Varenicline for Smoking Cessation in Hospitalized Patients With Acute Coronary SyndromeCLINICAL PERSPECTIVE
Background—Less than one-third of smokers hospitalized with an acute coronary syndrome (ACS) remain abstinent following discharge. We assessed whether varenicline, begun in-hospital, is efficacious for smoking cessation following ACS.
Methods and Results—We conducted a multi-center, double-blind, randomized, placebo-controlled trial in which smokers hospitalized with an ACS were randomized to varenicline or placebo for 12 weeks. All patients received low-intensity counseling. The primary end point was point-prevalence smoking abstinence assessed at 24 weeks by 7-day recall and biochemical validation using expired carbon monoxide. A total of 302 patients were randomized (mean age 55±9 years; 75% male; 56% ST-segment elevation myocardial infarction; 38% non-ST-segment elevation myocardial infarction; 6% unstable angina). Patients smoked a mean of 21±11 cigarettes/d at the time of hospitalization and had been smoking for a mean of 36±12 years. At 24 weeks, patients randomized to varenicline had significantly higher rates of smoking abstinence and reduction than patients randomized to placebo. Point-prevalence abstinence rates were 47.3% in the varenicline group and 32.5% in the placebo group (P=0.012; number needed to treat=6.8). Continuous abstinence rates were 35.8% and 25.8%, respectively (P=0.081; number needed to treat=10.0), and rates of reduction ≥50% in daily cigarette consumption were 67.4% and 55.6%, respectively (P=0.05; number needed to treat=8.5). Adverse event rates within 30 days of study drug discontinuation were similar between groups (serious adverse events: varenicline 11.9%, placebo 11.3%; major adverse cardiovascular events: varenicline 4.0%, placebo 4.6%).
Conclusions—Varenicline, initiated in-hospital following ACS, is efficacious for smoking cessation. Future studies are needed to establish safety in these patients.
Morbidity and mortality are substantially increased among patients who continue to smoke following hospitalization for an acute coronary syndrome (ACS).1–4 Smoking cessation is of critical importance in these patients, yet less than a third of smokers who experience an ACS are able to remain abstinent following hospital discharge.5–7
Clinical Perspective on p 30
Few randomized controlled trials have examined the efficacy of smoking cessation pharmacotherapies in hospitalized patients with ACS, despite the substantial benefits of quitting in this population. In-hospital initiation of nicotine replacement therapy, although frequently prescribed in North America, has not been examined in randomized controlled trials. Bupropion, a non-nicotine replacement therapy, was tested in 3 trials and was found not to be efficacious.5–7
Varenicline is an α4β2 nicotinic acetylcholine receptor partial agonist that reduces cravings and withdrawal symptoms during smoking abstinence and also decreases the reinforcing effects of nicotine.8 Although varenicline has been shown to be effective for smoking cessation in both healthy smokers and patients with stable cardiovascular disease,9–11 little is known about its efficacy in patients with acute cardiovascular disease. For this reason, we assessed the efficacy of varenicline in a high risk patient population of smokers hospitalized with ACS.
Study Design, Patient Population, and Sample Size Estimation
The EVITA (Evaluation of Varenicline in Smoking Cessation for Patients Post-Acute Coronary Syndrome) trial is a multicenter, double-blind, randomized, placebo-controlled trial examining the efficacy of varenicline for smoking cessation in patients hospitalized with ACS (NCT00794573). Details of the trial study design have been previously described.12
In brief, 302 patients who smoked ≥10 cigarettes/d, expressed motivation to quit smoking, and who were hospitalized in either Canada or the United States with an ACS were enrolled at 40 clinical centers (Figure 1). Patient motivation was assessed based on willingness to be randomized in the trial and willingness to attempt to quit smoking. No formal assessment of motivation to quit was performed. An ACS was defined as either a myocardial infarction or unstable angina. Myocardial infarction required the patient to have elevated cardiac enzymes plus ≥1 of the following: 1) ischemic symptoms, 2) electrocardiographic changes consistent with ischemia, or 3) development of pathological Q waves. Unstable angina required the patient to have all of the following: 1) nonelevated cardiac enzymes, 2) ischemic symptoms, and 3) ≥1 coronary lesion of ≥50% severity on a coronary angiogram performed during the hospital admission. Patients were randomized to either varenicline or matching placebo, and treatment was initiated prior to discharge from hospital. Randomization was performed by enrolling center personnel and stratified by center using a computer-generated list of permuted blocks of 2 and 4. The study was approved by an institutional review committee at each clinical center, and all subjects gave informed consent prior to randomization.
