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Nicotine is not a significant risk factor for cardiovascular events. The benefit of nicotine replacement therapy outweighs the risks of nicotine medication, even in smokers with cardiovascular disease.

Cigarette smoking increases the risk of cardiovascular disease, and smoking cessation significantly reduces the risk within 1-3 years. Therefore, patients with cardiovascular disease should be encouraged to use the most effective therapies available to reach this goal. The use of nicotine replacement therapy (NRT) doubles long-term cessation (Stead et al., 2008). While not all of the efficacy results in trials conducted in patients with cardiac disease show benefit for increased cessation (Joseph & Fu, 2003; Benowitz, 2003; Marsh et al., 2005; Meine et al., 2005), all trials confirm that NRT, even with concurrent smoking, is safe in this population (see Key Finding #11).

Some regulatory authorities in Europe have taken action supporting the use of NRT in patients with cardiovascular disease. In 2003, the AFSSAPS (French regulatory agency for medicines) recommended the changes to the Summary of Product Characteristics of NRT, deleting all cardiovascular and cerebrovascular disease contraindications (AFSSAPS, 2003). In 2005, the Committee on Safety of Medicines of the Medicines and Healthcare products Regulatory Agency (MHRA in UK) recommended similar changes (MHRA, 2005). Since 2006, the new Summary of Product Characteristics is now reflecting these recommendations.

The use of nicotine replacement therapy (NRT) in patients with atherosclerotic cardiovascular disease is of concern because some of the cardiotoxic effects of smoking may be attributable to nicotine. Nicotine increases sympathetic activity, which results in an increase in heart rate and blood pressure, and vasoconstriction. Nicotine may contribute to endothelial dysfunction and to the development of resistance to insulin, the latter resulting in glucose intolerance and precipitation, or aggravation, of diabetes (Benowitz, 2003).

Other factors that contribute to increased cardiovascular risk observed in smokers include increased thrombogenesis, oxidative damage, reduced oxygen availability due to carbon monoxide exposure and hyperlipidaemia. Studies suggest that smoking cessation using pharmacological nicotine has a favorable effect on these contributing factors (Ludviksdottir et al., 1999). Furthermore, nicotine levels achieved with replacement therapy are much lower than those found with smoking, and the nicotine dose-cardiovascular response curve demonstrates a plateau effect, that protects against increased cardiac effects with increased nicotine dose (Benowitz & Gourlay, 1997).

Two coronary perfusion studies, one using quantitative thallium tests and the other using coronary angiography, suggest no increase in cardiac ischaemia in subjects while using nicotine. The first study showed that patients with cardiovascular disease, who smoked and were treated with transdermal nicotine, had a significant decrease in the size of perfusion defects on quantitative exercise thallium tests in comparison to smoking (Mahmarian et al., 1997). Another study of normal and diseased coronary artery segments, as observed by angiography, showed that in subjects using nicotine gum there was neither reduction in the surface area of coronary artery segments nor enhancement of the effect of sympathetic stimulation on coronary vasoconstriction (Nitenberg & Antony, 1999).

Three randomized controlled trials have examined the efficacy and safety of NRT in patients with cardiovascular disease (Working Group, 1994; Tzivoni et al., 1998; Joseph et al., 1996). Although each study examined different endpoints, none showed significant differences in the rates of death, myocardial infarction, frequency of angina, arrhythmia, or withdrawal from therapy due to adverse events, comparing NRT to placebo. In one trial, smoking concurrently while using transdermal nicotine was not associated with an increase in adverse events (Joseph et al., 1996). Two of the trials showed a statistically significant increase in cessation rates with active treatment (Working Group, 1994; and Tzivoni et al., 1998); however one failed to demonstrate the efficacy of transdermal nicotine to accomplish long-term abstinence from smoking (Joseph et al., 1996).

