Coronary stent thrombosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-in-Chief: Smita Kohli, M.D.; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.

Stent thrombosis (ST) is a rare but devastating complication of coronary artery stenting that is associated with a high rate of morbidity and mortality ^{[1] [2] [3] [4]} This process should not be confused with restenosis, a fibro-proliferative disorder which is associated with recurrent angina and ischemia but uncommonly with myocardial infarction or death.

• Over the years stent thrombosis of bare metal stents (BMS) has been minimized by refining stent design, adopting optimal stenting strategies and improved antiplatelet medication usage from early rates of 24% ^[5] to a rare and acceptable 0.5-1.5% in the current environment.

• Following the approval by the FDA, the drug eluting stents (DES) largely replaced BMS, driven solely by the reduced revascularization with relatively little attention paid to the issue of stent thrombosis.
• Increased usage of DES and continued presentation of patients with ST beyond the first few months of implantation, coupled with the widespread awareness of ST, have led to a steady and increased stream of reporting of ST in DES.
• Recent description of frequent subclinical insitu thrombus formation within DES in the coronaries by Katani et al^[6], not only took the medical community by surprise but afforded a first hand in-vivo glimpse at the stent site itself.

• It should be noted that the term coronary stent thrombosis (ST) is commonly used for clinically significant episodes. ^[7]

• In this context, clinically significant ST appears to be a rare complication with devastating consequences if left untreated emergently, though the mileu for such probably exists in a much larger population.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Smita Kohli, M.D.; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.

Click here to see a rare case of very late stent thrombosis, 7 years after DES implantation.

Coronary stent thrombosis (ST) is the sudden occlusion of a stented coronary artery due to formation of thrombosis. The clinical consequences of ST are frequently catastrophic and include death in 20-48% or major myocardial infarction (MI) in 60-70% of the cases.^{[1] [2] [3]}

• Some clinical trials excluded patients who underwent repeat target vessel revascularization. Given that this is more likely to be on a bare metal stent (BMS), there might have been room for bias.

• In some studies definition of late ST may have underestimated the true incidence of ST due to the exclusion of unexplained myocardial infarction (MI)s in the territory of the stented vessels and late deaths, which may have been due to stent thromboses.

• In some trials the patient who presented for revascularization of BMS patients were exluded which may have biased the interpretation of the results.

To resolve this issue and standardize the diagnosis, Academic Research Consortium(ARC) came up with the definitions of stent thrombosis^[4] which will be discussed in this section.

• Acute stent thrombosis: 0 to 24 hrs after stent implantation
• Subacute stent thrombosis: > 24 hours to 30 days after stent implantation
• Late stent thrombosis: >30 days to 1 year after stent implantation
• Very late stent thrombosis: >1 year after stent implantation

1) Angiographic confirmation of stent thrombosis: The presence of intracoronary thrombus that originates in the stent or in the segment 5 mm proximal or distal to the stent and presence of at least 1 of the following criteria within a 48-hour time window:

• Acute onset of ischemic symptoms at rest
• New ischemic ECG changes that suggest acute ischemia
• Typical rise and fall in cardiac biomarkers
• Nonocclusive thrombus-Intracoronary thrombus is defined as a (spheric, ovoid, or irregular) noncalcified filling defect or lucency surrounded by contrast material (on 3 sides or within a coronary stenosis) seen in multiple projections, or persistence of contrast material within the lumen, or a visible embolization of intraluminal material downstream.
• Occlusive thrombus-TIMI 0 or TIMI 1 intrastent or proximal to a stent up to the most adjacent proximal side branch or main branch (if originates from the side branch).

2) Pathological confirmation of stent thrombosis: Evidence of recent thrombus within the stent determined at autopsy or via examination of tissue retrieved following thrombectomy.

Clinical definition of probable stent thrombosis is considered to have occurred after intracoronary stenting in the following cases:

• Any unexplained death within the first 30 days
• Irrespective of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause.

Clinical definition of possible stent thrombosis is considered to have occurred with any unexplained death from 30 days after intracoronary stenting until end of trial follow-up.

It should be noted that the incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not considered a confirmed stent thrombosis (silent occlusion).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editors-In-Chief: Smita Kohli, M.D.; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.

Stent thrombosis (ST) occurs due to variety of factors inducing thombogenesis. Being an invasive procedure, the trauma from coronary stenting can itself cause platelet activation and thombogenic cascade. There is either creation or an enhancement of a thrombogenic milieu by:

• Creating an environment conducive for platelet activation and/or
• Creating an environment conducive for in-stent thrombosis

These processes are facilitated by

• Creating a thrombogenic milieu by

• Slow coronary flow,
• Local dissection,
• Distal untreated critical lesion
• Poor out flow

• Persistence of, or creation of substrate for platelet activation

• Exposure of platelet activating factors due to trauma of stenting or ballooning – acutely
• Persistant incomplete endotheliazation^[1][2]
• Inadequate platelet inhibition – due to inadequate dosing or drug unresponsiveness.

• Acutely
• Subacutely
• Long term

• Dosing issues

• With anti thrombotic medications (acutely)
• Antiplatelet medications (acutely, sub-acutely or long term)
• Inadequate time for the loading dose to act
• Suboptimal/sub-therapeutic dosing during the procedure or thereafter

• Resistance to antiplatelet medications^[3]

• Aspirin resistance
• Clopidogrel resistance

• Deranged homeostasis due to disease creating a prothrombotic diathesis

• Sepsis
• Blood transfusions
• Surgery (In one study, following BMS, mortality rate among patients who had non cardiac surgery within two-weeks was 32%, almost exclusively due to ST).^[4]
• Dehydration
• Other states which may create hypotensive states. (eg. of anecdotal reports of stent thrombosis with defecation syncope)

After BMS implantation, near-complete endothelization has been shown to occur by 3 to 4 months.^[5] This coincides with the reduction of risk of ST.

