We sought to investigate the effect of smoking on infarct size (IS) and major adverse cardiac events (MACE) in patients with large anterior ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Participants from the Intracoronary Abciximab and Aspiration Thrombectomy in Patients with Large Anterior Myocardial Infarction study were categorized according to smoking status (current or previous smoking vs no history of smoking). The primary imaging outcome was cardiac magnetic resonance imaging–assessed IS of left ventricular mass (%) at 30 days. The primary clinical outcome was the rate of MACE at 30 days and 1 year, defined as the composite of death, reinfarction, new-onset heart failure, or rehospitalization. Of 447 patients enrolled in Intracoronary Abciximab and Aspiration Thrombectomy in Patients with Large Anterior Myocardial Infarction, 271 (60.6%) were current or past smokers. Compared with nonsmokers, smokers were almost 10 years younger and had a lower prevalence of clinical co-morbidities. Smokers had better procedural success and angiographic reperfusion compared with nonsmokers. At 30 days, there were no differences between smokers and nonsmokers in median IS (16.8% vs 17.4%, p = 0.67) or metrics of left ventricular function. By multivariable linear regression analysis, smoking was not significantly associated with IS at 30 days (beta coefficient: 0.83, p = 0.42). At 1 year, smokers had lower crude rates of MACE (7.6% vs 15%, p = 0.01). After multivariable adjustment, there were no significant differences in 1-year MACE between smokers and nonsmokers (adjusted hazard ratio 0.73, 95% CI 0.40 to 1.33, p = 0.30). In conclusion, smoking history had no significant effect on IS at 30 days. Although current or previous smokers had lower rates of 1-year MACE than those with no history of smoking, adjustment for baseline characteristics rendered this association nonsignificant. These findings support the hypothesis that the smoker’s paradox is largely attributable to differences in demographic and clinical baseline risk, rather than differences in IS after primary percutaneous coronary intervention.
Cigarette smoking is a major behavioral risk factor for atherothrombotic diseases. With a current prevalence of ≈20% in men and ≈15% in women, cigarette smoking is deemed to account for every 1 in 5 deaths in the United States annually. In a dose- and duration-dependent fashion, both active and passive exposure to cigarette smoking is associated with greater risk for future cardiovascular events. The adverse effects of smoking on cardiovascular risk are mostly related to changes in serum lipid profile and formation of proatherogenic oxidized lipoprotein particles. In addition, chronic smoking impairs endothelium-dependent coronary vasodilation, promotes acute plaque changes, and imbalances antithrombotic/prothrombotic factors that enhance the initiation and propagation of arterial thrombosis. Despite its recognized public health impact, smoking has been described as a protective factor for adverse events in patients with cardiovascular disease—the so-called “smoker’s paradox.” This phenomenon has been widely described in patients with acute myocardial infarction (MI) undergoing reperfusion therapies and also in other clinical scenarios. In patients with acute ST-elevation MI (STEMI) undergoing primary percutaneous coronary intervention (PCI), the impact of smoking status on myocardial injury has not been investigated in depth. Thus, we evaluated the effect of smoking on early cardiac magnetic resonance imaging (CMRI) metrics and on 1-year clinical outcomes in patients with large anterior STEMI undergoing primary PCI.
Methods
The Intracoronary Abciximab and Aspiration Thrombectomy in Patients with Large Anterior Myocardial Infarction (INFUSE-AMI) was an open-label, 2 × 2 factorial, prospective, randomized, multicenter, single-blind trial of intracoronary abciximab administration, and manual thrombus aspiration in patients undergoing primary PCI for anterior STEMI. The study design, end points, and results were previously reported in detail. In brief, patients aged ≥18 years with ≥1 mm of ST-segment elevation in ≥2 contiguous leads in V1 through V4 or new left bundle branch block with anticipated symptom onset to device time of ≤5 hours were enrolled. Key exclusion criteria were previous MI, bypass graft surgery, or left anterior descending artery stenting; a patent artery at initial angiography or distal left anterior descending artery lesion; contraindications to study medications; and contraindication to radiocontrast or CMRI. Patients received aspirin 324 mg orally or 250 to 500 mg intravenously and clopidogrel 600 mg or prasugrel 60 mg orally before angiography and procedural anticoagulation with bivalirudin (intravenous bolus 0.75 mg/kg plus infusion of 1.75 mg/kg/hour) without routine glycoprotein IIb/IIIa inhibition. Eligible patients were randomized equally to 1 of 4 groups: (1) thrombus aspiration followed by intralesional bolus abciximab; (2) thrombus aspiration without abciximab; (3) intralesional bolus abciximab without aspiration; or (4) no abciximab and no aspiration.
