International Journal of Cardiology 184 (2015) 576–580
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Increased risk of acute coronary syndrome among leptospirosis patients: A nationwide cohort analysis Wei-Sheng Chung a,b,c,1, Yung-Hua Chu a,1, Cheng-Li Lin d,e, Chia-Hung Kao f,g,⁎ a
Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan Department of Health Services Administration, China Medical University, Taichung, Taiwan Department of Healthcare Administration, Central Taiwan University of Science and Technology, Taichung, Taiwan d Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan e College of Medicine, China Medical University, Taichung, Taiwan f Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan g Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan b c
a r t i c l e
i n f o
Article history: Received 22 June 2014 Received in revised form 1 March 2015 Accepted 2 March 2015 Available online 4 March 2015 Keywords: Leptospirosis Acute coronary syndrome (ACS) Nationwide cohort study
a b s t r a c t Background: : Studies on the association between leptospirosis and acute coronary syndrome (ACS) are lacking. Therefore, this study identifies the effects of leptospirosis on the risks of developing ACS with a nationwide retrospective cohort study. Methods: : We identified adult patients aged ≥20 years who were newly diagnosed with leptospirosis. We also randomly selected a comparison cohort from the general population by using a propensity score matching method. We analyzed the risks of ACS by using Cox proportional hazard regression models. Results: : Among the 23.74 million people in the cohort, 3690 patients with leptospirosis (68% men, mean age of 52.2 years) and 3690 controls were followed for 13,677 and 15,652 person-years, respectively. The overall incidence of ACS was higher in the leptospirosis cohort than in the nonleptospirosis cohort (4.68 vs 3.71 per 1000 person-years), with a hazard ratio (HR) of 1.69 (95% confidence interval [CI] = 1.12–2.56). Men exhibited a 1.88-fold greater HR of ACS than women did (95% CI = 1.20–2.94). The risk of developing ACS was highest for leptospirosis patients aged ≥65 years (HR = 7, 51% CI = 4.35–12.9) compared with patients aged ≤49 years. Conclusion: : Leptospirosis is not a previously identified risk factor for ACS. The findings of this nationwide retrospective cohort study indicate that leptospirosis may become an independent risk factor for ACS. Future research to investigate the mechanism is warranted. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Leptospirosis, an increasingly emerging zoonosis throughout the world, greatly impacts public health in developing countries and tropical regions plagued by frequent flooding [1]. The protean manifestations of leptospirosis range from a mild, flu-like illness to a severe disease typically characterized by jaundice, acute renal and hepatic failure, pulmonary distress, and hemorrhage, which can lead to death [2,3]. However, the frequency and extent of cardiac events after leptospirosis are unclear. Acute coronary syndrome (ACS) comprises unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI) ⁎ Corresponding author at: Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 40447, Taiwan. E-mail addresses: [email protected], [email protected] (C.-H. Kao). 1 Yung-Hua Chu and Wei-Sheng Chung contributed equally to this work.
http://dx.doi.org/10.1016/j.ijcard.2015.03.021 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
and ST-segment elevation myocardial infarction (STEMI). This syndrome is a life-threatening disorder that leads to high morbidity and mortality despite advances in treatment [4,5]. Cerebrovascular diseases (CVAs) and cardiovascular diseases (CADs) share similar traditional risk factors for disorders of the circulatory system [6,7]. Studies have reported that chronic obstructive pulmonary disease (COPD) associated with reduced lung function is a strong risk factor for cardiovascular events, independent of smoking [8,9]. Recent studies on the relationship between infection and atherosclerosis-induced coronary heart disease have reported: an influenza infection can trigger acute myocardial infarction (AMI) [10]; chlamydia pneumonia might be associated with AMI [11]; an HCV infection is an independent predictor of increased coronary atherosclerosis [12]; and human immunodeficiency virus infection increases the risk of AMI [13]. However, the epidemiological relationship between people infected with leptospirosis and subsequent development of ACS remains unclear. Therefore, we conducted a longitudinal nationwide
W.-S. Chung et al. / International Journal of Cardiology 184 (2015) 576–580
