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Invited Review

A Mixed Method Review of Tobacco Cessation for the Cardiopulmonary Rehabilitation Clinician

Mola, Ana PhD, RN, ANP-C; Lloyd, Madeleine M. PhD, FNP-BC, PMHNP-BC; Villegas-Pantoja, Miguel A. BN, MNSc, DNSc

Author Information
Journal of Cardiopulmonary Rehabilitation and Prevention: May 2017 - Volume 37 - Issue 3 - p 160-174
doi: 10.1097/HCR.0000000000000268
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Tobacco smoking is an established and significant cardiopulmonary risk factor, which impacts morbidity and mortality.1 Tobacco smoking is the leading cause of preventable disease and death in the United States, accounting for more than 480 000 deaths and more than $300 billion in direct health care expenditures and productivity losses each year.2 In the United States, smoking causes 32% of coronary heart disease (CHD) deaths and 79% of all cases of chronic obstructive pulmonary disease (COPD).3 Cardiopulmonary rehabilitation (CPR) programs, as a comprehensive risk reduction lifestyle treatment model, provides an important clinical venue to address and treat tobacco use behaviors in all phases of CPR services from hospital to community.4,5 The purpose of this review is to highlight new tobacco cessation (TC) strategies for cardiopulmonary patients. This review aims to (1) update the CPR professional with current evidence-based knowledge of tobacco science; (2) provide a mixed method review of the tobacco treatment randomized controlled trials (RCTs) published circa the National Guidelines of Treating Tobacco Use and Dependence: 2008 Update (2008-TTUD)6; and (3) address new clinical updates, conclusions, and/or changes to enhance the professional competency of the CPR clinician in delivering current TC practices.


Smoking is estimated to increase the risk for CHD by 2 to 4 times and stroke by 1.5-fold. In addition, smokers are 12 to 13 times more likely to die from COPD than nonsmokers, as approximately 80% of all deaths from COPD are caused by smoking.3 Scientific evidence supports that TC has a substantial impact on improving life expectancy, reducing morbidity, and reducing health care costs associated with treating smoking-related conditions.6,7 Comprehensive lifestyle interventions in CPR include professional and program competencies in screening for tobacco use and providing TC treatment, which is evidence based and recommended by the 2008-TTUD guidelines.6,8


Properties of Cigarette Smoke

Cigarette smoke contains more than 4000 chemicals, including more than 60 carcinogens.9 Polycyclic aromatic hydrocarbons and volatile nitrosamines are a diverse group of carcinogens formed during the incomplete combustion of organic materials such as tobacco. The harm continuum that smokers experience is determined by their cumulative exposure to these chemicals.10 Cigarette smoke (CS), which is inhaled through the tobacco into the smoker's mouth, is known as mainstream smoke, and sidestream cigarette smoke (SCS) is the smoke released from the burning ends of a cigarette. Mainstream CS is composed of 8% tar and 92% gaseous components.11 Environmental tobacco smoke results from the combination of SCS (85%) and a small fraction of exhaled mainstream smoke (15%) from smokers.11 The SCS contains a higher concentration of toxic gaseous chemicals such as polycyclic aromatic hydrocarbons and nitrosamines than mainstream smoke, which is inhaled by the active smoker.12

Cardiopulmonary Pathophysiology of Smoking

There are biologic mechanistic risks by which smoking may impact the course of cardiovascular and pulmonary diseases. An oxidant substance in the cigarette smoke produces the following impaired endothelium-dependent dysfunction; a reduction of the endothelial-produced vasodilator, nitric oxide; an imbalance in endothelial function, which promotes an increase in blood coagulation, platelet aggregation, and thrombus formation; a reduction in oxygen delivery; increased oxidative stress and vascular inflammation; coronary vasoconstriction; and an increase in myocardial demand.13,14 In addition, smoking increases vascular resistance and contributes to coronary artery vasospasm, in part, by increasing the production of superoxide anions and other vasoconstriction agents.15 Furthermore, myocardial demand via smoking is also associated with the upregulation of metalloproteinases that are thought to weaken the arterial wall and contribute to the destabilization and rupture of existing atherosclerotic plaques. As smoking promotes these endothelium dysfunction activities, the risk of thrombus formation increases, placing the individual at risk for an acute coronary thrombosis, which can evolve to a myocardial infarction, and sudden cardiac death.15

