Exposure to polycyclic aromatic hydrocarbons, volatile organic compounds, and tobacco-specific nitrosamines and incidence of esophageal cancer.

BACKGROUND: Studying carcinogens in tobacco and nontobacco sources may be key to understanding the pathogenesis and geographic distribution of esophageal cancer. METHODS: The Golestan Cohort Study has been conducted since 2004 in a region with high rates of esophageal squamous cell carcinoma. For this nested study, the cases comprised of all incident cases by January 1, 2018; controls were matched to the case by age, sex, residence, time in cohort, and tobacco use. We measured urinary concentrations of 33 exposure biomarkers of nicotine, polycyclic aromatic hydrocarbons, volatile organic compounds, and tobacco-specific nitrosamines. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals for associations between the 90th vs the 10th percentiles of the biomarker concentrations and incident esophageal squamous cell carcinoma. RESULTS: Among individuals who did not currently use tobacco (148 cases and 163 controls), 2 acrolein metabolites, 2 acrylonitrile metabolites, 1 propylene oxide metabolite, and one 1,3-butadiene metabolite were significantly associated with incident esophageal squamous cell carcinoma (adjusted odds ratios between 1.8 and 4.3). Among tobacco users (57 cases and 63 controls), metabolites of 2 other volatile organic compounds (styrene and xylene) were associated with esophageal squamous cell carcinoma (OR = 6.2 and 9.0, respectively). In tobacco users, 2 tobacco-specific nitrosamines (NNN and N'-Nitrosoanatabine) were also associated with esophageal squamous cell carcinoma. Suggestive associations were seen with some polycyclic aromatic hydrocarbons (especially 2-hydroxynaphthalene) in nonusers of tobacco products and other tobacco-specific nitrosamines in tobacco users. CONCLUSION: These novel associations based on individual-level data and samples collected many years before cancer diagnosis, from a population without occupational exposure, have important public health implications.

Association Between Incident Type 2 Diabetes and Opium Use: Mediation by Body Mass and Adiposity.

Opiates can affect glucose metabolism and obesity, but no large prospective study (to our knowledge) has investigated the association between long-term opium use, body mass index (BMI; weight (kg)/height (m)2), and incident type 2 diabetes mellitus (T2DM). We analyzed prospective data from 50,045 Golestan Cohort Study participants in Iran (enrollment: 2004-2008). After excluding participants with preexisting diseases, including diabetes, we used adjusted Poisson regression models to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for T2DM in opium users compared with nonusers, using mediation analysis to assess the BMI-mediated association of opium use with incident T2DM. Of 40,083 included participants (mean age = 51.4 (standard deviation, 8.8) years; 56% female), 16% were opium users (median duration of use, 10 (interquartile range), 4-20) years). During follow-up (until January 2020), 5,342 incident T2DM cases were recorded, including 8.5% of opium users and 14.2% of nonusers. Opium use was associated with an overall decrease in incident T2DM (IRR = 0.83, 95% CI: 0.75, 0.92), with a significant dose-response association. Most (84.3%) of this association was mediated by low BMI or waist circumference, and opium use did not have a direct association with incident T2DM (IRR = 0.97, 95% CI: 0.87, 1.08). Long-term opium use was associated with lower incidence of T2DM, which was mediated by low body mass and adiposity.

Determinants of Left Ventricular Systolic Function One Year after Primary Percutaneous Coronary Intervention for ST-elevation Myocardial Infarction in a Middle-Income Country.

BACKGROUND: Little is known about the predictors of left ventricular ejection fraction (LVEF) -an important predictor of mortality- after primary percutaneous coronary intervention (PCI) in low- and middle-income countries. METHODS: In a prospective cohort study at Imam Ali hospital, Kermanshah, Iran, we enrolled consecutive ST-elevation myocardial infarction (STEMI) patients treated with primary PCI (2016-2018) and followed them up to one year. LVEF levels were measured by echocardiography, at baseline and one-year follow-up. Determinants of preserved/improved LVEF were assessed using multi-variable logistic regression models. RESULTS: Of 803 patients (mean age 58.53±11.7 years, 20.5% women), baseline LVEF levels of ≤35% were reported in 44%, 35- 50% in 40%, and ≥50% in 16% of patients. The mean ± SD of LVEF increased from 38.13%±9.2% at baseline to 41.49%±9.5% at follow-up. LVEF was preserved/improved in 629 (78.3%) patients. Adjusted ORs (95% CIs) for predictors of preserved/improved LVEF showed positive associations with creatinine clearance, 1.01 (1.00-1.02) and adherence to clopidogrel, 2.01 (1.33-3.02); and inverse associations with history of myocardial infarction (MI), 0.44 (0.25-0.78); creatine kinase MB (CK-MB), 0.997 (0.996- 0.999); door-balloon time (3rd vs. 1st tertile), 0.62 (0.39-0.98); number of diseased vessels (2 and 3 vs. 1: 0.63 (0.41-0.99) and 0.58 (0.36-0.93), respectively); and baseline LVEF (35-50% and ≥50% vs. ≤35%: 0.45 (0.28-0.71) and 0.19 (0.11-0.34), respectively). CONCLUSION: Adherence to clopidogrel, short door-balloon time, high creatinine clearance, and lower baseline LVEF were associated with preserved/improved LVEF, while history of MI, high CK-MB, and multi-vessel disease were predictors of reduced LVEF. Long-term drug adherence should be considered for LVEF improvement in low- and middle-income countries.

