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Increased risk of coronary heart disease among women
smokers compared with men
 
 
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"Thus, after allowing for classic cardiovascular risk factors, women had a significant 25% increased risk for coronary heart disease conferred by cigarette smoking compared with men. However, the precise mechanisms for this difference is unclear. Clinically, physicians and health professionals should be encouraged to increase their efforts at promotion of smoking cessation in all individuals. Present trends in female smoking, and this report, suggest that inclusion of a female perspective in tobacco-control policies is crucial."

August 11, 2011 | Michael O'Riordan

Minneapolis, MN - A large meta-analysis suggests that the harmful effects of tobacco smoking affect men and women differently [1]. In a study of more than two million people, researchers showed that the pooled adjusted female-to-male relative risk of coronary heart disease in smokers vs nonsmokers is 25% higher in women.

"It's an unusually large study," lead investigator Dr Rachel Huxley (University of Minnesota, Minneapolis) told heartwire. "In the main analysis, there are about 2.4 million people with data on 44 000 coronary heart disease events, and what was very nice about the study is that the results were very consistent across all of the studies. There was no heterogeneity between them, adding to the robustness of the findings. We're pretty confident that the estimate we came up with is a real approximation of the true risk."

If anything, said Huxley, the 25% increased risk might be on the conservative side. Women have not been smoking as long as men, so the true impact of smoking on women's health might not yet have manifested entirely, and women don't smoke as many cigarettes as men when they do smoke. In addition, it's still taboo for women to smoke in many cultures, and as a result women might underreport their smoking habits. "All three factors combined would suggest that the 25% is an underestimate," said Huxley.

The results of the study are published online August 11, 2011 in the Lancet.

Females still a growth market for tobacco companies

In the analysis, the researchers performed a systematic review and meta-analysis of prospective cohort studies published between 1966 and 2010. Studies that stratified by sex with measures of relative risk for coronary heart disease and current smoking compared with not smoking were included in the analysis.

As we all know, prevention is far better and far easier than trying to cure somebody of a habit.

In the 75 cohorts, which included 2.4 million participants, the pooled adjusted female-to-male relative risk ratios of smoking compared with not smoking for coronary heart disease was 1.25 (95% CI 1.12-1.39, p<0.0001). The relative risk ratio increased by 2% for every additional year of study follow-up, a finding that suggests the longer a woman smokes, the greater her risk of developing coronary heart disease compared with a man who has smoked the same length of time.

"If you looked at some countries, such as Asian-Pacific countries, this is still a growth market for tobacco companies, because the prevalence of smoking in women is still in the single digits," said Huxley. "For example, in China, about 60% of men smoke, whereas just 4% to 9% of women smoke. Tobacco-control programs really need to develop a female perspective to dissuade women from starting to smoke in the first place, because women often find it more difficult to quit smoking compared with men."

In an editorial accompanying the published study [2], Drs Matthew Steliga and Carolyn Dresler (University of Arkansas Medical Sciences, Little Rock) point out that coronary heart disease is predicted to remain the leading cause of death globally and is expected to cause approximately 14% of deaths annually by 2030. Most of coronary heart disease is attributable to lifestyle-related factors, including smoking.

"Thus, a large proportion of the most common cause of death worldwide is attributable to behavior or addiction," they write. "Although some people might view this statistic as discouraging, it can also be seen as a great opportunity to reduce the burden of disease through behavior modification and smoking-cessation programs."

The editorialists note that national and international organizations such as the International Network of Women Against Tobacco and the World Health Organization Tobacco Free Initiative are important reference organizations that can help promote more effective tobacco cessation in women.

To heartwire, Huxley said that an understanding of sex differences in smoking-cessation initiatives has not been fully explored. However, researchers are aware there are differences in smoking-related behavior between men and women. Men, for example, start smoking at a younger age, smoke more cigarettes than women, and always have a higher smoking prevalence across different age groups, the lone exception being adolescent and teenage girls.

