This document discusses in-stent restenosis (ISR), including definitions, incidence rates, pathogenic mechanisms, risk factors, classification, treatment options, and outcomes. Some key points: - ISR is defined as a renarrowing of the artery after percutaneous coronary intervention (PCI) with or without stent implantation. It can be angiographic or clinical. - Incidence is higher with balloon angioplasty (30-50%) compared to bare-metal stents (20-30%) and drug-eluting stents (<10%). - Pathogenic mechanisms include early elastic recoil, vascular remodeling, and neointimal hyperplasia. - Risk factors include diabetes,

1. INSTENT RESTENOSIS

2. a reduction in lumen diameter after percutaneous coronary intervention (PCI), either
with or without stent implantation.
• “ANGIOGRAPHIC” RESTENOSIS
• Late lumen loss with > 50% diameter stenosis at the stent segment or its edges (
5-mm segments adjacent to the stent) in follow-up

3. “CLINICAL” RESTENOSIS
– >50% DIAMETER STENOSIS AND ONE OF THE FOLLOWING:
– 1. Positive history of recurrent angina pectoris , related to target vessel.
– 2. Objective signs of ischemia at rest ( ecg changes ) or during exercise test related to
target vessel.
– 3. Abnormal results of any invasive functional diagnostic test ( coronary flow velocity
reserve FFR< 0.80 ; IVUS – minumum CSA - < 4 mm2 or <6 mm2 for lm stem ) has
been found to correlate with abnormal FFR and the need for subsequent tlr.
– 4. TLR with diameter stenosis >70% diameter stenosis without symptoms or signs of
ischemia

4. Incidence
POBA BMS DES
30-50% 20-30% <10%

5. • The three major pathogenic mechanisms:
• (I) Early elastic return (recoil)
• (II) Vascular remodeling
• (III) Neointimal hyperplasia

6. ER & VASCULAR REMODELING
• ER – seen after balloon angioplasty due to contraction of internal and
external elastic lamina.
• Seen few seconds after balloon angioplasty

7. ISR
• a non-specific inflammatory response to vessel wall injury due to the
persistent “insult” exercised by a foreign element as the metal struts of the
stent.
• Chronic wall stress due to media damage and stent struts protrusion in
tunica intima stimulates inflammatory processes
• migration of smooth muscle cells from tunica media and myofibroblasts from
tunica adventitia to tunica intima.

8. CLINICAL PRESENTATION
• 30 – 60% PRESENTS AS ACS MAINLY UNSTABLE ANGINA.
• UPTO 5%- PRESENTS AS STEMI
• REST PRESENTS AS STABLE ANGINA.

10. DES vs BMS
• DES have
• (I) An antimitotic/antiproliferative drug
• (II) A carrier/polymer.
• aim  was to counterbalance the excessive neointimal proliferation
stimulated by the presence of metallic struts.
• polymer  distributing the drug to the vessel wall and then remains intact
on the struts surface;

11. BMS:
– PRESENTS AS DIFFUSE ISR
– LATE LUMEN LOSS AT 6-9 MONTHS
– SMOOTH MUSCLE MORE
– NEO ATHEROSCLEROSIS LESS
DES :
- LOCAL ISR AFFECTING EDGE
- LATE LUMEN LOSS AT 5 YRS
- PROTEOGLYCAN MORE
- NEO ATHEROSCLEROSIS FREQUENT

13. BIOLOGICAL FACTORS:
• 1. GENETICS
• HYPERSENSITIVE REACTION TO POLYMER
• RESISTANCE TO DRUGS
• SERUM METALLOPROTEINASES
• HYPERSENSITIVE REACTION TO METALLIC STENT PLATFORM

14. PROCEDURE RELATED :
 STENT TYPE
 NUMBER OF STENTS AND TOTAL LENGTH
 STENT OVERLAP
 STENT UNDEREXPANSION
 MLD
 STENT FRACTURE

