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Association between orthostatic hypotension, mortality, and cardiovascular disease in Asians
International Journal of Cardiology 195 (2015) 40–44
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Association between orthostatic hypotension, mortality, and cardiovascular disease in Asians Ruey-Hsing Chou a,b, Chia-Jen Liu c,d, Tze-Fan Chao a,b,⁎, Su-Jung Chen d,e, Ta-Chuan Tuan a,b,f,⁎, Tzeng-Ji Chen g, Shih-Ann Chen a,b a
Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan d Institute of Public Health and School of Medicine, National Yang-Ming University, Taipei, Taiwan e Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan f Division of Cardiology, Taipei Municipal Gan-Dau Hospital, Taipei, Taiwan g Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 25 October 2014 Received in revised form 14 March 2015 Accepted 9 May 2015 Available online 13 May 2015 Keywords: Orthostatic hypotension Ischemic stroke Myocardial infarction Mortality
a b s t r a c t Background: Orthostatic hypotension (OH) is a common condition encountered in the elderly. The present study aimed to examine the relationship between OH and adverse events in Asians. Methods: We used the “National Health Insurance Research Database” in Taiwan. A total of 1226 patients with OH and without previous history of ischemic stroke and myocardial infarction were identified as the study group. For each study patient, ten age-, sex- and comorbidity-matched subjects without OH were selected to constitute the control group (n = 12,260). The clinical endpoints were ischemic stroke, myocardial infarction and all-cause mortality. Results: The mean age of the study population was 54.8 ± 19.0 years and males accounted for 47% of the patients. During the follow-up of 4.5 ± 2.9 years, 704 (5.2%) patients developed ischemic stroke, 190 (1.4%) patients developed myocardial infarction, and 733 (5.4%) patients died. In the multivariable Cox regression analyses which were adjusted for age, gender and differences in medication usages, OH was significantly associated with an increased risk of ischemic stroke (hazard ratio [HR] = 1.40, 95% confidence interval (CI) = 1.09–1.81, p = 0.009), all-cause mortality (HR = 1.35; 95% CI = 1.05–1.73, p = 0.018) and adverse events (ischemic stroke, myocardial infarction or mortality) (HR = 1.41; 95% CI = 1.18–1.68, p b 0.001). Conclusion: OH is an independent factor associated with ischemic stroke and mortality in Asians. Whether aggressive managements for stroke prevention could improve the outcome for OH patients deserves further study. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Orthostatic hypotension (OH), with prevalence from 5 to 20% in different populations, is a common symptom in the elderly. When autonomic reflexes are impaired, a significant reduction in blood pressure occurs upon standing. OH is defined as a decrease in systolic blood pressure of more than 20 mm Hg, or a decrease in diastolic of more than 10 mm Hg within 3 min of standing [1]. It was found to be associated with dizziness, syncope, falls, fractures, and potential morbidity. In addition to the neurologic symptoms, more and more investigators found that OH is related to cardiovascular diseases, such as coronary artery disease, ischemic stroke, heart failure, and cardiac death [2,3]. However, most available data came from clinical trials performed on Caucasians ⁎ Corresponding authors at: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan. E-mail address: [email protected] (T.-F. Chao).
http://dx.doi.org/10.1016/j.ijcard.2015.05.060 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
[2–4], who may have different etiologies and mechanisms of cardiovascular events compared to Asians. The aim of the present study is to investigate whether OH increases the risk of ischemic stroke, myocardial infarction and all-cause mortality in Asians using the National Health Insurance Research Database (NHIRD) in Taiwan. 2. Methods 2.1. Database This study used the NHIRD released by the Taiwan National Health Research Institutes (NHRI). The National Health Insurance (NHI) system is a mandatory universal health insurance program that offers comprehensive medical care coverage to all Taiwanese residents. The NHIRD is a cohort dataset that contains all medical claim data for 1,000,000 beneficiaries, who were randomly sampled from the 25.68 million enrollees under the NHI program. These random samples have been confirmed by
R.-H. Chou et al. / International Journal of Cardiology 195 (2015) 40–44
the NHRI to be representative of the Taiwanese population. In this cohort dataset, the patients' original identification numbers were encrypted to protect their privacy. The encrypting procedure was consistent, so that linking claims belonging to the same patient was feasible within the NHI database and could be followed continuously. The database has a large sample size and provides a good opportunity to study the risk of ischemic stroke, myocardial infarction and mortality among patients with or without orthostatic hypotension. Information about important comorbid conditions of each individual was retrieved from the medical claims based on the International Classification of Diseases (ICD), Ninth Revision, Clinical Modification (ICD-9-CM) codes. We defined patients with a certain disease only when it was a discharge diagnosis or confirmed more than twice in the outpatient department. The diagnostic accuracies of important comorbidities in NHIRD, such as hypertension, diabetes mellitus, heart failure, myocardial infarction, hyperlipidemia and chronic obstructive pulmonary disease, have been validated before [5,6]. 2.2. Study population From January 1, 2000 to December 31, 2011, the medical claim data of 1,000,000 beneficiaries were analyzed. Patients with history of stroke and myocardial infarction younger than 18 years were excluded. Thereafter, a total of 1226 patients having the diagnosis of orthostatic hypotension (ICD-9-CM code = 458.00) were identified as the study group. To ensure the accuracy of diagnosis, only those patients whose OH was confirmed more than twice in the outpatient department or diagnosed at discharge were included in the study. On the same date of enrollment of one study patient, we randomly selected ten age-, sex- and comorbidity-matched subjects without OH for each included study patient to constitute the control group (n = 12,260). Data about concomitant medication usages, including aspirin, warfarin, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers, and statins were also retrieved from the NHIRD. A flowchart of the enrollment of the study population is shown in Fig. 1. 2.3. Clinical endpoints The clinical endpoint was defined as the occurrence of ischemic stroke, with concomitant imaging studies of the brain, including computed tomography or magnetic resonance imaging. The accuracy of diagnosis of ischemic stroke in Taiwan's NHIRD has been reported to be around 94% [5]. Another validation study also demonstrated that
