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The Effects of a Smoking Cessation Intervention on 14.5-Year Mortality: A Randomized Clinical Trial FREE

Nicholas R. Anthonisen, MD; Melissa A. Skeans, MS; Robert A. Wise, MD; Jure Manfreda, MD; Richard E. Kanner, MD; John E. Connett, PhD, Lung Health Study Research Group*
[+] Article and Author Information

From University of Manitoba, Winnipeg, Manitoba, Canada; University of Minnesota, Minneapolis, Minnesota; Johns Hopkins University, Baltimore, Maryland; and University of Utah, Salt Lake City, Utah.


Grant Support: Lung Health Study III was supported by a cooperative agreement with the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI-1U10-HL59275).

Potential Financial Conflicts of Interest: Honoraria: J.E. Connett (National Institutes of Health/National Heart, Lung, and Blood Institute); Grants received: J.E. Connett (National Institutes of Health/National Heart, Lung, and Blood Institute).

Requests for Single Reprints: John E. Connett, PhD, Coordinating Centers for Biometric Research, University of Minnesota, 2221 University Avenue SE, Room 200, Minneapolis, MN 55414-3080; e-mail, john-c@ccbr.umn.edu.

Current Author Addresses: Dr. Anthonisen: University of Manitoba, Respiratory Hospital, 810 Sherbrook Street, Room 319, Winnipeg, Manitoba R3A 1R8, Canada.

Ms. Skeans and Dr. Connett: University of Minnesota, Coordinating Centers for Biometric Research, 2221 University Avenue SE, Room 200, Minneapolis, MN 55414-3080.

Dr. Wise: Johns Hopkins Asthma and Allergy Center, Division of Pulmonary and Critical Care Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD 21224.

Dr. Manfreda: University of Manitoba, Respiratory Hospital RS 115, 810 Sherbrook Street, Winnipeg, Manitoba R3A 1R8, Canada.

Dr. Kanner: University of Utah Medical Center, Pulmonary Division, 701 Wintrobe Building, 50 North Medical Drive, Salt Lake City, UT 84132.

Author Contributions: Conception and design: N.R. Anthonisen, R.A. Wise, R.E. Kanner, J.E. Connett.

Analysis and interpretation of the data: N.R. Anthonisen, M.A. Skeans, R.A. Wise, J.E. Connett.

Drafting of the article: N.R. Anthonisen, M.A. Skeans, J. Manfreda, R.E. Kanner.

Critical revision of the article for important intellectual content: N.R. Anthonisen, M.A. Skeans, R.A. Wise, J. Manfreda, R.E. Kanner, J.E. Connett.

Final approval of the article: N.R. Anthonisen, M.A. Skeans, R.A. Wise, J. Manfreda, R.E. Kanner, J.E. Connett.

Provision of study materials or patients: R.A. Wise, R.E. Kanner.

Statistical expertise: M.A. Skeans, J.E. Connett.

Obtaining of funding: R.A. Wise, R.E. Kanner, J.E. Connett.

Collection and assembly of data: R.A. Wise, J.E. Connett.


Ann Intern Med. 2005;142(4):233-239. doi:10.7326/0003-4819-142-4-200502150-00005
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Editors' Notes
Context

Although there are many health benefits for smokers who stop smoking, we still lack evidence from randomized, controlled trials that smoking cessation programs reduce mortality.

Contribution

In this randomized, controlled trial of a 10-week-long smoking cessation intervention in 5887 smokers with asymptomatic airway obstruction, 14-year mortality rates were higher in the usual care group than in the smoking cessation group (hazard ratio, 1.18 [95% CI, 1.02 to 1.37]). The mortality benefit was greatest among the 21.7% of the intervention group who actually managed to quit smoking.

Implications

Smoking cessation programs substantially reduce mortality even when only a minority of patients stop smoking.

–The Editors

Smoking cessation almost certainly has beneficial effects on subsequent mortality (1). However, the strongest support for this assertion comes from cohort studies, where smokers and quitters were self-selected. Results from randomized trials, which avoid the selection issue, have largely been disappointing because mortality benefits have not been clear or have not been clearly attributable to smoking cessation (1).

