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Tools in the Battle Against Smoking and Tobacco 3 -C CON, AHMEDABAD, FEBRUARY 2011 Tools in the Battle Against Smoking and Tobacco 3 -C CON, AHMEDABAD, FEBRUARY 2011 Chaim Lotan, MD Heart Institute, Hadassah Hospital, Jerusalem, ISRAEL

Smoking and coronary artery disease History Epidemiology CV Effects Importance of Cessation Smoking and coronary artery disease History Epidemiology CV Effects Importance of Cessation

Cigarette Smoking as a Risk Factor for Cardiovascular Disease was recognized in the results Cigarette Smoking as a Risk Factor for Cardiovascular Disease was recognized in the results of the Framingham Heart Study in 1960

Smoking kills more people each year than alcohol cocaine crack heroin homicide suicide car Smoking kills more people each year than alcohol cocaine crack heroin homicide suicide car accidents fires AIDS C O M B I N ED!!!

Smoking and coronary artery disease History Epidemiology CV Effects Importance of Cessation Smoking and coronary artery disease History Epidemiology CV Effects Importance of Cessation

Global Cigarette Consumption WHO World Health Report. Tobacco Atlas. 2008. Global Cigarette Consumption WHO World Health Report. Tobacco Atlas. 2008.

Section 2: The Hazards of Smoking Section 2: The Hazards of Smoking

Facts & Numbers 1. 25 billion smokers Worldwide 30 million smokers added every year Facts & Numbers 1. 25 billion smokers Worldwide 30 million smokers added every year 84% of smokers live in developing countries • Africa & Middle East (17% of World’s population) accounts for 7% of World’s total cigarette consumption 8 smokers die every minute Voute J, World Heart Foundation

Gender-specific Smoking Prevalence Across the World 1. 25 billion smokers worldwide 1 Sweden Iceland Gender-specific Smoking Prevalence Across the World 1. 25 billion smokers worldwide 1 Sweden Iceland 17% 25% Russian Federation 18% Belarus 20% 60% 53% France 16% Germany 7% 30% 37% China Portugal 21% 28% 67% 33% Spain Italy Iran 2% 39% 33% Egypt 10% 22% 25% 17% 45% 2% India Philippines Canada 22% 17% US 24% 19% Mexico 13% 5% Men Women 1. 12% Brazil 22% 14% Chile 48% 37% Kenya 21% 1% South Africa 47% 17% 23% 8% Mackay J, Eriksen M. The Tobacco Atlas. Second Ed. American Cancer Society, 2006. 41% 8% Australia 19% 16%

4 year-old addict to smoking in Indonesia 4 year-old addict to smoking in Indonesia

Smoking and coronary artery disease History Epidemiology CV Effects Importance of Cessation Smoking and coronary artery disease History Epidemiology CV Effects Importance of Cessation

Smoking: Leading Preventable Cause of Disease and Death 1 Cancer Reproductive Other Lung (#1) Smoking: Leading Preventable Cause of Disease and Death 1 Cancer Reproductive Other Lung (#1) Cardiovascular 2 -4 Respiratory Low-birth weight Leukemia (AML, ALL, CLL) Adverse surgical Ischemic heart disease COPD (#3) Oral cavity/pharynx Pregnancy outcomes/wound healing (#2) Laryngeal Pneumonia complications Hip fractures Stroke – vascular Esophageal Poor asthma control Reduced fertility Low-bone density dementia 5 Stomach SIDS Cataract Peripheral vascular Pancreatic Peptic ulcer disease in Kidney disease 6 Helicobacter pylori-positive Bladder Abdominal aortic aneurysm patients Cervical AML = acute myeloid leukemia; ALL = acute lymphocytic leukemia; CLL = chronic lymphocytic leukemia; COPD = chronic obstructive pulmonary disease; SIDS = sudden infant death syndrome. • • • Surgeon General’s Report. The Health Consequences of Smoking ; 2004. Sandler DP, et al. J Natl Cancer Inst. 1993; 85: 1994 -2003. Crane MM, et al. Cancer Epidemiol Biomarkers Prev. 1996; 5: 639 -644. Miligi L, et al. Am J Ind Med. 1999; 36: 60 -69. Roman GC. Cerebrovasc Dis. 2005; 20: 91 -100. Willigendael EM, et al. J Vasc Surg. 2004; 40: 1158 -1165.

