Advertisement

Effect of Nicotine Replacement Therapy on Cardiovascular Outcomes After Acute Coronary Syndromes

      The optimal approach to encourage smoking cessation after acute coronary syndrome (ACS) remains unclear. The safety of nicotine replacement therapy (NRT) after ACS is not well established. The aim of the present study was to determine the relationship between NRT use and adverse cardiovascular outcomes after ACS. Using a pre-existing database, 663 smokers with ACS were identified. The patients were separated into the NRT (n = 184) or control (n = 479) groups according to whether NRT was prescribed on hospital discharge. Multivariate logistic regression analysis was used to account for the baseline differences between the 2 groups. Of the 663 patients, 202 had adverse events in the first year after ACS. No significant differences were seen with NRT use for the 1-year combined end point of death, myocardial infarction), repeat revascularization, or rehospitalization for angina, congestive heart failure or arrhythmia (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.61 to 1.30, p = 0.54). There were no differences in the individual 1-year end points of death (odds ratio 0.80, 95% confidence interval 0.33 to 1.91, p = 0.61), myocardial infarction (odds ratio 0.90, 95% confidence interval 0.40 to 2.06, p = 0.80), repeat revascularization (odds ratio 0.77, 95% confidence interval 0.44 to 1.36, p = 0.37), or rehospitalization for angina, congestive heart failure, or arrhythmia (odds ratio 1.01, 95% confidence interval 0.66 to 1.53, p = 0.97). In conclusion, NRT use was not associated with an increased risk of adverse cardiovascular events in the first year after ACS.
      The ideal approach to encouraging smoking cessation in smokers remains unclear.
      • van Berkel T.F.
      • Boersma H.
      • Roos-Hesselink J.W.
      • Erdman R.A.
      • Simoons M.L.
      Impact of smoking cessation and smoking interventions in patients with coronary heart disease.
      However, some question remains regarding the safety of nicotine replacement therapy (NRT) immediately after acute coronary syndrome (ACS).
      Working Group for the study of transdermal nicotine in patients with coronary artery disease
      Nicotine replacement therapy for patients with coronary artery disease.
      • Ford C.L.
      • Zlabek J.A.
      Nicotine replacement therapy and cardiovascular disease.
      Recently, the safety of the use of varenicline, an alternative pharmaceutical agent to assist with smoking cessation, in patients with coronary artery disease (CAD) has been called into question,
      • Singh S.
      • Loke Y.K.
      • Spangler J.G.
      • Furberg C.D.
      Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis.
      FDA Drug Safety Communication Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease.
      limiting the available smoking cessation aids for this population. Previous studies have demonstrated the safety of the nicotine patch in patients without documented CAD
      • Kimmel S.E.
      • Berlin J.A.
      • Miles C.
      • Jaskowiak J.
      • Carson J.L.
      • Strom B.L.
      Risk of acute first myocardial infarction and use of nicotine patches in a general population.
      and outpatients with stable CAD
      • Joseph A.M.
      • Norman S.M.
      • Ferry L.H.
      • Prochazka A.V.
      • Westman E.C.
      • Steele B.G.
      • Sherman S.E.
      • Cleveland M.
      • Antonuccio D.O.
      • Hartman N.
      • McGovern P.G.
      • McGovern P.G.
      The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease.
      ; however, the safety and effectiveness of NRT for patients immediately after discharge from ACS remains unclear. We sought to determine the relation between NRT and adverse cardiovascular outcomes in smokers after ACS.

