To define the incremental risk of cigarette smoking in patients with coronary disease receiving contemporary medical therapy, we performed a post hoc analysis of 18,885 patients by combining data from the Treating to New Targets (TNT) and the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trials. These studies compared high-dose treatment (atorvastatin 80 mg/day) to moderate-dose treatment (atorvastatin 10 mg/day in TNT and simvastatin 20 to 40 mg/day in IDEAL) in patients with established coronary heart disease. The primary end point of this pooled analysis was major cardiovascular events, a composite of cardiac death, myocardial infarction, stroke, or resuscitated cardiac arrest. At baseline 4,196 patients had never smoked, 11,513 were ex-smokers, and 3,176 were current smokers. The adjusted hazard ratio for current smokers compared to never smokers was 1.68 (95% confidence interval 1.46 to 1.94) and that for current smokers compared to ex-smokers was 1.57 (95% confidence interval 1.41 to 1.76). Event rates for current smokers compared to ex-smokers were similarly increased in each treatment group. The difference in absolute event rates between current and ex-smokers in this pooled analysis was 4.5%, which is >2 times as large as the decrease in absolute event rates between high-dose and moderate-dose statin therapy found in the IDEAL (1.7%) and TNT (2.2%) trials, respectively. In conclusion, in patients with coronary disease receiving modern medical therapy, smoking cessation is of substantial benefit with a number needed to treat of 22 to prevent a major cardiovascular event over 5 years. Smoking cessation deserves greater emphasis in secondary prevention.
Despite increased public awareness and continued public health efforts, cigarette smoking remains the leading cause of preventable morbidity and mortality in the United States. An estimated 46 million Americans, or 20.6% of the adult population, continue to smoke. Smoking exerts detrimental effects through multiple mechanisms, but several of these might be attenuated or ameliorated by a statin. Endothelial function, a predictor of major cardiovascular events (MCVEs), is impaired in smokers but improves with administration of a statin. Smoking is prothrombotic, in part by increasing the propensity for platelet thrombus formation, whereas statins have antithrombotic properties. Smoking decreases and statin therapy slightly increases high-density lipoprotein (HDL) cholesterol levels. For these reasons one might speculate that the negative cardiovascular effects of smoking in the era of modern medical therapy, including intensive statin treatment, are not as pronounced as those reported in previous studies. The aim of this post hoc analysis of the Treating to New Targets (TNT) study and the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study was to more accurately define the cardiovascular event rates based on smoking status in a contemporary cohort of patients with coronary disease receiving excellent medical treatment.
Methods
The design and results of the TNT and IDEAL trials have been described and published previously. In summary, TNT and IDEAL are prospective, randomized, multicenter trials that evaluated the efficacy of high-dose statin treatment compared to moderate-dose statin treatment in patients with established coronary heart disease (CHD). All patients gave written informed consent, and the local research ethics committee or institutional review board at each participating center approved the study. TNT was a double-blind parallel-group trial in which 10,001 patients 35 to 75 years of age with CHD and low-density lipoprotein (LDL) cholesterol levels <130 mg/dl (2.6 mmol/L) after an 8-week run-in period on atorvastatin 10 mg/day were randomly assigned to atorvastatin 80 mg/day or 10 mg/day and followed for a median of 4.9 years. IDEAL was an open-label trial in which 8,888 patients ≤80 years of age with previous myocardial infarction were randomly assigned to receive atorvastatin 80 mg/day or simvastatin 20 to 40 mg/day and followed for a median of 4.8 years.
Although differences in the trial designs and study populations are noted, given the similarity of their hypotheses and inclusion criteria, we pooled data from the TNT and IDEAL trials for the present analysis to create a dataset of 18,885 patients in whom smoking status at baseline was known. The primary end point was MCVEs, a composite of cardiac death, myocardial infarction, stroke, or resuscitated cardiac arrest. This end point was chosen because it was previously reported in the TNT and IDEAL trials and was the primary end point of TNT. A secondary end point was any cardiovascular event, which was defined as MCVEs plus any coronary revascularization procedure, hospitalization for unstable angina, primary diagnosis of congestive heart failure, and peripheral artery disease. Participants were categorized as current smokers, ex-smokers, or never smokers by self-report at the pre-enrollment screening visit.
