ΑΣΠΙΡΙΝΗ ΜΙΑ ΕΠΑΝΕΚΤΙΜΗΣΗ

ΑΣΠΙΡΙΝΗ ΜΙΑ ΕΠΑΝΕΚΤΙΜΗΣΗ ΘΩΜΑΣ ΠΑΠΑΔΟΠΟΥΛΟΣ, MD,PhD,FESC,FSCAI,FACC ΕΠΕΜΒΑΤΙΚΟΣ ΚΑΡΔΙΟΛΟΓΟΣ, ΙΑΤΡΙΚΟ ΔΙΑΒΑΛΚΑΝΙΚΟ ΚΕΝΤΡΟ Α.ΕΠ.ΣΥΝΕΡΓΑΤΗΣ ΒΚΚ, ΙΠΠΟΚΡΑΤΕΙΟ, ΓΠΝΘ

ASPIRIN: THE MOLECULE O O O OH acetyl salicylic acid (aspirin)

Η ανάπτυξη της ασπιρίνης: Ιστορική διαδρομή (WILLOW BARK=ΦΛΟΙΟΣ ΙΤΙΑΣ) 500 B.C. Hippocrates bitter powder extracted from willow bark could ease aches, pains and fevers Circulation 2011;123:768-778

THE MOST PLAUSIBLE MECHANISM OF ASPIRIN IN REDUCING RISKS OF CARDIOVASCULAR DISEASE Aspirin irreversibly acetylates the active site of cyclooxygenase, which is required for the production of thromboxane A2, a powerful promoter of platelet aggregation Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action of aspirin like drugs. Nat New Biol. 1971;231:232-5.

Aspirin: Mechanism of action Μη αντιστρεπτή αναστολή της COX-1 αναστολή σχηματισμού TxA 2 αναστολή ενεργοποίησης και συσσώρευσης αιμοπεταλίων

Μηχανισμός αντιαιμοπεταλιακής δράσης της ασπιρίνης Μη αντιστρεπτή αναστολή της COX-1 Αναστολή σχηματισμού του TxA2 Αναστολή ενεργοποίησης των αιμοπεταλίων

ΑΣΠΙΡΙΝΗ ΣΤΗ ΔΕΥΤΕΡΟΓΕΝΗ ΠΡΟΛΗΨΗ ΣΤΑ ΚΑΡΔΙΑΓΓΕΙΑΚΑ ΝΟΣΗΜΑΤΑ

The Primary and Secondary Prevention of Cardiovascular Disease Per Olav Vandvik, MD, PhD A. Michael Lincoff, MD Joel M. Gore, MD David Gutterman, MD, FCCP Frank A. Sonnenberg, MD Pablo Alonso-Coello, MD Elie A. Akl, MD Maarten Lansberg, MD Gordon Guyatt, MD, FCCP Frederick A. Spencer, MD ----- Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Copyright: American College of Chest Physicians 2012

Choice of Long-term Antithrombotic Therapy in Patients With Established Coronary Artery Disease (CAD) For patients with established coronary artery disease (CAD), defined as patients 1-year post-acute coronary syndrome (ACS), with prior revascularization, coronary stenoses > 50% by coronary angiogram, and/or evidence for cardiac ischemia on diagnostic testing, (including patients after the first year post-acs and/or with prior coronary artery bypass graft [CABG] surgery): We recommend long-term single antiplatelet therapy with aspirin 75 to 100 mg daily or clopidogrel 75 mg daily over no antiplatelet therapy (Grade 1A). We suggest single over dual antiplatelet therapy with aspirin plus clopidogrel (Grade 2B).

