Pathophysiology of ACS

Transcription

1 Pathophysiology of ACS ~ 2.0 MM patients admitted to CCU or telemetry annually 0.6 MM ST-segment elevation MI 1.4 MM Non-ST-segment elevation ACS

2 NSTEMI vs STEMI

3 VANQWISH Boden et al N Engl J Med 1998;338: patients randomized to either invasive or conservative management, defined as medical therapy and noninvasive testing, with subsequent invasive management if indicated by the development of spontaneous or inducible ischemia, within 72 hours of the onset of a non Q-wave infarction. Results The number of patients who died at hospital discharge was significantly higher in the invasive-strategy group (36 vs. 15 patients, P=0.004), Overall mortality during follow-up did not differ significantly. Conclusions Most patients with non Q-wave MI do not benefit from routine, early invasive management consisting of coronary angiography and revascularization.

4 FRISC II Outcome at 1 Year N= 2,457 Swedish ACS patients conservative invasive Lancet 2000;356:9-16

5 Platelet adhesion Platelet aggregation Adhesive proteins fibrinogen vwf GPIIb/IIIa inhibitors

6 N= 29,570 pts in 6 randomized, double-blind placebo-controlled trials of GPIIb/IIIa antagonists in the management of ACS diabetics Roffi et al. Eur Heart J 2002;23,

7 2006;295: N=2,022 N=2,022 high high risk risk ACS ACS patients patients (unstable (unstable angina angina with with EKG abnormalities EKG abnormalities or or troponin troponin elevation) elevation) The The primary primary end end point point was was a a composite composite of of death, death, myocardial myocardial infarction, infarction, or or urgent urgent target target vessel vessel revascularization revascularization

8 Oral Anti-platelet Agents Sites of Action

9 GP IIb/IIIa inhibitor

10 CAPRIE - Primary Endpoints* N= 19,185 patients with atherosclerotic disease Cumulative Event Rate (%) % Overall Risk Reduction p= % 5.33% Aspirin Clopidogrel * MI, Ischemic Stroke, or Vascular Death Months of Follow-Up

11 MI/Stroke/CV Death Within 30 Days Cumulative Hazard Rate * In addition to other standard therapies. 0 Placebo + ASA* Clopidogrel + ASA* Days of Follow-Up The CURE Trial Investigators. N Engl J Med. 2001;345: % Relative Risk Reduction P = N = 12,562

12 Major Bleeding by ASA Dose ASA Dose Clopidogr el + ASA* Placebo + ASA* <100 mg 2.6% 2.0% mg 3.5% 2.3% >200 mg 4.9% 4.0%

13 Mortality (%) COMMIT: Effect of Clopidogrel on Death in Hospital Placebo + ASA: 1846 deaths (8.1%) Clopidogrel + ASA: 1728 deaths (7.5%) 7% (SE3) relative risk reduction (2P=.03) Time (d Since Randomization [ 28 d) Adapted with permission from COMMIT Collaborative Group. Lancet. 2005;366:

14 CLARITY TIMI TIMI 28: Primary Endpoint Occluded Artery (or Death/MI Through Angio/HD) Occluded Artery or Death/MI (%) % Odds Reduction 15.0 n=1752 n=1739 Clopidogrel 21.7 Placebo Odds Ratio: 0.64 (95% CI, ) P= Clopidogrel Better Placebo Better Sabatine MS et al N Engl J Med 2005;352:

15 COMMIT: Effects of metoprolol on death Placebo: 1798 deaths (7.8%) Metoprolol: 1776 deaths (7.7%) % dead 1% (SE 3) relative risk reduction (2P=0.7) Days since randomisation

16 COMMIT: Effects of metoprolol on cardiogenic shock by Killip class Baseline Metoprolol Placebo Odds ratio & 95% CI Killip class (22,927) (22,922) Metop. better I 611 (3.5%) 487 (2.8%) II 362 (7.9%) 296 (6.5%) Placebo better III 155 (16.2%) 100 (10.4%) ALL 1141 (5.0%) 888 (3.9%) -29% SE 5 (2P < )

17 Enhanced Platelet Activation on UFH Unstable angina patients Samples drawn before and after heparin infusion Light transmission aggregometry (0.625 μm) Maximum (max) platelet aggregation in PRP from volunteers after adding saline, UFH, enoxaparin, or argatroban Xiao and Theroux Circulation 1998;97:

