Long-Term Clinical Outcome After a First Angiographically Confirmed Coronary Stent Thrombosis
An Analysis of 431 Cases
Background— There are limited data on the long-term clinical outcome after an angiographically confirmed (definite) stent thrombosis (ST).
Methods and Results— Four hundred thirty-one consecutive patients with a definite ST were enrolled in this multicenter registry. The primary end point was the composite of cardiac death and definite recurrent ST. Secondary end points were all-cause death, cardiac death, definite recurrent ST, definite and probable recurrent ST, any myocardial infarction, and any target-vessel revascularization. The primary end point occurred in 111 patients after a median follow-up of 27.1 months. The estimated cumulative event rates at 30 days and 1, 2, and 3 years were 18.0%, 23.6%, 25.2%, and 27.9%, respectively. The cumulative incidence rates of definite recurrent ST, definite or probable recurrent ST, any myocardial infarction, and any target-vessel revascularization were 18.8%, 20.1%, 21.3%, and 32.0%, respectively, at the longest available follow-up. Independent predictors for the primary end point were diabetes mellitus, total stent length, severe calcification, American College of Cardiology/American Heart Association B2-C lesions, TIMI (Thrombolysis In Myocardial Infarction) flow grade <3 after percutaneous coronary intervention, and left ventricular ejection fraction <45%. The implantation of an additional coronary stent during the first ST was also associated with unfavorable outcome. Clinical outcome was not affected by the type of previously implanted stent (drug-eluting or bare-metal stent) or the category of ST (early versus late).
Conclusions— The long-term clinical outcome after a first definite ST is unfavorable, with a high mortality and recurrence rate. Diabetes mellitus, left ventricular ejection fraction <45%, long total stent length, complex coronary lesions, TIMI flow grade <3 after percutaneous coronary intervention, and implantation of an additional coronary stent during the emergent percutaneous coronary intervention for the ST were associated with this unfavorable outcome.
Received June 16, 2008; accepted November 30, 2008.
Stent thrombosis is a serious complication after percutaneous coronary intervention (PCI) manifesting as a myocardial infarction or even as cardiac death.1–6 Emergent PCI is the current treatment strategy to (re)establish vessel patency in patients with stent thrombosis. Previous studies, however, have provided limited information on the occurrence of major adverse cardiac events after a stent thrombosis because the follow-up was censored on end-point achievement. We conducted a multicenter registry that included all consecutive patients who presented with a definite first stent thrombosis with the specific purpose of examining the incidence of major adverse cardiac events after stent thrombosis and identifying determinants that are associated with these events.
Clinical Perspective p 834
Study Design and Patient Population
The Dutch stent thrombosis registry is a multicenter study conducted in 3 high-volume centers in the Netherlands. All consecutive patients with an angiographically confirmed stent thrombosis presenting from January 2004 to February 2007 were enrolled. The study was conducted according to the principles of the Declaration of Helsinki. Patients gave informed consent for the inclusion of data in the registry.
Stent thrombosis was defined according to the Academic Research Consortium definite definition.7 Stent thrombosis was categorized according to the timing of the event as acute (occurrence within the first 24 hours after the index procedure), subacute (from 24 hours to 30 days), late (from 30 days to 1 year), and very late (>1 year after the index procedure).
Detailed data on patient characteristics, the index PCI procedure, and the emergent PCI procedure for the first stent thrombosis were collected. Coronary angiograms of both the index procedure and the stent thrombosis were reviewed independently by 2 experienced interventional cardiologists. In case of disagreement, a consensus was established between the 2 reviewers, or a third interventional cardiologist was consulted.
Patients with stable angina pectoris who underwent a scheduled PCI were adequately pretreated with a 300-mg clopidogrel loading dose at least 48 hours before the PCI procedure. Patients presenting with an acute coronary syndrome that required an urgent PCI were given a 600-mg loading dose of clopidogrel at the time of intervention. All patients were given a 600-mg loading dose of clopidogrel at the time of the stent thrombosis. The use of glycoprotein IIb/IIIa therapy during index PCI and at the time of the stent thrombosis was left to the discretion of the interventional cardiologist.
Clinical follow-up information was obtained from telephone interviews with the patients, their relatives, and their general practitioners, as well as from pharmacy and hospital records. Information regarding the development of major adverse cardiac events, predefined as death, recurrent stent thrombosis, any myocardial infarction, and any coronary revascularization (either PCI or coronary artery bypass grafting [CABG]) was collected.
