Curr Atheroscler Rep (2010) 12:145–150
DOI 10.1007/s11883-010-0105-8
The Role of Smoking Cessation in the Prevention
of Coronary Artery Disease
Andrew L. Pipe & Sophia Papadakis & Robert D. Reid
Published online: 8 April 2010
# Springer Science+Business Media, LLC 2010
Abstract Smoking (tobacco addiction) is the most significant of the modifiable cardiovascular risk factors. Mistakenly described as a “habit” or “behavioral choice,” the
onset of tobacco addiction quickly follows the acquisition
of an ability to inhale cigarette smoke and is reflected in a
transformation of neurophysiologic function and nicotinereceptor density. Thereafter, comfort and a degree of
neurophysiologic “equanimity” require the regular administration of nicotine. Smokers inhale thousands of other
chemicals, many of which play critical roles in the initiation
and accentuation of atherosclerosis by influencing vasomotor activity, vascular dysfunction, oxidation of lipids,
atheroma development, and thrombosis. Smoking cessation
is a priority in the management of any patient with
cardiovascular disease. The benefits of cessation accrue
rapidly in such patients and have a pronounced effect on the
likelihood of disease progression, hospital readmission, and
mortality. All physicians must be familiar with the
principles of cessation practice and be able to initiate
smoking cessation attempts.
Keywords Nicotine . Tobacco addiction . Smoking .
Atherosclerosis . Coronary artery disease . Myocardial
infarction . Pharmacotherapy . Smoking cessation . Clinical
practice
Introduction
Overwhelming evidence of the effectiveness of smoking
cessation in the prevention and management of heart disease
A. L. Pipe (*) : S. Papadakis : R. D. Reid
Minto Prevention & Rehabilitation Centre,
University of Ottawa Heart Institute,
40 Ruskin Street,
Ottawa, ON K1Y 4W7, Canada
e-mail: apipe@ottawaheart.ca
has been accumulating for years [1]. Unfortunately, outdated
attitudes and misguided perspectives persist in the clinical
community about the genesis and persistence of smoking
behavior. To the uninformed, smoking still remains a
“habit” or “lifestyle choice” that can be simply addressed
with determination and the application of strong will. It
remains the case that despite the availability of effective
cessation interventions, smoking cessation has not figured
prominently among the interventions provided by cardiologists [2]. In part, this may be because cardiologists view
the responsibility for smoking cessation as resting with
others, typically the primary care physician. More likely,
the lack of an understanding of the neurophysiologic bases
of nicotine addiction, unfamiliarity with the therapeutic
principles of smoking cessation, and an unfortunate
misperception of its efficacy and effectiveness, have
contributed to an indifference to intervene in the cardiac
setting. Smoking cessation should be seen as a fundamental
responsibility of every cardiovascular specialist given the
central role that smoking plays in inducing atherosclerosis
and dramatically increasing the risk of myocardial infarction (MI), stroke, and peripheral vascular disease.
It has been noted that it is difficult to identify any
condition that is as prevalent, lethal, and yet so prone to
neglect as tobacco addiction [1]. One half of all smokers
will die prematurely as a consequence of their tobacco use
[3]. There can be no doubt of the causative role that tobacco
addiction plays in the development and accentuation of
cardiac disease; the evidence is overwhelming and has been
accumulating for decades [4]. Tobacco use is a principal
contributor to the development of coronary artery disease
(CAD), sudden cardiac death, acute MI, heart failure, and
the complications that inevitably follow. Deaths from CAD
in smokers below the age of 45 years exceed the mortality
produced by any other tobacco-related disease [5]. Smoking
cessation may have a greater effect on reducing mortality
among smoking patients with CAD than any other
146
intervention or treatment [6]. Sadly, tobacco use has been
described as “reflecting a rare confluence of circumstances:
a highly significant health threat; a disinclination among
clinicians to intervene consistently; and the presence of
effective interventions” [7].
Smoking and the Epidemiology of Cardiovascular
Disease
The relationship between smoking and the development
and evolution of atherosclerosis and the cardiovascular
crises that typically follow is unquestioned. More than
140,000 smoking-caused premature deaths are calculated to
occur annually in the United States [5], and it has been
calculated that 52% of ischemic heart disease deaths in
North America are attributable to smoking; the burden is
similar elsewhere in the developed world [8]. The risk of
MI is dramatically increased by cigarette smoking; the
relationship is dose-related and linear. There is an eightfold
elevation in the odds ratio for an MI in smokers consuming
more than 40 cigarettes a day [9]. Regrettably, while the
prevalence of smoking has been declining in many nations,
rates of smoking in developing nations continue to rise and
herald epidemics of tobacco-related disease for years to
come. Approximately 100 million deaths resulted from
tobacco use in the 20th century, and it has been estimated
that 1 billion more will occur in the 21st century [10]. A
significant proportion of these deaths will occur as a result
of the development of heart disease.