41
the diagnostic accuracy of ischemic stroke in NHIRD was high, with the positive predictive value and sensitivity of 88.4% and 97.3%, respectively [7]. The occurrences of myocardial infarction and all-cause mortality were also analyzed. 2.4. Statistical analysis The data are presented as the mean value and standard deviation for normally distributed continuous variables and proportions for categorical variables. The differences between continuous values were assessed using an unpaired 2-tailed t test for normally distributed continuous variables, Mann–Whitney rank-sum test for skewed variables, and chi-square testing for nominal variables. The survival curves of ischemic stroke, myocardial infarction, death, and adverse events (ischemic stroke, myocardial infarction, or death) were plotted using the Kaplan–Meier method with statistical significance examined by the log-rank test. To assess the independent effects of OH on clinical events, we conducted Cox proportional hazard regression models simultaneously adjusting for age, gender, and variables which had significant differences between study and control groups. Adjusted variables included the use of aspirin, warfarin, ACEIs, ARBs, beta-blockers, and statins. All statistical significances were set at p b 0.05 and all statistical analyses were carried out by SPSS 18.0 (SPSS Inc., USA). 3. Results 3.1. Patient characteristics A total of 13,486 patients were enrolled in this study, including 1226 subjects with OH and 12,260 controls without OH. The mean age of the study population was 54.8 ± 19.0 years and males accounted for 47% of the patients. The baseline characteristics of patients with and without OH are shown in Table 1. Since age, sex, and comorbidities between the study and control groups were matched, the usages of medications became the only statistically different factors between the two groups. Patients with OH were found to have a higher percentage of medication usages, including aspirin, warfarin, ACEIs, ARBs, beta-blockers, and statins. 3.2. Orthostatic hypotension and risk of clinical events During the mean follow-up of 4.5 ± 2.9 years, 704 (5.2%) patients developed ischemic stroke, 190 (1.4%) patients developed myocardial infarction, and 733 (5.4%) patients died. There were a total of 1420
Fig. 1. A flowchart of the enrollment of study patients.
42
R.-H. Chou et al. / International Journal of Cardiology 195 (2015) 40–44
Table 1 Baseline characteristics of the patients with and without orthostatic hypotension.
Age, years Male, n (%) Medical history, n (%) Diabetes mellitus Congestive heart failure Hypertension Dyslipidemia AF/AFL CKD Ischemic heart COPD Asthma PAD Sleep apnea Medications, n (%) Aspirin Warfarin ACEI/ARB Beta-blocker Statins
Study group (with orthostatic hypotension) n = 1226
Control group (no orthostatic hypotension) n = 12,260
54.79 ± 19.03 576 (47%)
54.82 ± 1.96 5762 (47%)
0.954 1.000
305 (25%) 179 (14%) 518 (42%) 365 (30%) 45 (4%) 245 (20%) 432 (35%) 372 (30%) 211 (17%) 9 (b1%) 2 (b1%)
3043 (25%) 1777 (15%) 5194 (42%) 3655 (30%) 457 (4%) 2432 (20%) 4299 (35%) 3724 (30%) 2104 (17%) 47 (1%) 6 (b1%)
0.965 0.920 0.939 0.976 0.920 0.902 0.905 0.981 0.965 0.161 0.329
80 (6%) 2 (b1%) 74 (5%) 106 (8%) 33 (2%)
23 (b1%) 0 (b1%) 9 (b1%) 11 (b1%) 4 (b1%)
p value
b0.001 b0.001 b0.001 b0.001 b0.001
ACEI = angiotensin-converting enzyme inhibitor, AF = atrial fibrillation, AFL = atrial flutter, ARB = angiotensin II receptor blocker, COPD = chronic obstructive pulmonary disease, CKD = chronic kidney disease, PAD = peripheral arterial disease.
(10.5%) patients suffering adverse events during the follow-up. The incidences of ischemic stroke (n = 83, 6.8%), myocardial infarction (n = 27, 2.2%), death (n = 92, 7.5%), and adverse events (n = 174, 14.2%) are higher among patients with OH than those without. Fig. 2 shows the Kaplan–Meier curves of event-free survival of ischemic stroke,
myocardial infarction, death, and adverse events. All the Kaplan–Meier curves demonstrate significant differences in the occurrence rate of clinical events between patients with and without OH (p b 0.01 by log-rank test). Using Cox proportional hazard analysis (Table 2), OH is significantly associated with a higher risk of ischemic stroke (hazard ratio [HR] = 1.39; 95% confidence interval [CI] = 1.10–1.75, p = 0.005), myocardial infarction (HR = 1.70; 95% CI = 1.13–2.55, p = 0.011), death (HR = 1.47; 95% CI = 1.18–1.83, p = 0.001), and adverse events (HR = 1.46; 95% = CI 1.24–1.71, p b 0.001). After adjustments for age, gender, and medication usages which were different between the study and control groups, OH remains as an independent factor associated with ischemic stroke (HR = 1.40; 95% CI = 1.09–1.81, p = 0.009), death (HR = 1.35; 95% CI = 1.05–1.73, p = 0.018), and adverse events (HR = 1.41; 95% CI = 1.18–1.69, p b 0.001). However, the relationship between OH and myocardial infarction is not statistically significant in the multivariable Cox regression model with a HR of 1.27 (95% CI = 0.77–2.10, p = 0.344). 4. Discussion In this nationwide cohort study, which enrolled 13,486 subjects with a mean follow-up duration of 4.5 years, OH was found to be an independent risk factor for ischemic stroke and all-cause mortality. To the best of our knowledge, this is the largest longitudinal cohort study which explored the relationship between OH and adverse clinical events in the Asian population. Early in 1997, Aronow and Ahn performed a prospective study enrolling 499 nursing home residents and reported that marked reduction in postprandial systolic blood pressure was associated with a higher incidence of falls, syncope, new coronary events, new stroke, and total mortality at 29-month follow-up [8]. In year 2000, the Atherosclerosis Risk in Communities (ARIC) study also demonstrated strong associations between OH and stroke [2], coronary artery disease [9], and mortality [10]. However, the proportions of subtypes
Fig. 2. Kaplan–Meier curves of freedom from ischemic stroke (2A), myocardial infarction (2B), death (2C), and adverse events (2D) in patients with and without orthostatic hypotension.
