Q J Med 1999; 92: 327-333
© 1999 Association of Physicians
Lower cardiac mortality in smokers following thrombolysis for acute myocardial infarction may be related to more effective fibrinolysis
From the Department of Cardiology, Sunderland Royal Hospital, Sunderland, UK, and 1 Department of Cardiac Medicine, National Heart and Lung Institute, London
Received 25 February 1999
Dr I.F. Purcell, Cardiac Medicine, Imperial College School of Medicine at National Heart and Lung Institute, Dovehouse Street, London SW3 6LY. e-mail: i.purcell{at}ic.ac.uk
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Summary |
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Smokers have unexplained lower cardiac mortality than non-smokers in the short term following acute myocardial infarction (AMI). We hypothesized that smokers may have enhanced systemic fibrinolysis following thrombolysis. We studied 185 consecutive patients receiving thrombolysis for first AMI. Cardiac mortality at 36 days after thrombolysis was 11.9% (22 deaths). Factors associated with cardiac mortality were: smoking (current 3.4% mortality, previous 11.4%, never 24.2%) (p<0.001); post-thrombolysis plasma fibrinogen at 60 min (p<0.05); diabetes (p<0.005); age (p<0.01); time to thrombolysis (p<0.05); and ECG evidence of reperfusion (p<0.05). In logistic regression analysis, smokers were at significantly lower risk of cardiac death compared with non-smokers: unadjusted odds ratio (OR) 0.3 (95% CI 0.2–0.7) (p<0.01). This was independent of age, diabetes, ECG evidence of reperfusion and pain to treatment time: OR 0.4 (95% CI 0.3–0.9) (p<0.05). Smoking was not an independent prognostic factor after adjustment for post-thrombolysis plasma fibrinogen OR 0.5 (95% CI 0.4–1.1) (p=0.1), although its insignificance may be due to lack of numbers. In non-smokers, there was a subgroup with persistent ST elevation, high post-thrombolysis fibrinogen and 40% short-term mortality. No similar high-risk subgroup was observed in smokers. Smoking was associated with lower mortality in patients receiving thrombolysis for first AMI, and post-thrombolysis fibrinogen concentrations were associated with this beneficial effect. Although patient numbers are small, and the hypothesis should be tested further in a larger group, the higher likelihood of incomplete reperfusion and of incomplete fibrinolysis in non-smokers supports the hypothesis that smokers may have enhanced systemic fibrinolysis following thrombolysis in AMI.
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Introduction |
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Cigarette smoking is an independent risk factor for coronary atherosclerosis, acute myocardial infarction and sudden death,1,2 but paradoxically the short-term mortality of smokers admitted with acute myocardial infarction (AMI) is 30 to 50% that of non-smokers.3–13 Smokers are younger than non-smokers and have fewer risk factors at presentation, but even after adjusting for these factors, smoking remains independently associated with lower mortality.7–11 The most important factor relating smoking to survival after thrombolysis for AMI appears to be that more smokers achieve TIMI grade 3 flow in the infarct-related vessel than do non-smokers.7,8,10–12 Smoking is associated with a hypercoagulable state, particularly higher fibrinogen, compared with non-smokers.14,15 This may predispose smokers to thrombotic vessel occlusion at an earlier stage of atheromatous disease than non-smokers, leading to coronary occlusions which are more susceptible to thrombolysis. Alternatively, smokers may have a more complete fibrinolytic response to thrombolysis, leading to improved vessel recanalization for the same degree of stenosis compared with non-smokers.
The majority of data on the effect of smoking on prognosis following thrombolysis in AMI have come from thrombolytic or angiographic trials, which excluded many patients encountered in routine practice.5–8,10–12 We chose to study unselected consecutively admitted patients with AMI, to determine if lower mortality was found in smokers treated in routine clinical practice, and to explore further explanatory variables linked to their better prognosis. We hypothesized that in addition to demographic differences and coronary factors encouraging vessel recanalization, smokers might also have a systemic fibrinolytic response to thrombolysis which is more favourable than that of non-smokers.
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Methods |
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Patients
Patients studied were a consecutive series with first myocardial infarction who received thrombolysis within 12 h of onset of chest pain. Criteria for thrombolytic administration were chest pain for 30 min or greater, and ST elevation in two or more leads on a standard 12-lead ECG (0.1 mV limb leads, 0.2 mV chest leads). There was no age limit, and the conventional contra-indications to thrombolysis were observed.16 Streptokinase (1.5 MU intravenously over 60 min) was given unless the patient was hypotensive on presentation (systolic blood pressure <90 mmHg) or where streptokinase intolerance or allergy was likely. Intravenous front-loaded tPA was given in these circumstances.16 Specific exclusion criteria were: previous AMI, or an initial ECG with an uninterpretable ST segment; bundle branch block; temporary or permanent cardiac pacemaker. Conventional post-infarction care was given in all cases and was not altered by additional ECGs performed or data from fibrinogen assays.
