Smokers With ST-Segment Elevation Myocardial Infarction and Short Time to Treatment Have Equal Effects of PCI and Fibrinolysis

Abstract: Objectives. The purpose of this study was to examine the effect of primary percutaneous coronary intervention (PCI) compared to fibrinolysis in smokers and non-smokers with ST-segment elevation myocardial infarction (STEMI). Smokers seem to have less atherosclerosis but are more prone to thrombotic disease. Compared to non-smokers, they have higher rates of early, complete reperfusion when treated with fibrinolysis for MI. Methods and Results. In the Second Danish Multicenter Trial in Acute Myocardial Infarction (DANAMI-2), a total of 1572 patients with STEMI were randomized to either fibrinolysis or PCI (1129 patients were enrolled at 24 referral hospitals and 443 patients at 5 invasive treatment centers). The primary endpoint for this substudy was death by any cause. Secondary endpoints were a composite of death by any cause, clinical re-infarction or disabling stroke. Follow-up was 3 years. The effect of PCI is reported according to time to treatment and smoking status. Data on smoking habits were available for 1534 patients (895 smokers and 639 non-smokers). Smokers with short time to treatment (<3 hours) benefited equally from PCI and fibrinolysis with a trend toward higher mortality in the PCI group (mortality [hazard ratio, 1.64 (0.79-3.41); P=.18], composite endpoint [hazard ratio, 1.06 (0.65-1.71); P=.82]). In non-smokers with short time to treatment PCI was superior to fibrinolysis (mortality [hazard ratio, 0.46 (0.22-0.93); P=.02], combined endpoint [hazard ratio, 0.45 (0.26- 0.79); P=.004]). Patients with >3 hours to treatment all showed a tendency toward a superior effect of PCI irrespective of smoking habits. Conclusions. PCI and fibrinolysis are equally beneficial in smokers with STEMI and short time to treatment.

J INVASIVE CARDIOL 2012;24(8):401-406

Key words: percutaneous coronary intervention, ST-segment elevation myocardial infarction, smoking, fibrinolysis

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Primary percutaneous coronary intervention (PCI) has shown to be superior to fibrinolytic therapy in decreasing major adverse cardiovascular events after ST-segment elevation myocardial infarction (STEMI). This has been demonstrated in patients admitted directly to hospitals with angioplasty facilities and in those who were admitted to referral hospitals and immediately transferred to invasive centers. Therefore, PCI is now the gold standard treatment of patients with STEMI.^1-7 Various factors around the world, though, challenge the dilemma that an invasive strategy is not feasible in all patients with STEMI. The invasive strategy requires a facility and operators for PCI who conduct enough procedures annually to remain proficient and these conditions are not present throughout the world. In rural regions, which lack invasive centers or have long distances to such facilities, an invasive approach is limited or even impossible.^6,7

In a community where a complete invasive strategy for every patient with STEMI is not feasible, identifying patients most likely to benefit from an invasive approach is very important. Risk stratification of patients at admission is one way to differentiate patients. An earlier study (DANAMI-2) used the Thombolysis in Myocardial Infarction (TIMI) risk score to identify a group of high-risk patients with significantly reduced mortality with primary angioplasty.⁸ There might still be other groups of patients who could benefit more from PCI than others compared to fibrinolysis.

Smoking is known as a major risk factor in the development of acute myocardial infarction (MI). The mechanism by which smokers develop MI seems to be different to non-smokers. The infarct lesions often have a greater thrombotic component with relatively less atherosclerotic burden,^9-11 and smokers are younger when they develop their MI.^9-15 They appear to have less multi-vessel disease and fewer infarctions are located in the territory of the left anterior descending coronary artery.⁹ Active smokers seem to be in a state of relative hypercoagulation with increased hematocrit and fibrinogen levels, impaired endothelial function, a tendency to vasospasm, and enhanced production of platelet thrombus. All these factors predispose smokers to the formation of thrombus in the setting of MI.^9,10 Randomized trials have shown that smokers with MI have higher rates of early, complete reperfusion when treated with fibrinolysis than non-smokers.^9,10,14 This suggests that smokers could benefit relatively more from fibrinolysis than non-smokers. This has, to our knowledge, not been well examined, and therefore our goal was to investigate whether an interaction between smoking status and the effect of primary PCI compared to fibrinolysis in patients with STEMI could be found. In the present study, we report a 3-year clinical outcome for smokers vs non-smokers in the Second Danish Multicenter Trial in Acute Myocardial Infarction (DANAMI-2) after STEMI randomized to either PCI or fibrinolysis.

