We assessed the impact of smoking on outcomes in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention using alternative antithrombotic regimens and stent types. In the HORIZONS-AMI trial 3,602 patients were randomly assigned to unfractionated heparin (UFH) plus a glycoprotein IIb/IIIa inhibitor (GPI) or bivalirudin alone and paclitaxel-eluting stents or bare-metal stents. Compared to nonsmokers, smokers had significantly lower rates of mortality and major bleeding at 30 days and at 1 year; however, the differences were no longer significant after covariate adjustment. Smoking was associated with increased rates of definite/probable stent thrombosis (ST) at 1 year (adjusted RR 1.99, 95% confidence interval 1.28 to 3.10) mainly because of a higher rate of late ST after paclitaxel-eluting stent implantation (1.9% vs 0.4%, p = 0.0006). In smokers bivalirudin monotherapy compared to UFH plus a GPI was associated with lower mortality at 30 days (0.5% vs 2.2%, p = 0.002) and at 1 year (1.8% vs 4.0%, p = 0.008). No decrease in mortality was seen with bivalirudin in nonsmokers. Major bleeding was significantly decreased with bivalirudin regardless of smoking status (smokers 3.7% vs 8.9%, p <0.0001; nonsmokers 6.5% vs 9.6%, p = 0.01). In conclusion, in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention, smoking is an independent predictor of definite/probable ST at 1 year. Bivalirudin monotherapy compared to UFH plus a GPI decreased major bleeding regardless of smoking status but may have different effects on individual components of ischemic events.
In this subanalysis from the multicenter randomized Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, we examined the impact of smoking on outcomes of patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention using the direct thrombin inhibitor bivalirudin versus unfractionated heparin (UFH) plus a glycoprotein IIb/IIIa inhibitor (GPI) and bare-metal stents (BMSs) versus paclitaxel-eluting stents (PESs).
Methods
The design and results of the HORIZONS-AMI trial have been previously published. Briefly, 3,602 patients with ST-segment elevation myocardial infarction were randomized in an open-label fashion and in a 1:1 ratio to treatment with bivalirudin alone (1,800 patients) or UFH plus a GPI (1,802 patients). Emergency coronary angiography with left ventriculography was performed after randomization with subsequent triage to treatment with percutaneous coronary intervention, coronary artery bypass grafting, or medical management at physician discretion. After patency was restored in the infarct-related vessel, eligible patients were randomly assigned in a 3:1 ratio to PESs (TAXUS Express, Boston Scientific, Natick, Massachusetts) or uncoated BMSs (Express, Boston Scientific). Aspirin, thienopyridine, and randomization medications were administered as previously described. Routine angiographic follow-up at 13 months was prespecified for 1,800 patients randomly assigned to receive a stent. Information on smoking status before index hospitalization was available from the electronic case-report form completed by each site. The study was approved by the institutional review board or ethics committee at each participating center and all patients gave written informed consent.
There were 2 prespecified primary 30-day end points including major bleeding (not related to coronary artery bypass grafting) and combined adverse clinical events consisting of major bleeding or a composite of major adverse cardiac events including death, reinfarction, target vessel revascularization for ischemia, and stroke. Stent thrombosis (ST) was defined based on Academic Research Consortium criteria. Binary angiographic restenosis was >50% diameter stenosis at angiographic follow-up. All end points were adjudicated by a clinical events committee blinded to treatment assignment and stent type. Anemia was a hematocrit value at initial presentation <39% for men and <36% for women. Renal insufficiency was a creatinine clearance <60 ml/min as calculated at baseline by the Cockcroft–Gault equation.
