Sleep Apnea and Risk of Peptic Ulcer Bleeding: A Nationwide Population-based Study

CLINICAL RESEARCH STUDY

Sleep Apnea and Risk of Peptic Ulcer Bleeding: A Nationwide Population-based Study Tsu-Hui Shiao, MD,a Chia-Jen Liu, MD,b,f,i,j Jiing-Chyuan Luo, MD,c Kang-Cheng Su, MD,a,e Yuh-Min Chen, MD, PhD,a,f Tzeng-Ji Chen, MD, PhD,d,g Kun-Ta Chou, MD,a,h Guang-Ming Shiao, MD,a,f Yu-Chin Lee, MDa,f a

Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; bDivision of Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; cDivision of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; dDepartment of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; eInstitute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan; fFaculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; gInstitute of Hospital and Health Care Administration, School of Medicine, National Yang-Ming University, Taipei, Taiwan; h Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; iDepartment of Internal Medicine, National Yang-Ming University Hospital, Yilan, Taiwan; jInstitute of Public Health, National Yang-Ming University, Taipei, Taiwan.

ABSTRACT OBJECTIVE: Patients with sleep apnea sustain cessation of breath during sleep, leading to intermittent hypoxia, systemic inflammation, and sympathetic activation. These insults may contribute to initiation or progression of peptic ulcers. This retrospective matched-control cohort study explored the relationship of sleep apnea and subsequent development of peptic ulcer bleeding. METHODS: From 2000 to 2009, patients with newly diagnosed sleep apnea were identified from the Taiwan National Health Insurance Research Database. A control group without sleep apnea, matched for age, gender, comorbidities, and medications, was selected for comparison. In both groups, subjects with history of peptic ulcer bleeding, nonspecific gastrointestinal bleeding, or malignancy were excluded. The 2 cohorts were followed up and observed for occurrence of peptic ulcer bleeding. RESULTS: Of the 35,480 sampled patients (7096 patients with sleep apnea vs 28,384 controls), 84 (0.24%) experienced peptic ulcer bleeding during a follow-up period of 3.57 ⫾ 2.61 years, including 32 (0.45% of patients with sleep apnea) from the sleep apnea cohort and 52 (0.18% of control) from the control group (log-rank test, P ⬍ .0001). In comparison with subjects without development of peptic ulcer bleeding, those with peptic ulcer bleeding were older and had a higher percentage of sleep apnea, coronary artery disease, peptic ulcer, ischemic stroke, and medication for nonsteroidal anti-inflammatory drugs. By Cox regression analysis, sleep apnea, older age, and peptic ulcer history were independent predictors of peptic ulcer bleeding. Patients with sleep apnea experienced a 2.400-fold (95% confidence interval, 1.544-3.731; P ⬍ .001) higher risk for incident peptic ulcer bleeding after adjusting for other variables. CONCLUSIONS: Sleep apnea may be an independent risk factor for peptic ulcer bleeding. © 2013 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2013) 126, 249-255 KEYWORDS: Intermittent hypoxia; Peptic ulcer bleeding; Sleep apnea; Sleep-disordered breathing

Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript. Drs Shiao and Liu contributed equally to the article. The institutional review board of Taipei Veterans General Hospital approved the study (VGHIRB No. 201009012IC). Requests for reprints should be addressed to Kun-Ta Chou, MD, Department of Chest Medicine, Taipei Veterans General Hospital, No 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan. E-mail address: [email protected].

0002-9343/$ -see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2012.08.017

Sleep apnea is a common disorder characterized by cessation of breathing during sleep, which is mostly attributed to repetitive pharyngeal airway collapse (ie, obstructive sleep apnea). Obstructive sleep apnea is estimated to affect 24% of men and 9% of women of the middle-aged population in the United States and is associated with a variety of diseases,1,2 most notable of which are cardiovascular diseases, such as hypertension, atherosclerosis, and arrhythmia.3-5 The resultant insults, including intermittent hypoxia, systemic inflammation, oxidative stress, and sympathetic activation after episodes of

