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La terapia antitrombotica e le complicanze emorragiche più frequenti:

SINDROMI CORONARICHE ACUTE: La gestione del rischio emorragico in UTIC Firenze, 27 Febbraio 2010. La terapia antitrombotica e le complicanze emorragiche più frequenti: evidenze dagli studi clinici e concetto di beneficio clinico netto. Leonardo De Luca, M.D., Ph.D., F.A.C.C.

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La terapia antitrombotica e le complicanze emorragiche più frequenti:

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  1. SINDROMI CORONARICHE ACUTE: La gestione del rischio emorragico in UTIC Firenze, 27 Febbraio 2010 La terapia antitrombotica e le complicanze emorragiche più frequenti: evidenze dagli studi clinici e concetto di beneficio clinico netto Leonardo De Luca, M.D., Ph.D., F.A.C.C. Department of Cardiovascular Sciences Interventional Cardiology Unit European Hospital Rome, Italy leo.deluca@libero.it Conflict of interest: none

  2. The Antithrombin Pathway The Antiplatelet Pathway Tissue factor Collagen Plasma clotting cascade ADP Thromboxane A2 Prothrombin Factor Xa Conformational activation of GPIIb/IIIa Thrombin Platelet aggregation Fibrinogen Fibrin Thrombus

  3. The Antithrombin Pathway The Antiplatelet Pathway Tissue factor Collagen Aspirin Plasma clotting cascade ADP Ticlopidine Clopidogrel Prasugrel Ticagrelor Fondaparinux Thromboxane A2 Prothrombin AT LMWH UFH Factor Xa Conformational activation of GPIIb/IIIa GPIIb/IIIa inhibitors AT Thrombin Platelet aggregation Bivalirudin Hirudin Argatroban Fibrinogen Fibrin Thrombus

  4. “Major” Bleedings Incidence in ACS Clinical Trials Eur Heart J 2007;28:1193

  5. ExcessDosingofAntiplatelet and AntithrombinAgents & Major Bleedings Major Bleedings (%) UFH LMWH GP IIb/IIIa 30.136 patients with NSTE ACS JAMA2005;294:3108

  6. Post-Procedural Bleeding (Major and Minor) and 1-Year Mortality 5,384 patients from 4 randomized trials (ISAR-REACT, -SWEET, -SMART-2 and –REACT-2) on the value of abciximab after pretreatment with 600 mg of clopidogrel OR 4.75, 95% CI 3.34 to 6.76 p<0.001 Any bleeding Mortality (%) No bleeding Months after randomization J Am Coll Cardiol 2008;51:690

  7. Defining the Problem * JAMA 2004;292:1555 ** N Engl J Med 1997;337:1360

  8. Bleeding Incidence: Impact of definitionN=15,858 ACS pts from PURSUIT & PARAGON B J Am Coll Cardiol 2006;47:809

  9. Clinical Impact ofBleeding Measured by Two Different Classifications Among ACS Patients Hazard ratios of 30-day death or MI Hazard ratios of 6-month death or MI 1.19 (1.01, 1.41) 1.19 (1.03, 1.38) GUSTO Mild GUSTO Mild 1.92 (1.58, 2.34) 1.48 (1.32, 1.79) GUSTO Moderate GUSTO Moderate 3.48 (2.56, 4.73) 3.22 (2.43, 4.26) GUSTO Severe GUSTO Severe TIMI Minimal TIMI Minimal 1.13 (0.97, 1.33) 1.02 (0.88, 1.18) TIMI Minor TIMI Minor 1.06 (0.86, 1.30) 1.08 (0.85, 1.36) TIMI Major TIMI Major 1.00 (0.85, 1.20) 0.94 (0.81, 1.10) 1.00 1.00 Rao SV et al. J Am Coll Cardiol 2006;47:809

  10. Major bleeding criteria used in recent trials evaluating antithrombotic drugs in ACS and PCI De Luca L, et al. J Cardiovasc Med 2009;10:667

  11. Variations in Major Bleeding Criteria Defined by Different ProtocolsUsed in Recent RCT on Antithrombotic Drugs in ACS and PCI

