Πφζν αζθαιή είλαη ηα θάξκαθα δηαθνπήο ηνπ θαπλίζκαηνο; Βαξεληθιίλε ζην νμχ ηζραηκηθφ ζχλδξνκν. Έρεη ζέζε; Γεψξγηνο. Γθνπκάο MD, PhD, FESC Αλ. Γηεπζπληήο Β Καξδηνινγηθήο Κιηληθήο, Δπξσθιηληθή Αζελψλ Μέινο Γηνηθεηηθνχ πκβνπιίνπ ΔΚΘΑ
ΓΖΛΩΖ ΤΓΚΡΟΤΖ ΤΜΦΔΡΟΝΣΩΝ Κακία ζρεηηθή κε ηε ζπγθεθξηκέλε νκηιία
Σν θάπληζκα είλαη κηα ρξφληα λφζνο Οη πεξηζζφηεξνη αζζελείο πνπ πξνζπαζνχλ λα θφςνπλ ην θάπληζκα δελ ζα πεηχρνπλ απνρή 6 κελψλ θαη ζα ππνηξνπηάζνπλ, ελψ θαη νη κηζνί απφ απηνχο πνπ απέρνπλ απφ ην θάπληζκα ζηνπο 6 κήλεο ζα ππνηξνπηάζνπλ κέζα ζηα επφκελα 8 ρξφληα. Ληγφηεξνη απφ ην 5% πνπ πξνζπαζνχλ λα δηαθφςνπλ ην θάπληζκα εμαθνινπζνχλ λα απέρνπλ 1 ρξφλν κεηά.
Φαξκαθεπηηθή αγσγή γηα ηε δηαθνπή ηνπ θαπλίζκαηνο Οη θιηληθνί ηαηξνί ζα πξέπεη λα ελζαξξχλνπλ φια ηα πξφζσπα πνπ επηρεηξνχλ λα δηαθφςνπλ ην θάπληζκα λα ρξεζηκνπνηνχλ απνηειεζκαηηθά θάξκαθα γηα ηε ζεξαπεία ηεο εμάξηεζεο απφ ηελ ληθνηίλε εθηφο αλ ππάξρεη αληέλδεημε ή αλ πξφθεηηαη γηα εηδηθνχο πιεζπζκνχο, γηα ηνπο νπνίνπο δελ ππάξρνπλ επαξθή ζηνηρεία γηα ηελ απνηειεζκαηηθφηεηα ηνπο (level of evidence Α) US Department of Health and Human Services, Public Health Service, 2008 www.surgeongeneral.gov/tobacco/treating_tobacco_use08.pdf
ACS in Smokers Morbidity and mortality are substantially increased among patients who continue to smoke following hospitalization for an acute coronary syndrome (ACS) 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 U.S. Department of Health and Human Services. The Health Consequences of Smoking: A Report of the Surgeon General. 2004. Eisenberg MJ, et al. J Am Coll Cardiol. 2013;61:524 532.
ACS in Smokers Hospitalization for an acute cardiovascular event provides an important opportunity for quitting smoking. Smokers are often strongly motivated to quit because the risks of smoking are now personal. Most hospitals are smoke-free, requiring smokers to stop smoking at least temporarily. So the question is, can you prevent them from relapsing once they leave? The duration of hospitalization for acute myocardial infarction is usually brief and the hospital stay is busy, so it is difficult to gain the patient s full attention for smoking-cessation counseling
ACS in Smokers Some clinicians are hesitant to add a smoking-cessation medication on top of a number of other medications that have been initiated or continued in the context of myocardial infarction and other medical conditions. Clinicians also may be concerned about the safety of smokingcessation medications in patients with heart disease.