The Lung Health Study (LHS) was a randomized clinical trial of smoking cessation and inhaled bronchodilator (ipratropium) therapy in smokers 35 to 60 years of age who did not consider themselves ill but had evidence of mild to moderate airway obstruction (2). Individuals with serious disease, hypertension, obesity, or excessive alcohol intake were excluded. The primary research questions were whether a smoking cessation program and use of inhaled ipratropium would decrease the rate of decline of lung function and would affect mortality and morbidity over 5 years. These results have been reported elsewhere (34). The smoking cessation program was associated with cumulative reduced decline in lung function (FEV1) that was largest in participants who stopped smoking early in the study; inhaled ipratropium produced a small noncumulative increase in FEV1 that disappeared when the drug was withdrawn (3). Intention-to-treat analysis after 5 years did not reveal differences in morbidity or mortality among treatment groups (4), although subgroup analysis showed that smoking cessation was associated with significant reductions in fatal or nonfatal cardiovascular disease and coronary heart disease. This paper reports the effects of the study intervention on mortality in LHS participants 14.5 years after randomization.

The design of the LHS has been described in detail elsewhere (2). The participants, all volunteers, were smokers who did not consider themselves ill but had evidence of airway obstruction and little evidence of other disease. Researchers recruited participants from the community using a wide variety of techniques (5). In 10 clinical centers, 5887 participants were randomly assigned to 3 groups. Two special intervention groups received an intensive 10-week smoking cessation program. Briefly, the cessation intervention consisted of a strong physician message and 12 two-hour group sessions, using behavior modification and nicotine gum. Quitters entered a maintenance program that stressed coping skills. One special intervention group also received ipratropium, while the other received a placebo inhaler. A third group received usual care. About 75% of the original participants were followed continuously for the subsequent 10 years by biannual telephone contacts and 1 clinic visit at approximately 11 to 12 years after randomization (6). Telephone contacts served to check smoking status, morbidity, and mortality and were not part of the intervention.

All study participants provided written informed consent for the original LHS before beginning the study. The consent documents stated that smoking increases the risk for chronic obstructive pulmonary disease, respiratory tract cancer, and cardiovascular disease and that smoking cessation would decrease such risks. Additional written informed consent was obtained from persons who participated in the biannual telephone calls. Institutional review boards at each of the 10 clinical centers and the coordinating center approved the study design and consent documents.

When biannual phone calls revealed a participant death, staff attempted to collect death certificates, autopsy reports, relevant medical records, and interviews with attending physicians or eyewitnesses. An independent mortality and morbidity review board examined these data and classified causes of death. In addition, a National Death Index review provided date and cause of death for all U.S. study participants through the end of 2001. Vital status at 31 December 2001 or 14.5 years, whichever was earlier, was successfully determined for 98.3% of all participants; missing individuals were Canadians who had been lost to follow-up and were not accessible through the National Death Index. Mortality end points were classified in 7 categories: coronary heart disease, cardiovascular disease including coronary heart disease, lung cancer, other cancer, respiratory disease excluding lung cancer, other, and unknown. The “other” category included but was not limited to liver disease, kidney disease, sepsis, accidents, suicide, and AIDS.

Analyses were performed on an intention-to-treat basis, comparing the special intervention group with the usual care group. The special intervention group was a combination of the groups originally assigned to receive inhaled ipratropium or placebo therapy. Both of these groups, which were very similar at baseline, received the smoking cessation program and exhibited similar rates of smoking cessation (3). Participants were also divided into 3 groups according to smoking history during the initial 5 years of the trial. Sustained quitters were participants who stopped smoking in the first year after randomization and maintained biochemically validated abstinence (3) throughout follow-up. Continuing smokers were participants who reported smoking at all follow-up visits. Intermittent quitters were participants who reported smoking at some but not all of their follow-up visits or during the time between visits.

Statistical Analysis

Baseline differences between the special intervention and usual care groups were tested by using t-tests for continuous variables and chi-square statistics for categorical variables. Cause-specific death rates and times to events were analyzed by using the Kaplan–Meier product-limit method (7). Survival was compared among groups by using the log-rank test. Hazard ratios and adjusted analyses were obtained by using the Cox proportional hazards model. Interactions were assessed by comparing hierarchically related proportional hazards models. All P values result from 2-sided tests; no adjustments were made for multiple comparisons.

Role of the Funding Source

This study was funded by a contract and grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The funding source had a role in the design of the study and approved the manuscript before it was submitted for publication.

