Key words: depression; fatigue; hypertension; obstructive sleep apnea syndrome; prevalence; prevalence odds ratio

Transcription

1 Simultaneous Use of Antidepressant and Antihypertensive Medications Increases Likelihood of Diagnosis of Obstructive Sleep Apnea Syndrome* Robert J. Farney, MD, FCCP; Alejandra Lugo, BA; Robert L. Jensen, PhD; James M. Walker, PhD; and Tom V. Cloward, MD, FCCP Background: Essential hypertension and symptoms of depression such as unexplained fatigue and tiredness are frequently encountered in primary medical care clinics. Although, exhaustive evaluation rarely detects unsuspected underlying disorders, obstructive sleep apnea (OSA) is commonly associated with each of these conditions. We tested the hypothesis that therapy with antihypertensive and antidepressant medications predicts the increased likelihood of OSA. Methods: We analyzed the computer archive of 212,972 patients for prescriptions for antihypertensive medications, antidepressant medications, and International Classification of Diseases, Ninth Revision codes for OSA. Prevalence, prevalence odds ratio (POR), and confidence intervals (CIs) were calculated correcting for gender and age group. Results: The prevalence rates of OSA were 0.8, 2.8, and 3.2 for men and 0.4, 1.4, and 1.8 for women aged 20 to 39 years, 40 to 59 years, and > 60 years, respectively. Compared to groups of corresponding age and gender who had not received prescriptions for either hypertension or depression, the highest PORs were found in patients receiving medications from both categories: (95 CI, to 25.66), 5.72 (95 CI, 4.10 to 6.70), and 4.47 (95 CI, 2.45 to 7.01) for men, and (95 CI, 9.54 to 28.67), 7.29 (95 CI, 5.20 to 9.29), and 2.72 (95 CI, 1.48 to 4.73) for women. Conclusions: We found that the likelihood of having a diagnosis of OSA increases when either antihypertensive or antidepressant medications have been prescribed. The probability is highest in the young and middle-age groups receiving prescriptions for both medications. The possibility of OSA should be considered in any patient with hypertension and depression or unexplained fatigue who is receiving antihypertensive and antidepressant medications. (CHEST 2004; 125: ) Key words: depression; fatigue; hypertension; obstructive sleep apnea syndrome; prevalence; prevalence odds ratio Abbreviations: AHI apnea-hypopnea index; CI confidence interval; ICD-9 International Classification of Diseases, Ninth Revision; IHC Intermountain Health Care; OSA obstructive sleep apnea; POR prevalence odds ratio *From the Intermountain Sleep Disorders Center (Drs. Farney, Walker, and Cloward), Medical Informatics (Ms. Lugo), and Pulmonary Division, Department of Medicine (Dr. Jensen), LDS Hospital, Salt Lake City, UT. This work was performed at the Intermountain Sleep Disorder Center, Pulmonary Division, LDS Hospital, Salt Lake City, UT. Data from this work was presented in abstract form at the World Congress on Lung Health meeting of the European Respiratory Society in Florence, Italy, September 2, Financial support was provided by the Deseret Foundation, LDS Hospital. In spite of increasing public awareness and the wide availability of sleep disorder centers, recognition by clinicians of obstructive sleep apnea (OSA) syndrome remains low. Consequently, patients are routinely treated for the symptoms and complications of OSA while the underlying pathophysiologic condition proceeds unabated. We have been impressed by the regular stream of patients whose risk factors are conspicuous and who ultimately present for evaluation of OSA after years of having been treated for the secondary manifestations of sleep apnea. Specifically, hypertension and chronic fatigue, possibly the most common conditions for Manuscript received September 2, 2003; revision accepted November 20, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( permissions@chestnet.org). Correspondence to: Robert J. Farney, MD, FCCP, Intermountain Sleep Disorders Center, LDS Hospital, 325 Eighth Ave and C St, Salt Lake City, UT 84143; rjfmd@msn.com CHEST / 125 / 4/ APRIL,

2 which patients seek or require medical attention, 1 3 are the cardinal elements of OSA. 4 Exhaustive laboratory evaluation for causes of hypertension and fatigue rarely detects unsuspected fundamental medical conditions that might provide more specific direction for therapy. For example, it is well known that patients with OSA have hypersomnia; however, it is not widely appreciated that the more frequent complaints are fatigue, lack of energy, and tiredness. 5 Depression or chronic fatigue syndrome is readily diagnosed in patients with the primary complaint of fatigue. Accordingly, these patients are frequently treated with antidepressant medications although unrecognized sleep apnea might be present. 