Journal Information
Vol. 37. Num. 10.
Pages 799-872 (October 2018)
Download PDF
More article options
Vol. 37. Num. 10.
Pages 799-872 (October 2018)
Original Article
DOI: 10.1016/j.repce.2017.12.011
Open Access
The smoker's paradox in acute coronary syndrome: Is it real?
O paradoxo dos fumadores nas síndromes coronárias agudas – será real?
Madalena Coutinho Cruz
Corresponding author

Corresponding author.
, Rita Ilhão Moreira, Ana Abreu, Ana Teresa Timóteo, Ramiro Sá Carvalho, Lurdes Ferreira, Rui Cruz Ferreira
Cardiology Department, Hospital de Santa Marta, Centro Hospitalar de Lisboa Central, Lisbon, Portugal
Related content
Rev Port Cardiol 2018;37:857-810.1016/j.repce.2018.10.002
Miguel Mendes
This item has received

Under a Creative Commons license
Article information
Full Text
Download PDF
Tables (5)
Table 1. Baseline characteristics of patients admitted with acute coronary syndrome according to smoking status.
Table 2. Clinical presentation of patients admitted with acute coronary syndrome according to smoking status.
Table 3. Laboratory, echocardiographic and angiographic data of patients admitted with acute coronary syndrome according to smoking status.
Table 4. Complications, treatment and outcome of patients admitted with acute coronary syndrome according to smoking status.
Table 5. Influence of smoking on in-hospital mortality and on the composite outcome of all-cause mortality, rehospitalization for cardiovascular causes, angiography, PCI and CABG at one year according to type of acute coronary syndrome.
Show moreShow less

Smoking is associated with atherosclerotic disease, but there is controversy about its protective nature after acute coronary syndrome (ACS).


To determine the impact of smoking on the presentation, treatment and outcome of ACS.


We analyzed all consecutive patients with ACS in a single center between 2005 and 2014. Current smokers and never-smokers were compared. Independent predictors of in-hospital mortality and of a composite of all-cause mortality, rehospitalization for cardiovascular causes, angiography, percutaneous coronary intervention and coronary artery bypass grafting were assessed by multivariate logistic regression.


A total of 2727 patients were included, 41.7% current smokers and 58.3% never-smokers. Current smokers were younger, more often male, had fewer comorbidities, a typical clinical presentation, lower heart rate, systolic blood pressure, Killip class, BNP/NT-pro-BNP and creatinine, better left ventricular systolic function and less severe coronary anatomy. ST-segment elevation myocardial infarction was more common in current smokers. Current smokers received more evidence-based treatments and had less in-hospital complications, in-hospital mortality and adverse outcomes at one year. More frequent percutaneous coronary intervention at one year was noted in current smokers. Smoking was not an independent predictor of outcome when the multivariate model was fully adjusted for baseline characteristics.


The smoker's paradox was not observed in this population, since all differences in outcome were explained by smokers’ more benign baseline characteristics.

Acute coronary syndrome
Myocardial infarction
Risk factors

O tabagismo está associado à doença aterosclerótica, mas persistem dúvidas sobre a sua natureza protetora após a ocorrência de uma síndrome coronária aguda.


Determinar o impacto do tabagismo na apresentação, tratamento e prognóstico das síndromes coronárias agudas.


Analisámos todos os doentes consecutivos com síndrome coronária aguda num centro único entre 2005 e 2014. Fumadores activos e não-fumadores foram comparados. Avaliámos os preditores independents de mortalidade intra-hospitalar e de um composto de mortalidade por todas as causas, re-hospitalização de causa cardiovascular, coronariografia, intervenção coronária percutânea e cirurgia de revascularização miocárdica através de regressão logística multivariada.


2727 dts foram incluídos, 41,7% fumadores e 58,3% não-fumadores. Os fumadores eram mais jovens, mais frequentemente do género masculino, tinham menos comorbilidades, uma apresentação clínica típica e frequência cardíaca, pressão arterial sistólica, classe Killip, BNP/NT-pro-BNP e creatinina mais baixos, função sistólica do ventrículo esquerdo mais alta e doença coronária menos grave. O enfarte agudo do miocárdio com supradesnivelamento do segmento ST foi mais comum nos fumadores. Os fumadores receberam mais frequentmente tratamentos baseados na evidência e tiveram menos complicações e mortalidade intra-hospitalares e eventos adversos no primeiro ano. Uma maior taxa de intervenção coronária percutânea ao primeiro ano foi observada nos fumadores. O tabagismo não foi um preditor independente de prognóstico quando o modelo multivariado foi ajustado para as características basais.


O paradoxo dos fumadores não foi observado nesta população, uma vez que todas as diferenças no prognóstico foram explicadas pelas características basais mais benignas.

