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Mechanisms of nonfatal acute myocardial infarction late after stent implantation: The relative impact of disease progression, stent restenosis, and stent thrombosis
Mechanisms of nonfatal acute myocardial infarction late after stent implantation: The relative impact of disease progression, stent restenosis, and stent thrombosis Dimitrios Alexopoulos, MD, PhD, FACC, FESC, Ioanna Xanthopoulou, MD, MCs, Periklis Davlouros, MD, PhD, Anastasia Damelou, MD, Andreas Mazarakis, MD, John Chiladakis, MD, PhD, and George Hahalis, MD, PhD Patras, Greece
Background The impact of stent restenosis, stent thrombosis, or progression of disease at another site as responsible mechanisms of acute myocardial infarction (AMI) after stent implantation is not clear. Methods By searching our catheterization laboratory database for a 4-year period, 91 cases of nonfatal AMI at least 1 month after stent implantation (32.6% drug-eluting stents) were identified. By detailed comparison of post-AMI with the initial percutaneous coronary intervention angiogram, the mechanism of AMI was analyzed. Results Acute myocardial infarction was attributed to disease progression at another site in 42 (46.2%), stent restenosis in 35 (38.4%), and stent thrombosis in 10 (11%) cases. The AMI mechanism could be either stent related or disease progression (nonidentifiable culprit lesion) in 4 cases (4.4%). The median time from percutaneous coronary intervention to AMI was 27, 19, and 9 months for disease progression at another site, restenosis, and stent thrombosis group, respectively (P = .03). ST-elevation myocardial infarction occurred in 38.1% of the disease progression, in 20% of the restenosis, and in 60% of the stent thrombosis cases (P = .046). Conclusions In a “real world” population, late after stent implantation, a patient has an almost equal probability to have suffered a nonfatal AMI from either stent restenosis/thrombosis or disease progression at another site. Continuous research efforts are necessary to equally address both stent therapy and disease progression. (Am Heart J 2010;159:439-45.)
After percutaneous coronary intervention (PCI) with stent implantation, clinical events including acute myocardial infarction (AMI) can originate from the index (target) lesion or the progression of disease at other sites in the coronary tree.1 Early studies focused on events after PCI attributed to restenosis, with clinical follow-up limited to 1 year, whereas studies with longer-term follow-up of the first-generation stent focused on late stability of the target lesion.1,2 Traditionally, bare metal stent (BMS) restenosis had been thought to manifest with a benign clinical presentation.3 However, this has been disputed,4,5 as restenosis can present as an acute coronary syndrome associated with adverse outcomes.6
From the Cardiology Department, Patras University Hospital, Rio, Patras, Greece. Submitted October 20, 2009; accepted December 14, 2009. Reprint requests: Dimitrios Alexopoulos, MD, FACC, FESC, Patras University Hospital, Rio, Patras, Greece. E-mail: [email protected] 0002-8703/$ - see front matter © 2010, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2009.12.011
Moreover, stent thrombosis has attracted attention mainly because of its possible incremental risk observed with drug-eluting stents (DESs)7–9 and the association with AMI and high mortality.7,10 Stent implantation, whether BMS or DES, is a “local” treatment, whereas disease progression at other sites is a continuous, insidious, and generalized phenomenon also responsible for impaired clinical outcome. The increasing rate of revascularization late post-PCI reflects mostly nonstented sites, indicating that late revascularization is performed predominantly to treat progressive disease at nontarget sites rather than late deterioration at the stent site itself.1,11 More recently, in a low-risk clinical trial population receiving second-generation coronary stent, the first-year events originated mostly from the target lesion, whereas nontarget lesions were considered responsible for most of the events thereafter.12 The relative incidence of disease progression at another site, stent restenosis, and stent thrombosis as responsible mechanisms of nonfatal AMI beyond the periprocedural period of stent implantation in the “real world,” with both BMS and DES use, is not known. To elucidate this,
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Figure 1
Cases selection diagram.
we assessed all identified poststenting AMI survivors who underwent coronary angiography in our institution and compared the post-AMI with the initial PCI angiogram.
Methods In our tertiary care center, the cardiac catheterization laboratory database was queried for patients who underwent coronary angiography between December 2004 and December 2008 and had a history of AMI at least 1 month after PCI and stent therapy. A detailed analysis of the cases selection process is depicted in Figure 1. In total, 91 pairs of cine films or CDs were considered for further analysis. The study complies with the Declaration of Helsinki. Access to the catheterization laboratory database and subsequent analysis were approved by the institutional ethical and research board. Percutaneous coronary intervention was performed with standard techniques. All patients were treated with aspirin (100-325 mg/d) before PCI and indefinitely thereafter. Clopidogrel was prescribed for a minimum of 1 month in BMS-treated patients, 3 months for sirolimus-eluting stent–treated patients, and 6 months for paclitaxel-eluting stent–treated patients. Additional clopidogrel use varied, with most recent patients (from 2006 and later) prescribed clopidogrel for at least 1 year. Angiograms were interpreted at the clinical site and evaluated independently by 2 investigators (D. A. and P. D.). In case of
disagreement, a consensus was achieved by the participation of a third observer. Each pair of angiograms in a given patient was assessed on 2 laptops side by side or a laptop and a TAGARNO 35AX projector (Horsens, Denmark) in 22 cases where the first angiogram had been recorded on a film. The angiograms were evaluated in similar angiographic angles for the presence of lesions with N20% diameter narrowing; and the percentage stenosis was determined with quantitative coronary angiography (PIE Medical's CAAS 2000; Philips, Eindhoven, the Netherlands) or—in case of angiograms recorded on a film—use of electronic calipers (Yansen Digital Caliper, 66-220, Central Tools, Inc, Cranston, RI). The projection with the most severe stenosis was chosen for the analysis of percentage diameter stenosis. If a segment had no visible narrowing, it was assigned as 0% stenosis. A significant lesion was defined as a luminal diameter stenosis ≥50%. Lesion data with the use of the criteria of Ambrose et al13 were recorded.
Definitions Acute myocardial infarction was judged to have occurred if prolonged (N20 minutes) chest pain was followed by elevation in troponin I or creatine kinase–MB N3 times normal. Acute myocardial infarction was divided into ST-segment elevation and non–ST-segment elevation MI. Discharge summaries, laboratory results, and catheterization reports were reviewed as needed to classify patients into the preceding categories.
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Stent thrombosis was defined according to the Academic Research Consortium criteria modified for our study.14 Particularly, definite stent thrombosis was defined as visible in stent thrombus, with or without vessel occlusion at angiography after AMI. Probable stent thrombosis was defined as AMI in the distribution of the treated vessel where stent thrombosis was not angiographically confirmed and in the absence of any other obvious cause.
