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1.  Interaction Between Cigarette Smoking and Clinical Benefit of Clopidogrel 
To examine the interaction between cigarette smoking and clinical efficacy of clopidogrel in STEMI.
Cigarette smoking induces CYP1A2, which converts clopidogrel into its active metabolite, and prior studies suggest greater inhibition of platelet aggregation by clopidogrel in smokers of ≥10 cigarettes/day.
The effect of clopidogrel compared with placebo on angiographic and clinical outcomes was examined in CLARITY-TIMI 28, a randomized trial of 3429 STEMI patients, stratified by smoking intensity as follows: not current smokers (N=1732), smokers of 1-9 (N=206), 10-19 (N=354), 20-29 (N=715), and ≥30 cigarettes/day (N=422). Logistic regression was used to adjust for other baseline characteristics and interaction terms to test for effect modification.
Although clopidogrel reduced the rate of the primary endpoint of a closed infarctrelated artery or death/MI before angiography in CLARITY-TIMI 28, the benefit was especially marked among those who smoked ≥10 cigarettes/day (adjusted OR 0.49, 95% CI 0.37-0.66; P<0.0001) as compared to those who did not (adjusted OR 0.72, 95% CI 0.57-0.91; P=0.006; Pinteraction=0.04). Similarly, clopidogrel was significantly more effective at reducing the rate of cardiovascular death, MI, or urgent revascularization through 30 days among those who smoked ≥10 cigarettes/day (adjusted OR 0.54, 95% CI 0.38-0.76; P=0.0004) compared with those who did not (adjusted OR 0.98; 95% CI 0.75-1.28; P=0.87; Pinteraction=0.006).
Cigarette smoking appears to positively modify the beneficial effect of clopidogrel on angiographic and clinical outcomes. This study demonstrates that common clinical factors that influence the metabolism of clopidogrel may impact its clinical effectiveness.
PMCID: PMC2675920  PMID: 19358940
clopidogrel; smoking; cytochrome P450
2.  Smoking-Related Health Risks Among Persons With HIV in the Strategies for Management of Antiretroviral Therapy Clinical Trial 
American journal of public health  2010;100(10):1896-1903.
We sought to determine smoking-related hazard ratios (HRs) and population-attributable risk percentage (PAR%) for serious clinical events and death among HIV-positive persons, whose smoking prevalence is higher than in the general population.
For 5472 HIV-infected persons enrolled from 33 countries in the Strategies for Management of Antiretroviral Therapy clinical trial, we evaluated the relationship between baseline smoking status and development of AIDS-related or serious non-AIDS events and overall mortality.
Among all participants, 40.5% were current smokers and 24.8% were former smokers. Adjusted HRs were higher for current than for never smokers for overall mortality (2.4; P<.001), major cardiovascular disease (2.0; P=.002), non-AIDS cancer (1.8; P=.008), and bacterial pneumonia (2.3; P<.001). Adjusted HRs also were significantly higher for these outcomes among current than among former smokers. The PAR% for current versus former and never smokers combined was 24.3% for overall mortality, 25.3% for major cardiovascular disease, 30.6% for non-AIDS cancer, and 25.4% for bacterial pneumonia.
Smoking contributes to substantial morbidity and mortality in this HIV-infected population. Providers should routinely integrate smoking cessation programs into HIV health care.
PMCID: PMC2936972  PMID: 20724677
3.  Smoking Induces Long-Lasting Effects through a Monoamine-Oxidase Epigenetic Regulation 
PLoS ONE  2009;4(11):e7959.
Postulating that serotonin (5-HT), released from smoking-activated platelets could be involved in smoking-induced vascular modifications, we studied its catabolism in a series of 115 men distributed as current smokers (S), never smokers (NS) and former smokers (FS) who had stopped smoking for a mean of 13 years.
Methodology/Principal Findings
5-HT, monoamine oxidase (MAO-B) activities and amounts were measured in platelets, and 5-hydroxyindolacetic acid (5-HIAA)—the 5-HT/MAO catabolite—in plasma samples. Both platelet 5-HT and plasma 5-HIAA levels were correlated with the 10-year cardiovascular Framingham relative risk (P<0.01), but these correlations became non-significant after adjustment for smoking status, underlining that the determining risk factor among those taken into account in the Framingham risk calculation was smoking. Surprisingly, the platelet 5-HT content was similar in S and NS but lower in FS with a parallel higher plasma level of 5-HIAA in FS. This was unforeseen since MAO-B activity was inhibited during smoking (P<0.00001). It was, however, consistent with a higher enzyme protein concentration found in S and FS than in NS (P<0.001). It thus appears that MAO inhibition during smoking was compensated by a higher synthesis. To investigate the persistent increase in MAO-B protein concentration, a study of the methylation of its gene promoter was undertaken in a small supplementary cohort of similar subjects. We found that the methylation frequency of the MAOB gene promoter was markedly lower (P<0.0001) for S and FS vs. NS due to cigarette smoke-induced increase of nucleic acid demethylase activity.