Smoking and the Development of Atherosclerosis
There is overwhelming evidence of the impact of cigarette
smoking on the development of CAD and MI as well as their
underlying pathologic processes [4]. Even exposure to
passive smoking is associated with a significant increase in
risk: non-smokers exposed to the smoke of their smoking
spouses experience a 30% excess risk of ischemic heart
disease death [11]. There is evidence of the adverse impact
of uterine exposure to maternal cigarette smoke in precipitating preatherosclerotic changes within the intima of fetal
coronary arteries [12]. Autopsy studies demonstrate that
smoking in young adults has been found to contribute to the
development of advanced atherosclerotic lesions in the LAD
vessels of those 15–34 years of age dying of external causes,
even in the absence of other CVD risk factors [13].
Distortion of normal vasomotor function, the development of inflammation, the oxidation of lipids, and distorted
coagulation mechanisms are central to the development and
evolution of the atherosclerotic process [14]. Cigarette
smoke contributes to each (Fig. 1).
Curr Atheroscler Rep (2010) 12:145–150
Normal vasodilatation is compromised as a consequence
of exposure to cigarette smoke and the resulting reduction
of the endothelial-produced vasodilator, nitric oxide (NO)
[15]. Smoking increases vascular resistance and contributes
to coronary artery vasospasm, in part, by increasing the
production of superoxide anions and other vasoconstricting
agents [16]. Nicotine itself has been shown to alter the
shape of endothelial cells, induce endothelial cell proliferation and intimal hyperplasia, and reduce prostacycline
function [17, 18]. Nicotine’s effect is much less than that of
cigarette smoke, arguing for the important role of many of
the other toxic constituents of smoke.
Oxidant substances present in cigarette smoke irritate
and damage endothelial surfaces. The resulting inflammation is a recognized promoter of endothelial damage, as
cytokines, white blood cells, and other constituents of the
atherosclerotic process are drawn to the site of injury.
Monocyte adhesion and trans-endothelial migration increase as a consequence of exposure to cigarette smoke.
Smokers demonstrate increased levels of total cholesterol, triglyceride, and low-density lipoprotein (LDL), and
their high-density lipoprotein levels are lower. Such a lipid
profile predisposes to the development of atherosclerosis.
Cigarette smoking also induces the oxidation of lipoproteins particularly LDL, accentuating the ability of these
compounds to assault the arterial wall. There is evidence
that in vivo oxidation injury associated with smoking
quickly decreases with cessation but increases dramatically
following the resumption of smoking [19]. In human males,
cigarette smoking has been shown to increase the likelihood
of plaque rupture and thrombosis, whereas in females,
plaque erosion with superimposed thrombosis has been
demonstrated to be more prevalent [20, 21].
Other constituents of tobacco smoke augment platelet
aggregability and promote the adherence of platelet clusters
to damaged endothelial surfaces [22]. Higher levels of
fibrinogen, red blood cell counts, and blood viscosity all
contribute to the prothrombotic environment noted in
smokers [23]. Smoking markedly impairs the ability of the
endothelium to release tissue plasminogen activator, adding
to the likelihood of persistent arterial thrombosis [24].
Oxidative stress is said to be a common feature of the
pathologic mechanisms unleashed by exposure to cigarette
smoke; distorted endothelial and vasomotor function,
proinflammatory changes at the vessel wall, increased
platelet reactivity and decreased fibrinolysis, and lipid
peroxidation can all be explained by this mechanism [14].
Nicotine Addiction: The Basis of Smoking
Smoking typically begins during adolescence in response to
an array of pressures from peers or a desire to emulate adult
Curr Atheroscler Rep (2010) 12:145–150
147
Mainstream smoke
Sidestream smoke
Active smoking
Passive smoking
Tar phase
Gas phase
Components of cigarette
smoke deposited in lung
Free radicals directly
from components of
cigarette smoke
Activation of endogenous
sources of free radicals?
(uncoupled NOS, xanthine
oxidase, METC, NADPH oxidase)
↑ Oxidative stress
(O2•–, H2O2, ONOO–)
?
