复旦大学：《循证医学》课程教学资源（参考教材）Unit 05 疾病预后证据的分析评价（主讲教师：胡予）.pdf_大学文库

original article The new england journal of medicine 2034 n engl j med 353;19 www.nejm.org november 10, 2005 Obstructive Sleep Apnea as a Risk Factor for Stroke and Death H. Klar Yaggi, M.D., M.P.H., John Concato, M.D., M.P.H., Walter N. Kernan, M.D., Judith H. Lichtman, Ph.D., M.P.H., Lawrence M. Brass, M.D., and Vahid Mohsenin, M.D. From the Section of Pulmonary and Critical Care Medicine, Yale Center for Sleep Medicine (H.K.Y., V.M.), the Section of General Medicine (J.C., W.N.K.), and the Departments of Epidemiology and Public Health (J.H.L., L.M.B.) and Neurology (L.M.B.), Yale University School of Medicine, New Haven, Conn.; and the Section of Pulmonary and Critical Care Medicine (H.K.Y.), the Clinical Epidemiology Research Center (H.K.Y., J.C.), and the Section of Neurology (L.M.B.), Veterans Affairs Connecticut Healthcare System, West Haven, Conn. Address reprint requests to Dr. Mohsenin at the Yale Center for Sleep Medicine, 300 Cedar St., TAC 441, P.O. Box 208057, New Haven, CT 06520. N Engl J Med 2005;353:2034-41. Copyright © 2005 Massachusetts Medical Society. background Previous studies have suggested that the obstructive sleep apnea syndrome may be an important risk factor for stroke. It has not been determined, however, whether the syndrome is independently related to the risk of stroke or death from any cause after adjustment for other risk factors, including hypertension. methods In this observational cohort study, consecutive patients underwent polysomnography, and subsequent events (strokes and deaths) were verified. The diagnosis of the obstructive sleep apnea syndrome was based on an apnea–hypopnea index of 5 or higher (five or more events per hour); patients with an apnea–hypopnea index of less than 5 served as the comparison group. Proportional-hazards analysis was used to determine the independent effect of the obstructive sleep apnea syndrome on the composite outcome of stroke or death from any cause. results Among 1022 enrolled patients, 697 (68 percent) had the obstructive sleep apnea syndrome. At baseline, the mean apnea–hypopnea index in the patients with the syndrome was 35, as compared with a mean apnea–hypopnea index of 2 in the comparison group. In an unadjusted analysis, the obstructive sleep apnea syndrome was associated with stroke or death from any cause (hazard ratio, 2.24; 95 percent confidence interval, 1.30 to 3.86; P=0.004). After adjustment for age, sex, race, smoking status, alcohol-consumption status, body-mass index, and the presence or absence of diabetes mellitus, hyperlipidemia, atrial fibrillation, and hypertension, the obstructive sleep apnea syndrome retained a statistically significant association with stroke or death (hazard ratio, 1.97; 95 percent confidence interval, 1.12 to 3.48; P=0.01). In a trend analysis, increased severity of sleep apnea at baseline was associated with an increased risk of the development of the composite end point (P=0.005). conclusions The obstructive sleep apnea syndrome significantly increases the risk of stroke or death from any cause, and the increase is independent of other risk factors, including hypertension. abstract Downloaded from www.nejm.org on January 23, 2010 . Copyright © 2005 Massachusetts Medical Society. All rights reserved

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 cessation, 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 treatable form of disordered breathing in which the upper airway closes repeatedly during sleep. The syndrome is associated with vascular risk factors and with substantial cardiovascular morbidity and mortality.3 Several studies have shown a prevalence of the syndrome among patients with stroke that exceeds 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 factors, such as hypertension, hyperlipidemia, diabetes mellitus, and smoking, is not clear. Several crosssectional 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, underwent at least two hours of attended sleep monitoring, 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 constituted 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 airway 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 University 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 questionnaire 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 included the daily use of beta-blockers, angiotensin-converting–enzyme inhibitors, other antihypertensive medications, antiplatelet therapy, anticoagulants, oral medications for the treatment of diabetes, insulin, and lipid-lowering medications. Risk-factor data included a history of hypertension, atrial fibrillation, 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 electrocardiography during polysomnography was considered sufficient 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 polysomnography 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