Categorical variables are presented as percentages and were compared using Fisher’s exact test. Continuous variables are presented as medians with interquartile ranges and were compared using Mann–Whitney U test. Kaplan–Meier method was applied to estimate outcomes, which were compared by log-rank test. Cox regression models were used to define independent predictors of death, reinfarction, stroke, ST, and noncoronary artery bypass grafting major bleeding. The model included age, gender, race, body mass index, history of hypertension, hyperlipidemia, diabetes, insulin-treated diabetes, previous myocardial infarction, previous percutaneous coronary intervention, previous coronary artery bypass grafting, congestive heart failure, renal insufficiency, Killip class at admission, baseline anemia, platelet count, white blood cell count, left ventricular ejection fraction, time from symptom onset to first balloon inflation, use of UFH before randomization, clopidogrel loading dose (300 vs 600 mg), administration of aspirin and/or thienopyridine, left anterior descending coronary artery infarct vessel, target vessel diameter, Thrombolysis In Myocardial Infarction flow grade 0 or 1 at baseline, presence of thrombus, final Thrombolysis In Myocardial Infarction flow grade 3, randomization to 1 of the antithrombotic regimens or stent type, and use of ≥1 stent.
Results
In the HORIZONS-AMI trial primary percutaneous coronary intervention was performed in 3,340 of 3,602 patients (93%). Information on smoking status was available for 3,328 of 3,340 patients (99.6%), of whom 1,563 (47%) were current smokers and 1,765 (53%) were nonsmokers.
As presented in Table 1 , smokers compared to nonsmokers were younger, more frequently men, had lower body mass index, less commonly had hypertension, hyperlipidemia, diabetes, renal insufficiency, and anemia at baseline, had higher baseline platelet count, and less frequently presented in Killip class ≥II.
| Variable | All Patients With PCI | p Value | Smokers | p Value | Nonsmokers | p Value | |||
|---|---|---|---|---|---|---|---|---|---|
| (n = 3,328) | (n = 1,563) | (n = 1,765) | |||||||
| Smokers (n = 1,563) | Nonsmokers (n = 1,765) | Bivalirudin (n = 806) | UFH + GPI (n = 757) | Bivalirudin (n = 864) | UFH + GPI (n = 901) | ||||
| Age (years), median (interquartile range) | 55 (49–62) | 66 (57–74) | <0.0001 | 56 (49–62) | 55 (49–62) | 0.93 | 66 (57–74) | 66 (58–74) | 0.22 |
| Men | 79.7% | 75.1% | 0.002 | 80.1% | 79.1% | 0.62 | 75.6% | 74.7% | 0.67 |
| Body mass index (kg/m 2 ), median (interquartile range) | 26.8 (24.3–29.8) | 27.3 (24.8–30.5) | 0.0002 | 26.7 (24.1–30.0) | 27.1 (24.5–29.7) | 0.25 | 27.5 (25.0–30.8) | 27.1 (24.8–30.3) | 0.08 |