Smoking status
Smoking status was obtained from the patient or next of kin on admission. Current smokers were defined as patients who had smoked within 7 days of admission. Non-smokers had never smoked on a daily basis. Ex-smokers were defined as patients who had not smoked within 7 days of admission.
Post-thrombolytic coagulation state
Blood samples were taken 60 min after thrombolysis initiation for plasma fibrinogen measurement which was carried out by the method of Clauss17 using the Sysmex Model CA-1000 coagulation analyser. This was accurate for fibrinogen levels from 0.05 to 50 g/l.
Electrocardiographic evidence of myocardial reperfusion
A 12-lead ECG was recorded immediately prior to initiation of thrombolysis and at 60, 90 and 180 min thereafter. The ST segment was measured by calliper at 80 ms beyond the J point. The lead of maximum ST elevation was determined from the baseline ECG, and used for subsequent measurements. ST segment deflection on serial 12-lead ECGs up to 180 min was compared with the baseline ECG. A 50% fall in ST segment elevation is a well-validated marker of coronary patency, while a failure to achieve a 25% fall in ST segment elevation is a good predictor of poor clinical outcome.18–22
Cardiac mortality
Patients were followed for 36 days. The cause of any deaths within 36 days was sought from hospital records or the General Practitioner after hospital discharge. Cardiac deaths were identified, and patients were excluded if they suffered non-cardiac death (n=5) or the cause of death was unknown (n=1). Follow-up was complete.
Statistics
Categorical data were compared by the 
2 test. Continuous data were log10-transformed, where required, to provide a normal distribution and compared by Students t-test. The assessment of association of multiple prognostic variables with cardiac mortality was carried out by multiple logistic regression analysis. Comparison of current and non-smoking as prognostic factors and calculation of odds ratios was performed by logistic regression with forward stepwise addition of variables. The fit of continuous variables in the statistical model as linear, polynomial or categorical terms was tested. Polynomial terms up to the fourth power were tested. The deviances of categorical models up to quintile divisions were compared with the deviance of the linear model by the likelihood ratio test. The overall goodness of fit of the model was tested by the Homser-Lemeshow test. Interactions between prognostic variables were investigated and included in the logistic regression model. Statistical significance was accepted as p<0.05. Analysis was carried out using SPSS statistical software.
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Results |
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Baseline characteristics
Of the 332 consecutive patients with AMI, 262 (79%) underwent thrombolysis. Forty-seven had had a previous myocardial infarction and were not enrolled in this trial. The remaining 215 patients were screened, and 30 were excluded: 14 because the baseline ECG or all subsequent ECGs had uninterpretable ST segments because of conduction abnormalities; five because of inappropriately-timed ECG recordings; five because of non-cardiac death (one cerebral infarction, two cerebral haemorrhage, one peripheral embolism, one pulmonary TB); one because of death of unknown cause; and five because of unknown smoking history. We therefore studied 185 patients who received thrombolysis for first myocardial infarction: 97% received streptokinase, 3% tPA. The baseline characteristics of this cohort have been published in detail.22
Patient characteristics according to smoking history
Table 1
summarizes patient baseline characteristics, ECG data and 60-min plasma fibrinogen level according to smoking history: 48% were current smokers, 19% previous smokers and 33% had never smoked. Current smokers were significantly younger than non-smokers (60.5 years vs. 67.0 years, p<0.001) and were less likely to have hypertension (15% vs. 33%, p<0.005). Pain-to-treatment time did not vary between groups defined by smoking history.
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Results of thrombolysis according to smoking history
A 50% fall in ST segment elevation 60 min after thrombolysis was achieved by 44% of current smokers compared with 43% of non-smokers. Failure to achieve a 25% fall in ST elevation by 180 min was seen in 35% of non-smokers compared with 16% of current smokers (p<0.05). Plasma fibrinogen after thrombolysis did not differ significantly between non-smokers, previous or current smokers.
Univariate analysis of cardiac mortality
Overall cardiac mortality was 11.9% (22 cardiac deaths). Factors associated with cardiac mortality (p<0.05) are given in Table 2. Cardiac mortality was significantly lower for current smokers (3.4%) than for previous (11.4%) or non-smokers (24.2%) (p<0.001). Inclusion of the six non-cardiac deaths in the analysis gives total mortality results for current smokers of 5.6% (5/90), previous smokers 16.2% (6/37) and non-smokers 26.6% (17/64). Inclusion of non-cardiac deaths did not affect the statistically significant association between smoking and mortality. Mortality was lower in patients with plasma fibrinogen <0.5 g/l at 60 min following initiation of thrombolysis, at 4.5% (5/112), compared with 17.1% (7/41) at 0.5 g/l or above (p<0.05). Age and 25% ST fall by 180 min were the only factors associated with mortality to differ between groups defined by smoking history.
