Thrombosis is a rare but potentially fatal complication of a coronary stent implantation. Advances in percutaneous coronary interventions and the routine use of antiplatelet therapy have helped curb the incidence of stent-associated thrombosis. Antiplatelet therapy typically consists of aspirin plus other currently available antithrombotic agents. The timing and duration of antiplatelet therapy have been shown to affect patient outcomes, and appropriate pre- and postprocedure dosages optimize survival. This article presents a case with a rare but dire in-stent complication and discusses the current evidence for preventing stent-related thrombosis.

Intracoronary stent thrombosis is a rare but serious complication of cardiac catheterization procedures. The incidence of stent thrombosis decreased from about 20% in the late 1980s to about 3.5% in the early 1990s, in part thanks to the superiority of balloon-expandable stents (eg, Palmaz-Schatz) over balloon angioplasty, and in part as a result of the use of aggressive anticoagulation, which carried a high price in the form of increased bleeding complications.¹ In the latter half of the 1990s, more advanced stent implantation techniques further lowered the rates of stent thrombosis, to the current range of between 0.5% and 1.9%, without increasing the risk of bleeding.¹

A 2001 pooled analysis of 6 major clinical trials of various first- and second-generation stents showed a 0.9% incidence of thrombosis, most of which occurred during the first 2 days after the stenting procedure.¹ This analysis, however, included patients with acute coronary syndromes (ACS) who had a stent implanted after an ACS-related event as well as during elective cardiac catheterization, and some of the studies did not randomize patients until the angiographic procedure was successfully completed, possibly creating selection bias. Consequently, the reported incidence of stent-related thrombosis may have been lower than that seen in clinical practice.

Results from the Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-acute Coronary Syndromes (SYMPHONY) and the 2nd SYMPHONY trials published in 2003 included only patients with ACS who underwent stenting after an acute coronary event.² Rates of stent thrombosis in this population were slightly higher (2.9%) than those observed in previous studies. These results may be more representative of outcomes seen in real-world settings of patients with ACS.

Risks and Consequences
Stent-related thrombosis has been associated with female gender, diabetes, previous myocardial infarction (MI) or percutaneous coronary intervention (PCI) procedure, Killip class II to IV,² premature discontinuation of antiplatelet therapy, renal failure, bifurcation lesions, low ejection fraction, and stent length.³ Six-month mortality rates in patients with clinically defined thrombosis are as high as 20.8% compared with only 1% in patients without thrombosis.¹ In a 2005 study of drug-eluting stents, almost half (45%) of the patients who developed stent-related thrombosis died.³

Illustrative Case
A 77-year-old woman presented to the emergency department complaining of 3 episodes of chest discomfort that began early in the morning. She described the pain as sharp, substernal, and without radiation, and said it lasted 5 to 10 minutes. She reported associated symptoms of mild shortness of breath, nausea, vomiting, and fatigue and said she took an aspirin before coming to the emergency department. The patient had a significant medical history that included MI several years earlier, hypertension, hyperlipidemia, and diabetes mellitus. She had a 45 pack-year smoking history. She was not compliant with any of her medications and only occasionally took an aspirin. She stated that her mother had died of a heart attack when she was in her 50s. The patient’s baseline exercise tolerance was 1 block. While in the emergency department, she was given 2 sublingual nitroglycerin tablets (NitroQuick, Nitrostat, NitroTab), aspirin, and two 5-mg doses of metoprolol (Lopressor) by intravenous (IV) push.

Physical examination showed she was alert and not in any acute distress. Her vital signs were stable, and her pain had resolved after taking the sublingual nitroglycerin. Her heart and lung examinations were unremarkable. There was no edema.

Laboratory test results revealed elevated levels of creatine kinase (170 U/L), creatine kinase-MB fraction (30.1 ng/mL), and troponin I (9.4 ng/mL). The other electrolyte values were normal. Her initial electrocardiogram (ECG) revealed 2- to 3-mm ST-segment elevation in leads V₁ and V₂, with ST-segment depression in the lateral leads (Figure 1).