Factors that serve as nidus for development stent thrombosis are:

• Delayed endothelialization^[6][1][7].
• Inflammatory response to the stent material^[8][9].
• Hypersensitivity reaction around the stent material in DES serving as nidus for ST^{[10][11][12][13][14]}.

• Antineoplastic therapy and delayed endothelialization had been an issue with late ST seen with brachytherapy^[2].
  • Coronary brachytherapy use has all but disappeared since the introduction of DES.

• An angioscopic study of stented coronary segments showed that neointimal coverage was complete only in 2 out of 15 patients with sirolimus stents and all of 22 BMS at three to six months. There were thrombi in most of the stented segments which were not seen on angiography which were more common with incomplete neointimal coverage.^[1][7] In a study involving serial angioscopy after sirolimus-eluting stent (SES) implantation at 4, 11, and 21.2 ±2.2 months showed that neointimal coverage after sirolimus-eluting stent implantation was incomplete even at that late stage.

• In a post mortem analysis, DES, compared to BMS had delayed endothelial healing. This group was more likely to have ST.^[12]

• A post mortem analysis of a patient dying from an unrelated cause but who also had a DES implanted, revealed poor endothelial cell junction formation and micro-thrombi of focal platelet aggregation at 16 months after rapamycin stent implantation.^[15]

• Evidence of an inflammatory response was present in nearly 9% of the sirolimus eluting stents (SES) and paclitaxel eluting stents (PES) by the demonstration of late aquired stent malaposition (LASMA) which was more than what was seen with BMS^[16][9].

• Cypher and Taxus DES were shown to provoke chronic eosinophilic infiltration and inflammation of the arterial wall potentially predisposing patients for thrombosis^{[10][11][12][13][14]}

• Both red and white thrombi have been demonstrated within sirolimus eluting stents (SES) as a cause of late stent thrombosis^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-in-Chief: Smita Kohli, M.D.; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.

A number of clinical, angiographic, and procedural factors increase the risk of stent thrombosis. Predictors of stent thrombosis can be classified into anatomic variables, procedure related variables and clinical variables. ASA and clopidogrel resistance are emerging risk factors for stent thrombosis.

Procedure related variables associated with an increased risk of stent thrombosis include ^[1].:

• Stent underexpansion
• Dissections at the stent margin
• Incomplete wall apposition
• Residual inflow and outflow disease
• Overlapping stents
• Polymer materials
• Self expanding or coil stents

Lesion-specific factors that increase the likelihood of stent thrombosis include^[1].:

• A residual dissection at the margin of the stent
• Impaired flow into or out of the stent
• Small stent diameters (<3 mm)
• Long stent lengths
• A thrombus containing lesions such as that observed in the treatment of an acute myocardial infarction

Clinical variables include^[1][2]. :

• Acute myocardial infarction
• Noncompliance and discontinuation of clopidogrel,
• Hyporesponsiveness to antiplatelet agents
• Higher baseline platelet count
• Diabetes mellitus
• Renal failure
• Congestive heart failure
• Prior radiation orbrachytherapy

Off-label indication of BMS and DES: In addition to these, stent implantation for off-label indication of both DES and BMS(such as restenotic lesions, bypass graft lesions, left main coronary artery disease, as well as ostial, bifurcated, and totally occluded lesions) has been associated with higher rates of ischemic complications, including stent thrombosis, as compared with standard indications^[3][4].

• In a case control study of 145 patients with stent thrombosis by Rinaldi et al^[1], presence of angiographic thrombus prior to stenting, greater total stent length, higher baseline platelet count, acute MI indication, the use of a self expanding or coil stent, and GpIIb-IIIa exposure were identified as the strongest predictors of stent thrombosis.

• In another study by Marroquin et al^[5] to compare the outcomes in bare-metal versus drug-elting stents for off-label indications showed that one year after intervention, there were no significant differences in the adjusted risk of death or myocardial infarction in patients with drug eluting stents as compared with those with bare metal stents. These findings implicate that the poorer outcome observed after stenting for off-label indications are related to patient and lesion characteristics but not to the stent itself. Therefore, large randomized clinical trial are needed to further study the use of DES for off label versus standard indications.

1. Premature discontinuation of antiplatelet/clopidogrel^[6][2][7]
2. Clopidogrel resistance: Absence/dysfunction of CYP2C19 allele which is required for the conversion of clopidogrel to its active metabolite.^[8]
3. Improper opposition of the stent or undersized stent^[6][9]
4. Length of the stent- greater the length, higher the risk^[10]
5. Malignancy^[6]
6. Cocaine use^[11][12]
7. Small caliber of the vessels^[10]
8. Slow intra coronary flow post PCI^[13]
9. Bifurcation lesion^[2]
10. Inadequate periprocedural anticoagulation^[14]
11. Low ejection fraction (<30%)^[13][2][6]
12. Nonionic contrast media^[15]
13. Prior brachytherapy
14. Small stent area on intracoronary ultrasound^[16]
15. Residual plaque/thrombus/dissection after stent placement^[17][13][10]
16. CAD ≥50% proximal of culprit lesion^[6]
17. Chronic kidney disease^[2][18]
18. Diabetes mellitus^[19][2]
19. Black race^[20]
20. Elevated C-reactive protein levels^[21]
21. Hypersensitivity to stents^[22]
22. Young age^[19]
23. Paclitaxel-eluting stent implantation^[19]
24. Multivessel disease^[23]
25. Acute coronary syndrome at presentation^[24]

1. Ongoing vessel inflammation^[25]
2. Delayed neointimal coverage which is usually seen with DES when compared to BMS^[26][25]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Smita Kohli, M.D.; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.

