Marie Pia d'Ortho

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

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.).

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

Central sleep apnoea/Cheyne–Stokes respiration (CSA/CSR) is a risk factor for increased mortality and morbidity in heart failure (HF). Adaptive servo‐ventilation (ASV) is a non‐invasive ventilation modality for the treatment of CSA/CSR in patients with HF.

Prognostic impact of sleep-disordered breathing and its treatment with nocturnal ventilation for chronic heart failure.

To determine whether severity patterns or nocturnal ventilation to treat sleep‐disordered breathing (SDB) during chronic heart failure (CHF) is associated with adverse outcomes. Although SDB is frequent during CHF, the relationships between SDB and CHF outcomes are unknown.

Increased expression of matrix metalloproteinase‐9 in nasal polyps

To investigate the role of gelatinases in nasal polyposis, a common and disabling airway disease characterized by chronic inflammation and tissue remodelling, matrix metalloproteinase‐2 (MMP‐2) and MMP‐9 expression was investigated in the nasal polyps (NP) of 24 patients undergoing ethmoidectomy and compared with 15 control nasal mucosal (CM) samples obtained from snorers during turbinectomy. Tissue samples were either frozen for enzymatic analysis or paraffin wax‐embedded for immunohistochemistry. Zymography and quantitative image analysis showed that MMP‐9 active forms were significantly increased (p<0.05) in NPs compared to CM (44±40 versus 13±19×103 AU/10 µg protein), while MMP‐2 expression was similar in both tissues. Concomitant studies of gelatinase immunoexpression showed that MMP‐9 expression was enhanced (4‐ to 16‐fold) in surface epithelium, glands (p<0.05), and submucosal inflammatory cells (p<0.05). In addition, MMP‐9 positivity was markedly increased in endothelial cells (p<0.01). In situ zymography demonstrated marked gelatinolytic activity, consistent with the immunolocalization of MMP‐2 and MMP‐9. These results suggest up‐regulation of active MMP‐9 in the glands and vessels characteristic of NPs. It is concluded that MMP‐9 may play a role in the upper airway remodelling observed during nasal polyposis. Copyright

Mechanisms underlying increased mortality risk in patients with heart failure and reduced ejection fraction randomly assigned to adaptive servoventilation in the SERVE-HF study : results of a secondary multistate modelling analysis

BACKGROUND 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. METHODS 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. FINDINGS 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). INTERPRETATION 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. FUNDING ResMed.

Adaptive servo-ventilation for central sleep apnoea in systolic heart failure: Results of the major substudy of SERVE-HF

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.

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. SERVE-HF on-treatment results showed increased cardiovascular risk similar to the intention-to-treat analysis http://ow.ly/hoO130dx4s9

Catalogue of knowledge and skills for sleep medicine

Sleep medicine is evolving globally into a medical subspeciality in its own right, and in parallel, behavioural sleep medicine and sleep technology are expanding rapidly. Educational programmes are being implemented at different levels in many European countries. However, these programmes would benefit from a common, interdisciplinary curriculum. This ‘catalogue of knowledge and skills’ for sleep medicine is proposed, therefore, as a template for developing more standardized curricula across Europe. The Board and The Sleep Medicine Committee of the European Sleep Research Society (ESRS) have compiled the catalogue based on textbooks, standard of practice publications, systematic reviews and professional experience, validated subsequently by an online survey completed by 110 delegates specialized in sleep medicine from different European countries. The catalogue comprises 10 chapters covering physiology, pathology, diagnostic and treatment procedures to societal and organizational aspects of sleep medicine. Required levels of knowledge and skills are defined, as is a proposed workload of 60 points according to the European Credit Transfer System (ECTS). The catalogue is intended to be a basis for sleep medicine education, for sleep medicine courses and for sleep medicine examinations, serving not only physicians with a medical speciality degree, but also PhD and MSc health professionals such as clinical psychologists and scientists, technologists and nurses, all of whom may be involved professionally in sleep medicine. In the future, the catalogue will be revised in accordance with advances in the field of sleep medicine.

Apnea–hypopnea and desaturations in heart failure with reduced ejection fraction: Are we aiming at the right target?

BACKGROUND Sleep disordered breathing (SDB) is common in patients with heart failure with reduced ejection fraction (HFrEF). An increased apnea-hypopnea index (AHI) is associated with poor outcomes. We examined whether an analysis of nocturnal desaturations (NDs) can improve the risk stratification. METHODS Three-hundred seventy-six consecutive patients with stable chronic HFrEF and LVEF ≤ 45% were prospectively screened using polygraphy. Sleep apnea (SA) was defined as an AHI ≥ 15. The mean age was 59 ± 13 years, the mean LVEF was 30 ± 6%, and the median AHI was 18 [IQR: 9.33). The composite end-point of death, heart transplantation or LV assistance occurred in 98 patients (26%) within 3 years. Minimal oxygen saturation (MOS) during sleep, the number of desaturations <90%/h and the time spent with oxygen saturation <90% were significantly associated with adverse events (adjusted HR 1.25 [1.03-1.52], 1.25 [1.03-1.53], and 1.28 [1.04-1.59]), whereas the AHI was not (1.10 [0.86-1.39]). The best MOS cut-off value for poor outcomes was ≤ 88%. The patients with an MOS ≤ 88% had a significantly higher event rate (31.9%) than those with an MOS >88% (15.6%; p<0.01). The risk assessment using an MOS of ≤ 88% in addition to established prognostic markers yielded a net reclassification index (NRI) of nearly 6% and was particularly useful in the subgroup of patients with events (NRI: 8.4%). CONCLUSIONS In HFrEF patients, ND ≤ 88% appears to be predictive of adverse events, independent of the presence of SA. This suggests that the risk assessment in HFrEF should also include ND in top of AHI.