No-reflow - microvascular obstruction

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1 Disclosures: Research grant from Medtronic to University of Ferrara Ad Board of Abbott, Medtronic, MEDCO, Eli lilly, Iroko Speaker s bureau from Cordis, Abbott, CID Vascular, Terumo, Medtronic, Astra Zeneca, Eli Lilly, Iroko No-reflow - microvascular obstruction M. Valgimigli, MD, PhD University of Ferrara ITALY Munich, Saturday 25 th August 2012

2 Prevention and treatment of microvascular obstruction and no-reflow 2012 ESC STEMI guidelines Inadequate myocardial perfusion after successful mechanical opening of the infarct-related artery is often referred to as no-reflow. The diagnosis of no-reflow is usually made when postprocedural TIMI flow is<3, or in the case of a TIMI flow of 3 when myocardial blush grade is 0 or 1, or when ST resolution within 4 h of the procedure is <70%. Other non-invasive techniques are contrast echocardiography, singlephoton emission tomography, positron emission tomography (PET), and contrast-enhanced magnetic resonance imaging (MRI). There have been many attempts to treat no-reflow using intracoronary vasodilators, i.v. infusion of adenosine or abciximab, but there is no definitive proof that these therapies affect clinical outcomes. Likewise, although it is widely used in clinical practice, there is no firm evidence that manual thrombus aspiration reduces distal embolization

3 Uniform and widely accepted No flow: issue#1 definition on how to detect Terminology no flow is lacking Inadequate myocardial perfusion through a given segment of the coronary circulation without angiographic evidence of mechanical obstruction Inadequate myocardial perfusion after successful mechanical opening of the infarct-related artery high impedance of microvascular blood flow encountered during opening of the infarct-related coronary artery deficient reperfusion of previously ischemic tissue even though the lumen of the artery that irrigates the territory has been opened. permanently ischemic tissue despite myocardial reperfusion EHJ 2001 ESC guidelines EHJ 2010 AJR 2008 Circ 2011 NHLBI Worshop

4 No flow: issue#1 Terminology From No/Slow Reflow to Microvascular Obstruction (MVO) Shift from the epicardial artery to Microcirculation/Microvessels

5 MVO: not one single entity! Reperfusion MVO adds on to Necrotic injury Reperfusion MVO Interventional MVO Preceeding ongoing ischemia No Ischemia Condition Prototype: ppci-stemi Elective PCI esp SVG Mechanism: Microvascular dys Distal Embolisation Reperfusion injury Consequence of 1 of the following: Distal coronary emboli of thrombus, platelet, atheroma In situ thrombosis Vasospasm Inflammation

6 Infarct size Myocardial Infarction: a two-component damage Ischemia Reperfusion reperfusion injury ischemic injury coronary occlusion time

7 Contribution of Lethal Reperfusion Injury to Final Myocardial Infarct Size As much as half of the final infarct size may be dictated by RI Yellon D. NEJM 2007;357:

8 Hypothetical Construt of the Therapeutic Window for Cardioprotection Prasad A et al. Circualtion 2009; 120: 2105

9 Major Differences between Animal Models and Clinical Studies of Patients with Acute Myocardial Infarction

10 MVO treatment/prevention Anti-thrombotics: 2b3a inhibitors Bivalirudin Thrombectomy: in Humans Manual or Mechanical Other, Specific, therapies: Mitochondrial Permeability Transition Pore modulation

11 % LV 40 BRAVE-3: Abciximab on top of 600 Primary Endpoint Final infarct size Mean mg Clopidogrel 800 pts recruited within 24 hours from symptoms onset Secondary Endpoint 30-d P =.47 6 >50% pts received drug >4 hour delay >50% pts received PCI >5 hour delay 2 Abciximab Placebo 0 Abciximab Placebo Circ 2009;119:

12 BRAVE-3: Abciximab on top of 600 mg Clopidogrel TIME Matters

13 ON-TIME 2 Trial Acute myocardial infarction diagnosed in ambulance or referral center ASA+600 mg Clopidogrel Placebo Tirofiban * Transportation Angiogram PCI centre Angiogram Tirofiban provisional PCI Tirofiban cont d *Bolus: 25 µg/kg & 0.15 µg/kg/min infusion

14 1 Year Survival: Patients with Primary PCI open label & double-blind, n = P = 0.007

15 Subgroup Analysis Does time matter only for GPI? What about other antiplatelet agents??

16 Effects of Clopidogrel on Death, Re-MI or Stroke by Time Delay and Fibrinolytic Use Baseline Clopidogrel Placebo features (n=22,958) (n=22,891) Odds ratio & 95% CI Clopidogrel better Placebo better Time delay (hours) (9.3%) 904 (10.9%) (9.7%) 735 (10.7%) (8.8%) 666 (8.7%) Fibrinolytic used Yes 1005 (8.8%) 1123 (9.9%) No 1120 (9.7%) 1188 (10.3%) ALL 2125 (9.3%) 2311 (10.1%) 9% reduction p= Chen ZM et al. Oral presentation ACC 2005, April 5, 2005.

17 BRAVE-3: Abciximab on top of 600 mg Clopidogrel TIME Matters

18 Intramyocardial hemorrhage and microvascular obstruction after primary PCI Reperfusion may cause intramyocardial hemorrhage (IMH) by extravasation of erythrocytes through severely damaged endothelial walls. Int J Cardiovasc Imaging (2010) 26:49 55

19 Hemorrhage has always been found to be associated with MVO, however, the causal relationship between the two is currently unknown. We speculate that blood spilt in the interstitium might have compressed the microvasculature that was already vulnerable due to the initial ischemic insult; in other words, hemorrhage may have created the MVO. Our preliminary study suggests that hemorrhage may not simply be a bystander but An active contributor to adverse left-ventricular remodeling following AMI.

20 Working hypothesis Bivalirudin (direct thrombin inhibitor) May reduced IMH as more gentle anti-thrombotic than UFH+GPI Thrombin seems to be Deeply invovled in MVO Prolonged full dose post-pci Infusion protocol with MRI being discussed in humans

21 Patients (%) Primary endpoint: Myocardial blush grade 60 P < / Thrombus aspiration Conventional PCI Svilaas T et al. NEJM 2008;358:557

22 Clinical Outcomes at 1 year Direct stenting: 55.1% in Thrombectomy arm vs. 28.6% in conventional PCI 12 Conventional PCI Thrombus-Aspiration 10 Mortality (%) Log-Rank p = Time (days) Death or Reinfarction (%) 12 Conventional PCI Thrombus-Aspiration Log-Rank p = Time (days)

23 Time Course of Distal Embolization 64 patients with distal embolization , ,4 17, ,7 Baseline Wire Balloon Stent Napodano M. TCT 2005

24 How does manual thrombectomy reduce mortality? No difference in infarct size in TAPAS based on peak cardiac enzyme Svilaas T et al. NEJM 2008;358:557 No difference in infarct size at MRI examination in the multicenter study INFUSE- MI Stone GW, JAMA. 2012;307(17)

25 RI Molecular Pathways Mitochondrial Permeability Transition pore opening

26 RI: Therapeutic targets/agents Statins ANP EPO Adenosine PI3, AKT, ERK Mechanical stimuli Ischemic pre and Post conditioning Cyclosporine

27 Protecting the heart against reperfusion injury: endogenous protection Prehospital remote ischaemic conditioning increases myocardial salvage in acute myocardial infarction. Lancet 2010;in press. Botker HE, Kharbanda RK, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Anderson NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HF, Redington AN, Nielsen TT. Intermitent arm ischemia before reperfusion Reduced reperfusion injury at PPCI

28 Remote Ischemic Conditioning to Protect against Ischemia-Reperfusion Injury: A Systematic Review and Meta-Analysis 23 studies including pts undergoing cardiac surgery n=15, PCI=4, vascular surgery=4 PLoS One. 2012; 7(7): e42179 Mortality

29 Adenosine as an Adjunct to Reperfusion in the Treatment of Acute Myocardial Infarction (n=2118) n = 243 (AMISTAD-2 et al. JACC 2005)

30 Adenosine as an Adjunct to Reperfusion in the Treatment of Acute Myocardial Infarction post hoc study (n=2118) % 1 month death Adenosine Placebo 0 < 3 hours > 3 hours (AMISTAD-2 et al. EHJ 2006)

31 3-day infusion of (p=0.016) ANP 1-day infusion of Nicorandil

32 A single dose of erythropoietin in ST-elevation myocardial infarction. HEBE III study Primary endpoint Secondary endpoints. All cardiovascular events Cardiovascular death EPO, n=263 Emergency re-pci for In-stent thrombosis/reinfarction Unstable angina Control, n=266 P-value Stroke Heart failure LVEF by planar radionucleide VTG-500 MBq of 99mTc-pertechnetate mean left ventricular ejection fraction (± SD), 6 weeks after a successful primary coronary intervention. Voors A A et al. Eur Heart J 2010;31:

33 Sinlge EPO (50K U) prior PCI Heart 2011;97:1560e1565

34 Protecting the heart against reperfusion injury: pharmacological protection csa CK release NMR imagaing

35 Closing note from the paper: Ultimately, convincing demonstrations of cardioprotection in patients with acute myocardial infarction can come only from rigorously designed trials that follow on from reliable laboratory studies, using the most appropriate drugs, administration protocols, and clinical scenarios.