SERVE-HF study

serve-HF-study-ResMedSERVE-HF was the first long-term randomised, controlled, international, multicentre study designed to assess the effects of adaptive servo-ventilation (ASV) on morbidity and mortality in patients with symptomatic chronic heart failure (HF) with reduced left ventricular ejection fraction (LVEF ≤ 45%) and predominant central sleep apnoea-Cheyne-Stokes respiration (CSA-CSR).

  • The SERVE-HF intention-to-treat analysis1 showed that ASV had no effect on the primary endpoint: composite of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalisation for heart failure.
  • The cardiovascular death risk observed in SERVE-HF has been confirmed as a true clinical finding.2
  • The mortality risk seen in SERVE-HF was seen only in patients with systolic heart failure and predominantly central sleep apnoea.3
  • The SERVE-HF additional analysis has confirmed that observed mortality risk occurs in patients with LVEF<45% and that the harmful effects of ASV correlate with pre-existing LV systolic impairment.3
  • ASV does not seem to worsen LV function.4
  • The mortality risk seen in SERVE-HF is unrelated to the magnitude of the PAP delivered.5

We can therefore conclude that, in the presence of significant LV dysfunction and predominantly central sleep apnoea, ASV may become a harmful intervention. People with enlarged and weakened left ventricles are a particularly vulnerable group, some of whom may also be at risk of sudden cardiac death from co-existing arrhythmias. In current clinical practice this has led to the increasing use of implantable defibrillators (ICDs).

Contraindication: ASV therapy is contraindicated in patients with chronic, symptomatic heart failure (NYHA 2-4) with reduced left ventricular ejection fraction (LVEF ≤ 45%) and moderate to severe predominant central sleep apnoea. Patients with LVEF>45% continue to be eligible for ASV.

SERVE-HF study design6

1,325 patients enrolled
651 events collected
91 study centres
215 sites
24-month minimum follow-up period
312 patients enrolled in the main sub-study

 

Study methodology

Primary endpoint was reached in April 2015.

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ASV therapy initiation

Adjustment of ASV was performed in the hospital using polysomnographic or polygraphic monitoring. Default settings were used (expiratory positive airway pressure, 5 cm of water; minimum pressure support, 3 cm of water; and maximum pressure support, 10 cm of water). The expiratory positive airway pressure was increased manually to control obstructive sleep apnoea (OSA), and the maximum pressure support was increased to control CSA. A full face mask was recommended for the initiation of ASV. Patients were advised to use the ASV device for at least 5 hours per night, 7 days per week. Adherence to therapy was defined as ASV use for an average of at least 3 hours per night.

 

Follow-up

Clinic visits took place at study entry, after 2 weeks, at 3 and 12 months, and every 12 months thereafter until the end of the study. Patients in the ASV group also underwent polygraphy or polysomnography at each visit and ASV device data were downloaded.

 

Major sub-study

312 of the patients involved in SERVE-HF were also enrolled in the major sub-study, that was aiming to assess changes in LVEF as measured by echocardiography from baseline to 12 months as its primary endpoint. It was also designed to examine changes in ventricular function and remodelling, biomarkers (such as brain natriuretic peptide), disease specific quality of life, cognitive function, anxiety and depression, and sleep and respiratory parameters.

 

ResMed provides update on phase IV SERVE-HF study of adaptive servo-ventilation (ASV) therapy in central sleep apnoea and chronic heart failure.

SERVE-HF study results

The SERVE-HF intention-to-treat analysis showed that ASV had no effect on the primary endpoint: composite of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalisation for heart failure (HF).1

However, both all-cause and cardiovascular mortality occurred significantly more often in the ASV group.1

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The cardiovascular death risk observed in SERVE-HF has been confirmed as a true clinical finding

 

serve-HF-study-cardiovascular-risk-ResMed

 

Following additional robust statistical analyses, it is now possible to discount any suspicions that potentially confounding factors – like low patient compliance with ASV or high cross-over between comparator arms – may have accounted for or substantially contributed to the observed mortality risk.2 The different on-treatment analysis confirmed that there was no impact of cross-over or compliance on the mortality risk in SERVE-HF.

