Treatment of Thrombotic Lesions Ramesh Daggubati, MD FACC FSCAI Director of Interventional Cardiology East Carolina University Greenville, NC USA

AMI: Pathophysiology Ruptured plaque with occlusive thrombus

Geoffrey Hartzler, M.D. First Primary Angioplasty in AMI,

0% 5% 10% 15% 20% 25% Months to event Months to event P< %22.4% 13.3%14.5% Stone GW et al. NEJM 2002;346: PTCA, abciximab PTCA, no abciximab Stent, abciximab Stent, no abciximab CADILLAC (n=2,082): 12 Month MACE

Slow flow, No reflow Increased infarct size Acute Early stent thrombosis Increased mortality 30 day Delayed stent mal-apposition Late / very late stent thrombosis Long term

THROMBUS MANAGEMENT IN AMI HOW ?

APPROACHES Pharmacologica l ThrombolysisBivalirudin GpIIbIIIa inhibitors antiplatelets ASPIRATION Export Thrombectom y Embolic Protection Distal Protection Proximal Protection Combination On site protection M Guard Self Expanding stent

MECHANICAL APPROACHES ASPIRATION ExportThrombectomy

MECHANICAL APPROACHES Embolic Protection Distal ProtectionProximal ProtectionCombination

Thrombectomy Thrombus aspiration Embolic Protection

TAPAS Trial-Results P < Patients (%) Thrombus aspiration Conventional PCI Primary end point: TIMI flow 1 Secondary endpoint (1 y) 2 N= 1071 STEMI pts 90 % Abciximab usage statistically significant MBG lower mortality at 1y Death/MI rate at 1 year FU Log rank p=0.040 Log rank p= Svilaas et al, TAPAS 30days results, NEJM 2008;358,p Vlaar et al., TAPAS 1 year results, Lancet 2008;371,9628,p.1915

 Myocardial blush grade predicts clinical outcome at 1 year  Thrombus aspiration results in a lower mortality and combined mortality and non- fatal reinfarction at 1 year FZ

Burzotta et al, EHJ 2009; 30: Potential additive benefits of Thrombus aspiration combined With pharmacological support by GPIIbIIIA -

Can we conclude “ proof of principle”? Not at all !!! Does thrombectomy improve : *ST segment resolution *TIMI 3 flow *corrected TIMI frame count * myocardial blush Some studies show benefit, not all Limit infarct size?No Improve clinical outcomes?Only in TAPAS In hospital AIMI death increased

 ESC 2010 myocardial revascularization guidelines: “Manual catheter thrombus aspiration should be considered during PCI of the culprit lesion in STEMI”.  ACC/AHA 2009 focused update: “Aspiration thrombectomy is reasonable for patients undergoing primary PCI. 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)

Ole Fröbert, MD, PhD - on behalf of the TASTE investigators Results and Methodology of a Registry based Randomized Clinical Trial (RRCT) UCR Uppsala Clinical Research Center Departement of Cardiology Örebro University Hospital Sweden

Vlaar, P.J. et al. The Lancet 2008; 371:1915 Fröbert, O. et al. Int J Cardiol. 2010; 145:572 TA+PCI (N=3 666) PCI alone (N=16 417) HR (95% CI): 1.21 ( ) / Swedish registry data

TASTE trial enrollment flow chart All patients with STEMI in Sweden and Iceland undergoing primary or rescue PCI. N= * ) Enrolled in TASTE N=7259 N=3621 assigned to thrombus aspiration N=3399 underwent thrombus aspiration N=222 underwent conventional PCI Not enrolled N=4697 N=3623 assigned to conventional PCI N=3535 underwent conventional PCI N=1162 underwent thrombus aspiration N=3445 underwent conventional PCI N=178 underwent thrombus aspiration N=3621 were followed up N=3623 were followed up N=1162 were followed up N=3535 were followed up Enrolled in Denmark N=247 Erroneous enrollments N=15 Randomized in TASTE N=7244 No patients (0) were lost to follow-up of the primary endpoint!