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Figure 2
AMI mechanism identification Patients were categorized according to the mechanism leading to AMI as having (1) disease progression at another site if a lesion had progressed to N70% or to new total occlusion in the absence of restenosis N70% and (2) stent restenosis of target lesion (total occlusion or restenosis N70% within the treated segment, encompassing the stent and the vessel 5mm proximal and distal to the stent, occurring without concomitant significant disease progression at another site) or stent thrombosis (definite or probable). Cases of total occlusion at the stent site were attributed to restenosis if there was no obvious thrombus or clinical presentation of ST-elevation myocardial infarction (STEMI). Localization of electrocardiographic (ECG) ischemic changes was used adjunctively as needed, and the AMI location was consistent with the ECG changes in all the cases of STEMI. Cases where the cause of AMI could not be attributed with certainty in only one of the above categories were considered as mechanism nonidentifiable.
Statistical analysis Demographics, medication, clinical, angiographic, and procedural characteristics were compared between the disease progression at another site and the stent restenosis and stent thrombosis groups. The χ2 test, Fisher exact test, and χ2 goodness of fit were used for analysis of categorical data. The Wilcoxon rank sum test, independent-samples t test, and 1-way analysis of variance were used for comparison of continuous data. Discrete data were summarized as frequencies and group percentages; continuous data were summarized as mean ± SD or median (range). The SPSS version 16 software (SPSS Inc, Chicago, IL) was used for computations. A value of P b .05 was considered significant. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.
Results Out of the 89 study patients, 76 were men (85.4%) and 13 women (14.6%). Two men initially had progression at another site leading to first AMI followed by restenosis leading to second AMI, accounting for the 91 cases of AMI analyzed in the study. A mechanism for the AMI could be attributed to either disease progression at another site or stent restenosis or thrombosis in 87 cases (95.6%). In 4 cases (4.4%), the mechanism of AMI could be either stent related or disease progression at another site and was considered as nonidentifiable. In 42 cases (46.2%), disease progression was considered responsible for
Relative incidence of nonfatal AMI mechanism after stent implantation.
AMI, whereas in 35 cases (38.5%), AMI was attributed to stent restenosis and, in 10 (10.9%), to stent thrombosis (6 definite and 4 probable) (Figure 2). Demographic and medication characteristics in patients with disease progression at another site and stent restenosis and thrombosis AMI are shown in Table I. History of prior coronary artery bypass grafting (CABG) was more frequent in the stent restenosis and thrombosis group than in the disease progression at another site AMI group. Angiographic and procedural characteristics of initial catheterization and PCI are shown in Table II. There were no significant differences between groups. The AMI mechanisms did not differ significantly between DES and BMS received at index PCI (Table III). Clinical and angiographic characteristics post-AMI are depicted in Table IV. The median time from the initial PCI and AMI overall was 24 months. Patients with AMI attributed to disease progression at another site suffered the event later (27 months) than the stent restenosis and thrombosis group (19 and 9 months, respectively) (P = .03). The temporal distribution of AMIs according to the involved mechanism is shown in Figure 3. Clinical presentation as STEMI occurred in 29 (32.9%) and non-STEMI in 62 (68.1%) of the cases. ST-elevation myocardial infarction was present in 38.1% of the disease progression at another site, 20% of the restenosis, and 60% of the stent thrombosis cases (P = .046). The number of significant lesions was smaller in the stent thrombosis group because of the fact that all the 4 probable stent thrombosis cases had a normal-appearing stent. Thrombus was more frequently observed in the disease progression group at another site and—by definition—the stent thrombosis group. Additional angiographic characteristics of the
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Table I. Demographic and medication characteristics in patients with disease progression at another site, stent restenosis, and stent thrombosis AMIs
Age, y Female gender Diabetes mellitus Hypertension Hypercholesterolemia Current or former smoking Peripheral vascular disease Prior MI Prior CABG Reason for initial intervention Asymptomatic CAD Stable angina Unstable angina AMI LVEF Use of IIb/IIIa inhibitors Creatinine clearance b60 mL/min Clopidogrel prescription b1 y Medication at the time of AMI Aspirin Clopidogrel Aspirin + clopidogrel ACE inhibitor β-Blocker Statin Calcium-channel blocker Diuretic Long-acting nitrates
Progression (n = 42)
Restenosis (n = 35)
Stent thrombosis (n = 10)
P
64.3 ± 11.6 4 (9.5) 15 (35.7) 28 (66.6) 27 (64.2) 27 (64.2) 7 (16.6) 6 (14.3) 1 (2.4)
65 ± 12.7 4 (11.4) 11 (31.4) 22 (62.8) 26 (74.3) 18 (51.4) 6 (17.1) 8 (22.9) 6 (17.1)
60 ± 15.3 2 (20) 2 (20) 5 (50) 4 (40) 3 (30) 0 (0) 1 (10) 2 (20)
.8 .5 .8 .6 .09 .1 .5 .6 .03
2 (4.7) 5 (11.9) 14 (33.3) 21 (50) 53 ± 8.1 8 (19) 13 (30.9) 26 (61.9)
4 (11.4) 3 (8.6) 14 (40) 14 (40) 54.3 ± 7.5 5 (14.3) 10 (28.6) 20 (57.1)
0 0 3 (30) 6 (60) 52.5 ± 8.6 4 (40) 1 (10) 3 (30)
.1 .2 .3 .1 .8 .3 .4 .2
35 22 18 23 36 39 4 9 19
31 20 19 27 29 33 3 7 14
(83.3) (52.5) (42.8) (54.7) (85.7) (92.8) (9.5) (21.4) (45.2)
(88.6) (57.1) (54.3) (77.1) (82.9) (94.3) (8.8) (20) (40)
7 4 3 6 8 8 1 1 2
(70) (40) (30) (60) (80) (80) (10) (10) (20)
.2 .6 .4 .08 1 .2 1 .8 .3
Values are expressed as mean ± SD or number (percentage). P refers to comparisons between disease progression at another site, restenosis, and stent thrombosis AMI groups. CAD, coronary artery disease; LVEF, left ventricle ejection fraction; ACE angiotensin-converting enzyme.
progression only group are shown in Table V. Disease progression at another site occurred more frequently in an artery different from the original PCI site (P = .02). In 47.6% of the cases in the progression at another site group, the stent appeared angiographically normal in the second angiogram, with the rest presenting mild/ moderate in-stent hyperplasia. In the group of AMI caused by restenosis, this was focal in 9 (25.7%) and diffuse in 21 (60%) cases.
Discussion Our study represents—to our knowledge—the first systematic effort to identify angiographically the causative mechanism of nonfatal AMI late after stent therapy. By comparison of pre- and post-AMI coronary angiograms in patients subjected to PCI with stent(s)—one third DES —we searched for the AMI culprit lesion globally, that is, both at the stent site (restenosed or thrombosed) and in the rest of the coronary tree. In our “real world” population, there was an equal probability to develop a nonfatal AMI late after stent implantation from either the stent site or disease progression at another site. In 4.4% of the cases, the attribution of AMI to either disease progression at another site or stent restenosis/thrombosis
was not feasible even though we used, apart from angiographic, adjunctive clinical and ECG data.