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nal bleeding, or malignancy before enrollment were exapnea, may well explain its link to these cardiovascular cluded (Appendix). comorbidities.5 Age, comorbidities, and ulcerogenic/anti-ulcer medicaHowever, the impact of these noxious insults may be tions were matched in the 2 groups. The covariate variables more widespread than we would expect, not exclusively on enrollment included age, preexisting hypertension, dialimited to the cardiovascular system. Problems or comorbetes mellitus, coronary artery disbidities of the gastrointestinal sysease, arrhythmia, heart failure, tem, which are likely to be afchronic obstructive lung disease, fected as well, are less frequently CLINICAL SIGNIFICANCE asthma, hepatic cirrhosis, chronic described, although gastroesophakidney disease, ischemic stroke, geal reflux, fatty liver disease, and ● Sleep apnea leads to intermittent hypintracerebral hemorrhage, and deliver injury have received more atoxia, systemic inflammation, and sympression (Appendix, online). Ultention.6-8 According to the underpathetic activation. cerogenic medications in this study lying pathogenesis, it may be pos● Several gastrointestinal diseases, such included nonsteroidal anti-inflammasible for sleep apnea to participate as gastroesophageal reflux disease, tory drugs, corticosteroids, aspirin, in the initiation or progression of ticlopidine, clopidogrel, and warfapeptic ulcer and one of its complifatty liver, and liver injury, were linked rin, and anti-ulcer drugs included cations: peptic ulcer bleeding. We to sleep apnea. proton pump inhibitor and H2 hypothesized sleep apnea may in● Patients with sleep apnea experienced a blocker. To investigate the associadependently contribute to peptic 2.400-fold higher risk for incident peption between increasing severity of ulcer bleeding and conducted this tic ulcer bleeding. sleep apnea and further risk of pepnationwide population study to tic ulcer bleeding, sample stratificainvestigate the relationship be● For peptic ulcer bleeding without appartion for use of continuous positive tween sleep apnea and the subseent risk factors, sleep apnea may be a airway pressure ventilator treatment quent development of peptic ulcer potential predisposing factor. was performed, which we used as a bleeding. surrogate marker of sleep apnea severity. MATERIALS AND METHODS Both the sleep apnea cohort and control cohort were followed up from enrollment to the date with a diagnosis of Database peptic ulcer bleeding, death, withdrawal from the insurance, The National Health Insurance Program in Taiwan has been or to December 31, 2009 (Figure 1). operated since 1995 and has enrolled approximately 97% of the inhabitants of Taiwan.9 The National Health Insurance Research Database (NHIRD) at the National Health Research Institutes (NHRI) (http://www.nhri.org.tw/nhird/) in Miaoli (Taiwan) is in charge of the entire National Health Insurance claims database, and it has published numerous extracted datasets for researchers. The NHRI released a cohort dataset consisting of 1,000,000 randomly sampled people with all their records from 1995 onward. It also is one of the largest nationwide population-based databases in the world. These random samples were confirmed by the NHRI to be representative of the Taiwanese population. In this cohort dataset, each patient’s original identification number has been encrypted to protect privacy. Despite this, the linkage of claims belonging to the same patient is feasible within the NHIRD datasets because of the consistent encryption procedure.

Main Outcome Measures The end point of the study was defined as occurrence of peptic ulcer bleeding (Appendix, online).10

Statistical Analysis Microsoft SQL Server 2005 (Microsoft Corp, Redmond, Wash) was used for data management and computing.

Study Sample and Control We identified patients who were newly diagnosed with sleep apnea from the 1,000,000 sampling cohort dataset from January 1, 2000. An age-, gender-, comorbidity-, and ulcerogenic medication–matched control group was selected from those patients without sleep apnea throughout the whole course of follow-up. In both groups, patients with preexisting peptic ulcer bleeding, nonspecific gastrointesti-

Figure 1 Flow diagram demonstrating the follow-up process in the current study.

Shiao et al Table 1

Sleep Apnea and Risk of Peptic Ulcer Bleeding

251

Demographic Data for Patients With Sleep Apnea and Controls (n ⫽ 35,480)

N Age, y Male (%) Follow-up period (y) Comorbidities (%) Hypertension Diabetes mellitus Coronary artery disease Arrhythmia Heart failure COPD Asthma Peptic ulcer Hepatic cirrhosis Chronic kidney disease Ischemic stroke Intracranial hemorrhage Hyperlipidemia Depression Ulcerogenic medication (%) NSAID Corticosteroid Aspirin Ticlopidine Clopidogrel Warfarin Anti-ulcer Medication (%) Proton pump inhibitor H2 blocker Development of PUB during follow-up

