No Reduction in CVD Events With PAP Treatment of Sleep Apnea

Fran Lowry

July 20, 2017

The use of positive airway pressure (PAP) to treat sleep apnea does not reduce the risk of cardiovascular events and death, a new analysis suggests[1].

In a meta-analysis of 10 randomized clinical trials comprising more than 7000 patients, PAP was not associated with a reduction in major adverse cardiovascular events (MACE), cardiovascular death, all-cause death, stroke, or heart failure compared with no or sham treatment.

"While sleep apnea is clearly associated in observational studies with risks of cardiovascular disease, it doesn't seem as if those risks can be reversed by treating people with PAP," coauthor Dr Bruce Neal (George Institute for Global Health, University of New South Wales, Sydney, Australia) said in an interview.

"Whether that's because our treatment method with PAP isn't very good or whether the association that we see in the observational studies is being driven by something else isn't really clear to us," Neal said.

The results were published online July 11, 2017 in the Journal of the American Medical Association.

"I guess the key take-home for clinicians is that PAP is a great treatment for managing symptoms such as sleepiness, but it's clearly not an effective treatment for preventing serious vascular complications associated with sleep apnea," he said.

The study highlights the importance of making sure that these patients also get all standard treatments, such as antiplatelet therapies, statins, blood-pressure–lowering drugs, where indicated, Neal added.

"There's little rationale for using these devices for PAP to prevent cardiovascular events, but lots of people with sleep apnea do get pretty bad symptoms like sleepiness in particular, and I suspect that many of them will still find the trade-off—the difficulty of using the device vs the benefits they get—will be favorable, so I don't think that we will see lots of people suddenly stopping [continuous positive airway pressure] CPAP, but I do think we will see a review among clinicians about why are we doing this," he said.

Last year, Neal and his group published results of the Sleep Apnea Cardiovascular Endpoints (SAVE) study in the New England Journal of Medicine[2], which coincided with presentation of the results at the European Society of Cardiology (ESC) 2016 Congress, as reported by theheart.org | Medscape Cardiology.   

The multicenter trial randomized 2717 participants with a diagnosis of coronary or cerebrovascular disease and moderate to severe apnea to PAP plus usual care or usual care alone. The mean duration of PAP adherence in the treated group was 3.3 hours/night.

After a mean follow-up of 3.7 years, there was no significant difference in the occurrence of cardiovascular events, death from cardiovascular causes, MI, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack when PAP was added to usual care.

The current meta-analysis was conducted to clarify how the SAVE results compared with data from observational studies.

"The SAVE study was the biggest trial to look at the effects of PAP on vascular outcomes to date," Neal said. "Whenever a big study comes out we try to put it in context in the bigger picture. After you report the study itself, the next questions are 'How does it fit in with everything that we already know? Is it an outlier?' That is why we did the meta-analysis."

He and his group searched MEDLINE, EMBASE, and the Cochrane Library and selected data from nine PAP and one adaptive servoventilation trial that included a total of 7266 patients with sleep apnea.

The mean age of patients was 60.9 years (range 51.5–71.1 years). Most were men (n=5847, 80.5%) and their mean (standard deviation) body mass index was 30 (5.2) kg/m2.

Among 356 MACE and 613 deaths reported in the analysis, there was no significant association of PAP with reduced cardiovascular outcomes or death.

Cardiovascular Outcomes: PAP vs No Treatment

Outcome Relative Risk 95% CI P
MACE 0.77 0.53–1.13 0.19
Cardiovascular death 1.15 0.88–1.50 0.30
All-cause death 1.13 0.99–1.29 0.08

A Premature Conclusion?

In an accompanying editorial[3], Dr Daniel J Gottlieb (Harvard Medical School, Boston, MA) writes the conclusion that PAP does not reduce cardiovascular risk from sleep apnea "appears premature."

Gottlieb notes that the estimated relative risk (RR) for the association between PAP and the composite MACE outcome (RR 0.77; 95% CI 0.53–1.13) is similar to the estimated risk reduction for recurrent vascular events associated with antiplatelet therapy, statins, and beta-blockers.

"Although this point estimate was not significant, if this relative risk reduction were real, it would be of substantial clinical importance. This finding argues strongly for further clinical trials to more precisely estimate the cardiovascular benefits, if any, of [obstructive sleep apnea] OSA treatment," he writes.

"Far from discouraging further research efforts, this analysis should serve as an impetus for additional studies that will allow the question 'Does OSA treatment reduce vascular disease risk?' to be properly answered," Gottlieb concludes. "Despite the complexity of OSA treatment trials, the rationale for conducting these trials remains strong."

The study was supported by the National Health and Medical Research Council (NHMRC) of Australia. Neal reports receipt of a grant and personal fees from Janssen, receipt of support from the NHMRC and that he was an investigator on the SAVE trial, which was supported by grants from Phillips Respironics, NHMRC, ResMed, and Fisher & Paykel. Disclosures for the coauthors are listed in the paper. Gottlieb reports a financial relationship with Vivus.

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