      Methods

      Using data from a pre-existing database, all patients who were current tobacco (including cigarettes, cigars, pipes, or smokeless) users who presented with an ACS (including unstable angina pectoris, non–ST-segment elevation myocardial infarction [MI], and ST-segment elevation MI) and underwent cardiac catheterization from January 2006 to June 2010 were identified. The patients who died during the index hospitalization and the patients who were current users of NRT on admission were excluded from the present analysis. The baseline characteristics, including demographic data, co-morbid conditions, revascularization status, and hospital discharge medications, were gathered from the database and confirmed by electronic chart review. The University of Rochester research subjects review board approved the study.
      The patients were divided into subgroups depending on whether they were discharged with a prescription for NRT (including nicotine patch, lozenges, gum, nasal spray, and inhalers) or not, as documented in the electronic health record. The outcome measures included all-cause death, MI, repeat revascularization, or rehospitalization for angina, arrhythmia, or congestive heart failure at 1 year. The prespecified primary end point was a composite of these outcomes, and the individual components were analyzed separately as secondary end points. The outcomes were identified using electronic chart review of the patients' inpatient and outpatient records and a search of publicly available death records. When these sources could not firmly establish whether an outcome had been reached, the patients were interviewed by telephone.
      Power calculations were performed based on the nonsignificant relative risk reduction seen previously,
      • Joseph A.M.
      • Norman S.M.
      • Ferry L.H.
      • Prochazka A.V.
      • Westman E.C.
      • Steele B.G.
      • Sherman S.E.
      • Cleveland M.
      • Antonuccio D.O.
      • Hartman N.
      • McGovern P.G.
      • McGovern P.G.
      The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease.
      as applied to an incidence of adverse events of 23% in the first year after ACS.
      • Kastrati A.
      • Mehilli J.
      • Schühlen H.
      • Dirschinger J.
      • Dotzer F.
      • ten Berg J.M.
      • Neumann F.J.
      • Bollwein H.
      • Volmer C.
      • Gawaz M.
      • Berger P.B.
      • Schömig A.
      Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment Study Investigators
      A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel.
      We estimated a sample size of 918 patients to ensure 90% power to detect a statistically significant benefit with NRT use. Univariate analyses between those with NRT versus those without were performed for all baseline characteristics using the chi-square test for categorical variables and the nonparametric Wilcoxon rank-sum test for continuous variables. Odds ratios for NRT use after ACS were estimated using multivariate logistic regression analysis. The best subsets method was used to select which clinical covariates were entered in the multivariate model. The subsets of patients with various revascularization strategies, (percutaneous intervention vs bypass surgery vs medical management) were analyzed, and adjustments for various medications were tested in the model to evaluate their statistical effect on NRT use. All p values were 2-sided, and p <0.05 was considered significant. The analyses were conducted with SAS software, version 9.2 (SAS Institute, Cary, North Carolina).

      Results

      A total of 904 patients were identified from the database. Of these 904 patients, 20 died during the index hospitalization and 221 (24.4%) were lost to follow-up or had incomplete data. These patients were excluded from the analysis. Data from the remaining 663 patients were analyzed, and categorized by NRT status on discharge from the index hospitalization. Of the 663 patients, 184 (27.7%) were in the NRT group and 479 (72.2%) in the no-NRT (control) group; 146 patients were interviewed directly because of incomplete electronic data. The baseline characteristics of the 2 groups are listed in Table 1. The revascularization strategy and discharge medications of the 2 groups are listed in Table 2.