Smoker pseudo-paradox in ST-segment elevation myocardial infarction patients.

INTRODUCTION: Cigarette smoking is a preventable cause of cardiovascular morbidity and mortality. Despite the adverse effects of smoking, some studies have reported the term "smoker's paradox', meaning better outcomes in smokers following acute myocardial infarction. AIM: The aim of the present study was to evaluate the relationship between smoking status and one-year mortality in patients with ST-segment elevation myocardial infarction (STEMI). MATERIALS AND METHODS: This was a registry-based cohort study of STEMI patients from Imam-Ali hospital, Kermanshah, Iran. Consecutive STEMI patients (July 2016-October 2018) were stratified by smoking status and followed for one year. Cox proportional models were used to estimate crude, age-adjusted, and full-adjusted hazard ratios with 95% confidence intervals (HR, 95%CI). RESULTS: Of 1975 patients (mean age 60.1 years, 76.6% male) included in the study, 48.1% (n=951) were smokers (mean age 57.7 years, 94.7% male). Crude and age-adjusted HR (95% CI) for the associations of smoking and mortality were 0.67 (0.50-0.92) and 0.89 (0.65-1.22), respectively. After adjusting for age, sex, hypertension, diabetes, body-mass index, anterior wall myocardial infarction, creatine kinase-MB, glomerular filtration rate, left ventricular ejection fraction, low-density lipoprotein cholesterol, and hemoglobin, smoking was associated with increased risk of mortality: HR (95% CI: 1.56 (1.04-2.35). CONCLUSIONS: In our study, smoking was associated with an increased risk of mortality. Although the smokers had a better outcome, this would be reversed after controlling for age and the other STEMI associated factors.

Opium consumption and long-term outcomes of CABG surgery in patients without modifiable risk factors.

Background: The question about the significance of opium consumption as a coronary artery disease (CAD) risk factor still remains open. The present study aimed to evaluate the association between opium consumption and long term outcomes of coronary artery bypass grafting (CABG) in patients without standard modifiable CAD risk factors (SMuRFs; hypertension, diabetes, dyslipidemia, and smoking). Methods: In this registry-based design, we included 23,688 patients with CAD who underwent isolated CABG between January 2006 to December 2016. Outcomes were compared in two groups; with and without SMuRF. The main outcomes were all-cause mortality, fatal and nonfatal cerebrovascular events (MACCE). Inverse probability weighting (IPW) adjusted Cox's proportional hazards (PH) model was used to evaluate the effect of opium on post-op outcomes. Results: During 133,593 person-years of follow-up, opium consumption was associated with increased risk of mortality in both patients with and without SMuRFs (weighted Hazard Ratio (HR)s: 1.248 [1.009, 1.574] and 1.410 [1.008, 2.038], respectively). There was no association between opium consumption and fatal and non-fatal MACCE in patients without SMuRF (HR = 1.027 [0.762-1.383], HR 0.700 [0.438-1.118]). Opium consumption was associated with earlier age of CABG in both groups; 2.77 (1.68, 3.85) years in SMuRF-less and 1.70 (1.11, 2.38) years in patients with SMuRFs. Conclusion: Opium users not only undergo CABG at younger ages but also have a higher rate of mortality regardless of the presence of traditional CAD risk factors. Conversely, the risk of MACCE is only higher in patients with at least one modifiable CAD risk factor.

Predictors of 1-Year Major Cardiovascular Events after ST-Elevation Myocardial Infarction in a Specialized Cardiovascular Center in Western Iran.

