A reflection on risk: the ASV safety alert 1 year later

     On May 13, 2015, ResMed announced a safety alert ahead of publication of a large trial of their adaptive PAP system (“ASV”) for heart failure patients with central apnea [1].  The primary endpoint that the trial was designed to answer showed no effect of ASV.  The unexpected finding came in an exploratory subset analysis (not the main goal of the trial): higher cardiovascular mortality in those using ASV (annual risk of 10% versus 7.5%).  On May 15, the American Academy of Sleep Medicine posted their initial response to this announcement.  In June 2015, the annual SLEEP conference hosted a special session in which cogent criticisms and concerns were raised in a balanced discussion about the trial, but the risk announcements had already been made public. A recent editorial detailed many points of uncertainty about the trial [2].  It remains unknown why the main outcome was negative, and why the subset analysis suggested increased cardiac risk with ASV use.
     As with the controversial SAVE trial results recently published (see blog entry of September 22, 2016), the details of a study influence how confidently one can interpret the findings.  This should come as no surprise:  extensive effort and resources go into trial design to ensure the data is the highest quality possible.  The MGH Sleep Division reviewed the ASV trial, called the “SERVE-HF” study, and admittedly our own physicians held diverse opinions about the results, and each brings their own calculus of risk tolerance.  Patients also are entitled to their own risk calculus – ideally formulated together with their treating physicians for any healthcare decision.
     The challenges of the SERVE-HF trial can be summarized in two major categories: experimental design, and therapy effectiveness.  In this trial, wearing ASV for sleep apnea, versus no treatment for sleep apnea, was randomly assigned.  The intention of randomization is to make sure that other factors that could impact the results are evenly distributed (by chance) in each group.  The problem is, it didn’t work for the SERVE-HF trial:  it turned out, by chance, that the group assigned to wear ASV had a crucial significant difference: a 42% higher rate of anti-arrhythmia medication use.  Why is this important?  Because being on such a drug was associated with a greater mortality risk for patients on all three major outcomes (combined endpoint, all-cause mortality, and cardiovascular mortality).  The trial did not report smoking status, or sleeping pill use, both of which are independently associated with mortality in other studies – might these have also been unevenly occurring (by chance) in the ASV group?  Might this have contributed to the excess cardiac mortality in the ASV group?
     Although the investigators made efforts to ensure the machines were working properly, many using ASV had significant levels of ongoing sleep apnea according to objective measures including oximetry.  A machine-reported event index of <10 per hour was taken to indicate adequate therapy – however, recent data suggests that the proprietary algorithms used are too lenient, meaning that breathing problems are often worse than the machine is reporting [3].  In addition, compliance with ASV was modest, only about 3.5hrs per night.  Other details of the study include that patients with <20% Cheyne-Stokes pattern showed benefit with ASV, and a non-significant trend toward worsening risk in those with LVEF<30%. 
     These and other factors complicate interpretation of the data.  What about the possibility that ASV is actually harmful to certain patients?  Some ideas include that high pressures and over-ventilation negatively impact cardiac function, and the patients in this trial were vulnerable due to their substantial heart failure.  Years before this trial, my colleague at BIDMC, Dr Robert Thomas, described several potential concerns about the “complexity” of complex apnea and the reliance on machine algorithms [4]. 
     As the field struggles with these concerns and awaits future data to help navigate the uncertainty, providers and patients must work together to balance risk-benefit trade-offs.  This may be easier said than done when risk tolerance may differ among regulators, physicians, and patients.  

References:
[1] Cowie et al (2015) Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure.
N Engl J Med. 373(12):1095-105.  Full text here:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779593/
 
[2] Javaheri et al (2016) SERVE-HF: More Questions Than Answers.  Chest. 2016 Apr;149(4):900-4.
 
[3] Reiter et al (2016) Residual Events during Use of CPAP: Prevalence, Predictors, and Detection Accuracy.  J Clin Sleep Med. 12(8):1153-8.
 
[4] Thomas (2011) The chemoreflex and sleep-disordered breathing: man and machine vs. the beast.
Sleep Med. 12(6):533-5.
 
Contributor:  Matt Bianchi MD PhD