| Hypertension | 44.5% | 60.1% | <0.0001 | 40.8% | 48.5% | 0.002 | 60.4% | 59.7% | 0.76 |
| Hyperlipidemia | 39.0% | 46.5% | <0.0001 | 37.3% | 40.7% | 0.18 | 48.5% | 44.6% | 0.10 |
| Diabetes | 12.5% | 19.7% | <0.0001 | 10.8% | 14.4% | 0.03 | 19.8% | 19.5% | 0.89 |
| Insulin-treated diabetes | 3.0% | 5.8% | 0.0001 | 2.4% | 3.7% | 0.12 | 5.4% | 6.1% | 0.55 |
| Previous myocardial infarction | 9.9% | 11.3% | 0.18 | 8.2% | 11.6% | 0.02 | 11.3% | 11.2% | 0.93 |
| Previous percutaneous coronary intervention | 9.9% | 11.2% | 0.24 | 8.9% | 11.0% | 0.18 | 11.4% | 11.0% | 0.81 |
| Previous coronary artery bypass grafting | 1.3% | 3.9% | <0.0001 | 1.2% | 1.3% | 0.89 | 4.5% | 3.2% | 0.16 |
| Killip class ≥II | 7.4% | 9.8% | 0.01 | 6.7% | 8.1% | 0.30 | 10.3% | 9.3% | 0.48 |
| Chronic renal insufficiency | 8.8% | 22.8% | <0.0001 | 8.5% | 9.1% | 0.71 | 21.5% | 24.0% | 0.23 |
| Anemia | 7.2% | 13.4% | <0.0001 | 6.7% | 7.7% | 0.47 | 14.0% | 12.9% | 0.48 |
| Hemoglobin (g/dl), median (interquartile range) | 14.9 (13.9–15.8) | 14.3 (13.3–15.3) | <0.0001 | 14.9 (14.0–15.8) | 14.8 (13.9–15.8) | 0.33 | 14.3 (13.3–15.3) | 14.3 (13.4–15.3) | 0.87 |
| Platelet count (×10 3 ), median (interquartile range) | 254 (215–298) | 241 (208–291) | <0.0001 | 255 (219–300) | 252 (212–295) | 0.15 | 242 (204–284) | 240 (202–286) | 0.56 |
Table 2 presents angiographic and procedural data. Smoking was associated with shorter time from symptom onset to first balloon inflation, higher rates of nonleft anterior descending coronary artery infarct vessel, higher rates of achievement of final Thrombolysis In Myocardial Infarction flow grade 3, larger final reference vessel diameter and minimal luminal diameter, smaller final diameter stenosis, and more frequent randomization to BMSs than to PESs. Smokers compared to nonsmokers had higher rates of thienopyridine treatment at discharge (98.5% vs 97.5%, p = 0.05) and at 30 days (98.2% vs 96.6%, p = 0.005) but the difference was no more significant at 6 months (91.1% vs 91.4%, p = 0.73) and at 1 year (69.0% vs 70.9%, p = 0.25).
| All Patients With PCI | p Value | Smokers | p Value | Nonsmokers | p Value | ||||
|---|---|---|---|---|---|---|---|---|---|
| (n = 3,328) | (n = 1,563) | (n = 1,765) | |||||||
| Smokers (n = 1,563) | Nonsmokers (n = 1,765) | Bivalirudin (n = 806) | UFH + GPI (n = 757) | Bivalirudin (n = 864) | UFH + GPI (n = 901) | ||||
| Symptom onset to balloon (hours), median (interquartile range) | 3.6 (2.6–5.3) | 3.8 (2.7–5.8) | 0.004 | 3.5 (2.6–5.3) | 3.7 (2.6–5.3) | 0.53 | 3.9 (2.8–5.8) | 3.7 (2.7–5.7) | 0.27 |
| Infarct-related artery | |||||||||
| Left anterior descending coronary artery | 35.5% | 43.8% | <0.0001 | 35.6% | 35.4% | 0.94 | 42.0% | 45.6% | 0.10 |
| Right coronary artery | 47.6% | 40.6% | <0.0001 | 47.8% | 47.5% | 0.90 | 40.7% | 40.4% | 0.87 |