Sleep Apnea

Control

P Value

7096 46.61 ⫾ 14.92 4462 (62.88) 3.62 ⫾ 2.61

28,384 46.61 ⫾ 14.92 17,848 (62.88) 3.56 ⫾ 2.60

1.000† 1.000 .070†

2205 930 1200 1013 321 1082 732 1962 87 447 271 75 1523 335

(31.07) (13.11) (16.91) (14.28) (4.52) (15.25) (10.32) (27.65) (1.23) (6.30) (3.82) (1.06) (21.46) (4.72)

8822 3719 4800 4054 1282 4328 2928 7844 344 1787 1081 298 6091 1337

(31.08) (13.10) (16.91) (14.28) (4.52) (15.25) (10.32) (27.64) (1.21) (6.30) (3.81) (1.05) (21.46) (4.71)

.991 .994 1.000 .988 .980 1.000 1.000 .981 .923 .991 .967 .958 .995 .970

1840 1470 1677 165 258 117

(25.93) (20.72) (23.63) (2.33) (3.64) (1.65)

7363 5884 6710 657 1028 464

(25.94) (20.73) (23.64) (2.31) (3.62) (1.63)

.986 .979 .990 .958 .955 .933

308 (4.34) 206 (2.90) 32 (0.45)

801 (2.82) 758 (2.67) 52 (0.18)

⬍.001 .281 .0000462*

COPD ⫽ chronic obstructive pulmonary disease; NSAID ⫽ nonsteroidal anti-inflammatory drug; PUB ⫽ peptic ulcer bleeding. Data are given as mean ⫾ standard deviation or percentage. P values for comparisons between 2 groups are determined by chi-square test unless mentioned otherwise. *Kaplan-Meier analysis. †Independent t test.

Statistical analysis was performed using the Statistical Package for the Social Sciences (v 15.0, SPSS Inc, Chicago, Ill). All data were expressed as mean ⫾ standard deviation or percentage. Comparisons between 2 groups were determined by independent Student t test for continuous variables or Pearson’s chi-square test for categoric variables as appropriate. Survival analysis was assessed using a Kaplan-Meier analysis, with the significance based on the log-rank test. Cox proportional hazards regression model was used to determine the factors independently associated with the development of peptic ulcer bleeding. A 2-sided P value ⬍ .05 was considered statistically significant.

RESULTS A total of 7096 patients with newly diagnosed sleep apnea (mean age, 46.61 ⫾ 14.92 years) were identified from the 1,000,000 sampling cohort dataset between January 2000

and December 2009. Another 28,384 subjects (4 for every patient in the sleep apnea group) without sleep apnea (mean age, 46.61 ⫾ 14.92 years) were matched for age, comorbidities, and medications, serving as the control group. The demographic parameters of study subjects are listed in Table 1. Most enrollees in both groups (96.72% in the sleep apnea cohort and 96.21% in the control group) remained active and were followed to the end of the study period (Figure 1). During an average of 3.57 ⫾ 2.61 years of follow-up, there was a significantly higher incidence of peptic ulcer bleeding among patients with sleep apnea compared with the control group (32 [0.45%] vs 52 [0.18%]; P ⬍ .0001). Incidences in the sleep apnea cohort and control groups were 1.24 and 0.51 persons per 1000 person-years, respectively. Medications prescribed for the 2 cohorts were not significantly different, except a higher rate of proton pump inhibitor use in those with sleep apnea (308 ([4.34%] vs 801 [2.82%]; P ⬍ .001).

252 Table 2

The American Journal of Medicine, Vol 126, No 3, March 2013 Characteristics of Subjects With and Without Development of Peptic Ulcer Bleeding

N Age, y Male (%) Comorbidities (%) Sleep apnea Hypertension Diabetes mellitus Coronary artery disease Arrhythmia Heart failure COPD Asthma Peptic ulcer Hepatic cirrhosis Chronic kidney disease Ischemic stroke Intracranial hemorrhage Hyperlipidemia Depression Ulcerogenic Medication NSAID Corticosteroid Aspirin Ticlopidine Clopidogrel Warfarin Anti-ulcer medication Proton pump inhibitor H2 blocker

PUB (⫹)

PUB (⫺)

P Value

84 52.27 ⫾ 13.57 51 (60.71)

35,396 46.60 ⫾ 14.92 22,259 (62.89)

⬍.001† .681

32 30 12 22 18 6 15 11 41 1 9 7 1

7064 10,997 4637 5978 5049 1597 5395 3649 9765 430 2225 1345 372

(19.96) (31.07) (13.10) (16.89) (14.26) (4.51) (15.24) (10.31) (27.59) (1.21) (6.29) (3.80) (1.05)