In a prospective study analyzing 1622 patients who received at least one DES, 14.4% discontinued at least 1 antiplatelet drug, predominantly clopidogrel with an incidence of 11.8% for at least five consecutive days during the first year post-implantation.^[1]

According to a prospective study analyzing 1622 patients^[1], the following were identified as the reason for discontinuation of one or both antiplatelet therapy:

• Nearly 50% patients had interventions or minor bleeding that did not require discontinuation.
• In patients who discontinued due to bleeding events/invasive procedures, predictors included renal impairment, prior major hemorrhage, or peripheral artery disease

32% of patients were either undergoing procedures in a private hospital or did not receive information as to who made the medical decision.

18% patients stopped antiplatelet therapy on their own accord or were on psychotropic drugs.

According to the PREMIER registry of MI patients^[2], predictors of premature thienopyridine discontinuation included:

• Older age,
• Lower level of education,
• Avoidance of healthcare because of cost,
• Unmarried marital status,
• Anemia,
• Preexisting cardiovascular disease,
• Absence of discharge instructions about the medication, and
• Lack of referral to a cardiac rehabilitation program.

In patients with DES^{[3] [4] [2] [5]}, the most important risk factor for late stent thrombosis (> 30 days to 1 year) was premature cessation (less than 6 months) of antiplatelet therapy.

• In a prospective observational cohort study^[3] of 3021 patients followed for 18 months, thienopyridine discontinuation during the first six months was the major determinant of stent thrombosis (hazard ratio 13.7). There is currently insufficient information regarding the benefit of continuing thienopyridine beyond 6 months.

• From a total cohort of 2974 consecutive patients treated with DES^[4], 38 patients presented with angiographic evidence of stent thrombosis.

• Acute ST occurred in 5 patients, subacute ST in 25 patients and late ST in 8 patients.
• Individuals who discontinued clopidogrel were more likely to sustain late stent thrombosis (36.8% versus 10.7% in those without stent thrombosis). The mean duration between cessation of clopidogrel and stent thrombosis was 153 days.

• Drug-eluting stents significantly reduce restenosis, but require 3 to 6 months of thienopyridine therapy to prevent stent thrombosis. The rate and consequences of prematurely discontinuing thienopyridine therapy were also evaluated in the PREMIER registry of MI patients^[2].

• Almost 14% MI patients treated with DES discontinued thienopyridine therapy at 30 days.
• Those who discontinued medication were more likely to die during the next 11 months (7.5% versus 0.7%).

The above studies suggest that dual antiplatelet therapy with thienopyridine plus aspirin for at least six months, reduces the likelihood of stent thrombosis during the first year after DES placement.

However, there is currently insufficient information available regarding the optimal duration of thienopyridine therapy. thienopyridine therapy.

Stent thrombosis (ST) has been documented in patients who have received dual antiplatelet therapy for 1 year or more and then had their thienopyridine or both their thienopyridine and aspirin discontinued^[6][7].

• In a study of 2,006 patients with DES^[8], late stent thrombosis developed in 8 cases.

• 3 cases were related to complete cessation of antiplatelet therapy,
• 2 cases occurred while patients were on aspirin therapy within one month of cessation of clopidogrel, and
• 3 cases occurred at a time when patients were apparently clinically stable on aspirin monotherapy.

There are several studies which indicate that even if aspirin therapy if used alone there is partial protection against late stent thrombosis.

• In a study of 1,236 patients hospitalized for acute coronary syndrome^[9], 20% of stent thrombosis developed after discontinuation of aspirin with mean delay between aspirin withdrawal and the acute coronary event being 10 +/- 1.9 days. This suggests that aspirin withdrawal in coronary patients may represent a real risk for the occurrence of a new coronary event.

• In an observational study in Japan^[10], 2 year outcomes were assessed in 10,778 patients undergoing sirolimus-eluting stent implantation. It was concluded that discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine therapy only, was associated with an increased risk of stent thrombosis.

The above studies suggest aspirin should be continued indefinitely in patients with coronary artery disease.

Class I

“1. Before implantation of drug eluting stent (DES), the interventional cardiologist should discuss with the patient the need for and duration of dual antiplatelet therapy (DAPT) and the ability of the patient to comply with and tolerate DAPT.[12] (Level of Evidence: C)”

“2. Drug eluting stent (DES) are useful as an alternative to BMS to reduce the risk of restenosis in cases in which the risk of restenosis is increased and the patient is likely to be able to tolerate and comply with prolonged dual antiplatelet therapy (DAPT). For elective PCI [13][14][15][16][17] (Level of Evidence: A); for UA/NSTEMI [15] (Level of Evidence: C); for STEMI [15][16][18][19][20] (Level of Evidence: A).”