retrospective cohort study to determine whether patients with leptospirosis are at an increased risk of subsequently developing ACS. 2. Methods 2.1. Data source The National Health Insurance Research Database (NHIRD), an electronic claims database of the National Health Insurance (NHI) program, covers more than 99% of the population of Taiwan (23.74 million) and has contracts with 97% of the healthcare institutions in Taiwan [14]. After the Taiwan Ministry of Health and Welfare authorized the National Health Research Institute (NHRI) to manage the claims data, the NHRI cooperated with the Bureau of National Health Insurance to establish the NHIRD for public use. We used the identification of residents to link 2 data files that included inpatient claims and demographic information. All data were confidential and all people were anonymous. The International Classification of Disease, Ninth Revision of Clinical Modification (ICD-9-CM), is available in the claims data to define disease diagnoses. This study was approved by the Institutional Review Board of China Medical University and Hospital (CMU-REC-101-012). 2.2. Sampled participants The leptospirosis cohort consisted of adult patients aged ≥20 years selected from inpatient claims who were newly diagnosed with leptospirosis (ICD-9-CM code 100) during 2000–2011. The admission date of initial leptospirosis diagnosis was set as the index date. Patients with a history of ACS (ICD-9-CM codes 410, 411.1, and 411.8) before the index date, or with incomplete age or sex data, were excluded. Using the same exclusion criteria, we randomly selected the nonleptospirosis patients from the NHIRD by 1:1 matching with the leptospirosis patient on a propensity score. The propensity score was calculated by a logistic regression to estimate the probability of each patient given the baseline variables, including age, sex, hypertension (ICD-9-CM codes 401–405), diabetes (ICD-9-CM code 250), hyperlipidemia (ICD-9-CM code 272), CVAs (ICD-9-CM codes 430–438), COPD (ICD-9-CM codes 490–492, 494, 496), and congestive heart failure (CHF; ICD-9-CM code 428). 2.3. Diagnosis of leptospirosis The clinicians collected urine and blood samples from patients with clinically suspected leptospirosis and confirmed diagnoses by conducting serologic tests (an enzyme-linked immunosorbent assay, a polymerase chain reaction, or a microscopic agglutination test).
matched pairs were also performed to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of developing ACS associated with leptospirosis, compared with nonleptospirosis cohort. The Kaplan–Meier method was used to estimate the cumulative incidence survival curves, the differences between which were compared using a likelihood-ratio test. 3. Results 3.1. Demographic characteristics and major CAD risk factors in the leptospirosis and comparison cohort Leptospirosis and nonleptospirosis participants were matched on the propensity score effectively (Table 1). Our study included 3690 leptospirosis patients and 3690 participants without leptospirosis, among the sampled participants 68.2% were men. The mean ages for the leptospirosis cohort and nonleptospirosis cohort were 52.2 years (SD = 16.4 years) and 52.8 years (SD = 16.3 years), respectively. Of the 3690 patients in the leptospirosis cohort, some had comorbid medical disorders as hypertension (21.0%), diabetes (14.7%), hyperlipidemia (5.83%), CVA (7.83%), COPD (5.18%) and CHF (4.34%). 3.2. The incidence and hazard ratio of acute coronary syndrome, STEMI, NSTEMI, and unstable angina between 2 cohorts by propensity score matching During the 12-year follow-up period, the overall incidences for ACS in the leptospirosis cohort, and the propensity score matched nonleptospirosis cohort were 4.68, and 3.71 per 1000 person-years, respectively (Table 2). Leptospirosis patients had a 1.69-fold risk compared with propensity score matched nonleptospirosis patients (95% CI = 1.12–2.56). Furthermore, we stratified different types of ACS into STEMI, NSTEMI, and unstable angina, and found that the incidence of STEMI and unstable angina subcategories of ACS in the leptospirosis cohort was greater than those of the nonleptospirosis cohort. Leptospirosis patients had a 1.92-fold risk (95% CI = 0.95–3.58) of developing STEMI and 1.80-fold risk (95% CI = 0.96–3.38) of developing unstable angina
Table 1 Distributions of demographic and comorbidity among cohorts with propensity score matching. Propensity score matched Leptospirosis No Characteristics
2.4. Main outcome We obtained the main outcome from the hospitalization records of patients with ACS diagnoses during the follow-up. All participants were followed until a diagnosis of ACS was made or until they were censored because of loss to follow-up, death, termination of insurance, or December 31, 2011. 2.5. Statistical analysis All data processing and statistical analyses were performed using SAS software (version 9.3 for Windows; SAS Institute Inc., Cary, NC). A 2-tailed P b .05 was considered statistically significant. A chi-square test examined the differences in the distribution of demographic factors and major CAD risk factors between the cohorts with and without leptospirosis. We calculated the sex-specific and age-specific incidence density rates of ACS with person-years in each cohort. Based on propensity score matching, Cox proportional hazards models stratifying on the
577
Sex Female Male Age, mean (SD)a Stratify age ≤34 35–49 50–64 ≥65 Major CAD risk factors Hypertension Diabetes Hyperlipidemia CVA COPD CHF
Yes
(N = 3690)
(N = 3690)
n (%)
n (%)
P-value
1178 (31.9) 2512 (68.1) 52.2 (16.4)
1173 (31.8) 2517 (68.2) 52.2 (16.3)
651 (17.6) 1039 (28.2) 1091 (29.6) 909 (24.6)
650 (17.6) 1044 (28.3) 1092 (29.6) 904 (24.5)
0.52
775 (21.0) 548 (14.9) 210 (5.69) 296 (8.02) 196 (5.31) 165 (4.47)
773 (21.0) 544 (14.7) 215 (5.83) 289 (7.83) 191 (5.18) 160 (4.34)
0.95 0.90 0.80 0.76 0.79 0.78
0.90
CVA denotes cerebrovascular accident. COPD denotes chronic obstructive pulmonary disease. CHF denotes congestive heart failure. a Chi-square test: two sample T-test.
