ΝΕΩΤΕΡΑ ΑΝΤΙΑΙΜΟΠΕΤΑΛΙΑΚΑ ΚΑΙ ΑΝΤΙΘΡΟΜΒΩΤΙΚΑ ΦΑΡΜΑΚΑ ΣΤΟ ΟΞΥ ΕΜΦΡΑΓΜΑ ΤΟΥ ΜΥΟΚΑΡΔΙΟΥ Δρ. Στέργιος Κ. Σαββάτης Καρδιολόγος Διευθυντής Ε.Σ.Υ. Β Καρδιολογική Κλινική Α.Π.Θ. Ιπποκράτειο Γεν. Νοσοκοµείο Θεσσαλονίκης
Observations of clinical benefit in key trials of antiplatelet therapy CAPRIE CURE Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events Clopidogrel in Unstable Angina to Prevent Recurrent Events COMMIT ClOpidogrel and Metoprolol in Myocardial Infarction Trial CURRENT-OASIS 7 Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS TRITON-TIMI 38 TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet INhibition with Prasugrel-Thrombolysis In Myocardial Infarction PLATO Study of PLATelet Inhibition and Patient Outcomes
CAPRIE primary endpoint Cumulative risk of ischemic stroke, MI or vascular death [CAPRIE 1996:G] RRR=8.7%, 95% CI, 0.3-16.5; P<0.04 RRR, relative risk reduction; CI, confidence interval CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.
CURE: Primary End Point MI/Stroke/CV Death Cumulative Hazard Rate 0.14 0.12 0.10 0.08 0.06 0.04 0.02 Placebo + Aspirin Clopidogrel + Aspirin 20% RRR P=.00009 (N=12,562) 0.00 0 3 6 9 12 Follow-up (mo) CURE, Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events; MI, myocardial infarction; CV, cardiovascular; RRR, relative risk reduction. Plavix [package insert]; 2002. Adapted with permission (2002) from the Massachusetts Medical Society. Yusuf S, et al. N Engl J Med. 2001;345:494-502.
COMMIT: Effects of CLOPIDOGREL on Death, Re-MI or Stroke Placebo + ASA: 2311 events (10.1%) Clopidogrel + ASA: 2125 events (9.3%) Event (%) 9% (SE3) relative risk reduction (2P=0.002) Days since randomisation (up to 28 days)
Study Design Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Fibrinolytic, ASA, Heparin randomize Study Drug Open-label clopidogrel per MD in both groups Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) 30-day clinical follow-up Placebo Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio
Primary Endpoint: Occluded Artery (or D/MI thru Angio/HD) Occluded Artery or Death/MI (%) 25 20 15 10 5 0 36% Odds Reduction 15,0 Clopidogrel 21,7 n=1752 n=1739 Placebo Odds Ratio 0.64 (95% CI 0.53-0.76) P=0.00000036 0.4 0.6 0.8 1.0 1.2 1.6 Clopidogrel better Placebo better
Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS (CURRENT OASIS-7): study design ACS patients (UA/NSTEMI or STEMI) planned for early invasive Strategy <72 hours of randomization Double crossover study design (N=25,087) Clopidogrel high dose 600 mg loading dose day 1 150 mg days 2-7 75 mg days 8-30 [Mehta 2008:A] Clopidogrel standard dose 300 mg (+ placebo) day 1 75 mg (+ placebo) days 2-7 75 mg days 2-30 Aspirin low dose 300 mg day 1 75-100 mg days 2-30 Aspirin high dose 300 mg day 1 300-325 mg days 2-30 Aspirin low dose 300 mg day 1 75-100 mg days 2-30 Aspirin high dose 300 mg day 1 300-325 mg days 2-30 Up to 30 days Primary endpoint: Composite of CV death, MI or stroke up to day 30 Secondary endpoints: First occurrence of CV death, MI, stroke or refractory ischemia up to day 30 Individual components of the primary endpoint Key safety endpoint: Major bleeding [Mehta 2008:B] Mehta SR, et al. Am Heart J. 2008;156:1080-1088. 18
Conclusions Clopidogrel Dose Comparison 1. Double-dose clopidogrel significantly reduced stent thrombosis and major CV events (CV death, MI or stroke) in PCI. 2. In patients not undergoing PCI, double dose clopidogrel was not significantly different from standard dose (70% had no significant CAD or stopped study drug early for CABG). 3. There was a modest excess in CURRENT-defined major bleeds but no difference in TIMI major bleeds, ICH, fatal bleeds or CABG-related bleeds.
Development of Oral Anti-Thrombotic Therapy Post-ACS Reduction in Ischemic Events Increases in Bleeding No Tx ASA Clopidogrel Prasugrel Ticagrelor Vorapaxar Anticoagulant www.escardio.org
Αναστέλλει**τον**σχηματισμό*θρομβίνης** μέσω*του*σχηματισμού*συμπλέγματος** ******AT-III+IIa Το*σύμπλεγμα**AT-III+IIa*αναστέλλει** επίσης*τον**παράγοντα**xa *********Αναστολή**συσσώρευσης**αιμοπεταλίων*
Coagulation Cascade Intrinsic Pathway (surface contact) Extrinsic Pathway (tissue factor) XIIa XIa aptt PT IXa VIIa Xa Thrombin (IIa) Courtesy of VTI Heparin / LMWH (AT-III dependent) Hirudin/Hirulog (direct antithrombin) Thrombin-Fibrin Clot 5/98 MedSlides.com 53
Inactivation of Thrombin by Heparin-AT Complexes Heparin F Thrombin S H C AT Heparin binds to antithrombin and increases the rate of thrombin inactivation 5/98 MedSlides.com 54
Variable response > Heparin resistance Thrombocytopenia ( HIT )*
Συνδέεται*τόσο*με*τη*θρομβίνη,*όσο*και*με* την*ατbiii.* Αναστέλλει*τον*παράγοντα*Χα.* Περιέχουν*τον*κρίσιμο*αριθμό*των*18* μονάδων*για*τη*σύνδεση*τόσο*της*ιια,*όσο* και*με*την*ατbιιι.* Υψηλή*βιοδιαθεσιμότητα*(90%).* Μακρά*ημιπερίοδος*ζωής*(4* *6*h).
