Patophysiology of ACS: Role of Thrombosis
- 1. PATHOPHYSIOLOGY of ACS : Role of Thrombosis Antonia Anna Lukito
- 2. What is Atherothrombosis? Atherothrombosis is characterized by a sudden (unpredictable) atherosclerotic plaque disruption (rupture or erosion) leading to platelet activation and thrombus formation Atherothrombosis is the underlying condition that results in events leading to myocardial infarction, ischemic stroke, and vascular death Plaque rupture1 Plaque erosion2 1. Falk E et al. Circulation 1995; 92: 657–71. 2. Arbustini E et al. Heart 1999; 82: 269–72.
- 3. Plaque Rupture With Thrombosis Process
- 4. Normal Fatty streak Fibrous plaque Athero- sclerotic plaque Plaque rupture/ fissure & thrombosis Myocardial infarction Ischemic stroke/TIA† Critical leg ischemia Clinically silent Cardiovascular death Increasing age Stable angina Intermittent claudication Unstable angina }ACS* The Development of Atherothrombosis – a Generalized and Progressive Process Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6, and Aronow WS, Ahn C. Am J Cardiol 194; 74: 64–5. *ACS, acute coronary syndrome †TIA, transient ischemic attack
- 6. STEMI
- 7. UAP/NSTEMI
- 8. Causes of UA/NSTEMI* • Thrombus or thromboembolism, usually arising on disrupted or eroded plaque – Occlusive thrombus, usually with collateral vessels† – Subtotally occlusive thrombus on pre-existing plaque – Distal microvascular thromboembolism from plaque-associated thrombus – Thromboembolism from plaque erosion • Non–plaque-associated coronary thromboembolism • Dynamic obstruction (coronary spasm‡ or vascoconstriction) of epicardial and/or microvascular vessels • Progressive mechanical obstruction to coronary flow • Coronary arterial inflammation • Secondary UA • Coronary artery dissection§ *These causes are not mutually exclusive; some patients have 2 or more causes. †DeWood MA, et al. N Engl J Med 1986;315:417–23. ‡May occur on top of an atherosclerotic plaque, producing missed-etiology angina or UA/NSTEMI. §Rare. Modified with permission from Braunwald E. Circulation 1998;98:2219–22. Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Table 3.
- 9. Acute Coronary Syndrome (ACS) A Major Cause of Mortality and Morbidity UA/NSTEMI • In-hospital death and re-infarction: 5-10%1 • Six-month mortality in the GRACE registry2 (from admission to 6 months): - NSTEMI: 13% - UA: 8% 1.Grech & Ramsdale. BMJ 2003;326:1259-61; 2Fox. Am Heart J 2004:148:S40-5; 3.Antman et al. Circulation 2004;110:e82-292; 4.van de Werf et al. Eur Heart J 2003;24:28-66 STEMI • 1/3 of STEMI patients will die within 24 h of the onset of ischemia1 • In-hospital death and reinfarction: 8-10%3 • One-month mortality: 6-7%4 ARI/PRN/06/27/09/13
- 10. Therapeutic Options in Acute Coronary Syndromes Anti-ischemic treatment Antiplatelet agents Anticoagulants Revascularization/Reperfusion/Thrombolysis Long term treatment/secondary prevention
- 11. Targets for antithrombotics Tissue factor Plasma clotting cascade Prothrombin Thrombin Fibrinogen Fibrin Thrombus Platelet aggregation Conformational activation of GPIIb/IIIa Collagen Thromboxane A2 ADP AT AT Aspirin Clopidogrel Prasugrel AZD 6140 GPIIb/IIIa inhibitors Bivalirudin Hirudin Dabigatran Factor Xa Fondaparinux LMWH Heparin Direct Xa inhib
- 12. Ischemic Complications Ischemic Complications Hemorrhage HIT Hemorrhage HIT ► Death ► MI ► Urgent TVR ► Death ► MI ► Urgent TVR ► Major Bleeding ► Minor Bleeding ► Thrombocytopenia ► Major Bleeding ► Minor Bleeding ► Thrombocytopenia Composite Adverse Event EndpointsComposite Adverse Event Endpoints Evolving Paradigm for Evaluating ACS Management Strategies
- 13. Major Bleeding is Associated with an Increased Risk of Hospital Death in ACS Patients Moscucci et al. Eur Heart J 2003;24:1815-23 GRACE Registry in 24,045 ACS patients *After adjustment for comorbidities, clinical presentation, and hospital therapies. **p<0.001 for differences in unadjusted death rates OR (95% CI) 1.64 (1.18 to 2.28)* 0 Overall ACS UA NSTEMI STEMI 10 20 30 40 ** ** ** ** 5.1 18.6 3.0 16.1 5.3 15.3 7.0 22.8 Inhospitaldeath(%) Inhospital major bleeding YesNo ARI/PRN/06/27/09/13