6 8 In addition to the overlap of symptoms, numerous reports 9 12 have documented an association between depression and OSA. The cause-and-effect relationship of hypertension as an independent risk factor for persistent diurnal hypertension has been disputed 13 ; however, epidemiologic studies have demonstrated a strong association. A prospective study by Peppard et al 21 demonstrated a dose-response relationship between OSA and the ultimate evolution of hypertension. The epidemiology, health consequences, and risk factors of OSA have been reviewed. 19 It is estimated that the diagnosis of sleep apnea is missed in 82 of men and 93 of women with moderate-to-severe OSA defined as 15 apneas and hypopneas per hour of sleep. 22 There is no uniformity of opinion regarding the minimum apnea-hypopnea index (AHI), which indicates the presence of disease, but the high prevalence of sleep-disordered breathing has been consistently found in large epidemiologic studies Young et al 23 used an AHI of 15/h to determine the minimum prevalence of sleepdisordered breathing in the middle-age population (30 to 60 years) but defined OSA as an AHI 5/h plus excessive daytime sleepiness. Sleep-disordered breathing was found in 9.1 of men and 4.0 of women, and OSA syndrome was found in 4 of men and 2 of women. Because of the associations between obstructive sleep-disordered breathing, hypertension, and depression or fatigue, we analyzed a large managedcare database and investigated the hypothesis that treatment with antihypertensive and/or antidepressant agents increases the likelihood of having the diagnosis of OSA. Because of the overlap of symptoms, we were particularly interested in the prevalence of OSA when both categories of medications were prescribed. If therapy with these medications represents a marker for OSA, then practicing clinicians should be alerted by this association to the possibility of a specific underlying pathophysiologic basis for which there is effective treatment in some patients with hypertension and unexplained fatigue or depression. Accurate diagnosis of sleepdisordered breathing is important because correction with nasal continuous positive airway pressure can ameliorate hypertension, 14,27 reverse depression and fatigue, 10 reduce health-care expenditure, 28,29 and improve quality-of-life measures, 30,31 even in those with mild sleep apnea or increased upper airway resistance syndrome. 32 Materials and Methods The Intermountain Health Care (IHC) organization consists of 24 hospitals, 26 clinics, 2,400 participating physicians, six health insurance plans, and various ancillary services that provide pharmaceuticals, durable medical equipment, and physical therapy. All physician encounters that result in a claim for payment generate an International Classification of Diseases, Ninth Revision (ICD-9) diagnostic code. 33 Similarly, all prescriptions or requests from patients for reimbursement for medications generate standard codes that are uniquely specific for each drug. IHC is integrated by a wide-area network that allows the assimilation and storage of information into a database that can then be accessed. The IHC Health Plans database includes ICD-9 diagnostic codes from physicians billing and drug codes from pharmacy records. Thus, by comparing diagnostic codes with medication records, we were able to analyze and match anonymous data of all persons enrolled in IHC Health Plans who were examined by a physician. The computer archive for all persons 20 years of age during the period from January 1, 2000, to December 31, 2000, was queried for the following variables: (1) therapy with an antihypertensive medication, (2) therapy with an antidepressant medication, and (3) diagnosis of sleep apnea. Patients were included in the antihypertension medication group if they had received at least one prescription for any single or combination standard medication that may be routinely used for hypertension regardless of the clinical diagnosis or specific medical indication for therapy. Similarly, patients were included in the antidepressant medication group if they had received at least one prescription for an antidepressant medication regardless of the clinical indication for therapy. A third group consisted of patients who had received at least one prescription for antihypertensive medication plus an antidepressant medication. Outpatient and hospital records were analyzed for the ICD-9 related diagnostic codes. Patients were included in the OSA groups if there was at least one encounter with an ICD-9 code of or Although we were not able to access results of sleep test results because of privacy issues, we were able to determine if the patients classified as having OSA had ever been tested with polysomnography at an IHC facility within at least 5 years of the survey by querying the entire data bank for current procedural technology codes of and We were also able to match the records of all patients who were classified as having OSA according to ICD-9 codes with specific physicians. If the diagnosis was made by physicians who routinely diagnose and treat OSA according to their specialty or if the patients had been formally tested with polysomnography, we could infer additional confidence for the diagnosis of OSA. The data were analyzed by gender and within the following age divisions: 20 to 39 years, 40 to 59 years, and 60 years Clinical Investigations