This is one of the first reports that smoking induces an epigenetic modification. A better understanding of the epigenome may help to further elucidate the physiopathology and the development of new therapeutic approaches to tobacco addiction. The results could have a larger impact than cardiovascular damage, considering that MAO-dependent 5-HT catabolism is also involved in addiction, predisposition to cancer, behaviour and mental health.
PMCID: PMC2775922  PMID: 19956754
4.  Smoking and health: the association between smoking behaviour, total mortality, and cardiorespiratory disease in west central Scotland. 
The relationship of smoking to total mortality and to the prevalence of cardiorespiratory symptoms has been studied in three prospective surveys in west central Scotland in which 18 786 people attended a multiphasic screening examination. The prevalence of respiratory symptoms, and to a lesser extent cardiovascular symptoms, increased with the number of cigarettes smoked, with inhalation, and with a younger age of starting to smoke. A lower prevalence of respiratory symptoms in both sexes was observed in smokers of filter cigarettes than in smokers of plain cigarettes, and in those who smoked cigarettes with lower tar levels, irrespective of whether these were filtered or plain. In general, the relationships found between smoking and mortality were similar to those reported by other workers. Current cigarette smokers had a death rate from all causes which was twice that of those who had never smoked. No difference was found between the mortality rates of smokers of plain and filter cigarettes.
PMCID: PMC1060966  PMID: 744817
5.  Rates of cardiovascular disease following smoking cessation in patients with HIV infection: results from the D:A:D Study 
HIV medicine  2011;12(7):412-421.
To estimate the rates of cardiovascular disease (CVD) events after stopping smoking in patients with HIV-infection.
Patients who reported smoking status, and no previous CVD prior to enrolment into D:A:D were included. Smoking status is collected at each visit as current smoker (yes/no) and ever smoker (yes/no). Duration since stopping smoking was calculated for persons who had reported current smoking during follow-up and no current smoking subsequently. Endpoints were: myocardial infarction (MI); coronary heart disease (CHD – MI plus invasive coronary artery procedure or death from other CHD); CVD (CVD – CHD plus carotid artery endarterectomy or stroke); and all-cause mortality.
Event rates were calculated for never, previous and current smokers, and smokers who stopped during follow-up. Incidence rate ratios (IRR) were determined using Poisson regression adjusted for age, sex, cohort, calendar year, family history of CVD, diabetes, lipids, blood pressure and antiretroviral treatment.
27,136 patients had smoking status reported, with a total of 432, 600, 746 and 1902 MI, CHD, CVD and mortality events respectively. The adjusted IRR of CVD in patients who stopped smoking during follow-up decreased from 2.32 within the first year of stopping to 1.49 after 3+ years compared to those who never smoked. Similar trends were observed for the MI and CHD endpoints. Reductions in risk were less pronounced for all cause mortality.
The risk of CVD events in HIV-positive patients decreased with increasing time since stopping smoking. Smoking cessation efforts should be a priority in the management of HIV positive patients.
PMCID: PMC3070963  PMID: 21251183
HIV-infection; smoking cessation; myocardial infarction; cardiovascular disease; cohort study
6.  Perioperative Clopidogrel and Postoperative Events after Hip and Knee Arthroplasties 
Hip and knee arthroplasties are widely performed and vascular disease among patients having these procedures is common. Clopidogrel is a platelet inhibitor that decreases the likelihood of thrombosis. It may cause intraoperative and postoperative bleeding, but its discontinuation increases the risk of vascular events. There is currently no consensus regarding the best perioperative clopidogrel regimen that balances these concerns.
We determined (1) the relationship between time of perioperative clopidogrel administration and postoperative bleeding-related events after hip and knee arthroplasties and (2) patient characteristics or surgical factors that may predict these events.
We retrospectively queried our inpatient pharmacy database for patients who received clopidogrel from 2007 to 2009 and identified 116 patients who underwent hip or knee arthroplasty. We recorded the time of perioperative clopidogrel administration, bleeding-related postoperative events, patient characteristics, and surgical factors.
Patients who withheld clopidogrel 5 or more days before hip or knee arthroplasty had lower rates of reoperation for infection and antibiotics prescribed for the surgical wound. Postoperative events did not vary with timing of clopidogrel resumption after surgery. Advanced age, an American Society of Anesthesiologists (ASA) score of 4, and revision surgery predicted increased readmission, reoperation for hematoma or infection, antibiotic use, and death.
Holding clopidogrel for at least 5 days before hip or knee arthroplasty may lower the rate of bleeding-related events. We found no increase in events when patients resumed clopidogrel immediately after surgery. Advanced age, ASA score of 4, and revision surgery may be risk factors for bleeding-related events.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3314755  PMID: 22402810
Medicine & Public Health; Conservative Orthopedics; Orthopedics; Sports Medicine; Surgery; Surgical Orthopedics; Medicine/Public Health, general
7.  Joint effect of cigarette smoking and alcohol consumption on mortality 
Preventive medicine  2007;45(4):313-319.
To evaluate the joint effect of cigarette smoking and alcohol consumption on mortality.
