OBSTRUCTIVE SLEEP APNEA AS A RISK FACTOR FOR STROKE AND DEATH TROKE IS THE SECOND LEADING CAUSE for reasons other than the evaluation of suspected of death worldwide and the leading cause of sleep-disordered breathing (e.g.,narcolepsy or ong-m disability.Strategies for stroke contro my ostomy:or tion.have reduced the disease burden.but stroke airway pressurization (e.g.continuous positiveair still remains an important public health challenge.way pressure for therap eutic purposes). risk factors for strok Participantsor heir family membe oen or or nt.The able form ofdisordered breathing in which the up by the Human nvestigtion Committee at Yale Uni versity School of Medicine. me is ass te ASSE aphic characteristics,sleep and the syndrome among patients with stroke that ex- medical history.medication use.and habits were as compared with 4 percentin wit the use of a standa alzed que stroke is independent of confounding risk fac- ed by a phy an Each patient's height and weight were recorded at the l cross time of polyso omnography and used to calculate the the risk of strok e with slee d hi that is similar in magnitude to the effect ofothe of daytime sleepiness(the Epworth Sleepiness cardiovascular risk factors.Astudy of patients with Scale) s and self-reported habitual snoring,which cute st demonstrated that obstructive apne was defined snonng occurring"freque that the obstructive sleep ap may have ed the daily use angiotensin-co predated the development of stroke.We therefore verting-enzyme inhibitors,other antihypertensive hypothesized that patients with the syndrome hav medications,antiplatelet therapy,ant that isnd roke or dea rom or the t factors data included a histo METHODS the patie he baselin atrial fbrillatio ng ph phy during polysomnography was considered suf of ficient evidence to esta hat diagnosis e sp Pauents were hether ntat least two hours ofattended sleep monit smoked:data were eli ing,completed a 10-page questionnaire on their number of pack-years of smoking The history of sleep an medical history,and w vas ed on ks per day an the a of year (five or more ents per hour of sleen):natients with an vent attended overnight poly had been referred N ENGLJ MED 353:19 www.NEjM.ORc NOVEMBER 10,2005 2035 Dowloaded from www.23.10.Massachusetts Medical Socety.All rights reserved n engl j med 353;19 www.nejm.org november 10, 2005 obstructive sleep apnea as a risk factor for stroke and death 2035 troke is the second leading cause of death worldwide and the leading cause of long-term disability.1,2 Strategies for stroke prevention, including the control of hypertension, treatment of atrial fibrillation, and smoking cessa￾tion, have reduced the disease burden, but stroke still remains an important public health challenge. A better understanding of the risk factors for stroke is needed to develop additional preventive strategies. The obstructive sleep apnea syndrome is a treat￾able form of disordered breathing in which the up￾per airway closes repeatedly during sleep. The syn￾drome is associated with vascular risk factors and with substantial cardiovascular morbidity and mor￾tality.3 Several studies have shown a prevalence of the syndrome among patients with stroke that ex￾ceeds 60 percent,4-7 as compared with 4 percent in the middle-aged adult population.8 Whether the relation between the syndrome and stroke is independent of confounding risk fac￾tors, such as hypertension, hyperlipidemia, diabetes mellitus, and smoking, is not clear. Several cross￾sectional analyses6,9-14 have shown an increase in the risk of stroke with sleep-disordered breathing that is similar in magnitude to the effect of other cardiovascular risk factors. A study of patients with acute stroke7 demonstrated that obstructive apnea persisted despite neurologic recovery, suggesting that the obstructive sleep apnea syndrome may have predated the development of stroke. We therefore hypothesized that patients with the syndrome have an increased risk of stroke or death from any cause that is independent of other cerebrovascular risk factors. study population We conducted an observational cohort study. The cohort consisted of patients who were referred to the Yale Center for Sleep Medicine specifically for the evaluation of sleep-disordered breathing, under￾went at least two hours of attended sleep monitor￾ing, completed a 10-page questionnaire on their sleep and medical history, and were 50 or more years old. The exposure group was defined a priori as having an apnea–hypopnea index of 5 or higher (five or more events per hour of sleep); patients with an apnea–hypopnea index of less than 5 con￾stituted the comparison group. Patients were excluded if they had been referred for reasons other than the evaluation of suspected sleep-disordered breathing (e.g., narcolepsy or movement disorder); if they had a history of stroke, myocardial infarction, or tracheostomy; or if the entire polysomnographic study was performed with airway pressurization (e.g., continuous positive air￾way pressure for therapeutic purposes). Participants or their family members gave either written or oral informed consent at the time of follow-up ascertainment. The study was approved by the Human Investigation Committee at Yale Uni￾versity School of Medicine. baseline assessment Data on demographic characteristics, sleep and medical history, medication use, and habits were obtained with the use of a standardized question￾naire administered by a trained technologist before the initiation of overnight polysomnography; the questionnaires were reviewed by a physician. Each patient’s height and weight were recorded at the time of polysomnography and used to calculate the body-mass index. Sleep-history data included a validated measure of daytime sleepiness (the Epworth Sleepiness Scale)15 and self-reported habitual snoring, which was defined as loud snoring occurring “frequently” or “constantly.” Data regarding medications includ￾ed the daily use of beta-blockers, angiotensin-con￾verting–enzyme inhibitors, other antihypertensive medications, antiplatelet therapy, anticoagulants, oral medications for the treatment of diabetes, in￾sulin, and lipid-lowering medications. Risk-factor data included a history of hypertension, atrial fibril￾lation, diabetes mellitus, or hyperlipidemia, either reported by the patient on the baseline medical questionnaire or noted by the referring physician. In addition, atrial fibrillation on electrocardiogra￾phy during polysomnography was considered suf￾ficient evidence to establish that diagnosis. Patients were classified according to whether they were current or former smokers or had never smoked; data were elicited, if applicable, on the number of pack-years of smoking. The history of alcohol consumption was based on the average number of drinks per day and the number of years of drinking. polysomnography Participants underwent attended overnight poly￾somnography with the use of Grass data-acquisition s methods Downloaded from www.nejm.org on January 23, 2010 . Copyright © 2005 Massachusetts Medical Society. All rights reserved