For the present analysis, all randomized patients were categorized according to smoking status at the time of presentation. Differences in baseline risk, imaging metrics, and outcomes were investigated between smokers (including current smokers and former smokers) versus nonsmokers. Former smoking was captured as smoking cessation that occurred more than 3 months before the STEMI presentation. The primary CMRI imaging outcome of interest was infarct size (IS; percentage of infarct mass of total myocardial mass) at 30 days after primary PCI. The primary clinical outcome of interest was major adverse cardiac events (MACE) defined as the composite of death, reinfarction, new-onset heart failure, or rehospitalization at 1 year. The secondary clinical outcome of interest was major adverse cardiac and cerebrovascular events (MACCE) defined as the composite of death, reinfarction, ischemia-driven target vessel revascularization, or stroke. An independent blinded clinical events committee adjudicated all adverse events using original source documents. CMRI, angiographic, and electrocardiographic end points were evaluated at independent blinded core laboratories.
Categorical variables are presented as percentages and compared by the chi-square test or Fisher’s exact test. Continuous variables, including IS are presented as median with interquartile range and compared by the Wilcoxon rank-sum test. Multivariable linear regression analysis using stepwise selection method with entry/stay criteria of 0.1/0.1 was performed to investigate the association between smoking status and IS. Candidate predictors for the model included smoking status, thrombus aspiration randomization, abciximab infusion randomization, age, gender, diabetes mellitus, hypertension, hyperlipidemia, body mass index, creatinine clearance, symptom-to-reperfusion time, proximal (vs mid) left anterior descending artery location, number of diseased vessels, baseline Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 or 1, final TIMI flow grade 3, β blocker on discharge, and angiotensin-converting enzyme inhibitor at discharge. Multivariable Cox regression analysis using stepwise selection method with entry/stay criteria of 0.1/0.1 was performed to investigate the association between smoking status and adverse outcomes at 1 year. Candidate covariates for the model, besides smoking, included only age, diabetes, and proximal left anterior descending artery location to avoid overfitting due to the low number of events. Kaplan–Meier time-to-event estimates for clinical outcomes were compared with the log-rank test. All statistical tests were 2 sided. A p value <0.05 was considered significant for all analyses. All statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc., Cary, North Carolina).
Results
Of 447 patients included in the INFUSE-AMI study, 271 (60.2%) were either current (206 of 271; 76.0%) or former (65 of 271; 24%) smokers. Compared with nonsmokers ( Table 1 ), smokers were almost 10 years younger, more commonly men, with lower body mass index, higher left ventricular (LV) ejection fraction, and had a lower prevalence of hypertension and chronic kidney disease. Angiographic and electrocardiographic characteristics are reported in Table 2 . Smokers more commonly achieved procedural success and angiographic reperfusion, with greater TIMI flow grade 3 and myocardial blush grade 3. There were no significant differences in ST-elevation resolution. Results of the 5-day and 30-day CMRI are reported in Table 3 and Figure 1 . At 5 days, smokers had lower median microvascular obstruction volume as a percentage of total myocardial mass (0.14% vs 1.48%, p = 0.04) and as a percentage of total infarct mass (1.4% vs 7.4%; p = 0.03). At both 5 days and 30 days, there were no differences in CMRI-assessed IS ( Figure 1 ) and in metrics of ventricular function. By multivariable linear regression analysis, smoking was not significantly associated with IS at 30 days (beta coefficient: 0.83; p = 0.42). Unadjusted 1-year outcomes according to smoking status are illustrated in Table 4 . At 1 year, smokers had lower rates of MACE ( Figure 2 ; 7.6% vs 15.0%, p = 0.01), MACCE ( Figure 2 ; 5.8% vs 13.3%; p = 0.006), and all-cause mortality ( Figure 2 ; 3.5% vs 9.8%, p = 0.006). However, by multivariable adjusted Cox regression modeling, smoking status lost its significant association with 1-year MACE (adjusted hazard ratio [HR] 0.73, 95% CI 0.40 to 1.33; p = 0.40), 1-year MACCE (adjusted HR 0.59, 95% CI 0.30 to 1.17; p = 0.30), and 1-year death (adjusted HR 0.50, 95% CI 0.22 to 1.15; p = 0.10).