Síndrome coronária aguda
Enfarte do miocárdio
Fatores de risco
List of abbreviations

acute coronary syndrome


brain natriuretic peptide


coronary artery bypass grafting


confidence interval


disability-adjusted life years


N-terminal pro-brain natriuretic peptide


non-ST-segment elevation myocardial infarction


odds ratio


percutaneous coronary intervention


ST-segment elevation myocardial infarction


upper limit of normal

Full Text

Tobacco smoking is the leading preventable cause of death worldwide1 and the second leading cause of disability-adjusted life years (DALYs) lost.2 Smoking is strongly associated with the development of atherosclerotic disease, particularly coronary heart disease.2 It is responsible for 10% of all deaths caused by cardiovascular disease and 31% of DALYs lost due to ischemic heart disease.2 However, some studies reported an apparent survival benefit of smokers in the setting of acute coronary syndrome (ACS), ranging from in-hospital mortality3 to three-year mortality,4 a phenomenon known as the ‘smoker's paradox’. Over the years, this concept has been widely disputed and different explanations for this phenomenon have been proposed, based on a biochemical effect or on unmeasured confounding factors.

Firstly, most studies that reported this paradox are from the pre-thrombolytic5,6 and thrombolytic eras,7–13 and smokers are known to have a higher thrombotic burden, which could confer a heightened response to thrombolysis.14–16 Secondly, it has been proposed that smokers also have an enhanced response to clopidogrel therapy.17–22 Thirdly, it has been noted that smokers suffer more out-of-hospital death, thus creating a selection bias when assessing in-hospital mortality.23,24 Lastly, smokers are younger, have fewer risk factors and comorbidities and are more aggressively treated, and this could also contribute to their better prognosis.13,25–27

Despite this evidence, there are still contemporary studies that show smoking to be an independent predictor of outcome.12,28,29

To shed more light on this discrepancy, our study aims to compare the characteristics of patients with ACS according to their smoking status.


A total of 3298 consecutive ACS patients were admitted to our tertiary cardiology center between 2005 and 2014. Of these, 203 patients who received fibrinolytic therapy were excluded, due to its possible influence on outcome. The remaining patients were stratified according to self-reported smoking status: current smokers (irrespective of quantity), never-smokers and former smokers. The 391 patients included in the latter group were also excluded from the analysis. The population was thus composed of 2727 subjects. Demographic, clinical, laboratory, echocardiographic, angiographic and treatment data were collected. This was a retrospective cohort study, but all data were collected prospectively during the index hospitalization. The clinical outcomes were in-hospital mortality and a composite of all-cause mortality, rehospitalization for cardiovascular causes, angiography, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) at one year after discharge. Categorical variables were expressed as percentages and continuous variables as medians ± interquartile range. A family history of premature cardiovascular disease was defined as a first-degree family member with a diagnosis of atherosclerotic cardiovascular disease before the age of 55 (for men) or 65 years (for women). There was a change in laboratory availability of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) to brain natriuretic peptide (BNP) in our center during the study period. Therefore, these values are expressed as the number of times above the upper limit of the normal reference range (ULN). Categorical data were analyzed by the chi-square test and continuous data by the Mann-Whitney U test. Logistic regression models were used to assess for independent predictors of the clinical outcomes. Two-sided p-values <0.05 were considered statistically significant.


Of the 2727 patients, 41.7% (n=1138) were current smokers and 58.3% (n=1589) never-smokers.

Baseline characteristics differed substantially between current smokers and never-smokers (Table 1). Smokers were significantly younger than never-smokers and more frequently male. They had less classic cardiovascular risk factors, except for dyslipidemia and family history of premature cardiovascular disease, which were more common in smokers. Previous history of coronary artery, cerebrovascular and chronic renal disease were less common in smokers, while chronic obstructive pulmonary and peripheral artery disease were more common, although the overall prevalence was low. Smokers received less treatment for risk factors and had less cardiovascular medication at admission.

Table 1.

Baseline characteristics of patients admitted with acute coronary syndrome according to smoking status.

