Temporal trends in all-cause mortality according to smoking status: Insights from the Global Registry of Acute Coronary Events

    Temporal trends in all-cause mortality according to smoking status: Insights from the Global Registry of Acute Coronary Events Yaron Arbel, Gordon FitzGerald, Andrew T. Yan, Mary K. Tan, Keith A.A. Fox, Joel M. Gore, Ph. Gabriel Steg, Kim A. Eagle, David Brieger, Gilles Montalescot, Andrzej Budaj, Jose Lopez-Sendon, Alvaro Avezum, Christopher B. Granger, Shaun G. Goodman PII: DOI: Reference:

S0167-5273(16)30934-2 doi: 10.1016/j.ijcard.2016.05.064 IJCA 22620

To appear in:

International Journal of Cardiology

Received date: Revised date: Accepted date:

12 February 2016 4 May 2016 12 May 2016

Please cite this article as: Arbel Yaron, FitzGerald Gordon, Yan Andrew T., Tan Mary K., Fox Keith A.A., Gore Joel M., Steg Ph. Gabriel, Eagle Kim A., Brieger David, Montalescot Gilles, Budaj Andrzej, Lopez-Sendon Jose, Avezum Alvaro, Granger Christopher B., Goodman Shaun G., Temporal trends in all-cause mortality according to smoking status: Insights from the Global Registry of Acute Coronary Events, International Journal of Cardiology (2016), doi: 10.1016/j.ijcard.2016.05.064

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ACCEPTED MANUSCRIPT Temporal Trends in All-Cause Mortality according to Smoking Status: Insights from the Global Registry of Acute Coronary Events

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Yaron Arbel MD*1, Gordon FitzGerald PhD*2, Andrew T Yan MD3, Mary K Tan MSc4, Keith

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AA Fox MB, ChB, FRCP5 , Joel M Gore MD6, Ph Gabriel Steg MD7, Kim A Eagle MD8, David

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Brieger MBBS, PhD9, Gilles Montalescot MD, PhD10, Andrzej Budaj MD, PhD11, Jose LopezSendon MD, PhD12, Alvaro Avezum MD, PhD13, Christopher B Granger MD14, Shaun G

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Goodman MD, MSc3,4

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*YA and GF contributed equally to this manuscript

Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada; 2 Center for

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Outcomes Research, University of Massachusetts Medical School, Worcester, USA; 3St.

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Michael's Hospital, University of Toronto, Toronto, Canada; 4 Canadian Heart Research

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Centre, Toronto, Canada; 5 Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK; 6 Department of Medicine, University of Massachusetts Medical School, Worcester, USA; 7 Département Hospitalo-Universitaire FIRE, Université Paris Diderot, APHP, Hôpital Bichat, and INSERM U-1148, Paris, France; 8Frankel Cardiovascular Center,University of Michigan Health System, Ann Arbor, MI; 9Concord Hospital and University of Sydney, Sydney, Australia; 10 Université Paris 06, ACTION Study Group, INSERM-UMRS 1166, Institut de Cardiologie, Pitié-Salpêtrière University Hospital (AP-HP) – Paris, France; 11 Postgraduate Medical School, Grochowski Hospital Warsaw, Poland; 12 Hospital Universitario La Paz, Instituto de Investigación La PAZ, Madrid, Spain; 13 Dante Pazzanese Institute of Cardiology and University of Santo Amaro, São Paulo, SP, Brazil; 14 Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.

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ACCEPTED MANUSCRIPT Word Count: 3,736 (excluding title page, tables, figures) GRACE was supported by an unrestricted educational grant from sanofi-aventis to the Center for

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Outcomes Research, University of Massachusetts Medical School. Sanofi-aventis had no

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and in the decision to submit the paper for publication.

