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Prevalence, Predictors, and Long-Term Prognosis of Premature Discontinuation of Oral Antiplatelet Therapy After Drug Eluting Stent Implantation

      To date, limited information is available on the long-term discontinuation rates of antiplatelet therapy after drug-eluting stent implantation. The aim of the present study was to determine the prevalence and predictors of premature discontinuation of oral antiplatelet therapy after drug-eluting stent implantation and to evaluate its effects on long-term prognosis. We studied 1,358 consecutive patients successfully treated with drug-eluting stents and discharged with dual oral antiplatelet therapy. Aspirin was to be maintained lifelong, and clopidogrel was prescribed for 12 months. The patients were followed for 36 months. The prevalence and predictors of aspirin and clopidogrel discontinuation were assessed. Major adverse cardiac events, defined as death, myocardial infarction, destabilizing symptoms leading to hospitalization, and nonfatal stroke, were recorded. Definite, probable, and possible stent thrombosis (ST) and major and minor bleeding were also determined. Of the 1,358 patients, 8.8% had discontinued one or both antiplatelet agents within the first 12 months (“early” discontinuation) and 4.8% had discontinued aspirin after 1 year (“late” discontinuation). Early discontinuation was predicted by in-hospital major bleeding, the use of oral anticoagulants at discharge, and the lack of a statin prescription. Previous stroke was the only independent predictor of late discontinuation. Patients with early discontinuation experienced a greater incidence of major adverse cardiac events (28.6% vs 13.7%, p <0.001) and ST (7.6% vs 3.4%, p = 0.038). All-cause mortality (13.4% vs 4.7%, p <0.001) and cardiovascular death (5% vs 1.2%, p = 0.007) were significantly more frequent among patients with early discontinuation. In patients with late discontinuation, a nonstatistically significant increase was seen in major adverse cardiac events (20% vs 13.3%, p = 0.128) and ST (6.2% vs 3.2%, p = 0.275). In conclusion, premature discontinuation of antiplatelet therapy is relatively common, especially within the first year, and strongly associated with increased cardiovascular events, including ST and death.
      Drug-eluting stents (DES) have shown to significantly reduce the risk of restenosis.
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      Previous reports have shown that >10% of patients prematurely discontinue antiplatelet therapy within 30 days after stent implantation.
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      Aspirin noncompliance is the major cause of “aspirin resistance” in patients undergoing coronary stenting.
      However, to date, limited information has been available on the discontinuation rates of antiplatelet therapy after 30 days. The optimal length of dual antiplatelet therapy has also been an important topic of debate. Although practice guidelines have advocated 12 months of dual antiplatelet therapy, this recommendation was not determined from any prospective randomized trial evidence associating an extended duration of dual antiplatelet therapy with a reduction in the incidence of late ST. In addition, the prognostic implications of antiplatelet therapy withdrawal after 6 months have not been consistent.
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      • Michev I.
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      • Sangiorgi G.M.
      • Qasim A.
      • Chieffo A.
      • Briguori C.
      • Grube E.
      Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment.
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      The aims of the present study were to determine the prevalence and predictors of premature discontinuation of long-term oral antiplatelet therapy after DES implantation and to evaluate its effects on prognosis in relation to the time and duration of the discontinuation.

      Methods

      We retrospectively analyzed 3,637 consecutive patients who had undergone percutaneous coronary intervention (PCI) at 2 institutions in the northern regions of Italy (Ospedali Riuniti di Bergamo and Ospedale Carlo Poma, Mantova) from June 2005 to March 2008. Of these, 1,379 patients (37.9%) were successfully treated with DES (707 with sirolimus-eluting stents and 672 paclitaxel-eluting stents) and constituted the study population for the present analysis. All patients were pretreated with aspirin and clopidogrel. Glycoprotein IIb/IIIa inhibitors were administered at the physician's discretion. The patients were discharged with an indication to continue with dual antiplatelet therapy with aspirin (100 mg/day) and clopidogrel (75 mg/day) for 12 months. Aspirin was to be maintained lifelong.
      Follow-up by telephone interview or outpatient clinical visits were scheduled at 1, 6, 12, 18, 24, and 36 months after the index procedure. A standard questionnaire was used to collect information on the medications the patients were taking and any adverse events. If aspirin and/or clopidogrel had been discontinued, the cause and timing when these occurred were assessed and recorded. “Early” discontinuation was defined as withdrawal of aspirin and/or clopidogrel within the first 12 months, and “late” discontinuation consisted of aspirin withdrawal after 12 months. Whenever adverse cardiac events and/or major bleeding events were reported, the patients' charts were reviewed.