R.-H. Chou et al. / International Journal of Cardiology 195 (2015) 40–44 Table 2 Risk of adverse events in patients with orthostatic hypotension compared to control group. Event
Ischemic stroke Myocardial infarction Mortality Any adverse event
Multivariate analysis⁎
Univariate analysis HR
95% CI
1.389 1.699
1.104–1.746 1.130–2.553
1.467 1.457
1.179–1.825 1.243–1.707
p value
43
of antithrombotic drugs for AF population was also a well-recognized problem in Taiwan and other Asian areas [19,20]. 5. Limitations
HR
95% CI
p value
0.005 0.011
1.403 1.272
1.089–1.806 0.772–2.096
0.009 0.344
0.001 b0.001
1.351 1.410
1.053–1.732 1.180–1.685
0.018 b0.001
ACEI = angiotensin-converting enzyme inhibitor, ARB = angiotensin II receptor blocker, CI = confidence interval, HR = hazard ratio. ⁎ Adjustment for age, gender, and variables whose p values were b0.05 in Table 1, including the use of aspirin, warfarin, ACEI/ARB, beta-blocker and statin.
of stroke are different for different ethnicities. Cardioembolism is the most common cause of ischemic stroke in Caucasians, whereas intracranial atherosclerotic stenosis is much more prevalent in Asians [11]. The ARIC study provided a good reference for Caucasians, but not for Asians. The Honolulu Heart Program, a prospective study of 3741 Japanese aged from 71 to 93 years, found that OH increased the risk of all-cause mortality [12]. But the subjects in the Honolulu Heart Program are relatively old, and the study population is relatively small. The findings of the present study further confirmed the significant relationship between OH and ischemic stroke and mortality in a large Asian cohort. Our study suggested OH to be an independent risk factor for ischemic stroke and mortality in middle-age Asian population. In fact, OH is not only a risk factor for cardiovascular events and allcause mortality, but also for congestive heart failure [3,13] and incidental atrial fibrillation [3,14]. The relationship between OH and cardiovascular events may be explained by several hypotheses. First of all, blood is displaced to the lower body and the thoracic blood volume decreases by almost one third when OH occurs [15]. The secondary reduction in coronary and cerebral flow may cause myocardial and cerebral ischemia [4]. Second, OH may also be the early expression of subclinical cardiovascular diseases. In previous studies, cerebral infarcts, myocardial infarction, and heart failure were reported to contribute to OH [16]. OH and cardiovascular diseases may simply be two events sharing the same risk factors. Many hemodynamic (hypertension, heart failure) and metabolic (diabetes) factors which could predispose patients to OH [3] are also risk factors for ischemic stroke and coronary artery disease. Although our study demonstrated a significant association between OH and an increased risk of clinical events, we were not able to conclude that OH is a causative factor for cardiovascular events. The most convincing way to examine the causative relationship between OH and cardiovascular events, such as a randomized controlled trial, is difficult to design to date as there is currently no pharmacological agent that conclusively shows improvement of OH. The results of our study remind clinicians to follow patients with OH more closely, and may consider early aggressive interventions for stroke prevention for these high-risk patients. In the present study, we noted that the treatment rates of hypertension and atrial fibrillation (AF) were low in the control group. The low rate about the usages of antihypertensive agents and warfarin may be partly explained by the following reasons. First, we defined the use of certain medication only when patients have received continuous prescriptions of drugs for more than 180 days in one year. This definition may result in underidentification of medical therapies which the patients received. Second, undertreatment for patients with hypertension and AF was an important issue in Taiwan. Based on the reports of the Taiwan Nutrition and Health Survey, the control rate of hypertension in patients older than 19 years was only 2% in men and 5% in women [17]. Even after the implementation of the National Health Insurance system in 1995, the well control rate of hypertension was still less than 10% for men in certain areas of Taiwan in 2010 [18]. The underuse
The strength of our study is the use of a population-based dataset which enrolled a large number of subjects. However, there are several limitations of the present study. First, the detailed data about heart rate and systolic and diastolic blood pressures, which are necessary to clarify and classify the diagnosis of OH, are lacking in this registry dataset. Second, some important confounding factors, such as the severity of comorbid diseases, family history of stroke or myocardial infarction, body mass index, smoking habit, and physical activity, were not available in our database. Lastly, the diagnosis of OH was based on the diagnostic code registered by the physicians responsible for the treatments of patients, and was not further checked externally. According to the subgroup analysis of Honolulu Heart Program [12], which enrolled 3522 Japanese American men (71 to 93 years old), the overall prevalence of OH was 6.9% which was higher than our study. Although the differences regarding the prevalence rates of OH can be partly explained by the fact that the study population in our study was younger than that enrolled in Honolulu Heart Program (mean age 54.8 years versus age range 71–93 years), the under diagnosis or under recognition of OH in the present study was possible. However, failing to identify all patients with OH as the study group would result in overestimating the risk of clinical events of the control group because some patients with unrecognized OH may be misclassified as controls. Therefore, this misclassification may not change the main findings of the present study demonstrating that the risk of clinical events was higher among the OH compared to control groups. Based on these limitations mentioned above, a prospective trial is necessary to confirm the findings presented in our study. 6. Conclusion In summary, OH is an independent factor associated with ischemic stroke and mortality in Asians. Whether aggressive interventions for stroke prevention could improve the outcome for OH patients deserves a further study. Conflict of interest None. Acknowledgments 1. This work was supported in part by grants from the National Science Council Taiwan (NSC98-2410-H-010-003-MY2), and Taipei Veterans General Hospital (V99C1-140, V99A-153, V100D-002-3, V101D-0012, and V102B-025). 2. This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of Bureau of National Health Insurance, Department of Health or National Health Research Institutes.
