“Very” Very Late Stent Thrombosis: Acute Myocardial Infarction From Drug-Eluting Stent Thrombosis More Than 5 Years After Implantation

Abstract: A serious long-term complication of drug-eluting stent (DES) implantation is the occurrence of very late stent thrombosis (VLST) beyond 1 year after implantation. While VLST has been observed as late as 3 to 5 years following the initial procedure, it remains unknown whether DES thrombosis is a finite phenomenon that abates over time or is a risk that persists indefinitely.  We identified a series of patients who presented with acute myocardial infarction (MI) due to “very” very late stent thrombosis (VVLST), defined as occurring more than 5 years after DES implantation. The study group consisted of 7 patients (6 men and 1 woman), ages 32 to 70 years, who had angiographically confirmed definite VVLST. Six patients were active smokers and 4 were diabetic. The interval between stent implantation and VVLST ranged from 5.6 to 7.1 years. The DES was sirolimus-eluting in 4 patients and paclitaxel-eluting in 3 patients. None of the patients were taking clopidogrel and only 2 patients were taking aspirin at the time of VVLST. Therefore, 5 of the 7 patients were not on any antiplatelet therapy prior to VVLST. The clinical presentation of VVLST was an acute MI in all patients, with ST-segment elevation in 6 of the 7 patients. Six patients were treated successfully by emergent repeat percutaneous coronary intervention and 1 patient who was postoperative from neurosurgery was managed medically. In conclusion, the risk of stent thrombosis persists even beyond 5 years after first-generation DES implantation. These sobering findings underscore the importance of long-term clinical vigilance in these patients and reinforce current PCI guidelines, which recommend continuing at least aspirin indefinitely after DES.

J INVASIVE CARDIOL 2014;26(9):413-416

Key words: acute myocardial infarction, drug-eluting stents, stent thrombosis

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Stent thrombosis (ST) remains a serious complication of percutaneous coronary intervention (PCI) resulting in myocardial infarction (MI) or death in up to 80% of patients.^1-3 Compared to bare-metal stent (BMS) implantation, drug-eluting stents (DESs) are more prone to develop ST late after their implantation.^4-9 Stent thrombosis occurring more than 1 year after PCI is classified as very late stent thrombosis (VLST) according to the definitions of the Academic Research Consortium (ARC).¹⁰ Most reported series of VLST have focused on events during the first 3 postprocedural years, with a few studies extended out to 5 years of follow-up.^11-15 It remains unknown whether the risk of DES thrombosis eventually abates over time or persists indefinitely. In this report, we describe a series of patients with acute MI due to DES thrombosis occurring beyond 5 years after initial stent implantation. To our knowledge, this is the first reported series of patients who sustained ST after such an extended (>5 years) postprocedural interval, or what may be characterized as “very” very late stent thrombosis (VVLST).

Methods

From April 2008 to December 2013, patients presenting >5 years after DES implantation with definite ST were identified at our institution. Definite ST was defined according to the criteria of the Academic Research Consortium.¹⁰ A retrospective inpatient and outpatient chart review and angiographic film review was performed. All patients had acute MI due to VVLST, which was confirmed angiographically. VVLST was defined as definite ST occurring >5 years after initial DES implantation.

Results

The major clinical characteristics, pharmacologic history, and angiographic features of the patients are summarized in Table 1. The study group consisted of 7 patients (6 men and 1 woman) with ages ranging from 32-70 years (median age, 56 years). Median body mass index (BMI) was 32 kg/m². All patients had prior tobacco abuse, and 6 of these patients were active smokers at the time of VVLST. All patients had documented hyperlipidemia. Diabetes was present in 4 patients, with median hemoglobin A1C of 6.7%. 

The interval between stent implantation and VVLST ranged from 5.6-7.1 years (mean interval, 6.0 ± 0.7 years). The initial stent placed was a sirolimus-eluting stent (SES) in 4 patients and a paclitaxel-eluting stent (PES) in 3 patients, with the date of stent placement ranging from March 25, 2004 to January 9, 2007. Two patients had DES placement to treat BMS restenosis at the same site. The target vessels included 3 left anterior descending, 2 left circumflex, and 2 right coronary arteries. Of note, 4 patients had their DES placed initially in the setting of a STEMI. 

None of the patients were taking clopidogrel and only 2 patients were taking aspirin at the time of VVLST. The interval between clopidogrel discontinuation and VVLST was 7-14 days (n=3), 3-6 months (n=2) and 5 years (n=2). The interval between aspirin discontinuation and VVLST was 7-14 days (n=3), 2 years (n=1), and 5 years (n=1). Documented non-compliance with antiplatelet medication was present in 3 patients upon VVLST presentation. Two patients had stopped antiplatelet therapy prior to elective surgery – one prior to orthopedic surgery and another for a neurosurgical procedure.

VVLST resulted in ST-elevation MI in 6 patients and non-ST elevation MI in 1 patient. Mean peak troponin-T/troponin-I was 27.7±67.0 ng/mL and peak creatinine kinase was 1296 ng/mL (range, 85-3462 ng/mL). Emergent coronary angiography demonstrated thrombotic total occlusion and TIMI grade 0 flow within the stent in all patients (Figure 1). Successful repeat percutaneous intervention was performed in 6 patients using BMS implantation. One patient was treated medically without PCI for a postoperative MI shortly after open neurosurgical repair of an intracranial aneurysm. There was no in-hospital mortality, but 1 patient had cardiac arrest with ventricular fibrillation requiring cardiopulmonary resuscitation and defibrillations prior to PCI.

