Composition of the study sample is shown in . Of the 6,441 subjects enrolled in the SHHS, individuals excluded from analyses included 136 subjects who had a history of stroke identified by the parent cohort at baseline, 21 subjects with missing censoring times, and 102 who reported use of continuous positive airway pressure for treatment of sleep apnea. All 760 subjects recruited from one of the field sites were excluded from this analysis due to data quality problems at this site. The analytic cohort therefore consisted of 2,462 men and 2,960 women.
Study schema showing derivation of the analytical sample. CPAP = continuous positive airway pressure.
The 5,422 participants without a history of stroke and untreated for OSA with pressure therapy at the baseline SHHS examination were followed for a median of 8.7 years (interquartile range 7.8–9.4 yr). Over this period, a total of 193 ischemic strokes were observed (85 in men and 108 in women). Assuming a constant risk of stroke over the follow-up time, the estimated incidence rates were 4.4 ischemic strokes per 1,000 person-years (95% confidence interval [CI], 3.5–5.4) in men and 4.5 (3.7–5.4) in women.
and show the demographic characteristics, cardiovascular risk factors, and OSA measures by stroke incidence and sex. In both men and women, incident stroke was associated with increasing age and systolic blood pressure, use of antihypertensive medication, and atrial fibrillation. In women, stroke also was associated with race (higher among African Americans and lower among Native Americans) and marginally associated with diabetes (P = 0.055). Stroke was not associated with BMI, smoking status, or alcohol use in men or women. At baseline, moderate or severe OSA (OAHI > 15) was approximately 30% more common in men and women who subsequently had an ischemic stroke compared with those who remained stroke-free. Furthermore, mean OAHI and categories of desaturation time were less favorable in both men and women who subsequently had a stroke compared with those who did not. In contrast, baseline arousal index did not differ by the occurrence of stroke.
DISTRIBUTIONS OF DEMOGRAPHIC RISK FACTORS, AND OBSTRUCTIVE SLEEP APNEA INDICES IN MALE SLEEP HEART HEALTH PARTICIPANTS BY ISCHEMIC STROKE STATUS
DISTRIBUTIONS OF DEMOGRAPHIC, RISK FACTORS, AND OSA INDICES IN FEMALE SLEEP HEART HEALTH PARTICIPANTS BY ISCHEMIC STROKE STATUS
and also provide the unadjusted odds ratios (OR) for representative variables. In men, the unadjusted increased odds of incident stroke for an individual with OSA compared with someone without OSA (OR, 2.26) is approximately equivalent to the increased risk associated with a 10-year increase in age (2.37). In women, a somewhat lower OR for stroke was observed (1.65), roughly equivalent to the risk of stroke associated with diabetes in this cohort (1.79). BMI was not significantly associated with incident stroke in either men or women.
Unadjusted rates of total and ischemic strokes in men and women by quartiles of OAHI and arousal index and overnight desaturation category are shown in . In both men and women, a progressively higher crude incidence rate of stroke is observed with increasing OAHI, with similar trends seen for desaturation index but not for arousal index.
CRUDE RATES OF ISCHEMIC STROKE (PER 1,000 PERSON-YEARS) BY OBSTRUCTIVE SLEEP APNEA INDICES
In men, a progressive increase in the unadjusted hazard ratios (HRs) for ischemic stroke was observed with increasing quartiles of OAHI (; P < 0.005). Attenuation of this association was observed with age adjustment, with a further modest attenuation after additional adjustment for BMI, race, smoking, systolic blood pressure, antihypertensive medication, and diabetes). After adjustment for these covariates (of which only age was significantly associated with ischemic stroke), increasing quartile of OAHI remained significantly associated with increased stroke risk. Among men with an OAHI in the top quartile (i.e., >19 events/h) there was an almost threefold increased risk of ischemic stroke relative to men with an OAHI less than 4.1 events/h. In adjusted analyses, incident stroke was not associated with the arousal index or desaturation levels.
RESULTS OF COX PROPORTIONAL HAZARD MODEL REGRESSION HAZARD OF DEVELOPING INCIDENT ISCHEMIC STROKE AMONG MEN
In women, adjusted analyses showed that stroke risk was significantly associated with age (HR, 2.77; 95% CI, 2.12–3.61 per 10 yr), diabetes (HR, 1.98; 95% CI, 1.17–3.35), hypertension medication use (HR, 1.94; 95% CI, 1.25–3.05), former smoking (HR, 1.53; 95% CI, 1.09–2.33), and current smoking (HR, 2.46; 95% CI, 1.27–4.75) but was not associated with OAHI quartile or desaturation levels (). In contrast to the findings in men, in women, a higher arousal index was associated with a reduced incidence of stroke, such that women who had an arousal index greater than 12 (i.e., the first quartile) had a 40 to 60% decreased hazard rate of ischemic stroke compared with women with a lower arousal index.
RESULTS OF COX PROPORTIONAL HAZARD MODEL REGRESSION HAZARD OF DEVELOPING INCIDENT ISCHEMIC STROKE AMONG WOMEN
show the stroke-free survival curves for men and women according to OAHI quartile.
Figure 2. Adjusted Kaplan-Meier stroke-free survival estimates as a function of obstructive apnea–hypopnea index (OAHI) quartile. Values are modeled in this graph for white current smoker (A) men and (B) women with no use of antihypertensive medications (more ...)
Additional analyses were conducted to explore the inverse association between arousal index and stroke incidence in women. Persistence of an inverse association between arousals and stroke in women was observed in regression models, which included both arousal index and OAHI, as well as in models stratified by OAHI category. These suggested that the inverse association of arousals was independent of OAHI severity. Because hypnotic medication use might reduce arousal frequency, we examined benzodiazepine use and found that those using this class of medication had a lower mean arousal index (16.4 events/h; 95% CI, 15.2–17.5 vs.19.2 events/h; 95% CI, 18.9–19.5, in users and nonusers, respectively; P < 0.0001). Among women, the probability of a stroke was higher among benzodiazepine users than nonusers (7.4% as compared with 3.4%; P = 0.005). However, arousal index remained a significant negative predictor of incident stroke in women even after excluding hypnotic users from the regression models, as well as in models that adjusted for benzodiazepine use. In men (3.7% reported hypnotic use), no association was observed between hypnotic use and stroke.
Secondary analyses also were conducted to further address potential confounding. Atrial fibrillation was present at the baseline examination in 37 men and 22 women. Excluding these individuals from the analyses did not materially change the findings (i.e., in men, the HR for the upper quartile of OAHI was significant at 2.70 (95% CI, 1.04–7.05). Including the additional set of extended covariates (none of which was significantly associated with stroke) modestly reduced the strength of the association between OAHI and stroke (e.g., in men the HR for the upper OAHI quartile was 2.64; 95% CI, 1.01–6.88).
We explored nonlinear, covariate adjusted associations with the OSA exposures and interactions with sex. In men, nonparametric modeling of OAHI identified a linear increase in HR between an OAHI of 5 and 25 events/h, with each unit of OAHI estimated to increase HR by 6% (95% CI, 2–10%). In women, a 2% increase (95% CI, 0–5%) in stroke HR with each unit increment in OAHI after a threshold of 25 events/h also was observed. In combined sex analyses, a significant interaction between sex and the highest OAHI quartile was observed (P = 0.0009), supporting the differences observed in sex-stratified analyses.