Use of continuous positive airway pressure (CPAP) after an acute stroke or transient ischemic attack (TIA) may improve neurologic functioning in patients with obstructive sleep apnea (OSA), new research suggests.
In a randomized controlled trial that included more than 250 participants, the best outcomes after an acute stroke or TIA occurred among 59% of patients treated for sleep apnea. In contrast, only 38% of patients randomly assigned to a control group achieved a National Institutes of Health Stroke Scale (NIHSS) score between 0 and 1.
The absolute risk reduction associated with CPAP was 21%, and the number needed to treat was 4.8 patients.
However, the researchers note that timing is important.
“Neurologists and other clinicians who care for patients with ischemic stroke and TIA should consider diagnosing and treating sleep apnea in the acute event period,” principal investigator Dawn M. Bravata, MD, an investigator at the Regenstrief Institute in Indianapolis, Indiana.
“The available evidence suggests that implementing CPAP as soon as possible after the index cerebrovascular event maximizes the neurological symptom benefit,” Bravata added.
Results of the Sleep Tight study were published online August 21 in the Journal of the American Heart Association.
Building on Evidence
In general, patients who experience a stroke or TIA and who have sleep apnea have worse outcomes, including higher mortality rates, than patients who do not have sleep apnea, said Bravata, who is also affiliated with the Department of Veterans Affairs Health Services Research and Development Service Center for Health Information and Communication in Indianapolis.
Several observational studies and smaller randomized controlled trials provided preliminary data demonstrating benefits of treating sleep apnea.
“That prior work provided the rationale for designing and conducting a large-scale randomized controlled trial,” Bravata said.
To learn more about an association between CPAP use and outcomes, including severity of neurologic symptoms, functional status, and recurrent vascular events, the researchers assessed 252 adults with ischemic stroke or TIA. They randomly assigned 84 patients to receive usual care (control group), 86 to receive standard CPAP intervention, and the remaining 82 to undergo an enhanced CPAP protocol.
Patients in the standard intervention group received five in-person contacts and one telephone contact during follow-up of up to 12 months. During the first visit, investigators educated participants about sleep apnea, CPAP, use of the CPAP equipment, and the results of their polysomnography session.
During subsequent visits, researchers checked the CPAP unit to monitor adherence, asked patients about symptom improvement and adverse events, and encouraged them to continue using the device.
The enhanced protocol group received the same educational session on the first visit. They also completed a questionnaire that addressed sleep apnea attitudes, beliefs, and social supports and that helped determine their individual risks for consequences of sleep apnea. They also completed the Self-Efficacy Measure in Sleep Apnea. A key component of this intervention was the development of a personalized positive pressure plan for each patient by a multidisciplinary intervention team.
Known Risk Factor
“Sleep apnea is a known risk factor for ischemic stroke and TIA. Moreover, sleep apnea is known to be very common among patients with stroke and TIA — about two thirds of stroke/TIA patients have sleep apnea,” Bravata said.
Investigators found that in the current study, the prevalence of OSA was similar; OSA affected 69% of the control group, 74% of the standard intervention group, and 80% of the enhanced treatment group.
Because not all participants had sleep apnea, the researchers assessed outcomes in both the subset who had OSA (an as-treated analysis) and the total study population (intent-to-treat [ITT] analysis).
Median CPAP use was 4.5 hours per night for both the standard-treatment and enhanced-protocol groups. The enhanced protocol did not improve long-term CPAP adherence compared with the standard protocol.
In the full study population (41% women, 36% black), 80% experienced stroke as their index event. All participants underwent brain imaging within 48 hours of symptom onset.
In the as-treated analysis, increasing CPAP use was associated with NIHSS score and functional (Modified Ranking Scale) improvements.
Table. Outcomes Associated With CPAP Treatment
| No or Poor CPAP Use | Mean Change | Some CPAP Use | Mean Change | Good CPAP Use | Mean Change | Overall P Value | |
|---|---|---|---|---|---|---|---|
| NIHSS Score | 32 | -0.6 +/- 2.9 | 19 | -0.9 ±1.4 | 27 | -0.3 ± 1.0 | .0064 |
| Modified Ranking Scale Score | 33 | -0.3 +/- 1.5 | 19 | -0.4 ± 1.0 | 28 | -0.9 ± 1.2 | .0237 |
| Based on as-treated analysis; NIHSS, National Institutes of Health Stroke Scale |
In contrast, in the ITT analysis, improvements in NIHSS score were modest and were similar across the control and intervention groups, the researchers note. The mean and standard deviation results were -0.5 ± 2.1 in the control group, -0.8 ± 1.9 in the standard intervention group, and -0.7 ± 2.1 in the enhanced protocol group (P = .80).