The pulmonary mechanistic risk of smoking includes the destruction of the alveolar structure, which is a major element of a large number of pulmonary diseases. A distinct pathological phenotype is the disappearance of alveolar septa, which is characteristic of emphysema, particularly in the setting of COPD caused by CS.16 Environmental stresses, such as those impacted by CS and pollutants, activate trigger molecules that govern harmful alveolar septal cell responses characterized by oxidative stress, apoptosis, and alveolar inflammation. In addition, alveolar cell apoptosis interacts with oxidative stress in the causation of emphysema induced by vascular endothelial growth factor receptor blockade and subsequently confirmed by genetic deletion of lung vascular endothelial growth factor receptor blockade. This added oxidative stress mediates alveolar destruction in emphysema.16,17

Tobacco Dependence

Tobacco dependence is a complex process in which nicotine activates nicotinic acetylcholine receptors in the brain, leading to release of the neurotransmitter dopamine into the mesolimbic area, corpus striatum, and frontal cortex. Dopamine release induces rewards, including pleasure, arousal, mental acuity, and modulation of mood.18 Repeated exposure to nicotine produces a neuroadaptation (tolerance) as the number of binding sites on the nicotinic receptors in the brain increases in response to the nicotine-mediated desensitization of receptors.19 The cycle of nicotine addiction is expressed when craving and withdrawal begin in smokers when desensitized alpha 4 and beta 2 (α4-β2) nicotinic cholinergic receptors become responsive during periods of smoking abstinence and is relieved when nicotine binding of these receptors during smoking alleviates craving and withdrawal.18

Nicotine has poor reinforcing effects when administered alone; hence, nonnicotine tobacco constituents and sensory stimuli from packaging and environmental cues also contribute to tobacco dependence.20 Through habitual smoking, the smoker associates specific moods, situations, and environmental factors with the rewarding effects of nicotine, and these cues manifest as triggers that can produce relapse in periods of abstinence.18 In addition, puff volume, speed of delivery, lung deposition, frequency of dosing, arterial absorption, and other parameters affect the efficiency of nicotine delivery and promote the cycle of nicotine addiction.3

Benefits of Tobacco Cessation

Tobacco cessation has several benefits for both cardiac and pulmonary health (Table 1). Clinicians need to use this knowledge of TC benefits to encourage patients to quit smoking.

Table 1
Table 1:
• Cardiovascular and Pulmonary Benefits of Smoking Cessation

A major mechanism by which TC appears to reduce CHD risk is by preventing nitric oxide inactivation by active agents in smoke and restoring endothelial function and integrity. Additional mechanisms for benefit include reducing release of cytokines, inflammatory factors, platelet aggregation, and oxidation of low-density lipid particles.36 Previous reviews of TC in patients with CHD have demonstrated a 36% reduction in the risk of mortality, and a 32% reduction in the risk of nonfatal myocardial infarction; most of the risk reduction is realized within the first 2 years of cessation.7 The rates of restenosis following percutaneous coronary intervention, in bypass grafts, and death following bypass surgery are all decreased following cessation.37 Tobacco cessation was associated with a 40% lower risk of all-cause mortality and a 30% lower risk of death, recurrent myocardial infarction, or heart failure hospitalization over a 42-month follow-up in 2231 patients with left ventricular systolic dysfunction after myocardial infarction.38