Οη κεραληζκνί δξάζεο ηεο ληθνηίλεο ζηνλ εγθέθαιν Ζ ληθνηίλε ζπλδέεηαη ζηνπο α4β2 ληθνηηληθνχο ππνδνρείο ηεο αθεηπιρνιίλεο θαη ππξνδνηεί ηελ έθθξηζε ληνπακίλεο Απηφ έρεη ζαλ απνηέιεζκα ην αίζζεκα ηθαλνπνίεζεο πνπ ζρεηίδεηαη κε ην θάπληζκα 4 2 2 2 4 NIC Ζ ειάηησζε ησλ επηπέδσλ ηεο ληθνηίλεο ζηνλ εγθέθαιν νδεγεί ζην ζχλδξνκν ηεο ζηέξεζεο απφ ηε ληθνηίλε α4β2 Υποδοχείς νικοτίνης NIC νικοτίνη ντοπαμίνη
Τπνθαηάζηαηα Νηθνηίλεο (διάρκεια θεραπείας 8-12 εβδομάδες, max=1 έτος) Διαδερμική χρήςη (αυτοκόλλητα) Patch 16h: 15, 10 ή 5mg Patch 24h: 21, 14 ή 7mg Τςίχλεσ 2 ή 4mg/τεμάχιο Ειςπνεόμενα Inhaler: 10mg Nasal spray: 10mg /ml, 0,5mg/ψεκαςμό Υπογλώςςια διςκία 1, 2 ή 4mg / διςκίο
Τπνθαηάζηαηα ληθνηίλεο (NRT) Υξήζηκν εξγαιείν γηα ππνθαηάζηαζε ηεο ληθνηίλεο αθνχ κεηψλεη ηα ζπκπηψκαηα ζηέξεζεο ΕΠΙΛΟΓΕΣ αστοκόλλητο Τσίτλα, εισπνεσστήρας, σπογλώσσιο, καραμέλα Σπρέϋ μύτης Αργή απορρόυηση Ελεγτόμενη απορρόυηση Τατεία απορρόυηση 12 εβδομάδες
Δπίπεδα ληθνηίλεο (ηζηγάξν vs ππνθαηάζηαζηαηα) Adapted from Sweeney et al. 1. Sweeney CT et al. CNS Drugs 2001; 15:453-467. 2. Stead LF et al. Cochrane Database of Systematic Reviews 2008
Τπνθαηάζηαηα Νηθνηίλεο: Παξελέξγεηεο Ξηροςτομία ςτεγνόσ λαιμόσ Δερματικοί ερεθιςμοί εφιάλτεσ Λόξυγκασ Ναυτία Κεφαλαλγία Αίςθημα παλμών West R. Thorax 2000;55:987-99
Τπνθαηάζηαηα Νηθνηίλεο (NRT) Nicotine medications increase heart rate, blood pressure, and myocardial contractility and have the potential to cause endothelial dysfunction and coronary vasoconstriction
Τπνθαηάζηαηα Νηθνηίλεο (NRT) Όρη κεηά απφ πξφζθαην ΔΜ αζηαζή ζηεζάγρε επηθίλδπλεο γηα ηε δσή αξξπζκίεο Ναη ζηαζεξή ζηεθαληαία λφζνο Αλ θαη απνηειεί ζπλεζηζκέλε πξαθηηθή ηφζν ζηελ Ακεξηθή φζν θαη ζηηο Δπξσπατθέο ρψξεο ε ρνξήγεζε NRT ζε αζζελείο κεηά απφ νμχ ζηεθαληαίν ζχλδξνκν, σζηφζν δελ ππάξρνπλ ηπραηνπνηεκέλεο κειέηεο.