- 14. UFH LMWH Pentasaccharides Presence of cofactor required +++ +++ +++ Renal clearance of clinical relevance ± ++ + Non-specific protein binding +++ + + Bioavailability by s.c or oral administration + ( for s.c administration ) ++ +++ Predictability of pharmacological effect - ++ ++ Inhibition of thrombin generation ++ ++ ++ Inhibition of thrombin activity +++ + - Inhibition of bound – thrombin - - - Rebound of thrombin generation after discontinuation +++ ++ - Platelet Activation +++ + - Immune thrombocytopenia +++ + - Decreased bone density +++ + - A comparison of relevant pharmacological properties of the different thrombin inhibitors in current clinical use Properties are semiquantitatively graded as : - absent,± barely present, + present-to a low degree, ++ present-to an intermediate degree, +++ present-to a high degree Raffaele D.C, Steen H, Lars W, Giancarlo A, Fedor B, Colin B , Jorgen J, Steen DK, Gilles M, Agneta S, Freek WAV, Jeffrey W. Anticoagulants in Heart Disease : Current Status and Perspectives. Eur Heart J 2007 ; 28 : 885-9
- 15. Fondaparinux Sodium, 2.5 mg/0.5 ml solution for injection, in pre-filled syringe is a pure factor Xa inhibitor that is given in a once daily injections unlike heparins or LMWH, fondaparinux is a synthetic compound and not derived from animal products has rapid onset of action, 100% bioavailability and undergoes no metabolism or protein binding (other than its target) has been extensively studied for prevention of VTE where it was superior to enoxaparin The 1st Synthetic Pentasaccharide of FXa Inhibitor
- 16. Thrombin Fibrinogen Extrinsic pathway Intrinsic pathway AT Fondaparinux XaAT Antithrombin Fibrin clot Xa Pro-thrombin Due to its synthetic nature, high efficacy, acceptable safety profile, and once-daily use without any laboratory monitoring, fondaparinux represents a major therapeutic advance in the prevention and treatment of thrombotic diseases Reutilized Olson et al. J Biol Chem 1992;267:12528-38 Turpie et al. N Engl J Med 2001;344:619-25
- 18. OASIS 5: An International, Multicenter, Randomized, Double- Blind, Double-Dummy Trial in 41 Countries 20,078 patients with UA/NSTEMI20,078 patients with UA/NSTEMI Fondaparinux 2.5 mg s.c. od up to 8 days Aspirin, Clopidogrel, anti-GPIIb/IIIa, planned Cath/PCI as per local practice Randomization Enoxaparin 1 mg/kg s.c. bid for 2-8 days 1 mg/kg s.c. od if ClCr<30mL/min 1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10 2. OASIS 5 Investigators. N Engl J Med 1464-76 Vital status ascertained in 20,066 (99.9%) Lost to follow-up at day 9: fondaparinux: n=7 and enoxaparin: n=5
- 19. Study Objectives and Outcomes Outcomes (centrally adjudicated) Primary efficacy: 1st occurrence of the composite of death, MI, or refractory ischemia (RI) up to day 9 Primary safety: Major bleeding up to day 9 Risk benefit: Death, MI, refractory ischemia, major bleeds up to day 9 Secondary: Above & each component separately at days 30 and 180 Objectives Primary efficacy objective: To demonstrate non-inferiority of fondaparinux compared with enoxaparin Primary safety objective: To determine whether fondaparinux was superior to enoxaparin in preventing major bleeding Objectives Primary efficacy objective: To demonstrate non-inferiority of fondaparinux compared with enoxaparin Primary safety objective: To determine whether fondaparinux was superior to enoxaparin in preventing major bleeding 1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10 2. OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
- 20. Fondaparinux: 2.2% (217 events) Enoxaparin: 4.1% (412 events) Days CumulativeHazard 0.0 0.01 0.02 0.03 0.04 0 1 2 3 4 5 6 7 8 9 HR: 0.52 95% CI: 0.44-0.61 p<0.001 Enoxaparin Fondaparinux Fondaparinux Patients Experienced Half the Rate of Major Bleeding Than Enoxaparin Patients at Day 9 (Primary Safety)
- 21. Fondaparinux Significantly Reduced Mortality vs. Enoxaparin up to Day 30 Fondaparinux: 2.9% (295 events) Enoxaparin: 3.5% (352 events) Days CumulativeHazard 0.0 0.01 0.02 0.03 0 3 6 9 12 15 18 21 24 27 30 HR: 0.83 95% CI: 0.71-0.97 p=0.02 Enoxaparin Fondaparinux 0.04
- 22. Fondaparinux Reduced the Rate of the Composite of Death, MI or Stroke up to 6 Months Fondaparinux: 11.3% (1113 events) Enoxaparin: 12.5% (1234 events) 0.0 Days 0 20 40 60 80 100 120 140 160 180 CumulativeHazard HR: 0.89 95% CI: 0.82-0.97 p=0.007 Enoxaparin Fondaparinux 0.02 0.04 0.06 0.08 0.10 0.12 0.14
- 23. 12,092 Pasien
- 24. Fondaparinux 2.5 mg s.c. once daily will show superior efficacy compared with usual care Study Hypothesis OASIS 6
