a Department of Epidemiology, German Centre for Research on Ageing, Bergheimer Str. 20, D-69115 Heidelberg, Germany
b Klinik Schwabenland, Isny-Neutrauchburg, Germany
c Klinik am Südpark, Bad Nauheim, Germany
Received April 21, 2004; revised August 12, 2004; accepted August 19, 2004 * Corresponding author. Tel.: +49 6221 54 8150; fax: +49 6221 54 8142 (E-mail: twardella{at}dzfa.uni-heidelberg.de).
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Abstract |
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METHODS AND RESULTS: Cohort study among participants of an in-patient 3-week rehabilitation programme following an acute coronary syndrome or coronary artery revascularization. Smoking status at baseline was assessed by self-report (beginning of the rehabilitation programme, rehab) and serum cotinine (end of rehab). Active follow-up was conducted one year later.
Subsequent CVD events were observed in 139 of the 967 patients. Both self-reported smoking status (odds ratio (OR) compared to continued smokers: recent quitters 0.96, former smokers 0.83, never smokers 0.54, p for trend 0.04) and serum cotinine (OR 0.59 (95% confidence interval (CI) 0.360.97) for cotinine-negative compared to cotinine-positive subjects) were associated with the occurrence of a secondary CVD event. After reclassification of all cotinine-positive subjects to continued smokers and cotinine-negative self-reported smokers to recent quitters, this association became even stronger. The OR now reached 0.71 (95% CI interval 0.381.33) for recent quitters, 0.64 (0.361.11) for former smokers and 0.44 (0.240.81) for never smokers (p-value for trend=0.009).
CONCLUSION: The benefits of non-smoking and smoking cessation in cardiac patients are beyond controversy and might even be larger than suggested by previous studies which exclusively relied on self-reported smoking status.
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Introduction |
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Yet, smoking continues to be prevalent in patients with newly diagnosed CHD. About 1217% of patients continue to smoke after the diagnosis of CHD in many countries, including Germany.78 To further motivate patients to quit smoking, full disclosure of the advantages associated with cessation would be of utmost importance. Most existing evidence,4,9 however, is exclusively based on self-reported smoking data. While self-report of smoking status appears to be accurate if compared to biochemical markers of tobacco exposure in general,10 there are indications that among patients with CHD, accuracy of self-report may be reduced.1112 Since smoking cessation is desired, some patients might be reluctant to admit continuation of smoking behaviour. Therefore self-reported data should be complemented with biological markers of exposure to give a more accurate categorization of the actual smoking status of participants, and hence to help to disclose the full benefits of smoking cessation.
Several biomarkers of cigarette smoking are available. Among them the measurement of cotinine levels in either plasma, urine or saliva is the test of choice for pertinent research protocols.1314 The measurement of cotinine has been used in a number of epidemiologic studies to validate self-reported smoking status,1516 with the proportion of self-reported "non-smokers" with positive cotinine levels in serum ranging widely from 1.4%17 to 17% 15, indicating under-reporting to various degrees.
The aim of this study was to assess the impact of smoking and smoking cessation measured by self-report and by serum cotinine level on the risk of secondary cardiovascular disease events during one year follow-up in patients with acute coronary syndrome or coronary artery revascularization.
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Methods |
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Germany has a very comprehensive in-patient rehabilitation programme and all patients who were hospitalised due to an acute coronary syndrome or coronary artery revascularization (i.e., coronary artery bypass grafting, coronary angioplasty, stent implantation) have the possibility (covered by health insurance plans or pension funds) to undergo an in-patient rehabilitation programme (rehab) after discharge from the acute care hospital. The aims of this 3-week programme are the reduction of cardiovascular disease risk factors, the improvement of health related quality of life, and the preservation of the ability to work (latter only if a subject was at work at onset of disease). This in-patient rehabilitation programme, which is utilised by about two thirds of eligible patients in Germany,18 begins approximately three weeks after the acute coronary syndrome or coronary artery revascularization procedure but this time interval may be longer in some cases. In the current study only patients who were admitted within 3 months from the acute coronary syndrome or coronary artery revascularization procedure were included. All subjects gave written consent to the study. The study was approved by the Ethics Boards of the Universities of Ulm and Heidelberg and of the medical associations of the States of Baden-Wuerttemberg and Hessen.