⬍.001 .358 .748 .023 .061 .281* .505 .402 ⬍.001 1.000* .095 .041* .589*

19 (22.62) 8 (9.52)

7595 (21.46) 1664 (4.70)

.796 .062*

37 21 27 3 4 1

9166 7333 8360 819 1282 580

(38.10) (35.71) (14.29) (26.19) (21.43) (7.14) (17.86) (13.10) (48.81) (1.19) (10.71) (8.33) (1.19)

(44.05) (25.00) (32.14) (3.57) (4.76) (1.19)

5 (5.95) 3 (3.57)

(25.90) (20.72) (23.62) (2.31) (3.62) (1.64)

1104 (3.12) 961 (2.71)

⬍.001 .333 .066 .448* .550* 1.000* .192* .499*

COPD ⫽ chronic obstructive pulmonary disease; NSAID ⫽ nonsteroidal anti-inflammatory drug; PUB ⫽ peptic ulcer bleeding. Data are given as mean ⫾ standard deviation or percentage. P values for comparisons between 2 groups are determined by the chi-square test unless mentioned otherwise. *Fisher exact test. †Independent t test.

Comparing subjects with and without peptic ulcer bleeding, those with incident peptic ulcer bleeding were older and had a higher percentage of sleep apnea, coronary artery disease, peptic ulcer, ischemic stroke, and medication with nonsteroidal anti-inflammatory drugs (Table 2). After adjusting for age, gender, comorbidities, and medications, by Cox regression, sleep apnea (hazard ratio [HR], 2.400; 95% confidence interval [CI], 1.544-3.731; P ⬍ .001), increasing age (HR, 1.021; 95% CI, 1.002-1.040; P ⫽ .028), and history of peptic ulcer (HR, 2.292; 95% CI, 1.437-3.653; P ⬍ .001) were independently associated with occurrence of peptic ulcer bleeding (Table 3). Compared with the control group, the adjusted risks of peptic ulcer bleeding in patients with sleep apnea who needed and did not need continuous positive airway pressure treatment were 4.660 (95% CI, 2.087-10.404; P ⬍ .001) and 2.114 (95% CI, 1.311-3.410; P ⫽ .002), respectively (Table 4).

DISCUSSION To our knowledge, we are the first to address the relationship of sleep apnea and subsequent peptic ulcer bleeding. By using a large-scale nationwide database, we identified sleep apnea as an independent predictor of peptic ulcer bleeding (relative risk, 2.400; 95% CI, 1.544-3.731; P ⬍ .001). By comparing patients with peptic ulcer bleeding with those without it, several well-established risk factors, such as old age, peptic ulcer, and use of nonsteroidal antiinflammatory drugs, also were confirmed. Because sleep apnea has important health consequences, our findings may further broaden the spectrum of its complications and prompt for its identification in patients with peptic ulcer bleeding without other apparent risk factors. Peptic ulcer, including gastric and duodenal ulcers, represents a substantial burden to patients, health care professionals, and the health care system, affecting 4 million patients and costing an estimated 10 billion US dollars

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Sleep Apnea and Risk of Peptic Ulcer Bleeding

Table 3 Predictors of Peptic Ulcer Bleeding by Cox Proportional Hazards Regression Analysis

Sleep apnea Age Male Comorbidity Hypertension Diabetes mellitus Coronary artery disease Arrhythmia Heart failure COPD Asthma Peptic ulcer Hepatic cirrhosis Chronic kidney disease Ischemic stroke Intracranial hemorrhage Hyperlipidemia Depression Ulcerogenic Medication NSAID Corticosteroid Aspirin Ticlopidine Clopidogrel Warfarin Anti-ulcer medication Proton pump inhibitor H2 blocker

HR

95% CI for HR

P Value

2.400 1.021 1.165

1.544-3.731 1.002-1.040 0.740-1.832

.000101 .027500 .509650

0.693 0.837 1.337 1.386 1.234 0.751 1.211 2.292 0.750 1.545 1.869 0.871 0.965 1.992

0.383-1.253 0.425-1.649 0.703-2.540 0.777-2.473 0.492-3.095 0.390-1.445 0.597-2.456 1.437-3.653 0.103-5.457 0.744-3.208 0.772-4.524 0.116-6.518 0.543-1.716 0.935-4.224