A population-based cohort of 66,743 Chinese men aged 30–89 in Shanghai, China recruited from 1996 to 2000. Lifestyle data were collected using structured questionnaires. As of November 2004, follow-up for the vital status of 64,515 men was completed and death information was further confirmed through record linkage with the Shanghai Vital Statistics Registry. Associations were evaluated by Cox regression analyses.
2,514 deaths (982 from cancers, 776 from cardiovascular diseases (CVD)) were identified during 297,396 person-years of follow-up. Compared to never-smokers, both former and current smokers had significantly elevated mortality from any cause, CVD, and cancer; risk increased with amount of smoking. Intake of 1–7 drinks/week was associated with reduced risk of death, particularly CVD death (hazard ratio (HR): 0.7, 95% confidence interval (CI): 0.5, 1.0), whereas intake of >42 drinks/week was related to increased mortality, particularly cancer-related death (HR: 1.7, 95% CI: 1.1, 2.5). The HR for total mortality associated with moderate alcohol consumption increased from 0.8 (95% CI: 0.6, 1.0) for non-smokers to 1.0 (0.9, 1.2) for moderate smokers and 1.4 (95% CI: 1.2, 1.7) for heavy smokers. Heavy drinkers and heavy smokers had the highest mortality (HR: 1.9, 95% CI: 1.6, 2.4).
Light and moderate alcohol consumption reduced mortality from CVD. This beneficial effect, however, was offset by cigarette smoking.
PMCID: PMC2997335  PMID: 17628652
cigarette smoking; alcohol consumption; mortality; Chinese men
8.  Smoking status and sex as indicators of differences in 2582 obese patients presenting for weight management 
Smoking remains the most common preventable cause of death. Very little tobacco exposure can increase cardiovascular disease risk. The relationship between smoking, sex, and weight remains unclear.
Between September 1992 and June 2007, 2582 consenting patients starting the Ottawa Hospital Weight Management program were grouped by sex and smoking status. “Former smokers” (771 females, 312 males) had quit for at least 1 year. “Smokers” (135 females, 54 males) smoked > 9 cigarettes daily. There were 979 females and 331 males who never smoked. Using SAS 9.2 statistical software, the prevalence of coronary artery disease (CAD), type 2 diabetes (T2DM), major depressive disorder (MDD), and medication use among the groups was compared (Chi-square [χ2]). Anthropometric measurements, lipid, glucose and thyroid levels were compared using analysis of variance (ANOVA). Interactions were assessed using 2-way ANOVA analysis for continuous data, and logistic regression for discrete data.
Smokers were more likely to have MDD (χ2), lower high-density lipoprotein levels and higher triglyceride levels than other groups. Former smokers had a greater prevalence of CAD, T2DM on pharmacotherapy, and impaired fasting glucose than other groups. They were also more likely to be taking lipid-lowering agents and antihypertensives (χ2). Never smokers had less MDD, CAD, and were less likely to be on antidepressants than the other groups. Males were more likely to have CAD and T2DM than females. Females were more likely to have MDD than males. Interactions between smoking status and sex were found for age, weight, fasting glucose and thyroid-stimulating hormone levels.
Obese never smokers suffer from the fewest chronic diseases. Obese former smokers have a greater prevalence of CAD, T2DM on pharmacotherapy, and impaired fasting glucose than other groups. Thus, clinicians and researchers should avoid combining former smokers with never smokers as “nonsmokers” in research and treatment decisions. The results of this study call for a longitudinal study comparing these groups over the weight management program.
PMCID: PMC3363146  PMID: 22661896
smoking status; weight management; obesity
9.  Operative Treatment of HIP Fractures in Patients on Clopidogrel: A Case-Control Study 
Clopidogrel, an inhibitor of ADP-induced platelet aggregation, is indicated for the reduction of atherosclerotic events in patients with atherosclerosis documented by recent stoke, myocardial infarction, acute coronary syndrome, and established peripheral arterial disease. In cardiovascular studies, clopidogrel has been associated with increased chest tube output, transfusion rates, and re-exploration rates. Few studies have addressed the possible complications of clopidogrel in hip fractures. Our study aims to assess the perioperative blood loss and transfusion rates in geriatric patients with hip fractures on clopidogrel. We hypothesize that patients on clopidogrel will have higher perioperative blood loss and transfusion rates.
Materials and Methods
A retrospective, case control study chart review over a five year span was conducted. Of the 2,766 geriatric hip fracture patients surgically treated, 52 patients taking clopidogrel upon admission to the hospital were compared to patients not on the drug. All of the patients in the study were taken to the operating room within two calendar days of admission. statistical analysis was performed using Wilcoxon's, Fisher exact, chi square, and logistic regression methods.
A total of 110 patients were included in the analysis, 52 (47%) were taking clopidogrel at the time of admission. these patients were compared to 58 (53%) patients not on the drug. No significant difference was found with respect to documented perioperative blood loss. Transfusion rates however, did vary. Patients who had been taking clopidogrel, prior to admission and subsequent surgery, had a transfusion rate of 56% while those patients not on the drug had a transfusion rate of 31%. Logistic regression analysis showed taking clopidogrel up to admission was significantly associated (p = .0121) with receiving a blood transfusion following surgical treatment of a hip fracture.