AMI caused by stent restenosis or thrombosis Restenosis has been thought to manifest a benign clinical presentation.3 However, in our population, half of the nonfatal AMIs late poststenting were attributed to the stent site, with the majority of the later (78%) having restenosis as the causative mechanism. Our study was not designed to identify what proportion of the restenosed stents leads to AMI, but this has been reported to approximate 10% of the cases at least after BMS4,12 implantation. After BMS implantation, a cumulative stent thrombosis rate of 0.8% at 1 year and 2% at 10 years is expected,15 whereas DES implantation is associated with a stent thrombosis rate of 0.4% to 0.6% per year16 up to 4 years.17 Although stent thrombosis is infrequent, it results in high rates of death and AMI.18 In our population with DES use in 33.3% of the cases, mostly off-label, definite or probable stent thrombosis was implicated in 10.9% of all the AMIs. In the pivotal DES trials, stent thrombosis accounted for 18% of all AMIs reported; but this number included the early (within 30 days) AMIs as well.14,19 We found a history of prior CABG more frequently in the restenosis or thrombosis group, whereas a saphenous
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Table II. Angiographic and procedural characteristics of initial catheterization and PCI Progression (n = 42)
Restenosis (n = 35)
Stent thrombosis (n = 10)
P
21 (50) 15 (35.7) 6 (14.3) 2.17 ± 1.1 1.7 ± 0.9 0.48 ± 0.5 73 ± 8.7 (n = 72) 31 (43.1) 13 (18.1) 26 (36.1) 2 (2.7) 0 (0)
17 (48.6) 17 (48.6) 1 (2.8) 1.74 ± 0.6 1.4 ± 0.5 0.37 ± 0.6 74.7 ± 8.5 (n = 48) 23 (47.9) 6 (12.5) 16 (33.3) 1 (2.1) 2 (4.2)
4 (40) 5 (50) 1 (10) 2.1 ± 0.8 1.7 ± 0.8 0.4 ± 0.5 75 ± 9.7 (n = 17) 4 (23.5) 0 8 (47.1) 0 5 (29.4)
.9 .5 .2 .1 .3 .7 .9 .2 .2 .6 1 b.001
1 (1.5) 15 (20.8) 51 (70.8) 5 (6.9) 4 (5.5) 6 (8.3) 1 (1.4) 1.86 ± 0.2 30.4 ± 3.4 3.1 ± 0.07
2 (4.2) 16 (33.3) 27 (56.3) 3 (6.25) 4 (8.33) 4 (8.33) 2 (4.2) 1.69 ± 0.2 25.1 ± 2.4 2.9 ± 0.07
0 3 (17.6) 14 (82.3) 0 1 (5.9) 4 (23.5) 0 2 ± 0.33 31.6 ± 4.2 3.3 ± 0.1
.7 .3 .1 .7 .9 .1 .7 .6 .4 .3
Vessels with significant disease 1 2 3 No. of significant lesions No. of treated lesions Lesions ≥70% left untreated Treated lesion % stenosis Treated lesion location LAD LCX RCA RI SVG Treated lesion morphology Concentric Eccentric type I Eccentric type II Total occlusion Bifurcation Thrombus Ostial No. of stents Length of stent(s) (mm) Stent diameter (mm)
Values are expressed as mean ± SD or number (percentage). P refers to comparisons between disease progression at another site, stent restenosis, and stent thrombosis AMI groups. LAD, Left anterior descending; LCX, left circumflex; RCA, right coronary artery; RI, ramus intermediate.
Table III. AMI mechanisms according to type of stent
Progression Restenosis Stent thrombosis
DES n = 29
BMS n = 58
P
15 (51.7) 10 (34.5) 4 (13.8)
27 (46.6) 25 (43.1) 6 (10.3)
.7 .5 .7
Values are expressed as number (percentage).
vein graft (SVG)–treated lesion was commonly the site of stent thrombosis, in accordance with previous studies.4,15
AMI caused by disease progression With the first-generation stent, only 8.6% of the patients suffering a Q wave AMI had problems at the stented lesions at 8 years.1 In contrast, we found a much higher chance of AMI by stent restenosis or thrombosis at a much shorter interval postintervention, despite the use of newer-generation stents, including DES. Different population studied, inclusion of non-STEMIs, detailed angiographic analysis of disease progression, and length of follow-up may account for these differences. Most recent significant studies of PCI outcome do not make a distinction whether the AMI resulted from the stent site or nontarget lesion site17,20 or even exclude events attributed to plaque rupture remote from the target lesion.21 Analysis of pivotal sirolimus stent trials showed that most deaths or MIs were not attributable to
target lesion revascularization or stent thrombosis, suggesting other potential causes such as progression of disease in nonculprit lesions or incomplete capture of etiology due to lack of angiographic or autopsy confirmation in all cases.19 In our study, we have complete angiographic analysis dealing with both disease progression and stent restenosis or thrombosis. In a low-risk clinical trial population receiving a second-generation stent, the first-year hazard rate was 18.3% for target lesion events and 12.4% for events unrelated to the target lesion. After the first year, the average annual hazard rate was 1.7% for target lesion events and 6.3% for non–target lesion events.12 In the recently presented PROSPECT study (TCT 2009, San Francisco, G. Stone et al), in 700 patients with acute coronary syndrome treated with PCI and followed up for at least 3 years, an equal proportion of major adverse cardiovascular events was attributed to the culprit lesion (12.9%) and to disease progression elsewhere (11.6%). Compared with our study, only 19 cases of AMI—including the periprocedural events— with angiographic analysis were described in the PROSPECT study, with 13 of them attributed to the stented site and 6 to disease progression. In our population, the median time from PCI to AMI was decreasing from the progression to the restenosis and to the stent thrombosis groups, with most of the latest cases occurring within the first year, in accordance to previous studies.15,17 Similarly to us, Doyle et al15
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Table IV. Clinical and angiographic characteristics post-AMI
Time from PCI to MI (m) Time from MI to 2nd angio (d) STEMI presentation Vessels with significant disease 1 2 3 No. of significant lesions Culprit lesion % stenosis Culprit lesion location LAD LCX RCA RI SVG Bifurcation Thrombus Ostial Total occlusion
Progression (n = 42)
Restenosis (n = 35)
Stent thrombosis (n = 10)
P
27 (2-114) 5.9 (1-60) 16 (38.1)
19 (2-160) 3 (1-18) 7 (20)
9 (3-49) 3.9 (1-10) 6 (60)
.03 .9 .046
21 (50) 16 (38.1) 5 (11.9) 1.9 ± 1.1 76 ± 13.4
12 (34.3) 16 (45.7) 7 (20) 2.3 ± 0.22 80.8 ± 15
3 (30) 3 (30) 1 (10) 1 ± 0.3 53.0 ± 43
.3 .6 .6 .006 .001
14 (33.3) 7 (16.7) 19 (45.2) 1 (2.4) 1 (2.4) 2 (4.8) 13 (30.9) 3 (7.1) 15 (35.7)
17 (48.6) 4 (11.4) 10 (28.6) 2 (5.7) 2 (5.7) 0 0 0 5 (14.3)
3 (30) 0 6 (60) 1 (10) 0 1 (10) 6 (60) 0 4 (40)
.3 .4 .1 1 .3 .2 b.001 .3 .07
Values are expressed as mean ± SD, median (range), or number (percentage). P refers to comparisons between disease progression at another site, stent restenosis, and stent thrombosis AMI groups.
