I. Stent Thrombosis: What Every Physician Needs to Know

Stent thrombosis is a thrombotic occlusion of a coronary stent. This is usually an acute process in contrast to restenosis, which is a gradual narrowing of the stent lumen due to neointimal proliferation. Stent thrombosis often results in an acute coronary syndrome, while restenosis often results in anginal symptoms. Stent thrombosis is further defined according to the following characteristics:

Timing: early (within 1 month), late (from 1 to 12 months), and very late (more than 12 months). Timing is also sometimes categorized as acute (within 24 hours) or subacute (more than 24 hours).
Clinical scenario: stent thrombosis usually results in symptoms of an acute coronary syndrome; however, it can occasionally be clinically silent.
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Underlying stent: bare-metal stent versus first generation drug-eluting stent versus second-generation drug-eluting stent thrombosis.

II. Diagnostic Confirmation: Are You Sure Your Patient Has Stent Thrombosis?

Consensus Definition of Stent Thrombosis—Academic Research Consortium

Definite stent thrombosis: a patient with clinical signs or symptoms of an acute coronary syndrome and angiographic or autopsy evidence of a thrombus 5 mm proximal or distal to the stent.
Probable stent thrombosis: an unexplained death within 30 days of stent implant or any myocardial infarction with ischemia in the same territory of the stent, but angiography was not performed.
Possible stent thrombosis: any unexplained death beyond 30 days of stent implant.

A. History Part I: Pattern Recognition

Any patient with prior percutaneous coronary intervention who presents with signs/symptoms consistent with an acute coronary syndrome, especially when there is ischemia in the territory of the prior stent, should be considered for stent thrombosis. A consideration which raises the likelihood of stent thrombosis is recent termination of an adenosine diphosphate(ADP) receptor antagonist (i.e., clopidogrel, prasugrel, or ticagrelor) and/or aspirin.

B. History Part 2: Prevalence

While stent thrombosis can be a devastating event, fortunately it is a rare problem after percutaneous coronary intervention (PCI). With bare-metal stents, most stent thromboses occur within the first month of implant at a frequency <1%.

Events beyond 6 months are exceedingly rare. With first generation drug-eluting stents, early events occur at the same low frequency as bare-metal stents.

First generation drug-eluting stents (paclitaxel-eluting and sirolimus-eluting) have a higher rate of late and especially very late stent thrombosis compared with bare-metal stents. Some registries have documented this event rate to occur at approximately 1% per year. Second generation drug-eluting stents (everolimus-eluting and zotarolimus-eluting) appear to have an enhanced safety profile since very late events are very uncommon with these devices. In fact, everolimus-eluting and zotarolimus-eluting stents are associated with a lower frequency of total and very late stent thrombosis not only compared with paclitaxel-eluting or sirolimus-eluting stents but also compared with bare-metal stents.

C. History Part 3: Competing Diagnoses That Can Mimic Stent Thrombosis

In-stent restenosis (i.e., neointimal proliferation) can be seen after percutaneous coronary intervention. This process was common with bare-metal stents (i.e., >10% among all-comers) and was significantly reduced with the advent of drug-eluting stents. In-stent restenosis usually presents as an insidious process in which patients have a gradual escalation of anginal symptoms 6 to 12 months after their index procedure. This is in contrast to stent thrombosis, which presents suddenly and can occur at any time after the procedure.

D. Physical Examination Findings

Since stent thrombosis patients present with an acute coronary syndrome, they may have signs/symptoms of heart failure or cardiogenic shock.

E. What Diagnostic Tests Should Be Performed?

The electrocardiogram is a first-line test in any patient with a chest pain syndrome. Ischemia in the territory of a prior stent is supportive stent thrombosis; however, the patient may also have progression of disease upstream or downstream of the stented segment, which would not be due to stent thrombosis per se. A silent electrocardiogram in a patient with chest pain and prior stent does not rule-out an acute coronary syndrome, since a myocardial infarction in the circumflex territory may not result in ischemic changes.

1. What Laboratory Studies (if any) Should Be Ordered to Help Establish the Diagnosis? How Should the Results Be Interpreted?

Laboratory studies are not necessary to establish the diagnosis of stent thrombosis. Suspected stent thrombosis is an emergent condition which needs to be handled like any acute myocardial infarction. Laboratory studies (i.e., CBC, chemistry, cardiac enzymes) can be obtained at the time of patient presentation, but they should not slow referral to the catheterization laboratory.

2. What Imaging Studies (if any) Should Be Ordered to Help Establish the Diagnosis? How Should the Results Be Interpreted?

Similar to laboratory studies, imaging studies (i.e., chest x-ray) are not necessary to establish the diagnosis of stent thrombosis. A chest x-ray can be obtained at the time of patient presentation, but it should not slow referral to the catheterization laboratory.