Overall, 1206 patients with a newly diagnosed CHD event (within the past 3 months) were included at baseline during the in-patient rehab. The median time between the acute event and admission to the rehab was 20 days. For this analysis 4 patients with missing data on self-reported smoking status and another 41 patients with missing data on serum cotinine had to be excluded. We further had to exclude 194 participants with missing follow-up information from physicians' questionnaire (see below). One year follow-up information and baseline smoking data were complete for 967 (80.1%) participants.
Data collection during rehab
At the beginning of the in-patient rehab, all subjects filled out a standardized questionnaire containing questions on sociodemographic factors, smoking history and medical history. In addition, information was taken from the patients' hospital charts, and a blood sample was drawn after overnight fast for determination of cardiovascular risk factors shortly before discharge.
Laboratory analyses
Analysis of blood lipids was performed by routine methods in two co-operating laboratories. Total cholesterol, HDL- and LDL-cholesterol in blood samples from Isny were quantified on Olympus-Analyser AU2700 and AU4500 with Olympus cholesterol reagent (Olympus Europe, Hamburg, Germany) and HDL-C and LDL-C reagent (Wako Chemicals, Neuss, Germany), and blood samples from Bad Nauheim on Hitachi 704 with cholesterol, HDL- and LDL-cholesterol reagents from Greiner BioChemika GmbH, Flacht, Germany. Cotinine levels in serum were determined by radioimmunoassay in a central laboratory according to the instructions of the manufacturer (Immundiagnostik AG, Bensheim, Germany). Blood drawn before discharge from the rehab clinic was used for the determination of these laboratory markers.
1 Year follow-up
Active follow-up was conducted one year after discharge from the rehab clinic. Information was obtained from patients via a mailed standardized questionnaire. A standardized questionnaire regarding physician-diagnosed cardiovascular disease events and treatment since discharge from the in-patient rehabilitation clinic was also obtained from the patient's primary care physician. If a subject died during follow-up the death certificate was obtained from local Public Health authorities, and the main cause of death was coded according to the International Classification of Diseases (9th Revision).
Statistical analyses
After describing the study population with respect to various sociodemographic and medical characteristics, the prevalence and distribution of smoking status was determined. Smoking status was alternatively classified according to self-report (obtained at the beginning of rehabilitation) and by cotinine level (measured at the end of rehabilitation). According to self-reports, four categories of smoking status were used: (1) never smokers, (2) former smokers (ex-smokers, who quit (at any time) before occurrence of the clinical manifestation of CHD at baseline), (3) recent quitters (ex-smokers, who quit after the occurrence of the clinical manifestation of CHD at baseline), (4) continued smokers (those who were still smoking at the beginning of rehab). Smoking was defined as regularly consuming at least one cigarette per day, no minimum time period of regular consumption was required to meet this definition. According to serum cotinine levels, subjects were classified as smokers in case of serum cotinine levels ⩾15 ng/ml and as non-smokers otherwise.19,20
We then compared the distribution of known cardiovascular risk factors among patients in the different smoking categories. Risk factor data included age at beginning of rehab, sex, years of school education (<10, 1011, 12 or more), self-reported history of diabetes, and the following information taken from patients' hospital charts: weight at the end of rehab and height to calculate body mass index, blood pressure (diastolic blood pressure at least 130 mmHg or systolic blood pressure at least 85 mmHg=increased/else=other)21, triglycerides, total, HDL- and LDL-cholesterol, the number of coronary vessels affected (<3, 3 or more), treatment with aspirin, ACE-inhibitors, β-blockers or lipid lowering drugs at the end of rehab. The statistical significance of differences between groups was determined using the MantelHaenszel-statistic of general association for categorical variables and the KruskalWallis statistic for continuous variables.
Next, the association of smoking status with the occurrence of secondary cardiovascular disease events was assessed. Secondary CVD events during follow-up were defined as main cause of death from CVD, physician diagnosed non-fatal myocardial infarction or ischemic cerebrovascular event, or a coronary-revascularization procedure, all as reported by the primary care physicians.
The association between self-reported, or cotinine-based, smoking status and the occurrence of secondary cardiovascular disease events was evaluated in bivariate analysis as well as by means of multivariable logistic regression, employing two-sided tests with an α-level of 5% (without adjustment for multiple testing). For multivariable analysis a forward variable selection procedure was employed. Age, sex and the indicator of smoking status were included in all models. Other variables from the set of earlier mentioned potential risk factors were added step by step until the 2log likelihood of the reduced model was no longer different from the 2log likelihood of the full model at p<0.2 (two-sided).