INTERHEART: Smoking and MI Odds of myocardial infarction 16 OR (99% CI) 8 4 INTERHEART: Smoking and MI Odds of myocardial infarction 16 OR (99% CI) 8 4 2 0 1 -5 6 -10 11 -15 16 -20 21 -25 26 -30 31 -40 #cigarettes smoked per day >40

Smoking Is Related To 5 of the Top 10 Leading Causes of Death Worldwide Smoking Is Related To 5 of the Top 10 Leading Causes of Death Worldwide 1 § 1 in 10 adult deaths are smoking-related 2 WHO top ten causes of death 3 § 500, 000 people alive today will die from smoking-related causes 2 Causes Related to Smoking 1. Surgeon General’s Report, 2004. 2. World Bank, 1999. 3. World Health Organization, 2003.

How does smoking induce ACS ? Platelet function Coagulation (PAI-1) Inflammation (hs-CRP, cytokine, chemokine) How does smoking induce ACS ? Platelet function Coagulation (PAI-1) Inflammation (hs-CRP, cytokine, chemokine) Smooth muscle cells Viscosity Endothelial function Collagen Macrophages MMPs LDL-C HDL-C TG

Role of AMI due to tobacco in India N=300 AMI, 300 Controls Pais P, Role of AMI due to tobacco in India N=300 AMI, 300 Controls Pais P, Fay MP, Yusuf S Indian Heart J 2001; 53: 731 -5

Tobacco associated mortality in Mumbai (Bombay) India. Results of the Bombay Cohort Study Gupta Tobacco associated mortality in Mumbai (Bombay) India. Results of the Bombay Cohort Study Gupta PC, Pednekar MS, Parkin DM, Sankaranarayanan R Background Little is known about the excess mortality from forms of tobacco use other than cigarette smoking that are widely prevalent in India, such as bidi smoking and the various forms of smokeless tobacco use. We report on absolute and relative risks of mortality among various kinds of ever tobacco users vs never-users in the city of Mumbai, India. (n=99570) Results The adjusted relative risk was 1. 37 (95% CI 1. 23– 1. 53) for (men) cigarette smokers and 1. 64 (95% CI 1. 47– 1. 81) for bidi smokers, with a significant dose– response relationship for number of bidis or cigarettes smoked. Women were essentially smokeless tobacco users; the adjusted relative risk was 1. 25 (95% CI 1. 15– 1. 35). Conclusions Bidi is no less hazardous than cigarette smoking, and smokeless tobacco use may also result in significantly increased mortality. Intl J Epidemiol 2005; 43(6): 1395 -1402

 Tobacco consumption is a major source of mortality and morbidity in India. Studies Tobacco consumption is a major source of mortality and morbidity in India. Studies have shown contradictory results regarding smokeless tobacco use as a cardiovascular risk factor, but many show conclusive connection. 2003 Study of adults males in a rural village in Haryana, northern India (chosen randomly)

smokeless tobacco With smoke-free laws, smokeless tobacco (ST) products are being marketed as smoking smokeless tobacco With smoke-free laws, smokeless tobacco (ST) products are being marketed as smoking substitutes: snuff, chewing tobacco, spitless pouched moist snuff, compressed tobacco lozenges. A recent US study found no reduction in smoking rates among people using ST as replacement, although a previous (2006) Swedish study showed an overall country reduction in smoking with increased overall ST consumption.

Chemical Composition of ST Products Similar to cigarettes, nicotine is the principal alkaloid Minor Chemical Composition of ST Products Similar to cigarettes, nicotine is the principal alkaloid Minor alkaloids: nornicotine, anatabine, anabasine Carcinogens: Nitrosamines - highest known nonoccupational exposure Nitrite, nitrate, formate, chloride, sulfate, phosphate Amount of total and free nicotine varies substantially - generally, concentration similar in oral snuff and cigarette tobacco, somewhat lower in chewing tobacco Carcinogens: Combustion-derived Benzo[a]pyrene and other polycyclics lower than in cigarette smoking

Impact of Smokeless Tobacco Products on Cardiovascular Disease: Implications for Policy, Prevention and Treatment: Impact of Smokeless Tobacco Products on Cardiovascular Disease: Implications for Policy, Prevention and Treatment: A Policy Statement From The American Heart Association 2010 Long-term use of smokeless tobacco products increases the odds of fatal heart attack or fatal stroke (according to analysis of several studies). The AHA advises against smokeless tobacco products for smoking cessation - they are not a “safe” alternative to smoking, and carry the risk of addiction and return to smoking.