Tobacco cessation is a vital step in the treatment of COPD and preventing other noxious effects of cigarette smoking.39 Overall, TC has several benefits in slowing the progression of COPD, including reduction of the incidence of acute exacerbations and bronchial infections.39 Tobacco cessation remains the most effective intervention for slowing lung function decline in COPD, measured by the annual decrease of forced expiratory volume in 1 second (FEV1), to a rate comparable to that of nonsmokers.40 FEV1 initially increases after TC, and quitters show a better response to bronchodilators and inhaled corticosteroids.41,42


Tobacco science supports the use of pharmacological and nonpharmacological treatments in both cardiovascular and pulmonary patients as discussed further.43,44

Pharmacological Treatments

The 2008-TTUD recommends the use of TC pharmacotherapy for smokers interested in quitting.6 Strong evidence supports the efficacy of 3 types of first-line medications to help smokers quit in the United States. Standard-dose monotherapy and dual-form nicotine replacement therapy (NRT) patch, lozenges, gum, inhaler, and nasal spray; bupropion either alone or in combination with NRT; and extended-release varenicline are first-line treatments for TC. All of these standard pharmacological treatments are Federal Drug Administration (FDA) licensed for smokers with COPD and cardiovascular disease (Table 2).6,39,45

Table 2
Table 2:
Tobacco Cessation Medications

Varenicline has been proven as an efficacious TC medication, with the largest treatment effects for both short-term and long-term cessation.46 Varenicline acts as a partial agonist-antagonist on the α4-β2 nicotinic acetylcholine receptors by completely inhibiting nicotine uptake and simultaneously releasing dopamine to alleviate the symptoms of nicotine cravings and withdrawals. With regard to bupropion, its main mechanisms of action include inhibition of neuronal reuptake of dopamine and norepinephrine and the blockade of nicotinic acetylcholinergic receptors. It works by blocking nicotine effects, relieving withdrawal and reducing depressed mood.6,46 It is through these mechanisms by varenicline and bupropion that abstinence from smoking is promoted.

Pharmacological TC treatment efficacy of first-line therapy (Figure 1) in a Cochrane review46 of 267 studies (101 804 participants) revealed that NRT (inhaler, spray, and lozenges) was marginally more effective than NRT gum (OR = 1.21), and combinations of NRT also outperformed single NRT formulations. Nicotine replacement therapy and bupropion were superior to placebo (OR = 1.84 and 1.82, respectively), and bupropion and NRT showed equal efficacy (OR = 0.99). Varenicline was superior to placebo (OR = 2.88), and varenicline was superior to single forms of NRT (OR = 1.57) and to bupropion (OR = 1.59). Varenicline was similar to combinations of NRT (OR = 1.06).46

Figure 1
Figure 1:
Cochrane review of pharmacotherapy.46 NRT indicates nicotine replacement therapy.

In 2013, the FDA changed labels to read “no safety concerns association with using more than one NRT and no significant safety concerns association with using NRT at the same time as cigarettes and for use of NRT longer than 12 weeks.”47 Nicotine replacement therapy treatment has been proven to assist the smoker with COPD to quit for up to 12 months.48

Previously, the FDA had issued a warning regarding serious cardiovascular events after meta-analyses provided conflicting results that may occur in patients taking varenicline and bupropion.49,50 However, recently a systematic review of 38 RCTs (n = 12 706) demonstrated no evidence that varenicline increases the rate of serious cardiovascular adverse events (relative risk [RR] = 1.03; 95% CI, 0.72-1.49).50

In a study of 8144 participants randomly assigned to a psychiatric cohort and to a nonpsychiatric cohort, no significant increases in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo were reported.51 Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo.51 Given varenicline's efficacy as a TC drug with no evidence of neuropsychiatric side effects and the long-term cardiovascular benefits of cessation, it should continue to be prescribed for TC.50,51