Figure 3
Table V. Angiographic characteristics of disease progression at another site group only Initial angiography Lesion that progressed to AMI Morphology Concentric Eccentric I Eccentric II Normal Severity–mean stenosis N70% stenosed without treatment Post-AMI angiography PCI in different/same artery than progression site Progression site proximal/distal from PCI lesion
Temporal distribution of AMIs after stent implantation according to the causative mechanism.
described half of their restenosis AMIs occurring beyond the first year. In almost two thirds of our cases, the clinical presentation of AMI was non-STEMI; and in one third, STEMI. ST-elevation myocardial infarction was particularly infrequent in the AMI caused by restenosis, but very frequent in AMI caused by stent thrombosis, similarly to
27 (64.3%) 10 (23.8%) 1 (2.4%) 4 (9.5%) 35.4 ± 19% 4 (9.5%)
29 (69%)/13 (31%), P = .02 6 (46.2%)/7 (53.8%), P = 1
other studies.4,14,15 We found disease progression at another site leading to AMI occurring more frequently in an artery different from the original PCI. Glaser et al22 also reported that lesion requiring additional PCI was in 61% of cases in a different artery.
Study limitations Our study is a retrospective analysis and is therefore subject to the limitations pertinent to this type of clinical investigation. Our analysis is based in post-PCI patients who had AMI and subsequent coronary angiography. Patients with a silent AMI and those treated conservatively without angiographic study or who died suddenly from AMI are not represented in our study. Although clinical follow-up rate was relatively low, it is very likely
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that we identified most of nonfatal AMIs in our 1.2 million people area because it is served solely by our interventional center. The reliability of angiographic assessment of thrombus is known to be poor, specially in the setting of total occlusion. As a result, in the restenosis cases with totally occluded vessel or even in those with patent but very severely narrowed stented segment, stent thrombosis cannot be excluded with certainty. This may have led to misclassification between stent restenosis and thrombosis, but does not weaken the main finding of our study, the importance of disease progression at another site. We may also have missed more stent thrombosis because of their more severe presentation/fatal AMI. One third of our patients had received DES. A higher penetration of DES use may alter the relative contribution of restenosis and stent thrombosis as mechanisms of stent-related AMI. Variable duration of antiplatelet treatment may have influenced our cases classification.
Clinical implications Current studies of stents for long-term hard events should look carefully for concomitant disease progression at another site as well. The difficulty in determination by the current clinical or angiographic means a priori which stenoses will subsequently demonstrate clinical instability further complicates the clinical problem. Our cohort of patients reflects current practice with contemporary rates of postprocedural antiplatelet therapy, β-blocker, angiotensin-converting enzyme inhibitor, and statin use.23 Nevertheless, a significant number of patients suffered an AMI poststenting because of disease progression at another site, underscoring the need for more effective medical therapy for secondary prevention post-PCI.
Conclusions In a “real world” population, a patient late after stent implantation has an equal probability to have suffered a nonfatal AMI from stent failure or disease progression. Further research should address not only stent-related inadequacies but also disease progression at another site.
References 1. Kimura T, Abe K, Shizuta S, et al. Long-term clinical and angiographic follow-up after coronary stent placement in native coronary arteries. Circulation 2002;105:2986-91. 2. Van Domburg RT, Foley DP, de Jaegere P, et al. Long term outcome after coronary stent implantation: a 10 year single center experience of 1000 patients. Heart 1999;82:II-27–II-34. 3. Greenberg D, Bakhai A, Cohen DJ. Can we afford to eliminate restenosis? Can we afford not to? J Am Coll Cardiol 2004;43:513-8. 4. Chen MS, John JM, Chew DP, et al. Bare metal stent restenosis is not a benign clinical entity. Am Heart J 2006;151:1260-4. 5. Bainey KR, Norris CM, Graham MM, et al. Clinical in-stent restenosis with bare metal stents: is it truly a benign phenomenon? Intern J Cardiol 2008;128:378-82.
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6. Assali AR, Moustapha A, Sdringola S, et al. Acute coronary syndrome may occur with in-stent restenosis and is associated with adverse outcomes (The PRESTO Trial). Am J Cardiol 2006;98: 729-33. 7. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-30. 8. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al, for the BASKET-LATE Investigators. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare metal stents. J Am Coll Cardiol 2006;48:2584-91. 9. Kuchulakanti PK, Chu WW, Torguson R, et al. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006;113: 1108-13. 10. Ong ATL, Hoye A, Aoki J, et al. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent Implantation. J Am Coll Cardiol 2005; 45:947-53. 11. Choussat R, Klersy C, Black AJR, et al. Long-term (8 years) outcome after Palmaz-Schatz stent implantation. Am J Cardiol 2001;88:10-6. 12. Cutlip DE, Chhabra AG, Baim DS, et al. Beyond restenosis. Five-year clinical outcomes from second-generation coronary stent trials. Circulation 2004;110:1226-30. 13. Ambrose JA, Winters SL, Stern A, et al. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol 1985;5:609-16. 14. Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007; 356:1020-9. 15. Doyle B, Rihal CS, O'Sullivan CJ, et al. Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents. Circulation 2007;116:2391-8. 16. Lagerqvist B, James SK, Stenestrand U, et al. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med 2007;356:1009-19. 17. Wenaweser P, Daemen J, Zwahlen M, et al. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice: 4-year results from a large 2-institutional cohort study. J Am Coll Cardiol 2008;52:1134-40. 18. Chechi T, Vecchio S, Vittori G, et al. ST-segment elevation myocardial infarction due to early and late stent thrombosis. A new group of high-risk patients. J Am Coll Cardiol 2008;51: 2396-402. 19. Kaul S, Shah PK, Diamond GA. As time goes by: current status and future directions in the controversy over stenting. J Am Coll Cardiol 2007;50:128-37. 20. Mauri L, Silbaugh TS, Wolf RE, et al. Long-term clinical outcomes after drug-eluting and bare-metal stenting in Massachusetts. Circulation 2008;118:1817-27. 21. Stone GW, Ellis SG, Colombo A, et al. Offsetting impact of thrombosis and restenosis on the occurrence of death and myocardial infarction after paclitaxel-eluting and bare metal stent implantation. Circulation 2007;115:2842-7. 22. Glaser R, Selzer F, Faxon DP, et al. Clinical progression of incidental, asymptomatic lesions discovered during culprit vessel coronary intervention. Circulation 2005;111:143-9. 23. EUROASPIRE II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries. Principal results from EUROASPIRE II. Euro Heart Survey Programme. Eur Heart J 2001;22:554-72.