A growing body of evidence supports early (within 48 hrs) surgery for elderly patients with hip fractures. the pharmacokinetics of clopidogrel do not allow for bleeding time to return to normal until the drug has been discontinued for five days. Our study shows that patients taking clopidogrel upon admission for hip fracture are at increased risk of blood transfusions when surgery is performed within two calendar days of admis-sion. this risk must be balanced by the potential benefits of early surgery.
PMCID: PMC3565422  PMID: 23576928
10.  Relationships among Smoking Habits, Airflow Limitations, and Metabolic Abnormalities in School Workers 
PLoS ONE  2013;8(11):e81145.
Chronic obstructive pulmonary disease is caused mainly by habitual smoking and is common among elderly individuals. It involves not only airflow limitation but also metabolic disorders, leading to increased cardiovascular morbidity and mortality.
We evaluated relationships among smoking habits, airflow limitation, and metabolic abnormalities.
Between 2001 and 2008, 15,324 school workers (9700 males, 5624 females; age: ≥30 years) underwent medical checkups, including blood tests and spirometry. They also responded to a questionnaire on smoking habits and medical history.
Airflow limitation was more prevalent in current smokers than in ex-smokers and never-smokers in men and women. The frequency of hypertriglyceridemia was higher in current smokers in all age groups, and those of low high-density-lipoprotein cholesterolemia and diabetes mellitus were higher in current smokers in age groups ≥ 40 s in men, but not in women. There were significant differences in the frequencies of metabolic abnormalities between subjects with airflow limitations and those without in women, but not in men. Smoking index was an independent factor associated with increased frequencies of hypertriglyceridemia (OR 1.015; 95% CI: 1.012–1.018; p<0.0001) and low high-density-lipoprotein cholesterolemia (1.013; 1.010–1.016; p<0.0001) in men. Length of smoking cessation was an independent factor associated with a decreased frequency of hypertriglyceridemia (0.984; 0.975–0.994; p = 0.007).
Habitual smoking causes high incidences of airflow limitation and metabolic abnormalities. Women, but not men, with airflow limitation had higher frequencies of metabolic abnormalities.
PMCID: PMC3843673  PMID: 24312268
11.  Impact of smoking on mortality and life expectancy in Japanese smokers: a prospective cohort study 
Objective To investigate the impact of smoking on overall mortality and life expectancy in a large Japanese population, including some who smoked throughout adult life.
Design The Life Span Study, a population-based prospective study, initiated in 1950.
Setting Hiroshima and Nagasaki, Japan.
Participants Smoking status for 27 311 men and 40 662 women was obtained during 1963-92. Mortality from one year after first ascertainment of smoking status until 1 January 2008 has been analysed.
Main outcome measures Mortality from all causes in current, former, and never smokers.
Results Smokers born in later decades tended to smoke more cigarettes per day than those born earlier, and to have started smoking at a younger age. Among those born during 1920-45 (median 1933) and who started smoking before age 20 years, men smoked on average 23 cigarettes/day, while women smoked 17 cigarettes/day, and, for those who continued smoking, overall mortality was more than doubled in both sexes (rate ratios versus never smokers: men 2.21 (95% confidence interval 1.97 to 2.48), women 2.61 (1.98 to 3.44)) and life expectancy was reduced by almost a decade (8 years for men, 10 years for women). Those who stopped smoking before age 35 avoided almost all of the excess risk among continuing smokers, while those who stopped smoking before age 45 avoided most of it.
Conclusions The lower smoking related hazards reported previously in Japan may have been due to earlier birth cohorts starting to smoke when older and smoking fewer cigarettes per day. In Japan, as elsewhere, those who start smoking in early adult life and continue smoking lose on average about a decade of life. Much of the risk can, however, be avoided by giving up smoking before age 35, and preferably well before age 35.
PMCID: PMC3481021  PMID: 23100333
12.  Prevalence rate of Metabolic Syndrome in a group of light and heavy smokers 
Smoking is an important cause of morbidity and mortality worldwide. It is widely accepted as a major risk factor for metabolic and cardiovascular disease. Smoking reduces insulin sensitivity or induces insulin resistance and enhances cardiovascular risk factors such as elevated plasma triglycerides, decreases high-density lipoprotein cholesterol and causes hyperglycemia. Several studies show that smoking is associated with metabolic abnormalities and increases the risk of Metabolic Syndrome. The aim of this study was to estimate the prevalence of the metabolic syndrome in a group of light and heavy smokers, wishing to give up smoking.
In this cross-sectional study all the enrolled subjects voluntary joined the smoking cessation program held by the Respiratory Pathophysiology Unit of San Matteo Hospital, Pavia, Northern Italy.
All the subjects enrolled were former smokers from at least 10 years and had no cancer or psychiatric disorders, nor history of diabetes or CVD or coronary artery disease and were not on any medication.