Patients were excluded from participating if they were unlikely to be available for follow-up; were pregnant or lactating; had cardiogenic shock or renal impairment at the time of randomization; had hepatic impairment prior to ACS; reported excessive alcohol use; reported current use of marijuana or noncigarette tobacco products; were currently using over-the-counter stimulants or anorectics; had previously used varenicline; or were using a pharmacotherapy for smoking cessation at the time of ACS. Patients were also excluded for a history of neuropsychiatric disorders including suicidal attempts or suicidal ideation, family history of suicide, panic disorder, psychosis, bipolar disorder, dementia, bulimia, anorexia or recent or recurring depression (as indicated by the Patient Health Questionnaire-9 or current antidepressant use). Participants were excluded based on the Patient Health Questionnaire-9 using the diagnostic algorithm for major depressive syndrome: five or more responses (at least one of which included question 1 or 2 of “more than half the days” or “nearly every day” on questions concerning: 1) little interest or pleasure in activities, 2) feeling down or depressed, 3) sleeping too little or too much, 4) fatigue, 5) poor appetite or overeating, 6) feeling bad about yourself, 7) difficulty concentrating, 8) moving too little or too much, and 9) suicidal ideation.13
Study-specific screening logs were not mandatory. However, 30 of the 40 centers (responsible for >70% of enrolled participants) contributed logs. Among the 7,768 patients screened at these centers, 7541 were excluded (Figure 1). Half of exclusions (n=3815; 51%) were attributable to patients not meeting the smoking criteria (eg, nonsmoker or smoked < 10 cigarettes/d). The other most common reasons for exclusion were: not meeting ACS criteria (14%), refusal to participate (7%), major depression in the past 5 years, or two or more lifetime episodes of major depression (4%), or not available for follow-up (4%). All other exclusions occurred in less than 5% of participants. Among patients who were approached at these centers and met all eligibility criteria, 31% agreed to participate.
The sample size was estimated assuming a 7 day point prevalence abstinence rate of 24% at 24 weeks in patients receiving placebo. With this assumption, 150 patients per study arm would achieve a >80% power to identify a ≥15% absolute increase in abstinence rates (24% to 39%) using a two-tailed α of 0.05. The EVITA trial was not powered to examine safety end points, but it was designed to describe the occurrence of serious adverse events in this high risk patient population during study treatment and follow-up.
Baseline Assessment and Intervention
Following randomization, demographic, smoking, and clinical characteristics of patients were collected via a case report form. Severity of dependence on nicotine was assessed by administering the Fagerström Test for Nicotine Dependence.14 Study medication was begun while patients were hospitalized, with at least the first dose taken prior to discharge. Patients randomized to varenicline received 0.5 mg once/d x 3 days, followed by 0.5 mg twice/d x 4 days, followed by 1.0 mg twice/d for the remainder of the 12 week treatment period. Patients randomized to matching placebo received the same treatment schedule. Patients were provided with bottles of study medication at hospital discharge and at week 4. Patients were instructed to come to follow-up visits with their bottles, and pill counts were conducted at weeks 4 and 12.
Patients in both treatment arms received low-intensity counseling. Counseling involved advice to stop smoking and emphasized the importance of smoking abstinence following ACS. Additional counseling was given during follow-up (telephone contact and clinic visits). Counseling was delivered by research personnel at each of the clinical centers. Counseling scripts were provided as a guide. However, centers with established programs were permitted to use their own counseling techniques. Scripts included discussing smoking history and previous quit attempts, the risks of continued smoking, concerns about quitting, coping with withdrawal symptoms, and providing educational materials. Patients could receive additional counseling outside of the study if they chose to do so. Following completion of the 12-week treatment period, patients who relapsed could use open-label smoking cessation therapies.