ΑΣΠΙΡΙΝΗ ΣΤΗ ΔΕΥΤΕΡΟΓΕΝΗ ΠΡΟΛΗΨΗ ΣΤΑ ΝΕΥΡΟΛΟΓΙΚΑ ΝΟΣΗΜΑΤΑ

ΑΣΠΙΡΙΝΗ ΣΤΗΝ ΠΡΩΤΟΓΕΝΗ ΠΡΟΛΗΨΗ ΣΕ ΚΑΡΔΙΑΓΓΕΙΑΚΑ ΝΟΣΗΜΑΤΑ

ACS IS THE TIP OF THE ATHEROTHROMBOTIC ICEBERG ACUTE PLAQUE RUPTURE ACS (UA/NSTEMI/STEMI) CLINICAL SUBCLINICAL PRESENCE OF MULTIPLE CORONARY PLAQUES PERSISTENT HYPERREACTIVE PLATELETS VASCULAR NFLAMMATION ACS, acute coronary syndrome; NSTEMI, non-st segment elevation myocardial infarction; STEMI, ST segment elevation myocardial infarction; UA, unstable angina. Goldstein JA. J Am Coll Cardiol 2002;39:1464 1467.

ΤΙ ΠΑΡΑΤΗΡΟΎΜΕ ΣΤΙΣ ΜΕΛΈΤΕΣ ΠΡΩΤΟΓΕΝΟΎΣ ΠΡΌΛΗΨΗΣ Μόνο η ασπιρίνη έχει μελέτες πρωτογενούς πρόληψης Πολύ ετερογενής πληθυσμοί Πληθυσμοί πολύ χαμηλού έως χαμηλού κινδύνου στις περισσότερες μελέτες Πολύ ετερογενές σχήμα χορήγησης ασπιρίνης (από 75mg μέρα παρ ημέρα έως 500mg/ημέρα). Γνωρίζουμε πλέον ότι αρκούν χαμηλές ημερήσιες δόσεις για την αντιαιμοπεταλιακή δράση & μειωμένο κίνδυνο αιμορραγίας Οι ασθενείς δεν λάμβαναν γαστροπροστασία

ΜΕΛΈΤΕΣ ΠΡΩΤΟΓΕΝΟΎΣ ΠΡΌΛΗΨΗΣ Halvorsen et al. JACC 2014

WHS 2.5% HOT 3.6% PPP 4.3% PHS 4.8% BMD 8.9% TPT 12.4%

RISK FACTORS FOR CARDIOVASCULAR EVENTS

ATC 2009-PRIMARY

<10% 10-20% >20% 10-y CHD risk

From: Aspirin Therapy in Primary Cardiovascular Disease Prevention: A Position Paper of the European Society of Cardiology Working Group on Thrombosis J Am Coll Cardiol. 2014;64(3):319-327. doi:10.1016/j.jacc.2014.03.049 Date of download: 5/22/2016 Copyright The American College of Cardiology. All rights reserved.

ASPIRIN FOR PRIMARY PREVENTION EFFECT OF GENDER Ridker PM et al. JAMA 2005

ΑΣΠΙΡΊΝΗ ΚΑΙ ΜΕΊΖΟΝΕΣ ΑΙΜΟΡΡΑΓΊΕΣ 2.5 μείζονες αιμορραγίες σε 1000 γυναίκες και 3 μείζονες αιμορραγίες σε 1000 άνδρες για 6.4 έτη θεραπείας με ασπιρίνη Berger J et al. JAMA 2006

Η γαστροπροστασία υπο-πολαπλασιάζει τον αιμορραγικό κίνδυνο Patrono C, et al. EHJ 2013

From: Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement Ann Intern Med. Published online April 12, 2016. doi:10.7326/m16-0577 Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: clinical summary. ACC/AHA = American College of Cardiology/American Heart Association; CVD = cardiovascular disease; GI = gastrointestinal; USPSTF = U.S. Preventive Services Task Force. Date of download: 5/25/2016 Copyright American College of Physicians. All rights reserved.

From: Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement Ann Intern Med. Published online April 12, 2016. doi:10.7326/m16-0577 Date of download: 5/25/2016 Copyright American College of Physicians. All rights reserved.