Background: Identifying the long-term predictors of recurrent cardiovascular events may help improve the quality of care and prevent subsequent events. We aimed to investigate the predictors of 1-year major cardiovascular events (MACE) in patients discharged after ST-elevation myocardial infarction (STEMI) in a tertiary hospital in Iran. Methods: This registry-based cohort study included consecutive STEMI patients between 2016 and 2019 in Imam-Ali Hospital, Kermanshah, Iran. All patients discharged alive from STEMI hospitalization were followed up for 1 year for MACE, consisting of all-cause mortality, nonfatal MI, and nonfatal stroke. We estimated the hazard ratio (HR) and the 95% confidence interval (95% CI) using Cox proportional-hazard models to evaluate potential predictors, including demographic characteristics, medical history, cardiovascular risk factors, laboratory tests, reperfusion therapy, and medications. Results: During 2187.2 person-years, 21 patients were lost to follow-up (success rate =99.1%). Of 2274 post-discharge STEMI patients (mean age =60.26 y; 21.9% female), 151 (6.6%) experienced MACE, including, all-cause mortality (n=115, 5.1%), nonfatal MI (n=20, 0.9%), and nonfatal stroke (n=16, 0.7%). Independent predictors of MACE were age (HR:1.02; 95% CI: 1.00-1.04), no education vs ≥12 years of formal schooling (HR: 2.07; 95% CI: 1.17-3.67), stroke history (HR: 2.37; 95% CI: 1.48-3.81), the glomerular filtration rate (HR: 0.98; 95% CI: 0.97-1.00), the body mass index (HR: 0.94; 95% CI:, 0.89-0.99), peak creatine kinase-MB (HR: 1.00; 95% CI: 1.00-1.002), thrombolysis vs primary percutaneous coronary intervention (HR: 1.85; 95% CI: 1.21-2.81), and left ventricular ejection fraction <35% vs ≥50% (HR: 2.82; 95% CI: 1.46-5.47). Conclusion: Age, education, stroke history, the glomerular filtration rate, the body mass index, peak creatine kinase-MB, reperfusion therapy, and left ventricular function can be independently associated with 1-year MACE.

Pictogram Is a Valid Instrument to Classify At-Risk Adult Population Based on Abdominal Obesity: Results from Pars Cohort Study.

BACKGROUND: Abdominal obesity is associated with increased risk of myocardial infarction and death events. Thus, obtaining data on the status of abdominal obesity is important in risk factor assessment and prevention of non-communicable diseases. This study aimed to evaluate the validity of using pictograms to classify abdominal obesity indices (waist circumference [WC], waist-hip ratio [WHR], and waist-height ratio [WHtR]) into normal and at-risk categories and determine the effects of demographic characteristics on this validity. METHODS: This cross-sectional study used data from Pars Cohort Study (PCS). Participants chose the most similar pictogram scores to their body size at 15, 30 years, and current age. Optimal normal/at-risk cut-off values for pictograms were calculated using sensitivity/specificity plots. Receiver operating characteristic curves were used to evaluate the validity of pictograms. Validity measures were analyzed across different subgroups of demographic characteristics. RESULTS: A total of 9263 participants (46% males) were included in the study. The estimated area under the curves were 84% for WC, 77% for WHR, and 89% for WHtR in males, and 84% for WC, 73% for WHR, and 90% for WHtR in females. Optimal pictogram cutoffs to classify central obesity for WC, WHR, and WHtR were 4, 4, and 5 in males and 4, 4, and 6 in females, respectively. The majority of demographic characteristics were not associated with the validity of pictograms. CONCLUSION: Using pictograms to determine normal and at-risk categories of abdominal obesity indices is valid among adult population with a wide range of demographic characteristics. However, the results need to be interpreted with caution in those with a positive history of weight fluctuation.

Incidence, early case fatality and determinants of stroke in Iran: Golestan Cohort Study.

OBJECTIVES: While few studies investigated the incidence of stroke in Iran, no Iranian cohort has estimated the standardized-incidence rate and early fatality of first-ever-stroke subtypes along with associated factors. METHODS: Golestan Cohort Study is a prospective study launched in northeastern Iran in 2004, including 50,045 individuals aged 40-75 at baseline. Age-standardized incidence rate of first-ever-stroke was calculated per 100,000 person-years, according to World Standard Population. The 28-day case fatality was calculated by dividing the number of fatal first-ever-stroke during the first 28 days by total events. Cox proportional hazard models were conducted to assess incidence and fatality risk factors. We used Population Attributable Fractions to estimate the incidence and early fatality proportions reduced by ideal risk factor control. RESULTS: 1,135 first-ever-strokes were observed during 8.6 (median) years follow-up. First-ever-stroke standardized incidence rate was estimated 185.2 (95% CI: 173.2-197.2) per 100,000 person-years. The 28-day case fatality was 44.1% (95% CI: 40.4-48.2). Hypertension and pre-stroke physical activity were the strongest risk factors associated with first-ever-stroke incidence (Hazard ratio: 2.83; 2.47-3.23) and 28-day case fatality (Hazard ratio: 0.59; 0.44-0.78), respectively. Remarkably, opium consumption was strongly associated with hemorrhagic stroke incidence (Hazard ratio: 1.52; 1.04-2.23) and ischemic stroke fatality (Hazard ratio: 1.44; 1.01-2.09). Overall, modifiable risk factors contributed to 83% and 61% of first-ever-stroke incidence and early fatality, respectively. CONCLUSION: Efficient risk factor control can considerably reduce stroke occurrence and fatality in our study. Establishing awareness campaigns and 24-hour stroke units seem necessary for improving the stroke management in this area.

