Reperfusion Decision Making in 2014 New Insights from STREAM

Reperfusion Decision Making in 2014 New Insights from STREAM ACC Rockies 2014 Paul W Armstrong MD

Disclosure Statement Paul W. Armstrong MD Details available @ http://www.vigour.ualberta.ca Research Grants Boehringer Ingelheim Bristol Myers Squibb Eli Lilly GlaxoSmithKline Regado Biosciences Merck Consultant Regado Biosciences Astra Zeneca Data & Safety Monitoring Boards Roche Orexigen Eli Lilly Bayer 2014

Reperfusion Decision Making Overview Brief re-cap key primary result PCI-related delay: It s about time Rescue PCI Aborted MI Aligning STEMI care with guidelines: a reality check

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 STelevation in 2 contiguous leads presenting within 3 hours of symptom onset and unable to undergo primary PCI within 1 hour. N Engl J Med online March 2013

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 Aspirin Clopidogrel: 75 mg QD Enoxaparin: 0.75 mg/kg SC Q12h Antiplatelet and antithrombin treatment according to local standards ECG at 90 min: ST resolution 50% YES NO angio >6 to 24 hrs PCI/CABG if indicated immediate angio + rescue PCI if indicated Standard primary PCI Primary endpoint: composite of all cause death or shock or CHF or reinfarction up to day 30 N Engl J Med online March 2013

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 After 75y: 20% ½ dose of the TNK planned recruitment, the TNK dose was reduced by 50% among patients 75 years Aspirin Clopidogrel: 75 mg QD Enoxaparin: of age. 0.75 mg/kg SC Q12h no lytic Antiplatelet and antithrombin treatment according to local standards ECG at 90 min: ST resolution 50% YES NO angio >6 to 24 hrs PCI/CABG if indicated immediate angio + rescue PCI if indicated Standard primary PCI Primary endpoint: composite of all cause death or shock or CHF or reinfarction up to day 30 N Engl J Med online March 2013

Median Times To Treatment (Min) Sx onset 1st Medical contact Randomize IVRS TNK DANAMI 2 lysis 160 vs 188 for PCI @ PCI Hospitals 28 min diff! 62 29 9 100 min Sx onset 1st Medical contact Randomize IVRS 78 min difference PPCI 61 31 86 n=1892 1 Hour 2 Hours 178 min N Engl J Med 2013

Mortality Reduction, % Time to Rx: STREAM 100 80 60 40 20 178 min median symptom onset to sheath insertion 0 Hours 1 3 6 12 24 Gersh JAMA 2005; Armstrong: NEJM 2013

Median Times To Treatment (min) Sx onset 62 1st Medical contact Randomize IVRS 29 9 TNK 36% Rescue PCI at 2.2h 100 min 64% non-urgent cath at 17h Sx onset 1st Medical contact Randomize IVRS PPCI 61 31 86 n=1892 1 Hour 2 Hours 178 min N Engl J Med 2013

Rescue: Objectives Evaluate 30-day events in 3 subsets of per protocol Rx STEMI pts using ECG core laboratory: Rescue angio/pci for unsuccessful fibrinolysis Scheduled angio post successful fibrinolysis Primary PCI a Welsh et al AHA 2013

Definition:Pharmacoinvasive Strategy Following fibrinolysis with appropriate conjunctive anticoagulant and antiplatelet therapy; Rescue angiography/pci Failed reperfusion i.e. <50% ST resolution in worst lead ST elevation @ 60-90 min or hemodynamic instability or refractory ventricular arrhythmia Scheduled angiography Following successful reperfusion angio 6-24 hrs later Armstrong et al, Am Heart J. 2010

Reperfusion Failure 6 mm 12 mm Baseline ECG Random ization TNK 90 min Post TNK ECG - 11-0 0 97 08:40 08:51 08:51 10:28 22 Aug 2010

Reperfusion Succeeds: but Urgent PCI Required Baseline 90-min Pre-Cath Baseline ECG Random ization TNK 90 min Post TNK ECG Pre Cath ECG -33-16 0 90 85 175 19:57 20:14 20:30 22:00 23:25 29 July 2008

Per Protocol Study Cohorts 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 (n=1892) No TNK given (n=20) Cross over to Primary PCI Group A Pharmacoinvasive n=944 Randomized Group B Primary PCI n=948 TNK/other lytic given (n=8) Cross over to Pharmacoinvasive Per-Protocol/Treatment Strategy A: pharmaco-invasive (n=932) Strategy B: primary PCI (n-960) No Disease of Interest (n=4) Did not undergo cath (n=1) Urgent angio (n=32) No Disease of Interest (n=6) Did not undergo cath (n=25) No Disease of Interest (n=16) Did not undergo Cath (n=17) Rescue Angiography n=348 Scheduled angiogrpahy N=516 Primary PCI N=927 Primary endpoint: Death, shock, CHF or re MI day 30 a Welsh et al AHA 2013