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involvement in the collection, analysis, and interpretation of data; in the writing of the report;

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Corresponding author: Dr Shaun G. Goodman, St. Michael’s Hospital, Division of Cardiology, 30 Bond Street, Room 6-034 Donnelly, Toronto, Ontario, Canada M5B 1W8; Fax

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416-864-5407 Telephone 416-864-5722. E-mail [email protected]

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ACCEPTED MANUSCRIPT ABSTRACT Objective

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Smoking has been shown to be a risk factor for heart disease. However, it was recently reported

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that despite the evolution in therapy for acute coronary syndrome (ACS), smokers have not

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demonstrated improved outcomes.

The aim of the present study was to evaluate the temporal trends in the treatments and outcomes

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across a broad spectrum of ACS patients (STEMI and non-ST-elevation ACS [NSTEACS])

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according to smoking status on presentation in the Global Registry of Acute Coronary Events

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(GRACE).

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Methods

Our cohort was stratified into 3 groups: current smokers, former smokers and never smokers. We

1999 to 2007.

Results

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evaluated trends in demographics, treatment modalities and outcomes in these 3 groups from

The study population comprised a total of 63,015 patients admitted to hospital with an ACS and with identifiable baseline smoking status. Smokers presented with STEMI more often than nonsmokers. There was an unadjusted decline in 30-day mortality in all 3 groups. However, the adjusted decline was not statistically significant among current smokers (HR= 0.98 per study year, 95% CI 0.94-1.01, p=0.20). A subgroup analysis of 22,894 STEMI patients demonstrated no reduction in annual adjusted 30-day mortality rates among smokers (HR= 1.01, 95% CI 0.961.06 (Table 5), whereas former and never smokers’ mortality declined.

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ACCEPTED MANUSCRIPT Conclusions Over the years 1999-2007, 30-day mortality declined in patients presenting with acute coronary

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syndrome. However, smokers presenting with STEMI did not demonstrate a reduction in

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mortality.

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Keywords: smoking, acute coronary syndrome, trends, outcomes

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ACCEPTED MANUSCRIPT INTRODUCTION Smoking has been shown to be an important risk factor for heart disease. However, despite the

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increased risk for coronary artery disease and acute myocardial infarction, smokers have a paradoxically lower mortality early after myocardial infarction than non-smokers. This

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observation has been coined the smokers paradox. 1, 2 The explanation for their relatively lower

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mortality is that smokers suffer their myocardial infarction (MI) at a younger age, have fewer co-

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morbid conditions, and have less advanced coronary disease and fewer anterior MIs.3, 4 This paradox has been demonstrated in both the fibrinolytic and primary percutaneous coronary

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intervention (PCI) eras. 3, 5, 6

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While the evidence-based management of acute coronary syndrome (ACS) has evolved rapidly,7, one recent study suggested that current smokers presenting with ST-elevation myocardial

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infarction (STEMI) have not benefited from newer therapies over the past decade.9 However, this study was limited to just over 4,500 patients from a single country and did not include the broad spectrum of ACS, including non-ST-segment elevation MI (NSTEMI) or unstable angina patients.

We therefore sought to determine whether smokers, compared to former smokers and nonsmokers, with an ACS have experienced improved outcomes associated with increased uptake of evidence-based treatment over the study period. Thus, the aim of the present study was to evaluate the temporal trends in treatments and outcomes across a broad spectrum of ACS patients (STEMI and non-ST-elevation ACS [NSTEACS]) according to smoking status on

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ACCEPTED MANUSCRIPT presentation in the Global Registry of Acute Coronary Events (GRACE) conducted from 1999 to

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2007.

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METHODS:

GRACE enrolled more than 70,000 ACS patients from 94 hospitals in 14 countries (Argentina,

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Australia, Austria, Belgium, Brazil, Canada, France, Germany, Italy, New Zealand, Poland,

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Spain, United Kingdom, United States).10 It is the largest multinational registry to date

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evaluating the care of patients presenting with ACS.