3 Statistical Analysis The control groups consisted of all persons matched for gender and corresponding age divisions who had not received a prescription for either antihypertensive or antidepressant medications. The prevalence rate, prevalence odds, and prevalence odds ratios (PORs) were calculated according to standard equations. 34 Using the method described by Fleiss, confidence limits (CIs) were calculated for each category of the prevalence odds. Then using the upper and lower limits from the prevalence odds, we calculated the upper and lower 95 confidence limits for the POR. A 2 analysis and significance (p 0.01) were performed by comparing the control groups with various subgroups defined by age, gender, and medication prescription. Results Data were collected on 212,972 patients receiving medical insurance from IHC Health Plans from January 1, 2000, to December 31, Table 1 shows the medication profiles and prevalence of OSA for the entire age groups. The population was relatively young (54 were in the 20- to 39-year age group) with no important gender difference (51.8 women). According to ICD-9 codes and , there were 2,746 patients (1.29 of all patients) who received a diagnosis of OSA. When those patients who were classified as having OSA were matched with specific physicians, diagnoses in 1,271 patients (50.3) were made by certified sleep medicine specialists; of these patients, 79 underwent polysomnography within the last 5 years at an IHC facility. The percentage of patients receiving prescriptions for antihypertensive medications correlated positively with increasing age without a difference in gender. However, antidepressant medications were consistently prescribed more often for female than male patients, with the highest rate of 16.8 for women compared to 7.3 for men, both in the 40- to 59-year age group. Medications from both categories were prescribed most often in the oldest age groups (6.2 of men and 10.2 of women). The antidepressant medications were dominated by selective serotonin reuptake inhibitors (52), while antihypertension medications were more diverse. Consistent with previously published data, the prevalence of OSA in men was approximately twice that of women; however, the prevalence in all categories was less than previous studies. For example, in the middleage division (40 to 59 years), the prevalence was 2.8 for men and 1.4 for women compared to 4 and 2, respectively. 23 Table 2 shows the prevalence and PORs with 95 CIs according to age group and medications prescribed. The prevalence of OSA increased with prescriptions for either an antidepressant or antihypertensive medication or both. The highest prevalence for OSA was in the middle-age category (40 to 59 years), who had received prescriptions from both medication categories (10.0 in men and 5.38 in women). The POR varied inversely with increasing age category but remained elevated in almost every category. The POR ranged from 1.36 (women 60 years old and antihypertensive medication) to 18.3 (men 20 to 39 years and antihypertensive plus antidepressant medications). The CIs were largest in the younger ages because of the smaller numbers of patients with the diagnosis of OSA, but almost all comparisons were highly significant (p ). The only comparisons that were not significant were in the oldest men (antidepressant medication) and women (antihypertensive medication, antidepressant medication). When both classes of medications were prescribed at any time during the year, the likelihood of having OSA was always additive, but in the young groups, an interaction was evident resulting in a greater than additive effect. The degree of interaction varied according to the age group and prevalence. Although the prevalence of OSA was the lowest in the 20- to 39-year-old men and women, the interaction was Table 1 Medication Profiles and Prevalence of OSA According to Age Group and Gender* Age, yr Patients, No. No Med, BP Med, Dep Med, BP Med Plus Dep Med, OSA, Men , , , All 102, Women , , , All 110, *Med medication; BP Med antihypertensive medication; Dep Med antidepressant medication. CHEST / 125 / 4/ APRIL,

4 Table 2 PORs According to Age Group and Medication Prescription* Variables Patients, No. Prevalence POR 95 Low 95 High p Value Men Age 20 to 39 yr Control 50, BP Med 1, Dep Med 3, BP Med plus Dep Med Age 40 to 59 yr Control 29, BP Med 4, Dep Med 2, BP Med plus Dep Med 1, Age 60 yr Control 4, BP Med 2, Dep Med BP Med plus Dep Med Women Age 20 to 39 yr Control 48, BP Med 1, Dep Med 8, BP Med plus Dep Med Age 40 to 59 yr Control 28, BP Med 3, Dep Med 7, BP Med plus Dep Med 2, Age 60 yr Control 4, BP Med 2, Dep Med BP Med plus Dep Med *See Table 1 for expansion of abbreviations. most dramatic in these young persons. The POR was 18.3 for men (95 CI, to 25.66) and for women (95 CI, 9.54 to 28.67) in the 20- to 39-year-old patients who received prescriptions for both antihypertensive and antidepressant medications. In