Spatial environmental factors predict cardiovascular and all-cause mortality: Results of the SPACE study.

BACKGROUND: Environmental exposures account for a growing proportion of global mortality. Large cohort studies are needed to characterize the independent impact of environmental exposures on mortality in low-income settings. METHODS: We collected data on individual and environmental risk factors for a multiethnic cohort of 50,045 individuals in a low-income region in Iran. Environmental risk factors included: ambient fine particular matter air pollution; household fuel use and ventilation; proximity to traffic; distance to percutaneous coronary intervention (PCI) center; socioeconomic environment; population density; local land use; and nighttime light exposure. We developed a spatial survival model to estimate the independent associations between these environmental exposures and all-cause and cardiovascular mortality. FINDINGS: Several environmental factors demonstrated associations with mortality after adjusting for individual risk factors. Ambient fine particulate matter air pollution predicted all-cause mortality (per µg/m3, HR 1.20, 95% CI 1.07, 1.36) and cardiovascular mortality (HR 1.17, 95% CI 0.98, 1.39). Biomass fuel use without chimney predicted all-cause mortality (reference = gas, HR 1.23, 95% CI 0.99, 1.53) and cardiovascular mortality (HR 1.36, 95% CI 0.99, 1.87). Kerosene fuel use without chimney predicted all-cause mortality (reference = gas, HR 1.09, 95% CI 0.97, 1.23) and cardiovascular mortality (HR 1.19, 95% CI 1.01, 1.41). Distance to PCI center predicted all-cause mortality (per 10km, HR 1.01, 95% CI 1.004, 1.022) and cardiovascular mortality (HR 1.02, 95% CI 1.004, 1.031). Additionally, proximity to traffic predicted all-cause mortality (HR 1.13, 95% CI 1.01, 1.27). In a separate validation cohort, the multivariable model effectively predicted both all-cause mortality (AUC 0.76) and cardiovascular mortality (AUC 0.81). Population attributable fractions demonstrated a high mortality burden attributable to environmental exposures. INTERPRETATION: Several environmental factors predicted cardiovascular and all-cause mortality, independent of each other and of individual risk factors. Mortality attributable to environmental factors represents a critical opportunity for targeted policies and programs.

Sex difference in the risk factor distributions and outcomes after coronary artery bypass graft surgery in the young population.

OBJECTIVES: Coronary artery disease is becoming a major health concern in the young population. Male and female patients may experience different journeys after coronary artery disease events. We aimed to evaluate risk factors and compare outcomes between young male and female patients undergoing coronary artery bypass graft surgery (CABG). METHODS: In this registry-based large sample size study, patients undergoing isolated CABG at a young age (premature isolated CABG) between 2007 and 2016 were included and followed up until 2020. Premature was defined as women and men younger than 55 years old. The main end points of the study were 7-year all-cause mortality and 7-year major adverse cardiovascular and cerebrovascular events (MACCEs). RESULTS: Of a total of 24 428 patients who underwent CABG, 7217 patients (men-to-women ratio ≈4:1) with premature isolated CABG were included. The median follow-up duration was 78.5 months (75.2-81.6 months). The prevalence rates of diabetes mellitus, hypertension, dyslipidaemia and obesity were significantly higher in women than in men (58.3% vs 28.6%, 64.2% vs 38.5%, 69.7% vs 55.3% and 44.7 vs 23.9, respectively; all Ps < 0.05). The risk factor burden (mean of the risk factor count per year) was also higher among the female population. Diabetes mellitus was the common mortality predictor between men and women. In the subgroup analysis (interaction analysis in the adjusted model), hypertensive females had a higher rate of MACCE and a higher rate of mortality than hypertensive males; however, this difference was not significant in the non-hypertensive population. Opium addiction was a strong predictor of MACCE and all-cause mortality among men. Female patients had a higher rate of 7-year MACCE (hazard ratio, 1.33; 95% confidence interval, 1.16-1.51) and a higher rate of 7-year all-cause mortality (hazard ratio, 1.23; 95% confidence interval, 0.98-1.53). CONCLUSIONS: The risk factor profile and predictors of outcomes were different between our female and male patients. Women carried a higher risk of events and mortality after CABG at a young age.