Background The impact of stent restenosis, stent thrombosis, or progression of disease at another site as responsible mechanisms of acute myocardial infarction (AMI) after stent implantation is not clear. Methods By searching our catheterization laboratory database for a 4-year period, 91 cases of nonfatal AMI at least 1 month after stent implantation (32.6% drug-eluting stents) were identified. By detailed comparison of post-AMI with the initial percutaneous coronary intervention angiogram, the mechanism of AMI was analyzed. Results Acute myocardial infarction was attributed to disease progression at another site in 42 (46.2%), stent restenosis in 35 (38.4%), and stent thrombosis in 10 (11%) cases. The AMI mechanism could be either stent related or disease progression (nonidentifiable culprit lesion) in 4 cases (4.4%). The median time from percutaneous coronary intervention to AMI was 27, 19, and 9 months for disease progression at another site, restenosis, and stent thrombosis group, respectively (P = .03). ST-elevation myocardial infarction occurred in 38.1% of the disease progression, in 20% of the restenosis, and in 60% of the stent thrombosis cases (P = .046). Conclusions In a “real world” population, late after stent implantation, a patient has an almost equal probability to have suffered a nonfatal AMI from either stent restenosis/thrombosis or disease progression at another site. Continuous research efforts are necessary to equally address both stent therapy and disease progression. (Am Heart J 2010;159:439-45.)
After percutaneous coronary intervention (PCI) with stent implantation, clinical events including acute myocardial infarction (AMI) can originate from the index (target) lesion or the progression of disease at other sites in the coronary tree.1 Early studies focused on events after PCI attributed to restenosis, with clinical follow-up limited to 1 year, whereas studies with longer-term follow-up of the first-generation stent focused on late stability of the target lesion.1,2 Traditionally, bare metal stent (BMS) restenosis had been thought to manifest with a benign clinical presentation.3 However, this has been disputed,4,5 as restenosis can present as an acute coronary syndrome associated with adverse outcomes.6
From the Cardiology Department, Patras University Hospital, Rio, Patras, Greece. Submitted October 20, 2009; accepted December 14, 2009. Reprint requests: Dimitrios Alexopoulos, MD, FACC, FESC, Patras University Hospital, Rio, Patras, Greece. E-mail: [email protected] 0002-8703/$ - see front matter © 2010, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2009.12.011
Moreover, stent thrombosis has attracted attention mainly because of its possible incremental risk observed with drug-eluting stents (DESs)7–9 and the association with AMI and high mortality.7,10 Stent implantation, whether BMS or DES, is a “local” treatment, whereas disease progression at other sites is a continuous, insidious, and generalized phenomenon also responsible for impaired clinical outcome. The increasing rate of revascularization late post-PCI reflects mostly nonstented sites, indicating that late revascularization is performed predominantly to treat progressive disease at nontarget sites rather than late deterioration at the stent site itself.1,11 More recently, in a low-risk clinical trial population receiving second-generation coronary stent, the first-year events originated mostly from the target lesion, whereas nontarget lesions were considered responsible for most of the events thereafter.12 The relative incidence of disease progression at another site, stent restenosis, and stent thrombosis as responsible mechanisms of nonfatal AMI beyond the periprocedural period of stent implantation in the “real world,” with both BMS and DES use, is not known. To elucidate this,
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Figure 1
Cases selection diagram.
we assessed all identified poststenting AMI survivors who underwent coronary angiography in our institution and compared the post-AMI with the initial PCI angiogram.
Methods In our tertiary care center, the cardiac catheterization laboratory database was queried for patients who underwent coronary angiography between December 2004 and December 2008 and had a history of AMI at least 1 month after PCI and stent therapy. A detailed analysis of the cases selection process is depicted in Figure 1. In total, 91 pairs of cine films or CDs were considered for further analysis. The study complies with the Declaration of Helsinki. Access to the catheterization laboratory database and subsequent analysis were approved by the institutional ethical and research board. Percutaneous coronary intervention was performed with standard techniques. All patients were treated with aspirin (100-325 mg/d) before PCI and indefinitely thereafter. Clopidogrel was prescribed for a minimum of 1 month in BMS-treated patients, 3 months for sirolimus-eluting stent–treated patients, and 6 months for paclitaxel-eluting stent–treated patients. Additional clopidogrel use varied, with most recent patients (from 2006 and later) prescribed clopidogrel for at least 1 year. Angiograms were interpreted at the clinical site and evaluated independently by 2 investigators (D. A. and P. D.). In case of
disagreement, a consensus was achieved by the participation of a third observer. Each pair of angiograms in a given patient was assessed on 2 laptops side by side or a laptop and a TAGARNO 35AX projector (Horsens, Denmark) in 22 cases where the first angiogram had been recorded on a film. The angiograms were evaluated in similar angiographic angles for the presence of lesions with N20% diameter narrowing; and the percentage stenosis was determined with quantitative coronary angiography (PIE Medical's CAAS 2000; Philips, Eindhoven, the Netherlands) or—in case of angiograms recorded on a film—use of electronic calipers (Yansen Digital Caliper, 66-220, Central Tools, Inc, Cranston, RI). The projection with the most severe stenosis was chosen for the analysis of percentage diameter stenosis. If a segment had no visible narrowing, it was assigned as 0% stenosis. A significant lesion was defined as a luminal diameter stenosis ≥50%. Lesion data with the use of the criteria of Ambrose et al13 were recorded.
Definitions Acute myocardial infarction was judged to have occurred if prolonged (N20 minutes) chest pain was followed by elevation in troponin I or creatine kinase–MB N3 times normal. Acute myocardial infarction was divided into ST-segment elevation and non–ST-segment elevation MI. Discharge summaries, laboratory results, and catheterization reports were reviewed as needed to classify patients into the preceding categories.
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Stent thrombosis was defined according to the Academic Research Consortium criteria modified for our study.14 Particularly, definite stent thrombosis was defined as visible in stent thrombus, with or without vessel occlusion at angiography after AMI. Probable stent thrombosis was defined as AMI in the distribution of the treated vessel where stent thrombosis was not angiographically confirmed and in the absence of any other obvious cause.