↓ NO generation or bioavailability
Vasomotor
dysfunction
↑ Prothrombotic
and ↓ fibrinolytic
factors
Activation of neutrophil,
monocytes, platelets, T cells
↑ Cytokines
Inflammatory gene activation
Leukocyte
and platelet
activation
↑ Lipid
peroxidation
↑ Adhesion and
inflammatory
molecules
Smooth muscle
proliferation
Genetic predisposition and other
cardiovascular risk factors,
including insulin resistance
Initiation and progression of
atherothrombotic diseases
Fig. 1 Potential pathways and mechanisms for cigarette smoking-mediated cardiovascular dysfunction. METC—mitocondrial electron-transport
train; NO—nitric oxide; NOS—nitric oxide synthase. (From Ambrose and Barua [14]; with permission)
behavior. Once inhalation has been mastered, regular
inhalations will rapidly entrain a number of neurophysiologic adaptations that result in addiction. Following
inhalation, nicotine is rapidly delivered to the arterial
circulation, quickly transported to the brainstem, and
attaches to the α4β2 nicotinic acetylcholine receptors. This
receptor, a pentameric trans-membrane structure, opens in
response to the conformational effects of the nicotine ligand
and the result is a flow of ions into, and the resulting
stimulation of, a neuron [25]. Neuronal stimulation in the
brain stem initiates a cascade of neurologic stimulation
culminating in the release of dopamine and other neuro-
148
transmitters (including serotonin, glutamate, and γaminobutyric acid) in the forebrain [26]. The brain very
quickly becomes accustomed to regular stimulation of the
nicotine receptors and elevated levels of dopamine and
other factors; the discomfort of withdrawal symptoms and
craving become apparent when dopamine levels and
nicotine receptor stimulation decline. Simply put, the desire
to smoke a cigarette occurs in the face of falling levels of
nicotine stimulation and declining levels of dopamine and
other neurotransmitters. The addictive nature of any drug is
in part determined by the speed with which it can be
ingested or consumed [26••] The inhalation of tobacco
smoke delivers nicotine very rapidly to the arterial
circulation, a delivery process facilitated by the drug
delivery device, the cigarette, which is engineered to deliver
a precise aliquot of nicotine as rapidly as possible. During
smoking, arterial levels of nicotine are 10-fold those in the
venous circulation [27]. No one should underestimate the
addictive nature of nicotine. It is likely the most tenaciously
addictive drug we confront. Smoking cessation may be far
more difficult than those who have never smoked can
imagine. There is a high degree of heritability in cigarette
smoking and the ability to quit.
In many communities, the introduction of smoking
bylaws, the elimination of tobacco advertising and sponsorship, and the creation of smoke-free environments have
had a significant impact on reducing smoking rates. In
Canada, only 17% of the population are now smokers [28].
Those for whom cessation was easier have largely quit; the
remaining population of smokers reflects, arguably, those
for whom cessation is more difficult. Many of today’s
smokers admitted to hospitals will require more help with
cessation than those who quit smoking in the past with
minimal or no assistance. Most smokers know why they
should not smoke, most smokers do not wish to smoke, and
many smokers will make at least one or two quit attempts
each year, but they are almost universally unsuccessful
[26••]. Nicotine addiction is anchored in the brain stem.
The majority of smokers already understand that smoking is
harmful, so smokers require help and not lectures.
Curr Atheroscler Rep (2010) 12:145–150
dramatically [29, 30]. For the patient with CAD, the result
is a highly significant reduction in the likelihood of
progression or complication of existing disease, and there
is a significant reduction in the possibility of hospital readmission, morbidity, and all-cause mortality [31••]. The
risk of MI decreases by 50% within 2 years of smoking
cessation [32]. Successful smoking cessation in patients
diagnosed with heart disease results in a 36% crude relative
risk (RR) reduction of death (RR=0.64; 95% CI, 0.58–
0.71), and a 32% relative risk reduction of the likelihood of
re-infarction (crude RR=0.68; 95% CI, 0.57–0.82) [6]. The
likelihood of death following MI is reduced more by
smoking cessation than by any other secondary prevention
strategies, exceeding that achieved by thrombolysis, acetyl
salicylic acid, β-blockers, or statins [33]. The rates of
restenosis following percutaneous coronary intervention, in
bypass grafts, and death following bypass surgery are all
decreased following cessation [34]. Consistent, international experience demonstrates that the incidence of acute MI in
public places and workplaces has been significantly
reduced following the introduction of smoking bans [35•].
Smoking cessation is the only prevention strategy that is
actually cost-saving over a 30-year period [36].
Smoking cessation should be the priority in the
secondary prevention of cardiac disease [37]. Cardiologists
do not typically effectively address this preventive priority
[38]. It is important to ensure that a systematic approach is
Identification
Documentation
Of smoking status and acquisition of smoking history
Counseling
Pharmacotherapy
Provision of pharmacotherapy (NRT) to address withdrawal/cessation etc.
