Updated and Guideline Based Treatment of Patients with STEMI

Updated and Guideline Based Treatment of Patients with STEMI Eli I. Lev, MD Director, Cardiac Catheterization Laboratory Hasharon Hospital, Rabin Medical Center Associate Professor of Cardiology Tel-Aviv University, Israel

Treatment goals: 1. Achieve early and effective reperfusion 2. Reduce MI complications and mortality, and preserve LV function Methodology: 1. Primary PCI restore flow in the culprit artery 2. Reduce thrombus load 3. Early and effective anti-platelet therapy

Primary PCI in STEMI Occluded RCA RCA Post PCI

23 Randomized Trials of PCI vs. Lysis 12% 10% 9.3% N = 7,739 Lysis PCI Event rate 8% 6% 4% 7.0% 7.4% 5.3% 2% 0% p=0.0002 Death p=0.0003 Death (excl shock) Keeley, Grines. Lancet 2003;361:13-20

23 Randomized Trials of PCI vs. Lysis Event rate 8% 6% 4% 2% 0% 6.8% P<0.0001 2.5% N = 7,739 P<0.0001 Lysis PCI p=0.0002 2.0% 1.0% 1.0% 0.1% Reinfarction Hemorrhagic stroke Total stroke Keeley, Grines. Lancet 2003;361:13-20

AHA/ACC, ESC Guidelines I IIa IIb III AHA/ACC 2007-2009 STEMI patients presenting to a hospital with PCI capability should be treated with primary PCI within 90 min of first medical contact as a systems goal. ESC 2010 Primary PCI is recommended in patients with chest pain <12 hrs + persistent ST-seg. elevation or previously undocumented LBBB, ASAP and at any rate <2 hrs from FMC (> 12 hrs from chest pain class IIa recom.) Based on the 2007 Focused Update of the ACC/AHA Guidelines for Management of Patients With STEMI (Circulation and JACC 2007), and the ESC guidelines for myocardial revascularization (Eur Heart J 2010)

ESC 2010 myocardial revascularization guidelines

Primary PCI in 1336 consecutive STEMI patients: Rabin Medical Center Experience 1336 pts (2001-2009) with STEMI (about 170 per year) mean age 61±13 years [range 24-101]. PCI successful in 94% of non-shock pts and 84% of shock pts. Mortality 30 day 6 months 12 months Non shock pts [n=1224] 3.5% 5.9% 7.7% Age >75yrs [n=207] 8.2% 16.2% 19.4% Age <75yrs [n=1017] 2.3% 3.8% 8.8% Male [n=982] 2.9% 4.9% 6.2% Female [n=242] 6.2% 10% 13.2% Cardiogenic shock [n=112] 55% 60% 64% RMC Database 12/2010

Markers of myocardial perfusion - ST Resolution and Myocardial Blush in STEMI Mortality-180 days(%) Sub-Analysis of the CADILLAC Trial (N=456) 12 10 8 6 4 2 10.1 P=0.01 6.3 5.1 <70%ST-Blush 0/1 >70%ST-Blush 0/1 <70%ST-Blush 2/3 >70%ST-Blush 2/3 1.2 0 One year Mortality Sorajja P. et al Eur Heart J 2005

TAPAS: Thrombus Aspiration with aspiration catheter. 1,071 patients with STEMI randomized Blush score ST Resolution @60 min 50 45 40 Control Aspiration 41 37 P=0.001 46 60 50 Control Aspiration P=0.001 44 57 35 30 25 26 32 40 30 38 31 20 15 10 5 17 20 10 18 13 0 Blush 0-1 Blush 2 Blush 3 0 <30% 30%-70% >70% Svilaas T et al. N Engl J Med 2008

TAPAS Study: Clinical Events Sig. reduction of cardiac death or non-fatal MI in Aspiration Group at 1 year -43%. Vlaar et al (TAPAS): a 1-year follow-up study, Lancet 2008; 371: 2008; 1915-20 13

TAPAS Study: Clinical Events Mortality P=0.04 Svilaas T et al. N Engl J Med 2008 Vlaar PG et al. Lancet 2008

Aspiration Meta-analysis TIMI 3 post MBG 3 8 STEMI studies, 2417 patients in aspiration group, De Luca et al, EHJ 2008

Aspiration Meta-analysis 6 month mortality 13 trials 5 trials 9 trials Bavry et al, EHJ 2008

