(Circulation. 1996;94:279-285.)
© 1996 American Heart Association, Inc.
Articles |
Platelet Activation and Coronary Stent Implantation
Effect of Antithrombotic Therapy
the First Medizinische Klinik der Technischen Universitat Munchen (Germany).
Correspondence to Dr med Meinrad Gawaz, First Medizinische Klinik, Technische Universitat Munchen, Ismaningerstr 22, 81675 Munchen, Germany.
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Abstract |
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Background Platelet activation and surface expression of adhesive glycoproteins play a key role in ischemic thrombotic complications after coronary intervention. The purpose of this case-control study was to evaluate the effects of two different antithrombotic regimens on platelet function after coronary Palmaz-Schatz stent implantation.
Methods and Results The study group consisted of 46 "low-risk" patients who were treated with ticlopidine (250 mg BID) and aspirin (100 mg BID) after stenting. The control group was derived from a cohort of 151 patients receiving conventional anticoagulation therapy, including phenprocoumon (target international normalized ratio, 3.5), heparin (activated partial thromboplastin time, 80 to 120 seconds), and aspirin (100 mg BID) after stenting. Criteria for matching were indication for stenting, target vessel, balloon size, inflation pressure, and number of inserted stents. Matches were obtained for 38 patients. Platelet function was evaluated before and daily for 12 days after stenting in venous blood samples with immunologic activation markers. Patients receiving anticoagulation therapy showed a significantly increased surface exposure of LIBS1 (activated fibrinogen receptor; P<.05) and CD62P (P-selectin; P<.001) above prestent values, peaking days 3 to 6 after stenting. In contrast, in patients receiving ticlopidine, expression of LIBS1 decreased (P<.01) and expression of CD62P remained basically unchanged after stenting. Platelet count significantly decreased after stenting in patients treated by anticoagulation (day 3; P<.01), whereas no significant changes were found in the ticlopidine group.
Conclusions Significant platelet activation occurs in patients receiving anticoagulation therapy after stenting, while platelet deactivation is found in patients treated with combined antiplatelet therapy. This may contribute to a lowering of the incidence of subacute stent thrombosis.
Key Words: angioplasty • stents • platelets • glycoproteins • ticlopidine
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Introduction |
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Deployment of coronary stents is an established method for treating threatened or abrupt vessel closure after coronary balloon angioplasty.1 2 3 4 5 6 In selected patients, elective implantation of intracoronary stents improves early and long-term clinical success rates of angioplasty.7 8 However, several limitations of coronary stenting are of significant clinical importance. Because currently used stent devices represent foreign surfaces that reveal thrombogenic activity, intense anticoagulation after stenting is recommended at the cost of increased risk of major bleeding and vascular complications.9 10 11 Nevertheless, subacute stent thrombosis occurs in
3.5% of patients who undergo elective stent placement1 2 3 4 6 9 and in 5% to 15% of those in whom stent implantation is used as a bailout technique.7 8 Subacute stent thrombosis occurs most frequently during the first 2 weeks after intervention3 6 and carries a high incidence of unfavorable clinical outcome, including mortality and acute myocardial infarction.12 Our previous studies showed that coronary stenting results in significant platelet activation despite anticoagulation treatment with phenprocoumon and heparin in combination with aspirin.13 In addition, we13 and others14 found that enhanced surface exposure of adhesion receptors on activated platelets plays a key role in the development of subacute vessel closure after coronary intervention. The results of these studies challenge the established anticoagulation regimen for patients with newly implanted coronary stents and emphasize the need for the development of more effective antiplatelet strategies. Recently, preliminary studies suggested ticlopidine to be effective in patients undergoing coronary stenting.15 16 17 The effect of ticlopidine on platelet function in patients treated with a stent implantation has not yet been proved. Thus, the present studies were performed to evaluate platelet function in coronary stent patients receiving ticlopidine and aspirin as antiplatelet therapy and to compare the results with those from a group of individuals treated by standard anticoagulation regimen.