.224816 .607136 .375746 .269234 .653791 .390631 .596294 .000492 .775999 .243029 .165291 .892893 .903442 .074214

1.509 0.701 0.768 0.751 0.788 0.381

0.889-2.560 0.401-1.227 0.413-1.428 0.214-2.638 0.262-2.370 0.051-2.839

.127220 .214062 .404326 .655082 .671801 .346567

1.201 0.798

0.476-3.028 0.247-2.581

.698146 .706860

CI ⫽ confidence interval; COPD ⫽ chronic obstructive pulmonary disease; HR ⫽ hazard ratio; NSAID ⫽ nonsteroidal anti-inflammatory drug.

annually.11 Its pathogenesis may lie in the imbalance between the gastroduodenal mucosal defense and secretion of acid in gastric juice as a result of Helicobacter pylori infection, stress, ulcerogenic medications, and so forth.12-14 Peptic ulcer bleeding is one of its potentially lethal complications and is commonly encountered in the elderly and patients with chronic comorbidities or taking ulcerogenic medications.15 Accumulated evidence has shown that sleep apnea may pose a threat to the cardiovascular system,16-19 cognitive function,20-23 and glucose homeostasis24-26 by several ways,5 including chronic intermittent hypoxia, excessive oxidative stress, sympathetic hyperactivation, and systemic inflammation.27-29 These injuries also may be harmful to the gastrointestinal system, which may manifest as gastroesophageal reflux, liver injury, and fatty liver disease. During sleep, primary peristalsis and acid clearance of esophagus decreased. Although mechanism underlying the link between sleep apnea and gastroesophageal reflux is not fully elucidated, it is believed to have an association with mechanical factors, such as negative intrathoracic pressure, decreased esophageal body pressure, and transient lower esophageal sphincter relaxation during apnea epi-

253 sodes.4,30,31 However, the link of sleep apnea to liver injury and fatty liver disease may be mediated by chronic intermittent hypoxia-induced hepatocyte inflammation and lipid peroxidation, which was further complicated with lobular necrosis and fibrosis. Chronic intermittent hypoxia especially is considered now an important trigger in nonalcoholic fatty liver disease.6,32-35 It is not surprising that sleep apnea might contribute to peptic ulcer bleeding via similar mechanisms.5 Cycles of hypoxia/reoxygenation after episodes of apnea and hypopnea may cause cytotoxic injury of gastric or duodenal mucosa by producing reactive oxygen species. Hyperactivation of the sympathetic system also may facilitate the development of peptic ulcer bleeding in a manner similar to how stress ulcer occurs.12,36-38 Furthermore, systemic inflammation provoked by sleep apnea may orchestrate with that from Helicobacter pylori infection through a common cytokine network, including interleukin-1␤, 6, and 8, and tumor necrosis factor alpha,5,39,40 further dampening the defense of gastric and duodenal mucosa and favoring the occurrence of peptic ulcer bleeding. All these putative mechanisms may predispose peptic ulcer bleeding to occur in patients with sleep apnea. However, the exact mechanism awaits more delicate research to clarify. We also have demonstrated the possible association between severity of sleep apnea and risk of peptic ulcer bleeding. Patients who are indicated for continuous positive airway pressure treatment generally have more severe disease severity or responded less to other conservative treatment, such as an oral appliance. Our results showed that patients indicated for continuous positive airway pressure treatment carried a further higher risk for development of peptic ulcer bleeding, suggesting that sleep apnea increased such a risk in a severity-dependent manner. However, factors associated with increasing severity of sleep apnea, such as obesity and underlying comorbidities, also may predispose to the occurrence of peptic ulcer bleeding. Although statistically significant, the clinical relevance between increased severity of sleep apnea and increased risk of peptic ulcer bleeding needs further research to elucidate. One particular strength of this study is its matchedcontrol cohort study design, by which we took many vari-

Table 4 Association Between Severity of Sleep Apnea and the Risk of Peptic Ulcer Bleeding

Control SA, CPAP not indicated SA, CPAP indicated

HR

95% CI

P Value*

Referent 2.114 4.660

1.311-3.410 2.087-10.404

.002138 .000173

CI ⫽ confidence interval; CPAP ⫽ continuous positive airway pressure; HR ⫽ hazard ratio; SA ⫽ sleep apnea. *Cox proportional hazard regression analysis.