To minimise potential bias due to imperfect classification of smoking status, the analysis on the association of smoking with secondary cardiovascular disease events was repeated after reclassification of all cotinine positive subjects (including self-reported recent quitters, former or never smokers) as continued smokers and of cotinine negative self-reported continued smokers as recent quitters.
In sensitivity analyses, the serum cotinine cut-off point to distinguish smokers from non-smokers was changed to 10 ng/ml and 20 ng/ml, respectively, and the final analysis (the multivariable model after reclassification of subjects with discordant information in self-reported and cotinine-based smoking-status) was repeated. Additionally, we used serum cotinine levels to categorize patients into non-smokers (cotinine <15 ng/ml), smokers with low (serum cotinine 15 to <280 ng/ml) and smokers with high serum cotinine (serum cotinine ⩾280 ng/ml) and estimated the OR of secondary CVD events in the latter two groups in comparison to non-smokers in the multivariable model.
The analysis was performed using the statistical software SAS®, release 8.222 (SAS Institute, Cary, NC, USA).
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Results |
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Considering self-report on smoking, a minority of participants (n=43, 4.3%) reported to continue to smoke at the beginning of the rehab (Table 1). One third of patients reported to have never smoked, the remaining two thirds reported having quit smoking. Of all 655 patients who reported to have ever smoked, 65% had already quit before the clinical manifestation of CHD at baseline ("former smokers"), while 28% stopped after the manifestation ("recent quitters").
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Table 2 shows the distribution of known cardiovascular risk factors among the categories of smokers as defined by self-report. The proportion of males was lowest among never smokers. Continued smokers and recent quitters were, on average, younger than former and never smokers. Level of school education was highest in recent quitters and never smokers and high alcohol consumption most frequent in continued smokers. While increased blood pressure was less common among continued smokers and recent quitters, continued smokers on average had a more unfavourable lipid profile, along with a higher frequency of treatment with lipid lowering drugs, but they less often had three vessel coronary heart disease compared to the other groups.
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In the additional analysis, in which 127 patients (13%) with discordant information on smoking status from self-report and from serum cotinine were reclassified, the association between smoking and smoking cessation with secondary CVD events was further strengthened. Compared to continued smokers, the odds ratio of a secondary CVD event in adjusted analysis was 0.71 (95% CI: 0.381.33) for recent quitters, 0.64 (95% CI: 0.361.11) for former smokers, and 0.44 (95% CI: 0.240.81) for never smokers (p-value for trend=0.009).
Results of adjusted analysis after reclassification were not affected by change in cotinine cut-off point (10 ng/ml: OR=0.71, 0.68, and 0.46 for recent quitters, former smokers, and never smokers, respectively; 20 ng/ml: OR=0.71, 0.68, and 0.44 for recent quitters, former smokers, and never smokers, respectively). Compared to cotinine-negative subjects, smokers with low serum cotinine showed essentially the same increase in risk of secondary CVD events (OR=1.80) than smokers with high serum cotinine (OR=1.71).
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Discussion |
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While most previous studies addressed the impact of smoking cessation on long term prognosis (mean length of follow-up in previous studies between 3 and 7 years,4 range 210 years9), there are limited data concerning the reduction of recurrent coronary events in the first two years following diagnosis. While a recent study from the United States of America suggested a time lag of about 18 months until manifestation of risk reduction,5 our results support the hypothesis that risk reduction occurs relatively quickly after smoking cessation. These findings require further corroboration.
The rapid decline of risk for CVD events after smoking cessation in patients with diagnosed CHD can be explained by a reversible effect of smoking on development and progression of cardiovascular disease. The effects of smoking on cardiovascular disease are mediated by multiple mechanisms, some of which appear to be reversible within days or weeks, such as the increase in platelet activation, clotting factors, coronary artery spasm, and increased susceptibility to ventricular arrhythmias.3 Other effects, including the development of atherosclerosis as a result of smooth muscle cell proliferation and lipid deposition in the arterial intima, may not be reversible at all or only over a prolonged period of time, which may explain the gradual decrease in risk from recent quitters to former and never smokers.