      Major adverse cardiac events (MACE) were defined as death, myocardial infarction (MI), destabilizing symptoms leading to hospitalization, and nonfatal stroke. Death was considered cardiac in origin unless obvious noncardiac causes could be identified. Sudden death was defined as unexplained death in previously stable patients. MI was diagnosed if any troponin elevation with symptoms suggestive for acute coronary syndrome was detected. The presence of new pathologic Q waves on the electrocardiogram was also diagnosed as MI. Within 1 week of the index procedure, only Q-wave MI was adjudicated as MI. Peri- PCI MI was defined by a new Q wave lasting >0.03 seconds in 2 contiguous electrocardiographic leads or elevations in creatine kinase and the MB fraction of creatine kinase, including an increase in the MB fraction of creatine kinase level that was ≥3 times the local upper limit of the normal range and, when biomarkers were elevated before PCI, an additional 50% greater than baseline. The diagnosis of destabilizing symptoms was defined as the occurrence of ischemic symptoms requiring hospitalization without any biochemical evidence of myocardial necrosis. Stroke was defined as an ischemic cerebral infarction caused by an embolic or thrombotic occlusion of a major intracranial artery. ST was defined according to the Academic Research Consortium Definition.
      • Mauri L.
      • Hsieh W.H.
      • Massaro J.M.
      • Ho K.K.
      • D'Agostino R.
      • Cutlip D.E.
      Stent thrombosis in randomized clinical trials of drug-eluting stents.
      Not only sudden death, but also those deaths without enough information to exclude sudden death were regarded as possible ST. Bleeding complications were classified as major or minor according to the Thrombolysis In Myocardial Infarction criteria.
      • Rao A.K.
      • Pratt C.
      • Berke A.
      • Jaffe A.
      • Ockene I.
      • Schreiber T.L.
      • Bell W.R.
      • Knatterud G.
      • Robertson T.L.
      • Terrin M.L.
      Thrombolysis In Myocardial Infarction (TIMI) Trial—phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase.
      Major bleeding included any intracranial bleeding or any bleeding associated with clinically overt signs associated with a decrease in hemoglobin of >5 g/dl. Minor bleeding was defined as any clinically overt sign of bleeding (including observation using imaging techniques) associated with a decrease in hemoglobin of ≥3 to ≤5 g/dl.
      Continuous variables are presented as the mean ± SD or as the median and interquartile range and were compared using Student's unpaired t test or the Mann-Whitney rank sum test, as appropriate. Categorical variables are presented as counts and percentages and were compared using the chi-square test, as appropriate (expected frequency >5). Otherwise, Fisher's exact test was used. Patients lost to follow-up were considered at risk until the date of the last follow-up interview, at which point they were censored. Multivariate logistic regression models were applied to identify predictors of antiplatelet therapy discontinuation. The results are reported as the odds ratio and 95% confidence interval. Variables that were candidates for entry into the models included the sociodemographic and clinical factors listed in Table 1.
      Table 1Baseline and discharge features of patients with versus without any antiplatelet therapy discontinuation
      VariableNo Early Discontinuation of Dual Antiplatelet Therapy (n = 1,239)Early Discontinuation of Dual Antiplatelet Therapy (n = 119)p ValueNo Late Discontinuation of Aspirin (n = 1,174)Late Discontinuation of Aspirin (n = 65)p Value
      Age (years)63.7 ± 11.264.8 ± 10.90.31063.7 ± 11.364.4 ± 9.30.594
      Men986 (79.6%)90 (75.6%)0.310929 (79.1%)57 (87.7%)0.096
      Height (m)170.9 ± 8.4169.4 ± 8.50.085170.9 ± 8.4170.9 ± 7.60.995
      Weight (kg)77.5 ± 12.576.6 ± 12.80.46977.5 ± 12.477.0 ± 13.70.749
      Body mass index (kg/m2)26.5 ± 3.426.7 ± 4.00.51426.5 ± 3.426.1 ± 3.80.434
      Married659 (86.1%)73 (84.9%)0.749625 (86.2%)24 (85.0%)0.830
      Education0.8290.091
       No formal education92 (13.2%)8 (9.9%)85 (12.8%)7 (20.6%)
       Primary school110 (15.8%)14 (17.3%)105 (15.9%)5 (14.7%)
       Secondary school261 (37.5%)31 (38.3%)254 (38.4%)7 (20.6%)
       High school184 (26.4%)24 (29.6%)170 (25.7%)14 (41.2%)