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Methods |
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Patient Selection
The study was designed as a matched case-control study on patients undergoing coronary stenting for inadequate immediate results of balloon angioplasty. All patients in both the study and control groups received Palmaz-Schatz stents. The indications for coronary stenting were inadequate luminal gain (residual stenosis >50%) and large dissections, the latter being the most frequent cause. Patients were not enrolled in the study if they had any hemostatic disorders or other contraindications to anticoagulation treatment or if they presented with acute myocardial infarction.
The study group comprised 46 patients with coronary stent implantation who were treated with ticlopidine instead of strict anticoagulation (see below). The decision for this therapeutic regimen was based on an estimated "low risk" of subacute stent thrombosis. Table 1
gives the criteria for assessment of the risk of stent thrombosis, derived from published clinical experience.6 A low risk of subacute stent thrombosis was assumed if fewer than two criteria were met. Table 2 gives the baseline characteristics of the study and control patients.
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For case-control matching, we reviewed 151 consecutive patients with coronary Palmaz-Schatz stenting between May 1993 and November 1994 who were treated by conventional anticoagulation with unfractionated heparin and oral vitamin K antagonist (see below). Of these, 63 met the criteria for an estimated low risk of stent thrombosis. These patients would have been potential candidates for treatment with ticlopidine and therefore were eligible for case-control matching. Criteria for case-control matching were indication for stenting, vessel of the target lesion, number of stents, nominal size of the balloon used for stent deployment within 0.5 mm, and maximal inflation pressure within 2 atm (Table 3). A total of 38 patient pairs were assigned in this manner; 8 study patients remained unmatched because of the limited number of suitable control subjects.
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Stenting Procedure and Poststenting Management of Patients
During the study period, we did not change stenting procedures. Coronary balloon angioplasty was performed by the femoral approach with the same nonionic contrast medium (Solutrast 370, Byk-Gulden). Standard medication for the intervention included an initial intra-arterial dose of 15 000 IU heparin and an additional dose of 5000 IU for procedures longer than 1 hour. Aspirin 500 mg IV was injected during angioplasty. If inadequate lumen could not be managed by the use of larger balloons or if a relevant dissection was visible, the decision to stent was made early. We tried to avoid severe vessel injury by multiple balloon inflations or vessel closure before stenting. Palmaz-Schatz stents (Johnson & Johnson Interventional Systems) were hand crimped onto the angioplasty balloon and deployed as described in detail elsewhere.3 6 If feasible, we optimized stent expansion by additional balloon inflations with short balloons (10 mm) and high inflation pressures. Within the first 4 hours after the intervention, we removed the arterial sheath as soon as the activated partial prothrombin time fell below 80 seconds.
After sheath removal, study patients were continued on intravenous heparin for 12 hours. All patients received daily aspirin (Bayer) 100 mg BID and ticlopidine (Tiklyd) 250 mg BID starting on the day of intervention. All control patients had been put on a standardized anticoagulation regimen. Heparin infusion was started immediately after pressure bandage application and titrated to maintain the activated partial prothrombin time between 80 and 120 seconds. Therapy with the vitamin K antagonist phenprocoumon (Marcumar R, Hoffmann-La Roche) was begun on the day of intervention. Heparin infusion was continued for 7 to 10 days until a stable level of oral anticoagulation was achieved at an international normalized ratio for prothrombin time of between 3.5 and 4.5. The vitamin K antagonist was given for 4 weeks. All patients were taking aspirin 100 mg/d BID while continuing their usual therapies.
Immunologic Detection of Platelet Activation
Peripheral venous blood samples were taken with mild tourniquet application through a short venous catheter inserted into a forearm vein just before and then daily in the morning for 12 days after coronary intervention. By use of a multiple-syringe sampling technique, the first 2 mL blood was discarded. Thereafter, 2.5 mL blood collected in disodium EDTA was used to determine platelet count by use of a Coulter counter (Corning). Blood (4 m/L) was collected in 3.8% citrate for coagulation parameters; 5 mL was collected for serum chemistry. Thereafter, 1.6 mL of blood was collected for flow cytometric analysis in a polypropylene syringe containing 0.4 mL citrate phosphate dextrose acid adenine.