| Left circumflex coronary artery | 16.3% | 14.3% | 0.08 | 16.1% | 16.4% | 0.86 | 15.8% | 12.8% | 0.04 |
| Thrombolysis In Myocardial Infarction flow | |||||||||
| Baseline | |||||||||
| Grade 0 or 1 | 62.5% | 64.5% | 0.24 | 63.0% | 61.9% | 0.65 | 64.8% | 64.2% | 0.78 |
| Grade 2 | 12.8% | 14.9% | 0.08 | 12.5% | 13.1% | 0.72 | 14.6% | 15.2% | 0.75 |
| Grade 3 | 24.7% | 20.6% | 0.005 | 24.5% | 25.0% | 0.82 | 20.6% | 20.7% | 0.96 |
| Final | |||||||||
| Grade 0 or 1 | 2.5% | 3.5% | 0.10 | 2.0% | 3.0% | 0.23 | 3.9% | 3.0% | 0.31 |
| Grade 2 | 8.0% | 13.5% | <0.0001 | 8.0% | 8.1% | 0.92 | 14.6% | 12.5% | 0.19 |
| Grade 3 | 89.5% | 83.0% | <0.0001 | 90.0% | 88.9% | 0.49 | 81.4% | 84.5% | 0.09 |
| Reference vessel diameter (mm) | |||||||||
| Baseline | 2.9 ± 0.5 | 2.8 ± 0.5 | <0.0001 | 2.9 ± 0.5 | 2.9 ± 0.5 | 0.10 | 2.9 ± 0.5 | 2.9 ± 0.5 | 0.95 |
| Final | 3.0 ± 0.5 | 2.9 ± 0.5 | <0.0001 | 3.0 ± 0.5 | 3.0 ± 0.5 | 0.85 | 2.9 ± 0.5 | 2.9 ± 0.5 | 0.65 |
| Minimal luminal diameter (mm) | |||||||||
| Baseline | 0.3 ± 0.4 | 0.2 ± 0.4 | 0.28 | 0.3 ± 0.4 | 0.3 ± 0.4 | 0.45 | 0.2 ± 0.4 | 0.2 ± 0.3 | 0.98 |
| Final | 2.3 ± 0.6 | 2.2 ± 0.6 | <0.0001 | 2.3 ± 0.6 | 2.3 ± 0.6 | 0.34 | 2.2 ± 0.6 | 2.2 ± 0.6 | <0.05 |
| Diameter stenosis (%) | |||||||||
| Baseline | 90.8 ± 13.1 | 91.5 ± 12.2 | 0.41 | 91.1 ± 13.0 | 90.5 ± 13.3 | 0.43 | 91.5 ± 12.2 | 91.5 ± 12.3 | 0.71 |
| Final | 21.3 ± 14.0 | 23.2 ± 16.0 | 0.0007 | 20.9 ± 13.4 | 21.7 ± 14.6 | 0.31 | 22.7 ± 15.8 | 23.6 ± 16.1 | 0.17 |
| Thrombus | 80.6% | 80.8% | 0.86 | 82.5% | 78.5% | <0.05 | 81.7% | 80.0% | 0.37 |
| Stent randomization | |||||||||
| Paclitaxel-eluting stent | 67.4% | 70.7% | <0.05 | 67.9% | 66.8% | 0.65 | 71.2% | 71.0% | 0.64 |
| Bare-metal stent | 26.2% | 22.3% | 0.01 | 26.6% | 25.8% | 0.71 | 22.8% | 21.8% | 0.65 |
| Total stent length (mm), median (interquartile range) | 24 (20–36) | 24 (20–36) | 0.40 | 24 (20–36) | 24 (20–36) | 0.80 | 24 (20–36) | 24 (20–36) | 0.69 |
| Left ventricular ejection fraction (%), median (interquartile range) | 50 (45–60) | 50 (41–48) | 0.02 | 50 (45–60) | 50 (41–60) | 0.53 | 50 (42–59) | 50 (40–57) | 0.24 |
At 30 days and 1 year smokers compared to nonsmokers had significantly lower rates of combined adverse clinical events owing to lower rates of all-cause death and major bleeding ( Table 3 ). However, after multivariable adjustment, differences in outcomes were no longer significant.
| Events | Patients Treated With PCI | Unadjusted p Value | Adjusted Relative Risk (95% CI) | Adjusted p Value | Smokers | p Value | Nonsmokers | p Value | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| (n = 3,328) | (n = 1,563) | (n = 1,765) | |||||||||