0.99 0.99
578
W.-S. Chung et al. / International Journal of Cardiology 184 (2015) 576–580
Table 2 Overall incidence (per 1000 person-years) and hazard ratio of ACS with propensity score matching. Propensity score matched leptospirosis
Person-years Overall No. of event Incidence rate HR (95% CI) STEMI No. of event Incidence rate HR (95% CI) NSTEMI No. of event Incidence rate HR (95% CI) Unstable angina No. of event Incidence rate HR (95% CI)
No
Yes
(N = 3690)
(N = 3690)
15,652
13,677
58 3.71 1 (reference)
64 4.68 1.69 (1.12–2.56)⁎
19 1.21 1 (reference)
23 1.68 1.92 (0.95-3.58)
18 1.15 1 (reference)
12 0.88 1.22 (0.51–2.95)
21 1.34 1 (reference)
29 2.12 1.80 (0.96–3.38)
Abbreviations: HR, hazard ratio. ⁎ P b 0.05.
compared with propensity score matched nonleptospirosis patients despite no statistical significance.
3.3. Comparison of incidence and hazard ratios of acute coronary syndrome stratified by sex, and age between 2 cohorts The incidence rate of ACS was greater in the patients with leptospirosis than that in the comparison cohort for both sexes. In addition, men exhibited a significantly higher risk of developing ACS compared with women (HR = 1.88, 95% CI = 1.20–2.94). After adjusting for covariates, the risk of developing ACS was highest for leptospirosis patients aged ≥ 65 years (HR = 7, 51% CI = 4.35–12.9) compared with patients aged ≤49 years (Table 3).
3.4. Trends of acute coronary syndrome event risk according to follow-up years Fig. 1 illustrates that the cumulative incidence of ACS was higher in the leptospirosis cohort than in the nonleptospirosis cohort over followup period (P = 0.01). The cumulative incidence of STEMI and unstable angina was higher in leptospirosis patients than the nonleptospirosis cohort but the HR does not reach statistical significance.
Table 3 Comparison of incidence and hazard ratio of ACS stratified by sex, and age between with and without leptospirosis patients. Leptospirosis No Variables Sex Female Male Age group ≤49 50–64 ≥65
Yes Event
PY
Rate#
HR (95% CI)
2.02 4.48
14 50
4395 9282
3.19 5.39
1 (reference) 1.88 (1.20, 2.94)⁎
0.67 4.54 8.89
12 28 24
6681 4154 2842
1.80 6.74 8.45
1 (reference) 4.72 (2.72, 8.21)⁎⁎ 7.51 (4.35, 12.9)⁎⁎
Event
PY
Rate
10 48
4945 10,706
5 21 32
7428 4623 3601
#
Rate#, incidence rate, per 1000 person-years. Abbreviations: HR, hazard ratio; PY, person-years. ⁎ P b 0.01. ⁎⁎ P b 0.001.
