1. DR.MANISH VINAYAK PDT-CARDIOLOGY IPGMER

2. In 1977, using a wire-tipped balloon, Dr Andreas Gruentzig performed the first percutaneous coronary intervention on a blockage in Mr Adolph Bachmanns left anterior descending coronary artery. The continued success of this pioneering event has been documented by follow-up angiography at 10 years and again at 23 years postprocedure. It is indeed very fortunate for the field of interventional cardiology that Mr Bachmanns left anterior descending artery blockage did not recur. 3. IMPORTANT POINTS TO DIFFERENTIATE STENT THROMBOSIS FROM INSTENT RESTENOSIS: 1. MODE OF PRESENTATION 2. TIME FRAME FROM ORIGINAL IMPLANTATION 3. ANGIOGRAPHIC FEATURES 4. IVUS 5. INTRAPROCEDURAL FINDINGS ( Neointimal tissue is hard and is associated with balloon slippage, whereas thrombus is soft ) 4. STENT THROMBOSIS ST is a rare but usually catastrophic event, leading to acute vessel closure, frequently manifests as STEMI or sudden cardiac death. The problem was rst highlighted during the 2006 European Society of Cardiology and World Congress of Cardiology Meeting in Barcelona, Spain, when the results of two independent meta-analyses were presented demonstrating a higher mortality with DES. This rapidly became known as the ESC Firestorm. 5. ARC (2007) DEFINITION OF STENT THROMBOSIS Definite: Clinical syndrome (ACS or AMI) and angiographic evidence of thrombus or occlusion or pathologic evidence of acute thrombosis Probable: Unexplained death < 30 days or target vessel AMI without angiographic confirmation of thrombosis or other identified culprit lesion Possible: Unexplained death after 30 days. 6. TIMING OF STENT THROMBOSIS TYPE OCCURENCE INCIDENCE ACUTE 1 day + SUBACUTE 2-30 days +++ LATE 2-12 months ++ VERY LATE > 1 year ++ 7. INCIDENCE OF STENT THROMBOSIS Stent thrombosis after BMS typically occurs within the first 30 days after implantation In contrast, stent thrombosis after DES can occur years afterward, with an annual incidence of 0.2% to 0.3% in patients with noncomplex coronary artery disease and 0.4% to 0.6% after unrestricted use. 8. If we take into account stent thrombotic events after procedures for restenosis (so called secondary stent thrombosis events, which occur more commonly after BMS than DES), the overall incidence of stent thrombosis (primary plus secondary) does not seem to be increased with DES compared to BMS, and the overall late rates of death and MI are similar with DES and BMS. 9. PROGNOSIS FOLLOWING STENT THROMBOSIS Stent thrombosis has been associated with 30-day mortality rates of 10% to 25%. 20% of patients with a first stent thrombosis experience a recurrent stent thrombosis episode within 2 years. Furthermore, a study of 985 patients who underwent primary angioplasty for STEMI, which included 102 patients with denite ST, demonstrated a higher occurrence of in- hospital death or recurrent MI in those presenting with ST rather than STEMI secondary to a de novo lesion (P = 0.05) Also in STEMI secondary to ST, there was a larger thrombus burden, more frequent distal embolization and less successful results from PCI 10. Mechanisms of stent thrombosis PATIENT FACTORS LESION FACTORS PROCEDURAL & MEDICAL RX FACTORS 11. PREDICTORS OF STENT THROMBOSIS PATIENT LESION PROCEDURE 1. Diabetes 2. Chronic kidney disease 3. Acute presentation 4. Smoker 5. Reduced left ventricular function 6. Cancer 7. DAPT nonresponsiveness 8. Premature cessation of DAPT 9. Advanced age 10. Thrombocythaemia 11. Hypersenstivity to polymer or drug. 1. Long segment disease 2. Small vessel diameter 3. Saphenous venous graft 4. Chronic total occlusion 5. Bifurcation lesion. 1. Stent underexpansion 2. Stent malapposition 3. Struct fracture 4. Edge dissection 5. Multiple stents 6. Stent overlap 7. Geographic miss and residual stenosis 8. Reduced TIMI flow 12. THROMBOGENICITY OF THE STENT A predisposition for the development of stent thrombosis has been observed with certain stent materials; for example, platelet activation was greater with an open-cell versus a closed-cell stent. Stent strut thickness and polymer type and thickness also play an important role. It has been reported that the nonerodable polymers of the Cypher and Taxus DES provoke chronic eosinophilic infiltration of the arterial wall, suggestive of hypersensitivity reactions. All cases of hypersensitivity occur 4 months after DES implantation i.e hypersensitivity reaction peaks after the complete release of the drug and so is likely related to the polymer. 13. DRUGS LOADED ON DES EXERT PROTHROMBOGENIC EFFECT Lscher T F et al. Circulation. 2007;115:1051-1058 Copyright American Heart Association, Inc. All rights reserved. 14. In sirolimus-eluting stents, 80% of the rapamycin has eluted by 30 days, whereas paclitaxel-eluting stents have a biphasic drug release profile in with an initial burst during the first 48 hours after implantation followed by a sustained low-level release for at least 2 weeks. However, both rapamycin and paclitaxel easily penetrate into cells of the vessel wall owing to their lipophilic properties, which leads to chronic retention of the drug in the arterial tissue. Thus, both rapamycin and paclitaxel-induced tissue factor expression may contribute to a prothrombotic environment after deployment of DES, particularly in the acute and subacute setting and possibly in late stent thrombosis. 15. IMPAIRED ENDOTHELIZATION Lscher T F et al. Circulation. 2007;115:1051-1058 Copyright American Heart Association, Inc. All rights reserved. 16. Temporal sequence of Reendothelialization in BMS and DES. Lscher T F et al. Circulation. 2007;115:1051-1058 Copyright American Heart Association, Inc. All rights reserved. 17. Risk Factors for Different Time Points of DES Thrombosis When a ST develops acutely, it is generally due to procedural-related factors & in setting of Primary PCI. The commonest reason for subacute and late ST is the discontinuation of DAPT. Risk factors for the development of very late ST are not so well dened. Possible explanation for such late occurrence are incomplete neointimal coverage, ongoing vessel wall inammation and late acquired stent malapposition (LASM). 18. HOW TO MINIMIZE STENT THROMBOSIS Risk factors pertaining to the patients history and lesion characteristics are non-modiable; however, the procedure can be performed optimally to reduce the incidence of ST. Assess likely adherence to the necessary DAPT regimen, the bleeding risk and the need for any planned surgical procedures in the following 12 months. 19. PROCEDURAL OPTIMIZATION Regarding Anticoagulation: Conventinally UFH GPIIb/IIIa inhibtors CADILLAC trial, abciximab use was an independent predictor of no ST (P = 0.026). (HORIZONS-AMI) trial : Acute ST occurred in patients assigned to bivalirudin more frequently (P208PRU by VerifyNow) was observed less frequently than expected and there was a low occurrence of the primary endpoint of cardiac death or MI. 27. Newer antiplatelet agents, prasugrel and ticagrelor , are more potent, with a consequent reduction in ST. Non responders to clopidogrel also respond well to these newer agents . There is also the option of adding in therapy such as cilostazol, a phosphodiesterase inhibitor . This has been shown in a registry study of 3,099 patients to reduce the risk of ST at 12 months as compared to DAPT only (P = 0.0036), with no increase in bleeding complications. However, most studies of cilostazol have been performed in Asians and have not been validated in the Western population. 28. Stent Thrombosis in new-generation drug-eluting stents in patients with ST-Elevation Myocardial Infarction undergoing primary percutaneous coronary intervention: a report from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) Giovanna Sarno, Bo Lagerqvist, Johan Nilsson, Ole Frobert, Kristina Hambraeus, Christoph Varenhorst, Ulf Jensen, Tim Tdt, Matthias Gtberg, Stefan James Department of Cardiology and Uppsala Clinical Research Center Uppsala University Sweden 29. Purpose To evaluate stent thrombosis (ST) rate up to 3 years in patients with STEMI, treated by primary PCI with new generation drug-eluting stents (n-DES) as compared with bare metal stents (BMS) and old generation drug eluting stents (o-DES) 30. Stent Classification BMS stents: Multilink, Multilink MiniVision and Flexmaster Driver and Micro Driver (Medtronic Inc), Braun Coroflex Blue o-DES stents: Cypher and Cypher Select (Cordis), Taxus Express and Taxus Libert (Boston) Endeavor (Medtronic Inc.) n-DES stents: Resolute (Medtronic ), XienceV, Xience Prime, Promus, Promus Element (Boston ) 31. New generation DES Thinner polymer, more biocompatible In some devices also bio-absorbable Cobalt-chromium or Platinum-chromium stent alloy Higher flexibility, conformability and deliverability Alternative anti-proliferative eluting- drugs Everolimus, Biolimus, Zotarolimus 32. Methods Primary endpoint: Rates of definite stent thrombosis Secondary endpoint: Death Source: - SCAAR (the Swedish Coronary Angiography and Angioplasty Registry) data from 2007 to 2013 with consecutive enrolment in all 29 PCI centers in Sweden - Patients with cardiogenic shock were excluded The adjusted hazard ratio (HR) of the primary and secondary endpoints was calculated using Propensity Score adjustments and Logistic Regression 33. Stent Thrombosis up to 3 years Landmark analysis Adjusted risks of definite stent thrombosis n-DES vs. BMS o-DES vs. BMS n-DES vs. o-DES Early/Late ST HR 0.65; 95% CI: 0.43-0.99, HR 0.60; 95% CI: 0.41-0.89, HR 0.73; 95% CI: 0.44-1.21, p= 0.04 p= 0.01 p= 0.22 Very Late ST HR 1.52; 95% CI: 0.78-2.98, HR 2.88; 95% CI: 1.70-4.89, HR 0.77; 95% CI: 0.23-1.47, p= 0.21 p40%, B / C-type lesions >85%) BASE-ACS study suggest that a stent coated with Titanium- Nitride-Oxide (TITAN-2 BAS) represents a safe and effective alternative to Xience-V EES in ACS patients COULD A BARE METAL STENT BE NONINFERIOR TO A LEADING DES? 54. GENOUS STENT The Genous Stent (Genous Bio-engineered Stent, OrbusNeich Medical Technologies) was the first to capture EPCs to the stent site through a coating of anti-CD34 antibodies immobilized on the stent surface, with the aim of improving the poor endothelialization associated with DES. The antibodies bind to the CD34 membrane protein expressed on the cell surface of EPCs, thus anchoring the cells to the stent. This novel technology was shown to promote the coronary vascular repair response and reduce neointimal hyperplasia up to 18 months after stent implantation. The beneficial effects of the Genous Stent did not, however, decrease the rate of target lesion failure compared with DES. 55. The Combo Dual Therapy Stent (OrbusNeich Medical Technologies) is the first stent to combine a luminal anti-CD34 antibody with antiproliferative abluminal sirolimus elution. It is composed of a stent that has an abluminal (facing the vessel wall) coating of bioabsorbable polymer matrix formulated with sirolimus (5 mcg/mm of stent length) for sustained release and a luminal anti-CD34 antibody cell capture coating. This is an attractive concept because sirolimus minimizes the probability of stent restenosis through the inhibition of neointimal formation, whereas anti-CD34 capture of EPCs reverses sirolimus-mediated inhibition of local endothelial cells and thus prevents delayed re-endothelialization. 56. COMBO STENT 57. The REMEDEE study, which is the only study to date that has been conducted in humans comparing the Combo Stent and DES, randomly assigned 183 patients undergoing PCI in a 2:1 fashion to either Combo Stents (n=124) or paclitaxel-eluting stents (Taxus, Boston Scientific; n=59). The primary endpoint of noninferiority regarding angiographic in-stent late lumen loss at 9 months was met (noninferiority P=.001; superiority P=.55). Additionally, the Combo group when compared with the DES group, although not statistically significant, showed a trend toward less MACE (8.7% vs. 11%), TLR (5.2% vs. 9.5%), in-segment late lumen loss (0.27 mm vs. 0.41 mm) and 17% less neointimal hyperplasia volume (21.53 21.71 vs. 25.95 18.65). 58. EGO-Combo Study Oral presentation Prof. Stephen Lee, TCT 2013 Note: Strut coverage assessed by OCT Mean covered struts % increased rapidly from 84.3%, 90.2%, 90.5% to 92% from 2nd to 5th months. Interpolated 100% coverage at around 150 days The first DES with a Healing Profile established 3 months DAPT is enough for 70% coverage 5 months DAPT is enough for 100% coverage 28 59. Temporal sequence of Reendothelialization in BMS and DES. Lscher T F et al. Circulation. 2007;115:1051-1058 Copyright American Heart Association, Inc. All rights reserved. 60. COMBO Stent So COMBO is ideally positioned for ACS Excellent endothelial coverage (2 months) reduces need for long term DAPT: - No expected difference on common safety parameters CV death / MI - Reduction of bleeding risk DES like efficacy (12 months) BMS like safety (Long Term) - Polymer matrix biodegrades within 90 days - Eliminates chronic inflammatory effects 29 61. Ev Th Therapy In Patients With Acute Coronary Syndrome 30 62. Protocol Trial Summary Population: all comer ACS patients: STEMI, non-STEMI, Unstable Angina 1500 patients (Asia & EU), 25 - 30 sites Study treatment arms Combo stent with 12 months DAPT Combo stent with 3 months DAPT Randomization 1 : 1 randomization (per site) before hospital discharge after successful implantation of the COMBO stent at index procedure Allows for adequate information of the (acute) patient prior to randomization Eliminates acute (peri-procedural) events Electronic randomization via eCRF 31 63. Protocol Endpoints MACE @ 12 months - Composite of all cause mortality, Myocardial Infarction, Stroke, Major Bleeding (BARC type 2, 3 or 5) Secondary Endpoints - Bleeding (BARC II, III, V) at 12 months - All cause mortality, MI, ST, stroke, bleeding (BARC II, III, V) at 24 months - All cause mortality, MI, ST, stroke at 12 and 24 months - Cardiac Mortality at 12 and 24 months - Any MI at 12 and 24 months - ST at 12 and 24 months - Repeat revascularization at 12 and 24 months - Time to event analysis primary endpoint Pre-specified landmark analysis of Primary Endpoint from 3 to 12 months 33 64. Coating of stents with substances that potentially facilitate reendothelialization may represent a novel therapeutic approach. Similarly, stents loaded with an integrin-binding cyclic Arg- Gly-Asp peptide accelerated endothelialization by attracting endothelial progenitor cells in a porcine model. Furthermore, a combination of prohealing substances (such as vascular endothelial growth factor) with established antirestenosis drugs may represent an interesting approach to obtain the benefit of reduced restenosis without the cost of an increased risk for stent thrombosis. 65. The use of peroxisome proliferatoractivated receptor- gamma agonists, which not only diminish inflammation but also enhance endothelialization, may also represent an interesting new approach for DES. Dimethyl sulfoxide as a novel coating strategy for DES. Dimethyl sulfoxide prevents vascular smooth muscle cell proliferation and migration, ie, the key mechanisms of restenosis; at the same time, dimethyl sulfoxide inhibits tissue factor upregulation in endothelial cells. 66. DEFINED AS RENARROWING TO A DIAMETER STENOSIS >50%, EITHER WITHIN THE STENT OR WITHIN 5mm PROXIMAL OR DISTAL TO THE STENT MARGIN. 67. RESTENOSIS RATE POBA BMS DES 30-50% 20-30%