Study End Points and Definitions
The predefined primary end point of the present study was a composite of cardiac death and definite recurrent stent thrombosis (according to the Academic Research Consortium criteria).1 The secondary end points were all-cause mortality, cardiac mortality, recurrent definite stent thrombosis, recurrent definite or probable stent thrombosis, myocardial infarction (target-vessel and non–target-vessel–related), and any ischemia-driven target-vessel revascularization (TVR).
Deaths were classified as cardiac or noncardiac on the basis of the information obtained from hospital records and telephone contact with relatives of the patient or the attending physician. Recurrent stent thrombosis was defined according to the Academic Research Consortium definite and probable definitions. The diagnosis of myocardial infarction required an elevation of creatine kinase levels to twice the upper limit of normal, together with a rise in creatine kinase-MB fraction. TVR was defined as ischemia-driven PCI performed in the same vessel as the index PCI with or without implantation of a stent or CABG.
Statistical analysis was performed with SAS version 9.1 (SAS Institute Inc, Cary, NC). Continuous data are expressed as mean±SD or median and interquartile range. Categorical data are presented as percentages.
Predictors of cardiac death and recurrent stent thrombosis were assessed with a stepwise Cox proportional hazards model. First, a univariate analysis was performed. Then, variables with a probability value <0.10 were entered into the multivariate model. Kaplan-Meier survival analyses were used to show the cumulative incidence of the primary and secondary end points. Kaplan-Meier survival analyses were used to show the cumulative incidence of the primary and secondary end points. When death was not part of the end point used in the analysis at hand, we censored patients if none of the events of interest had occurred; nonfatal events that were not part of an end point were not a reason for censoring.
All authors had full access to and take full responsibility for the integrity of the. All authors have read and agree to the manuscript as written.
Characteristics of the Patients
During the study period, 437 patients with a definite stent thrombosis were enrolled. Of these, 6 patients were excluded from analysis because they had had a previous stent thrombosis before the start of the inclusion period. The timing of the definite first stent thrombosis in the remaining 431 patients was acute in 140 patients (total group 32.5%; 33% for bare-metal stent [BMS], 30% for drug-eluting stent [DES]), subacute in 177 (total group 41.1%; 42% for BMS, 40% for DES), late in 57 (total group 13.2%; 12% for BMS, 16% for DES), and very late in 57 (total group 13.2%; 12% for BMS, 15% for DES). No significant differences between DES and BMS were observed according to the timing of the ST (P=0.51). Clinical, angiographic, and index procedural characteristics are shown in Tables 1, 2, and 3⇓⇓. The stent thrombosis was related to a DES in 150 patients (34.8%) and to a BMS in 265 (61.5%). In the remaining 16 patients (3.7%), a thrombus was visualized in a segment in which both a DES and BMS were placed. One hundred thirty-four patients (31.1%) were not undergoing therapy with clopidogrel at the time of the first stent thrombosis, and 56 patients (13.0%) did not use aspirin.
Treatment of First Stent Thrombosis
The characteristics of the emergent PCI for stent thrombosis are also listed in Table 3. The thrombosis was limited to 1 stent or multiple stents in 1 coronary vessel in 417 patients (96.8%); however, a thrombosis was diagnosed in multiple stents in different coronary arteries in 14 patients (3.2%). The vast majority of the patients (n=421; 97.7%) underwent emergent PCI on presentation with stent thrombosis. Of these, 203 patients (48.2%) were treated with balloon angioplasty, 214 (50.8%) underwent balloon angioplasty followed by implantation of an additional stent (113 BMS, 100 DES), and 4 (1%) were treated with thrombus aspiration only. Fifty-one patients (12.8%) underwent thrombus aspiration for the ST before the emergent PCI.
In 6 patients, the emergent angioplasty for the stent thrombosis was not successful. Two patients underwent emergent CABG after urgent coronary angiography. Thirteen patients (3%) underwent CABG in a later stage of the hospitalization after balloon angioplasty in the acute phase of the stent thrombosis. This was mainly due to imperfect procedural success (TIMI [Thrombolysis In Myocardial Infarction] flow grade <3) or residual coronary vessel disease.
The median follow-up time for the 431 patients was 27.1 months (interquartile range 17.4 to 37.1 months). Clinical follow-up was available in 416 patients (96.5%). Vital status could not be ascertained in 15 patients (10 of whom had moved abroad), and therefore, the last available follow-up was used.
