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Increased risk of peripheral arterial disease in patients with alcohol intoxication: A population-based retrospective cohort study
Accepted Manuscript Increased Risk of Peripheral Arterial Disease in Patients with Alcohol Intoxication: A Population-Based Retrospective Cohort Study Jin-Yuan Huang, Wei-Kung Chen, Cheng-Li Lin, Ching-Yuan Lai, Chia-Hung Kao, Tse-Yen Yang PII:
S0741-8329(16)30018-0
DOI:
10.1016/j.alcohol.2017.06.003
Reference:
ALC 6734
To appear in:
Alcohol
Received Date: 22 January 2016 Revised Date:
13 June 2017
Accepted Date: 15 June 2017
Please cite this article as: Huang J.-Y., Chen W.-K., Lin C.-L., Lai C.-Y., Kao C.-H. & Yang T.-Y., Increased Risk of Peripheral Arterial Disease in Patients with Alcohol Intoxication: A Population-Based Retrospective Cohort Study, Alcohol (2017), doi: 10.1016/j.alcohol.2017.06.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Increased Risk of Peripheral Arterial Disease in Patients with Alcohol Intoxication: A Population-Based Retrospective Cohort
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Jin-Yuan Huang a, b, Wei-Kung Chen a, b, *, Cheng-Li Lin c, d, Ching-Yuan Lai a, b, Chia-Hung Kao e, f, g, Tse-Yen Yang h, i, j, * Department of Emergency Medicine, China Medical University Hospital, Taichung, Taiwan
b
School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
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Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
d
College of Medicine, China Medical University, Taichung, Taiwan
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Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
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Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
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Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
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Molecular and Genomic Epidemiology Center, China Medical University Hospital
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Department of Medical Research, China Medical University Hospital
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Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
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*Tse-Yen Yang and Wei-Kung Chen contributed equally.
Corresponding author: Tse-Yen Yang, PhD, Assistant Research Fellow Department of Medical Research China Medical University No. 2, Yuh-Der Road Taichung40447 Taiwan, Republic of China
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Telephone: +886 4 2205 2121 ext. 7412 Fax: +886 4 2233 6174 E-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract Previous studies have reported that light-to-moderate drinkers have a lower risk of
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peripheral arterial disease (PAD) than abstainers, and that heavy drinking increases the risk of PAD. However, reports of the effects of severe alcohol drinking on PAD are lacking within a population-based cohort. Alcohol intoxication is typically considered a medical emergency at
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clinics in Taiwan and is commonly attributed to excessive alcohol use. The present study
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aimed to investigate the association between alcohol intoxication and PAD risk. We conducted a retrospective, population-based, health insurance cohort study consisting of 56,544 adult patients with alcohol intoxication between January 1, 2000 and December 31, 2009, using claims data from the National Health Insurance Research Database (NHIRD) of
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Taiwan. This database included a control cohort of 226,176 residents without alcohol intoxication. The patients were age- and gender-matched. The incidence rate of PAD, after
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data regarding alcohol intoxication were obtained, was 12.8 per 10,000 person-years, and the
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adjusted hazard ratio (aHR) of PAD was 3.80 (95% confidence interval [CI] = 3.35–4.32, p < 0.05). The log-rank test showed that patients with alcohol intoxication had a considerably higher PAD cumulative incidence rate than those without alcohol intoxication. Alcohol intoxication was significantly associated with an increased risk of PAD in men (hazard ratio [HR] = 3.77, 95% CI = 3.30–4.31) and women (HR = 4.26, 95% CI = 2.60–6.97). The aHRs of PAD risk were 7.64 (95% CI = 4.39–13.3), 4.51 (95% CI = 3.83–5.29), and 2.16
ACCEPTED MANUSCRIPT (95% CI = 1.69–2.77) for patients with alcohol intoxication compared to participants of the control group aged <35 years, 35–64 years, and ≥65 years, respectively. The individuals with
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alcohol intoxication and without any comorbidities had a 3.77-fold increased risk of PAD in comparison to that of the control cohorts (HR = 3.77, 95% CI = 3.30–4.30). The aHR of PAD in patients with alcohol intoxication was 4.53 (95% CI = 2.51–8.16) in comparison to the
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control cohort, which consisted of patients with at least one existing comorbidity. Alcohol
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intoxication, along with the severe complications of excessive alcohol use, should be considered as major risk factors of PAD in the setting of a medical emergency. Further research needs to be performed to evaluate the quantitative effect of alcohol use on PAD. Highlights
The purpose of the study was to investigate whether a link exists between peripheral arterial disease risk and alcohol intoxication.
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Alcohol intoxication-related PAD incidence rate was 12.8 per 10,000 person-years.
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Alcohol intoxication-related adjusted risk for PAD was 3.8-fold greater than for matched controls.
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Excessive alcohol use might be a pivotal risk factor for PAD.
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An important public health policy should be the avoidance of excessive alcohol use to prevent PAD.
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Keywords: peripheral arterial disease (PAD); alcohol intoxication; population-based cohort List of abbreviations: CIs: confidence interval; ICD-9-CM: International Classification of Diseases, Ninth Revision, Clinical Modification; HR: hazard ratio; LHID 2000: Longitudinal Health Insurance Database 2000; NHI: National Health Insurance; NHIRD: National Health Insurance Research Database; PAD: peripheral arterial disease; SD: standard deviation
ACCEPTED MANUSCRIPT Introduction Peripheral arterial disease (PAD) is defined as an atherosclerotic disease of the noncardiac vessels (Creager et al., 2012). The lower extremity vessels are affected more
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commonly than the upper extremity vessels. The worldwide prevalence of lower extremity PAD is between 3–12% (Creager et al., 2012; Hirsch et al., 2006a, 2006b; Novo, 2002; Olin
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& Sealove, 2010; Rooke et al., 2011; Tendera et al., 2011). Various abnormalities of vascular endothelial cells, smooth muscle cells, and platelets are linked to etiological factors of PAD
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(Kitta et al., 2009; Libby, Ridker, & Hansson, 2009). The most important risk factors involved are aging, smoking, diabetes mellitus, dyslipidemia, and hypertension (FélixRedondo et al., 2012; Hirsch et al., 2001; Murabito, D’Agostino, Silbershatz, & Wilson, 1997;
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Selvin & Erlinger, 2004; Smith et al., 2004). In several previous epidemiological studies, the risk of PAD has been shown to be lower in light-to-moderate alcohol drinkers than in
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abstainers (Athyros et al., 2008; Camargo et al., 1997; Fabsitz et al., 1999; Jepson, Fowkes,
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Donnan, & Housley, 1995; Movva & Figueredo, 2013; Vliegenthart et al., 2002). The longterm burden of alcohol use has been considerably associated with the risk of PAD (Athyros et al., 2008; Rehm et al., 2003). In 2011, one animal study showed a controversial effect of daily-moderate and weekend-excessive alcohol consumption on atherosclerotic plaque development and highlighted the importance of patterns of alcohol consumption, as opposed to the total amount consumed, in relation to the cardiovascular effects of alcohol use (Liu, Redmond, Morrow, & Cullen, 2011). The pattern of excessive alcohol use has also been
ACCEPTED MANUSCRIPT linked to risk of cardiovascular diseases (Roerecke & Rehm, 2010). The cardioprotective effect of low-risk patterns of alcohol use might disappear completely in the presence of
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excessive alcohol use (Roerecke & Rehm, 2010, 2011, 2012). Currently, the effect of excessive alcohol use, like alcohol intoxication, on PAD risk remains uncertain.