       College or postgraduate49 (7%)4 (4.9%)48 (7.3%)1 (2.9%)
      Smoking status0.8740.030
       Nonsmoker606 (50.2%)62 (52.5%)578 (50.5%)28 (44.4%)
       Active102 (8.4%)9 (7.6%)91 (7.9%)11 (17.5%)
       Previous500 (41.4%)47 (39.8%)476 (41.6%)24 (38.1%)
      Hypertension746 (65.5%)72 (64.3%)0.797716 (65.9%)30 (57.7%)0.226
      Dyslipidemia848 (70.4%)74 (62.7%)0.084805 (70.4%)43 (69.4%)0.857
      Family history of coronary artery disease449 (37.2%)31 (26.5%)0.021427 (37.3%)22 (34.9%)0.701
      Diabetes mellitus341 (28.3%)38 (32.3%)0.465323 (28.2%)18 (29.0%)0.889
      Previous myocardial infarction301 (24.8%)32 (27.1%)0.585286 (24.9%)15 (23.8%)0.847
      Previous stroke41 (3.4%)9 (7.8%)0.03532 (2.8%)9 (14.8%)<0.001
      Previous percutaneous coronary intervention320 (26.4%)27 (22.9%)0.408300 (26.1%)20 (31.7%)0.321
      Previous coronary artery bypass grafting110 (9.1%)8 (6.8%)0.402101 (8.8%)9 (14.1%)0.154
      Atrial fibrillation36 (3.0%)8 (6.8%)0.02435 (3.1%)1 (1.7%)1.00
      Previous peptic ulcer175 (14.7%)23 (20.0%)0.129170 (15.0%)5 (8.6%)0.181
      Left ventricular ejection fraction52.0 ± 8.550.6 ± 9.50.11752 ± 8.452.6 ± 10.80.620
      Multivessel coronary disease665 (56.6%)54 (46.2%)0.030623 (56.1%)42 (64.6%)0.180
      Chronic renal failure107 (8.9%)14 (12.2%)0.25198 (8.6%)9 (15.3%)0.081
      Serum creatinine at admission (mg/dl)1.1 ± 0.71.2 ± 1.20.3461.1 ± 0.71.2 ± 1.50.644
      Anemia at admission92 (9.0%)11 (11.2%)0.46786 (8.8%)6 (13.0%)0.295
      Hemoglobin at admission13.8 ± 1.513.5 ± 1.60.05813.8 ± 1.514.1 ± 1.70.228
      Hematocrit at admission40.7 ± 4.340.4 ± 4.30.43540.6 ± 4.242.4 ± 4.80.008
      Admission diagnosis0.9960.014
       Stable angina pectoris367 (31.2%)37 (31.6%)353 (31.5%)14 (25.5%)
       ST-segment elevation myocardial infarction339 (28.9%)33 (28.2%)330 (29.5%)10 (18.2%)
       Non–ST-segment elevation myocardial infarction269 (22.9%)26 (22.2%)255 (22.8%)9 (16.4%)
       Unstable angina pectoris200 (17.0%)21 (17.9%)182 (16.3%)14 (25.5%)
      Participation in clinical trial281 (22.7%)30 (25.2%)0.537264 (22.5%)17 (26.2%)0.497
      Use of glycoprotein IIb/IIIa inhibitors415 (33.5%)44 (37.0%)0.447402 (34.3%)13 (20.0%)0.018
      Radial access233 (18.8%)11 (9.2%)0.009214 (18.2%)19 (29.2%)0.027
      Target coronary vessel0.3640.371
       Left main35 (2.8%)3 (2.5%)27 (2.3%)1 (1.5%)
       Left anterior descending542 (43.7%)52 (43.7%)529 (45%)29 (44.6%)
       Left circumflex301 (24.3%)30 (25.2%)292 (24.8%)16 (24.6%)
       Right coronary315 (25.4%)31 (26%)297 (25.3%)17 (26.1%)
       Venous bypass graft46 (3.7%)43 (2.5%)29 (2.4%)2 (3%)
      Vessel reference diameter (mm)3.1 ± 0.73.0 ± 0.80.4023.0 ± 0.62.9 ± 0.50.415
      Stents (n)1.3 ± 0.71.3 ± 0.60.5371.3 ± 0.81.3 ± 0.50.551
      Length of stented segment (mm)23.8 ± 7.823.7 ± 8.60.30523.7 ± 9.623.9 ± 9.10.339
      Oral anticoagulants at discharge21 (1.8%)14 (12.2%)<0.00117 (1.5%)4 (6.9%)0.017
      β Blocker at discharge1,012 (86.1%)92 (79.3%)0.049968 (86.6%)44 (75.9%)0.022
      Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers at discharge825 (70.2%)82 (70.7%)0.904793 (70.9%)32 (55.2%)0.011
      Statin at discharge1,080 (92.4%)95 (81.9%)<0.0011,031 (92.7%)49 (86.0%)0.071
      Proton pump inhibitor at discharge1,079 (90.1%)106 (89.1%)0.7111,028 (90.1%)51 (91.1%)0.811
      Serum creatinine at discharge (mg/dl)1.1 ± 0.61.3 ± 1.10.1091.1 ± 0.61.1 ± 0.30.888
      Hemoglobin at discharge (g/dl)13.0 ± 1.612.5 ± 1.90.01213.0 ± 1.513.1 ± 2.00.896
      Hematocrit at discharge (%)38.6 ± 3.838.2 ± 4.40.38238.5 ± 3.839.5 ± 4.70.108
      The association of antiplatelet therapy discontinuation (early and late) with subsequent clinical outcomes was explored. The predictors of MACE, ST, and mortality were identified using multivariate logistic regression analysis. Survival curves were generated using the Kaplan-Meier method, and the log-rank test was used to evaluate differences between groups. Crude event rates were estimated using the Kaplan-Meier method. The MACE, ST, and death rates were investigated according to the status of aspirin and clopidogrel therapy. The analyses were stratified by the interval after the index PCI (i.e., within 30 days, 31 to 180 days, 181 to 365 days, and after 365 days) in accordance with previous reports.