Likewise, the changes in Modified Rankin Scale score did not differ significantly across groups in the ITT analysis: 0.1 ± 1.5 in the control group, -0.6 ± 1.2 in the standard intervention group, and -0.3 ± 1.5 in the enhanced intervention group (P = .60).
A combined recurrent vascular event endpoint included stroke, acute myocardial infarction, unstable angina hospitalization, urgent coronary revascularization, and all-cause mortality. Results showed 13.1 events per 100 person-years of follow-up in the control group and 11.0 such events in the intervention groups.
Six people died during the study period, including two in the control group and four in the enhanced intervention group.
Clinical Implications?
The study results demonstrate that CPAP therapy for patients with ischemic stroke or TIA who have sleep apnea was associated with statistically significant and clinically relevant improvements in neurologic symptoms and functional status, the researchers note.
“If neurologists want to realize the neurological benefits of treating sleep apnea post stroke or post TIA, then they must include sleep apnea management as part of the acute stroke or TIA work-up,” Bravata said.
The researchers add that despite the fact that about three quarters of the patients had OSA, only 8% had sleep apnea as part of usual care. This indicates “that the guideline recommendations to screen and treat for sleep apnea are not being widely implemented,” they write.
The investigators suggest a benefit from adjunctive CPAP therapy.
“One of the most promising aspects of implementing sleep apnea management for stroke and TIA patients is that it can be applied with other effective interventions,” Bravata added. For example, patients can receive thrombolytic therapy in addition to sleep apnea management.
The researchers used unattended polysomnography to diagnose OSA in the study. Apnea was defined as the complete cessation of airflow for 10 seconds or longer.
“Given that the screening tools that are commonly used in general populations to identify a higher risk of having sleep apnea perform poorly in the stroke-TIA population, polysomnography is the recommended diagnostic test to identify sleep apnea in [this] population,” Bravata said.
Potential Limitations
A potential study limitation is that some data were missing as a consequence of participants being lost to follow-up over 12 months. However, the authors note that the losses “were equally distributed across all 3 randomization groups; therefore, it is unlikely that missing data biased the results.”
Another limitation was the delay of approximately 1 month between symptom onset and initiation of CPAP. “Although this is within the typical time it takes for CPAP delivery in routine clinical settings, earlier initiation of CPAP therapy might have produced greater changes in the vascular risk domains,” they write.
“There are many key questions left to answer, two of which are of great interest to our team,” Bravata said.
“First, we need to understand how hospitals should organize their care so that stroke and TIA patients can receive polysomnography and CPAP as soon as possible after an index stroke or TIA,” she said.
A second focus of future research could be determination of the minimum CPAP dose needed to achieve maximal neurologic recovery.
“The Sleep Tight data suggest thatanyCPAP use is better than no CPAP use; therefore, we must establish a dose-response relationship among patients with stroke and TIA in order to inform healthcare policy,” Bravata said.
Questions Remain
Asked to comment on the findings, James Burke, MD, associate professor of neurology at the University of Michigan, Ann Arbor, said that his “big-picture perspective” is that the findings, although interesting, aren’t “sufficiently robust to influence care.”
“This study wasn’t really designed to test the specific hypothesis that PAP treatment reduces post-stroke disability for a number of reasons,” said Burke, who was not involved with this research.
He cited a reliance on as-treated analysis, evaluation of many different hypotheses in the study, and the fact that results were only significant when outcome variables were dichotomized in a somewhat atypical pattern (for example, NIHSS 0-1 vs 2-8) but not when the whole distribution was analyzed.
“The results are of marginal statistical significance, and it’s a fairly small study,” he added. “These factors raise the possibility that the finding here is either a false positive — that PAP therapy doesn’t truly improve outcomes — or that the magnitude of the effect size is misestimated.”
However, he noted that the analysis “was a very useful exploratory and hypothesis-generating analysis. Based on this study, I’m more optimistic that PAP therapy, when robustly tested, will improve stroke outcomes. But I wouldn’t recommend PAP therapy to stroke patients with that goal in mind based on these data.”
The study was funded by a grant from the National Institutes of Health National Heart, Lung, and Blood Institute. Dr Bravata and Dr Burke have reported no relevant financial relationships.
J Am Heart Assoc. Published online August 15, 2018.