Alcohol intoxication is typically caused by excessive alcohol use, especially in binge
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drinking (Naimi et al., 2003; World Health Organization, 2014). Binge drinking is defined as
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an episode of excessive alcohol use in which the blood alcohol concentration level reaches 0.08% or more, which is commonly associated with the occasional consumption of four or more drinks for women or five or more drinks for men (Kanny, Liu, Brewer, & Lu, 2013). Approximately 38 million U.S. adults report binge drinking an average of four times per
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month, consuming an average of eight drinks per episode (Kanny et al., 2015). Worldwide, there are about 16% of drinkers aged 15 years or older who engage in heavy drinking (World
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Health Organization, 2014). Excessive alcohol use in patients that leads to alcohol
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intoxication may cause a differential, individual health burden on PAD risk. Therefore, the aim of this study was to investigate the association between alcohol intoxication, in the form of excessive alcohol use, and PAD risk. Methods Data source We collected the data for this study from the National Health Insurance Research Database (NHIRD). The NHIRD was established by the National Health Research Institutes
ACCEPTED MANUSCRIPT (NHRI) and contained data from the Taiwan National Health Insurance (NHI) program. The Taiwan NHI program has been a nationwide, single-payer health insurance provider since
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1995. Because the Taiwan NHI program was compulsory for Taiwan citizens, the coverage rate of the Taiwan NHI was over 99% of the 23 million citizens who lived in Taiwan in 1998. The NHIRD contained comprehensive claims data from the Taiwan NHI program, including
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beneficiary registry disease records and other medical services. All the data were renewed
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every year. In this study, disease history of the insured people was collected from the inpatient files. The Taiwan NHI program constructed the disease record system based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). To safeguard the privacy of the insured people, the NHRI had a procedure for releasing the
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database that removed the original identification numbers and provided a scrambled, anonymous number to link each insured person’s file. Furthermore, this study was approved
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by the Ethics Review Board of China Medical University (CMUH104-REC2-115-CR1). The
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IRB specifically waived the requirement for informed consent for the NHIRD application. Study population
This study was a retrospective, population-based, health insurance cohort study. To
interpret the association between alcohol intoxication and PAD risk, we selected an alcohol intoxication cohort and a comparison cohort and observed them. The selected alcohol intoxication cohort included patients with new-onset alcohol intoxication, whose diagnosis
ACCEPTED MANUSCRIPT codes using the ICD-9-CM were 303, 305.0, and V113, between January 1, 2000 and December 31, 2009. We set the index date as the first diagnosed day. Based on the 1:4
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matching, we randomly selected four control subjects who were without a history of alcohol intoxication per alcohol intoxication patients from the NHIRD and matched them for
frequency by age, sex, and index year. We excluded participants with a history of PAD
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(ICD-9-CM 440.2, 440.3, 440.8, 440.9, 443, 444.22, 444.8, 447.8, and 447.9). The study
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participants started from the index date and ended when the participants either withdrew from health insurance, developed PAD, or until December 31, 2011.
We considered the confounding factors including age, sex, and PAD-associated comorbidity. The participants with comorbidity were defined as the participants with a
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disease history before the end of the follow-up period. PAD-associated comorbidities included hypertension (ICD-9-CM 401-405), hyperlipidemia (ICD-9-CM 272), diabetes
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(ICD-9-CM 250), atrial fibrillation (ICD-9-CM 427.31), chronic renal disease (ICD-9-CM
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585), stroke (ICD-9-CM 430–438), heart failure (ICD-9-CM 428), ischemic heart disease (ICD-9-CM 410–414), chronic obstructive pulmonary disease (ICD-9-CM 490–496), cirrhosis (ICD-9-CM 571), and obesity (ICD-9-CM 278.0). Statistical analysis The mean and standard deviation (SD) were presented to describe ages, while numbers and percentages were presented to describe sex and comorbidity. To assess the
ACCEPTED MANUSCRIPT distribution difference between the alcohol intoxication and the comparison cohorts, the t test and chi-square test were performed for the continuous variable (age) and categorical variables
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(sex and comorbidity), respectively. The incidence density of developing PAD was calculated by the number of PAD events divided by the sum of observation time (per 10,000 personyears). The cumulative incidence curves for the two study cohorts were drawn using the
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Kaplan-Meier method, and we tested the curves’ difference using the log-rank test. To present
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the PAD risk in patients with alcohol intoxication relative to the comparison participants, the crude hazard ratios (HRs), adjusted hazard ratios (aHRs), and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model. The multiplicative interaction between alcohol intoxication and sex and comorbidity for PAD risk were also estimated
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using the Cox proportional hazards model.
SAS 9.4 software (SAS Institute, Cary, NC, USA) was used for data management and
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statistical analysis, and the incidence curve was plotted using R software (R Foundation for
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Statistical Computing, Vienna, Austria). The significance level was set at less than 0.05 for two-sided testing of the p value. Results
In total, this study included 56,544 patients with alcohol intoxication and 226,176 comparison participants (Table 1). Due to the matching for age and sex, we found no significant differences between these two cohorts. The mean age of the study cohort was
ACCEPTED MANUSCRIPT 44.4 ± 12 years, and most study participants were between 35–65 years old. Ninety percent of patients with alcohol intoxication were men. The alcohol intoxication cohort was more likely
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to have PAD-associated comorbidity than the comparison participants (all p values < 0.0001). In this study, 979 study participants developed PAD during the follow-up; 400 PAD events were from the alcohol intoxication cohort and 579 PAD events arose from the
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comparison cohort (Table 2). The incidences of PAD were 12.8 and 3.74 per 10,000 person-
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years in the alcohol intoxication cohort and the comparison cohort, respectively. The log-rank test showed that patients with alcohol intoxication had a significantly higher PAD incidence than patients without alcohol intoxication (Fig. 1; p < 0.001). After adjusting for age, sex, and PAD-associated comorbidity, the patients with alcohol intoxication were significantly
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associated with a 3.80-fold increased risk of PAD compared to the participants without alcohol intoxication (aHR = 3.80, 95% CI = 3.35–4.32).