Study population

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Patients entered in the registry had to be at least 18 years old and alive at the time of hospital presentation, and be admitted with an ACS as the main diagnosis. Data were collected at each

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site by a trained coordinator using a standardized case report form developed for GRACE. Demographic characteristics, medical history, presenting symptoms, duration of prehospital delay, biochemical and electrocardiographic findings, treatment practices, and a variety of hospital outcome data were collected. 11

Definition of Study Groups Our cohort was stratified into 3 groups: current smokers, former smokers and never smokers. Current smokers were people who reported active cigarette smoking (pipe and cigar smoking was excluded from this definition) within the past month prior to hospital admission. Former smokers were defined as those who reported having stopped smoking more than 1 month before hospital admission. Other patients were considered non-smokers.

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ACCEPTED MANUSCRIPT Statistical analysis Unadjusted results are summarized as percentages for discrete variables, means and standard

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deviations or median and interquartile range for continuous variables. Annual trends were

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estimated as unit increase or decrease per year for continuous variables, and increase or decrease in rate per year for discrete variables. In both cases, year was treated as a continuous variable. P-

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values are not shown for selected univariate comparisons between smoking groups, since large

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sample sizes (≥17,000 in each group) may make clinically unimportant differences statistically

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significant (Table 1).

The primary outcome was trend in 30-day mortality over the 9-year study period for each of the

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three smoking groups. Unadjusted 30-day mortality rates were estimated using the Kaplan-Meier method; the log-rank test was used to assess differences by smoking group. 76% of patients had

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6-month follow-up available; patients discharged alive within 30 days of admission without further follow-up were censored at the time of discharge. Adjusted annual linear mortality trends for each smoking group are reported as hazard ratios (HR) (and 95% confidence intervals (CI)) per year from a Cox model adjusted for the GRACE risk score (the score includes age)12. Since a previous study demonstrated no apparent benefit from newer therapies over the past decade among STEMI patients,9 we additionally tested for differences in mortality trends between STEMI and NSTEMI/UA patients, in each of the 3 smoking groups. We created propensity scores as a sensitivity analysis for our main findings: one set of scores for current versus former, and a second set for current versus never smokers. We then reran the regression models, excluding patients whose propensities did not overlap in the smoking groups (approximately half the patients), adjusting for the GRACE risk score and propensity for current smoking.

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Trends for other dichotomous variables over the 9-year study period (1999-2007) were estimated

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as annual percentage increase or decrease using linear regression (p-values were assessed using logistic regression with year as a continuous variable; in most cases these p-values coincide with

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linear regression p-values for a continuous year variable, due to large sample asymptotics).

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A two-sided alpha level of 0.05 was used to assess statistical significance. All analyses were

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conducted using the SAS software package, version 9.3 (SAS Institute).

RESULTS

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The study population comprised a total of 63,015 patients admitted to hospital with an ACS and with identifiable baseline smoking status. Of these, 27% were current smokers; the rates of

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current, former, and never smokers at the time of incident ACS were fairly constant over the 9 years of the study (Table 1).

Compared with non-smokers, current smokers were significantly younger and had a lower frequency of baseline clinical risk factors, including hypertension and diabetes mellitus. Smokers also presented with STEMI more often than non-smokers.

Admission characteristics The baseline overall risk of the patients, exemplified by the GRACE risk score, did not change materially over the study period (Table 1).

Short term outcomes

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ACCEPTED MANUSCRIPT Considering the entire study period as a whole, unadjusted 30-day mortality was lowest among current smokers (4.0%), higher among former (5.4%) and never smokers (7.7%) (Table 2). After

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adjusting for the GRACE risk score, these differences were reduced: no significant difference

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remained between current and former smokers (HR 1.01, 95% CI 0.90-1.13), while both current and former smokers continued to have a lower 30-day mortality compared to never smokers (HR

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0.89, 95% CI 0.80-0.98 and HR 0.88, 95% CI 0.81-0.96, respectively- data not shown).