Τπνθαηάζηαηα Νηθνηίλεο OEM >30 000 ρξήζηεο NRT -861 κε ηζηνξηθό CVD -506 κε ηζηνξηθό ΑΕΕ AEE ηηο 56 πξψηεο εκέξεο απφ ηελ έλαξμε ηεο ζεξαπείαο ν θίλδπλνο γηα KA ζπκβάκαηα δελ απμήζεθε ζεκαληηθά Hubbard et al Tobacco Control 2005
NRT was prescribed on hospital discharge NRT use after ACS was not associated with an increased risk of adverse cardiovascular events Woolf Κ. Am J Cardiol 2012
Τπνθαηάζηαηα Νηθνηίλεο Γηαηί ε NRT ιηγφηεξν επηθίλδπλε απφ ην θάπληζκα; -Μηθξόηεξε αύμεζε ηωλ επηπέδωλ ληθνηίλεο ζπγθξηηηθά κε ην θάπληζκα. - Δελ απμάλνληαη ηα επίπεδα ηνπ κνλνμεηδίνπ ηνπ άλζξαθα θαη δελ ηξνπνπνηείηαη ε πεθηηθόηεηα πνπ απνηεινύλ ηνπο θύξηνπο κεραληζκνύο αύμεζεο ηωλ ΚΑ ζπκβακάηωλ ιόγω ηνπ θαπλίζκαηνο Benowitz et al. J Am Coll Cardiol 1997 - Παξόιν πνπ ε ρξεζηκνπνίεζε NRT είλαη ιηγόηεξν επηθίλδπλε ζε ζρέζε κε ην θάπληζκα, ν θίλδπλνο πνπ ζρεηίδεηαη κε NRT, δελ πξέπεη λα ππνεθηηκάηαη ζε αζζελείο κε κεηωκέλε ζηεθαληαία εθεδξεία θαη απμεκέλν θίλδπλν εκθάληζεο επεηζνδίωλ ηζραηκίαο
Βνππξνπηφλε SR (Zyban ) κε ληθνηηληθφ δηζθίν παξαηεηακέλεο απνδέζκεπζεο γηα ηε δηαθνπή ηνπ θαπλίζκαηνο αλαπηχρζεθε αξρηθά σο αληηθαηαζιηπηηθφ, ζηε ζπλέρεηα βξέζεθε φηη είλαη απνηειεζκαηηθφ γηα ηε δηαθνπή ηνπ θαπλίζκαηνο 2 πηζαλνί κεραληζκνί δξάζεο: αλαζηνιή επαλαπξφζιεςεο ληνπακίλεο Με αληαγσληζηηθή αλαζηνιή ησλ 3 2 θαη 4 2 ληθνηηληθψλ ππνδνρέσλ 1. Ένθετο Σσσκεσασίας. bupropion SR hydrocloride [Zyban ]. GlaxoSmithKline. 2. Henningfield JE, et al. CA Cancer J Clin. 2005;55:281 299. 3. Foulds J, et al. Expert Opin Emerg Drugs. 2004;9:39 53. 4. Slemmer JE, et al. J Pharmacol Exp Ther. 2000;295:321 327. 5. Roddy E. Br Med J. 2004;328:509 511.
Αληελδείμεηο Βνππξνπηφλεο Έγθπκνζχλε - ζειαζκφο Δπηιεςία φγθνη ΚΝ Ζιηθία <18 εηψλ Γηπνιηθή δηαηαξαρή Κίξξσζε Υξήζε αλαζηνιέσλ ΜΑΟ εληφο 14 εκεξψλ Αλνξεμία -βνπιηκία
Παξελέξγεηεο Βνππξνπηφλεο Αυπλία (35 40 %) Ξεξνζηνκία (10 %) Αχμεζε ηεο αξηεξηαθήο πίεζεο Κεθαιαιγία Ρηλίηηδα Ναπηία Εάιε Νεπξνςπρηαηξηθέο δηαηαξαρέο
Υνξήγεζε βνππξνπηφλεο θαηά ηε δηάξθεηα ηεο λνζειείαο θαη γηα 8 εβδνκάδεο Γελ παξαηεξήζεθε αχμεζε ησλ θιηληθψλ ζπκβακάησλ ή αχμεζε ηεο πίεζεο Η βνππξνπηόλε δελ αύμεζε ην πνζνζηό απνρήο από ην θάπληζκα. Η πηζαλόηεηα δηαθνπήο ηνπ θαπλίζκαηνο απμαλόηαλ ζε απηνύο πνπ θαηά ηε δηάξθεηα ηεο λνζειείαο ηνπο αληηκεηωπίζηεθαλ επεκβαηηθά θαη κεηωλόηαλ ζε απηνύο πνπ εκθάληζαλ παξελέξγεηεο από ηε βνππξνπηόλε (πρ δαιάδα) Planer et al. Arch Intern Med. 2011