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Table 2 also shows PAD risk stratified by age, sex, and comorbidity. Relative to the
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comparison cohort, patients of the alcohol intoxication cohort were significantly associated with an increased risk of PAD in men (aHR = 3.77, 95% CI = 3.30–4.31) and in women (aHR = 4.26, 95% CI = 2.60–6.97). The aHRs of PAD risk were 7.64 (95% CI = 4.39–13.3), 4.51 (95% CI = 3.83–5.29), and 2.16 (95% CI = 1.69–2.77) for patients with alcohol intoxication relative to the comparison participants aged <35 years, 35–65 years, and ≥65 years, respectively. In both study cohorts consisting of participants without any
ACCEPTED MANUSCRIPT comorbidities, the individual with alcohol intoxication had a 3.77-fold increased risk of PAD (aHR = 3.77, 95% CI = 3.30–4.30) compared to the individual without alcohol intoxication.
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The aHR of PAD in patients with alcohol intoxication was 4.53 (95% CI = 2.51–8.16) relative to the comparison cohort in study subjects with at least one comorbidity.
Table 3 shows the interaction risk of PAD when alcohol intoxication interacted with
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sex and comorbidity. Compared with the female comparison participants, the aHRs of PAD
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were 1.37 (95% CI = 0.98–1.92), 4.43 (95% CI = 2.73–7.19), and 5.16 (95% CI = 3.66–7.26) for the men comparison participants, the female patients with alcohol intoxication, and the male patients with alcohol intoxication, respectively. For the comparison participants without comorbidity who were used as a reference cohort, the aHR was increased when they were
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compared to the following participants: participants with comorbidity (aHR = 1.03, 95% CI = 0.68–1.58), patients with alcohol intoxication without comorbidity (aHR = 3.77,
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95% CI = 3.30–4.30), and patients with alcohol intoxication with comorbidity (aHR = 4.79,
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95% CI = 3.16–7.27). However, there was no interaction effect of alcohol intoxication on sex (p = 0.5266) and on comorbidity (p = 0.4990). Table 4 demonstrates the differences in PAD risk between patients with alcohol
intoxication and comparison participants based on follow-up years. We observed that patients with alcohol intoxication demonstrated a significantly greater risk of PAD than those in the comparison cohort for the various follow-up durations. The highest aHR of PAD for patients
ACCEPTED MANUSCRIPT with alcohol intoxication relative to the comparison cohort was 4.99 (95% CI = 3.45–7.21) during a follow-up of <1 year.
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Discussion Based on our research, this study is the first to demonstrate a correlation between alcohol intoxication and PAD. The incidence rate of PAD following admission for alcohol
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intoxication was 12.8 per 10,000 person-years, and the adjusted HR of PAD was 3.80
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(95% CI = 3.35–4.32, p < 0.001). Among patients with alcohol intoxication, the PAD risk was higher in women aged <35 years and in patients with at least one comorbidity. However, there was no interaction effect of alcohol intoxication on sex and comorbidity. Athyros et al. (2008) previously reported that heavy drinking, i.e., excessive alcohol
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use, is associated with an increase in the prevalence of PAD. However, not only the volume of alcohol consumed, but also the pattern of drinking over time affects the risk of harm
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(Rehm et al., 2003). In 2011, Liu et al. (2011) reported in an animal study involving a daily-
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moderate alcohol-use group of subjects, there was a decrease in atherosclerotic plaque volume when compared to the no-alcohol-use group. In contrast, after 4 weeks of weekendexcessive alcohol use, there was an increase in atherosclerotic plaque volume (Liu et al., 2011). Therefore, different patterns of drinking may have a main effect on the development of atherosclerotic disease. Acute alcohol intoxication is generally caused by excessive alcohol use, which is generally defined as consuming ≥5 alcoholic drinks on a single occasion (Naimi
ACCEPTED MANUSCRIPT et al., 2003; World Health Organization, 2014). Additionally, most people who use alcohol (90%) are not alcohol-dependent (Esser et al., 2014). In other words, the effect of an
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increased PAD risk in patients with alcohol intoxication may be most related to the cumulative exposure level of alcohol use, especially in people with alcohol intoxication
following excessive alcohol use. Excessive alcohol use should be considered as a major risk
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factor of PAD in those who are exposed to extremely high levels of alcohol intake. However,
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future study will be necessary to clarify the dose-dependent effect of alcohol use on the risk of PAD.
The strengths of our study include the use of population-based, health insurance data, demonstrating the traditional risk factors for PAD comparable to previous studies of general
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populations. In addition, we were able to identify the association between two comorbid diseases, which posed potential implications for prevention. Our findings should be
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interpreted in the context of the inherent limitations of an observational study using
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administrative databases. First, the NHIRD does not contain detailed information regarding individual environmental factors, alcohol consumption, smoking habits, and a family history of PAD. The relevant clinical variables, including history of alcohol use (e.g., the amount used and patterns of use), image, pathology findings, and laboratory data such as blood alcohol levels were unavailable in the present insurance data-based cohort study. As recently mentioned, these variables could not be adjusted in the analysis. However, the claims data
ACCEPTED MANUSCRIPT regarding the diagnoses of alcohol intoxication, PAD, and comorbidities including chronic renal disease from the NHIRD were nonetheless reliable (Cheng, Kao, Lin, Lee, & Lai, 2011;
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Yu et al., 2012). Second, the evidence derived from a retrospective cohort study is generally of lower statistical quality than that derived from randomized trials because of potential
biases. Although we matched the controls to balance the demographic characteristics of the
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study cohorts and multivariate analysis was used to add robustness to our results, bias
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resulting from residual confounders might have affected the results. However, residual confounders were unlikely to explain the association observed between alcohol intoxication and PAD. Conclusion
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Patients with alcohol intoxication had a significantly higher PAD incidence than patients without alcohol intoxication. The adjusted HR of patients with alcohol intoxication
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was 3.80 (95% CI = 3.35–4.32), which is significantly higher than that of the participants
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without alcohol intoxication. Among patients with alcohol intoxication, the PAD risk was higher in women aged <35 years and in patients with at least one comorbidity. Excessive alcohol use, possibly resulting in alcohol intoxication, should be considered as a major risk factor of PAD. In spite of the PAD risk associated with the alcohol intoxication population of the present study, further research is needed to evaluate the biological gradient effects of differential patterns of excessive alcohol use on PAD; such potential factors of PAD
ACCEPTED MANUSCRIPT development should be considered. In conclusion, we recommend that people who habitually use alcohol avoid excessive alcohol consumption, especially alcohol intoxication, in order to
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lower their risk of PAD. Author contributions
All authors have contributed significantly, and all authors agreed with the content of
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the manuscript. Conception/Design: Jin-Yuan Huang, Chia-Hung Kao; Provision of study
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materials: Chia-Hung Kao; Collection and/or assembly of data: all authors; Data analysis and interpretation: all authors; Manuscript writing: all authors; Final approval of manuscript: all authors. Acknowledgments
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This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW106-TDU-B-212-113004), China Medical University Hospital,
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Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10601010036), Taiwan
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Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan received the above grants. Conflict of interest Cheng-Li Lin received a salary from Management Office for Health Data, China
ACCEPTED MANUSCRIPT Medical University Hospital, Taichung, Taiwan. Jin-Yuan Huang, Wei-Kung Chen, Ching-
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Yuan Lai, Chia-Hung Kao, Tse-Yen Yang declare that they have no conflict of interest.