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Hospital complication rates tended to decrease over time in all three groups (Table 2). All three groups showed unadjusted (Figure 1) and adjusted (Table 2) declines in 30-day

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mortality rates from 1999 to 2007; the adjusted decline was not statistically significant among current smokers (HR= 0.98 per study year, 95% CI 0.94-1.01, p=0.20). Estimated adjusted HR’s

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were 0.96 (95% CI 0.93-0.99, p=0.004) and 0.97 per study year (95% CI 0.95-0.99, p=0.01) for former and never smokers, respectively (Table 2). When the 3 smoking groups were combined,

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the adjusted HR mortality estimate was 0.97 per study year (95% CI 0.95-0.98). In an adjusted model combining all 3 smoking groups, no statistically significant differences in annual 30-day mortality trends were found between the 3 groups (p=0.62 in a test for a study year by smoking group interaction).

Treatment differences Patients were more likely to be treated by evidence based medications and therapies in later years, regardless of smoking status (Figure 2). Individual medication rates and adherence were similar in the 3 groups, both for those prescribed at discharge and those in use 6 months after discharge (Tables 3 and 4).Smokers were more likely to receive PCI and primary PCI than others groups regardless of their clinical presentation.

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ACS subgroups

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STEMI:

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A subgroup analysis of 22,894 STEMI patients demonstrated no reduction in annual adjusted 30day mortality rates over time among smokers (HR= 1.01, 95% CI 0.96-1.06 (Table 5), whereas

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former and never smokers’ mortality declined.

NSTEMI/UA:

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Smokers with NSTEMI/UA did however demonstrate a significant reduction in 30-day mortality (adjusted HR=0.93 per study year, 95% CI 0.88-0.99, p=0.02). The difference in mortality trend

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among current smokers with STEMI compared to NSTEMI/UA did not quite achieve statistical significance (p=0.055 in a test for a study year by ACS status interaction). A similar test for

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former and never smokers showed no mortality trend differences by ACS group (p=0.53 and 0.67, respectively). Propensity Scores

Propensity-adjusted results demonstrated similar results (not shown). In both sets of propensity analyses, current smokers with STEMI demonstrated no change in annual 30-day mortality over time.

DISCUSSION Our main finding is that over the years 1999-2007, adjusted 30-day mortality rates decreased significantly in ACS patients. The reduction was similar in all 3 smoking groups, though not statistically significant among current smokers. The difference in annual 30-day mortality rates 10

ACCEPTED MANUSCRIPT of decline between STEMI and NSTEMI/UA current smokers did not achieve statistical significance (p=0.055; HR 1.01 and 0.93 per study year, respectively), but was consistent with a

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prior study.9

It has been repeatedly shown that those who start smoking in early adult life and continue

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smoking lose on average about a decade of life.13, 14 This has been shown to be especially true

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following myocardial infarction.15 Cigarette smoking produces a myriad of unfavorable pathophysiological processes including endothelial dysfunction16, constriction of blood vessels,

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platelet activation17, chronic inflammation, metabolic abnormalities, impaired rheology18, 19, activation of the thrombotic factors20, and DNA changes.21 These changes have been linked to

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more advanced atherosclerosis and vulnerable plaques.

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Smokers with ACS have lower unadjusted mortality rates.1 Past studies have shown that smokers have fewer comorbidities compared to non-smokers.3, 4, 9 This paradox has been shown both in the fibrinolysis and PCI eras.3, 5, 6 .

We demonstrated that among the 3 patient groups, all 3 groups had comparable reduction in mortality rates but perhaps due to smaller cohort size, the smokers’ change did not achieve statistical significance. Previous studies have shown that smokers are less adherent to follow up visits and therapy.22, 23 However, in our cohort, smokers were treated more aggressively (earlier PCI) and the rate of adherence to medications, in-hospital and 6-months, was similar among the 3 groups. We conducted a sub-group analysis of the STEMI patients that showed that smoking patients who presented with STEMI did not have improved mortality over the study period. This

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ACCEPTED MANUSCRIPT finding is similar to a study from Israel that evaluated temporal trends over 2000-2010 and found

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no improvement in outcomes in smokers.9

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Use of guideline based medications improved over the years in all 3 groups; adherence has been shown to be related to subsequent fewer adverse cardiovascular events, angina and mortality in

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different patient populations.24-27 Behavioral modification (smoking, adherence, depression) has