15. PATIENT RELATED :
Age
Female sex
Diabetes mellitus
 Genetic factors

16. LESION RELATED :
• LESION TYPE/LENGTH: LENGTH > 28 mm 2.8 TIMES HIGHER RISK
•COMPLEX LESIONS (B2/C)
•OSTIAL LESIONS AND BIFURCATIONS
•VESSEL CALIBER: SMALL VESSELS ( DIAMETER < 2.5 mm )
•MULTIVESSEL CORONARY ARTERY DISEASE

17. CLASSIFICATION
ISR classification :
• Type I focal
– ≤10 mm in length intrastent
– IA articulation or gap
– IB margin
– IC focal body
– ID multifocal
• Type 2 diffuse >10 mm intrastent
• Type 3 proliferative 10 mm extending beyond the stent margins
• Type 4 total occlusion Restenotic lesions with TIMI flow grade of 0

18. DIABETES
• Increased blood viscosity
• Decrease in biological activity of antithrombin iii
• Increased fibrinogen and factor viii
• Enhanced platelet aggregation

19. RESISTANCE TO ANTIPROLIFERATIVE
DRUGS
• Can be present in genetically predetermined individuals or be acquired following
exposure to the drug
• Genes for resistance may operate in :
– Hampering drug delivery
– Drug metabolism
– Apoptosis regulation
– Dna repair

20. HYPERSENSITIVE REACTION TO
POLYMER
• SES – GIANT CELL REACTION
• PES – EOSINOPHILIC REACTIONS
• INFLAMMATORY RESPONSES ASSOCIATD WITH SES – PERSISTS BEYOND 180 DAYS
UPTO 2 YRS
• BMS & EVEROLIMUS ELUTING STENT: INF REACTION LIMITED TO LESS THAN 90
DAYS
• DELAYED INF REACTION ASSOCIATED WITH DELAYED HEALING AND LONG TERM
RESTENOSIS.

21. MMP ACTIVITY
• CIRCULATING MMP LEVELS – HELPFUL IN IDENTIFYING PTS AT RISK OF
DEVELOPING ISR
• ELEVATED LEVELS OF MMP 2 & 9 – ASSOCIATED WITH INCREASED RISK OF ISR
• LOW AND NEAR LEVELS OF MMP 2 & 9 – ASSOCIATED WITH LACK OF SIGNIFICANT
ISR

22. WALL SHEAR STRESS
• WALL SHEAR STRESS – FLUID DYNAMICS AND VESSEL GEOMETRY MAY PLAY A POTENTIAL ROLE IN THE
CAUSE OF FOCAL PLAQUE OR NEOINTIMAL FORMATION.
• LOW SHEAR STRESS MAY LEAD TO THE ACCUMULATION OF GROWTH FACTORS ,MITOGENIC
CYTOKINES , AND PLATELETS, WHICH MAY PROMOTE ATHEROSCLEROSIS OR NEOINTIMAL FORMATION
AFTER VESSEL INJURY.
• HIGH SHEAR STRESS - INHIBIT SMC PROLIFERATION AND LIMIT ATHEROSCLEROSIS OR RESTENOSIS
UNLESS IT PROGRESS FROM A LOW SHEAR STRESS AREA
• PAPAFAKLIS ET AL – SIGNIFICANT NUMBER OF POCKETS OF LOW SHEAR STRESS WITHIN STENTED
SEGMENTS SECONDARY TO LOCAL GEOMETRIC FACTORS LIKE ANGULATIO AND CURVATURE
• ASSOCIATED WITH NIH

23. TIMING OF ATHEROSCLEROSIS
• FOAMY MACROPHAGES FORMATION:
- DES– 4 MONTHS AFTER STENT IMPLANTATION
- BMS – 2 YRS OR LATER
EARLIEST NECROTIC CORE FORMATION:
- DES – 9 MONTHS
- BMS – 5 YRS
INCIDENCE OF NEOATHEROSCLEROSIS
- BMS – 16%
- DES – 31%
MEDIAN STENT DURATION WITH ATHEROSCLEROSIS:
- BMS – 13 MONTHS
- DES – 5 YRS