254 ables into consideration to diminish potential confounding factors as much as possible. The large sample size of our subjects allowed a powerful conclusion to be drawn. Because National Health Insurance is a single payer and mandatory health insurance program with affordable payment, the majority of events could be traced and referral bias minimized.

Study Limitations Nonetheless, there are still some limitations of this study. First, enrollment of subjects by administrative claims data may be less accurate, which is a weak point inherent to all database research. The NHIRD does not contain some personal factors, such as tobacco smoking status, body mass index, and habits of tea drinking and alcohol consumption, which could be potential confounding factors for analysis. Some research indicated that cigarette smoking and obesity, albeit less reported, are risk factors for peptic ulcer.41-43 Moreover, ethnic difference in factors predisposing to sleep apnea and peptic ulcer bleeding may exist. For instance, the general obesity rate, defined by a body mass index greater than 30 kg/m2, seems lower in Taiwanese than in Americans (6.1% vs 32.2% for men, 6.4% vs 35.5% for women).44,45 Our study subjects are of Chinese ethnicity, and the generalizability of our results to other non-Asian ethnic groups requires further evaluation. The relatively fewer peptic ulcer bleeding events observed may be a limitation, which could be explained by the relatively younger age of our study population (mean age, 46.60 years).46 We also did not clarify the role of H. pylori in this study because there is a substantial percentage of asymptomatic H. pylori infection in the general population, which may not be identified on the basis of the currently available data without a prospective survey.47,48 Although this is still in debate and needs further investigation, a preliminary study reported a higher H. pylori prevalence in patients with obstructive sleep apnea, and that might be involved in the pathogenesis of sleep apnea.49,50 Finally, we did not further stratify sleep apnea into obstructive type or other subtypes because the 2001 version of the International Classification of Disease, Ninth Revision coding system, deployed in our National Health Insurance registry system, had not done so either. Except for obstructive sleep apnea, sleep apnea can be caused by a central neurologic cause, termed “central sleep apnea.” However, Bixler et al51 reported that sleep apnea presenting on polysomnography in the majority of patients (⬎90%) was of an obstructive type in nature.51 Compatible with their findings, the current study reviewed the patients with polysomnography-confirmed sleep apnea in our hospital from 2000 to 2009 (3633 patients), disclosing that only 0.8% of patients had a centraltype predominant sleep apnea, whereas the remaining had obstructive sleep apnea. Whether the obstructive- or centraltype sleep apnea differs in the predisposition to peptic ulcer bleeding awaits further exploration.

The American Journal of Medicine, Vol 126, No 3, March 2013

CONCLUSIONS Sleep apnea may be an independent predictor of peptic ulcer bleeding using a nationwide database. For patients with peptic ulcer bleeding without apparent risk factors identified, we may survey for sleep apnea as a potential predisposing factor.

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255.e1 Appendix

The American Journal of Medicine, Vol 126, No 3, March 2013 International Classification of Diseases, Ninth Revision, Clinical Modification

Codes in Study Sample Sleep apnea: ICD-9-CM codes 780.51, 780.53, 780.57 Peptic ulcer bleeding: ICD-9-CM codes 531.0, 531.2, 531.4, 531.6, 532.0, 532.2, 532.4, 532.6, 533.0, 533.2, 533.4, 533.6 Nonspecific gastrointestinal bleeding: ICD-9-CM codes 578.xx Malignancy: ICD-9-CM codes 140.xx-208.xx Hypertension: ICD-9-CM codes 401.xx-405.xx Diabetes mellitus: ICD-9-CM codes 250.xx Coronary artery disease: ICD-9-CM codes 410.xx-414.xx Arrhythmia: ICD-9-CM codes 427.xx, 785.0, 785.1 Heart failure: ICD-9-CM codes 425.4, 425.9, 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 428.xx COPD: ICD-9-CM codes 491.xx, 492.xx, 494.xx, 496.xx Asthma: ICD-9-CM codes 493.xx Hepatic cirrhosis: ICD-9-CM codes 571.5, 571.2, 571.6 Chronic kidney disease: ICD-9-CM codes 580.xx-587.xx Ischemic stroke: ICD-9-CM codes 433.xx-434.xx, 436, 437.1 Intracerebral hemorrhage: ICD-9-CM codes 430.xx–432.9x Depression: ICD-9-CM codes 296.2x, 296.3x, 296.5x, 331.xx, 309.xx COPD ⫽ chronic obstructive pulmonary disease; ICD-9-CM ⫽ International Classification of Diseases, Ninth Revision, Clinical Modification.