The Effects of Second-Hand Smoke Short-term effects of second-hand smoke: § Coughing § Headache The Effects of Second-Hand Smoke Short-term effects of second-hand smoke: § Coughing § Headache § Eye irritation § Sore throat § Sneezing and runny nose § Feeling sick § Breathing problems (and possibly an asthma attack) attack § Irregular heartbeat (a particular problem for people with heart disease) Long-term effects of second-hand smoke: § Worsening of chest problems and allergies like asthma, hay fever, bronchitis and emphysema § Increased risk of heart disease § Increased risk of lung cancer § Pregnant women exposed to second hand smoke can pass on the harmful gases and chemicals onto their babies.

The health consequences of smoking and second hand smoke evolve over a lifetime. Infant The health consequences of smoking and second hand smoke evolve over a lifetime. Infant health Pregnancy Fetal growth Birth weight Abortions Premature Birth Fetal Death SIDS Child Health and Smoking Adulthood Physical Growth Behavior and cognitive development Respiratory infections More hospitalization Adolescence Small airway Chronic bronchitis Emphysema Lung cancer by 20%– 30% Coronary heart disease Stroke COPD 1. 2. 3. 4. 5. 6. News release, June 27, 2006; US Department of Health & Human Services. Available at: http: //www. hhs. gov/news/press/2006 pres/20060627. html. Mackay J, et al. The Tobacco Atlas. World Health Organization, 2006. Teo KK, et al. Lancet. 2006; 368: 647 -658. Fagerström K. Drugs. 2002; 62: 1 -9. Blizzard L, et al. Arch Pediatr Adolesc Med. 2004; 158: 687 -693. Leung GM, et al. Arch Pediatr Adolesc Med. 2004; 158: 687 -693. dysfunction Cough Wheezing Phlegm production other respiratory symptoms

Passive Smoking and CV Disability Have a clear relationship to CV disability & mortality Passive Smoking and CV Disability Have a clear relationship to CV disability & mortality ~ 37, 000 to 40, 000 people die from cardiovascular disease caused by other people’s smoke every year. Of these, year 35, 000 non-smokers die from coronary heart disease. American Heart Association 2007

Smoking and coronary artery disease History Epidemiology CV Effects Importance of Cessation Smoking and coronary artery disease History Epidemiology CV Effects Importance of Cessation

Why Quit? Potential Health Benefits of Quitting Smoking 1. 2. 15 years 10 years Why Quit? Potential Health Benefits of Quitting Smoking 1. 2. 15 years 10 years 5 years 1 year 3 months Cessation CHD risk is similar to never smokers Lung cancer risk is 30%– 50% that of continuing smokers Stroke risk returns to the level of people who have never smoked at 5– 15 years post-cessation Cardiovascular Heart Disease (CHD): excess risk is reduced by 50% among ex-smokers Lung function may start to improve with decreased cough, sinus congestion, fatigue, and shortness of breath USDHHS. The Health Benefits of Smoking Cessation: A Report of the Surgeon General, 1990. Available at: http: //profiles. nlm. nih. gov/NN/B/B/C/T/. American Cancer Society. Guide to Quitting Smoking. Available at: http: //www. cancer. org.

Quitting at Any Age May Increase Life Expectancy Age Stopped Smoking: 45– 54 Years Quitting at Any Age May Increase Life Expectancy Age Stopped Smoking: 45– 54 Years Old Results From a Study of Male Physician Smokers in the UK Nonsmokers Percentage Survival from Age 50 Age Stopped: 45– 54 Cigarette Smokers Age (Years) 1. Even quitting smoking later in life can lead to longer life expectancy Doll R, et al. BMJ. 2004; 328: 1519 -1527.

Smoking bans in public places and workplaces are significantly associated with a reduction in Smoking bans in public places and workplaces are significantly associated with a reduction in AMI incidence, particularly if enforced over several years.