Preparation and immunolabeling of platelets with monoclonal antibodies were performed immediately after blood was drawn as described earlier.18 19 In brief, immediately after blood collection, citrated whole blood was centrifuged at 50g for 10 minutes to obtain platelet-rich plasma. Then, 5 µL platelet-rich plasma was added to the polypropylene tubes (Becton-Dickinson) preloaded with 45 µL modified Tyrode's buffer containing saturating concentrations of FITC-conjugated antibodies. Nonspecific membrane immunofluorescence was determined by use of an irrelevant isotype-matched FITC-conjugated IgG (Dianova). Samples were incubated in the dark for 15 minutes at room temperature without agitation. Immunolabeled samples were fixed by addition of 1 mL of 0.2% paraformaldehyde in PBS, pH 7.4, and stored at 4°C until flow cytometric analysis within 24 hours. The platelet population was identified by size and granularity (>98% positive for CD41). Antibody binding of anti-LIBS1 and anti-CD62P was measured as the percentage of platelets positive for both epitopes after subtracting nonspecific fluorescence. In contrast, anti-CD41 antibody binding was determined as the relative change in fluorescence intensity per platelet. The platelet assay used in the present study obtains reproducible results without significant artifactual platelet activation and has proved suitable for platelet analysis in a variety of clinical settings.20 21 Platelets from 20 healthy volunteers were evaluated as reference.
Monoclonal antibodies anti-CD41 and anti-CD62P were commercially obtained as FITC conjugates (Dianova). Anti-CD41 is raised against the glycoprotein complex IIb-IIIa (GPIIb-IIIa) and detects the receptor regardless of whether it is in its resting or activated form. Anti-LIBS1 monoclonal antibody (generously provided by Dr Mark Ginsberg, Scripps Clinic) recognizes a cryptic epitope on GPIIIa that becomes exposed only on the activated and ligand-occupied GPIIb-IIIa complexes.22 Thus, anti-LIBS1 binding indicates fibrinogen receptor activity. Anti-CD62P recognizes the 
-granule membrane glycoprotein P-selectin (GMP-140, PADGEM) that is expressed on the activated platelet surface23 and was used as a marker for -degranulation. Plasma fibrinogen concentration and platelet count were determined in the hospitals' clinical chemistry departments.
Statistical Analysis
Student's t test was used to test quantitative coronary angiography data. The Kolmogorov-Smirnov test showed that the platelet function data were not normally distributed. Results are reported as median (interquartile range) unless otherwise indicated. To analyze the time courses, differences were tested with Friedman's test followed by Wilcoxon's rank sum test. Differences between matched patients also were tested with Wilcoxon's rank sum test. We first tested differences in the entire time course by comparing the sum of each measurement in a patient. If this evaluation revealed significant differences, we compared the variable at individual time points. A value of P<.05 was regarded as significant.
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Results |
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Baseline Characteristics
Matched patients were comparable with respect to demographic (Table 2
) and angiographic (Table 4) characteristics. Intracoronary stents were successfully deployed in all patients, and no angiographically detectable dissection was present. No evaluated patients developed subacute stent thrombosis within the observation period of the study. False aneurysm at puncture site occurred in three patients (6.6%) receiving phenprocoumon and heparin and in one patient (2.2%) receiving ticlopidine. Upper gastrointestinal bleeding that required blood transfusion was shown in one patient (2.2%) treated with phenprocoumon and heparin. Other major vascular or bleeding complications were not encountered.
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Platelet Membrane Glycoproteins
Baseline values (before stent) of fibrinogen receptor activity (LIBS1 immunofluorescence), GPIIb-IIIa, and P-selectin platelet surface expression were not different between the study and control groups (Table 5).