Minutes Median times to treatment (min) according to treatment received 99 min 60 29 10 Rescue PCI 130 Rx TNK Sheath insertion 61 30 9 1092 100 min Scheduled PCI Sx onset 1st Medical contact Randomize IVRS Rx PPCI 60 32 76 177 min a 1 Hour 2 Hours 3 Hours 4 Hours 19.9 Hours

Angiography and Revascularization Rescue n=348 p-value Scheduled n=516 p-value Primary PCI n=927 Multi-vessel disease, % 45.7 0.305 49.3 0.164 45.4 Baseline angio TIMI Grade, % <0.001 <0.001 0/1 42.0 12.0 70.4 2 18.1 13.9 10.1 3 39.9 74.1 19.5 Post-angio/PCI TIMI Grade 3, % 85.3 <0.001 95.1 0.124 92.2 Patients receiving PCI, % 86.5 <0.001 76.2 <0.001 91.5 Stent placement during PCI, % 93.0 0.001 98.0 0.023 95.3 Post-PCI TIMI Grade 3, % 86.8 <0.001 97.3 0.027 93.6 CABG, % 4.3 0.459 5.4 0.001 2.2 Total Revascularization, % 88.5 <0.001 81.4 <0.001 92.7 a Chi-square test; the Fisher exact test was applied when the cell count was less than five patients

Baseline ECG Core laboratory evaluated ECG characteristics by treatment received Rescue n=348 p-value Scheduled n=516 p-value Primary PCI n=927 Worst lead ST-E, mm 3.0(2.0-5.0) <0.001 2.5(2.0-4.0) 0.21 3.0(2.0-4.0) Sum ST-deviation, mm 15.0(10.0-21.0) 0.004 13.5(9.0-19.5) 0.625 13.5(9.0-19.0) Q wave, % 35.8 0.088 30.2 0.506 31.9 Post-treatment ECG 90-min post-tnk 30-min Postangio/PCI Worst lead ST-E Resolution 32.7 <0.001 89.0 0.002 82.8 50%, % Worst lead residual ST-E, % <0.001 <0.001 < 1 mm 8.8 46.3 37.5 1 to < 2 mm 24.5 39.0 37.7 2 mm 66.7 14.7 24.8 Post PCI N=301 N=393 N=848 Worst lead ST-E Resolution, % <0.001 <0.001 < 1 mm 32.9 60.7 36.8 1 to < 2 mm 38.3 31.8 38.0 2 mm 28.8 7.5 25.2 a Chi-square test; the Fisher exact test was applied when the cell count was less than five patients

Dth/Shock/CHF/ReMI (%) PRIMARY ENDPOINT TNK vs PPCI Relative Risk 0.86, 95%CI (0.68-1.09) PPCI 14.3% TNK 12.4% p=0.24 a Armstrong et al N Engl J Med online publication March 2013

Dth/Shock/CHF/ReMI (%) PRIMARY ENDPOINT TNK vs PPCI Relative Risk 0.86, 95%CI (0.68-1.09) The 95% CI of the observed incidence in the pharmacoinvasive arm would exclude a 9% relative excess compared with PPCI PPCI 14.3% TNK 12.4% p=0.24 a Armstrong et al N Engl J Med online publication March 2013

Dth/Shock/CHF/ReMI (%) Primary Endpoint by treatment received 20 15 10 Rescue vs Scheduled Log-Rank: p<0.001 Relative Risk 2.92, 95%CI (1.92-4.45) PPCI vs Scheduled Relative Risk 2.32, 95%CI (1.57-3.44) Rescue 18.7% PPCI 13.9% 5 Scheduled 5.5% 0 0 5 10 15 20 25 30 Days since randomization Number at risk: Rescue: 348 291 287 284 284 283 282 PPCI: 927 822 810 804 801 797 797 Scheduled: 516 499 492 489 487 487 486 a Poisson regression model with robust error variance. Relative risks (RR) with two-side 95% CI were reported, and these associations were adjusted for the TIMI Risk Score for STEMI.

PI Strategy: Rescue angiography 40% STEMI pts presenting <3 h failed to reperfuse & received rescue angiography ~ 130 min post TNK Had higher baseline risk by clinical and ECG parameters ; Only ant MI & body weight predicted need for rescue; Following rescue PCI, ECG metrics and angio outcomes worse than those undergoing schedule angio post TNK Had increased 30 day events compared to successful fibrinolysis & ppci Welsh et al AHA 2013

Welsh et al AHA 2013 PI Strategy: Scheduled Angiography 60% of STEMI pts presenting < 3 h Sx onset successfully reperfused. Subsequent scheduled angio 18 hours revealed: Excellent angiographic, ECG metrics & clinical outcomes; A 2 fold lower risk of the composite 30 day endpoint than those receiving primary PCI (caveat post hoc sub gp) Measured approach to revasc: more medical Rx & CABG 1/5 th pts were managed medically i.e. no clinical need for revascularization after successful fibrinolysis 5.4% underwent CABG vs. 2.2% with primary PCI