Champix (βαξεληθιίλε):ηδηαίηεξα Δθιεθηηθφο Μεξηθφο Αγσληζηήο ηνπ 4 2 Τπνδνρέα Νηθνηίλε Champix Δπηθιηλήο ππξήλαο (nacc) Κνηιηαθφ θαιππηξηθφ πεδίν (VTA) Νηθνηίλε Νηνπακίλε Ζ πξφζδεζε ηεο ληθνηίλεο ζηνλ 4 2 ληθνηηληθφ ππνδνρέα ζην VTA πηζηεχεηαη φηη πξνθαιεί ηελ απειεπζέξσζε ληνπακίλεο Δπηθιηλήο ππξήλαο (nacc) Κνηιηαθφ θαιππηξηθφ πεδίν (VTA) Νηθνηίλε Νηνπακίλε πηζηεχεηαη φηη νδεγεί απνδέζκεπζε ρακειφηεξεο πνζφηεηαο ληνπακίλεο πξφιεςε ηεο πξφζδεζεο ληθνηίλεο ζηνπο 4 2 ππνδνρείο κεηψλεη ηελ επηζπκία θαη ηα ζπκπηψκαηα ζηέξεζεο (δξάζε αγσληζηή) κεηψλεη ηελ αίζζεζε επηβξάβεπζεο θαη ησλ εληζρπηηθψλ επηδξάζεσλ ηνπ θαπλίζκαηνο (δξάζε αληαγσληζηή)
Hypothetical effects of smoking on Dopamine release: effect of a partial agonist Response to nicotine Smoking NRT + smoking Partial agonist + smoking = cigarette smoked Time
Αληελδείμεηο Βαξεληθιίλεο Έγθπκνζχλε ζειαζκφο Ζιηθία <18 εηψλ Δπηιεςία φγθνη ΚΝ Νεθξηθή αλεπάξθεηα Νεπξνςπρηαηξηθέο δηαηαξαρέο
Πξνζαξκνγή ηεο Γφζεο ζε Δηδηθνχο Πιεζπζκνχο Αζζελείο κε λεθξηθή αλεπάξθεηα Κακία πξνζαξκνγή ηεο δνζνινγίαο δελ είλαη απαξαίηεηε γηα αζζελείο κε ήπηα έωο κέηξηα λεθξηθή δπζιεηηνπξγία Γηα αζζελείο κε κέηξηα λεθξηθή δπζιεηηνπξγία, νη νπνίνη εκθαλίδνπλ αλεπηζύκεηεο ελέξγεηεο πνπ δελ κπνξνύλ λα γίλνπλ αλεθηέο, ε δνζνινγία κπνξεί λα ειαηηωζεί ζε 1 mg άπαμ εκεξεζίωο Γηα αζζελείο κε ζνβαξή λεθξηθή δπζιεηηνπξγία, ε ζπληζηώκελε δόζε είλαη 1 mg/εκέξα. Η δνζνινγία ζα πξέπεη λα μεθηλά κε 0,5 mg άπαμ εκεξεζίωο γηα ηηο πξώηεο 3 εκέξεο θαη ζηε ζπλέρεηα λα απμάλεηαη ζε 1 mg άπαμ εκεξεζίωο. Σε αζζελείο κε λεθξνπάζεηα ηειηθνύ ζηαδίνπ, δελ ζπληζηάηαη ε ρνξήγεζε ζεξαπείαο Αζζελείο κε επαηηθή δπζιεηηνπξγία Κακία πξνζαξκνγή ηεο δνζνινγίαο δελ είλαη απαξαίηεηε
Παξελέξγεηεο βαξεληθιίλεο Ναπηία Γηαηαξαρέο χπλνπ Κεθαιαιγία δάιε Γηαηαξαρή ζπγθέληξσζεο Μεηεσξηζκφο Γπζθνηιηφηεηα Νεπξνςπρηαηξηθέο δηαηαξαρέο?
Varenicline and suicidal behaviour: a cohort study based on data from the General Practice Research Database BMJ 2009;339:b3805
FDA Drug Safety Communication: Safety review update of Chantix (varenicline) and risk of neuropsychiatric adverse events 24-10-2011 The FDA has reviewed the results from two FDA-sponsored epidemiological studies that evaluated the risk of neuropsychiatric adverse events associated with the smoking cessation drug Chantix (varenicline). Neither study found a difference in risk of neuropsychiatric hospitalizations between Chantix and nicotine replacement therapy
FDA Drug Safety Communication: Safety review update of Chantix (varenicline) and risk of neuropsychiatric adverse events 24-10-2011 Although these two studies did not suggest an increased risk of neuropsychiatric events that result in hospitalization, they do not rule out an increased risk of other neuropsychiatric events with Chantix. Healthcare professionals and patients should continue to follow the recommendations in the physician label and the patient Medication Guide, and to monitor for neuropsychiatric symptoms when prescribing or using Chantix.
Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis 1% vs 0.8% CMAJ 2011;10.1503
CMAJ Hays Commentary CMAJ July 2011 Δίλαη ε βαξεληθιηλε έλα αζθαιέο θάξκαθν? Γηάθνξεο ηπραηνπνηεκέλεο θιηληθέο κειέηεο θαη κεηα-αλαιχζεηο αλαθέξνπλ φηη είλαη. Δίλαη ε βαξεληθιίλε έλα αθίλδπλν θάξκαθν? αθψο φρη, φπσο παξνπζίαζε ε κεηα-αλάιπζε απηή ηνπ Singh. Ωζηφζν, ν θίλδπλνο εκθάληζεο ζνβαξψλ Κ/Α ζπκβακάησλ είλαη κηθξφο, θαη αληηζηαζκίδεηαη ζε κεγάιν βαζκφ απφ ηα νθέιε ηεο κείσζεο ησλ πξαγκαηηθά επηβιαβψλ επηδξάζεσλ ηνπ θαπλίζκαηνο
FDA Drug Safety Communication (June 16, 2011) Ο FDA ελεκέξσζε ην θνηλφ φηη ην Chantix (varenicline) κπνξεί λα ζρεηίδεηαη κε έλαλ κηθξφ, απμεκέλν θίλδπλν θάπνησλ Κ/Α αλεπηζχκεησλ ελεξγεηψλ ζε αζζελείο κε Κ/Α λφζν. Ο FDA ζπλερίδεη λα αμηνινγεί ηελ Κ/Α αζθάιεηα ηνπ Chantix θαη δεηά απφ ηε Pfizer λα δηεμάγεη κία κεγάιε, ζπλδπαζηηθή αλάιπζε (κεηά-αλάιπζε) ησλ ηπραηνπνηεκέλσλ, ειεγρφκελσλ κε εηθνληθφ θάξκαθν θιηληθψλ κειεηψλ. Ο FDA ζα ελεκεξψζεη ην θνηλφ φηαλ ππάξμεη θάπνηα επηπξφζζεηε πιεξνθνξία ζρεηηθά. Οη εγθεθξηκέλεο νδεγίεο ηνπ θαξκάθνπ ζηελ Ακεξηθή έρνπλ αλαλεσζεί (July 2011) Πεξηιακβάλνπλ ηα δεδνκέλα απνηειεζκαηηθφηεηαο ηεο βαξεληθιίλεο ζηε δηαθνπή ηνπ θαπλίζκαηνο ζε αζζελείο κε Κ/Α λφζν Έρεη πξνζηεζεί ζπκβνπιή ζηνπο αζζελείο κε Κ/Α λφζν λα πιεξνθνξνχλ ηνπο ηαηξνχο ηνπο γηα νπνηαδήπνηε αιιαγή παξαηεξήζνπλ σο πξνο ηα Κ/Α ζπκπηψκαηα θαηά ηε δηάξθεηα πνπ ιακβάλνπλ ην CHANTIX θαη λα θαινχλ ηα επείγνληα ακέζσο εάλ παξαηεξήζνπλ ζπκπηψκαηα θαξδηαθήο πξνζβνιήο (ΔΜ)
-Πεξηζζφηεξεο Μειέηεο -Γηαθνξά ζηε Μεζνδνινγία, πρ εμεηάζηεθαλ κφλν ηα ζπκβάκαηα θαηά ηε δηάξθεηα ηεο ζεξαπείαο The absolute difference in risk for the primary outcome did not reach statistical significance (risk difference = 0.27%, 95% CI - 0.10% to 0.63%). Prochaska et al BMJ 2012
1) the study end points were pre-specified 2) the composite end point focused on ischemic events; 3) all serious CV events were adjudicated by an independent adjudication committee blind to treatment assignment 4) subject-level data were available, making it possible to conduct a time-to-first-event analysis rather than a metaanalysis of summary data.