For persons aged 50 years or older without symptomatic cardiovascular disease and with a >10%, 10 years risk of CVD, we suggest low-dose aspirin 75 to 100 mg daily over no aspirin therapy (Grade 2B).

Patrono C. JACC 2015

ADA-ΑΗΑ 2014: ΑΜΕΡΙΚΑΝΙΚΈΣ ΚΑΤΕΥΘΥΝΤΉΡΙΕΣ ΟΔΗΓΊΕΣ ΓΙΑ ΑΣΠΙΡΊΝΗ ΣΕ ΔΙΑΒΗΤΙΚΟΎΣ ΚΑΡΔΙΑΓΓΕΙΑΚΟΣ ΚΙΝΔΥΝΟΣ ΠΟΣΟΣΤΟ 10-ΕΤΟΥΣ ΚΙΝΔΥΝΟΥ ΣΥΣΤΑΣΗ ΓΙΑ ΑΣΠΙΡΙΝΗ ΧΑΜΗΛΟΣ <5% ΌΧΙ ΜΕΤΡΙΟΣ 5-10% ΠΙΘΑΝΟΝ (ΑΠΟΦΑΣΗ ΙΑΤΡΟΥ) ΥΨΗΛΟΣ (εμφραγματίες, διαβητικοί, πολλοί παράγοντες κινδύνου) >10% ΝΑΙ

ASPIRIN: ΣΤΗΝ ΠΡΩΤΟΓΕΝΉ ΠΡΌΛΗΨΗ ΕΥΡΩΠΑΙΚΕΣ ΚΑΤΕΥΘΥΝΤΉΡΙΕΣ ΟΔΗΓΊΕΣ ESH 2013

ΕΠΌΜΕΝΕΣ ΜΕΓΆΛΕΣ ΜΕΛΈΤΕΣ ΣΤΗΝ ΠΡΩΤΟΓΕΝΉ ΠΡΌΛΗΨΗ ΜΕ ΣΑΛΙΚΥΛΙΚΌ ΟΞΎ DESIGN Number of SUBJECTS AGE RISK FACTORS ARRIVE Aspirin to Reduce Risk of Initial Vascular Event Randomised 1:1 Double Blind placebo controlled 12.000, no known CVD No diabetes Men >55y Women >60y With 2-4 RF With 3 RF ASPREE Aspirin in reducing events in the Elderly Randomised 1:1 Double Blind placebo controlled 15.000 no overt CVD Men & Women 70y Multiple RFs ASCEND A study of Cardiovascular Events in Diabetes Randomised Double Blind placebo controlled 2x2 factorial 15.480 Type I&II Diabetes, no overt CVD Men & Women 40y With Diabetes ACCEPT-D Aspirin & Simvastatin Combination for CV Event Prevention Trial in Diabetes Randomised Open Label Controlled 5.170 Type I&II Diabetes, on, or eligible for statin therapy No overt CVD Men & Women 50y With Diabetes On statin therapy ENVIS - ion Elderly NeuroVascular Imaging Study (ASPPREE Substudy) Randomised 1:1 Double Blind placebo controlled 600, No overt CVD Normal cognitive function Men & Women 70y Multiple RFs

32% 34%

CONCLUSIONS ASPIRE & WARFASA study, provide consistent and convincing evidence that low-dose aspirin prevents recurrent VTE and major vascular events in patents with first unprovoked VTE Aspirin is an effective option for patients unable or who do not wish to continue anticoagulation beyond their initial therapy Simple therapy Widely available Low cost Well tolerated with low risks bleeding Benefits not solely restricted to prevention of recurrent VTE

ΑΣΠΙΡΙΝΗ ΚΑΙ ΠΡΟΛΗΨΗ ΤΟΥ ΚΑΡΚΙΝΟΥ

ΚΑΡΚΙΝΟΣ ΕΝΤΕΡΟΥ Ο 2 ος σε συχνότητα στις ανεπτυγμένες χώρες Δια βίου κίνδυνος = 5% 1.000.000 νέοι ασθενείς/έτος παγκόσμια Screening κολονοσκόπηση >50-55 έτη

