The Strategic Reperfusion Early After STEMI study Implications for clinical practice

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1 The Strategic Reperfusion Early After STEMI study Implications for clinical practice Robert C. Welsh, MD, FRCPC Associate Professor of Medicine Director, Adult Cardiac Catheterization and Interventional Cardiology Co-Chair, Vital Heart Response Co-director, U of A Chest Pain Program

2 Disclosures past 5 years Research funding: Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers-Squibb, Eli Lilly, Johnson and Johnson, Pfizer, Portola, Regado, Roche, sanofi aventis Consultant/honorarium: Astra Zeneca, Bayer, Bristol Myers-Squibb, Edwards Lifesciences, Eli Lilly, Medtronic, Roche, sanofi-aventis

3 Reperfusion Therapy

4 Reperfusion Therapy Experiments in animal models -Ischemic necrosis begins in the subendocardium within 20 minutes of coronary occlusion -Reperfusion achieved within the first hour salvages nearly two-thirds of the myocardium at risk thereafter abrupt declining such that little or no salvage is evident after three to six hours of ischemia. Reimer KA, Lowe JE, Rasmussen MM, et al. The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation 1977; 56:

5 Primary PCI is the dominant reperfusion strategy but Regional STEMI programs have diminished reperfusion treatment delay but timely primary PCI remains improbable for many Primary PCI is a complex, multi-disciplinary and time-sensitive intervention only available in a minority of hospitals (one out of five U.S. hospitals have primary PCI capacity) 2. The acceptable delay for withholding pharmacological reperfusion in anticipation of PCI is not static and is dependent upon individual patient and temporal characteristics In patients with high-risk clinical presentation and/or characteristics that predict complications of pharmacological reperfusion; a longer delay to mechanical reperfusion is justified In early presenting patients (<3 hours) the acceptable delay is abbreviated

6 Primary Percutaneous Coronary Intervention Door-to-Balloon Time and Mortality in Patients Hospitalized with ST-Elevation Myocardial Infarction: Is 90 Minutes Fast Enough? 30 day mortality Time (min) 30-d Mortality 1-Year Mortality Adjusted Adjusted ( ) 8.8 ( ) ( ) 12.9 ( ) ( ) 16.6 ( ) ( ) 19.9 ( ) ( ) 22.9 ( ) ( ) 25.5 ( ) ( ) 27.7 ( ) ( ) 29.5 ( ) ( ) 30.9 ( ) N= year mortality N=1932 Rathore SS, et al, Am J Cardiol Nov 1;104(9):

7 Which Early ST Elevation Myocardial Infarction Therapy?

8 Primary efficacy endpoint (%) Primary 30-day Composite 30-day Death, Re-MI, Refractory Ischemia, CHF, Cardiogenic Shock or Major ventricular arrhythmia A 25.0% B 24.0% 20 C 23.0% Days Armstrong PW. Eur Heart J Jul;27(13):1530-8

9 30-day Death / MI (%) Death & Re-MI 30-days p=0.02 log rank A vs C A 13.0% B 6.7% C 4.0% Days Armstrong PW. Eur Heart J Jul;27(13):1530-8

10 A pooled analysis of an early fibrinolytic strategy versus expediated primary PCI from CAPTIM and WEST Sx to Rand n<2h n=364 Sx to Rand n 2h n=275 Sx to Rand n<2h n=289 Sx to Rand n 2h n=234 Westerhout et al, Am Heart J Feb;161(2):283-90

11 A pooled analysis of an early fibrinolytic strategy versus primary PCI from CAPTIM and WEST One year survival by time to treatment p=0.021 FL<2h versus PCI<2h Westerhout et al, Am Heart J Feb;161(2):283-90

12 STREAM STRATEGIC REPERFUSION EARLY AFTER MYOCARDIAL INFARCTION F. Van de Werf, ACC 2013

13 F. Van de Werf, ACC 2013

14 STUDY AIM A strategy of early fibrinolysis followed by coronary angiography within 6-24 hours or rescue PCI if needed was compared with standard primary PCI in STEMI patients with at least 2 mm ST-elevation in 2 contiguous leads presenting within 3 hours of symptom onset and unable to undergo primary PCI within 1 hour. Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

15 PCI Hospital Ambulance/ER STUDY PROTOCOL STEMI <3 hrs from onset symptoms, PPCI <60 min not possible, 2 mm ST-elevation in 2 leads RANDOMIZATION 1:1 by IVRS, OPEN LABEL Strategy A: pharmaco-invasive Strategy B: primary PCI <75y:full dose 75y: ½ dose TNK no lytic Aspirin Clopidogrel: LD 300 mg + 75 mg QD Enoxaparin: 30 mg IV + 1 mg/kg SC Q12h ECG at 90 min: ST resolution 50% YES angio >6 to 24 hrs PCI/CABG if indicated Aspirin Clopidogrel: 75 mg QD Enoxaparin: 0.75 mg/kg SC Q12h NO immediate angio + rescue PCI if indicated Antiplatelet and antithrombin treatment according to local standards Standard primary PCI Primary endpoint: composite of all cause death or shock or CHF or reinfarction up to day 30 Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