Reperfusion Therapy and Predictors of 30-Day Mortality after ST-Segment Elevation Myocardial Infarction in a University Medical Center in Western Iran.

BACKGROUND: Considerable variability in survival rate after ST-segment elevation myocardial infarction (STEMI) is present and outcomes remain suboptimal, especially in low- and middle-income contraries. This study aimed to investigate predictors of 30- day mortality after STEMI, including reperfusion therapy, in a tertiary hospital in western Iran. METHODS: In this registry-based cohort study (2016-2019), we investigated reperfusion therapies - primary percutaneous coronary intervention (PPCI), pharmaco-invasive (thrombolysis followed by angiography/percutaneous coronary intervention), and thrombolysis alone - used in Imam-Ali hospital, the only hospital with a PPCI capability in the Kermanshah Province. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs), using Cox proportional-hazard models, to investigate the potential predictors of 30-day mortality including reperfusion therapy, admission types (direct admission/referral from non-PPCI-capable hospitals), demographic variables, coronary risk factors, vital signs on admission, medical history, and laboratory tests. RESULTS: Data of 2428 STEMI patients (mean age: 60.73; 22.9% female) were available. Reperfusion therapy was performed in 84% of patients (58% PPCI, 10% pharmaco-invasive, 16% thrombolysis alone). Only 17% of the referred patients had received thrombolysis at non-PPCI-capable hospitals. Among patients with thrombolysis, only 38.2% underwent coronary angiography/ percutaneous coronary intervention. The independent predictors of mortality were: no reperfusion therapy (HR: 2.01, 95% CI: 1.36-2.97), referral from non-PPCI-capable hospitals (1.73, 1.22-2.46), age (1.03, 1.01-1.04), glomerular filtration rate (0.97, 0.96-0.97), heart rate>100 bpm (1.94, 1.22-3.08), and systolic blood pressure<100 mm Hg (4.92, 3.43-7.04). Mortality was lower with the pharmaco-invasive approach, although statistically non-significant, than other reperfusion therapies. CONCLUSION: Reperfusion therapy, admission types, age, glomerular filtration rate, heart rate, and blood pressure were independently associated with 30-day mortality. Using a comprehensive STEMI network to increase reperfusion therapy, especially pharmaco-invasive therapy, is recommended.

Prevalence and trends of coronary artery disease risk factors and their effect on age of diagnosis in patients with established coronary artery disease: Tehran Heart Center (2005-2015).

BACKGROUND: Coronary artery disease (CAD) is a universal public health challenge, more prominently so in the low- and middle-income countries. In this study, we aimed to determine prevalence and trends of CAD risk factors in patients with documented CAD and to determine their effects on the age of CAD diagnosis. MATERIALS AND METHODS: We conducted a registry-based, serial cross-sectional study using the coronary angiography data bank of the Tehran Heart Center. Adult patients who had obstructive (> 50% stenosis) CAD were included in the study. The prevalence and 11-year trends of conventional CAD risk factors were analyzed by sex and age, and their adjusted effects on the age of CAD diagnosis were calculated. RESULTS: From January 2005 to December 2015, data for 90,094 patients were included in this analysis. A total of 61,684 (68.5%) were men and 28,410 (31.5%) were women. Men were younger at diagnosis than women, with a mean age of 60.1 in men and 63.2 in women (p < 0.001), and had fewer risk factors at the time of diagnosis. Mean age at diagnosis had an overall increasing trend during the study period. Increasing trend was seen in body-mass index, hypertension prevalence, diabetes mellitus. All lipid profile components (total cholesterol, low-density lipoprotein cholesterol, triglycerides, and high-density lipoprotein cholesterol) decreased over time. Of particular interest, opium consumption was associated with 2.2 year earlier age of CAD diagnosis. CONCLUSION: The major results of this study (lower age of CAD diagnosis in men, lower age of diagnosis associated with most risk factors, and lower prevalence of serum lipids over time) were expected. A prominent finding of this study is confirming opium use was associated with a much younger age of CAD onset, even after adjusting for all other risk factors. In addition to recommendations for control of the traditional risk factors, spreading information about the potential adverse effect of opium use, which has only recently been associated with higher risk of CAD, may be necessary.

Obesity and incident gastrointestinal cancers: overall body size or central obesity measures, which factor matters?