  All (n=2727)  Current smokers (n=1138)  Never-smokers (n=1589)  p-value 
Age, years  61±20  55±15  70±18  <0.001 
Male gender, %  66.9  85.2  53.7  <0.001 
Cardiovascular risk factors
Overweight/obesity, %  65.0  60.9  68.2  <0.001 
Family history, %a  12.0  16.3  8.9  <0.001 
Hypertension, %  65.6  48.2  78.0  <0.001 
Diabetes, %  26.0  14.7  34.1  <0.001 
Dyslipidemia, %  77.7  82.3  74.4  <0.001 
Treated hypertension, %  43.4  25.4  56.3  <0.001 
Treated diabetes, %  18.6  9.1  25.4  <0.001 
Treated dyslipidemia, %  24.6  16.9  30.1  <0.001 
Previous history
CAD, %  35.8  29.7  40.2  <0.001 
Stable CAD, %  23.5  19.8  26.2  <0.001 
MI, %  14.2  13.0  15.0  0.133 
PCI, %  10.5  10.9  10.2  0.556 
CABG, %  3.4  1.1  5.2  <0.001 
Stroke/TIA, %  5.9  2.6  8.2  <0.001 
CKD, %  2.7  1.0  3.9  <0.001 
PAD, %  3.1  4.0  2.5  0.025 
COPD, %  2.0  2.9  1.4  0.006 
Cancer, %  1.7  1.1  2.1  0.030 
Previous medication
Aspirin, %  22.3  15.1  27.4  <0.001 
P2Y12 inhibitor, %  5.8  4.3  6.9  0.005 
ACEI/ARB, %  33.8  19.2  44.2  <0.001 
Beta-blocker, %  16.6  10.9  20.7  <0.001 
Statin, %  25.1  17.2  30.7  <0.001 
Oral anticoagulation, %  2.2  0.8  3.3  <0.001 
Amiodarone, %  1.3  0.4  2.0  <0.001 
Oral nitrate, %  4.7  1.1  7.2  <0.001 
CCB, %  10.5  4.7  14.5  <0.001 
Diuretic, %  12.5  5.4  17.6  <0.001 

Family history of premature cardiovascular disease.

ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; CABG: coronary artery bypass grafting; CAD: coronary artery disease; CCB: calcium channel blocker; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; MI: myocardial infarction; PAD: peripheral artery disease; PCI: percutaneous coronary intervention; TIA: transient ischemic attack.

A typical clinical presentation, with lower heart rate, systolic blood pressure and Killip class, and a greater proportion of sinus rhythm at admission were seen among current smokers. ST-elevation myocardial infarction (STEMI) was more common in smokers and non-ST-elevation ACS in non-smokers (Table 2).

Table 2.

Clinical presentation of patients admitted with acute coronary syndrome according to smoking status.

  All (n=2727)  Current smokers (n=1138)  Never-smokers (n=1589)  p-value 
Main symptoms
Typical pain, %  86.2  90.0  83.5  <0.001 
Atypical pain, %  7.4  6.4  8.2  0.085 
Heart failure, %  1.9  0.8  2.7  <0.001 
Syncope, %  1.7  1.1  2.2  0.027 
Cardiac arrest, %  0.8  0.9  0.7  0.471 
Vital signs and ECG features
SBP, mmHg  134±35  130±38  138±40  <0.001 
DBP, mmHg  80±20  80±21  80±23  0.828 
HR, bpm  79±25  77±26  80±23  0.004 
Sinus rhythm, %  92.2  97.0  88.8  <0.001 
AF, %  6.8  2.8  9.7  <0.001 
Paced rhythm, %  1.0  0.2  1.5  0.001 
LBBB, %  3.7  1.4  5.3  <0.001 
RBBB, %  4.5  3.3  5.4  0.007 
Complete AV block, %  2.2  2.6  1.8  0.151 
Killip class
I, %  85.8  90.8  82.1  <0.001 
II, %  9.1  5.7  11.5  <0.001 
III, %  2.7  1.4  3.6  0.001 
IV, %  2.3  2.1  2.6  0.377 
Type of ACS
STEMI, %  61.3  69.8  56.3  <0.001 
NSTEMI, %  32.4  25.2  36.6  <0.001 
Unstable angina, %  6.3  4.9  7.1  0.021 

ACS: acute coronary syndrome; AF: atrial fibrillation; AV: atrioventricular; bpm: beats per min; DBP: diastolic blood pressure; ECG: electrocardiographic; HR: heart rate; LBBB: left bundle branch block; RBBB: right bundle branch block; STEMI: ST-segment elevation myocardial infarction; NSTEMI: non-ST-segment elevation myocardial infarction; SBP: systolic blood pressure.

Table 3 displays the laboratory, echocardiographic and angiographic data of the population. Median BNP/NT-pro-BNP, creatinine and glucose values were lower and median hemoglobin levels were higher in smokers compared to never-smokers. Left ventricular systolic dysfunction as assessed by transthoracic echocardiography (left ventricular ejection fraction <50%) was observed less often in smokers, who also had a lower proportion of multivessel, left main and left anterior descending artery disease.

Table 3.

Laboratory, echocardiographic and angiographic data of patients admitted with acute coronary syndrome according to smoking status.