24. • MORE RAPID ATHEROSCLEROTIC CHANGES IN SES THAN IN PES.
• FREQUENCY OF NEOATHEROSCLEROSIS :
• - CUMULATIVE INCIDENCE UPTO 6 YRS ( SES – 38% VS PES – 24 % VS BMS – 10 % ).
• PISCES ( PACLITAXEL IN STETNT CONTROLLED ELUTION STUDY ) – DURATION OF THE DRUG
RELEASE HAD A GREATER IMPACT ON THE INHIBITION OF NIH THAN THE DOSE DELIVERED.
• LESION LENGTH > 30mm
• STENT LENGTH > 28 mm
• STENT DIAMETER > 2.5 mm
• THICKER STRUTS

25. GEOGRAPHICAL MISS
 FAILURE TO APPROPRIATELY COVER THE INJURED VESSEL .
 LONGITUDINAL GM – INJURED OR DISEASED STENOTIC SEGMENT NOT FULLY COVERED BY
DES
 AXIAL GM : POTENTIALLY UNDER SIZING OR OVERSIZING THE BALLOON
 > 2 FOLD INCREASE IN TARGET VESSEL REVASCULARISATION
 3 FOLD INCREASE IN MI IN PTS WITH GM
 EXCLUSIVELY SEEN IN LONGITUDINAL GM AND NOT IN AXIAL GM

26.  Stent fracture related to DES implantation in coronary arteries was first
reported in 2004.
 Subsequent retrospective and prospective registries have quoted restenosis
rates ranging from 15% to
100% in patients identified to have stent fractures.
 In the only randomized controlled trial reporting the incidence of stent
fracture and outcomes after DES
implantation is (LONG-DES-II study)*,in whch a 14% incidence of
restenosis was observed.
 The restenosis associated with DES fractures tends to occur fairly late and
focally, reflecting the local trauma sustained by the vessel at the fracture
site

27.  First, mechanical fatigue of the metallic stent can occur because of excessive
movements during cardiac contraction, especially at a hinge-point where the potential
for 2 opposing forces may occur at the same site.
 In particular, this may occur in the right coronary artery or a saphenous vein graft,
because of
their greater propensity for angulation and tortuosity
 Second, a closed-cell design, is less likely to be able to withstand the pressures related
to excessive movements compared with the open-cell design. The incidence of stent
fracture is reported at less than 0.1% with the open cell design and approximately
2.3% with closed cell design*

28.  Long stents,
 overlapping stents,
 tight lesions that have been vigorously post dilated and
expanded,
 myocardial bridge sites, and
 areas of significant curvature are all factors that may
predispose patients to DES fracture.

29.  A smaller post procedural minimal lumen diameter (MLD) and a greater residual
stenosis
have been shown to be significant predictors of long-term patency and clinical
outcomes.
 The most plausible theory to explain the underlying mechanism relating
stent under expansion to restenosis is the so-called bigger-is-better
paradigm
 Effectively, if the minimum stent area is smaller at baseline, then the expected NIH
formation post-DES implantation would be more likely to be of more significance,
whereas if the minimum stent area was larger, then the same amount of NIH would
be clinically less relevant in causing binary restenosis

30.  In a classical meta-analysis (n=2972 patients) investigating IVUS versus
angiographic-
guided BMS implantation, Casella et al demonstrated at 6-month follow-up a
reductionin TVR (OR 0.62; 95% CI 0.49 to 0.78; P<0.00003), binary restenosis
(OR 0.75; 95%CI 0.60 to 0.94; P<0.01), and major adverse cardiovascular
events (OR 0.79; 95% CI 0.64to 0.98; P<0.03)

31.  Thrombocyte Activity Evaluation and Effects of Ultrasound Guidance in Long
IntracoronaryStent Placement (TULIP) STUDYAND The Angiography Versus
Intravascular Ultrasound- Directed (AVID) STUDY.
 Showed that there was definite benefit in lowering binary restenosis and TLR at
rate at angiographic follow-up in IVUS guided arm . [lower binary restenosis rate at 6-
months angiographic follow-up (23% vs. 46%, p=0.0082) and a subsequent
decrease in TLR (4% vs. 14%, p=0.037)]