The subjects smoke 32.3 ± 16.5 mean Pack Years. The prevalence of the metabolic syndrome is 52.1%: 57.3% and 44.9% for males and females respectively. Analysing the smoking habit influence on the IDF criteria for the metabolic syndrome diagnosis we found that all the variables show an increasing trend from light to heavy smokers, except for HDL cholesterol. A statistical significant correlation among Pack Years and waist circumference (R = 0.48, p < 0.0001), Systolic Blood Pressure (R = 0.18, p < 0.05), fasting plasma glucose (R = 0.19, p < 0.005) and HDL cholesterol (R = −0.26, p = 0.0005) has been observed.
Currently smoking subjects are at high risk of developing the metabolic syndrome.
Therapeutic lifestyle changes, including smoking cessation are a desirable Public health goal and should successfully be implemented in clinical practice at any age.
PMCID: PMC3673853  PMID: 23721527
Metabolic syndrome; Smoking habit; Insulin resistance; Overweight; Waist circumference
13.  Cigarette Smoking and Prostate Cancer Recurrence After Prostatectomy 
Toward the establishment of evidence-based recommendations for the prevention of prostate cancer recurrence after treatment, we examined the association between smoking and prostate cancer recurrence in a retrospective cohort study of 1416 men who underwent radical prostatectomy. Surgeries were performed by a single surgeon at Johns Hopkins Hospital between January 1, 1993, and March 31, 2006. Smoking status at 5 years before and 1 year after surgery was assessed by survey. Prostate cancer recurrence was defined as confirmed re-elevation of prostate-specific antigen levels, local recurrence, metastasis, or prostate cancer death. The cumulative incidence of recurrence was 34.3% among current smokers, 14.8% among former smokers, and 12.1% among never smokers, with a mean follow-up time of 7.3 years. Men who were current smokers at 1 year after surgery were more likely than never smokers to have disease recurrence after adjusting for pathological characteristics, including stage and grade (hazard ratio for recurrence = 2.31, 95% confidence interval = 1.05 to 5.10). This result suggests an association between cigarette smoking and risk of prostate cancer recurrence.
PMCID: PMC3096800  PMID: 21498781
14.  Chronic illness and smoking cessation 
Nicotine & Tobacco Research  2009;11(8):933-939.
Smoking is among the leading causes of premature mortality and preventable death in the United States. Although smoking contributes to the probability of developing chronic illness, little is known about the relationship between quitting smoking and the presence of chronic illness. The present study investigated the association between diagnoses of one or more chronic diseases (diabetes, hypertension, or high cholesterol) and smoking status (former or current smoker).
The data analyzed were a subset of questions from a 155-item telephone-administered community survey that assessed smoking status, demographic characteristics, and presence of chronic disease. The study sample consisted of 3,802 randomly selected participants.
Participants with diabetes were more likely to report being former smokers, after adjusting for sociodemographic characteristics, whereas having hypertension or high cholesterol was not associated significantly with smoking status. The likelihood of being a former smoker did not increase as number of diagnosed chronic diseases increased. Participants who were women, older (aged 65+), or single were significantly less likely to be former smokers. Participants with at least a college degree, those with incomes of US$50,000+, and those who were underweight or obese were more likely to be former smokers.
These findings were inconsistent with research that has suggested that having a chronic illness or experiencing a serious medical event increases the odds of smoking cessation. Supporting prior research, we found that being male, having a higher income, and being obese were associated with greater likelihood of being a former smoker.
PMCID: PMC2734285  PMID: 19516050
15.  Cohort Life Tables By Smoking Status Removing Lung Cancer as a Cause of Death 
The purpose of this study was to develop life tables by smoking status removing lung cancer as a cause of death. These life tables are inputs to studies that compare the effectiveness of lung cancer treatments or interventions, and provide a way to quantify time until death from causes other than lung cancer. The study combined actuarial and statistical smoothing methods, as well as data from multiple sources, to develop separate life tables by smoking status, birth cohort, by single year of age, and by sex. For current smokers, separate life tables by smoking quintiles were developed based on the average number of cigarettes smoked per day by birth cohort. The end product is the creation of six non-lung cancer life tables for males and six tables for females: five current smoker quintiles and one for never smokers. Tables for former smokers are linear combinations of the appropriate table based on the current smoker quintile prior to quitting smoking and the never smoker probabilities, plus added covariates for the smoking quit age and time since quitting.
PMCID: PMC3594098  PMID: 22882890
Life Tables; Competing Risks; Lung Cancer and Smoking
16.  Smoking, quitting and mortality in an elderly cohort of 56 000 Hong Kong Chinese 
Tobacco Control  2007;16(3):182-189.
Although the harms of smoking are well established, it is unclear how they extend into old age in the Chinese.
To examine the relationship of smoking with all‐cause and major cause‐specific mortality in elderly Chinese men and women, respectively, in Hong Kong.
Mortality by smoking status was examined in a prospective cohort study of 56 167 (18 749 men, 37 416 women) Chinese aged ⩾65 years enrolled from 1998 to 2000 at all the 18 elderly health centres of the Hong Kong Government Department of Health.