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been associated with improved outcomes.26

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The translation of guidelines to changes in clinical care is a complex area and often has a considerable lag. Past studies have shown that with time, physicians are more adherent to

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guidelines.28-30 However, the time lag between publication of the guidelines and widespread

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uptake can be greater than 15 years.29 Therefore, recent years might demonstrate even lower

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mortality as patients are treated by more evidence based medications.30

Smokers have fewer conventional risk factors, therefore, unless they stop smoking, might be at increased risk for recurrent events. Past studies have shown that regardless of physician recommendations and family pressure, most patients continue to smoke at one year following STEMI, and may stop medications by themselves. 31, 32 Patients who quit smoking have reduced rates of recurrent events.26 This should be emphasized to the patients. Notably, the INTERHEART study demonstrated a linear relationship between the number of cigarettes smoked per day and the risk of future events.33 Therefore, reduction of smoking is also a worthy approach in patients failing to achieve abstinence. Recent studies have demonstrated that nicotine replacement, varenicline and bupropion are safe methods to help patients stop smoking,

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ACCEPTED MANUSCRIPT 34, 35

but their overall effectiveness is still controversial. 35-37 Banning public use of smoking has

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not been associated with reduced admission or mortality rates at a population level.38

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Limitations

Our study has several limitations. First, we do not know the number of patients that discontinued

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smoking during follow up. In addition, we do not have data regarding the number of pack years

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in the smokers group. Third, we do not have data on patient compliance with guideline-based medications during follow up. Many patients stop medications without instruction from their

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doctor.32 Lastly, the follow up ended in 2007 and might be different from current practice. However, the potential to determine changes in outcomes over time in association with increased

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utilization of evidence-based treatments would be possible given that improved trends in

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outcomes have already been demonstrated in this cohort.33 Furthermore, we believe that this is

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the largest study to date evaluating temporal trends in smokers presenting with ACS. Thus, it appears that the results are important because they suggest that smokers, particularly those who present with STEMI, should be regarded as a group that need further study in order to improve their outcomes.

CONCLUSIONS: In conclusion, over the years 1999-2007, 30-day mortality declined in patients presenting with acute coronary syndrome across all groups of patients regardless of smoking status. Smokers presented with STEMI more often than non-smokers. However, smokers presenting with STEMI did not demonstrate a reduction in mortality rates. These findings suggest the continued need to promote smoking cessation among ACS patients.

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ACKNOWLEDGEMENT

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Gordon FitzGerald had full access to all of the data in the study and takes responsibility for the

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integrity of the data and the accuracy of the data analysis. Dr. Shaun Goodman is supported by the Heart and Stroke Foundation of Ontario in his role as Heart and Stroke Foundation (Polo)

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Chair at the University of Toronto.

FUNDING

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This study was supported by a Heart & Stroke Foundation of Ontario/University of Toronto Polo Chair Award. GRACE was supported by an unrestricted educational grant from sanofi-aventis to

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the Center for Outcomes Research, University of Massachusetts Medical School. Sanofi-aventis had no involvement in the collection, analysis, and interpretation of data; in the writing of the

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report; and in the decision to submit the paper for publication.

RELATIONSHIP WITH INDUSTRY Yaron Arbel, None. Gordon FitzGerald, None. Andrew T Yan, Research grants from Sanofi. Mary K Tan, None. Keith AA Fox, Research grants and/or speaking and consulting honoraria from Sanofi. Joel M Gore, None. Ph Gabriel Steg, Research grants (to INSERM U1148) from Sanofi, Servier; speaker and/or consulting honoraria from Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, CSL-Behring, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Lilly, Novartis, Pfizer, Regeneron, Roche, Sanofi, Servier, The Medicines Company; stockholding, Aterovax. Kim A Eagle, None. David Brieger, None. Gilles Montalescot, Research grants (to the Institution) or Consulting/Lecture Fees from Acuitude, ADIR, Amgen,

