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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

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Summary

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.

Introduction

The Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF) study investigated the effect of adaptive servoventilation added to optimum medical treatment (according to the relevant European Society of Cardiology guidelines for treatment of heart failure) on outcomes in patients with heart failure and reduced ejection fraction (HFREF) and predominant central sleep apnoea.1 The main study findings were neutral for the composite primary endpoint, which was time to first event of death from any cause, life-saving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate life-saving shock), or unplanned hospital admission for worsening heart failure. However, all-cause mortality (and in particular cardiovascular mortality) was significantly increased in patients treated with adaptive servoventilation compared with the control group.1 Previous studies, although small and often uncontrolled, had suggested that adaptive servoventilation should have beneficial effects on the individual components of the SERVE-HF primary endpoint.2, 3, 4, 5, 6

The unexpected finding of increased mortality risk in the adaptive servoventilation group in SERVE-HF could bring into question the appropriateness of the composite primary endpoint used in this study. Also, associations between adaptive servoventilation and the individual components of the composite endpoint might reveal important information about potential mechanisms underlying the excess mortality seen in the adaptive servoventilation group.

Research in context

Evidence before this study

The primary intention-to-treat analysis of the Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnea by Adaptive Servo-Ventilation in Patients With Heart Failure (SERVE-HF) was neutral for the primary endpoint (time to first event of death from any cause, life-saving cardiovascular intervention [cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate life-saving shock], or unplanned hospital admission for worsening heart failure) but showed a significant increase in all-cause, and cardiovascular, mortality in the adaptive servoventilation group versus the control group. However, mechanisms underlying this increase in mortality risk and outcomes in specific patient subgroups remain unclear.

Added value of this study

This multistate modelling analysis of SERVE-HF data allows the effects of adaptive servoventilation treatment on different elements of the study's composite endpoint to be determined, providing insight into potential mechanisms underlying the increased risk of cardiovascular death in patients receiving adaptive servoventilation, and defining a subgroup of heart failure patients with more severely reduced ejection fraction with predominant central sleep apnoea who do particularly badly when adaptive servoventilation is added to optimum medical treatment.

Implications of all the available evidence

Adaptive servoventilation treatment should not be used in patients with systolic heart failure with predominant central sleep apnoea due to the increased mortality risk. This risk is for sudden death, presumably due to arrhythmia, and is particularly marked in patients with the lowest ejection fraction; however, the pathophysiological mechanism of this effect remains to be elucidated.

Multistate modelling is a methodological approach for the statistical analysis of multiple endpoints and the relationships between them.7, 8 Multistate models can provide examples of disease progression that include several potential endpoints, each of which might affect the probability that another endpoint will occur. Such multistate analyses can accurately describe the transitions between disease states (defined by the potential endpoints) and their associations with potential risk factors.

This analysis of SERVE-HF used multistate modelling to investigate associations between randomised allocation to adaptive servoventilation and the individual components of the study's endpoints in order to better understand the mechanisms behind the increased mortality observed with adaptive servoventilation treatment in this population.

Section snippets

Study design and participants

SERVE-HF was a multinational, multicentre, randomised, parallel-group, event-driven study. Full details of the study design have been reported previously.1, 9 Briefly, the study assessed the effect of adding adaptive servoventilation to optimised guideline-based management compared with guideline-based management alone (control group) in patients with symptomatic chronic heart failure, left ventricular ejection fraction (LVEF) less than or equal to 45%, and predominant central sleep apnoea. The

Results

1325 patients enrolled in the SERVE-HF study between February, 2008, and May, 2013, were included in this analysis. 666 (50%) patients were randomly assigned to the optimum medical treatment plus adaptive servoventilation treatment group and 659 (50%) were assigned to the control group (optimum medical treatment alone). Follow-up was 0–80 months (median 31). The number of patients who had an implantable cardioverter defibrillator at baseline was 316 (47%) in the adaptive servoventilation group

Discussion

The SERVE-HF primary intention-to-treat analysis1 formed the basis of the present multistate modelling analysis. It showed a neutral result for the primary composite endpoint and identified significantly increased all-cause and cardiovascular mortality in the adaptive servoventilation versus control group.1

Our multistate modelling analysis provided additional differentiation of these results by investigating individual components of the composite endpoint. Each component was analysed separately

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