Baseline characteristics of LHS participants are shown in Table 1. Most were middle-aged; smoked heavily; and had substantial smoking histories, airway obstruction (FEV1–FVC ratio ≤ 70%), and borderline low FEV1 values. On average, participants were normotensive and had normal body mass indices. Most participants were of white ethnicity; 37% were women. The average participant had some postsecondary education and did not drink heavily. The special intervention and usual care groups did not significantly differ at baseline, except in percentage of participants who were married, which was higher in the special intervention group (P = 0.04). Smoking status after the first 5 years differed significantly between treatment groups (P ≤ 0.001). Among special intervention participants and usual care participants, respectively, 21.7% and 5.4% were sustained quitters, 29.3% and 23.3% were intermittent quitters, and 49.0% and 71.3% were continuing smokers.

Table Jump PlaceholderTable 1.  Baseline Characteristics of Lung Health Study Participants

There were 731 known deaths among LHS participants, as shown in Table 2. Lung cancer was the most common cause of death (n = 240 [33%]). Coronary heart disease accounted for 77 deaths (10.5%), and cardiovascular disease including coronary heart disease accounted for 163 deaths (22%). One hundred fifty-four participants (21%) died of cancer of organs other than the lung. Deaths due to respiratory disease other than cancer were relatively uncommon (n = 57 [7.8%]). The cause of death was unknown in only 17 participants (2.3%). Mortality did not significantly differ between the special intervention groups originally assigned to ipratropium or placebo (Table 2).

Table Jump PlaceholderTable 2.  Causes of Death by Treatment Group

Figure 1 shows all-cause survival rates in the 2 treatment groups. Death rates were significantly higher in the usual care group than in the special intervention group (10.38 per 1000 person-years vs. 8.83 per 1000 person-years; P = 0.03). The hazard ratio for mortality in the usual care group was 1.18 (95% CI, 1.02 to 1.37) compared with the special intervention group. Figure 2 shows categorical causes of death in the 2 treatment groups. In all categories except “other,” death rates were higher in the usual care group than in the special intervention group, but the difference was significant only for deaths from respiratory diseases not related to lung cancer (1.08 per 1000 person-years vs. 0.56 per 1000 person-years; P = 0.01).

Grahic Jump Location
Figure 1.
All-cause 14.5-year survival.

461 of 3923 patients died in the special intervention group vs. 270 of 1964 patients in the usual care group (  = 0.031, log-rank test). LHS = Lung Health Study.

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Figure 2.
Mortality rates at 14.5 years by cause.

The only significant difference was in respiratory disease other than lung cancer (log-rank test). CHD = coronary heart disease; CVD = cardiovascular disease.

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When survival was analyzed according to smoking habit, it differed significantly between groups (P < 0.001), even after adjustment for baseline differences (data not shown). Mortality was 6.04 per 1000 person-years in sustained quitters, 7.77 per 1000 person-years in intermittent quitters, and 11.09 per 1000 person-years in continuing smokers. No significant differences in death rates were seen between special intervention and usual care participants in any of the 3 smoking categories. Figure 3 shows categorical causes of death among the 3 smoking groups. Death rates were significantly related to smoking habit for coronary heart disease (P = 0.02), cardiovascular disease (P ≤ 0.001), lung cancer (P = 0.001), and other causes (P = 0.03). Death rates were not significantly related to smoking habit for cancer other than lung cancer and for respiratory deaths not related to lung cancer. Baseline FEV1, expressed as a percentage of the predicted normal value, was inversely related to all-cause mortality (P ≤ 0.001) and to deaths from coronary heart disease (P = 0.003), cardiovascular disease (P = 0.002), lung cancer (P = 0.02), other cancer (P = 0.03), and respiratory disease other than cancer (P ≤ 0.001).

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Figure 3.
Mortality rates at 14.5 years by cause and smoking status.

Rates were significantly different for coronary heart disease (CHD ), cardiovascular disease (CVD ), lung cancer, and other causes of death (log-rank test).