After a mean follow‐up of 4.1 years, 1848 male and 2035 female deaths occured among 54 214 subjects (96.5% successful follow‐up). At baseline, more men than women were current smokers (20.3% vs 4.0%) and former smokers (40.8% vs 7.9%). The adjusted RRs (95% CI) for all‐cause mortality in former and current smokers, compared with never smokers, were 1.39 (1.23 to 1.56) and 1.75 (1.53 to 2.00) in men and 1.43 (1.25 to 1.64) and 1.38 (1.14 to 1.68) in women, respectively. For current smokers, the RRs (95% CI) for all‐cause mortality were 1.59 (1.39 to 1.82), 1.72 (1.48 to 2.00) and 1.84 (1.43 to 2.35) for daily consumption of 1–9, 10–20 and >21 cigarettes, respectively (p for trend <0.001). RRs (95% CI) were 1.49 (1.30 to 1.72) and 2.20 (1.88 to 2.57) in former and current smokers for all deaths from cancer, and 1.24 (1.04 to 1.47) and 1.57 (1.28 to 1.94) for all cardiovascular deaths, respectively. Quitters had significantly lower risks of death than current smokers from all causes, lung cancer, all cancers, stroke and all cardiovascular diseases.
In old age, smoking continues to be a major cause of death, and quitting is beneficial. Smoking cessation is urgently needed in rapidly ageing populations in the East.
PMCID: PMC2598507  PMID: 17565138
17.  Clinical evidence of interaction between clopidogrel and proton pump inhibitors 
World Journal of Cardiology  2011;3(5):153-164.
Clopidogrel is approved for reduction of atherothrombotic events in patients with cardiovascular (CV) and cerebrovascular disease. Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after acute coronary syndrome or percutaneous coronary intervention, compared with aspirin alone. Due to concern about gastrointestinal bleeding in patients who are receiving clopidogrel and aspirin therapy, current guidelines recommend combined use of a proton pump inhibitor (PPI) to decrease the risk of bleeding. Data from previous pharmacological studies have shown that PPIs, which are extensively metabolized by the cytochrome system, may decrease the ADP-induced platelet aggregation of clopidogrel. Results from retrospective cohort studies have shown a higher incidence of major CV events in patients receiving both clopidogrel and PPIs than in those without PPIs. However, other retrospective analyses of randomized clinical trials have not shown that the concomitant PPI administration is associated with increased CV events among clopidogrel users. These controversial results suggest that large specific studies are needed. This article reviews the metabolism of clopidogrel and PPIs, existing clinical data regarding the interaction between clopidogrel and PPIs, and tries to provide recommendations for health care professionals.
PMCID: PMC3110904  PMID: 21666816
Antiplatelet therapy; Aspirin; Clopidogrel; Proton pump inhibitor
18.  Antithrombotic strategies in patients undergoing percutaneous coronary intervention for acute coronary syndrome 
In patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS), both periprocedural acute myocardial infarction and bleeding complications have been shown to be associated with early and late mortality. Current standard antithrombotic therapy after coronary stent implantation consists of lifelong aspirin and clopidogrel for a variable period depending in part on the stent type. Despite its well-established efficacy in reducing cardiac-related death, myocardial infarction, and stroke, dual antiplatelet therapy with aspirin and clopidogrel is not without shortcomings. While clopidogrel may be of little beneficial effect if administered immediately prior to PCI and may even increase major bleeding risk if coronary artery bypass grafting is anticipated, early discontinuation of the drug may result in insufficient antiplatelet coverage with thrombotic complications. Optimal and rapid inhibition of platelet activity to suppress ischemic and thrombotic events while minimizing bleeding complications is an important therapeutic goal in the management of patients undergoing percutaneous coronary intervention. In this article we present an overview of the literature on clinical trials evaluating the different aspects of antithrombotic therapy in patients undergoing PCI and discuss the emerging role of these agents in the contemporary era of early invasive coronary intervention. Clinical trial acronyms and their full names are provided in Table 1.
PMCID: PMC2939764  PMID: 20856846
acute coronary syndrome; percutaneous coronary intervention; aspirin; clopidogrel; glycoprotein IIb/IIIa inhibitors; bivalirudin
19.  Cigarette tar yields in relation to mortality from lung cancer in the cancer prevention study II prospective cohort, 1982-8 
BMJ : British Medical Journal  2004;328(7431):72.
Objective To assess the risk of lung cancer in smokers of medium tar filter cigarettes compared with smokers of low tar and very low tar filter cigarettes.
Design Analysis of the association between the tar rating of the brand of cigarette smoked in 1982 and mortality from lung cancer over the next six years. Multivariate proportional hazards analyses used to assess hazard ratios, with adjustment for age at enrolment, race, educational level, marital status, blue collar employment, occupational exposure to asbestos, intake of vegetables, citrus fruits, and vitamins, and, in analyses of current and former smokers, for age when they started to smoke and number of cigarettes smoked per day.
Setting Cancer prevention study II (CPS-II).
Participants 364 239 men and 576 535 women, aged ≥ 30 years, who had either never smoked, were former smokers, or were currently smoking a specific brand of cigarette when they were enrolled in the cancer prevention study.
Main outcome measure Death from primary cancer of the lung among participants who had never smoked, former smokers, smokers of very low tar (≤ 7 mg tar/cigarette) filter, low tar (8-14 mg) filter, high tar (≥ 22 mg) non-filter brands and medium tar conventional filter brands (15-21 mg).