 

The mortality risk was seen only in patients with systolic heart failure and predominant central sleep apnoea

A robust statistical methodology called multivariate and multi-state modelling has been applied to SERVE-HF.3 The main findings are that:

  • The risk is of sudden death, which is very likely to be arrhythmic
  • There is a clear, statistically significant relationship between the mortality risk and the patient’s left ventricular ejection fraction (LVEF), i.e. the risk is greatest in those with the lowest ejection fraction.
  • Associations between adaptive servo-ventilation therapy and cardiovascular death without prior hospitalisation for worsening heart failure or life-saving event

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As a result, we can confirm that the observed mortality risk occurs in patients with LVEF ≤45% and that the harmful effects of ASV correlate with pre-existing LV systolic impairment.

* Adjusted for implantable cardioverter defibrillator (ICD), Cheyne-Stokes respiration (CSR) proportion at baseline and baseline left ventricular ejection fraction (LVEF).

 

ASV may not worsen LV function3

The major SERVE-HF sub-study showed that ASV may have no effect on left ventricular function or remodelling and does not affect systemic markers associated with the heart failure syndrome, such as circulating neuro-hormones.

There was also no meaningful increase in hospitalisation due to worsening heart failure in the study.4 Therefore the possibility that the mortality risk might be attributable to deterioration in LV function appears remote.

 

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The mortality risk seen in SERVE-HF is unrelated to the magnitude of the PAP delivered5

The possibility that use of excessive inspiratory positive airway pressures might be to blame for the mortality risk also now seems remote. A new subgroup analysis has confirmed that the risk bears no relation to the magnitude of the inspiratory positive airway pressure delivered, which was individually adjusted for each patient in the trial.

 

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Conclusion

We can therefore conclude that, in the presence of significant LV dysfunction and predominantly central sleep apnoea, ASV may become a harmful intervention. People with enlarged and weakened left ventricles are a particularly vulnerable group, some of whom may also be at risk of sudden cardiac death from co-existing arrhythmias. In current clinical practice this has led to the increasing use of implantable defibrillators (ICDs).

ASV therapy is contraindicated in patients with chronic, symptomatic heart failure (NYHA 2-4) with reduced left ventricular ejection fraction (LVEF≤45%) and moderate to severe predominant central sleep apnoea.

Patients with LVEF>45% continue to be eligible for ASV

Experts’ statements agree that patients with LVEF>45% remain eligible for ASV when there is a clinical rationale for using it.7,8,9,10

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Implications for clinical practice

Reduced LVEF should be excluded before using ASV9

SERVE-HF identified a specific at-risk patient population. The harmful effects of ASV correlate with pre-existing LV systolic impairment and the mortality risk is in patients with LVEF<45%. ASV therapy is contraindicated in patients with chronic, symptomatic heart failure with reduced left ventricular ejection fraction (LVEF≤45%) and moderate to severe predominant central sleep apnoea. Reduced LVEF should be excluded before using ASV.9 It is therefore important to ensure that LVEF is >45% and echocardiography is recommended for this purpose.

Some patients – especially if referred by a cardiologist – may already have undergone echocardiography so it is worthwhile checking their medical notes. If not, a cardiology referral may be worth considering, as a high proportion of patients with SDB have some form of underlying cardiac disease.

Experts’ statements

French Language Pneumology Society

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It was essential to [ensure] that these results, obtained in a very precise and very fragile population which is not representative of the majority of current indications of ASV, [would not be extrapolated to] pathologies with different mechanisms and for which the use of ASV remains fully effective. This is of course the case of the treatment of central sleep apnoea secondary to stroke or related to a complex sleep apnoea syndrome for example. However, this is also the case of heart failure with preserved ejection fraction.