Nonpharmacological Treatments

Nonpharmacological TC treatments include behavioral interventions such as individual and group behavioral therapy, self-help programs and materials, patient education and advice, brief counseling, telephone support, and newer alternate delivery models such as telehealth and mobile application counseling.52–55 In people with CHD, behavioral interventions or self-help programs appear to be more effective than usual care for increased smoking abstinence rates at 6 to 12 months. In a Cochrane review of psychosocial interventions in patients with CHD, the risk ratios for TC for different strategies were similar (behavioral therapies: RR = 1.23; 95% CI, 1.12-1.34; telephone support: RR = 1.21; 95% CI, 1.12-1.30; self-help: RR = 1.22, 95% CI, 1.12-1.33).53 Smoking quit rates improved when interventions continued for more than 1 month (RR = 1.28; 95% CI, 1.17-1.40) whereas brief interventions (either 1 single initial contact of lasting less than 1 hour with no follow-up, 1 or more contacts in total over 1 hour with no follow-up, or any initial contact plus follow-up of less than 1 month) did not appear effective (RR = 1.01; 95% CI, 0.91-1.12).53 The optimal amount of behavioral support required for TC is a challenge because of the statistical heterogeneity of the research trials for behavioral intervention and the lack of shared language for these interventions. The 2008-TTUD recommends health care personnel to utilize nonpharmacological treatment alone or in combination with pharmacological intervention for TC at every client encounter by using 5 steps known as the “5 As” (Figure 2).6,55

Figure 2
Figure 2:
Model for treatment of tobacco use and dependence. Based on information from Fiore et al (2008).6

Individual, group, and telephone counseling are effective in TC, and their effectiveness increases with treatment intensity.53,56 Two components of counseling are especially effective: brief counseling (problem solving/skills training) and social support (smoking quitline). Telephone quitline counseling reaches diverse populations with a broad reach, and quit rates have been shown to increase when patients receive at least 2 telephone calls.56 Mobile phone technology provides potential delivery advances over the internet and is more likely to be available when smokers have an urge to smoke. A number of studies have shown that short messaging service programs double the rate of abstinence versus minimal intervention control conditions.54

Providing the smoker with quitlines and supplementary material is part of the assisting and arranging of the 5 As, and both clinicians and health care delivery systems should ensure that patients have access to quitlines.56 Seventy percent of smokers want to stop smoking at some stage; however, only 12% are ready to stop next month.52 To help support patients to quit smoking, several resources from the United States Department of Health and Human Services are available—such as 1-800-QUIT NOW—the national access number to state-based quitline services.57

Motivational interviewing is a technique influenced by theories of stages of change models58 and is designed to promote a behavioral change by exploring and resolving a patient's discordant values (eg, a desire to be healthy vs pleasure from smoking). The interview is done in a supportive and nonthreatening manner, and is typically provided in 1 or more face-to-face sessions lasting anywhere from 10 to 60 minutes. Moderate quality evidence indicates that motivational interviewing appears to help more people quit smoking for at least 6 months than brief advice or usual care. Sessions lasting 20 minutes or less appear to be more effective than longer ones, and a single session may be just as efficacious as several. Motivational interviewing delivered entirely by telephone may be as successful as a face-to-face session.58Table 3 summarizes the efficacy of nonpharmacological therapy for smoking cessation.

Table 3
Table 3:
• Efficacya of Nonpharmacological Treatment for Smoking Cessation

Combined Pharmacological and Nonpharmacological Treatments

Two independent systematic reviews of COPD and TC concluded that a combination of pharmacological and nonpharmacological interventions was more effective than each alone.52,53 However, no clear evidence was found, supporting that any nonpharmacological treatment strategy was more efficacious than others in patients with CHD.53 Behavioral support (brief advice and counseling) with pharmacological treatment increases the changes of quitting after 6 months and increases the chance of success by 70% to 100% compared with just brief advice (<20 minutes) or support alone.52


To further analyze current TC research, a mixed method review of RCTs was performed only on the cardiopulmonary patient population. A mixed method review consists of a combination of review approaches including a literature review.64 In this case, the authors conducted an extensive search on major databases and employed an instrument for study appraisal. Findings and synthesis are presented as narrative and summarized in Table 4 and Figure 3, 4, and 5.