“3. Balloon angioplasty or BMS should be used in patients with high bleeding risk, inability to comply with 12 months of dual antiplatelet therapy (DAPT), or anticipated invasive or surgical procedures within the next 12 months, during which time dual antiplatelet therapy (DAPT) may be interrupted.[21][22][2][23] (Level of Evidence: B)”

Class III (No Benefit)

“1. PCI with coronary stenting should not be performed if the patient is not likely to be able to tolerate and comply with dual antiplatelet therapy (DAPT).[21][24][25] (Level of Evidence: B)”

“2. Drug eluting stent (DES) should not be implanted if the patient is not likely to be able to tolerate and comply with prolonged dual antiplatelet therapy (DAPT) or this cannot be determined before stent implantation.[21][22][2][23] (Level of Evidence: B)”

Supportive trial data:

• A study^[26] that combined two randomized trials- REAL-LATE and ZEST-LATE analyzed 2701 patients who had received DES and had been free of major adverse cardiac or cerebrovascular events and major bleeding for a period of at least 12 months to receive clopidogrel plus aspirin or aspirin alone. The primary end point was a composite of MI or death from cardiac causes and the median duration of follow up of 19.2 months.

• The cumulative risk of the primary outcome at 2 years showed no significant difference between dual antiplatelet therapy and aspirin monotherapy (1.8% versus 1.2% respectively).
• Between the two groups there were no significant difference in the individual risks of MI, stroke, stent thrombosis, need for repeat revascularization, major bleeding, and death from any cause.
• The trial also did not study the impact of cilostazol use during the first year after DES placement^[27].

• The role for prolonged dual antiplatelet therapy (DAT) comes from observational studies and meta-analyses of randomized trials that evaluated the rates of stent thrombosis, MI or death after discontinuation of clopidogrel in patients who received DES or BMS.

• Some studies benefit associated with continuation of dual antiplatelet therapy (DAT) for longer than 12 months^{[28] [12]}, although the strongest evidence is for the maintenance of therapy during the first six months.^{[3] [10] [29] [30]}.

• An ongoing trial DAPT study is a double blind randomized controlled trial intended to determine the appropriate duration for dual antiplatelet therapy (DAPT) as well as the safety and effectiveness of DAPT to protect patients from stent thrombosis and major adverse cardiovascular and cerebrovascular events following the implantation of DES.

Premature discontinuation of dual antiplatelet therapy (DAT)is a risk factor for stent thrombosis (ST), however it is important to note that administration of dual antiplatelet therapy does not prevent the occurrence of ST and many patients are on DAT at the time of the event.

An observational study^[10] in Japan analyzed 10,778 patients undergoing sirolimus-eluting stent placement.

• Incidences of definite stent thrombosis were 0.34% at 30 days, 0.54% at 1 year, and 0.77% at 2 years.

• Patients who discontinued both thienopyridine and aspirin had a significantly higher rate of ST than those who continued both (1.76% vs 0.1% at an interval of 31 to 180 days; 0.72% vs 0.07% at an interval of 181 to 365 days; 2.1% vs 0.14% at an interval of 366 to 548 days).

Discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine therapy only, was associated with an increased risk of stent thrombosis.

There was no apparent clinical benefit observed with thienopyridine use beyond 6 months after sirolimus-eluting stent implantation.

Dual antiplatelet therapy which includes thienopyridine and aspirin has become the mainstay treatment strategy for prevention of stent thrombosis. As mentioned above, premature discontinuation of antiplatelet therapy markedly increases the risk of stent thrombosis, which may have catastrophic consequences. The key modifiable contributors to premature discontinuation of antiplatelet therapy are:

• Inadequate patient education and understanding about importance of compliance of antiplatelet therapy
• Drug costs
• Physician/dentists’ instructions to patients to discontinue therapy before procedures

Combined recommendations ^[31] from AHA, ACC, SCAI, ACS, ADA and ACP are as follows:

“

1. Before implantation of a stent, the physician should discuss the need for dual antiplatelet therapy. In patients not expected to comply with 12 months of thienopyridine therapy, whether for economic or other reasons, strong consideration should be given to avoiding a DES. 2. In patients who are undergoing preparation for percutaneous coronary intervention and are likely to require invasive or surgical procedures within the next 12 months, consideration should be given to implantation of a bare metal stent or performance of balloon angioplasty with provisional stent implantation instead of the routine use of a DES. 3. A greater effort by healthcare professionals must be made before patient discharge to ensure patients are properly and thoroughly educated about the reasons they are prescribed thienopyridines and the significant risks associated with prematurely discontinuing such therapy. 4. Patients should be specifically instructed before hospital discharge to contact their treating cardiologist before stopping any antiplatelet therapy, even if instructed to stop such therapy by another healthcare provider. 5. Healthcare providers who perform invasive or surgical procedures and are concerned about periprocedural and postprocedural bleeding must be made aware of the potentially catastrophic risks of premature discontinuation of thienopyridine therapy. Such professionals who perform these procedures should contact the patient’s cardiologist if issues regarding the patient’s antiplatelet therapy are unclear, to discuss optimal patient management strategy. 6. Elective procedures for which there is significant risk of perioperative or postoperative bleeding should be deferred until patients have completed an appropriate course of thienopyridine therapy (12 months after DES implantation if they are not at high risk of bleeding and a minimum of 1 month for bare-metal stent implantation). 7. For patients treated with DES who are to undergo subsequent procedures that mandate discontinuation of thienopyridine therapy, aspirin should be continued if at all possible and the thienopyridine restarted as soon as possible after the procedure because of concerns about late-stent thrombosis. 8. The healthcare industry, insurers, the US Congress, and the pharmaceutical industry should ensure that issues such as drug cost do not cause patients to prematurely discontinue thienopyridine therapy and to thus incur catastrophic cardiovascular complications.

”

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief:Anum Ijaz M.B.B.S., M.D.[2] Smita Kohli, M.D.; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.