References [1] H. Lahrmann, P. Cortelli, M. Hilz, et al., EFNS guidelines on the diagnosis and management of orthostatic hypotension, Eur. J. Neurol. 13 (2006) 930–936. [2] M.L. Eigenbrodt, K.M. Rose, D.J. Couper, et al., Orthostatic hypotension as a risk factor for stroke: The Atherosclerosis Risk in Communities (ARIC) study, 1987–1996, Stroke 31 (2000) 2307–2313. [3] A. Fedorowski, L. Stavenow, B. Hedblad, et al., Orthostatic hypotension predicts allcause mortality and coronary events in middle-aged individuals (The Malmo Preventive Project), Eur. Heart J. 31 (2010) 85–91.
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[4] G.C. Verwoert, F.U. Mattace-Raso, A. Hofman, et al., Orthostatic hypotension and risk of cardiovascular disease in elderly people: the Rotterdam study, J. Am. Geriatr. Soc. 56 (2008) 1816–1820. [5] C.C. Lin, M.S. Lai, C.Y. Syu, et al., Accuracy of diabetes diagnosis in health insurance claims data in Taiwan, J. Formos. Med. Assoc. 104 (2005) 157–163. [6] C.L. Cheng, Y.H. Kao, S.J. Lin, et al., Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan, Pharmacoepidemiol. Drug Saf. 20 (2011) 236–242. [7] C.Y. Hsieh, C.H. Chen, C.Y. Li, et al., Validating the diagnosis of acute ischemic stroke in a National Health Insurance claims database, J. Formos. Med. Assoc. 114 (2013) 254–259. [8] W.S. Aronow, C. Ahn, Association of postprandial hypotension with incidence of falls, syncope, coronary events, stroke, and total mortality at 29-month follow-up in 499 older nursing home residents, J. Am. Geriatr. Soc. (9) (1997) 1051–1053. [9] K.M. Rose, H.A. Tyroler, C.J. Nardo, et al., Orthostatic hypotension and the incidence of coronary heart disease: The Atherosclerosis Risk in Communities Study, Am. J. Hypertens. (2000) 571–578. [10] K.M. Rose, M.L. Eigenbrodt, R.L. Biga, et al., Orthostatic hypotension predicts mortality in middle-aged adults: The Atherosclerosis Risk in Communities (ARIC) Study, Circulation (2006) 630–636. [11] B.J. Kim, J.S. Kim, Ischemic stroke subtype classification: an Asian viewpoint, J. Stroke (2014) 8–17.
[12] K.H. Masaki, I.J. Schatz, C.M. Burchfiel, et al., Orthostatic hypotension predicts mortality in elderly men: The Honolulu Heart Program, Circulation (1998) 2290–2295. [13] C.D. Jones, L. Loehr, N. Franceschini, et al., Orthostatic hypotension as a risk factor for incident heart failure: the atherosclerosis risk in communities study, Hypertension 59 (2012) 913–918. [14] S.K. Agarwal, A. Alonso, S.P. Whelton, et al., Orthostatic change in blood pressure and incidence of atrial fibrillation: results from a bi-ethnic population based study, PLoS One (11) (2013) e79030. [15] J.J. Smith, C.M. Porth, M. Erickson, Hemodynamic response to the upright posture, J. Clin. Pharmacol. (1994) 375–386. [16] I. Raiha, S. Luutonen, J. Piha, et al., Prevalence, predisposing factors, and prognostic importance of postural hypotension, Arch. Intern. Med. (1995) 930–935. [17] W.H. Pan, H.Y. Chang, W.T. Yeh, et al., Prevalence, awareness, treatment and control of hypertension in Taiwan: results of Nutrition and Health Survey in Taiwan (NAHSIT) 1993–1996, J. Hum. Hypertens. 15 (2001) 793e8. [18] C.E. Chiang, T.D. Wang, Y.H. Li, et al., 2010 guidelines of the Taiwan Society of Cardiology for the management of hypertension, J. Formos. Med. Assoc. 109 (2010) 740e73. [19] Y. Guo, S. Apostolakis, A.D. Blann, et al., Validation of contemporary stroke and bleeding risk stratification scores in non-anticoagulated Chinese patients with atrial fibrillation, Int. J. Cardiol. 168 (2013) 904–909. [20] L.J. Lin, M.H. Cheng, C.H. Lee, et al., Compliance with antithrombotic prescribing guidelines for patients with atrial fibrillation—a nationwide descriptive study in Taiwan, Clin. Ther. (9) (2008) 1726–1736.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Association between orthostatic hypotension, mortality, and cardiovascular disease in Asians Ruey-Hsing Chou a,b, Chia-Jen Liu c,d, Tze-Fan Chao a,b,⁎, Su-Jung Chen d,e, Ta-Chuan Tuan a,b,f,⁎, Tzeng-Ji Chen g, Shih-Ann Chen a,b a
Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan d Institute of Public Health and School of Medicine, National Yang-Ming University, Taipei, Taiwan e Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan f Division of Cardiology, Taipei Municipal Gan-Dau Hospital, Taipei, Taiwan g Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 25 October 2014 Received in revised form 14 March 2015 Accepted 9 May 2015 Available online 13 May 2015 Keywords: Orthostatic hypotension Ischemic stroke Myocardial infarction Mortality
a b s t r a c t Background: Orthostatic hypotension (OH) is a common condition encountered in the elderly. The present study aimed to examine the relationship between OH and adverse events in Asians. Methods: We used the “National Health Insurance Research Database” in Taiwan. A total of 1226 patients with OH and without previous history of ischemic stroke and myocardial infarction were identified as the study group. For each study patient, ten age-, sex- and comorbidity-matched subjects without OH were selected to constitute the control group (n = 12,260). The clinical endpoints were ischemic stroke, myocardial infarction and all-cause mortality. Results: The mean age of the study population was 54.8 ± 19.0 years and males accounted for 47% of the patients. During the follow-up of 4.5 ± 2.9 years, 704 (5.2%) patients developed ischemic stroke, 190 (1.4%) patients developed myocardial infarction, and 733 (5.4%) patients died. In the multivariable Cox regression analyses which were adjusted for age, gender and differences in medication usages, OH was significantly associated with an increased risk of ischemic stroke (hazard ratio [HR] = 1.40, 95% confidence interval (CI) = 1.09–1.81, p = 0.009), all-cause mortality (HR = 1.35; 95% CI = 1.05–1.73, p = 0.018) and adverse events (ischemic stroke, myocardial infarction or mortality) (HR = 1.41; 95% CI = 1.18–1.68, p b 0.001). Conclusion: OH is an independent factor associated with ischemic stroke and mortality in Asians. Whether aggressive managements for stroke prevention could improve the outcome for OH patients deserves further study. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Orthostatic hypotension (OH), with prevalence from 5 to 20% in different populations, is a common symptom in the elderly. When autonomic reflexes are impaired, a significant reduction in blood pressure occurs upon standing. OH is defined as a decrease in systolic blood pressure of more than 20 mm Hg, or a decrease in diastolic of more than 10 mm Hg within 3 min of standing [1]. It was found to be associated with dizziness, syncope, falls, fractures, and potential morbidity. In addition to the neurologic symptoms, more and more investigators found that OH is related to cardiovascular diseases, such as coronary artery disease, ischemic stroke, heart failure, and cardiac death [2,3]. However, most available data came from clinical trials performed on Caucasians ⁎ Corresponding authors at: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan. E-mail address: [email protected] (T.-F. Chao).
http://dx.doi.org/10.1016/j.ijcard.2015.05.060 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
[2–4], who may have different etiologies and mechanisms of cardiovascular events compared to Asians. The aim of the present study is to investigate whether OH increases the risk of ischemic stroke, myocardial infarction and all-cause mortality in Asians using the National Health Insurance Research Database (NHIRD) in Taiwan. 2. Methods 2.1. Database This study used the NHIRD released by the Taiwan National Health Research Institutes (NHRI). The National Health Insurance (NHI) system is a mandatory universal health insurance program that offers comprehensive medical care coverage to all Taiwanese residents. The NHIRD is a cohort dataset that contains all medical claim data for 1,000,000 beneficiaries, who were randomly sampled from the 25.68 million enrollees under the NHI program. These random samples have been confirmed by
R.-H. Chou et al. / International Journal of Cardiology 195 (2015) 40–44
the NHRI to be representative of the Taiwanese population. In this cohort dataset, the patients' original identification numbers were encrypted to protect their privacy. The encrypting procedure was consistent, so that linking claims belonging to the same patient was feasible within the NHI database and could be followed continuously. The database has a large sample size and provides a good opportunity to study the risk of ischemic stroke, myocardial infarction and mortality among patients with or without orthostatic hypotension. Information about important comorbid conditions of each individual was retrieved from the medical claims based on the International Classification of Diseases (ICD), Ninth Revision, Clinical Modification (ICD-9-CM) codes. We defined patients with a certain disease only when it was a discharge diagnosis or confirmed more than twice in the outpatient department. The diagnostic accuracies of important comorbidities in NHIRD, such as hypertension, diabetes mellitus, heart failure, myocardial infarction, hyperlipidemia and chronic obstructive pulmonary disease, have been validated before [5,6]. 2.2. Study population From January 1, 2000 to December 31, 2011, the medical claim data of 1,000,000 beneficiaries were analyzed. Patients with history of stroke and myocardial infarction younger than 18 years were excluded. Thereafter, a total of 1226 patients having the diagnosis of orthostatic hypotension (ICD-9-CM code = 458.00) were identified as the study group. To ensure the accuracy of diagnosis, only those patients whose OH was confirmed more than twice in the outpatient department or diagnosed at discharge were included in the study. On the same date of enrollment of one study patient, we randomly selected ten age-, sex- and comorbidity-matched subjects without OH for each included study patient to constitute the control group (n = 12,260). Data about concomitant medication usages, including aspirin, warfarin, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers, and statins were also retrieved from the NHIRD. A flowchart of the enrollment of the study population is shown in Fig. 1. 2.3. Clinical endpoints The clinical endpoint was defined as the occurrence of ischemic stroke, with concomitant imaging studies of the brain, including computed tomography or magnetic resonance imaging. The accuracy of diagnosis of ischemic stroke in Taiwan's NHIRD has been reported to be around 94% [5]. Another validation study also demonstrated that
41