Guidelines ESC 2010 myocardial revascularization guidelines: Manual catheter thrombus aspiration should be considered during PCI of the culprit lesion in STEMI. Class IIa recommendation, level of evidence A. ACC/AHA 2009 focused update: Aspiration thrombectomy is reasonable for patients undergoing primary PCI. Class IIa recommendation, level of evidence B. Based on the 2009 Focused Update of the ACC/AHA Guidelines for Management of Patients With STEMI (Circulation and JACC 2009), and the ESC guidelines for myocardial revascularization (Eur Heart J 2010)

Effect of Clopidogrel Pretreatment on TIMI Perfusion Grade and Clinical Outcomes in Patients Undergoing Primary PCI for AMI 292 pts with STEMI treated with primary PCI allocated into 2 groups: TMP grade 3 1. those who received clopidogrel loading before the PCI (n=165) 2. those who received clopidogrel loading immediately after PCI (n=127) P=0.01 No differences in baseline clinical characteristics. Lev E et al, AJC 2008

SCARR REGISTRY Effect of upstream clopidogrel treatment in patients with STEMI undergoing PCI. 13847 patients who underwent PCI for STEMI (2003-08) - 71% received upstream clopidogrel Rx, 29% did not After propensity score adjustment, a significant relative risk reduction (HR 0.82, 95% CI 0.73-0.93) in death/mi at 1 year was observed. The secondary endpoint of total 1-year death was significantly reduced (HR 0.76, 95% CI: 0.64-0.90). Koul S, et al. Eur Heart J 2011

New Antiplatelet Medications

Prasugrelvs. Clopidogrel : Higher IPA During Loading and Maintenance Phases Inhibition of Platelet Aggregation (%) 100 80 60 40 20 0 Loading Dose Pras 60 mg * *! * * * * Clop 600 mg! Clop 300 mg Maintenance Doses * * * Pras 10 mg * * * * Clop 75 mg Clop 75 mg mean ± SEM 20 µm M ADP * P<0.001 vs. Clop 300 mg or 600 mg LD P<0.001 vs. Clop 300! P<0.05 vs. Clop 300 P<0.05 vs Clop 300/75 0 0.25 0.5 1 2 4 6 24 3 4 5 6 7 8 9 Hours Time Days Payne CD et al. Presented at TCT 2006.

End Point (%) 15 10 5 0 TRITON-TIMI 38: Rates of Key Study End Points (All ACS, n=13,500) Clopidogrel CV Death, MI, Stroke Non-CABG TIMI Major Bleeds Prasugrel Prasugrel Clopidogrel 0 30 60 90 120 180 270 360 450 Days After Randomization 12.1 (781) 9.9 (643) P<0.001 138 events P=0.03 35 events 2.4 (146) 1.8 (111) Wiviott SD et al. New Engl J Med 2007;357:2001-2015

Stent Thrombosis (%) 3 2 1 TRITON-TIMI 38: ARC Definite/Probable Any Stent at Index PCI n=12,844 Stent Thrombosis: Clopidogrel Prasugrel 2.35 1.13 HR 0.48 (0.36-0.64) P<0.0001 RRR 52% NNT=77 ARR 1.22% 0 0 30 60 90 180 270 360 450 Days Wiviott SD et al. Lancet 2008;371:1353-1363

TRITON-TIMI 38: STEMI Subgroup (n=3,534) 7 6 5 P=0.01 Prasugrel Clopidogrel 4 3 P=0.05 P=0.045 P=0.01 P=0.4 2 1 0 All cause Death CV death RE-MI Stent thrombosis Non CABG bleeding Montalescot et al, Lancet 2009

TRITON-TIMI TIMI 38: STEMI Subgroup (n=3,534) Death MI Stroke Death MI UTVR Stent Thrombosis Non-CABG Related TIMI Major Bleeding Montalescot et al, Lancet 2009

100 Ticagrelor (180 / 90 mg) vs.clopidogrel (600 / 75 mg) IPA 90 80 70 Loading Dose * * * * * Last Maintenance Dose // * * * Ticagrelor (n=54) Clopidogrel (n=50) Placebo (n=12) 60 IPA % 50 * // 40 30 20 10 0 // // 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240 Onset Maintenance Time (hours) Offset Gurbel PA et al. Circulation 2009

PLATO -Primary efficacy endpoint (composite of CV death, MI or stroke), n=18,624 ACS patients Cumulative incidence (%) 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Clopidogrel Ticagrelor HR 0.84 (95% CI 0.77 0.92), p=0.0003 11.7 9.8 0 60 120 180 240 300 360 No. at risk Days after randomisation Ticagrelor9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel9,291 8,521 8,362 8,124 6,743 5,096 4,047 Wallentin et al., New Eng J Med. 2009;361:1045 1057