III. Management

The management of stent thrombosis is the same as the management of an acute coronary syndrome.

A. Immediate Management

The immediate management of stent thrombosis is the same as the management of an acute coronary syndrome. Patients who present with a non-ST-elevation acute coronary syndrome are usually managed invasively accordingly to local practice patterns. For example, these patients would usually undergo urgent catheterization. Medical management consists of antiplatelet therapy (i.e., aspirin, and an ADP receptor antagonist), antithrombin therapy (i.e., heparin or direct thrombin inhibitor), statin, beta-blocker, and nitroglycerin. Patients who present with an ST-elevation acute coronary syndrome should undergo emergent reperfusion therapy according to local practice patterns (i.e., normally by primary PCI). Successful reperfusion of an acute myocardial infarction from stent thrombosis is less likely than for acute myocardial infarction due to native artery/plaque rupture. Supportive medical therapy is the same as for non-ST-elevation acute coronary syndrome.

The intravenous ADP receptor antagonist cangrelor has been shown to reduce intra-procedural stent thrombosis versus clopidogrel. This is important because intra-procedural stent thrombosis can increase subsequent rates of cardiovascular ischemic events, including death.

B. Physical Examination Tips to Guide Management

The physical examination is nonspecific with stent thrombosis; however, there may be findings of heart failure (i.e., rales, elevated jugular venous distention, hypotension, etc.).

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management

Tests that assay for platelet reactivity are sometimes used in stent thrombosis; however, clinical studies have been unable to document an improvement in clinical outcomes by testing for platelet reactivity. If the patient had a stent thrombosis event on single antiplatelet therapy, use of indefinite dual antiplatelet therapy would be reasonable. If the patient had a stent thrombosis event on dual antiplatelet therapy (i.e., aspirin and clopidogrel), replacing clopidogrel with a more potent ADP receptor antagonist would be reasonable.

D. Long-Term Management

The perioperative period can pose unique risks to patients with coronary stents. The following recommendations are taken from the American College of Cardiology/American Heart Association:

Bare-metal stents. Delay elective surgery for 4 to 6 weeks after stenting at which time clopidogrel can be stopped. An important caveat is that patients who received a bare-metal stent for treatment of an acute coronary syndrome should receive up to 3 to 12 months of therapy, and elective surgery should be delayed depending on how elective it is.

Aspirin must be maintained during the perioperative period, other than very delicate surgery, such as brain surgery. For emergent/urgent surgeries, it is recommended that patients proceed to the operating room on dual antiplatelet therapy.

Drug-eluting stents. Delay elective surgery for 12 months at which time clopidogrel can be stopped. Aspirin must be maintained during the perioperative period.

For emergent/urgent surgeries, it is recommended that patients proceed to the operating room on dual antiplatelet therapy. The question of using a glycoprotein IIb/IIIa inhibitor as a bridge often comes up as a mechanism to perform surgery sooner than 12 months.

Since most stent thromboses occur in the perioperative or postoperative period rather than the preoperative period, a preoperative glycoprotein IIb/IIIa inhibitor bridge is likely ineffective at preventing thrombotic events. Therefore, there are no guideline recommendations endorsing the use of a glycoprotein IIb/IIIa inhibitor bridge. An unfractionated heparin (or low-molecular weight heparin) bridge would not be expected to prevent stent thrombosis since these thrombotic events are prevented by antiplatelet (not antithrombin) therapy.

With either type of stent, aspirin therapy should be maintained; however, this may be problematic with certain types of surgical procedures (i.e., intracranial, spinal canal, and posterior chamber of the eye). Studies have shown that when stent thrombosis occurs in the setting of complete termination of antiplatelet therapy, the median time that antiplatelet agents were held was 7 days. Therefore, antiplatelet agents should be held for the shortest possible duration (i.e., not longer than 7 days).

E. Common Pitfalls and Side-Effects of Management

When stent thrombosis occurs, it is imperative to determine the cause for the event; however, the suspected cause of stent thrombosis is often not reported. Likely in the majority of cases, this is due to lack of antiplatelet therapy. This is especially a concern in the perioperative period. Other reasons for stent thrombosis can lie with the stent itself, such as stent underexpansion or malapposition (acute or delayed). This would only be discerned by intravascular ultrasound or optical coherence tomography, which should be considered in all cases of stent thrombosis.

IV. Management with Co-Morbidities

Patient noncompliance is an important comorbidity thatmay have resulted in the stent thrombosis. For example, such a patient may not have taken the recommended aspirin/ADP receptor antagonist. This history might influence if an additional stent is used during PCI for the stent thrombosis and if an additional stent is used, a bare-metal stent might be a better choice.

V. Patient Safety and Quality Measures

A. Appropriate Prophylaxis and Other Measures to Prevent Readmission

Patient education is critically important to prevent stent thrombosis. It is mandatory that patients who receive a stent are educated about the importance of dual antiplatelet therapy and the recommended duration of therapy. Any deviation from this recommendation (i.e., for a surgical procedure) should be under the direction of a cardiologist.