the diagnostic accuracy of ischemic stroke in NHIRD was high, with the positive predictive value and sensitivity of 88.4% and 97.3%, respectively [7]. The occurrences of myocardial infarction and all-cause mortality were also analyzed. 2.4. Statistical analysis The data are presented as the mean value and standard deviation for normally distributed continuous variables and proportions for categorical variables. The differences between continuous values were assessed using an unpaired 2-tailed t test for normally distributed continuous variables, Mann–Whitney rank-sum test for skewed variables, and chi-square testing for nominal variables. The survival curves of ischemic stroke, myocardial infarction, death, and adverse events (ischemic stroke, myocardial infarction, or death) were plotted using the Kaplan–Meier method with statistical significance examined by the log-rank test. To assess the independent effects of OH on clinical events, we conducted Cox proportional hazard regression models simultaneously adjusting for age, gender, and variables which had significant differences between study and control groups. Adjusted variables included the use of aspirin, warfarin, ACEIs, ARBs, beta-blockers, and statins. All statistical significances were set at p b 0.05 and all statistical analyses were carried out by SPSS 18.0 (SPSS Inc., USA). 3. Results 3.1. Patient characteristics A total of 13,486 patients were enrolled in this study, including 1226 subjects with OH and 12,260 controls without OH. The mean age of the study population was 54.8 ± 19.0 years and males accounted for 47% of the patients. The baseline characteristics of patients with and without OH are shown in Table 1. Since age, sex, and comorbidities between the study and control groups were matched, the usages of medications became the only statistically different factors between the two groups. Patients with OH were found to have a higher percentage of medication usages, including aspirin, warfarin, ACEIs, ARBs, beta-blockers, and statins. 3.2. Orthostatic hypotension and risk of clinical events During the mean follow-up of 4.5 ± 2.9 years, 704 (5.2%) patients developed ischemic stroke, 190 (1.4%) patients developed myocardial infarction, and 733 (5.4%) patients died. There were a total of 1420
Fig. 1. A flowchart of the enrollment of study patients.
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Table 1 Baseline characteristics of the patients with and without orthostatic hypotension.
Age, years Male, n (%) Medical history, n (%) Diabetes mellitus Congestive heart failure Hypertension Dyslipidemia AF/AFL CKD Ischemic heart COPD Asthma PAD Sleep apnea Medications, n (%) Aspirin Warfarin ACEI/ARB Beta-blocker Statins
Study group (with orthostatic hypotension) n = 1226
Control group (no orthostatic hypotension) n = 12,260
54.79 ± 19.03 576 (47%)
54.82 ± 1.96 5762 (47%)
0.954 1.000
305 (25%) 179 (14%) 518 (42%) 365 (30%) 45 (4%) 245 (20%) 432 (35%) 372 (30%) 211 (17%) 9 (b1%) 2 (b1%)
3043 (25%) 1777 (15%) 5194 (42%) 3655 (30%) 457 (4%) 2432 (20%) 4299 (35%) 3724 (30%) 2104 (17%) 47 (1%) 6 (b1%)
0.965 0.920 0.939 0.976 0.920 0.902 0.905 0.981 0.965 0.161 0.329
80 (6%) 2 (b1%) 74 (5%) 106 (8%) 33 (2%)
23 (b1%) 0 (b1%) 9 (b1%) 11 (b1%) 4 (b1%)
p value
b0.001 b0.001 b0.001 b0.001 b0.001
ACEI = angiotensin-converting enzyme inhibitor, AF = atrial fibrillation, AFL = atrial flutter, ARB = angiotensin II receptor blocker, COPD = chronic obstructive pulmonary disease, CKD = chronic kidney disease, PAD = peripheral arterial disease.
(10.5%) patients suffering adverse events during the follow-up. The incidences of ischemic stroke (n = 83, 6.8%), myocardial infarction (n = 27, 2.2%), death (n = 92, 7.5%), and adverse events (n = 174, 14.2%) are higher among patients with OH than those without. Fig. 2 shows the Kaplan–Meier curves of event-free survival of ischemic stroke,
myocardial infarction, death, and adverse events. All the Kaplan–Meier curves demonstrate significant differences in the occurrence rate of clinical events between patients with and without OH (p b 0.01 by log-rank test). Using Cox proportional hazard analysis (Table 2), OH is significantly associated with a higher risk of ischemic stroke (hazard ratio [HR] = 1.39; 95% confidence interval [CI] = 1.10–1.75, p = 0.005), myocardial infarction (HR = 1.70; 95% CI = 1.13–2.55, p = 0.011), death (HR = 1.47; 95% CI = 1.18–1.83, p = 0.001), and adverse events (HR = 1.46; 95% = CI 1.24–1.71, p b 0.001). After adjustments for age, gender, and medication usages which were different between the study and control groups, OH remains as an independent factor associated with ischemic stroke (HR = 1.40; 95% CI = 1.09–1.81, p = 0.009), death (HR = 1.35; 95% CI = 1.05–1.73, p = 0.018), and adverse events (HR = 1.41; 95% CI = 1.18–1.69, p b 0.001). However, the relationship between OH and myocardial infarction is not statistically significant in the multivariable Cox regression model with a HR of 1.27 (95% CI = 0.77–2.10, p = 0.344). 4. Discussion In this nationwide cohort study, which enrolled 13,486 subjects with a mean follow-up duration of 4.5 years, OH was found to be an independent risk factor for ischemic stroke and all-cause mortality. To the best of our knowledge, this is the largest longitudinal cohort study which explored the relationship between OH and adverse clinical events in the Asian population. Early in 1997, Aronow and Ahn performed a prospective study enrolling 499 nursing home residents and reported that marked reduction in postprandial systolic blood pressure was associated with a higher incidence of falls, syncope, new coronary events, new stroke, and total mortality at 29-month follow-up [8]. In year 2000, the Atherosclerosis Risk in Communities (ARIC) study also demonstrated strong associations between OH and stroke [2], coronary artery disease [9], and mortality [10]. However, the proportions of subtypes
Fig. 2. Kaplan–Meier curves of freedom from ischemic stroke (2A), myocardial infarction (2B), death (2C), and adverse events (2D) in patients with and without orthostatic hypotension.