HR analysis for MACE+ for treatment plus 30 days Νεώτερα δεδομένα Ware J et al. Am J of Therapeutics 2013 MACE+: MACE plus new onset, worsening or any procedure for peripheral vascular disease, hospitalization for unstable angina, and performance of coronary revascularization.
Lancet Respir Med 2015 3:761-68
% abstinents patients Varenicline in combination with intense individual counselling for smoking cessation in patients with an acute coronary syndrome Goumas G, Athanassias D, Kribas P,, Alexopoulos N, Papamichail N, Roumeliotaki G, Richter D. 2 nd Cardiology Department, Athens Euroclinic Background and Aims Smoking is a major risk factor for coronary artery disease (1) while acute coronary syndromes are the most dangerous manifestation of atherosclerosis. Individual counselling for smoking cessation during and after hospitalization has shown limited efficacy (2). We examined the efficacy of varenicline in combination with an intensive individual counselling program for smoking cessation for patients admitted to our hospital with a diagnosis of acute coronary syndrome. Methods 56 sequential patients (mean age 52.4 y, all white, 40 male, 16 female) with unstable angina or acute myocardial infarction (NSTEMI or STEMI) were included in the study. Treatment with varenicline was initiated in all patients on the second day of their admission and was also prescribed along with their other medication after their discharge (0.5 mg once daily for 3 days, 0.5 mg twice daily for 4 days, and then 1.0 mg twice daily for a total of 12 weeks), the quitting patients were given a second three months varenicline treatment period to prevent relapses. Furthermore, all patients underwent intensive individual counselling program which included 30 minutes ofbedside counselling twice during hospitalisation (2 nd day and day of discharge), printed material with advices, 30 minutes counselling during their reevaluation visits at our outpatient cardiology department, 1 and 3 months after hospitalization and 6 nurse-initiated counselling calls. Figure 1. Abstinence rate at 1, 3 and 6 months 80 70 60 50 40 30 20 10 0 76 71 71 1 month 3 months 6 months References 1. Critchley JA, Capewell S. Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: a systematic review. JAMA. 2003;290:86 97. 2. Hajek P, Taylor TZ, Mills P. Brief intervention during hospital admission to help patients to give up smoking after myocardial infarction and bypass surgery: randomised controlled trial. BMJ 2002;324:87-9. Treatment with varenicline continued after month 3 only in those who had stopped smoking. Smoking behaviour was assessed by self-report 1, 3 and 6 months after hospitalization. The prevalence of abstinence at 1, 3 and 6 months after hospital discharge was the primary outcome of our study. Results During 6 months of follow-up, one patient died (death not related to varenicline) and one was lost to followup. Among 54 remaining patients, the rate of abstinence (fig.1) was 76 % at 1 month, 71 % at 3 months and it remained 71 % through 6 months after their hospitalization. Among the 56 patients, 48 underwent coronary vascularisation (41 PTCA, 7 CABG). All 7 patients that underwent CABG quit smoking. In this population of ACS varenicline was well tolerated: 14 patients reported nausea and 3 reported insomnia, but no one discontinued treatment because of the side effects. Varenicline administration showed to be as safe and probably better tolerated than in the general population. Conclusion The combination of varenicline with an intensive individual counselling program appears to be an extremely efficient policy for smoking cessation after an acute coronary syndrome, but also a safe one.