"That's a particular concern, because more young girls will start to smoke than young boys, so we really do need to develop effective campaigns that can dissuade young girls from starting in the first place," said Huxley. "As we all know, prevention is far better and far easier than trying to cure somebody of a habit."

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The Lancet, Early Online Publication, 11 August 2011

Cigarette smoking as a risk factor for coronary heart disease in women compared with men: a systematic review and meta-analysis of prospective cohort studies

Summary

Background


Prevalence of smoking is increasing in women in some populations and is a risk factor for coronary heart disease. Whether smoking confers the same excess risk of coronary heart disease for women as it does for men is unknown. Therefore, we aimed to estimate the effect of smoking on coronary heart disease in women compared with men after accounting for sex differences in other major risk factors.

Methods

We undertook a systematic review and meta-analysis of prospective cohort studies published between Jan 1, 1966, and Dec 31, 2010, from four online databases. We selected cohort studies that were stratified by sex with measures of relative risk (RR), and associated variability, for coronary heart disease and current smoking compared with not smoking. We pooled data with a random effects model with inverse variance weighting, and estimated RR ratios (RRRs) between men and women.

Findings

We reviewed 8005 abstracts and included 26 articles with data for 3 912 809 individuals and 67 075 coronary heart disease events from 86 prospective trials. In 75 cohorts (2·4 million participants) that adjusted for cardiovascular risk factors other than coronary heart disease, the pooled adjusted female-to-male RRR of smoking compared with not smoking for coronary heart disease was 1·25 (95% CI 1·12-1·39, p<0·0001). This outcome was unchanged after adjustment for potential publication bias and there was no evidence of important between-study heterogeneity (p=0·21). The RRR increased by 2% for every additional year of study follow-up (p=0·03). In pooled data from 53 studies, there was no evidence of a sex difference in the RR between participants who had previously smoked compared with those who never had (RRR 0·96, 95% CI 0·86-1·08, p=0·53).

Interpretation

Whether mechanisms underlying the sex difference in risk of coronary heart disease are biological or related to differences in smoking behaviour between men and women is unclear. Tobacco-control programmes should consider women, particularly in those countries where smoking among young women is increasing in prevalence.

Introduction

Worldwide, there are 1·1 billion smokers, of whom a fifth are women.1 Every year, more than 5 million deaths occur that are directly attributed to tobacco, with 1·5 million of these deaths occurring in women.2 These figures are projected to increase to 8 million female smokers and 2·5 million deaths in women by 2030 if present patterns of smoking persist.2 However, these estimates are based on two assumptions: first, that the male-to-female smoking ratio persists, which is an unlikely scenario because of the reported increased uptake of smoking in young women compared with young men in some countries;3, 4 and second, that smoking affects men and women equally, which might not be true for all diseases. For example, women who smoke have a significantly greater relative risk (RR) of lung cancer than do male smokers,5-8 and there is some debate about whether this sex difference is also true for smoking and coronary heart disease.9

In 1998, Prescott and colleagues9 reported that women who smoked had a 50% greater coronary risk than did their male counterparts, leading them to conclude that "women may be more sensitive than men to some of the harmful effects of smoking". Estimates of the sex-specific associations between smoking and subsequent coronary heart disease from large prospective studies such as the Nurses Health Studies (all women),10 and the British Doctors Study (separate studies for men11 and women12) vary, possibly because of differences in study design, classification of smoking status, and amount of adjustment for confounders. Therefore, whether any reported sex difference between these studies is real or an artifact of methodological differences cannot be established. Direct comparisons of the relation between smoking and coronary heart disease in men and women can be made through internal, within-study comparisons in studies with male and female participants, thereby reducing the role of extraneous, between-study factors. The largest meta-analysis to date to do this comparison is the Asia Pacific Cohort Studies Collaboration (APCSC),13 which reported evidence of a sex difference in the effect of smoking on risk of coronary heart disease (smoking was more hazardous in women than it was in men) but only for the heaviest smokers. However, this study was restricted in geographical scope, and thus did not take account of all the available data, and did not directly estimate the relative effects of smoking between the sexes.

