
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
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.
In patients with COPD, it has not been comprehensively assessed whether the predictive value of comorbidities for mortality differs between men and women. We therefore aimed to examine sex ...differences of COPD comorbidities in regard with prognosis by classifying comorbidities into a comorbidome related to extrapulmonary disorders and a pulmorbidome, referring to pulmonary disorders. The study population comprised 1044 women and 1531 men with the diagnosis of COPD from COSYCONET, among them 2175 of GOLD grades 1-4 and 400 at risk. Associations of comorbidities with mortality were studied using Cox regression analysis for men and women separately. During the follow-up (median 3.7 years) 59 women and 159 men died. In men, obesity, hypertension, coronary artery disease, liver cirrhosis, osteoporosis, kidney disease, anaemia and increased heart rate (HR) predict mortality, in women heart failure, hyperuricemia, mental disorders, kidney disease and increased HR (p < 0.05 each). Regarding the pulmorbidome, significant predictors in men were impairment in diffusion capacity and hyperinflation, in women asthma and hyperinflation. Similar results were obtained when repeating the analyses in GOLD 1-4 patients only. Gender differences should be considered in COPD risk assessment for a tailored approach towards the treatment of COPD.Clinical Trial Registration: ClinicalTrials.gov NCT01245933.
Aims
Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing prevalence. Sleep‐disordered breathing (SDB) is an important co‐morbidity in HFpEF. The SchlaHF‐XT registry ...evaluated the sex‐specific prevalence and predictors of SDB, including obstructive (OSA) and central sleep apnoea, in patients with HFpEF compared with heart failure with mildly reduced (HFmrEF) or reduced (HFrEF) ejection fraction.
Methods and results
Consecutive adults with chronic heart failure treated according to current guidelines were enrolled. The presence of moderate‐to‐severe SDB (apnoea–hypopnoea index ≥15/h) was determined using Type 3 polygraphic devices. Of 3289 patients included, 2032 had HFpEF, 559 had HFmrEF, and 698 had HFrEF, of whom 34, 21, 23, and 42%, respectively, were female. Prevalence of SDB in HFpEF was high, but significantly lower than in HFmrEF or HFrEF (36% vs. 41 and 48%, respectively). Rates of SDB in males and females were 41 and 28% in HFpEF, 44 and 30% in HFmrEF, and 50 and 40% in HFrEF. The proportion of males and females with SDB who had OSA was significantly greater in those with HFpEF vs. HFrEF. Male sex, older age, higher body mass index, and New York Heart Association functional Class III/IV were significant predictors of moderate‐to‐severe SDB in HFpEF patients.
Conclusions
Prevalence of SDB in HFpEF was high, but lower than in patients with HFmrEF or HFrEF. Moderate‐to‐severe SDB occurred more frequently in males than in females across the whole spectrum of heart failure. In both sexes, the proportion of OSA in SDB patients with HFpEF was higher than in those with HFrEF.
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 (HFrEF) 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 HFrEF patients with SDB.
Methods and Results
The German SchlaHF registry enrolled patients with HFrEF 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 HFrEF 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 (Pco2). Periodic breathing was more likely in men, patients with atrial fibrillation, older patients, and as left ventricular ejection fraction and awake Pco2 decreased, and less likely as body mass index increased and minimum oxygen saturation decreased.
Conclusions
SchlaHF data show that there is wide interindividual variability in the SDB phenotype of HFrEF patients, suggesting that individualized management is appropriate.
Clinical Trial Registration
URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01500759.
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