Methods

The present study included 1572 patients from the DANAMI-2 multi-center study, which was a randomized trial to determine whether patients with STEMI could benefit from PCI compared to fibrinolysis. The DANAMI-2 study has been described in detail previously.^1,2,16 In brief, a total of 4278 STEMI patients were screened for enrollment in the study, with 1572 patients randomized to either PCI or fibrinolysis with intravenous alteplase. Of these, 1129 patients were enrolled at 24 referral hospitals without angioplasty capability and 443 patients at 5 invasive centers.

The study was approved by the National Ethics Committee of Denmark and all patients provided written informed consent.

Criteria for eligibility. In brief, the criteria for inclusion were age ≥18 years, presence of symptoms for >30 minutes but <12 hours, and a cumulative ST-segment elevation a minimum of 4 mm in at least two contiguous leads.

The criteria for exclusion were contraindications to fibrinolysis, left bundle branch block, MI or fibrinolysis in the last 30 days, pulseless femoral arteries, previous coronary artery bypass graft (CABG), known renal failure (defined as a serum creatinine above 2.83 mg/dL or 250 µmol/L), diabetes treated with metformin, non-ischemic heart disease, non-cardiac disease with life expectancy <12 months and high risk during transfer because of cardiogenic shock (severe heart failure with persistent systolic blood pressure ≤65 mm Hg), sustained life-threatening arrhythmia, or a need for mechanic ventilation.

Smoking status. Smoking status was classified according to self-report. Patients who were currently smoking at the time of admission were considered smokers and patients who had never smoked or ceased smoking previously were considered non-smokers.

Treatment. A detailed description of the revascularization treatment has been published previously.¹ The fibrinolysis group was treated with aspirin, b-blocker, accelerated plasminogen activator (alteplase), and intravenously unfractionated heparin. Alteplase was administered as a bolus of 15 mg followed by infusion with 0.75 mg/kg over 30 minutes and subsequent infusion of 0.5 mg/kg over 60 minutes.

Angioplasty was preceded by treatment with aspirin, b-blocker, and intravenous unfractionated heparin. Platelet glycoprotein IIb/IIIa administration was left to the discretion of the treating physician. Stenting of the culprit lesion was attempted in all patients unless the vascular diameter was <2.0 mm. All stents were bare-metal stents. After stent implantation, ticlopidine or clopidogrel was administered for 1 month according to the guidelines at the time of the trial. Judgment of the angiograms was carried out by an independent core laboratory (Cardialysis).

Endpoints and definitions. In the present paper, the primary endpoint was death by any cause within 3 years. Secondary endpoints were a composite of death by any cause, clinical re-infarction, or disabling stroke within 3 years. A procedure-related re-infarction was not included as a secondary endpoint.

Detailed definitions of the endpoints are available elsewhere.¹ A re-infarction was defined as an increase in creatine kinase and MB isoenzyme activity and either symptoms of chest pain or presence of electrocardiographic changes. A clinical re-infarction was defined as an increase in the creatine kinase MB in a patient with normalized levels after the index infarction or as an increase of at least 50% compared to the previous level. Disabling stroke was defined as a fatal stroke or a stroke causing a clinically significant mental or physical disability, ranging from slight handicap (ie, patients could not engage in all previous activities, but could still take care of himself or herself) to severe (ie, patients in a bedridden state with requirement for constant care and nursing).²