Results Irrespective of the tar level of their current brand, all current smokers had a far greater risk of lung cancer than people who had stopped smoking or had never smoked. Compared with smokers of medium tar (15-21 mg) filter cigarettes, risk was higher among men and women who smoked high tar (≥ 22 mg) non-filter brands (hazard ratio 1.44, 95% confidence interval 1.20 to 1.73, and 1.64, 1.26 to 2.15, respectively). There was no difference in risk among men who smoked brands rated as very low tar (1.17, 0.95 to 1.45) or low tar (1.02, 0.90 to 1.16) compared with those who smoked medium tar brands. The same was seen for women (0.98, 0.80 to 1.21, and 0.95, 0.82 to 1.11, respectively).
Conclusion The increase in lung cancer risk is similar in people who smoke medium tar cigarettes (15-21 mg), low tar cigarettes (8-14 mg), or very low tar cigarettes (≤ 7 mg). Men and women who smoke non-filtered cigarettes with tar ratings ≥ 22 mg have an even higher risk of lung cancer.
PMCID: PMC314045  PMID: 14715602
20.  Disparities in Health Care Utilization by Smoking Status – NHANES 1999–2004 
The objective of this study was to assess disparities in health care utilization, by smoking status, among adults in the United States. We used 1999–2004 National Health and Nutrition Examination Survey (NHANES) data from 15,332 adults. Multivariate logistic regressions were used to examine the relationship between smoking status (current, former, and never smoker), with health care utilization. After controlling for demographic characteristics, current smokers and former smokers who quit either <2 years or ≥10 years prior to the survey were more likely to have had inpatient admission in the past year than never smokers. Current smokers did not differ from never smokers on whether they had an outpatient visit in the past year. They were, however, more likely than never smokers to have ≥4 outpatient visits. Smokers who quit either <2 years ago or ≥10 years ago were more likely to have had an outpatient visit than never smokers. Former smokers were more likely than never smokers to have ≥4 outpatient visits regardless of when they quit. Our results show that cigarette smoking is associated with higher health care utilization for current and former smokers than for never smokers. Frequent hospitalization and outpatient visits translate into higher medical costs. Therefore, more efforts are needed to promote interventions that discourage smoking initiation and encourage cessation.
PMCID: PMC2672402  PMID: 19440435
Smoking; tobacco use; health care; cessation; utilization
21.  Temporal relationship between cigarette smoking and risk of Parkinson disease 
Neurology  2007;68(10):764-768.
To characterize further the relationship between smoking history and Parkinson disease (PD) risk by considering temporal and qualitative features of smoking exposure, including duration, average intensity, and recentness, as well as the relative importance of smoking during different periods of life.
We prospectively assessed incident PD from 1992 to 2001 among 79,977 women and 63,348 men participating in the Cancer Prevention Study II Nutrition Cohort, according to their cigarette smoking status and lifetime smoking histories.
During follow-up, 413 participants had definite or probable PD confirmed by their treating neurologists or medical record review. Compared with never smokers, former smokers had a relative risk (RR) of 0.78 (95% CI 0.64 to 0.95) and current smokers had an RR of 0.27 (95% CI 0.13 to 0.56). On average, participants with more years smoked, more cigarettes per day, older age at quitting smoking, and fewer years since quitting smoking had lower PD risk. The relative risks and trends did not vary significantly by sex. The cumulative incidence of PD was lowest among participants who quit smoking at later ages. A 30% to 60% decreased risk of PD was apparent for smoking as early as 15 to 24 years before symptom onset, but not for smoking 25 or more years before onset.
The lower risk of Parkinson disease among current and former smokers varied with smoking duration, intensity, and recentness. The dependence of this association on the timing of smoking during life is consistent with a biologic effect.
PMCID: PMC2225169  PMID: 17339584
22.  Smoking and Smoking Cessation in Relation to Mortality 
Smoking causes death in many ways, but the rate of risk reduction after quitting, compared to continuing to smoke, is uncertain. There is inadequate or insufficient evidence to infer the presence or absence of a causal relationship between smoking and ovarian cancer and colorectal cancer.
To assess the relation between cigarette smoking and smoking cessation on total and cause-specific mortality in women.
Design, Setting, and Participants
Prospective observational study of 104,519 female participants in the Nurses’ Health Study followed from 1980 to 2004.
Main Outcome Measure
Hazard ratios for total mortality, further categorized into vascular and respiratory diseases, cancers and other causes.