Follow-up involved phone calls by research personnel at weeks 1, 2, and 8 as well as clinic visits at weeks 4, 12, and 24. Side effects, symptoms of withdrawal, medication adherence, and smoking status were assessed during follow-up contacts. At follow-up clinic visits, smoking status was assessed by self-report of smoking in the preceding 7 days. Self-reported abstinence was confirmed using biochemical validation via exhaled carbon monoxide levels (Micro 3 and 4 Smokerlyzer, Bedfont Scientific Ltd., Rochester, United Kingdom) with a threshold of exhaled carbon monoxide ≤ 10 ppm.
End Point Assessment
The primary end point was point prevalence smoking abstinence at 24 weeks following randomization. Point prevalence smoking abstinence was defined by self-report of complete abstinence in the 7 days before the 24 week clinic visit confirmed by a measured exhaled carbon monoxide ≤10 ppm. Participants with self-reported abstinence who had exhaled carbon monoxide values >10 ppm were classified as smoking. Similarly, participants who reported any smoking in the 7 days before the 24 week visit but who had an exhaled carbon monoxide value <10 ppm were classified as smoking. Secondary end points included point prevalence abstinence at other study follow-ups, continuous abstinence, and ≥50% reduction in number of cigarettes smoked/d. Continuous abstinence was defined by self-report of complete abstinence at all follow-up contacts and exhaled carbon monoxide ≤10 ppm at all follow-up visits. In order to be considered continuously abstinent, participants must have completed all follow-up visits. A ≥50% reduction in number of cigarettes smoked/d was defined as reduction of at least 50% in the number of cigarettes smoked/d compared to the patient’s baseline just prior to hospital admission.
Additional secondary end points included measures of adherence to study medication, effectiveness of patient blinding, and use of nonstudy smoking cessation therapy. Other secondary end points included measures of side effects and safety assessments of serious adverse events. Serious adverse events were defined according to the International Conference on Harmonization and Good Clinical Practice guidelines.15 An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the trial drug, whether or not considered related to the trial drug. In addition, a serious adverse event is an adverse event that requires inpatient hospitalization or prolongation of existing hospitalization, causes congenital malformation, results in persistent or significant disability or incapacity, is life threatening, or results in death. Any other significant clinical event, not falling into the criteria above, but which in the opinion of the investigator requires reporting, may also be considered a serious adverse event. A major adverse cardiovascular event was defined as death, myocardial infarction, or hospitalization for unstable angina. All serious adverse events were adjudicated by the End Points Evaluation Committee (data provided blinded to treatment assignment), and the trial was monitored by an external Data and Safety Monitoring Board. The Data and Safety Monitoring Board conferred on enrollment of the first participant as well as six additional times during the course of the trial. Safety data were reviewed at each meeting, and a blinded interim analysis was performed after the enrollment of 50% of participants.
An initial descriptive analysis involved an examination of the demographic, smoking, and clinical characteristics of the two treatment groups. The primary data analysis examined point prevalence smoking abstinence at 24 weeks. All analyses were intention-to-treat. Similar to other smoking cessation trials, our analyses assumed that patients who withdrew from the study or who were lost to follow-up returned to smoking at their baseline rate. Secondary data analyses examined other measures of smoking cessation including point prevalence abstinence at 4 and 12 weeks, continuous abstinence, and ≥50% reduction in number of cigarettes smoked/d. Secondary data analyses also examined measures of side effects and adherence to study medication as well as assessments of serious adverse events. Similar to other trials, the primary safety analyses involved measures at 30 days after treatment discontinuation. For all analyses, patients who died were censored at the time of death. In the event of withdrawal from the trial, participants consented for the use of data collected up to the time of withdrawal.