| Smokers (n = 1,563) | Nonsmokers (n = 1,765) | Bivalirudin (n = 806) | UFH + GPI (n = 757) | Bivalirudin (n = 864) | UFH + GPI (n = 901) | ||||||
| At 30 days | |||||||||||
| Combined adverse clinical events | 9.3% | 12.3% | 0.005 | 0.91 (0.70–1.17) | 0.46 | 6.6% | 12.3% | 0.0001 | 11.2% | 13.3% | 0.19 |
| Major adverse cardiac events | 4.5% | 6.1% | 0.04 | 1.07 (0.72–1.59) | 0.74 | 3.8% | 5.2% | 0.23 | 6.5% | 5.7% | 0.45 |
| Death | 1.3% | 3.3% | 0.0002 | 0.38 (0.07–1.99) | 0.25 | 0.5% | 2.2% | 0.003 | 3.0% | 3.6% | 0.54 |
| Cardiac death | 1.2% | 3.1% | 0.0002 | 0.29 (0.05–1.75) | 0.18 | 0.4% | 2.1% | 0.002 | 2.8% | 3.5% | 0.44 |
| Reinfarction | 2.2% | 1.7% | 0.35 | 1.54 (0.88–2.68) | 0.13 | 2.4% | 2.0% | 0.61 | 1.8% | 1.7% | 0.90 |
| Stroke | 0.5% | 0.6% | 0.81 | 1.03 (0.38–2.83) | 0.95 | 0.5% | 0.5% | 0.93 | 0.6% | 0.6% | 0.94 |
| Ischemic target vessel revascularization | 2.6% | 2.4% | 0.78 | 1.04 (0.65–1.65) | 0.87 | 2.9% | 2.3% | 0.45 | 2.9% | 1.9% | 0.16 |
| Major bleeding | 6.2% | 8.1% | 0.04 | 0.89 (0.66–1.20) | 0.44 | 3.7% | 8.9% | <0.0001 | 6.5% | 9.6% | 0.01 |
| Any stent thrombosis | 2.6% | 2.2% | 0.39 | 1.60 (0.95–2.68) | 0.08 | 2.9% | 2.3% | 0.46 | 2.5% | 1.9% | 0.41 |
| Definite/probable stent thrombosis | 2.6% | 2.2% | 0.39 | 1.60 (0.95–2.68) | 0.08 | 2.9% | 2.3% | 0.46 | 2.5% | 1.9% | 0.41 |
| Definite stent thrombosis | 2.3% | 1.6% | 0.13 | 1.46 (0.87–2.45) | 0.16 | 2.9% | 1.7% | 0.10 | 2.0% | 1.2% | 0.19 |
| At 1 year | |||||||||||
| Combined adverse clinical events | 15.5% | 18.3% | 0.02 | 0.94 (0.76–1.17) | 0.59 | 13.7% | 17.4% | 0.03 | 16.8% | 19.8% | 0.11 |
| Major adverse cardiac events | 11.3% | 12.5% | 0.25 | 1.25 (0.93–1.69) | 0.14 | 11.5% | 11.1% | 0.87 | 12.1% | 12.9% | 0.64 |
| Death | 2.9% | 5.0% | 0.002 | 1.64 (0.77–3.50) | 0.20 | 1.8% | 4.0% | 0.008 | 4.4% | 5.5% | 0.32 |
| Cardiac death | 1.9% | 3.7% | 0.002 | 1.98 (0.74–5.27) | 0.17 | 0.9% | 3.1% | 0.002 | 3.0% | 4.4% | 0.15 |
| Reinfarction | 4.6% | 3.7% | 0.21 | 1.35 (0.94–1.93) | 0.10 | 4.8% | 4.4% | 0.67 | 2.7% | 4.6% | <0.05 |
| Stroke | 1.2% | 0.8% | 0.23 | 1.69 (0.82–3.48) | 0.16 | 1.0% | 1.4% | 0.53 | 0.8% | 0.7% | 0.72 |
| Ischemic target vessel revascularization | 7.1% | 6.9% | 0.83 | 1.13 (0.86–1.50) | 0.38 | 8.5% | 5.6% | 0.03 | 7.0% | 6.9% | 0.88 |
| Major bleeding | 6.7% | 8.6% | 0.04 | 0.94 (0.68–1.29) | 0.68 | 4.5% | 9.0% | 0.0003 | 7.0% | 10.2% | 0.01 |
| Any stent thrombosis | 4.5% | 2.9% | 0.02 | 1.94 (1.27–2.96) | 0.002 | 4.7% | 4.3% | 0.76 | 3.0% | 2.8% | 0.75 |
| Definite/probable stent thrombosis | 4.2% | 2.6% | 0.02 | 1.99 (1.28–3.10) | 0.002 | 4.5% | 3.9% | 0.55 | 2.7% | 2.5% | 0.75 |
| Definite stent thrombosis | 3.8% | 1.9% | 0.003 | 1.93 (1.24–3.01) | 0.004 | 4.4% | 3.1% | 0.18 | 2.2% | 1.7% | 0.40 |
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