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      Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment.
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      • Morimoto T.
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      • Tamura T.
      • Kadota K.
      • Yasumoto H.
      • Nishikawa H.
      • Hiasa Y.
      • Muramatsu T.
      • Meguro T.
      • Inoue N.
      • Honda H.
      • Hayashi Y.
      • Miyazaki S.
      • Oshima S.
      • Honda T.
      • Shiode N.
      • Namura M.
      • Sone T.
      • Nobuyoshi M.
      • Kita T.
      • Mitsudo K.
      j-Cypher Registry Investigators
      Antiplatelet therapy and stent thrombosis after sirolimus-eluting stent implantation.
      Receiver operating characteristic analysis was performed for an exploratory evaluation of the best cutoff point of antiplatelet discontinuation duration to predict MACE, ST, and death in our study population. The sensitivity, specificity, and positive and negative predictive values were derived using this cutoff value. Significance was set at the 2-tailed 0.05 level. Computations were performed using the Statistical Package for Social Sciences, version 15.0 (SPSS, Chicago, IL).

      Results

      Of the overall study population (n = 1,379), complete follow-up data were available for 1,358 patients (98.5%). The remaining patients were excluded from the present analysis, assuming a nonsignificant difference with regard to the distribution of clinical events. Of the patients who discontinued one or both antiplatelet agents, early (<12 months) and late (>12 months) discontinuation occurred in 119 (8.8%) and 65 (4.8%) patients, respectively. The baseline demographics, clinical characteristics, and discharge data of patients with (n = 184) and without (n = 1,174) antiplatelet discontinuation are listed in Table 1. The trends in antiplatelet discontinuation over time are shown in Figure 1.
      Figure thumbnail gr1
      Figure 1Trends in antiplatelet discontinuation over time. Estimates of cumulative incidence were obtained with the Kaplan-Meier method.
      The causes of antiplatelet therapy discontinuation are summarized in Table 2. Bleeding events represented the most frequent cause of early discontinuation and the second-most frequent cause of late discontinuation. Surgery was the leading cause of late discontinuation and the second-most frequent cause of early discontinuation. The predictors of antiplatelet therapy discontinuation are summarized in Table 3. Early discontinuation of one or both antiplatelet agents within the first year was predicted by in-hospital major bleeding, oral anticoagulant use at discharge, and the lack of statin prescription. A history of previous stroke was the only independent predictor of late discontinuation. During the overall study period, the discontinuation of aspirin was predicted by the prescription of oral anticoagulants at discharge. In contrast, diabetes mellitus, serum creatinine at admission, statins at discharge, and oral anticoagulants at discharge predicted thienopyridine discontinuation.
      Table 2Causes of antiplatelet therapy discontinuation
      EventPatients (n)
      Early discontinuation of dual antiplatelet therapy (n = 119)
       Bleeding41 (34.5%)
       Surgery25 (21.0%)
       Medical decision21 (17.6%)
       Dental procedure9 (7.6%)
       Economic issues7 (5.9%)
       Oral anticoagulation started6 (5.0%)
       Allergy/intolerance3 (2.5%)
       Unknown2 (1.7%)
       Patient decision2 (1.7%)
       Patient mistake2 (1.7%)
       Trauma1 (0.8%)
      Late discontinuation of aspirin (n = 65)
       Surgery32 (49.2%)
       Bleeding11 (16.9%)
       Dental procedure8 (12.3%)
       Medical decision4 (6.2%)
       Unknown3 (4.6%)
       Allergy/intolerance3 (4.6%)
       Oral anticoagulation started2 (3.1%)
       Trauma2 (3.1%)
      Table 3Predictors of antiplatelet therapy discontinuation
      EventIndependent Multivariate Predictor
      OR95% CIp Value
      Early (<12 months) discontinuation of dual antiplatelet therapy
       Statin at discharge0.3640.212–0.625<0.001
       Oral anticoagulants at discharge8.2133.975–16.969<0.001
       In-hospital major bleeding9.0073.323–24.414<0.001
      Late (>12 months) discontinuation of aspirin
       Previous stroke5.2102.225–12.067<0.001
      Overall discontinuation of aspirin
       Oral anticoagulants at discharge6.8242.750–16.935<0.001
      Overall discontinuation of clopidogrel
       Diabetes mellitus1.9641.225–3.1490.005
       Serum creatinine at admission1.2281.023–1.4750.028
       Statin at discharge0.3190.168–0.604<0.001
       Oral anticoagulants at discharge4.6201.839–11.6080.001
      CI = confidence interval; OR = odds ratio.