      Table 1Baseline characteristics
      VariableNRT (n = 184)Control (n = 479)p Value
      Age (years)55 ± 1056 ± 110.148
      Women62 (34%)151 (32%)0.592
      White152 (83%)406 (85%)0.497
      Black22 (12%)51 (11%)0.630
      Hypertension (systolic blood pressure >140 mm Hg or therapy)125 (68%)312 (65%)0.496
      Dyslipidemia (low-density lipoprotein >160 ng/dl or therapy)111 (60%)280 (58%)0.661
      Diabetes mellitus41 (22%)121 (25%)0.424
      Heart failure7 (4%)28 (6%)0.290
      Previous myocardial infarction37 (20%)115 (24%)0.285
      Previous coronary artery bypass11 (6%)34 (7%)0.608
      Previous percutaneous intervention31 (17%)98 (20%)0.293
      Current dialysis2 (1%)6 (1%)1.000
      Peripheral arterial disease13 (7%)51 (11%)0.160
      ST-segment elevation myocardial infarction81 (44%)185 (39%)0.204
      Non–ST-elevation myocardial infarction76 (41%)191 (40%)0.737
      Acute coronary syndrome without myocardial infarction27 (15%)103 (22%)0.047
      Table 2Revascularization approach/discharge medications
      VariableNRT (n = 184)Control (n = 479)p Value
      Percutaneous intervention145 (79%)305 (64%)<0.001
      p <0.1
      Coronary artery bypass5 (3%)67 (14%)<0.001
      p <0.1
      Aspirin178 (97%)457 (95%)0.445
      Clopidogrel165 (90%)372 (78%)<0.001
      p <0.1
      β Blockers172 (93%)443 (92%)0.658
      Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers167 (91%)403 (84%)0.028
      p <0.1
      Statins177 (96%)443 (92%)0.082
      p <0.1
      low asterisk p <0.1
      The results were adjusted for the independent variables of dialysis status, gender, previous coronary artery bypass grafting, and race by multivariate logistic regression analysis using the r-square best subsets method, because these variables showed interaction with the primary end point. The remainder of the measured variables, including age, other baseline characteristics, revascularization strategy, and differences in discharge medications, were not statistically significant predictors in the multivariate regression model. More patients in the NRT group underwent percutaneous intervention, and this group had a greater cardiovascular medication rate; however, these were not statistically significant predictors in the multivariate regression model.
      A total of 202 patients had an adverse outcome in the first year after discharge, including 53 (29%) in the NRT group and 149 (31%) in the control group. NRT use was not significantly predictive of the 1-year combined end point of death, MI, repeat revascularization, or rehospitalization for angina, congestive heart failure, or arrhythmia. No differences were seen in the individual 1-year end points of death, MI, repeat revascularization or rehospitalization for angina, congestive heart failure, or arrhythmia. The results are summarized in Table 3.
      Table 3One-year outcomes and adjusted odds ratios (95% confidence intervals)
      Adjusted for the independent variables of dialysis status, gender, prior coronary artery bypass grafting, and race.
      OutcomeNRTControlOR (95% CI)
      Composite
      Death, myocardial infarction, repeat revascularization, or hospitalization for angina, congestive heart failure, or arrhythmia.
      53 (29%)149 (31%)0.89 (0.61–1.30)
      Death7 (4%)24 (5%)0.80 (0.33–1.91)
      Myocardial infarction8 (4%)23 (5%)0.90 (0.40–2.06)
      Repeat revascularization18 (10%)58 (12%)0.77 (0.44–1.36)
      Hospitalization
      For angina, congestive heart failure, or arrhythmia.
      41 (22%)104 (22%)1.01 (0.66–1.53)
      OR = odds ratio; CI = confidence interval.
      low asterisk Adjusted for the independent variables of dialysis status, gender, prior coronary artery bypass grafting, and race.
      Death, myocardial infarction, repeat revascularization, or hospitalization for angina, congestive heart failure, or arrhythmia.
      For angina, congestive heart failure, or arrhythmia.