Primary End Point
During the hospitalization for the first stent thrombosis, 26 patients died of a cardiac cause, and 44 patients experienced a definite recurrent stent thrombosis. The timing was acute in 12 patients and subacute in 32; median timing was 4 days after the emergent PCI for the first stent thrombosis.
At the longest available follow-up point, the primary end point (cardiac death and definite recurrent stent thrombosis) had occurred in 111 patients. Estimated cumulative event rates at 30 days and 1, 2, and 3 years were 18.0%, 23.6%, 25.2%, and 27.9%, respectively (Figure, A).
Secondary End Points
Twenty-seven patients died during hospitalization, including 26 cardiac deaths. Forty-four cases of angiographically confirmed recurrent stent thrombosis were observed, and stent thrombosis could not be excluded in 6 patients who died suddenly during hospitalization (probable recurrent stent thrombosis). A total of 53 patients underwent TVR, with 45 repeat PCIs (including 44 emergent PCIs for definite recurrent stent thrombosis) and 13 CABGs (5 of these patients also had a recurrent stent thrombosis).
At the longest available follow-up, 45 (80.4%) of 56 deaths were classified as cardiac deaths. The cumulative incidences of all-cause mortality and cardiac mortality were 7.7% and 7.3% at 30 days, 10.7% and 9.5% at 1 year, 12.0% and 10.0% at 2 years, and 15.4% and 12.3% at the end of the available follow-up, respectively (Figure, A and B).
A total of 75 patients had experienced at least 1 episode of a definite recurrent stent thrombosis. Of these patients, 62 had 1 recurrent stent thrombosis, 11 had 2 episodes of recurrent stent thrombosis, and 2 had 3 episodes of recurrent stent thrombosis. The timing of the first definite recurrent stent thrombosis was acute in 14 patients subacute in 40, late in 15, and very late in 6. Definite or probable recurrent stent thrombosis occurred in 81 patients (18.8%). The cumulative incidences of definite or probable recurrent stent thrombosis at 30 days and 1, 2, and 3 years were 14.4%, 18.2%, 19.6%, and 20.1%, respectively (Figure, B). Except for recurrent stent thrombosis, myocardial infarction did not occur frequently, and the cumulative incidences at 30 days and 1, 2, and 3 years are shown in Figure, B.
At the longest available follow-up, TVR (including the emergent PCI for definite recurrent stent thrombosis) was performed in 124 patients; 87 TVRs were related to a BMS and 37 to a DES. After the exclusion of all emergent PCIs for definite recurrent stent thrombosis, the cumulative incidence of TVR remained relatively high (22% for BMS and 15% for DES). Although not statistically significant, there was a trend toward a lower TVR rate with DES than with BMS (Figure, C).
Predictors for the Combined End Point of Cardiac Mortality and Definite Recurrent Stent Thrombosis
After adjustment in the stepwise Cox proportional hazard model, diabetes mellitus, left ventricular ejection fraction <45%, severe calcification of the target vessel, and implantation of an additional stent during the emergent PCI for the first stent thrombosis were independent predictors of the primary end point (Table 4). This observation was not influenced by the type of coronary stent (either DES or BMS).
Importantly, the type of coronary stent (DES or BMS) that was implanted during the index PCI and the timing of the stent thrombosis (either acute, subacute, late, or very late) were not independently associated with the primary end point (hazard ratio 1.12, 95% CI 0.75 to 1.69, P=0.58 for stent type and hazard ratio 1.18, 95% CI 0.60 to 2.3, P=0.64 for timing of stent thrombosis; Figure, D). Of note, the independent correlates in the Cox proportional hazard model did not change substantially when the combined primary end point was replaced by 1 of its single components (either cardiac death or definite recurrent stent thrombosis) or when the composite end point of cardiac death and definite recurrent stent thrombosis was replaced by a composite of cardiac death and any myocardial infarction (data not shown).
Although case reports, registries, and meta-analyses have identified several correlates that are associated with an increased risk for stent thrombosis,1–3,6,8 limited information to date is available about the long-term clinical outcome after a first definite stent thrombosis in the real world of mixed BMS and DES use.6,9 The present multicenter observational study comprises the largest cohort of patients with stent thrombosis thus far and demonstrates that the clinical outcome in patients who experience a first definite stent thrombosis is unfavorable. Although the presented mortality rates are lower than those reported by others,2,3 the high incidence rate of recurrent stent thrombosis is remarkable: Nearly 1 in 5 patients with a first definite stent thrombosis experienced another definite recurrent stent thrombosis. Moreover, it was not uncommon to have more than 1 recurrence of stent thrombosis in the studied population.