9% 35% 27%

STUDY POPULATION: QRESEARCH DATABASE Currently largest primary care database in the UK 574 general practices across the UK > 9 million patients including those who have died or left, as well as patients still registered > 30 million person-years of observation

STUDY DESIGN & SETTING Nested case control study Study period Jan 1998-July 2008 Cases were incident colorectal cancer patients 5 controls matched by Age Sex Practice Calendar year

STUDY SAMPLE 14,948 incident cases of colorectal cancer 1998/2008 9534 cases with 10 years of medical records 35,013 controls with 10 years of medical records 6643 cases with 15 years of medical records 20,652 controls with 15 years of medical records

ASPIRIN MEDIAN DOSE PRESCRIBED 10 year cohort 15 year cohort Tablet dose (n = 10,073) (n = 6,506) 75 mg 77% 78% 76 150 mg 16% 15% 151 300 mg 5% 5% >300 mg 2% 2%

CONCLUSIONS Patients taking low dose aspirin have a reduced risk of Colorectal cancer An 18% reduction in risk is evident after more than 7yrs of aspirin use Effect not consistent with being COX-2 mediated

Κυρίως αδενοκαρκινώματα

ΑΣΠΙΡΙΝΗ ΜΕΤΑ ΤΗ ΔΙΑΓΝΩΣΗ ΤΟΥ ΚΑΡΚΙΝΟΥ

ΠΙΘΑΝΟΙ ΜΗΧΑΝΙΣΜΟΙ ΤΗΣ ΑΝΤΙΝΕΟΠΛΑΣΜΑΤΙΚΗΣ ΔΡΑΣΗΣ ΑΣΠΙΡΙΝΗΣ

ΣΥΜΠΕΡΑΣΜΑΤΑ

H ΚΑΘΗΜΕΡΙΝΗ ΧΟΡΗΓΗΣΗ ΑΣΠΙΡΙΝΗΣ (>75 mg) ΜΕΙΩΝΕΙ ΣΗΜΑΝΤΙΚΑ ΤΗΝ ΕΠΙΠΤΩΣΗ ΚΑΙ ΤΟΥΣ ΘΑΝΑΤΟΥΣ ΑΠΟ ΚΑΡΚΙΝΟ (ΚΥΡΙΩΣ ΓΑΣΤΡΕΝΤΕΡΙΚΟΥ) ΤΟ ΟΦΕΛΟΣ ΕΜΦΑΝΙΖΕΤΑΙ ΚΑΘΥΣΤΕΡΗΜΕΝΑ >5-10 ΕΤΗ ΤΟ ΟΦΕΛΟΣ ΑΠΟ ΤΗΝ ΠΡΟΛΗΨΗ ΤΟΥ ΚΑΡΚΙΝΟΥ ΕΙΝΑΙ ΠΙΘΑΝΑ ΜΕΓΑΛΥΤΕΡΟ ΑΠΟ ΤΟ ΚΑΡΔΙΑΓΓΕΙΑΚΟ ΟΦΕΛΟΣ ΜΗ ΔΙΑΚΟΠΗ Ή ΚΑΙ ΕΝΑΡΞΗ ΑΣΠΙΡΙΝΗΣ ΜΕ ΤΗ ΔΙΑΓΝΩΣΗ ΜΙΑΣ ΝΕΟΠΛΑΣΙΑΣ-ΚΥΡΙΩΣ ΓΑΣΤΡΕΝΤΕΡΙΚΟΥ

ΚΑΡΚΙΝΟΥ + ΚΑΡΔΙΑΓΓΕΙΑΚΩΝ

DO YOU KNOW ALL YOU NEED TO KNOW ABOUT ASPIRIN? Minimum questions before starting treatment : Have you taken ASA before? Any problems? Peptic ulcers/anaemia? Asthma? Bleeding tendency?