      Discussion

      The results of the present study suggest that NRT use after ACS was not associated with an increased risk of adverse cardiovascular events. These results might be particularly important in the treatment of smokers with CAD, because the use of medication to stop smoking roughly doubles the success rates in long-term abstinence by reducing withdrawal symptoms.
      • Fiore M.
      US Tobacco Use and Dependence Guideline Panel
      Treating Tobacco Use and Dependence: 2008 Update.
      Tobacco affects the cardiovascular system in numerous ways. Nicotine itself causes some, but not all, of these effects. Nicotine is sympathoexcitatory, causing catecholamine release and chemoreceptor sensitivity increase. Nicotine increases myocardial work
      • Benowitz N.L.
      Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment.
      ; however, when administered alone it has no effect on physiologic coronary vasodilation. Nicotine is characterized by a rapid onset of tolerance to the physiologic effects, suggesting that these effects might not make an important contribution to chronic cardiovascular risk.
      • Adamopoulos D.
      • van de Borne P.
      • Argacha J.F.
      New insights into the sympathetic, endothelial and coronary effects of nicotine.
      However, components of tobacco smoke have profound effects on the cardiovascular system. In a recent analysis, 98 components of tobacco smoke were found to have measurable harm in humans.
      • Talhout R.
      • Schulz T.
      • Florek E.
      • van Benthem J.
      • Wester P.
      • Opperhuizen A.
      Hazardous compounds in tobacco smoke.
      In addition, particulate matter exposure has a recognized association with the risk of cardiovascular disease; cigarettes have very high concentrations of particulate matter.
      • Polichetti G.
      • Cocco S.
      • Spinali A.
      • Trimarco V.
      • Nunziata A.
      Effects of particulate matter (PM(10), PM(2.5) and PM(1) on the cardiovascular system.
      Tobacco smoke has a proinflammatory effect, causing release of inflammatory cytokines and inhibiting anti-inflammatory mediators in a chronic manner.
      • Arnson Y.
      • Shoenfeld Y.
      • Amital H.
      Effects of tobacco smoke on immunity, inflammation and autoimmunity.
      These effects might lead to endothelial damage and platelet activation, potentially exacerbating CAD.
      • Vardavas C.I.
      • Panagiotakos D.B.
      The causal relationship between passive smoking and inflammation on the development of cardiovascular disease: a review of the evidence.
      • Czernin J.
      • Waldherr C.
      Cigarette smoking and coronary blood flow.
      The effects of nicotine on endothelial damage, platelet activation, and thrombotic cascade appear to be minimal,
      • Ambrose J.A.
      • Barua R.S.
      The pathophysiology of cigarette smoking and cardiovascular disease: an update.
      suggesting that other components of tobacco smoke are more likely to be causing this effect.
      Numerous pathophysiologic and clinical investigations have suggested that NRT is safe for use in patients with CAD. The use of NRT does not appear to increase platelet activity.
      • Mundal H.H.
      • Hjemdahl P.
      • Gjesdal K.
      Acute effects of low dose nicotine gum on platelet function in non-smoking hypertensive and normotensive men.
      • Blann A.D.
      • Steele C.
      • McCollum C.N.
      The influence of smoking and of oral and transdermal nicotine on blood pressure, and haematology and coagulation indices.
      As mentioned previously, NRT was not associated with an increase in the incidence of a first MI
      • Kimmel S.E.
      • Berlin J.A.
      • Miles C.
      • Jaskowiak J.
      • Carson J.L.
      • Strom B.L.
      Risk of acute first myocardial infarction and use of nicotine patches in a general population.
      and appeared to be safe in 2 randomized-controlled studies of patients with stable CAD.
      • Joseph A.M.
      • Norman S.M.
      • Ferry L.H.
      • Prochazka A.V.
      • Westman E.C.
      • Steele B.G.
      • Sherman S.E.
      • Cleveland M.
      • Antonuccio D.O.
      • Hartman N.
      • McGovern P.G.
      • McGovern P.G.
      The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease.
      Working Group for the Study of Transdermal Nicotine in Patients With Coronary Artery Disease
      Nicotine replacement therapy for patients with coronary artery disease.
      NRT appeared to reduce the extent of myocardial ischemia on nuclear perfusion imaging
      • Mahmarian J.J.
      • Moyé L.A.
      • Nasser G.A.
      • Nagueh S.F.
      • Bloom M.F.
      • Benowitz N.L.
      • Verani M.S.
      • Byrd W.G.
      • Pratt C.M.
      Nicotine patch therapy in smoking cessation reduces the extent of exercise-induced myocardial ischemia.
      and did not worsen endothelial function or reduce the cross-sectional area of the coronary arteries.
      • Nitenberg A.
      • Antony I.
      Effects of nicotine gum on coronary vasomotor responses during sympathetic stimulation in patients with coronary artery stenosis.
      Hesitation persists in NRT prescription in patients with recent ACS, however, because of a lack of data from the ACS population and the existing cautions. A previous retrospective study showed no increase in the mortality rate in patients prescribed NRT after ACS
      • Meine T.J.
      • Patel M.R.
      • Washam J.B.
      • Pappas P.A.
      • Jollis J.G.
      Safety and effectiveness of transdermal nicotine patch in smokers admitted with acute coronary syndromes.
      ; however, that study did not fully evaluate other important cardiac end points such as MI or cardiac readmission. To date, our study is the first to consider such end points.
      The present study did have some limitations. As with any retrospective analysis, the possibility of bias exists; the presence of unmeasured confounders might have influenced the apparent effect of NRT despite the logistic regression analysis. The end points were assessed at the 1-year point; thus, an early risk of NRT that equilibrates later in follow-up could not be ruled out. Also, compliance with the NRT could not be verified. Although NRT has previously been shown to provide lasting maintenance of tobacco abstinence, tobacco use during follow-up could not be accurately assessed because of the variability in documentation and, therefore, was not included in the present analysis. Although the intention was to power the study to detect a statistically significant benefit from NRT to the degree suggested previously,
      • Joseph A.M.
      • Norman S.M.
      • Ferry L.H.
      • Prochazka A.V.
      • Westman E.C.
      • Steele B.G.
      • Sherman S.E.
      • Cleveland M.
      • Antonuccio D.O.
      • Hartman N.
      • McGovern P.G.
      • McGovern P.G.
      The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease.
      the intended number of patients to be enrolled (918) was not reached.