Prognosis and Scope of the Problem

Patients who suffer from stent thrombosis have a poor prognosis. Up to two thirds of patients who have stent thrombosis will die or have a large myocardial infarction.

Predictors of Early Stent Thrombosis

Early stent thrombosis is often due to a technical aspect related to the procedure. This includes issues such as stent underexpansion, stent asymmetry, incomplete apposition, tissue prolapse through stent struts, residual dissection, thrombus, persistent slow flow, or untreated upstream or downstream lesions.

Lack of adequate antiplatelet therapy during this early period increases the risk of stent thrombosis. Examples of inadequate antiplatelet therapy would be aspirin without a periprocedural glycoprotein IIb/IIIa inhibitor or an adenosine diphosphate (ADP) receptor antagonist (i.e., clopidogrel, prasugrel, or ticagrelor).

After bare-metal stent PCI, aspirin is recommended for life and an ADP receptor antagonist for a minimum of 4 to 6 weeks and ideally up to 12 months. Early drug-eluting stent thrombosis shares the same predictors of early bare-metal stent thrombosis.

Predictors of Late Stent Thrombosis

Late and very late stent thrombosis is usually due to the type of stent (i.e., first generation drug-eluting) and antiplatelet therapy (i.e., premature termination of ADP receptor antagonist within 6 months or complete termination of antiplatelet agents at any time). As mentioned previously, late stent thrombosis of a bare-metal stent is exceedingly rare and based on available data, stent thrombosis of a second generation drug-eluting stent also appears quite rare.

While restenosis usually presents with gradually worsening anginal symptoms, the culminating event of this process is sometimes an acute coronary syndrome (up to one third of the time). For example, during PCI, restoration of flow through a thrombotic occlusion may sometimes reveal severe underlying restenosis. This could be the mechanism of very late stent thrombosis of a bare-metal stent.

For completeness, the following other characteristics have been associated with late stent thrombosis: acquired incomplete stent apposition, diabetes, small vessels/small stents, long stent length/multiple stents, stent underexpansion, renal failure, acute coronary syndrome at the index procedure, bifurcation lesion, left ventricular dysfunction, residual disease in the culprit vessel, left main or left anterior descending artery stent, malignancy, calcified vessel, chronic total occlusion, in-stent restenosis, younger age, peripheral artery disease, current smoking, and prior stroke.

Management of antiplatelet therapy in the perioperative period is especially problematic and will be discussed below.

Risk of Stent Thrombosis with Second Generation Drug-Eluting Stents

The risk of stent thrombosis with second generation drug-eluting stents appears to be quite low. Meta-analyses have documented lower rates of stent thrombosis with everolimus-eluting stents than first generation drug-eluting stents.

Although it is recommended that patients who receive a second generation drug-eluting stent receive 12 months of uninterrupted antiplatelet therapy, some lines of evidence suggest that durations as short as 6 months may be safe; however, other data support a longer duration of therapy. Further research is needed and ongoing to clarify what the optimal duration of dual antiplatelet therapy should be with these newer devices.

What’s the evidence?

Iakovou, I. “Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents”. JAMA. vol. 293. 2005. pp. 2126-31. (Observation study that describes the incidence, predictors, and outcome of drug-eluting stent thrombosis.)

Bavry, AA. “Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials”. Am J Med. vol. 119. 2006. pp. 1056-61. (Meta-analysis of randomized clinical trials that documented a 5-fold increased risk of very late stent thrombosis with drug-eluting stents versus bare-metal stents.)

Stone, GW. “Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents”. N Engl J Med. vol. 356. 2007. pp. 998-1008. (Pooled analysis of randomized clinical trials that documented an increased rate of very late stent thrombosis with drug-eluting stents versus bare-metal stents.)

Daemen. “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”. Lancet. vol. 369. 2007. pp. 667-78. (Large observational study which documented an increasing cumulative incidence of drug-eluting stent thrombosis during the follow-up period.)

“ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery”. Circulation. vol. 116. 2007. pp. 1971-96. (Guideline document that defines the minimum duration of dual antiplatelet therapy for bare-metal and drug-eluting stents.)

Genereux, P. “Impact of Intraprocedural stent thrombosis during percutaneous coronary intervention”. J Am Coll Cardiol. vol. 63. 2014. pp. 619-29. (Observational study from CHAMPION PHOENIX trial, which documented a reduction in intra-procedural stent thrombosis with cangrelor.)

Palmerini, T. “Long-term safety of drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis”. J Am Coll Cardiol. vol. 65. 2015. pp. 2496-507. (Comprehensive network meta-analysis, which documented very low rates of stent thrombosis with second generation drug-eluting stents.)

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