Statistical analysis. All analyses were based on intention-to-treat. Categorical variables are expressed as percentages and continuous variables are reported as medians and interquartile ranges or mean ± standard deviation. Differences in baseline characteristics for smokers and non-smokers were assessed using chi-square test for discrete variables and Kruskal-Wallis test for continuous variables. A P-value <.05 was considered statistically significant. Median time to treatment was 3 hours, and this was prespecified as the cut-off for subgroup analyses of benefit from treatment. Cumulated event rates were illustrated with the use of Kaplan-Meier curves. The curves were compared for differences with the log-rank test. Hazard ratios were analyzed with Cox regression analysis. Interaction analyses were performed by the Cox proportional hazard model including interaction variables. As patients were randomized to angioplasty or fibrinolysis, multi-variable adjustments were not performed when the effect of treatment allocation was tested. All calculations were performed using SAS, version 9.1 (SAS Institute).

Results

Baseline characteristics. Of the total population of 1572 patients, 895 were smokers and 639 were non-smokers. Smoking status was missing in 38 cases. Baseline characteristics for smokers and non-smokers according to randomization groups are illustrated in Table 1. There were no differences between the randomized groups except from the time to treatment. Thus, patients randomized to PCI had the same baseline characteristics as patients randomized to fibrinolysis. However, there were significant differences between smokers and non-smokers. Smokers were nearly a decade younger than non-smokers (in total, 59.5 years vs 67.5 years, respectively; P<.001). There were no differences in age among non-smokers (P=.73) or smokers (P=.30) in the PCI versus the fibrinolysis group. There were no gender differences between the two treatment groups, irrespective of smoking status, but smokers were less likely to have a clinical history of hypertension (P<.0001) and diabetes (P=.02), but more likely to have a history of intermittent claudication (P=.02) compared to non-smokers. Non-smokers were more likely to be treated with aspirin (P=.002), b-blockers (P=.0002), ACE-inhibitors (P=.002), and calcium-antagonists (P=.0001) prior to hospitalization than smokers. They also had a higher rate of anterior myocardial infarction (P=.0002). Whereas time to randomization was similar, time to treatment was longer in the PCI versus the fibrinolysis group in both non-smokers (P<.0001) and smokers (P<.0001).

Complications & angiographic characteristics. In Table 2, the complications and angiographic characteristics data are shown. Of the 447 smokers treated with fibrinolysis, 6 patients had a rescue PCI performed (data not shown).

Of the smokers, 58% were completely revascularized vs 54% of the non-smokers (P=.28). In 31% of the smokers, a thrombus was found during angiography vs 26% in the non-smoking population (P=.32). Smokers received a mean of 1.2 stents versus 1.3 stents in the non-smokers (P=.43). TIMI flow17 was 3 prior to PCI in 18% of the smokers vs 15% of the non-smokers (P=.31). TIMI flow was 3 after PCI in 90% of the smokers vs 82% of the non-smokers (P=.004).

There was no difference in complication rates after PCI between smokers and non-smokers. Cardiogenic shock occurred in 7.1% of non-smokers vs 6.0% of smokers (P=.54), 1.2% of non-smokers suffered from a transient ischemic attack vs 0.2% of smokers (P=.08), and 8.8% of non-smokers suffered from undiscovered dissection vs 10.1% of smokers (P=.70). Frequencies of disabling stroke were 3.8% in non-smokers vs 4.0% in smokers in the fibrinolysis group (P=.87) and 4.3% in non-smokers vs 1.3% in smokers in the PCI group (P=.01).

Composite endpoint and all-cause mortality. Smokers with STEMI had significantly lower overall cumulative event rates of death by any cause, clinical re-infarction, or disabling stroke (P=.0016) compared to non-smokers. In addition, their overall mortality was significantly lower than non-smokers (P<.0001) (Figure 1). However, the prognostic importance of smoking was not significant, with a hazard ratio (HR) of 1.13 (0.83-1.55) in a multivariable model including other significant predictors of mortality (age, time to treatment, cardiogenic shock, ventricular arrhythmias, heart rate, and heart failure). We found an overall favor of treatment with PCI regarding the combined endpoint, but not mortality where there was no difference (HR, 0.75 [0.61-0.92] and P=.007 vs HR, 0.91 [0.70-1.18] and P=.46) (Figure 2).