Grahic Jump Location

Differences between the special intervention group and the usual care group in all-cause mortality were examined in relation to subgroups identified at baseline (Table 3). There was a significant mortality difference between the special intervention and usual care groups in the youngest tertile of participants, those younger than 45 years of age (hazard ratio, 1.88; P = 0.001), but not in the middle tertile (45 to 52 years of age) or oldest tertile (53 to 60 years of age). Interaction between treatment group and age was significant (P = 0.04). Mortality did not differ significantly between groups by sex, and no significant interaction between treatment group and sex was observed. There was a significant mortality difference between the usual care and special intervention groups among participants smoking at least 40 cigarettes per day (hazard ratio, 1.30; P = 0.03), but not among those smoking 25 to 39 cigarettes per day or fewer than 25 cigarettes per day. In addition, no significant interactive effect on mortality was observed between smoking intensity and treatment group. There was a significant difference in mortality between the special intervention and usual care groups for participants in the middle tertile of baseline FEV1(75% to 83% predicted) (hazard ratio, 1.39; P = 0.01), but not in tertiles with higher or lower values of FEV1. No significant interactive effect on mortality was observed between treatment group and FEV1.

Table Jump PlaceholderTable 3.  Hazard Ratios for Death for Usual Care Compared with the Special Intervention, by Subgroup

The striking feature of our findings is the statistically significant difference in all-cause mortality in the intention-to-treat analysis. Mortality was higher in the usual care group than in the special intervention group even though the intervention—smoking cessation—was successful in only a minority of special intervention participants. Since death rates between special intervention and usual care participants with similar smoking habits did not differ, the differences observed in the groups as a whole were almost certainly due to differential cessation rates. It must be emphasized that this finding applied to a special group of heavy smokers who had preexisting airway obstruction.

From its inception, the LHS was characterized by very high follow-up rates. Of the original cohort, only 75 participants (1.27%), all of whom were Canadian, were censored because of loss to follow-up at less than 12.5 years. Cause of death was adjudicated by a mortality and morbidity review board, which had access to data in 653 of the 731 deaths. In the remaining cases, cause of death was derived from the National Death Index. The 17 deaths due to unknown causes showed trends similar to the remainder of deaths in terms of treatment group and smoking status (Figures 2 and 3) and therefore were probably not a source of bias. Smoking status was ascertained at the fifth year following entry into the LHS, that is, 5 years after randomization. We have shown that smoking status established at 5 years changed relatively little in the next 6 years, especially among sustained quitters (6).

To our knowledge, no directly comparable studies have examined the long-term effects of a randomly applied smoking intervention. Many intervention trials aimed at cardiovascular disease have used smoking cessation along with other interventions. Of these, the most directly comparable to the LHS was the Multiple Risk Factor Intervention Trial (MRFIT), which was conducted in North America, enrolled participants of similar age, and had similar follow-up periods (8). At 16 years after randomization, MRFIT had slightly lower all-cause mortality than the LHS at 14.5 years (10.5% vs. 12.4%). More than 50% of MRFIT deaths were attributed to cardiovascular disease, reflecting the fact that MRFIT participants were selected for cardiovascular risk factors while the LHS attempted to avoid them. However, LHS participants had substantially higher death rates for lung cancer and respiratory disease than did MRFIT participants, reflecting their heavier tobacco use and abnormal lung function. All-cause mortality did not differ significantly between treatment groups in MRFIT at 10.5 years (9) or at 16 years, perhaps in part because smoking habits did not differ greatly between the intervention and control groups after the initial 6-year follow-up (10). Similar convergence in smoking habits was observed in long-term follow-up of 2 European cardiovascular trials (1112), both of which initially reported significant decreases in cardiac events in the intervention groups but did not observe significant differences in all-cause mortality at 8.5 and 10 years, respectively. All-cause mortality probably differed between the special intervention and usual care groups in our study because smoking cessation has a powerful effect on mortality in heavy smokers with airway obstruction and because more than 90% of LHS participants who quit smoking during the first 5 years of the study were able to maintain cessation thereafter (6, 13).

We did not measure the cost of the LHS smoking cessation program, and researchers who worked with the intervention group had other roles in the study, such as obtaining follow-up data. However, a unit price of $2000 would probably cover the LHS smoking intervention, including intensive initial counseling, nicotine replacement therapy, and the long-term maintenance program. This seems a modest price for a life-saving intervention. An inexpensive intervention with a relatively low success rate can make an important difference if it has great potential and is applied early in the course of the diseases of interest. Indeed, the most prominent difference between the special intervention and usual care groups was observed in the youngest participants. It could be argued, therefore, that smoking cessation was most effective in preventing truly premature death.