Discrete data are described using proportions, and continuous data are described using means and standard deviations or, in the presence of skewed distributions, medians and 25th to 75th percentiles. Length of stay and length of time from hospital admission to 1st dose of medication are presented as medians with 25th to 75th percentiles. Rate differences are presented as % differences with corresponding 95% confidence intervals based on the binomial distribution. Fisher’s Exact Test was used for statistical comparisons of rates between groups. Number needed to treat was calculated as the number of ACS patients needed to be treated with varenicline in order to produce 1 nonsmoker at 24 weeks. Statistical analyses were performed using SAS statistical software (Version 9.2).
A total of 302 patients were randomized (mean age 55±9 years; 75% male; 56% ST-segment elevation myocardial infarction; 38% non-ST-segment elevation myocardial infarction; 6% unstable angina; Table 1). Patients smoked a mean of 21±11 cigarettes/d at the time of hospital admission and had been smoking for a mean of 36±12 years. Two-thirds of patients were enrolled in Canada and one-third in the United States. The scores on the Fagerström Test for Nicotine Dependence ranged from 0 to 10, with 80% of patients having scores ≥4 indicating moderate or severe dependence on nicotine. Demographic, smoking, and clinical characteristics were well balanced between the two study arms.
Nearly all patients had cardiac catheterization during the index admission (98%), with 84% undergoing percutaneous coronary intervention and 6% coronary artery bypass graft surgery (Table 1). Comparatively few cases of ventricular arrhythmia, congestive heart failure, or recurrent ischemia occurred during hospitalization. Median length of stay was 3 days, and median time from admission to 1st dose of study medication was 2 days. Discharge medications were similar between groups.
Over the course of the trial, there was a progressive decline in smoking cessation rates. By 24 weeks, less than one third of patients receiving placebo were abstinent (32.5% point prevalence abstinence; 25.8% continuous abstinence). However, at 4, 12, and 24 weeks, patients randomized to varenicline had significantly higher rates of smoking abstinence and reduction than patients randomized to placebo (Figure 2). For the primary end point of point prevalence smoking cessation at 24 weeks, 47.3% of varenicline patients were abstinent versus 32.5% of placebo patients (% difference 14.8%; 95% CI 3.9, 25.8%; number needed to treat = 6.8). Continuous abstinence rates were significantly different at 4 and 12 weeks, but not at 24 weeks - absolute rates 35.8% and 25.8%, respectively (% difference 10.0%; 95% CI -0.4, 20.4%; number needed to treat = 10.0). Reduction ≥50% in number of cigarettes smoked/d was significantly different at 4, 12, and 24 weeks - absolute rates 67.4% and 55.6%, respectively at week 24 (% difference 11.8%; 95% CI 0.75, 22.7%; number needed to treat = 8.5).
Over the course of the trial, patients received a mean of 46±30 minutes of counseling from study personnel, with an average of 8±4 minutes per follow-up contact. Patients were encouraged to seek supplemental counseling at their study center or elsewhere. However, only 3% of patients (equal in both groups) reported receiving supplementary counseling at any time through week 24.
Adherence, Patient Blinding, and Non-Study Smoking Cessation Therapy
At the end of the 12-week treatment period, 78% of patients in the varenicline group reported taking ≥1 pill of study medication/d in the previous week compared with 85% of patients in the placebo group (adherence data available for n=218). At all follow-ups, patients who had reduced or discontinued use of the study drug were encouraged to continue participation in the trial. At 12 weeks, patients were asked to guess the treatment group to which they had been assigned. In both the varenicline and placebo groups, 49% of patients guessed correctly. Importantly, patients and study personnel remained blinded to treatment allocation until the conclusion of the trial. A total of 16% of patients reported the use of a nonstudy smoking cessation therapy at any follow-up through week 24 (varenicline 22% versus placebo 11%).
Side Effects and Safety
Side effects were common during the 12-week treatment period with the most frequent being insomnia (15.2%) and nausea (11.3%; Table 2). The occurrence of side effects was similar in the two treatment arms with the exception of abnormal dreams (varenicline 15.2% versus placebo 4.6%). Similar numbers of participants in each treatment arm discontinued study treatment because of adverse events (varenicline 11.3% versus placebo 12.8%).