4. Discussion Using a nationwide retrospective cohort study, this study is the first to indicate that patients with leptospirosis exhibited a 1.69-fold greater risk of subsequently developing ACS than that of the general population. The pathogenesis of ACS involves a complex interplay among the endothelium, inflammatory cells, and blood thrombogenicity [15,16]. Atherosclerosis is the continual process of plaque formation on the intima of arteries that progresses throughout a person's life before eventually manifesting as an acute ischemic event [17]. When the endothelium has been damaged, the inflammatory cells migrate to the subendothelium, attaching to endothelial adhesion molecules and differentiating to release chemoattractants and cytokines at the plaque site, which eventually leads to plaque disruption [18,19]. The underlying mechanism to explain leptospirosis with an increased risk of developing ACS is unclear. Leptospirosis activates human immune and inflammatory mediators that generalize systemic inflammatory responses [20]. Inflammation may induce endothelial dysfunction and evolve into the pathogenesis of arteriosclerosis [21, 22]. In addition, the inflammatory process can activate clotting, thereby decreasing the activity of natural anticoagulant mechanisms and impairing the fibrinolytic system [23,24]. When the interactions between inflammation–coagulation and inflammation–endothelial dysfunction overwhelm natural defense systems, catastrophic events may occur, such as those manifested in ACS. Recent epidemiological studies have also reported a relationship between infection and subsequent cardiac events [10,13,25,26]. Despite the study finding demonstrates that the leptospirosis cohort exhibited a greater risk of ACS development than did the comparison cohort, most of the study participants seemed at low and intermediate risk. We further categorized the different types of ACS, and found that the incidence of unstable angina and STEMI was higher in the patients with leptospirosis compared with that in the comparison cohort despite no statistical significance of HR. The findings may be attributed to limited events and a propensity score matching. The propensity score matching method is frequently used to estimate the treatment effect in randomized controlled trials [27]. The comparison cohort may not generalize to the general population because of matching major CAD risk factors with the leptospirosis cohort. In addition, the interaction of infection with leptospirosis and medical comorbid disorders may be masked after using a propensity score matching method. In the current study, we discovered a higher ACS incidence in men than in women in both cohorts. Moreover, men showed a 1.88-fold greater risk of developing ACS compared with women, a finding that is consistent with that of a previous report [28]. The incidence of ACS increased with age in both cohorts. Furthermore, after controlling for covariates, we determined that older adults were also at an increased risk of developing ACS compared with younger adults. As people age, the risk of developing atherosclerosis increases, and daily life factors cause plaque to gradually accumulate in the arteries [29]. The strength of this study is that we determined that leptospirosis increases the risk of subsequent ACS development by using a nationwide epidemiologic method. We enrolled a large sample of participants, and because NHI is universal and mandatory in Taiwan, the NHI beneficiaries were assigned unique personal identification numbers that enabled tracing them throughout the follow-up period. However, limitations must be considered when interpreting these findings. First, the NHIRD does not provide personal information, such as smoking habits, body mass index, physical activity levels, socioeconomic status, and family history, all of which are potential confounding factors in this study. Second, we may have underdiagnosed patients with a leptospirosis infection that presented with a flu-like illness, which may have caused us to underestimate the risk of developing ACS. Finally, the lack of drug-treatment data, such as those on statin therapy and the use of anticoagulants and antiplatelet drugs, is another limitation of this study.
W.-S. Chung et al. / International Journal of Cardiology 184 (2015) 576–580
579
Fig. 1. Cumulative incidence of acute coronary syndrome compared between patients with and without leptospirosis.
In conclusion, the findings of this nationwide retrospective cohort study indicate that patients with leptospirosis are at a 1.69-fold increased risk of developing ACS compared with the nonleptospirosis cohort. Clinicians should be aware of this risk in patients with leptospirosis and provide appropriate cardiovascular management in addition to leptospirosis treatment. However, because our findings are based on a retrospective observational study, future prospective studies should be conducted to confirm this epiphenomenon.
Tseng-Lien Lin Foundation, Taichung, Taiwan; Taiwan Brain Disease Foundation, Taipei, Taiwan; Katsuzo and Kiyo Aoshima Memorial Funds, Japan; and Health and Welfare Surcharge of Tobacco Products, China Medical University Hospital Cancer Research Center of Excellence (MOHW104-TDU-B-212-124-002, Taiwan). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.
These authors' individual contributions were as follows
Conflict of interest
Conception and design: Wei-Sheng Chung, Chia-Hung Kao. Administrative support: Chia-Hung Kao. Collection and assembly of data: All authors. Data analysis and interpretation: Wei-Sheng Chung, Chia-Hung Kao. Manuscript writing: All authors. Final approval of manuscript: All authors. Funding This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104TDU-B-212-113002); China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM104010092); NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039-006);
All authors report no conflicts of interest. References [1] L.S. Cruz, R. Vargas, A.A. Lopes, Leptospirosis: a worldwide resurgent zoonosis and important cause of acute renal failure and death in developing nations, Ethn. Dis. 19 (S1) (2009) 37–41. [2] W.D. Binder, L.A. Mermel, Leptospirosis in an urban setting: case report and review of an emerging infectious disease, J. Emerg. Med. 16 (1998) 851–856. [3] K.V. Evangelista, J. Coburn, Leptospira as an emerging pathogen: a review of its biology, pathogenesis and host immune responses, Future Microbiol 5 (2010) 1413–1425. [4] K.C. Nikus, M.J. Eskola, V.K. Virtanen, et al., Mortality of patients with acute coronary syndromes still remains high: a follow-up study of 1188 consecutive patients admitted to a university hospital, Ann. Med. 39 (2007) 63–71. [5] D.M. Kolansky, Acute coronary syndromes: morbidity, mortality, and pharmacoeconomic burden, Am. J. Manag. Care 15 (2009) S36–S41.