Stents are usually placed in the proximal segments of major epicardial vessels, hence in-stent thrombotic occlusion clinically present as severe ischemia or infarction^[1].Stent thrombosis is a medical emergency and is managed as an acute coronary syndrome, with emergent revascularization to restore vessel patency. Because the underlying abnormality is usually a mechanical or biological problem of the previously implanted stent rather than de novo atherothrombosis, restoring flow alone is not sufficient treatment. Intracoronary imaging is used at the time of the procedure to establish which mechanism is responsible; stent underexpansion, strut malapposition, uncovered struts, neoatherosclerosis, in-stent restenosis or edge-related disease; and the intervention is then directed at that mechanism. Balloon dilatation is the preferred treatment where underexpansion or malapposition is found, and a further stent is reserved for significant residual or edge dissection. The antiplatelet regimen is reviewed in every case, and a potent P2Y12 inhibitor is preferred to clopidogrel afterwards, chosen according to its own contraindications. Despite successful revascularization, mortality and recurrent thrombosis after a first stent thrombosis remain high.

The probable cause for stent thrombosis should be evaluated as the treatment varies with etiology.

While the patient is undergoing cardiac catheterization, a careful evaluation should be undertaken to exclude procedure related variables that could be amenable to further treatment such as:

• Suboptimal stent expansion and poor apposition,
• Procedure-related variables of persistent dissection, total stent length, and final lumen diameter were significantly associated with the probability of stent thrombosis^[1].
• Angiography alone cannot reliably demonstrate these abnormalities, so the search for a procedure-related cause should be made with intracoronary imaging rather than by angiographic appearance.^[2]

Likewise, the patient should be questioned thoroughly for the following clinical risk factors for stent thrombosis:

• Noncompliance with dual antiplatelet therapy,
• Premature discontinuation of dual antiplatelet therapy
• Cessation of dual antiplatelet therapy within the first month after implantation is among the strongest predictors of the event and should be asked about directly; many events nevertheless occur on uninterrupted therapy, so continued treatment does not exclude a mechanical cause.^[2]

If neither angiographic, procedural nor clinical variables appear to play a role, then clopidogrel resistance should be considered. This diagnosis can of course be confirmed through platelet function testing and genetic testing. If this is the case consideration should be made to switching the patient to prasugrel.^[3] The TIMI 38 or TRITON trial demonstrated that newer antiplatelet agents such as prasugrel^[4] may be used after weighing the risks of bleeding against benefits of decreased recurrence of stent thrombosis/coronary events. Patients who present with stent thrombosis after completing the recommended duration of treatment with clopidogrel restarting clopidogrel 75 mg daily along with aspirin and continuing for a minimum of one year should be considered.

• A potent P2Y12 inhibitor — prasugrel or ticagrelor — should be preferred to clopidogrel as the second antiplatelet agent after stent thrombosis, since these patients are by definition at heightened risk of a further ischemic event; agent selection should account for each drug’s own contraindications, below.^[5]
• Treatment with a new-generation P2Y12 inhibitor rather than clopidogrel after the event is associated with fewer subsequent myocardial infarctions, but this is supported only by observational data and should not be regarded as established.^[6]
• Platelet function testing or genetic testing should be considered in a patient with a history of recurrent ischemic events — a category that explicitly includes previous stent thrombosis — particularly where clinical or procedural ischemic risk is high, and should be performed early after the index procedure, since the first weeks to months carry the greatest combined bleeding and ischemic risk.^[7]
• High on-treatment platelet reactivity by the VerifyNow P2Y12 assay is defined as a reaction unit value above 208 (above 252 in Asian patients); where high on-treatment platelet reactivity or a CYP2C19 loss-of-function allele is identified, treatment should be escalated to prasugrel or ticagrelor rather than to a higher dose of clopidogrel.^[7]
• Where residual thrombus is seen after intervention, prolonged anticoagulation and antiplatelet therapy may be of benefit, and adherence and drug resistance should be evaluated in detail.^[8]
• Long-term oral anticoagulation is rarely necessary but may be considered in selected patients with recurrent stent thrombosis.^[8]

• Intracoronary imaging by intravascular ultrasound or optical coherence tomography should be performed when stent thrombosis is treated, because angiography alone cannot assess stent-related pathology.^[2][11]
• Imaging is prioritized once the patient is stabilized and where dual antiplatelet therapy has not been interrupted, to assess stent apposition, expansion, and the presence of edge dissection or intramural hematoma.^[8]
• Optical coherence tomography may be preferred to intravascular ultrasound for determining the mechanism of stent thrombosis, particularly for late and very late presentations, given its higher resolution for strut-level findings such as uncovered struts, malapposition and neoatherosclerosis.^[8]
• An abnormality is demonstrable in almost every stent treated for thrombosis; strut malapposition, neoatherosclerosis and major stent underexpansion account for most events, with uncovered struts, coronary evagination, edge-related disease progression and neointimal hyperplasia making up the remainder.^[12]
• Malapposition and underexpansion predominate in acute and subacute events, whereas malapposition and neoatherosclerosis predominate in late and very late events, so the timing of presentation should shape what the operator looks for.^[12]
• Ruptured neoatherosclerotic lesions are the more frequent finding after bare metal stent implantation, and coronary evagination after drug-eluting stent implantation.^[12]
• Malapposition is regarded as significant at a strut-to-intima distance greater than 350 µm, or greater than 200 µm over a length exceeding 600 µm, and underexpansion at a stent cross-sectional area below 75% of the reference lumen area.^[5]
• Imaging-guided management of stent thrombosis is associated with better two-year survival free of cardiac death and target lesion revascularization than angiographic guidance alone, but is supported only by observational, propensity-matched data and should not be regarded as established.^[13]
• Where a new stent is implanted, imaging guidance should be used, since imaging-guided drug-eluting stent implantation reduces definite or probable stent thrombosis, target lesion failure, cardiac death and target vessel myocardial infarction compared with angiography alone.^[14]
• Imaging should be repeated after treatment and the result optimised before the procedure is concluded, targeting a minimal stent area above 5.5 mm² by intravascular ultrasound outside the left main coronary artery, above 4.5 mm² by optical coherence tomography, and stent expansion of at least 80% of the reference lumen.^[15]
• Acute malapposition of less than 0.4 mm in axial distance and less than 1 mm in longitudinal extent may be accepted without further intervention.^[15]