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Fibrinogen Receptor Activity
In the control group (phenprocoumon and heparin), fibrinogen receptor activity (LIBS1 signals) significantly increased above starting values day 2 after stent placement, peaking at day 3 (percentage of positive platelets: median [interquartile range] 15.4% [11.3% to 18.7%] on day 3 versus 10.9% [9.8% to 19.9%] at prestent; P<.001) and remained elevated for 6 days before it returned to baseline values (Figs 1 and 2). Surface density of GPIIb-IIIa on circulating platelets remained basically unchanged in the control group throughout the observation period (Fig 3).
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indicates patients receiving heparin, phenprocoumon, and aspirin; 
, patients receiving ticlopidine and aspirin as antithrombotic therapy after coronary stenting; and shadowed box, median (quartiles) of fibrinogen receptor activity of 20 normal individuals. *Significant difference between groups (P<.05).
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In the study group (ticlopidine), the percentage of LIBS1-positive platelets decreased below baseline values after stent implantation, reaching statistical significance at day 3 and with a nadir at day 8 (7.3 [6.1 to 11.2] on day 8 versus 10.8 [9.6 to 11.3] at prestent; P<.01; Fig 1). Surface exposure of GPIIb-IIIa remained basically unchanged (Fig 3). Fibrinogen receptor activity was significantly higher in the control group between days 3 and 8 after stenting compared with the study group (P<.05; Fig 1).
P-Selectin Degranulation
In the control group, surface exposure of P-selectin significantly increased above baseline values the day after stent placement, peaking at day 4 (percentage of positive platelets, 22.4% [18.4% to 27.1%] versus 14.9% [12.9% to 17.5%]; P<.001) and remaining elevated for 6 days until it again reached baseline values (Figs 4 and 5). No significant change in surface expression of P-selectin was found in the study group (Figs 4 and 5). Compared with patients in the study group, patients receiving phenprocoumon and heparin had significantly higher P-selectin expression between days 3 and 8 after stenting (P<.05; Fig 4).
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Platelet Count and Plasma Fibrinogen
Platelet count dropped below baseline values after stenting in the control group, with the lowest values found at day 4 (181 [131 to 214] versus 211 [156 to 211] at prestent; P<.01; Figs 6 and 7).Thereafter, platelet count increased and reached values above baseline after 9 days (Fig 6). No significant change in platelet count was shown in the study group (Figs 6 and 7).
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Plasma fibrinogen concentration significantly increased after stenting in the control group, reaching maximal levels at day 6 (554 [492 to 723] versus 375 [325 to 481] at prestent; P<.001; Fig 8). No change in plasma fibrinogen levels was shown in the study group (Fig 8).
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Discussion |
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Despite strict anticoagulation, coronary stenting is associated with significant platelet activation that increases the risk for development of subacute stent thrombosis.13 The present study shows that platelet activation after coronary stenting can be modified by selection of antithrombotic treatment. Specifically, fibrinogen receptor activity increases after coronary stenting in patients receiving phenprocoumon and heparin as antithrombotic therapy, whereas it decreases in patients receiving ticlopidine. Platelet degranulation of P-selectin is enhanced in patients receiving phenprocoumon and heparin but not in patients treated with ticlopidine. Consistent with an increase in platelet activation, a significant drop in platelet count, indicating enhanced platelet sequestration, is found in patients receiving phenprocoumon and heparin but not in patients treated with ticlopidine. Moreover, plasma concentration of fibrinogen increases after stenting in the phenprocoumon and heparin but not in the ticlopidine group, implying a systemic inflammatory response.
Immunologic Detection of Platelet Activation in Coronary Stent Patients
Evaluation of platelet function by flow cytometry uses monoclonal antibodies that recognize membrane glycoproteins present only on activated platelets.23 As evidenced by a variety of clinical studies, immunologic characterization of platelet function is useful for detecting activation of the platelet system.24 25 26 27 Our present findings show that despite intense anticoagulation, coronary stenting is followed by significant platelet activation for days after stent delivery. Acute vessel occlusion after angioplasty is associated with platelet activation, and immunologic analysis of platelets has been shown to predict acute ischemic events after coronary interventions.13 14 Consistent with these findings, we previously showed that surface expression of platelet activation markers is significantly enhanced both in patients undergoing coronary stenting and compared with conventional angioplasty.28 We recently reported that patients with increased surface expression of GPIIb-IIIa before stenting are at increased risk for developing subacute vessel occlusion independent of known angiographic risk factors.13 This underlines the importance of platelet membrane glycoproteins in the pathophysiology of subacute stent thrombosis. Thus, in the present study we used immunologic characterization of platelet activation to evaluate the effect of two different antithrombotic regimens on platelet function in coronary stent patients.