  All (n=2727)  Current smokers (n=1138)  Never-smokers (n=1589)  p-value 
Laboratory features
BNP/NT-pro-BNP (admission), times ULN  1.98±4.33  2.19±4.85  4.10±6.52  <0.001 
BNP/NT-pro-BNP (maximum), times ULN  5.00±16.00  6.00±10.00  8.00±19.00  <0.001 
Creatinine (admission), mg/dl  1.06±0.31  1.03±0.23  1.10±0.30  <0.001 
Glucose (admission), mg/dl  145±67  132±60  141±78  <0.001 
Glucose (maximum), mg/dl  163±84  147±64  165±93  <0.001 
Hemoglobin (admission), 10 g/dl  14.0±3.0  14.0±2.0  13.0±2.0  <0.001 
Hemoglobin (minimum), 10 g/dl  12.0±3.0  13.0±3.0  12.0±3.0  <0.001 
>50%, %  65.6  70.4  62.7  <0.001 
35%-50%, %  26.8  24.3  28.3  0.022 
<35%, %  7.6  5.3  9.0  <0.001 
Angiographic features
1-vessel disease, %  48.1  55.0  43.0  <0.001 
2-vessel disease, %  28.7  28.0  29.2  0.590 
3-vessel disease, %  15.1  11.7  17.6  0.001 
Left main disease, %  3.1  2.2  3.7  0.019 
LAD disease, %  51.0  47.3  53.7  0.011 
LCx disease, %  22.7  22.1  23.1  0.633 
RCA disease, %  39.9  45.2  36.0  <0.001 

BNP: brain natriuretic peptide; LAD: left anterior descending artery; LCx: left circumflex artery; LVEF: left ventricular ejection fraction; NT-pro-BNP: N-terminal pro-brain natriuretic peptide; RCA: right coronary artery; times ULN: times above the upper limit of normal.

In-hospital complications were least frequent in smokers. They were more often treated by PCI, but there was no difference in CABG. Prescription of aspirin, P2Y12 inhibitors, statin and diuretics during hospital stay and after discharge was significantly lower in never-smokers. Beta-blockers were more widely used in the smokers group at discharge. There was no difference in the use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), either in-hospital or at discharge. Smokers were more frequently discharged on a combination of aspirin, P2Y12 inhibitors and statins, and also on a combination of these three drugs plus ACEIs/ARBs and beta-blockers (Table 4).

Table 4.

Complications, treatment and outcome of patients admitted with acute coronary syndrome according to smoking status.

  All (n=2727)  Current smokers (n=1138)  Never-smokers (n=1589)  p-value 
In-hospital complicationsa
No complications, %  70.3  77.0  66.4  <0.001 
Acute pulmonary edema, %  3.5  1.9  4.3  <0.001 
Acute renal failure, %  4.5  1.8  6.1  <0.001 
Asystole, %  2.7  1.1  3.6  <0.001 
Blood transfusion, %  2.3  1.5  2.8  0.023 
Cardiogenic shock, %  5.1  3.3  6.2  <0.001 
Free wall rupture, %  0.4  0.1  0.5  0.047 
Mechanical ventilation, %  5.7  4.0  6.6  0.003 
Recurrent ischemia, %  0.4  0.1  0.6  0.032 
In-hospital treatment
Revascularization, %  73.8  84.1  67.0  <0.001 
PCI71.1  82.4  65.3  <0.001 
CABG, %  1.8  1.7  1.9  0.672 
Aspirin, %  97.5  98.2  97.0  0.037 
P2Y12 inhibitor, %  93.7  96.4  92.1  <0.001 
Statin, %  92.2  94.4  91.0  0.001 
ACEI/ARB, %  87.5  87.2  87.6  0.707 
Beta-blocker, %  60.1  61.9  59.0  0.119 
Diuretic, %  22.2  13.4  27.8  <0.001 
Triple therapy, %b  87.6  91.9  84.5  <0.001 
Quintuple therapy, %c  49.8  52.7  47.8  0.011 
Discharge treatment
Aspirin, %  89.4  94.0  86.7  <0.001 
P2Y12 inhibitor, %  82.7  90.0  78.5  <0.001 
Statin, %  86.8  91.9  83.8  <0.001 
ACEI/ARB, %  78.8  80.0  78.1  0.228 
Beta-blocker, %  55.8  59.4  53.7  0.002 
Diuretic, %  22.1  12.7  27.5  <0.001 
Triple therapy, %b  78.5  86.0  73.1  <0.001 
Quintuple therapy, %c  42.9  45.6  41.0  0.016
In-hospital mortality, %  5.2  2.3  6.9  <0.001 
Composite outcome at 1 year, %  19.2  16.2  21.4  0.014 
All-cause mortality, %  5.3  3.9  6.1  0.008 
Rehospitalization, %  7.9  9.0  7.1  0.194 
Angiography, %  5.0  6.6  3.9  0.019 
PCI, %  3.0  4.1  2.2  0.031 
CABG, %  1.6  1.1  2.0  0.179 

In-hospital complications with non-significant differences between the groups: complete atrioventricular heart block, first or second degree atrioventricular heart block, minor or major bleeding, need for hemodialysis, new bundle branch block, new Q-wave development, reinfarction, severe mitral regurgitation, tamponade, septal rupture, stroke/transient ischemic attack, ventricular fibrillation, ventricular tachycardia.


