Environmental tobacco smoke exposure and ischaemic heart disease: an evaluation of the evidence

Risk in non-smokers who live with smokers

Figure 1 shows the results of the 19 studies as the risk of ischaemic heart disease in never smokers whose spouses currently smoked relative to the risk in those whose spouses had never smoked (detail of design of the studies has been summarised previously1 2).18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 There were 6600 ischaemic heart disease events in total. There was no significant heterogeneity (²25=26), and figure 1 shows that the estimates from the individual studies are consistent with each other. The summary estimate of relative risk was 1.30 (95% confidence interval 1.22 to1.38; P<0.001), similar to the estimates from earlier meta-analyses with fewer studies.1 2 3 4 5 Summary estimates were similar in women and men in cohort studies (in which almost all ischaemic heart disease events were deaths) and case-control studies (in which most events were non-fatal infarcts) and with or without inclusion of three unpublished studies.

Fig 1

Relative risk estimates (with 95% confidence intervals), adjusted for age and sex, from nine prospective studies (solid circles) and 10 case-control studies (open circles) comparing ischaemic heart disease in lifelong non-smokers whose spouse currently smoked with those whose spouse had never smoked (16 published studies (from left to right18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33) and three with results cited by others from abstracts or theses2 34)

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It has been proposed that publication bias accounts for the association.36 The number of unpublished studies would need to be implausibly large. As a simple approximation, eight of the 19 individual studies (fig 1) were significantly positive (a probability for each of less than 1 in 40 if there were no association). The total number of studies needed to generate these by chance would be more than 320 (8 × 40), of which only 19 were published. Exclusion from the analysis of all studies recording fewer than 100 events (as selective publication is more likely to affect small studies) made no difference to the relative risk estimate.

Risk of smoking one cigarette per day

Figure 2 shows the dose-response relation in each of the five studies of smoking and ischaemic heart disease (age standardised to age 65). The risk of ischaemic heart disease increases continuously with daily cigarette consumption, but in all five studies linear extrapolation of the regression line back to zero dose (no cigarettes per day) does not yield the expected relative risk estimate of 1.0. The estimates from the five individual studies of the risk at low dose are consistent with each other, and the weighted average relative risk at one cigarette per day (defining risk in non-smokers as 1.0) was 1.39 (1.18 to 1.64; P<0.001). At 20 cigarettes per day this risk was 1.78.

Fig 2

Estimates (with 95% confidence limits) from five studies6 7 8 9 10 11 12 of the risk of ischaemic heart disease in current cigarette smokers according to number of cigarettes smoked relative to never smokers (age standardised to age 65). Scale on the horizontal axis is linear with respect not to the number of cigarettes smoked but to the corresponding concentrations of biochemical markers38

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Table 1 shows the relative risk of ischaemic heart disease associated with smoking one cigarette per day according to age, from the five cohort studies. The estimates decline with increasing age at death (P<0.001). The average age of ischaemic heart disease events in the studies of exposure to environmental tobacco smoke was about 65 years and the estimate of 1.39 is close to the estimate of 1.30 from these studies. With a linear dose-response relation the expected excess risk from smoking one cigarette per day is 4% (1/20th the excess risk of 78% from smoking 20 cigarettes per day); with environmental exposure it is 0.8% (1% of 78%). A high risk at low dose is therefore seen in the studies of smoking (39% excess risk v 4% expected) and in studies of environmental exposure (30% v 0.8%).

Direct estimate

The diet of smokers and of non-smokers who live with them differs from that of non-smokers who live with non-smokers. This dietary difference, rather than the exposure itself, may account for the high risk of ischaemic heart disease.39 40 The most pronounced difference is a lower consumption of fruit and vegetables,45 49 51 53 56 57 which contain nutrients that may protect against ischaemic heart disease, including folic acid,70 potassium, and linoleic acid.41 These were not measured as potential confounding factors in studies of passive smoking and ischaemic heart disease. Fruit, vegetables, carotenes, vitamin C, and vitamin E are highly correlated with each other, and the regression analyses for each nutrient were not adjusted for these correlations, so each nutrient will serve as a marker for the risk of ischaemic heart disease associated with fruit and vegetable consumption in general, even though carotene and vitamin E do not themselves reduce mortality from ischaemic heart disease.41 71 72 Table 2 shows summary estimates from cohort studies of the relative risk of ischaemic heart disease associated with a difference of 1 SD in consumption of all fruit, all vegetables, carotenes, vitamin C, and vitamin E as markers of fruit and vegetable consumption.

