Επιλογή αντιαιμοπεταλιακής αγωγής σε ασθενείς με STEMI ή ACS. Πόσο μας βοήθησαν οι κλινικές μελέτες; Ανδρουλάκης Αριστείδης, F.E.S.C. Κρατική Καρδιολογική Κλινική Ιπποκράτειο Νοσοκομείο Αθηνών
ΟΞΥ ΣΤΕΦΑΝΙΑΙΟ ΣΥΝΔΡΟΜΟ Οξεία μυοκαρδιακή ισχαιμία απο αποφρακτική νόσο των στεφανιαίων, >99% αθηροθρομβωτικής αιτίας 30% των θανάτων ετησίως (ΗΠΑ) ΠΑΘΟΛΟΓΙΚΗ ΑΝΑΤΟΜΙΑ Οξείαρήξηήδιάσχισηήδιάβρωσηπλάκας Έκθεση tissue factor στην κυκλοφορία Ενεργοποίηση αιμοπεταλίων
E. Braunwald et al. The problem of persistent platelet activation in acute coronary syndromes and following percutaneous coronary intervention. Clin Cardiol 2008;31(Suppl. 1):I 17 17 I 20 οξέα στεφανιαία σύνδρομα o υπερδραστηριότητα αιμοπεταλίων οξεία φάση, ενδονοσοκομειακή φάση απώτερη μεσο-μακροπρόθεσμη μακροπρόθεσμη φάση αυξημένη επίπτωση MACEs
ΑΝΑΣΤΟΛΕΙΣ ΜΕΜΒΡΑΝΗΣ ΑΙΜΟΠΕΤΑΛΙΩΝ 1. Αναστολείς θρομβοξάνης (Αspirine) 2. Αναστολείς υποδοχέων ADP (clop, pras, tica) 3. Αναστολείς υποδοχέων GP IIb/IIIa (absiximab, integrillin, tirofiban 4. Αναστολείς υποδοχέων θρομβίνης (Vorapaxar)
ΑΝΑΣΤΑΛΤΕΣ ΕΝΔΟΚΥΤΤΑΡΙΩΝ ΜΕΤΑΒΙΒΑΣΤΩΝ Cyclic adenosine 3',5'-monophosphate (camp) Cyclic guanosine 3',5'-monophosphate (cgmp) Είναι δύο σημαντικοί ενδοκυττάριοι ΙΙγενείς μεταβιβαστές με ισχυρή ανασταλτική δράση στην ενεργοποίηση των αιμοπεταλίων. Οι Φωσφοδιεστεράσες (PDEs) καταλύουν την υδρόλυση των camp και cgmp και μειώνουν τα επίπεδα των κυκλικών νουκλεοτιδίων. Η αναστολή των PDEs τα αυξάνει και έτσι προκαλεί σημαντική ανασταλτική της ενεργοποίησης των αιμοπεταλίων δράση
Antiplatelet Therapy for STEMI Class I Aspirin 162 to 325 mg should be given in all pts (LoE: B) After PCI, aspirin 81-150 mg should be continued indefinitely. (LoE: A)
RANDOMISED TRIAL OF INTRAVENOUS STREPTOKINASE, ORAL ASPIRIN, BOTH, OR NEITHER AMONG 17 187 CASES OF SUSPECTED ACUTE MYOCARDIAL INFARCTION: ISIS-2 The Lancet,1988; 8607 (332), 349-360 Randomised 17187 patients 417 hospitals AMI < 24 h 35-day mortality Aspirin dose 160 mg/day
Antiplatelet Therapy to Support Primary PCI for STEMI Class I Aspirin 162 to 325 mg should be given before primary PCI. (LoE: B) After PCI, aspirin should be continued indefinitely. (LoE: A) Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010;376(9748):1233-43. 597 centres, 39 countries, 25,086 individuals with ACS randomly assigned to double-dose (600 mg on day 1, 150 mg on days 2-7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily) clop, and high-dose (300-325 mg daily) versus low-dose (75-100 mg daily) aspirin. The primary outcome was CV death, MI, or stroke at 30 days.