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Figure 2
AMI mechanism identification Patients were categorized according to the mechanism leading to AMI as having (1) disease progression at another site if a lesion had progressed to N70% or to new total occlusion in the absence of restenosis N70% and (2) stent restenosis of target lesion (total occlusion or restenosis N70% within the treated segment, encompassing the stent and the vessel 5mm proximal and distal to the stent, occurring without concomitant significant disease progression at another site) or stent thrombosis (definite or probable). Cases of total occlusion at the stent site were attributed to restenosis if there was no obvious thrombus or clinical presentation of ST-elevation myocardial infarction (STEMI). Localization of electrocardiographic (ECG) ischemic changes was used adjunctively as needed, and the AMI location was consistent with the ECG changes in all the cases of STEMI. Cases where the cause of AMI could not be attributed with certainty in only one of the above categories were considered as mechanism nonidentifiable.
Statistical analysis Demographics, medication, clinical, angiographic, and procedural characteristics were compared between the disease progression at another site and the stent restenosis and stent thrombosis groups. The χ2 test, Fisher exact test, and χ2 goodness of fit were used for analysis of categorical data. The Wilcoxon rank sum test, independent-samples t test, and 1-way analysis of variance were used for comparison of continuous data. Discrete data were summarized as frequencies and group percentages; continuous data were summarized as mean ± SD or median (range). The SPSS version 16 software (SPSS Inc, Chicago, IL) was used for computations. A value of P b .05 was considered significant. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.
Results Out of the 89 study patients, 76 were men (85.4%) and 13 women (14.6%). Two men initially had progression at another site leading to first AMI followed by restenosis leading to second AMI, accounting for the 91 cases of AMI analyzed in the study. A mechanism for the AMI could be attributed to either disease progression at another site or stent restenosis or thrombosis in 87 cases (95.6%). In 4 cases (4.4%), the mechanism of AMI could be either stent related or disease progression at another site and was considered as nonidentifiable. In 42 cases (46.2%), disease progression was considered responsible for
Relative incidence of nonfatal AMI mechanism after stent implantation.
AMI, whereas in 35 cases (38.5%), AMI was attributed to stent restenosis and, in 10 (10.9%), to stent thrombosis (6 definite and 4 probable) (Figure 2). Demographic and medication characteristics in patients with disease progression at another site and stent restenosis and thrombosis AMI are shown in Table I. History of prior coronary artery bypass grafting (CABG) was more frequent in the stent restenosis and thrombosis group than in the disease progression at another site AMI group. Angiographic and procedural characteristics of initial catheterization and PCI are shown in Table II. There were no significant differences between groups. The AMI mechanisms did not differ significantly between DES and BMS received at index PCI (Table III). Clinical and angiographic characteristics post-AMI are depicted in Table IV. The median time from the initial PCI and AMI overall was 24 months. Patients with AMI attributed to disease progression at another site suffered the event later (27 months) than the stent restenosis and thrombosis group (19 and 9 months, respectively) (P = .03). The temporal distribution of AMIs according to the involved mechanism is shown in Figure 3. Clinical presentation as STEMI occurred in 29 (32.9%) and non-STEMI in 62 (68.1%) of the cases. ST-elevation myocardial infarction was present in 38.1% of the disease progression at another site, 20% of the restenosis, and 60% of the stent thrombosis cases (P = .046). The number of significant lesions was smaller in the stent thrombosis group because of the fact that all the 4 probable stent thrombosis cases had a normal-appearing stent. Thrombus was more frequently observed in the disease progression group at another site and—by definition—the stent thrombosis group. Additional angiographic characteristics of the
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Table I. Demographic and medication characteristics in patients with disease progression at another site, stent restenosis, and stent thrombosis AMIs
Age, y Female gender Diabetes mellitus Hypertension Hypercholesterolemia Current or former smoking Peripheral vascular disease Prior MI Prior CABG Reason for initial intervention Asymptomatic CAD Stable angina Unstable angina AMI LVEF Use of IIb/IIIa inhibitors Creatinine clearance b60 mL/min Clopidogrel prescription b1 y Medication at the time of AMI Aspirin Clopidogrel Aspirin + clopidogrel ACE inhibitor β-Blocker Statin Calcium-channel blocker Diuretic Long-acting nitrates
Progression (n = 42)
Restenosis (n = 35)
Stent thrombosis (n = 10)
P
64.3 ± 11.6 4 (9.5) 15 (35.7) 28 (66.6) 27 (64.2) 27 (64.2) 7 (16.6) 6 (14.3) 1 (2.4)
65 ± 12.7 4 (11.4) 11 (31.4) 22 (62.8) 26 (74.3) 18 (51.4) 6 (17.1) 8 (22.9) 6 (17.1)
60 ± 15.3 2 (20) 2 (20) 5 (50) 4 (40) 3 (30) 0 (0) 1 (10) 2 (20)
.8 .5 .8 .6 .09 .1 .5 .6 .03
2 (4.7) 5 (11.9) 14 (33.3) 21 (50) 53 ± 8.1 8 (19) 13 (30.9) 26 (61.9)
4 (11.4) 3 (8.6) 14 (40) 14 (40) 54.3 ± 7.5 5 (14.3) 10 (28.6) 20 (57.1)
0 0 3 (30) 6 (60) 52.5 ± 8.6 4 (40) 1 (10) 3 (30)
.1 .2 .3 .1 .8 .3 .4 .2
35 22 18 23 36 39 4 9 19
31 20 19 27 29 33 3 7 14
(83.3) (52.5) (42.8) (54.7) (85.7) (92.8) (9.5) (21.4) (45.2)
(88.6) (57.1) (54.3) (77.1) (82.9) (94.3) (8.8) (20) (40)
7 4 3 6 8 8 1 1 2
(70) (40) (30) (60) (80) (80) (10) (10) (20)
.2 .6 .4 .08 1 .2 1 .8 .3
Values are expressed as mean ± SD or number (percentage). P refers to comparisons between disease progression at another site, restenosis, and stent thrombosis AMI groups. CAD, coronary artery disease; LVEF, left ventricle ejection fraction; ACE angiotensin-converting enzyme.
progression only group are shown in Table V. Disease progression at another site occurred more frequently in an artery different from the original PCI site (P = .02). In 47.6% of the cases in the progression at another site group, the stent appeared angiographically normal in the second angiogram, with the rest presenting mild/ moderate in-stent hyperplasia. In the group of AMI caused by restenosis, this was focal in 9 (25.7%) and diffuse in 21 (60%) cases.