- 25. Fondaparinux An International, Multicenter, Randomized, Double-Blind, Double- Dummy Trial in 41 Countries 12,092 patients with STEMI <12 h of symptom onset Randomization Standard Care Reff : 1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007). 2. The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI. Jama 2006; 259:1519-30. ARI/PRN/06/27/09/13
- 26. • Vital status known at hospital discharge in 12,085 (99.9%) • Follow-up: Day 30=12,072 (99.8%) – Study end=12,052 (99.7%) 12,092 patients with STEMI12,092 patients with STEMI Thrombolytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion Randomization Stratum 1 UFH not indicated Stratum 2 UFH Indicated Fondaparinux s.c. 2.5 mg od/8 days* Placebo 8 days* UFH i.v. 24-48 h Fondaparinux s.c. 2.5 mg od/8 days* Reff : 1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007). 2. The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI. Jama 2006; 259:1519-30. ARI/PRN/06/27/09/13
- 27. Study Objectives Primary efficacy objective To evaluate whether fondaparinux was superior to usual care (UFH or placebo) in preventing death or recurrent MI in patients with STEMI Primary safety objective To evaluate the safety of fondaparinux compared with usual care, in terms of severe bleeding, in patients with STEMI Primary efficacy objective To evaluate whether fondaparinux was superior to usual care (UFH or placebo) in preventing death or recurrent MI in patients with STEMI Primary safety objective To evaluate the safety of fondaparinux compared with usual care, in terms of severe bleeding, in patients with STEMI Reff : 1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007). 2. The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI. Jama 2006; 259:1519-30. ARI/PRN/06/27/09/13
- 28. The Benefit of Fondaparinux Appeared at Day 9 HR 95%CI Death/Reinfarction Death Reinfarction 0.83 0.73-0.94 0.003 0.87 0.75-1.00 0.043 0.67 0.52-0.88 0.004 1.0 100.1 Fondaparinux better Placebo/UFH better Hazard Ratio (log scale) Fondaparinux n=6056 Placebo/UFH n=6036 7.4% 8.9% 6.1% 7.0% 1.6% 2.3% p value9-day outcomes Reff : 1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007). 2. The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI. Jama 2006; 259:1519-30. ARI/PRN/06/27/09/13
- 29. UFH or placebo Fondaparinux HR: 0.86 95% CI: 0.77-0.96 p=0.008 0 0.02 0.04 0.06 0.08 0.10 0.12 0.14 0.16 0 3 6 9 12 15 18 21 24 27 30 CumulativeHazard Days Fondaparinux Significantly Reduced the Rate of Death/Reinfarction up to Day 30 Reff : 1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007). 2. The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI. Jama 2006; 259:1519-30. ARI/PRN/06/27/09/13
- 30. 0 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.016 HR: 0.79 (95% CI: 0.58-1.09) p=0.15 CumulativeHazard Days 0 3 6 9 12 3015 18 21 24 27 UFH or placebo Fondaparinux There Was No Increased Risk of 30-Day Severe Bleeding in the Fondaparinux Group Fondaparinux: 1.0% (61 events) UFH or placebo: 1.3% (79 events) Reff : 1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007). 2. The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI. Jama 2006; 259:1519-30. ARI/PRN/06/27/09/13
- 31. The OASIS-6 Trial Group. JAMA 2006;295:1519-30 ACC Presentation. Atlanta, March 2006 HR 95%CI Death/reinfarction, day 30 Death, day 90/180 Severe bleeding, day 9 0.79 0.68-0.92 0.85 0.73-0.99 0.66 0.44-0.98 1.0 100.1 Fondaparinux better Placebo/UFH better Hazard Ratio (log scale) A Significant Benefit of Fondaparinux in the 5436 Patients Who Received Thrombolytics (sub group analysis OASIS 6)
- 32. A Significant Benefit of Fondaparinux in the 2867 Patients Who Received No Reperfusion Therapy (Sub Group Analysis OASIS 6) The OASIS-6 Trial Group. JAMA 2006;295:1519-30 ACC Presentation. Atlanta, March 2006 HR 95%CI Death/reinfarction, day 30 Death, day 90/180 Severe bleeding, day 9 0.80 0.65-0.98 0.84 0.69-1.01 0.84 0.47-1.50 1.0 100.1 Fondaparinux better Placebo/UFH better Hazard Ratio (log scale)
- 36. Take Home Messages OASIS 5 & 6 has identified an excellent regime for anticoagulation in ACS. While other antithrombotic agents reduced death/MI but increased bleeding, Fondaparinux reduced death/MI without increasing bleeding events. The OASIS 5 & 6 trials showed that Fondaparinux 2.5 mg once daily was effective & safe in the full spectrum of ACS with up to 50% significantly fewer bleed vs. LMWH. Fondaparinux may therefore become the new reference anticoagulant drug in UA/NSTEMI and STEMI patients