A total of 12483 deaths occurred in this cohort, 4485 (35.9%) among never smokers, 3602 (28.9%) among current smokers, and 4396 (35.2%) among past smokers. Compared to never smokers, current smokers had an increased risk of total mortality (hazard ratio = 2.81, 95% confidence interval (CI) = 2.68–2.95) and all major cause-specific mortality evaluated. The hazard ratio for cancers classified by the 2004 Surgeon General’s report to be smoking-related was 7.25 (CI:6.43–8.18) and for other cancers, 1.58 (CI:1.45–1.73). The hazard ratio for colorectal cancer was 1.63 (CI:1.29–2.05) for current smokers and 1.23 (CI:1.02–1.49) for former smokers, compared to never smokers. A significant association was not observed for ovarian cancer. Significant trends were observed for earlier age at initiation for total mortality (P=0.003), respiratory disease mortality (P=0.001), and all smoking-caused cancer mortality (P=0.001). The excess risk for all-cause mortality decreases to the level of a never smoker 20 years after quitting, with different timeframes for risk reduction observed across outcomes. Approximately 64% of deaths among current smokers and 28% of deaths among former smokers were attributable to cigarette smoking.
Most of the excess risk of vascular mortality due to smoking can be eliminated rapidly upon cessation and within 20 years for lung diseases. Postponing the age of smoking initiation has a dramatic impact on risk of respiratory disease, lung cancer, and other smoking-caused cancer deaths and little effect on other cause-specific mortality. These data suggest that smoking increases the risk of colorectal cancer mortality but not ovarian cancer mortality.
PMCID: PMC2879642  PMID: 18460664
23.  Clopidogrel 
Canadian Family Physician  2000;46:1070-1079.
Clopidogrel (Plavix ®), an antiplatelet drug chemically similar to ticlopidine, is marketed for secondary prevention of thrombotic complications in patients with a history of myocardial infarction (MI), ischemic stroke, or peripheral arterial disease.
Marketing authorization was based mainly on the CAPRIE trial, a study that involved 19 185 patients. In this trial of secondary cardiovascular prevention, clopidogrel was slightly more effective than acetylsalicylic acid (ASA) (325 mg/d) according to statistical analysis of a combined end point (ischemic stroke or MI or death of vascular causes). The difference was more marked in the subgroup of patients with obstructive arterial disease of the lower limbs.
Clopidogrel was well tolerated in this trial. The only adverse effects more frequent with clopidogrel than with ASA were rash and diarrhea.
Clopidogrel showed no hematologic toxicity, an adverse effect that restricts use of ticlopidine.
Lack of long-term follow up in real clinical settings prevents meaningful estimation of the safety profile or of risk of drug interactions.
PMCID: PMC2144869
24.  Environmental tobacco smoke and mortality in Chinese women who have never smoked: prospective cohort study 
BMJ : British Medical Journal  2006;333(7564):376.
Objective To evaluate the association of environmental exposure to tobacco smoke from husbands and from work, as well as from family members in early life, with all cause mortality and mortality due to cancer or cardiovascular disease in Chinese women.
Design Ongoing prospective cohort study in Shanghai, China.
Participants Of 72 829 women who had never smoked, 65 180 women provided information on smoking by their husbands, and 66 520 women provided information on exposure to tobacco smoke at work and in early life from family members.
Main outcome measures All cause mortality and cause specific mortality with the main focus on cancer and cardiovascular disease. Cumulative mortality according to exposure status, and hazard ratios.
Results Exposure to tobacco smoke from husbands (mainly current exposure) was significantly associated with increased all cause mortality (hazard ratio 1.15, 95% confidence interval 1.01 to 1.31) and with increased mortality due to cardiovascular disease (1.37, 1.06 to 1.78). Exposure to tobacco smoke at work was associated with increased mortality due to cancer (1.19, 0.94 to 1.50), especially lung cancer (1.79, 1.09 to 2.93). Exposure in early life was associated with increased mortality due to cardiovascular disease (1.26, 0.94 to 1.69).
Conclusions In Chinese women, exposure to environmental tobacco smoke is related to moderately increased risk of all cause mortality and mortality due to lung cancer and cardiovascular disease.
PMCID: PMC1550443  PMID: 16837487
25.  Obesity and Smoking: Comparing Cessation Treatment Seekers with the General Smoking Population 
Obesity (Silver Spring, Md.)  2009;17(6):1301-1305.
Obesity and smoking represent the leading preventable causes of morbidity and mortality in the United States. This study compared the prevalence of obesity among smokers seeking cessation treatment (n = 1428) versus a general population (n = 4081) of never smokers, former smoker, and current smokers. Data from treatment-seeking smokers in the Wisconsin Smokers’ Health Study (WSHS) and individuals who completed the National Health and Nutrition Examination Survey (NHANES) 2005-06 were pooled and obesity rates and other health characteristics were compared. The prevalence of obesity was significantly higher among WSHS treatment-seeking smokers (36.8%) versus NHANES current smokers (29.6%), but the obesity rates of WSHS treatment-seeking smokers did not differ from NHANES former smokers (36.5%) or never smokers (36.5%). Treatment-seeking smokers were more likely to be female and to have higher educational attainment compared to NHANES participants. Analysis of health characteristics revealed treatment-seeking smokers had higher levels of dietary fiber and vitamin C and lower blood levels of total cholesterol, triglycerides, and fasting glucose compared to NHANES current smokers. Results suggest that treatment-seeking smokers may have a different health profile than current smokers in the general population. Health care providers should be aware of underlying heath issues, particularly obesity, in patients seeking smoking cessation treatment.
PMCID: PMC2918403  PMID: 19247276

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