The leading causes of death in the LHS were lung cancer and coronary heart disease, and smoking cessation was of benefit in both (Figure 3). These results are not unprecedented. In MRFIT, smoking cessation in conjunction with other risk modification strategies was shown to decrease morbidity and mortality from coronary heart disease (14), and we observed such an effect within the first 5 years of LHS follow-up (4). These results are compatible with those of many cohort and case–control studies that have shown a decline in death from coronary heart disease within 2 years of smoking cessation (15). In MRFIT, risk for myocardial infarction in participants who still smoked was roughly 3 times that in participants who had stopped smoking more than 5 years previously (15); this finding was similar to our data on death from coronary heart disease (Figure 3).

The mechanisms by which smoking induces coronary events are apparently reversible to some extent in the short term. To our knowledge, our data are the first to show an effect of smoking cessation on the rate of death from lung cancer in the context of a clinical trial. Our data are consistent with those of previous cohort and case–control studies showing that measurable effects of cessation on lung cancer are usually not evident in the first 5 years and that lung cancer risk is probably still elevated 15 years after smoking cessation (16). In our study, death from lung cancer was roughly 2.2 times more common in current smokers than in sustained quitters (Figure 3), a finding similar to data from cohorts observed for similar lengths of time (16). Smoking is thought to cause potentially irreversible genetic changes in epithelial cells. Therefore, the effects of cessation are probably due to the absence of further insult rather than to reversal of existing disease.

To some extent, the LHS was a study about the FEV1, and our results again demonstrate the prognostic value of this test. It is obvious and axiomatic that death from lung disease other than cancer should be related to FEV1. However, it is not yet clear why FEV1, independent of smoking habits, predicts death from cardiovascular disease (17) and lung cancer (1819). The mechanisms involved are likely to be different because FEV1 predicts coronary artery disease in both smokers and nonsmokers (20) but apparently predicts lung cancer only in smokers and former smokers (21). Of interest, our data showed that death from other types of cancer was related to FEV1 but not to smoking habits. These results differ from those of the larger Renfrew and Paisley population study (22), which found that death due to nonrespiratory cancer was not related to FEV1 after smoking had been considered. In addition, good data link smoking to many types of nonpulmonary cancer.

The LHS was one of the few studies that examined a substantial cohort of smoking women (Table 1). Of interest, lung cancer mortality was very similar between sexes: 3.02 per 1000 person-years in men and 3.14 per 1000 person-years in women. This is in agreement with most of the other studies that have examined this issue (2223) but is at variance with a case–control study suggesting that women are more likely to develop lung cancer than men given the same smoking exposure (24). In the LHS, female continuing smokers smoked an average of approximately 3 fewer cigarettes per day than did male continuing smokers (5). However, it is difficult to argue that our results support the hypothesis that women are more sensitive to cigarette smoke than men.

In summary, we demonstrated that an intensive smoking cessation program followed by 5 years of reinforcement leads to a substantial and significant reduction in all-cause mortality in people with mild to moderate airway obstruction.

Appendix

The principal investigators and senior staff of the clinical and coordinating centers, the National Heart, Lung, and Blood Institute, members of the Safety and Data Monitoring Board, and members of the Mortality and Morbidity Review Board are as follows.

Case Western Reserve University, Cleveland, Ohio: M.D. Altose, MD, Principal Investigator; C.D. Deitz, PhD, Project Coordinator.

Henry Ford Hospital, Detroit, Michigan: M.S. Eichenhorn, MD, Principal Investigator; K.J. Braden, AAS, Project Coordinator; P.A. Fantuz, RN, BSN; R.L. Jentons, MALLP, Project Coordinator.

Johns Hopkins University School of Medicine, Baltimore, Maryland: R.A. Wise, MD, Principal Investigator; C.S. Rand, PhD, Co-Principal Investigator; K.A. Schiller, Project Coordinator.

Mayo Clinic, Rochester, Minnesota: P.D. Scanlon, MD, Principal Investigator; G.M. Caron, Project Coordinator; K.S. Mieras, L.C. Walters.

Oregon Health Sciences University, Portland, Oregon: A.S. Buist, MD, Principal Investigator; L.R. Johnson, PhD, LHS Pulmonary Function Coordinator; V.J. Bortz, Project Coordinator.

University of Alabama at Birmingham: W.C. Bailey, MD, Principal Investigator; L.B. Gerald, PhD, MSPH, Project Coordinator.