Effect of Antithrombotic Therapy on Platelet Function
We found significant platelet activation primarily in coronary stent patients treated with an antithrombotic regimen that included phenprocoumon, heparin, and the antiplatelet drug aspirin. In patients in whom the anticoagulation treatment was substituted by ticlopidine, no significant platelet activation could be detected. Because patients of both groups were comparable with respect to basic clinical characteristics and stent procedure–related parameters, the differences in platelet activation cannot be explained by the heterogeneity of both groups. Thus, we conclude that the antithrombotic regimens used in our patients are not equally effective in suppressing platelet activation. Ticlopidine is a potent antiplatelet drug that has been proved effective in secondary prevention of patients with atherosclerotic vessel disease.29 However, its function is delayed, starting 2 to 4 days after administration of the drug, with maximal efficacy after 1 week, depending on the dosage used per day.30 Thus, administration of ticlopidine cannot fully account for the reduced platelet activation observed the first few days after stenting. Experimental and clinical data show that unfractionated heparin activates platelets in vitro and in vivo.31 32 Thus, high doses of heparin administered to patients in the phenprocoumon and heparin group might account, at least in part, for enhanced and sustained platelet activation after stenting.
Study Limitations
Although flow cytometric detection of platelet activation provides useful findings about platelets that continue to circulate, it provides no insight into platelet activation events that may have caused platelet removal from the circulation by thrombogenic processes. Thus, we might have underestimated platelet activation in our studies, which might become a factor, especially in patients with minor systemic platelet activation.
The study of platelet function is always hampered by the possibility of artifactual platelet activation in vitro during blood sampling or further processing. Thus, we kept methodological variables constant among all investigated individuals, which should allow comparisons between groups of patients. In addition, the reproducibility of the platelet assay was confirmed by evaluation of samples obtained from healthy control subjects on the day of patient evaluation. The platelet assay described here has been shown to be useful in evaluating platelet function in a variety of clinical settings.13 18 19 20 21 28
During the time of the study, our antithrombotic strategies changed in patients receiving coronary stents, so we could not prospectively evaluate platelet function of both treatment arms. However, case-control evaluation of treatment is an established statistical method, and the number of patients matched with similar clinical and angiographic characteristics was sufficiently large for us to compare the effect of two different antithrombotic therapies. Nevertheless, we could not control for all potential criteria; eg, criteria such as minimal lumen diameter after stenting and stenting of recanalized chronic occlusion were not chosen for matching. However, quantitative angiographic parameters were not significantly different between the two groups. During the study, there were no major changes in the stenting procedure. Yet we cannot exclude that advances in technology and operator skills during the study period might have affected the results.
No subacute stent thrombosis occurred in the patients studied. Thus, we currently cannot definitely conclude whether administration of ticlopidine is more effective than anticoagulation in preventing thrombotic events after stenting. The present study yields the rationale for a randomized study in this field.
Pathophysiological and Therapeutic Considerations
The main determinants of stent thrombogenicity are the stent material itself, the recipient vessel wall, and the circulating blood. We found that platelets circulate in an active state in coronary stent patients. This coincides with a drop in platelet count, which indicates enhanced sequestration. Activated platelets might be entrapped in the thrombogenic surroundings at the site of stent placement, which might induce thrombotic plug formation and increase the risk of thrombotic vessel occlusion.
The fibrinogen receptor on platelets plays a central role in platelet aggregation and thrombus formation.33 Antagonism of platelet fibrinogen receptor during high-risk angioplasty has been shown to reduce acute ischemic coronary events.34 Ticlopidine is characterized by delayed onset of action for days after the start of treatment.30 Thus, in patients with high-risk coronary stenting, a more specific and rapidly effective antiplatelet therapy peri-interventional may be desirable to prevent thrombotic complications.