| Variable | Smokers (n=271) | Non-Smokers (n=176) | p-value |
|---|---|---|---|
| Age (years) | 57.0 (49.0, 66.0) | 65.0 (57.0, 75.0) | <0.0001 |
| Men | 77.5% (210/271) | 68.8% (121/176) | 0.04 |
| Body mass index (kg/m 2 ) | 26.1 (23.7, 29.4) | 27.3 (24.9, 30.0) | 0.005 |
| Heart rate (bpm) | 78.7 ± 16.7 | 77.2 ± 15.4 | 0.34 |
| Systolic blood pressure (mm Hg) | 139.1 ± 25.5 | 140.4 ± 26.4 | 0.62 |
| Diastolic blood pressure (mm Hg) | 85.2 ± 15.9 | 84.2 ± 16.8 | 0.55 |
| Killip classification | |||
| I | 81.5% (220/270) | 81.8% (144/176) | 0.93 |
| II | 7.4% (20/270) | 11.4% (20/176) | 0.15 |
| III | 1.5% (4/270) | 1.1% (2/176) | 1 |
| IV | 0% (0/270) | 0% (0/176) | — |
| Left ventricular ejection fraction (%) | 41.5 (35.0, 50.0) | 40.0 (35.0, 45.0) | 0.03 |
| Hypertension | 24.4% (66/271) | 42.0% (74/176) | <0.0001 |
| Hyperlipidemia | 14.8% (40/270) | 17.0% (30/176) | 0.53 |
| Diabetes mellitus | 8.9% (24/270) | 13.6% (24/176) | 0.11 |
| Insulin-treated | 2.6% (7/270) | 4.0% (7/175) | 0.41 |
| Angina prior to ST-elevation myocardial infarction | 6.7% (18/269) | 12.1% (21/174) | 0.051 |
| Family history of coronary artery disease | 21.5% (55/256) | 24.9% (42/169) | 0.42 |
| Peripheral artery disease | 2.2% (6/270) | 0.6% (1/176) | 0.25 |
| History of stroke or transient ischemic attack | 1.1% (3/271) | 2.3% (4/176) | 0.44 |
| Chronic kidney disease ∗ | 10.7% (26/243) | 19.6% (31/158) | 0.01 |
| Platelet count (10 3 /μL) | 243.5 (198.0, 287.5) | 240.0 (210.0, 278.0) | 0.72 |
| White blood cell count (10 3 /μL) | 12.0 (9.6, 15.0) | 10.5 (8.4, 13.2) | 0.0006 |
| Hemoglobin (g/dL) | 14.7 (13.7, 15.6) | 14.6 (13.5, 15.4) | 0.18 |
| Peak cardiac enzymes | |||
| Creatine kinase ≥3 upper limit of normal | 83.6% (188/225) | 80.7% (121/150) | 0.47 |
| Creatine kinase-MB ≥3 upper limit of normal | 84.1% (153/182) | 81.0% (102/126) | 0.48 |
| Troponin I or T ≥3 upper limit of normal | 80.3% (204/254) | 83.9% (135/161) | 0.36 |
| Medication at discharge | |||
| Aspirin | 100.0% (271/271) | 100.0% (176/176) | 1.00 |
| Thienopyridine | 99.6% (270/271) | 100.0% (176/176) | 1.00 |
| Beta blockers | 93.1% (230/247) | 93.5% (143/153) | 0.89 |
| Angiotensin-converting enzyme inhibitors | 87.0% (215/247) | 91.5% (140/153) | 0.17 |
| Statins | 92.3% (228/247) | 93.5% (143/153) | 0.66 |
| Variable | Smokers (n=271) | Non-Smokers (n=176) | p-value |
|---|---|---|---|
| Procedural success | 94.1% (254/270) | 82.9% (145/175) | 0.0001 |
| Proximal left anterior descending artery lesions | 55.6% (170/306) | 57.0% (118/207) | 0.75 |
| Stent type | |||
| Any drug-eluting stent | 79.7% (216/271) | 69.9% (123/176) | 0.02 |
| Any bare metal stent | 19.6% (53/271) | 30.1% (53/176) | 0.01 |
| Number of diseased vessels | 1.5 ± 0.7 (271) | 1.5 ± 0.7 (176) | 0.68 |
| Number of lesions treated | 1.1 ± 0.4 (271) | 1.2 ± 0.4 (176) | 0.29 |
| Total stent length (mm) | 24.1 ± 10.4 (291) | 25.4 ± 12.6 (193) | 0.27 |