The patient was administered IV heparin and IV nitroglycerin, titrated based on her blood pressure (110/74 mm Hg) and chest pain symptoms. A bedside transthoracic echocardiogram showed moderately depressed left ventricular systolic function and mild anterior apical hypokinesis. She underwent a cardiac catheterization procedure the next morning, which showed 80% to 90% mid-left anterior descending artery stenosis, with a thrombolysis in MI (TIMI) flow grade of 2; 30% to 40% mid-right coronary artery stenosis; and 70% to 80% mid-posterior descending artery stenosis. Her mid-left anterior descending artery lesion was dilated with the placement of 2 stents.

She appeared to tolerate the procedure and was discharged several days later with prescriptions for clopidogrel (Plavix), enalapril maleate (Vasotec), simvastatin (Zocor), aspirin, and metoprolol.

Four hours after being discharged, she returned to the emergency department with complaints of severe, sudden-onset shortness of breath. In the emergency department she was noted to have respiratory distress and diaphoresis.

Initial laboratory analysis now showed: creatine kinase, 51 U/L; creatine kinase-MB fraction, 3.5 ng/mL; troponin I, 0.7 ng/mL. Several hours later, repeat laboratory test results were: creatine kinase, 1573 U/L; creatine kinase-MB fraction, 129 ng/mL; and troponin I, 499 ng/mL. A second ECG was taken in the emergency department (Figure 2).

The patient was immediately taken to the catheterization laboratory. A repeat catheterization showed a totally occluded proximal left anterior descending artery within the stent, with TIMI-0 flow and blood clots along the length of the left anterior descending artery. Attempts to relieve the occlusion were complicated by a linear dissection of the left main coronary artery. Two additional stents were placed, and TIMI-2 flow was achieved.

The patient was improving, but several days later she developed acute shortness of breath. Advanced cardiopulmonary life support protocol was initiated after she became hypotensive and pulseless. Attempts at resuscitation failed, and the patient was pronounced dead 2 hours later.

Preventing Stent Thrombosis: Antithrombotic Regimens
Various antithrombotic regimens have been studied for their ability to minimize the incidence of acute and subacute in-stent thrombosis while reducing the risks of hemorrhagic complications. The cornerstone of therapy is the antiplatelet agent aspirin and the antithrombotic agent adenosine diphosphate P2y12 receptor antagonists clopidogrel and ticlopidine HCl (Ticlid). The use of antiplatelet and antithrombotic agents has been shown to reduce the risk of thrombotic complications after coronary stenting.^4,5

Anticoagulant and antiplatelet agents
Early trials that compared the ability of anticoagulation and antiplatelet agents to prevent in-stent thrombosis showed that the latter were overwhelmingly superior. In one study, patients treated with warfarin sodium (Coumadin, Jantoven) anticoagulation had substantial increases in both in-stent thrombosis and hemorrhagic complications.⁴ In contrast, the Full Anticoagulation Versus Aspirin and Ticlopidine (FANTASTIC) trial showed a similar incidence of coronary stent thrombosis with ticlopidine and anticoagulation therapy.⁶ The time when the thrombosis occurred, however, differed; those receiving ticlopidine developed acute thrombosis during the initial 24 hours after stent placement, whereas those receiving anticoagulation therapy in the initial postprocedure period developed it in the subacute period (>24 hours postprocedure). The reason for this disparity is thought to be related to the delayed onset of action of ticlopidine, which takes 72 hours to reach peak effects.

Most of the early trials of antiplatelet therapy after PCI involved ticlopidine, an effective agent but one with an unfavorable side-effect profile. More than half of all patients taking ticlopidine have at least 1 side effect, usually gastrointestinal disturbances (eg, diarrhea, nausea, dyspepsia).