Discussion

A serious complication of DES is the occurrence of ST, which leads to significant adverse clinical sequelae including death or MI in the majority of patients.^1-3 The ARC classifies ST based on the time to thrombotic event as acute (up to 24 hours post PCI), subacute (1-30 days post PCI), late (between 1 month and 1 year post PCI), or very late (>1 year post PCI).¹⁰ By ARC criteria, definite ST event requires either angiographic confirmation (with appropriate clinical signs or symptoms) or pathologic confirmation at autopsy.¹⁰ All of the patients in the current study fulfilled the criteria for definite ST.

The pathology related to late ST has been elucidated by Virmani and colleagues. Compared to BMS implantation, DESs are associated with delayed arterial healing, localized inflammatory hypersensitivity reactions, and increased late stent malapposition with uncovered struts.¹⁶ An additional potential factor contributing to late thrombotic events is the development of neoatherosclerosis with plaque rupture.¹⁷

While most of the literature has focused on events during the initial 3 years, recent reports have extended follow-up after first-generation DES out to 5 years post procedure.^4-7,11-15 A pooled analysis of 1748 patients from randomized trials comparing sirolimus- and paclitaxel-eluting stents to BMS concluded that DES implantation had a higher rate of VLST between 1-4 years post procedure (14 events vs 2 events in the BMS group).⁵ In a study of 8146 patients treated with first-generation DESs, the cumulative incidence of ST at 4 years was 3.3%.¹¹ Of the subset of patients who presented with VLST (36% of total ST events), over 80% were on single or no antiplatelet therapy at the time of the event.¹¹ Recently, clinical outcomes after SES and BMS up to 7 years post implantation revealed a cumulative incidence of VLST that was significantly higher in SES patients than in BMS patients (1.43% vs 0.68%, respectively).¹⁸

To our knowledge, the current study is the first reported series to describe patients with ST occurring beyond 5 years of DES implantation. A single case study of a patient with ST occurring 2037 days (5.6 years) after DES implantation had been previously reported.¹⁹ Our data, combined with this prior case report, render it apparent that cessation of antiplatelet therapy is a risk factor for VVLST. In the current series, most of the patients were taking no antiplatelet medication and none were on dual-antiplatelet therapy. This finding underscores the need for continued antiplatelet therapy in patients with prior DES implantation regardless of the number of years since stent placement. This is particularly important when considering discontinuation of both aspirin and clopidogrel in the perioperative period, as was observed in 2 patients with DES stent thrombosis after orthopedic and neurosurgical procedures. There appears to be no definable “safe” time when antiplatelet therapy may be discontinued without potential ST. These observations support recent ACCF/AHA/SCAI PCI guidelines, which recommend that after PCI and DES, “aspirin should be continued indefinitely.”²⁰ Dual-antiplatelet therapy is recommended for a minimum of 12 months after DES placement. The ACCF/AHA/SCAI PCI guidelines give continuation of dual-antiplatelet therapy beyond 12 months a class IIb, level of evidence C in patients after DES implantation.²⁰ The risks of bleeding counterbalanced by the benefits of ST risk reduction raise ambiguity as to the length of time patients should be kept on DAPT after DES placement.²¹ 

Previously reported clinical predictors of patients at increased risk for late and very late DES thrombosis include diabetes, active cigarette smoking, and prior MI.¹⁵ These risk factors were common in our patients. It is notable that 6 of the 7 patients were active smokers. In 4 patients, the DES had originally been placed during an ST-elevation MI. As the pathological studies by Nakazawa et al demonstrated, the vascular healing after DES is substantially delayed when placed in the setting of acute MI compared to stable angina.²² Variables such as long stents, multiple lesions, overlapping stents, ostial or bifurcation lesions, small vessel size, and suboptimal stent results have all been cited as factors to consider prolonging dual-antiplatelet therapy.²¹ Of our patients with VVLST, 2 had a known stent “sandwich,” with DES placed to treat BMS restenosis. 

There are limitations to this study. All patients had first-generation DES (PES and SES) implantation, which may have higher rates of VLST compared to second-generation everolimus-eluting and zotarolimus-eluting stents.²³ Whether second-generation DESs will be prone to VVLST is currently unknown, since these newer stents have only been available for 5 years. Another limitation is the lack of intravascular imaging with ultrasound or optical coherence tomography, which could have provided further mechanistic information regarding delayed vascular healing, stent malapposition, and neoatherosclerosis. Lastly, our case series is limited due to analysis of patients from a single center and a small number of patients. The true incidence of VVLST cannot be determined from this study given its retrospective nature with lack of systematic late patient follow-up, inclusion of patients who had DES originally placed at outside hospitals, and incorporation of only cases of definite ST. 

As we have surpassed the 10-year anniversary of Food and Drug Administration approval of DESs in the United States, the threat of VVLST is apparent. Ongoing trials of prolonged dual-antiplatelet therapy will help to address unsettled questions regarding the optimal duration of dual-antiplatelet therapy after DES. Following DES implantation, current guidelines recommend aspirin indefinitely and clopidogrel (or alternative P2Y12 inhibitor) for at least 1 year.²⁰

Conclusion

The risk of ST continues to persist beyond 5 years after first-generation DES implantation. These sobering findings underscore the need for long-term clinical vigilance in these patients and reinforce current PCI guidelines, which recommend continuing at least aspirin indefinitely.

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From the Division of Cardiology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted March 6, 2014, provisional acceptance given April 18, 2014, final version accepted May 8, 2014.

Address for correspondence: Michael P. Savage, MD, Jefferson Heart Institute, 925 Chestnut Street, Mezzanine, Philadelphia, PA 19107. Email: michael.savage@jefferson.edu