To establish whether women who smoke are at greater risk of coronary heart disease than are men who smoke, irrespective of smoking intensity and independent of other risk factors, we undertook a meta-analysis of prospective cohort studies (including APCSC) that reported sex-specific effects of smoking on subsequent risk of coronary heart disease.

Discussion

Cigarette smoking is one of the main causes of coronary heart disease worldwide and will remain so as populations that have so far been relatively unscathed by the smoking epidemic begin to smoke to a degree previously noted only in high-income countries. This expectation is especially true for young women in whom the popularity of smoking, particularly in some low-income and middle-income countries, might be on the rise.3, 4 The effects of this rise are particularly concerning as evidence from our review of data from more than 2·4 million people and more than 44 000 coronary heart disease events suggests that, compared with non-smokers, women who smoke have a 25% greater RR of coronary heart disease than do male smokers, independent of other cardiovascular risk factors.

Furthermore, our primary analysis might have underestimated the true RR difference between the sexes for several reasons. First, compared with men, smoking is relatively infrequent in women in some regions of the world, especially in regions of Asia where the prevalence of smoking in women is typically less than 10%.48 As the health effects of smoking in a population only become fully apparent about 50 years after a substantial proportion of young adults have adopted the habit, it will be some years before the full effect of smoking on coronary heart disease risk is known in women. Nonetheless, most of the studies we identified reported higher, not lower, RRs of coronary heart disease in female smokers than in male smokers.

Second, the number of cigarettes smoked per day and the percentage of heavy smokers is generally higher in men than it is in women. For example, data from the US 2004 National Health Interview Survey49 reported that the mean consumption of cigarettes per day was 18·1 for men and 15·3 for women. In APCSC, women in Asia and Australia and New Zealand smoked fewer cigarettes than did their male equivalents (10 vs 15 cigarettes per day in Asia and 16 vs 18 cigarettes per day in Australia and New Zealand).13 Consequently, if the risks were equivalent then male smokers should have a greater RR of coronary heart disease than should female smokers, which is contrary to the findings of our analysis.

Finally, previous studies have reported striking discrepancies, especially in women from some ethnic groups, between self-reported smoking habits and serum cotinine concentrations-a specific biomarker of nicotine absorption-suggesting that more women than men underreport their smoking habit.50 Underreporting of smoking status would have resulted in misclassification of some current smokers as non-smokers (more so in women than in men), resulting in an attenuation of the magnitude of the relationship between smoking and coronary heart disease, particularly in women, and further underestimating the RR difference between male and female smokers.

Duration of smoking is an important determinant of smoking-related coronary heart disease risk, and might thus have an effect on the sex ratio of RRs. Although direct examination of the effect of duration of smoking was not possible in this meta-analysis, the length of study follow-up was used as a proxy measure. The finding that, among smokers, the excess risk of coronary heart disease in women compared with men increases by 2% for every extra year of study follow-up lends support to the idea of a pathophysiological basis for the sex difference. For example, women might extract a greater quantity of carcinogens and other toxic agents from the same number of cigarettes than men.51 This occurrence could explain why women who smoke have double the risk of lung cancer compared with their male counterparts.6 Excess risk of coronary heart disease in female smokers might be an artifact of the data due to competing risks: men who smoke might die from some other smoking-related disease such as lung cancer before they have the chance to develop coronary heart disease. This effect could be especially relevant to Asian cohorts, in which men have been smoking for much longer and at a higher intensity than have women. However, in several cohorts from the USA and high-income countries in Europe where the maturity of the smoking epidemic is comparable in men and women, the sex-risk differential was still apparent. Therefore, the underlying mechanisms by which smoking might be more hazardous in female smokers are unclear.