More recent trials have looked at other antiplatelet agents that have the same efficacy but better tolerability, specifically clopidogrel.⁷ The results of the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial supported the use of clopidogrel for the secondary prevention of cardiovascular events. This trial was conducted after interventional cardiologists began using clopidogrel post-PCI, an off-label use prompted by the unfavorable side-effect profile of ticlopidine.^8,9

The Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) showed that clopidogrel was comparable to ticlopidine in the primary end points of bleeding, neutropenia, and thrombocytopenia, but was superior to ticlopidine with regards to drug discontinuation because of noncardiac events.¹⁰ The CLASSICS and several other trials have shown that although clopidogrel and ticlopidine have similar efficacy, the relative safety of clopidogrel favors its use after a PCI.^7,9,11,12 Based on the data from these clinical studies, clopidogrel and aspirin have now been widely adopted by clinicians as the standard of care. A more recent study, however, sheds some doubt on the efficacy of this combination on thrombotic stent occlusion and mortality.¹³

New regimens
Because of the lack of well-defined, randomized, controlled trials in this context with clopidogrel plus aspirin, other drug combinations are being investigated. Recently, the role of cilostazol (Pletal), an antiplatelet agent that is mainly used for the treatment of symptomatic intermittent claudication, has been studied. One recent study showed a higher incidence of subacute thrombosis in patients receiving cilostazol plus aspirin compared with ticlopidine plus aspirin.¹⁴ A meta-analysis of studies with cilostazol, clopidogrel, and ticlopidine, however, showed no statistically significant difference in the efficacy of cilostazol compared with either clopidogrel or ticlopidine when combined with aspirin.¹⁵

The use of triple antiplatelet therapy (aspirin, cilostazol, and either clopidogrel or ticlopidine) was recently compared with dual antiplatelet therapy.¹⁶ Results showed that triple therapy was more effective in preventing thrombotic complications after stenting than standard dual antiplatelet therapy, without an increased risk of side effects.¹⁶ It becomes apparent from these studies that more clinical trials are needed before a single combination drug regimen can be advocated as the optimal approach.

Clopidogrel: timing
Recent studies have evaluated the optimal timing and duration of clopidogrel therapy after a PCI. The double-blind, randomized Clopidogrel for the Reduction of Events During Observation (CREDO) trial examined the effects of preprocedure and long-term clopidogrel therapy.¹⁷ In patients receiving a loading dose of 300 mg clopidogrel or placebo 3 to 24 hours before PCI, no difference was found in the number of events at 28 days in the pretreatment group. A subgroup analysis, however, suggested that those given a pretreatment dose of clopidogrel at least 6 hours before the PCI had a 38.6% relative reduction in the combined risk of all-cause death, MI, or urgent target-vessel revascularization at 28 days compared with no risk reduction in patients who were treated with clopidogrel less than 6 hours before PCI.

In a subset of patients from that study, long-term use of 75 mg/day clopidogrel therapy showed a 26.9% relative risk reduction in the combined end points of all-cause death, MI, or stroke at 1 year compared with placebo, without a significantly increased risk of major bleeding.

These findings support the results of the PCI-Clopidogrel in Unstable Angina to Prevent Recurrent Events (PCI-CURE) trial, a retrospective analysis of data gathered from the CURE study, which showed a 25% relative risk reduction in cardiovascular death, MI, or any revascularization with the use of clopidogrel for 1 year, without any significant increased risk of bleeding.¹⁸

Stent Deployment Speed
Stent deployment speed is an important factor in the development of stent thrombosis. The American College of Cardiology (ACC) Expert Consensus Document on Coronary Artery Stents recommends high-pressure deployment (>12-16 atmospheres [atm]) for optimal results, citing initial experience that demonstrated low-pressure stent deployment was inadequate, because of incomplete apposition of the stent to the vascular endothelium, which increased susceptibility to subacute closure.¹⁹ More recent studies have concurred with this conclusion.^20,21 One study of the use of low-pressure stent deployment (8 atm) combined with ticlopidine and aspirin showed a 30-day stent thrombosis rate of 6.4%, confirming the ACC’s conclusion that low-pressure stent deployment is an additional risk factor for coronary thrombosis, despite the use of antiplatelet agents.²¹ The use of very-high-pressure (20 atm) balloon inflation has also been studied but has been shown to worsen long-term outcomes compared with standard high-pressure inflation (12 atm).²²

Brachytherapy and Drug-eluting Stents
Stent occlusion can be the result of neointimal proliferation. New therapies, including gamma-radiation therapy and drug-eluting stents, have helped reduce this complication. Even though these therapies have been shown to significantly reduce the incidence of intimal hyperplasia, they are not without thrombotic complications.