P-selectin associated with the platelet membrane was used as a marker for platelet degranulation in the present study. Along with P-selectin, other granule-stored compounds are released into the plasma compartment. This includes release of thrombin and mitogenic factors such as platelet-derived growth factors, transforming growth factor, and serotonin.35 These mediators have been shown to trigger proliferation and migration of vascular smooth muscle cells, resulting in fibrocellular intimal hyperplasia, which is implicated in the pathophysiology of restenosis after angioplasty.36 Thus, antithrombotic regimens that inhibit platelet activation after stenting may provide further protection against restenotic processes.
Plasma fibrinogen is an acute-phase reactant that determines the prognosis in patients who survive acute myocardial infarction.37 Moreover, plasma fibrinogen correlates with platelet aggregation.38 Thus, the increase in fibrinogen concentration after stenting in patients receiving phenprocoumon and heparin may enhance the risk of coronary thrombotic events. Moreover, platelet activation contributes to the triggering of acute inflammatory reactions.39 This may explain why fibrinogen concentration showed only minor changes in the study group. Inflammatory responses to prolonged healing of the access site might have contributed to the marked increase in fibrinogen in the control group. Effective inhibition of platelet function may present an anti-inflammatory strategy that may assist in the protection against complications derived from systemic inflammatory responses.
In conclusion, we have shown that in contrast to anticoagulation, systemic platelet activation after coronary stenting does not occur under combined antiplatelet therapy. The method described here for evaluating platelet function may be helpful in testing the efficacy of anti-platelet strategies in future clinical trials.
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Acknowledgments |
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This study was supported by grants from Deutsche Forschungsgemeinschaft (Ga381/2-1) and Johnson & Johnson Interventional Products, Hamburg, Germany. We wish to thank Kathrin Gloth and Caroline Bogner for expert technical assistance.
Received September 11, 1995; revision received January 31, 1996; accepted February 1, 1996.
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S. R. Kapadia, C. T. Bajzer, K. M. Ziada, D. L. Bhatt, O. M. Wazni, M. J. Silver, E. G. Beven, K. Ouriel, and J. S. Yadav Initial Experience of Platelet Glycoprotein IIb/IIIa Inhibition With Abciximab During Carotid Stenting: A Safe and Effective Adjunctive Therapy Stroke, October 1, 2001; 32(10): 2328 - 2332. [Abstract] [Full Text] [PDF]
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M. Gawaz, F.-J. Neumann, and A. Schomig Evaluation of Platelet Membrane Glycoproteins in Coronary Artery Disease : Consequences for Diagnosis and Therapy Circulation, January 12, 1999; 99 (1): e1 - e11. [Full Text] [PDF]
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J. K. Mickelson, M. N. Ali, N. S. Kleiman, N. M. Lakkis, T. W. Chow, B. J. Hughes, and C. W. Smith Chimeric 7e3 Fab (ReoPro) decreases detectable CD11b on neutrophils from patients undergoing coronary angioplasty J. Am. Coll. Cardiol., January 1, 1999; 33(1): 97 - 106. [Abstract] [Full Text] [PDF]
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S. R. Steinhubl, M. S. Lauer, D. P. Mukherjee, D. J. Moliterno, A. M. Lincoff, S. G. Ellis, and E. J. Topol The duration of pretreatment with ticlopidine prior to stenting is associated with the risk of procedure-related non-Q-wave myocardial infarctions J. Am. Coll. Cardiol., November 1, 1998; 32(5): 1366 - 1370. [Abstract] [Full Text] [PDF]
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H. J. Rupprecht, H. Darius, U. Borkowski, T. Voigtlander, B. Nowak, S. Genth, and J. Meyer Comparison of Antiplatelet Effects of Aspirin, Ticlopidine, or Their Combination After Stent Implantation Circulation, March 24, 1998; 97(11): 1046 - 1052. [Abstract] [Full Text] [PDF]
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