The combination of self-reported smoking status at the beginning of the rehab and of cotinine measurement at the end of the rehab can be considered a unique strength of this study. In our study, about half of self-reported continued smokers at the beginning of the rehab were cotinine negative at the end of the rehab. These figures appear highly plausible given that smoking cessation is one major aim of cardiac rehabilitation.6 Because there is no reason for these individuals to provide inaccurate information regarding their continued smoking when they began rehab, it can safely be inferred, that these patients quit smoking during rehab, which was confirmed biochemically by their negative serum cotinine levels.
On the other hand, a non-negligible relapse rate has to be assumed among recent quitters, and it is highly questionable whether honest self-reports of resumption might have been obtained in the rehab setting. The finding of 25% cotinine positive patients among recent quitters might provide a rough estimate of the resumption rate during rehab. This is a clear indication that efforts during rehab should focus not only on continued smokers but also on recent quitters to prevent relapse. In addition, approximately 6% and 10% of self-reported former and never smokers were cotinine positive thereby providing an estimate of misreporting of smoking status. Reclassification of these subjects to the group of continued smokers therefore appears to be a reasonable strategy to reduce potential bias.
Different cut-off points for distinguishing smokers from non-smokers using serum cotinine have been reported.11 To evaluate the sensitivity of our results to changes in cut-off point we repeated analyses using 10 and 20 ng/ml as cut-off points. No substantial differences of results were seen. Passive smoking can cause some increase in serum cotinine. However, cotinine levels of passive smokers typically range between 0.1 and 1.4 ng/ml20and thus are unlikely to reach our cut-off point of 15 ng/ml.
The absence of any difference in risk between smokers with high and low cotinine may be due to the fact that, although serum cotinine levels seem to increase with increasing cigarette consumption, the variability of cotinine within the consumption groups is high and thus serum cotinine might not be a sensitive marker for level of cigarette consumption.19,28
Upon examining the results, the following limitations should be considered: Despite the large overall size of the cohort, the numbers of patients and CVD events in subgroups defined by smoking status (particularly in continued smokers) were small, leading to rather wide confidence intervals for the estimated effects. Nevertheless, a clear and statistically significant doseresponse relationship with patterns of smoking and smoking cessation emerged.
Although we were able to determine vital status for all but seven participants, about 20% of patients or their general practitioners did not provide sufficient data to determine the occurrence of non-fatal secondary CVD events during follow-up. The participants thus not included in analyses were, on average, slightly younger, but showed somewhat more unfavourable risk factor levels in terms of BMI, triglyceride level and smoking as measured by serum cotinine level. Thus the risk of non-fatal secondary events for the total cohort might be somewhat higher than estimated from participants included in this analysis, although these would not necessarily affect estimates of the association between smoking and the occurrence of secondary CVD events.
The low number of secondary CVD events might additionally be due to the fact that mortality from myocardial infarction is highest within the pre- and early in-hospital phase. As the acute event leading to diagnosis of CHD had occurred at least 3 weeks before inclusion in this study, we were dealing with a selection of patients with a better prognosis compared to a patient population within the early phase of a newly diagnosed CHD. Furthermore, even though Germany has a very comprehensive in-patient rehabilitation programme which is utilised by the majority of patients who are hospitalised due to acute coronary syndromes, not all patients are willing or able to participate in a rehab program. This is another reason why severely ill patients may be somewhat underrepresented in our study sample.
Although we adjusted for a number of prognostic factors, some residual confounding of results, e.g., by dietary factors for which detailed information was not available, cannot be excluded. It can be argued that those patients who quit smoking after the clinical manifestation of CHD at baseline (i.e., the recent quitters) may be those patients who are more motivated to follow physicians' instructions in general, including taking their medication and modifying other risk factors apart from smoking, such as an increase in physical activity or improvement of diet. This argument, however, would not explain the even more favourable prognosis of former and never smokers, and the "doseresponse patterns" observed in this study.
Despite these limitations, we conclude that the benefits of non-smoking in cardiac patients are beyond controversy and might even be larger than reported from former studies, which exclusively relied on self-reported smoking status. In particular, our study suggests that major beneficial effects of smoking cessation are expected even within the first year after acute manifestation of coronary heart disease. These results underline the importance of efforts to support smoking cessation and to prevent relapse during and after rehab of patients with coronary heart disease.
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Acknowledgments |
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Footnotes |
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References |
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