Previous studies suggested that disease associations with risk factors are strongest in the youngest age groups. For example, the International Studies of Infarct Survival reported that at 30-49 years of age the rates of myocardial infarction in smokers were about five times those in non-smokers whereas at ages 50-59 years they were only three times those in non-smokers.52 To examine whether this finding would extend to age-specific differences in sex RRR we examined this issue among the three cohorts with age-specific data available across common age ranges. However, our analysis did not provide clear evidence of either systematic strengthening or attenuation of the sex ratio with age.

The main strengths of this meta-analysis were its size and diversity of study populations. The consistency in study findings, combined with no evidence of important publication bias, supports the robustness of the study findings. There are, however, some limitations of this meta-analysis, in addition to the lack of standardisation for dose and duration of smoking. We were unable to adjust for the use of oral contraceptives, which are associated with substantially increased risk of coronary heart disease in women who smoke. Rates of use of oral contraceptives vary considerably by country, and tend to be much higher in high-income countries than they are in low-income and middle-income countries in Asia.53 Hence, given the low use of oral contraceptives in Asian women, their use is unlikely to explain the higher coronary heart disease risks noted in female smokers than in male smokers from the Asian cohorts we analysed. Furthermore, use of oral contraceptives in women who smoke has also been reported to be significantly lower than it is in non-smoking women (26·9% vs 34·6%),54 suggesting that their use is unlikely to have been a major source of confounding.

A further limitation of our findings was the inconsistency between studies in how non-smokers were defined. Some studies defined non-smokers as people who had never smoked whereas others defined them as not-current smokers (implying that at some point they had smoked but had quit). However, the results from our sensitivity analysis suggested that the results did not differ significantly depending on how non-smokers were classified. Furthermore, any error in interpretation of our primary analysis will be to underestimate the true excess risk incurred by smoking in women (because the RRR was reduced in those studies with non-smoking as the reference). Another limitation was the lack of individual participant data, which precluded the undertaking of more in-depth sensitivity analyses than were reported here. Instead, we used between-study meta-regressions, when possible.

Thus, after allowing for classic cardiovascular risk factors, women had a significant 25% increased risk for coronary heart disease conferred by cigarette smoking compared with men. However, the precise mechanisms for this difference is unclear. Clinically, physicians and health professionals should be encouraged to increase their efforts at promotion of smoking cessation in all individuals. Present trends in female smoking, and this report, suggest that inclusion of a female perspective in tobacco-control policies is crucial.

Results

We identified 8005 articles, of which 56 (1%) included data for the association between smoking and coronary heart disease. 30 (54%) of these 56 studies were excluded, mainly because they did not provide sex-stratified estimates of RR (figure 1). 26 articles with information from 86 cohort studies were eligible for inclusion.13,15,16,22-44 Two of these articles contained information about 60 cohort studies; 21 cohorts contributed to one publication from the Diverse Populations Collaboration25 (webappendix p 1) and 39 cohorts contributed to one publication from the Asia Pacific Cohort Studies Collaboration (webappendix p 2).13 One article included data from three cohorts.29 Additional data from the CPS-I study16 were sourced from tabulated data that were available online,17 whereas age-adjusted16 and multiple-adjusted24 RRs from CPS-II were sourced from separate articles. Three other articles with information for the secondary analysis were identified from our searching of citations.45-47

Overall, data for 3 912 809 individuals were available for the primary analysis, in whom there were at least 67 075 fatal and non-fatal coronary heart disease events (three of the included studies of 28 106 individuals did not report the number of coronary heart disease events and therefore the actual number of events was unable to be precisely determined (table and webappendix p 1). Mean duration of follow-up varied from 5 years to 40 years. 39 cohorts were from Asia (24% of individuals), 22 from the USA (65%), 16 from Europe (8%), and nine from Australia, New Zealand, and the Pacific islands (3%). The two American Cancer Society studies16, 24 had 57% of all individuals and 42% of all coronary heart disease events.