University of California, Los Angeles, California: D.P. Tashkin, MD, Principal Investigator; I.P. Zuniga, Project Coordinator.

University of Manitoba, Winnipeg, Manitoba, Canada: N.R. Anthonisen, MD, Principal Investigator, Steering Committee Chair; J. Manfreda, MD, Co-Principal Investigator; R.P. Murray, PhD, Co-Principal Investigator; S.C. Rempel-Rossum, Project Coordinator.

University of Minnesota Coordinating Center, Minneapolis, Minnesota: J.E. Connett, PhD, Principal Investigator; P.G. Lindgren, MS; M.A. Skeans, MS; H.T. Voelker.

University of Pittsburgh, Pittsburgh, Pennsylvania: R.M. Rogers, MD, Principal Investigator; M.E. Pusateri, Project Coordinator.

University of Utah, Salt Lake City, Utah: R.E. Kanner, MD, Principal Investigator; G.M. Villegas, Project Coordinator.

Safety and Data Monitoring Board: C. Furberg, MD, PhD; J.R. Landis, PhD; E. Mauger, PhD; J.R. Maurer, MD; Y. Phillips, MD; J.K. Stoller, MD; I. Tager, MD; A. Thomas Jr., MD.

Mortality and Morbidity Review Board: R.S. Crow, MD; T.E. Cuddy, MD; R.S. Fontana, MD; R.E. Hyatt, MD; C.T. Lambrew, MD; M. Lertzman, MD; B.A. Mason, MD; D.M. Mintzer, MD; R.B. Wray, MD.

National Heart, Lung, and Blood Institute, Bethesda, Maryland: T. Croxton, MD, PhD (Project Officer); J.P. Kiley, PhD (Division of Lung Diseases), G. Weinmann, MD (Airway Biology and Disease Program, Division of Lung Diseases), M.C. Wu, PhD (Division of Epidemiology and Clinical Applications).

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Figures

Grahic Jump Location
Figure 1.
All-cause 14.5-year survival.

461 of 3923 patients died in the special intervention group vs. 270 of 1964 patients in the usual care group (  = 0.031, log-rank test). LHS = Lung Health Study.

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Grahic Jump Location
Figure 2.
Mortality rates at 14.5 years by cause.

The only significant difference was in respiratory disease other than lung cancer (log-rank test). CHD = coronary heart disease; CVD = cardiovascular disease.

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Grahic Jump Location
Figure 3.
Mortality rates at 14.5 years by cause and smoking status.

Rates were significantly different for coronary heart disease (CHD ), cardiovascular disease (CVD ), lung cancer, and other causes of death (log-rank test).

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Tables

Table Jump PlaceholderTable 1.  Baseline Characteristics of Lung Health Study Participants
Table Jump PlaceholderTable 2.  Causes of Death by Treatment Group
Table Jump PlaceholderTable 3.  Hazard Ratios for Death for Usual Care Compared with the Special Intervention, by Subgroup

Videos

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References

U.S. Department of Health and Human Services.  Smoking cessation and overall mortality and morbidity. In: The Health Benefits of Smoking Cessation. Washington, DC: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, Centers for Chronic Disease Prevention and Health Promotion, Office of Smoking and Health; 1990:75-87. DHHS publication no. [CDC] 90-8416.
 
Connett JE, Kusek JW, Bailey WC, O'Hara P, Wu M.  Design of the Lung Health Study: a randomized clinical trial of early intervention for chronic obstructive pulmonary disease. Control Clin Trials. 1993; 14:3S-19S. PubMed
 
Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS. et al.  Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA. 1994; 272:1497-505. PubMed
 
Anthonisen NR, Connett JE, Enright PL, Manfreda J.  Hospitalizations and mortality in the Lung Health Study. Am J Respir Crit Care Med. 2002; 166:333-9. PubMed
 
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Letters

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Smoking Cessation and Mortality
Posted on February 21, 2005
Gregory J. Bombassei
No Affiliation
Conflict of Interest: None Declared

I read with interest Anthonisen and colleagues' article on smoking cessation and mortality in a recent issue of the Annals. Because this report dealt with the effectiveness and cost of a smoking cessation strategy, its endpoints were concerned with treatment differences between those patients who were offered the smoking cessation intervention and those who were not.