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ACCEPTED MANUSCRIPT AstraZeneca, Bayer, Berlin Chimie AG, Boehringer Ingelheim, Bristol-Myers Squibb, Brigham Women’s Hospital, Cardiovascular Research Foundation, Celladon, CME resources, Daiichi-

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Sankyo, Eli-Lilly, Europa, Fédération Française de Cardiologie, Gilead, Hopitaux Universitaires

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Genève, ICAN, Janssen-Cilag, Lead-Up, Medcon International, Menarini, Medtronic, MSD, Pfizer, Recor, Sanofi-Aventis, Stentys, The Medicines Company, TIMI Study Group, Universitat

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Basel, WebMD, Zoll Medical. Andrzej Budaj, Research grants and honoraria for lectures from

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AstraZeneca, GlaxoSmithKline, Bristol Myers Squibb/Pfizer, Sanofi-Aventis; investigators fee Boehringer Ingelheim, Novartis, Eisai. Jose Lopez-Sendon, None. Alvaro Alvezum, Consulting

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and advisory board fees from Boehringer Ingelheim, Pfizer, BMS, Bayer. Christopher Granger, None. Shaun G Goodman, Research grants and/or speaking and consulting honoraria from

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Sanofi.

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I, Fisman EZ, Tenenbaum A and Arbel Y. Temporal trends in management and outcome of diabetic and non-diabetic patients with acute coronary syndrome (ACS): residual risk of longterm mortality persists: Insights from the ACS Israeli Survey (ACSIS) 2000-2010. Int J Cardiol. 2015;179:546-51. 31.

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on outcome in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Journal of thrombosis and thrombolysis. 2012;34:397-403.

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Bagnall AJ, Yan AT, Yan RT, Lee CH, Tan M, Baer C, Polasek P, Fitchett DH, Langer

A and Goodman SG. Optimal medical therapy for non-ST-segment-elevation acute coronary

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patients discontinue medications after discharge. Circulation Cardiovascular quality and outcomes. 2010;3:530-7.

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nicotine replacement therapy on cardiovascular outcomes after acute coronary syndromes. Am J

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Xuereb R, Distefano S, Magri C, Calleja N and Grech V. Smoking Ban: A long-term

analysis of the Malta paradox in a population of over 400,000 subjects. Int Cardiovasc Forum J.

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ACCEPTED MANUSCRIPT FIGURE LEGEND Figure 1- 30 day mortality- Unadjusted

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Current smokers 16,785

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Current smokers 16,785 Former 17,874 Never 26,734

Unadjusted 30 days Mortality rate

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2004

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Adherence to medications

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Adherence to medications-Past SMOKERS

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17 49 44 21

.2 (.04) 1.3 (***) 1.1 (***) 1.1 (***)

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27 66 56 42

.3 (.03) 1.2 (***) 1.5 (***) 1.2 (***)

29 68 46 30

.2 (.17) 1.1 (***) 1.2 (***) 1.3 (***)

4.5

-.2 (.02)

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-.4 (***)

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-.4 (***)

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-.1 (.31)

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-.4 (.01)

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0 (.80)

44 13 6 5.3 8.9

-3.6 (***) .8 (***) .1 (.47) 0 (.53) -.3 (***)

59 24 18 9.8 13

-3.5 (***) 1.0 (***) -.2 (.08) -.1 (.28) -.4 (***)

53 16 12 9.2 7.2

-3.5 (***) .9 (***) .1 (.43) 0 (.67) -.3 (***)

48 29 23 12(446)

-.3 (.12) 1.5 (***) -1.2 (***) -1.9 (***)

30 35 36 26(6-64)

-.1 (.31) 1.7 (***) -1.5 (***) -1.4 (***)

34 34 32 20(5-58)

.1 (.29) 2.0 (***) -2.1 (***) -1.2 (***)

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History of Diabetes Mellitus Hypertension Dyslipidemia Coronary artery disease Congestive heart failure Myocardial infarction Angina PCI CABG TIA/stroke Peripheral arterial disease