  12. Rates of Major Bleeding in the STEEPLE Trial According to Bleeding Definitions p=.007 p=.004 Patients with Bleeding Events (%) p=.13 p=.03 p=.069 p=1.0 Bleeding Definition modified from NEJM 2006;355:1006

  13. Academic Bleeding Consensus Group Standards for Collection and Reporting of BleedingComplications Rao SV et al. Am Heart J 2009;158:881

  14. Shifting the Paradigm: From a Triangle to a Square Bleeding: Not Safety, but Efficacy! 2008 1998 Death Major Bleedings Death Urgent TVR* Urgent TVR* MI MI *= Target Vessel Revascularization modified from J Am Coll Cardiol 2008;51:696

  15. Endpoints REPLACE-II Primary Quadruple Endpoint Triple IschemicEndpoint % of Patients OR 0.92 0.77 - 1.09 p = 0.32 OR 1.09 0.90 - 1.32 p = 0.40 UFH + GP IIb/IIIa UFH + GP IIb/IIIa Bivalirudin Bivalirudin JAMA 2003;289:853

  16. REPLACE-II Components of Primary Quadruple Endpoint through 30 days p < 0.001 % of Patients p = 0.26 p = 0.44 p = 0.32 p = 0.23 JAMA 2003;289:853

  17. Bleeding Definition ICH TIMI Major Bleedingwith 5 g/dLfail in HgB Bloodtransfusion ≥ 2 units REPLACE-2 Definition of Major Bleed Clinicallyovertbleedwith 3 g/dLdrop in HgB 4 g/dLfail in HgBwithoutovertbleeding TIMI Minor Retroperitonealhemorrhage Grosshematuria or hematemesis

  18. REPLACE-II Bleeding: REPLACE-2 Defined and TIMI Bleeding Criteria % of Patients p < 0.001 p < 0.001 p = NS p < 0.001 REPLACE-2 Definition TIMI Definition JAMA 2003;289:853

  19. UFH or Enoxaparin Routine upstream GPI in all pts (4,605) Routine upstream GPI in all pts GPI started in CCL for PCI only Bivalirudin Routine upstream GPI in all pts Deferred GPI for PCI only (n=4,602) R R GPI started in CCL for PCI only Bivalirudin Alone (n=4,612) ACUITY Study Design Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) UFH, Enoxaparin, or Bivalirudin VS. Moderate- high risk ACS (n=13,819) Aspirin in all Clopidogrel dosing and timing per local practice Am Heart J 2004;148:764

  20. ACUITY Primary Results by Treatment NEJM 2006;355:2203

  21. ACUITY Impact of Major Bleedings on 30-Day Mortality Log Rank p Value: <0.001 Mortality (%) Pts with major bleedings Pts without major bleedings Days from randomization J Am Coll Cardiol 2007;49:1362

  22. ACUITY Impact of Major Bleedings on 1-Year Mortality HR 0.96; IC 95% 0.77-1.18; p = 0.67 Mortality (%) Heparin + GP IIb/IIIa inhibitors Bivalirudin + GP IIb/IIIa inhibitors Bivalirudin monotherapy Log-rank P=.90 Days from randomization Major bleedings in ACUITY: hematoma 5 cm in diameter or transfusion criterion on its own with 1 units of blood regardless a decrease in Hb JAMA 2007;298:2497

  23. Influenceof Major Bleeding and MI in The First 30 Days on Riskof Death Over 1 Year Cox model adjusted for 36 baseline predictors, with MI and Major bleeding (non-CABG) as time-updated covariates Attributable deaths HR (95% CI) P Value HR 95% CI Myocardial Infarction 2.51 (1.95-3.25) <0.0001 51.5* Major bleeding without or before transfusion 2.00 (1.30-3.06) <0.0001 66.5** Major bleeding after transfusion 3.93 (2.95-5.24) <0.0001 *9.8% of all deaths **12.7% of all deaths 0 6 Attributable deaths=N deaths Among pts with the time updated Event (attribute) X (adj. HR-1)/adj. HR Mehran RM et al., Eur Heart J 2009;30:1457