Countries Banning Smoking in Public Places Nigeria Andorra (partial) Argentina-Buenos Aires 2006 Armenia (partial) Countries Banning Smoking in Public Places Nigeria Andorra (partial) Argentina-Buenos Aires 2006 Armenia (partial) Australia 2007 -10 Austria (partial) Albania 2007 Bahrain 2008 Bosnia-Herzegv. 2007 Brazil 2009 Bulgaria (partial) Canada Chile (partial) China (partial) Colombia 2009 Croatia 2008 -9 Cyprus 2009 Source: Wikipedia Czech Rep. (partial) Kazakhstan 2003 -9 Norway 2004 Denmark 2007 Kenya 2007 Paraguay Finland 2007 France 2008 Germany (contested) Greece 1010 Guatemala Hong Kong 2007 Hungary (partial) Iceland India (partial) Indonesia (partial) Ireland 2004 Israel Estonia (partial) Lithuania (partial) Luxemburg (partial) Macedonia 2010 Malta Malaysia Mexico 2008 Monaco (partial) Montenegro Morocco Mozambique 2007 Namibia 2010 Netherlands Latvia 2010 New Zealand 2004 Peru Philippines (partial) Poland (partial) Portugal 2007 Puerto Rico Singapore Serbia Slovenia South Africa 2001 Spain 2006 -10 Sweden (partial) Syria 2009 Thailand 2008 and more!

Beneficial Effects of Smoking Ban for Employees Number of barmen with symptoms 40 Symptoms Beneficial Effects of Smoking Ban for Employees Number of barmen with symptoms 40 Symptoms among 67 barmen before and after ban dyspnea morning cough sputum eye irritation nose irritation throat irritation 30 20 10 0 Before ban After Ban Source: Eisner M et coll. , JAMA 1998, 280, 1909 -1914

Smoking and coronary artery disease History Epidemiology CV Effects Importance of Cessation Nicotine addiction Smoking and coronary artery disease History Epidemiology CV Effects Importance of Cessation Nicotine addiction

Nicotine Addictive or Just a Bad Habit? ? ? Nicotine Addictive or Just a Bad Habit? ? ?

Mechanism of Action of Nicotine in the Central Nervous System 2 2 4 4 Mechanism of Action of Nicotine in the Central Nervous System 2 2 4 4 2 nicotinic acetylcholine receptor (n. ACh. R) Nicotine binds preferentially to n. ACh. Rs in the central nervous system; one key area is the α 4β 2 nicotinic receptor in the VTA After nicotine binds to the α 4β 2 n. ACh. R in the VTA, dopamine is released in the n. Acc which is believed to be linked to reward

The Cycle of Nicotine Addiction Nicotine binding causes an increase in release of dopamine The Cycle of Nicotine Addiction Nicotine binding causes an increase in release of dopamine 1, 2 Dopamine gives feelings of pleasure and calmness 1 Nicotine competitive binding of nicotine to nicotinic acetylcholine receptors causes prolonged activation, desensitization, and upregulation 2 1. 2. Jarvis MJ. BMJ. 2004; 328: 277 -279. Picciotto MR, et al. Nicotine and Tob Res. 1999: Suppl 2: S 121 -S 125.

Withdrawal Syndrome: A Combination of Physical and Psychological Conditions, Making Smoking Hard to Treat Withdrawal Syndrome: A Combination of Physical and Psychological Conditions, Making Smoking Hard to Treat Decreased heart rate Irritability, frustration, or anger Anxiety (may increase or decrease with quitting) Restlessness or impatience Insomnia/sleep disturbance Increased appetite or weight gain Dysphoric or depressed mood Difficulty concentrating 1. DSM-IV-TR. APA; 2006: Available at: http: //psychiatryonline. com

 The greatest risk of relapse is during the first three months after quitting. The greatest risk of relapse is during the first three months after quitting. 37% have their first lapse between 8: 00 pm and midnight 50% are likely to relapse in the first month 67% are likely to relapse in the first three months DSM-IV-TR. APA; 2006: Available at: http: //psychiatryonline. com

“Nine out of ten ex-smokers who have a cigarette after quitting later return to “Nine out of ten ex-smokers who have a cigarette after quitting later return to smoking” (Brandon, 1990)

