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J C!lh Qhmbl Vol. 44, No. 1, pp. 99402, 1991 Printal in Great Britain. All rights mend
Letter to the Editors MISTAKES
IN “ESTABLISHED WISDOM” ABOUT CIGARETTE SMOKING?
In his article, “Framingham Study data and ‘established wisdom’ about cigarette smoking and coronary heart disease” [l], Carl C. Seltzer compares the Framingham Study results concerning the association between cigarette smoking and CHD with the conclusions in the U.S. Surgeon General’s report on cardiovascular disease [2]. Seltzer is of the opinion that the Surgeon General’s report is the best representation of the “established wisdom”-we agree with him as to this opinion. Seltzer concludes that the Framingham data substantially disagree with the “established wisdom” and that the anomaly remains unexplained. According to Seltzer this discrepancy is an intriguing challenge for future research. In our opinion Seltzer commits a number of methodological mistakes when he goes through the Framingham Study results. We list below the three mistakes which we find to be the gravest: 1. In the first place Seltzer writes that the univariate association between cigarette smoking and CHD is weak. This conclusion is based on a review of the Framingham results, where the “unexposed” group consists of never smokers as well as of ex-smokers and pipe and cigar smokers [ 1, Table 11. It is evident that, in the calculation of a risk ratio, a really unexposed group should be used as a reference population (in this case: never smokers). Furthermore, it is a fact that crude risk ratios, which have not been adjusted for relevant confounders, do not contain any real information on the risk associated with tobacco smoking. Our eonelusion is therefore that Seltzer’s remarks on a “weak association’* rest on slender foundations. 99
2. In the second place, an important part of the Framingham results are, according to Seltzer, inconclusive because important confounding factors were omitted from the multivariate analyses. Seltzer seems to be of the opinion that all factors havingbeen found to be associated with CHD should be measured and included in the multivariate analyses. As many such factors are mentioned in the scientific literature available, it would be a considerable task, rendering impossible in practise cardiovascular epidemiological research., Seltzer would seem to be overlooking two circumstances: (i) that a factor is only a confounder if it is associated to not only the endpoint measured .(in this case CHD) but also to the risk factor which we are interested in (in this case tobacco smoking); and (ii) that a confounding variable is not the same as an intermediate factor [3]. The latter is illustrated by Seltzer himself, in as much as he writes that, when plasma fibrinogen is controlled for, the association between tobacco smoking and CHD disappears. In this connection Seltzer describes fibrinogen as a confounder [ 1, p. 7461. However, there is ample documentation that an increased fibrinogen level is a result of tobacco smoking [4-g]. That the association between tobacco smoking and CHD disap pears when fibrinogen is controlled for thus ‘does not make a causal relation unlikely. It is more correct to say that fibrinogen explains the association and thus that fibrinogen is an intermediate factor. 3. The third issue we would lie to focus on is the discussion of the effect of smoking cessation. Here Seltzer shows us univariate analyses demonstrating that ex-smokers have a lower CHD incidence than never smokers,
loo
Letter to the Editors
and he writes that “this anomalous finding requires further consideration, because of the odd implication that it is better to have smoked and stopped than never to have smoked at all” [l, p. 7471. However, he himself offers an explanation of this “anomalous finding”, i.e. that the ex-smokers constitute a self-selected group, who had a more favourable cardiovascular risk profile already before they stopped smoking. There is thus no contradiction between the Framingham Study and “established wisdom” here. It will of course never be possible to carry out a proper randomized trial of the effect of smoking cessation-as desired by Seltzer. We therefore believe that in his analysis of the Framingham Study results, Seltzer commits a number of mistakes and that, to a large extent, it is necessary for him to commit these mistakes in order that he may arrive at the conclusions he reaches in his article. The fundamental fault in Seltzer’s article is however-in our opinion-that there is no clear formulation of a problem. Does Seltzer believe that the “established wisdom” on smoking and CHD is wrong or is it simply the Framingham Study that fails to support this wisdom? It is correct that the Framingham Study is an important study, but it is important to establish that “established wisdom” is based on a thorough review of several hundred studies [2]. If the intention is to question “established wisdom”-something which it is of course legitimate to do-then the point of departure must be all research undertaken in this field and not only one single study. Seltzer finishes his
article by asking if “conventional wisdom” or Framingham is wrong. We suggest that Seltzer considers a third possibility. TAGE S. KRISTBNSEN OLE OLSEN* LARS MILLER Institute of Social Medicine University of Copenhagen Blegdamwej 3, DK-2200 Copenhagen N Denmark
REFERENCES 1. Seltzer CC. Framingham Study data and “established wisdom” about cigarette smoking and coronary heart disease. J CIIn Epidemiol 1989; 42: 743-750. 2. U.S. Department of Health and Human Services. Car~Bovaaenlar Disease. A report of the Surgeon General. Public Health Service; Washington, D.C.: U.S. Government Printing Office; 1983. 3. Rothman KJ. Modem Epidemiology. Boston, Mass.: Little, Brown; 1986. 4. Wilhelmsen L, Svlrdsudd K, Korsan-Bengtsen K, Larsson B. Welin L. Tibblin G. Fibrinoeen as a risk factor for stroke and myocardial infarcti&. N EngI J Med 1984; 311: 501-505. 5. Kannel WB, D’Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: Insights from the Framingham Study. Am Heart J 1987; 113: 10061010. 6. Meade TW, Imeson J, Stirling Y. Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease. Lancet 1987; II: 986-988.