Differential inhibitory activity against factor Xa and IIa activity Unfractionated Heparin LMWH F H Thrombin (IIa) S C AT F H Thrombin (IIa) S C AT By binding to AT, most UH and LMWH can inhibit Xa activity. Fewer than half the chains of LMWH are of sufficient length to also bind factor IIa, therefore has decreased anti-iia activity. MedSlides.com 5/98 58
BIVALIRUDIN, -.. 70%
Coagulation Cascade Intrinsic Pathway (surface contact) Extrinsic Pathway (tissue factor) XIIa XIa aptt PT IXa VIIa Xa Thrombin (IIa) Courtesy of VTI Heparin / LMWH (AT-III dependent) Hirudin/Hirulog (direct antithrombin) Thrombin-Fibrin Clot 5/98 MedSlides.com 62
OASIS-6: Fondaparinux benefits in STEMI Dr Salim Yusuf
OASIS-6 stratum 2: Fondaparinux vs UFH, death/reinfarction in patients undergoing primary PCI Time point Fondaparinux (%) UFH (%) HR (95% CI) 30 d 6.1 5.1 1.20 (0.91 1.57) 9 d 4.2 4.1 1.01 (0.74 1.38) 3 6 mo 8.5 8.2 1.06 (0.84 1.33) p 0.19 0.96 0.61 OASIS-6 Trial Group. JAMA 2006:available at: http://www.jama.com.
DABIGATRAN(PRADAXA)> RE-DEEM STUDY (Direct inhibitor of thrombin) RIVAXOBAN(XARELTO)>ATLAS-TIMI 46 (Antagonist of factor Xa) APIXABAN(ELIQUIS)>APPRAISE STUDY (Antagonist of factor Xa)
Η post-hot *ανάλυση*της*r*e-ly*έδειξε*ότι*σε:** Ασθενείς*με*ΟΕΜ*+ΚΜ*και*υψηλό*θροεμβολικό* κίνδυνο*η*χορήγηση* Dabigatran 110 mg vs warfarin έδειξε**μη**κατωτερότητα**και* μεγαλύτερη*ασφάλεια(μικρότερο*ποσοστό* αιμορραγιών).*
Recent ACS: STEMI, NSTEMI, UA Stabilized 1-7 Days Post-Index Event Exclusions: increased bleeding risk, warfarin use, ICH, prior stroke if on ASA + thienopyridine ASA 75 to 100 mg/day Stratified by Thienopyridine Use at MD Discretion Placebo n=5,176 Rivaroxaban 2.5 mg BID n=5,174 Rivaroxaban 5.0 mg BID n=5,176 PRIMARY ENDPOINTS: EFFICACY: CV Death, MI, Stroke (Ischemic, Hemorrhagic, or Uncertain Origin) SAFETY: TIMI major bleeding not associated with CABG Event driven trial with 1,002 primary efficacy events www.escardio.org Mega NEJM 2012;366:9-19
Low Dose Rivaroxaban 5.0 mg BID CV Death / MI / Stroke Cardiovascular Death Estimated Cumulative Incidence (%) 10 5 0 0 HR 0.85 mitt p=0.028 ITT p=0.010 1 Months Placebo Rivaroxaban 5 mg BID NNT=53 24 10.7% 8.8% HR 0.94 mitt p=0.63 ITT p=0.57 Placebo Rivaroxaban 5 mg BID 0 24 Months 4.1% 4.0% www.escardio.org Mega NEJM 2012;366:9-19
Very Low Dose Rivaroxaban 2.5 mg BID CV Death / MI / Stroke Cardiovascular Death Estimated Cumulative incidence (%) 12% HR 0.84 mitt p=0.020 ITT p=0.007 Placebo Rivaroxaban 2.5 mg BID NNT = 63 10.7% 9.1% 5% HR 0.66 mitt p=0.002 ITT p=0.005 Placebo Rivaroxaban 2.5 mg BID NNT = 71 4.1% 2.7% 0 12 24 0 12 24 Months Months www.escardio.org Mega NEJM 2012;366:9-19
Primary Outcome CV Death, MI, Ischemic Stroke Apixaban 279 (7.5%) Placebo 293 (7.9%) HR 0.95; 95% CI 0.80-1.11; p=0.509 www.escardio.org Alexander NEJM 2011;365:699-708
TIMI Major Bleeding Apixaban 48 (1.3%) Placebo 18 (0.5%) HR 2.59; 95% CI 1.50 4.46; p=0.001 www.escardio.org Alexander NEJM 2011;365:699-708
ADP- ( ),., (15 18%).. Fondaparinux
ΕΥΧΑΡΙΣΤΩ