PLATO -Primary safety event-major bleeding 15 K-M estimated rate (% per year) 10 5 0 Ticagrelor Clopidogrel HR 1.04 (95% CI 0.95 1.13), p=0.434 11.58 11.20 0 60 120 180 240 300 360 No. at risk Days from first IP dose Ticagrelor9,235 7,246 6,826 6,545 5,129 3,783 3,433 Clopidogrel9,186 7,305 6,930 6,670 5,209 3,841 3,479 Wallentin et al., New Eng J Med. 2009;361:1045 1057

Primary safety event Major bleeding and secondary efficacy endpoint CV death Major Bleeding 7 Cardiovascular death K-M estimated rate (% per year) 15 10 5 0 Ticagrelor 11.58 Clopidogrel 11.20 HR 1.04 (95% CI 0.95 1.13), p=0.434 Cumulative incidence (%) 6 5 4 3 2 1 0 Clopidogrel 5.1 4.0 Ticagrelor HR 0.79 (95% CI 0.69 0.91), p=0.001 No. at risk 0 60 120 180 240 300 360 Days after randomisation 0 60 120 180 240 300 360 Days after randomisation Ticagrelor 9,235 7,246 6,826 6,545 5,129 3,783 3,433 9,333 8,294 8,822 8,626 7119 5,482 4,419 Clopidogrel 9,186 7,305 6,930 6,670 5,209 3,841 3,479 9,291 8,865 8,780 8,589 7079 5,441 4,364 Wallentin et al., New Eng J Med. 2009;361:1045 1057

PLATO STEMI substudy 8,430 patients K-M estimated rate (% per year) 12 Primary endpoint: CV death, MI or stroke 11 Clopidogrel 11.0 10 9.3 9 Ticagrelor 8 7 6 5 4 3 2 1 HR: 0.85 (95% CI = 0.74 0.97), p=0.02 0 12 No. at risk Ticagrelor 4,201 Clopidogrel 4,229 11 10 3,887 3,892 9 8 3,834 3,823 7 6 5 4 Months 3,732 3,011 3,730 3,022 3 2 2,297 2,333 1 0 1,891 1,868 Steg G et al, Circulation 2010

PLATO STEMI: 8,430 patients -All cause 7 mortality K-M estimated rate (% per year) 6 5 4 3 2 1 Clopidogrel 6.0 4.9 Ticagrelor HR 0.82 (95% CI = 0.68 0.99), p=0.04 0 12 No. at risk Ticagrelor1,993 Clopidogrel1,980 11 10 2,413 2,471 9 8 3,150 3,195 7 6 Months 3,876 3,912 5 4 3,962 3,989 3 2 4,005 4,029 1 0 4,201 4,229

K-M estimated rate (% per year) PLATO STEMI -8,430 patients: major bleeding 10 Clopidogrel 9.3 9.0 Ticagrelor 8 6 4 2 0 HR 0.96 (95% CI = 0.83 1.12), p=0.63 No. at risk Ticagrelor Clopidogrel 12 1,640 1,635 11 10 1,786 1,804 9 8 2,440 2,441 7 6 Months 3,137 3,159 5 4 3,254 3,297 3 2 3,431 3,430 1 0 4,165 4,181 Steg G et al, Circulation 2010

ACC/AHA 2009 Focused Update STEMI Guidelines Class I:A loading dose of thienopyridine is recommended for STEMI patients for whom PCI is planned. Regimens should be 1 of the following: a At least 300 to 600 mg of clopidogrel should be given as early as possible before or at the time of primary or nonprimary PCI. (Level of Evidence: C) b Prasugrel 60 mg should be given as soon as possible for primary PCI. (Level of Evidence: B)

ACC/AHA 2009 Focused update STEMI Guidelines The duration of thienopyridine therapy should be as follows: In patients receiving a stent during PCI, clopidogrel 75 mg daily, or prasugrel 10 mg daily (in pts weighing < 60 kg, consider lowering maintenance to 5 mg) should be given for 12 mo. (unless risk of bleeding is high - earlier d/c should be considered) In patients taking a thienopyridine in whom CABG is planned and can be delayed, it is recommended that the drug be discontinued withdrawal should be 5 days in pts receiving clopidogrel and 7 days in pts receiving prasugrel Prasugrel is not recommended for pts with h/o stroke or TIA