16 PCI Hospital Ambulance/ER STUDY PROTOCOL STEMI <3 hrs from onset symptoms, PPCI <60 min not possible, 2 mm ST-elevation in 2 leads RANDOMIZATION 1:1 by IVRS, OPEN LABEL Strategy A: pharmaco-invasive Strategy B: primary PCI <75y:full dose Aspirin Clopidogrel: LD 300 mg + 75 mg QD Enoxaparin: 30 mg IV + 1 mg/kg SC Q12h ECG at 90 min: ST resolution 50% YES angio >6 to 24 hrs PCI/CABG if indicated After 75y: 20% ½ of dose the TNK planned recruitment, the TNK dose was reduced by 50% among patients 75 Aspirin Clopidogrel: 75 mg QD Enoxaparin: 0.75 years mg/kg of SC age. Q12h NO immediate angio + rescue PCI if indicated no lytic Antiplatelet and antithrombin treatment according to local standards Standard primary PCI Primary endpoint: composite of all cause death or shock or CHF or reinfarction up to day 30 Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

17 BASELINE CHARACTERISTICS (1) Pharmaco-invasive (N=944) PPCI (N=948) Age (yrs) 59.7 (12.4) 59.6 (12.5) Age 75 y (%) 14% 13% Women (%) 21% 22% Weight (kg) 80.5 (14.8) 80.0 (14.9) Killip class (%) I II/III IV 94% 6% <1% 94% 5% <1% Heart rate (bpm) 74.9 (18.4) 75.5 (18.1) Systolic BP (mmhg) (22.7) (23.3) Infarct location Data are mean (SD) or % Anterior Inferior Other 48% 50% 2% 46% 53% 2% Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

18 BASELINE CHARACTERISTICS (2) Pharmaco-invasive (N=944) PPCI (N=948) Previous MI 9% 10% Previous PCI 6.4% 8.8% Previous CABG <1% <1% Previous congestive heart failure <1% 2% Hypertension 47% 44% Diabetes 12% 13% Data are % Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

19 MEDIAN TIMES TO TREATMENT (min) Rx TNK min Sx onset 1st Medical contact Randomize IVRS 78 min difference Rx PPCI n= Hour 2 Hours 178 min Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

20 MEDIAN TIMES TO TREATMENT (min) Rx TNK 36% Rescue PCI at 2.2h 100 min 64% non-urgent cath at 17h Sx onset 1st Medical contact Randomize IVRS Rx PPCI n= Hour 2 Hours 178 min Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

21 TIMI FLOW RATES P<0.001 P=0.41 TIMI before PCI TIMI after PCI Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

22 INVASIVE PROCEDURES Pharmaco-invasive (N=944) PPCI (N=948) P-value PCI performed 80% 90% <0.001 Stents deployed 96% 96% 0.95 CABG performed 4.7% 2.1% Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

23 Dth/Shock/CHF/ReMI (%) PRIMARY ENDPOINT TNK vs PPCI Relative Risk 0.86, 95%CI ( ) PPCI 14.3% TNK 12.4% p=0.24 All cause death or shock or CHF or reinfarction up to day 30 Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

24 SINGLE ENDPOINTS UP TO 30 DAYS Pharmaco-invasive PPCI P-value (N=944) (N=948) All cause death (43/939) 4.6% (42/946) 4.4% 0.88 Cardiac death (31/939) 3.3% (32/946) 3.4% 0.92 Congestive heart failure (57/939) 6.1% (72/943) 7.6% 0.18 Cardiogenic shock (41/939) 4.4% (56/944) 5.9% 0.13 Reinfarction (23/938) 2.5% (21/944) 2.2% 0.74 Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

25 IN-HOSPITAL BLEEDING COMPLICATIONS Pharmaco-invasive (N=944) PPCI (N=948) P-value Major non-ich bleeding 6.5% 4.8% 0.11 Minor non-ich bleeding 21.8% 20.2% 0.40 Blood transfusions 2.9% 2.3% 0.47 Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

26 Subgroup analyses for primary endpoint within 30 days OVERALL Age <75 years 75 years Time to randomization 0 to <2h 2h Male Female Systolic blood pressure <100 mmhg 100 to <140 mmhg 140 to <160 mmhg 160 mmhg Killip class I II-IV Anterior MI Inferior MI Other MI Relative Risk (95%CI) P(interaction) > TNK Better PPCI Better Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