BMI does not reflect the location or amount of body fat. We aimed to investigate the role of general and central obesity measures in the prediction of incident gastrointestinal cancers. In this analysis of the Golestan Cohort Study, we included 47 586 cancer-free individuals followed for 12.3 years (IQR: 10.5-13.2). We investigated the association of obesity measures including BMI, waist circumference and waist-to-hip ratio (WHR) at enrollment and the incidence of esophageal, gastric, colorectal and pancreatic cancers. Cox proportional hazard models were used to estimate the association between covariates and gastrointestinal cancer risk. We observed no significant associations between obesity measures and incidence of the above-mentioned gastrointestinal cancers in men. In women, BMI, waist circumference and WHR were associated with significant reductions in the risk of esophageal squamous cell carcinoma (ESCC): hazard ratio (HR): 0.67 [95% confidence interval (CI): 0.56-0.81], HR: 0.71 (95% CI: 0.60-0.84) and HR: 0.80 (95% CI: 0.68- 0.94), respectively. In addition, WHR was associated with significantly increased risks for colorectal cancer (HR: 1.39, 95% CI: 1.08-1.78) and gastric cancer (HR: 1.24, 95% CI: 1.01-1.51) in women. In this study, statistically significant associations between obesity measures and incident esophageal, gastric and colorectal cancers were seen in women.

Long-term opiate use and risk of cardiovascular mortality: results from the Golestan Cohort Study.

AIMS: Tens of millions of people worldwide use opiates but little is known about their potential role in causing cardiovascular diseases. We aimed to study the association of long-term opiate use with cardiovascular mortality and whether this association is independent of the known risk factors. METHODS AND RESULTS: In the population-based Golestan Cohort Study-50 045 Iranian participants, 40-75 years, 58% women-we used Cox regression to estimate hazard ratios and 95% confidence intervals (HRs, 95% CIs) for the association of opiate use (at least once a week for a period of 6 months) with cardiovascular mortality, adjusting for potential confounders-i.e. age, sex, education, wealth, residential place, marital status, ethnicity, and tobacco and alcohol use. To show independent association, the models were further adjusted for hypertension, diabetes, waist and hip circumferences, physical activity, fruit/vegetable intake, aspirin and statin use, and history of cardiovascular diseases and cancers. In total, 8487 participants (72.2% men) were opiate users for a median (IQR) of 10 (4-20) years. During 548 940 person-years-median of 11.3 years, >99% success follow-up-3079 cardiovascular deaths occurred, with substantially higher rates in opiate users than non-users (1005 vs. 478 deaths/100 000 person-years). Opiate use was associated with increased cardiovascular mortality, with adjusted HR (95% CI) of 1.63 (1.49-1.79). Overall 10.9% of cardiovascular deaths were attributable to opiate use. The association was independent of the traditional cardiovascular risk factors. CONCLUSION: Long-term opiate use was associated with an increased cardiovascular mortality independent of the traditional risk factors. Further research, particularly on mechanisms of action, is recommended.

Joint effect of diabetes and opiate use on all-cause and cause-specific mortality: the Golestan cohort study.

BACKGROUND: Many diabetic individuals use prescription and non-prescription opioids and opiates. We aimed to investigate the joint effect of diabetes and opiate use on all-cause and cause-specific mortality. METHODS: Golestan Cohort study is a prospective population-based study in Iran. A total of 50 045 people-aged 40-75, 28 811 women, 8487 opiate users, 3548 diabetic patients-were followed during a median of 11.1 years, with over 99% success follow-up. Hazard ratio and 95% confidence intervals (HRs, 95% CIs), and preventable death attributable to each risk factor, were calculated. RESULTS: After 533 309 person-years, 7060 deaths occurred: 4178 (10.8%) of non-diabetic non-opiate users, 757 (25.3%) diabetic non-users, 1906 (24.0%) non-diabetic opiate users and 219 (39.8%) diabetic opiate users. Compared with non-diabetic non-users, HRs (95% CIs) for all-cause mortality were 2.17 (2.00-2.35) in diabetic non-opiate users, 1.63 (1.53-1.74) in non-diabetic opiate users and 2.76 (2.40-3.17) in diabetic opiate users. Among those who both had diabetes and used opiates, 63.8% (95% CI: 58.3%-68.5%) of all deaths were attributable to these risk factors, compared with 53.9% (95% CI: 50%-57.4%) in people who only had diabetes and 38.7% (95% CI: 34.6%-42.5%) in non-diabetic opiate users. Diabetes was more strongly associated with cardiovascular than cancer mortality. The risk of early mortality in known cases of diabetes did not depend on whether they started opiate use before or after their diagnosis. CONCLUSIONS: Using opiates is detrimental to the health of diabetic patients. Public awareness about the health effects of opiates, and improvement of diabetes care especially among individuals with or at risk of opiate use, are necessary.

