Temporal Relation Between Clopidogrel Cessation and Stent Thrombosis After Drug-Eluting Stent Implantation

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1 Temporal Relation Between Clopidogrel Cessation and Stent Thrombosis After Drug-Eluting Stent Implantation Probal Roy, MD, Laurent Bonello, MD, Rebecca Torguson, MPH, Teruo Okabe, MD, Tina L. Pinto Slottow, MD, Daniel H. Steinberg, MD, Kimberly Kaneshige, BS, Zhenyi Xue, MS, Lowell F. Satler, MD, Kenneth M. Kent, MD, PhD, William O. Suddath, MD, Augusto D. Pichard, MD, Joseph Lindsay, MD, and Ron Waksman, MD* The risk of late thrombotic events and the need for prolonged dual antiplatelet therapy detract from the clinical advantage offered by drug-eluting stents (DESs). Short-term studies have shown premature clopidogrel cessation to be a strong predictor of stent thrombosis (ST) after DES implantation. Data pertaining to the utility of clopidogrel therapy and its optimal duration to prevent late ST remain limited. The study population consisted of 2,889 patients who underwent unrestricted intracoronary DES implantation from April 2003 to January 2007 for whom clopidogrel compliance data were available. Definite ST proved by angiography or autopsy within 12 months of the index procedure occurred in 61 patients. Comparisons of clinical and procedural characteristics in addition to outcomes (death and Q-wave myocardial infarction) were made between the ST and no-st (2,828 patients) groups. Clopidogrel compliance was assessed at all follow-up time points. For patients in the ST group, clopidogrel compliance status for the remaining study period was defined as that at the time of ST. Logistic regression analysis was performed at 30 days, 6 months, and 12 months to identify independent predictors of cumulative ST. Patients with ST were more likely to have previous congestive heart failure and worse left ventricular ejection fraction. ST was associated with significantly higher mortality at 12 months (23.5% vs 3.2%, p <0.001). Clopidogrel compliance was 80.2% in the overall population and 73.8% in patients presenting with ST (82.6% in patients presenting with early ST and 43.8% in those with late ST). By logistic regression analysis, clopidogrel cessation was an independent predictor of cumulative ST at 30 days and 6 months but not at 12 months. In conclusion, high rates of clopidogrel compliance can be achieved in contemporary practice. Clopidogrel cessation by 12 months is no longer predictive of ST, thus suggesting the optimal duration of therapy for the prevention of ST to be 6 to 12 months Elsevier Inc. (Am J Cardiol 2009;103: ) Whether or not drug-eluting stents (DESs) truly are associated with increased stent thrombosis (ST) has been an issue of contention in recent times. Reports suggesting that DES use is associated with increased rates of death and nonfatal myocardial infarction (MI) 1,2 have been refuted by meta-analyses of long-term follow-up from pivotal randomized trials, which have shown no increase in overall ST with DES versus bare metal stent use. 3,4 Nevertheless, an increase in late ST with DESs has been consistently observed. Data from real-world registries studying unselected populations have shown a small continual increase in the occurrence of late ST at rates of up to 0.6%/year. 5 The use of DES in contemporary clinical practice has extended beyond its approved indications where safety data are relatively sparse. Although there is more late ST with DESs compared with bare metal stents, 4,5 the optimal duration of dual antiplatelet therapy after DES implantation remains unresolved. Division of Cardiology, Washington Hospital Center, Washington, DC. Manuscript received October 1, 2008; revised manuscript received and accepted November 15, *Corresponding author: Tel: ; fax: address: ron.waksman@medstar.net (R. Waksman). Though premature cessation of clopidogrel has consistently been identified as a predictive factor for ST, 6 8 the utility of clopidogrel in preventing late ST is uncertain. Based on American Heart Association/American College of Cardiology/Society for Cardiovascular Angiography and Interventions recommendations, it is current routine practice to prescribe dual antiplatelet therapy for 12 months after