• Emergent target lesion or target vessel revascularization is the treatment of choice in stent thrombosis to restore vessel patency.
• Revascularization may be carried out by PCI or in some instances, thrombolytics if PCI is not available ^[16].
• If revascularization is not successful, urgent CABG should be considered.
• Most stent thrombosis occlusions can be treated initially with balloon angioplasty alone; adjunctive manual thrombus aspiration should be reserved for a large clot burden.^[8]
• After flow is re-established, the angiographic and clinical picture should be checked for evidence of distal embolization, which should be treated before the procedure is considered complete.^[8]
• Reopening the vessel is only the first half of the procedure; the mechanism responsible for the event must be identified and corrected at the same sitting, because recurrence is common when it is not.^[2]
• Most patients treated for stent thrombosis receive dual antiplatelet therapy afterwards, and additional stent implantation, mechanical thrombus removal and glycoprotein IIbIIIa inhibition are each used in roughly half of cases in contemporary practice.^[6]

• Balloon angioplasty alone is the preferred treatment where stent underexpansion or malapposition is the mechanism, and is effective in that setting.^[2][13]
• A further stent should be implanted where the mechanism is significant residual or edge dissection, particularly where dual antiplatelet therapy has recently been discontinued, and may be required for neoatherosclerosis.^[8][13][2]
• Underexpansion must be corrected at the index procedure, since a stent cross-sectional area below 75% of the reference lumen area is among the imaging findings most strongly associated with a further event.^[5]
• Where late stent thrombosis has occurred on a background of in-stent restenosis, a drug-coated balloon is a reasonable alternative to a further drug-eluting stent once lesion preparation has left less than 30% residual stenosis; drug-eluting stent implantation has nevertheless yielded lower target lesion failure than drug-coated balloon treatment for restenosis of a previous drug-eluting stent.^[5]

• Peri-stent calcium underlying an underexpanded segment may itself require modification before the stent can be re-expanded; an arc of calcium greater than 270°, or a thickness greater than 0.67 mm, favours calcium-modification before high-pressure balloon re-expansion, and if expansion remains inadequate, coronary artery bypass grafting may become necessary.^[8]
• A stepwise, imaging-guided escalation is preferred: a conventional non-compliant balloon at high pressure is used first; a cutting or scoring balloon, or a super-high-pressure non-compliant balloon, is used next, particularly where intimal hyperplasia or calcific underexpansion resists a standard balloon.^[17][18]
• Intravascular lithotripsy is preferred where underexpansion is calcium-dominant; excimer laser coronary atherectomy, preferably with concurrent contrast injection to potentiate the photomechanical effect, is an alternative for extensive peristent calcium, though contrast injection increases the risk of no reflow, dissection and perforation.^[17][18]
• Rotational atherectomy or orbital atherectomy should be reserved for bailout, given the risk of burr entrapment and disruption of stent struts — particularly within the first three to six months after implantation — and repeat stenting or a drug-coated balloon should be anticipated afterward because stent integrity has been compromised.^[17][18]
• Intravascular lithotripsy has reduced efficacy when delivered through multiple stent layers, and a super-high-pressure balloon inflated above 30 atmospheres may fuse to a hydrophilic-coated guidewire.^[17]
• Where adequate expansion cannot be achieved despite these measures — especially with multiple stent layers or severe circumferential calcium — escalation to further high-risk mechanical maneuvers should be avoided and surgical revascularization considered instead.^[17][18]

• Manual thrombus aspiration may be considered where thrombus burden is large, to limit distal embolization and improve myocardial perfusion, but it has produced favourable angiographic rather than clear clinical benefit and is supported only by observational data.^[5]
• Mechanical or extraction thrombectomy has been used anecdotally in stent thrombosis, but no large-scale study has evaluated its benefit or identified which patients are most likely to gain from it.^[8]
• Glycoprotein IIbIIIa inhibition should be reserved for bailout use where there is no reflow or a thrombotic complication during the procedure.^[5][11]
• Cangrelor may be considered on a case-by-case basis in a patient who is P2Y12 inhibitor-naive at the time of the procedure.^[11]
• Intracoronary abciximab, with or without preceding manual aspiration, improves angiographic measures of myocardial perfusion and infarct size relative to standard PCI; benefit on clinical endpoints has not been established.^[5]
• Intracoronary fibrinolysis may be considered as an adjunct where thrombus burden is large, but is supported only by angiographic results and should not be regarded as established treatment.^[5]