Statistical analysis of baseline characteristics by smoking status was based on 1-way analysis of variance with pairwise comparison for continuous variables and chi-square test and logistic regression with pairwise comparison for categorical variables. All analyses were adjusted for the trial. The association between smoking status and the primary outcome was initially examined using a univariate Cox proportional hazards model. A multivariate Cox proportional hazards model was then constructed, adjusting for the following clinical covariates: age, gender, systolic and diastolic blood pressures, body mass index, history of cardiovascular disease, peripheral vascular disease, heart failure, hypertension, diabetes, previous use of antihypertensive and antidiabetic medications, previous use of aspirin, β blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, baseline LDL cholesterol, HDL cholesterol, triglycerides, and apolipoproteins A1 and B. Primary and secondary composite end points were analyzed from time of first dose of the study drug to the first event according to the Kaplan-Meier method. All authors have read and agree to the report as written.
Results
Of the pooled cohort of 18,885 patients, at baseline 4,196 (22%) had never smoked, 11,513 (61%) were ex-smokers, and 3,176 (17%) were current smokers. Overall 9,434 (50%) received atorvastatin 80 mg/day, 5,006 (27%) received atorvastatin 10 mg/day, and 4,445 (24%) received simvastatin 20 to 40 mg/day. Baseline clinical characteristics of patients according to smoking status are listed in Table 1 .
| Characteristics | Current Smokers (n = 3,176) | Former Smokers (n = 11,513) | Never Smokers (n = 4,196) | Pairwise Comparison (p value ⁎ ) | Overall p Value ⁎ | ||
|---|---|---|---|---|---|---|---|
| Current Versus Former | Current Versus Never | Former Versus Never | |||||
| Treatment | |||||||
| Atorvastatin 80 mg | 1,561 (49.2%) | 5,732 (49.8%) | 2,141 (51.0%) | 0.525 | 0.111 | 0.170 | 0.2376 |
| Atorvastatin 10 mg | 672 (21.2%) | 3,167 (27.5%) | 1,167 (27.8%) | <0.0001 ⁎ | <0.0001 ⁎ | 0.706 | <0.0001 ⁎ |
| Simvastatin 20–40 mg | 943 (29.7%) | 2,614 (22.7%) | 888 (21.2%) | <0.0001 ⁎ | <0.0001 ⁎ | 0.040 ⁎ | <0.0001 ⁎ |
| Overall across 3 treatment groups | <0.0001 ⁎ | ||||||
| Age (years) | 57.5 ± 9.1 | 61.5 ± 8.9 | 63.8 ± 8.9 | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ |
| Women | 622 (19.6%) | 1,694 (14.7%) | 1,286 (30.7%) | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ |
| Blood pressure (mm Hg) | |||||||
| Systolic | 132.2 ± 18.8 | 133.5 ± 18.6 | 134.9 ± 18.5 | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ |
| Diastolic | 79.3 ± 10.0 | 79.0 ± 10.0 | 79.3 ± 9.5 | 0.998 | 0.109 | 0.0363 ⁎ | 0.0977 |
| Cardiovascular history | |||||||
| Cerebrovascular disease | 199 (6.3%) | 698 (6.1%) | 275 (6.6%) | 0.879 | 0.305 | 0.241 | 0.4530 |
| Peripheral vascular disease | 318 (10.0%) | 1,026 (8.9%) | 203 (4.8%) | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ |
| Congestive heart failure | 233 (7.3%) | 817 (7.1%) | 268 (6.4%) | 0.354 | 0.049 ⁎ | 0.114 | 0.1180 |
| Risk factors | |||||||
| Body mass index (kg/m 2 ) | 27.33 ± 4.43 | 28.18 ± 4.21 | 27.74 ± 4.26 | <0.0001 ⁎ | 0.0119 | <0.0001 ⁎ | <0.0001 ⁎ |