27 Subgroup analyses for primary endpoint within 30 days Hypertension, Yes No Diabetes, Yes No Weight, <60 kg 60 to <90 kg 90 kg Place of randomization, Ambulance Community hospital TIMI Risk Score, <5 points 5 points Before Amendment After Amendment Relative Risk (95%CI) p=0.07 P(interaction) > > TNK Better PPCI Better F. Van de Werf, ACC Armstrong PW et al. NEJM, 2013

28 STROKE RATES Pharmaco-invasive PPCI P-value TOTAL POPULATION (N=1892) Total stroke 15/939 (1.60%) 5/946 (0.53%) 0.03 fatal stroke 7/939 (0.75%) 4/946 (0.42%) 0.39 Haemorrhagic stroke 9/939 (0.96%) 2/946 (0.21%) 0.04 fatal haemorrhagic stroke 6/939 (0.64%) 2/946 (0.21%) 0.18 POST AMENDMENT POPULATION (N=1503) Total stroke 9/747 (1.20%) 5/756 (0.66%) 0.30 fatal stroke 3/747 (0.40%) 4/756 (0.53%) >0.999 Haemorrhagic stroke 4/747 (0.54%) 2/756 (0.26%) 0.45 fatal haemorrhagic stroke 2/747 (0.27%) 2/756 (0.26%) >0.999 Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

29 CONCLUSIONS - STREAM A strategy of fibrinolysis with bolus tenecteplase and contemporary antithrombotic therapy given before transport to a PCI-capable hospital coupled with timely coronary angiography: circumvents the need for an urgent procedure in about two thirds of fibrinolytic treated STEMI patients. is associated with a small increased risk of intracranial bleeding (not observed post amendment). is as effective as primary PCI in STEMI patients presenting within 3 hours of symptom onset who cannot undergo primary PCI within one hour of first medical contact. Armstrong PW F. Van et de al. Werf, NEJM, ACC 2013

30 Clinical implications Long Term Impact of Heart Failure Post MI 40% Ezekowitz JA et al. J Am Coll Cardiol Jan 6;53(1):13-20.

31 Vital Heart Response Contemporary Management of Acute MI Pre-hospital ambulance Pre-hospital fibrinolysis Pre-hospital triage for PCI or in-hospital fibrinolysis higher 0 Patient Risk Pre-hospital fibrinolysis Pre-hospital triage for in-hospital fibrinolysis lower Tertiary hospital Rescue PCI Transfer for Primary PCI Community hospital Adapted from Welsh et al AHJ, Jan 2003

32 Vital Heart Response -Reperfusion Strategy Metropolitan (MP) and Non-Metropolitan patients (NM) Shavadia et al. CJC, 2013

33 In-hospital outcomes Metro (n=1990) Nonmetro (n=1602) P Death n,(%) 136 (6.8) 69 (4.3) Congestive heart failure n,(%) 129 (6.5) 94 (5.9) Cardiogenic shock n,(%) 247 (12.4) 202 (12.6) Cardiac arrest n,(%) 227 (11.4) 180 (11.2) Re-infarction n,(%) 13 (0.65) 10 (0.62) Cerebrovascular event n,(%) 21 (1) 11 (0.67) Hemorrhage n Ischemic n Composite of death, re-mi, card arrest 335 (16.8) 242 (15.1) Shavadia et al. CJC, 2013

34 Multivariable logistic regression model 5 of the composite event of death, re-mi, cardiogenic shock and congestive heart failure Adjusted OR (95% CI) p-value Age (yrs) 1.03 (1.02, 1.04) < Hypercholesterolemia 0.74 (0.60, 0.90) Diabetes 1.75 (1.38, 2.21) < Non-metropolitan site 0.81 (0.50, 1.30) 0.37 Fibrinolysis 0.41 (0.26, 0.67) < The overall model is significant (LR χ 2 (6) = with p-value < ). The model fits the data well (Hosmer-Lemeshow χ 2 (6) = 1.17 with p-value = 0.979; C-statistic=0.66). Shavadia et al. CJC, 2013

35 Vital Heart Response Clinical impact of aborted STEMI * * * N= * P <= 0.05 comparison between aborted MI vs. STEMI Bainey et al. ACC 2013, abstract

36 Vital Heart Response 35% 30% 25% 20% 15% 10% 5% 0% Temporal analysis of aborted MI rates according to reperfusion therapy Time of symptom onset to reperfusion P total therapy trend <0.001 PCI Fibrinolysis Total Bainey et al. ACC 2013, abstract

37 STREAM Implications for clinical practice 1. STREAM supports maintenance of a dual STEMI reperfusion strategy within appropriately designed systems of care 2. In patients 75 yrs. ½ TNK may (should) be considered 3. Additional analysis including CVC ECG core lab analysis and 1 year follow up will further define optimal STEMI reperfusion strategies