Non-smokers treated with PCI had lower event rates of death by any cause, clinical re-infarction, or disabling stroke compared to fibrinolysis (P=.01), and the overall mortality also tended to be lower in the PCI group (P=.06; data not shown). Non-smokers had superior effect from PCI compared to fibrinolysis concerning the combined endpoint, and the mortality tended to be lower after treatment with PCI (HR, 0.69 [0.50-0.94] and P=.02 vs HR, 0.71 [0.49-1.05] and P=.08) (Figure 2).

Smokers with STEMI treated with PCI tended to have lower cumulative event rates of death by any cause, re-infarction, or disabling stroke (P=.08). When comparing the cumulative event curves of mortality after PCI vs fibrinolysis, there was no statistical difference (P=.50; data not shown). The interaction between effect of intervention and smoking status was non-significant for mortality (P=.10) and for the combined endpoint (P=.62). Smokers tended to have better effect from PCI compared to fibrinolysis regarding the combined endpoint, but regarding mortality there was no difference (HR, 0.77 [0.56-1.04] and P=.09 vs HR, 1.14 [0.76-1.72] and P =.52) (Figure 2).

In order to explore the effect of primary PCI compared to fibrinolysis, we analyzed whether the treatment effect was dependent on the combination of smoking status and time to randomization or time to actual treatment. Non-smokers with a short time to treatment (defined as treatment within 3 hours of symptoms) had a survival benefit when treated with PCI compared to fibrinolysis (HR, 0.46 [0.22-0.93]; P=.03) while smokers with short time to treatment had a trend in the opposite direction (HR, 1.64 [0.79-3.41]; P=.18) (Figure 2). However, the interaction between time to treatment and benefit of PCI on mortality was non-significant (P=.13). Analysis of the combined endpoint in patients with short time to treatment showed similar results, with a large reduction in the combined endpoint for non-smokers (HR, 0.45 [0.26-0.79]; P=.004) and much smaller effect for smokers (HR, 1.06[0.65-1.71]; P=.82; P-value for interaction =.056) (Figure 2). For all patients with longer time to treatment, there was a similar tendency toward beneficial effect of PCI treatment on both mortality and the combined endpoint (Figure 2).

Time to randomization and time to treatment were correlated with a chi-square of 0.97, and calculations using time to randomization instead of time to treatment were almost identical.

Discussion

We found that PCI was superior to fibrinolysis in non-smokers with short time to treatment in regard to both the primary and secondary endpoints. All patients with longer time to treatment had a similar tendency toward beneficial effect of PCI on both endpoints. Therefore, PCI should still be the standard when treating non-smokers with STEMI.

The other important finding was that smokers with short time to treatment benefit equally from PCI and fibrinolysis. The implications of this subgroup analysis, which is only hypothesis generating, could be that fibrinolysis might be the treatment of choice in smokers with short time to treatment. Nevertheless, this is important in communities where a complete invasive strategy for every patient with STEMI is not feasible and where every patient should be carefully selected before choosing an invasive strategy. In these cases, smokers with short time to treatment could represent a group in which it would be rational to choose treatment with fibrinolysis over PCI.

A great amount of data supports the association between smoking and cardiovascular morbidity and sudden cardiac death, but the precise mechanisms by which smoking contributes to these events remains to be fully determined.^11,18

Regarding MI, several large clinical studies demonstrate lower mortality as well as short-term morbidity for smokers compared to non-smokers.^9-13,19 This is consistent with our findings (P<.0001 and P=.0016 for the primary and secondary endpoints, respectively), but smoking in itself was no prognostic indicator. This may partly be explained by the younger age, different presentation with respect to extent of coronary vessel disease, and that lesions are more thrombogenic than atherosclerotic in smokers.^9-11