Impaired fasting glucose and major adverse cardiovascular events by hypertension and dyslipidemia status: the Golestan cohort study.

BACKGROUND: Whether pre-diabetes in the absence of hypertension (HTN) or dyslipidemia (DLP) is a risk factor for occurrence of major adverse cardiovascular events (MACE) is not fully established. We investigated the effect of impaired fasting glucose (IFG) alone and in combination with HTN, DLP or both on subsequent occurrence of MACE as well as individual MACE components. METHODS: This longitudinal population-based study included 11,374 inhabitants of Northeastern Iran. The participants were free of any cardiovascular disease at baseline and were followed yearly from 2010 to 2017. Cox proportional hazard models were fitted to measure the hazard of IFG alone or in combination with HTN and DLP on occurrence of MACE as the primary endpoint. RESULTS: Four hundred thirty-seven MACE were recorded during 6.2 ± 0.1 years follow up. IFG alone compared to normal fasting glucose (NFG) was not associated with an increase in occurrence of MACE (HR, 0.87; 95% CI, 0.19-4.02; p, 0.854). However, combination of IFG and HTN (HR, 2.88; 95% CI, 2.04-4.07; p, 0.000) or HTN + DLP (HR, 2.98; 95% CI, 1.89-4.71; p, 0.000) significantly increased the risk for MACE. Moreover, IFG + DM with or without HTN, DLP, or both was also associated with an increase in the incidence of MACE. CONCLUSION: IFG, per se, does not appear to increase hazard of MACE. However, IFG with HTN or HTN + DLP conferred a significant hazard for MACE in an incremental manner. Moreover, IFG without HTN, adjusted for DLP, can be associated with an increase in the risk for CVD- death.

Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial.

BACKGROUND: A fixed-dose combination therapy (polypill strategy) has been proposed as an approach to reduce the burden of cardiovascular disease, especially in low-income and middle-income countries (LMICs). The PolyIran study aimed to assess the effectiveness and safety of a four-component polypill including aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan for primary and secondary prevention of cardiovascular disease. METHODS: The PolyIran study was a two-group, pragmatic, cluster-randomised trial nested within the Golestan Cohort Study (GCS), a cohort study with 50 045 participants aged 40-75 years from the Golestan province in Iran. Clusters (villages) were randomly allocated (1:1) to either a package of non-pharmacological preventive interventions alone (minimal care group) or together with a once-daily polypill tablet (polypill group). Randomisation was stratified by three districts (Gonbad, Aq-Qala, and Kalaleh), with the village as the unit of randomisation. We used a balanced randomisation algorithm, considering block sizes of 20 and balancing for cluster size or natural log of the cluster size (depending on the skewness within strata). Randomisation was done at a fixed point in time (Jan 18, 2011) by statisticians at the University of Birmingham (Birmingham, UK), independent of the local study team. The non-pharmacological preventive interventions (including educational training about healthy lifestyle-eg, healthy diet with low salt, sugar, and fat content, exercise, weight control, and abstinence from smoking and opium) were delivered by the PolyIran field visit team at months 3 and 6, and then every 6 months thereafter. Two formulations of polypill tablet were used in this study. Participants were first prescribed polypill one (hydrochlorothiazide 12·5 mg, aspirin 81 mg, atorvastatin 20 mg, and enalapril 5 mg). Participants who developed cough during follow-up were switched by a trained study physician to polypill two, which included valsartan 40 mg instead of enalapril 5 mg. Participants were followed up for 60 months. The primary outcome-occurrence of major cardiovascular events (including hospitalisation for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularisation procedures, and non-fatal and fatal stroke)-was centrally assessed by the GCS follow-up team, who were masked to allocation status. We did intention-to-treat analyses by including all participants who met eligibility criteria in the two study groups. The trial was registered with ClinicalTrials.gov, number NCT01271985. FINDINGS: Between Feb 22, 2011, and April 15, 2013, we enrolled 6838 individuals into the study-3417 (in 116 clusters) in the minimal care group and 3421 (in 120 clusters) in the polypill group. 1761 (51·5%) of 3421 participants in the polypill group were women, as were 1679 (49·1%) of 3417 participants in the minimal care group. Median adherence to polypill tablets was 80·5% (IQR 48·5-92·2). During follow-up, 301 (8·8%) of 3417 participants in the minimal care group had major cardiovascular events compared with 202 (5·9%) of 3421 participants in the polypill group (adjusted hazard ratio [HR] 0·66, 95% CI 0·55-0·80). We found no statistically significant interaction with the presence (HR 0·61, 95% CI 0·49-0·75) or absence of pre-existing cardiovascular disease (0·80; 0·51-1·12; pinteraction=0·19). When restricted to participants in the polypill group with high adherence, the reduction in the risk of major cardiovascular events was even greater compared with the minimal care group (adjusted HR 0·43, 95% CI 0·33-0·55). The frequency of adverse events was similar between the two study groups. 21 intracranial haemorrhages were reported during the 5 years of follow-up-ten participants in the polypill group and 11 participants in the minimal care group. There were 13 physician-confirmed diagnoses of upper gastrointestinal bleeding in the polypill group and nine in the minimal care group. INTERPRETATION: Use of polypill was effective in preventing major cardiovascular events. Medication adherence was high and adverse event numbers were low. The polypill strategy could be considered as an additional effective component in controlling cardiovascular diseases, especially in LMICs. FUNDING: Tehran University of Medical Sciences, Barakat Foundation, and Alborz Darou.