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ST change, plasma fibrinogen and cardiac mortality
Table 3
summarizes the relationship between plasma fibrinogen at 60 min, 25% ST segment change by 180 min and subsequent cardiac mortality for current smokers compared with non-smokers. In current and non-smokers, failure to achieve a 25% fall in ST segment elevation was associated with higher mortality, although this was considerably higher for non-smokers. There was no difference in plasma fibrinogen at 60 min after thrombolysis between current smokers who achieved a 25% ST fall at 180 min compared with smokers who did not achieve a 25% fall in ST segments. However in non-smokers, persistent ST elevation was associated with higher fibrinogen. In the whole population, mean plasma fibrinogen at 60 min was higher in patients who subsequently did not achieve a 25% fall in ST elevation by 180 min than in those who did: 0.36 g/l (range 0.16–0.81) compared with 0.25 g/l (0.12–0.55) (p<0.05).
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Multivariate analysis of cardiac mortality
All prognostic factors were entered into a multiple logistic regression analysis with cardiac death as the dependent variable. This analysis was carried out on patients with complete data available for all prognostic variables (n=121). The best model-fitting was achieved with age expressed as quintiles (p<0.05 for comparison of deviances of quintile and linear models), while the other continuous variables were expressed appropriately as linear terms. Interactions between all the prognostic variables included in the model were tested. There was a significant interaction between post-thrombolysis fibrinogen and smoking history in predicting cardiac mortality. When all prognostic variables were entered into the statistical model, time to thrombolysis and post-thrombolysis fibrinogen were independent predictors of cardiac mortality. Smoking history was not independently associated with cardiac mortality after adjustment for other prognostic factors. After fitting the interaction between fibrinogen and smoking in the model, fibrinogen was not an independent predictor of cardiac mortality. The overall goodness of fit of the model was satisfactory (Homser-Lemeshow test, p=0.9).
Figure 1 shows the odds ratios for cardiac mortality, comparing current with non-smokers after stepwise adjustment for other relevant variables. The unadjusted odds ratio for cardiac mortality in current smokers was 0.3 (95% CI 0.2–0.7) (p<0.01). Current smoking was independently associated with lower cardiac mortality after adjustment for age, hypertension, diabetes mellitus, ECG evidence of reperfusion and time to thrombolysis: odds ratio 0.4 (95%CI 0.3–0.9), (p<0.05). After adjustment for post-thrombolysis fibrinogen, current smoking was not associated with lower cardiac mortality at the 5% confidence level: odds ratio 0.5 (95%CI 0.4–1.1) (p=0.1).
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Discussion |
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A strong relationship between cigarette smoking and mortality following thrombolysis for AMI has been consistently found but the nature of this relationship remains unknown. This study is the first to investigate the effect of smoking on cardiac mortality in unselected, consecutive patients all receiving thrombolysis by standard indications for first AMI. It is also the first to investigate the systemic fibrinolytic response to thrombolysis as a prognostic factor related to better outcome in smokers.
Relationship between smoking and cardiac mortality
Current smokers had significantly lower 36-day mortality than previous or non-smokers. This confirms the findings of previous studies but extends the observation to routine clinical practice.3–13 Previous data have mostly come from patients selected for studies designed to evaluate thrombolytic agents or post-AMI angiography.5–8,10–12 Three previous trials involving unselected patients included a mix of thrombolysed and non-thrombolysed subjects,3,9,13 whereas our aim was specifically to investigate the interaction between smoking and outcome after thrombolysis. Mortality in current smokers (3.4%) was comparable to that in previous studies, but mortality in non-smokers was higher than reported for recent thrombolysis trials, at 24.2% compared with 9–12%.7,8,10 This is likely to be due to the exclusion of older, higher-risk, predominantly non-smokers from thrombolytic trials. In this study, an ex-smoker was defined as a subject who had not smoked for at least one week prior to presentation. This cut-off was chosen as the acute effects of smoking on coagulation and endothelial function are likely to have diminished by this time; however, the effects of smoking in promoting premature atherosclerosis would not change within a week. These two mechanisms of smoking-related disease presumably lead to the intermediate mortality result in ex-smokers. However, there were insufficient numbers of ex-smoker deaths to allow meaningful statistical analysis of ex-smokers as a separate group in multivariate analysis.
Demographic factors
In this and previous studies, smokers had demographic characteristics at presentation, particularly lower age, which were associated with survival advantage compared with non-smokers.3–13 However in multivariate analysis, we and others found that smoking was independently associated with lower mortality even after statistical adjustment for demographic factors.3,7,8,10,11 In this study, the odds ratio for cardiac mortality after adjustment for demographics was 0.4 (95% CI 0.3–0.9) for current compared with non-smokers.