CURRENT-OASIS 7: Main Results for Aspirin in Overall Population Outcome High-dose ASA (%) Low-dose ASA (%) HR (95% CI) p CV death/mi/stroke* 4.2 4.4 0.97 (0.86 1.09) 0.61 Major bleeding 2.3 2.3 0.99 (0.84 1.17) 0.90 Major GI bleeding 0.4 0.2 0.04 ΔΕΝ ΥΠΑΡΧΕΙ ΜΕΓΑΛΥΤΕΡΟ ΚΕΡΔΟΣ ΜΕ ΑΣΠΙΡΙΝΗ >100 mg
EFFECTS OF CLOPIDOGREL IN ADDITION TO ASPIRIN IN PATIENTS WITH ACUTE CORONARY SYNDROMES WITHOUT ST-SEGMENT ELEVATION THE CLOPIDOGREL IN UNSTABLE ANGINA TO PREVENT RECURRENT EVENTS TRIAL INVESTIGATORS (CURE TRIAL) N Engl J Med 2001;345: 494-502 12,562 patients with NSTE-ACS Randomised to either a loading dose of 300 mg clopidogrel followed by 75 mg daily maintenance for 9 12 months in addition to aspirin, or with aspirin + placebo during the same time period. Θεωρητική βάση της μελέτης(χρηση ΔΙΠΛΗΣ ΑΙΜΟΠΕΤΑΛΙΑΚΗΣ ΑΝΑΣΤΟΛΗΣ): 1. Η προηγηθείσα χρήση των IV. Αναστολέων GP IIb/IIIa υπήρξε επωφελής επί επεμβατικής αγωγής, αλλά δεν υπάρχει per os μορφή 2. Η παρατεταμένη χρήση LMWH επί ACS δεν απέβη επωφελής 3. Η βραχεία χρήση ΚΑΙ κλοπιδογρέλης επί PCI υπήρξε πολύ χρήσιμη σε προκαταρκτικές μελέτες
9.3% vs 11.4%; RR 0.80; P < 0.001 major bleeding (16.5% vs 18.8%; RR 0.86; P < 0.001 Με πρόσθεση και της υποτροπής ισχαιμίας, 33% σχετική μείωση Πρωιμη εμφάνιση οφέλους
Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial COMMIT The Lancet 2005; 9497 (366): 1607-1621 45 852 patients admitted to 1250 hospitals within 24 h of suspected acute MI Μείωση συνδυασμού θανάτου, ΑΕΕ, νέου ΑΜΙ
Antiplatelet Therapy to Support Primary PCI for STEMI: Recommendations Class I 3. A loading dose of a P2Y12 receptor inhibitor should be given as early as possible or at time of primary PCI to patients with STEMI. Options include: a. Clopidogrel 600 mg; b. Prasugrel 60 mg; c. Ticagrelor 180 mg. (LoE: B) 4. P2Y12 inhibitor therapy should be given for 1 year to patients with STEMI who receive a stent (BMS or DES) during primary PCI using the following maintenance doses: Clopidogrel 75 mg; Prasugrel 10 mg daily. Ticagrelor 90 mg twice a day. (LoE: B) Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010;376(9748):1233-43 597 centres, 39 countries, 25,086 individuals with ACS randomly assigned to double-dose (600 mg on day 1, 150 mg on days 2-7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily) clop, and high-dose (300-325 mg daily) versus low-dose (75-100 mg daily) aspirin. The primary outcome was CV death, MI, or stroke at 30 days.
CURRENT-OASIS 7: Main Results for Clopidogrel in Overall Population Outcome Double-dose clopidogrel (%) Standard-dose clopidogrel (%) HR (95% CI) p CV Death/MI/stroke* 4.2 4.4 0.94 (0.83 1.06) 0.30 Major bleeding 2.5 2.0 1.24 (1.05 1.46) 0.01 despite impressive reductions in MI and stent thrombosis with double-dose clopidogrel in patients who had PCI, the 30-day rates of cardiovascular death were identical in the standard-dose and double-dose clopidogrel groups. "Presumably, any benefits from reduced ischemic complications in reducing mortality were offset by increased rates of major bleeding with double-dose clopidogrel, Outcome CURRENT-OASIS 7: Results for Clopidogrel in PCI Subgroup Double-dose Standard-dose HR (95% CI) clopidogrel (%) clopidogrel (%) CV death/mi/stroke* 3.9 4.5 0.86 (0.74 0.99) 0.039 Definite stent thrombosis 0.7 1.3 0.54 0.0001 Major bleeding 1.6 1.1 1.41(1.09 1.83) 0.009 p
Double-dose versus standard-dose clopidogrel and high-dose versus lowdose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet. 2010;376(9748):1233-43. A double-dose clopidogrel regimen can be considered for all patients with ACS treated with an early invasive strategy and intended early PCI.