7.
8.
9.
FitzGerald GA, Oates JA, Nowak J. Cigarette smoking and hemostatic function. Am Heart J 1988; 115: 267-27 1. Belch JJF, McArdle BM, Burns P, Lowe GDO, Forbes CD. The effects of acute smoking on platelet behaviour, fibrinolysis and haemorheology in habitual smokers. Thromb Haemost 1984; 51: 6-8. Balleisen L, Bailey J, Epping P-H, Schulte H, Loo J van de. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population: I. Baseline data on the relation to age, gender, bodyweight, smoking, alcohol, pill-using, and menopause. Tbromb Haemost 1985; 54: 475-479.
*Author for correspondence.
Response To Kristensen et al.‘s [l] headline question “Mistakes in ‘established wisdom’ about cigarette smoking?“, my answer to the question is YES when the “mistakes” refer to a causal connection between cigarette smoking and coronary heart disease (CHD). This was the import of my article on the Framingham Study data [2] on which Kristensen et al. commented. The gravamen of their position turns on their opinion that my article committed three
methodological mistakes. The first mistake, they claim, was my reporting that the association between cigarette smoking in the Framingham data was a “weak association”, resting on “slender foundations”. Their argument is that the Framingham risk ratios in my article’s Table 1 should be based on a “really unexposed group”, namely never smokers, not on “none” or “non-cigarette smokers”. However, the risk ratios in my Table 1 are based on “none” or
J C!lh Qhmbl Vol. 44, No. 1, pp. 99402, 1991 Printal in Great Britain. All rights mend
Letter to the Editors MISTAKES
IN “ESTABLISHED WISDOM” ABOUT CIGARETTE SMOKING?
In his article, “Framingham Study data and ‘established wisdom’ about cigarette smoking and coronary heart disease” [l], Carl C. Seltzer compares the Framingham Study results concerning the association between cigarette smoking and CHD with the conclusions in the U.S. Surgeon General’s report on cardiovascular disease [2]. Seltzer is of the opinion that the Surgeon General’s report is the best representation of the “established wisdom”-we agree with him as to this opinion. Seltzer concludes that the Framingham data substantially disagree with the “established wisdom” and that the anomaly remains unexplained. According to Seltzer this discrepancy is an intriguing challenge for future research. In our opinion Seltzer commits a number of methodological mistakes when he goes through the Framingham Study results. We list below the three mistakes which we find to be the gravest: 1. In the first place Seltzer writes that the univariate association between cigarette smoking and CHD is weak. This conclusion is based on a review of the Framingham results, where the “unexposed” group consists of never smokers as well as of ex-smokers and pipe and cigar smokers [ 1, Table 11. It is evident that, in the calculation of a risk ratio, a really unexposed group should be used as a reference population (in this case: never smokers). Furthermore, it is a fact that crude risk ratios, which have not been adjusted for relevant confounders, do not contain any real information on the risk associated with tobacco smoking. Our eonelusion is therefore that Seltzer’s remarks on a “weak association’* rest on slender foundations. 99
2. In the second place, an important part of the Framingham results are, according to Seltzer, inconclusive because important confounding factors were omitted from the multivariate analyses. Seltzer seems to be of the opinion that all factors havingbeen found to be associated with CHD should be measured and included in the multivariate analyses. As many such factors are mentioned in the scientific literature available, it would be a considerable task, rendering impossible in practise cardiovascular epidemiological research., Seltzer would seem to be overlooking two circumstances: (i) that a factor is only a confounder if it is associated to not only the endpoint measured .(in this case CHD) but also to the risk factor which we are interested in (in this case tobacco smoking); and (ii) that a confounding variable is not the same as an intermediate factor [3]. The latter is illustrated by Seltzer himself, in as much as he writes that, when plasma fibrinogen is controlled for, the association between tobacco smoking and CHD disappears. In this connection Seltzer describes fibrinogen as a confounder [ 1, p. 7461. However, there is ample documentation that an increased fibrinogen level is a result of tobacco smoking [4-g]. That the association between tobacco smoking and CHD disap pears when fibrinogen is controlled for thus ‘does not make a causal relation unlikely. It is more correct to say that fibrinogen explains the association and thus that fibrinogen is an intermediate factor. 3. The third issue we would lie to focus on is the discussion of the effect of smoking cessation. Here Seltzer shows us univariate analyses demonstrating that ex-smokers have a lower CHD incidence than never smokers,