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Increased risk of acute coronary syndrome among leptospirosis patients: A nationwide cohort analysis Wei-Sheng Chung a,b,c,1, Yung-Hua Chu a,1, Cheng-Li Lin d,e, Chia-Hung Kao f,g,⁎ a
Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan Department of Health Services Administration, China Medical University, Taichung, Taiwan Department of Healthcare Administration, Central Taiwan University of Science and Technology, Taichung, Taiwan d Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan e College of Medicine, China Medical University, Taichung, Taiwan f Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan g Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan b c
a r t i c l e
i n f o
Article history: Received 22 June 2014 Received in revised form 1 March 2015 Accepted 2 March 2015 Available online 4 March 2015 Keywords: Leptospirosis Acute coronary syndrome (ACS) Nationwide cohort study
a b s t r a c t Background: : Studies on the association between leptospirosis and acute coronary syndrome (ACS) are lacking. Therefore, this study identifies the effects of leptospirosis on the risks of developing ACS with a nationwide retrospective cohort study. Methods: : We identified adult patients aged ≥20 years who were newly diagnosed with leptospirosis. We also randomly selected a comparison cohort from the general population by using a propensity score matching method. We analyzed the risks of ACS by using Cox proportional hazard regression models. Results: : Among the 23.74 million people in the cohort, 3690 patients with leptospirosis (68% men, mean age of 52.2 years) and 3690 controls were followed for 13,677 and 15,652 person-years, respectively. The overall incidence of ACS was higher in the leptospirosis cohort than in the nonleptospirosis cohort (4.68 vs 3.71 per 1000 person-years), with a hazard ratio (HR) of 1.69 (95% confidence interval [CI] = 1.12–2.56). Men exhibited a 1.88-fold greater HR of ACS than women did (95% CI = 1.20–2.94). The risk of developing ACS was highest for leptospirosis patients aged ≥65 years (HR = 7, 51% CI = 4.35–12.9) compared with patients aged ≤49 years. Conclusion: : Leptospirosis is not a previously identified risk factor for ACS. The findings of this nationwide retrospective cohort study indicate that leptospirosis may become an independent risk factor for ACS. Future research to investigate the mechanism is warranted. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Leptospirosis, an increasingly emerging zoonosis throughout the world, greatly impacts public health in developing countries and tropical regions plagued by frequent flooding [1]. The protean manifestations of leptospirosis range from a mild, flu-like illness to a severe disease typically characterized by jaundice, acute renal and hepatic failure, pulmonary distress, and hemorrhage, which can lead to death [2,3]. However, the frequency and extent of cardiac events after leptospirosis are unclear. Acute coronary syndrome (ACS) comprises unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI) ⁎ Corresponding author at: Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 40447, Taiwan. E-mail addresses: [email protected], [email protected] (C.-H. Kao). 1 Yung-Hua Chu and Wei-Sheng Chung contributed equally to this work.