Study Design EV TA Multicenter 40 Canadian and US centers Double-blind Randomized Placebo-controlled Investigator-initiated Funding & study drug/placebo from Pfizer Inc. No role in design, conduct, analysis, or reporting
Trial Schematic EV TA Varenicline for 12 Weeks Smokers Hospitalized for ACS Informed Consent & Eligibility Assessment Randomization Baseline Visit & 1 st Dose In-Hospital Placebo for 12 Weeks Follow-Up Visits Telephone: Weeks 1, 2 & 8 Clinic: Weeks 4, 12 & 24 Primary Endpoint Smoking abstinence at Week 24 Low-Intensity Counselling at Baseline & All Follow-Up Contacts
Inclusion/Exclusion EV TA Main Inclusion Criteria Age 18 years and motivated to quit smoking Smoke 10 cigarettes/day on average in the past year Hospitalized with ACS Main Exclusion Criteria History of neuropsychiatric disorders Prior varenicline use, or use of smoking cessation pharmacotherapy at the time of ACS Cardiogenic shock or renal impairment at randomization Hepatic impairment prior to ACS Excessive alcohol use, or current use of: marijuana, noncigarette tobacco products, OTC stimulants or anorectics
Endpoints EV TA Primary Endpoint (ITT) 7-day point prevalence abstinence at week 24 Self-reported abstinence in past week and exhaled CO 10 ppm Secondary Endpoints (ITT) Continuous abstinence at week 24 Self-reported abstinence since baseline and exhaled CO 10 ppm at all follow-up visits up to and including week 24 50% reduction in daily cigarette consumption at week 24 Safety Endpoints Side effects, SAEs, MACE, neuropsychiatric events SAEs adjudicated by an EEC (blinded to treatment status) Trial monitored by an external DSMB
Trial Flow EV TA Patients Randomized n=302 Varenicline n=151 Placebo n=151 Treatment Weeks 1-12 Died n=2 Withdrew Consent n=9 Lost to Follow-Up n=16 Died n=0 Withdrew Consent n=10 Lost to Follow-Up n=18 Follow-Up Weeks 13-24 Died n=1 Withdrew Consent n=0 Lost to Follow-Up n=5 Died n=0 Withdrew Consent n=2 Lost to Follow-Up n=7 Week 24 Smoking Status for ITT Analysis* n=148 Smoking Status for ITT Analysis* n=151 * Assumed that patients who withdrew or who were lost to follow-up returned to smoking at their baseline rate
Primary Endpoint EV TA 100 80 p<0.001 Varenicline Placebo p<0.001 NNT: 6.8 7-Day Point Prevalence Smoking Abstinence (%) 60 40 60,0 57,7 37,7 36,4 p=0.012 47,3 32,5 20 0 4 weeks 12 weeks 24 weeks Primary Endpoint
Safety Endpoints EV TA SAEs Within 30 Days of Treatment Discontinuation, n (%) Varenicline (n = 151) Placebo (n = 151) P- Value Patients with any SAE 18 (11.9) 17 (11.3) >0.99 Composite MACE 6 (4.0) 7 (4.6) >0.99 Death 2 (1.3) 0 0.50 Myocardial infarction 3 (2.0) 3 (2.0) 1.00 Unstable angina 1 (0.7) 5 (3.3) 0.21 Other cardiovascular events 3 (2.0) 2 (1.3) >0.99 Neuropsychiatric events Seizure, suicidal ideation 0 0 ---- Other 1 (0.7) 0 >0.99 Other 9 (6.0) 8 (5.3) >0.99 Most Common Side Effects 12-Week Cumulative, n (%) Insomnia 27 (17.9) 19 (12.6) 0.26 Nausea 21 (13.9) 13 (8.6) 0.20 Abnormal dreams 23 (15.2) 7 (4.6) <0.01
Limitations EV TA Only enrolled patients motivated to quit smoking Smoking abstinence rates likely optimistic vs. real-world Small sample size Limits ability to definitively address the cardiovascular safety of varenicline Smokers represent a challenging patient population As with other smoking cessation trials, a not insubstantial number of patients withdrew or were lost to follow-up Low-intensity counseling High-intensity counselling could have improved quit rates
ACS in Smokers Managing withdrawal with nicotine-replacement therapy inhospital in the context of ACS is extremely important in addition to, based on EVITA trial, starting varenicline to prevent relapse Varenicline will reduce the craving for cigarettes, but the impact is not immediate. Using nicotine-replacement therapy will immediately affect that craving. So the combination of the two may be very powerful.
ACS in Smokers Effective counseling in the hospital for all smokers Effective transition from inpatient to outpatient smoking cessation treatment, with a minimum of 1-month follow-up and preferably longer Personalized prescription of medication Management of co-occurring mental health conditions, such as depression
ACS in Smokers Beyond short-term, acute-care measures, smoking-cessation treatment should be consistent with a chronic disease model, similar to management of other diseases, such as hypertension and diabetes. At present, the quit rates for smokers after myocardial infarction are higher than those for the general population of smokers, yet given the enormous health risks, still much too low.
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