ESC 2010 Myocardial Revascularization STEMI Guidelines d Depending on approval and availability

GP IIb/IIIa inhibitors in the updated ACC/AHA 2009 STEMI guidelines

GP IIb/IIIa Inhibitors in STEMI abciximab meta-analysis Overall 46% reduction in death, reinfarction, and TVR; a 34% reduction in death or reinfarction; and 26% reduction in death Death, MI, TVR at 30 d Death, MI at 30 d Death at 30 d Topol E, Neumann FJ, Montalescot G. JACC 2003; 42:1886-9

European Meta-analysis on Individual Patient Data (n=1101) with Long-Term Follow-up Survival distribution function 1.00 0.95 0.90 0.85 0.80 Number at risk ACE, ADMIRAL, ISAR-2 Primary Endpoint Event free survival (Death/MI up to 3 years) P-value = 0.008 Abciximab Placebo 0 200 400 600 800 1000 Time Placebo 551 471 297 294 291 290 Abciximab 550 505 311 307 304 301 37% RRR 6.1% ARR NNT=19 Montalescot G, et al. Eur Heart J 2007;28:443 449.

Value of GPIIb/IIIa Inhibitors in Patients with STEMI receiving prasugrel, ticagrelor or 600 mg clopidogrel Clopidogrel BRAVE-3 trial: 800 patients with STEMI, given 600 mg clopidogrel in ICCU before PCI, randomized to receive abciximab vs. placebo. No effect on infarct size (by SPECT) or on MACE. No direct information for prasugrel and ticagrelor from dedicated studies to this question, but in TRITON and PLATO in subgroup analyses no significant differences in outcomes between pts receiving vs. not receiving GP IIb/IIIa inhibitors

Guidelines anticoagulant Rx ACC/AHA 2009 STEMI guidelines : Class I recommendation for both UFH (LOE C) (target ACT depending on whether GPIIb/IIIa inhibitors have been administered), and for bivalirudin treatment (with or without prior UFH Rx) (LOE B) ESC 2010 myocardial revascularization guidelines:

HORIZONS 1-Year Major Adverse CV Events MACE (%) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months 1800 1627 1579 1544 1394 1802 1619 1573 1540 1380 *MACE = All cause death, reinfarction, ischemic TVR or stroke Diff [95%CI] = 0.0% [-2.1, 2.2] HR [95%CI] = 1.00 [0.83, 1.21] P=0.98 11.9% 11.9% Stone G et al, NEJM 2008, Lancet 2009

Number at risk Bivalirudin alone Heparin+GPIIb/IIIa HORIZONS AMI Study 1-Year Mortality: Cardiac and Non Cardiac Mortality (%) 5 4 3 2 1 0 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 2.9% 1.8% Time in Months HR [95%CI] = 0.57 [0.38, 0.84] P=0.005 Cardiac 1800 1705 1684 1669 1520 1802 1678 1663 1646 1486 3.8% 2.1% = 1.1% P=0.03 Non Cardiac 1.3% 1.1% 0 1 2 3 4 5 6 7 8 9 10 11 12 = 1.7% Stone G et al, NEJM 2008, Lancet 2009

HORIZONS 1-Year Major Bleeding (non-cabg) Major Bleeding (%) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 12 11 10 9 8 7 6 5 4 3 2 1 0 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Diff [95%CI] = -3.4% [-5.2,[ -1.7] 1.7]2 HR [95%CI] = 0.61 [0.48, 0.78] P<0.0001 1800 1621 1601 1586 1448 1802 1544 1532 1515 1368 9.2% 5.8% Stone G et al, NEJM 2008, Lancet 2009

Bail-out indications for GP IIb/IIIa inhibitors in HORIZONS: Hemodynamic instability Inadequate reflow / No reflow Large thrombus burden

Summary: Improved outcomes in patients with STEMI can be achieved by: 1. Early and effective primary PCI 2. Reduction of thrombus load - aspiration 3. Early and effective anti-platelet therapy advantage for the new anti-platelet meds

STEMI Oral Antiplatelet Protocol Example Patient with STEMI Prior TIA/Stroke? >= 75 years old? On Warfarin Rx? High bleeding risk? No Yes Prasugrel Loading 60mg + ASA Clopidogrel Loading 600mg + ASA < 60kg? No Yes Clopidogrel 75mg + ASA Prasugrel10mg + ASA Prasugrel 5mg +ASA * Note: Ticagrelor is not yet approved in Israel

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