18 Should we inhibit thrombin directly or indirectly? Indirect Inhibition Direct Inhibition Heparin binding site Active site Fibrin/ogen binding site Anti-Xa:Anti-IIa ratio Hirudin Argatroban Bivalent versus univalent

19 REPLACE-2 2 Trial Design Bivalirudin vs Heparin + GP IIb/IIIa During PCI N ~ 6000 Patients: Urgent or Elective PCI Randomization - double blind, triple dummy Heparin 65 U/kg initial bolus Planned GP IIb/IIIa (abciximab or eptifibatide) target ACT > 225 sec Bivalirudin 0.75 mg/kg initial bolus, 1.75 mg/kg-hr during PCI Provisional GP IIb/IIIa (abciximab or eptifibatide) abciximab: 0.25 mg/kg bolus, μg/kg-min (max 10 μg/min) x 12 hrs eptifibatide: : 180 μg/kg double bolus, 2.0 μg/kg-min x hrs Quadruple Endpoint at 30 Days

20 Primary Quadruple Endpoint Death, MI, URev, Maj Bld (%) Odds Ratio = ( ) 10.0 Heparin+ GP IIb/IIIa (n=3008) p = Bivalirudin (n=2994) Heparin superiority boundary Heparin Better Bivalirudin Better Heparin + GP IIb/IIIa non-inferiority boundary = Odds Ratio & 95% CI 1

21 Prospective, Randomized Comparison of Heparin Plus IIb/IIIa Inhibition and Bivalirudin With or Without IIb/IIIa Inhibition in Patients with Acute Coronary Syndromes 21

22 Study Design First Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) Moderatehigh risk ACS Aspirin in all Clopidogrel dosing and timing per local practice R* UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone Angiography within 72h Medical management PCI CABG *Stratified by pre-angiography thienopyridine use or administration ACUITY Design. Stone GW et al. AHJ 2004;148:764 75

23 Canada (26) USA (246) ACUITY Enrollment 13,819 pts randomized at 448 centers in 17 countries (4) Norway Sweden (6) (5) Denmark (4) Netherlands Finland (3) (5) Belgium Poland (1) (12) UK Germany (66) (8) France Austria (4) Italy (15) (25) Spain (4) New Zealand (17) Australia

24 Primary Endpoint Measures (ITT) UFH/Enoxaparin + GPI vs. Bivalirudin Alone UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612) 30 day events (%) P NI < P Sup = % 10.1% P NI = P Sup = % 7.8% P NI < P Sup < % 3.0% Net clinical outcome Ischemic composite Major bleeding

25 Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Risk ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa RR (95% CI) P P int Age <65 (n=5051) Age 65 (n=4164) 7.8% 12.9% 9.2% 14.7% 0.86 ( ) 0.88 ( ) Men (n=6444) Women (n=2771) 9.5% 11.6% 10.9% 13.5% 0.87 ( ) 0.86 ( ) Diabetes (n=2585) No diabetes (n=6630) 10.8% 9.8% 13.7% 10.9% 0.79 ( ) 0.90 ( ) CrCl 60 (n=6993) CrCl <60 (n=1644) 8.9% 16.1% 10.4% 16.8% 0.86 ( ) 0.96 ( ) US (n=5224) OUS (n=3991) 10.6% 9.5% 11.8% 11.5% 0.90 ( ) 0.82 ( ) Bivalirudin alone better UFH/Enox + IIb/IIIa better

26 Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Risk ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa RR (95% CI) P P int Biomarkers (CK/Trop) Elevated (n=5368) Normal (n=3841) 12.2% 7.1% 13.3% 9.4% 0.92 ( ) 0.75 ( ) ST Deviation Yes (n=3197) No (n=6008) 13.0% 8.6% 13.7% 10.6% 0.96 ( ) 0.81 ( ) TIMI Risk Score Low (0-2) (n=1291) Intermed (3-4) (n=4407) High (5-7) (n=2449) Pre Thienopyridine Yes (n=5192) No (n=4023) 6.4% 10.2% 0.63 ( ) % 10.2% 0.92 ( ) % 15.2% 0.92 ( ) % 11.3% 12.2% 11.1% 0.76 ( ) 1.02 ( ) < Bivalirudin alone better UFH/Enox + IIb/IIIa better