ACCEPTED MANUSCRIPT Figure legend
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Fig. 1. The cumulative incidence of peripheral arterial disease (PAD) among alcohol intoxication (dashed line) and non-alcohol intoxication cohorts (solid line).
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Rehm, J., Room, R., Graham, K., Monteiro, M., Gmel, G., & Sempos, C. T. (2003). The relationship of average volume of alcohol consumption and patterns of drinking to burden of disease: an overview. Addiction, 98, 1209–1228.
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Roerecke, M., & Rehm, J. (2010). Irregular heavy drinking occasions and risk of ischemic heart disease: a systematic review and meta-analysis. American Journal of Epidemiology, 171, 633–644. doi: 10.1093/aje/kwp451
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Roerecke, M., & Rehm, J. (2011). Ischemic heart disease mortality and morbidity rates in former drinkers: a meta-analysis. American Journal of Epidemiology, 173, 245–258. doi: 10.1093/aje/kwq364 Roerecke, M., & Rehm, J. (2012). Alcohol intake revisited: risks and benefits. Current Atherosclerosis Reports, 14, 556–562. doi: 10.1007/s11883-012-0277-5 Rooke, T. W., Hirsch, A. T., Misra, S., Sidawy, A. N., Beckman, J. A., Findeiss, L. K., et al. (2011). 2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology, 58, 2020– 2045. doi: 10.1016/j.jacc.2011.08.023
ACCEPTED MANUSCRIPT Selvin, E., & Erlinger, T. P. (2004). Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation, 110, 738–743. doi: 10.1161/01.CIR.0000137913.26087.F0
doi: 10.1161/01.CIR.0000128519.60762.84
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Smith, S. C., Jr., Milani, R. V., Arnett, D. K., Crouse, J. R., 3rd, McDermott, M. M., Ridker, P. M., et al. (2004). Atherosclerotic Vascular Disease Conference: Writing Group II: risk factors. Circulation, 109, 2613–2616.
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Tendera, M., Aboyans, V., Bartelink, M. L., Baumgartner, I., Clément, D., Collet, J. P., et al. (2011). ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the
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Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). European Heart Journal, 32, 2851–2906. doi: 10.1093/eurheartj/ehr211 Vliegenthart, R., Geleijnse, J. M., Hofman, A., Meijer, W. T., van Rooij, F. J., Grobbee, D. E., et al. (2002). Alcohol consumption and risk of peripheral arterial disease: the Rotterdam study. American Journal of Epidemiology, 155, 332–338.
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World Health Organization. (2014). Global status report on alcohol and health, 2014. (Luxembourg, World Health Organization). Yu, Y.-B., Gau, J.-P., Liu, C.-Y., Yang, M.-H., Chiang, S.-C., Hsu, H.-C., et al. (2012). A nation-wide analysis of venous thromboembolism in 497,180 cancer patients with
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the development and validation of a risk-stratification scoring system. Thrombosis and Haemostasis, 108, 225–235. doi: 10.1160/TH12-01-0010
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ACCEPTED MANUSCRIPT Table 1. Comparison of demographics and history of comorbidity between alcohol intoxication and non-alcohol intoxication cohorts. Alcohol intoxication No (N = 226,176) n
%
Yes (N = 56,544) n
%
Sex
p value 0.99
22,388 203,788
9.90 90.1
5,597 50,947
9.90 90.1
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Women Men Age, years
0.99
Comorbidity Hypertension Hyperlipidemia
3,259 3,107 2,028 1,808 3,811
Stroke Cirrhosis Heart failure CRD
1,161 3,503 388 297
13,067 39,587 3,890 44.4 (12.5)
23.1 70.0 6.88
0.47
1.44 1.37
1,247 992
2.21 1.75
<.0001 <.0001
0.90 0.80 1.68
948 682 1,231
1.68 1.21 2.18
<.0001 <.0001 <.0001
0.51 1.55 0.17 0.13
770 1,846 223 167
1.36 3.26 0.39 0.30
<.0001 <.0001 <.0001 <.0001
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Diabetes IHD COPD
23.1 70.0 6.88
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52,268 158,348 15,560 44.4 (12.6)
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<35 35-65 ≥65 Mean age (SD) #
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Obesity 182 0.08 144 0.25 <.0001 Atrial fibrillation 136 0.06 70 0.12 <.0001 # Chi-square test ; Student’s t test; SD, standard deviation; CRD, chronic renal disease; IHD, ischemic heart disease; COPD, chronic obstructive pulmonary disease
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No
Yes #
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Table 2. Incidence and adjusted hazard ratio of peripheral arterial disease (PAD) stratified by sex, age and comorbidity (yes/no) Alcohol intoxication Compared to non-alcohol intoxication cohort
#
IRR (95% CI) 3.41(3.32-3.51)***
Adjusted HR† (95% CI) 3.80(3.35-4.32)***
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Variables Event PY Rate Event PY Rate Overall 579 1,546,869 3.74 400 313,050 12.8 Sex Women 36 151,760 2.37 30 33,462 8.97 3.78(3.47-4.11)*** 4.26(2.60-6.97)*** Men 543 1,395,110 3.89 370 279,588 13.2 3.40(3.31-3.50)*** 3.77(3.30-4.31)*** Age, years <35 20 367,222 0.54 34 82,436 4.12 7.57(7.12-8.05)*** 7.64(4.39-13.3)*** 35-65 325 1,086,312 2.99 279 213,447 13.1 4.37(4.23-4.51)*** 4.51(3.83-5.29)*** ≥65 234 93,335 25.1 87 17,167 50.7 2.02(1.84-2.23)*** 2.16(1.69-2.77)*** Comorbidity No 557 1,498,006 3.72 377 299,371 12.6 3.39(3.30-3.48)*** 3.77(3.30-4.30)*** Yes 22 48,863 4.50 23 13,679 16.8 3.73(3.26-4.28)*** 4.53(2.51-8.16)*** PY, person-year; Rate#, incidence rate (per 10,000 person-years); IRR, incidence rate ratio; Adjusted HR† : multiple analysis including age, sex, and comorbidity history of hypertension, hyperlipidemia, diabetes, atrial fibrillation, stroke, heart failure, CRD, IHD, COPD, obesity and cirrhosis. ***p < .001 between two cohorts.