DES implantation. The threat of late ST has prompted suggestions of more prolonged clopidogrel use. 9 Such recommendations carry long-term bleeding risks and costs, which detract from the clinical advantages DESs offer. Given the uncertainties that surround clopidogrel use after DES implantation, we attempted to define the temporal relation between clopidogrel use and ST. Methods This was a single-center observational study. The patient population consisted of 2,889 patients who underwent intracoronary DES implantation from April 2003 to January 2007 from whom clopidogrel compliance data were available. In this cohort 61 patients were identified to have definite ST within 12 months of the index procedure. Comparisons were made between the ST and no-st populations /09/$ see front matter 2009 Elsevier Inc. doi: /j.amjcard

2 802 The American Journal of Cardiology ( Table 1 Baseline clinical characteristics Variable ST p Yes (n 61) No (n 2,828) Value Demographics and clinical history Men 34 (55.7%) 1,878 (66.4%) 0.08 Age (yrs) Diabetes mellitus 27 (45.0%) 940 (33.5%) 0.06 Insulin requiring diabetes 9 (15.0%) 273 (9.7%) 0.18 mellitus Current smoker 15 (24.6%) 512 (18.1%) 0.19 Systemic hypertension 49 (80.3%) 2,345 (83.1%) 0.57 Dyslipidemia* 52 (85.2%) 2,452 (87.4%) 0.63 Familial history 28 (50.0%) 1,499 (54.9%) 0.46 Chronic renal insufficiency 11 (18.3%) 325 (11.6%) 0.1 Previous MI 19 (32.8%) 877 (32.9%) 0.98 Previous coronary artery 9 (15.3%) 517 (18.4%) 0.54 bypass surgery Previous percutaneous 21 (37.5%) 743 (27.3%) 0.09 coronary intervention Previous congestive heart 13 (23.2%) 344 (12.9%) 0.02 failure Presentation Unstable angina pectoris 24 (40.0%) 1,307 (46.3%) 0.33 Acute MI 9 (15.0%) 293 (10.4%) 0.25 Cardiogenic shock 2 (3.4%) 61 (2.3%) 0.39 Left ventricular ejection fraction (%) Values are means SDs or numbers of patients (percentages). * Includes patients with a previously documented diagnosis of dyslipidemia. The patient may be treated with diet or medication. A new diagnosis can be made during this hospitalization with an increased total cholesterol level 160 mg/dl. Does not include increased triglycerides. All patients underwent their procedure at Washington Hospital Center, a tertiary referral hospital with 11 catheterization laboratories serviced by 31 independent interventional cardiologists. All patients signed a consent document for the procedure and the study was conducted under institutional review board approval. Percutaneous coronary intervention was performed by a standard technique through the femoral approach in most cases. Patients received sirolimus-eluting stents (Cypher, Cordis, Johnson & Johnson, Miami Lakes, Florida) and/or paclitaxel-eluting stents (Taxus, Boston Scientific Corp., Natick, Massachusetts). Use of adjunctive devices (intravascular ultrasound, atherectomy, distal protection, etc.) was at each operator s discretion. All patients were treated with aspirin 325 mg before percutaneous coronary intervention and were loaded with clopidogrel 300 or 600 mg orally, if not on a maintenance dose. Dual antiplatelet therapy for 12 months was strongly recommended to all patients. Aspirin was to continue indefinitely thereafter. During percutaneous coronary intervention, patients blood was anticoagulated with bivalirudin (bolus of 0.75 mg/kg, followed by an intravenous infusion of 1.75 mg/kg/hour) or unfractionated heparin (bolus of 40 U/kg and additional heparin to achieve an activated clotting time of 250 to 300 seconds). Platelet glycoprotein IIb/IIIa inhibitors were administrated at each operator s discretion. Table 2 Procedural characteristics Variable ST p Value Yes (n 74) No (n 5,194) Target vessel Left main coronary artery 0 94 (1.8%) 0.64 Left anterior descending 37 (50.0%) 1,926 (37.1%) 0.02 coronary artery Left circumflex coronary 13 (17.6%) 1,223 (23.5%) 0.23 artery Right coronary artery 20 (27.0%) 1,680 (32.3%) 0.33 Saphenous vein graft 4 (5.4%) 251 (4.8%) 0.78 Lesion location Ostial 5 (6.8%) 247 (4.8%) 0.41 Proximal 37 (50.0%) 2,374 (46.5%) 0.55 Mid 24 (32.4%) 1,886 (36.9%) 0.43 Distal 8 (10.8%) 584 (11.4%) 0.87 Lesion type (ACC/AHA classification) A 1 (1.4%) 275 (5.6%) 0.19 B 51 (68.9%) 3,632 (73.7%) 0.36 C 22 (29.7%) 1,024 (20.8%) 0.06 In-stent restenosis 