middle-aged men (40 to 59 years), who are often considered the most at-risk population, the POR measured 3.00 (95 CI, 2.35 to 3.53 [antihypertensive medication]), 2.57 (95 CI, 1.95 to 3.21 [antidepressant medication]) and 5.72 (95 CI, 4.10 to 6.70 [antihypertensive plus antidepressant medications]), compared to middle-aged women in whom the POR was 2.95 (95 CI, 2.07 to 4.09), 2.25 (95 CI, 1.64 to 3.03), and 7.29 (95 CI, 5.20 to 9.29), respectively. Discussion The major findings from this study are as follows: (1) the likelihood of having a diagnosis of OSA increases when either antihypertensive or antidepressant medications have been prescribed, even without knowledge of any specific clinical risk factors for OSA or of the exact medical indications for the prescriptions; (2) the likelihood of having OSA increases remarkably when antihypertensive and antidepressant medications have been prescribed together sometime within a single year, especially in the youngest and middle-age groups (20 to 39 years and 40 to 59 years); and (3) the prevalence of OSA based on ICD-9 diagnostic codes was lower in this study compared to previously published prospective epidemiologic series 23,24 that required polysomnography as the gold standard. The association of antihypertensive and antidepressant medications and OSA is predictable; however, the magnitude of this relationship was striking and not anticipated, particularly in the young, in whom the frequency of sleep apnea is low. The POR indicates the risk of having a diagnosis such as OSA when a specific group is compared to a corresponding control group. In this study, the control group for each age and gender category was defined as those who were not receiving any antihypertensive or 1282 Clinical Investigations

5 antidepressant type of medication. In the youngmale age group (20 to 39 years) who were prescribed an antihypertensive medication, an antidepressant medication, or both, the PORs were 6.84, 4.12, and 18.30, respectively. These data indicate that a man 20 to 39 years old who has been given a prescription for an antihypertensive medication has a 6.84 times greater probability of having OSA compared to one not receiving either an antihypertensive or antidepressant medication. The likelihood increases to fold when he has received prescriptions for both classes of medication. In the oldest men ( 60 years), the PORs were 2.07, 2.15, and 4.47, respectively. The same patterns and trends were observed in women. The most important limitation of this study is the use of ICD-9 diagnostic codes from patient and physician encounters to define the presence of OSA syndrome. Obviously, the true prevalence of OSA in this population is not known with certainty. However, 50.3 of the diagnoses of OSA were made by specialists who routinely require polysomnography to make the diagnosis of OSA. In spite of the inherent constraints of a retrospective analysis and the use of ICD-9 codes to define OSA, the conclusions from this study are further strengthened by the large number of subjects (n 212,972) and the consistent results with high statistical significance. Based on our own extensive experience and previously published data that indicate the prevalence of OSA is 4 to 6 in men and 1 to 2 in women, we believe that the actual prevalence of OSA in our population is probably greater than what we found, especially in the older groups. For the comparable age populations (age 40 to 59 years), the prevalence of OSA in this study measured 2.8 in men and 1.4 in women. Therefore, if the prevalence of OSA is underdiagnosed, what is the effect on calculation of the POR? The impact of undercoding for sleep apnea on the POR will depend on the distribution of unreported cases. If the distribution is proportional across all categories, there would be no important difference on the POR calculations. However, if there were a substantial number of missed cases in only the control group, then the prevalence odds or the denominator of the POR would be artificially low. This would result in a falsely elevated POR and indicate a greater risk for OSA than what exists. We think this is an unlikely occurrence especially in the young age groups where the prevalence of OSA is known to be very low. However, a more important effect results from underestimating the diagnosis of OSA in the group being treated for hypertension. If the prevalence of OSA for this entire subset measured 4 and the prevalence of OSA for those receiving only an antihypertensive medication measured 25 (consistent with published data), the POR would increase. For these reasons, we believe that more accurate coding would have the net effect of increasing the POR values than what we found and would thereby strengthen the conclusions of our study. Despite the controversial issues regarding the link between OSA, hypertension, and depression, the use of antihypertensive and antidepressant medications per se appears to be a marker for OSA syndrome. Obviously, medications may be administered for various purposes and some