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Table 3. The adjusted hazard ratios of peripheral arterial disease (PAD) associated alcohol intoxication interaction with sex and comorbidity (yes/no). Adjusted HR Variable N Event (95% CI) p value# 0.5266 Alcohol intoxication Sex a No Women 22,388 36 1.00 No Men 203,788 543 1.37(0.98-1.92) Yes Women 5,597 30 4.43(2.73-7.19)*** Yes Men 50,947 370 5.16(3.66-7.26)*** 0.4990 Alcohol intoxication Comorbidity No No 219,217 557 1.00b No Yes 6,959 22 1.03(0.68-1.58) Yes No 54,123 377 3.77(3.30-4.30)*** Yes Yes 2,421 23 4.79(3.16-7.27)*** a b Model adjusted for age; Model adjusted for sex and age. # p value for interaction; ***p < .001
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Table 4. Incidence of peripheral arterial disease (PAD) between alcohol intoxication and non-alcohol intoxication cohorts by follow-up year. Alcohol intoxication
Variables
Event
PY
Rate
Event
Follow time (year) <1 1-3 3-5 5-7
53 127 148 97
224,313 430,025 357,296 266,127
2.36 2.95 4.14 3.64
61 91 99 70
PY
Compared to non-alcohol intoxication cohort IRR (95% CI)
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Yes Rate
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No
53,337 94,641 72,033 49,094
11.4 9.62 13.7 14.3
4.84(4.70-4.99)*** 3.26(3.16-3.36)*** 3.32(3.21-3.43)*** 3.91(3.77-4.05)***
Adjusted HR† (95% CI) 4.99(3.45-7.21)*** 3.45(2.64-4.52)*** 3.56(2.76-4.60)*** 4.34(3.19-5.91)***
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≥7 154 269,108 5.72 79 43,945 18.0 3.14(3.01-3.28)*** 3.56(2.71-4.68)*** PY, person-year; Rate, incidence rate, per 10,000 person-years; IRR, incidence rate ratio; Adjusted HR†: multiple analysis including age, sex, and comorbidity history of hypertension, hyperlipidemia, diabetes, atrial fibrillation, stroke, heart failure, CRD, IHD, COPD, obesity and cirrhosis. ***p < .001
S0741-8329(16)30018-0
DOI:
10.1016/j.alcohol.2017.06.003
Reference:
ALC 6734
To appear in:
Alcohol
Received Date: 22 January 2016 Revised Date:
13 June 2017
Accepted Date: 15 June 2017
Please cite this article as: Huang J.-Y., Chen W.-K., Lin C.-L., Lai C.-Y., Kao C.-H. & Yang T.-Y., Increased Risk of Peripheral Arterial Disease in Patients with Alcohol Intoxication: A Population-Based Retrospective Cohort Study, Alcohol (2017), doi: 10.1016/j.alcohol.2017.06.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Increased Risk of Peripheral Arterial Disease in Patients with Alcohol Intoxication: A Population-Based Retrospective Cohort
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Study
Jin-Yuan Huang a, b, Wei-Kung Chen a, b, *, Cheng-Li Lin c, d, Ching-Yuan Lai a, b, Chia-Hung Kao e, f, g, Tse-Yen Yang h, i, j, * Department of Emergency Medicine, China Medical University Hospital, Taichung, Taiwan
b
School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
c
Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
d
College of Medicine, China Medical University, Taichung, Taiwan
e
Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
f
Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
g
Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
h
Molecular and Genomic Epidemiology Center, China Medical University Hospital
i
Department of Medical Research, China Medical University Hospital
j
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
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a
*Tse-Yen Yang and Wei-Kung Chen contributed equally.
Corresponding author: Tse-Yen Yang, PhD, Assistant Research Fellow Department of Medical Research China Medical University No. 2, Yuh-Der Road Taichung40447 Taiwan, Republic of China
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Telephone: +886 4 2205 2121 ext. 7412 Fax: +886 4 2233 6174 E-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract Previous studies have reported that light-to-moderate drinkers have a lower risk of
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peripheral arterial disease (PAD) than abstainers, and that heavy drinking increases the risk of PAD. However, reports of the effects of severe alcohol drinking on PAD are lacking within a population-based cohort. Alcohol intoxication is typically considered a medical emergency at
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clinics in Taiwan and is commonly attributed to excessive alcohol use. The present study
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aimed to investigate the association between alcohol intoxication and PAD risk. We conducted a retrospective, population-based, health insurance cohort study consisting of 56,544 adult patients with alcohol intoxication between January 1, 2000 and December 31, 2009, using claims data from the National Health Insurance Research Database (NHIRD) of
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Taiwan. This database included a control cohort of 226,176 residents without alcohol intoxication. The patients were age- and gender-matched. The incidence rate of PAD, after
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data regarding alcohol intoxication were obtained, was 12.8 per 10,000 person-years, and the
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adjusted hazard ratio (aHR) of PAD was 3.80 (95% confidence interval [CI] = 3.35–4.32, p < 0.05). The log-rank test showed that patients with alcohol intoxication had a considerably higher PAD cumulative incidence rate than those without alcohol intoxication. Alcohol intoxication was significantly associated with an increased risk of PAD in men (hazard ratio [HR] = 3.77, 95% CI = 3.30–4.31) and women (HR = 4.26, 95% CI = 2.60–6.97). The aHRs of PAD risk were 7.64 (95% CI = 4.39–13.3), 4.51 (95% CI = 3.83–5.29), and 2.16
ACCEPTED MANUSCRIPT (95% CI = 1.69–2.77) for patients with alcohol intoxication compared to participants of the control group aged <35 years, 35–64 years, and ≥65 years, respectively. The individuals with
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alcohol intoxication and without any comorbidities had a 3.77-fold increased risk of PAD in comparison to that of the control cohorts (HR = 3.77, 95% CI = 3.30–4.30). The aHR of PAD in patients with alcohol intoxication was 4.53 (95% CI = 2.51–8.16) in comparison to the
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control cohort, which consisted of patients with at least one existing comorbidity. Alcohol
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intoxication, along with the severe complications of excessive alcohol use, should be considered as major risk factors of PAD in the setting of a medical emergency. Further research needs to be performed to evaluate the quantitative effect of alcohol use on PAD. Highlights
The purpose of the study was to investigate whether a link exists between peripheral arterial disease risk and alcohol intoxication.
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Alcohol intoxication-related PAD incidence rate was 12.8 per 10,000 person-years.
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Alcohol intoxication-related adjusted risk for PAD was 3.8-fold greater than for matched controls.
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Excessive alcohol use might be a pivotal risk factor for PAD.
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An important public health policy should be the avoidance of excessive alcohol use to prevent PAD.