Gamma-radiation therapy, also known as intracoronary brachytherapy, provides direct radiation to the coronary endothelium to help prevent excessive scar formation after stent placement. The rationale for using intracoronary radiation is to minimize endothelial tissue proliferation within the stent that can result in restenosis.²³ Based on the results of clinical trials, the Food and Drug Administration (FDA) approved the use of local intracoronary radiation for reducing the recurrence of in-stent restenosis.²⁴ At about the same time, the Gamma-One Trial described a new phenomenon associated with gamma-radiation therapy—namely, late thrombosis—which resulted in an increased incidence of MI.²⁵ Late thrombosis, defined as occurring between 31 and 270 days after the stenting procedure, was shown to be significantly more likely to occur in those undergoing gamma-radiation therapy than in those treated with a placebo therapy. However, the Washington Radiation for In-Stent Restenosis Trial (WRIST) demonstrated that prolonged use of antiplatelet agents (>6 months) reduced the incidence of late thrombosis in patients treated with gamma-radiation therapy, making this treatment a feasible option.²⁶

The development of drug-eluting stents has virtually eliminated intimal hyperplasia as a cause of stent restenosis. Despite representing an important advance in the elimination of in-stent restenosis, drug-eluting stents came under fire from the FDA in 2003 because of concerns about an increased risk for stent thrombosis. Between April and October 2003, approximately 300 thromboses involving the sirolimus-eluting stent (marketed under the name Cypher) were reported.²⁷ This led the FDA to issue a public health notification in October 2003, warning physicians of the potential for adverse events. Within 1 month, however, additional clinical trial data were available, showing no evidence of increased stent thrombosis with the Cypher stent compared with bare-metal stents (eg, Palmaz-Schatz, Vision).^27,28 As a result, the FDA revised its notification to inform the public that the stent was safe and effective when used as indicated.²⁷ Indeed, previous clinical trials involving Cypher stents showed no increased incidence of stent thrombosis.

It remains unclear whether this concern is legitimate or merely the result of increased publicity. However, a 2005 trial of more than 2000 patients who were implanted with a third-generation sirolimus-eluting or paclitaxel-eluting stent (Taxus) between April 2002 and January 2004 showed that 1.3% of them had stent thrombosis at 9-month follow-up, a rate that was much higher than those reported in earlier clinical trials.³ Thus, further studies are needed to determine the safety of drug-eluting stents.

Conclusion
The incidence of in-stent thrombosis has decreased dramatically with the use of antiplatelet agents and techniques, such as high-pressure stent deployment. In certain studies, however, antiplatelet agents have been found to be ineffective in preventing thrombotic complications during the initial 24 hours after stent placement. Starting these agents before cardiac catheterization and continuing their use for a prolonged period of time after the procedure may improve their efficacy. Additional clinical trials are needed to determine the risk of stent thrombosis associated with drug-eluting stents and with brachytherapy when combined with the extended use of antiplatelet therapy.

Self-assessment test
1. Which of the following factors has NOT been linked to stent thrombosis?
A. Male gender
B. Diabetes
C. Renal failure
D. Stent length

2. All these statements about the prevention of stent thrombosis are true, except:
A. Anticoagulation is superior to ticlopidine in preventing acute thrombosis within 24 hours post-PCI
B. Ticlopidine is superior to anticoagulation in preventing subacute thrombosis
C. Clopidogrel is superior to ticlopidine in preventing stent thrombosis
D. Administering clopidogrel at least 6 hours before PCI can reduce the risk of thrombosis

3. Which of these deployment strategies is currently recommended?
A. Low pressure
B. Very low pressure
C. High pressure
D. Very high pressure

4. All the following statements about intracoronary brachytherapy are true, except:
A. It prevents excessive scar formation
B. It prevents the proliferation of endothelial tissue
C. It reduces the incidence of in-stent restenosis
D. It reduces the incidence of late thrombosis

5. Which of these stent types was the subject of a 2003 FDA public health notification to physicians about potential adverse events?
A. Bare-metal stents
B. Drug-coated stents
C. Sirolimus-eluting stents
D. Paclitaxel-eluting stents

References
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