27 Study Design Second Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Moderatehigh risk ACS (n=13,819) UFH or Enoxaparin Routine upstream GPI in all pts R GPI started in CCL for PCI only R Bivalirudin Routine upstream GPI in all pts GPI started in CCL for PCI only Routine upstream GPI in all pts (4,605) VS. Deferred GPI for PCI only (n=4,602) UFH, Enoxaparin, or Bivalirudin Aspirin in all Clopidogrel dosing and timing per local practice Bivalirudin Alone (n=4,612) ACUITY Design. Stone GW et al. AHJ 2004;148:764 75

28 Ischemic Composite Endpoint Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone Cumulative Events (%) Routine Upstream IIb/IIIa (N=4605) Estimate 7.1% 7.9% % P (log rank) Deferred PCI IIb/IIIa (n=4602) Bivalirudin alone (N=4612) Days from Randomization

29 Major Bleeding Endpoint Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone Cumulative Events (%) Routine Upstream IIb/IIIa (N=4605) Estimate P 6.1% (log rank) 4.9% % Deferred PCI IIb/IIIa (n=4602) Bivalirudin alone (N=4612) < Days from Randomization

30 ST Elevation Myocardial Infarction (STEMI) 8 6 Relationship Between Time to Reperfusion and Mortality: GUSTO-IIb 6.4 p= day mortality (%) < > 91 N: Berger et al. Circulation 1999;100:14 Time to PTCA (minutes)

31 Myocardial viability (%) Wavefront Theory of Myocardial Loss Transmural necrosis (%) min 3h 6h 24h 96h 0 3h 6h 24h Duration of occlusion Time post-occlusion 0 Reimer et al Circulation 1977;56:786-94

32 ASA vs Placebo in ISIS-II: II: Odds of Vascular Death Astrological Gemini/Libra (n=1442) Birthsign All Others (n=7157) Odds ratio and 95% CI Play of chance Unrecognized randomization error True effect Prior MI Yes No Diabetic Yes No Sex Male Female Age < Systolic BP < Heart Rate < EKG BBB IMI AMI ST ALL PATIENTS (9.4 vs 11.8% mortality) 23% When in a trial with a clearly positive result many subgroups are considered, false negative results in some particular subgroups must be expected It is clear that the best estimate of the real effect is given by the overall results derived from all subgroups combined. Modified from: ISIS-2 Lancet 1988 Aug 13;2(8607): ASA better 1 Placebo better 1.5

33 19 Randomized Trials of PCI vs Lysis N = 5,066 12% 10% 10.0% Lysis PCI Event rate 8% 6% 4% 2% 0% p= % 6.7% p= % 7.2% p< % Death Death (excl shock) Reinfarction Keeley, Grines; Lancet 2003

34 19 Randomized Trials of PCI vs Lysis N = 5,066 3% Lysis PCI 2.2% Event rate 2% 1% 1.3% P< p= % 0% 0.08% Hemorrhagic stroke Total stroke Keeley, Grines; in press

35 DANAMI-2: Patient Flow ST- elevation MI (n=1,900) Randomize 100 mg accelerated t-pat PCI (+ stent)

36 DANAMI-2 DENMARK 5.4 mill. inhabitants 5 PCI centers 24 referral hospitals 62% of the Danish population Transport distance up to 95 US miles (mean 35 miles) 100 US miles

37 DANAMI-2: Primary Results Death / MI / Stroke (%) 16% 12% 8% 4% 14% Combined P= RRR 45% 8% 16% 12% 8% 4% Transfer Sites 14% P=0.002 RRR 40% 9% 16% 12% 8% 4% Non-Transfer Sites 12% P=0.048 RRR 45% 7% 0% Lytic 0% Primary PCI 0% Lytic Primary PCI Lytic Primary PCI

38 Early Presenting Patients: Primary PCI vs Fibrinolytics 20% Lytic (STK) Transfer for PCI 10% Prehosp t-pa PCI 30-d Mortality (%) 15% 10% 5% P< d Mortality (%) 8% 6% 4% 2% P= P= % <3 hr (n=551) >3 hr (n=299) PRAGUE-2 0% <2 hr (n=460) >2 hr (n=374) CAPTIM Widimsky P, et al. Eur Heart J. 2003;24(1): Steg PG, et al. Circulation. 2003;108(23):

39 Gersh, Stone, White, Holmes JAMA 2005;293:

40 The Evolution of Optimal Myocardial Infarction Therapy Eisenhower Cheney Year: Therapy: Morphine Angioplasty/Stent Heparin Heparin Warfarin Aspirin Atropine Abciximab Clopidogrel β-blocker Statin Bed Rest: 7 Weeks < 2 Days Expected Mortality: 30% < 5%