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Keywords: peripheral arterial disease (PAD); alcohol intoxication; population-based cohort List of abbreviations: CIs: confidence interval; ICD-9-CM: International Classification of Diseases, Ninth Revision, Clinical Modification; HR: hazard ratio; LHID 2000: Longitudinal Health Insurance Database 2000; NHI: National Health Insurance; NHIRD: National Health Insurance Research Database; PAD: peripheral arterial disease; SD: standard deviation
ACCEPTED MANUSCRIPT Introduction Peripheral arterial disease (PAD) is defined as an atherosclerotic disease of the noncardiac vessels (Creager et al., 2012). The lower extremity vessels are affected more
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commonly than the upper extremity vessels. The worldwide prevalence of lower extremity PAD is between 3–12% (Creager et al., 2012; Hirsch et al., 2006a, 2006b; Novo, 2002; Olin
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& Sealove, 2010; Rooke et al., 2011; Tendera et al., 2011). Various abnormalities of vascular endothelial cells, smooth muscle cells, and platelets are linked to etiological factors of PAD
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(Kitta et al., 2009; Libby, Ridker, & Hansson, 2009). The most important risk factors involved are aging, smoking, diabetes mellitus, dyslipidemia, and hypertension (FélixRedondo et al., 2012; Hirsch et al., 2001; Murabito, D’Agostino, Silbershatz, & Wilson, 1997;
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Selvin & Erlinger, 2004; Smith et al., 2004). In several previous epidemiological studies, the risk of PAD has been shown to be lower in light-to-moderate alcohol drinkers than in
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abstainers (Athyros et al., 2008; Camargo et al., 1997; Fabsitz et al., 1999; Jepson, Fowkes,
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Donnan, & Housley, 1995; Movva & Figueredo, 2013; Vliegenthart et al., 2002). The longterm burden of alcohol use has been considerably associated with the risk of PAD (Athyros et al., 2008; Rehm et al., 2003). In 2011, one animal study showed a controversial effect of daily-moderate and weekend-excessive alcohol consumption on atherosclerotic plaque development and highlighted the importance of patterns of alcohol consumption, as opposed to the total amount consumed, in relation to the cardiovascular effects of alcohol use (Liu, Redmond, Morrow, & Cullen, 2011). The pattern of excessive alcohol use has also been
ACCEPTED MANUSCRIPT linked to risk of cardiovascular diseases (Roerecke & Rehm, 2010). The cardioprotective effect of low-risk patterns of alcohol use might disappear completely in the presence of
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excessive alcohol use (Roerecke & Rehm, 2010, 2011, 2012). Currently, the effect of excessive alcohol use, like alcohol intoxication, on PAD risk remains uncertain.
Alcohol intoxication is typically caused by excessive alcohol use, especially in binge
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drinking (Naimi et al., 2003; World Health Organization, 2014). Binge drinking is defined as
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an episode of excessive alcohol use in which the blood alcohol concentration level reaches 0.08% or more, which is commonly associated with the occasional consumption of four or more drinks for women or five or more drinks for men (Kanny, Liu, Brewer, & Lu, 2013). Approximately 38 million U.S. adults report binge drinking an average of four times per
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month, consuming an average of eight drinks per episode (Kanny et al., 2015). Worldwide, there are about 16% of drinkers aged 15 years or older who engage in heavy drinking (World
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Health Organization, 2014). Excessive alcohol use in patients that leads to alcohol
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intoxication may cause a differential, individual health burden on PAD risk. Therefore, the aim of this study was to investigate the association between alcohol intoxication, in the form of excessive alcohol use, and PAD risk. Methods Data source We collected the data for this study from the National Health Insurance Research Database (NHIRD). The NHIRD was established by the National Health Research Institutes
ACCEPTED MANUSCRIPT (NHRI) and contained data from the Taiwan National Health Insurance (NHI) program. The Taiwan NHI program has been a nationwide, single-payer health insurance provider since
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1995. Because the Taiwan NHI program was compulsory for Taiwan citizens, the coverage rate of the Taiwan NHI was over 99% of the 23 million citizens who lived in Taiwan in 1998. The NHIRD contained comprehensive claims data from the Taiwan NHI program, including
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beneficiary registry disease records and other medical services. All the data were renewed
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every year. In this study, disease history of the insured people was collected from the inpatient files. The Taiwan NHI program constructed the disease record system based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). To safeguard the privacy of the insured people, the NHRI had a procedure for releasing the
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database that removed the original identification numbers and provided a scrambled, anonymous number to link each insured person’s file. Furthermore, this study was approved
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by the Ethics Review Board of China Medical University (CMUH104-REC2-115-CR1). The
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IRB specifically waived the requirement for informed consent for the NHIRD application. Study population
This study was a retrospective, population-based, health insurance cohort study. To
interpret the association between alcohol intoxication and PAD risk, we selected an alcohol intoxication cohort and a comparison cohort and observed them. The selected alcohol intoxication cohort included patients with new-onset alcohol intoxication, whose diagnosis
ACCEPTED MANUSCRIPT codes using the ICD-9-CM were 303, 305.0, and V113, between January 1, 2000 and December 31, 2009. We set the index date as the first diagnosed day. Based on the 1:4
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matching, we randomly selected four control subjects who were without a history of alcohol intoxication per alcohol intoxication patients from the NHIRD and matched them for
frequency by age, sex, and index year. We excluded participants with a history of PAD
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(ICD-9-CM 440.2, 440.3, 440.8, 440.9, 443, 444.22, 444.8, 447.8, and 447.9). The study
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participants started from the index date and ended when the participants either withdrew from health insurance, developed PAD, or until December 31, 2011.
We considered the confounding factors including age, sex, and PAD-associated comorbidity. The participants with comorbidity were defined as the participants with a
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disease history before the end of the follow-up period. PAD-associated comorbidities included hypertension (ICD-9-CM 401-405), hyperlipidemia (ICD-9-CM 272), diabetes
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(ICD-9-CM 250), atrial fibrillation (ICD-9-CM 427.31), chronic renal disease (ICD-9-CM
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585), stroke (ICD-9-CM 430–438), heart failure (ICD-9-CM 428), ischemic heart disease (ICD-9-CM 410–414), chronic obstructive pulmonary disease (ICD-9-CM 490–496), cirrhosis (ICD-9-CM 571), and obesity (ICD-9-CM 278.0). Statistical analysis The mean and standard deviation (SD) were presented to describe ages, while numbers and percentages were presented to describe sex and comorbidity. To assess the
ACCEPTED MANUSCRIPT distribution difference between the alcohol intoxication and the comparison cohorts, the t test and chi-square test were performed for the continuous variable (age) and categorical variables
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(sex and comorbidity), respectively. The incidence density of developing PAD was calculated by the number of PAD events divided by the sum of observation time (per 10,000 personyears). The cumulative incidence curves for the two study cohorts were drawn using the
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Kaplan-Meier method, and we tested the curves’ difference using the log-rank test. To present
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the PAD risk in patients with alcohol intoxication relative to the comparison participants, the crude hazard ratios (HRs), adjusted hazard ratios (aHRs), and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model. The multiplicative interaction between alcohol intoxication and sex and comorbidity for PAD risk were also estimated
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using the Cox proportional hazards model.