Combination of aspirin, P2Y12 inhibitor and statin.


Combination of aspirin, P2Y12 inhibitor, statin, ACEI/ARB and beta-blocker.

ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; CABG: coronary artery bypass grafting; CAD: coronary artery disease; PCI: percutaneous coronary intervention; STEMI: ST-elevation myocardial infarction.

In-hospital mortality in smokers was a third of that for never-smokers (2.3% vs. 6.9%, p<0.001). The composite outcome of all-cause mortality, rehospitalization for cardiovascular causes, angiography, PCI and CABG at one year was significantly lower in smokers (16.2% vs. 21.4%, p=0.014), driven by lower all-cause mortality (3.6% vs. 6.1%, p=0.008). There was an increased proportion of PCI in smokers at one year (3.9% vs. 2.9%, p=0.029) (Table 4).

When only STEMI was analyzed, the distribution among current and never-smokers of all studied variables was similar to that previously described for the whole spectrum of ACS. There was a tendency for decreased time from symptom onset to first medical contact (90±79 min vs. 106±89 min, p=0.059) and a significantly decreased time from first medical contact to reperfusion (123±113 min vs. 142±131 min, p=0.002) in smokers. Differences in the studied variables were less pronounced for non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina. In-hospital mortality and the composite endpoint at one year were significantly lower in smokers with STEMI (2.6 vs. 10.1, p<0.001 and 16.2 vs. 21.4, p=0.038, respectively), but there were no differences in patients with NSTEMI or unstable angina.

Smoking was a predictor of in-hospital mortality across the full spectrum of ACS, with an unadjusted odds ratio (OR) of 0.279 (95% confidence interval [CI] 0.181-0.428, p<0.001). However, after adjusting for age, this association was weaker (OR 0.591, 95% CI 0.362-0.965, p=0.036) and when the multivariate model was fully adjusted for all variables with known prognostic significance (age, gender, heart rate, systolic blood pressure, Killip class, creatinine at admission and type of ACS), smoking was not an independent predictor of in-hospital mortality (OR 1.129, 95% CI 0.345-3.696 p=0.842). A similar interaction was seen for STEMI, while for NSTEMI, smoking was not a significant predictor of in-hospital mortality in the univariate analysis. There were no in-hospital deaths in patients with unstable angina. This distribution was reproduced for the composite outcome at one year, and additionally, smoking was also not a predictor in univariate analysis in patients with unstable angina (Table 5).

Table 5.

Influence of smoking on in-hospital mortality and on the composite outcome of all-cause mortality, rehospitalization for cardiovascular causes, angiography, PCI and CABG at one year according to type of acute coronary syndrome.

  Crude OR (95% CIAge-adjusted OR (95% CIFully-adjusted ORa (95% CI
In-hospital mortality
All ACS  0.279 (0.181-0.428), p<0.001  0.591 (0.362-0.965), p=0.036  0.903 (0.472-1.727), p=0.757 
STEMI  0.236 (0.144-0.387), p<0.001  0.521 (0.295-0.921), p=0.025  0.835 (0.394-1.770), p=0.638 
NSTEMI  0.427 (0.174-1.048), p=0.063  1.094 (0.391-3.059), p=0.864  1.024 (0.274-3.827), p=0.972 
Composite outcome of all-cause mortality, rehospitalization for cardiovascular causes, angiography, PCI and CABG at 1 year
All ACS  0.675 (0.509-0.894), p<0.001  0.873 (0.624-1.220), p=0.426  0.925 (0.623-1.373), p=0.699 
STEMI  0.772 (0.540-1.104), p=0.156  0.781 (0.513-1.190), p=0.250  0.822 (0.503-1.344), p=0.435 
NSTEMI  0.548 (0.325-0.923), p=0.024  1.158 (0.616-2.175), p=0.648  1.174 (0.564-2.445), p=0.667 
UA  0.972 (0.254-3.726), p=0.967  1.434 (0.311-6.613), p=0.644  1.604 (0.191-13.449), p=0.663 

Variables inserted in the model were age, gender, heart rate, systolic blood pressure, Killip class, creatinine at admission and type of ACS (only when considering the full spectrum of ACS).

ACS: acute coronary syndrome; NSTEMI: non-ST-elevation myocardial infarction; STEMI: ST-elevation myocardial infarction; UA: unstable angina.


Our analysis portrays a significant number of patients with ACS admitted to a tertiary cardiology center. We excluded patients who were treated by thrombolysis in view of the need to adjust for the previously described enhanced effect of this therapy in smokers.14–16

The overall prevalence of smoking in this study is similar to those previously published.3,26,30 The decision to exclude former smokers was based on the fact that they are known to have a profile and prognosis intermediate between current smokers and never-smokers, and also include a significant number of patients with previously known coronary artery disease, including myocardial infarction,12,26,31 which could have biased the results.

