Blood Pressure, Smoking, and the Incidence of Lung Cancer in Hypertensive Men in North Karelia, Finland

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1 American Journal of Epidemiology Copyright 2003 by the Johns Hopkins Bloomberg School of Public Health All rights reserved Vol. 158, No. 5 Printed in U.S.A. DOI: /aje/kwg179 Blood Pressure, Smoking, and the Incidence of Lung Cancer in Hypertensive Men in North Karelia, Finland Annamarja Lindgren 1, Eero Pukkala 2, Aulikki Nissinen 3,4, and Jaakko Tuomilehto 3 1 Department of Public Health and General Practice, University of Kuopio, Kuopio, Finland. 2 Finnish Cancer Registry, Helsinki, Finland. 3 Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland. 4 Department of Neurology, Kuopio University Hospital, Kuopio, Finland. Received for publication June 19, 2002; accepted for publication March 20, Few studies have suggested that elevated blood pressure might be associated with increased risk of lung cancer and that this association might vary according to smoking status. The aim of this study was to assess the effect of blood pressure and its possible interaction with smoking on lung cancer incidence in hypertensive patients. Lung cancer incidence was determined for 7,908 men enrolled in the hypertension register of the North Karelia Project between 1972 and 1988 by record linkage to the nationwide Finnish Cancer Registry. In a Cox regression model, both systolic and diastolic blood pressures were significant predictors of lung cancer, with a 10% increase in risk per 10-mmHg increment in blood pressure. In smokers, the age-adjusted hazard ratio associated with a 10-mmHg increment in diastolic blood pressure was 1.17 (95% confidence interval: 1.05, 1.29), and in nonsmokers it was 0.98 (95% confidence interval: 0.80, 1.16). For systolic blood pressure, these hazard ratios were 1.11 (95% confidence interval: 1.05, 1.17) for smokers and 1.04 (95% confidence interval: 0.95, 1.14) for nonsmokers. These findings suggest that high blood pressure levels are associated with increased risk of lung cancer in smoking, hypertensive men. hypertension; incidence; lung neoplasms; medical record linkage; risk; smoking Lung cancer is the most common malignancy in men worldwide, with increasing significance also in women. Smoking is the well-established and prime risk factor for lung cancer (1), but other factors also play a role in the development of lung cancer, and some other factors may modify the effect of smoking. Further clarification in the etiology of lung cancer, as well as better identification of the factors causing the heterogeneity in lung cancer risk among smokers, requires attention. In some studies reporting a positive association between hypertension and all-site cancer risk (2 11), lung cancer has been found to be one of the cancer types related to elevated blood pressure (2, 9, 11). Wannamethee and Shaper (9) showed that the risk of lung cancer remained similar in nonsmokers regardless of their blood pressure level, but in current smokers the risk increased sharply with increasing systolic blood pressure. Studies reporting no association between hypertension and lung cancer also exist (3 5, 10, 12). In the present study, we have assessed the effects of systolic and diastolic blood pressures and their interaction with smoking on lung cancer incidence among a large, population-based cohort of hypertensive patients in North Karelia, Finland. MATERIALS AND METHODS The study cohort consisted of 8,029 male hypertensive patients included in the community-based hypertension register of the North Karelia Project. The details of the register are described elsewhere (13 15). This provincewide register was established in 1972, and new cases were entered into the register until The register was run within the primary health care system in North Karelia as part of the North Karelia Project (16, 17). All subjects who either were previously on antihypertensive drug treatment or had elevated blood pressure in three subsequent measurements were eligible to be registered. The blood pressure criteria were as follows: 150 and/or 90 mmhg ( 29 years), Correspondence to Annamarja Lindgren, Department of Public Health and General Practice, University of Kuopio, P.B. 1627, Kuopio, Finland ( Lindgren@hytti.uku.fi). 442

2 Blood Pressure, Smoking, and Lung Cancer and/or 95 mmhg (30 64 years), and 170 and/or 95 mmhg ( 65 years). Blood pressure was measured from the right arm of the patient who was in a sitting position by local nurses and physicians after a 5- to 10-minute rest. Diastolic blood pressure was recorded as the fifth phase of Korotkoff sounds. The local nurses and physicians, following the common protocol of the hypertension register, completed the record forms after clinical examination of the patient. The functional diagnosis of hypertension was based on World Health Organization recommendations (18). Stage I denoted elevated blood pressure without evidence of organic changes in the cardiovascular system. Stage II denoted high blood pressure with left ventricular hypertrophy