  24. Concerns Regarding the Composition of the Composite Endpoint in REPLACE-2 and ACUITY • “Combining efficacy and safety into one composite end point can be problematic from a regulatory perspective because drugs that are ineffective but have a safety advantage can appear to be better than drugs with • proven efficacy.” • EM Antman JAMA 2003; 289, No. 7, pp 903-905. 29 MIs 54 Bleeds

  25. MI, Bleeding and All-CauseMortality LargeRCTsWithoutSignificantReductions in Death *TIMI Major + Minor or Protocol Major

  26. MI, Bleeding and All-CauseMortality LargeRCTsWithSignificantReductions in Death *TIMI Major + Minor or Protocol Major

  27. Discharge Medication Use in Patients Who Bleed: PREMIER Registry (STEMI) 1433 STEMI pts treated with primary stenting p=0.001 p=0.002 p<0.001 p=0.05 Wang TY et al. Circulation 2008;118:2139

  28. Balance of Efficacy and Safety 15 138 events Clopidogrel HR 0.81(0.73-0.90)P=0.0004 12.1 CV Death / MI / Stroke 9.9 10 NNT = 46 Endpoint (%) Prasugrel 5 35 events TIMI Major NonCABG Bleeds Prasugrel 2.4 HR 1.32(1.03-1.68)P=0.03 1.8 Clopidogrel 0 NNH = 167 0 30 60 90 180 270 360 450 Days NEJM 2007;357: 2001

  29. Bleeding EventsSafety Cohort (N=13,457) ICH in Pts w Prior Stroke/TIA (N=518) Clopidogrel Prasugrel Clop 0 (0) %Pras 6 (2.3)% (P=0.02) % Events ARD 0.6%HR 1.32P=0.03NNH=167 ARD 0.5%HR 1.52P=0.01 ARD 0.2%P=0.23 ARD 0.3%P=0.002 ARD 0%P=0.74 NEJM 2007;357: 2001

  30. Net Clinical BenefitDeath, MI, Stroke, Major Bleed (non CABG) Events per 1000 pts + Major Bleed(non CABG) MI 15 Clopidogrel 13.9 ITT= 13,608 12.2 HR 0.87P=0.004 10 Prasugrel Endpoint (%) 5 0 0 30 60 90 180 270 360 450 Days NEJM 2007;357: 2001

  31. Non-CABG and CABG-related Major Bleeding NS NS p=0.026 p=0.025 Wallentin L, et al. N Engl J Med 2009;361:1045

  32. Net Clinical Benefit or Net Adverse Clinical Events: Do We Need A More Reliable Scale?

  33. Stent Thrombosis: Expanding the Primary Endpoint to a Square The STARS Trial p=0.005 Incidence of Stent Thrombosis (%) NEJM 1998;339:1665

  34. Stent Thrombosis: Expanding the Primary Endpoint to a Square The STARS Trial p=NS by chi square Incidence of Stent Thrombosis and Major Bleedings(%) modified from NEJM 1998;339:1665

  35. PCI Pharmacology Trials: Expanding the Primary Endpoint to a Square The ESPRIT Trial p=0.0015 Incidence of Primary Triple* Endpoint (%) * Death, Q-wave MI and Urgent TVR Lancet 2000;356:2037

  36. PCI Pharmacology Trials: Expanding the Primary Endpoint to a Square The ESPRIT Trial p=0.05 by chi-square Crude addition Incidence of Primary Quadruple* Endpoint (%) * Death, Q-wave MI, Urgent TVR and Major Bleedings (TIMI classification) modified from Lancet 2000;356:2037

  37. Conclusions • The evolution of PCI over the past two decades has consistently led to improved ischaemic outcomes, but at the cost of increased risk of bleeding and blood transfusion. • Variability in definitions of bleeding across clinical trials and registries makes it difficult to accurately compare the true rates of bleeding. • There are emerging data that the traditional safety endpoint of bleeding affects at least two components of the efficacy composite (death and MI). • A composite clinical benefit endpoint, which includes death, MI, TVR, and bleeding, will probably implicate a small decrease in efficacy for a large benefit in safety.

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