Class I 3. A loading dose of a P2Y12 receptor inhibitor should be given as early as possible or at time of primary PCI to patients with STEMI. Options include: a. Clopidogrel 600 mg; b. Prasugrel 60 mg; c. Ticagrelor 180 mg. (LoE: B) Outcome comparison of 600- and 300-mg loading doses of clopidogrel in patients undergoing primary percutaneous coronary intervention for STsegment elevation myocardial infarction: results from the ARMYDA-6 MI (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Myocardial Infarction) randomized study. J Am Coll Cardiol 2011;58(15):1592-9. UNDERPOWERED prospective, randomized study, 202 patients primary PCI for STEMI randomly received a 600-mg (n = 103) or 300-mg (n = 98) clopidogrel loading dose before the procedure reduction of the infarct size compared with a 300-mg loading dose, as well as with improvement of angiographic results, residual cardiac function, and 30-day major adverse cardiovascular events; further studies are warranted to evaluate impact of such strategy on survival.
ΟΜΩΣ Η κλοπιδογρέλη είναι προφάρμακο και πρέπει να μετατραπεί στην ενεργό μορφή του από ένζυμα του κυτοχρώματος P450 στο ήπαρ Επηρεασμός από πολυμορφισμούς, συγχορηγούμενα φάρμακα Ποικιλία βαθμού αντιαιμοπεταλιακής αναστολής Μόνιμη αναστολή ΝΕΩΤΕΡΑ ΑΝΤΙΑΙΜΟΠΕΤΑΛΙΑΚΑ με στόχο: Ισχυρότερη αναστολή Ταχύτερη βιοδιαθεσιμότητα Μικρότερης κλίμακας ποικιλομορφία βαθμού δραστικότητος PRASOUGREL Προφάρμακο, αλλα μεταβολίζεται αποτελεσματικά από εστεράσες στην ενεργό μορφή Επιτυγχάνει αποτέλεσμα < 1 ώρα. Μόνιμη αναστολή TICAGRELOR Ενεργό όπως απορροφάται. Επιτυγχάνει αποτέλεσμα < 1 ώρα. Αναστρέψιμη αναστολή
Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes TRITON TIMI 38 Investigators N Engl J Med 2007; 357:2001-2015 13,608 patients with moderate-to-high-risk ACS with scheduled PCI Prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose) in addition to aspirin Follow-up for 6 to 15 months.