Rescue: Clinical Implications* Pre-specified evaluation STEMI pts presenting <3 hrs affirms: Importance of vigilance with prompt coronary angio for STEMI pts who fail to reperfuse following fibrinolysis Enhanced understanding of PI strategy dynamics in early presenting STEMI pts unable to receive ppci < 60 min Key prognostic insights provided by post reperfusion worst lead residual ST elevation Per protocol, post hoc sub groups but unique large data set & pre-specified analysis * Welsh et al AHA 2013

Aborted MI Pre Reperfusion Post

Aborted MI: Background Aborted MI is defined by : 50 % resolution in ST-segment elevation Absent or minimal rise in cardiac biomarkers AbMI has been associated with smaller infarcts, better LV function and improved outcomes. 3 Prior studies examined AbMI after both fibrinolysis & P- PCI but no direct prospective comparison has been performed. ¹ Lamfers EJ et al., Am J Cardiol. 1999; ² Taher T et al. J Am Coll Cardiol. 2004; ³ Patel MR et al., Am Heart J 2013

Aborted MI: Objectives Compare incidence AbMI in pharmaco-invasive vs. P-PCI arms of STREAM (pre-specified) Evaluate characteristics associated with AbMI & relationship to 30-day events irrespective of Rx Examine the relationship between AbMI & the clinical outcomes according to Rx

Aborted MI: Study Cohort Study Population 1754 Group A, Pharmaco-invasive (893) Group B, Primary PCI (861) AbMI (99:11.1%) P <0.001 AbMI (59: 6.9%)

STREAM Group A Aborted MI (for presentation AHA 2013) Baseline 90-min post TNK Pre-cath Baseline ECG Random ization TNK 90min post T ECG - 18-7 0 91 12:22 12:33 12:40 14:11 11 July 2009

AbMI: Sig Associated Factors Significant factors Q wave at baseline in the infarct territory ΣST-deviation at baseline per mm OR, 95% CI Wald P value 0.44 (0.28-0.69) 0.96 (0.94-0.98) 12.6 <0.001 10.3 0.001 Symptom onset to first medical contact (hr) 0.74 (0.57-0.96) 5.3 0.021

* Adjusted for the TIMI Risk Score. AbMI: Clinical Outcomes

AbMI: Conclusions Overall incidence of AbMI was 9.0% (n=158) Rate of AbMI significantly higher for pharmaco-invasive strategy vs P-PCI, (11.1 vs. 6.9%). AbMI was associated with: improved overall 30-day outcomes; less frequent baseline Q waves; shorter time to FMC from symptom onset; less extensive territory at risk i.e. less ΣST-deviation at baseline. AbMI after pharmaco-invasive therapy had better outcomes primarily related to less shock & heart failure.

Questions have been raised about the overreliance on primary PCI for reperfusion, especially in the United States, and the unintended consequences that have evolved as familiarity with fibrinolysis has waned. The writing committee reiterates the principle highlighted in the 2004 ACC/AHA STEMI guideline, namely that the appropriate and timely use of some form of reperfusion therapy is likely more important than the choice of therapy. Greatest emphasis is to be placed on the delivery of reperfusion therapy to the individual patient as rapidly as possible. ACC/AHA STEMI Guidelines 2013

STEMI 2014 Take Home Messages We are all interventionalists Time from Sx onset is often imprecise: think baseline Q Rx delayed is Rx denied & costs myocardium & lives Time to reliably achieve successful PCI in an expert 24/7 facility is difficult to predict Dynamic Intersection between risk & time ~ efficacy Build effective STEMI teams: use systems approach incorporating full power novel IT in practice & research

Reperfusion Decision-Making 2014 Develop nimble & versatile pre hospital care system including ability to use fibrinolysis: and don t forget the large cohort of STEMI that self present Assess risk of MI & of lysis: ½ dose in 75 yrs* If lysis given: evaluate need rescue/urgent intervention especially in first few hours Transfer high risk lytic pts to PCI centre using a well organized systems based approach(with frequent QA)

FAST MI 2005: 5 yr Survival n=1492 Danchin et al ESC 2013

If the reperfusion therapy is primary PCI, the goal should be a delay (FMC to wire passage into the culprit artery) of 90 min In high-risk cases with large anterior infarcts & early presenters < 2 h, it should be 60 min) If reperfusion therapy is fibrinolysis, goal is to reduce this delay (FMC to needle) to 30 min.

Let s Settle on Achieving Quality Effective: Right drugs / procedures Timely: at right time Rapid Dx and treatment Safe: at right dose and done right Equitable: in all eligible pts Patient centered: considering the individual risks benefits, and values of this patient Cost-effective: and avoiding over-treatment IOM Definition