TASTE

HR 0.94 ( ), P=0.63 Per protocol analysis based on actual treatment: HR 0.88 ( ), P=0.38 Fröbert, O. et al. N Engl J Med 2013; 369:

HR 0.61 ( ), P=0.09 Per protocol analysis based on actual treatment: HR 0.67 ( ), P=0.19

 This large, prospective, RRCT trial showed: ◦ no reduction of mortality at 30 days ◦ no significant reduction of hospitalization for MI or of stent thrombosis at 30 days ◦ no reduction of other important clinical endpoints during hospitalization  Our findings leave little role for manual thrombus aspiration as a routine adjunct to PCI in STEMI  The RRCT concept may help to reverse the decline in randomized trials in a cheap, fast and efficient way

SS Jolly, JA Cairns, S Yusuf, B Meeks, J Pogue, MJ Rokoss, S Kedev, L Thabane, G Stankovic, R Moreno, A Gershlick, S Chowdhary, S Lavi, K Niemelä, PG Steg, I Bernat, Y Xu, WJ Cantor, C Overgaard, C Naber, AN Cheema, RC Welsh, OF Bertrand, A Avezum, R Bhindi, S Pancholy, SV Rao, MK Natarajan, JM ten Berg, O Shestakovska, P Gao, P Widimsky, V Džavík on behalf of the TOTAL Investigators

PCI Alone (only bailout thrombectomy) Routine Upfront Manual Thrombectomy followed by PCI Primary Outcome: CV death, MI, cardiogenic shock and class IV heart failure ≤180 days Safety Outcome: Stroke ≤30 days 1:1 Randomization between strategies Bailout Thrombectomy allowed if PCI alone strategy fails: Persistent TIMI 0 or 1 flow with large thrombus after balloon pre- dilatation Persistent large thrombus after stent deployment at target lesion STEMI* with Primary PCI ≤12 hours of symptom onset Sample size of 10,700 for 80% power to detect a 20% Relative Risk Reduction

North America 3863 South America 387 Europe 5617 Asia Pacific ,732 patients randomized between August 2010 and July 2014

10,732 enrolled and randomized Cross-over to Thrombectomy as initial strategy in 69 (1.4%) Bailout Thrombectomy in 355 (7.1%) Crossover to PCI alone in 230 (4.6%) TOTAL 5033 Manual Thrombectomy 5030 PCI Alone 5030 included in analysis 5033 included in analysis 10,066 underwent PCI for STEMI

Day 180Thrombect omy (N=5033) (%) PCI alone (N=5030) (%) HR95% CIp CV death, MI, shock or class IV heart failure 347 (6.9%)351 (7.0%) CV death157 (3.1%)174 (3.5%) Recurrent MI99 (2.0%)92 (1.8%) Cardiogenic Shock92 (1.8%)100 (2.0%) Class IV heart failure98 (1.9%)90 (1.8%)

Thrombecto my (N=5033) (%) PCI alone (N=5030) (%) HR95% CIp Stroke within 30 days 33 (0.7%)16 (0.3%) Stroke or TIA within 30 days 42 (0.8%)19 (0.4%) Stroke within 180 days 52 (1.0%)25 (0.5%)

Months of Follow-up Cumulative % of Stroke Thrombectomy PCI alone Hazard ratio, 2.08 (95%CI, ); P=0.0021

Thrombecto my (N=5033) (%) PCI alone (N=5030) (%) HR95% CIp CV Death, MI, shock or class IV heart failure 281 (5.6%)287 (5.7%) Stent Thrombosis59 (1.2%)69 (1.4%) Target Vessel Revascularization 126 (2.5%)132 (2.6%)

 Routine thrombectomy compared to PCI alone with only bailout thrombectomy did not reduce CV death, MI, shock or heart failure within 180 days  Routine thrombectomy was associated with increased risk of stroke within 30 days  TOTAL and TASTE emphasize the need to conduct large randomized trials of common interventions even when small trials appear positive

MECHANICAL APPROACHES On site protection M Guard

 Micro-Mesh Technology for Embolic Protection  Coronary Stent System

strut net neointima intima lumen

M GuardDES BMS

Primary and major secondary endpoints of MAGICAL Study* * ST resolution obtained from 46 patients due to technical issues TIMI 3 & MGB 3 & Complete STR

STEMI with symptom onset within 12 hours at 432 pts at 50 sites in 9 countries Substudies: Cardiac MRI: 60 pts (30 pts in each arm) at 3-5 days Angio FU: 50 pts in MGuard arm at 13 months Follow-up: 30 days, 6 months, 1 year Primary endpoint: ST-segment resolution at minutes PCI with BMS or DES PCI with MGuard R Stratified by infarct vessel and thrombus aspiration