Smoking is an important determinant of coronary artery disease, as shown by the fact that the smokers’ cohort suffered an ACS on average 15 years before never-smokers, despite having fewer conventional cardiovascular risk factors. The prevalence of dyslipidemia was higher in current smokers, an association that has been described previously.32 Current smokers were also more frequently male, which emphasizes an association with another studied ‘paradox’ in ACS.33–35

The comorbidity profile of smokers is less severe and their presentation is more typical, an observation that could have accounted for patients seeking help more promptly, which is in part suggested by the tendency for lower time from symptom onset to first medical contact (reported only in STEMI). Smoking has been associated with delay in seeking treatment,36 which was not seen in our analysis; this could be related to smokers’ younger age and larger proportion of male subjects.37 Smokers are also more prone to present with ACS as the first manifestation of coronary artery disease, since a history of this entity is less frequent in this group.

Smokers have lower heart rate and systolic blood pressure at admission, as well as lower Killip class and creatinine levels, which are known predictors of better outcome and puts them at an advantage when compared to never-smokers.38

Current smokers have a greater propensity for STEMI.3,26,28,30 Their coronary anatomy is less complex, with less three-vessel disease and fewer left main and left anterior descending lesions, features that are typically associated with a worse prognosis.39

The rate of adherence to evidence-based treatment was greater in smokers, both during the index hospitalization (revascularization and medical treatment)12,26,29–31 and at discharge (medical treatment).31 Moreover, smokers were treated more promptly than never-smokers, as shown by a significantly shorter time from first medical contact to reperfusion (reported only in STEMI).11

In-hospital mortality in smokers was a third of that for never-smokers. Although the composite outcome of all-cause mortality, rehospitalization for cardiovascular causes, angiography, PCI and CABG at one year was lower in smokers, mainly due to lower all-cause mortality, there was a significantly increased rate of repeat PCI in this group. This association has been described in previous reports.40–42

Smoking was associated with in-hospital mortality and adverse outcome at one year, particularly in STEMI, but this association was weaker after adjustment for age and disappeared when other variables with known prognostic impact38 were inserted into the model. Other reports have shown that age may be the sole factor responsible for the smoker's paradox.25,26 This was not the case in our population, in which other variables related to clinical presentation were also important. Smoking had no influence on outcome in patients with NSTEMI and unstable angina, which is in agreement with the initial reports of the smoker's paradox, which referred to STEMI only.9,26,43

This study has some limitations. First, it was retrospective in nature and thus susceptible to inherent limitations. Second, it was not possible to determine the number of pack-years in all smokers. Third, out-of-hospital deaths were not recorded. Fourth, there were no data regarding adherence to medical treatment after discharge.


Current smokers with ACS were significantly younger and more frequently male, had fewer risk factors and comorbidities, more benign clinical presentation and fewer complications, and received more aggressive treatment. These differences completely explained the lower in-hospital and one-year mortality initially observed in current smokers. Thus, in our population, we did not find a real smoker's paradox. Besides, the apparent benefit was only seen in the subset of patients with STEMI, while differences in overall characteristics were less marked in other types of ACS and no benefit in mortality was seen. Importantly, ACS in smokers occurs around 15 years before never-smokers, which makes smoking a major cardiovascular risk factor and a target for primary and secondary prevention of ischemic heart disease.

Conflicts of interest

The authors have no conflicts of interest to declare.


The authors wish to thank Tiago Pereira da Silva, Pedro Rio, Marta Afonso Nogueira, Andé Viveiros Monteiro, Guilherme Portugal, Pedro Pinto Teixeira, Sílvia Aguiar Rosa, Inês Rodrigues, Luís Almeida Morais and Pedro Modas Daniel for their contributions to the data collection.