SAS 9.4 software (SAS Institute, Cary, NC, USA) was used for data management and
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statistical analysis, and the incidence curve was plotted using R software (R Foundation for
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Statistical Computing, Vienna, Austria). The significance level was set at less than 0.05 for two-sided testing of the p value. Results
In total, this study included 56,544 patients with alcohol intoxication and 226,176 comparison participants (Table 1). Due to the matching for age and sex, we found no significant differences between these two cohorts. The mean age of the study cohort was
ACCEPTED MANUSCRIPT 44.4 ± 12 years, and most study participants were between 35–65 years old. Ninety percent of patients with alcohol intoxication were men. The alcohol intoxication cohort was more likely
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to have PAD-associated comorbidity than the comparison participants (all p values < 0.0001). In this study, 979 study participants developed PAD during the follow-up; 400 PAD events were from the alcohol intoxication cohort and 579 PAD events arose from the
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comparison cohort (Table 2). The incidences of PAD were 12.8 and 3.74 per 10,000 person-
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years in the alcohol intoxication cohort and the comparison cohort, respectively. The log-rank test showed that patients with alcohol intoxication had a significantly higher PAD incidence than patients without alcohol intoxication (Fig. 1; p < 0.001). After adjusting for age, sex, and PAD-associated comorbidity, the patients with alcohol intoxication were significantly
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associated with a 3.80-fold increased risk of PAD compared to the participants without alcohol intoxication (aHR = 3.80, 95% CI = 3.35–4.32).
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Table 2 also shows PAD risk stratified by age, sex, and comorbidity. Relative to the
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comparison cohort, patients of the alcohol intoxication cohort were significantly associated with an increased risk of PAD in men (aHR = 3.77, 95% CI = 3.30–4.31) and in women (aHR = 4.26, 95% CI = 2.60–6.97). The aHRs of PAD risk were 7.64 (95% CI = 4.39–13.3), 4.51 (95% CI = 3.83–5.29), and 2.16 (95% CI = 1.69–2.77) for patients with alcohol intoxication relative to the comparison participants aged <35 years, 35–65 years, and ≥65 years, respectively. In both study cohorts consisting of participants without any
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The aHR of PAD in patients with alcohol intoxication was 4.53 (95% CI = 2.51–8.16) relative to the comparison cohort in study subjects with at least one comorbidity.
Table 3 shows the interaction risk of PAD when alcohol intoxication interacted with
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sex and comorbidity. Compared with the female comparison participants, the aHRs of PAD
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were 1.37 (95% CI = 0.98–1.92), 4.43 (95% CI = 2.73–7.19), and 5.16 (95% CI = 3.66–7.26) for the men comparison participants, the female patients with alcohol intoxication, and the male patients with alcohol intoxication, respectively. For the comparison participants without comorbidity who were used as a reference cohort, the aHR was increased when they were
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compared to the following participants: participants with comorbidity (aHR = 1.03, 95% CI = 0.68–1.58), patients with alcohol intoxication without comorbidity (aHR = 3.77,
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95% CI = 3.30–4.30), and patients with alcohol intoxication with comorbidity (aHR = 4.79,
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95% CI = 3.16–7.27). However, there was no interaction effect of alcohol intoxication on sex (p = 0.5266) and on comorbidity (p = 0.4990). Table 4 demonstrates the differences in PAD risk between patients with alcohol
intoxication and comparison participants based on follow-up years. We observed that patients with alcohol intoxication demonstrated a significantly greater risk of PAD than those in the comparison cohort for the various follow-up durations. The highest aHR of PAD for patients
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Discussion Based on our research, this study is the first to demonstrate a correlation between alcohol intoxication and PAD. The incidence rate of PAD following admission for alcohol
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intoxication was 12.8 per 10,000 person-years, and the adjusted HR of PAD was 3.80
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(95% CI = 3.35–4.32, p < 0.001). Among patients with alcohol intoxication, the PAD risk was higher in women aged <35 years and in patients with at least one comorbidity. However, there was no interaction effect of alcohol intoxication on sex and comorbidity. Athyros et al. (2008) previously reported that heavy drinking, i.e., excessive alcohol
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use, is associated with an increase in the prevalence of PAD. However, not only the volume of alcohol consumed, but also the pattern of drinking over time affects the risk of harm
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(Rehm et al., 2003). In 2011, Liu et al. (2011) reported in an animal study involving a daily-
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moderate alcohol-use group of subjects, there was a decrease in atherosclerotic plaque volume when compared to the no-alcohol-use group. In contrast, after 4 weeks of weekendexcessive alcohol use, there was an increase in atherosclerotic plaque volume (Liu et al., 2011). Therefore, different patterns of drinking may have a main effect on the development of atherosclerotic disease. Acute alcohol intoxication is generally caused by excessive alcohol use, which is generally defined as consuming ≥5 alcoholic drinks on a single occasion (Naimi
ACCEPTED MANUSCRIPT et al., 2003; World Health Organization, 2014). Additionally, most people who use alcohol (90%) are not alcohol-dependent (Esser et al., 2014). In other words, the effect of an
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increased PAD risk in patients with alcohol intoxication may be most related to the cumulative exposure level of alcohol use, especially in people with alcohol intoxication
following excessive alcohol use. Excessive alcohol use should be considered as a major risk
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factor of PAD in those who are exposed to extremely high levels of alcohol intake. However,
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future study will be necessary to clarify the dose-dependent effect of alcohol use on the risk of PAD.
The strengths of our study include the use of population-based, health insurance data, demonstrating the traditional risk factors for PAD comparable to previous studies of general
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populations. In addition, we were able to identify the association between two comorbid diseases, which posed potential implications for prevention. Our findings should be
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interpreted in the context of the inherent limitations of an observational study using
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administrative databases. First, the NHIRD does not contain detailed information regarding individual environmental factors, alcohol consumption, smoking habits, and a family history of PAD. The relevant clinical variables, including history of alcohol use (e.g., the amount used and patterns of use), image, pathology findings, and laboratory data such as blood alcohol levels were unavailable in the present insurance data-based cohort study. As recently mentioned, these variables could not be adjusted in the analysis. However, the claims data
ACCEPTED MANUSCRIPT regarding the diagnoses of alcohol intoxication, PAD, and comorbidities including chronic renal disease from the NHIRD were nonetheless reliable (Cheng, Kao, Lin, Lee, & Lai, 2011;
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Yu et al., 2012). Second, the evidence derived from a retrospective cohort study is generally of lower statistical quality than that derived from randomized trials because of potential
biases. Although we matched the controls to balance the demographic characteristics of the
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study cohorts and multivariate analysis was used to add robustness to our results, bias
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resulting from residual confounders might have affected the results. However, residual confounders were unlikely to explain the association observed between alcohol intoxication and PAD. Conclusion
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Patients with alcohol intoxication had a significantly higher PAD incidence than patients without alcohol intoxication. The adjusted HR of patients with alcohol intoxication
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was 3.80 (95% CI = 3.35–4.32), which is significantly higher than that of the participants
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without alcohol intoxication. Among patients with alcohol intoxication, the PAD risk was higher in women aged <35 years and in patients with at least one comorbidity. Excessive alcohol use, possibly resulting in alcohol intoxication, should be considered as a major risk factor of PAD. In spite of the PAD risk associated with the alcohol intoxication population of the present study, further research is needed to evaluate the biological gradient effects of differential patterns of excessive alcohol use on PAD; such potential factors of PAD
ACCEPTED MANUSCRIPT development should be considered. In conclusion, we recommend that people who habitually use alcohol avoid excessive alcohol consumption, especially alcohol intoxication, in order to
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lower their risk of PAD. Author contributions
All authors have contributed significantly, and all authors agreed with the content of
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the manuscript. Conception/Design: Jin-Yuan Huang, Chia-Hung Kao; Provision of study
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materials: Chia-Hung Kao; Collection and/or assembly of data: all authors; Data analysis and interpretation: all authors; Manuscript writing: all authors; Final approval of manuscript: all authors. Acknowledgments
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This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW106-TDU-B-212-113004), China Medical University Hospital,
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Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10601010036), Taiwan
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Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan received the above grants. Conflict of interest Cheng-Li Lin received a salary from Management Office for Health Data, China
ACCEPTED MANUSCRIPT Medical University Hospital, Taichung, Taiwan. Jin-Yuan Huang, Wei-Kung Chen, Ching-
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Yuan Lai, Chia-Hung Kao, Tse-Yen Yang declare that they have no conflict of interest.