32. Patterns of In-Stent
Restenosis
Articulation
or Gap
Margin
Focal
Body
Multifocal
Focal
Intra-stent Proliferative
Total
Occlusion
Diffuse

33. From: Current Treatment of In-Stent Restenosis
J Am Coll Cardiol. 2014;63(24):2659-2673. doi:10.1016/j.jacc.2014.02.545
Figure Legend:
Pathological Images of In-Stent Restenosis
Low-power (A and B, 4×) and high-power (C and D, 10×) magnification images of restenosis within (A and C) a bare-metal stent
(BMS) and (B and D) a drug-eluting stent (DES), both implanted 5 years antemortem. In the BMS, the dominant pathology is
smooth muscle cell-rich neointimal hyperplasia. There is also some chronic inflammation with neovascularization around
stent struts (green arrowhead). In the DES, there is presence of neoatherosclerosis with formation of a necrotic core (black
arrowheads) and
calcification (grey arrowheads).
.

34. From: Current Treatment of In-Stent Restenosis
J Am Coll Cardiol. 2014;63(24):2659-2673. doi:10.1016/j.jacc.2014.02.545
Figure Legend:
Patterns of In-Stent Restenosis as Depicted by Optical Coherence Tomography
(A) Homogeneous bright neointimal proliferation. (B) Uniform neointimal proliferation with microvessels (arrows). (C) Layered pattern
with multiple microvessels (arrows) in the dark layer overlying the stent struts. (D) Multilayered pattern. *Wire artifact.

35. Treatment of In-Stent Restenosis
• IVUS, OCT role
• balloon angioplasty
• Brachytherapy
• BMS
• DCB
• DES
• balloon angioplasty
• Brachytherapy
• BMS
• DCB
• DES

36. BALLOON ANGIOPLASTY
• ONE OF THE EARLIEST TECHNIQUE
• MOSTLY USED FOR FOCAL STENOSIS
• POOR RESULTS IN DIFFUSE STENOSIS
• HIGH RECURRENT RESTENOSIS RATES.
• A BALLOON-TO-ARTERY RATIO OF 1.1:1 IS SELECTED.
• HIGH-PRESSURE BALLOON DILATION IS USED IN UNDER EXPANDED STENT.

37. BALLOON ANGIOPLASTY
•SUBACUTE TISSUE RE-INTRUSION BACK TO THE LUMEN TENDS TO OCCUR WITHIN
MINUTES AFTER THE LAST BALLOON INFLATION - EARLY LUMEN LOSS.
•BALLOON SLIPPAGE OUTSIDE THE STENT (“WATERMELON SEEDING” PHENOMENON)
•MORE OFTEN IN SEVERE AND DIFFUSE NARROWING, ESPECIALLY WHEN BALLOONS ARE
OVERSIZED.
• ASSOCIATED WITH SUBOPTIMAL ACUTE RESULTS AND ADVERSE CLINICAL AND
ANGIOGRAPHIC OUTCOMES THAT MIGHT BE RELATED TO GEOGRAPHIC MISS.
• THE USE OF A BUDDY-WIRE TECHNIQUE TO STABILIZE THE BALLOON PREVENTS THIS
COMPLICATION.

38. CUTTING BALLOONS
• HAS LATERAL BLADES – HELPS IN ANCHORING THE BALLOON TO THE WALLS OF THE VESSEL –
PREVENTS SLIPPAGE .
• RESCUT (Restenosis Cutting Balloon Evaluation Trial), 428 patients with BMS-ISR were
randomized to receive either cutting BA or conventional BA .
• At late follow-up, the angiographic restenosis rate, minimal lumen diameter, and rates of
clinical events were similar in both arms.
• NO SPECIFIC ADVANTAGE OF CUTTING BALLOONS OVER CONVENTIONAL BALLOON
ANGIOPLASTY.