The rates of serious adverse events were similar in the varenicline and placebo arms of the trial (Table 2). There were a total of 39 serious adverse events, occurring in 35 patients, within 30 days of treatment discontinuation. A single neuropsychiatric event occurred involving hospitalization for depression in a patient 25 days after taking one dose of study medication (varenicline). There were no cases of seizure or suicidal ideation.
Among the serious adverse events, 19 events (occurring in 18 patients) were cardiovascular (Tables 2 and 3), with 13 of these events being adjudicated as major adverse cardiovascular events. These events included 2 deaths (does not include a third death which occurred more than 30 days after treatment discontinuation), 6 myocardial infarctions, and 5 cases of unstable angina. Composite major adverse cardiovascular event rates were 4.0% in the varenicline arm and 4.6% in the placebo arm (P>0.99).
Two deaths occurred within 30 days of treatment discontinuation and a third occurred beyond this window, all three in the varenicline arm. The first was attributable to congestive heart failure, the second was attributable to sudden death, and the third was attributable to a perforated ulcer.
In the first patient, study medication was discontinued after 22 days, and death occurred 18 days later. This patient was admitted with an ST-segment elevation myocardial infarction and was found to have an ischemic cardiomyopathy with an ejection fraction of 20%. The patient subsequently developed refractory heart failure and was found not to be a candidate for either heart transplant or a ventricular assist device. Death occurred 40 days after randomization while the patient was still hospitalized.
In the second patient, study medication was presumed to have been taken until the time of death. This patient had a history of chronic lymphocytic leukemia and was admitted with a non-ST-segment elevation myocardial infarction. The patient was found to have an ejection fraction of 35% and underwent a single vessel bypass of the left anterior descending coronary artery using a left internal mammary artery bypass graft. An 80% lesion in an obtuse marginal was not bypassed. No autopsy was performed in this patient.
In addition to these 2 deaths, a third death was reported in a patient in the varenicline arm that occurred outside the 30 day window following treatment discontinuation. This death was attributable to a perforated ulcer and occurred 63 days after study drug discontinuation and 152 days after treatment initiation.
Our study was designed to examine whether varenicline, begun in-hospital, is efficacious for smoking cessation following ACS. We found that varenicline significantly increased smoking abstinence in this patient population. At 24 weeks, there was a 14.9% absolute difference in our primary end point of point prevalence abstinence with a number needed to treat of 6.8. Importantly, for those patients who did not receive varenicline, less than a third were abstinent at 24 weeks (point prevalence abstinence 32.5% and continuous abstinence 25.8%). These findings suggest that smoking remains a persistent problem in patients experiencing an ACS and that varenicline is an efficacious pharmacotherapy for smoking cessation in these patients. Our results are important, because clinical trials have not examined the efficacy of nicotine replacement therapy in this patient population and because several trials of bupropion in these patients suggest that it is not efficacious.5–7
The benefits of smoking cessation in patients with cardiovascular disease should not be underestimated. Multiple studies have demonstrated substantial reductions in both morbidity and mortality among patients with cardiovascular disease who are able to stop smoking. Critchley and Capewell pooled data from 20 studies involving 12,603 smokers with coronary heart disease, of whom 5,659 ceased smoking and 6,944 who continued to smoke.1 The investigators found a 36% reduction in mortality among patients who quit smoking compared to those who continued. Gerber et al performed a population-based cohort study among 1,521 patients with a first acute myocardial infarction and found that for each reduction of 5 cigarettes smoked daily, there was an 18% decline in mortality risk.16 Colivicchi et al examined a cohort of 1,294 smokers with ACS and found that 62.8% of patients resumed smoking (median interval to relapse 19 days), and that smoking relapse was independently associated with increased mortality.2 Persistent smoking has also been associated with adverse clinical outcomes in patients undergoing revascularization with PCI or CABG. Zhang et al analyzed results of the SYNTAX trial at 5-year follow-up.17 The investigators found that persistent smoking after revascularization was an independent predictor of the composite end point of death/MI/stroke.