20% μείωση του πρωτογενούς καταληκτικού σημείου
Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes TRITON TIMI 38 Investigators N Engl J Med 2007; 357:2001-2015 ΑΝΑΛΥΣΗ ΥΠΟΟΜΑΔΩΝ Μεγάλα ποσοστά ισχαιμικών και αιμορραγικών επιπλοκών Ιστορικό ΤΙΑ / ΑΕΕ Ηλικία >75 ετών ΒΣ <60 kg
TRILOGY-ACS: Angiographic Cohort Analysis Primary Endpoint and MI Risks End point Prasugrel, n=1534 (%) Clopidogrel, n=1561 (%) Hazard ratio (95% CI) Angiography cohort 3085 pts Cardiovascular death, MI, and stroke 10.7 14.9 0.77 (0.61 0.98) MI 7.2 10.3 0.74 (0.55 1.00) No angiography cohort 4158 pts Cardiovascular death, MI, and stroke 16.3 16.7 1.01 (0.84 1.20) MI 9.2 10.6 1.00 (0.79 1.26) Prasugrel versus Clopidogrel for Acute Coronary Syndromes without Revascularization N Engl J Med 2012; 367:1297-1309
Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes for the PLATO Investigators N Engl J Med 2009; 361:1045-1057 Multicenter, double-blind, randomized trial, At 12 months 18,624 patients with an ACS (with or without ST-segment elevation). Comparison of ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events Ticagrelor was superior to clopidogrel in the overall ACS population, (65% PCI, 35% medical Tx) A sub-analysis of PLATO showed that ticagrelor was superior to clopidogrel even in NSTE-ACS patients initially intended for non-invasive management The primary end point CV death+mi+stroke- 9.8% in tica vs. 11.7% in clop (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). MI alone (5.8% vs 6.9%, P = 0.005) CV death (4.0% vs 5.1%, P = 0.001) Stroke alone (1.5% vs 1.3%, P = 0.22). Death from any cause (4.5%, vs 5.9%; P<0.001). Major bleeding (11.6% vs. 11.2%, respectively; P = 0.43), Major bleeding not related to CABG (4.5% vs 3.8%, P = 0.03),
PLATO STEMI Results End point Primary end point: CV death, MI, or stroke Secondary end points Ticagre lor (%) Clopidogrel (%) Hazard ratio for ticagrelor 9.3 11.0 0.85 0.02 All-cause mortality 4.9 6.0 0.82 0.04 CV mortality 4.5 5.4 0.84 0.09 Definite stent thrombosis 1.6 2.5 0.61 0.01 MI 4.7 6.1 0.77 0.01 Primary safety event: major 9.0 9.3 0.96 0.63 bleeding Definite stent thrombosis was also significantly lower among the STEMI patients taking ticagrelor compared with those receiving clopidogrel, as was MI. And there was an 18% reduction in all-cause mortality among those STEMI patients taking ticagrelor vs clopidogrel (p=0.04), p
Antiplatelet Therapy to Support Primary PCI for STEMI: Recommendations Class I 3. A loading dose of a P2Y12 receptor inhibitor should be given as early as possible or at time of primary PCI to patients with STEMI. Options include: a. Clopidogrel 600 mg; b. Prasugrel 60 mg; c. Ticagrelor 180 mg. (LoE: B) 4. P2Y12 inhibitor therapy should be given for 1 year to patients with STEMI who receive a stent (BMS or DES) during primary PCI using the following maintenance doses: Clopidogrel 75 mg; Prasugrel 10 mg daily. Ticagrelor 90 mg twice a day. (LoE: B)
ΑΝΑΣΤΟΛΕΙΣ ΥΠΟΔΟΧΕΩΝ ΓΛΥΚΟΠΡΩΤΕΙΝΗΣ IIb/IIIa ACUITY Trial: Prospective, Randomized, >9000 ασθενείς ACS, Am Heart J. 2004;148(5):764-75 EARLY ACS Trial: Rx, >9492 NSTEMI ασθενείς N Engl J Med. 2009;360(21):2176-90 FINESSE Trial: 2452 ασθενείς με STEMI Οι GPI επιτυγχάνουν μείωση των ισχαιμικών επιπλοκών Δεν έχουν να επιδείξουν διαφορές στους θανάτους ή τα ΜΙ Σε επιλεγμένες υψηλού κινδύνου περιπτώσεις Στο Αιμοδυναμικό Εργαστήριο (bail out) Σε υψηλού κινδύνου NSTEMI που δεν σταθεροποιούνται (εν όψει PCI) Class IIa Inravenous abciximab (LoE: A), high-bolus-dose tirofiban (LoE: B), or doublebolus eptifibatide (LoE: B) at the time of primary PCI in selected patients with STEMI who are receiving (UFH). Class IIb 1. Intravenous GP IIb/IIIa receptor antagonist in the precatheterization laboratory setting (eg, ambulance, ED) to patients with STEMI for whom primary PCI is intended (LoE: B) 2. It may be reasonable to administer intracoronary abciximab to patients with STEMI undergoing primary PCI (LoE: B)