Smoking is associated with an impairment of acute coronary tissue plasminogen activator (tPA) release, an endogen fibrinolytic factor that regulates the degradation of intravascular fibrin. By rapid mobilization of tPA from the intracellular storage pool to the coronary vessel, an endogen fibrinolysis is initiated in the formation of a thrombus. The impairment of tPA release in smokers influences the local fibrinolytic balance in the coronary circulation, providing a direct link between endothelial dysfunction, artherothrombosis, and MI.²⁰ Smoking also precipitates agglutination of platelets.^11,21 This might suggest that smokers with their impaired tPA release and thus impaired endogen fibrinolysis and precipitated agglutination of platelets might benefit relatively more from treatment with fibrinolysis than non-smokers. In the present study, we found (contrary to non-smokers) no significant difference in primary or secondary endpoints in smokers with short time to treatment treated with PCI or fibrinolysis. These findings might represent a relatively better responsiveness to fibrinolysis in smokers compared to non-smokers. Nevertheless, we found a mean TIMI flow at the end of revascularization of 2.9 for smokers vs 2.8 for non-smokers (P=.04), and TIMI 3 flow in 90% of smokers vs 82% in non-smokers (P=.004). The statistical difference between smokers and non-smokers may be explained by the different extent of coronary artery disease.

It has been demonstrated in previous studies that older age is consistently regarded as the most important factor influencing the early prognosis after MI.^11,22 In this study, we found that smokers were a decade younger than non-smokers in the setting of STEMI which is consistent with other studies.^9-15,21 We also demonstrated that smokers with STEMI had significantly lower mortality rates compared to non-smokers. This has previously been termed “the smokers paradox” and may in part be explained by younger age and a more favorable risk-profile with less comorbidity.^9-15

In other studies regarding acute MI and smoking, there has been a greater proportion of males in the smoking population.^9,11,12,15 In the present study we did not find any gender difference between smokers and non-smokers (P=.22).

The time to treatment was longer in the PCI versus the fibrinolysis group (P<.0001 for both smokers and non-smokers). This is obviously because patients had to be transported and prepared for PCI, and is considered counterbalanced by a delayed time to opening of the occluded vessel by fibrinolysis compared to PCI. In the PCI group, smokers had a shorter time to treatment compared to non-smokers (P=.006), which was driven by age differences. The same trend was seen in the fibrinolysis group, but did not reach statistical significance (P=.12).

Study limitations. This study is a post hoc subgroup analysis. On the other hand, a relatively long follow-up is provided, and the DANAMI-2 study has complete follow-up in all patients. With 639 non-smokers, there is a risk that the study is underpowered to show a difference.

Smoking status was classified according to self-report. It is uncertain whether patient reporting was accurate in every case. The study does not include data on extent of smoking of former or current smokers. There are no data on how many patients ceased smoking after MI in this study.

The benefit of long-term treatment with clopidogrel in both angioplasty²³ and fibrinolysis²⁴ and the benefit of using platelet glycoprotein IIb/IIIa-receptor blockers in primary angioplasty²⁵ and enoxaparin in fibrinolysis²⁶ had not yet been shown at the time of the planning of DANAMI-2. Thus, improved long-term outcome might be achieved with contemporary pharmacotherapy in both reperfusion strategies today.

Since patients with cardiogenic shock or post-acute MI bypass were excluded from this study, the findings cannot be generalized to all STEMI patients undergoing reperfusion therapy, but possibly only to lower-risk patients.

Conclusion

The present study suggests that smokers with STEMI and short time to treatment benefit equally from fibrinolysis and PCI. Therefore, fibrinolysis could be an acceptable treatment in this group of patients. Conversely, non-smokers, who tend to be elderly and more atherosclerotic, seem to have a mortality benefit from PCI compared to fibrinolysis, especially if time to treatment is short.

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From the ¹Department of Cardiology, Rigshospitalet, University of Copenhagen, Denmark, ²Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark, ³Department of Cardiology, Odense University Hospital, Denmark, ⁴Department of Cardiology, Skejby Hospital, University of Aalborg, Denmark.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted February 13, 2012, provisional acceptance given March 15, 2012, final version accepted April 10, 2012.
Address for correspondence: Dr Thomas Rasmussen, Rigshospitalet, University of Copenhagen, Cardiology, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark 2100. Email: drrasmussen@hotmail.com