39. DEBULKING THERAPY
• USED FOR DIFFUSE LESIONS WHERE AMOUNT OF NEOINTIMAL TISSUE IS MORE.
• NOT USEFUL FOR SMALL AND DISTAL VESSEL LESIONS WHERE ISR IS MORE COMMON.
• ARTIST (Angioplasty Versus Rotational Atherectomy for Treatment of Diffuse In-Stent
Restenosis Trial), - a larger multicenter randomized study (298 patients with diffuse ISR)
comparing rotational atherectomy with BA alone, failed to show benefit with rotational
atherectomy.
• the restenosis rate, as well as the rates of acute complications and long-term clinical events,
were higher in the rotational atherectomy arm.
• STILL USED IN severely underexpanded stents or calcified intrastent neoatherosclerosis.
• The value of ablative techniques in patients with DES-ISR has not been evaluated.

40. BRACHYTHERAPY
• EMISSION OF BETA AND GAMMA RADIATION
• SUPPRESSED THE PROLIFERATIVE RESPONSE AND SUPPRESSED THE RESTENOSIS
• Gamma emitters had profound tissue penetration
• beta emitters had less tissue penetration.
• Radioprotection was a major problem with gamma emitters;
• dosimetry problems frequently arose with beta emitters.
• CAUSES LATE ARTERIAL HEALING – LEADING TO LATE STENT THROMBOSIS AND LATE STENT
RESTENOSIS DUE TO LATE CATCH UP PHENOMENON.

41. • THE SISR (SIROLIMUSELUTING STENT VS. BRACHYTHERAPY IN PATIENTS WITH BARE METAL IN-STENT
RESTENOSIS) TRIAL:
• ALLOCATED 384 PATIENTS WITH BMS-ISR TO UNDERGO BRACHYTHERAPY OR SIROLIMUS-ELUTING STENT
IMPLANTATION .
• AT FOLLOW-UP, THE RATES OF TARGET VESSEL FAILURE WERE 2-FOLD HIGHER AFTER BRACHYTHERAPY.
• TAXUS V ISR (A PROSPECTIVE, RANDOMIZED TRIAL EVALUATING SLOW-RELEASE FORMULATION TAXUS
PACLITAXEL-ELUTING CORONARY STENT IN THE TREATMENT OF IN-STENT RESTENOSIS) TRIAL :
• RANDOMIZED 396 PATIENTS WITH BMS-ISR TO RECEIVE EITHER BRACHYTHERAPY OR PACLITAXEL-ELUTING
STENTS .
• AT 9-MONTH FOLLOW-UP, PACLITAXEL-ELUTING STENTS SIGNIFICANTLY REDUCED ANGIOGRAPHIC
RESTENOSIS RATES AND THE NEED FOR TARGET VESSEL REVASCULARIZATION.
• CONCLUSION – DES BETTER THAN BRACHYTHERPY.

42. STENT FOR ISR
• BOTH BMS AND DES ARE AVAILABLE FOR ISR.
• THE RIBS I (RESTENOSIS INTRA-STENT BALLOON ANGIOPLASTY VERSUS ELECTIVE
STENTING) TRIAL RANDOMIZED 450 PATIENTS WITH BMS-ISR TO RECEIVE EITHER BA OR
REPEAT BMS IMPLANTATION.
• ACUTE ANGIOGRAPHIC RESULTS WERE SIGNIFICANTLY BETTER AFTER STENT IMPLANTATION
DUE TO A LARGER ACUTE GAIN.
• AT 6-MONTH FOLLOW-UP, THE LATE LOSS WAS ALSO SIGNIFICANTLY LARGER IN THE STENT
GROUP.
• AS A RESULT, FINAL MINIMAL LUMEN DIAMETER AND PERCENT DIAMETER STENOSIS WERE
SIMILAR IN BOTH ARMS. LIKEWISE, RECURRENT RESTENOSIS RATES WERE HIGH AND SIMILAR
IN THE 2 GROUPS .

43. WHO WILL BENEFIT FROM STENT:
• LUMEN DIAMETER > 3 mm
• ISR AFFECTING STENT EDGES

44. DRUG ELUTING STENT FOR ISR
• The ISAR-DESIRE (Intracoronary Stenting or Angioplasty for Restenosis Reduction–Drug-
Eluting Stents for In-Stent Restenosis) trial :
• first randomized study assessing the value of DES in patients with BMS-ISR.
• 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%).