CHAMPION PHOENIX Trial N Engl J Med. 2013 Apr 4;368(14):1303-13
Cangrelor Cangrelor is an intravenous ADP receptor antagonist that is rapidly acting, potent, and reversible, with return of normal platelet function within an hour. Direct platelet P2Y 12 receptor antagonist T1/2 = 3 to 6 minutes Offset = 60 minutes you'll have to treat 1000 patients to prevent, maybe, three MIs or deaths at the cost of three or four major bleeds
Primary Efficacy Endpoint Death/MI/IDR/ST within 48 hours Event Rate (%) clopidogrel 5.9% cangrelor 4.7% Log Rank P Value = 0.006 Patient at Risk Hours from Randomization Cangrelor: 5472 5233 5229 5225 5223 5221 5220 5217 5213 Clopidogrel: 5470 5162 5159 5155 5152 5151 5151 5147 5147 CHAMPION PHOENIX Trial Bhatt et al. N Engl J Med. 2013 Apr 4;368(14):1303-13
Secondary Efficacy Outcomes Stent Thrombosis within 48 hours Event Rate (%) clopidogrel 1.4% 0.8% cangrelor Log Rank P Value = 0.01 Patient at Risk Hours from Randomization Cangrelor: 5472 5426 5421 5419 5419 5418 5417 5416 5414 Clopidogrel: 5470 5392 5389 5388 5386 5385 5385 5383 5383 CHAMPION PHOENIX Trial Bhatt et al. N Engl J Med. 2013 Apr 4;368(14):1303-13
ΟΜΩΣ
you'll have to treat 1000 patients to prevent, maybe, 3 MIs or deaths at the cost of 3-4 major bleeds However, the declared impressive cangrelor vascular non-fatal benefit was contradicted by identical deaths at 48 h, and a trend toward excess mortality at 30 days. Earlier this week, the FDA posted a review of the cangrelor data by its own internal reviewers. One reviewer was extremely critical of the data and argued that the "CHAMPION trials do not show superiority or noninferiority of a cangrelor regimen to clopidogrel or to standard of care." Two other reviewers, however, believed the overall risk/benefit profile, which weighed the risk of bleeding vs the benefit of reducing thrombotic events, showed mixed results. They ultimately concluded, however, there was a "marginal" benefit in the PCI setting that was driven by a reduction in periprocedural MIs. cangrelor went up against clopidogrel when it was given "early" the benefit of cangrelor would be diminished.
ΟΜΩΣ WILMINGTON, DE The US Department of Justice (DoJ) is investigating AstraZeneca's PLATO trial of ticagrelor (Brilinta). A company spokesperson confirmed to heartwire that the company received a civil investigative demand from the DoJ's civil division on October 21 "seeking documents and information regarding PLATO.... AstraZeneca intends to cooperate with the inquiry.«31 Οκτ 2013 Outcomes for Ticagrelor Worse in North America The overall results of the 18 000-patient PLATO trial, conducted in 43 countries around the world, showed that ticagrelor plus aspirin reduced the primary end point--a composite of death from vascular causes, MI, or stroke--by 16% compared with clopidogrel plus aspirin over 12 months (9.8% of patients receiving ticagrelor suffered a primary end point event compared with 11.7% of those taking clopidogrel p<0.001]). But the outcome in 1814 patients in the US and Canada was worse in those taking ticagrelor than in those on clopidogrel, with a primary end point occurring in 11.9% of ticagrelor-treated patients compared with 9.6% of those on clopidogrel, although the difference was not significant.
ΕΡΩΤΗΜΑΤΑ Για πόσο πρέπει να διαρκεί η DAPT Τι μπορεί να γίνει στην οξεία φάση έως ότου αρχίσει η αντιαιμοπεταλιακή δράση To CANGRELOR μείωσε τα ισχαιμικά συμβάντα αλλά vorapaxar (Zontivity), a novel protease-activated receptor 1 (PAR-1) inhibitor that targets thrombin-induced platelet activation for treatment post-mi TRA 2 P TIMI-50, 26 499-patient study Θα βρούν ρόλο οι ενδοκυττάριοι αναστολείς;
Antiplatelet therapy: efficacy vs. safety benefit - 100 / 1000 risk to harm risk to harm 18 / 1000 18 / 1000 + 50% NNT 10 180% ( x3) NNH 56
VESSELS Salvador Dali ευχαριστώ