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Table 1 Patient admission characteristics and annual trends in characteristics (1999-2007) by baseline smoking status (Mean (SD) for continuous variables unless otherwise noted; % for discrete variables) (units for trend are annual percentage increase or decrease per year for categorical variables, or annual unit change for continuous variables; p-values(in parentheses) test for lack of a linear trend over the study period) Variable Current Annual Former Annual Never Annual trend Smokin trend Smokin trend Smoked g g N=17,1 .06 (.45) N=18,33 -.12 (.13) N=27,48 .06 (.47) 91 6 8 Age, years 57 (11) -.01 (.73) 67 (12) .15 (***) 70 (13) .04 (.26) Female Gender 22 .1 (.48) 21 .2 (.10) 47 -.8 (***) 2 BMI, kg/m 27.5 .07 (***) 28.1 .01 (.59) 27.6 .07 (***) (5.3) (5.4) (5.4) Initial creatinine, 1.08 -.004 (.11) 1.25 .002 (.44) 1.24 -.003 (.17) mg/dL (.69) (.84) (.91) GRACE risk score 120 -.07 (.57) 132 (36) .33 (.01) 139 (39) .12 (.25) (34)

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*** p<0.001 for linear trend over years 1999-2007

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Table 2 Post admission mortality and in-hospital complication rates, and annual trends in rates (1999-2007), by baseline smoking status Mortality rates (95% confidence intervals) are estimated using the Kaplan-Meier method (%); units for annual mortality trends and 95% confidence intervals are estimated annual changes in mortality hazard adjusted for the GRACE risk score Other hospital complications are reported as percentages; units for trend are annual percentage increase or decrease per year, adjusted for GRACE risk score; p-values (in parentheses) test for lack of a linear trend over the study period using multiple logistic regression Event Current Annual Former Annual Never Annual trend Smoking trend Smoking trend Smoked N=17,191 N=18,336 N=27,488 30-day 4.0 (3.7.98 (.945.4 (5.0-5.7) .96 (.937.7 (7.4-8.0) .97 (.95-.99) mortality 4.3) 1.01) .99) Complicatio ns Index AV 1.4 -.10 (.02) 1.2 -.03 (.35) 1.3 -.02 (.45) block Later AV 2.5 -.31 (***) 1.9 -.10 (.02) 2.0 -.21 (***) block AV block at 3.3 -.30 (***) 2.6 -.10 (.06) 2.8 -.16 (***) any time in hospital New LBBB 1.2 .10 (.01) 1.8 0 (.90) 2.1 .09 (.02) Cardiogenic 3.5 -.24 (***) 3.3 -.14 (.03) 4.9 -.17 (.01) shock CHF/Pulmon 10 -.85 (***) 14 -1.3 (***) 15 -1.3 (***) ary edema Major 2.0 -.10 (.04) 2.7 -.17 (.002) 2.8 -.18 (***) bleeding Free wall .19 0 (.92) .14 -.02 (.17) .26 -.04 (.03) rupture *** p<0.001 for linear trend over years 1999-2007

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Table 3 In-hospital care and discharge recommendations, and annual trends in care (19992007), by baseline smoking status In- hospital care and discharge prescriptions are reported as percentages; units for trend are annual percentage increase or decrease per year, adjusted for GRACE risk score; p-values (in parentheses) test for lack of a linear trend over the study period using multiple logistic regression Hospital stay is reported in days; annual trend units are annual decrease in days stayed, adjusted for GRACE risk score using multiple logistic regression (p-value for trend is in parentheses) Treatment Current Annual Former Annual trend Never Annual trend Smokin trend Smoking Smoked g N=17,19 N=18,336 N=27,488 1 Cardiac catheter 69 3.1 (***) 63 2.1 (***) 56 2.7 (***) PCI 47 2.9 (***) 37 2.1 (***) 34 2.3 (***) PCI within 12 h, 35 4.7 (***) 28 3.1 (***) 28 3.8 (***) STEMI Thrombolytics 21 -2.4 (***) 10 -1.0 (***) 11 -1.2 (***) CABG 4.8 -.16 (.03) 6.2 -.32 (***) 4.9 -.25 (***) Hospital stay, 5 (3-9) -.32 (***) 5 (3-9) -.25 (***) 6 (3-9) -.31 (***) days median (IQR)

