Η θέση της ασπιρίνης στην πρωτογενή πρόληψη

Η θέση της ασπιρίνης στην πρωτογενή πρόληψη Γενοβέφα Κολοβού, MD, PhD, FESC, SFASA, FRSH Διευθύντρια Καρδιολογικού Τομέα Υπεύθυνη Εξωτερικών Ιατρείων και Προληπτικής Καρδιολογίας Υπεύθυνη Λιπιδαιμικού Ιατρείου και Μονάδας LDL Αφαίρεσης Ωνάσειο Καρδιοχειρουργικό Κέντρο

Δήλωση σύγκρουσης συμφερόντων Τα τελευταία 2 χρόνια Συμμετοχή στις μελέτες με: MIPO, PSCK9 Attended conferences, advisory boards and gave talks sponsored by MSD, Astra Zeneca, Abbott, Amgen, Sanofi, Lilly, ELPEN Chairperson: Expert Panel on 1. Postprandial Lipemia, 2. Longevity Syndrome

Η θέση της ασπιρίνης στην πρωτογενή πρόληψη Ιστορικά δεδομένα Δράση Χορήγηση Αντίσταση Οδηγίες

Ιστορικά Δεδομένα Ιπποκράτης 4 ος π. Χ. αιώνας Συνιστά ως ίαμα κατά του πυρετού και των πόνων ουσία που περιέχεται στον φλοιό της Ιτιάς (Salix) και ονομάζεται σαλικίνη

Ιστορικά Δεδομένα >100 έτη χρήσης της ασπιρίνης Αντιπυρετικό Αναλγητικό Πρόληψη ΚΑΝ (τελευταίες δεκαετίες)

Ιστορικά Δεδομένα 1763, Stone ΟE περιγράφει σκόνη από το φλοιό της Ιτιάς με αντιπυρετικές ιδιότητες 1828, Buchner ΟJ αναφέρεται σε μια κίτρινη, πικρή κρυσταλλική σκόνη και την ονομάζει σαλικίνη 1853, Gerchard OCF είναι ο πρώτος που παρασκευάζει το ακετυλοσαλικυλικό οξύ αναμιγνύοντας ακετυλοχλωρίδιο με σαλικυλικό Να

Ιστορικά Δεδομένα 1897, Hoffmann F, χημικός της γερμανικής εταιρείας Bayer, άρχισε την έρευνα πάνω στο ακετυλοσαλικυλικό οξύ 1900, η Bayer είχε δημιουργήσει νέο φάρμακο και το κυκλοφορεί στο εμπόριο με την επωνυμία "Ασπιρίνη". Οι πωλήσεις εκτοξεύονται 1915, κυκλοφορεί σε δισκία 1919, σπάει η πατέντα της ασπιρίνης

Ιστορικά Δεδομένα 1948, ο Craven L παρατηρεί ότι κανείς από τους 400 ασθενείς του, στους οποίους είχε χορηγήσει ασπιρίνη, δεν είχε υποστεί καρδιακή προσβολή. Καταλήγει στο συμπέρασμα ότι "μια ασπιρίνη την ημέρα" μπορεί να μειώσει σημαντικά τον κίνδυνο καρδιακής προσβολής 1950, οι πωλήσεις της ασπιρίνης γνωρίζουν σημαντική πτώση, λόγω κυκλοφορίας της παρακεταμόλης

Ιστορικά Δεδομένα 1 ο σκεύασμα Ασπιρίνης (1899) Διαφήμιση (1923)

Βραβείο Nobel Ιατρικής 1982 Sir John Vane Για την ανακάλυψη του τρόπου δράσης της ασπιρίνης

Φαρμακοκινητική της ασπιρίνης Ταχεία απορρόφηση από το γαστρεντερικό με peak επιπέδων στο πλάσμα σε 30-40 Χρόνος ημίσειας ζωής 20 Mόνιμη δράση στα PLT σε 60 από τη λήψη

Vascular disorders for which Aspirin has been shown to be effective Disorder Lowest Effective Daily Dose in mg TIA and ischemic stroke * 50 Men at high cardiovascular risk 75 Hypertension 75 Stable angina 75 Unstable angina * 75 Severe carotid artery stenosis * 75 Polycythemia vera 100 Acute MI 160 Acute ischemic stroke * 160 *Higher doses have been tested and were not found to confer any greater risk reduction

Aspirin Efficacy - Plays an important role in primary and secondary prevention of CV events - Effective for AMI treatment (ISIS-2, mortality by 23%