ΟΧΙ ΧΟΡΗΓΗΣΗ ΑΣΠΙΡΙΝΗΣ ΣΕ ΑΣΘΕΝΕΙΣ ΜΕ ΑΡΡΥΘΜΙΣΤΗ ΑΡΤΗΡΙΑΚΗ ΠΙΕΣΗ ΚΙΝΔΥΝΟΥ ΕΓΚΕΦΑΛΙΚΗΣ ΑΙΜΟΡΡΑΓΙΑΣ

H ΧΟΡΗΓΗΣΗ ΧΑΜΗΛΗΣ ΔΟΣΗΣ ΑΣΠΙΡΙΝΗΣ ΣΤΗΝ ΠΡΩΤΟΓΕΝΗ ΠΡΟΛΗΨΗ ΠΡΕΠΕΙ ΝΑ ΕΞΕΤΑΖΕΤΑΙ ΣΕ ΑΣΘΕΝΕΙΣ ΥΨΗΛΟΥ ΚΑΡΔΙΑΓΓΕΙΑΚΟΥ ΚΙΝΔΥΝΟΥ (HELLENIC SCORE >5%) ΜΕΣΗΣ ΗΛΙΚΙΑΣ ΜΕ ΧΑΜΗΛΟ ΚΙΝΔΥΝΟ ΑΙΜΟΡΡΑΓΙΑΣ Καρδιαγγειακού κινδύνου Καρκίνου (κυρίως εντέρου)

ΣΑΣ ΕΥΧΑΡΙΣΤΩ

Events

WILLOW BARK-ΦΛΟΙΟΣ ΙΤΙΑΣ Acetylsalicylic acid also known as ASPIRIN is a salicylate drug, often used as an analgesic, antipyretic and anti-inflammatory medication. Aspirin was first isolated by Felix Hoffmann, a chemist with the German company Bayer in 1897. Salicylic acid, the main metabolite of aspirin, is an integral part of human and animal metabolism. While in humans much of it is attributable to diet, a substantial part is synthesized endogenously. DATE NAME PARTICULAR 500 B.C. Hippocrates bitter powder extracted from willow bark could ease aches, pains and fevers 1700 Edmund Stone found out that the part of willow bark that was bitter was good for fever and pain is a chemical known assalicin. 1829 Leroux This chemical can be converted by the body after it is eaten to salicylic acid Jan 21, 1868 Felix Hoffman invented aspirin Mar 6, 1889 Bayer Aspirin patented

From: Aspirin Therapy in Primary Cardiovascular Disease Prevention: A Position Paper of the European Society of Cardiology Working Group on Thrombosis J Am Coll Cardiol. 2014;64(3):319-327. doi:10.1016/j.jacc.2014.03.049 Figure Legend: A Proposed Practical Stepwise Approach to the Use of Aspirin in Primary CV Prevention The first step should be an assessment of patient s eligibility to the treatment, by assessing the 10-year risk of major cardiovascular (CV) events (death, myocardial infarction, and stroke), according to local population risk estimates. Eligible patients will be those with an estimated 10-year risk >20%. Patients with a 10-year risk between 10% and 20% will be deemed as potentially eligible, and those with a risk <10% will be considered noneligible. The second step will be assessing safety in eligible and potentially-eligible patients, through a history of bleeding without reversible causes, and concurrent use of other medications that increase bleeding risk. In the absence of such conditions, patients with a risk >20% should be given low-dose aspirin, and those with a risk 10% to 20% should be engaged in a case-by-case discussion, factoring family history of gastrointestinal cancer (especially colon cancer) and patient values and preferences; particularly motivated patients can then be prescribed low-dose aspirin. Date of download: 5/22/2016 Copyright The American College of Cardiology. All rights reserved.