Discussion Our study represents—to our knowledge—the first systematic effort to identify angiographically the causative mechanism of nonfatal AMI late after stent therapy. By comparison of pre- and post-AMI coronary angiograms in patients subjected to PCI with stent(s)—one third DES —we searched for the AMI culprit lesion globally, that is, both at the stent site (restenosed or thrombosed) and in the rest of the coronary tree. In our “real world” population, there was an equal probability to develop a nonfatal AMI late after stent implantation from either the stent site or disease progression at another site. In 4.4% of the cases, the attribution of AMI to either disease progression at another site or stent restenosis/thrombosis
was not feasible even though we used, apart from angiographic, adjunctive clinical and ECG data.
AMI caused by stent restenosis or thrombosis Restenosis has been thought to manifest a benign clinical presentation.3 However, in our population, half of the nonfatal AMIs late poststenting were attributed to the stent site, with the majority of the later (78%) having restenosis as the causative mechanism. Our study was not designed to identify what proportion of the restenosed stents leads to AMI, but this has been reported to approximate 10% of the cases at least after BMS4,12 implantation. After BMS implantation, a cumulative stent thrombosis rate of 0.8% at 1 year and 2% at 10 years is expected,15 whereas DES implantation is associated with a stent thrombosis rate of 0.4% to 0.6% per year16 up to 4 years.17 Although stent thrombosis is infrequent, it results in high rates of death and AMI.18 In our population with DES use in 33.3% of the cases, mostly off-label, definite or probable stent thrombosis was implicated in 10.9% of all the AMIs. In the pivotal DES trials, stent thrombosis accounted for 18% of all AMIs reported; but this number included the early (within 30 days) AMIs as well.14,19 We found a history of prior CABG more frequently in the restenosis or thrombosis group, whereas a saphenous
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Table II. Angiographic and procedural characteristics of initial catheterization and PCI Progression (n = 42)
Restenosis (n = 35)
Stent thrombosis (n = 10)
P
21 (50) 15 (35.7) 6 (14.3) 2.17 ± 1.1 1.7 ± 0.9 0.48 ± 0.5 73 ± 8.7 (n = 72) 31 (43.1) 13 (18.1) 26 (36.1) 2 (2.7) 0 (0)
17 (48.6) 17 (48.6) 1 (2.8) 1.74 ± 0.6 1.4 ± 0.5 0.37 ± 0.6 74.7 ± 8.5 (n = 48) 23 (47.9) 6 (12.5) 16 (33.3) 1 (2.1) 2 (4.2)
4 (40) 5 (50) 1 (10) 2.1 ± 0.8 1.7 ± 0.8 0.4 ± 0.5 75 ± 9.7 (n = 17) 4 (23.5) 0 8 (47.1) 0 5 (29.4)
.9 .5 .2 .1 .3 .7 .9 .2 .2 .6 1 b.001
1 (1.5) 15 (20.8) 51 (70.8) 5 (6.9) 4 (5.5) 6 (8.3) 1 (1.4) 1.86 ± 0.2 30.4 ± 3.4 3.1 ± 0.07
2 (4.2) 16 (33.3) 27 (56.3) 3 (6.25) 4 (8.33) 4 (8.33) 2 (4.2) 1.69 ± 0.2 25.1 ± 2.4 2.9 ± 0.07
0 3 (17.6) 14 (82.3) 0 1 (5.9) 4 (23.5) 0 2 ± 0.33 31.6 ± 4.2 3.3 ± 0.1
.7 .3 .1 .7 .9 .1 .7 .6 .4 .3
Vessels with significant disease 1 2 3 No. of significant lesions No. of treated lesions Lesions ≥70% left untreated Treated lesion % stenosis Treated lesion location LAD LCX RCA RI SVG Treated lesion morphology Concentric Eccentric type I Eccentric type II Total occlusion Bifurcation Thrombus Ostial No. of stents Length of stent(s) (mm) Stent diameter (mm)
Values are expressed as mean ± SD or number (percentage). P refers to comparisons between disease progression at another site, stent restenosis, and stent thrombosis AMI groups. LAD, Left anterior descending; LCX, left circumflex; RCA, right coronary artery; RI, ramus intermediate.
Table III. AMI mechanisms according to type of stent
Progression Restenosis Stent thrombosis
DES n = 29
BMS n = 58
P
15 (51.7) 10 (34.5) 4 (13.8)
27 (46.6) 25 (43.1) 6 (10.3)
.7 .5 .7
Values are expressed as number (percentage).
vein graft (SVG)–treated lesion was commonly the site of stent thrombosis, in accordance with previous studies.4,15
AMI caused by disease progression With the first-generation stent, only 8.6% of the patients suffering a Q wave AMI had problems at the stented lesions at 8 years.1 In contrast, we found a much higher chance of AMI by stent restenosis or thrombosis at a much shorter interval postintervention, despite the use of newer-generation stents, including DES. Different population studied, inclusion of non-STEMIs, detailed angiographic analysis of disease progression, and length of follow-up may account for these differences. Most recent significant studies of PCI outcome do not make a distinction whether the AMI resulted from the stent site or nontarget lesion site17,20 or even exclude events attributed to plaque rupture remote from the target lesion.21 Analysis of pivotal sirolimus stent trials showed that most deaths or MIs were not attributable to
target lesion revascularization or stent thrombosis, suggesting other potential causes such as progression of disease in nonculprit lesions or incomplete capture of etiology due to lack of angiographic or autopsy confirmation in all cases.19 In our study, we have complete angiographic analysis dealing with both disease progression and stent restenosis or thrombosis. In a low-risk clinical trial population receiving a second-generation stent, the first-year hazard rate was 18.3% for target lesion events and 12.4% for events unrelated to the target lesion. After the first year, the average annual hazard rate was 1.7% for target lesion events and 6.3% for non–target lesion events.12 In the recently presented PROSPECT study (TCT 2009, San Francisco, G. Stone et al), in 700 patients with acute coronary syndrome treated with PCI and followed up for at least 3 years, an equal proportion of major adverse cardiovascular events was attributed to the culprit lesion (12.9%) and to disease progression elsewhere (11.6%). Compared with our study, only 19 cases of AMI—including the periprocedural events— with angiographic analysis were described in the PROSPECT study, with 13 of them attributed to the stented site and 6 to disease progression. In our population, the median time from PCI to AMI was decreasing from the progression to the restenosis and to the stent thrombosis groups, with most of the latest cases occurring within the first year, in accordance to previous studies.15,17 Similarly to us, Doyle et al15
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Table IV. Clinical and angiographic characteristics post-AMI
Time from PCI to MI (m) Time from MI to 2nd angio (d) STEMI presentation Vessels with significant disease 1 2 3 No. of significant lesions Culprit lesion % stenosis Culprit lesion location LAD LCX RCA RI SVG Bifurcation Thrombus Ostial Total occlusion
Progression (n = 42)
Restenosis (n = 35)
Stent thrombosis (n = 10)
P
27 (2-114) 5.9 (1-60) 16 (38.1)
19 (2-160) 3 (1-18) 7 (20)
9 (3-49) 3.9 (1-10) 6 (60)
.03 .9 .046
21 (50) 16 (38.1) 5 (11.9) 1.9 ± 1.1 76 ± 13.4
12 (34.3) 16 (45.7) 7 (20) 2.3 ± 0.22 80.8 ± 15
3 (30) 3 (30) 1 (10) 1 ± 0.3 53.0 ± 43
.3 .6 .6 .006 .001
14 (33.3) 7 (16.7) 19 (45.2) 1 (2.4) 1 (2.4) 2 (4.8) 13 (30.9) 3 (7.1) 15 (35.7)
17 (48.6) 4 (11.4) 10 (28.6) 2 (5.7) 2 (5.7) 0 0 0 5 (14.3)
3 (30) 0 6 (60) 1 (10) 0 1 (10) 6 (60) 0 4 (40)
.3 .4 .1 1 .3 .2 b.001 .3 .07
Values are expressed as mean ± SD, median (range), or number (percentage). P refers to comparisons between disease progression at another site, stent restenosis, and stent thrombosis AMI groups.