Thus, multiple studies demonstrate the benefits of smoking cessation among patients with stable coronary artery disease, among patients with ACS, and among patients who have undergone coronary revascularization. Despite the plethora of data demonstrating the benefits of smoking cessation in patients with cardiovascular disease, the optimal strategy for obtaining these results has been elusive.
Previous studies have demonstrated that varenicline is effective for smoking cessation in both healthy smokers and in smokers with stable cardiovascular disease. Jorenby et al randomized 1,027 healthy smokers to varenicline, bupropion SR, or placebo.10 The investigators found that for weeks 9 through 52, 23.0% of participants in the varenicline group were continuously abstinent compared with 10.3% in the placebo group and 14.6% in the bupropion SR group. In a similar study, Gonzales et al randomized 1,025 smokers to varenicline, bupropion SR, or placebo.18 The authors found that for weeks 9 through 52, continuous abstinence rates were 21.9% for varenicline versus 8.4% for placebo and 16.1% for bupropion SR.
Among patients with stable cardiovascular disease, Rigotti et al randomized 714 smokers to varenicline or placebo.11 The investigators found that continuous abstinence rates were higher for varenicline than placebo during weeks 9 through 12 (47.0% versus 13.9%) and weeks 9 through 52 (19.2% versus 7.2%). They also found that there were no differences between varenicline and placebo groups for cardiovascular mortality, cardiovascular events, or serious adverse events. Thus, multiple studies suggest that varenicline is an efficacious pharmacotherapy for smoking cessation in both healthy smokers and in smokers with stable cardiovascular disease. The EVITA trial extends the results of these previous studies and suggests that varenicline is also efficacious in patients with ACS.
Despite the well-established efficacy of varenicline for smoking cessation, questions have been raised about its safety – particularly with respect to a potential association with adverse cardiovascular events. The cardiovascular safety of varenicline was first called into question in 2011 with the publication of a meta-analysis by Singh et al.19 These investigators reported that, compared with patients receiving placebo, patients receiving varenicline had a numerically but not statistically increased risk of serious adverse cardiovascular events. The methodology of this study was criticized on several counts, one of which was the exclusion of trials that reported no adverse cardiovascular events. Another meta-analysis by Prochaska and Hilton20 and a patient-level meta-analysis by Ware et al21 also found no statistically significant differences in adverse cardiovascular events between patients receiving varenicline and those receiving placebo. Despite these results, concerns about the cardiovascular safety of varenicline persist. The FDA issued a safety announcement in 2011 alerting the public that, in pooled analyses of clinical trials, patients receiving varenicline had a numerically (but not statistically) greater rate of adverse cardiovascular events than patients receiving placebo.22,23
The EVITA trial adds to the data regarding the safety of varenicline. Although EVITA was not powered to examine safety end points, the patient population enrolled in the trial was the highest risk patient population treated with varenicline to date. Over 90% of the patients enrolled in EVITA had a myocardial infarction within the few days preceding their first dose of study medication. If varenicline is associated with an increase in adverse cardiovascular events, one would expect to see a signal to that effect among the EVITA patient population. Although we found no significant differences in either serious adverse event rates or major adverse cardiovascular event rates, the 2 deaths that occurred in the varenicline arm within 30 days of treatment discontinuation require further scrutiny.
Our study had several potential limitations. First, EVITA only enrolled patients who were motivated to quit smoking. Many hospitalized patients with ACS are either not motivated to quit or express their intent to quit without the use of pharmacotherapy. Thus, cessation rates among the general population of patients with ACS are likely to be even worse than those observed in EVITA.
Second, the small sample size of EVITA limits our ability to definitively address the cardiovascular safety of varenicline. Despite the fact that multiple meta-analyses have not found statistically significant associations between varenicline use and cardiovascular event rates, questions about varenicline’s safety persist.
Third, the EVITA trial enrolled participants from a very challenging patient population. Similar to other smoking cessation trials, a not insubstantial number of patients withdrew from the study or were lost to follow-up. Dropout rates >30% have been reported in some trials. Our results are better than those observed in many previous trials and likely attest to a higher motivation among patients with ACS.
