Study methodology

Primary endpoint was reached in April 2015.

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 apnea (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 apnea and chronic heart failure.

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

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 apnea

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

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.

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.

Conclusion

We can therefore conclude that, in the presence of significant LV dysfunction and predominantly central sleep apnea, 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 apnea.

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