ISIS2 (162.5mg ASA within 24h of the onset of a suspected MI and continued daily for 5weeks) shown: risk of CVD mortality 23% Non fatal reinfraction 49% Non fatal stroke 46% Treatment of 1,000 pts with suspected MI for 5weeks in ~ 40 pts CV event will be prevented (odds reduction 30%)

Lancet. 2009;373:1849 1860

Event free survival curves in patients with and without aspirin resistance. J.W. Chu et al. QJM 2010;103:405-412

Αίτια της αντίστασης στην ασπιρίνη Διαταραχές στη φαρμακοκινητική Μη συμμόρφωση, Ακατάλληλη δοσολογία, Αλληλεπίδραση με άλλα φάρμακα όπως NSAIDs και PPIs Κλινικές καταστάσεις Σοβαρή CHD, ACS, HF, CABG, DM, παχυσαρκία, λοιμώξεις, δυσλιπιδαιμίες, υπέρταση Γενετικά αίτια COX-1 γονιδιακή μετάλλαξη, COX-2 υπερέκφραση, GpIIb-IIIa πολυμορφισμοί Μοριακά αίτια παραγωγή των PLT

Έλεγχος για την αντίσταση στην ασπιρίνη In vivo Θρομβοξάνη Β2 στα ούρα Χρόνος ροής Διάρκεια αιμορραγίας μετά από τρύπημα στο δέρμα.

Platelet Function Tests PLT aggregation Flow Cytometry GPIIb/IIIa receptors activation P-selectin expression Monocyte-platelet aggregates Vasodilator-associated stimulated phosphoprotein (VASP) Point-of-care Ultegra rapid PLT function analyzer (Verify Now) Thromboelastagraph (TEG) PLT works Cone and platel(let) analyzer (IMPACT) Genetic testing

The evidence for routine use of aspirin in middle-aged adults who are at increased risk for CHD has been markedly diluted by excellent studies in the last decade Studies done after 2,000 showed no benefit of aspirin, possibly due to greater use of life-saving medication such as statins, ACE inhibitors and beta-blockers

Low-dose aspirin therapy Associated with a 2-fold GI bleeding (absolute risk of 10 to 27 cases/10,000 aspirin user-years Risk of bleeding is: 10-fold chronic kidney disease 4-fold when combined with clopidogrel, anticoagulants, NSAIDS 8-fold with high dose corticosteroids Hernandez-Diaz S, Garcia Rodriguez LA. Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications. BMC Med. 2006;4:22. Garcia Rodriguez LA, Lin KJ, Hernandez-Diaz S, Johansson S. Risk of upper gastrointestinal bleeding with lowdose acetylsalicylic acid alone and in combination with clopidogrel and other medications. Circulation. Mar 15 2011;123(10):1108-1115.

Aspirin for Asymptomatic Atherosclerosis

-When used in the primary prevention, aspirin prevents CVD events by 10%, primarily by a reduction in non-fatal heart attacks by 20%. -There is no significant reduction in CVD or cancer death -but increases hemorrhagic stroke (36%), GI (37%) and major bleeding (66%) -For every heart attack prevented with aspirin, almost 2 major bleeding is produced when given to people without heart disease.

Εκτίμηση του κινδύνου Framingham CHD risk score (1) predicts the 10-year risk of developing a coronary event (composite of MI and coronary death), and individuals are categorized as low (<10%), moderate (10% to 20%), or high (>20%) risk AHA/ACC Task Force risk equations (2) ESC s SCORE (Systematic Coronary Risk Evaluation) estimates the 10-year risk of a fatal atherosclerotic event: low risk with a SCORE <1%, moderate 1%-<5%, high risk 5%-<10%, and at very high 10% (3).

1,000,000 people with low-dose aspirin 1 year prevents 1,300 CVD events causes 14,800 total bleeding events (2,300 major) Routine use of aspirin for primary prevention is not warranted, and treatment decisions need to be considered on a case-by case basis. The risk may even outweigh the benefits among those receiving intensive statin therapy Berger J S, et al. Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: a meta-analysis of randomized trials. Am Heart J 2011;162(1):115-124 e112. Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of Aspirin on Vascular and Nonvascular Outcomes: Metaanalysis of Randomized Controlled Trials. Arch Intern Med. 2012;172(3):209-216

Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of Aspirin on Vascular and Nonvascular Outcomes: Meta-analysis of Randomized Controlled Trials. Arch Intern Med. Feb 13 2012;172(3):209-216

Vandvik P, et al. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th edition: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 141 (2012), pp. e637s e668s Perk J, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J, 33 (2012), pp. 1635 1701 Goff Jr, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 63 (2014), pp. 2935 2959