Figure 3
Table V. Angiographic characteristics of disease progression at another site group only Initial angiography Lesion that progressed to AMI Morphology Concentric Eccentric I Eccentric II Normal Severity–mean stenosis N70% stenosed without treatment Post-AMI angiography PCI in different/same artery than progression site Progression site proximal/distal from PCI lesion
Temporal distribution of AMIs after stent implantation according to the causative mechanism.
described half of their restenosis AMIs occurring beyond the first year. In almost two thirds of our cases, the clinical presentation of AMI was non-STEMI; and in one third, STEMI. ST-elevation myocardial infarction was particularly infrequent in the AMI caused by restenosis, but very frequent in AMI caused by stent thrombosis, similarly to
27 (64.3%) 10 (23.8%) 1 (2.4%) 4 (9.5%) 35.4 ± 19% 4 (9.5%)
29 (69%)/13 (31%), P = .02 6 (46.2%)/7 (53.8%), P = 1
other studies.4,14,15 We found disease progression at another site leading to AMI occurring more frequently in an artery different from the original PCI. Glaser et al22 also reported that lesion requiring additional PCI was in 61% of cases in a different artery.
Study limitations Our study is a retrospective analysis and is therefore subject to the limitations pertinent to this type of clinical investigation. Our analysis is based in post-PCI patients who had AMI and subsequent coronary angiography. Patients with a silent AMI and those treated conservatively without angiographic study or who died suddenly from AMI are not represented in our study. Although clinical follow-up rate was relatively low, it is very likely
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that we identified most of nonfatal AMIs in our 1.2 million people area because it is served solely by our interventional center. The reliability of angiographic assessment of thrombus is known to be poor, specially in the setting of total occlusion. As a result, in the restenosis cases with totally occluded vessel or even in those with patent but very severely narrowed stented segment, stent thrombosis cannot be excluded with certainty. This may have led to misclassification between stent restenosis and thrombosis, but does not weaken the main finding of our study, the importance of disease progression at another site. We may also have missed more stent thrombosis because of their more severe presentation/fatal AMI. One third of our patients had received DES. A higher penetration of DES use may alter the relative contribution of restenosis and stent thrombosis as mechanisms of stent-related AMI. Variable duration of antiplatelet treatment may have influenced our cases classification.
Clinical implications Current studies of stents for long-term hard events should look carefully for concomitant disease progression at another site as well. The difficulty in determination by the current clinical or angiographic means a priori which stenoses will subsequently demonstrate clinical instability further complicates the clinical problem. Our cohort of patients reflects current practice with contemporary rates of postprocedural antiplatelet therapy, β-blocker, angiotensin-converting enzyme inhibitor, and statin use.23 Nevertheless, a significant number of patients suffered an AMI poststenting because of disease progression at another site, underscoring the need for more effective medical therapy for secondary prevention post-PCI.
Conclusions In a “real world” population, a patient late after stent implantation has an equal probability to have suffered a nonfatal AMI from stent failure or disease progression. Further research should address not only stent-related inadequacies but also disease progression at another site.
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6. Assali AR, Moustapha A, Sdringola S, et al. Acute coronary syndrome may occur with in-stent restenosis and is associated with adverse outcomes (The PRESTO Trial). Am J Cardiol 2006;98: 729-33. 7. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-30. 8. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al, for the BASKET-LATE Investigators. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare metal stents. J Am Coll Cardiol 2006;48:2584-91. 9. Kuchulakanti PK, Chu WW, Torguson R, et al. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006;113: 1108-13. 10. Ong ATL, Hoye A, Aoki J, et al. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent Implantation. J Am Coll Cardiol 2005; 45:947-53. 11. Choussat R, Klersy C, Black AJR, et al. Long-term (8 years) outcome after Palmaz-Schatz stent implantation. Am J Cardiol 2001;88:10-6. 12. Cutlip DE, Chhabra AG, Baim DS, et al. Beyond restenosis. Five-year clinical outcomes from second-generation coronary stent trials. Circulation 2004;110:1226-30. 13. Ambrose JA, Winters SL, Stern A, et al. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol 1985;5:609-16. 14. Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007; 356:1020-9. 15. Doyle B, Rihal CS, O'Sullivan CJ, et al. Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents. Circulation 2007;116:2391-8. 16. Lagerqvist B, James SK, Stenestrand U, et al. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med 2007;356:1009-19. 17. Wenaweser P, Daemen J, Zwahlen M, et al. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice: 4-year results from a large 2-institutional cohort study. J Am Coll Cardiol 2008;52:1134-40. 18. Chechi T, Vecchio S, Vittori G, et al. ST-segment elevation myocardial infarction due to early and late stent thrombosis. A new group of high-risk patients. J Am Coll Cardiol 2008;51: 2396-402. 19. Kaul S, Shah PK, Diamond GA. As time goes by: current status and future directions in the controversy over stenting. J Am Coll Cardiol 2007;50:128-37. 20. Mauri L, Silbaugh TS, Wolf RE, et al. Long-term clinical outcomes after drug-eluting and bare-metal stenting in Massachusetts. Circulation 2008;118:1817-27. 21. Stone GW, Ellis SG, Colombo A, et al. Offsetting impact of thrombosis and restenosis on the occurrence of death and myocardial infarction after paclitaxel-eluting and bare metal stent implantation. Circulation 2007;115:2842-7. 22. Glaser R, Selzer F, Faxon DP, et al. Clinical progression of incidental, asymptomatic lesions discovered during culprit vessel coronary intervention. Circulation 2005;111:143-9. 23. EUROASPIRE II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries. Principal results from EUROASPIRE II. Euro Heart Survey Programme. Eur Heart J 2001;22:554-72.