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Fig. 1. The cumulative incidence of peripheral arterial disease (PAD) among alcohol intoxication (dashed line) and non-alcohol intoxication cohorts (solid line).
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ACCEPTED MANUSCRIPT Table 1. Comparison of demographics and history of comorbidity between alcohol intoxication and non-alcohol intoxication cohorts. Alcohol intoxication No (N = 226,176) n
%
Yes (N = 56,544) n
%
Sex
p value 0.99
22,388 203,788
9.90 90.1
5,597 50,947
9.90 90.1
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Women Men Age, years
0.99
Comorbidity Hypertension Hyperlipidemia
3,259 3,107 2,028 1,808 3,811
Stroke Cirrhosis Heart failure CRD
1,161 3,503 388 297
13,067 39,587 3,890 44.4 (12.5)
23.1 70.0 6.88
0.47
1.44 1.37
1,247 992
2.21 1.75
<.0001 <.0001
0.90 0.80 1.68
948 682 1,231
1.68 1.21 2.18
<.0001 <.0001 <.0001
0.51 1.55 0.17 0.13
770 1,846 223 167
1.36 3.26 0.39 0.30
<.0001 <.0001 <.0001 <.0001
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Diabetes IHD COPD
23.1 70.0 6.88
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52,268 158,348 15,560 44.4 (12.6)
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<35 35-65 ≥65 Mean age (SD) #
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Obesity 182 0.08 144 0.25 <.0001 Atrial fibrillation 136 0.06 70 0.12 <.0001 # Chi-square test ; Student’s t test; SD, standard deviation; CRD, chronic renal disease; IHD, ischemic heart disease; COPD, chronic obstructive pulmonary disease
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No
Yes #
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Table 2. Incidence and adjusted hazard ratio of peripheral arterial disease (PAD) stratified by sex, age and comorbidity (yes/no) Alcohol intoxication Compared to non-alcohol intoxication cohort
#
IRR (95% CI) 3.41(3.32-3.51)***
Adjusted HR† (95% CI) 3.80(3.35-4.32)***
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Variables Event PY Rate Event PY Rate Overall 579 1,546,869 3.74 400 313,050 12.8 Sex Women 36 151,760 2.37 30 33,462 8.97 3.78(3.47-4.11)*** 4.26(2.60-6.97)*** Men 543 1,395,110 3.89 370 279,588 13.2 3.40(3.31-3.50)*** 3.77(3.30-4.31)*** Age, years <35 20 367,222 0.54 34 82,436 4.12 7.57(7.12-8.05)*** 7.64(4.39-13.3)*** 35-65 325 1,086,312 2.99 279 213,447 13.1 4.37(4.23-4.51)*** 4.51(3.83-5.29)*** ≥65 234 93,335 25.1 87 17,167 50.7 2.02(1.84-2.23)*** 2.16(1.69-2.77)*** Comorbidity No 557 1,498,006 3.72 377 299,371 12.6 3.39(3.30-3.48)*** 3.77(3.30-4.30)*** Yes 22 48,863 4.50 23 13,679 16.8 3.73(3.26-4.28)*** 4.53(2.51-8.16)*** PY, person-year; Rate#, incidence rate (per 10,000 person-years); IRR, incidence rate ratio; Adjusted HR† : multiple analysis including age, sex, and comorbidity history of hypertension, hyperlipidemia, diabetes, atrial fibrillation, stroke, heart failure, CRD, IHD, COPD, obesity and cirrhosis. ***p < .001 between two cohorts.
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Table 3. The adjusted hazard ratios of peripheral arterial disease (PAD) associated alcohol intoxication interaction with sex and comorbidity (yes/no). Adjusted HR Variable N Event (95% CI) p value# 0.5266 Alcohol intoxication Sex a No Women 22,388 36 1.00 No Men 203,788 543 1.37(0.98-1.92) Yes Women 5,597 30 4.43(2.73-7.19)*** Yes Men 50,947 370 5.16(3.66-7.26)*** 0.4990 Alcohol intoxication Comorbidity No No 219,217 557 1.00b No Yes 6,959 22 1.03(0.68-1.58) Yes No 54,123 377 3.77(3.30-4.30)*** Yes Yes 2,421 23 4.79(3.16-7.27)*** a b Model adjusted for age; Model adjusted for sex and age. # p value for interaction; ***p < .001
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Table 4. Incidence of peripheral arterial disease (PAD) between alcohol intoxication and non-alcohol intoxication cohorts by follow-up year. Alcohol intoxication
Variables
Event
PY
Rate
Event
Follow time (year) <1 1-3 3-5 5-7
53 127 148 97
224,313 430,025 357,296 266,127
2.36 2.95 4.14 3.64
61 91 99 70
PY
Compared to non-alcohol intoxication cohort IRR (95% CI)
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Yes Rate
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53,337 94,641 72,033 49,094
11.4 9.62 13.7 14.3
4.84(4.70-4.99)*** 3.26(3.16-3.36)*** 3.32(3.21-3.43)*** 3.91(3.77-4.05)***
Adjusted HR† (95% CI) 4.99(3.45-7.21)*** 3.45(2.64-4.52)*** 3.56(2.76-4.60)*** 4.34(3.19-5.91)***
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≥7 154 269,108 5.72 79 43,945 18.0 3.14(3.01-3.28)*** 3.56(2.71-4.68)*** PY, person-year; Rate, incidence rate, per 10,000 person-years; IRR, incidence rate ratio; Adjusted HR†: multiple analysis including age, sex, and comorbidity history of hypertension, hyperlipidemia, diabetes, atrial fibrillation, stroke, heart failure, CRD, IHD, COPD, obesity and cirrhosis. ***p < .001