ΠΡΟΤΕΙΝΌΜΕΝΟΣ ΑΛΓΌΡΙΘΜΟΣ ESC WG ON THROMBOSIS Halvorsen et al. JACC 2014

Choice of Antithrombotic Therapy Following ACS For patients in the first year after an ACS who have not undergone percutaneous coronary intervention (PCI): We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low-dose aspirin 75-100 mg daily or clopidogrel 75 mg daily plus low-dose aspirin 75-100 mg daily) over single antiplatelet therapy (Grade 1B). We suggest ticagrelor 90 mg daily plus low-dose aspirin over clopidogrel 75 mg daily plus low-dose aspirin (Grade 2B).

Choice of Antithrombotic Therapy Following ACS For patients in the first year after an ACS who have undergone PCI with stent placement: We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low-dose aspirin 75-100 mg daily, clopidogrel 75 mg daily plus low-dose aspirin, or prasugrel 10 mg daily plus lowdose aspirin over single antiplatelet therapy) (Grade 1B). Remarks: Evidence suggests that prasugrel results in no benefit net harm in patients with a body weight of < 60 kg, age >75 years, or with a previous stroke/transient ischemic attack. We suggest ticagrelor 90 mg twice daily plus low-dose aspirin over clopidogrel 75 mg daily plus low-dose aspirin (Grade 2B).

1. Aspirin is reasonable in diabetic patients whose 10-year risk of >10% (men age >50 years and women age >60 years with at least 1 additional risk factor: smoking, hypertension, dyslipidemia, albuminuria, or family history of premature cardiovascular events) and who are not at increased risk of bleeding (no history of gastrointestinal bleeding or peptic ulcer disease, no concurrent use of other medications that increase bleeding risk) 2. Aspirin may be considered for diabetes patients at intermediate risk of cardiovascular events (younger patients with at least 1 risk factor, older patients with no risk factors, or patients with a 10-year risk of 5% to 10%)

ASPIRE RESULTS 2 OUTCOME ALL VASCULAR EVENTS Combined venous-arterial events: ~WARFASA, ASA reduced all vascular events by 34% without significant bleeding complication

10-YEAR RISK OF A FIRST CHD EVENT IN THE SIX MAJOR TRIALS OF ASPIRIN IN PRIMARY PREVENTION OF CVD WHS 2.5% HOT 3.6% PPP 4.3% PHS 4.8% BMD 8.9% TPT 12.4%

WARFASA TRIAL NEJM May 24, 2012; 366: 1959-1967 403 patients Italy, Austria Single, unprovoked VTE

6-18 months OAC Randomly assigned to ASA 100 mg vs. placebo Median Study Time ~24 months

NO SIGNIFICANT DIFFERENCE BETWEEN TWO STUDY GROUPS New Engl J Med, 2012;366(21):1963

EXCLUSION: Cancer Clinically significant thrombophilia (APLS... NOT excluded if heterozygous FV or prothrombin gene) Bleeding occurred during OAC tx

1 OUTCOME 1.VTE Recurrence 2.Major Bleeding Fatal, critical location (CNS, spinal, retroperit, MS leading to compartment syndrome) 2 gm drop in Hb

2 OUTCOME 1.VTE recurrence AND nonfatal MI, unstable angina, CVA, TIA, acute ischemia LE, or death 2.Non-major but clinically relevant bleeding OR bleeding requiring medical intervention, but did not meet definition of major bleeding 3.Mortality

WARFASA CONCLUSION 100 mg ASA initiated after 6-18 mo OAC Tx Reduced VTE recurrence ~40% compared to placebo with no increase in major bleeding risk

ASPIRE New Engl J Med, 2012;367(21):1979-1987 822 patients 56 sites; 5 countries

After 1 st unprovoked VTE after completion OAC therapy ---randomized ASA 100 mg vs. placebo Median time receiving study drug 27 months

ASPIRE PATIENTS Similar baseline characteristics although slightly younger and fewer males in ASPIRE

INCLUSION CRITERIA ~WARFASA Although 2% active cancer

ASPIRE RESULTS 1 OUTCOME Unlike WARFASA, this trial did NOT show significant reduction VTE recurrence - ASA vs. Placebo