T.A. Gaziano, D. Prabhajaran, J.M. Gaziano.
Global burden of cardiovascular disease. Chapter 1.
Braunwald's Heart Disease. A textbook of cardiovascular medicine, pp. 1-20
S.S. Lim, T. Vos, A.D. Flaxman, et al.
Comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study.
Lancet, 380 (2010), pp. 2224-2260
N. Bettencourt, P. Mateus, C. Dias, et al.
The smoker's paradox – a hemodynamic reality?.
Rev Port Cardiol, 23 (2004), pp. 547-555
H.J. Jaatun, S.C. Sutradhar, K. Dickstein, OPTIMAAL Study Group.
Comparison of mortality rates after acute myocardial infarction in smokers versus nonsmokers.
Am J Cardiol, 94 (2004), pp. 632-636
C. Helmers.
Short and long-term prognostic indices in acute myocardial infarction. A study of 606 patients initially treated in a coronary care unit.
Acta Med Scand Suppl, 555 (1973), pp. 7-26
T.L. Kelly, E. Gilpin, S. Ahnve, et al.
Smoking status at the time of acute myocardial infarction and subsequent prognosis.
Am Heart J, 110 (1985), pp. 535-541
P. Molstad.
First myocardial infarction in smokers.
Eur Heart J, 12 (1991), pp. 753-759
G.I. Barbash, H.D. White, M. Modan, et al.
Significance of smoking in patients receiving thrombolytic therapy for acute myocardial infarction. Experience gleaned from the International Tissue Plasminogen Activator/Streptokinase Mortality Trial.
Circulation, 87 (1993), pp. 53-58
G.I. Barbash, J. Reiner, H.D. White, et al.
Evaluation of paradoxic beneficial effects of smoking in patients receiving thrombolytic therapy for acute myocardial infarction: mechanism of the “smoker's paradox” from the GUSTO-I trial, with angiographic insights. Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries.
J Am Coll Cardiol, 26 (1995), pp. 1222-1229
S.G. Gourlay, A.C. Rundle, H.V. Barron.
Smoking and mortality following acute myocardial infarction: results from the National Registry of Myocardial Infarction (NRMI 2).
Nicotine Tob Res, 4 (2002), pp. 101-107
M. Ruiz-Bailen, E.A. de Hoyos, A. Reina-Toral, et al.
Paradoxical effect of smoking in the Spanish population with acute myocardial infarction or unstable angina: results of the ARIAM Register.
Chest, 125 (2004), pp. 831-840
R. Elosua, G. Vega, I. Rohlfs, et al.
IBERICA investigators: smoking and myocardial infarction case-fatality: hospital and population approach.
Eur J Cardiovasc Prev Rehabil, 14 (2007), pp. 561-567
E. Aune, J. Røislien, M. Mathisen, et al.
The “smoker's paradox” in patients with acute coronary syndrome: a systematic review.
C.F. Lundergan, J.S. Reiner, W.F. McCarthy, et al.
Clinical predictors of early infarct-related artery patency following thrombolytic therapy: importance of body weight, smoking history, infarct-related artery and choice of thrombolytic regimen: the GUSTO-I experience. Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries.
J Am Coll Cardiol, 32 (1998), pp. 641-647
A.J. Kirtane, P. Martinezclark, A.M. Rahman, et al.
Association of smoking with improved myocardial perfusion and the angiographic characterization of myocardial tissue perfusion after fibrinolytic therapy for ST-segment elevation myocardial infarction.
J Am Coll Cardiol, 45 (2005), pp. 321-323
V.G. Nielsen, D.T. Hafner, E.B. Steinbrenner.
Can divergent plasmin-antiplasmin-carbon monoxide interactions in young, healthy tobacco smokers explain the ‘smoker's paradox’?.
Blood Coagul Fibrinolysis, 24 (2013), pp. 381-385
K.P. Bliden, J. Dichiara, L. Lawal, et al.
The association of cigarette smoking with enhanced platelet inhibition by clopidogrel.
J Am Coll Cardiol, 52 (2008), pp. 531-533
N.R. Desai, J.L. Mega, S. Jiang, et al.
Interaction between cigarette smoking and clinical benefit of clopidogrel.
J Am Coll Cardiol, 53 (2009), pp. 1273-1278
J.S. Berger, D.L. Bhatt, S.R. Steinhubl, CHARISMA Investigators, et al.
Smoking, clopidogrel, and mortality in patients with established cardiovascular disease.
Circulation, 120 (2009), pp. 2337-2344
K.W. Park, J.J. Park, K.H. Jeon, et al.
Enhanced clopidogrel responsiveness in smokers’ paradox is dependent on cytochrome P450 CYP1A2 status.
Arterioscler Thromb Vasc Biol, 31 (2011), pp. 665-671
K.W. Park, S.H. Kang, J. Kang, et al.
Enhanced clopidogrel response in smokers is reversed after discontinuation as assessed by VerifyNow assay: additional evidence for the concept of ‘smokers’ paradox’.
P.A. Gurbel, K.P. Bliden, D.K. Logan, et al.
The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: the PARADOX study.
J Am Coll Cardiol, 62 (2013), pp. 505-512
G.S. Sonke, A.W. Stewart, R. Beaglehole, et al.
Comparison of case fatality in smokers and non-smokers after acute cardiac event.
BMJ, 315 (1997), pp. 992-993