      The cumulative incidence of MACE and ST was 14.9%, and 3.8%, respectively. Patients with early discontinuation of antiplatelet therapy experienced a greater incidence of MACE (28.6% vs 13.7%, p <0.001) and ST (7.6% vs 3.4%, p = 0.038) compared to those who did not (Table 4). Overall mortality (13.4% vs 4.7%, p <0.001) and cardiovascular death (5% vs 1.2%, p = 0.007) were significantly more frequent among patients with early discontinuation. Also, the incidence of MI and destabilizing symptoms requiring hospitalization was greater, albeit not statistically significant, in patients with early discontinuation. In patients with late discontinuation, a nonstatistically significant increase in MACE and ST and a significantly greater incidence of MI and nonfatal stroke were seen. No significant differences were found in cardiovascular death and overall death between patients with and without late discontinuation.
      Table 4Short and long-term events of patients with versus without antiplatelet therapy discontinuation
      Early Discontinuation of Dual Antiplatelet TherapyLate Discontinuation of Aspirin
      No

      (n = 1,239)
      Yes

      (n = 119)
      p ValueNo

      (n = 1,174)
      Yes

      (n = 65)
      p Value
      In-hospital major adverse cardiac events28 (2.3%)3 (2.5%)0.74925 (2.1%)3 (4.6%)0.19
      In-hospital major bleeding10 (0.8%)7 (6.0%)<0.0019 (0.8%)1 (1.7%)0.469
      In-hospital minor bleeding40 (3.4%)11 (9.5%)0.00437 (3.3%)3 (5.0%)0.467
      Cumulative major adverse cardiac events169 (13.7%)34 (28.6%)<0.001156 (13.3%)13 (20.0%)0.128
      Any death58 (4.7%)16 (13.4%)<0.00157 (4.9%)1 (1.5%)0.361
      Myocardial infarction52 (4.2%)9 (7.6%)0.0946 (3.9%)6 (9.2%)0.05
      Unstable angina leading to hospitalization51 (4.1%)9 (7.6%)0.0848 (4.1%)3 (4.6%)0.747
      Nonfatal stroke8 (0.6%)0 (0%)1.005 (0.4%)3 (4.6%)0.006
      Cumulative death58 (4.7%)16 (13.4%)<0.00157 (4.9%)1 (1.5%)0.361
      Cumulative cardiac death15 (1.2%)6 (5.0%)0.00715 (1.3%)0 (0%)1.00
      Cumulative major bleeding23 (1.9%)22 (18.6%)<0.00115 (1.3%)8 (13.1%)<0.001
      Cumulative minor bleeding73 (6.1%)34 (29.1%)<0.00159 (5.2%)14 (22.6%)<0.001
      Cumulative definite stent thrombosis31 (2.8%)8 (6.7%)0.02727 (2.3%)4 (6.2%)0.075
      Cumulative definite or probable stent thrombosis32 (2.8%)8 (6.7%)0.04828 (2.4%)4 (6.2%)0.083
      Cumulative definite, probable or possible stent thrombosis42 (3.4%)9 (7.6%)0.03838 (3.2%)4 (6.2%)0.275
      Data are expressed as counts and percentages, unless otherwise specified.
      The Kaplan-Meier curves showed that MACE and ST were significantly greater for patients with early discontinuation compared to without discontinuation (Figure 2). Also, the cumulative rate curves showed a significantly greater incidence of overall death in patients with early discontinuation compared to patients with late discontinuation and those without discontinuation (Figure 2). The incidence of MACE, ST, and death was greater when discontinuation occurred within the first 30 days and decreased over time (Figure 3). Early antiplatelet therapy discontinuation was shown to be an independent predictor of cumulative death and MACE at follow-up, although late discontinuation did not emerge as an independent predictor (Table 5). From the receiver operating characteristic analysis, most MACE events occurred 5.5 days after premature discontinuation of antiplatelet therapy, with a sensitivity of 30%, specificity of 87%, positive predictive value of 24%, and negative predictive value of 90%.