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 described previously.4 A single, attended polysomnographic 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 cessation 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 seconds and associated with oxygen desaturation of 4 percent or more, was termed hypopnea.18 Calculated 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 responded 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 determined according to criteria of the National Institute 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 confirm 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 required in order to achieve 80 percent power to detect 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 obstructive 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 contacted 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 patients with and those without the obstructive sleep apnea syndrome. With the use of proportionalhazards analysis, hazard ratios and 95 percent confidence 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 baseline characteristics, including age, sex, race, smoking status, alcohol-consumption status, body-mass index, and the presence or absence of diabetes mellitus, hyperlipidemia, atrial fibrillation, and hypertension. Because of the possibility that controlling for hypertension could constitute “overadjustment” (i.e., accounting for a variable on the causal pathway),24 models were created both with and without the inclusion of hypertension. Finally, a trend analysis, with the use of the chi-square test for linear trend, was performed to analyze whether an increased 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 values at baseline among patients who had the obstructive sleep apnea syndrome with those in the comparison 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 softDownloaded from www.nejm.org on January 23, 2010 . Copyright © 2005 Massachusetts Medical Society. 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 2037 ware was used to generate the Kaplan–Meier survival curves (Mathsoft Engineering and Education). Between January 1, 1997, and December 31, 2000, 3635 consecutive patients were referred to the sleep center, of whom 1022 were eligible to participate in the study. A total of 2402 patients were ineligible because they were less than 50 years of age, and 159 patients were ineligible because they had clinical evidence of previous myocardial infarction or stroke at entry. Another 52 patients were excluded because of unavailability of baseline data, having undergone a tracheostomy, or having been referred for conditions other than sleep-disordered breathing. A total of 697 of the 1022 study participants (68 percent) were classified as having the obstructive sleep apnea syndrome (Table 1). The mean (±SD) apnea–hypopnea index among the patients with the syndrome was 35±29, as compared with 2.0±1.5 in the comparison group. As expected, the prevalence of hypertension and diabetes mellitus was higher in the group with the syndrome than in the comparison group (Table 1). Patients with the syndrome also were more obese, as reflected by the higher body-mass index, and had lower nadir oxygen saturations and a higher arousal index. Obstructive apnea was the predominant apneic event; central apnea was rare. Many patients with the obstructive sleep apnea syndrome received some type of treatment for sleep apnea after the initial evaluation. Thirty-one percent achieved a weight reduction of 10 percent or more; 58 percent were using airway pressurization for at least four hours per night for five nights or more per week; 15 percent underwent upperairway surgery. Follow-up after the single sleep study took place between June 1, 2002, and December 31, 2003. Patients with the syndrome had a median duration of follow-up of 3.4 years (interquartile range, 2.6 to 3.9), and the comparison group had a median duration of follow-up of 3.3 years (interquartile range, 2.8 to 4.2). Among the 1022 study patients, data on stroke events and death from any cause were obtained for 842 patients (82 percent). Investigators were unable to contact the remaining 180 patients (18 percent), and the vital-records search did not indicate that they had died. This group included 124 patients with the syndrome and 56 patients in the comparison group. The baseline characteristics of these patients were similar to the characteristics of the group with complete follow-up (data not shown). Incident stroke or death from any cause occurred in 88 patients (9 percent). The 88 confirmed events among these patients included 22 strokes and 50 deaths in the group with the obstructive sleep apnea syndrome (3.48 events per 100 person-years), as compared with 2 strokes and 14 deaths in the comparison group (1.60 events per 100 personyears). Figure 1 shows the Kaplan–Meier estimates of the time to the composite event of stroke or death. The probability of event-free survival was significantly lower for patients with the syndrome than for the comparison group (P=0.003 by the log-rank test). A time-to-event analysis for death only showed a similar result (P=0.02 by the logrank test) (Fig. 2). In an unadjusted analysis (Table 2), a significant results * Race was determined by the investigators. † The body-mass index is the weight in kilograms divided by the square of the height in meters. Table 1. Baseline Characteristics of Patients with the Obstructive Sleep Apnea Syndrome and Controls. Characteristic Patients with the Syndrome (N=697) Controls (N=325) P Value Mean age (yr) 60.9 58.7 0.005 Male sex (%) 77 59 <0.001 White race (%)* 84 89 0.02 Mean body-mass index† 33.8 30.5 <0.001 Current smoker (%) 10 11 0.61 Current consumption of alcohol (%) 24 20 0.04 Hypertension (%) 60 43 <0.001 Diabetes mellitus (%) 16 10 0.03 Atrial fibrillation (%) 7 4 0.07 Hyperlipidemia (%) 25 21 0.20 Lipid-lowering therapy (%) 25 21 0.20 Antiplatelet therapy (%) 34 32 0.62 Mean score on Epworth Sleepiness Scale 11 10 0.004 Habitual snoring (%) 83 64 <0.001 Mean apnea–hypopnea index 35 2 <0.001 Lowest level of arterial oxygen saturation during sleep (%) 80.5 87.2 <0.001 Mean arousal index 53 26 <0.001 Downloaded from www.nejm.org on January 23, 2010 . Copyright © 2005 Massachusetts Medical Society. All rights reserved