Almost all studies showed a lower consumption of these nutrients in active smokers than non-smokers, but the differences were heterogeneous across studies (which is not surprising since fruit and vegetable consumption varies in different communities and different seasons, so the difference between smokers and non-smokers is likely to vary). Table 2 shows, from all studies reporting on each nutrient, the median difference and the largest difference. The estimates of the excess risk of ischaemic heart disease corresponding to the median estimates of the dietary difference in no case exceed 3% (suggesting that diet explains only a 3% excess risk of ischaemic heart disease in smokers); the largest estimates (based on the largest estimate of the dietary difference from any study and the upper confidence limits of the estimates of the association between the nutrients and ischaemic heart disease) do not exceed 9%.

The difference between smokers and non-smokers in plasma low density lipoprotein cholesterol is small—an estimated 0.07 mmol/l,73 corresponding to an excess risk of ischaemic heart disease (at age 65) of about 3%.74 The overall excess risk of ischaemic heart disease attributable to dietary differences in smokers (fruit and vegetables and serum cholesterol) is thus about 6%. Blood pressure is no greater in smokers than non-smokers (and body mass index is less); these and other risk factors for ischaemic heart disease have a negligible effect on the relation between smoking and ischaemic heart disease.75

For exposure to environmental tobacco smoke the median difference in fruit and vegetable consumption between non-smokers who do and do not live with smokers, based on all available studies (2-3 for each marker), was 0.10 SD for fruit,53 57 0.06 for vegetables,53 57 0.26 for carotenes,53 58 59 and 0.18 for vitamin C.53 55 58 These are generally smaller than the median estimates for smokers (table 2). The corresponding estimates of the excess risk of ischaemic heart disease are 1-2%.

The differences in serum cholesterol,19 21 22 25 blood pressure,19 21 25 and body mass index19 21 25 58 59 in never smokers according to whether or not the spouse smoked were imperceptible (as expected since the differences between active smokers and non-smokers are so small). Combining the differences showed no significant difference, with upper confidence limits inconsistent with a serum cholesterol more than 2% higher, blood pressure more than 4% higher, and body mass index more than 6% higher. Estimates of the relative risk of ischaemic heart disease unadjusted and adjusted for blood pressure, serum cholesterol, body mass index, and a measure of social class (published in six epidemiological studies21 22 23 25 27 32) were similar: the weighted average of the adjusted estimates, 1.57 (1.00 to 2.13), was no lower than that of the unadjusted estimates, 1.47 (1.00 to 2.19).

Indirect estimate

Three of the five smoking cohort studies cited above followed the men for 20 or more years. Almost all the excess risk reversed (table 3); the residual excess risk was 6% (2% to 10%). This sets an upper limit to any effect of confounding that is similar to our direct estimate of confounding.

People who gave up smoking in recent years also changed their diet.43 44 We based our analysis on older studies, in which the former smokers would have given up before 1955, when dietary change was not widely advocated on health grounds (indeed, consumption of saturated fat increased in the United States between 1945 and 195576). Significant dietary change in these studies is unlikely but even the recent data on dietary change after stopping smoking43 44 would increase the estimate of 6% to no more than 12%, similar to the direct estimate of the largest effect.

Size of the causal association

Confounding due to dietary differences accounts for a relative risk estimated as 1.06 in smokers. Of the overall relative risk of ischaemic heart disease associated with environmental exposure to tobacco smoke of 1.30, the estimated relative risk for the causal relation is therefore 1.23 (1.30/1.06). It will in fact be a little higher since dietary confounding is less than in smokers. Even when based on the largest estimate of confounding in smokers it is 1.16 (1.30/1.12). For smoking one cigarette per day the overall relative risk is 1.39 and the estimate of the causal relation is 1.31 (1.39/1.06). Table 4 summarises the estimates.

People who gave up smoking in recent years also changed their diet.43 44 We based our analysis on older studies, in which the former smokers would have given up before 1955, when dietary change was not widely advocated on health grounds (indeed, consumption of saturated fat increased in the United States between 1945 and 195576). Significant dietary change in these studies is unlikely but even the recent data on dietary change after stopping smoking43 44 would increase the estimate of 6% to no more than 12%, similar to the direct estimate of the largest effect.

Size of the causal association

Confounding due to dietary differences accounts for a relative risk estimated as 1.06 in smokers. Of the overall relative risk of ischaemic heart disease associated with environmental exposure to tobacco smoke of 1.30, the estimated relative risk for the causal relation is therefore 1.23 (1.30/1.06). It will in fact be a little higher since dietary confounding is less than in smokers. Even when based on the largest estimate of confounding in smokers it is 1.16 (1.30/1.12). For smoking one cigarette per day the overall relative risk is 1.39 and the estimate of the causal relation is 1.31 (1.39/1.06). Table 4 summarises the estimates.

