Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Grüntzig Lecture ESC 2014

Modern-day stenting procedures leverage advances in pharmacotherapy and device innovation. Patients treated with contemporary antiplatelet agents, peri-procedural antithrombin therapy and new-generation drug-eluting stents (DES) have excellent outcomes over the short to medium term. Indeed, coupled with the reducing costs of these devices in most countries there remain very few indications where patients should be denied treatment with standard-of-care DES therapy. The two major causes of stent failure are stent thrombosis (ST) and in-stent restenosis (ISR). The incidence of both has reduced considerably in recent years. Current clinical registries and randomized trials with broad inclusion criteria show rates of ST at or <1% after 1 year and ∼0.2–0.4% per year thereafter; rates of clinical ISR are 5% respectively. Angiographic surveillance studies in large cohorts show rates of angiographic ISR of ∼10% with new-generation DES. The advent of high-resolution intracoronary imaging has shown that in many cases of late stent failure neoatherosclerotic change within the stented segment represents a final common pathway for both thrombotic and restenotic events. In future, a better understanding of the pathogenesis of this process may translate into improved late outcomes. Moreover, the predominance of non-stent-related disease as a cause of subsequent myocardial infarction during follow-up highlights the importance of lifestyle and pharmacological interventions targeted at modification of the underlying disease process. Finally, although recent developments focus on strategies which circumvent the need for chronically indwelling stents—such as drug-coated balloons or fully bioresorbable stents—more data are needed before the wider use of these therapies can be advocated.

[1]  G. Dangas,et al.  Stent thrombosis and restenosis , 2017 .

[2]  W. Desmet,et al.  Histopathological evaluation of thrombus in patients presenting with stent thrombosis. A multicenter European study: a report of the prevention of late stent thrombosis by an interdisciplinary global European effort consortium† , 2015, European heart journal.

[3]  Patrick W Serruys,et al.  Report of a European Society of Cardiology-European Association of Percutaneous Cardiovascular Interventions task force on the evaluation of coronary stents in Europe: executive summary. , 2015, European heart journal.

[4]  R. Virmani,et al.  Neoatherosclerosis: overview of histopathologic findings and implications for intravascular imaging assessment. , 2015, European heart journal.

[5]  G. Keating Cangrelor: A Review in Percutaneous Coronary Intervention , 2015, Drugs.

[6]  A. Jacobs,et al.  Benefits and Risks of Extended Duration Dual Antiplatelet Therapy After PCI in Patients With and Without Acute Myocardial Infarction. , 2015, Journal of the American College of Cardiology.

[7]  Walter Desmet,et al.  ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. , 2015, European heart journal.

[8]  P. Serruys,et al.  Stent Thrombosis and Dual Antiplatelet Therapy Interruption With Everolimus-Eluting Stents: Insights From the Xience V Coronary Stent System Trials , 2015, Circulation. Cardiovascular interventions.

[9]  H. Schunkert,et al.  Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug-Eluting Stent Implantation: The ISAR-TRIPLE Trial. , 2015, Journal of the American College of Cardiology.

[10]  H. Schunkert,et al.  Prolonged dual antiplatelet therapy after drug-eluting stenting: meta-analysis of randomized trials , 2015, Clinical Research in Cardiology.

[11]  C. Terkelsen,et al.  Zotarolimus-eluting durable-polymer-coated stent versus a biolimus-eluting biodegradable-polymer-coated stent in unselected patients undergoing percutaneous coronary intervention (SORT OUT VI): a randomised non-inferiority trial , 2015, The Lancet.

[12]  J. Wójcik,et al.  6- versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. , 2015, Journal of the American College of Cardiology.

[13]  Antonio Colombo,et al.  Percutaneous coronary intervention with everolimus-eluting bioresorbable vascular scaffolds in routine clinical practice: early and midterm outcomes from the European multicentre GHOST-EU registry. , 2015, EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology.

[14]  J. Tijssen,et al.  Initial experience and clinical evaluation of the Absorb bioresorbable vascular scaffold (BVS) in real-world practice: the AMC Single Centre Real World PCI Registry. , 2015, EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology.

[15]  H. Schunkert,et al.  Prognostic role of restenosis in 10 004 patients undergoing routine control angiography after coronary stenting. , 2015, European heart journal.

[16]  P. Serruys,et al.  A bioresorbable everolimus-eluting scaffold versus a metallic everolimus-eluting stent for ischaemic heart disease caused by de-novo native coronary artery lesions (ABSORB II): an interim 1-year analysis of clinical and procedural secondary outcomes from a randomised controlled trial , 2015, The Lancet.

[17]  A. Kastrati,et al.  Bioresorbable drug-eluting stents: an immature technology in need of mature application. , 2015, JACC. Cardiovascular interventions.

[18]  P. Kirchhof,et al.  Triple antithrombotic therapy in atrial fibrillation patients with acute coronary syndromes or undergoing percutaneous coronary intervention or transcatheter aortic valve replacement. , 2015, EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology.

[19]  C. Hamm,et al.  Current status of bioresorbable scaffolds in the treatment of coronary artery disease. , 2014, Journal of the American College of Cardiology.

[20]  Braunwald,et al.  Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. , 2014, The New England journal of medicine.

[21]  Antonio Colombo,et al.  Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. , 2014, Journal of the American College of Cardiology.

[22]  E. Vicaut,et al.  Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial , 2014, The Lancet.

[23]  A. Kastrati,et al.  Pharmacological inhibition of coronary restenosis: systemic and local approaches , 2014, Expert opinion on pharmacotherapy.

[24]  T. Lüscher,et al.  Feasibility of second-generation bioresorbable vascular scaffold implantation in complex anatomical and clinical scenarios , 2014, Clinical Research in Cardiology.

[25]  S. Silber,et al.  Lack of association between dual antiplatelet therapy use and stent thrombosis between 1 and 12 months following resolute zotarolimus-eluting stent implantation. , 2014, European heart journal.

[26]  P. Kolh,et al.  Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis , 2014, BMJ : British Medical Journal.

[27]  Fernando Alfonso,et al.  Current treatment of in-stent restenosis. , 2014, Journal of the American College of Cardiology.

[28]  Yohei Ohno,et al.  Mechanisms, pathophysiology, and clinical aspects of incomplete stent apposition. , 2014, Journal of the American College of Cardiology.

[29]  Ryo Torii,et al.  Incomplete Stent Apposition Causes High Shear Flow Disturbances and Delay in Neointimal Coverage as a Function of Strut to Wall Detachment Distance: Implications for the Management of Incomplete Stent Apposition , 2014, Circulation. Cardiovascular interventions.

[30]  H. Schunkert,et al.  Randomised, double-blind trial on the value of tapered discontinuation of clopidogrel maintenance therapy after drug-eluting stent implantation , 2014, Thrombosis and Haemostasis.

[31]  M. Jeong,et al.  Optimal Duration of Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation: A Randomized, Controlled Trial , 2014, Circulation.

[32]  R. Virmani,et al.  Pathology of Second-Generation Everolimus-Eluting Stents Versus First-Generation Sirolimus- and Paclitaxel-Eluting Stents in Humans , 2014, Circulation.

[33]  J. Wójcik,et al.  Six-month versus 24-month dual antiplatelet therapy after implantation of drug eluting stents in patients non-resistant to aspirin: ITALIC, a randomized multicenter trial , 2014 .

[34]  M. Joner,et al.  Drug-coated balloon therapy in coronary and peripheral artery disease , 2014, Nature Reviews Cardiology.

[35]  Deepak L. Bhatt,et al.  Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. , 2013, JAMA.

[36]  Michael Joner,et al.  Risk of stent thrombosis among bare-metal stents, first-generation drug-eluting stents, and second-generation drug-eluting stents: results from a registry of 18,334 patients. , 2013, JACC. Cardiovascular interventions.

[37]  Antonio Colombo,et al.  Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study , 2013, The Lancet.

[38]  M. Joner,et al.  Incidence and predictors of restenosis after coronary stenting in 10 004 patients with surveillance angiography , 2013, Heart.

[39]  R. Virmani,et al.  Human autopsy study of drug-eluting stents restenosis: histomorphological predictors and neointimal characteristics. , 2013, European heart journal.

[40]  S. Windecker,et al.  Coronary stents: novel developments , 2013, Heart.

[41]  Peter L Duffy,et al.  Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study , 2013, The Lancet.

[42]  O. Meilhac,et al.  The promises of PCSK9 inhibition , 2013, Current opinion in lipidology.

[43]  Seung‐Jung Park,et al.  OCT analysis in patients with very late stent thrombosis. , 2013, JACC. Cardiovascular imaging.

[44]  Michael Joner,et al.  Tissue Characterization After Drug-Eluting Stent Implantation Using Optical Coherence Tomography , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[45]  Tom Adriaenssens,et al.  Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial , 2013, The Lancet.

[46]  A. Kastrati,et al.  Clinical impact of extended dual antiplatelet therapy after percutaneous coronary interventions in the drug-eluting stent era: a meta-analysis of randomized trials. , 2012, European heart journal.

[47]  E. Vicaut,et al.  Bedside monitoring to adjust antiplatelet therapy for coronary stenting. , 2012, The New England journal of medicine.

[48]  P. Serruys,et al.  Everolimus-eluting stent versus bare-metal stent in ST-segment elevation myocardial infarction (EXAMINATION): 1 year results of a randomised controlled trial , 2012, The Lancet.

[49]  Y. Jang,et al.  A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). , 2012, Journal of the American College of Cardiology.

[50]  L. Køber,et al.  Clopidogrel discontinuation after myocardial infarction and risk of thrombosis: a nationwide cohort study. , 2012, European heart journal.

[51]  M. Joner,et al.  Restenosis in bare metal and drug-eluting stents: distinct mechanistic insights from histopathology and optical intravascular imaging. , 2012, Minerva cardioangiologica.

[52]  Bo Yu,et al.  Predictors for Neoatherosclerosis: A Retrospective Observational Study From the Optical Coherence Tomography Registry , 2012, Circulation. Cardiovascular imaging.

[53]  G. Stone,et al.  A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placem , 2012, Journal of the American College of Cardiology.

[54]  J. Marchesini,et al.  Short- Versus Long-Term Duration of Dual-Antiplatelet Therapy After Coronary Stenting: A Randomized Multicenter Trial , 2012, Circulation.

[55]  P. Serruys,et al.  Very Late Coronary Stent Thrombosis of a Newer-Generation Everolimus-Eluting Stent Compared With Early-Generation Drug-Eluting Stents: A Prospective Cohort Study , 2012, Circulation.

[56]  J. Spertus,et al.  Clinical presentation, management, and outcomes of angiographically documented early, late, and very late stent thrombosis. , 2012, JACC. Cardiovascular interventions.

[57]  M. Jeong,et al.  Six-Month Versus 12-Month Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stents: The Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) Randomized, Multicenter Study , 2012, Circulation.

[58]  S. Scott,et al.  Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. , 2011, JAMA.

[59]  A. Kastrati,et al.  No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. , 2011, European heart journal.

[60]  Seung‐Jung Park,et al.  Optical Coherence Tomographic Analysis of In-Stent Neoatherosclerosis After Drug–Eluting Stent Implantation , 2011, Circulation.

[61]  F. Eberli,et al.  Five-Year Clinical and Angiographic Outcomes of a Randomized Comparison of Sirolimus-Eluting and Paclitaxel-Eluting Stents: Results of the Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization LATE Trial , 2011, Circulation.

[62]  N. Schork,et al.  Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. , 2011, JAMA.

[63]  Masataka Nakano,et al.  The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. , 2011, Journal of the American College of Cardiology.

[64]  E. Edelman,et al.  Stent Thrombogenicity Early in High-Risk Interventional Settings Is Driven by Stent Design and Deployment and Protected by Polymer-Drug Coatings , 2011, Circulation.

[65]  Akiko Maehara,et al.  A prospective natural-history study of coronary atherosclerosis. , 2011, The New England journal of medicine.

[66]  M. Valgimigli PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY , 2011 .

[67]  E. Antman,et al.  Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. , 2010, JAMA.

[68]  Yoshihisa Nakagawa,et al.  Very Long-Term (15 to 20 Years) Clinical and Angiographic Outcome After Coronary Bare Metal Stent Implantation , 2010, Circulation. Cardiovascular interventions.

[69]  T. Kume,et al.  Comparisons of Baseline Demographics, Clinical Presentation, and Long-Term Outcome Among Patients With Early, Late, and Very Late Stent Thrombosis of Sirolimus-Eluting Stents: Observations From the Registry of Stent Thrombosis for Review and Reevaluation (RESTART) , 2010, Circulation.

[70]  A. Kastrati,et al.  A double-blind, randomized study on prevention and existence of a rebound phenomenon of platelets after cessation of clopidogrel treatment. , 2010, Journal of the American College of Cardiology.

[71]  Seung‐Jung Park,et al.  C-Reactive Protein and the Risk of Stent Thrombosis and Cardiovascular Events After Drug-Eluting Stent Implantation , 2009, Circulation.

[72]  A. Kastrati,et al.  Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period. , 2009, European heart journal.

[73]  M. Joner,et al.  Polymer coatings and delayed arterial healing following drug-eluting stent implantation. , 2009, Minerva cardioangiologica.

[74]  M. Kimura,et al.  Predictors of angiographic restenosis after drug eluting stents in the coronary arteries: contemporary practice in real world patients. , 2009, EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology.

[75]  Gijs van Soest,et al.  Optical coherence tomography patterns of stent restenosis. , 2009, American heart journal.

[76]  Renu Virmani,et al.  One step forward and two steps back with drug-eluting-stents: from preventing restenosis to causing late thrombosis and nouveau atherosclerosis. , 2009, JACC. Cardiovascular imaging.

[77]  F. Verheugt,et al.  Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry. , 2009, Journal of the American College of Cardiology.

[78]  A. Kastrati,et al.  Durability of antirestenotic efficacy in drug-eluting stents with and without permanent polymer. , 2009, JACC. Cardiovascular interventions.

[79]  Adnan Kastrati,et al.  Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. , 2009, Journal of the American College of Cardiology.

[80]  Steve D. M. Brown,et al.  IDENTIFICATION OF NOVEL MOUSE MODELS OF CARDIOVASCULAR DEVELOPMENTAL MALFORMATIONS USING ETHYLNITROSOUREA MUTAGENESIS , 2009 .

[81]  A. Kastrati,et al.  Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. , 2008, European heart journal.

[82]  S. Bhattacharya,et al.  Pre-procedural C-reactive protein levels and clinical outcomes after percutaneous coronary interventions with and without abciximab: pooled analysis of four ISAR trials , 2008, Heart.

[83]  William Wijns,et al.  Stent thrombosis late after implantation of first-generation drug-eluting stents: a cause for concern. , 2007, Circulation.

[84]  Simon Wandel,et al.  Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis , 2007, The Lancet.

[85]  L. Räber,et al.  Local vascular dysfunction after coronary paclitaxel-eluting stent implantation. , 2007, International journal of cardiology.

[86]  Michael Joner,et al.  Vascular Responses to Drug Eluting Stents: Importance of Delayed Healing , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[87]  P. Serruys,et al.  Clinical End Points in Coronary Stent Trials: A Case for Standardized Definitions , 2007, Circulation.

[88]  S. Pocock,et al.  Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. , 2007, The New England journal of medicine.

[89]  Marco Valgimigli,et al.  Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. , 2007, The New England journal of medicine.

[90]  Michael Joner,et al.  Drug-Eluting Stent and Coronary Thrombosis: Biological Mechanisms and Clinical Implications , 2007, Circulation.

[91]  Neville Kukreja,et al.  Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study , 2007, The Lancet.

[92]  Deepak L. Bhatt,et al.  Bare metal stent restenosis is not a benign clinical entity. , 2006, American heart journal.

[93]  A. Kastrati,et al.  Predictive Factors of Restenosis After Coronary Implantation of Sirolimus- or Paclitaxel-Eluting Stents , 2006, Circulation.

[94]  A. Aggarwal,et al.  Inflammatory response after intervention assessed by serial C-reactive protein measurements correlates with restenosis in patients treated with coronary stenting. , 2006, American heart journal.

[95]  I. Iakovou,et al.  Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. , 2005, JAMA.

[96]  D. Simon,et al.  Molecular Basis of Restenosis and Drug-Eluting Stents , 2005, Circulation.

[97]  Jeffrey W Moses,et al.  Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. , 2003, The New England journal of medicine.

[98]  A. Kastrati,et al.  Intracoronary Stenting and Angiographic Results: Strut Thickness Effect on Restenosis Outcome (ISAR-STEREO) Trial , 2001, Circulation.

[99]  M. Nobuyoshi,et al.  Long-Term Clinical and Angiographic Follow-Up After Coronary Stent Placement in Native Coronary Arteries , 2002, Circulation.

[100]  Ousa,et al.  A RANDOMIZED COMPARISON OF A SIROLIMUS-ELUTING STENT WITH A STANDARD STENT FOR CORONARY REVASCULARIZATION , 2002 .

[101]  B. Meier The first patient to undergo coronary angioplasty--23-year follow-up. , 2001, The New England journal of medicine.

[102]  R. Virmani,et al.  Pathology of acute and chronic coronary stenting in humans. , 1999, Circulation.

[103]  S. Pocock,et al.  A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. , 1999, The New England journal of medicine.

[104]  S. Pocock,et al.  A Clinical Trial Comparing Three Antithrombotic-Drug Regimens after Coronary-Artery Stenting , 1998 .

[105]  M. Leon,et al.  Treatment of in-stent restenosis. , 1998, Seminars in interventional cardiology : SIIC.

[106]  M. Hadamitzky,et al.  A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. , 1996, The New England journal of medicine.

[107]  H Yokoi,et al.  Three-year follow-up after implantation of metallic coronary-artery stents. , 1996, The New England journal of medicine.

[108]  P Hall,et al.  Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. , 1995, Circulation.

[109]  A. Kastrati,et al.  Four‐Year Experience With Palmaz‐Schatz Stenting in Coronary Angioplasty Complicated by Dissection With Threatened or Present Vessel Closure , 1994, Circulation.

[110]  W Rutsch,et al.  A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. , 1994, The New England journal of medicine.

[111]  P. Teirstein,et al.  A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. , 1994, The New England journal of medicine.

[112]  A. Kastrati,et al.  Time Course of Restenosis During the First Year After Emergency Coronary Stenting , 1993, Circulation.

[113]  B Meier,et al.  Angiographic follow-up after placement of a self-expanding coronary-artery stent. , 1991, The New England journal of medicine.

[114]  F Joffre,et al.  Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. , 1987, The New England journal of medicine.

[115]  William Wijns,et al.  A Cause for Concern , 2007 .

[116]  A Gruntzig,et al.  Transluminal dilatation of coronary-artery stenosis. , 1978, Lancet.