Figure 3
Figure 3:
Workflow of review process. CINAHL indicates Cumulative Index to Nursing and Allied Health Literature; TC, tobacco cessation.aAfter removing duplicate records.
Figure 4
Figure 4:
Forest plot of continuous abstinence rates. CI indicates confidence interval;df, degrees of freedom.
Figure 5
Figure 5:
Forest plot of point prevalence cessation rates. CI indicates confidence interval;df, degrees of freedom.
Table 4
Table 4:
• Randomized Controlled Trials From Systematic Review: 6-Month (24-26 Weeks) Continuous Abstinence

Search Strategy

The MEDLINE search was conducted on major resource databases (PubMed, PsycINFO, CINAHL, and the Cochrane Library) along with hand searching of bibliographies of included trials to identify other potentially relevant studies published from January 1, 2007, to June 30, 2016. The key words (Medical Subject Headings and text search terms) describing the study population were “cardiovascular disease,” “pulmonary disease,” “cardiac rehabilitation,” “pulmonary rehabilitation.” The keywords describing smoking cessation interventions were “smoking,” “smoking cessation,” “tobacco,” “tobacco cessation,” “pharmacological,” “non-pharmacological,” and “behavioral interventions.”

Study Selection

Abstracts of identified publications were screened for inclusions. If relevant abstracts did not provide enough information, full articles were retrieved. Studies were selected by applying the inclusion criteria: (1) English language; (2) RCTs with a minimum follow-up of 6 months published between January 1, 2007, and June 30, 2016; (3) TC interventions directed at adult smokers ≥18 years of age with cardiovascular and/or pulmonary disease; (4) initiation of subject recruitment from hospital or community; (5) TC as main aim of the study outcome; (6) biometric validation of smoking status; (7) and USA FDA first-line TC medications and nonpharmacological modalities (brief or intensive counseling). Studies included were assessed using the Cochrane Risk of Bias Tool—an instrument used to assess the risk of bias in RCTs.65 This tool was to minimize bias and to ensure that the review methodology was transparent and consistent. Two reviewers (AM and ML) screened titles and abstracts of all identified citations, and full manuscripts were retrieved on the basis of the predefined patient population, intervention, and study design. If consensus could not be reached, a third reviewer (MVP) was consulted.


Identification of Studies

Results of the search strategy are presented in Figure 3. Ten RCTs (Table 4) revealed similar characteristics: (1) cardiopulmonary population; (2) types of TC interventions; (3) duration of follow-up; and (4) outcome measures; hence the pooling of data was analyzed using forest plots (Figures 4 and 5).

As described in Table 4, 6 of the 10 included studies were conducted outside of the United States. Nine of the studies included a pharmacological treatment combined with a nonpharmacological treatment (predominantly counseling). Investigated pharmacological treatments were used in 8 studies, of which 4 were varenicline66,68,73,74 versus placebo and 4 were NRT.8,69,70,75 Treatment period was variable, but 6 of the 8 studies reported 12 months or greater follow-up. According to the Cochrane instrument, the included studies had the following risks of bias: 50% had low random sequence66–68,70,75 and 80% of them8,70,71,74–78 incurred unclear allocation or vague allocation concealment (allocation concealment is an action directed to prevent selection and confounding biases by safeguarding the assignment sequence before allocation to intervention or control groups).65 In addition, there was 60% undefined or incomplete outcome data.66–70,73,74

Forest plots were calculated considering a random-effects model and to provide a visual representation of the amount of variation between the results of the studies. The first forest plot (Figure 4) displays the ORs for tobacco continuous abstinence rates of both populations that initiated their TC treatments in the community and hospital. The overall effect of studies was statistically significant (Z = 7.02; P < .00001), and most RCTs favored continuous abstinence rates at the 3-month (OR = 4.29; 95% CI, 2.09-8.81), 6-month (OR = 3.45; 95% CI, 1.96-6.08), and 12-month end points (OR = 3.60; 95% CI, 1.71-7.59).