      Figure thumbnail gr2
      Figure 2Kaplan-Meier curves showing MACE (A), ST (B), and all-cause death (C) stratified by no unplanned antiplatelet discontinuation (green line), early discontinuation of dual antiplatelet therapy (red line), and late discontinuation of aspirin (blue line).
      Figure thumbnail gr3
      Figure 3Outcome in relation to point of antiplatelet therapy discontinuation. Incidence of MACE, ST, and death was greater when discontinuation occurred within first 30 days and decreased over time.
      Table 5Predictors of adverse events
      Adverse EventOR95% CIp Value
      In-hospital major adverse cardiac event
       Left ventricular ejection fraction0.9320.896–0.969<0.001
       In-hospital major bleeding5.4571.151–25.8840.033
       In-hospital minor bleeding5.4321.919–15.3760.001
      In-hospital major bleeding
       Hemoglobin at admission0.6720.481–0.9390.020
       Use of glycoprotein IIb/IIIa inhibitors5.1991.612–16.7720.006
      In-hospital minor bleeding
       Male gender0.2540.126–0.511<0.001
       Previous coronary artery bypass grafting3.8501.642–9.0270.002
       Hemoglobin at admission0.6170.493–0.772<0.001
       β Blocker at discharge0.3880.186–0.8110.012
       Oral anticoagulants at discharge10.6043.897–28.858<0.001
      Cumulative death at follow-up
       Age1.0521.015–1.0900.005
       Admission diagnosis (ST-segment elevation myocardial infarction vs other)0.1100.025–0.4910.004
       Hematocrit at admission0.8240.770–0.882<0.001
       Left ventricular ejection fraction0.9450.913–0.9790.001
       Statin at discharge0.3920.162–0.9460.037
       Early (<12 months) dual antiplatelet therapy discontinuation2.6901.159–6.2470.021
      Cumulative major adverse cardiac events at follow-up
       Male gender2.2111.248–3.9170.007
       Hemoglobin at discharge0.7420.653–0.844<0.001
       Left ventricular ejection fraction0.9400.919–0.961<0.001
       Multivessel coronary disease2.2061.423–3.421<0.001
       Use of glycoprotein II/IIIa inhibitors0.6000.385–0.9340.024
       Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers at discharge0.5650.368–0.8680.009
       Any antiplatelet discontinuation2.1511.349–5.7910.004
       Early (<12 months) dual antiplatelet therapy discontinuation2.1421.185–3.8710.012
      Cumulative major bleeding at follow-up
       Hemoglobin at discharge0.4440.353–0.559<0.001
      Cumulative minor bleeding at follow-up
       Hemoglobin at discharge0.6290.546–0.726<0.001
       β Blocker at discharge0.5370.303–0.9510.033
       Oral anticoagulation agents at discharge5.5962.285–13.704<0.001
      Cumulative definite, probable, or possible stent thrombosis at follow-up
       Left ventricular ejection fraction0.9320.903–0.961<0.001
       Chronic renal failure3.2451.581–6.6610.001
      Figure 4 shows the relation between aspirin and/or thienopyridine discontinuation and MACE by interval after stent implantation. Compared to no discontinuation, thienopyridine withdrawal was associated with a greater incidence of MACE at 30 days (33% vs 2%, p <0.001), from 30 days to 6 months (19% vs 2%, p <0.001), and from 6 months to 1 year (7.4% vs 1.9, p = 0.007). This protective effect, however, was not maintained after the first year, when thienopyridine discontinuation was not associated with any significant differences in MACE (9.7% vs 7.6%, p = 0.35). Discontinuation of both antiplatelet agents was associated with the greatest risk of MACE at 30 days to 6 months, 6 months to 1 year, and after 1 year (Figure 4).
      Figure thumbnail gr4
      Figure 4Landmark analysis of clopidogrel and/or aspirin discontinuation and MACE after stent implantation. Compared to no discontinuation, clopidogrel withdrawal was associated with significantly greater rate of MACE at 30 days, 30 days to 6 months, and 6 months to 1 year. After first year, clopidogrel discontinuation was not associated with any significant differences in MACE.
      Definite ST was observed in 2.9% of patients in the follow-up period. The rate of definite, probable, or possible ST was 3.8%. The independent predictors of any ST were left ventricular ejection fraction (odds ratio 0.932, 95% confidence interval 0.903 to 0.961, p <0.001) and chronic renal failure (odds ratio 3.245, 95% confidence interval 1.581 to 6.661, p = 0.001). The status of the antiplatelet treatment regimen at ST is reported in Table 6. Among patients with ST, 43.6% were receiving dual antiplatelet therapy at the event and 16% of patients had prematurely discontinued thienopyridine therapy.