• Routine aspiration thrombectomy is not recommended, and should not be used in place of establishing and correcting the underlying stent abnormality.^[11][5]
• Pretreatment with glycoprotein IIbIIIa inhibition before angiography is not recommended, and routine systemic use should be limited to the bailout indications above.^[11][5]
• Additional stent implantation should be avoided unless significant residual dissection or neoatherosclerosis requires it, because it adds metal without addressing underexpansion or malapposition.^[8][2]
• The procedure should not be concluded while stent underexpansion or significant malapposition remains uncorrected.^[5][15]
• Prasugrel is contraindicated in a patient with a prior transient ischemic attack or stroke; ticagrelor is the potent P2Y12 inhibitor of choice in this setting instead.^[19]
• Prasugrel is contraindicated in active pathological bleeding, including intracranial hemorrhage.^[19]
• Prasugrel should generally be avoided at 75 years of age or older because of increased fatal and intracranial bleeding risk and uncertain benefit, except in high-risk patients with diabetes mellitus or a prior myocardial infarction, where it may still be considered; the maintenance dose should be reduced to 5 mg daily in patients weighing less than 60 kg.^[19]
• Prasugrel should not be started in a patient likely to need urgent CABG, and should be stopped at least 7 days before any surgery.^[19]
• Ticagrelor is contraindicated in a prior intracranial hemorrhage and in active pathological bleeding.^[20]
• Ticagrelor should be avoided in severe hepatic impairment and with concomitant strong CYP3A4 inhibitors, and should not be started in a patient likely to need urgent CABG; it should be stopped at least 5 days before major bleeding-risk surgery.^[20]

Step 1: Restore vessel patency

• Emergent target lesion or target vessel revascularization by PCI.^[16]
• Treat most occlusions with balloon angioplasty alone; add manual thrombus aspiration only where thrombus burden is large.^[8]
• Use glycoprotein IIbIIIa inhibition as bailout for no reflow or a thrombotic complication.^[5]

Step 2: Address distal embolization and stabilize

• Once flow is restored, look for and treat angiographic or clinical evidence of distal embolization before proceeding further.^[8]

Step 3: Establish the mechanism

• Image the stented segment with intravascular ultrasound or optical coherence tomography in every case where dual antiplatelet therapy has not been interrupted.^[8][11]
• Acute or subacute presentation → look first for malapposition and underexpansion.^[12]
• Late or very late presentation → look first for malapposition and neoatherosclerosis.^[12]

Step 4: Treat according to the mechanism found

• Underexpansion or malapposition → high-pressure balloon angioplasty alone.^[2][13]
• Underexpansion refractory to balloon dilatation → calcium-modification (cutting/scoring balloon, intravascular lithotripsy or excimer laser) before re-attempting high-pressure balloon expansion, escalating to atherectomy only as bailout.^[17][18]
• Significant residual or edge dissection → implant a new stent.^[8][13]
• Neoatherosclerosis → implant a new stent where balloon treatment is inadequate.^[2]
• In-stent restenosis as the substrate → drug-coated balloon once residual stenosis is below 30%, or a drug-eluting stent.^[5]
• No modality achieves adequate expansion (multilayer stent, severe circumferential calcium) → consider surgical revascularization rather than further high-risk mechanical maneuvers.^[17]

Step 5: Confirm optimisation before finishing

• Repeat imaging and post-dilate until minimal stent area and expansion targets are met.^[15]
• Use imaging guidance for any new stent implanted.^[14]

Step 6: Secure long-term antiplatelet therapy

• Prescribe a potent P2Y12 inhibitor in preference to clopidogrel, selecting between prasugrel and ticagrelor according to each drug’s contraindications.^[5][19][20]
• Address adherence and any interruption of dual antiplatelet therapy; consider platelet function or genetic testing where risk is high or the event recurs.^[2][7]

• No reflow and distal embolization are the principal immediate complications; angiography-derived measures of coronary microvascular obstruction are present in about 40% of patients treated for stent thrombosis.^[5]
• Mortality remains high despite successful revascularization, at roughly 5% in hospital, 13% at one year and 24% at five years, and cardiac death occurs in about one in five patients by five years.^[21][6]
• Recurrent stent thrombosis is common after treatment, affecting roughly 10% to 25% of patients within five years depending on the definition applied, so a further event should be anticipated rather than regarded as unexpected.^[21][6]
• Cardiogenic shock at presentation, a left anterior descending artery culprit and a history of stroke or transient ischemic attack identify the patients at highest risk of further events after treatment.^[6]
• Increasing age, diabetes mellitus, current smoking and a bifurcation location of the thrombosed stent are independently associated with major adverse cardiac and cerebrovascular events to five years.^[21]
• Atherectomy performed within a previously implanted stent for refractory underexpansion carries a specific risk of burr or crown entrapment and physical disruption of the stent struts, and repeat stenting should be anticipated after such a procedure because stent integrity has been compromised.^[17]

Class IIa

“1. In patients undergoing coronary stent implantation, IVUS can be useful for procedural guidance, particularly in cases of left main or complex coronary artery stenting, to reduce ischemic events. (Level of Evidence: B-R)”

“2. In patients undergoing coronary stent implantation, OCT is a reasonable alternative to IVUS for procedural guidance, except in ostial left main disease. (Level of Evidence: B-R)”

“3. In patients with stent failure, IVUS or OCT is reasonable to determine the mechanism of stent failure. (Level of Evidence: C-LD)”

Class III (No Benefit)

“1. In patients with STEMI, routine aspiration thrombectomy before primary PCI is not useful. (Level of Evidence: A)”

Class III (Harm)

“1. In patients undergoing PCI who have a history of stroke or transient ischemic attack, prasugrel should not be administered. (Level of Evidence: B-R)”

Class IIa

“1. Intravascular imaging should be considered to guide PCI. (Level of Evidence: A)”

Class III (No Benefit)

“1. Among patients with STEMI undergoing PPCI, manual aspiration thrombectomy should not be performed routinely prior to PCI given lack of clinical benefit. (Level of Evidence: A)”

Class I

“1. In patients with ACS undergoing coronary stent implantation in left main artery or in complex lesions, intracoronary imaging with intravascular ultrasound (IVUS) or optical coherence tomography (OCT) is recommended for procedural guidance to reduce ischemic events. (Level of Evidence: A)”

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Smita Kohli, M.D.; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.