http://dx.doi.org/10.1016/j.ijcard.2015.03.021 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
and ST-segment elevation myocardial infarction (STEMI). This syndrome is a life-threatening disorder that leads to high morbidity and mortality despite advances in treatment [4,5]. Cerebrovascular diseases (CVAs) and cardiovascular diseases (CADs) share similar traditional risk factors for disorders of the circulatory system [6,7]. Studies have reported that chronic obstructive pulmonary disease (COPD) associated with reduced lung function is a strong risk factor for cardiovascular events, independent of smoking [8,9]. Recent studies on the relationship between infection and atherosclerosis-induced coronary heart disease have reported: an influenza infection can trigger acute myocardial infarction (AMI) [10]; chlamydia pneumonia might be associated with AMI [11]; an HCV infection is an independent predictor of increased coronary atherosclerosis [12]; and human immunodeficiency virus infection increases the risk of AMI [13]. However, the epidemiological relationship between people infected with leptospirosis and subsequent development of ACS remains unclear. Therefore, we conducted a longitudinal nationwide
W.-S. Chung et al. / International Journal of Cardiology 184 (2015) 576–580
retrospective cohort study to determine whether patients with leptospirosis are at an increased risk of subsequently developing ACS. 2. Methods 2.1. Data source The National Health Insurance Research Database (NHIRD), an electronic claims database of the National Health Insurance (NHI) program, covers more than 99% of the population of Taiwan (23.74 million) and has contracts with 97% of the healthcare institutions in Taiwan [14]. After the Taiwan Ministry of Health and Welfare authorized the National Health Research Institute (NHRI) to manage the claims data, the NHRI cooperated with the Bureau of National Health Insurance to establish the NHIRD for public use. We used the identification of residents to link 2 data files that included inpatient claims and demographic information. All data were confidential and all people were anonymous. The International Classification of Disease, Ninth Revision of Clinical Modification (ICD-9-CM), is available in the claims data to define disease diagnoses. This study was approved by the Institutional Review Board of China Medical University and Hospital (CMU-REC-101-012). 2.2. Sampled participants The leptospirosis cohort consisted of adult patients aged ≥20 years selected from inpatient claims who were newly diagnosed with leptospirosis (ICD-9-CM code 100) during 2000–2011. The admission date of initial leptospirosis diagnosis was set as the index date. Patients with a history of ACS (ICD-9-CM codes 410, 411.1, and 411.8) before the index date, or with incomplete age or sex data, were excluded. Using the same exclusion criteria, we randomly selected the nonleptospirosis patients from the NHIRD by 1:1 matching with the leptospirosis patient on a propensity score. The propensity score was calculated by a logistic regression to estimate the probability of each patient given the baseline variables, including age, sex, hypertension (ICD-9-CM codes 401–405), diabetes (ICD-9-CM code 250), hyperlipidemia (ICD-9-CM code 272), CVAs (ICD-9-CM codes 430–438), COPD (ICD-9-CM codes 490–492, 494, 496), and congestive heart failure (CHF; ICD-9-CM code 428). 2.3. Diagnosis of leptospirosis The clinicians collected urine and blood samples from patients with clinically suspected leptospirosis and confirmed diagnoses by conducting serologic tests (an enzyme-linked immunosorbent assay, a polymerase chain reaction, or a microscopic agglutination test).
matched pairs were also performed to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of developing ACS associated with leptospirosis, compared with nonleptospirosis cohort. The Kaplan–Meier method was used to estimate the cumulative incidence survival curves, the differences between which were compared using a likelihood-ratio test. 3. Results 3.1. Demographic characteristics and major CAD risk factors in the leptospirosis and comparison cohort Leptospirosis and nonleptospirosis participants were matched on the propensity score effectively (Table 1). Our study included 3690 leptospirosis patients and 3690 participants without leptospirosis, among the sampled participants 68.2% were men. The mean ages for the leptospirosis cohort and nonleptospirosis cohort were 52.2 years (SD = 16.4 years) and 52.8 years (SD = 16.3 years), respectively. Of the 3690 patients in the leptospirosis cohort, some had comorbid medical disorders as hypertension (21.0%), diabetes (14.7%), hyperlipidemia (5.83%), CVA (7.83%), COPD (5.18%) and CHF (4.34%). 