Mechanism of effect: platelet aggregation

Figure 3 shows the risk of ischaemic heart disease in a cohort of 2398 men (162 of whom had had a myocardial infarction) divided into five groups according to ranked measures of platelet aggregation (from the Caerphilly collaborative heart disease study60). The association is linear. The estimate from the logistic regression line fitted to the data was that an increase in platelet aggregation of 1 SD (from any point on the distribution) is associated with a relative risk of ischaemic heart disease of 1.33 (1.19 to 1.48; P<0.001).

Fig 3

Risk (95% confidence interval) of ischaemic heart disease relative to lowest group according to measurements of platelet aggregation (induced by ADP), expressed as SDs from the mean, with fitted regression line (data from Elwood et al60)

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Table 5 summarises the experimental studies on smoking and platelet aggregation (from three different research groups).61 62 63 64 65 66 67 68 The effects of smoking and environmental exposure are similar. The effect of smoking was similar in non-smokers who smoked on the one occasion (for experimental purposes)62 63 64 and in habitual smokers abstinent for 8–10 hours.64 65 66 67 68 From the relation between platelet aggregation and ischaemic heart disease estimated above, the immediate increase in the risk of ischaemic heart disease attributable to effects on platelet aggregation is estimated to be 43% for smoking and 34% for environmental exposure (table 5). These estimates of the immediate effect are, as expected, a little higher than those of the long term effect of intermittent exposure over the day in table 4.

The actions of smoking on other factors that increase risk of ischaemic heart disease are likely to increase continuously with dose such that the effect of exposure to environmental tobacco smoke is imperceptible. Thus plasma fibrinogen concentration is higher in active smokers but not detectably greater in non-smokers who live with smokers than in those who do not (the 95% confidence limits from combining three studies26 29 79 were 4% lower and 4% higher). The effects on high density lipoprotein cholesterol21 22 and carboxyhaemoglobin15 16 are also imperceptible. The more gradual increase in the excess risk from 39% smoking one cigarette per day to 78% at 20 per day (at age 65) is attributable to these and other non-platelet factors.

Evidence for a large effect from a small exposure

Environmental exposure to tobacco smoke is associated with an excess risk of ischaemic heart disease of 30% and is estimated to cause an excess risk of 23% (95% confidence interval 14% to 33%), increasing the risk of death from ischaemic heart disease between the ages of 60 and 69 in British men who do not smoke from about 5% to 6%. So large an effect from a relatively small exposure, though unlikely on first impression, is supported by a great deal of evidence.

The association cannot be explained by bias in the studies of environmental exposure to tobacco smoke. Publication bias can be rejected, as discussed above. Misclassification bias arises because some people who claim never to have smoked are former or current smokers; they are at greater risk of ischaemic heart disease and more likely to have spouses who smoke. This bias has been found to be of minor importance in studies of lung cancer13; it will be negligible in studies of ischaemic heart disease because the relative risk of ischaemic heart disease in smokers is so much smaller than that of lung cancer (about 2 compared to 20).

The cohort studies of smokers also show a substantial risk at low dose (table 1).

Studies directly measuring the extent of atheromatous disease in arteries have confirmed a similar effect in smokers and in non-smokers exposed to environmental tobacco smoke, and a smaller effect in unexposed non-smokers.17 80

The association cannot be explained by confounding. If all the excess risk of ischaemic heart disease in non-smokers who live with smokers compared with those who live with non-smokers were to be explained by their dietary differences, about half the excess risk in smokers would also have to be attributable to differences in diet. The excess risk largely reverses on stopping smoking, indicating that this is not the case. The estimate of the extent of confounding as the excess risk that is not reversed many years after stopping smoking (6%) corroborates the estimate of the excess risk to be expected from the dietary differences.