      References

        • van Berkel T.F.
        • Boersma H.
        • Roos-Hesselink J.W.
        • Erdman R.A.
        • Simoons M.L.
        Impact of smoking cessation and smoking interventions in patients with coronary heart disease.
        Eur Heart J. 1999; 20: 1773-1782
        • Working Group for the study of transdermal nicotine in patients with coronary artery disease
        Nicotine replacement therapy for patients with coronary artery disease.
        Arch Intern Med. 1994; 154: 989-995
        • Ford C.L.
        • Zlabek J.A.
        Nicotine replacement therapy and cardiovascular disease.
        Mayo Clin Proc. 2005; 80: 652-656
        • Singh S.
        • Loke Y.K.
        • Spangler J.G.
        • Furberg C.D.
        Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis.
        Can Med Assoc J. 2011; 183: 1359-1366
      1. FDA Drug Safety Communication.
        (Accessed September 9, 2011)
        • Kimmel S.E.
        • Berlin J.A.
        • Miles C.
        • Jaskowiak J.
        • Carson J.L.
        • Strom B.L.
        Risk of acute first myocardial infarction and use of nicotine patches in a general population.
        J Am Coll Cardiol. 2001; 37: 1297-1302
        • Joseph A.M.
        • Norman S.M.
        • Ferry L.H.
        • Prochazka A.V.
        • Westman E.C.
        • Steele B.G.
        • Sherman S.E.
        • Cleveland M.
        • Antonuccio D.O.
        • Hartman N.
        • McGovern P.G.
        • McGovern P.G.
        The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease.
        N Engl J Med. 1996; 335: 1792-1798
        • Kastrati A.
        • Mehilli J.
        • Schühlen H.
        • Dirschinger J.
        • Dotzer F.
        • ten Berg J.M.
        • Neumann F.J.
        • Bollwein H.
        • Volmer C.
        • Gawaz M.
        • Berger P.B.
        • Schömig A.
        • Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment Study Investigators
        A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel.
        N Engl J Med. 2004; 350: 232-238
        • Fiore M.
        • US Tobacco Use and Dependence Guideline Panel
        Treating Tobacco Use and Dependence: 2008 Update.
        Dept. of Health and Human Services, Public Health Service, Rockville, MD2008 (xvii, 256)
        • Benowitz N.L.
        Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment.
        Prog Cardiovasc Dis. 2003; 46: 91-111
        • Adamopoulos D.
        • van de Borne P.
        • Argacha J.F.
        New insights into the sympathetic, endothelial and coronary effects of nicotine.
        Clin Exp Pharmacol Physiol. 2008; 35: 458-463
        • Talhout R.
        • Schulz T.
        • Florek E.
        • van Benthem J.
        • Wester P.
        • Opperhuizen A.
        Hazardous compounds in tobacco smoke.
        Int J Environ Res Public Health. 2011; 8: 613-628
        • Polichetti G.
        • Cocco S.
        • Spinali A.
        • Trimarco V.
        • Nunziata A.
        Effects of particulate matter (PM(10), PM(2.5) and PM(1) on the cardiovascular system.
        Toxicology. 2009; 261: 1-8
        • Arnson Y.
        • Shoenfeld Y.
        • Amital H.
        Effects of tobacco smoke on immunity, inflammation and autoimmunity.
        J Autoimmun. 2010; 34: J258-J265
        • Vardavas C.I.
        • Panagiotakos D.B.
        The causal relationship between passive smoking and inflammation on the development of cardiovascular disease: a review of the evidence.
        Inflamm Allergy Drug Targets. 2009; 8: 328-333
        • Czernin J.
        • Waldherr C.
        Cigarette smoking and coronary blood flow.
        Prog Cardiovasc Dis. 2003; 45: 395-404
        • Ambrose J.A.
        • Barua R.S.
        The pathophysiology of cigarette smoking and cardiovascular disease: an update.
        J Am Coll Cardiol. 2004; 43: 1731-1737
        • Mundal H.H.
        • Hjemdahl P.
        • Gjesdal K.
        Acute effects of low dose nicotine gum on platelet function in non-smoking hypertensive and normotensive men.
        Eur J Clin Pharmacol. 1995; 47: 411-416
        • Blann A.D.
        • Steele C.
        • McCollum C.N.
        The influence of smoking and of oral and transdermal nicotine on blood pressure, and haematology and coagulation indices.
        Thromb Haemost. 1997; 78: 1093-1096
        • Working Group for the Study of Transdermal Nicotine in Patients With Coronary Artery Disease
        Nicotine replacement therapy for patients with coronary artery disease.
        Arch Intern Med. 1994; 154: 989-995
        • Mahmarian J.J.
        • Moyé L.A.
        • Nasser G.A.
        • Nagueh S.F.
        • Bloom M.F.
        • Benowitz N.L.
        • Verani M.S.
        • Byrd W.G.
        • Pratt C.M.
        Nicotine patch therapy in smoking cessation reduces the extent of exercise-induced myocardial ischemia.
        J Am Coll Cardiol. 1997; 30: 125-130
        • Nitenberg A.
        • Antony I.
        Effects of nicotine gum on coronary vasomotor responses during sympathetic stimulation in patients with coronary artery stenosis.
        J Cardiovasc Pharmacol. 1999; 34: 694-699
        • Meine T.J.
        • Patel M.R.
        • Washam J.B.
        • Pappas P.A.
        • Jollis J.G.
        Safety and effectiveness of transdermal nicotine patch in smokers admitted with acute coronary syndromes.
        Am J Cardiol. 2005; 95: 976-978