A meta-analysis of adverse events, recorded in the course of 35 trials to evaluate the efficacy of nicotine patches, also failed to document a difference in the rate of acute myocardial infarction between active (n=5501) and placebo (n=3752) treatment groups (Greenland et al., 1998). A more recent meta-analysis (Mills et al., 2010) included 120 studies (92 randomised clinical trials and 28 observational studies) for a total of 177,390 individuals, and found no increased risk for myocardial infarction or death from NRT (for a review on adverse effects and tolerability see also Hays & Ebbert, 2010). The majority of these studies, however, specifically excluded patients with cardiac disease at baseline. A secondary analysis of subjects in the Lung Health Study, a randomized, controlled trial for the prevention of chronic obstructive pulmonary disease, demonstrated that cardiovascular deaths were associated with continuing smoking, but not among those who used nicotine gum for five years. The use or dose of nicotine gum, or concurrent smoking and gum use, was not associated with increased cardiovascular morbidity or mortality (Murray et al., 1996). A case control study of acute myocardial infarction, stroke and death in the UK found no evidence of increased risk in the 56 days after starting NRT for smoking cessation (Hubbard et al., 2005).

Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews 2008; 1.

Joseph AM, Fu SS. Safety issues in pharmacotherapy for smoking in patients with cardiovascular disease. Prog Cardiovasc Dis. 2003; 45: 429-441.

Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog Cardiovasc Dis. 2003; 46: 91-111.

Marsh HS, Dresler CM, Choi JH, Targett DA, Gamble ML, Strahs KR. Safety profile of a nicotine lozenge compared with that of nicotine gum in adult smokers with underlying medical conditions: a 12-week, randomized, open-label study. Clin Ther. 2005; 27: 1571-1587.

Meine TJ, Patel MR, Washam JB, Pappas PA, Jollis JG. Safety and effectiveness of transdermal nicotine patch in smokers admitted with acute coronary syndromes. Am J Cardiol. 2005; 95: 976-978.

Medicines and Healthcare products Regulatory Agency. Report of the committee on safety of Medicines working group on nicotine Replacement therapy, London, November 2005.

Agence française de sécurité sanitaire des produits de santé (AFSSAPS) - Mai 2003 - les stratégies thérapeutiques médicamenteuses et non médicamenteuses de l'aide a l'arrêt du tabac [French Regulatory Agency - Pharmacological and non-pharmacological interventions for smoking cessation].

Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy. J Am Coll Cardiol. 1997; 29: 1422-1431.

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.

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.

Tzivoni D, Keren A, Meyler S, Khoury Z, Lerer T, Brunel P. Cardiovascular safety of transdermal nicotine patches in patients with coronary artery disease who try to quit smoking. Cardiovasc Drugs Ther. 1998; 12: 239-244.

Lúdvíksdóttir D, Blöndal T, Franzon M, Gudmundsson TV, Säwe U
. Effects of nicotine nasal spray on atherogenic and thrombogenic factors during smoking cessation. J Intern Med. 1999; 246: 61-66.

Joseph AM, Norman SM, Ferry LH, Prochazka AV, Westman EC, Steele BG, Sherman SE, Cleveland M, Antonuccio DO, Hartman N, McGovern PG. The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Eng J Med. 1996; 335: 1792-1798.

Greenland S, Satterfield MH, Lanes SF. A meta-analysis to assess the incidence of adverse effects associated with the transdermal nicotine patch. Drug Safety. 1998; 18: 297-308.

Mills EJ, Wu P, Lockhart I, Wilson K, Ebbert JO. Adverse events associated with nicotine replacement therapy (NRT) for smoking cessation. A systematic review and meta-analysis of one hundred and twenty studies involving 177,390 individuals. Tob Induc Dis. 2010; 8: 8.

Hays JT, Ebbert JO. Adverse effects and tolerability of medications for the treatment of tobacco use and dependence. Drugs. 2010; 70(18): 2357-2372.

Mahmarian JJ, Moyé LA, Nasser GA, Nagueh SF, Bloom MF, Benowitz NL, Verani MS, Byrd WG, Pratt CM
. Nicotine patch therapy in smoking cessation reduces the extent of exercise-induced myocardial ischemia. J Am Coll Cardiol. 1997; 30: 125-130.

Murray RP, Bailey WC, Daniels K, Bjornson WM, Kurnow K, Connett JE, Nides MA, Kiley JP
. Safety of nicotine polacrilex gum used by 3,094 participants in the Lung Health Study. Chest. 1996; 109: 438-445.

Hubbard R, Lewis S, Smith C, Godfrey C, Smeeth L, Farrington P, Britton J. Use of nicotine replacement therapy and the risk of acute myocardial infarction, stroke, and death. Tob Control. 2005; 14: 416–421. logo
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