3.2. The incidence and hazard ratio of acute coronary syndrome, STEMI, NSTEMI, and unstable angina between 2 cohorts by propensity score matching During the 12-year follow-up period, the overall incidences for ACS in the leptospirosis cohort, and the propensity score matched nonleptospirosis cohort were 4.68, and 3.71 per 1000 person-years, respectively (Table 2). Leptospirosis patients had a 1.69-fold risk compared with propensity score matched nonleptospirosis patients (95% CI = 1.12–2.56). Furthermore, we stratified different types of ACS into STEMI, NSTEMI, and unstable angina, and found that the incidence of STEMI and unstable angina subcategories of ACS in the leptospirosis cohort was greater than those of the nonleptospirosis cohort. Leptospirosis patients had a 1.92-fold risk (95% CI = 0.95–3.58) of developing STEMI and 1.80-fold risk (95% CI = 0.96–3.38) of developing unstable angina
Table 1 Distributions of demographic and comorbidity among cohorts with propensity score matching. Propensity score matched Leptospirosis No Characteristics
2.4. Main outcome We obtained the main outcome from the hospitalization records of patients with ACS diagnoses during the follow-up. All participants were followed until a diagnosis of ACS was made or until they were censored because of loss to follow-up, death, termination of insurance, or December 31, 2011. 2.5. Statistical analysis All data processing and statistical analyses were performed using SAS software (version 9.3 for Windows; SAS Institute Inc., Cary, NC). A 2-tailed P b .05 was considered statistically significant. A chi-square test examined the differences in the distribution of demographic factors and major CAD risk factors between the cohorts with and without leptospirosis. We calculated the sex-specific and age-specific incidence density rates of ACS with person-years in each cohort. Based on propensity score matching, Cox proportional hazards models stratifying on the
577
Sex Female Male Age, mean (SD)a Stratify age ≤34 35–49 50–64 ≥65 Major CAD risk factors Hypertension Diabetes Hyperlipidemia CVA COPD CHF
Yes
(N = 3690)
(N = 3690)
n (%)
n (%)
P-value
1178 (31.9) 2512 (68.1) 52.2 (16.4)
1173 (31.8) 2517 (68.2) 52.2 (16.3)
651 (17.6) 1039 (28.2) 1091 (29.6) 909 (24.6)
650 (17.6) 1044 (28.3) 1092 (29.6) 904 (24.5)
0.52
775 (21.0) 548 (14.9) 210 (5.69) 296 (8.02) 196 (5.31) 165 (4.47)
773 (21.0) 544 (14.7) 215 (5.83) 289 (7.83) 191 (5.18) 160 (4.34)
0.95 0.90 0.80 0.76 0.79 0.78
0.90
CVA denotes cerebrovascular accident. COPD denotes chronic obstructive pulmonary disease. CHF denotes congestive heart failure. a Chi-square test: two sample T-test.
0.99 0.99
578
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Table 2 Overall incidence (per 1000 person-years) and hazard ratio of ACS with propensity score matching. Propensity score matched leptospirosis
Person-years Overall No. of event Incidence rate HR (95% CI) STEMI No. of event Incidence rate HR (95% CI) NSTEMI No. of event Incidence rate HR (95% CI) Unstable angina No. of event Incidence rate HR (95% CI)
No
Yes
(N = 3690)
(N = 3690)
15,652
13,677
58 3.71 1 (reference)
64 4.68 1.69 (1.12–2.56)⁎
19 1.21 1 (reference)
23 1.68 1.92 (0.95-3.58)
18 1.15 1 (reference)
12 0.88 1.22 (0.51–2.95)
21 1.34 1 (reference)
29 2.12 1.80 (0.96–3.38)
Abbreviations: HR, hazard ratio. ⁎ P b 0.05.
compared with propensity score matched nonleptospirosis patients despite no statistical significance.
3.3. Comparison of incidence and hazard ratios of acute coronary syndrome stratified by sex, and age between 2 cohorts The incidence rate of ACS was greater in the patients with leptospirosis than that in the comparison cohort for both sexes. In addition, men exhibited a significantly higher risk of developing ACS compared with women (HR = 1.88, 95% CI = 1.20–2.94). After adjusting for covariates, the risk of developing ACS was highest for leptospirosis patients aged ≥ 65 years (HR = 7, 51% CI = 4.35–12.9) compared with patients aged ≤49 years (Table 3).
3.4. Trends of acute coronary syndrome event risk according to follow-up years Fig. 1 illustrates that the cumulative incidence of ACS was higher in the leptospirosis cohort than in the nonleptospirosis cohort over followup period (P = 0.01). The cumulative incidence of STEMI and unstable angina was higher in leptospirosis patients than the nonleptospirosis cohort but the HR does not reach statistical significance.
Table 3 Comparison of incidence and hazard ratio of ACS stratified by sex, and age between with and without leptospirosis patients. Leptospirosis No Variables Sex Female Male Age group ≤49 50–64 ≥65
Yes Event
PY
Rate#
HR (95% CI)
2.02 4.48
14 50
4395 9282
3.19 5.39
1 (reference) 1.88 (1.20, 2.94)⁎
0.67 4.54 8.89
12 28 24
6681 4154 2842
1.80 6.74 8.45
1 (reference) 4.72 (2.72, 8.21)⁎⁎ 7.51 (4.35, 12.9)⁎⁎
Event
PY
Rate
10 48
4945 10,706
5 21 32
7428 4623 3601
#
Rate#, incidence rate, per 1000 person-years. Abbreviations: HR, hazard ratio; PY, person-years. ⁎ P b 0.01. ⁎⁎ P b 0.001.