      Table 6Antiplatelet therapy among patients with definite, probable or possible stent thrombosis
      Feature
      Dual antiplatelet therapy at stent thrombosis43.6%
      No discontinuation of dual antiplatelet therapy78.0%
      Premature discontinuation of aspirin6.0%
      Premature discontinuation of thienopyridine16.0%
      Premature discontinuation of aspirin or thienopyridine22.0%
      Premature discontinuation of both aspirin and thienopyridine4.0%
      Interval between thienopyridine discontinuation and stent thrombosis during first 12 months (days)
       Mean12 ± 13
       Range0–31
      Interval between thienopyridine discontinuation and stent thrombosis after first 12 months (days)
       Mean0.5 ± 0.7
       Range0–1

      Discussion

      The present study assessed the prevalence and predictors of premature discontinuation of long-term oral antiplatelet therapy after DES implantation and evaluated its effects on prognosis in relation to the time and duration of the discontinuation. The main findings of the present study are as follows. First, discontinuation of antiplatelet therapy was relatively common (>1 patient in 10), particularly within the first year after DES implantation. Second, the most common causes of discontinuation were bleeding events and surgery or dental procedures. Third, discontinuation of antiplatelet therapy within the first year was associated with a poor prognosis. Finally, thienopyridine therapy for >6 months and within the first year seemed to provide a beneficial effect.
      Our data have demonstrated that >1 in 10 DES-treated patients prematurely withdrew aspirin and/or thienopyridine therapy. The rate of discontinuation of antiplatelet therapy was greater within the first year than afterward. Patients who discontinued antiplatelet therapy within the first year were more likely to have had in-hospital major bleeding, to have been discharged with oral anticoagulation, and were less likely to have been discharged with statins. Discontinuation of antiplatelet therapy after 1 year was predicted only by previous stroke. These findings were consistent with previous data,
      • Spertus J.A.
      • Kettelkamp R.
      • Vance C.
      • Decker C.
      • Jones P.G.
      • Rumsfeld J.S.
      • Messenger J.C.
      • Khanal S.
      • Peterson E.D.
      • Bach R.G.
      • Krumholz H.M.
      • Cohen D.J.
      Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry.
      demonstrating that anemia was associated with thienopyridine discontinuation within the first 30 days, underscoring the effect of bleeding on a patient's compliance. Oral anticoagulation also emerged as the predominant reason for the nonuse of aspirin in patients with ST in a recently published study.
      • van Werkum J.W.
      • Heestermans A.A.
      • Zomer A.C.
      • Kelder J.C.
      • Suttorp M.J.
      • Rensing B.J.
      • Koolen J.J.
      • Brueren B.R.
      • Dambrink J.H.
      • Hautvast R.W.
      • Verheugt F.W.
      • Ten B.J.M.
      Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry.
      However, oral anticoagulation had an opposite effect in the Prospective Registry Evaluating Outcomes After Myocardial Infarction: Events and Recovery Quality Improvement Registry (PREMIER) registry, where it was associated with a reduced risk of discontinuation.
      • Spertus J.A.
      • Kettelkamp R.
      • Vance C.
      • Decker C.
      • Jones P.G.
      • Rumsfeld J.S.
      • Messenger J.C.
      • Khanal S.
      • Peterson E.D.
      • Bach R.G.
      • Krumholz H.M.
      • Cohen D.J.
      Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry.
      This discrepancy might, in part, have resulted from the different durations of follow-up, which was only 30 days in the registry and thus probably inadequate to assess the bleeding complications responsible for antiplatelet therapy discontinuation.
      • Spertus J.A.
      • Kettelkamp R.
      • Vance C.
      • Decker C.
      • Jones P.G.
      • Rumsfeld J.S.
      • Messenger J.C.
      • Khanal S.
      • Peterson E.D.
      • Bach R.G.
      • Krumholz H.M.
      • Cohen D.J.
      Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry.
      In contrast, in our study, long-term therapy with oral anticoagulants was associated with a greater risk of bleeding, which might have enhanced the risk of discontinuation. The protective effect of statins on a patient's adherence to antiplatelet therapy was less obvious and could be explained by the lower compliance to medical therapy. Such patients might have probably reported a previous “intolerance” to statins, which, therefore, were not prescribed. The same patients might have discontinued oral antiplatelet therapy probably because of “adverse effects.” Moreover, patients who were prescribed statins were probably at greater risk and, thus, more carefully monitored. Among the reasons that led to discontinuation, surgery, dental procedures, and medical decisions represented almost one half of the causes of early discontinuation and more than two thirds of the causes of late discontinuation. The balance between the ischemic risk from antiplatelet therapy discontinuation and the perioperative hemorrhagic risk because of concomitant antiplatelet therapy is a challenge underscoring the need for dedicated trials.
      • Riddell J.W.
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      • Hamon M.
      Coronary stents and noncardiac surgery.