manifestations of OSA overlap with other primary disorders. For example, nocturia may be secondary to prostatic hypertrophy for which an -receptor blocker might be prescribed, but nocturia may also be a primary manifestation of OSA. 36 An antidepressant may have been prescribed for chronic unexplained fatigue, disrupted sleep, lethargy, poor concentration, and decreased libido, all of which are common in patients with OSA. We do not believe that these uncertainties diminish the importance of our findings. It does not seem to matter why the medications are being used. Treatment with any of these drugs alone or in combination is a risk factor or marker for OSA syndrome. The lower prevalence of OSA compared to other studies may be secondary to inaccurate coding, failure to diagnose, or reluctance to actively pursue the diagnosis of sleep apnea because of economic concerns. The discrepancy between the known prevalence of OSA and that found in our study, especially in the subgroup being treated with antihypertensive medications, deserves special emphasis. The recognized prevalence of OSA in patients with essential hypertension is higher than in the general population (30 to 40 vs 10). 14 In our study, the prevalence of OSA measured 5.49 in men and 2.25 in women in the 40- to 59-year age groups treated with an antihypertensive medicine. It appears that the association of hypertension and OSA is still not widely recognized by primary care physicians. According to the National Health and Nutrition Examination Survey III, phase 2 (from 1991 to 1994), 37 only 24 of patients with a diagnosis of hypertension were adequately controlled. Berlowitz et al 38 emphasized the importance of providing more intensive therapy in order to control essential hypertension. In a prospective study 8 involving 800 hypertensive men over a 2-year period, many patients had inadequate therapy despite many opportunities to increase antihypertensive medications, but the possibility of looking for a common correctable underlying condition such as OSA that might also reduce BP was not discussed. Failure to recognize and diagnose OSA by primary CHEST / 125 / 4/ APRIL,

6 care physicians may be related to inadequate medical education. 39,40 In a review of commonly used medical textbooks, 41 the content related to sleep medicine is scant and uneven. Based on the number of pages devoted to sleep disorders, sleep medicine content was greatest in a psychiatry textbook (3.2 of pages) and the least in a standard textbook of internal medicine (0.3 of pages). Until more recent publications, 42,43 the rare secondary causes of hypertension, such as pheochromocytoma and renal artery stenosis, have always been discussed, but the association of essential hypertension or other cardiovascular diseases with OSA received little attention in major treatises 44 and textbooks of internal medicine. 7,8 Screening for OSA requires little more than asking a few directed questions, observing for obvious anatomic risk factors (eg, body mass index and neck circumference), and possibly performing limited respiratory measurements before obtaining comprehensive sleep tests. As stated by Silverberg and Oksenberg, 14 if OSA can cause hypertension, its high prevalence in essential hypertension patients would make it the most common cause of hypertension and raise the possibility of nonpharmacological approaches to essential hypertension through treatment of sleep-disordered breathing. Thus, recognition of OSA in patients with hypertension is important because therapy may reduce cardiovascular consequences and health-care expenditures. 45 In summary, we have found that in this managedcare population, therapy with either antihypertensive or antidepressant medications is a marker for persons with OSA, and that the prevalence of OSA based on the ICD-9 diagnosis codes is substantially less than predicted. The association of these medications and presence of OSA increases substantially with combination therapy, especially in young persons (20 to 39 years old). The clinical importance is obvious. The diagnosis of OSA should be made early, and it is easy once the possibility is considered. Unless risk factors for OSA are recognized, the opportunity of correcting an underlying disorder with specific therapy will be missed resulting in adverse health and economic consequences. Obstructive sleep-disordered breathing must be at least considered in any person who is being treated with both antihypertensive and antidepressant medications or who has essential hypertension with fatigue or other symptoms of depression. If clinically appropriate and other important risk factors are present, then the patient should be referred for objective documentation and therapy of OSA. ACKNOWLEDGMENT: We thank Robert O. Crapo, MD, and Alan H. Morris, MD, for critical reviews and suggestions. References 1 Rosenblatt RA, Cherkin DC, Schneeweiss R, et al. The content of ambulatory medical care in the United States: an interspecialty comparison. 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