Comparing Anthropometric Indicators of Visceral and General Adiposity as Determinants of Overall and Cardiovascular Mortality.

BACKGROUND: It is unclear which anthropometric obesity indicator best predicts adverse health outcomes. This study aimed to investigate the association of body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), and hip-adjusted WC with all-cause and cardiovascular mortality. METHODS: 50045 people aged 40-75 (58% women, median BMI: 26.3 kg /m2 ) participated in the population-based Golestan Cohort Study. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for the association of obesity indicators with mortality. We also examined the association of these indicators with intermediate outcomes, including hypertension, blood glucose, dyslipidemia, carotid atherosclerosis, nonalcoholic fatty liver, and visceral abdominal fat. RESULTS: After a median follow-up of 10.9 years (success rate: 99.1%), 6651 deaths (2778 cardiovascular) occurred. Comparing 5th to the 1st quintile, HRs (95% CIs) for all-cause and cardiovascular mortality were 1.12 (1.02-1.22) and 1.59 (1.39-1.83) for BMI, 1.16 (1.07-1.27) and 1.66 (1.44-1.90) for WC, 1.28 (1.17-1.40) and 1.88 (1.63-2.18) for WHtR, 1.44 (1.32-1.58) and 2.04 (1.76-2.36) for WHR, and 1.84 (1.62-2.09) and 2.72 (2.23-3.32) for hip-adjusted WC, respectively. Hip-adjusted WC had the strongest associations with the intermediate outcomes. CONCLUSION: Indicators of visceral adiposity (e.g., hip-adjusted WC) were much stronger predictors of overall and cardiovascular mortality than were indicators of general adiposity (e.g., BMI). The full-strength effect of visceral adiposity becomes apparent only when both WC, as a risk factor, and hip circumference, as a protective factor, are individually and simultaneously taken into consideration.

Causes of premature death and their associated risk factors in the Golestan Cohort Study, Iran.

OBJECTIVES: To examine the causes of premature mortality (<70 years) and associated risk factors in the Golestan Cohort Study. DESIGN: Prospective. SETTING: The Golestan Cohort Study in northeastern Iran. PARTICIPANTS: 50 045 people aged 40 or more participated in this population-based study from baseline (2004-2008) to August 2017, with over 99% success follow-up rate. MAIN OUTCOME MEASURES: The top causes of premature death, HR and their 95% CI and population attributable fraction (PAF) for risk factors. RESULTS: After 444 168 person-years of follow-up (median of 10 years), 6347 deaths were reported, of which 4018 (63.3%) occurred prematurely. Ischaemic heart disease (IHD) accounted for 33.9% of premature death, followed by stroke (14.0%), road injuries (4.7%), stomach cancer (4.6%) and oesophageal cancer (4.6%). Significant risk/protective factors were: wealth score (HR for highest vs lowest quintile: 0.57, PAF for lowest four quintiles vs top quintile: 28%), physical activity (highest vs lowest tertile: 0.67, lowest two tertiles vs top tertile: 22%), hypertension (1.50, 19%), opium use (1.69, 14%), education (middle school or higher vs illiterate: 0.84, illiterate or primary vs middle school or higher: 13%), tobacco use (1.38, 11%), diabetes (2.39, 8%) and vegetable/fruit consumption (highest vs lowest tertile: 0.87, lowest two tertiles vs top tertile: 8%). Collectively, these factors accounted for 76% of PAF in men and 69% in women. CONCLUSION: IHD and stroke are the leading causes of premature mortality in the Golestan Cohort Study. Enhancing socioeconomic status and physical activity, reducing opium and tobacco use, increasing vegetable/fruit consumption and controlling hypertension and diabetes are recommended to reduce premature deaths.