However, I who counsel patients in practice to quit smoking am even more interested in treatment differences between those patients who actually quit smoking compared to those who continue to smoke, either continuously or intermittently. Knowing these data from a randomized clinical trial would improve my ability to inform my patients of the health benefits of smoking cessation.

It took a close read of the data, for example, to determine that among 5887 patients in this study, 957 were sustained quitters and 4930 were continuous or intermittent smokers. Even Figure 3 in the article, giving rates of death "per 1000 person-years" for each of several causes of death, is not straightforward. That is, the raw data are unknown to the reader, who is instead treated to a "sanitized" version, in which the "rate of death per 1000 person-years" is substituted for a simpler quantity, the proportion of patients who died.

I am interested to know to what extent quitting smoking reduces mortality. I am particularly interested in a Kaplan-Meier curve plotting the proportion of patients surviving versus time for sustained quitters compared to continuous or intermittent smokers.

Can the authors provide this information?

The authors write that "since death rates between special [smoking cessation] intervention and usual care participants with similar smoking habits did not differ, the differences observed in the groups as a whole were almost certainly due to differential cessation rates." Comparing the Kaplan-Meier curve depicted in Figure 1 (All-cause 14.5-year survival in the smoking cessation intervention group and the usual care group) to the Kaplan-Meier curve I suggest (All-cause 14.5-year survival in those who quit smoking and those who did not) would allow the reader to judge that for himself.

Conflict of Interest:

None declared

Political Conclusions From An Activist
Posted on February 24, 2005
Stephen L. Hansen
AMA/CMA/ACP
Conflict of Interest: None Declared

1)It's an outrage that most health plans still do not cover tobacco cessation services by physician! The Calif.Tobacco Control Alliance has a bill this year to fix that here.

2)The good news is that Medicare will begin cessation coverage in March,and has finally espoused a new preventive medicine ethic.

3)The relative ease and benignity of the abrupt cessation experienced by inmates in prisons (with no tobacco cues)is quite interesting,also. The mileau matters. And quitting is easier in smokefree states,too. California's 32 prisons go tobacco-free (no person may take any form of tobacco inside the gates) on 1 July,2005. Six pilot programs showed very few problems even with psychiatric and violent inmates. Most said:"Thanks,Doc,I couldn't have done this with everyone else still smoking."

4)Cessation reduces disease costs best in those most at risk of serious illness in the near-term.Therefore, teach all clinicians to do cessation,fund clinical efforts,provide support for quitters---including discounted premiums. Or increase premiums for smokers:KY,WV and AL have done this,a la life insurance actuaries (Actuaries ALWAYS knew the results of quitting on life expectancy!) Cheers,SH

Conflict of Interest:

None declared

The Effects of Smoking Cessation Intervention on Mortality: The "Interventions"
Posted on March 9, 2005
Milan C Mathew
Memorial Hospital of Rhode Island/Brown University
Conflict of Interest: None Declared

I read with great interest the article by Anthonisen et.al., regarding the effects of a smoking cessation intervention on 14.5 year mortality in the Lung Health Study. The authors conclude that 'smoking cessation intervention programs can have a substantial effect on subsequent mortality, even when successful in a minority of participants.' The generalizability of the study results being potentially limited to heavy smokers with pre-existing airway obstruction.

The study provides convincing evidence that smoking cessation lowers all-cause mortality. The mortality experience between the two study groups, the 'usual' care group and 'special' intervention group, did not differ significantly between those with similar smoking habits and hence the decrease in mortality is attributable to differential cessation rates between the two study groups.

However, the article fails to adequately recognize and/or address the role of the 'other' intervention received by those in the special intervention group. In addition to the smoking cessation program that included a strong physician message and 12 two-hour group sessions, using behavior modification and nicotine gum and followed by 5-years of reinforcement, they received either an 'iptratopium' or a 'placebo' inhaler. It is noteworthy that mortality did not differ significantly between those assigned to iptratropium or placebo groups. The presence of an additional intervention raises the question of what led to the differential smoking cessation rates between the special intervention and usual care groups: Was it the cessation program, the inhaler, or was it a combination of both. It can be argued that use of inhalers, irrespective of the ingredient, by heavy smokers in the special intervention group encouraged them to quit when compared to the usual care group. Furthermore, it can be argued that the role played by the inhalers in promoting cessation in this study is as significant or even more significant than the smoking cessation intervention itself. Of note is that smoking status established at 5 years in the study, changed relatively little over the next six years, especially among sustained quitters.