but without evidence of other organ damage, and stage III denoted high blood pressure with other organ damage attributable to hypertension. Since January 1, 1967, all residents of Finland have had a unique personal identifier, which is used in all the main registers in Finland. The validity of the personal identifiers of the cohort members was checked with a linkage to Population Register of Finland. Dates of death and emigrations were obtained from the same source. Eighteen subjects (0.2 percent) were excluded from the cohort because they could not be identified. All incident cancer cases since 1953 were identified through the population-based country-wide Finnish Cancer Registry. The 103 men with cancer diagnosed before the baseline blood pressure measurement were excluded. After that exclusion, 7,908 men remained in the cohort. The follow-up started at the date when the patient was enrolled into the hypertension register and ended at death, emigration, or December 31, 1996, whichever occurred first. A total of 118,396 person-years of follow-up were accumulated, 38,045 in men who smoked and 79,535 in men who did not smoke. A Cox regression model was used to analyze the independent effects of blood pressure and functional diagnosis of hypertension on the lung cancer incidence within the cohort. Diastolic and systolic blood pressures were analyzed by quartiles (table 1) and as continuous variables. Functional diagnosis was coded in three stages. Antihypertensive drug treatment indicated use of any blood pressure-lowering drug at least five times a week during the preceding 3 weeks prior to the entry into the hypertension register. Other variables used in the analysis were smoking in three categories (nonsmokers, smoking 1 10 cigarettes a day, and smoking more than 10 cigarettes a day) or as a continuous variable (number of cigarettes per day), age (continuous), year of registration (continuous), and body mass index as a continuous variable or by quartiles (table 1). All variables were recorded in the beginning of the follow-up and thus refer to the baseline situation. The data did not allow the separation of never smokers from former smokers. For multivariate models, only variables significantly improving the fit of the model were included. Systolic and diastolic blood pressures were never analyzed in the same model because of their multicollinearity. TABLE 1. Baseline characteristics of the 7,908 men included in the hypertension register of the North Karelia Project in 1972 No. % Smoking Nonsmokers 5, cigarettes/day >10 cigarettes/day 1, Use of antihypertensive drug No 3, Yes 4, Functional diagnosis of hypertension Stage I 4, Stage II 1, Stage III 1, Systolic blood pressure (mmhg) Quartile 1 (<151) 2,292 Quartile 2 ( ) 1,774 Quartile 3 ( ) 2,186 Quartile 4 (>180) 1,641 Diastolic blood pressure (mmhg) Quartile 1 (<95) 2,122 Quartile 2 (95 100) 2,229 Quartile 3 ( ) 2,346 Quartile 4 (>110) 1,196 Body mass index (kg/m 2 ) Quartile 1 (<24) 1,836 Quartile 2 (24 26) 1,852 Quartile 3 (27 29) 1,860 Quartile 4 (>29) 1,858 RESULTS The mean age of hypertensive men at the beginning of the follow-up, that is, at the referral to the hypertension register, was 51 (standard deviation, 13) years. One third of the men were smokers, and 21 percent smoked more than 10 cigarettes per day (table 1). The mean systolic blood pressure was 166 (standard deviation, 23) mmhg, and the mean diastolic blood pressure was 101 (standard deviation, 12) mmhg. The mean length of follow-up was 15 (standard deviation, 7) years. A total of 271 incident lung cancer cases were diagnosed during the follow-up. The expected number of lung cancer cases, corresponding to the age- and period-specific person-year patterns of the cohort and calculated from population-based incidence rates for eastern Finland, was 298. Table 2 shows the relative hazards for lung cancer associated with selected variables both adjusted only for age and using a multivariate model. The use of antihypertensive drugs, functional diagnosis of hypertension, and the year of registration of hypertension were not significant predictors for lung cancer in any of the models. With functional diagnosis there was, however, a modest but nonsignificant

3 444 Lindgren et al. TABLE 2. Hazard ratios for lung cancer by selected variables in an age-adjusted model and in a multivariate model, with 95% confidence intervals and number of cancer cases in each category, among hypertensive men in North Karelia, Finland, in Age adjusted Multivariate Variable No. 95% 95% Hazard ratio confidence Hazard ratio confidence interval interval Smoking category* Nonsmoker cigarettes/day , , 6.91 >10 cigarettes/day , , 9.59 Use of antihypertensive drugs No Yes , , 1.31 Functional diagnosis of hypertension Stage I Stage II , , 1.60 Stage III , , 1.71 Systolic blood pressure (per 10 mmhg) , , 1.15 Systolic blood pressure Quartile Quartile , , 1.86 Quartile , , 2.56 Quartile , , 2.74 Diastolic blood pressure (per 10 mmhg) , , 1.25 Diastolic blood pressure Quartile Quartile , , 1.86 Quartile , , 1.89 Quartile , , 2.62 