Fourth, our study only used low-intensity counseling. EVITA was intentionally designed in this fashion, because many centers are not equipped to deliver high-intensity counseling for large numbers of smokers. Nevertheless, some studies suggest that high-intensity behavioral interventions that begin in-hospital promote the success of smoking cessation.24
Finally, there is a difference of opinion among authorities regarding the best measure to use when assessing smoking cessation. Many smoking cessation trials use point prevalence abstinence as the primary end point and continuous abstinence as a secondary end point. We have done the same. The reason for this is that we, as clinicians, are most concerned about long-term smoking cessation. It is not unusual for a smoker who is attempting to quit to experience several “slips” during the period when they are actively quitting. Continuous abstinence is a very rigorous end point which does not allow for “slips”. Continuous abstinence requires that a patient not have one puff of a cigarette during the entire follow-up period and that expired carbon monoxide level is ≤10 ppm at all follow-up visits. It is quite possible that a patient has one or more “slips” early on during the follow-up period but is completely abstinent by 6 months. Similarly, rates of reduction ≥50% in daily cigarette consumption also has limitations as a measure of smoking cessation. No level of smoking is safe, and the risks of smoking are likely not linearly related to number of cigarettes smoked. Nevertheless, most authorities (as well as longtime smokers) would agree that a ≥50% reduction in daily cigarette consumption is a positive finding.
The EVITA trial was designed to assess whether varenicline, begun in-hospital, is efficacious for smoking cessation following ACS. We found that less than a third of smokers hospitalized with an ACS remain abstinent following discharge. However, patients who received varenicline had significantly higher rates of smoking abstinence compared to patients who received placebo. These findings suggest that varenicline, initiated in-hospital following ACS, and in conjunction with low-intensity counseling, is efficacious for smoking cessation. Future studies are needed to establish safety in these patients.
The EVITA investigators thank all patients who participated in the trial as well as the study personnel involved in enrollment and follow-up. We also thank Joseph Mancini for his assistance in maintaining the trial database, Patrick Belisle for his help with data analysis, Renée Atallah for editorial assistance with the manuscript, and Dr Louise Pilote for helpful insights during the conduct of the trial and editorial assistance with the manuscript.
Sources of Funding
EVITA was an investigator-initiated trial, which received funding and study drug/placebo from Pfizer Inc. Pfizer Inc had no role in the design, conduct, analysis, interpretation of data, or reporting of the EVITA trial.
Drs Eisenberg, Dehghani, and Madan received honoraria from Pfizer Inc for providing continuing medical education on smoking cessation. The other authors report no conflicts.
A complete list of EVITA Investigators is provided in the online-only Data Supplement.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.019634/-/DC1.
- Received September 25, 2015.
- Accepted October 19, 2015.
- © 2015 American Heart Association, Inc.
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Fewer than a third of smokers hospitalized with an acute coronary syndrome are able to abstain from smoking after leaving the hospital. Those who continue to smoke experience substantially higher morbidity and mortality compared with those who quit. In a multicenter, double-blind, randomized, placebo-controlled trial, we examined the efficacy of initiating varenicline in-hospital for smokers admitted with an acute coronary syndrome. In the Evaluation of Varenicline in Smoking Cessation for Patients Post-Acute Coronary Syndrome (EVITA) trial, 302 patients (average age 55 years, 75% male) were randomized in the United States and Canada to either varenicline (1.0 mg twice daily) or placebo for 12 weeks. In addition, all patients received low-intensity counseling. Patients smoked a mean of 21 cigarettes/d at the time of hospitalization and had been smoking for a mean of 36 years. We found that, in comparison with placebo, varenicline increased smoking abstinence rates at 4, 12, and 24 weeks. At 24 weeks, 47.3% of varenicline patients were not smoking compared to 32.5% of placebo patients—a 14.8% difference (P=0.012; number needed to treat, 6.8). The rate of major adverse cardiovascular events was similar between groups within 30 days of drug discontinuation: 4.0% among varenicline patients and 4.6% among placebo patients. We conclude that in-hospital initiation of varenicline significantly increases smoking abstinence among patients with acute coronary syndromes. Further studies are needed to establish safety in these patients.