MGuard stent (n=217) Control stent (n=214) P value MACE 4 (1.8%) 5 (2.3%) 0.75 – Cardiac mortality* – Cardiac mortality* 0 (0.0%) 4 (1.9%) 0.06 – Reinfarction – Reinfarction 3 (1.4%) 2 (0.9%) 1.00 – TLR, ischemia-driven – TLR, ischemia-driven 4 (1.8%) 1 (0.5%) 0.37 TVR, ischemia-driven 6 (2.8%) 1 (0.5%) 0.12 Stent thrombosis, def/prob 3 (1.4%) 2 (0.9%) 1.00 Stroke 1 (0.5%) 0 (0.0%) 1.00 TIMI bleeding, major/minor 4 (1.8%) 4 (1.9%) 1.00 * There were no non-cardiac mortalities Mortality at 30 days occurred in 0/211 pts with complete STR and in 4/198 pts with partial or absent STR (0% vs 2.0%, p=0.05)

Among pts with acute STEMI undergoing emergent PCI, the MGuard micronet mesh covered stent compared to conventional metallic stents resulted in superior rates of epicardial coronary flow and complete STRAmong pts with acute STEMI undergoing emergent PCI, the MGuard micronet mesh covered stent compared to conventional metallic stents resulted in superior rates of epicardial coronary flow and complete STR A larger randomized trial is warranted to verify these findings, and determine whether these benefits result in reduced infarct size and/or improved clinical outcomes (MASTER II)A larger randomized trial is warranted to verify these findings, and determine whether these benefits result in reduced infarct size and/or improved clinical outcomes (MASTER II)

In the 2010 European Guidelines on Myocardial revascularization, mesh-based protection, is now recommended for use: “Mesh-based protection may be considered for PCI of highly thrombotic or SVG lesions” (class IIb/c recommendation) *European Heart Journal (31): doi: /eurheartj/ehq277 Mesh based protection may be considered for PCI of highly thrombotic or SVG lesions M GUARD is approved by FDA for investigational use MASTER II IDE regulatory trial 2013

MECHANICAL APPROACHES On site protection Self expanding stent STENTYS

Self-expanding stents will reduce malapposition in acute MI compared to balloon-expandable stents resulting in less stent thrombosis at long term follow-up STENTYS Technology Nitinol, self-expanding stent Retractable sheath Low crossing profile 6F single-wire, rapid exchange 22 or 27 mm length

DESIGN Prospective, randomized, two- arm multicenter study OBJECTIVE To compare the STENTYS ® Stent with a balloon-expandable stent in AMI PRIMARY ENDPOINT Stent strut apposition at 3 days by OCT STUDY ORGANIZATION CEC, DSMB, Core Lab, Independent monitoring 80 STEMI patients randomized between December 2009 and June 2010 in 9 European clinical sites Control group VISION/Driver 37 pts STENTYS® 43 pts OCT & QCA at 3 days Clinical FU at 30 days and 6 months 53

C7 XR LightLab Imaging Analysis by an independent Core lab (Cardialysis) Analyzed region: stented segment plus 5 mm proximal and distal Lumen and stent area were measured at 1 mm intervals Malapposition defined as the distance between the leading edge of the strut and the leading edge of the contour bigger than the strut thickness 54 MALAPPOSEDAPPOSED Day 0Day 3 Balloon Expandable Stent Self Expandable Stent

STENTYS n = 40 Control n = 36 P Value Post PCI 2.20%5.99%< days 0.51%5.33%<0.001 Stent strut malapposition at 3 days struts per patient 10-fold reduction in malapposition with STENTYS self-expanding stent

DEFINITION MALAPPOSED STENT: ≥ 5% MALAPPOSED STRUTS STENTYS n = 40 Control n = 36 P Value 0 % 28 % < P. Barlis et al. Eur Heart J (2010) 31 (2):

 Prospective, single-arm, multi-center study designed  To assess the long term performance of Stentys Self- Apposing Stents in routine clinical practice in patients suffering from ST-elevation myocardial infarction (STEMI).  The primary endpoint, ◦ Major Adverse Cardiac Events rate (MACE, defined as cardiac death, target vessel re-MI, emergent by-pass, or clinically-driven TVR) at one year, was 9.3%, where conventional stents average 11.1% in a pooled analysis from ACTION Study Group (Pitié-Salpêtrière Hospital, Paris). ◦ At the one-year time point, the cardiac death rate was 2%, as compared with rates for conventional stents in other published trials which average 3.9%, the lowest rate being 2.2%.

Improved outcomes in patients with Thrombus Burden in STEMI can be achieved by: 1.Early and effective primary PCI 2.Reduction of thrombus load – upstream DAPT, bail out ASPIRATION or Angiojet 3.Preventing embolization of thrombus debris by onsite protection using newer stents