| SYNTAX score | 17.88 ± 6.92 (271) | 18.34 ± 7.28 (176) | 0.50 |
| Number of plaques >50% diameter stenosis | |||
| Left anterior descending artery | 1.29 ± 0.53 (271) | 1.30 ± 0.58 (176) | 0.94 |
| Right coronary artery | 0.53 ± 0.74 (146) | 0.57 ± 0.76 (99) | 0.69 |
| Left circumflex artery | 0.62 ± 0.73 (126) | 0.62 ± 0.70 (91) | 0.97 |
| Pre-percutaneous coronary intervention | |||
| TIMI flow grade 0 or 1 | 69.4% (188/271) | 75.0% (132/176) | 0.20 |
| Myocardial blush grade 0 or 1 | 81.8% (220/269) | 87.5% (154/176) | 0.11 |
| Thrombus area (mm 3 ) | 19.49 ± 11.38 (171) | 19.86 ± 10.50 (108) | 0.79 |
| Post-percutaneous coronary intervention | |||
| TIMI flow grade 3 | 94.1% (255/271) | 86.9% (153/176) | 0.009 |
| Myocardial blush grade 3 | 74.9% (203/271) | 60.6% (106/175) | 0.001 |
| Slow reflow | 1.5% (4/273) | 1.7% (3/177) | 1.00 |
| No reflow | 0.4% (1/273) | 1.1% (2/177) | 0.56 |
| Relative ST elevation resolution ∗ | |||
| >70% | 57.0% (142/249) | 56.8% (88/155) | 0.96 |
| 30%-70% | 31.7% (79/249) | 29.7% (46/155) | 0.66 |
| <30% | 11.2% (28/249) | 13.5% (21/155) | 0.49 |
| Endpoint | 5 days (n = 168) | 30 days (n = 352) | MRI change (5 to 30 days; n = 160) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Smokers (n=114) | Non-Smokers (n=54) | p-value | Smokers (n=215) | Non-Smokers (n=137) | p-value | Smokers (n=108) | Non-Smokers (n=52) | p-value | |
| Infarct size of total left ventricular mass (%) | 22.1 (12.7, 32.0) | 22.8 (17.7, 28.8) | 0.56 | 16.8 (7.2, 23.2) | 17.4 (9.2, 24.5) | 0.67 | -4.0 (-7.6, -0.4) | -4.7 (-8.4, -0.4) | 0.51 |
| Total infarct mass (g) | 30.8 (14.6, 49.2) | 32.9 (21.8, 46.0) | 0.50 | 20.4 (9.1, 32.9) | 21.1 (11.2, 32.3) | 0.96 | -7.6 (-16.7, -1.2) | -9.1 (-14.4, -2.5) | 0.55 |
| Microvascular obstruction of total left ventricular mass (%) | 0.14 (0.00, 2.39) | 1.48 (0.00, 2.80) | 0.04 | — | — | — | — | — | — |
| Total microvascular obstruction (g) | 0.2 (0.0, 3.8) | 2.1 (0.0, 3.8) | 0.055 | — | — | — | — | — | — |
| Microvascular obstruction of total infarct mass (%) | 1.4 (0.0, 8.4) | 7.4 (0.0, 11.0) | 0.03 | — | — | — | — | — | — |
| Left ventricular ejection fraction (%) | 48.1 (40.5, 53.8) | 48.1 (41.3, 52.5) | 0.69 | 49.6 (43.2, 57.0) | 49.3 (42.3, 57.0) | 0.89 | 2.6 (-2.2, 5.9) | 1.0 (-1.3, 5.0) | 0.49 |
| Left ventricular end-diastolic volume index (mL/m 2 ) | 87.1 (77.3, 101.7) | 88.2 (77.7, 100.7) | 0.94 | 90.7 (77.4, 103.9) | 87.5 (73.6, 103.2) | 0.54 | 3.0 (-4.8, 9.3) | 4.9 (-3.5, 14.6) | 0.15 |
| Left ventricular end-systolic volume index (mL/m 2 ) | 46.7 (35.7, 55.7) | 48.1 (37.5, 57.9) | 0.75 | 49.6 (43.2, 57.0) | 49.3 (42.3, 57.0) | 0.89 | -1.9 (-6.3, 4.8) | 0.9 (-4.1, 8.6) | 0.09 |
| Left ventricular stroke volume index (mL/m 2 ) | 41.5 (35.3, 47.1) | 42.1 (33.7, 46.3) | 0.70 | 43.9 (39.2, 49.8) | 42.4 (37.1, 49.0) | 0.28 | 2.3 (-1.5, 7.5) | 3.3 (-2.1, 8.8) | 0.47 |
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