45. • The RIBS II (Restenosis Intrastent: Balloon Angioplasty Versus Elective
Sirolimus-Eluting Stenting) trial.
• compared sirolimus-DES versus BA in patients with BMS-ISR.
• Compared with the BA arm, patients treated with sirolimus-DES had a significantly lower
restenosis rate (11%) and superior longterm clinical outcome.
• The long-term (4-year) follow-up of this study was reassuring.

46. DES ISR
• TREATMENT OF DES-ISR IS ASSOCIATED WITH POORER LATE OUTCOMES THAN
THOSE OBTAINED AFTER TREATMENT FOR BMS-ISR .
• INITIAL OBSERVATIONAL STUDIES SUGGESTED THAT DES PROVIDED SUPERIOR
RESULTS COMPARED WITH OTHER STRATEGIES SUCH AS BA OR CUTTING
BALLOON ANGIOPLASTY .

47. • THE ISAR-DESIRE 2 (INTRACORONARY STENTING AND ANGIOGRAPHIC RESULTS:
DRUG ELUTING STENTS FOR IN-STENT RESTENOSIS 2) TRIAL :
• randomly allocated 450 patients with sirolimus-DES-ISR to undergo repeat stenting
with sirolimus-DES versus switching to stenting with paclitaxelDES.
• NO SIGNIFICANT DIFFERENCE BETWEEN THOSE TWO IN PREVENTING RESTENOSIS.

48. • RIBS III TRIAL :
• a prospective multicenter registry including 363 patients with DES-ISR.
• use of a hetero-DES approach was recommended.
• The main finding was that the hetero-DES approach (or switch DES strategy) was
associated with better clinical outcomes.
• Also proved that second generation stent was superior to first generation DES.

49. DRUG COATED BALLOON
• RIBS V (Restenosis Intra-stent: Drug-eluting
Balloon vs. Everolimus-eluting Stent) trial:
• randomized comparison of DCB with second-generation everolimus-DES in 189
patients with BMS-ISR .
• In this study, the minimal lumen diameter at follow-up was better after
everolimus-DES (2.01 mm vs. 2.36 mm; p < 0.001).
• binary restenosis (4.7% vs. 9.5%; p ¼ 0.22) and clinical events at 1 year were
low and similar in both groups.

50. • ISAR-DESIRE 3 (INTRACORONARY STENTING AND
ANGIOGRAPHIC RESULTS:
• COMPARED BA VS DCB( PACLITAXEL ) VS DES (PACLITAXEL)
• DCB WAS NON INFERIOR TO DES AND BOTH WERE SUPERIOR TO CONVENTIONAL
BA.
• DCB MAINLY CONTAIN PACLITAXEL AND SIROLIMUS
• TRAILS INVOLVING EVEROLIMUS COATED BALLOONS ARE TO BE DONE.

51. PROBLEMS WITH RECURRENT DES ISR:
• DUE TO RECURRENT DES IMPLANTATION SEVERE UNDER EXPANSION PROBLEM WILL BE
FACED EVEN WITH HIGHPRESSURE BALLOONS.
• FORMATION OF MULTIPLE METAL LAYERS WITHIN VESSEL
• RESULTS IN SMALL MINIMAL LUMEN DIAMETER AFTER STENTING PROMOTING FURTHER
FUTURE RESTENOSIS.
• WILL LEAD TO CABG IN FUTURE.
• IN SUCH SCENARIOS ROTATION ATHERECTOMY ( STENT ABLATION ) TECHNIQUE OR DCB VERY
USEFUL.

52. • DCB MAY BE PREFERRED OVER DES :
• in patients with ISR and multiple metal layers
• in those with large side branches,
• at high bleeding risk undergoing prolonged dual antiplatelet therapy.
DES MAY BE PREFERRED OVER DCB :
• in patients with stent fracture
• restenosis extending outside the stent edge
• in patients with suboptimal results after lesion predilation.

54. • THANK YOU