The next forest plot (Figure 5) demonstrates the tobacco point prevalence rates of both populations that initiated their TC treatments in the community and hospital. The overall effect of studies was significant (Z = 5.83; P < .00001), and most of them improved the point prevalence cessation rates at the different end points (total OR = 2.63; 95% CI, 1.90-3.64). The higher OR for TC was found in the 3-month end point (OR = 4.28; 95% CI, 2.22-8.25) and decreased at the 6- and 12-month points.

The mix method review of the cardiopulmonary population yielded 10 articles with similar characteristics; however, there were heterogeneous designs between the pharmacological and nonpharmacological treatments in each study. Review of forest plots (Figures 4 and 5) shows that point estimates for TC interventions are consistent. No studies used pharmacotherapy alone. Lou et al71 was 1 study out of 370,75 with behavioral intervention only versus usual care that demonstrated statistical significance. Using motivational interviewing, abstinence rates doubled at 24 to 36 months in behavioral intervention versus usual care (46.4% vs 3.4%; P < .001). The other 2 studies70,75 reduced nicotine addiction using brief advice, telephone calls, and group support, but after 12 months there was no statistical significance from usual care.


A review of the TC science and the mixed method review supported the continued clinical efficacy of 2008-TTUD first-line pharmacotherapy of NRT combinations, bupropion, and varenicline, with greater support of the safety profile in the prescribing of bupropion or varenicline in cardiopulmonary and psychiatric patients. Clinical evidence supports the long-term use of medications for up to 3 months or longer and is FDA approved.8,51,66–68,76

The findings of this review suggest that CPR clinicians in TC services can be integral to ensure optimal TC adherence rates. Many cardiopulmonary patients continue to smoke after hospital discharge or relapse within the few weeks after a TC attempt especially after hospital discharge.77 Intensive nonpharmacological intervention, when initiated in the hospital with a follow-up in the community within 1 month, was found to significantly increase quit rates.8,66–68,70,76 Furthermore, the intensity of the behavioral intervention appears to be proportional to the cessation rates as there were no statistical benefits for less intensive counseling.8,70,76

Gaalema et al78 reported that continued smoking after a cardiac event predicts lack of attendance in, and completion of, CPR. The CPR clinicians who are educated and trained in TC interventions such as motivational interviewing, relapse prevention counseling, and 2008-TTUD first-line pharmacological interventions (Table 2) that include NRT alone, NRT combination (patch and gum/lozenges or nasal spray), bupropion, or varenicline can bridge TC services across care settings. When patients are adherent to a CPR program, a long-term patient engagement with the CPR clinicians is created and allows the opportunity to assist the patient to adapt to a smoke-free lifestyle behavior. As the evidence presented in this article supports, long-term use of first-line cessation medications, especially varenicline, combined with behavioral interventions, appears to have better TC outcomes than either alone.


Tobacco cessation interventions are targeted to treat the physical addiction to nicotine, the psychological dependence on the effects of smoking, and the behavioral aspects of tobacco use.6 In patients with cardiovascular diseases and COPD, TC programs with behavioral support over several months significantly increase quit rates. Recommendations for CPR professionals are to adhere to the 2008-TTUD national guidelines and optimize comprehensive TC (pharmacotherapy and behavioral interventions) opportunities for their cardiopulmonary patients during hospitalizations and in the delivery of CPR services in the community.


The authors would like to acknowledge Bryan Dextradeur at Holy Cross University for his assistance in organizing the review of literature format.


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      cardiopulmonary diseases; cardiopulmonary rehabilitation; risk factor modification; smoking cessation; tobacco cessation

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