French Society of Sleep Research and Medicine

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Data from the literature advocates the continued use of ASV in different indications, including heart failure with preserved LVEF, complex sleep apnoea syndrome, opioid-induced central sleep apnoea syndrome, idiopathic central SAS, and central SAS due to a stroke.

German Society of Sleep Research and German Society of Sleep Medicine Pneumology

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It should be stressed that all statements relate exclusively to patients with heart failure New York Heart Association Functional Classification II-IV (NYHA II-IV) and an ejection fraction ≤45%. That is that the therapy can be continued unchanged in patients:

  • with less impaired cardiac function
  • where it is not predominantly central sleep apnoea
  • in which the therapy is carried out because of other underlying diseases (e.g. coexisting sleep apnoea, complex sleep apnoea, sleep apnoea and opiate induced-CSA).

American Academy of Sleep Medicine

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Adaptive servo-ventilation (ASV) targeted to normalise the apnoea-hypopnea index (AHI) can be used for the treatment of CSAS related to CHF in adults with an ejection fraction >45% or mild CHF-related CSAS.

Support for investigator initiated research

ResMed believes in the need to support ethical, independent clinical research, conducted by qualified third-party investigators.

 

References:
*ASV therapy is contraindicated in patients with chronic, symptomatic heart failure (NYHA 2-4) with reduced left ventricular ejection fraction (LVEF ≤ 45%) and moderate to severe predominant central sleep apnoea.

    1. Cowie MR & al. Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure. New England Journal of Medicine, 17 Sept 2015;373(12):1095-105.
    2. Woehrle H, Cowie MR, Christine Eulenburg C et al. Adaptive servo ventilation for central sleep apnoea in heart failure: results of the SERVE-HF on-treatment analysis. submitted to JAMA and presented at ATS congress 2016.
  1. Eulenburg C & al. 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 modeling analysis. Lancet Respiratory Medicine, 2016 Aug 31, pii: S2213-2600(16)30244-2.
  2. Cowie MR, Woehrle H, Karl Wegscheider K et al. Adaptive Servo-Ventilation for Central Sleep Apnoea in Systolic Heart Failure: Echocardiographic, cMRI and biomarker results of the major substudy of SERVE-HF (Major sub-study – presented at ATS. Submitted to Eur Heart J).
  3. Woehrle et al. Adaptive Servo-ventilation (ASV) pressures and cardiovascular mortality risk in SERVE-HF. European Respiratory Journal, 01 Sept 2016, volume 48, issue suppl 60.
  4. Cowie et al. Eur J Heart Fail 2013;15:937-43.
  5. Randerath W et al. ERJ Express. Published on December 5, 2016 as doi: 10.1183/13993003.00959-2016.
  6. Aurora et al. Journal of Clinical Sleep Medicine, Vol. 12, No. 5, 2016 http://dx.doi.org/10.5664/jcsm.5812.
  7. d’Ortho et al. European Respiratory & Pulmonary Diseases, 2016;2(1) http://doi.org/10.17925/ERPD.2016.02.01.1
  8. Priou P & al. Adaptive servo-ventilation: How does it fit into the treatment of central sleep apnoea syndrome Expert opinions. Revue des Maladies Respiratoires, 2015 Dec, 32(10):1072-81
  9. d’Ortho et al. European Respiratory & Pulmonary Diseases, 2016;2(1):Epub ahead of print. http://doi.org/10.17925/ERPD.2016.02.01.1
  10. Aurora RN & al. Updated Adaptive Servo-Ventilation Recommendations for the 2012 AASM Guideline: “The Treatment of Central Sleep Apnea Syndromes in Adults: Practice Parameters with an Evidence-Based Literature Review and Meta-Analyses”. Journal of Clinical Sleep Medicine, 2016 May 15, 12(5):757-61.
  11. AirCurve 10 CS PaceWave clinical manual July 2015