21 papers reported the sex-specific prevalence of smoking, which varied substantially by study and sex. The prevalence of smoking was 2-71% in men and 1-44% in women. In all but two studies,15, 42 the prevalence of smoking was higher in men than it was in women, particularly in Asia, where typically less than 10% of women were smokers compared with more than 50% of men. Smoking cessation was also higher in men (10-40%) than it was in women (2-21%; table).

13 articles with data for 54 cohort studies for 3 349 001 (86%) individuals and at least 43 606 (63%) events (three studies25, 35, 42 did not report the number of coronary heart disease events) reported age-adjusted RR estimates for fatal and non-fatal coronary heart disease associated with smoking (webappendix p 5). The age-adjusted pooled RRR (female to male) was 1·11 (95% CI 0·99-1·26, p=0·06; webappendix p 6). There was significant heterogeneity between the studies (I2=68·0%, p<0·0001). Visual inspection of the funnel plot (webappendix p 7) suggests that there was some publication bias, adjustment for which had marginal effect on the age-adjusted estimate (RRR 1·10, 95% CI 0·99-1·24, p=0·08).

17 reports with information from 75 cohort studies with data for 2 409 955 (62%) individuals and 43 995 (66%) coronary heart disease events reported estimates of the association of fatal and non-fatal coronary heart disease with smoking after adjustment for other cardiovascular risk factors (webappendix p 8). The amount of adjustment between studies varied but the variables that were most frequently included were total cholesterol, diabetes, systolic blood pressure, and body-mass index. The multiple-adjusted pooled RRR (female to male) of smoking versus non-smoking was 1·25 (95% CI 1·12-1·39, p<0·0001; figure 2) with no evidence of between-study heterogeneity (I2 20·0%, p=0·21). There was no evidence of publication bias (webappendix p 9), correction for which left the RRR and its 95% CI unchanged. There was no evidence that the results differed significantly (p=0·20) according to whether the non-smoking reference group was defined as never smokers (RRR 1·31, 95% CI 1·15-1·50) or not smokers (1·08, 0·91-1·28). After exclusion of the four studies33, 40, 41, 43 that included non-fatal coronary heart disease events (7307 [10·9%] events), the pooled multiple-adjusted RRR for fatal coronary heart disease was 1·19 (1·06-1·34, p=0·004).

The pooled RRR (female to male) increased by 2% for every extra year of study follow-up (RRR 1·02, 95% CI 1·002-1·03, p=0·03; webappendix p 10). There was no evidence of any difference in the RRR according to the percentage of female smokers (p=0·49) or the ratio of female-to-male smokers in the cohorts (p=0·42). Neither was there evidence that the association differed by region (p=0·63); the multiple adjusted RRR (female to male) for studies undertaken in the Asia-Pacific region was 1·41 (95% CI 0·89-2·23) compared with 1·25 (1·12-1·39) for those undertaken in Europe and North America.

We examined the association between smoking and coronary heart disease in current smokers versus non-smokers across consecutive age-groups from 30 years to 80 years or older with data from CPS-II,24 and new analyses from APCSC13 and the SHHEC15 cohorts. We obtained data for 16 327 coronary heart disease events (24·3% of the total number of events). In all age groups with the exception of the youngest (30-44 years), the effect of smoking on risk of coronary heart disease was greater in women than it was in men although the difference was only significant for the group aged 60-69 years. There was no clear evidence that the sex differential was either attenuated or strengthened with increasing age (webappendix p 11).

13 articles with data from 53 cohort studies reported the risk of coronary heart disease in former smokers compared with never smokers (webappendix pp 3 and 12). In eight studies, the RRR were below unity (suggesting an increased beneficial effect of smoking cessation in men compared with women), whereas in the remaining seven studies the reverse pattern was reported. There was no statistical evidence that the beneficial effects of quitting smoking on subsequent risk of coronary heart disease differed between men and women (RRR 0·96, 95% CI 0·86-1·08, p=0·53 [I2=28·1%, p=0·15]; figure 3). Adjustment for publication bias did not change outcomes (0·95, 0·84-1·07, p=0·41; webappendix p 13).

 
 
 
 
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