loo
Letter to the Editors
and he writes that “this anomalous finding requires further consideration, because of the odd implication that it is better to have smoked and stopped than never to have smoked at all” [l, p. 7471. However, he himself offers an explanation of this “anomalous finding”, i.e. that the ex-smokers constitute a self-selected group, who had a more favourable cardiovascular risk profile already before they stopped smoking. There is thus no contradiction between the Framingham Study and “established wisdom” here. It will of course never be possible to carry out a proper randomized trial of the effect of smoking cessation-as desired by Seltzer. We therefore believe that in his analysis of the Framingham Study results, Seltzer commits a number of mistakes and that, to a large extent, it is necessary for him to commit these mistakes in order that he may arrive at the conclusions he reaches in his article. The fundamental fault in Seltzer’s article is however-in our opinion-that there is no clear formulation of a problem. Does Seltzer believe that the “established wisdom” on smoking and CHD is wrong or is it simply the Framingham Study that fails to support this wisdom? It is correct that the Framingham Study is an important study, but it is important to establish that “established wisdom” is based on a thorough review of several hundred studies [2]. If the intention is to question “established wisdom”-something which it is of course legitimate to do-then the point of departure must be all research undertaken in this field and not only one single study. Seltzer finishes his
article by asking if “conventional wisdom” or Framingham is wrong. We suggest that Seltzer considers a third possibility. TAGE S. KRISTBNSEN OLE OLSEN* LARS MILLER Institute of Social Medicine University of Copenhagen Blegdamwej 3, DK-2200 Copenhagen N Denmark
REFERENCES 1. Seltzer CC. Framingham Study data and “established wisdom” about cigarette smoking and coronary heart disease. J CIIn Epidemiol 1989; 42: 743-750. 2. U.S. Department of Health and Human Services. Car~Bovaaenlar Disease. A report of the Surgeon General. Public Health Service; Washington, D.C.: U.S. Government Printing Office; 1983. 3. Rothman KJ. Modem Epidemiology. Boston, Mass.: Little, Brown; 1986. 4. Wilhelmsen L, Svlrdsudd K, Korsan-Bengtsen K, Larsson B. Welin L. Tibblin G. Fibrinoeen as a risk factor for stroke and myocardial infarcti&. N EngI J Med 1984; 311: 501-505. 5. Kannel WB, D’Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: Insights from the Framingham Study. Am Heart J 1987; 113: 10061010. 6. Meade TW, Imeson J, Stirling Y. Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease. Lancet 1987; II: 986-988.
7.
8.
9.
FitzGerald GA, Oates JA, Nowak J. Cigarette smoking and hemostatic function. Am Heart J 1988; 115: 267-27 1. Belch JJF, McArdle BM, Burns P, Lowe GDO, Forbes CD. The effects of acute smoking on platelet behaviour, fibrinolysis and haemorheology in habitual smokers. Thromb Haemost 1984; 51: 6-8. Balleisen L, Bailey J, Epping P-H, Schulte H, Loo J van de. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population: I. Baseline data on the relation to age, gender, bodyweight, smoking, alcohol, pill-using, and menopause. Tbromb Haemost 1985; 54: 475-479.
*Author for correspondence.
Response To Kristensen et al.‘s [l] headline question “Mistakes in ‘established wisdom’ about cigarette smoking?“, my answer to the question is YES when the “mistakes” refer to a causal connection between cigarette smoking and coronary heart disease (CHD). This was the import of my article on the Framingham Study data [2] on which Kristensen et al. commented. The gravamen of their position turns on their opinion that my article committed three
methodological mistakes. The first mistake, they claim, was my reporting that the association between cigarette smoking in the Framingham data was a “weak association”, resting on “slender foundations”. Their argument is that the Framingham risk ratios in my article’s Table 1 should be based on a “really unexposed group”, namely never smokers, not on “none” or “non-cigarette smokers”. However, the risk ratios in my Table 1 are based on “none” or