TVR rates (after exclusion of the emergent PCI for recurrent stent thrombosis) were also high in the present study population. This might be a reflection of the complexity of the coronary lesions in these patients. Although it did not reach statistical significance, the advantage of DES in reducing restenosis was also notable.10,11
There are a number of possible explanations for the difference in mortality rates between the results of the present study (15.4%) and those of previous studies (up to 40%). First, we used a very conservative definition of stent thrombosis at the time of inclusion (only patients with a definite stent thrombosis). As a result, patients with a previously implanted coronary stent who died before hospital presentation (probable or even possible stent thrombosis) were not included. Second, the present study was performed in the settings of the well-organized Dutch ambulance system, with a very effective prehospital triage, short call-to-balloon times, and national guidelines that support primary PCI in every patient with an ST-elevation myocardial infarction. In a setting of longer transfer distances and the unavailability of interventional centers, mortality rates are probably higher. Third, only high-volume PCI centers participated in the presented study, and it is commonly known that mortality rates are considerably lower in these centers than in centers with a lower procedure volume.12 An examination of the factors that are associated with an unfavorable clinical outcome can improve patient selection criteria for coronary stenting and/or optimize the current adopted treatment for stent thrombosis. In the present study, the presence of diabetes mellitus, male gender, and an impaired left ventricular ejection fraction were identified as important clinical predictors of poor outcome. These findings are consistent with previous studies4,5 and are surprisingly similar to the reported determinants that are associated with an increased risk of stent thrombosis.2,3,8 Severely calcified and complex lesions (American College of Cardiology/American Heart Association B2-C) and a long total stent length were also important angiographic and procedural predictors for an unfavorable outcome. This strongly suggests that the index PCI was performed for more complex lesion characteristics, and it has been known for almost 2 decades that these patients experience higher event rates, including death. Another important observation in the present study is that clinical outcome was affected by neither the type of the previously implanted stent (DES or BMS) nor the category of stent thrombosis (early versus late).
Given the observational nature of the present registry, the optimal treatment strategy for stent thrombosis cannot be determined. Nonetheless, the present data do offer certain guidance on the management of patients with stent thrombosis. Patients who were treated with an additional coronary stent during the first stent thrombosis faired less well. Randomized trials are urgently needed to determine the optimal treatment strategy in patients with stent thrombosis. In conclusion, long-term clinical outcome after a first definite stent thrombosis is unfavorable, with a high mortality and stent thrombosis recurrence rate. Diabetes mellitus, left ventricular ejection fraction <45%, long stent length, complex coronary lesions, postprocedural TIMI flow less than grade 3, and the implantation of an additional coronary stent during the emergent PCI for the stent thrombosis were associated with an unfavorable outcome.
This study was presented as a late-breaking clinical trial at the American College of Cardiology-Society for Cardiovascular Angiography and Interventions Scientific Sessions, March 29–April 2, 2008, Chicago, Illinois.
Sources of Funding
The Dutch stent thrombosis registry was supported by an unrestricted research grant from Sanofi-aventis. The sponsor had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Dr van Werkum and Dr ten Berg served on scientific advisory boards for the Medicines Company. Prof Verheugt received speaker fees from Sanofi-aventis and received funding for research from Bayer and Eli Lilly. The remaining authors report no conflicts.
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Stent thrombosis is a rare but serious complication after percutaneous coronary intervention. In the present study, the long-term clinical outcome of 431 consecutive patients who experienced an angiographically confirmed (definite) stent thrombosis was evaluated. The primary end point was the composite of cardiac death and definite recurrent stent thrombosis, which occurred in 111 patients after a median follow-up of 27.1 months. The cumulative Kaplan-Meier estimates of definite recurrent stent thrombosis, definite or probable recurrent stent thrombosis, any myocardial infarction, and any target-vessel revascularization were 18.8%, 20.1%, 21.3%, and 32.0%, respectively, at the longest available follow-up. Multivariate analysis identified that implantation of an additional coronary stent at the first stent thrombosis was associated with unfavorable outcome, in addition to other established predictors such as diabetes mellitus, total stent length, severe calcification, American College of Cardiology/American Heart Association B2-C lesions, TIMI (Thrombolysis In Myocardial Infarction) flow grade <3 after percutaneous coronary intervention, and left ventricular ejection fraction <45%. Recurrent stent thrombosis is not an infrequent event after a first stent thrombosis, and randomized trials are urgently needed to determine the optimal treatment strategy in patients with a first stent thrombosis.