4. Discussion Using a nationwide retrospective cohort study, this study is the first to indicate that patients with leptospirosis exhibited a 1.69-fold greater risk of subsequently developing ACS than that of the general population. The pathogenesis of ACS involves a complex interplay among the endothelium, inflammatory cells, and blood thrombogenicity [15,16]. Atherosclerosis is the continual process of plaque formation on the intima of arteries that progresses throughout a person's life before eventually manifesting as an acute ischemic event [17]. When the endothelium has been damaged, the inflammatory cells migrate to the subendothelium, attaching to endothelial adhesion molecules and differentiating to release chemoattractants and cytokines at the plaque site, which eventually leads to plaque disruption [18,19]. The underlying mechanism to explain leptospirosis with an increased risk of developing ACS is unclear. Leptospirosis activates human immune and inflammatory mediators that generalize systemic inflammatory responses [20]. Inflammation may induce endothelial dysfunction and evolve into the pathogenesis of arteriosclerosis [21, 22]. In addition, the inflammatory process can activate clotting, thereby decreasing the activity of natural anticoagulant mechanisms and impairing the fibrinolytic system [23,24]. When the interactions between inflammation–coagulation and inflammation–endothelial dysfunction overwhelm natural defense systems, catastrophic events may occur, such as those manifested in ACS. Recent epidemiological studies have also reported a relationship between infection and subsequent cardiac events [10,13,25,26]. Despite the study finding demonstrates that the leptospirosis cohort exhibited a greater risk of ACS development than did the comparison cohort, most of the study participants seemed at low and intermediate risk. We further categorized the different types of ACS, and found that the incidence of unstable angina and STEMI was higher in the patients with leptospirosis compared with that in the comparison cohort despite no statistical significance of HR. The findings may be attributed to limited events and a propensity score matching. The propensity score matching method is frequently used to estimate the treatment effect in randomized controlled trials [27]. The comparison cohort may not generalize to the general population because of matching major CAD risk factors with the leptospirosis cohort. In addition, the interaction of infection with leptospirosis and medical comorbid disorders may be masked after using a propensity score matching method. In the current study, we discovered a higher ACS incidence in men than in women in both cohorts. Moreover, men showed a 1.88-fold greater risk of developing ACS compared with women, a finding that is consistent with that of a previous report [28]. The incidence of ACS increased with age in both cohorts. Furthermore, after controlling for covariates, we determined that older adults were also at an increased risk of developing ACS compared with younger adults. As people age, the risk of developing atherosclerosis increases, and daily life factors cause plaque to gradually accumulate in the arteries [29]. The strength of this study is that we determined that leptospirosis increases the risk of subsequent ACS development by using a nationwide epidemiologic method. We enrolled a large sample of participants, and because NHI is universal and mandatory in Taiwan, the NHI beneficiaries were assigned unique personal identification numbers that enabled tracing them throughout the follow-up period. However, limitations must be considered when interpreting these findings. First, the NHIRD does not provide personal information, such as smoking habits, body mass index, physical activity levels, socioeconomic status, and family history, all of which are potential confounding factors in this study. Second, we may have underdiagnosed patients with a leptospirosis infection that presented with a flu-like illness, which may have caused us to underestimate the risk of developing ACS. Finally, the lack of drug-treatment data, such as those on statin therapy and the use of anticoagulants and antiplatelet drugs, is another limitation of this study.
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Fig. 1. Cumulative incidence of acute coronary syndrome compared between patients with and without leptospirosis.
In conclusion, the findings of this nationwide retrospective cohort study indicate that patients with leptospirosis are at a 1.69-fold increased risk of developing ACS compared with the nonleptospirosis cohort. Clinicians should be aware of this risk in patients with leptospirosis and provide appropriate cardiovascular management in addition to leptospirosis treatment. However, because our findings are based on a retrospective observational study, future prospective studies should be conducted to confirm this epiphenomenon.
Tseng-Lien Lin Foundation, Taichung, Taiwan; Taiwan Brain Disease Foundation, Taipei, Taiwan; Katsuzo and Kiyo Aoshima Memorial Funds, Japan; and Health and Welfare Surcharge of Tobacco Products, China Medical University Hospital Cancer Research Center of Excellence (MOHW104-TDU-B-212-124-002, Taiwan). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.
These authors' individual contributions were as follows
Conflict of interest
Conception and design: Wei-Sheng Chung, Chia-Hung Kao. Administrative support: Chia-Hung Kao. Collection and assembly of data: All authors. Data analysis and interpretation: Wei-Sheng Chung, Chia-Hung Kao. Manuscript writing: All authors. Final approval of manuscript: All authors. Funding This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104TDU-B-212-113002); China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM104010092); NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039-006);
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