Aspirin Therapy in Primary Cardiovascular Disease Prevention : A Position Paper of the European Society of Cardiology Working Group on Thrombosis Halvorsen S, Andreotti F, ten Berg J, Cattaneo M, Coccheri S, Marchioli S, Morais J, Verheugt F, De Caterina R. JACC, 2014

ESC guidelines, aspirin or clopidogrel is not recommended in individuals without CVD due to the increased risk of major bleeding (Class III, Level of Evidence: B) American College of Chest Physicians guidelines suggest low-dose aspirin 75 to 100 mg daily for persons 50 y without symptomatic CVD (Grade 2B)* *slightly reduces total mortality regardless of CV risk profile if taken over 10 years. In people at moderate-to-high risk of CV events, the reduction in MIs is closely balanced by an increase in major bleeds, prompting aspirin use in individuals who value preventing an MI substantially more than avoiding a GI bleed

Guidelines for DM American College of Chest Physicians: Relative benefit of aspirin is similar in patients with and without DM. American Diabetes Association, the AHA, and the ACC recommend as follows: Primary CV prevention with aspirin is reasonable in DM pts whose 10-year risk of events is >10% (men >50 ys and women >60 ys + 1 RF: smoking, hypertension, dyslipidemia, albuminuria, or family history of premature CV events) and who are not at increased risk of bleeding (no history of GI bleeding or peptic ulcer, no concurrent use of other medications that increase bleeding risk). Aspirin should not be recommended in DM pts at low risk of CV Aspirin may be considered for DM pts at intermediate risk of CV events (younger patients with 1 RF, older pts with no risk factors, or pts with a 10-year risk of 5% to 10%).

Red =benefit likely equals risk Yellow = uncertainty Green = benefit most likely exceeds risk Continuous line = linear regression dotted line = lower and higher 95% (CI). PHS (Physicians Health Study, BDT (British Doctors Trial), TPT (Thrombosis Prevention Trial), HOT (Hypertension Optimal Treatment) study PPP (Primary Prevention Project), Women s Health Study POPAPDAD study (Prevention of Progression of Arterial Disease and Diabetes), JPAD study AAA (Aspirin for Asymptomatic Atherosclerosis) trial Figure 1. Relationships Between Magnitude of Antithrombotic Benefit and of Bleeding Risk Connected With the Use of Aspirin, and Absolute Cardiovascular Risk, in Various Subsets of Subjects in Primary PreventionTo examine the strength of the association between... Sigrun Halvorsen, Felicita Andreotti, Jurriën M. ten Berg, Marco Cattaneo, Sergio Coccheri, Roberto Marchioli, João Morais, Freek W.A. Verheugt, Raffaele De Caterina Aspirin Therapy in Primary Cardiovascular Disease Prevention : A Position Paper of the European Society of Cardiology Working Group on Thrombosis Journal of the American College of Cardiology, Volume 64, Issue 3, 2014, 319 327 http://dx.doi.org/10.1016/j.jacc.2014.03.049

Arguments for and Against the Use of Aspirin in Primary Prevention Contra Bleeds induced numerically equal ischemic events prevented Bleeds induced have a similar prognostic implication as ischemic events averted Pro Although this may be true in some of the primary prevention studies, this is unlikely to hold for high-risk primary prevention, in which no data are so far available and projections would indicate an NNH higher than the NNT This is, with the exception of the rare occurrence of intracranial hemorrhage (~ 1/5 of all major bleeds), unlikely to be true, as nonfatal ischemic events averted are mostly spontaneous MI and (ischemic) strokes. Patients preferences: most patients would prefer nonfatal major bleeding to a nonfatal myocardial infarction or stroke. Aspirin may cancer in the long-term, extending the benefit beyond CVD prevention, and so far is underestimated in the relatively short follow-up of CVD prevention studies

Arguments for and Against the Use of Aspirin in Primary Prevention Contra Risk estimates based on relatively old charts or algorithms ( Framingham Risk Score, ESC SCORE) may overestimate the current risk of CVD Pro This is an unavoidable limitation of all analyses based on risk calculations. The effect is likely in any case to be minor.

Conclusions Aspirin use in the primary prevention of acute MI and other atherothrombotic CV events in subjects of both sexes is guided by an assessment of the underlying CV risk (Grade of Recommendation: I, Level of Evidence: B) Aspirin be considered in the primary prevention of CVD in both sexes at a level of risk of major CV events (death, MI, and stroke) >2/100 subject-years, provided they have no clear evidence of increased risk of bleeding (GI bleeding or peptic ulcer disease, no concurrent use of other medications that increase bleeding risk) (Class of Recommendation: IIa, Level of Evidence: B).