75 93 57 81 63 2.9

5.8 (***) .60 (***) 6.1 (***) 1.8 (***) 3.3 (***) .64 (***)

73 91 51 78 62 5.9

5.5 (***) .52 (***) 5.6 (***) 2.0 (***) 2.2 (***) 1.1 (***)

Stopped smoking 53 -.23 (.59) n/a by 6 months post-ACS* * current smoker at admission, former smoker at 6 m. *** p<0.001 for linear trend over years 1999-2007

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66 89 47 77 62 6.2 n/a

6.1 (***) .56 (***) 5.5 (***) 2.1 (***) 2.0 (***) 1.1 (***)

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Table 4 Current use of medications at 6 month follow-up among survivors, and annual trends in follow-up medications (1999-2007), by smoking status 6-month medication use is reported as a percentage; units for trend are annual percentage increase or decrease per year, adjusted for GRACE risk score; p-values (in parentheses) test for lack of a linear trend over the study period using multiple logistic regression Event Current Annual Former Annual Never Annual trend Smoking trend Smoking trend Smoked N=12,849 N=13,858 N=19,379 Aspirin 92 .80 (***) 89 .78 (***) 87 .70 (***) Beta blocker 79 1.2 (***) 78 1.6 (***) 78 1.7 (***) Ticlopidine 1.3 -.32 (.001) 1.1 -.35 (***) 1.7 -.40 (***) Clopidogrel 43 7.5 (***) 41 6.1 (***) 38 7.3 (***) ACE 60 3.0 (***) 59 1.5 (***) 59 1.0 (***) inhibitor Statin 78 4.1 (***) 77 4.0 (***) 72 4.6 (***)

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Compliant* 85 2.8 (***) 84 2.4 (***) 82 * on 3 or more of aspirin, beta blocker, thienopyridine, ACE inhibitor, or statin *** p<0.001 for linear trend over years 1999-2007

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2.9 (***)

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Table 5 Post admission mortality and in-hospital complication rates, and annual trends in rates (1999-2007), by baseline smoking status, among patients diagnosed with STEMI at discharge Mortality rates (95% confidence intervals) are estimated using the Kaplan-Meier method (%); units for annual mortality trends and 95% confidence intervals are estimated annual changes in mortality hazard adjusted for the GRACE risk score Other hospital complications are reported as percentages; units for trend are annual percentage increase or decrease per year, adjusted for GRACE risk score; p-values (in parentheses) test for lack of a linear trend over the study period using multiple logistic regression Event Current Annual trend Former Annual trend Never Annual trend Smoking Smoking Smoked N=8197 N=5460 N=9237 30-day 4.9 (4.41.01 (.968.5 (7.7.95 (.91-.99) 13 (12-13) .98 (.95mortality 5.4) 1.06) 9.3) 1.003) Complication s Index AV 2.3 -.10 (.19) 2.4 -.04 (.71) 2.2 -.07 (.35) block Later AV 4.0 -.45 (***) 3.5 -.30 (.01) 3.7 -.45 (***) block AV block at 5.2 -.41 (***) 4.8 -.21 (.11) 4.9 -.32 (.002) any time in hospital New LBBB 1.9 .20 (.01) 4.6 .19 (.17) 4.9 .28 (.01) Cardiogenic 5.2 -.26 (.02) 6.2 -.22 (.22) 9.4 -.36 (.01) shock CHF/Pulmona 13 -.95 (***) 20 -1.3 (***) 22 -1.8 (***) ry edema Major 2.3 -.10 (.21) 3.7 -.29 (.02) 3.9 -.28 (.003) bleeding Free wall .32 -.02 (.61) .34 -.03 (.57) .65 -.08 (.07) rupture *** p<0.001 for linear trend over years 1999-2007

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