P. McElduff, A.J. Dobson.
Case fatality after an acute cardiac event: the effect of smoking and alcohol consumption.
J Clin Epidemiol, 54 (2001), pp. 58-67
G.K. Andrikopoulos, D.J. Richter, P.E. Dilaveris, et al.
In-hospital mortality of habitual cigarette smokers after acute myocardial infarction: the “smoker's paradox” in a countrywide study.
Eur Heart J, 22 (2001), pp. 776-784
D. Himbert, M. Klutman, G. Steg, for the GRACE Investigators, et al.
Cigarette smoking and acute coronary syndromes: a multinational observational study.
Int J Cardiol, 100 (2005), pp. 109-117
G. Weisz, D.A. Cox, E. Garcia, et al.
Impact of smoking status on outcomes of primary coronary intervention for acute myocardial infarction: the smoker's paradox revisited.
Am Heart J, 150 (2005), pp. 358-364
K.Y. Chen, S.W. Rha, Y.J. Li, Korea Acute Myocardial Infarction Registry Investigators, et al.
‘Smoker's paradox’ in young patients with acute myocardial infarction.
Clin Exp Pharmacol Physiol, 39 (2012), pp. 630-635
S.F. Ali, E.E. Smith, M.J. Reeves, et al.
Smoking paradox in patients hospitalized with coronary artery disease or acute ischemic stroke: findings from get with the guidelines.
Circ Cardiovasc Qual Outcomes, 8 (2015), pp. S73-S80
A. Gaspar, S. Nabalis, S. Rocha, et al.
Smoking in acute coronary syndromes – the “smoker's paradox” revisited.
Rev Port Cardiol, 28 (2009), pp. 425-437
Y. Gerber, L.J. Rosen, U. Goldbourt, Israel Study Group on First Acute Myocardial Infarction, et al.
Smoking status and long-term survival after first acute myocardial infarction a population-based cohort study.
J Am Coll Cardiol, 54 (2009), pp. 2382-2387
M. Masulli, G. Riccardi, R. Galasso, et al.
Relationship between smoking habits and the features of the metabolic syndrome in a non-diabetic population.
Nutr Metab Cardiovasc Dis, 16 (2006), pp. 364-370
K. Loboz-Grudzień, J. Jaroch.
Women with acute coronary syndromes have a worse prognosis – why? The need to reduce ‘treatment-seeking delay’.
Cardiol J, 18 (2011), pp. 219-221
Z. Zhang, J. Fang, C. Gillespie, et al.
Age-specific gender differences in in-hospital mortality by type of acute myocardial infarction.
Am J Cardiol, 109 (2012), pp. 1097-1103
N. Akhter, S. Milford-Beland, M.T. Roe, et al.
Gender differences among patients with acute coronary syndromes undergoing percutaneous coronary intervention in the American College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR).
Am Heart J, 157 (2009), pp. 141-148
K. Dracup, D.K. Moser, M. Eisenberg, et al.
Causes of delay in seeking treatment for heart attack symptoms.
Soc Sci Med, 40 (1995), pp. 379-392
D.K. Moser, L.P. Kimble, M.J. Alberts, American Heart Association Council on Cardiovascular Nursing and Stroke Council, et al.
Reducing delay in seeking treatment by patients with acute coronary syndrome and stroke: a scientific statement from the American Heart Association Council on cardiovascular nursing and stroke council.
Circulation, 114 (2006), pp. 168-182
K.A. Fox, O.H. Dabbous, R.J. Goldberg, et al.
Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE).
P.W. Serruys, Y. Onuma, S. Garg, et al.
Assessment of the SYNTAX score in the Syntax study.
EuroIntervention, 5 (2009), pp. 50-56
S. Ma, D. Yang, X. Zhang, et al.
Comparison of restenosis rate with sirolimus-eluting stent in STEMI patients with and without diabetes at 6-month angiographic follow-up.
Acta Cardiol, 66 (2011), pp. 603-606
S.J. Hong, M.H. Kim, T.H. Ahn, et al.
Multiple predictors of coronary restenosis after drug-eluting stent implantation in patients with diabetes.
Heart, 92 (2006), pp. 1119-1124
T. Ishikawa, H. Yagi, T. Ogawa, et al.
Deteriorative effect of smoking on target lesion revascularization after implantation of coronary stents with diameter of 3.0 mm or less.
Circ J, 69 (2005), pp. 227-231
A.P. Maggioni, F. Piantadosi, G. Tognoni, et al.
Smoking is not a protective factor for patients with acute myocardial infarction: the viewpoint of the GISSI-2 Study.
G Ital Cardiol, 28 (1998), pp. 970-978
Copyright © 2018. Sociedade Portuguesa de Cardiologia
Revista Portuguesa de Cardiologia (English edition)

Subscribe to our newsletter

Article options
en pt

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos

en pt
Cookies policy Política de cookies
To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here. Utilizamos cookies próprios e de terceiros para melhorar nossos serviços e mostrar publicidade relacionada às suas preferências, analisando seus hábitos de navegação. Se continuar a navegar, consideramos que aceita o seu uso. Você pode alterar a configuração ou obter mais informações aqui.