Th NEW ENGLAND IOURNAL FMEDICINE ns (Astro-Med)on the basis of a p ocol de. for sleep apnea in our coho and an incidence of iously.*a singl nded polso f1 5 ntduring a fou that was conducted during an entire follow-up period.a sampl of0 patients wasre night was used to establish the presence of sleep pne stages we ect a relat 0 at th e5 percent(two-ta the nose and mouth for at leas A series ofn specified time-to ent analyse 10 seconds was classified as apnea(as obstructive were performed to examine the effect of the ob apnea if respiratory etforts v ere present and as structive slee ep apnea syndrome on the outcme to be the airflow by more than 30 percent for at least 10 sec tacted and found to have had a stroke.and the time onds and associated with oxygen desaturation of ideath,if the patint was not reached but was more,was erme tound to have c Data were ce the opnea index and the arousal index (the found not to have had a strokeand number ofarousals per hour ofsleep) at day 1 if the patient was not reached (or unwilling OUTCOMES er me ne log-rank nt a folle which included questions regarding current state tients with and those without the of health,occurrence of stroke,hospitalizations apnea syndrome. With the use of proportional and treatment of sleep dis ince the zards analy hazard ratios pe nt co taine questionnaire designed to bea practical and reliable baseline characteristics and the end point of stroke means of ascertaining stroke status.9 Attempts or death from any cause.Hazard ratios were then nad not ed for the confo ling effects of other ba asked to ovide infor mation abou status achol-oonsum patients who were not able to participate owing to index,and the presenceorabsence ofdiabetes mel- death,illness,or dementia. litus,hyperlipidem atrial fibrillation,and hype tension.Bec se or 巧ytha by reviewing medical records.Diagnoses were de vav),2+models were created both with and without a of t naly Th d to n in date of the suroke or TA was recorded.Vital records creased severity of the obstructive sleep apnea from the Connecticut De nt of Public Health syndrome (on the basis of quartiles of the apnea regarding te c s)an al se an increa 122 -ofstate deaths) used to determin Student's t-test was used to co mpare mean val. firm death.The exact date of death was recorded ues at baselineamong patients who had theobstruc tive sleep apnea syndrom ith those in the compa STATISTICAL A 80 mp of incident stroke (including TIA.which hereafter were performed with the use of sas software (sas sided,and 2036 N ENGL J MED 353:19 WWW.NEJM.ORG NOVEMBER 10,2005 Downloaded from www.nejm.org on January 23,2010.Massachusetts Medical Socety.All rights reserved.n engl j med 353;19 www.nejm.org november 10, 2005 The new england journal of medicine 2036 systems (Astro-Med) on the basis of a protocol de￾scribed previously.4 A single, attended polysomno￾graphic study that was conducted during an entire night was used to establish the presence of sleep apnea.16 Sleep stages were scored in 30-second epochs according to standard criteria.17 Total ces￾sation of airflow at the nose and mouth for at least 10 seconds was classified as apnea (as obstructive apnea if respiratory efforts were present and as central apnea if respiratory efforts were absent). Partial airway closure, resulting in a diminution of airflow by more than 30 percent for at least 10 sec￾onds and associated with oxygen desaturation of 4 percent or more, was termed hypopnea.18 Cal￾culated polysomnographic variables included the apnea–hypopnea index and the arousal index (the number of arousals per hour of sleep). outcomes Each patient was sent a follow-up questionnaire, which included questions regarding current state of health, occurrence of stroke, hospitalizations, and treatment of sleep disorders since the baseline assessment. Strokes and transient ischemic attacks (TIA) were ascertained with the use of a validated questionnaire designed to be a practical and reliable means of ascertaining stroke status.19 Attempts were made to telephone patients who had not re￾sponded to the initial mailed questionnaire. Family members were asked to provide information about patients who were not able to participate owing to death, illness, or dementia. A physician investigator who was unaware of the patient’s status with regard to the obstructive sleep apnea syndrome validated reported strokes and TIAs by reviewing medical records. Diagnoses were de￾termined according to criteria of the National Insti￾tute of Neurological Disorders and Stroke20 for the classification of cerebrovascular events. The exact date of the stroke or TIA was recorded. Vital records from the Connecticut Department of Public Health (regarding in-state deaths) and the Social Security Administration Death Master File21,22 (regarding out-of-state deaths) were used to determine or con￾firm death. The exact date of death was recorded. statistical analysis The primary outcome was the composite end point of incident stroke (including TIA, which hereafter will be reported as stroke) or death from any cause. With the assumption of a prevalence of 60 percent for sleep apnea in our cohort and an incidence of stroke per year of 1.5 percent23 during a four-year follow-up period, a sample of 840 patients was re￾quired in order to achieve 80 percent power to de￾tect a relative risk of 2.0 at the 5 percent (two-tailed) significance level. A series of prespecified time-to-event analyses were performed to examine the effect of the ob￾structive sleep apnea syndrome on the outcome. The time until the composite end point was taken to be the time until stroke, if the patient was con￾tacted and found to have had a stroke, and the time until death, if the patient was not reached but was found to have died. Data were censored at the time of the contact if the patient was reached and was found not to have had a stroke and were censored at day 1 if the patient was not reached (or unwilling to be contacted) and was not found to have died. The Kaplan–Meier method and the log-rank test were used to compare event-free survival among pa￾tients with and those without the obstructive sleep apnea syndrome. With the use of proportional￾hazards analysis, hazard ratios and 95 percent con￾fidence intervals were generated for the unadjusted association between sleep-apnea status or other baseline characteristics and the end point of stroke or death from any cause. Hazard ratios were then adjusted for the confounding effects of other base￾line characteristics, including age, sex, race, smok￾ing status, alcohol-consumption status, body-mass index, and the presence or absence of diabetes mel￾litus, hyperlipidemia, atrial fibrillation, and hyper￾tension. Because of the possibility that controlling for hypertension could constitute “overadjustment” (i.e., accounting for a variable on the causal path￾way),24 models were created both with and without the inclusion of hypertension. Finally, a trend analy￾sis, with the use of the chi-square test for linear trend, was performed to analyze whether an in￾creased severity of the obstructive sleep apnea syndrome (on the basis of quartiles of the apnea– hypopnea index) was associated with an increased risk of stroke or death from any cause. Student’s t-test was used to compare mean val￾ues at baseline among patients who had the obstruc￾tive sleep apnea syndrome with those in the compar￾ison group. Categorical data were compared with the use of the chi-square test. All statistical tests were performed with the use of SAS software (SAS Institute). All reported P values are two-sided, and no interim analyses were conducted. S-Plus soft￾Downloaded from www.nejm.org on January 23, 2010 . Copyright © 2005 Massachusetts Medical Society. All rights reserved