Body mass index Quartile Quartile , , 0.96 Quartile , , 0.93 Quartile , , 0.75 * Multivariate model includes the following variables: age, systolic blood pressure, and body mass index. Multivariate model includes the following variables: age, systolic blood pressure, body mass index, and number of cigarettes/day. Multivariate model includes the following variables: age, body mass index, and number of cigarettes/day. Multivariate model includes the following variables: age, systolic blood pressure, and number of cigarettes/day. increasing trend of lung cancer risk. Both systolic and diastolic blood pressures were significant predictors of lung cancer, with about a 10 percent increase in risk per 10- mmhg increase in blood pressure. Adjustment for number of cigarettes per day and body mass index did not change these results. As expected, smoking was strongly related to lung cancer risk, and its effect became even more pronounced in multivariate analysis after adjusting for other factors. Men in the lowest quartile of body mass index had a significantly increased risk of lung cancer, and this risk remained after adjustment for the number of cigarettes smoked per day and blood pressure. In the analyses carried out stratifying by smoking, the effect of blood pressure remained apparent in smokers only. The age-adjusted hazard ratio associated with a 10-mmHg increment in diastolic blood pressure was 1.17 (95 percent confidence interval: 1.05, 1.29) in smokers and 0.98 (95 percent confidence interval: 0.80, 1.16) in nonsmokers. For a 10-mmHg increment in systolic blood pressure, the hazard ratios were 1.11 (95 percent confidence interval: 1.05, 1.17) for smokers and 1.04 (95 percent confidence interval: 0.95, 1.14) for nonsmokers. The interaction terms between smoking and systolic blood pressure or between smoking and diastolic blood pressure were not statistically significant (p = 0.17 and 0.25, respec-

4 Blood Pressure, Smoking, and Lung Cancer 445 FIGURE 1. Hazard ratios for lung cancer by smoking status and by diastolic (<95, , , >110 mmhg) and systolic (<151, , , >180 mmhg) blood pressure quartiles, adjusted for age and body mass index, among hypertensive men in North Karelia, Finland, in BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure. Bars, 95% confidence intervals. tively). However, when compared with nonsmokers in the lowest quartile of blood pressure, the nonsmokers showed no increase in risk in any of the higher blood pressure quartiles, while in smokers the risk of lung cancer increased with increasing blood pressure (figure 1). The pattern was similar for both systolic blood pressure and diastolic blood pressure. Because preclinical lung cancer may cause hypertension, the analyses were repeated, excluding the first 2 years of follow-up. The results remained virtually unchanged; the age-adjusted hazard ratio for a 10-mmHg increment in systolic blood pressure was 1.11 (95 percent confidence interval: 1.06, 1.17) and for that in diastolic blood pressure was 1.11 (95 percent confidence interval: 1.01, 1.22). DISCUSSION In our cohort of 7,908 hypertensive men, high systolic and diastolic blood pressures were significantly associated with an increased risk of lung cancer. This association was attributable almost entirely to smokers. The incidence of lung cancer for the total cohort of hypertensive patients was lower than that in men in eastern Finland in general according to the national cancer registry data. The observed/expected ratio was 0.91 (95 percent confidence interval: 0.81, 1.02). This was in keeping with the lower proportion of smokers among these hypertensive men than that observed in the general population. The crosssectional survey in 1972 showed that the proportion of current smokers among men years of age in North Karelia was 52 percent (19), while in our data, among hypertensive men who were registered in 1972 at the age of years, the prevalence of smoking was 42 percent. The role of hypertension as a possible risk factor for cancer was first proposed by Dyer et al. in 1975 (2) and has later been studied in various cohort studies. Some association between high blood pressure and elevated overall cancer risk has been noted by most studies (3 11), but not by all (12, 20, 21). Many of these studies have also reported cancer site-specific risks, but the results for lung cancer have been variable. The majority of studies have failed to show an association between blood pressure and lung cancer (3, 5, 10, 12), but none of these previous studies had analyzed the data stratified by smoking status. Peeters et al. (11) reported a hazard ratio of 2.2 (95 percent confidence interval: 1.2, 4.0) for dying of lung cancer for women who were hypertensive at baseline compared with normotensive women (controlled for age, smoking, and body mass index). They also reported that the effect of hypertension for total cancer mortality was stronger for current smokers than for never smokers, but for lung cancer mortality the results are not given stratified by smoking. The risk of lung cancer associated with