Follow-up
The Cardiovascular Benefits of Smoking Cessation
There is no intervention in cardiovascular medicine in
which significant patient benefits accrue so rapidly, or so
profoundly, as with smoking cessation. The removal of
tobacco smoke results in the elimination of the deleterious
effects of the thousands of chemicals contained in cigarette
smoke. Within weeks of cessation endothelial function,
coagulation parameters, carboxyhemoglobin levels, lipoproteins, proinflammatory agents, and inflammatory biomarkers decline and circulatory function improves
By IVR telephone system and nurse counselors
at relapse-sensitive time points
Fig. 2 “The Ottawa Model”: A systematic approach to the management of all smokers admitted to a tertiary care cardiovascular
institution (University of Ottawa Heart Institute). Hospital systems
and processes were designed to ensure that all smokers were
identified, smoking status was documented, and counseling provided
addressing the importance of cessation. Nicotine replacement therapy
(NRT) was employed to assist with the treatment of withdrawal and to
support cessation. Patients are followed for up to 6 months using an
integrated voice-recognition (IVR) telephone system, and counseling
is provided as needed by nurses. (Adapted from Reid et al. [41])
Curr Atheroscler Rep (2010) 12:145–150
adopted in every professional environment (office, clinic,
and in-patient settings) that quickly permits the documentation of smoking status, stimulates the delivery of nonjudgmental quitting advice, prompts an offer of assistance,
ensures familiarity with the prescription of cessation
pharmacotherapies, and facilitates appropriate referral to
other physicians or programs for follow-up where appropriate
[7, 39].
Consistency is the hallmark of a successful intervention
system, so unless a systematic approach is adopted in every
professional setting, the potential to dramatically enhance
the cardiac health of patients will be diminished [1].
Contemporary recommendations clearly note that delivering
minimal, “tactical” advice regarding cessation strategies is as
effective as more highly structured behavioral treatments [7,
40]. Given that many cardiac patients are smokers, there is
a unique opportunity in any hospital setting to provide
specific, systematic assistance with cessation. Such programs can significantly enhance rates of cessation [41–43].
In our center, 20% of admitted cardiac patients are smokers
[41]. The development and application of a systematic
program (“The Ottawa Model”) involving identification,
documentation, counseling, pharmacotherapy, and followup resulted in 44% of admitted smokers being smoke-free
at 6-month follow-up (Fig. 2). In another setting, the
delivery of an intensive smoking cessation intervention to
patients admitted to a coronary care unit resulted in a
dramatic reduction in readmission (RR reduction=44%)
and all-cause mortality (RR reduction=77%) over a 24-month
period and further demonstrates the potential of hospital-based
interventions for cessation [31••].
The benefits of pharmacotherapy are distinct and well
documented; it is the mainstay of successful cessation
treatment. Physicians have access to three generations of
first-line pharmacotherapies, each of which have significant, proven efficacy in enhancing the likelihood of
successful cessation. These therapies are nicotine replacement therapy (NRT), bupropion, and varenicline.
The safety of NRT use in cardiac patients has been
established in a variety of settings [44–47]. All cardiac
professionals should be adept in its use. Bupropion
effectively doubles the rate of smoking cessation when
compared with placebo. Its safety and effectiveness have
been specifically evaluated in the treatment of smokers with
cardiovascular disease [48]. Varenicline, a partial α4β2
nicotinic acetylcholine receptor agonist, is effective in
smokers with cardiovascular disease [49]. Clinical trials
have consistently demonstrated the superiority of varenicline when compared with placebo (odds ratio=3.2) and
bupropion (odds ratio=1.66) [50]. Evidence continues to
emerge of the additional efficacy of modifying the dose of,
prolonging the period of treatment with, and/or combining
smoking cessation therapies.
149
Conclusions
The devastation wrought by tobacco and the important role it
plays in the initiation and accentuation of heart disease is
well understood. All cardiovascular physicians should
become familiar with the initiation of smoking cessation
treatments. Stopping smoking in those who have cardiac
disease produces substantial clinical benefits that accrue
more rapidly than those of any other preventive intervention.
Cardiovascular specialists can dramatically reduce the
predictable excess morbidity and mortality in their smoking
patients by assisting with cessation. The development and
implementation, in every professional setting, of a systematic
approach to smoking cessation will significantly enhance the
quality of care provided to all patients and optimize the
likelihood of cessation. Smoking cessation is a fundamental
clinical responsibility of all who treat smoking patients.
Disclosure No potential conflicts of interest relevant to this article
were reported.
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