In summary, it would have been more appropriate to conclude that smoking cessation intervention programs in conjunction with use of inhalers lead to increased smoking cessation and decreased all-cause mortality among heavy smokers with pre-existing air-way disease. By not recognizing the role played by the co-intervention, the 'inhalers,' the article inordinately focuses the readers attention on only one of the interventions.

Conflict of Interest:

None declared

Letter to Editor
Posted on March 18, 2005
Balavenkatesh Kanna
Weill Medical College of Cornell University
Conflict of Interest: None Declared

In reference to the article by Anthonisen et al (1) on the effects of a smoking cessation intervention on 14.5-year mortality among chronic obstructive pulmonary disease subjects, we would like to submit the following comments.

In this randomized controlled trial, a subgroup analysis shows significant increase in mortality among younger subjects and those who smoked more than 40 cigarettes per day (p < 0.05). However, United States population data(2) suggests that the prevalence of smoking is higher among the age groups 45 and 64 years. As study subjects between 35 and 44 years of age at baseline would have aged during the course of the study, one may conclude that the number of cigarettes smoked per day may reflect age related increase in smoking behavior. Therefore, cigarette smoking or age alone may not have an independent effect on the mortality as described in the study. The readers will certainly be interested to learn whether there is an interaction between age and number of cigarettes smoked. In addition, the relatively high prevalence of smoking among the study groups (31 cigarettes per day) compared to the general population (2) (11 "“ 18 cigarettes per day) may limit this study finding to heavy cigarette smokers.

References: 1.Anthonisen NR et al. for the Lung Health Study Research Group. The Effects of a Smoking Cessation Intervention on 14.5-Year Mortality: A Randomized Clinical Trial. Ann Intern Med 2005; 142: 233-239 2.Schoenborn CA, Adams PF, Barnes PM, Vickerie JL, Schiller JS. Health Behaviors of Adults: United States, 1999"“2001. National Center for Health Statistics. Vital Health Stat 10(219). 2004.

Conflict of Interest:

None declared

In Response
Posted on April 13, 2005
Nicholas R Anthonisen
University of Manitoba
Conflict of Interest: None Declared

Dr. Mathew rightly points out that the Lung Health Study smoking cessation program was accompanied by the prescription of inhalers, and believes that we may not have considered the latter adequately. He agrees that the content of the inhalers [placebo or bronchodilator] didn't make any difference, and appears to accept that it was differences in smoking habits that determined the improved survival in the special intervention group. It therefore follows that if the inhalers were important, it was because they made the smoking cessation program more effective. Maybe so, but we are unapologetic about attributing smoking cessation largely to the program we designed to induce it. Inhalers per se probably have little to no effect on smoking habits, as evidenced by the fact that smoking rates are about as high in asthmatics as they are in the general population [1,2].

Dr. Bombassi is interested in Kaplan-Meier survival curves in Lung health Study participants who quit smoking as compared to those who did not. In the paper we indicated that mortality was 6.04 per 1000 person- years in sustained quitters, 7.77 per 1000 person years in intermittent quitters, and 11.09 per 1000 person-years in continuing smokers. We have sent a figure that will be published in the Annals.

N.R. Anthonisen, MD

Nicholas R. Anthonisen, MD nanthonisen@exchange.hsc.mb.ca University of Manitoba, Winnipeg, Manitoba, Canada

References 1. Higenbottam TW, Feyeraband C, Clark TJ. Cigarette smoking in asthma. Br J Dis Chest 1980; 49: 881-884. 2. Silverman RA, Boudreaux ED, Woodruff PG, Clark S, Camargo CA. Cigarette smoking among asthmatic adults presenting to 64 emergency departments. Chest 2003; 123: 1472-1479.

Conflict of Interest:

None declared

Submit a Comment

Summary for Patients

The Effects of a Smoking Cessation Program on Long-Term Survival in Smokers with Mild Lung Disease

The summary below is from the full report titled “The Effects of a Smoking Cessation Intervention on 14.5-Year Mortality. A Randomized Clinical Trial.” It is in the 15 February 2005 issue of Annals of Internal Medicine (volume 142, pages 233-239). The authors are N.R. Anthonisen, M.A. Skeans, R.A. Wise, J. Manfreda, R.E. Kanner, and J.E. Connett, PhD, for the Lung Health Study Research Group.

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