R.-H. Chou et al. / International Journal of Cardiology 195 (2015) 40–44 Table 2 Risk of adverse events in patients with orthostatic hypotension compared to control group. Event
Ischemic stroke Myocardial infarction Mortality Any adverse event
Multivariate analysis⁎
Univariate analysis HR
95% CI
1.389 1.699
1.104–1.746 1.130–2.553
1.467 1.457
1.179–1.825 1.243–1.707
p value
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of antithrombotic drugs for AF population was also a well-recognized problem in Taiwan and other Asian areas [19,20]. 5. Limitations
HR
95% CI
p value
0.005 0.011
1.403 1.272
1.089–1.806 0.772–2.096
0.009 0.344
0.001 b0.001
1.351 1.410
1.053–1.732 1.180–1.685
0.018 b0.001
ACEI = angiotensin-converting enzyme inhibitor, ARB = angiotensin II receptor blocker, CI = confidence interval, HR = hazard ratio. ⁎ Adjustment for age, gender, and variables whose p values were b0.05 in Table 1, including the use of aspirin, warfarin, ACEI/ARB, beta-blocker and statin.
of stroke are different for different ethnicities. Cardioembolism is the most common cause of ischemic stroke in Caucasians, whereas intracranial atherosclerotic stenosis is much more prevalent in Asians [11]. The ARIC study provided a good reference for Caucasians, but not for Asians. The Honolulu Heart Program, a prospective study of 3741 Japanese aged from 71 to 93 years, found that OH increased the risk of all-cause mortality [12]. But the subjects in the Honolulu Heart Program are relatively old, and the study population is relatively small. The findings of the present study further confirmed the significant relationship between OH and ischemic stroke and mortality in a large Asian cohort. Our study suggested OH to be an independent risk factor for ischemic stroke and mortality in middle-age Asian population. In fact, OH is not only a risk factor for cardiovascular events and allcause mortality, but also for congestive heart failure [3,13] and incidental atrial fibrillation [3,14]. The relationship between OH and cardiovascular events may be explained by several hypotheses. First of all, blood is displaced to the lower body and the thoracic blood volume decreases by almost one third when OH occurs [15]. The secondary reduction in coronary and cerebral flow may cause myocardial and cerebral ischemia [4]. Second, OH may also be the early expression of subclinical cardiovascular diseases. In previous studies, cerebral infarcts, myocardial infarction, and heart failure were reported to contribute to OH [16]. OH and cardiovascular diseases may simply be two events sharing the same risk factors. Many hemodynamic (hypertension, heart failure) and metabolic (diabetes) factors which could predispose patients to OH [3] are also risk factors for ischemic stroke and coronary artery disease. Although our study demonstrated a significant association between OH and an increased risk of clinical events, we were not able to conclude that OH is a causative factor for cardiovascular events. The most convincing way to examine the causative relationship between OH and cardiovascular events, such as a randomized controlled trial, is difficult to design to date as there is currently no pharmacological agent that conclusively shows improvement of OH. The results of our study remind clinicians to follow patients with OH more closely, and may consider early aggressive interventions for stroke prevention for these high-risk patients. In the present study, we noted that the treatment rates of hypertension and atrial fibrillation (AF) were low in the control group. The low rate about the usages of antihypertensive agents and warfarin may be partly explained by the following reasons. First, we defined the use of certain medication only when patients have received continuous prescriptions of drugs for more than 180 days in one year. This definition may result in underidentification of medical therapies which the patients received. Second, undertreatment for patients with hypertension and AF was an important issue in Taiwan. Based on the reports of the Taiwan Nutrition and Health Survey, the control rate of hypertension in patients older than 19 years was only 2% in men and 5% in women [17]. Even after the implementation of the National Health Insurance system in 1995, the well control rate of hypertension was still less than 10% for men in certain areas of Taiwan in 2010 [18]. The underuse
The strength of our study is the use of a population-based dataset which enrolled a large number of subjects. However, there are several limitations of the present study. First, the detailed data about heart rate and systolic and diastolic blood pressures, which are necessary to clarify and classify the diagnosis of OH, are lacking in this registry dataset. Second, some important confounding factors, such as the severity of comorbid diseases, family history of stroke or myocardial infarction, body mass index, smoking habit, and physical activity, were not available in our database. Lastly, the diagnosis of OH was based on the diagnostic code registered by the physicians responsible for the treatments of patients, and was not further checked externally. According to the subgroup analysis of Honolulu Heart Program [12], which enrolled 3522 Japanese American men (71 to 93 years old), the overall prevalence of OH was 6.9% which was higher than our study. Although the differences regarding the prevalence rates of OH can be partly explained by the fact that the study population in our study was younger than that enrolled in Honolulu Heart Program (mean age 54.8 years versus age range 71–93 years), the under diagnosis or under recognition of OH in the present study was possible. However, failing to identify all patients with OH as the study group would result in overestimating the risk of clinical events of the control group because some patients with unrecognized OH may be misclassified as controls. Therefore, this misclassification may not change the main findings of the present study demonstrating that the risk of clinical events was higher among the OH compared to control groups. Based on these limitations mentioned above, a prospective trial is necessary to confirm the findings presented in our study. 6. Conclusion In summary, OH is an independent factor associated with ischemic stroke and mortality in Asians. Whether aggressive interventions for stroke prevention could improve the outcome for OH patients deserves a further study. Conflict of interest None. Acknowledgments 1. This work was supported in part by grants from the National Science Council Taiwan (NSC98-2410-H-010-003-MY2), and Taipei Veterans General Hospital (V99C1-140, V99A-153, V100D-002-3, V101D-0012, and V102B-025). 2. This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of Bureau of National Health Insurance, Department of Health or National Health Research Institutes.