The effect of tobacco smoke on platelet aggregation provides a plausible mechanism for the low dose effect. The immediate effect of a single environmental exposure is to increase risk by an estimated 34% (table 5). This will be an underestimate because of regression dilution bias (which could not be allowed for because repeat measures were not available), but will also tend to be an overestimate because it does not reflect typical intermittent exposure to environmental tobacco smoke over the day, which will be somewhat less. One hour after a single exposure the effect on platelet aggregation is attenuated by about half,67 so the likely effect of intermittent exposure throughout the day could be consistent with our estimate of a 23% increase in risk. Simple corroboration is provided by the observation that aspirin abolishes the effect of tobacco smoke on platelet aggregation65 68 and reduces the risk of ischaemic heart disease by about 25%.81 The experimental evidence of a similar effect of smoking and environmental exposure on platelet aggregation is corroborated by studies showing that the generation of thromboxane A2 from arachidonic acid (which leads to platelet aggregation) was also similar.82 A small dose of an agonist seems to have a maximal effect on platelet aggregation.83

A meta-analysis of the studies of occupational exposure to environmental tobacco smoke exposure indicated a disproportionately large effect: relative risk 1.36 (1.08 to 1.71).84 The occupational studies lack the susceptibility to confounding because non-smokers who work with smokers will not share their diet.

In animal experiments, eight studies on four species (involving exposure to the smoke from simultaneous combustion of between one and 10 cigarettes, generally for 4–6 hours per day over 6–16 weeks) all showed pronounced vascular toxicity of the exposure.85 86 87 88 89 90 91 92 The size of the resulting infarct after experimental occlusion of a coronary artery was 50-100% greater85 86 87 and arterial atheromatous disease was about twice as extensive88 89 90 91 92 in exposed animals than in unexposed controls.

Evidence against a large effect at low dose

Pipe and cigar smokers have a low risk of ischaemic heart disease (the risk relative to non-smokers was estimated as 1.13 for pipe smokers, 1.30 for cigar smokers, and 1.75 for cigarette smokers93). Pipe and cigar smokers tend not to inhale when smoking and because of characteristics of the smoke can absorb nicotine through the mouth,93 but they must inhale their own environmental tobacco smoke in the same way that non-smokers inhale other people's smoke. Their low risk might at first sight weigh against the view that inhaling environmental tobacco smoke poses a material risk of ischaemic heart disease. However, men who smoke only pipes or cigars smoke much less frequently than cigarette smokers. In a study of 21 520 men, 2618 current pipe or cigar smokers smoked on average three times a day whereas 4184 cigarette smokers smoked on average 20 times a day.94 The difference in this frequency, in view of the short term nature of the effect on platelet aggregation (half life less than an hour67), may well reconcile the observations of passive smokers and the risk of ischaemic heart disease among pipe smokers.

Excluded studies

A separate analysis of one of the studies of environmental tobacco smoke exposure and ischaemic heart disease in the set of 19 studies (fig 1), and of two data sets not published elsewhere (from the US National Center for Health Statistics and the American Cancer Society) has been published by Layard and LeVois, consultants to the tobacco industry.35 36 They reported a combined relative risk estimate from the three studies of 1.00, with a narrow 95% confidence interval (0.97 to 1.04).36 This negative result is statistically inconsistent with the estimate of 1.30 (1.22 to 1.38) from the above analysis of 19 studies (P<0.001). The difference is too great for the two groups of studies to be combined as separate valid estimates; one must be flawed. We took the estimate from the 19 studies as valid and rejected that of Layard and LeVois, since there is no reason to reject an analysis based on 19 independent studies in favour of one from a single group with a vested interest.

Direct evidence supports this decision. Firstly, in one of the three studies the relative risk estimate (men and women combined) of Layard and LeVois of 0.98 (0.90 to1.07)36 was inconsistent with that from an independent analysis of the same data commissioned by the American Cancer Society (the owners of the data) of 1.21 (1.06 to 1.38).31 Secondly, even in the absence of a causal effect, the combined estimate of 1.00 is inconsistent with any confounding from the dietary differences. Thirdly, the result is inconsistent with the data on low dose active smoking, the evidence on platelet aggregation, the animal studies and the other evidence summarised above.

Conclusions

We believe that there is no satisfactory alternative interpretation of the evidence reviewed here than that environmental exposure to tobacco smoke causes an increase in risk of ischaemic heart disease of the order of 25%. In proportionate terms this is of similar magnitude to the effects of exposure to environmental tobacco smoke on lung cancer,13 but the number of excess deaths from heart disease will be far greater because heart disease is so much more common than lung cancer in non-smokers. Reversal of the effect would reduce the risk of ischaemic heart disease by about as much as taking aspirin, or by what many people could achieve through dietary change. The effect of environmental tobacco smoke is not trivial, as is often thought. It is a serious environmental hazard, and one that is easily avoided. The evidence on ischaemic heart disease warrants further action in preventing smoking in public buildings and enclosed working environments. The hazard in the home requires greater public education so that smokers recognise the risk to which they expose members of their family. It is also important that clinicians advise that families of patients with known coronary artery disease do not smoke in their presence.