10 (13.5%) 222 (4.3%) Procedural details No. of lesions treated Sirolimus-eluting stent 51 (69.9%) 2,646 (53.0%) Paclitaxel-eluting stent 18 (24.7%) 1,746 (34.9%) 0.07 Stent diameters (mm) Stent lengths (mm) No. of implanted stents Intravascular ultrasound 36 (48.6%) 3,345 (65.9%) Rotational atherectomy (2.8%) 0.27 After dilatation 16 (21.9%) 1,117 (24.4%) 0.62 Glycoprotein IIb/IIIa use 12 (19.7%) 297 (10.6%) 0.02 Values are means SDs or numbers of lesions (percentages). ACC/AHA American College of Cardiology/American Heart Association. ST was defined as angiographic or autopsy-proved partial or complete stent occlusion in the presence of an acute coronary syndrome. Early ST was defined as occurring within 30 days of the index procedure and late ST as that occurring after 30 days. Mortality was death from all causes. Q-wave MI was defined as an increase in creatine kinase-mb 2 times the upper normal value (2.6 ng/ml) in the presence of new Q waves on electrocardiogram in 2 contiguous leads. Angiographic success was defined as a residual stenosis 30% with Thrombolysis In Myocardial Infarction grade 3 flow. Patient compliance with clopidogrel at the time of ST was designated as a patient s clopidogrel compliance status for the remainder of the study period. Clopidogrel compliance status of patients in the no-st group was self-reported at specified follow-up time points. Demographic, clinical, and procedural data and in-hospital outcomes were collected and entered into a prospective database. Data were obtained from hospital chart review by independent research personnel blinded to study objectives. All data management and analyses were performed by a dedicated data co-ordinating center (Data Center, Cardiovascular Research Institute, Washington, DC). Clinical follow-up was performed at 1 month, 6 months, and 12 months

3 Coronary Artery Disease/Clopidogrel Cessation and Stent Thrombosis 803 Table 3 Independent predictors of cumulative stent thrombosis at one month, six months, and 12 months Variable Odds Ratio Confidence Interval p Value Figure 1. Rates of clopidogrel compliance in patients with ST (cumulative) (black bars),no ST(white bars), and the overall study population (gray bars). by trained quality-assurance nurses who worked exclusively with the database to determine clinical events after percutaneous coronary intervention. Clinical follow-up was performed by telephone contact or office visit. A committee independently adjudicated all subsequent clinical events. Statistical analysis was performed using SAS 9.1 (SAS Institute, Cary, North Carolina). Continuous variables were expressed as mean SD and compared using Student s t test. Categorical variables were expressed as percentages and compared with chi-square test or Fisher s exact test. Independent predictors for cumulative ST at 30 days, 6 months, and 12 months were determined using logistic regression analysis. Given the limited number of events, a restricted number of variables was entered into multivariate analysis. The following variables were entered into the model at 30 days: acute MI, diabetes mellitus, number of stents implanted, in-stent restenosis, clopidogrel cessation, vessel size, and stent length. At 6 and 12 months the variables were diabetes mellitus, chronic renal insufficiency, number of stents implanted, in-stent restenosis, and clopidogrel cessation. A p value of 0.05 was considered to indicate statistical significance. Results Baseline clinical and procedural details are listed in Tables 1 and 2. There were several baseline differences between groups. Patients with ST were more likely to have previous congestive heart failure and worse left ventricular ejection fraction. They were also more likely to undergo treatment of left anterior descending coronary artery and in-stent restenotic lesions, receive sirolimus-eluting stents and a larger number of stents, and have less intravascular ultrasound-guided stent implantation. Of 61 patients presenting with ST, 45 patients presented with early ST and 16 patients presented with late events (4 patients presented after 6 months). Mortality and Q-wave MI were significantly higher in the ST group at 12 months (23.5% vs 3.2%, p 0.001; 52.8% vs 1.2%, p 0.001, respectively). In