Pre-admission mortality
Smoking is associated with an increased risk of sudden death, and it has been suggested that better survival in smokers following hospital admission could be explained by the pre-hospital death of high-risk smokers.23 This suggestion was based on the observation that although hospital mortality was lower in smokers following AMI, total mortality (pre- and post-hospital admission) was not. However, pre-admission mortality in that study was unexpectedly high at 34.0–38.4%, and did not differ significantly between groups according to smoking history. In addition, post-admission mortality in current smokers was higher than in this and previous studies.3–13 It is unlikely that lower hospital mortality in smokers can be explained solely by higher pre-admission mortality.
Reperfusion in smokers
We chose to investigate myocardial reperfusion because it strongly predicts short-term mortality and can be estimated non-invasively by ST segment measurement. Significantly more non-smokers failed to achieve a 25% fall in ST elevation by 180 min compared with current smokers. This level of persistent ST elevation is associated with suboptimal infarct-related vessel recanalization, and high short-term mortality.22,24 These ECG data are consistent with angiographic studies, where more non-smokers than smokers had suboptimal vessel recanalization (TIMI grades 0–2) after thrombolysis.7,8,10–12 Higher rates of suboptimal recanalization were associated with higher mortality in non-smokers which, when entered into multivariate analysis, accounted for the statistical difference in mortality between smokers and non-smokers.7,8,10–12
Enhanced systemic fibrinolytic response to thrombolysis in smokers?
Better post-thrombolysis coronary artery recanalization has been attributed to relatively more thrombotic and less atheromatous coronary occlusions in smokers compared with non-smokers.7,12 However, in all studies where it was measured, the severity of residual stenoses in infarct-related vessels after thrombolysis did not differ between smokers and non-smokers.8,10,11 The occlusive thrombus in smokers may have a different composition to that in non-smokers making it more susceptible to thrombolysis, but we hypothesize that smokers may have enhanced intrinsic fibrinolysis resulting in improved vessel recanalization.
Data presented in this study provide some support for this hypothesis. Post-thrombolysis plasma fibrinogen and smoking history were both strongly associated with cardiac mortality. In multivariate analysis, there was a significant interaction between post-thrombolysis plasma fibrinogen and smoking history in predicting cardiac mortality. In logistic regression analysis comparing risk of cardiac mortality between current smokers and non-smokers, current smoking was associated with survival independent of all prognostic variables except post-thrombolysis fibrinogen. However, the last result should be cautiously interpreted because, although not significant at the 5% level, the odds ratio for current smokers mortality was only 0.5 compared with non-smokers after adjustment for fibrinogen. Thus statistical insignificance may simply be a consequence of the relatively small number of end-points. The residual odds ratio of 0.5 after adjustment for all available prognostic variables indicates that there are further important associations with mortality, for example coronary anatomy, which were not in our model.
The mechanism associating cigarette smoking, systemic fibrinolysis and cardiac mortality is likely to be via more effective post-thrombolysis vessel recanalisation. Among non-smokers there was a large subgroup with suboptimal myocardial reperfusion by ECG criteria and less complete systemic fibrinolysis who had 36-day mortality of 40%. A similar high-risk subgroup was not evident among smokers. This is consistent with the hypothesis that current smokers as a group are less likely than non-smokers to have a suboptimal fibrinolytic response to thrombolysis and therefore have overall better coronary recanalization and lower mortality. The potential mechanism which relates enhanced post-thrombolytic systemic fibrinolysis in smokers is unknown, but could involve increased plasma fibrinolytic activity.26–29
It is important that this study is considered as hypothesis-generating and not hypothesis-proving. In multivariate analyses of this size, non-significant results are inconclusive, and very strong associations are necessary for a variable to be significant. This new hypothesis in the smokers' paradox should now be tested in a larger patient group.
Conclusions
Cigarette smoking was associated with lower short-term cardiac mortality in unselected patients receiving thrombolysis for first AMI. Current cigarette smoking was associated with lower mortality independent of all prognostic variables except plasma fibrinogen at 60 min after initiation of thrombolysis. Fewer smokers had ECG evidence of failed reperfusion than non-smokers. Non-smokers with ECG evidence of failed reperfusion had 40% short-term mortality and had significantly higher plasma fibrinogen than current smokers. These data suggest that lower cardiac mortality in smokers relates to more complete systemic fibrinolysis compared with non-smokers. This in turn may be associated with better myocardial reperfusion in response to thrombolytic therapy and better prognosis.
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Acknowledgments |
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We thank the nursing and technical staff in the Department of Cardiology, and the manager and staff in the Audit Unit at Sunderland Royal Hospital for their assistance during this study. We are grateful to Mrs Amy Hider for expert advice given on statistical analysis.
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References |
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