Stent thrombosis(ST) is associated with a mortality rate of 25%.

• Recurrence of stent thrombosis
• Myocardial infarction secondary to stent thrombosis has worse prognosis compared to those who develop MI secondary to thrombus else where in the arteries.^[1] Stent thrombosis induced MI have higher incidence of in-hospital major cardiovascular and cerebrovascular adverse events including higher death rates.
• Death occurs in approximately 25% of patients.

• Incidence of recurrent stent thrombosis has been reported as high as 12% at 6-months.^[2]

• 1 year recurrence rate of 4.6% was reported in patients with DES.^[3]

• The Dutch stent thrombosis registry reported a 3 year recurrence rate of stent thombosis of 20.1%.^[4]

• A sub-analysis of TRITON-TIMI 38 study showed that stent thrombosis was associated with death or myocardial infarction in 89% (186/210) of patients^[5]. In follow up studies after stent thrombosis, recurrent stent thrombosis has also been noticed, especially during the following six months^[6].

• Van Werkum et al^[4] studied the long term outcome after definite stent thrombosis (ST). 431 patients with definite stent thrombosis were enrolled in this multicenter registry. The primary end point was the composite of cardiac death and definite recurrent ST. The primary end point occurred in 111 patients after a median follow-up of 27.1 months. Clinical outcome was not affected by the type of previously implanted stent (drug-eluting stent or bare-metal stent) or the category of ST (early versus late). Authors concluded that the long-term clinical outcome after a first definite ST is unfavorable, with a high mortality and recurrence rate. Diabetes mellitus, left ventricular ejection fraction < 45%, long total stent length, complex coronary lesions, TIMI flow grade < 3 after percutaneous coronary intervention, and implantation of an additional coronary stent during the emergent percutaneous coronary intervention for the ST were associated with this unfavorable outcome.

• A pooled analysis of multicenter coronary stent clinical trials showed that in patients with angiographic stent thrombosis the incidence of death or myocardial infarction was 64.4% at the time of stent thrombosis and had a 6-month mortality rate of 8.9%.^[7]

• One year mortality rate was 16% and stent thrombosis recurrence was 4.6% in a multicenter study in Spain.^[3]

• The mortality rate was 31% and MI was seen in 83% of patients with stent thrombosis at 4 years follow-up in a pooled analysis.^[8]

• In a study to investigate the efficacy and outcome of emergency percutaneous coronary interventions (PCI) in patients with stent thrombosis, 6 month major adverse clinical events were comprised of death (11%), reinfarction (16%), and recurrent stent thrombosis (12%).^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Smita Kohli, M.D.; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.

The main principle of the preventive treatment for stent thrombosis is to perform the best PCI possible, including good expansion and apposition of the stent. In this context, the role of intravascular ultrasound has been studied extensively and can be helpful^[1][2].

Combined antiplatelet therapy for the preventive treatment has been extensively studied and are routinely recommended.

• There are better outcomes noted with the use of aspirin plus ticlopidine or clopidogrel than with aspirin plus warfarin or aspirin alone^{[3][4][5][6][7]}.
• Preliminary evidence suggests prasugrel resulted in fewer ischaemic outcomes including stent thrombosis than with standard clopidogrel^[8].

• In STARS trial^[3], studying 1653 patients showed superiority of aspirin and ticlopidine over combination of aspirin and warfarin or aspirin alone for reducing subacute stent thrombosis, although there were more hemorrhagic complications than with aspirin alone.

• A similar benefit for combined aspirin plus ticlopidine was noted in another randomized controlled trial^[4].

• Results from double blinded randomized studies- PCI-CURE trial^[9], analyzing 2658 patients and CREDO trial^[10], analyzing 2116 patients, revealed the benefit of clopidogrel therapy increased with time and provide evidence for at least one year therapy in patients with BMS. However both the studies did not evaluate DES.

• TRITON TIMI-38^[8]trial analyzing 12,844 patients who underwent stenting for ACS revealed intensive antiplatelet therapy with prasugrel resulted in fewer ischaemic outcomes including stent thrombosis than with standard clopidogrel.These findings were statistically robust irrespective of stent type, and the data affirm the importance of intensive platelet inhibition in patients with intracoronary stents.

The 2008 American College of Chest Physician illustrates the following guidelines for primary and secondary prevention of coronary artery disease^[11].

“

1. For patients after myocardial infarction, after ACS, and those with stable CAD and patients after percutaneous coronary intervention (PCI) with stent placed, we recommend daily aspirin (75–100 mg) as indefinite therapy. (Grade 1A). 2. For patients who undergo bare metal stent placement, we recommend the combination of aspirin and clopidogrel for at least 4 weeks (Grade 1A). 3. For patients undergoing PCI with BMS placement following ACS, we recommend 12 months of aspirin (75–100 mg/d) plus clopidogrel (75 mg/d) over aspirin alone (Grade 1A). 4. For patients undergoing PCI with a DES, we recommend aspirin (75–100 mg/d) plus clopidogrel (75 mg/d for at least 12 months) [Grade 1A for 3 to 4 months; Grade 1B for 4 to 12 months]. Beyond 1 year, we suggest continued treatment with aspirin plus clopidogrel indefinitely if no bleeding or other tolerability issues (Grade 2C).

”

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