References [1] H. Lahrmann, P. Cortelli, M. Hilz, et al., EFNS guidelines on the diagnosis and management of orthostatic hypotension, Eur. J. Neurol. 13 (2006) 930–936. [2] M.L. Eigenbrodt, K.M. Rose, D.J. Couper, et al., Orthostatic hypotension as a risk factor for stroke: The Atherosclerosis Risk in Communities (ARIC) study, 1987–1996, Stroke 31 (2000) 2307–2313. [3] A. Fedorowski, L. Stavenow, B. Hedblad, et al., Orthostatic hypotension predicts allcause mortality and coronary events in middle-aged individuals (The Malmo Preventive Project), Eur. Heart J. 31 (2010) 85–91.
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[4] G.C. Verwoert, F.U. Mattace-Raso, A. Hofman, et al., Orthostatic hypotension and risk of cardiovascular disease in elderly people: the Rotterdam study, J. Am. Geriatr. Soc. 56 (2008) 1816–1820. [5] C.C. Lin, M.S. Lai, C.Y. Syu, et al., Accuracy of diabetes diagnosis in health insurance claims data in Taiwan, J. Formos. Med. Assoc. 104 (2005) 157–163. [6] C.L. Cheng, Y.H. Kao, S.J. Lin, et al., Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan, Pharmacoepidemiol. Drug Saf. 20 (2011) 236–242. [7] C.Y. Hsieh, C.H. Chen, C.Y. Li, et al., Validating the diagnosis of acute ischemic stroke in a National Health Insurance claims database, J. Formos. Med. Assoc. 114 (2013) 254–259. [8] W.S. Aronow, C. Ahn, Association of postprandial hypotension with incidence of falls, syncope, coronary events, stroke, and total mortality at 29-month follow-up in 499 older nursing home residents, J. Am. Geriatr. Soc. (9) (1997) 1051–1053. [9] K.M. Rose, H.A. Tyroler, C.J. Nardo, et al., Orthostatic hypotension and the incidence of coronary heart disease: The Atherosclerosis Risk in Communities Study, Am. J. Hypertens. (2000) 571–578. [10] K.M. Rose, M.L. Eigenbrodt, R.L. Biga, et al., Orthostatic hypotension predicts mortality in middle-aged adults: The Atherosclerosis Risk in Communities (ARIC) Study, Circulation (2006) 630–636. [11] B.J. Kim, J.S. Kim, Ischemic stroke subtype classification: an Asian viewpoint, J. Stroke (2014) 8–17.
[12] K.H. Masaki, I.J. Schatz, C.M. Burchfiel, et al., Orthostatic hypotension predicts mortality in elderly men: The Honolulu Heart Program, Circulation (1998) 2290–2295. [13] C.D. Jones, L. Loehr, N. Franceschini, et al., Orthostatic hypotension as a risk factor for incident heart failure: the atherosclerosis risk in communities study, Hypertension 59 (2012) 913–918. [14] S.K. Agarwal, A. Alonso, S.P. Whelton, et al., Orthostatic change in blood pressure and incidence of atrial fibrillation: results from a bi-ethnic population based study, PLoS One (11) (2013) e79030. [15] J.J. Smith, C.M. Porth, M. Erickson, Hemodynamic response to the upright posture, J. Clin. Pharmacol. (1994) 375–386. [16] I. Raiha, S. Luutonen, J. Piha, et al., Prevalence, predisposing factors, and prognostic importance of postural hypotension, Arch. Intern. Med. (1995) 930–935. [17] W.H. Pan, H.Y. Chang, W.T. Yeh, et al., Prevalence, awareness, treatment and control of hypertension in Taiwan: results of Nutrition and Health Survey in Taiwan (NAHSIT) 1993–1996, J. Hum. Hypertens. 15 (2001) 793e8. [18] C.E. Chiang, T.D. Wang, Y.H. Li, et al., 2010 guidelines of the Taiwan Society of Cardiology for the management of hypertension, J. Formos. Med. Assoc. 109 (2010) 740e73. [19] Y. Guo, S. Apostolakis, A.D. Blann, et al., Validation of contemporary stroke and bleeding risk stratification scores in non-anticoagulated Chinese patients with atrial fibrillation, Int. J. Cardiol. 168 (2013) 904–909. [20] L.J. Lin, M.H. Cheng, C.H. Lee, et al., Compliance with antithrombotic prescribing guidelines for patients with atrial fibrillation—a nationwide descriptive study in Taiwan, Clin. Ther. (9) (2008) 1726–1736.