Many Health Organizations Emphasise the Important Role Physicians Can Play in Helping Their Patients Many Health Organizations Emphasise the Important Role Physicians Can Play in Helping Their Patients Quit Smoking World Health Organization 1 Health Professionals Against Smoking 2 The American Academy of Family Physicians 3 American Medical Association 2 National Institute for Health and Clinical Excellence 4 1. 2. 3. 4. World Health Organization. Mayo report on addressing the worldwide tobacco epidemic through effective, evidence-based treatment. Report of an expert meeting, March 1999, Rochester (Minnesota) USA. Available at: http: //www. who. int/tobacco/resources/publications/mayo/en/print. html. Accessed July 2006. American Cancer Society. Tobacco control strategy planning, companion guide #2: Engaging doctors in tobacco control. Available at: http: //strategyguides. globalink. org/doctors. htm. The American Academy of Family Physicians. Tobacco use, prevention and cessation. Available at: http: //www. aafp. org/online/en/home/policy/policies/t/tobacco. printerview. html. National Institute for Health and Clinical Excellence. Brief interventions and referral for smoking cessation in primary care and other settings. Available at: www. nice. org. uk/page. aspx? o=299611.

US PHS Guideline – Treating Tobacco Use and Dependence: 2008 Update Tobacco Dependence Support US PHS Guideline – Treating Tobacco Use and Dependence: 2008 Update Tobacco Dependence Support – The “ 5 A’s” ASK about tobacco USE ADVISE tobacco users to QUIT ASSESS READINESS to make a quit attempt ASSIST with the QUIT ATTEMPT ARRANGE FOLLOW-UP care

US PHS Guideline – Treating Tobacco Use and Dependence: 2008 Update First-line Pharmacotherapies for US PHS Guideline – Treating Tobacco Use and Dependence: 2008 Update First-line Pharmacotherapies for Tobacco Dependence 1 Nicotine replacement therapy (NRT) Patch Gum Inhaler Nasal spray Sublingual tablets/lozenges Bupropion SR Champix (Varenicline) § All decrease cravings, withdrawal § 20 -25% quit rates at 1 year 1. Fiore MC, et al. Clinical Practice Guideline. Treating Tobacco Use and Dependence: 2008 Update. USDHHS. PHS. Rockville, MD. 2008.

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(varenicline) A Selective 4 2 Nicotinic Acetylcholine Receptor Partial Agonist (varenicline) A Selective 4 2 Nicotinic Acetylcholine Receptor Partial Agonist

Champix (varenicline): A Highly Selective 4 2 Receptor Partial Agonist Nicotine Varenicline Binding of Champix (varenicline): A Highly Selective 4 2 Receptor Partial Agonist Nicotine Varenicline Binding of nicotine at the 4 2 nicotinic receptor in the Ventral Tegmental Area (VTA) is believed to cause large amounts of dopamine to be released at the Nucleus Accumbens (n. Acc) Binding of nicotine at the 4 2 nicotinic receptor in the Ventral Tegmental Area (VTA) is believed to cause release of dopamine at the Nucleus Accumbens (n. Acc) Varenicline is an 4 2 nicotinic receptor partial agonist, a compound with dual agonist and antagonist activities. This is believed to result in both a lesser amount of dopamine release from the VTA at the n. Acc as well as the prevention of nicotine binding at the 4 2 receptors 1. Coe JW et al. Presented at the 11 th Annual Meeting and 7 th European Conference of the Society for Research on Nicotine and Tobacco. 2005. Prague, Czech Republic. 2. Picciotto MR et al. Nicotine Tob Res. 1999; Suppl 2: S 121 -125.

Champix (varenicline) Efficacy Measurements: Continuous Abstinence Rate (%) CO-Confirmed 4 -Wk Continuous Abstinence Rates Champix (varenicline) Efficacy Measurements: Continuous Abstinence Rate (%) CO-Confirmed 4 -Wk Continuous Abstinence Rates Wks 9– 12 100 P < 0. 001 60 P < 0. 001 40 44. 0 P < 0. 001 P = 0. 001 43. 9 P < 0. 001 29. 8 29. 5 20 17. 7 0 n=352 n=329 17. 6 n=344 Gonzales et al. Varenicline n=342 n=341 Jorenby et al. Bupropion SR Placebo The 9 -12 week Continuous Abstinence Rate is defined as the percentage of subjects who abstained from smoking (not even a puff) from Week 9 through 12 of the study as confirmed by both subject self-report and by end-expiratory carbon monoxide (CO) measurement 1. Gonzalez D et al. JAMA. 2006; 296: 47 -55. 2. Jorenby DE et al. JAMA. 2006; 296: 56 -63.

Prevention of smoking Prevention of smoking

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