the overall population 80.2% reported to be still taking clopidogrel at 12-month follow-up. At the time of ST, 73.8% of patients were clopidogrel compliant. Compliance 1mo Acute MI Diabetes mellitus In-stent restenosis No. of stents implanted Clopidogrel cessation mos Diabetes mellitus Chronic renal insufficiency In-stent restenosis No. of stents implanted Clopidogrel cessation mos Diabetes mellitus Chronic renal insufficiency In-stent restenosis No. of stents implanted Clopidogrel cessation Figure 2. Rates of freedom from cumulative ST in patients noncompliant with clopidogrel at 1 month, 6 months, and 12 months. rates were 82.6% and 43.5% in patients presenting with early and late ST, respectively. Figure 1 illustrates clopidogrel compliance rates at 30 days, 6 months, and 12 months in patients with ST (cumulative), no ST, and the overall study population. A total of 93.6% of patients taking clopidogrel at 12 months were on aspirin. Similarly, at 30 days and 6 months the rates of aspirin usage in clopidogrelcompliant patients were 93.5% and 91.1%, respectively. The percentage of patients no longer on clopidogrel at 12 months who were taking aspirin was 77.2%. Predictors of cumulative ST at 30 days, 6 months, and 12 months are listed in Table 3. Independent predictors of early ST were acute MI presentation, diabetes mellitus, treatment of restenotic lesions, number of stents implanted, and clopidogrel cessation. At 6 months treatment of restenotic lesions, number of stents implanted, and clopidogrel cessation were predictive of cumulative ST. Treatment of restenotic lesions and number of stents implanted remained the only predictors of cumulative ST at 12 months. Clopidogrel cessation at 12 months was no longer found to be predictive of ST (odds ratio 1.7, confidence interval 0.9 to 3.1, p 0.1). Figure 2 displays a higher rate of freedom from ST at

4 804 The American Journal of Cardiology ( 12 months versus 30 days and 6 months in those patients no longer taking clopidogrel. Discussion The present study focuses on the relation between clopidogrel use and ST in patients undergoing intracoronary DES implantation. In keeping with previous studies, ST occurred infrequently and was associated with a high mortality rate. The findings of most interest are the high rate of clopidogrel compliance in patients presenting with ST and the changing temporal relation between clopidogrel cessation and ST. The study also highlights that high rates of clopidogrel compliance can be achieved in contemporary practice. The finding that clopidogrel cessation at 12 months was not predictive of ST but was predictive at 30 days and 6 months challenges the utility of dual antiplatelet therapy in preventing ST beyond 12 months. This finding is driven by those patients who ceased clopidogrel therapy by 12 months and remained free of ST, thus suggesting the safety of this practice. The findings of the present study do not suggest a benefit to the overall patient population of sustained clopidogrel therapy in preventing ST beyond the current recommendation of 12 months. Furthermore, the findings do emphasize the importance of an inadequate response to clopidogrel and other causes leading to ST. Premature cessation of clopidogrel has been a consistent and strong predictor of ST in a number of short-term studies. 6 8 This strong association within at least the first 6 to 9 months heightens the importance of clopidogrel compliance. Assessment of compliance in registry studies is problematic because it is self-reported. The prognostic significance of premature clopidogrel cessation was reported from the Prospective Registry Evaluating Myocardial Infarction: Events and Recovery (PREMIER) study. The investigators reported a thienopyridine discontinuation rate of 13.6% at 30 days in patients presenting with acute MI and receiving DESs. Despite confounders, these patients were shown to have increased mortality and higher rates of hospitalization over the ensuing 11 months. 10 In the Duke Heart Center registry, the rate of clopidogrel use at 12 months in patients who received DESs was 72.9%. 