      In our study, premature discontinuation of antiplatelet therapy was associated with a poor prognosis, which was more evident if it occurred within the first year after stent implantation. Patients who discontinued antiplatelet therapy within the first 12 months had a significantly greater incidence of overall MACE, ST, and death. A trend toward a greater incidence of MACE and ST was present in patients with aspirin discontinuation after the first 12 months. Our study showed that the risk of events did not seem relevant if the discontinuation duration was <5.5 days, as demonstrated by the negative predictive value of 90. These data are consistent with those from Eisenberg et al,
      • Eisenberg M.J.
      • Richard P.R.
      • Libersan D.
      • Filion K.B.
      Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents.
      who performed a systematic review of all the reported cases of late and very late ST and showed that the median interval from antiplatelet therapy discontinuation to ST was 7 days. However, it increased to ≤122 days if aspirin use was maintained. Consistent with previous data, our study has demonstrated that ST is often associated with unplanned discontinuation of antiplatelet therapy.
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      Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment.
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      Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period.
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      Among patients with ST, >1 of 4 patients had prematurely withdrawn either aspirin or clopidogrel and almost 1 of 5 patients had withdrawn clopidogrel.
      Previous studies have argued against the role of prolonging dual antiplatelet therapy >6 months because the risk of ST after discontinuation of thienopyridines after this period is small.
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      • Michev I.
      • Montorfano M.
      • Sangiorgi G.M.
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      • Briguori C.
      • Grube E.
      Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment.
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      • Schömig A.
      • Kastrati A.
      Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period.
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      Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents.
      However, the largest, and thus more greatly powered, registry assessing this topic showed that the lack of clopidogrel therapy for >6 months after the index PCI was a predictor of angiographic ST.
      • van Werkum J.W.
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      • Verheugt F.W.
      • Ten B.J.M.
      Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry.
      The protective effect of prolonged thienopyridine therapy was not only in relation to ST, as described in previously mentioned studies, but also in relation to overall MACE, because ST represents only one of the ischemic events that can occur in patients with coronary artery disease. In the present study, clopidogrel use for >6 months and within 1 year was associated with a reduction in MACE. These findings are consistent with those from another large registry that demonstrated that, after DES implantation, ongoing clopidogrel use for >6 months was associated with lower rates of death and MI.
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      A possible protective mechanism of clopidogrel unrelated to stenting was advocated in a recent study, which demonstrated a clustering of adverse events in the initial 90 days after stopping clopidogrel among both medically treated and PCI-treated patients with acute coronary syndrome.
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      The protective effects of clopidogrel might result not only from its platelet-inhibiting properties, but also its potential anti-inflammatory properties.
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      The ELAPSE (Evaluation of Long-Term Clopidogrel Antiplatelet and Systemic Anti-Inflammatory Effects) study.
      However, the optimal duration of dual antiplatelet therapy after DES implantation still remains unknown. In a recent combined analysis of 2 randomized trials, no significant benefit was associated with clopidogrel continuation after 12 months in patients who had undergone DES implantation, and a trend toward harm was found.
      • Park S.-J.
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      Duration of dual antiplatelet therapy after implantation of drug-eluting stents.
      Larger size, ongoing, clinical studies are warranted to fully address the benefits of prolonging thienopyridine therapy for >12 months.
      • Kandzari D.E.
      • Angiolillo D.J.
      • Price M.J.
      • Teirstein P.S.
      Identifying the “optimal” duration of dual antiplatelet therapy after drug-eluting stent revascularization.
      The present study had several limitations. Follow-up information was obtained mostly by telephone interviews with the patients, and the dates of discontinuation of aspirin and clopidogrel were determined by retrospective recall by the patients or relatives, with the potential for a recall bias. Moreover, some patients who reported taking antiplatelet therapy might not have been fully compliant with the medication. Thus, we might have underestimated the true rates of antiplatelet therapy discontinuation. Furthermore, it is likely that failure to adhere to prescribed antiplatelet therapy is a marker of overall medical noncompliance, which might have accounted for some of the excess mortality and MACE we observed. In addition, the present study was conducted in Northern Italy for a selected period. Therefore, we could not exclude that this could have led to a selection bias in the patient population and influenced our results. Finally, the relatively low number of events owing to the limited population weakened the power to make definitive statements regarding the safety of clopidogrel discontinuation. Ongoing investigations specifically powered to understand the prognostic implications of extending thienopyridine therapy will provide more insights into this topic.
      • Kandzari D.E.
      • Angiolillo D.J.
      • Price M.J.
      • Teirstein P.S.
      Identifying the “optimal” duration of dual antiplatelet therapy after drug-eluting stent revascularization.
      These will allow us to better define the predictors and prognostic implications of treatment discontinuation and how these might differ between clinical trials and real world registries, such as described in the present analysis.

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