| Hypertension | 1,135 (35.7%) | 5,079 (44.1%) | 2,121 (50.6%) | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ |
| Diabetes | 328 (10.3%) | 1,568 (13.6%) | 674 (16.1%) | <0.0001 ⁎ | <0.0001 ⁎ | 0.0001 ⁎ | <0.0001 ⁎ |
| Statin therapy before randomization | 2,112 (66.5%) | 7,879 (68.4%) | 2,929 (69.8%) | <0.0001 ⁎ | <0.0001 ⁎ | 0.0738 | <0.0001 ⁎ |
| Concomitant therapy | |||||||
| Aspirin | 2,645 (83.3%) | 9,508 (82.6%) | 3,532 (84.2%) | 0.0311 ⁎ | 0.9403 | 0.0232 ⁎ | 0.0185 ⁎ |
| β Blocker | 2,088 (65.7%) | 7,248 (63.0%) | 2,698 (64.3%) | 0.926 | 0.203 | 0.074 | 0.1919 |
| Calcium antagonist | 730 (23.0%) | 2,708 (23.5%) | 976 (23.3%) | 0.612 | 0.450 | 0.672 | 0.7522 |
| Angiotensin-converting enzyme inhibitors or angiotensin II blockers | 933 (29.4%) | 3,973 (34.5%) | 1,455 (34.7%) | <0.0001 ⁎ | <0.0001 ⁎ | 0.814 | <0.0001 ⁎ |
⁎ The p values are based on 1-way analysis of variance with pairwise comparisons for continuous variables and chi-square test and logistic regression with pairwise comparison for categorical variables. All analyses are adjusted for study.
At baseline current smokers compared to ex-smokers were younger (57.5 vs 61.5 years), were more likely to be women (19.6% vs 14.7%), were less likely to have hypertension, were more likely to have peripheral vascular disease, were less likely to have diabetes, and were more likely to have a lower body mass index. Current smokers compared to ex-smokers were less likely to be taking angiotensin-converting enzyme inhibitors or angiotensin II blockers. As presented in Table 2 , current smokers had higher LDL cholesterol and triglyceride levels at baseline and lower HDL cholesterol levels compared to former or never smokers. Baseline was defined as the visit before randomization after a run-in period of 8 weeks on atorvastatin 10 mg/day.
| Characteristics | Current Smokers (n = 3,176) | Former Smokers (n = 11,513) | Never Smokers (n = 4,196) | Pairwise Comparison (p value ⁎ ) | Overall p Value ⁎ | ||
|---|---|---|---|---|---|---|---|
| Current Versus Former | Current Versus Never | Former Versus Never | |||||
| Total cholesterol (mg/dl) | 190.9 ± 36.2 | 184.1 ± 33.2 | 182.7 ± 33.0 | <0.0001 ⁎ | <0.0001 ⁎ | 0.0369 ⁎ | <0.0001 ⁎ |
| Low-density lipoprotein cholesterol (mg/dl) | 115.5 ± 31.9 | 107.6 ± 28.8 | 106.5 ± 28.7 | <0.0001 ⁎ | <0.0001 ⁎ | 0.0603 | <0.0001 ⁎ |
| High-density lipoprotein cholesterol (mg/dl) | 44.6 ± 11.3 | 46.8 ± 11.4 | 48.1 ± 11.8 | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ |
| Triglycerides (mg/dl) | 158.1 ± 84.7 | 150.3 ± 73.8 | 142.1 ± 67.2 | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ |
| Low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio | 2.72 ± 0.98 | 2.42 ± 0.90 | 2.34 ± 0.86 | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ |
| Apolipoprotein A1 (mg/dl) | 138.7 ± 22.8 | 143.4 ± 23.7 | 145.0 ± 25.2 | <0.0001 ⁎ | <0.0001 ⁎ | 0.0002 ⁎ | <0.0001 ⁎ |
| Apolipoprotein B (mg/dl) | 120.8 ± 28.3 | 114.3 ± 26.0 | 112.0 ± 25.7 | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ |
| Apolipoprotein B/A1 ratio | 0.89 ± 0.26 | 0.82 ± 0.24 | 0.80 ± 0.23 | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ | <0.0001 ⁎ |
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