9 Rates of compliance in the present study are similarly high and illustrate that thienopyridine compliance can be achieved with appropriate patient education and follow-up. A further observation of the present study is the occurrence of ST in patients on dual antiplatelet therapy. Ong et al 11 initially reported a series of 8 patients with late angiographic ST of whom none were on dual antiplatelet therapy. This suggested that dual antiplatelet therapy might be prohibitive of late ST. In the present study we observed 16 cases of definite late ST, of which 7 patients were taking dual antiplatelet therapy at time of presentation. Furthermore, 73.8% of patients with early and late ST were clopidogrel compliant at time of presentation. Similar rates of clopidogrel compliance in patients presenting with ST have been reported from other large registries. 5,8 This observation suggests that the mechanism underlying late ST is complex and multifactorial. The optimal duration of dual antiplatelet therapy after intracoronary DES implantation remains unresolved. Results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial showed that sustained dual antiplatelet therapy to 12 months after bare metal stent implantation was advantageous in decreasing a combined end point of death, MI, and stroke in patients undergoing percutaneous coronary intervention. 12 The benefit seen with clopidogrel may reflect primary prevention of vascular events arising from disease elsewhere in the coronary and cerebrovascular trees. The DES era differs from that of bare metal stents in that there is an increased risk of late ST. There are insufficient data pertaining to an optimal duration of clopidogrel after DES implantation. Findings from the Basel Stent Kosten Effektivitäts Trial (BASKET)-LAte Thrombotic Events (LATE) trial showed an increase in death and MI in patients undergoing DES implantation 6 to 18 months after the procedure after 6 months of clopidogrel therapy. 2 Registry data from the Duke Heart Center revealed clopidogrel use at 12 months in patients receiving DES to be associated with lower rates of death and MI at 24-month follow-up. 9 From these observational studies it can be inferred that DESs are associated with late adverse events, presumably secondary to late ST, and prolonged clopidogrel use may be protective against such events. However, recommendations for prolonged dual antiplatelet therapy need to be made with caution given the heightened bleeding risk and increased financial costs. Rates of significant bleeding with sustained dual antiplatelet therapy at 1-year follow-up in large randomized studies such as CRE- DO 12 and Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) 13 were 8.8% and 3.7%, respectively. In contrast to these findings there have been reports similar to the present study that show that clopidogrel cessation is not a predictor of ST at longer-term follow-up. 5,14 These findings suggest that clopidogrel may be ceased safely in the majority of patients at 12 months and, furthermore, question the clinical utility of prolonged therapy beyond 12 months for the population at large. Although our study does not intend to challenge the use of dual antiplatelet therapy for patients with an acute coronary syndrome, it does challenge the mandatory continuation of this therapy beyond 6 months in patients who undergo DES implantation. This is a single-center observational study with limitations inherent to this type of analysis. The number of events beyond 30 days and 6 months was relatively small and may have affected the statistical power of the study. The definition of ST included only those events that were angiographically or autopsy proved. Because clopidogrel compliance data were not available in patients with sudden death, the Academic Research Consortium definition was not adopted. The study population was restricted to those in whom clopidogrel compliance data were known, which may have led to enrichment of the study cohort with patients presenting with ST. Therefore, this study should be viewed as hypothesis generating rather than a confirmation for the safe discontinuation of clopidogrel at 6 months or 1 year. 1. Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implantation of first-generation drug-eluting stents: a cause for concern. Circulation 2007;115:

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