hypertension in different smoking strata has so far been studied only by Wannamethee and Shaper (9) and by Lee et al. (22), and both report a more marked effect among smokers. The results of our study among the representative series of hypertensive patients show a pattern very similar to those presented in these two studies, although the cohorts are quite different, for example, in terms of their blood pressure distributions. The lower limit of the highest quintile of systolic blood pressure in the study by Wannamethee and Shaper (9) was 161 mmhg, which is close to the median among men in our study (164 mmhg). Among the Korean cohort (22), the blood pressures were even lower, and only less than 3 percent of the person-years fell in the category of systolic blood pressure of 160 mmhg or higher. This suggests that the association between systolic blood pressure and risk of lung cancer among smokers might stretch over a wide range of blood pressure levels. One major potential weakness in our study arises from the limitations in the smoking measurements. Information on current smoking was gathered only at one point in time, and the past smoking history was not assessed. Thus, a distinction between former smokers and those who quit smoking during the follow-up time could not be done, and the length of smoking exposure could not be determined. Because of this lack of correct estimates of the true overall smoking exposure, the quantification of risks as presented may not be valid. In addition, the overall smoking exposure remains a potential source of residual confounding in our results. This is possible, even though the number of cigarettes smoked per se was not positively associated with the blood pressure

5 446 Lindgren et al. levels. Rather, in fact, among the smokers in our study, the correlation between the reported number of cigarettes smoked per day and systolic blood pressure was negative (r = 0.037, p = 0.055). Among the Finnish population, it has been shown that smoking habits are rather persistent. With regard to lung cancer risk, the cross-sectional rate of smoking at the beginning of follow-up gave results comparable to those of the cumulative lifetime smoking exposure (23). In addition, among the previous studies, Lee et al. (22) analyzed the former smokers separately, and the increase in lung cancer incidence associated with hypertension was confined only to current smokers, while the former smokers showed a pattern fairly similar to that of never smokers. The possible pathophysiologic mechanisms that could relate hypertension to elevated cancer risk remain unclear. It has been suggested that there may exist a link between the pathway leading to proliferative abnormalities in vascular smooth muscle cells associated with hypertension and cancer pathogenesis (24). This might be related, for example, to abnormal apoptotic function, which is observed in spontaneously hypertensive rats (25), or to shortening of telomers (26). It is known that some lung cancers can secrete substances capable of elevating blood pressure (27). To reduce the possible bias resulting from preclinical cancers as a cause of hypertension, an alternative analysis was done excluding the first 2 years after the blood pressure measurement. Such exclusion did not change our results. The cancer registration system in Finland is virtually complete (28), and the computerized record linkage procedure is precise (29). Therefore, incompleteness in case ascertainment of cancer events during the follow-up does not cause bias. Our cohort comprised only hypertensive patients with a varying severity of hypertension; thus, no comparisons between normotensive and hypertensive populations can be made. However, this setting makes the cohort relatively homogenous and the analyses within the cohort are powerful. Our result that the lung cancer incidence is highest in subjects with a low body mass index is consistent with findings from several (30, 31) but not all (32) previous studies. Smoking, body mass index, and hypertension can be related to each other, and the possibility of a more complex pattern among these factors in the risk of lung cancer cannot be ruled out. There was an elevated risk of lung cancer associated with high blood pressure among the smoking, hypertensive men in our cohort. This association may not be causal, but it may reflect residual confounding by smoking or the effect of some common risk factor for hypertension and lung cancer. These risk factors might include, for example, lack of physical activity or the presence of nutritional factors, such as antioxidants, the effect of which could not be controlled for in the settings of this study. Unfortunately, there is a lack of experimental studies in this area, which limits our ability to better understand the underlying pathophysiologic pathways leading to an increased lung cancer risk in hypertensive smokers. The detected association, if real, may have public health importance even if the relative risk is modest, since both smoking and hypertension have a high prevalence among many populations. ACKNOWLEDGMENTS The study was supported by a grant from the Foundation for the Finnish Cancer Institute. REFERENCES 1. International Agency for Research on Cancer. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Vol 38. Tobacco smoking. Lyon, France: World Health Organization, Dyer AR, Stamler J, Berkson DM, et al. High blood pressure: a risk factor for cancer mortality? Lancet 1975;1: Svärdsudd K, Tibblin G. Mortality and morbidity during 13.5 years follow-up in relation to blood pressure. Acta Med Scand 1979;205: Raynor WJ Jr, Shekelle RB, Rossof AH, et al. High blood pressure and 17-year cancer mortality in the Western Electric Health Study. Am J Epidemiol 1981;113: Khaw K-T, Barrett-Connor E. Systolic blood pressure and cancer mortality in an elderly population. Am J Epidemiol 1984; 120: Goldbourt U, Holtzman E, Yaari S, et al. Elevated systolic blood pressure as a predictor of long-term cancer mortality: analysis by site and histologic subtype in 10,000 middle-aged and elderly men. J Natl Cancer Inst 1986;77: Buck C, Donner A. Cancer incidence in hypertensives. Cancer 1987;59: Filipovský J, Ducimetière P, Darné B, et al. Abdominal body mass distribution and elevated blood pressure are associated with increased risk of death from cardiovascular diseases and cancer in middle-aged men. The results of a 15- to 20-year follow-up in the Paris prospective study I. Int J Obes Relat Metab Disord 1993;17: Wannamethee G, Shaper AG. Blood pressure and cancer in middle-aged British men. Int J Epidemiol 1996;25: Rosengren A, Himmelmann A, Wilhelmsen L, et al. Hypertension and long-term cancer incidence and mortality among Swedish men. J Hypertens 1998;16: Peeters PHM, van Noord PAH, Hoes AW, et al. Hypertension, antihypertensive drugs, and mortality from cancer among women. J Hypertens 1998;16: Grove JS, Nomura A, Severson RK, et al. The association of blood pressure with cancer incidence in a prospective study. Am J Epidemiol 1991;134: Nissinen A, Tuomilehto J, Puska P. The hypertension register of the North Karelia Project. Clin Sci Mol Med Suppl 1978;4: 355s 8s. 14. Elo J, Tuomilehto J, Nissinen A, et al. A community-based hypertension register as a part of a systematic hypertension control project: experiences from the North Karelia Project. Med Inform (Lond) 1981;6: Nissinen A, Enlund H, Tuomilehto J, et al. Hypertension care in the community a comparison between an active community programme (the North Karelia Project) and the general situation. Public Health 1982;96: Puska P, Tuomilehto J, Nissinen A, et al. The North Karelia Project: 20 years results and experience. Helsinki, Finland: National Public Health Institute, 1995.

6 Blood Pressure, Smoking, and Lung Cancer Tuomilehto J. Feasibility of a community programme for control of hypertension. A part of the North Karelia Project. Kuopio, Finland: University of Kuopio, (Community health series A:2). 18. Arterial hypertension. Report of a WHO expert committee. World Health Organ Tech Rep Ser 1978;(628): Vartiainen E, Puska P, Jousilahti P, et al. Twenty-year trends in coronary risk factors in North Karelia and in other areas of Finland. Int J Epidemiol 1994;23: Taylor OJ, Cornoni-Huntley J, Curb JD, et al. Blood pressure and mortality risk in the elderly. Am J Epidemiol 1991;134: Clausen J, Jensen G. Blood pressure and mortality: an epidemiological survey with 10 years follow-up. J Hum Hypertens 1992;6: Lee S, Kim M, Jee S, et al. Does hypertension increase mortality from lung cancer? A prospective cohort study on smoking, hypertension and lung cancer risk among Korean men. J Hypertens 2002;20: Hakulinen T, Pukkala E, Puska P, et al. Various measures of smoking as predictors of cancer of different types in two Finnish cohorts. In: Colditz GA, ed. Proceedings of the Consensus Conference on Smoking and Prostate Cancer, Brisbane, Australia, February 12 14, Canberra, Australia: Australian Publishing Service, 1997: Hamet P. Cancer and hypertension: a potential for crosstalk? J Hypertens 1997;15: Moreau P, Tea BS, Dam TV, et al. Altered balance between cell replication and apoptosis in hearts and kidneys of newborn SHR. Hypertension 1997;29: Aviv A, Aviv H. Reflections on telomers, growth, aging and essential hypertension. Hypertension 1997;29: Rees LH. The biosynthesis of hormones by nonendocrine tumours. J Endocrinol 1975;67: Teppo L, Pukkala E, Lehtonen M. Data quality and quality control of a population-based cancer registry. Experience in Finland. Acta Oncol 1996;33: Pukkala E. Use of record linkage in small-area studies. In: Elliot P, Guzick J, English D, et al, eds. Geographical and environmental epidemiology. Oxford, England: Oxford University Press, 1992: Kark JD, Yaari S, Rasooly I, et al. Are lean smokers at increased risk of lung cancer? The Israel Civil Servant Cancer Study. Arch Intern Med 1995;155: Knekt P, Heliovaara M, Rissanen A, et al. Leanness and lungcancer risk. Int J Cancer 1991;49: Rauscher GH, Mayne ST, Janerich DT. Relation between body mass index and lung cancer risk in men and women never and former smokers. Am J Epidemiol 2000;152: