In-stent Restenosis Diagnostic and Therapeutic Challenges. Kostis Raisakis General Hospital of Athens «G. Gennimatas»

Transcription

1 In-stent Restenosis Diagnostic and Therapeutic Challenges Kostis Raisakis General Hospital of Athens «G. Gennimatas»

2 Introduction With POBA, rates of acute and chronic vessel occlusion at 30% to 60%, secondary to acute and chronic recoil and constrictive remodeling The advent of bare-metal stents (BMS) appeared to eliminate the issue of acute and chronic recoil but introduced a new entity, neointimal hyperplasia (NIH) Various studies has demonstrated a strong and linear relationship between NIH formation and late lumen loss (LLL) The restenosis rates with BMS were reported to be between 16% and 44%, (with, in particular, long lesion length and small vessel caliber) Despite the significant advances in the technology to reduce DES restenosis, incidence of in-stent restenosis (ISR) requiring target vessel revascularization (TVR), so-called DES failure, to be 5% to 10%

3 Cassese et al. Heart 2015

4 Definition of Restenosis The definition of ISR remains an angiographic one: recurrent diameter stenosis >50% at the stent segment or its edges (5-mm segments adjacent to the stent)

5 The Underlying Mechanisms of Restenosis With Drug-Eluting Stent Biological Factors Arterial Factors Stent Factors Implantation Factors

6 The Underlying Mechanisms of Restenosis With Drug-Eluting Stent Resistance to antiproliferative drugs Hypersensitivity reaction (polymer Genetics Biological Factors Hypersensitivity reaction (metallic stent platform)

7 The Underlying Mechanisms of Restenosis With Drug-Eluting Stent Thromborestenosis Vessel remodeling Neoatherosclerosis Wall shear stress Arterial factors Small vessels

8 The Underlying Mechanisms of Restenosis With Drug-Eluting Stent Stent gap, non- uniform strut distribution, and drug deposition Polymer disruption, peeling, and cracking Type of DES? Type of drug? Polymer drug release kinetics Stent Factors Stent fractures

9 The Underlying Mechanisms of Restenosis With Drug-Eluting Stent

10 In-Stent Restenosis Angiographic Classification Focal (< 10mm) Unscafolded (gap or anticulation) Body (or edges) Margin Diffuse (>10mm) Intra-stent Proliferative (extends beyond margins) Total occlusion Multifocal Mehran et al. Circulation 1999

11 In-Stent Restenosis Angiographic Classification Mehran et al. Circulation 1999

12 Pattern of Restenosis BMS has been shown to be primarily diffuse In DES it has been demonstrated to be usually focal 60% of ISR located at the proximal DES edge, as demonstrated in with either paclitaxel-eluting stent (PES) or sirolimus-eluting stent (SES) implantation However, over one-fifth of ISR cases remain diffuse, and 10% to 20% are even occlusive

13 Clinical Presentation ISR traditionally has been suggested as being potentially benign, with the recurrence of anginal symptoms alone. However, emerging evidence now suggests that between 30% to 60% of ISR cases present with an acute coronary syndrome with unstable angina being the most common presentation. Up to 5% of patients reported to present with ST-elevation myocardial infarction (STEMI). Rest present as stable angina profile

14 Cassese et al. Heart 2015

15 Prognostic role of restenosis the presence of restenosis predicts an increased risk of 4-year mortality restenosis provides prognostic information that is independent of that provided by other relevant clinical factors the prognostic value associated with restenosis is maintained even if patients present without symptoms at time of follow-up angiography. Cassese et al. Eur. Heart Journal, 2015

16 Intravascular Imaging

17 IVUS OCT Underlying mechanical factors Research tool

18 Role of Intravascular Imaging play an important role in evaluation of underlying mechanical factors that contribute to ISR readily detects the presence of neointimal hyperplasia obstructing the stent, underexpansion, edge problems or stent fractures the external elastic lamina is usually well delineated behind the stent struts, and thus provides potentially valuable insights on vessel sizing for optimization of stent expansion limited axial resolution (150 mm) lumen neointimal interface may be difficult to delineate in some areas

19 Role of Intravascular Imaging

20 Role of Intravascular Imaging Inaba et al. Eurointervention, 2014

21 much better axial resolution (15 mm), yielding detailed images of lumen interface, the neointimal tissue, and the strut distribution. allows evaluation of the presence of neoatherosclerotic tissue allows evaluation of the presence of unstable features (e.g., plaque rupture, nonocclusive intracoronary thrombus), which may play a strong role in prognostic assessment and clinical decision making.

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23 ISR caused by severe homogeneous smooth muscle proliferation represents just one end of the spectrum. At the other extreme are patients thrombosis in a widely patent stent. experiencing cell stent In the middle, neoatherosclerosis manifests clinically as a multifaceted and elusive condition causing both ISR and stent thrombosis.

24 Treatment of Restenosis

25 Treat ment Opt ions TREATMENT STRATEGIES Balloon Angioplasty Debulking Methods Brachytherapy DES BMS Homo DCB Hetero

26 Conventional Balloon Angioplasty

27 Conventional Balloon Angioplasty High bleeding risk/ Bail out-bridging strategy High recurrent restenosis rate Technical considerations balloon to artery ratio 1,1:1 noncompliant balloon water-melon seeding/geographic miss Cassese et al. Eur. Heart Journal, 2015

28 Cutting/Scoring Balloon New Role of CB in the DES/DEB era Cutting Balloon vs Conventional Balloon: no differences in QCA measurements, recurrence of binary restenosis, or ISAR-DESIRE clinical event rates at seven-month follow-up 4 lower incidence of water-melon seeding lower need for additional stent implantation Albiero et al. (RESCUT Trial), JACC, 2004

29 Scheller et al. Cath.Cardiovasc.Interv. 2015

30 Debulking Methods

31 Rotational Atherectomy Rationale: Plaque or tissue debulking Trials: ARTIST, ROSTER

32 Rotablation +Balloon Angioplasty vs Balloon Angioplasty Underdeployed stents were excluded by IVUS PRCA resulted in: similar angiographic acute gain less residual intimal hyperplasia lower repeat stent use decreased TLR Sharma et al. Am Heart J, 2004

33 Rotablation +Balloon Angioplasty vs Balloon Angioplasty No IVUS used no differences in the short term success rate worse angiographic results at 6m follow-up lower event-free survival rate Vom Dahl et al. Circulation, 2002

34 Vascular Brachytherapy

35 Vascular Brachytherapy suppress proliferative response reduces clinical and angiographic restenosis rate geographic miss/edge restenosis Sabate et al. Circulation, 2000 late thrombosis/late catch up Costa et al. Circulation, 1999

36 beta or gamma VBT 400 patients Sirolimus-eluting Bx VELOCITY stent Endpoints 1ry: 9 m Angiographic: all 6 m IVUS:5-7 centers 6m Holmes et al. JAMA. 2006

37 Brachytherapy TVR SES Segment Restenosis Segment Late Loss Holmes et al. JAMA. 2006

38 no significant differences in survival free from TLR, target vessel revascularization, or major adverse cardiac events between the 2 groups at 5 years Alli et al. Am Heart J 2012

39 Stone GW et al. JAMA 2006

40 9 Month Revascularization Rates Brachytherapy TLR TAXUS Express Stent System TVR Remote TVR Primary end point Stone GW et al. JAMA 2006

41 9 Month MACE Composition Brachytherapy Cardiac Death STEMI TAXUS Express Stent System Non STEMI Ischemic TVR TVF MACE Stone GW et al. JAMA 2006

42 DES are associated with a decreased incidence of revascularization procedures when compared to VBT in a 2- to 5-year follow up both procedures are associated with a similar incidence of MI, ST and mortality Benjo et al. Cath. Cardiov. Interv. 2015

43 BMS

44 death, myocardial infarction, or target vessel revascularization Stenting resulted in: better immediate angiographic results failure to reduce the rate of recurrent restenosis similar event-free survival at one year clinical and angiographic benefits in patients with large vessels ( 3 mm) Alfonso et al. JACC, 2003

45 DES

46 (ISAR DESIRE) 300 patients were randomly allocated to treatment with sirolimus-des, paclitaxel-des, or BA The rate of recurrent restenosis was significantly reduced with sirolimus-des (14.3%) and paclitaxel-des (21.7%) compared with BA (44.6%). Patients treated with sirolimus-des tended to have lower rates of angiographic restenosis and target vessel revascularization compared with those receiving paclitaxel-des Kastrati et al. JAMA, 2005

47 patients treated with sirolimus-des had a significantly lower restenosis rate (11%) and superior long-term clinical outcome, mainly as a result of a reduced TVR Alfonso et al. JACC, 2006

48 Drug-eluting stents are markedly superior to conventional techniques (balloon angioplasty and vascular brachytherapy) and should be considered as first-line treatment for patients with bare-metal in-stent restenosis Dibra et al. JACC, 2007

49 (ISAR DESIRE 2) no differences between the 2 arms in late loss (0.40 vs mm), binary restenosis (19.6% vs. 20.6%), or target lesion revascularization (16.6% vs. 14.6%). These observations argue against a clear benefit from a switch DES strategy Mehilli et al. JACC, 2010

50 (RIBS III) Alfonso et al. JACC Intv, 2012

51 (RIBS III) hetero-des approach (or switch DES strategy) was associated with better clinical outcomes. the use of second-generation DES was superior to first generation DES intracoronary imaging guidance was associated with better long-term results Alfonso et al. JACC Intv, 2012

52 Bioresorbable vascular scaffolds Bioresorbable vascular scaffolds have also been proposed as treatment for patients with ISR The chief advantage is that the device should eventually disappear from the vessel wall, avoiding the presence of multiple stent layers ( onionskin phenomena). Potential limitations of Bioresorbable vascular scaffolds in this setting include: Lumen crowding due to strut thickness (particularly in small vessels), Device flexibility that may affect access to restenotic lesions, and Questions regarding radial strength and recoil, which may be particularly important in treating cases of ISR.

53 DCB

54 The primary endpoint, late lumen loss at the target lesion, was significantly reduced. Patients treated with PCB required significantly less repeat interventions Rittger et al. JACC, 2012

55 paclitaxel-coated balloon was at least as efficacious and as well tolerated as the paclitaxel-eluting stent inhibition of re-restenosis does not require a second stent implantation Unverborden et al. Circulation2009

56 At 9 months, in-segment late lumen loss in the PCB group was non-inferior to that of the paclitaxel-eluting stent group. The 9-month rate of binary restenosis was not significantly different between groups. The 12-month composite clinical event rates was not significantly different between groups. Xu et al. J Am Coll Cardiol Intv 2014

57 Byrne et al. Lancet, 2013

58 PEB is non-inferior to repeat stenting with PES PEB or PES is superior to balloon angioplasty alone Byrne et al. Lancet, 2013

59 At 3 years, the use of PEB as compared with PES to treat patients with limus-eluting stent restenosis has similar efficacy and safety PEB remains superior to BA Kufner et al. JACC Intv 2015

60 DES vs DEB Metanalysis Mamuti et al. International Journal of Cardiology, 2015

61 (RIBS V) Alfonso et al. JACC, 2014

62 (RIBS V) first data from a randomized comparison of DCB with second-generation everolimus-des in 189 patients with BMS-ISR. minimal lumen diameter at follow-up was better after everolimus-des (2.01 mm vs mm; p < 0.001) binary restenosis (4.7% vs. 9.5%; p <0.22) and clinical events at 1 year were low and similar in both groups Alfonso et al. JACC, 2014

63 Alfonso et al. JACC 2015

64 EES arm had a significantly larger minimal lumen diameter, net lumen gain, lower percent diameter stenosis and binary restenosis rate Alfonso et al. JACC 2015

65 At the 1-year clinical follow-up, the main clinical outcome measure was significantly reduced in the EES arm (10% vs. 18%; p. 0.04), mainly driven by a lower need for target vessel revascularization (8% vs. 16%; p ). Alfonso et al. JACC 2015

66 Habara, S. et al. J Am Coll Cardiol. 2015

67 Habara, S. et al. J Am Coll Cardiol. 2015

68 EES are the most effective strategy for treatment of ISR, with 27 trials eligible, 5923 patients, with follow-up ranging from 6 months the lowest risksincluding of restenosis and repeat revascularisation to 60 months compared with other treatments The primary outcome was percent diameter stenosis at angiographic follow-up DCB ranked second in terms of angiographic and clinical effectiveness BA, VBT, ROTA, and BMS cannot be deemed effective alternatives to ISR treatment results were consistent, irrespective of the type of stent underlying ISR Siontis et al. Lancet 2015

69 CABG in cases with diffuse, recalcitrant ISR or involvement of other major vessels could be an alternative solution

70 Conclusions Treatment of ISR remains a prevailing clinical problem. ISR substrate encompasses a pathological spectrum ranging from smooth muscle cell proliferation to neoatherosclerosis. Intracoronary imaging provides unique insights into the underlying etiology of ISR. DES and DCB provide the best clinical and angiographic results in patients with ISR. EES possible are the most effective strategy for treatment of ISR. Further studies are required to identify clinical and anatomic characteristics that may help to refine selection and tailor available therapeutic strategies to improve clinical outcomes.

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